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Salix Pharmaceuticals and Pharming receive FDA approval for Ruconest

July 22, 2014 5:46 am / Leave a comment

Ruconest

Ruconest® is the first recombinant human C1 esterase inhibitor (rhC1INH) approved for use in patients with HAE.
rhC1INH and plasma-derived C1INH have an identical amino acid sequence. ¹⁸

The in vitro inhibitory potency of rhC1INH toward target enzymes is comparable with that of plasma-derived C1INH. ^{1, 6, 19}

Ruconest® is the first recombinant human C1 esterase inhibitor (rhC1INH) developed and approved for the treatment of acute angioedema attacks in HAE patients. Use of a well-controlled transgenic platform for the production of Ruconest® ensures that product supply is virtually unlimited and avoids the risk of transmission of human blood-borne infections.

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm405526.htm

fda …..July 17, 2014 approved

Salix Pharmaceuticals and Pharming receive FDA approval for Ruconest
Salix Pharmaceuticals and Pharming have announced US Food and Drug Administration (FDA) approval of Ruconest for treatment of acute angioedema attacks in adult and adolescent patients with hereditary angioedema (HAE).

Salix Pharmaceuticals and Pharming receive FDA approval for Ruconest

Salix Pharmaceuticals and Pharming have announced US Food and Drug Administration (FDA) approval of Ruconest for treatment of acute angioedema attacks in adult and adolescent patients with hereditary angioedema (HAE).

The FDA has approved the company’s biologics licence application for Ruconest, a C1 esterase inhibitor [recombinant], based on a Phase III trial (RCT) that included an open-label extension (OLE) phase and is supported by results of two additional RCTs and two additional OLE studies.

read at

http://www.pharmaceutical-technology.com/news/newssalix-pharmaceuticals-pharming-receive-fda-approval-for-ruconest-4322007?WT.mc_id=DN_News

Salix Pharmaceuticals, Ltd.SLXP -1.30% and Pharming Group NV today announced that the Food and Drug Administration has approved RUCONEST® (C1 Esterase Inhibitor [Recombinant]) 50 IU/kg for the treatment of acute angioedema attacks in adult and adolescent patients with hereditary angioedema (HAE). Because of the limited number of patients with laryngeal attacks, effectiveness was not established in HAE patients with laryngeal attacks.

“We are pleased that RUCONEST® provides the HAE community with another FDA-approved option for treating painful and debilitating HAE attacks,” said Anthony Castaldo, President of the Hereditary Angioedema Association (US HAEA), a non-profit patient services and research organization with a membership of over 5,000 HAE patients in the United States.

RUCONEST® is a recombinant C1 esterase inhibitor that can be administered by the patient after receiving training by a healthcare provider. HAE attacks stem from a deficiency of the C1 inhibitor protein in the blood. HAE is a rare inherited genetic condition that is often not properly diagnosed until later in a patient’s life as the symptoms of an attack can mirror someone experiencing an allergic reaction. Severe, painful swelling can occur at any time, which means most people suffering from HAE deal with the constant fear of when their next attack might surface and how that might impair their lives and those around them.

“Results in the pivotal clinical trial demonstrate RUCONEST® is a safe and effective option for the treatment of acute hereditary angioedema attacks,” said Dr. Marc Riedl of the US HAEA Angioedema Center at the University of California – San Diego and primary investigator of the phase III study. “At the US HAEA Angioedema Center, we strive to better the lives of those suffering from hereditary angioedema and part of that is ensuring patients have access to advanced treatments that have been proven to work in clinical trials. RUCONEST is an important addition to those treatment options.”

Sijmen de Vries, CEO of Pharming, said: “The approval of RUCONEST® in the US is a very significant milestone for Pharming. For many years we have strived to make RUCONEST® – the first recombinant replacement therapy for C1Inhibitor deficiency – available to the HAE patient community in the US, because we were aware of the great value and benefit this product adds to patients’ lives. Today we are proud to have achieved this goal in the US.”

“RUCONEST® is a much needed treatment option for patients suffering from acute attacks of hereditary angioedema. Until now, there hasn’t been an FDA approved recombinant C1 esterase inhibitor option to treat symptoms of HAE,” said Carolyn J. Logan, President and Chief Executive Officer of Salix. “The unpredictability of HAE can make patients feel uncertain about when their next attack might strike, which is why it is important to have a medicine that can be administered by the patient that resolves an attack. Salix is proud to make RUCONEST® available.”

The FDA approval of the Biologics License Application (BLA) for RUCONEST® for treatment of acute angioedema attacks in patients with HAE is based on a randomized, double-blind, placebo-controlled, phase III trial (RCT) which included an open-label extension (OLE) phase and is supported by the results of two additional RCTs and two additional OLE studies. The pivotal RCT and OLE studies analyzed the results from 44 subjects who experienced 170 HAE attacks. The primary efficacy endpoint was the time to beginning of symptom relief, assessed using patient-reported responses to two questions about the change in overall severity of their HAE attack symptoms after the start of treatment. These were assessed at regular time points for each of the affected anatomical locations for up to 24 hours. To achieve the primary endpoint, a patient had to have a positive response to both questions along with persistence of improvement at the next assessment time (i.e., the same or better response).

A statistically significant difference in the time to beginning of symptom relief was observed in the intent-to-treat population (n=75) between RUCONEST and placebo (p=0.031, log-rank test); the median time to beginning of symptom relief was 90 minutes for RUCONEST patients (n=44) and 152 minutes for placebo patients (n=31).

RUCONEST® is manufactured by Pharming Group NV in the Netherlands. Salix has licensed exclusive rights from Pharming to commercialize RUCONEST® in North America and market RUCONEST® for the treatment of acute HAE attack symptoms.

Salix currently plans on making RUCONEST® accessible to patients later in 2014.

About RUCONEST ®

RUCONEST® (C1 Esterase Inhibitor [Recombinant]) 50 IU/kgis an injectable medicine that is used to treat acute angioedema attacks in adult and adolescent patients with hereditary angioedema (HAE). HAE is caused by a deficiency of the C1 esterase inhibitor protein, which is present in blood and helps control inflammation (swelling) and parts of the immune system. A shortage of C1 esterase inhibitor can lead to repeated attacks of swelling, pain in the abdomen, difficulty breathing and other symptoms. RUCONEST® contains C1 esterase inhibitor at 50 IU/kg.

When administered at the onset of HAE attack symptoms at the recommended dose, RUCONEST® works to return a patient’s C1-INH levels to normal range and quickly relieve the symptoms of an HAE attack with a low recurrence of symptoms.

RUCONEST® is the first and only plasma-free, recombinant C1-INH approval from the U.S. Food and Drug Administration (FDA) and was approved in July 2014.

About HAE

RUCONEST has been granted Orphan Drug designation by the FDA for the treatment of acute angioedema attacks in patients with hereditary angioedema (HAE). With RUCONEST now approved by the FDA, Salix believes this designation should provide seven years of marketing exclusivity in the United States.

Hereditary angioedema (HAE) is a genetic condition occurring between 1 in 10,000 to 1 in 50,000 people. Those with HAE experience episodes of swelling in their extremities, face and abdomen, with potentially life-threatening swelling of the airway. When it occurs in the abdomen, this swelling can be accompanied by bouts of nausea, vomiting and severe pain. Swelling in the face or extremities can be painful, disfiguring, and disabling.

HAE patients have a defect in the gene that controls production of a protein found in the blood vessels, called C1 inhibitor or C1-INH. When a person’s C1-INH levels are low, fluid from blood vessels can leak into nearby connective tissues, causing severe pain and swelling and, in rare cases, death from asphyxiation from airway swelling.

About Pharming Group NV

Pharming Group NV is developing innovative products for the treatment of unmet medical needs. RUCONEST® (conestat alfa) is a recombinant human C1 esterase inhibitor approved for the treatment of angioedema attacks in patients with HAE in the USA, Israel, all 27 EU countries plus Norway, Iceland and Liechtenstein. RUCONEST® is distributed in the EU by Swedish Orphan Biovitrum. RUCONEST® is partnered with Salix Pharmaceuticals Inc. SLXP -1.30% in North America. The product is also being evaluated for various follow-on indications. Pharming has a unique GMP compliant, validated platform for the production of recombinant human proteins that has proven capable of producing industrial volumes of high quality recombinant human protein in a more economical way compared to current cell based technologies. In July 2013, the platform was partnered with Shanghai Institute for Pharmaceutical Industry (SIPI), a Sinopharm Company, for joint global development of new products. Pre- clinical development and manufacturing will take place at SIPI and are funded by SIPI. Pharming and SIPI initially plan to utilize this platform for the development of rhFVIII for the treatment of Haemophilia A. Additional information is available on the Pharming website; www.pharming.com .

About Salix Pharmaceuticals

Salix Pharmaceuticals, Ltd., headquartered in Raleigh, North Carolina, develops and markets prescription pharmaceutical products and medical devices for the prevention and treatment of gastrointestinal diseases. Salix’s strategy is to in-license late-stage or marketed proprietary therapeutic products, complete any required development and regulatory submission of these products, and commercialize them through the Company’s 500-member specialty sales force.

Salix markets XIFAXAN® (rifaximin) tablets 200 mg and 550 mg, MOVIPREP® (PEG 3350, sodium sulfate, sodium chloride, potassium chloride, sodium ascorbate and ascorbic acid for oral solution, 100 g/7.5 g/2.691 g/1.015 g/5.9 g/4.7 g), OSMOPREP® (sodium phosphate monobasic monohydrate, USP, and sodium phosphate dibasic anhydrous, USP) Tablets, APRISO® (mesalamine) extended-release capsules 0.375 g, UCERIS® (budesonide) extended release tablets, for oral use, GIAZO® (balsalazide disodium) tablets, COLAZAL® (balsalazide disodium) Capsules, GLUMETZA® (metformin hydrochloride extended-release tablets) 500 mg and 1000 mg, ZEGERID® (omeprazole/sodium bicarbonate) Powder for Oral Suspension, ZEGERID® (omeprazole/sodium bicarbonate) Capsules, METOZOLV® ODT (metoclopramide hydrochloride), RELISTOR® (methylnaltrexone bromide) Subcutaneous Injection, FULYZAQ® (crofelemer) delayed-release tablets, SOLESTA®, DEFLUX®, PEPCID® (famotidine) for Oral Suspension, DIURIL® (chlorothiazide) Oral Suspension, AZASAN® (azathioprine) Tablets, USP, 75/100 mg, ANUSOL-HC® 2.5% (Hydrocortisone Cream, USP), ANUSOL-HC® 25 mg Suppository (Hydrocortisone Acetate), PROCTOCORT® Cream (Hydrocortisone Cream, USP) 1% and PROCTOCORT® Suppository (Hydrocortisone Acetate Rectal Suppositories) 30 mg, CYCLOSET® (bromocriptine mesylate) tablets, FENOGLIDE® (fenofibrate) tablets. UCERIS (budesonide) rectal foam, RELSITOR®, encapsulated bowel prep and rifaximin for additional indications are under development.

FDA Approves Beleodaq (belinostat) for Peripheral T-Cell Lymphoma

July 4, 2014 3:18 am / Leave a comment

Belinostat (PXD101)

FAST TRACK FDA , ORPHAN STATUS

Approved by FDA……http://www.drugs.com/newdrugs/fda-approves-beleodaq-belinostat-peripheral-t-cell-lymphoma-4052.html?utm_source=ddc&utm_medium=email&utm_campaign=Today%27s+news+summary+-+July+3%2C+2014

July 3, 2014 — The U.S. Food and Drug Administration today approved Beleodaq (belinostat) for the treatment of patients with peripheral T-cell lymphoma (PTCL), a rare and fast-growing type of non-Hodgkin lymphoma (NHL). The action was taken under the agency’s accelerated approval program.

PDX101
PX 105684
PXD-101
PXD101
UNII-F4H96P17NZ

Belinostat (PXD101) is a novel HDAC inhibitor with IC50 of 27 nM, with activity demonstrated in cisplatin-resistant tumors.

CLINICAL TRIALS…http://clinicaltrials.gov/search/intervention=Belinostat+OR+PXD101

Chemical structure for belinostat

Identifiers
IUPAC name (2E)-N-Hydroxy-3-[3-(phenylsulfamoyl)phenyl]prop-2-enamide
Other names PXD101
CAS	414864-00-9
PubChem	6918638
ChemSpider	5293831
UNII	F4H96P17NZ
ChEBI	CHEBI:61076
ChEMBL	CHEMBL408513
Jmol-3D images	Image 1


Properties
Molecular formula	C₁₅H₁₄N₂O₄S
Molar mass	318.35 g mol⁻¹

Belinostat inhibits the growth of tumor cells (A2780, HCT116, HT29, WIL, CALU-3, MCF7, PC3 and HS852) with IC50 from 0.2-0.66 μM. PD101 shows low activity in A2780/cp70 and 2780AD cells. Belinostat inhibits bladder cancer cell growth, especially in 5637 cells, which shows accumulation of G0-G1 phase, decrease in S phase, and increase in G2-M phase. Belinostat also shows enhanced tubulin acetylation in ovarian cancer cell lines. A recent study shows that Belinostat activates protein kinase A in a TGF-β signaling-dependent mechanism and decreases survivin mRNA.

PTCL comprises a diverse group of rare diseases in which lymph nodes become cancerous. In 2014, the National Cancer Institute estimates that 70,800 Americans will be diagnosed with NHL and 18,990 will die. PTCL represents about 10 to 15 percent of NHLs in North America.

Beleodaq works by stopping enzymes that contribute to T-cells, a type of immune cell, becoming cancerous. It is intended for patients whose disease returned after treatment (relapsed) or did not respond to previous treatment (refractory).

“This is the third drug that has been approved since 2009 for the treatment of peripheral T-cell lymphoma,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Today’s approval expands the number of treatment options available to patients with serious and life-threatening diseases.”

The FDA granted accelerated approval to Folotyn (pralatrexate) in 2009 for use in patients with relapsed or refractory PTCL and Istodax (romidepsin) in 2011 for the treatment of PTCL in patients who received at least one prior therapy.

The safety and effectiveness of Beleodaq was evaluated in a clinical study involving 129 participants with relapsed or refractory PTCL. All participants were treated with Beleodaq until their disease progressed or side effects became unacceptable. Results showed 25.8 percent of participants had their cancer disappear (complete response) or shrink (partial response) after treatment.

The most common side effects seen in Beleodaq-treated participants were nausea, fatigue, fever (pyrexia), low red blood cells (anemia), and vomiting.

The FDA’s accelerated approval program allows for approval of a drug based on surrogate or intermediate endpoints reasonably likely to predict clinical benefit for patients with serious conditions with unmet medical needs. Drugs receiving accelerated approval are subject to confirmatory trials verifying clinical benefit. Beleodaq also received orphan product designation by the FDA because it is intended to treat a rare disease or condition.

Beleodaq and Folotyn are marketed by Spectrum Pharmaceuticals, Inc., based in Henderson, Nevada. Istodax is marketed by Celgene Corporation based in Summit, New Jersey.

MW 318.07
MF	C15H14N2O4S

414864-00-9 cas no

866323-14-0

(2E)-N-hydroxy-3-[3-(phenylsulfamoyl)phenyl]acrylamide

A novel HDAC inhibitor

…………………………

BELINOSTAT

Belinostat (PXD101) is experimental drug candidate under development byTopoTarget for the treatment of hematological malignancies and solid tumors. It is a histone deacetylase inhibitor.[1]

A hydroxamate-type inhibitor of histone deacetylase.

NCI: A novel hydroxamic acid-type histone deacetylase (HDAC) inhibitor with antineoplastic activity. Belinostat targets HDAC enzymes, thereby inhibiting tumor cell proliferation, inducing apoptosis, promoting cellular differentiation, and inhibiting angiogenesis. This agent may sensitize drug-resistant tumor cells to other antineoplastic agents, possibly through a mechanism involving the down-regulation of thymidylate synthase

In 2007 preliminary results were released from the Phase II clinical trial of intravenous belinostat in combination with carboplatin and paclitaxel for relapsedovarian cancer.[2] Final results in late 2009 of a phase II trial for T cell lymphomawere encouraging.[3] Belinostat has been granted orphan drug and fast trackdesignation by the FDA.[4]

The study of inhibitors of histone deacetylases indicates that these enzymes play an important role in cell proliferation and differentiation. The inhibitor Trichostatin A (TSA) (Yoshida et al., 1990a) causes cell cycle arrest at both G1 and G2 phases (Yoshida and Beppu, 1988), reverts the transformed phenotype of different cell lines, and induces differentiation of Friend leukaemia cells and others (Yoshida et al., 1990b). TSA (and SAHA) have been reported to inhibit cell growth, induce terminal differentiation, and prevent the formation of tumours in mice (Finnin et al., 1999).

Trichostatin A (TSA)

Suberoylanilide Hydroxamic Acid (SAHA)

Cell cycle arrest by TSA correlates with an increased expression of gelsolin (Hoshikawa et al., 1994), an actin regulatory protein that is down regulated in malignant breast cancer (Mielnicki et al., 1999). Similar effects on cell cycle and differentiation have been observed with a number of deacetylase inhibitors (Kim et al., 1999). Trichostatin A has also been reported to be useful in the treatment of fibrosis, e.g., liver fibrosis and liver cirrhosis. See, e.g., Geerts et al., 1998.

Recently, certain compounds that induce differentiation have been reported to inhibit histone deacetylases. Several experimental antitumour compounds, such as trichostatin A (TSA), trapoxin, suberoylanilide hydroxamic acid (SAHA), and phenylbutyrate have been reported to act, at least in part, by inhibiting histone deacetylase (see, e.g., Yoshida et al., 1990; Richon et al., 1998; Kijima et al., 1993). Additionally, diallyl sulfide and related molecules (see, e.g., Lea et al., 1999), oxamflatin (see, e.g., Kim et al., 1999), MS-27-275, a synthetic benzamide derivative (see, e.g., Saito et al., 1999; Suzuki et al., 1999; note that MS-27-275 was later re-named as MS-275), butyrate derivatives (see, e.g., Lea and Tulsyan, 1995), FR901228 (see, e.g., Nokajima et al., 1998), depudecin (see, e.g., Kwon et al., 1998), and m-carboxycinnamic acid bishydroxamide (see, e.g., Richon et al., 1998) have been reported to inhibit histone deacetylases. In vitro, some of these compounds are reported to inhibit the growth of fibroblast cells by causing cell cycle arrest in the G1 and G2 phases, and can lead to the terminal differentiation and loss of transforming potential of a variety of transformed cell lines (see, e.g., Richon et al, 1996; Kim et al., 1999; Yoshida et al., 1995; Yoshida & Beppu, 1988). In vivo, phenybutyrate is reported to be effective in the treatment of acute promyelocytic leukemia in conjunction with retinoic acid (see, e.g., Warrell et al., 1998). SAHA is reported to be effective in preventing the formation of mammary tumours in rats, and lung tumours in mice (see, e.g., Desai et al., 1999).

The clear involvement of HDACs in the control of cell proliferation and differentiation suggest that aberrant HDAC activity may play a role in cancer. The most direct demonstration that deacetylases contribute to cancer development comes from the analysis of different acute promyelocytic leukaemias (APL). In most APL patients, a translocation of chromosomes 15 and 17 (t(15;17)) results in the expression of a fusion protein containing the N-terminal portion of PML gene product linked to most of RARσ (retinoic acid receptor). In some cases, a different translocation (t(11 ;17)) causes the fusion between the zinc finger protein PLZF and RARα. In the absence of ligand, the wild type RARα represses target genes by tethering HDAC repressor complexes to the promoter DNA. During normal hematopoiesis, retinoic acid (RA) binds RARα and displaces the repressor complex, allowing expression of genes implicated in myeloid differentiation. The RARα fusion proteins occurring in APL patients are no longer responsive to physiological levels of RA and they interfere with the expression of the RA- inducible genes that promote myeloid differentiation. This results in a clonal expansion of promyelocytic cells and development of leukaemia. In vitro experiments have shown that TSA is capable of restoring RA-responsiveness to the fusion RARα proteins and of allowing myeloid differentiation. These results establish a link between HDACs and oncogenesis and suggest that HDACs are potential targets for pharmaceutical intervention in APL patients. (See, for example, Kitamura et al., 2000; David et al., 1998; Lin et al., 1998).

BELINOSTAT

Furthermore, different lines of evidence suggest that HDACs may be important therapeutic targets in other types of cancer. Cell lines derived from many different cancers (prostate, coloreetal, breast, neuronal, hepatic) are induced to differentiate by HDAC inhibitors (Yoshida and Horinouchi, 1999). A number of HDAC inhibitors have been studied in animal models of cancer. They reduce tumour growth and prolong the lifespan of mice bearing different types of transplanted tumours, including melanoma, leukaemia, colon, lung and gastric carcinomas, etc. (Ueda et al., 1994; Kim et al., 1999).

Psoriasis is a common chronic disfiguring skin disease which is characterised by well-demarcated, red, hardened scaly plaques: these may be limited or widespread. The prevalence rate of psoriasis is approximately 2%, i.e., 12.5 million sufferers in the triad countries (US/Europe/Japan). While the disease is rarely fatal, it clearly has serious detrimental effects upon the quality of life of the patient: this is further compounded by the lack of effective therapies. Present treatments are either ineffective, cosmetically unacceptable, or possess undesired side effects. There is therefore a large unmet clinical need for effective and safe drugs for this condition. Psoriasis is a disease of complex etiology. Whilst there is clearly a genetic component, with a number of gene loci being involved, there are also undefined environmental triggers. Whatever the ultimate cause of psoriasis, at the cellular level, it is characterised by local T-cell mediated inflammation, by keratinocyte hyperproliferation, and by localised angiogenesis. These are all processes in which histone deacetylases have been implicated (see, e.g., Saunders et al., 1999; Bernhard et al, 1999; Takahashi et al, 1996; Kim et al , 2001 ). Therefore HDAC inhibitors may be of use in therapy for psoriasis. Candidate drugs may be screened, for example, using proliferation assays with T-cells and/or keratinocytes.

………………………………………………………………………..

PXD101/Belinostat®

(E)-N-hydroxy-3-(3-phenylsulfamoyl-phenyl)-acrylamide, also known as PXD101 and Belinostat®, shown below, is a well known histone deacetylate (HDAC) inhibitor. It is being developed for treatment of a range of disorders mediated by HDAC, including proliferative conditions (such as cancer and psoriasis), malaria, etc.

PXD101 was first described in WO 02/30879 A2. That document describes a multi-step method of synthesis which may conveniently be illustrated by the following scheme.

…………………………………..

GENERAL SYNTHESIS

WO2002030879A2

IGNORE 10

ENTRY 45 IS BELINOSTAT

Scheme 1

By using amines instead of aniline, the corresponding products may be obtained. The use of aniline, 4-methoxyaniline, 4-methylaniline, 4-bromoaniline, 4-chloroaniline, 4-benzylamine, and 4-phenethyamine, among others, is described in the Examples below.

In another method, a suitable amino acid (e.g., ω-amino acid) having a protected carboxylic acid (e.g., as an ester) and an unprotected amino group is reacted with a sulfonyl chloride compound (e.g., RSO₂CI) to give the corresponding sulfonamide having a protected carboxylic acid. The protected carboxylic acid is then deprotected using base to give the free carboxylic acid, which is then reacted with, for example, hydroxylamine 2-chlorotrityl resin followed by acid (e.g., trifluoroacetic acid), to give the desired carbamic acid.

One example of this approach is illustrated below, in Scheme 2, wherein the reaction conditions are as follows: (i) RSO₂CI, pyridine, DCM, room temperature, 12 hours; (ii) 1 M LiOH or 1 M NaOH, dioxane, room temperature, 3-48 hours; (iii) hydroxylamine 2-chlorotrityl resin, HOAt, HATU, DIPEA, DCM, room temperature, 16 hours; and (iv) TFA/DCM (5:95, v/v), room temperature, 1.5 hours.

Scheme 2

Additional methods for the synthesis of compounds of the present invention are illustrated below and are exemplified in the examples below.

Scheme 3A

Scheme 3B

Scheme 4

Scheme 8

Scheme 9

……………………………………………………………………..

SYNTHESIS

WO2002030879A2

Example 1

3-Formylbenzenesulfonic acid, sodium salt (1)

Oleum (5 ml) was placed in a reaction vessel and benzaldehyde (2.00 g, 18.84 mmol) was slowly added not exceeding the temperature of the reaction mixture more than 30°C. The obtained solution was stirred at 40°C for ten hours and at ambient temperature overnight. The reaction mixture was poured into ice and extracted with ethyl acetate. The aqueous phase was treated with CaC0₃ until the evolution of C0₂ ceased (pH~6-7), then the precipitated CaSO₄was filtered off and washed with water. The filtrate was treated with Na₂CO₃ until the pH of the reaction medium increased to pH 8, obtained CaCO3 was filtered off and water solution was evaporated in vacuum. The residue was washed with methanol, the washings were evaporated and the residue was dried in desiccator over P₂Oβ affording the title compound (2.00 g, 51%). ¹H NMR (D₂0), δ: 7.56-8.40 (4H, m); 10.04 ppm (1 H, s).

Example 2 3-(3-Sulfophenyl)acrylic acid methyl ester, sodium salt (2)

Sodium salt of 3-formylbenzenesulfonic acid (1) (1.00 g, 4.80 mmol), potassium carbonate (1.32 g, 9.56 mmol), trimethyl phosphonoacetate (1.05 g, 5.77 mmol) and water (2 ml) were stirred at ambient temperature for 30 min., precipitated solid was filtered and washed with methanol. The filtrate was evaporated and the title compound (2) was obtained as a white solid (0.70 g, 55%). ¹H NMR (DMSO- d_βl HMDSO), δ: 3.68 (3H, s); 6.51 (1 H, d, J=16.0 Hz); 7.30-7.88 (5H, m).

Example 3 3-(3-Chlorosulfonylphenyl)acrylic acid methyl ester (3)

To the sodium salt of 3-(3-sulfophenyl)acrylic acid methyl ester (2) (0.670 g, 2.53 mmol) benzene (2 ml), thionyl chloride (1.508 g, 0.9 ml, 12.67 mmol) and 3 drops of dimethylformamide were added and the resultant suspension was stirred at reflux for one hour. The reaction mixture was evaporated, the residue was dissolved in benzene (3 ml), filtered and the filtrate was evaporated to give the title compound (0.6’40 g, 97%).

Example 4 3-(3-Phenylsulfamoylphenyl)acrylic acid methyl ester (4a)

A solution of 3-(3-chlorosulfonylphenyl)acrylic acid methyl ester (3) (0.640 g, 2.45 mmol) in dichloromethane (2 ml) was added to a mixture of aniline (0.465 g, 4.99 mmol) and pyridine (1 ml), and the resultant solution was stirred at 50°C for one hour. The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and 10% HCI. The organic layer was washed successively with water, saturated NaCl, and dried (Na₂S0 ). The solvent was removed and the residue was chromatographed on silica gel with chloroform-ethyl acetate (7:1 , v/v) as eluent. The obtained product was washed with diethyl ether to give the title compound (0.226 g, 29%). ¹H NMR (CDCI₃, HMDSO), δ: 3.72 (3H, s); 6.34 (1H, d, J=16.0 Hz); 6.68 (1 H, br s); 6.92-7.89 (10H, m).

Example 5 3-(3-Phenylsulfamoylphenyl)acrylic acid (5a)

3-(3-Phenylsulfamoylphenyl)acrylic acid methyl ester (4a) (0.220 g, 0.69 mmol) was dissolved in methanol (3 ml), 1N NaOH (2.08 ml, 2.08 mmol) was added and the resultant solution was stirred at ambient temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was acidified with 10% HCI and stirred for 30 min. The precipitated solid was filtered, washed with water and dried in desiccator over P₂Os to give the title compound as a white solid (0.173 g, 82%). Example 6 3-(3-Phenylsulfamoylphenyl)acryloyl chloride (6a)

To a suspension of 3-(3-phenylsulfamoylphenyl)acrylic acid (5a) (0.173 g, 0.57 mmol) in dichloromethane (2.3 ml) oxalyl chloride (0.17 ml, 1.95 mmol) and one drop of dimethylformamide were added. The reaction mixture was stirred at 40°C for one hour and concentrated under reduced pressure to give crude title compound (0.185 g).

Example 7

N-Hydroxy-3-(3-phenylsulfamoylphenyl)acrylamide (7a) (PX105684) BELINOSTAT

To a suspension of hydroxylamine hydrochloride (0.200 g, 2.87 mmol) in tetrahydrofuran (3.5 ml) a saturated NaHCOβ solution (2.5 ml) was added and the resultant mixture was stirred at ambient temperature for 10 min. To the reaction mixture a 3-(3-phenylsulfamoylphenyl)acryloyl chloride (6a) (0.185 g) solution in tetrahydrofuran (2.3 ml) was added and stirred at ambient temperature for one hour. The reaction mixture was partitioned between ethyl acetate and 2N HCI. The organic layer was washed successively with water and saturated NaCl, the solvent was removed and the residue was washed with acetonitrile and diethyl ether.

The title compound was obtained as a white solid (0.066 g, 36%), m.p. 172°C. BELINOSTAT

¹H NMR (DMSO-d6, HMDSO), δ: 6.49 (1 H, d, J=16.0 Hz); 7.18-8.05 (10H, m); 9.16 (1 H, br s); 10.34 (1 H, s); 10.85 ppm (1 H, br s).

HPLC analysis on Symmetry C₁₈column: impurities 4% (column size 3.9×150 mm; mobile phase acetonitrile – 0.1 M phosphate buffer (pH 2.5), 40:60; sample concentration 1 mg/ml; flow rate 0.8 ml/ min; detector UV 220 nm).

Anal. Calcd for C₁₅Hι₄N₂0₄S, %: C 56.59, H 4.43, N 8.80. Found, %: C 56.28, H 4.44, N 8.56.

……………………………………………………………………….

SYNTHESIS

US20100286279

Figure US20100286279A1-20101111-C00034

…………………………………………………….

SYNTHESIS AND SPECTRAL DATA

Journal of Medicinal Chemistry, 2011 , vol. 54, 13 pg. 4694 – 4720

(E)-N-Hydroxy-3-(3-phenylsulfamoyl-phenyl)-acrylamide (28, belinostat, PXD101).

http://pubs.acs.org/doi/full/10.1021/jm2003552

http://pubs.acs.org/doi/suppl/10.1021/jm2003552/suppl_file/jm2003552_si_001.pdf

The methyl ester (27) (8.0 g) was prepared according to reported synthetic route,

(Watkins, C. J.; Romero-Martin, M.-R.; Moore, K. G.; Ritchie, J.; Finn, P. W.; Kalvinsh, I.;
Loza, E.; Dikvoska, K.; Gailite, V.; Vorona, M.; Piskunova, I.; Starchenkov, I.; Harris, C. J.;
Duffy, J. E. S. Carbamic acid compounds comprising a sulfonamide linkage as HDAC
inhibitors. PCT Int. Appl. WO200230879A2, April 18, 2002.)
but using procedure D (Experimental Section) or method described for 26 to convert the methyl ester to crude
hydroxamic acid which was further purified by chromatography (silica, MeOH/DCM = 1:10) to
afford 28 (PXD101) as off-white or pale yellow powder (2.5 g, 31%).

LC–MS m/z 319.0 ([M +H]+).

1H NMR (DMSO-d6)  12–9 (very broad, 2H), 7.90 (s, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.70 (d, J

= 7.8 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.44 (d, J = 15.8 Hz, 1H), 7.22 (t, J = 7.8 Hz, 2H), 7.08 (d,
J = 7.8 Hz, 2H), 7.01 (t, J = 7.3 Hz, 1H), 6.50 (d, J = 15.8 Hz, 1H);

13C NMR (DMSO-d6)  162.1,
140.6, 138.0, 136.5, 135.9, 131.8, 130.0, 129.2, 127.1, 124.8, 124.1, 121.3, 120.4.

Anal.
(C15H14N2O4S) C, H, N

………………………………………………..

SYNTHESIS

WO2009040517A2

PXDIOI / Belinostat®

PXD101 was first described in WO 02/30879 A2. That document describes a multi-step method of synthesis which may conveniently be illustrated by the following scheme.

Scheme 1

Not isolated

ed on (A)

on (D)

d on (H)

There is a need for alternative methods for the synthesis of PXD101 and related compounds for example, methods which are simpler and/or employ fewer steps and/or permit higher yields and/or higher purity product.

Scheme 5

DMAP, toluene

Synthesis 1 3-Bromo-N-phenyl-benzenesulfonamide (3)

To a 30 gallon (-136 L) reactor was charged aniline (2) (4.01 kg; 93.13 g/mol; 43 mol), toluene (25 L), and 4-(dimethylamino)pyridine (DMAP) (12 g), and the mixture was heated to 50-60⁰C. 3-Bromobenzenesulfonyl chloride (1) (5 kg; 255.52 g/mol; 19.6 mol) was charged into the reactor over 30 minutes at 50-60⁰C and progress of the reaction was monitored by HPLC. After 19 hours, toluene (5 L) was added due to losses overnight through the vent line and the reaction was deemed to be complete with no compound (1) being detected by HPLC. The reaction mixture was diluted with toluene (10 L) and then quenched with 2 M aqueous hydrochloric acid (20 L). The organic and aqueous layers were separated, the aqueous layer was discarded, and the organic layer was washed with water (20 L), and then 5% (w/w) sodium bicarbonate solution (20 L), while maintaining the batch temperature at 45-55°C. The batch was then used in the next synthesis.

Synthesis 2 (E)-3-(3-Phenylsulfamoyl-phenyl)-acrylic acid ethyl ester (5)

To the batch containing 3-bromo-N-phenyl-benzenesulfonamide (3) (the treated organic layer obtained in the previous synthesis) was added triethylamine (2.97 kg; 101.19 g/mol; 29.4 mol), tri(o-tolyl)phosphine (119 g; 304.37 g/mol; 0.4 mol), and palladium (II) acetate (44 g; 224.51 g/mol; 0.2 mol), and the resulting mixture was degassed four times with a vacuum/nitrogen purge at 45-55°C. Catalytic palladium (0) was formed in situ. The batch was then heated to 80-90⁰C and ethyl acrylate (4) (2.16 kg; 100.12 g/mol; 21.6 mol) was slowly added over 2.75 hours. The batch was sampled after a further 2 hours and was deemed to be complete with no compound (3) being detected by HPLC. The batch was cooled to 45-55°C and for convenience was left at this temperature overnight.

The batch was then reduced in volume under vacuum to 20-25 L, at a batch temperature of 45-55°C, and ethyl acetate (20 L) was added. The batch was filtered and the residue washed with ethyl acetate (3.5 L). The residue was discarded and the filtrates were sent to a 100 gallon (-454 L) reactor, which had been pre-heated to 60⁰C. The 30 gallon (-136 L) reactor was then cleaned to remove any residual Pd, while the batch in the 100 gallon (-454 L) reactor was washed with 2 M aqueous hydrochloric acid and water at 45-55°C. Once the washes were complete and the 30 gallon (-136 L) reactor was clean, the batch was transferred from the 100 gallon (-454 L) reactor back to the 30 gallon (-136 L) reactor and the solvent was swapped under vacuum from ethyl acetate/toluene to toluene while maintaining a batch temperature of 45-55°C (the volume was reduced to 20-25 L). At this point, the batch had precipitated and heptanes (10 L) were added to re-dissolve it. The batch was then cooled to 0-10⁰C and held at this temperature over the weekend in order to precipitate the product. The batch was filtered and the residue was washed with heptanes (5 L). A sample of the wet-cake was taken for Pd analysis. The Pd content of the crude product (5) was determined to be 12.9 ppm.

The wet-cake was then charged back into the 30 gallon (-136 L) reactor along with ethyl acetate (50 L) and heated to 40-50⁰C in order to obtain a solution. A sparkler filter loaded with 12 impregnated Darco G60® carbon pads was then connected to the reactor and the solution was pumped around in a loop through the sparkler filter. After 1 hour, a sample was taken and evaporated to dryness and analysed for Pd content. The amount of Pd was found to be 1.4 ppm. A second sample was taken after 2 hours and evaporated to dryness and analysed for Pd content. The amount of Pd had been reduced to 0.6 ppm. The batch was blown back into the reactor and held at 40-50⁰C overnight before the solvent was swapped under vacuum from ethyl acetate to toluene while maintaining a batch temperature of 45-55°C (the volume was reduced to 20-25 L). At this point, the batch had precipitated and heptanes (10 L) were added to re-dissolve it and the batch was cooled to 0-10⁰C and held at this temperature overnight in order to precipitate the product. The batch was filtered and the residue was washed with heptanes (5 L). The filtrate was discarded and the residue was dried at 45-55°C under vacuum for 25 hours. A first lot of the title compound (5) was obtained as an off-white solid (4.48 kg, 69% overall yield from 3-bromobenzenesulfonyl chloride (1)) with a Pd content of 0.4 ppm and a purity of 99.22% (AUC) by HPLC.

Synthesis 3 (E)-3-(3-Phenylsulfamoyl-phenyl)-acrvlic acid (6)

To the 30 gallon (-136 L) reactor was charged the (E)-3-(3-phenylsulfamoyl-phenyl)- acrylic acid ethyl ester (5) (4.48 kg; 331.39 g/mol; 13.5 mol) along with 2 M aqueous sodium hydroxide (17.76 L; -35 mol). The mixture was heated to 40-50°C and held at this temperature for 2 hours before sampling, at which point the reaction was deemed to be complete with no compound (5) being detected by HPLC. The batch was adjusted to pH 2.2 using 1 M aqueous hydrochloric acid while maintaining the batch temperature between 40-50⁰C. The product had precipitated and the batch was cooled to 20-30⁰C and held at this temperature for 1 hour before filtering and washing the cake with water (8.9 L). The filtrate was discarded. The batch was allowed to condition on the filter overnight before being charged back into the reactor and slurried in water (44.4 L) at 40-50⁰C for 2 hours. The batch was cooled to 15-20°C, held for 1 hour, and then filtered and the residue washed with water (8.9 L). The filtrate was discarded. The crude title compound (6) was transferred to an oven for drying at 45-55°C under vacuum with a slight nitrogen bleed for 5 days (this was done for convenience) to give a white solid (3.93 kg, 97% yield). The moisture content of the crude material was measured using Karl Fischer (KF) titration and found to be <0.1% (w/w). To the 30 gallon (-136 L) reactor was charged the crude compound (6) along with acetonitrile (47.2 L). The batch was heated to reflux (about 80°C) and held at reflux for 2 hours before cooling to 0-10°C and holding at this temperature overnight in order to precipitate the product. The batch was filtered and the residue was washed with cold acetonitrile (7.9 L). The filtrate was discarded and the residue was dried under vacuum at 45-55°C for 21.5 hours. The title compound (6) was obtained as a fluffy white solid (3.37 kg, 84% yield with respect to compound (5)) with a purity of 99.89% (AUC) by HPLC.

Synthesis 4 (E)-N-Hvdroxy-3-(3-phenylsulfamoyl-phenyl)-acrylamide (PXD101) BELINOSTAT

To the 30 gallon (-136 L) reactor was charged (E)-3-(3-phenylsulfamoyl-phenyl)-acrylic acid (6) (3.37 kg; 303.34 g/mol; 11.1 mol) and a pre-mixed solution of 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in isopropyl acetate (IPAc) (27 g in 30 L; 152.24 g/mol; 0.18 mol). The slurry was stirred and thionyl chloride (SOCI₂) (960 mL; density ~1.631 g/mL; 118.97 g/mol; -13 mol) was added to the reaction mixture and the batch was stirred at 20-30⁰C overnight. After 18.5 hours, the batch was sampled and deemed to be complete with no compound (6) being detected by HPLC. The resulting solution was transferred to a 100 L Schott reactor for temporary storage while the

30 gallon (-136 L) reactor was rinsed with isopropyl acetate (IPAc) and water. Deionized water (28.9 L) was then added to the 30 gallon (-136 L) reactor followed by 50% (w/w) hydroxylamine (6.57 L; -1.078 g/mL; 33.03 g/mol; -214 mol) and another charge of deionized water (1.66 L) to rinse the lines free of hydroxylamine to make a 10% (w/w) hydroxylamine solution. Tetrahydrofuran (THF) (6.64 L) was then charged to the

30 gallon (-136 L) reactor and the mixture was stirred and cooled to 0-10⁰C. The acid chloride solution (from the 100 L Schott reactor) was then slowly charged into the hydroxylamine solution over 1 hour maintaining a batch temperature of 0-10°C during the addition. The batch was then allowed to warm to 20-30⁰C. The aqueous layer was separated and discarded. The organic layer was then reduced in volume under vacuum while maintaining a batch temperature of less than 30⁰C. The intention was to distill out 10-13 L of solvent, but this level was overshot. A larger volume of isopropyl acetate (IPAc) (16.6 L) was added and about 6 L of solvent was distilled out. The batch had precipitated and heptanes (24.9 L) were added and the batch was held at 20-30°C overnight. The batch was filtered and the residue was washed with heptanes (6.64 L). The filtrate was discarded and the residue was dried at 45-55°C under vacuum with a slight nitrogen bleed over the weekend. The title compound (PXD101) was obtained as a light orange solid (3.11 kg, 89% yield with respect to compound (6)) with a purity of 99.25% (AUC) by HPLC.

The title compound (PXD101) (1.2 kg, 3.77 mol) was dissolved in 8 volumes of 1:1 (EtOH/water) at 60⁰C. Sodium bicarbonate (15.8 g, 5 mol%) was added to the solution. Water (HPLC grade) was then added at a rate of 65 mL/min while keeping the internal temperature >57°C. After water (6.6 L) had been added, crystals started to form and the water addition was stopped. The reaction mixture was then cooled at a rate of 10°C/90 min to a temperature of 0-10^cC and then stirred at ambient temperature overnight. The crystals were then filtered and collected. The filter cake was washed by slurrying in water (2 x 1.2 L) and then dried in an oven at 45°C for 60 hours with a slight nitrogen bleed. 1.048 kg (87% recovery) of a light orange solid was recovered. Microscopy and XRPD data showed a conglomerate of irregularly shaped birefringant crystalline particles. The compound was found to contain 0.02% water.

As discussed above: the yield of compound (5) with respect to compound (1) was 69%. the yield of compound (6) with respect to compound (5) was 84%. the yield of PXD101 with respect to compound (6) was 89%.

……………….

FORMULATION

WO2006120456A1

Formulation Studies

These studies demonstrate a substantial enhancement of HDACi solubility (on the order of a 500-fold increase for PXD-101) using one or more of: cyclodextrin, arginine, and meglumine. The resulting compositions are stable and can be diluted to the desired target concentration without the risk of precipitation. Furthermore, the compositions have a pH that, while higher than ideal, is acceptable for use.

UV Absorbance

The ultraviolet (UV absorbance E\ value for PXD-101 was determined by plotting a calibration curve of PXD-101 concentration in 50:50 methanol/water at the λ_max for the material, 269 nm. Using this method, the E¹i value was determined as 715.7.

Methanol/water was selected as the subsequent diluting medium for solubility studies rather than neat methanol (or other organic solvent) to reduce the risk of precipitation of the cyclodextrin.

Solubility in Demineralised Water

The solubility of PXD-101 was determined to be 0.14 mg/mL for demineralised water. Solubility Enhancement with Cvclodextrins

Saturated samples of PXD-101 were prepared in aqueous solutions of two natural cyclodextrins (α-CD and γ-CD) and hydroxypropyl derivatives of the α, β and Y cyclodextrins (HP-α-CD, HP-β-CD and HP-γ-CD). All experiments were completed with cyclodextrin concentrations of 250 mg/mL, except for α-CD, where the solubility of the cyclodextrin was not sufficient to achieve this concentration. The data are summarised in the following table. HP-β-CD offers the best solubility enhancement for PXD-101.

Phase Solubility Determination of HP-β-CD

The phase solubility diagram for HP-β-CD was prepared for concentrations of cyclodextrin between 50 and 500 mg/mL (5-50% w/v). The calculated saturated solubilities of the complexed HDACi were plotted against the concentration of cyclodextrin. See Figure 1.

………………………..

Links

Plumb, Jane A.; Finn, Paul W.; Williams, Robert J.; Bandara, Morwenna J.; Romero, M. Rosario; Watkins, Claire J.; La Thangue, Nicholas B.; Brown, Robert (2003). “Pharmacodynamic Response and Inhibition of Growth of Human Tumor Xenografts by the Novel Histone Deacetylase Inhibitor PXD101”. Molecular Cancer Therapeutics 2 (8): 721–728. PMID 12939461.
“CuraGen Corporation (CRGN) and TopoTarget A/S Announce Presentation of Belinostat Clinical Trial Results at AACR-NCI-EORTC International Conference”. October 2007.
Final Results of a Phase II Trial of Belinostat (PXD101) in Patients with Recurrent or Refractory Peripheral or Cutaneous T-Cell Lymphoma, December 2009
“Spectrum adds to cancer pipeline with $350M deal.”. February 2010.
Helvetica Chimica Acta, 2005 , vol. 88, 7 PG. 1630 – 1657, MP 172
WO2009/40517 A2, ….
WO2006/120456 A1, …..
Synthetic Communications, 2010 , vol. 40, 17 PG. 2520 – 2524, MP 172
Journal of Medicinal Chemistry, 2011 , vol. 54, 13 PG. 4694 – 4720, NMR IN SUP INFO


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US2008227845	9-19-2008	CYCLOOXYGENASE-2 INHIBITOR/HISTONE DEACETYLASE INHIBITOR COMBINATION
US2008213399	9-5-2008	Combination Therapies Using Hdac Inhibitors
US2008194690	8-15-2008	Pharmaceutical Formulations Of Hdac Inhibitors
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US6888027	5-4-2005	Carbamic acid compounds comprising a sulfonamide linkage as hdac inhibitors

WO2002030879A2	Sep 27, 2001	Apr 18, 2002	Prolifix Ltd	Carbamic acid compounds comprising asulfonamide linkage as hdac inhibitors

US7973181	7-6-2011	HYDROXAMIC ACID DERIVATIVES AS INHIBITORS OF HDAC ENZYMATIC ACTIVITY
US7928081	4-20-2011	Combined Use of Prame Inhibitors and Hdac Inhibitors
US2011077305	3-32-2011	5-LIPOXYGENASE INHIBITORS
US2011003777	1-7-2011	Methods of Treatment Employing Prolonged Continuous Infusion of Belinostat
US2010286279	11-12-2010	Methods of Synthesis of Certain Hydroxamic Acid Compounds
US2010190694	7-30-2010	Methods for identifying patients who will respond well to cancer treatment
US2010010010	1-15-2010	HDAC INHIBITORS
US2009312311	12-18-2009	COMBINATION OF ORGANIC COMPOUNDS
US2009192211	7-31-2009	CYCLOOXYGENASE-2 INHIBITOR/HISTONE DEACETYLASE INHIBITOR COMBINATION
US7557140	7-8-2009	CARBAMIC ACID COMPOUNDS COMPRISING A SULFONAMIDE LINKAGE AS HDAC INHIBITORS

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………………………..

SPECTRUM

Tiny Biotech With Three Cancer Drugs Is More Alluring Takeover Bet Now
Forbes
The drug is one of Spectrum’s two drugs undergoing phase 3 clinical trials. Allergan paid Spectrum $41.5 million and will make additional payments of up to $304 million based on achieving certain milestones. So far, Raj Shrotriya, Spectrum’s chairman, …

http://www.forbes.com/sites/genemarcial/2013/07/14/tiny-biotech-with-three-cancer-drugs-is-more-alluring-takeover-bet-now/

……………………………..

Copenhagen, December 10, 2013

Topotarget announces the submission of a New Drug Application (NDA) for belinostat for the treatment of relapsed or refractory (R/R) peripheral T-cell lymphoma (PTCL) to the US Food and Drug Administration (FDA). The NDA has been filed for Accelerated Approval with a request for Priority Review. Response from the FDA regarding acceptance to file is expected within 60 days from the FDA receipt date.

read all this here

…………………….

SEE COMPILATION ON SIMILAR COMPOUNDS AT …………..http://drugsynthesisint.blogspot.in/p/nostat-series.html

FDA approves Cubist’s Sivextro Tedizolid to treat skin infections

June 23, 2014 3:34 am / Leave a comment

June 21, 2014

Regulators in the USA have given the green light to Cubist Pharmaceuticals’ antibiotic Sivextro for serious skin infections, including those caused by MRSA.

The US Food and Drug Administration has approved Sivextro (tedizolid) for acute bacterial skin and skin structure infections (ABSSSI) caused by certain susceptible bacteria, including Staphylococcus aureus (MRSA) and enterococcus faecalis. The thumbs-up is based in two trials of 1,315 adults with ABSSSI which showed that Sivextro was as effective as linezolid, another antibacterial.

Read more at: http://www.pharmatimes.com/Article/14-06-21/FDA_approves_Cubist_s_Sivextro_to_treat_skin_infections.aspx#ixzz35QhW3gVU

OLD POST

TEDIZOLID (torezolid)

January 4, 2014

https://newdrugapprovals.org/2014/01/04/tedizolid-torezolid/

TEDIZOLID PHOSPHATE

[(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl]phenyl}-2-oxo-5-oxazolidinyl]methyl]phosphate,

DA 7157

THERAPEUTIC CLAIM Treatment of complicated skin and skin structure infections
CHEMICAL NAMES
1. 2-Oxazolidinone, 3-[3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)-3-pyridinyl]phenyl]-5- [(phosphonooxy)methyl]-, (5R)-
2. [(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl]phenyl}-2-oxooxazolidin-5- yl]methyl hydrogen phosphate

http://www.ama-assn.org/resources/doc/usan/tedizolid-phosphate.pdf

MOLECULAR FORMULA C17H16FN6O6P

MOLECULAR WEIGHT 450.3
TRADEMARK None as yet
SPONSOR Trius Therapeutics
CODE DESIGNATION TR-701 FA
CAS REGISTRY NUMBER 856867-55-5
Note: This adoption statement supersedes the USAN torezolid phosphate (N09/81), which is hereby rescinded and replaced by the USAN tedizolid phosphate (N10/118).\

……………………………..

Tedizolid, 856866-72-3

(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl]phenyl}-5-(hydroxymethyl)-1,3-oxazolidin-2-one

(5R)-3-[3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)-3-pyridinyl]phenyl]-5-(hydroxymethyl)-2-oxazolidinone,

TR 700

Molecular Formula: C17H15FN6O3

Average mass: 370.337799

Torezolid (also known as TR-701 and now tedizolid[1]) is an oxazolidinone drug being developed by Trius Therapeutics (originator Dong-A Pharmaceuticals) for complicated skin and skin-structure infections (cSSSI), including those caused by Methicillin-resistantStaphylococcus aureus (MRSA).[2]

As of July 2012, tedizolid had completed one phase III trial, with another one under way. [3]Both trials compare a six-day regimen of tedizolid 200mg once-daily against a ten-day regimen of Zyvox (linezolid) 600mg twice-daily.

The prodrug of tedizolid is called “TR-701″, while the active ingredient is called “TR-700″.[4][5]

Trius Therapeutics will soon be reporting data from its second phase III trial (ESTABLILSH-2) and the recently announced publication of the data from its first phase III trial (ESTABLISH-1) in the Journal of the American Medical Association (JAMA)

“Trius grows as lead antibiotic moves forward”. 31 Oct 2011.

“Trius Completes Enrollment In Phase 2 Clinical Trial Evaluating Torezolid (TR-701) In Patients With Complicated Skin And Skin Structure Infections”. Jan 2009.

http://clinicaltrials.gov/ct2/results?flds=Xf&flds=a&flds=b&term=tedizolid&phase=2&fund=2&show_flds=Y

PMID 19528279 In vitro activity of TR-700, the active ingredient of the antibacterial prodrug TR-701, a novel oxazolidinone antibacterial agent.

PMID 19218276 TR-700 in vitro activity against and resistance mutation frequencies among Gram-positive pathogens.

…………………………………………………….

Emergence of bacterial resistance to known antibacterial agents is becoming a major challenge in treating bacterial infections. One way forward to treat bacterial infections, and especially those caused by resistant bacteria, is to develop newer antibacterial agents that can overcome the bacterial resistance. Coates et al. (Br. J. Pharmacol. 2007; 152(8), 1147-1154.) have reviewed novel approaches to developing new antibiotics. However, the development of new antibacterial agents is a challenging task. For example, Gwynn et al. (Annals of the New York Academy of Sciences, 2010, 1213: 5-19) have reviewed the challenges in the discovery of antibacterial agents.

Several antibacterial agents have been described in the prior art (for example, see PCT International Application Nos. PCT/US2010/060923, PCT/EP2010/067647, PCT/US2010/052109, PCT/US2010/048109, PCT/GB2009/050609, PCT/EP2009/056178 and PCT/US2009/041200). However, there remains a need for potent antibacterial agents for preventing and/or treating bacterial infections, including those caused by bacteria that are resistant to known antibacterial agents.

Various oxazolidinone-containing compounds have been disclosed for use asantibiotics. For example, oxazolidinone-containing compounds have been described in U.S. patent application Ser. No. 10/596,412 (filed Dec. 17, 2004), and WO 04/048350, WO 03/022824 and WO 01/94342, which are incorporated herein by reference.

U.S. patent application Ser. No. 12/577,089 (filed Oct. 9, 2009) and U.S. patent application Ser. No. 12/699,864 (filed Feb. 3, 2010), which are assigned to the same assignee as in the present application, disclose phosphate dimer impurities made during the process of making of the compounds disclosed therein. Surprisingly, it has been found that compounds containing at least two phosphates binding two oxazolidinone-containing moieties, such as dimers of oxazolidinone-containing compounds have antibacterial activity similar to their dihydrogen monophosphate analog

active drug of Formula I is (5R)-3-[3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)-3-pyridinyl]phenyl]-5-(hydroxymethyl)-2-oxazolidinone, i.e.,

These active compounds have been disclosed in WO 05/058886 and US Patent Publication No. 20070155798, while processes for making these and related compounds have been disclosed in U.S. patent application Ser. No. 12/577,089 (filed Oct. 9, 2009), and a crystalline form of the phosphate ester and related salts of the above compound has been disclosed in U.S. patent application Ser. No. 12/699,864 (filed Feb. 3, 2010).

US Patent Publication No. 20070155798, recently disclosed a series of potently anti-bacterial oxazolidinones including

wherein R═H, PO(OH)₂, and PO(ONa)₂.

Cubist Announces Submission of New Drug Application for Investigational Antibiotic Tedizolid for Treatment of Serious Skin Infections

LEXINGTON, Mass.–(BUSINESS WIRE)– Cubist Pharmaceuticals, Inc. today announced that it has submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for approval of its investigational antibiotic tedizolid phosphate (TR-701). Cubist is seeking approval of tedizolid phosphate for the treatment of acute bacterial skin and skin structure infections (ABSSSI). Tedizolid phosphate is a once daily oxazolidinone being developed for both intravenous (I.V.) and oral administration for the treatment of serious Gram-positive infections, including those caused by methicillin-resistant Staphylococcus aureus (MRSA).

http://www.drugs.com/nda/tedizolid_131023.html

…………………………………………………………..

Efficacy of DA-7218, a new oxazolidinone prodrug, in the treatment of experimental actinomycetoma produced by Nocardia brasiliensis.

Espinoza-González NA, Welsh O, de Torres NW, Cavazos-Rocha N, Ocampo-Candiani J, Said-Fernandez S, Lozano-Garza G, Choi SH, Vera-Cabrera L.

Molecules. 2008 Jan 11;13(1):31-40.

…………………………………………..

imp patents

US2010305069

12-3-2010

OXAZOLIDINONE CONTAINING DIMER COMPOUNDS, COMPOSITIONS AND METHODS TO MAKE AND USE

US7816379

10-20-2010

Oxazolidinone derivatives

US2009192197

7-31-2009

NOVEL OXAZOLIDINONE DERIVATIVES

…………………………………………..

TEDIZOLID disodium salt

59 nos in

http://www.google.com/patents/US20130102523

38 nos

Tedizolid (formerly known as torezolid or TR-700) is the active hydroxymethyl oxazolidinone having the following formula:

Pharmaceutical prodrugs such as tedizolid phosphate (also referred to as TR-701, torezolid phosphate, and TR-701 “free acid” or FA) have the following formula:

The disodium salt of tedizolid phosphate, has the following structure:

…………………………………………………………………………………………………………………………………………………………….

US20100305069

Example 1 Preparation of the Phosphate Monohydrogen Diester, Formula III
In this and the following Examples, “Formula III” refers to a compound wherein Z is
Figure US20100305069A1-20101202-C00024
and M=OH.
A 1-L, three-neck round-bottom flask equipped with a magnetic stirrer, nitrogen inlet/outlet and thermocouple was charged with the compound of Formula Ia below (16.0 g, 0.0499 mol], THF (320 mL, 20 vol) and Et3N (21.9 g, 0.216 mol, 5.0 equiv.).
Figure US20100305069A1-20101202-C00025
POCl3 (3.31 g, 0.0216 mol, 0.5 equiv.) was added dropwise via syringe over 5 minutes. The reaction temperature was maintained below 25° C. The batch was aged for 16 hours at room temperature at which point HPLC analysis (XBridge, C18) indicated that the reaction was complete. The reaction vessel was then immersed in an ice-water bath and a 500-mL addition funnel charged with 320 mL of H2O was attached to the reaction vessel. When the temperature of the reaction reached 2.7° C., H2O was added drop wise over 30 minutes. The temperature of the reaction was maintained below 10° C. Upon completion of the H2O addition, the ice-water bath was removed and the batch was aged for 3 hours. The solution was transferred to a 2-L round-bottom flask and concentrated under reduced pressure on a rotary evaporator. After removal of most of the THF from the solution, the aqueous mixture was extracted with 5 1-L portions of CH2Cl2:MeOH (9:1). The CH2Cl2 layers were combined and concentrated to a dark oil. This crude material was purified on 200 g of silica gel, eluting with 10% MeOH/CH2Cl2 to 20% 2 N NH3 in MeOH/CH2Cl2. Fractions containing mostly the bis-ester (as judged by TLC Rf=0.3 eluting with 20% 2 N NH3 in MeOH/CH2Cl2) were combined and concentrated under reduced pressure on a rotary evaporator, during which time a white precipitate was observed. The flask containing the slurry was removed from the rotary evaporator and equipped with a magnetic stir bar and allowed to stir while cooling to room temperature over 3 hours, during which time the slurry thickened. The solid was filtered and dried in a vacuum oven at 45° C. for 16 hours to give 3.55 g of bis-ester as an off-white solid (20% yield). HPLC analysis (Method A): 99.0% (AUC), tR=16.3 min. This reaction was repeated and the combined lots of the compound of Formula III (6.7 g) were slurried in 100 mL of MeOH (15 vol). The slurry was heated to 40° C. for 30 minutes and then allowed to cool to room temperature over 1 hour. The off-white solid was filtered and dried in a vacuum oven at 40° C. for 16 hours to give 6.15 g of the compound of Formula III (92% yield). The 1H NMR analysis of the product was consistent with the assigned structure. HPLC analysis (Method A): 99.0% (AUC), tR=16.3 min.

Example 2 Preparation of the Diphosphate Dihydrogen Diester, Formula IV
In Examples 2-5, “Formula IV” refers to a compound wherein Z is
Figure US20100305069A1-20101202-C00026
n=0 and M=O-imidazolium salt.

A 250-mL 3-neck round-bottom flask equipped with a magnetic stirrer, nitrogen inlet/outlet and thermocouple was charged with the compound of Formula IIa below (5.0 g, 11.1 mmol), carbonyldiimidazole (890 mg, 5.55 mmol, 0.5 equiv.) and DMF (100 mL, 20 vol).
Figure US20100305069A1-20101202-C00027
The suspension was heated to 50° C. and held at that temperature for 4 hours at which point HPLC analysis (XBridge, C18) indicated that the reaction was complete. The reaction was filtered at 50° C. and dried in a vacuum oven at 50° C. for 24 hours to give 5.15 g of the imidazolium salt (i.e., the compound of Formula IV) as an off-white solid (98% yield). The 1H NMR analysis of the product was consistent with the assigned structure. HPLC analysis (Method A): 94.5% (AUC), tR=14.6 min.
TABLE 1
Method A (Waters XBridge C18 Column)
Time (min) Flow (mL/min) % A % B
0.0 1.0 98.0 2.0
15.0 1.0 5.0 95.0
25.0 1.0 5.0 95.0
27.0 1.0 98.0 2.0
30.0 1.0 98.0 2.0
A = 87% 25 mM ammonium bicarbonate solution in water/13% Acetonitrile
B = Acetonitrile
Wavelength = 300 nm

disodium salt is TR 701

……………………………………

US8580767

Various oxazolidinone-containing compounds have been disclosed for use as antibiotics. For example, oxazolidinone-containing compounds have been described in U.S. patent application Ser. No. 10/596,412 (filed Dec. 17, 2004), and WO 04/048350, WO 03/022824 and WO 01/94342, which are incorporated herein by reference.

U.S. patent application Ser. No. 12/577,089 (filed Oct. 9, 2009) and U.S. patent application Ser. No. 12/699,864 (filed Feb. 3, 2010), which are assigned to the same assignee as in the present application, disclose phosphate dimer impurities made during the process of making of the compounds disclosed therein. Surprisingly, it has been found that compounds containing at least two phosphates binding two oxazolidinone-containing moieties, such as dimers of oxazolidinone-containing compounds have antibacterial activity similar to their dihydrogen monophosphate analog,

These active compounds have been disclosed in WO 05/058886 and US Patent Publication No. 20070155798, while processes for making these and related compounds have been disclosed in U.S. patent application Ser. No. 12/577,089 (filed Oct. 9, 2009), and a crystalline form of the phosphate ester and related salts of the above compound has been disclosed in U.S. patent application Ser. No. 12/699,864 (filed Feb. 3, 2010). The latter two applications are assigned to the same assignee as in the present application

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SYNTHESIS

US20070155798

DESCRIPTION OF COMPDS

10,

(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxymethyl oxazolidin-2-on (compound 10)

………………………………………………………………………………………………………………………….

18

Preparation of (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-fluoromethyl oxazolidin-2-on (compound 18)

………………………………………………………………………………………………………………………………………………………….

33

(R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-methoxymethyl oxazolidin-2-on (compound 33)

…………………………………………………………………………………………………………………………………………..

59

(R)-[3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl disodiumphosphate (compound 59)

………………………………………………………………………………………………………………………………………………………

72

mono-[(R)-[3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl]phosphate (compound 72)

COMPLETE SYNTHESIS

Example 5

Preparation of 2-cyano-5-bromopyridine

In 1 L of dimethylformamide was dissolved 100 g of 2,5-dibromopyridine, 32 g of cupper cyanide and 17.8 g of sodium cyanide were added to the solution at room temperature and the solution was stirred at the temperature of 150° C. for 7 hours for reaction. After being cooled to room temperature, the reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with brine, dehydrated, filtered and concentrated in vacuo. The title compound 54 g was obtained. Yield 70%.

¹HNMR(CDCl₃) δ 8.76(s,1H), 7.98(dd,1H), 7.58(dd,1H)

Example 6

Preparation of 2-(tetrazol-5-yl)-5-bromopyridine

10 g of 2-cyano-5-bromopyridine prepared in the Preparation example 5 was dissolved in 100 ml of dimethylformamide, 5.33 g of sodiumazide, and 4.4 g of ammonium chloride were added to the solution at room temperature, and the solution was stirred at the temperature of 110° C. for 3 hours for reaction. The reaction mixture was added with water and then was extracted with ethyl acetate. The organic layer, thus separated, was washed with brine, dehydrated, filtrated and concentrated in vacuo thereby to obtain 10.5 g of the title compound. Yield 85%.

Preparation Example 7 Preparation of 2-(1-methyltetrazol-5-yl)-5-bromopyridine and 2-(2-methyltetrazol-5-yl)-5-bromopyridine

10.5 g of 2-(tetrazol-5-yl)-5-bromopyridine prepared in the Preparation example 6 was dissolved in 100 ml of dimethylformamide. And then 6.5 g of sodium hydroxide was added to the solution and 9.3 g of iodomethane was slowly added to the solution at the temperature of 0° C. The solution was stirred for 6 hours at room temperature, added with water, extracted with ethyl acetate. And then the organic layer was washed with brine, dehydrated, filtrated, concentrated in vacuo and purified by column chromatography to obtain 4 g of 2-(1-methyltetrazol-5-yl)-5-bromopyridine and 5 g of 2-(2-methyltetrazol-5-yl)-5-bromopyridine.

1) 2-(1-methyltetrazol-5-yl)-5-bromopyridine

¹HNMR(CDCl₃) δ 8.77(t,1H), 8.23(dd,1H), 8.04(dd,1H), 4.46(s,3H)

2) 2-(2-methyltetrazol-5-yl)-5-bromopyridine

¹HNMR(CDCl₃) δ 8.80(t,1H), 8.13(dd,1H), 7.98(dd,1H), 4.42(s,3H)

Example 1

Preparation of N-Carbobenzyloxy-3-fluoroaniline

3-fluoroaniline 100 g was dissolved in 1 L of tetrahydrofuran (THF) and the solution was added with 150 g (1.8 mol) of sodium bicarbonate (NaHCO₃). After being cooled to 0° C., the solution was slowly added with 154 ml of N-carbobenzyloxy chloride (CbzCl) for reaction. While the temperature was maintained at 0° C., the reaction mixture was let to react for 2 hours with stirring. Afterwards, the reaction was extracted with 0.5 L of ethyl acetate. The organic layer, after being separated, was washed with brine, dried over anhydrous magnesium sulfate (MgSO₄) and concentrated in vacuo. The residue was washed twice with n-hexane to afford the title compound as white crystal. 132 g. Yield 85%.

Example 2

Preparation of (R)-3-(3-fluorophenyl)-2-oxo-5-oxazolidinylmethanol

132 g of N-carbobenzyloxy-3-fluoroaniline 132 g prepared in the Preparation example 1 was dissolved in 1.3 L of tetrahydrofuran and the solution was cooled to −78° C. 370 ml of n-buthyllitium (n-BuLi, 1.6M/n-hexane) was slowly added to the solution in a nitrogen atmosphere, followed by stirring for 10 min. And 84 ml of (R)-(−)-glycidylbuthylate was slowly added to the reaction mixture, stirred at the same temperature for 2 hours and allowed to react for 24 hours at room temperature. After completion of the reaction, the solution was added with ammonium chloride (HH₄Cl) solution and extracted with 0.5 L of ethyl acetate at room temperature. The organic layer, thus separated, was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was dissolved in 100 ml of ethyl acetate and washed with n-hexane to give white crystals, which were purified to the title compound. 80 g. Yield 70%.

¹H NMR (DMSO-d₆) δ 7.85(t,1H), 7.58(dd,1H), 7.23(dd,1H), 4.69(m,1H), 4.02 (t,1H), 3.80(dd,1H), 3.60(br dd,2H).

Example 3

Preparation of (R)-3-(4-iodo-3-fluorophenyl)-2-oxo-5-oxazolidinylmethanol

In 300 ml of acetonitryl was dissolved 30 g of (R)-3-(3-fluorophenyl)-2-oxo-5-oxazolidinylmethanol prepared in the Preparation example 2, and 46 g of trifluoroacetic acid silver salt (CF₃COOAg) and 43 g of iodide were added to the solution. After being stirred for one day at room temperature, the solution was added with water and was extracted with ethyl acetate. The organic layer, thus separated, was washed with brine and dehydrated. And then the residue was filtered, concentrated in vacuo and dried thereby to form the title compound 44 g. Yield 94%.

¹H NMR (DMSO-d₆) δ 7.77(t,1H), 7.56(dd,1H), 7.20(dd,1H), 5.20(m,1H), 4.70 (m,1H), 4.07(t,1H), 3.80(m,1H), 3.67(m,2H), 3.56(m,3H)

Example 4

Preparation of (R)-3-(4-tributhylstannyl-3-fluorophenyl)-2-oxo-5-oxazolidinylmethanol

In 660 ml of 1,4-dioxan was dissolved 50 g of (R)-3-(4-iodo-3-fluorophenyl)-2-oxo-5-oxazolidinylmethanol prepared in the Preparation example 3, 52 g of hexabutylditin ((Bu₃Sn)₂) and 9.3 g of dichlorobistriphenylphosphinpalladium were added into the solution, and stirred for 2 hours. The solution was filtered using celite and concentrated in vacuo. The residue was purified by column chromatography and 45 g of the title compound was formed.

¹H NMR (DMSO-d₆) δ 7.74(m,3H), 5.20(t,1H), 4.71(m,1H), 4.08(t,1H), 3.82(dd,1H), 3.68(m,1H), 3.52(m,1H), 1.48(m, 6H), 1.24(m, 6H), 1.06(m,6H), 0.83(t,9H)

COMPD 10

Example 1 Preparation of (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxymethyl oxazolidin-2-on (compound 10)

In 150 ml of 1-methyl-2-pyrrolidone was dissolved 37 g of (R)-3-(4-tributhylstannyl-3-fluorophenyl)-2-oxo-5-oxazolidinylmethanol. The solution was added with 19.7 g of 2-(2-methyltetrazol-5-yl)-5-bromopyridine, 10.44 g of lithium chloride and 2.9 g of dichlorobistriphenylphospine palladium(II) at room temperature and then stirred at the temperature of 120° C. for 4 hours. The reaction mixture was added with water and then extracted with ethyl acetate. The organic layer, thus separated, was washed with brine, dehydrated, filtrated, concentrated in vacuo and purified by column chromatography to provide 8 g of the title compound. Yield 26%.

¹H NMR (DMSO-d₆) δ 8.90(s,1H), 8.18(m,2H), 7.70(m,2H), 7.49(dd,1H), 5.25(t,1H), 4.74(m,1H), 4.46(s,3H), 4.14(t,1H), 3.88(dd,1H), 3.68(m,1H), 3.58 (m,1H)

COMPD 18

Example 28 Preparation of (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-fluoromethyl oxazolidin-2-on (compound 18)

In 5 ml of methylenchloride was dissolved 100 mg of the compound 10. The solution was added with 43 mg of diethylaminosulfurtrifloride (DAST) and 0.078 ml of triethylamine and then stirred for 24 hours. After being concentrating, the reaction mixture was purified by column chromatography to obtain the title compound 75 mg. Yield 75%.

¹H NMR (DMSO-d₆) δ 8.91(s,1H), 8.19(m,2H), 7.74(t,1H), 7.66(dd,1H) 7.49 (dd,1H), 5.06(m,1H), 4.89(m,2H), 4.46(s,3H), 4.23(t,1H), 3.95(dd,1H)

COMPD 33

Example 37 Preparation of (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-methoxymethyl oxazolidin-2-on (compound 33)

In 10 ml of methanol was dissolved 400 mg of (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-methansulfonyloxymethyl oxazolidin-2-on prepared in the secondary step of the Example 24. The solution was added with 90 mg of sodium methoxide at room temperature and then stirred for one day at room temperature. The solution was extracted with ethyl acetate and the organic layer, thus separated, was washed with water and brine. The organic layer was dehydrated, filtered, concentrated in vacuo and purified by column chromatography to provide the title compound 200 mg. Yield 58%.

¹H NMR(CDCl₃) δ 8.90(s,1H), 8.29(d,1H), 8.04(d,1H), 7.61(dd,1H), 7.58 (t,1H), 7.38(dd,1H), 4.80(m,1H), 4.45(s,3H), 4.08(t,1H), 3.96(dd,1H), 3.67 (m,2H), 3.43(s,3H)

COMPD 59

Example 58 Preparation of mono-[(R)-[3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl]phosphate (compound 72) and (R)-[3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl disodiumphosphate (compound 59)

1. The Primary Step

In 10 ml of mixture solvent (tetrahydrofuran:methylenchloride=1:1) was dissolved 1 g of compound 10. The solution was added with 0.6 g of tetrazole and 2.3 g of di-tetrabutyl diisoprophylphosphoamidite and stirred for 15 hours at room temperature. The reaction mixture was refrigerated to −78° C., added with 0.7 g of metachloroperbenzoic acid and stirred for 2 hours. After being cooling to −78° C., the reaction mixture was added with metachloroperbenzoic acid (0.7 g). When the reaction mixture was stirred for 2 hours, the temperature of the reaction mixture was raised to room temperature. The reaction mixture was then added with ethyl acetate. The organic layer, thus separated, was washed with sodium bisulfate, sodium bicarbonate and brine, dehydrated, filtered and concentrated in vacuo, followed by purification with column chromatography thereby to provide (R)-[3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl phosphoric acid ditetrabuthylester (0.71 g, 71%).

¹H NMR (DMSO-d₆) δ 8.90(s,1H), 8.18(m,2H), 7.74(t,1H), 7.68 (dd,1H), 7.49(dd,1H), 4.98(m,1H), 4.46(s,3H), 4.23(t,1H), 4.18(m,1H), 4.09(m,1H), 3.89 (dd,1H), 1.39(s,9H), 1.38(s,9H)

The crystal prepared the above method was dissolved in a mixture of methanol and chloroform. And then the solution added with 3.4 ml of sodium methoxide (0.3M methanol solution) at the room temperature and stirred for 10 hours. The reaction mixture was concentrated to prepare the residue. The residue was crystallized and filtered thereby to obtain the title compound (compound 59) 300 mg.

¹H NMR (D₂O) δ 8.27(s,1H), 7.56(dd,2H), 7.06(m,2H), 6.90(m,1H), 4.79 (m,1H), 4.63(s,3H), 3.90(m,4H)

COMPD 72

The Secondary Step

In 30 ml of methylenchloride was dissolved the compound (0.7 g) in the Primary Step. The solution was added with 15 ml of trifluoroacetic acid and then stirred for 1 hour at room temperature. The reaction mixture was concentrated in vacuo to prepare the residue. The residue was crystallized with ethanol and ethyl ether to obtain mono-[(R)-[3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl]phosphate (compound 72) 400 mg.

¹H NMR (DMSO-d₆) δ 8.92(s,1H), 8.20(m,2H), 7.74(t,1H), 7.66(dd,1H), 7.500(dd,1H), 4.95 (m,1H), 4.46(s,3H), 4.21(t,1H), 4.05(m,2H), 3.91(dd,1H)

US20070155798

………………………………………………………

IMPURITIES

US8426389

Organic Impurities in TR-701 FA Drug Substance

Impurity

‘Name’ Structure and Chemical Name

Rx600013 ‘Des-methyl TR- 701’

dihydrogen ((5R)-3-{3-fluoro-4-[6-(2H-1,2,3,4-tetrazol-5-

yl)-3-pyridinyl]phenyl}-2-oxo-1,3-oxazolan-5-yl)methyl

phosphate

Rx600024 ‘Pyrophosphate’

trihydrogen ((5R)-3-{3-fluoro-4-[6-(1-methyl-1H-1,2,3,4-

tetraazol-5-yl)-3-pyridinyl]phenyl}-2-oxo-1,3-oxazolan-5-

yl)methyl pyrophosphate

Rx600014 ‘Ring opened’

dihydrogen 3-{3-fluoro-4-[6-(2-methyl-2H-1,2,3,4-tetraazol-5-

yl)-3-pyridinyl]aniline}-2-hydroxypropyl phosphate

Rx600023 ‘Me-isomer’

dihydrogen ((5R)-3-{3-fluoro-4-[6-(1-methyl-1H-1,2,3,4-

tetraazol-5-yl)-3-pyridinyl]phenyl}-2-oxo-1,3-oxazolan-5-

yl)methyl phosphate

Rx600025 ‘Overalkylated- phosphorylated impurity’

(R)-1-((3-(3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-

yl)pyridin-3-yl)phenyl)-2-oxooxazolidin-5-yl)methoxy)-3-

hydroxypropan-2-yl dihydrogen phosphate;

(R)-3-((3-(3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-

yl)pyridin-3-yl)phenyl)-2-oxooxazolidin-5-yl)methoxy)-2-

hydroxypropyl dihydrogen phosphate

Rx600020 ‘Dimer impurity’

dihydrogen bis-O-O′-[(5R)-3-{3-fluoro-4-[6-(2-methyl-

2H-1,2,3,4-tetrazol-5-yl)-3-pyridinyl]phenyl}-2-oxo-1,3-

oxazolidin-5-yl]methyl pyrophosphate

Rx600026 “Chloro”

(R)-5-(chloromethyl)-3-(3-fluoro-4-(6-(2-methyl-2H-

tetrazol-5-yl)pyridin-3-yl)phenyl)oxazolidin-2-one

Rx600001 TR-700

5R)-3-{3-Fluoro-4-[6-(2-methyl-2H-1,2,3,4-tetrazol-5-yl)-

pyridin-3-yl]-phenyl}-5-hydroxymethyl-1,3-oxazolidin-2-one

Rx600022 ‘Bis phosphate’

hydrogen bis-O-O′-[(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-1,2,3,4-

tetrazol-5-yl)-3-pyridinyl]phenyl}-2-oxo-1,3-oxazolidin-5-yl]methyl

phosphate

Rx600042

3-{[(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-

yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl]methoxy}-2-hydroxypropyl

[(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-

yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl]methyl hydrogen phosphate

Rx600043

2-{[(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-

yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl]methoxy}-1-hydroxyethyl

[(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-

yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl]methyl hydrogen phosphate

……………………………………………..

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US20080064689 24 May 2004 13 Mar 2008 Astrazeneca Ab 3-[4-(6-Pyridin-3-Yl)-3-Phenyl] -5-(1H-1,2,3-Triazol-1-Ylmethyl)-1,3-Oxazolidin-2-Ones as Antibacterial Agents

US20090018123 19 Jun 2006 15 Jan 2009 Milind D Sindkhedkar Oxazolidinones Bearing Antimicrobial Activity Composition and Methods of Preparation

US20090192197 16 Sep 2008 30 Jul 2009 Dong-A Pharm. Co., Ltd. Novel oxazolidinone derivatives

US20100093669 9 Oct 2009 15 Apr 2010 Trius Therapeutics Methods for preparing oxazolidinones and compositions containing them

US20100227839 3 Feb 2010 9 Sep 2010 Trius Therapeutics Crystalline form of r)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin- 5-yl)-3-fluorophenyl)-5-hydroxymethyl oxazolidin-2-one dihydrogen phosphate

AU2004299413A1 Title not available

AU2009200606A1 Title not available

CA2549062A1 17 Dec 2004 30 Jun 2005 Chong Hwan Cho Novel oxazolidinone derivatives

CN101982468A 17 Dec 2004 2 Mar 2011 东亚制药株式会社 Novel oxazolidinone derivatives and pharmaceutical compositions comprising the derivatives

EP0312000A1 12 Oct 1988 19 Apr 1989 The Du Pont Merck Pharmaceutical Company Aminomethyl oxooxazolidinyl aroylbenzene derivatives useful as antibacterial agents

EP0352781A2 27 Jul 1989 31 Jan 1990 The Du Pont Merck Pharmaceutical Company Aminomethyloxooxazolidinyl arylbenzene derivatives useful as antibacterial agents

EP1699784A1 17 Dec 2004 13 Sep 2006 Dong-A Pharmaceutical Co., Ltd. Novel oxazolidinone derivatives

EP2305657A2 17 Dec 2004 6 Apr 2011 Dong-A Pharmaceutical Co., Ltd. Oxazolidinone derivatives

EP2435051A1 27 May 2010 4 Apr 2012 Trius Therapeutics Oxazolidinone containing dimer compounds, compositions and methods to make and use

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WO1993009103A1 5 Oct 1992 13 May 1993 Upjohn Co Substituted aryl- and heteroarylphenyloxazolidinones useful as antibacterial agents

WO1993023384A1 21 Apr 1993 25 Nov 1993 Michael Robert Barbachyn Oxazolidinones containing a substituted diazine moiety and their use as antimicrobials

WO1995007271A1 16 Aug 1994 16 Mar 1995 Michael R Barbachyn Substituted oxazine and thiazine oxazolidinone antimicrobials

WO1995014684A1 27 Sep 1994 1 Jun 1995 Michel R Barbachyn Esters of substituted-hydroxyacetyl piperazine phenyl oxazolidinones

WO2001094342A1 18 May 2001 13 Dec 2001 Cho Jong Hwan Novel oxazolidinone derivatives and a process for the preparation thereof

WO2002081470A1 3 Apr 2002 17 Oct 2002 Astrazeneca Ab Oxazolidinones containing a sulfonimid group as antibiotics

WO2003022824A1 9 Sep 2002 20 Mar 2003 Astrazeneca Ab Oxazolidinone and/or isoxazoline as antibacterial agents

WO2003035648A1 23 Oct 2002 1 May 2003 Astrazeneca Ab Aryl substituted oxazolidinones with antibacterial activity

WO2003047358A1 2 Dec 2002 12 Jun 2003 Vaughan Leslie Crow Cheese flavour ingredient and method of its production

WO2003072575A1 25 Feb 2003 4 Sep 2003 Astrazeneca Ab 3-cyclyl-5-(nitrogen-containing 5-membered ring) methyl-oxazolidinone derivatives and their use as antibacterial agents

WO2003072576A2 25 Feb 2003 4 Sep 2003 Astrazeneca Ab Oxazolidinone derivatives, processes for their preparation, and pharmaceutical compositions containing them

WO2004048350A2 24 Nov 2003 10 Jun 2004 Astrazeneca Ab Oxazolidinones as antibacterial agents

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WO2005005398A2 29 Jun 2004 20 Jan 2005 Yasumichi Fukuda Cyclopropyl group substituted oxazolidinone antibiotics and derivatives thereof

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WO2010138649A1 27 May 2010 2 Dec 2010 Trius Therapeutics, Inc. Oxazolidinone containing dimer compounds, compositions and methods to make and use

……………………………………………………………………………………….

THANKS AND REGARD’S
DR ANTHONY MELVIN CRASTO Ph.D

GLENMARK SCIENTIST , NAVIMUMBAI, INDIA

did you feel happy, a head to toe paralysed man’s soul in action for you round the clock

need help, email or call me

amcrasto@gmail.com

MOBILE-+91 9323115463

web link

http://about.me/amcrasto
http://anthonymelvincrasto.brandyourself.com/

I was paralysed in dec2007

The US Food and Drug Administration (FDA) has approved Bayer HealthCare’s Gadavist (gadobutrol) injection as the first magnetic resonance contrast agent for evaluation of breast cancer in the US

June 17, 2014 3:59 am / Leave a comment

GADOBUTROL

gadolinium(III) 2,2′,2”-(10-((2R,3S)-1,3,4-trihydroxybutan-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate

Gadobutrol, SH-L-562, Gadovist,138071-82-6

The US Food and Drug Administration (FDA) has approved Bayer HealthCare’s Gadavist (gadobutrol) injection as the first magnetic resonance contrast agent for evaluation of breast cancer in the US.

The agency has approved the new indication for Gadavist injection for intravenous use with magnetic resonance imaging of the breast to assess the presence and extent of malignant breast disease.

Approval is based on priority review of two Phase III studies with identical design (GEMMA-1 and GEMMA-2).

Bayer HealthCare’s Gadavist (gadobutrol)

Bayer’s Gadavist injection cleared for breast cancer evaluation

UPDATE……. Gadoteridol 279.3 mg/ml for injection , CDSCO INDIA 29.07.2021

For intravenous use in magnetic
reasonance imaging (MRI) in adults and
pediatric patients over 2 years of age for
whole body MRI including the head, neck,
liver, breast, musculoskeletal system and
soft tissue pathologies
The US Food and Drug Administration (FDA) has approved Bayer HealthCare’s Gadavist (gadobutrol) injection as the first magnetic resonance contrast agent for evaluation of breast cancer in the US.

http://www.pharmaceutical-technology.com/news/newsbayer-gadavist-injection-cleared-breast-cancer-evaluation-4293723?WT.mc_id=DN_News

GADOBUTROL

Clinical data
AHFS/Drugs.com	International Drug Names
Licence data	US FDA:link
Pregnancy cat.	C (US)
Legal status	POM (UK) ℞-only (US)
Routes	IV
Identifiers
CAS number	138071-82-6
ATC code	V08CA09
PubChem	CID 72057
DrugBank	DB06703
UNII	1BJ477IO2L
KEGG	D07420


Chemical data
Formula	C₁₈H₃₁Gd N₄O₉
Mol. mass	604.710 g/mol

………………………..

Gadobutrol (INN) (Gd-DO3A-butrol) is a gadolinium-based MRI contrast agent (GBCA).

It received marketing approval in Canada^[1] and in the United States.^[2]^[3]^[4]

As of 2007, it was the only GBCA approved at 1.0 molar concentrations.^[5]

Gadobutrol is marketed by Bayer Schering Pharma as Gadovist, and by Bayer HealthCare Pharmaceuticals as Gadavist.^[6]

Gadobutrol, SH-L-562, Gadovist

A different synthesis started from the previously reported tetraaza cyclopentaacenaphthylene (XV). Treatment of (XV) with a solution of piperazine at pH 6 gave rise to the bicyclic lactam (XVI). Alkylation of (XVI) with bromoacetic acid, followed by basic lactam hydrolysis furnished the tris(carboxymethyl) derivative (X), which was processed as in Scheme 3.

Argese, M.; Ripa, G. (Bracco SpA; Dibra SpA); 1,4,7,10-Tetraazabicyclo[8.2.2]tetradecan-2-one, a process for the preparation thereof and the use thereof for the preparation of tetraazamacrocycles. EP 0998476; JP 2002511884; WO 9905145

Gadobutrol, SH-L-562, Gadovist

In a related method for obtaining the precursor (V), epoxide (II) was condensed with the tosyl-protected tetraamine (XIII) in an autoclave at 170 C to give (XIV). The N-tosyl groups of (XIV) were then removed by treatment with lithium metal in liquid ammonia, yielding intermediate (III), which was then subjected to alkylation with bromoacetic acid, followed by acid hydrolysis

Platzek, J.; Gries, H.; Weinmann, H.-J.; Schuhmann-Giampieri, G.; Press, W.-R. (Schering AG); 1,4,7,10-Tetraazacyclododecane-butyl-triols, process for their preparation, and pharmaceutical agents containing these cpds.. DE 4009119; EP 0448191;

Gadobutrol, SH-L-562, Gadovist

The macrocyclic tetraamine (I) was protected as the triaminomethane derivative (VIII) by treatment with either triethyl orthoformate (4) or with dimethylformamide dimethylacetal (5). Alkylation of (VIII) with bromoacetic acid gave rise to the N-formyl N’,N”,N”’-tris(carboxymethyl) compound (IX). After basic hydrolysis of the formamide function of (IX), the resultant N-deprotected amine (X) was condensed with epoxide (II) to yield (XI). Further complexation with GdCl3 and ketal group hydrolysis led to the target compound

Murru, M.; Ripa, G.; Scala, A.; Viscardi, C.F.; Ausonio, M.; Scotti, C.; Cossuta, P. (Bracco SpA; Dibra SpA); A process for the preparation of macrocyclic chelants and the chelates thereof with paramagnetic metal ions. WO 9856775

WORLDCUP FOOTBALL WEEK 2014 BRAZIL

……………………………………………….

http://www.google.com/patents/EP0988294B1?cl=en

This type of complexes with metal ions, in particular with paramagnetic metal ions; is used for the preparation of non-ionic contrast agents for the diagnostic technique known as magnetic resonance (MRI, Magnetic Resonance Imaging), among which are ProHance^(R) (Gadoteridol, gadolinium complex of 10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid), and Gadobutrol (gadolinium complex of [10-[2,3-dihydroxy-1-(hydroxymethyl)propyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid).
[0003]

Two different synthetic approaches are described in literature for the preparation of this kind of complexes, said approaches differing in the strategy taken to discriminate one of the four nitrogen atoms: the first one (Dischino et al., Inorg. Chem., 1991, 30, 1265 or EP 448191, EP 292689, EP 255471) is based on the selective protection of one of the nitrogen atoms by formation of the compound of formula (III), 5H,9bH-2a,4a,7-tetraazacycloocta[cd]pentalene, and on the subsequent hydrolysis to compound of formula (IV), 1-formyl-1,4,7,10-tetraazacyclododecane, followed by the carboxymethylation of the still free nitrogen atoms and by the deprotection and alkylation of the fourth nitrogen atom, according to scheme 1.
[0004]

The step from 1,4,7,10-tetraazacyclododecane disulfate (a commercially available product) to compound (III) is effected according to the conventional method disclosed in US 4,085,106, followed by formation of the compound of formula (IV) in water-alcohol medium.
[0005]

This intermediate is subsequently tricarboxymethylated with tert-butyl bromoacetate (TBBA) in dimethylformamide at 2.5°C and then treated with a toluene-sodium hydroxide diphasic mixture to give the compound of formula (V), 10-formyl-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic, tris(1,1-dimethylethyl) ester, which is subsequently hydrolysed to compound of formula (II) in acidic solution.
[0006]

In the process described in WO 93/24469 for the synthesis of Gadobutrol, at first one of the nitrogen atoms is alkylated in conditions such as to minimize the formation of polyalkylated derivatives, then the monoalkylderivative is purified and carboxymethylated, according to scheme 2.
[0007]

The alkylation of 1,4,7,1,0-tetraazacyclododecane with the epoxide of formula (VI), 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane, is carried out in anhydrous n-BuOH under reflux and the reaction mixture is extracted with water, evaporated to dryness and the residue is subsequently diluted with water and extracted with methylene chloride.
[0008]

The aqueous phase containing the mono-alkylated product (65% yield in Example 7 which reports the procedure for the preparation of 5 kg of Gadobutrol) is directly carboxymethylated at 70°C with chloroacetic acid, keeping pH 9.5 by addition of NaOH. The reaction mixture is adjusted to pH 1, concentrated to dryness and dissolved in methanol to remove the undissolved salts. The filtrate is then concentrated under vacuum, dissolved in water, and loaded onto a cation exchanger in the H⁺ form to fix the product. The subsequent elution with ammonia displaces the desired product, which is concentrated to small volume and subsequently complexed with gadolinium oxide according to conventional methods, and the resulting complex is purified by means of ion exchange resins. The overall yield is 42%.
[0009]

Although the first of these two processes could theoretically provide a higher yield, in that all the single steps (protection, carboxymethylation and deprotection) are highly selective, the complexity of the operations required to remove salts and solvents and to purify the reaction intermediates makes such theoretical advantage ineffective: the overall yield is in fact, in the case of Gadoteridol, slightly higher than 37%.
[0010]

The preparation of Gadobutrol according to the alternative process (WO 93/24469) provides a markedly better yield (72%) only on laboratory scale (example 2): example 7 (represented in the above Scheme 2) actually evidences that, when scaling-up, the yield of this process also remarkably decreases (42%).
[0011]

In addition to the drawback of an about 40% yield, both processes of the prior art are characterized by troublesome operations, which often involve the handling of solids, the use of remarkable amounts of a number of different solvents, some of them having undesirable toxicological or anyway hazardous characteristics.
[0012]

Moreover, the synthesis described by Dischino makes use of reagents which are extremely toxic, such as tert-butyl bromoacetate, or harmful and dangerous from the reactivity point of view, such as dimethylformamide dimethylacetal.
[0013]

An alternative to the use of dimethyl formamide dimethylacetal is suggested by J. Am. Chem. Soc. 102(20), 6365-6369 (1980), which discloses the preparation of orthoamides by means of triethyl orthoformate.
[0014]
EP 0596 586 discloses a process for the preparation of substituted tetraazacyclododecanes, among them compounds of formula (XII), comprising:
- formation of the tricyclo[5.5.1.0] ring;
- alkylation with an epoxide;
- hydrolysis of the 10-formyl substituent;
- reaction with an acetoxy derivative bearing a leaving group at the alpha-position.
[0015]

Nevertheless, this method requires quite a laborious procedure in order to isolate the product of step b).
[0016]

It is the object of the present invention a process for the preparation of the complexes of general formula (XII)

wherein

R₁ and R₂

are independently a hydrogen atom, a (C₁-C₂₀) alkyl containing 1 to 10 oxygen atoms, or a phenyl, phenyloxy group, which can be unsubstituted or substituted with a (C₁-C₅) alkyl or hydroxy, (C₁-C₅) alkoxy, carbamoyl or carboxylic groups,

Me³⁺

is the trivalent ion of a paramagnetic metal;

comprising the steps represented in the following Scheme 3:

The process of the present invention keeps the high selectivity typical of the protection/deprotection strategy described by Dischino in the above mentioned paper, while removing all its drawbacks, thus providing for the first time a reproducible industrial process for the preparation of the concerned compounds in high yields and without use of hazardous substances.
[0019]

The preparation of the gadolinium complex of 10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-tri-acetic) acid (Gadoteridol), according to scheme 4, is particularly preferred:

in which the synthetic steps a), b), c), d), e), and f) have the meanings defined above and the epoxide of formula (XI) in step d) is propylene oxide.
[0020]

The preparation of the gadolinium complex of [10-[2,3-dihydroxy-1-(hydroxymethyl)propyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic) acid (Gadobutrol), according to the scheme 5, is also preferred.

in which the synthetic steps a), b), c), d), e), and f) have the meanings defined above and the epoxide of formula (XI) in step d) corresponds to the one of formula (VI), defined above.
[0021]

On the other hand, step a) of the process of the present invention involves the use of triethyl orthoformate in the presence of an acid catalyst, instead of dialkylformamide-dialkylacetal.
[0022]

Triethyl orthoformate can be added in amounts ranging from 105% to 200% on the stoichiometric value.
[0023]

The reaction temperature can range from 110 to 150°C and the reaction time from 5 to 24 h.
[0024]

The catalyst is a carboxylic acid having at least 3 carbon atoms, C₃-C₁₈, preferably selected from the group consisting of propionic, butyric and pivalic acids.
[0025]

Triethyl orthoformate is a less toxic and less expensive product than N,N-dimethylformamide-dimethylacetal and does not involve the formation of harmful, not-condensable gaseous by-products. Moreover, triethyl orthoformate is less reactive than N,N-dimethylformamide-dimethylacetal, which makes it possible to carry out the loading procedures of the reactives as well as the reaction itself in utterly safe conditions even on a large scale, allows to better monitor the progress of the reaction on the basis of such operative parameters as time and temperature, without checking the progress by gas chromatography, and makes dosing the reactive less critical, in that it can be added from the very beginning without causing the formation of undesired by-products: all that rendering the process suitable for the production of compound (III) on the industrial scale in easily reproducible conditions.
[0026]

The subsequent step b) involves the carboxymethylation of compound (III) in aqueous solution, using a haloacetic acid, to give compound (IX), i.e. the 10-formyl-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid salt with an alkali or alkaline-earth metal, the salts of compound (IX) with sodium, potassium or calcium being most preferred.

Example 2

[0065]
[0066]

The procedure of Example 1 is followed until step C included, to obtain a solution of DO3A trisodium salt.
[0067]

pH is adjusted to 12.3 with conc. HCl and 57.7 kg (0.4 kmol) of 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]-octane are added. After reaction for 4 h at 40°C and for 8 h at 80°C, the solution is cooled to 50°C, 120 kg of an aqueous solution containing 0.135 kmol of gadolinium trichloride are added. After 1 h the mixture is cooled at 17°C and acidified to pH 1.7 with conc. HCl, keeping this pH for 2 h. The solution is subsequently warmed to 50°C, pH is adjusted to 7 with sodium hydroxide, keeping these conditions for 1 h.
[0068]

After that, the resulting crude Gadobutrol is purified repeating exactly the same process as in steps E and F of Example 1.

Recovery of the product (Gadobutrol)

[0069]

The product-rich fraction is then thermally concentrated to a viscous residue and the residue is added with 350 kg of ethanol at 79°C.
[0070]

The resulting suspension is refluxed for 1 h, then cooled, centrifuged and dried under reduced pressure to obtain 66.0 kg of Gadobutrol (0.109 kmol), HPLC assay 99.5% (A%).
Overall yield: 79.1%
[0071]

The IR and MS spectra are consistent with the indicated structure.

References

Cheng, KT (2007). “Gadobutrol”. Molecular Imaging and Contrast Agent Database (MICAD) (Bethesda, MD: National Center for Biotechnology Information (NCBI)). PMID 20641787. NBK23589.
http://bayerimaging.com/products/gadavist/index.php
“FDA approves imaging agent for central nervous system scans” (Press release). U.S. Food and Drug Administration (FDA). March 15, 2011. Retrieved March 31, 2011.
“U.S. FDA Approves Bayer’s Gadavist (Gadobutrol) Injection for MRI of the Central Nervous System” (Press release). Bayer HealthCare Pharmaceuticals. March 14, 2011. Retrieved March 31, 2011.
“Gadobutrol 1.0-molar in Cardiac Magnetic Resonance Imaging (MRI) – Further Enhancing the Capabilities of Contrast-enhanced MRI in Ischaemic and Non-ischaemic Heart Disease?”
“Gadavist full prescribing information”. Retrieved 2011-03-14.

FDA Approves Incruse Ellipta…(Med-Chemist)

June 16, 2014 7:40 am / Leave a comment

read at

http://www.med-chemist.com/2014/06/fda-approves-incruse-ellipta.html

GlaxoSmithKline plc today announced that the US Food and Drug Administration (FDA) has approved Incruse Ellipta (umeclidinium) as an anticholinergic indicated for the long-term, once-daily, maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. – See more at: http://www.med-chemist.com/2014/06/fda-approves-incruse-ellipta.html#sthash.yVleIn3C.dpuf

Valeant Pharmaceuticals Announces FDA Approval Of Jublia, Efinaconazole for the Treatment of Onychomycosis

June 10, 2014 3:38 am / 1 Comment on Valeant Pharmaceuticals Announces FDA Approval Of Jublia, Efinaconazole for the Treatment of Onychomycosis

Efinaconazole

(2R,3R)-2-(2,4-Difluorophenyl)-3-(4-methylene-1-piperidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol

(2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidine-1-yl)-1-(1H-1,2,4-triazole-1-yl)-butane-2-ol

cas 164650-44-6

cas of 4-methylbenzenesulfonate (1:1)164650-61-7

Butanedioic acid, 2-hydroxy-, (2S)-, compd with efinaconazole……..1648711-85-6

NMR PREDICT…….SEEhttp://orgspectroscopyint.blogspot.in/2014/06/efinaconazole.html

1H NMR

Displaying image001.png

13 C NMR

1H NMR PREDICT

1H NMR PREDICT (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylidenepiperidin-1-yl)-1-(1,2,4-triazol-1-yl)butan-2-ol NMR spectra analysis, Chemical CAS NO. 164650-44-6 NMR spectral analysis, (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylidenepiperidin-1-yl)-1-(1,2,4-triazol-1-yl)butan-2-ol H-NMR spectrum

………………………………………
13C NMR PREDICT
(2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylidenepiperidin-1-yl)-1-(1,2,4-triazol-1-yl)butan-2-ol NMR spectra analysis, Chemical CAS NO. 164650-44-6 NMR spectral analysis, (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylidenepiperidin-1-yl)-1-(1,2,4-triazol-1-yl)butan-2-ol C-NMR spectrum

(2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylidenepiperidin-1-yl)-1-(1,2,4-triazol-1-yl)butan-2-ol NMR spectra analysis, Chemical CAS NO. 164650-44-6 NMR spectral analysis, (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylidenepiperidin-1-yl)-1-(1,2,4-triazol-1-yl)butan-2-ol C-NMR spectrum

…………………..
COSY

HSQC
………………………….SEE MORE SPECTROSCOPY AT http://orgspectroscopyint.blogspot.in/2014/06/efinaconazole.html

“Drugs at FDA: JUBLIA”. Retrieved 26 June 2014.

NDA Appl No		RLD	Active Ingredient	Dosage Form; Route	Strength	Proprietary Name	Applicant
N203567		Yes	EFINACONAZOLE	SOLUTION; TOPICAL	10%	JUBLIA	DOW PHARM

JUNE6 2014 APPROVED

Patent Data

Appl No	Prod No	US Patent No	Patent Expiration	Drug Product Claim	Patent Use Code
N203567	001	7214506	Oct 5, 2021		U – 281
N203567	001	8039494	Jul 8, 2030		U – 281
N203567	001	8486978	Oct 24, 2030	Y

Exclusivity Data

Appl No	Prod No	Exclusivity Code	Exclusivity Expiration
N203567	001	NCE	Jun 6, 2019

Efinaconazole is a triazole antifungal. It is approved for use in Canada as 10% topical solution for the treatment of onychomycosis (fungal infection of the nail).^[1]^[2] Efinaconazole acts as a 14α-demethylase inhibitor.^[3]

Systematic (IUPAC) name
(2R,3R)-2-(2,4-Difluorophenyl)-3-(4-methylene-1-piperidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol
Clinical data
Trade names	Jublia
Licence data	US FDA:link
Legal status	US: ℞-only
Routes	Topical
Identifiers
CAS number	164650-44-6
ATC code	None
PubChem	CID 489181
ChemSpider	428538
Chemical data
Formula	C₁₈H₂₂F₂N₄O
Mol. mass	348.39 g/mol

http://www.drugs.com/newdrugs/valeant-pharmaceuticals-announces-fda-approval-jublia-onychomycosis-4046.html?utm_source=ddc&utm_medium=email&utm_campaign=Today%27s+news+summary+-+June+9%2C+2014

SEE AT

LAVAL, Quebec, June 9, 2014 /PRNewswire/ — Valeant Pharmaceuticals International, Inc. (NYSE: VRX) (TSX: VRX) today announced that that its wholly owned subsidiary, Valeant Pharmaceuticals North America LLC, received notice that the U.S. Food and Drug Administration (FDA) has approved the New Drug Application (NDA) for Jublia® (efinaconazole 10% topical solution), the first topical triazole approved for the treatment of onychomycosis of the toenails

EFINACONAZOLE,

KP-103,

cas 164650-44-6, Efinaconazole [INN], UNII-J82SB7FXWB, AC1LAJ21, Efinaconazole [USAN:INN],

Efinaconazole
Jublia
KP-103
UNII-J82SB7FXWB

(2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylidenepiperidin-1-yl)-1-(1,2,4-triazol-1-yl)butan-2-ol

Molecular Formula: C₁₈H₂₂F₂N₄O Molecular Weight: 348.390286

efinaconazole

……………………………….

PAPER

Chemical and Pharmaceutical Bulletin, 1999 , vol. 47, 10 pg. 1417 – 1425

https://www.jstage.jst.go.jp/article/cpb1958/47/10/47_10_1417/_article

2-Aryl-1-azolyl-3-(substituted amino)-2-butanol derivatives I were prepared by ring-opening reaction of epoxides II with excess amine, and their antifungal activities were evaluated as topical agents. Azolyl-cyclic amine derivatives with a methylene group showed extremely strong activity with a broad spectrum in vitro. In general, anti-Trichophyton mentagrophytes activities of most of the topical antifungal agents are substantially reduced by addition of keratin (a major constituent of the keratinized tissue).

However, the triazole derivative (2R, 3R)-2-(2, 4-difluorophenyl)-3-(4-methylenepiperidino)-1-(1H-1, 2, 4-triazol-1-yl)-2-butanol ((-)-40, KP-103) showed very little deactivation by addition of keratin. This biological characteristic of triazole derivative (-)-40 resulted in excellent therapeutic efficacy on dermatophytosis superior to that of the corresponding imidazole derivative ((-)-41).

https://www.jstage.jst.go.jp/article/cpb1958/47/10/47_10_1417/_pdf

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PATENT

http://www.google.com/patents/US20130150586

Example 1Production of (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (KP-103)21.26 g (119.4 mmol) of the 4-methylenepiperidine hydrobromide (4-MP.HBr) obtained in Production 1 and 2.859 g (119.4 mmol) of lithium hydroxide were added to 80 mL of acetonitrile and stirred for a while. Thereafter, 20 g (79.6 mmol) of (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane was added and the mixture was heated under reflux in an oil bath (external temperature: 100° C.) for 14 hours. After the reaction completed, ethanol and distilled water were added to the reaction mixture, whereupon a crystal was precipitated. Thereafter, the crystal was filtered off, washed with 40 mL of an ethanol/water mixture, dried with air at room temperature and further dried under reduced pressure at 40° C. for 12 hours to give a pale yellow crystal of KP-103 in an amount of 24.2 g (yield, 87.3%; purity on HPLC, 95.3%).¹H-NMR (500 MHz, CDCl₃)δ: 0.96 (3H, dd, J=2.68, 7.08 Hz), 2.13-2.26 (4H, m), 2.35 (2H, br), 2.70 (2H, br), 2.90-2.94 (1H, q, J=7.08 Hz), 4.64 (2H, s), 4.82 (1H, dd, J=0.73, 14.39 Hz), 4.87 (1H, dd, J=0.73, 14.39 Hz), 5.45 (1H, s), 6.72-6.81 (2H, m), 7.51 (1H, dt, J=6.59, 9.03 Hz), 7.78 (1H, s), 8.02 (1H, s).FAB-MS m/z: 349 [M+H]⁺melting point: 86-89° C.

optical rotation: [α]_D ²⁵−87 to −91° (C=1.0, methanol)

………………………………….

Journal of Organic Chemistry, 2014 , vol. 79, 7 pg. 3272 – 3278

http://pubs.acs.org/doi/abs/10.1021/jo500369y

http://pubs.acs.org/doi/suppl/10.1021/jo500369y/suppl_file/jo500369y_si_001.pdf

A new synthetic route, the shortest reported to date, to access a key intermediate for the synthesis of various triazole antifungal agents was developed. The elusive tetrasubstituted stereogenic center that is essential in advanced triazole antifungal agents was constructed via the catalytic asymmetric cyanosilylation of a ketone. The subsequent transformations were performed in two one-pot operations, enhancing the overall synthetic efficiency toward the intermediate. This streamlined synthetic approach was successfully applied to efficient enantioselective syntheses of efinaconazole (Jublia) and ravuconazole.

Scheme 3. Synthesis of Efinaconazole (Jublia)

(2R,3R)-2-(2,4-Difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (Efinaconazole)

To a solution of 1 (54.2 mg, 0.216 mmol) in EtOH (217 μL) was added 4-methylenepiperidine (147 mg, 1.51 mmol), ……………………deleted………………. see original…………….. was purified using silica gel column chromatography (CHCl₃/MeOH = 10:1) to give 67.6 mg of efinaconazole (90% yield) as a colorless amorphous solid.

[α]_D²⁰ −87.8 (c 1.12, CHCl₃);

¹H NMR (400 MHz, CDCl₃) δ 8.00 (s, 1H), 7.76 (s, 1H), 7.51–7.45 (m, 1H), 6.78–6.68 (m, 2H), 5.50 (brs, 1H), 4.85 (d,J = 14.4 Hz, 1H), 4.78 (d, J = 14.4 Hz, 1H), 4.61 (s, 2H), 2.88 (q, J = 6.9 Hz, 1H), 2.66 (br s, 2H), 2.32 (br s, 2H), 2.21–2.17 (m, 4H), 0.93 (dd, J = 6.9, 2.1 Hz, 3H);

¹³C NMR (150 MHz, CDCl₃) δ 162.5 (dd, J = 250, 13 Hz), 158.5 (dd, J = 246, 12 Hz), 151.3, 145.9, 144.4, 130.6 (dd, J = 8.7, 5.8 Hz), 124.7 (dd, J = 14, 3.6 Hz), 111.4 (dd, J = 20, 2.9 Hz), 108.1, 104.1 (dd, J = 28, 25 Hz), 77.7 (d, J = 5.8 Hz), 64.4, 55.9 (d, J = 8.7 Hz), 52.4, 35.2, 7.63 (d, J = 2.9 Hz);

¹⁹F NMR (376 MHz, CDCl₃) δ −105.8, −110.7;

IR (CHCl₃, cm^–1) ν 3423, 3073, 2979, 2939, 2899, 2810, 1615, 1498, 1418, 1273, 1138;

HRMS (ESI-TOF) calcd for C₁₈H₂₃ON₄F₂ [M + H]⁺ m/z 349.1834, found 349.1828.

http://pubs.acs.org/doi/suppl/10.1021/jo500369y/suppl_file/jo500369y_si_001.pdf

…………………………………..

PATENT

http://www.google.com/patents/WO2012029836A1?cl=en

Method for producing butanol derivatives – 1 – 2 – triazole Is a (compound described in Example 1 of Patent Document 1) a compound of formula 1 to be effective against fungal diseases of humans and animals are known, the present invention, (2R, 3R) – 2 – (2,4 – difluorophenyl) -3 – (4 – methylene piperidin-1 – yl) -1 – (1H-1, 2,4 – triazol-1 – yl) butan-2 – (generic name ol ( The present invention relates to preparation of their salts that Fina et Kona zole (Efinaconazole)), hereinafter abbreviated as “KP-103” or even) in: INN).

The method for obtaining the amino alcohol by ring-opening addition reaction of the amine to the epoxide, in general, using a large excess of amine, and is performed for a long time at a high temperature. In the conventional method, in order to use the amine of the large excess of byproducts is large and requires a recovery step of an amine, also in terms of production costs, it is desirable as a production method on an industrial scale if the amine is expensive no. In order to increase the reactivity of the reaction, the reaction using a Lewis acid have been proposed, also, difficult to use industrially Lewis acid to be used is unstable or expensive, perchlorate, etc., are those toxic-risk is less secure high, there is a problem such as needing attention in use (Non-Patent Documents 1 and 2). It is also reported that could be the use of lithium bromide, to enhance the reactivity under solvent-free conditions at room temperature (Non-Patent Document 3). It is believed that since the liquid at normal temperature and epoxides, amines are used, the method reported in the literature, was achieved by reaction at a high concentration under solvent-free conditions starting material. Thus, a solid at room temperature and can not be applied to epoxides and amines, particularly high melting point.

On the other hand, as described in Patent Document 1, formula 1 compound is produced by ring-opening addition reaction of the amine to the epoxide. In this production process, as the epoxide (2R, 3S) -2 – (2,4 – difluorophenyl) -3 – methyl -2 – [(1H-1, 2,4 – triazol-1 – yl) methyl] oxirane and ( used that methylene piperidine (hereinafter, abbreviated as “4-MP” also) some – is used will hereinafter be abbreviated as “epoxy triazole” also) some, 4 as the amine. In this manufacturing process, it has the disadvantage for heating under reflux for a long time by using the 4-MP solution in large excess in the ring-opening addition reaction, and it is necessary to by-products are produced much in the reaction step to remove them. Furthermore, 4 – methylene-piperidine is prepared by the method described in Patent Document 2, but the purity is low because it is obtained in an aqueous solution, and also affects the reactivity when the distillation isolation there is a problem of impurities by heat generated.

WO 94/26734 pamphlet WO 97/11939 pamphlet

Synthesis, 2004, No.10, pp 1563-1565 J. Org. Chem., 2007, vol. 72, pp 3713-3722 Eur. J. Org. Chem., 2004, No.17, pp 3597-3600

The purpose of the present invention, (2R, 3S) -2 – to oxirane (2,4 – difluorophenyl) -3 – methyl-2 – [methyl-(yl 1H-1, 2,4 – – -1 triazole)] that without using methylene piperidine may yield a compound of Formula 1 under mild conditions to provide a manufacturing method with a reduced formation of by-product – 4 large excess of ring-opening addition reaction of methylene piperidine – 4 some.

As a result of intensive investigations, 4 the present inventors found that – if the acid addition salt of methylene-piperidine, 4 – impurities incorporated in the acquisition phase of the methylene piperidine has been removed, will be isolated as a solid high purity It can, therefore, four of the starting raw material in the ring-opening addition reaction of the amine to epoxy triazole – and that is able to increase the purity of methylene piperidine, the reaction solvent, the ring-opening addition reaction of amines to the epoxy triazole medium, is performed in the presence of hydroxides of alkali metals or alkaline earth metals in particular, 4 – there is no need to use excess methylene piperidine, high yield, by-products and a compound of Formula 1 under mild conditions to discover that it can be produced by reducing things, and have completed the present invention.

I will explain in detail the methods of the present invention are described below.
As indicated by the following reaction formula, the present invention, (2R, 3S) -2 – (2,4 – difluorophenyl) -3 – methyl -2 – [(1H-1, 2,4 – triazol – hydrate thereof or a hydroxide of an alkali metal or alkaline earth metal is selected from the group the reaction solvent, consisting of strontium lithium, sodium, and calcium, and a methylene piperidine acid addition salt and 4 – yl) methyl] oxirane including the presence of a, is reacted relates to a manufacturing method of the formula (1) compound.

(Wherein HX represents an acid addition salt of the acid)

Starting material of the process of the present invention
It can be also performed by using a starting compound of any amount ranging ton level from the g level, the method of the present invention may be determined the amount of solvent depending on the amount of the starting compound used.

(2R, 3S) -2 – (2,4 – difluorophenyl) -3 – methyl -2 – [(1H-1, 2,4 – -1 triazole – yl) methyl] oxirane, JP 2-191262 issue It can be obtained by methods described in the Gazette.
4 – is represented by the following formula methylenepiperidine acid addition salts:

Wherein an acid of the acid addition salts with HX, 4 – The acid forming the methylene piperidine acid addition salts may, for example, hydrochloric, hydrobromic, if an acid that forms a salt with an amine is basically inorganic acid acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, boric acid, chloric acid, carbonic acid, etc.; formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, methanesulfonic acid, benzenesulfonic acid, p – organic acids such as toluenesulfonic acid and the like, but is not limited thereto. Hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, trifluoroacetic acid and the like, more preferably, preferred examples of the acid is a hydroiodic acid or hydrobromic acid.

4 – methylene-piperidine acid addition salt, 4 – can be obtained by reacting a conventional manner with an acid corresponding to the acid addition salt with methylene piperidine.

Here, the 4 – methylenepiperidine may be preferable in terms of production on an industrial scale, prepared by the method described in WO 97/11939 pamphlet. 4 is manufactured here – methylene-piperidine, and also are obtained in the form of an aqueous solution, impurities produced by heat during the distillation isolation is included, according to the manufacturing method described below, 4 – methylene-piperidine the impurities are removed, acid addition salts can be isolated as a solid high purity.

That is, 4 – preferred method of methylenepiperidine acid addition salts, the following steps:
(1) 4 – reacting with an acid corresponding to the acid addition salt, a solution of methylene-piperidine, and (2) the solvent is evaporated as necessary, washed suspension crystallization or a product obtained , it is a method comprising the step of purifying.

Here, 4 (1) Step – A solution of methylene piperidine solution in a mixed solvent of alcohol or water and aqueous alcohol solution or (such as methanol), and the like. 0.9-1.0 equivalents is preferably used amount of the methylene piperidine – 4 of the acid corresponding to the acid addition salt. Reaction conditions (1) is carried out at room temperature from 0 ℃, the reaction time is several hours 15 minutes.
After the step (1), if necessary, by conventional methods, for example, under reduced pressure, the temperature is carried out by heating from room temperature solvent was evaporated. In the case of decreasing the water content of the reaction system, for example, by azeotropic toluene or use of the desiccant.
How to purify washed suspension or crystallization in step (2) The method of cleaning is suspended in a solvent crystals or recrystallized after being dissolved in a solvent, obtained by filtration, or distilling off the solvent I may be mentioned.

The acid addition salts, conditions of the production method is different, for example, after the reaction of step (1), the solvent was evaporated, the case of hydrochloride and hydrobromide and acetone crystals was then obtained After washing the suspension and filtered. For p-toluenesulfonate, After the reaction of step (1), the solvent was evaporated, and dissolved in ethyl acetate (10:1) / isopropanol mixture and the residue is recrystallized. For nitrate hydroiodide, and trifluoroacetic acid salt, after the reaction of step (1) to dryness by distilling off the solvent, washed and suspended by addition of diisopropyl ether to the residue.

Reaction conditions of the process of the present invention
4 – triazole for the epoxy, the amount of methylene piperidine acid addition salt is 1 to 5 equivalents, preferably 1 to 1.5 equivalents.

As the hydroxide of alkali metal or alkaline earth metal in the reaction of the present invention, a hydrate thereof or strontium hydroxide lithium hydroxide, sodium hydroxide, calcium hydroxide and the like. More preferably, lithium hydroxide, a hydrate thereof or calcium hydroxide, more preferably a hydrate thereof or a lithium hydroxide.

The amount of the hydroxide of alkaline earth metals varies depending on the basicity and the type of compound used or the alkali metals, 4 – for methylenepiperidine acid addition salt is 1 to 5 equivalents usually preferably is 1 to 1.5 equivalents.

Production Example 1
Methanol / water mixture methylene piperidine (4-MP) – 4 obtained by the method described in the manufacture WO 97/11939 pamphlet methylene piperidine hydrobromide salt of (4-MP · HBr) – 4 was cooled by stirring in an ice bath under a solution 0.8M 500mL (0.4mol). Thereafter, the solution is added in several portions (0.36mol) 48% hydrobromic acid 61.3g, followed by stirring for 1 hour in an ice bath. Thereafter, to precipitate white crystals by evaporating the solvent by heating under reduced pressure. Subsequently, we conducted two times operation for azeotropic water by distilling off the solvent by heating under reduced pressure and toluene was added to 50mL, and added acetone 192mL, was 2 hours under stirring ice bath. Thereafter, The crystals are filtered, washed crystals with 60mL (cooled in an ice bath) of acetone, 4-MP · HBr58g as colorless crystals (yield: 90%) After air-drying at room temperature, for 12 hours and dried under reduced pressure at 40 ℃ I got.
¹ H-NMR (500MHz, CDCl ₃₎
δ: 2.62 (4H, t, J = 6.09 Hz), 3.26 (4H, t, J = 6.09 Hz), 4.90 (2H, s), 9.18 (1H, br).
Melting point (DSC): 147 ~ 147.9 ℃

Production Example 2
Water removal operation (4-MP) methylene piperidine – 4 obtained by the method described in the manufacture WO 97/11939 pamphlet methylene piperidine p-toluenesulfonic acid salt of (4-MP · PTSA) – 4 isopropanol (9.7g, 0.1mol) of (IPA) in (50mL) solution, 4-MP, which is subjected to, the resulting p-toluenesulfonic acid monohydrate (PTSA · H ₂ O) (18.1g, 0.095mol) / was added (80mL) IPA, (weak exothermic) after which the mixture was stirred for 30 minutes at room temperature, evaporated under reduced pressure IPA, and was heated and dissolved in (250mL) with ethyl acetate / IPA mixture = 10:1 residue. After cooling to room temperature and allowed to stand for 20 hours at 0 ~ 5 ℃, filtered washing the precipitated crystals were obtained (91.2% yield) 4-MP · PTSA 23.34g of white crystals to dry.
¹ H-NMR (400MHz, DMSO-d ₆₎
δ: 2.29 (3H, s), 2.35 (4H, t, J = 6.4 Hz), 3.08 (4H, t, J = 6.4 Hz), 4.85 (2H, s), 7.13 (2H, d, J = 8.2 Hz ), 7.49 (2H, d, J = 8.2 Hz), 8.58 (2H, brs).

Production Example 3
4 obtained by the method described in the manufacture WO 97/11939 pamphlet methylene piperidine hydrochloride (4-MP · HCl) – – 4 subjected to moisture removal operation methylene piperidine (4-MP), obtained was cooled by stirring in an ice bath under (4.12mol) 4-MP 400g that is. Thereafter, the solution was added concentrated hydrochloric acid and 350mL (4.08mmol), and the mixture was stirred in an ice bath. After concentration under reduced pressure was performed 3 times operation for azeotropic water and concentrated under reduced pressure and toluene was added to 300mL. The washed suspension under ice-cooling and addition of acetone 300mL. The filtered crystals were washed with acetone crystals, 4 and dried under reduced pressure at room temperature – was obtained (46% yield) methylene-piperidine hydrochloride (4-MP · HCl) 336.8g.
¹ H-NMR (500MHz, CDCl ₃₎
δ: 2.58 (4H, t, J = 6.1Hz), 3.22 (4H, t, J = 6.1Hz), 4.89 (2H, s), 9.70 (1H, br s).

Preparation Example 4
Methanol / water mixture methylene piperidine (4-MP) – 4 obtained by the method described in the manufacture WO 97/11939 pamphlet methylene piperidine hydriodic acid salt of (4-MP · HI) – 4 was cooled by stirring in an ice bath under a solution 0.66M 20mL (13.19mmol). Thereafter, the solution was added 57% hydroiodic acid and 2.66g (11.84mmol), and the mixture was stirred for 15 minutes in an ice bath. After concentrated under reduced pressure, to precipitate a white solid by performing twice the operation for azeotropic water and concentrated under reduced pressure and toluene was added to 1.6mL. The washed suspension for 1 hour at room temperature by addition of diisopropyl ether 6mL. Thereafter, The crystals are filtered, washed and crystallized with diisopropyl ether, 4 and dried under reduced pressure at room temperature – was obtained (90% yield) methylene piperidine hydroiodide (4-MP · HI) 2.66g.
¹ H-NMR (500MHz, CDCl ₃₎
δ: 2.66 (4H, t, J = 6.1Hz), 3.31-3.33 (4H, m), 4.91 (2H, s), 8.34 (1H, br s).

Preparation Example 5
The reaction was carried out similarly to the above method by using trifluoroacetic acid (TFA) 1.35g and (11.87mmol) in place of hydriodic acid production 57% methylene piperidine trifluoroacetate salt of (4-MP · TFA), – 4 I got a (92% yield) methylene piperidine trifluoroacetate (4-MP · TFA) 2.55g – 4.
¹ H-NMR (500MHz, CDCl ₃₎
δ: 2.50 (4H, t, J = 6.1Hz), 3.16 (4H, t, J = 6.1Hz), 4.89 (2H, s), 9.52 (1H, br s).

Preparation Example 6
The reaction was carried out in the same manner as the above-described method using 69% nitric acid 1.08g the (11.87mmol) instead of hydroiodic acid production 57% methylene piperidine nitrate (4-MP · HNO _3), 4 – – 4 methylenepiperidine nitrate I got a (89% yield) (4-MP · HNO ₃₎ 1.87g.
¹ H-NMR (500MHz, CDCl ₃₎
δ: 2.53 (4H, t, J = 6.1Hz), 3.28 (4H, t, J = 6.1Hz), 4.89 (2H, s), 8.85 (1H, br s).

Example 1
(2R, 3R) -2 – (2,4 – difluorophenyl) -3 – (4 – methylene-piperidin-1 – yl) -1 – (1H-1, 2,4 – triazol-1 – yl) butan-2 – manufacture ol (KP-103)

Was stirred while addition of acetonitrile 80mL, lithium hydroxide 2.859g methylene piperidine hydrobromide (4-MP · HBr) 21.26g and (119.4mmol) and (119.4mmol) – 4 obtained in Production Example 1. Then, (2R, 3S) -2 – (2,4 – difluorophenyl) -3 – methyl -2 – [(1H-1, 2,4 – triazol-1 – yl) methyl] oxirane and 20g (79.6mmol) was added, and the mixture was heated under reflux for 14 hours at (external temperature 100 ℃) oil bath. After completion of the reaction, to precipitate the crystals by the addition of ethanol and distilled water to the reaction solution. Thereafter, the crystals were filtered, washed with ethanol / water mixture 40mL, and naturally dried at room temperature for 12 hours and dried under reduced pressure at 40 ℃, KP-103 24.2g light yellow 87.3% (yield, HPLC purity 95.3 % I got).
¹ H-NMR (500MHz, CDCl ₃₎
δ: 0.96 (3H, dd, J = 2.68, 7.08 Hz), 2.13-2.26 (4H, m), 2.35 (2H, br), 2.70 (2H, br) ,2.90-2 .94 (1H, q, J = 7.08 Hz), 4.64 (2H, s), 4.82 (1H, dd, J = 0.73, 14.39 Hz), 4.87 (1H, dd, J = 0.73, 14.39 Hz), 5.45 (1H, s), 6.72-6.81 (2H , m), 7.51 (1H, dt, J = 6.59, 9.03 Hz), 7.78 (1H, s),
8.02 (1H, s).
FAB-MS m / z: 349 [M ⁺ H] +
:86-89 ℃ melting point
Optical rotation: [α] _D ²⁵ -87 ~ -91 ° (C = 1.0, methanol)

Example 2
Epoxy triazole 0.50g (1.99mmol), 4 – in addition to acetonitrile 2mL lithium hydroxide 0.07g methylene piperidine hydrobromide (4-MP · HBr) 0.53g and (2.98mmol) and (2.96mmol), oil bath ( I was heated under reflux for 14 hours at an external temperature of 100 ℃). After the solvent was evaporated under reduced pressure of the reaction solution obtained, the solution was separated by the addition of ethyl acetate and water to the residue. The organic layer was concentrated under reduced pressure and purified by silica gel column chromatography (1:1) hexane / ethyl acetate solvent, to give (86% yield) KP-103 0.59g.

Example 3
The reaction was carried out in the same manner as in Example 2 using the calcium hydroxide 0.22g (2.97mmol) instead of lithium hydroxide, to give (82% yield) KP-103 0.57g.

Example 4
Was performed for 19 hours and the reaction in the same manner as in Example 2 using strontium hydroxide 0.36g a (2.98mmol) in place of lithium hydroxide, to give (68% yield) KP-103 0.47g.

Example 5
Was added 2mL of acetonitrile lithium hydroxide monohydrate 0.13g methylene piperidine hydrobromide (4-MP · HBr) 0.53g and (2.98mmol) and (2.96mmol) – epoxy-triazole 0.50g (1.99mmol), 4 , I was heated under reflux for 14 hours at (external temperature of 100 ℃) oil bath. Was determined to (relative area percentage of KP-103) reaction rate by HPLC measurements by sampling the reaction mixture, it was confirmed the formation of KP-103 at 81% response rate.

Example 6
The reaction was carried out in the same manner as in Example 2 using cyclopentyl methyl ether (CPME) 2mL instead of acetonitrile, to give (91% yield) KP-103 0.63g.

Example 7
1,2 instead of acetonitrile – The reaction was carried out in the same manner as in Example 2 using dimethoxyethane (DME) 2mL, was obtained (79% yield) KP-103 0.55g.

Example 8
1 in place of acetonitrile – The reaction was carried out in the same manner as in Example 2 using butanol 2mL, was obtained (72% yield) KP-103 0.59g.

Example 9
The reaction was carried out in the same manner as in Example 2 using isopropanol 2mL instead of acetonitrile, to give (86% yield) KP-103 0.50g.

Example 10
Methyl – 2 – 4 instead of acetonitrile reaction was carried out in the same manner as in Example 2 using the pentanone (MIBK) 2mL, to give (88% yield) KP-103 0.61g.

Example 11
Example Using methylene piperidine hydrochloride (4-MP · HCl) 0.40g and (2.99mmol) – 4 obtained in Production Example 3 in place of methylene piperidine hydrobromide salt of (4-MP · HBr) – 4 The reaction was carried out in the same manner as 2, was obtained (67% yield) KP-103 0.47g.

Example 12
Using methylene piperidine hydroiodide (4-MP · HI) 0.67g and (2.99mmol) – 4 obtained in Production Example 4 in place of methylene piperidine hydrobromide salt of (4-MP · HBr) – 4 The reaction was carried out in the same manner as in Example 2 upgrade does not give (90% yield) KP-103 0.62g.

Example 13
Using methylene piperidine trifluoroacetate (4-MP · TFA) 0.63g and (2.98mmol) – 4 obtained in Production Example 5 in place of methylene piperidine hydrobromide salt of (4-MP · HBr) – 4 The reaction was carried out in the same manner as in Example 2, was obtained (78% yield) KP-103 0.54g.

Example 14
Example Using methylenepiperidine nitrate (4-MP · HNO ₃₎ 0.48g and (3.00mmol) – 4 obtained in Production Example 6 in place of methylene piperidine hydrobromide salt of (4-MP · HBr) – 4 The reaction was carried out in the same manner as 2, was obtained (71% yield) KP-103 0.49g.

Example 15
Methylenepiperidine hydroiodic acid – 4 obtained in Production Example 4 in place of methylene piperidine hydrobromide salt of (4-MP · HBr) – Sodium hydroxide 0.12g (2.98mmol), 4 instead of lithium hydroxide was performed 18 hours and the reaction in the same manner as in Example 2 using salt (4-MP · HI) 0.67g and (2.99mmol), to give (73% yield) KP-103 0.51g.

Conventional methods for producing formula 1 compound of the starting material 4 – impurity contamination at the acquisition stage of methylene piperidine, and by-products to be produced during the manufacture of the formula 1 compound was a problem. In the method of the present invention, as a starting material of the production method of the formula 1 compound, 4 – by making the acid addition salt of methylene-piperidine, 4 – impurities incorporated in the acquisition phase of the methylene piperidine has been removed, high purity it is possible to use a solid. In the method of the present invention, since the ring-opening addition of the amine to epoxy triazole is promoted, 4 – there is no need to use excess methylene piperidine, high yield, and by-products of the compound of Formula 1 under mild conditions It can be produced by reducing compound. Therefore, by the method of the present invention to produce an industrial scale formula 1 compound became possible.

Patent Citations

Cited Patent	Filing date	Publication date	Applicant	Title
WO1994026734A1	May 2, 1994	Nov 24, 1994	Tadashi Arika	Azolylamine derivative
WO1997011939A1	Sep 26, 1996	Apr 3, 1997	Kaken Pharma Co Ltd	Process for the preparation of 4-methylenepiperidines
JPH02191262A				Title not available

Non-Patent Citations

Reference
1		EUR. J. ORG. CHEM. 2004, pages 3597 – 3600
2		J. ORG. CHEM. vol. 72, 2007, pages 3713 – 3722
3	*	MIMURA, MITSUO ET AL.: ‘Synthesis and evaluation of (piperidinomethylene)bis (phosphonic acid) derivatives as anti- osteoporosis agents‘ CHEMICAL & PHARMACEUTICAL BULLETIN vol. 41, no. 11, 1993, pages 1971 – 1986
4	*	OGURA, HIRONOBU ET AL.: ‘Synthesis and antifungal activities of (2R,3R)-2-aryl-1-azolyl-3-(substituted amino)-2-butanol derivatives as topical antifungal agents‘ CHEMICAL & PHARMACEUTICAL BULLETIN vol. 47, no. 10, 1999, pages 1417 – 1425, XP002296880
5		SYNTHESIS 2004, pages 1563 – 1565

PATENTS

US5962476	10-6-1999	Azolylamine derivative
US5716969	2-11-1998	Azolylamine derivative
EP0698606	12-18-1997	AZOLYLAMINE DERIVATIVE
US5620994	4-16-1997	Azolylamine derivative

References

Patel T, Dhillon S (Nov 2013). “Efinaconazole: first global approval”. Drugs 73 (17): 1977–1983. doi:10.1007/s40265-013-0152-x. PMID 24249649.
Tschen EH, Bucko AD, Oizumi N, Kawabata H, Olin JT, Pillai R (Feb 2013). “Efinaconazole solution in the treatment of toenail onychomycosis: a phase 2, multicenter, randomized, double-blind study”. J Drugs Dermatol 12 (2): 186–192. PMID 23377392.
Tatsumi Y, Nagashima M, Shibanushi T, et al. (May 2013). “Mechanism of action of efinaconazole, a novel triazole antifungal agent”. Antimicrob Agents Chemother 57 (5): 2405–2509.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

COCK WILL TEACH YOU NMR

COCK SAYS MOM CAN TEACH YOU NMR

DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO …..FOR BLOG HOME CLICK HERE

https://newdrugapprovals.org/

amcrasto@gmail.com

FDA Approves Zontivity (vorapaxar) to Reduce the Risk of Heart Attacks and Stroke

May 9, 2014 3:38 am / Leave a comment

May 8, 2014 — The U.S. Food and Drug Administration today approved Zontivity (vorapaxar) tablets to reduce the risk of heart attack, stroke, cardiovascular death, and need for procedures to restore the blood flow to the heart in patients with a previous heart attack or blockages in the arteries to the legs.

Zontivity is the first in a new class of drug, called a protease-activated receptor-1 (PAR-1) antagonist. It is an anti-platelet agent, designed to decrease the tendency of platelets to clump together to form a blood clot. By decreasing the formation of blood clots, Zontivity decreases the risk of heart attack and stroke.

Like other drugs that inhibit blood clotting, Zontivity increases the risk of bleeding, including life-threatening and fatal bleeding. Bleeding is the most commonly reported adverse reaction in people taking Zontivity. The drug’s prescribing information (label) includes a Boxed Warning to alert health care professionals about this risk.

Zontivity must not be used in people who have had a stroke, transient ischemic attack (TIA), or bleeding in the head, because the risk of bleeding in the head is too great.

“In patients who have had a heart attack or who have peripheral arterial disease, this drug will lower the risk of heart attack, stroke, and cardiovascular death. In the study that supported the drug’s approval, Zontivity lowered this risk from 9.5 percent to 7.9 percent over a 3-year period – about 0.5 percent per year,” said Ellis Unger, M.D., director of the Office of Drug Evaluation I in the FDA’s Center for Drug Evaluation and Research.

Health care professionals should inform patients that they may bleed and bruise more easily when taking Zontivity. Patients should report to their health care professional any unanticipated, prolonged or excessive bleeding, or blood in their stool or urine. Zontivity will be dispensed with an FDA-approved patient Medication Guide that provides instructions for its use and important safety information.

In a clinical trial with over 25,000 participants, Zontivity, added to other anti-platelet agents (generally aspirin and clopidogrel), reduced the rate of a combined endpoint of heart attack, stroke, cardiovascular death, and urgent procedures to improve blood flow to the heart (coronary revascularization) when compared to an inactive pill (placebo).

Zontivity is made by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. of Whitehouse Station, N.J.

Source: FDA

synthesis

https://newdrugapprovals.org/2014/01/17/vorapaxar-fda-advisory-panel-votes-to-approve-merck-cos-vorapaxar/

my earlier post

https://newdrugapprovals.org/2014/01/17/vorapaxar-fda-advisory-panel-votes-to-approve-merck-cos-vorapaxar/

DASABUVIR, ABT 333 for the chronic Hepatitis C treatment.

May 8, 2014 6:12 am / 1 Comment on DASABUVIR, ABT 333 for the chronic Hepatitis C treatment.

1132935-63-7 ABT-333

DASABUVIR, ABT 333,

CAS 1132935-63-7,

N-[6-[3-tert-butyl-5-(2,4-dioxopyrimidin-1-yl)-2-methoxyphenyl]naphthalen-2-yl]methanesulfonamide; Dasabuvir; N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide

Non-nucleoside NS5B polymerase inhibitor

Methanesulfonamide, N-(6-(5-(3,4-dihydro-2,4-dioxo-1(2H)-pyrimidinyl)-3-(1,1-dimethylethyl)-2-methoxyphenyl)-2-naphthalenyl)-
N-(6-(3-tert-Butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide
Methanesulfonamide, N-(6-(5-(3,4-dihydro-2,4-dioxo-1(2H)-pyrimidinyl)-3-(1,1-dimethylethyl)-2-methoxyphenyl)-2-naphthalenyl)-
N-(6-(3-tert-Butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide

C26-H27-N3-O5-S

493.5813
UNII-DE54EQW8T1,

ChemSpider 2D Image | Sodium {6-[5-(2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)-2-methoxy-3-(2-methyl-2-propanyl)phenyl]-2-naphthyl}(methylsulfonyl)azanide | C26H26N3NaO5S

Dasabuvir sodium anhydrous
RN: 1132940-11-4
UNII: R2M8F5TK9T

http://chem.sis.nlm.nih.gov/chemidplus/rn/1132940-11-4

Sodium {6-[5-(2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)-2-methoxy-3-(2-methyl-2-propanyl)phenyl]-2-naphthyl}(methylsulfonyl)azanide

Methanesulfonamide, N-(6-(5-(3,4-dihydro-2,4-dioxo-1(2H)-pyrimidinyl)-3-(1,1-dimethylethyl)-2-methoxyphenyl)-2-naphthalenyl)-, sodium salt (1:1)

Sodium {6-[5-(2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)-2-methoxy-3-(2-methyl-2-propanyl)phenyl]-2-naphthyl}(methylsulfonyl)azanide

ABT-333 sodium

dasabuvir sodium

DASABUVIR SODIUM ANHYDROUS

sodium {6-[3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl]naphthalen-2-yl}(methanesulfonyl)azanide

Molecular FormulaC₂₆H₂₆N₃NaO₅S
Average mass515.557

Dasabuvir (ABT-333), an oral non-nucleoside NS5B polymerase inhibitor, is a component of an all-oral hepatitis C treatment regimen under FDA review for the chronic Hepatitis C treatment.
On April 22, 2014, AbbVie submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) seeking approval for its investigational, all-oral, interferon-free regimen for the treatment of adult patients with chronic genotype 1 (GT1) hepatitis C virus (HCV) infection.

Dasabuvir (trade name Exviera in Europe) is an antiviral drug for the treatment of hepatitis C virus (HCV) infection. In the United States, it is approved by the Food and Drug Administration for use in combination with ombitasvir, paritaprevir, and ritonavir in the product Viekira Pak.^[1]

Dasabuvir acts as a NS5B (an RNA-directed RNA polymerase) inhibitor.^[2]

Patent

WO2009039127

http://www.google.com/patents/WO2009039127A1?cl=en

Example 4A. Preparation of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxyphenyl)naphthalen-2-yl)methanesulfonamide (compound IB-LO-2.3).

[00768] Part A. Preparation of N-(6-bromonaphthalen-2-yl)methanesulfonamide. [00769] A solution of the product from Example 3, Part B (4.48g, 20.17mmol) in pyridine (10OmL) was treated drop wise with methanesulfonyl chloride (1.97mL, 2.89 g, 25.2mmol) followed by stirring at room temperature for Ih. Diluted with toluene and concentrated under vacuum twice. The residue was extracted with EtOAc and washed with water, IM citric acid and brine. Treated with Darco G-60, dried over Na₂SO₄, filtered through celite and concentrated under vacuum. Solid was triturated with ether- hexane, collected by filtration and dried under vacuum to give the title compound as a faint pink solid (3.32g, 55 %).

[00770] Part B. Preparation of N-(6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen-2-yl) methanesulfonamide .

[00771] A mixture of the product from Part A (1.0Og, 3.33mmol), bis(pincolato)diboron (1.27g,

5.00mmol), potassium acetate (0.98 g, 9.99mmol) and Combiphos Pd6 (84mg, 0.17mmol) in toluene

(22mL) was heated at reflux for 3h. Cooled and diluted with ethyl acetate and water. The mixture was treated with Darco G-60 and filtered through celite. The filtrate was washed with water and brine. Dried over Na₂SO₄, filtered and concentrated under vacuum. Oil was dissolved in ether and precipitated by addition of hexanes. The product was collected by filtration and washed with hexanes. Evaporation of the filtrate and purification by silica gel column chromatography eluting with EtOAc/hexanes. The title compound from crystallization and chromatography was obtained as a white solid (927mg, 80%).

Part C. Preparation of tert-butyl 3-tert-butyl-4-methoxy-5-(6-(methylsulfonamido) naphthalen-

2-yl)phenylcarbamate.

Combined the product from Example 3, Part H (87mg, 0.243mmol), the product from Part B

(169mg, 0.486mmol), toluene (1.0ml), ethanol (1.0ml) and sodium carbonate (0.243ml, 0.243mmol) in a sealed tube and de-gassed with N₂ gas for 20min. Tetrakis(triphenylphosphine)palladium(0) (5.61mg,

4.86μmol) was added and de-gassing was continued another 5-10 min. Heated at 90-95⁰C for 16h.

Cooled and concentrated under vacuum. Purification by silica gel column chromatography eluting with

EtOAc/hexanes gave the title compound (92.2mg, 76 %).

[00774] Part D. Preparation of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxyphenyl)naphthalen-2-yl)methanesulfonamide.

[00775] A solution of the product from Part C (90mg, 0.180mmol) in CH₂Cl₂ (2.0ml) was treated with trifluoroacetic acid (1.0ml, 12.98mmol) at room temperature for Ih. Concentrated under vacuum, dissolved residue in EtOAc, washed with 10% NaHCO₃, and brine. Dried over Na₂SO₄, filtered and concentrated under vacuum. Dissolved in DMF (1.4ml) and cooled to -25⁰C and added (E)-3-methoxy- acryloyl isocyanate (0.633ml, 0.361mmol) drop wise while maintaining the temperature below -1O⁰C. Warmed to room temperature and stirred for 2h. Poured into ether, washed with water, and brine. Dried over Na₂SO₄, filtered and concentrated under vacuum. Added a mixture OfH₂SO₄ (0.1ml, 1.876mmol), water (1.0ml) and EtOH (1.0ml) and stirred at 100⁰C 16h. Cooled and concentrated under vacuum. Poured into water, extracted with EtOAc, combined extracts and washed with brine. Dried over Na₂SO₄, filtered and concentrated under vacuum. Purification by silica gel column chromatography eluting with MeOH/CHCl₃ gave the title compound (53mg, 59%). ¹H NMR (300 MHz DMSO-J6) δ 1.42 (s, 9 H) 3.08 (s, 3 H) 3.25 (s, 3 H) 5.65 (d, J=7.72 Hz, 1 H) 7.34 (dd, J=15.81, 2.57 Hz, 2 H) 7.42 (dd, J=8.82, 1.84 Hz, 1 H) 7.65 – 7.76 (m, 2 H) 7.80 (d, J=8.09 Hz, 1 H) 7.96 (t, J= 8.27 Hz, 2 H) 8.02 (s, 1 H) 10.04 (s, 1 H) 11.41 (s, 1 H); MS (ESI+) m/z 494 (M+H)⁺; (ESI-) m/z 492 (M-H)^“.

Example 4B. Preparation of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxyphenyl)naphthalen-2-yl)methanesulfonamide (compound IB-LO-2.3).

Part A. Preparation of 2-tert-butyl-6-iodo-4-nitrophenol.

To the product from Example 3, Part E (4.5g, 23.05mmol) dissolved in MeOH (120ml) and water (3OmL) was added iodine monochloride (1.155ml, 23.05mmol) drop wise over a period of lOmin.

The mixture was stirred for 2h and diluted into IL of water and allowed to stand overnight. The solid material was collected by filtration and washed 3 x 5OmL with water and dried under vacuum overnight to give a tan solid (7.14g, 96%).

Part B. Preparation of l-tert-butyl-3-iodo-2-methoxy-5-nitrobenzene.

To an ice bath cooled solution of the product from Part A (5.5g, 17.13mmol) in MTBE (15ml) in a 5OmL pressure vessel was added 2.0M trimethylsilyl diazomethane (12.85ml, 25.7mmol) followed by drop-wise addition of methanol (1.OmL) resulting in calm bubbling. The vessel was sealed and stirred at room temperature for 16h, cooled and the pressure was released. The solution was partitioned between

EtOAc and water. The organic layer was washed with 1.0M HCl, saturated potassium carbonate solution, and saturated NaCl. The organic layer was dried over sodium sulfate, filtered and concentrated to give a red oil that was used without purification (5.4g, 84%).

Part C. Preparation of 3-tert-butyl-5-iodo-4-methoxyaniline.

[00782] A mixture of the product from Part B (5.80g, 17.31mmol), ammonium chloride (1.389g,

26.0mmol), and iron (4.83g, 87mmol) in THF/MeOH/water (20OmL total, 2/2/1) was refluxed for 2h, cooled and filtered through Celite. The filtrate was evaporated and the residue was partitioned between water and EtOAc. The organic layer was washed with saturated brine, dried with sodium sulfate, filtered and evaporated to give a brown oil (5.28g, 100% yield).

[00783] Part D. Preparation of (E)-N-(3-tert-butyl-5-iodo-4-methoxyphenylcarbamoyl)-3-methoxy acrylamide.

[00784] To a solution of the product from Part C (3.05g, lOmmol) in DMF (50ml) at -20 ⁰C under N₂ was added at a fast drip a 0.4M solution in benzene of (E)-3-methoxyacryloyl isocyanate (50.0ml,

20.00mmol, prepared by the method of Santana et al., J. Heterocyclic. Chem. 36:293 (1999). The solution was stirred for 15min at -20 ⁰C, warmed to room temperature for 45min and diluted with EtOAc. The organic was washed with water and brine. Dried over Na₂SO₄, filtered and concentrated to a brown solid. The residue was triturated in Et₂θ/hexane to give a fine powder that was collected by filtration and dried under vacuum to give the title compound as a tan powder (2.46g, 57%).

[00785] Part E. Preparation of l-(3-tert-butyl-5-iodo-4-methoxyphenyl)dihydropyrimidine-2,4(lH,3H)- dione.

[00786] To a suspension of the product from Part D (2.46g, 5.69mmol) in ethanol (50ml) was added a solution of 5.5mL OfH₂SO₄ in 5OmL water and the mixture was heated at 110⁰C for 2.5h to give a clear solution. Cooled and diluted with 5OmL of water while stirring to give an off-white solid that was collected by filtration, washed with water and dried under vacuum to give the title compound (2.06g,

90%).

[00787]Part F. Preparation of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxyphenyl)naphthalen-2-yl)methanesulfonamide.

[00788] In a microwave tube, the product from Part E (104mg, 0.26mmol), the product from Example

4A, Part B (108mg, 0.31mmol), and 1.0M sodium carbonate solution (312μL, 0.31mmol) in 1: 1 ethanol- toluene (1.7mL) was degassed by nitrogen sparge for 15min. l,l’-Bis(diphenylphosphino) ferrocene palladium (II) chloride dichloromethane complex (9mg, 0.01 lmmol) was added, and degassing was continued for another 5min. The tube was sealed and heated in the microwave at 100⁰C for Ih. Diluted with dichloromethane and washed with IM citric acid solution and brine. The organic layer was then stirred with (3-mercaptopropyl) silica gel for Ih. Filtered through celite and concentrated under vacuum.

Triturated with ether, methanol, and then again with ether to give the title compound as a nearly white solid (32mg, 25 %). ¹H NMR (300 MHz, DMSO-J₆): δ 11.41 (d, J=I.84 Hz, 1 H) 10.04 (s, 1 H) 8.03 (s,

1 H) 7.96 (t, J=8.09 Hz, 2 H) 7.80 (d, J=8.09 Hz, 1 H) 7.63 – 7.79 (m, 2 H) 7.35 – 7.45 (m, 1 H) 7.37 (d,

J=2.57 Hz, 1 H) 7.32 (d, J=2.57 Hz, 1 H) 5.65 (dd, J=8.09, 2.21 Hz, 1 H) 3.25 (s, 3 H) 3.09 (s, 3 H) 1.43

(s, 9 H). MS (+ESI)m/z (rel abundance): 494 (100,M+H), 511 (90, M+NH4), 987 (20, 2M+H), 1009

(8, 2M+Na).

PATENT

http://www.google.com/patents/WO2009039134A1?cl=en

Example 2A. Preparation of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxyphenyl)naphthalen-2-yl)methanesulfonamide (compound IB-LO-2.3).

[00511] Part A. Preparation of N-(6-bromonaphthalen-2-yl)methanesulfonamide. [00512] A solution of the product from Example 1, Part B (4.48g, 20.17mmol) in pyridine (10OmL) was treated drop wise with methanesulfonyl chloride (1.97mL, 2.89 g, 25.2mmol) followed by stirring at room temperature for Ih. Diluted with toluene and concentrated under vacuum twice. The residue was extracted with EtOAc and washed with water, IM citric acid and brine. Treated with Darco G-60, dried over Na₂SO₄, filtered through celite and concentrated under vacuum. Solid was triturated with ether- hexane, collected by filtration and dried under vacuum to give the title compound as a faint pink solid (3.32g, 55 %).

Part B. Preparation of N-(6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen-2-yl) methanesulfonamide .

[00514] A mixture of the product from Part A (1.0Og, 3.33mmol), bis(pincolato)diboron (1.27g,

5.00mmol), potassium acetate (0.98 g, 9.99mmol) and Combiphos Pd6 (84mg, 0.17mmol) in toluene

[00515] Part C. Preparation of tert-butyl 3-tert-butyl-4-methoxy-5-(6-(methylsulfonamido) naphthalen-

2-yl)phenylcarbamate.

[00516] Combined the product from Example 1, Part H (87mg, 0.243mmol), the product from Part B

4.86μmol) was added and de-gassing was continued another 5-10 min. Heated at 90-95⁰C for 16h.

Cooled and concentrated under vacuum. Purification by silica gel column chromatography eluting with

EtOAc/hexanes gave the title compound (92.2mg, 76 %).

[00517]Part D. Preparation of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxyphenyl)naphthalen-2-yl)methanesulfonamide.

[00518] A solution of the product from Part C (90mg, 0.180mmol) in CH₂Cl₂ (2.0ml) was treated with trifluoroacetic acid (1.0ml, 12.98mmol) at room temperature for Ih. Concentrated under vacuum, dissolved residue in EtOAc, washed with 10% NaHCO₃, and brine. Dried over Na₂SO₄, filtered and concentrated under vacuum. Dissolved in DMF (1.4ml) and cooled to -25⁰C and added (E)-3-methoxy- acryloyl isocyanate (0.633ml, 0.361mmol) drop wise while maintaining the temperature below -1O⁰C. Warmed to room temperature and stirred for 2h. Poured into ether, washed with water, and brine. Dried over Na₂SO₄, filtered and concentrated under vacuum. Added a mixture Of H₂SO₄ (0.1ml, 1.876mmol), water (1.0ml) and EtOH (1.0ml) and stirred at 100⁰C 16h. Cooled and concentrated under vacuum. Poured into water, extracted with EtOAc, combined extracts and washed with brine. Dried over Na₂SO₄, filtered and concentrated under vacuum. Purification by silica gel column chromatography eluting with MeOH/CHCl₃ gave the title compound (53mg, 59%). ¹H NMR (300 MHz OMSO-d6) δ 1.42 (s, 9 H) 3.08 (s, 3 H) 3.25 (s, 3 H) 5.65 (d, J=7.72 Hz, 1 H) 7.34 (dd, J=15.81, 2.57 Hz, 2 H) 7.42 (dd, J=8.82, 1.84 Hz, 1 H) 7.65 – 7.76 (m, 2 H) 7.80 (d, J=8.09 Hz, 1 H) 7.96 (t, J= 8.27 Hz, 2 H) 8.02 (s, 1 H) 10.04 (s, 1 H) 11.41 (s, 1 H); MS (ESI+) m/z 494 (M+H)⁺; (ESI-) m/z 492 (M-H)^“.

[00519] Example 2B. Preparation of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxyphenyl)naphthalen-2-yl)methanesulfonamide (compound IB-LO-2.3).

[00520] Part A. Preparation of 2-tert-butyl-6-iodo-4-nitrophenol.

[00521] To the product from Example 1, Part E (4.5g, 23.05mmol) dissolved in MeOH (120ml) and water (3OmL) was added iodine monochloride (1.155ml, 23.05mmol) drop wise over a period of lOmin.

[00522]Part B. Preparation of l-tert-butyl-3-iodo-2-methoxy-5-nitrobenzene.

[00523] To an ice bath cooled solution of the product from Part A (5.5g, 17.13mmol) in MTBE (15ml) in a 5OmL pressure vessel was added 2.0M trimethylsilyl diazomethane (12.85ml, 25.7mmol) followed by drop-wise addition of methanol (1.OmL) resulting in calm bubbling. The vessel was sealed and stirred at room temperature for 16h, cooled and the pressure was released. The solution was partitioned between

[00524] Part C. Preparation of 3-tert-butyl-5-iodo-4-methoxyaniline.

[00525] A mixture of the product from Part B (5.8Og, 17.31mmol), ammonium chloride (1.389g,

[00526] Part D. Preparation of (E)-N-(3-tert-butyl-5-iodo-4-methoxyphenylcarbamoyl)-3-methoxy acrylamide.

[00527] To a solution of the product from Part C (3.05g, lOmmol) in DMF (50ml) at -20 ⁰C under N₂ was added at a fast drip a 0.4M solution in benzene of (E)-3-methoxyacryloyl isocyanate (50.0ml,

20.00mmol, prepared by the method of Santana et al., J. Heterocyclic. Chem. 36:293 (1999). The solution was stirred for 15min at -20 ⁰C, warmed to room temperature for 45min and diluted with EtOAc. The organic was washed with water and brine. Dried over Na₂SO₄, filtered and concentrated to a brown solid. The residue was triturated in Et₂O/hexane to give a fine powder that was collected by filtration and dried under vacuum to give the title compound as a tan powder (2.46g, 57%).

[00528] Part E. Preparation of l-(3-tert-butyl-5-iodo-4-methoxyphenyl)dihydropyrimidine-2,4(lH,3H)- dione.

[00529] To a suspension of the product from Part D (2.46g, 5.69mmol) in ethanol (50ml) was added a solution of 5.5mL OfH₂SO₄ in 5OmL water and the mixture was heated at 110°C for 2.5h to give a clear solution. Cooled and diluted with 5OmL of water while stirring to give an off-white solid that was collected by filtration, washed with water and dried under vacuum to give the title compound (2.06g,

[00530] Part F. Preparation of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxyphenyl)naphthalen-2-yl)methanesulfonamide.

[0053I]In a microwave tube, the product from Part E (104mg, 0.26mmol), the product from Example 2A, Part B (108mg, OJ lmmol), and 1.0M sodium carbonate solution (312μL, 0.31mmol) in 1:1 ethanol- toluene ( 1.7mL) was degassed by nitrogen sparge for 15min. 1 , 1 ‘-Bis(diphenylphosphino) ferrocene palladium (II) chloride dichloromethane complex (9mg, O.Ol lmmol) was added, and degassing was continued for another 5min. The tube was sealed and heated in the microwave at 100⁰C for Ih. Diluted with dichloromethane and washed with IM citric acid solution and brine. The organic layer was then stirred with (3-mercaptopropyl) silica gel for Ih. Filtered through celite and concentrated under vacuum. Triturated with ether, methanol, and then again with ether to give the title compound as a nearly white solid (32mg, 25 %). ¹H NMR (300 MHz, OMSO-d₆): δ 11.41 (d, J=1.84 Hz, 1 H) 10.04 (s, 1 H) 8.03 (s, 1 H) 7.96 (t, J=8.09 Hz, 2 H) 7.80 (d, J=8.09 Hz, 1 H) 7.63 – 7.79 (m, 2 H) 7.35 – 7.45 (m, 1 H) 7.37 (d, J=2.57 Hz, 1 H) 7.32 (d, J=2.57 Hz, 1 H) 5.65 (dd, J=8.09, 2.21 Hz, 1 H) 3.25 (s, 3 H) 3.09 (s, 3 H) 1.43 (s, 9 H). MS (+ESI) m/z (rel abundance): 494 (100, M+H), 511 (90, M+NH4), 987 (20, 2M+H), 1009 (8, 2M+Na).

PATENT

WO 2014031791

https://www.google.com/patents/WO2014031791A1?cl=en

Example 4. Preparation of ^-(6-(3-?eri-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxyphenyl)naphthalen-2-yl)methanesulfonamide (compound (A-l)).

[00254] A 3-L, 3 -neck, round-bottom flask was equipped with an overhead stirrer, a thermocouple, a Claisen condenser and a reflux condenser. Tris(dibenzylideneacetone)dipalladium(0) (0.330 g, 0.360 mmol), di-?er?-butyl(2′,4′,6′-triisopropyl-3,4,5,6-tetramethylbiphenyl-2-yl)phosphine (0.416 g, 0.864 mmol) and milled potassium phosphate tribasic (21.0 g, 99.0 mmol) were charged to the 3-L flask. The flask was purged with argon for not less than 90 minutes with constant stirring of the solids. i-Amyl alcohol (250 ml) was charged to a separate 500-mL round-bottom flask and was purged with argon for not less than 30 minutes and was transferred to the 3-L flask using a cannula under argon atmosphere. The contents of the 3-L flask were heated to 80 °C and stirred at this temperature for 30 minutes. A 1-L round-bottom flask equipped with a magnetic stir bar was charged with 6-(3-teri-butyl-5-(2,4-dioxo-3,4- dihydropyrimidin- 1 (2H)-yl)-2-methoxyphenyl)naphthalen-2-yl 1 , 1 ,2,2,3,3,4,4,4-nonafluorobutane- 1 – sulfonate (62.9 g, 90 mmol), methanesulfonamide (12.85 g, 135 mmol) and i-amyl alcohol (505 mL), purged with argon and heated to 60 °C. The reagent mixture was stirred under argon for not less than 30 minutes. A clear yellow solution was observed. This solution was transferred to the 3-L flask using a cannula under argon atmosphere. The temperature of the 3-L flask was raised to 85 °C and the contents were stirred for 14 hours under a positive pressure of argon. The temperature was then raised to 95 °C and the contents were stirred for an additional 4 hours under a positive pressure of argon. The reaction mixture was allowed to cool down to room temperature, diluted with tetrahydrofuran (2200 mL) and water (800 mL) and was transferred to a 6-L separatory funnel. The organic layer was washed thrice with water (2000 mL) containing L-cysteine (17.3 g) and NaCl (235 g). The organic layer was collected, filtered through a pad of diatomaceous earth and was concentrated in vacuo to approximately 250 mL. Ethyl acetate (775 mL) was added over 7 hours with stirring, and the mixture was allowed to stir for an additional 14 hours. White solid was isolated by filtration, and the solid was washed with ethyl acetate (1000 mL). The solid was then dissolved in tetrahydrofuran (1500 mL) and filtered through a pad of diatomaceous earth to obtain a clear solution. The diatomaceous earth was washed with tetrahydrofuran (300 mL). The combined tetrahydrofuran solution was concentrated in vacuo to approximately 250 mL, and then ethyl acetate (775 mL) was added over 7 hours with stirring. The product solution was allowed to stir for an additional 14 hours. White solid was isolated by filtration. The solid was washed with ethyl acetate (1000 mL) and dried in a vacuum oven at 60 °C for 24 hours. The solid was slurried in 308 mL of 200 proof ethanol for 1.5 hours, then isolated by filtration. The solid was washed with 132 mL of 200 proof ethanol and dried in a vacuum oven at 50 °C for 18 hours. The title compound was isolated as a white solid (32.6 g, 100% potency vs. standard, 73% yield). ^!H NMR (400 MHz, DMSO-i¾) δ ppm 1 1.41 (d, J= 2.1 Hz, 1H), 10.04 (s, 1H), 8.02 (d, J= 0.9 Hz, 1H), 7.98 – 7.91 (m, 2H), 7.79 (d, J = 7.9 Hz, 1H), 7.72 (d, J= 2.0 Hz, 1H), 7.69 (dd, J = 8.5, 1.7 Hz, 1H), 7.41 (dd, J = 8.8, 2.2 Hz, 1H), 7.36 (d, J= 2.7 Hz, 1H), 7.31 (d, J= 2.7 Hz, 1H), 5.65 (dd, J = 7.9, 2.2 Hz, 1H), 3.24 (s, 3H), 3.08 (s, 3H), 1.42 (s, 9H). ¹³C NMR (101 MHz, DMSO-i¾) δ ppm 163.1 (C), 156.0 (C), 150.0 (C), 145.3 (CH), 142.9 (C), 136.0 (C), 134.3 (C), 134.2 C(), 133.5 (C), 132.2 (C), 129.5 (C), 129.0 (CH), 127.6 (CH), 127.1 (CH), 127.0 (CH), 126.5 (CH), 124.3 (CH), 120.2 (CH), 1 14.5 (CH), 101.1 (CH), 60.3 (CH₃), 39.4 (CH₃), 35.1(C), 30.5 (CH₃).

Example 5. Preparation of the sodium salt of /V-(6-(3-teri-butyl-5-(2,4-dioxo-3,4- dihydropyrimidin- 1 (2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide (compound (A-sl)).

[00286] A solution of 2-propanol and water was prepared by combining 18.5 g of water and 512 g of 2- propanol. Hereafter, this solution is referred to as the “antisolvent solution.”

[00287] A solution of 2-propanol and water was prepared by combining 23.94 g of water and 564 g of 2- propanol. This solution was cooled in a refrigerator prior to use. Hereafter, this solution is referred to as the “chilled wash solution.”

[00288] A jacketed reactor was equipped with an overhead stirrer and charged with 32.0 g (64.8 mmol) of A^-(6-(3-?er^butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2-methoxyphenyl)naphthalen-2- yl)methanesulfonamide and 105.9 g of dimethyl sulfoxide. With stirring the mixture was heated to an internal temperature of 68 °C. A solution of 2.66 g of sodium hydroxide (66.5 mmol, 1.026 equiv) in 16 g of water was added to the reactor over several minutes, followed by 12.4 g of 2-propanol while maintaining the internal temperature at 68 °C. Antisolvent solution (24.5 g) was added to the reactor while maintaining the internal temperature at 68 °C. A slurry of 0.32 g of seed crystals of the final product in 22.8 g of antisolvent solution was added to the reactor, followed by a 2.6 g rinse of the flask with antisolvent solution. The reaction mixture was stirred for 1.5 hours while maintaining the internal temperature at 68 °C. Antisolvent solution (354 g) was added to the reactor over 7 hours while maintaining the internal temperature at 68 °C. The contents of the reactor were cooled to an internal temperature of 0 °C over 7 hours and then mixed at 0 °C for 7 hours. The solids were isolated by filtration and washed with 252 g of the chilled wash solution. The isolated solids were dried in a vacuum oven at 50 °C for 19 hours. The title compound was isolated as a white solid (30.7 g, 92% potency vs. free acid standard, 57.2 mmol free acid equivalent, 88% yield). ^!H NMR (400 MHz, DMSO-i¾) δ ppm 7.75 (s, 1H), 7.72 (d, J= 7.8 Hz, 1H), 7.59 (dd, J = 8.8, 2.2 Hz, 2H), 7.45 (dd, J = 8.5, 1.8 Hz, 1H), 7.27 (d, J = 2.6 Hz, 2H), 7.21 (d, J = 2.7 Hz, 1H), 7.06 (dd, J = 8.8, 2.2 Hz, 1H), 5.62 (d, J = 7.8 Hz, 1H), 3.24 (s, 3H), 2.68 (s, 3H), 1.40 (s, 9H).

PATENT

http://www.google.com/patents/EP2593439A2?cl=en

Example 2. Preparation of l -(3-teri-butyl-5-(6-hydroxynaphthalen-2-yl)-4- methoxyphenyl)pyrimidine-2,4(l f,3H)-dione (compound (4)).

[00165] This reaction is sensitive to oxygen, and so all vessels were sealed with rubber septa. All solution transfers were accomplished by cannula technique using nitrogen as the inert gas. Anhydrous tetrahydrofuran was sparged with nitrogen gas for 2 hours prior to use to render it anaerobic. Hereafter this is referred to as degassed tetrahydrofuran. [00166] A 100-mL round-bottom flask was charged with 12.9 g of potassium phosphate tribasic (60.8 mmol, 2.0 equivalents), a magnetic stir bar, and 60 mL of water. The mixture was stirred to dissolve the solids, and the aqueous solution was sparged with nitrogen gas for 2 hours prior to use. Hereafter this is referred to as the phosphate solution.

[00167] A 100-mL round-bottom flask was purged with nitrogen gas and charged with 282 mg of tris(dibenzylideneacetone)dipalladium(0) (0.31 mmol, 0.02 equivalents Pd), 413 mg ofphosphine ligand, l ,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphatricyclo[3.3.1.1 ‘⁷]decane (1.4 mmol, 2.3 equivalents relative to Pd) and a magnetic stir bar. The flask was sealed with a septum and the atmosphere above the solids was purged with nitrogen gas. Sixty mL of degassed tetrahydrofuran was added to the flask and the mixture was stirred under a nitrogen atmosphere. This solution was sparged for 15 minutes prior to use and is hereafter referred to as the catalyst solution.

[00168] A 500-mL jacketed reactor was equipped with an overhead stirrer and reflux condenser and the atmosphere was purged with nitrogen gas. The reactor was charged with 12.1 g of l -(3-?er?-butyl-5-iodo- 4-methoxyphenyl)pyrimidine-2,4(l f,3 /)-dione, (30.3 mmol, 1.0 equivalent) and 5.98 g of 6- hydroxynaphthalen-2-ylboronic acid (31.8 mmol, 1.05 equivalents). The atmosphere was purged with nitrogen gas with stirring of the solid reagents for 20 minutes. The reactor was charged with 120 mL of degassed tetrahydrofuran, and the mixture was stirred to dissolve the solids. The solution was sparged with nitrogen gas for 10 minutes. The phosphate solution was added to the reactor by cannula, followed by the catalyst solution. The resulting biphasic mixture was stirred aggressively to ensure adequate phase mixing, and the jacket was warmed to 65 °C. The reaction jacket was cooled to room temperature prior to quench.

[00169] After 2.5 hours, the reaction jacket was cooled to room temperature prior to quench.

[00170] The workup of the reaction was also conducted under anaerobic conditions. Fifty-seven grams of sodium chloride and 4.2 g of cysteine (15 weight equivalents relative to palladium catalyst) were dissolved in 300 mL of water, and the resulting solution was sparged for 2 hours prior to use. To quench the reaction, approximately 1/3 of this solution was transferred to the reaction mixture by cannula under nitrogen gas and the resulting biphasic mixture was stirred vigorously for 2 hours. The mechanical agitation was halted, the two solutions were allowed to separate, and the aqueous solution was drained out of the reactor through the bottom valve. Approximately 1/3 of the quench solution was transferred to the reaction mixture by cannula under nitrogen gas and the resulting biphasic mixture was stirred vigorously for 45 minutes. The mechanical agitation was halted, the two solutions were allowed to separate, and the aqueous solution was drained out of the reactor through the bottom valve. The final portion of the quench solution was transferred to the reaction mixture by cannula, the resulting biphasic mixture was stirred vigorously for 45 minutes and the aqueous solution was drained out of the reactor through the bottom valve. [00171] The remainder of the workup was not conducted under anaerobic conditions. The pale yellow organic solution was drained from the reactor through the bottom valve and filtered over a pad of grade 4 Filtrol® (1 cm deep by 4.5 cm diameter). The reactor and filter cake were rinsed with 70 mL of tetrahydrofuran. The bulk of the solvent was distilled in vacuo (ca 90-130 torr) at ca 40 °C with good agitation from an overhead stirrer. The solution was concentrated to approximately 50 mL volume, during which time the product began to precipitate out. Ethyl acetate (100 mL, 8 volume/weight relative to product) was added to the mixture, and the resultant slurry was stirred overnight at room temperature. The crystalline material was isolated by filtration and the filter cake was washed twice with 20 mL portions of ethyl acetate. The wet-cake was air-dried on the filter and dried in a vacuum oven at 50 °C at approximately 250 torr with a gentle nitrogen sweep overnight.

[00172] The desired product was isolated as a white solid (11.6 g, 96.4% potency vs. standard, 88% potency-adjusted yield).^!H NMR (400 MHz, DMSO-4) δ ppm δ 1 1.39 (d, J = 2.1 Hz, 1H), 9.82 (s, 1H), 7.91 (d, J = 0.8 Hz, 1H), 7.80 (d, J= 8.9 Hz, 1H), 7.77 – 7.74 (m, 2H), 7.58 (dd, J = 8.5, 1.7 Hz, 1H), 7.32 (d, J = 2.7 Hz, 1H), 7.27 (d, J= 2.7 Hz, 1H), 7.16 (d, J = 2.3 Hz, 1H), 7.10 (dd, J = 8.8, 2.4 Hz, 1H), 5.64 (dd, J = 7.9, 2.2 Hz, 1H), 3.23 (s, 3H), 1.41 (s, 9H).

Example 3. Preparation of 6-(3-?eri-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l (2H)-yl)-2- methoxyphenyl)naphthalen-2-yl 1 ,1 ,2,2,3,3,4,4,4-nonafluorobutane-l -sulfonate (compound (5a)).

[00174] A reactor was equipped with an overhead stirrer in the central neck and charged with 45.0 g of 1- (3-?eri-butyl-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(l f,3H)-dione (97.8 weight%>, 106 mmol, 1.0 equivalent) and 21.9 g of 325 mesh potassium carbonate (159 mmol, 1.5 equivalents). The atmosphere was purged with nitrogen gas while the solids were stirred. The flask was charged with 445 mL of Λ^Λ^-dimethylformamide, and the slurry was stirred to dissolve the l-(3-?eri- butyl-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(l f,3H)-dione. The purge was stopped and the reaction was conducted under a slight positive pressure of nitrogen gas.

Perfluorobutanesulfonyl fluoride (35.2 g, 117 mmol, 1.1 equivalents) was added in one portion, and the mixture was stirred vigorously to mix the immiscible liquids overnight.

[00175] The inorganic solids were separated by filtration, and the flask and filter cake were rinsed with approximately 30 mL of Λ^,Λ^-dimethylformamide. The Λ^,Λ^-dimethylformamide solution was filtered directly into a second flask with an overhead stirrer. With stirring, 1 12 g of water (25 weight% of total Λ^,Λ^-dimethylformamide employed) was added to the Λ^,Λ^-dimethylformamide solution of product over approximately 0.5 hour to induce precipitation of the desired product, and the mixture was allowed to stir for 5 hours. The wet-cake was isolated by filtration with recirculation of the liquors to recover all the solids. The wet-cake was washed with 60 mL of 25% (v/v) water yV-dimethylformamide, then 85 mL water.

[00176] The solids were dissolved in 760 mL of isopropyl acetate. The resultant organic solution was washed once with 200 mL of water, twice with 270 mL portions of water and once with 200 mL of water to remove residual AyV-dimethylformamide. Solvent was removed by distillation at approximately 130 torr with heating to 55 °C until the total volume was approximately 200 mL. With efficient stirring, heptane (450 mL) was added to the warm (55 °C) slurry. The slurry was allowed to cool to room temperature overnight with stirring. The desired product was isolated by filtration, with recycling of the liquors to isolate all of the solids material. The wet-cake was washed twice with 100 mL portions of 20% (v/v) isopropyl acetate/heptane. The wet-cake was air-dried on the filter and dried in a vacuum oven at 50 °C at approximately 250 torr with a gentle nitrogen sweep overnight. The title compound was isolated as a white solid (64.0 g, 100% potency vs. standard, 87% yield). ^!H NMR (600 MHz, DMSO- d₆) δ ppm 1 1.42 (s, 1H), 8.21 – 8.15 (m, 4H), 7.84 (dd, J = 8.6, 1.7 Hz, 1H), 7.77 (d, J = 7.9 Hz, 1H), 7.60 (dd, J = 9.0, 2.5 Hz, 1H), 7.39 (d, J = 2.7 Hz, 1H), 7.35 (d, J = 2.7 Hz, 1H), 5.66 (d, J = 7.9 Hz, 1H), 3.21 (s, 3H), 1.41 (s, 9H).

[00177] Example 3-1. Alternative Preparation of 6-(3-teri-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin- 1 (2//)-yl)-2-methoxyphenyl)naphthalen-2-yl 1 , 1 ,2,2,3 ,3 ,4,4,4-nonafluorobutane- 1 -sulfonate (compound (5a)).

[00178] A 250-L, 3-neck round-bottom flask equipped with an overhead stirrer was charged with 10 g of 1 -(3-ier?-butyl-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4( l//,3//)-dione (98 wt%>, 23.5 mmol, 1.0 equiv) and 6.5 g of milled potassium carbonate (325 mesh, 47.1 mmol, 2.0 equiv). Acetonitrile (MeCN, 60 mL, 6 volumes with respect to naphthol) and dimethylformamide (dimethylformide, 40 mL, 4 volumes with respect to naphthol) was charged to the reactor and the slurry was stirred. Perfluorobutanesulfonyl fluoride (96 wt%>, 8.3 g, 26 mmol, 1.1 equiv) was charged to the well-stirred mixture over 60 minutes by syringe pump. A trace (<0.1 area%) of starting material was detected by HPLC analysis of an aliquot at 20 minutes reaction time. The

acetonitrile/dimethylformamide solution was filtered over a coarse fritted funnel to separate the inorganic solids, and the flask and filter was rinsed with 15 mL of 3 :2 (v/v)

acetonitrile/dimethylformamide. The total mass of solvents employed was approximately 92 g.

[00179] First crystallization: The acetonitrile/dimethylformamide solution was transferred to a 3- neck flask equipped with an overhead stirrer. Water (50 g, 54 wt%> with respect to total solution charged) was added to the well-stirred solution over 100 minutes. This adjusts the solvent

composition to 35 wt% water. During the addition of water the mixture self-seeded, and the solution was held for approximately 1 hour after complete addition of water. The solids were isolated by filtration, and the wetcake was washed with two 30 mL portions of a rinse solution of 40 wt%

water/27 wt% dimethylformamide/33 wt% acetonitrile and then once with 40 mL of water.

[00180] Aqueous washing: A 500-L jacketed cylindrical reactor equipped with an overhead stirrer and Teflon baffle to aid in vertical mixing was charged with the wetcake and 133 g of ethyl acetate (8^X theoretical mass of product, 150 mL). The mixture was stirred to dissolve the substrate and the solution was washed twice with 40 mL portions of water.

[00181] Concentration and crystallization: A constant-volume distillation was conducted with heptanes, in vacuo (ca 100 mmHg, jacket temperature of 50 °C), to adjust the solvent composition to approximately 12 wt% ethyl acetate/88 wt% heptanes. During the distillation, solids begin to crystallize out of the solution. Once the distillation was complete, the solution was cooled to ambient temperature (23 °C). The solids were isolated by filtration and the wet cake was washed with a 50-mL portions heptane. The wet cake was dried to give the final product (14.0 g). The solids were 98.1% pure by HPLC analysis and 100% potent vs. reference standard, for an isolated yield of 85%o.

[00182] Example 4. Preparation of ^-(6-(3-ier?-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2- methoxyphenyl)naphthalen-2-yl)methanesulfonamide (compound (A)).

[00183] A 3-L, 3-neck, round-bottom flask was equipped with an overhead stirrer, a thermocouple, a Claisen condenser and a reflux condenser. Tris(dibenzylideneacetone)dipalladium(0) (0.330 g, 0.360 mmol), di-ier?-butyl(2′,4′,6′-triisopropyl-3,4,5,6-tetramethylbiphenyl-2-yl)phosphine (0.416 g, 0.864 mmol) and milled potassium phosphate tribasic (21.0 g, 99.0 mmol) were charged to the 3-L flask. The flask was purged with argon for not less than 90 minutes with constant stirring of the solids. i-Amyl alcohol (250 ml) was purged with argon for not less than 30 minutes and was transferred to the 3-L flask using a cannula under argon atmosphere. The contents of the 3-L flask were heated to 80 °C and stirred at this temperature for 30 minutes. A 1-L round bottom flask equipped with a magnetic stir bar was charged with 6-(3-ier?-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-l-sulfonate (62.9 g, 90 mmol), methanesulfonamide (12.85 g, 135 mmol) and i-amyl alcohol (505 mL), purged with argon and heated to 60 °C. The reaction mixture was stirred under argon for not less than 30 minutes. A clear yellow solution was observed. This solution was transferred to the 3-L flask using a cannula under argon atmosphere. The temperature of the 3-L flask was raised to 85 °C and the contents were stirred for 14 hours under a positive pressure of argon. The temperature was then raised to 95 °C and the contents were stirred for an additional 4 hours under a positive pressure of argon. The reaction mixture was allowed to cool down to room temperature, diluted with tetrahydrofuran (2200 mL) and water (800 mL) and was transferred to a 6-L separatory funnel. The organic layer was washed thrice with water (2000 mL) containing L-cysteine (17.3 g) and NaCl (235 g). The organic layer was collected, filtered through a pad of diatomaceous earth and was concentrated in vacuo to approximately 250 mL. Ethyl acetate (775 mL) was added over 7 hours with stirring, and the mixture was allowed to stir for an additional 14 hours. White solid was isolated by filtration, and the solid was washed with ethyl acetate (1000 mL). The solid was dissolved in tetrahydrofuran (1500 mL) and filtered through a pad of diatomaceous earth to obtain a clear solution. The diatomaceous earth was washed with tetrahydrofuran (300 mL). The combined tetrahydrofuran solution was concentrated in vacuo to approximately 250 mL, and then ethyl acetate (775 mL) was added over 7 hours with stirring. The product solution was allowed to stir for an additional 14 hours. White solid was isolated by filtration. The solid was washed with ethyl acetate (1000 mL) and dried in a vacuum oven at 60 °C for 24 hours. The solid was slurried in 308 mL of 200 proof ethanol for 1.5 hours, then isolated by filtration. The solid was washed with 132 mL of 200 proof ethanol and dried in a vacuum oven at 50 °C for 18 hours. The title compound was isolated as a white solid (32.6 g, 100% potency vs. standard, 73% yield). ^!H NMR (400 MHz, DMSO-i/₆) δ ppm 11.41 (d, J = 2.1 Hz, 1H), 10.04 (s, 1H), 8.02 (d, J = 0.9 Hz, 1H), 7.98 – 7.91 (m, 2H), 7.79 (d, J = 7.9 Hz, 1H), 7.72 (d, J = 2.0 Hz, 1H), 7.69 (dd, J = 8.5, 1.7 Hz, 1H), 7.41 (dd, J = 8.8, 2.2 Hz, 1H), 7.36 (d, J = 2.7 Hz, 1H), 7.31 (d, J = 2.7 Hz, 1H), 5.65 (dd, J = 7.9, 2.2 Hz, 1H), 3.24 (s, 3H), 3.08 (s, 3H), 1.42 (s, 9H).

[00184] Other ligands such as 2,2,7,7-tetramethyl-l-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphepane; 7,7,9,9-tetramethyl-8-(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)-l,4-dioxa-8- phosphaspiro[4.5]decane; and 8-(2-(2-methoxynaphthalen- 1 -yl)phenyl)-7,7,9,9-tetramethyl- 1 ,4-dioxa-8- phosphaspiro[4.5]decane were tested under the conditions described above and produced favorable yields of greater than 50% of the sulfonamidated product.

PREPN OF SODIUM SALT

Example 5. Preparation of the sodium salt of V-(6-(3-teri-butyl-5-(2,4-dioxo-3,4- dihydropyrimidin- 1 (2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide (compound (As)).

[00192] A solution of 2-propanol and water was prepared by combining 18.5 g of water and 512 g of 2- propanol. Hereafter, this solution is referred to as the “antisolvent solution.”

[00193] A solution of 2-propanol and water was prepared by combining 23.94 g of water and 564 g of 2- propanol. This solution was cooled in a refrigerator prior to use. Hereafter, this solution is referred to as the “chilled wash solution.”

[00194] A jacketed reactor was equipped with an overhead stirrer and charged with 32.0 g (64.8 mmol) of A^-(6-(3-?er^butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-2-methoxyphenyl)naphthalen-2- yl)methanesulfonamide and 105.9 g of dimethyl sulfoxide. With stirring the mixture was heated to an internal temperature of 68 °C. A solution of 2.66 g of sodium hydroxide (66.5 mmol, 1.026 equiv) in 16 g of water was added to the reactor over several minutes, followed by 12.4 g of 2-propanol while maintaining the internal temperature at 68 °C. Antisolvent solution (24.5 g) was added to the reactor while maintaining the internal temperature at 68 °C. A slurry of 0.32 g of seed crystals of the final product in 22.8 g of antisolvent solution was added to the reactor, followed by a 2.6 g rinse of the flask with antisolvent solution. The reaction mixture was stirred for 1.5 hours while maintaining the internal temperature at 68 °C. Antisolvent solution (354 g) was added to the reactor over 7 hours while maintaining the internal temperature at 68 °C. The contents of the reactor were cooled to an internal temperature of 0 °C over 7 hours and then mixed at 0 °C for 7 hours. The solids were isolated by filtration and washed with 252 g of the chilled wash solution. The isolated solids were dried in a vacuum oven at 50 °C for 19 hours. The title compound was isolated as a white solid (30.7 g, 92% potency vs. free acid standard, 57.2 mmol free acid equivalent, 88% yield). ^!H NMR (400 MHz, DMSO-i¾) δ ppm 7.75 (s, 1H), 7.72 (d, J= 7.8 Hz, 1H), 7.59 (dd, J= 8.8, 2.2 Hz, 2H), 7.45 (dd, J= 8.5, 1.8 Hz, 1H), 7.27 (d, J = 2.6 Hz, 2H), 7.21 (d, J= 2.7 Hz, 1H), 7.06 (dd, J= 8.8, 2.2 Hz, 1H), 5.62 (d, J= 7.8 Hz, 1H), 3.24 (s, 3H), 2.68 (s, 3H), 1.40 (s, 9H).

CLIP

DASABUVIR, ABT 333,

CLIP

Dasabuvir sodium (Exviera) Dasabuvir sodium (Exviera), an oral non-nucleoside NS5B polymerase inhibitor discovered and developed by Abbvie, is a component of an all-oral hepatitis C treatment regimen Viekira Pak approved by the US FDA in December 2014 for the treatment of adult patients with chronic genotype 1 (GT1) hepatitis C virus (HCV) infection.84 The investigational regimen consists of the fixed-dose combination of paritaprevir (XXVII) (veruprevir, ABT- 450, vide infra) with ritonavir booster (150/100 mg) co-formulated with the NS5A inhibitor ombitasvir (XXV) (ABT-267, vide infra)25 mg, dosed once daily, and nonnucleoside NS5B polymerase inhibitor dasabuvir (X) (ABT-333) 250 mg with or without ribavirin (weight-based), dosed twice daily.85,86 The drug was granted breakthrough therapy designation by the US FDA in May 2013. AbbVie’s application is supported by the data from six Phase III studies covering over 2300 patients in 25 countries representing one of the largest clinical programs in hepatitis C research and development.87 Across six studies, the 12-week therapeutic regimen achieved impressive cure rates, notching a 99% sustained virologic response mark in some populations.88 Although several syntheses of dasabuvir sodium (X) have been disclosed,89–91 the most likely scale approach is outlined in Scheme 12.91 Commercially available 2-tert-butyl phenol (65) was polyiodinated to furnish diiodophenol 66 in 93% yield. Thiswas followed by methylation of the phenol to provide methyl phenyl ether 67 in 99% yield. Next, sequential couplings were employed to install the periphery about the central phenyl core. First, Goldberg coupling of 67 with pyrimidine-2,4-(1H,3H)-dione 68 in presence of CuI (10 mol %) and 69 provided compound 70 in 70% yield. Subsequently, the remaining iodide underwent Suzuki coupling with boronic acid 71 in the presence of Pd2(dba)3 and 72 to yield the naphthol 73 in high yield. Naphthol 73 was then converted to the corresponding polyfluorinated naphthol sulfonate 75, which was subsequently converted to dasabuvir through a palladium- mediated installation of methyl sulfonamide 76. Dasabuvir sodium (X) was then crystallized upon treatment with aq NaOHin i-PrOH and DMSO in 88% yield.

84. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm427530.htm.

85. Poordad, F.; Lawitz, E.; Kowdley, K. V.; Cohen, D. E.; Podsadecki, T.; Siggelkow,S.; Heckaman, M.; Larsen, L.; Menon, R.; Koev, G.; Tripathi, R.; Pilot-Matias, T.;

Bernstein, B. N. Engl. J. Med. 2013, 368, 45.

86. Kowdley, K. V.; Lawitz, E.; Poordad, F.; Cohen, D. E.; Nelson, D. R.; Zeuzem, S.;Everson, G. T.; Kwo, P.; Foster, G. R.; Sulkowski, M. S.; Xie, W.; Pilot-Matias, T.;Liossis, G.; Larsen, L.; Khatri, A.; Podsadecki, T.; Bernstein, B. N. Engl. J. Med.2014, 370, 222.

87. http://www.marketwatch.com/story/abbvie-submits-new-drug-applicationto-us-fda-for-its-investigational-all-oral-interferon-free-therapy-for-thetreatment-of-hepatitis-c-2014-04-22.

88. Feld, J. J.; Kowdley, K. V.; Coakley, E.; Sigal, S.; Nelson, D. R.; Crawford, D.;Weiland, O.; Aguilar, H.; Xiong, J.; Pilot-Matias, T.; DaSilva-Tillmann, B.;Larsen, L.; Podsadecki, T.; Bernstein, B. N. Engl. J. Med. 2014, 370, 1594.

89. Flentge, C., A.;; Hutchinson, D. K.; Betebenner, D. A.; Degoey, D. A.; Donner, P.L.; Kati, W. M.; Krueger, A. C.; Liu, D. C.; Liu, Y.; Longenecker, K. L.; Maring, C.J.; Motter, C. E.; Pratt, J. K.;

PATENT

http://www.google.com/patents/US20130224149

Example 2 Preparation of 1-(3-tert-butyl-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione (compound (4a))

This reaction is sensitive to oxygen, and care was taken to establish and maintain an inert atmosphere in the handling and use of air-sensitive materials or mixtures. All solution transfers were accomplished by cannula technique using nitrogen as the inert gas. Anhydrous tetrahydrofuran was sparged with nitrogen gas for 2 hours prior to use to render it anaerobic. Hereafter this is referred to as degassed tetrahydrofuran.

A 100-mL round-bottom flask was charged with 12.9 g of potassium phosphate tribasic (60.8 mmol, 2.0 equivalents), a magnetic stir bar, and 60 mL of water. The mixture was stirred to dissolve the solids, and the aqueous solution was sparged with nitrogen gas for 2 hours prior to use. Hereafter this is referred to as the phosphate solution.

A 100-mL round-bottom flask was purged with nitrogen gas and charged with 282 mg of tris(dibenzylideneacetone)dipalladium(0) (0.31 mmol, 0.02 equivalents Pd), 413 mg of phosphine ligand, 1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphatricyclo[3.3.1.1^3,7]decane (1.4 mmol, 2.3 equivalents relative to Pd) and a magnetic stir bar. The flask was sealed with a septum and the atmosphere above the solids was purged with nitrogen gas. Sixty mL of degassed tetrahydrofuran was added to the flask and the mixture was stirred under a nitrogen atmosphere. This solution was sparged with nitrogen for 15 minutes prior to use and is hereafter referred to as the catalyst solution.

A 500-mL jacketed reactor was equipped with an overhead stirrer and reflux condenser and the atmosphere was purged with nitrogen gas. The reactor was charged with 12.1 g of 1-(3-tert-butyl-5-iodo-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione, (30.3 mmol, 1.0 equivalent) and 5.98 g of 6-hydroxynaphthalen-2-ylboronic acid (31.8 mmol, 1.05 equivalents). The atmosphere was purged with nitrogen gas with stirring of the solid reagents for 20 minutes. The reactor was charged with 120 mL of degassed tetrahydrofuran, and the mixture was stirred to dissolve the solids. The solution was sparged with nitrogen gas for 10 minutes. The phosphate solution was added to the reactor by cannula, followed by the catalyst solution. The resulting biphasic mixture was stirred aggressively to ensure adequate phase mixing, and the jacket was warmed to 65° C. The reaction jacket was cooled to room temperature prior to quench.

After 2.5 hours, the reaction jacket was cooled to room temperature prior to quench.

The workup of the reaction was also conducted under anaerobic conditions. Fifty-seven grams of sodium chloride and 4.2 g of cysteine (15 weight equivalents relative to palladium catalyst) were dissolved in 300 mL of water, and the resulting solution was sparged with inert gas for 2 hours prior to use. To quench the reaction, approximately ⅓ of this solution was transferred to the reaction mixture by cannula under nitrogen gas and the resulting biphasic mixture was stirred vigorously for 2 hours. The mechanical agitation was halted, the two solutions were allowed to separate, and the aqueous solution was drained out of the reactor through the bottom valve. Approximately ⅓ of the quench solution was transferred to the reaction mixture by cannula under nitrogen gas and the resulting biphasic mixture was stirred vigorously for 45 minutes. The mechanical agitation was halted, the two solutions were allowed to separate, and the aqueous solution was drained out of the reactor through the bottom valve. The final portion of the quench solution was transferred to the reaction mixture by cannula, the resulting biphasic mixture was stirred vigorously for 45 minutes and the aqueous solution was drained out of the reactor through the bottom valve.

The remainder of the workup was not conducted under anaerobic conditions. The pale yellow organic solution was drained from the reactor through the bottom valve and filtered over a pad of grade 4 Filtrol® (1 cm deep by 4.5 cm diameter). The reactor and filter cake were rinsed with 70 mL of tetrahydrofuran. The bulk of the solvent was distilled in vacuo (ca 90-130 torr) at ca 40° C. with good agitation from an overhead stirrer. The solution was concentrated to approximately 50 mL volume, during which time the product began to precipitate out. Ethyl acetate (100 mL, about 8 mL of solvent per gram of the product) was added to the mixture, and the resultant slurry was stirred overnight at room temperature. The crystalline material was isolated by filtration and the filter cake was washed twice with 20 mL portions of ethyl acetate. The wet cake was air-dried on the filter and dried in a vacuum oven at 50° C. at approximately 250 torr with a gentle nitrogen sweep overnight.

The desired product was isolated as a white solid (11.6 g, 96.4% potency vs. standard, 88% potency-adjusted yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.39 (d, J=2.1 Hz, 1H), 9.82 (s, 1H), 7.91 (d, J=0.8 Hz, 1H), 7.80 (d, J=8.9 Hz, 1H), 7.77-7.74 (m, 2H), 7.58 (dd, J=8.5, 1.7 Hz, 1H), 7.32 (d, J=2.7 Hz, 1H), 7.27 (d, J=2.7 Hz, 1H), 7.16 (d, J=2.3 Hz, 1H), 7.10 (dd, J=8.8, 2.4 Hz, 1H), 5.64 (dd, J=7.9, 2.2 Hz, 1H), 3.23 (s, 3H), 1.41 (s, 9H).

Example 2-1 Alternative preparation of 1-(3-tert-butyl-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione (compound (4a))

This reaction is air-sensitive and the reaction was conducted under anaerobic conditions. A 100-mL round-bottom flask was purged with nitrogen gas and charged with 229 mg of tris(dibenzylideneacetone)dipalladium(0) (0.25 mmol, 0.02 equivalents Pd), 323 mg of 1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphatricyclo[3.3.1.1^3,7]decane (1.13 mmol, 0.045 equivalents) and a magnetic stir bar. The flask was sealed with a septum and the atmosphere above the solids was purged with nitrogen gas. Sixty mL of degassed tetrahydrofuran was added to the flask and the mixture was stirred under a nitrogen atmosphere for 20 minutes. This solution is hereafter referred to as the catalyst solution.

A 500-mL jacketed reactor was equipped with an overhead stirrer and reflux condenser and the atmosphere was purged with nitrogen gas. The reactor was charged with 10.0 g of 1-(3-tert-butyl-5-iodo-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione, (25.1 mmol, 1.0 equivalent), 4.98 g of 6-hydroxynaphthalen-2-ylboronic acid (26.6 mmol, 1.06 equivalents) and 10.3 g of potassium phosphate tribasic (48.7 mmol, 2.0 equivalents). The atmosphere was purged with nitrogen gas with stirring of the solid reagents for 20 minutes. The reactor was charged with 100 mL of tetrahydrofuran, 50 mL of water, and the mixture was stirred to dissolve the solids. The biphasic mixture was sparged with nitrogen gas for 30 minutes. The catalyst solution was transferred to the main reactor by positive nitrogen pressure through a cannula. The resulting biphasic mixture was stirred aggressively and warmed to an internal temperature between 60 and 65° C. under nitrogen for 2 hours. The reaction mixture was cooled to an internal temperature between 50 and 55° C. before quench.

The workup of the reaction was conducted under anaerobic conditions at an internal temperature between 50 and 55° C. Fifteen grams of sodium chloride and 1.0 g of cysteine were dissolved in 80 mL of water, and the resulting solution was sparged for 1 hour. This solution was transferred to the reaction mixture by cannula with nitrogen gas pressure and the resulting biphasic mixture was stirred vigorously for 45 minutes. The mechanical agitation was halted, the two solutions were allowed to separate, and the aqueous solution was drained out of the reactor through the bottom valve. Fifteen grams of sodium chloride and 1.0 g of cysteine were dissolved in 80 mL of water, and the resulting solution was sparged for 1 hour. This solution was transferred to the reaction mixture by cannula with nitrogen gas pressure and the resulting biphasic mixture was stirred vigorously for 45 minutes. The mechanical agitation was halted, the two solutions were allowed to separate, and the aqueous solution was drained out of the reactor through the bottom valve.

The pale yellow organic solution was drained from the reactor through the bottom valve and filtered over a polypropylene filter to remove palladium black. The reactor and filter cake were rinsed with 22 mL of tetrahydrofuran and 50 mL of ethyl acetate was added to the organic solution. The solution was distilled at atmospheric pressure (approximately 66° C. internal temperature) with continuous addition of 110 mL of ethyl acetate, keeping the volume of the solution roughly constant during the distillation. During the constant-volume distillation, solids began to precipitate in the reactor. After the ethyl acetate was charged, the distillation was continued at atmospheric pressure, concentrating the slurry to approximately 60 mL total volume. The solution was cooled to an internal temperature of approximately 30° C. and held for 3 hours with stirring. The crystalline material was isolated by filtration and the filter cake was washed twice with 20 mL portions of ethyl acetate. The wet cake was dried in a vacuum oven at 50° C. with a gentle nitrogen sweep overnight. The desired product was isolated as an off-white solid (8.33 g, 80% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm δ 11.39 (d, J=2.1 Hz, 1H), 9.82 (s, 1H), 7.91 (d, J=0.8 Hz, 1H), 7.80 (d, J=8.9 Hz, 1H), 7.77-7.74 (m, 2H), 7.58 (dd, J=8.5, 1.7 Hz, 1H), 7.32 (d, J=2.7 Hz, 1H), 7.27 (d, J=2.7 Hz, 1H), 7.16 (d, J=2.3 Hz, 1H), 7.10 (dd, J=8.8, 2.4 Hz, 1H), 5.64 (dd, J=7.9, 2.2 Hz, 1H), 3.23 (s, 3H), 1.41 (s, 9H).

Example 2-2 Alternative preparation of 1-(3-tert-butyl-5-(6-hydroxynaphthalen-2-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione (compound (4a))

This reaction is air-sensitive and the reaction was conducted under nitrogen atmosphere. A 100-mL round-bottom flask was purged with nitrogen gas and charged with 303 mg of tris(dibenzylideneacetone)dipalladium(0) (0.33 mmol, 0.02 equivalents Pd), 411 mg of 1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphatricyclo[3.3.1.1^3,7]decane (1.40 mmol, 0.045 equivalents) and a magnetic stir bar. The flask was sealed with a septum and the atmosphere above the solids was purged with nitrogen gas. Seventy-five (75) mL of degassed tetrahydrofuran was added to the flask and the mixture was stirred under a nitrogen atmosphere for 25 minutes. This solution is hereafter referred to as the catalyst solution.

A 500-mL jacketed reactor was equipped with an overhead stirrer and reflux condenser and the atmosphere was purged with nitrogen gas. The reactor was charged with 12.5 g of 1-(3-tert-butyl-5-iodo-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione, (31.2 mmol, 1.0 equivalent), 6.20 g of 6-hydroxynaphthalen-2-ylboronic acid (33.0 mmol, 1.06 equivalents) and 13.0 g of potassium phosphate tribasic (61.2 mmol, 2.0 equivalents). The reactor was charged with 130 mL of tetrahydrofuran, 65 mL of water, and the mixture was stirred to dissolve the solids. The biphasic mixture was sparged with nitrogen gas for 30 minutes. The catalyst solution was transferred to the main reactor by positive nitrogen pressure through a cannula. The resulting biphasic mixture was stirred aggressively and warmed to an internal temperature between 60 and 65° C. under nitrogen for 2.5 hours. The reaction mixture was cooled to an internal temperature between 50 and 55° C. before quench.

The workup of the reaction was conducted under anaerobic conditions at an internal temperature between 50 and 55° C. Sodium chloride (18.8 g) and cysteine (1.25 g) were dissolved in 100 mL of water, and the resulting solution was sparged with nitrogen for 40 minutes. This solution was transferred to the reaction mixture by cannula with nitrogen gas pressure and the resulting biphasic mixture was stirred vigorously for 45 minutes. The mechanical agitation was halted, the two solutions were allowed to separate, and the aqueous solution was drained out of the reactor through the bottom valve. Sixty-three (63) mL of degassed tetrahydrofuran were added to the reactor by cannula with positive nitrogen pressure. Sodium chloride (18.9 g) and cysteine (1.333 g) were dissolved in 100 mL of water, and the resulting solution was sparged with nitrogen for 40 minutes. This solution was transferred to the reaction mixture by cannula with nitrogen gas pressure and the resulting biphasic mixture was stirred vigorously for 45 minutes. The mechanical agitation was halted, the two solutions were allowed to separate, and the aqueous solution was drained out of the reactor through the bottom valve.

The pale yellow organic solution was drained from the reactor through the bottom valve and filtered through a thin pad of filter aid on a polyethylene filter while warm. The reactor and filter cake were rinsed with 32 mL of tetrahydrofuran, and 65 mL of ethyl acetate was added to the organic solution. The solution was distilled at atmospheric pressure (approximately 66° C. internal temperature) with continuous addition of 190 mL of ethyl acetate, keeping the volume of the solution roughly constant during the distillation. During the constant-volume distillation, solids began to precipitate in the reactor. After the ethyl acetate was charged, the distillation was continued at atmospheric pressure, concentrating the slurry to approximately 90 mL total volume. The slurry was cooled to an internal temperature of approximately 40° C. and was concentrated further in vacuo to a total volume of approximately 50 mL. The slurry was cooled to an internal temperature of 30° C. and held for 16 hours with stirring. The crystalline material was isolated by filtration, and the filter cake was washed twice with 25 mL portions of ethyl acetate. The wet cake was dried in a vacuum oven at 50° C. with a gentle nitrogen sweep overnight. The desired product was isolated as an off-white solid (11.4 g, 99.5% potent vs. standard, 87% potency-adjusted yield).

Example 4 Preparation of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide (compound (A-1))

A 3-L, 3-neck, round-bottom flask was equipped with an overhead stirrer, a thermocouple, a Claisen condenser and a reflux condenser. Tris(dibenzylideneacetone)dipalladium(0) (0.330 g, 0.360 mmol), di-tert-butyl(2′,4′,6′-triisopropyl-3,4,5,6-tetramethylbiphenyl-2-yl)phosphine (0.416 g, 0.864 mmol) and milled potassium phosphate tribasic (21.0 g, 99.0 mmol) were charged to the 3-L flask. The flask was purged with argon for not less than 90 minutes with constant stirring of the solids. t-Amyl alcohol (250 ml) was charged to a separate 500-mL round-bottom flask and was purged with argon for not less than 30 minutes and was transferred to the 3-L flask using a cannula under argon atmosphere. The contents of the 3-L flask were heated to 80° C. and stirred at this temperature for 30 minutes. A 1-L round-bottom flask equipped with a magnetic stir bar was charged with 6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl-1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (62.9 g, 90 mmol), methanesulfonamide (12.85 g, 135 mmol) and t-amyl alcohol (505 mL), purged with argon and heated to 60° C. The reagent mixture was stirred under argon for not less than 30 minutes. A clear yellow solution was observed. This solution was transferred to the 3-L flask using a cannula under argon atmosphere. The temperature of the 3-L flask was raised to 85° C. and the contents were stirred for 14 hours under a positive pressure of argon. The temperature was then raised to 95° C. and the contents were stirred for an additional 4 hours under a positive pressure of argon. The reaction mixture was allowed to cool down to room temperature, diluted with tetrahydrofuran (2200 mL) and water (800 mL) and was transferred to a 6-L separatory funnel. The organic layer was washed thrice with water (2000 mL) containing L-cysteine (17.3 g) and NaCl (235 g). The organic layer was collected, filtered through a pad of diatomaceous earth and was concentrated in vacuo to approximately 250 mL. Ethyl acetate (775 mL) was added over 7 hours with stirring, and the mixture was allowed to stir for an additional 14 hours. White solid was isolated by filtration, and the solid was washed with ethyl acetate (1000 mL). The solid was then dissolved in tetrahydrofuran (1500 mL) and filtered through a pad of diatomaceous earth to obtain a clear solution. The diatomaceous earth was washed with tetrahydrofuran (300 mL). The combined tetrahydrofuran solution was concentrated in vacuo to approximately 250 mL, and then ethyl acetate (775 mL) was added over 7 hours with stirring. The product solution was allowed to stir for an additional 14 hours. White solid was isolated by filtration. The solid was washed with ethyl acetate (1000 mL) and dried in a vacuum oven at 60° C. for 24 hours. The solid was slurried in 308 mL of 200 proof ethanol for 1.5 hours, then isolated by filtration. The solid was washed with 132 mL of 200 proof ethanol and dried in a vacuum oven at 50° C. for 18 hours. The title compound was isolated as a white solid (32.6 g, 100% potency vs. standard, 73% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.41 (d, J=2.1 Hz, 1H), 10.04 (s, 1H), 8.02 (d, J=0.9 Hz, 1H), 7.98-7.91 (m, 2H), 7.79 (d, J=7.9 Hz, 1H), 7.72 (d, J=2.0 Hz, 1H), 7.69 (dd, J=8.5, 1.7 Hz, 1H), 7.41 (dd, J=8.8, 2.2 Hz, 1H), 7.36 (d, J=2.7 Hz, 1H), 7.31 (d, J=2.7 Hz, 1H), 5.65 (dd, J=7.9, 2.2 Hz, 1H), 3.24 (s, 3H), 3.08 (s, 3H), 1.42 (s, 9H). ¹³C NMR (101 MHz, DMSO-d₆) δ ppm 163.1 (C), 156.0 (C), 150.0 (C), 145.3 (CH), 142.9 (C), 136.0 (C), 134.3 (C), 134.2 CO, 133.5 (C), 132.2 (C), 129.5 (C), 129.0 (CH), 127.6 (CH), 127.1 (CH), 127.0 (CH), 126.5 (CH), 124.3 (CH), 120.2 (CH), 114.5 (CH), 101.1 (CH), 60.3 (CH₃), 39.4 (CH₃), 35.1 (C), 30.5 (CH₃).

Other ligands such as 2,2,7,7-tetramethyl-1-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphepane; 7,7,9,9-tetramethyl-8-(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)-1,4-dioxa-8-phosphaspiro[4.5]decane; and 8-(2-(2-methoxynaphthalen-1-yl)phenyl)-7,7,9,9-tetramethyl-1,4-dioxa-8-phosphaspiro[4.5]decane were tested under the conditions described above and produced favorable yields of greater than 50% of the sulfonamidated product.

Example 4-1 Alternative Preparation of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide (compound (A-1))

A 450-mL, stainless steel Parr® pressure reactor equipped with an overhead stirrer was charged with tris(dibenzylideneacetone)dipalladium(0) (0.131 g, 0.143 mmol), di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine (0.167 g, 0.344 mmol) and milled potassium phosphate tribasic (6.69 g, 31.5 mmol). The flask was purged with argon for not less than 90 minutes. Tetrahydrofuran (90 mL) was taken in a 100-mL round bottom flask, purged with argon for not less than 30 minutes and was transferred to the 450-mL reactor using a cannula under argon atmosphere. The contents of the 450-mL reactor were heated to 80° C. and stirred at this temperature for 30 minutes. A 250-mL, round-bottom flask equipped with a magnetic stir bar was charged with 6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl-1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (20.0 g, 28.6 mmol), methanesulfonamide (3.27 g, 34.4 mmol) and tetrahydrofuran (160 mL), purged with argon for not less than 45 minutes. A clear yellow solution was observed. This solution was transferred to the 450-mL reactor that has been cooled to the room temperature using a cannula under argon atmosphere. The temperature of the 450-mL reactor was raised to 90° C. and the contents were stirred for 20 hours. The reaction mixture was allowed to cool down to 50° C., diluted with tetrahydrofuran (70 mL) and water (70 mL) containing L-cysteine (0.875 g) and sodium chloride (7.7 g). The contents were stirred for 2 hours at 50° C. The aqueous layer was discarded and the organic layer was filtered through an approximately 2-inch pad of diatomaceous earth and rinsed with tetrahydrofuran (45 mL) to obtain a clear, light yellow solution. The total weight of reaction mixture was 363.43 g. HPLC analysis of the reaction mixture revealed 13.71 g (97%) of the title compound was present in the reaction mixture. A portion of the reaction mixture (50 g) was concentrated to a final volume of 12-14 mL under vacuum. Ethyl acetate (45 mL) was added slowly and the reaction mixture was stirred over night at room temperature to obtain white slurry. Product was collected by filtration, washed with ethyl acetate (7 mL) and dried overnight in a vacuum oven at 50-60° C. to obtain 2.02 g of white solid. Ethanol (14 mL) was added to the solid and stirred overnight at the room temperature. The product was collected by filtration, washed with ethanol (4 mL) and dried overnight in a vacuum oven at 50-60° C. to obtain the title compound (1.79 g, 95.4%).

Example 4-2 Alternative preparation of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide (compound (A-1))

A 450-mL, stainless steel Parr® pressure reactor equipped with an overhead stirrer was charged with tris(dibenzylideneacetone)dipalladium(0) (0.105 g, 0.115 mmol), di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine (0.133 g, 0.275 mmol) and milled potassium phosphate tribasic (5.35 g, 25.2 mmol). The flask was purged with argon for not less than 90 minutes. 2-Methyltetrahydrofuran (70 mL) was taken in a 100-mL round bottom flask, purged with argon for not less than 30 minutes and was transferred to the 450-mL reactor using a cannula under argon atmosphere. The contents of the 450-mL reactor were heated to 80° C. and stirred at this temperature for 30 minutes. A 250-mL, round bottom flask equipped with a magnetic stir bar was charged with 6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl-1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (16.0 g, 22.9 mmol), methanesulfonamide (2.61 g, 27.5 mmol) and 2-methyltetrahydrofuran (155 mL), purged with argon for not less than 60 minutes. This solution was transferred to the 450-mL reactor that has been cooled to the room temperature using a cannula under argon atmosphere. The temperature of the 450-mL flask was raised to 90° C. and the contents were stirred for 14 hours. The reaction mixture was allowed to cool down to 70° C., diluted with ethyl acetate (190 mL) and stirred for 3 hours at 70° C., cooled to the room temperature, stirred for an additional 4 hours, filtered through a fine frit filter funnel and rinsed with ethyl acetate (90 mL) to obtain 29.4 g of light brown solid. A portion of this solid (13.04 g) was transferred to a 500-mL, 3-neck round bottom flask equipped with an overhead stirrer and a thermocouple. Tetrahydrofuran (175 mL) was added, followed by the addition of water 50 mL containing L-cysteine (0.63 g) and sodium chloride (5.5 g). The reaction mixture was stirred for 2 hours at 50° C. under a slight positive pressure of argon. The reaction mixture was transferred to a 500-mL separatory funnel and the aqueous layer was discarded. The organic layer was filtered through an approximately 2-inch pad of diatomaceous earth and rinsed with tetrahydrofuran (45 mL) to obtain a clear, light yellow solution. The organic layer was concentrated to a total weight of 45.59 g. A portion of this organic solution (41.58 g) was charged to a 250-mL, 3-neck round bottom flask fitted with an overhead stirrer. Ethyl acetate (80 mL) was added over 6 hours by a pump with constant stirring at room temperature. The product was collected by filtration, rinsed with ethyl acetate (20 mL) and dried in a vacuum oven for 2 hours to obtain 3.17 g of the title compound (>99.8 pure and 94.6% potent vs. standard).

Example 4-3 Alternative preparation of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide (compound (A-1))

A 600-mL, stainless steel Parr® pressure reactor equipped with an overhead stirrer was charged with tris(dibenzylideneacetone)dipalladium(0) (0.229 g, 0.251 mmol), di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine (0.291 g, 0.601 mmol) and milled potassium phosphate tribasic (11.70 g, 55.1 mmol). The flask was purged with argon for not less than 90 minutes. Ethyl acetate (140 mL) was taken in a 250-mL, round bottom flask, purged with argon for not less than 30 minutes and was transferred to the 600-mL reactor using a cannula under argon atmosphere. The contents of the 600-mL reactor were heated to 80° C. and stirred at this temperature for 30 minutes. A 500-mL round bottom flask equipped with a magnetic stir bar was charged with 6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl-1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (35.0 g, 50.1 mmol), methanesulfonamide (5.72 g, 60.1 mmol) and ethyl acetate (280 mL), purged with argon for not less than 60 minutes while stirring at 50° C. This solution was transferred to the 600-mL reactor that had been cooled to room temperature using a cannula under argon atmosphere. The temperature of the 600-mL flask was raised to 90° C., and the contents were stirred for 18 hours. The reaction mixture was allowed to cool down to 40° C., filtered and rinsed with ethyl acetate (140 mL). Solid (41.50 g) was obtained after drying for 2 hours on high vacuum. This solid contained the titled product (23.06 g, 93%).

Example 4-4 Alternative preparation of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide (compound (A-1))

Tris(dibenzylideneacetone)dipalladium(0) (0.0066 g, 7.16 μmol), di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine (0.0083 g, 17 μmol) and milled potassium phosphate tribasic (0.334 g, 1.58 mmol) were charged to a 40-mL reaction vial inside an inert atmosphere glove box. t-Amyl alcohol (4 mL) was added, the vial was capped, and the contents were heated to 80° C. and stirred at this temperature for 30 minutes. The reaction mixture was cooled down to the room temperature. 6-(3-tert-Butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl-1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (1.0 g, 1.43 mmol), methanesulfonamide (0.163 g, 1.72 mmol) and t-amyl alcohol (8 mL) were added to the 40-mL reaction vial, and the vial was capped. The reaction temperature was raised to 90° C. and the contents were stirred for 5 hours. HPLC analysis of the reaction mixture showed that the product was formed in 94 area % at 210 nm.

Example 4-5 Alternative preparation of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide (compound (A-1))

A 600-mL, stainless steel, Parr® reactor was equipped with an overhead stirrer, thermocouple and a heating mantle. Tris(dibenzylideneacetone)dipalladium(0) (0.164 g, 0.179 mmol), di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine (0.208 g, 0.429 mmol) and milled potassium phosphate tribasic (8.36 g, 39.4 mmol) were charged to the 600-mL reactor. The reactor was purged with argon for not less than 90 minutes. 2-Methyltetrahydrofuran (100 mL) was purged with argon for not less than 30 minutes and was transferred to the 600-mL reactor using a cannula under argon atmosphere. The reactor was tightly sealed, the contents were heated to 80° C. and stirred at this temperature for 30 minutes. A 500-mL round bottom flask equipped with a magnetic stir bar was charged with 6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (25 g, 35.8 mmol), methanesulfonamide (4.09 g, 42.9 mmol) and ethyl acetate (200 mL), purged with argon for not less than 30 minutes with stirring and heated to 60° C. A clear solution was observed. This solution was transferred to the 600-mL reactor using a cannula under argon atmosphere. The reactor was tightly sealed, the contents were heated to 90° C. and stirred at this temperature for 14 hours. The reaction mixture was cooled to 35° C., solids were collected by filtration, washed with ethyl acetate (300 mL) and dried under high vacuum for 2-4 hours. The solids were then transferred to a 1-L, three-neck, round-bottom flask equipped with an overhead stirrer and a thermocouple. N-Acetyl-L-cysteine (0.58 g, 3.5 mmol), dimethylformamide (DMF) (100 mL) and glacial acetic acid (0.85 g) were charged to the 1-L flask; the contents were heated to 60° C. and mixed for 1 hour. The mixture was filtered through approximately 2-inch pad of diatomaceous earth and washed with DMF (50 mL). The dark-brown/black-colored solid collected on diatomaceous earth was discarded and the light yellow/clear filtrate was charged to a separate 1-L, three-neck, round-bottom flask equipped with an overhead stirrer, a thermocouple and a syringe pump. The DMF solution was mixed and methanol (300 mL) was added over 8 hours, while maintaining the internal temperature at 25±5° C. The white solid was collected by filtration washed with methanol (150 mL) and dried in a vacuum oven at 50° C. for not less than 8 hours. The title compound was isolated as a white solid (15.8 g, 89% yield).

Example 4-6 Alternative preparation of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide (compound (A-1))

A 600-mL, stainless steel, Parr® reactor was equipped with an overhead stirrer, thermocouple and a heating mantle. Tris(dibenzylideneacetone)dipalladium(0) (0.164 g, 0.179 mmol), 7,7,9,9-tetramethyl-8-(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)-1,4-dioxa-8-phosphaspiro[4.5]decane (0.238 g, 0.429 mmol) and milled potassium phosphate tribasic (8.36 g, 39.4 mmol) were charged to the 600-mL reactor. The reactor was purged with argon for not less than 90 minutes. 2-Methyltetrahydrofuran (100 mL) was purged with argon for not less than 30 minutes and was transferred to the 600-mL reactor using a cannula under argon atmosphere. The reactor was tightly sealed, the contents were heated to 80° C. and stirred at this temperature for 30 minutes. A 500-mL round bottom flask equipped with a magnetic stir bar was charged with 6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (25 g, 35.8 mmol), methanesulfonamide (4.09 g, 42.9 mmol) and ethyl acetate (200 mL), purged with argon for not less than 30 minutes with stirring and heated to 60° C. A clear solution was observed. This solution was transferred to the 600-mL reactor using a cannula under argon atmosphere. The reactor was tightly sealed, the contents were heated to 90° C. and stirred at this temperature for 14 hours. The reaction mixture was cooled to 35° C., 5% aqueous N-acetyl-L-cysteine solution (100 mL) was added and the contents were mixed for 1 hour at 35° C. Solids were collected by filtration, washed with water (2×25 mL) and ethyl acetate (3×80 mL) and were dried under high vacuum for 2-4 hours. The solids were then transferred to a 1-L, three-neck, round-bottom flask equipped with an overhead stirrer and a thermocouple. N-Acetyl-L-cysteine (0.58 g, 3.5 mmol), dimethylformamide (DMF) (100 mL) and glacial acetic acid (0.85 g) were charged to the 1-L flask; the contents were heated to 60° C. and mixed for 1 hour. The mixture was filtered through an approximately 2-inch pad of diatomaceous earth and washed with DMF (50 mL). The dark-brown/black-colored solid collected on the diatomaceous earth was discarded and the light yellow/clear filtrate was charged to a separate 1-L, three-neck, round-bottom flask equipped with an overhead stirrer, a thermocouple and a syringe pump. The DMF solution was mixed and methanol (300 mL) was added over 8 hours, while maintaining the internal temperature at 25±5° C. The white solid was collected by filtration washed with methanol (150 mL) and dried in a vacuum oven at 50° C. for not less than 8 hours. The title compound was isolated as a white solid (15.6 g, 88% yield).

Example 4-7 Alternative preparation of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide (compound (A-1))

Tris(dibenzylideneacetone)dipalladium(0) (0.0026 g, 2.80 μmol), di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine (0.0033 g, 6.72 μmol) and milled potassium phosphate tribasic (0.131 g, 0.616 mmol) were charged to a 40-mL reaction vial inside an inert atmosphere glove box. 2-Methyltetrahydrofuran (1.5 mL) was added, the vial was capped, and the contents were heated to 80° C. and stirred at this temperature for 30 minutes. The reaction mixture was cooled down to room temperature. 6-(3-tert-Butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl 1,1,2,2-tetrafluoro-2-(perfluoroethoxy)ethanesulfonate (0.4 g, 0.560 mmol, Example 3-7, compound (5f)), methanesulfonamide (0.064 g, 0.672 mmol) and ethyl acetate (3 mL) were added to the 40-mL reaction vial. The temperature of the closed vial was raised to 90° C. and the contents were magnetically stirred for 16 hours. HPLC analysis of the reaction mixture showed that the product was formed in 97 area % at 210 nm.

Example 4-8 Alternative preparation of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide (compound (A-1))

Tris(dibenzylideneacetone)dipalladium(0) (0.0071 g, 7.71 μmol), di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine (0.0089 g, 19.0 μmol) and milled potassium phosphate tribasic (0.360 g, 1.696 mmol) were charged to a 40-mL reaction vial inside an inert atmosphere glove box. 2-Methyltetrahydrofuran (4 mL) was added, and the closed vial and its contents were heated to 80° C. with magnetic stirring for 30 minutes. The reaction mixture was cooled down to room temperature. 6-(3-tert-Butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl 1,1,1,2,3,3,3-heptafluoropropane-2-sulfonate (1.0 g, 1.542 mmol, Example 3-4, compound (5c)), methanesulfonamide (0.176 g, 1.850 mmol) and ethyl acetate (8 mL) were added to the 40-mL reaction vial. The temperature of the closed vial and its contents was raised to 90° C. and stirred for 20 hours. HPLC analysis of the reaction mixture showed that the product was formed in 95 area % at 210 nm.

Example 4-9 Alternative preparation of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide (compound (A-1))

Tris(dibenzylideneacetone)dipalladium(0) (0.0055 g, 6.02 μmol), di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine (0.0070 g, 14.0 μmol) and milled potassium phosphate tribasic (0.281 g, 1.324 mmol) were charged to a 40-mL reaction vial inside an inert atmosphere glove box. 2-Methyltetrahydrofuran (3.4 mL) was added, and the closed vial and its contents were heated to 80° C. with magnetic stirring for 30 minutes. The reaction mixture was cooled down to room temperature. 6-(3-tert-Butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl sulfofluoridate (0.6 g, 1.204 mmol, Example 3-8, compound (5g)), methanesulfonamide (0.137 g, 1.444 mmol) and ethyl acetate (6.7 mL) were added to the 40-mL reaction vial. The temperature of the closed reaction vial and its contents was raised to 90° C. and the contents were stirred for 20 hours. HPLC analysis of the reaction mixture showed that the product was formed in 79 area % at 210 nm.

Example 4-10 Alternative preparation of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide (compound (A-1))

Tris(dibenzylideneacetone)dipalladium(0) (0.0042 g, 4.56 μmol), di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine (0.0053 g, 12.0 μmol) and milled potassium phosphate tribasic (0.213 g, 1.003 mmol) were charged to a 40-mL reaction vial inside an inert atmosphere glove box. 2-Methyltetrahydrofuran (1.9 mL) was added, and the closed vial and its contents were heated to 80° C. with magnetic stirring for 30 minutes. The reaction mixture was cooled down to room temperature. 6-(3-tert-Butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl trifluoromethanesulfonate (0.5 g, 0.912 mmol, Example 3-6, compound (5e)), methanesulfonamide (0.104 g, 1.094 mmol) and ethyl acetate (5.7 mL) were added to the 40-mL reaction vial. The temperature of the closed vial and its contents was raised to 90° C. and stirred for 14 hours. HPLC analysis of the reaction mixture showed that the product was formed in 91 area % at 210 nm.

Example 4-11 Alternative preparation of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide (compound (A-1))

Tris(dibenzylideneacetone)dipalladium(0) (0.0037 g, 4.04 μmol), di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine (0.0047 g, 9.7 μmol) and milled potassium phosphate tribasic (0.094 g, 0.445 mmol) were charged to a 40-mL reaction vial inside an inert atmosphere glove box. tert-Amyl alcohol (1.0 mL) was added, the contents were heated to 80° C. and stirred at this temperature for 30 minutes. The reaction mixture was cooled down to room temperature. 6-(3-tert-Butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl methanesulfonate (0.2 g, 0.404 mmol), methanesulfonamide (0.046 g, 0.485 mmol) and tert-amyl alcohol (1.5 mL) were added to a 40-mL reaction vial. The reaction temperature was raised to 110° C., and the contents were stirred for 14 hours. HPLC analysis of the reaction mixture showed that the titled compound was formed in 7 area % at 210 nm.

Example 4-12 Alternative preparation of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide (compound (A-1))

Palladium acetate (0.0018 g, 8.09 μmol), di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine (0.0086 g, 0.018 mmol) and water (0.6 μL, 0.032 mmol) were charged to a 40-mL reaction vial inside an inert atmosphere glove box. tert-Amyl alcohol (1.0 mL) was added, and the contents were heated to 80° C. and stirred at this temperature for 15 minutes. The reaction mixture was cooled down to room temperature. Potassium phosphate tribasic (0.094 g, 0.445 mmol), 6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl methanesulfonate (0.2 g, 0.404 mmol), methanesulfonamide (0.046 g, 0.485 mmol) and tert-amyl alcohol (1.5 mL) were added to the 40-mL reaction vial. The reaction temperature was raised to 110° C., and the contents were stirred for 14 hours. HPLC analysis of the reaction mixture showed that the titled compound was formed in 5 area % at 210 nm.

REF…

Wagner, Rolf et al, Uracil or thymine derivative for treating hepatitis C and their preparation, PCT Int. Appl., WO2009039127, 26 Mar 2009

Flentge, Charles A. et al, Preparation of anti-infective pyrimidines for treating hepatitis C,PCT Int. Appl., WO2009039134, 26 Mar 2009

Shekhar, Shashank et al,N-(6-(3-tert-Butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide as HCV polymerase inhibitor and its preparation, pharmaceutical compositions and use in the treatment of hepatitis C,PCT Int. Appl., WO2012009699, 19 Jan 2012

Shekhar, Shashank et al,Process for preparing antiviral pyrimidinylphenylnaphthalenyl sulfonamide compounds,PCT Int. Appl.,US20130224149, 29 Aug 2013

Shekhar, Shashank et al,Preparation and use of phosphine ligands for catalytic reactions,U.S. Pat. Appl. Publ., US20130217876, 22 Aug 2013

Want to know everything on vir series

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http://medcheminternational.blogspot.in/p/vir-series-hep-c-virus.html

Reference

^ “FDA approves Viekira Pak to treat hepatitis C”. Food and Drug Administration. December 19, 2014.
Gentile I, Buonomo AR, Borgia G (2014). “Dasabuvir: A Non-Nucleoside Inhibitor of NS5B for the Treatment of Hepatitis C Virus Infection”. Rev Recent Clin Trials. PMID 24882169.
https://uu.diva-portal.org/smash/get/diva2:787019/FULLTEXT01.pdf

Dasabuvir
Systematic (IUPAC) name

N-{6-[5-(2,4-Dioxo-3,4-dihydro-1(2H)-pyrimidinyl)-2-methoxy-3-(2-methyl-2-propanyl)phenyl]-2-naphthyl}methanesulfonamide
Clinical data
Trade names	Viekira Pak (withombitasvir/paritaprevir/ritonavirtablets), Exviera
AHFS/Drugs.com	viekira-pak
Pregnancy category	US: B (No risk in non-human studies)
Legal status
Legal status	US: ℞-only
Identifiers
CAS Number	1132935-63-7
ATC code	J05AX16 (WHO)
ChemSpider	29776744
ChEBI	CHEBI:85182
ChEMBL	CHEMBL3137312
Synonyms	ABT-333
Chemical data
Formula	C₂₆H₂₇N₃O₅S
Molar mass	493.58 g/mol

///////////////////Dasabuvir sodium, Exviera, FDA 2014, Hepatitis C treatment, Dasabuvir

[Na+].COc1c(cc(cc1C(C)(C)C)N2C=CC(=O)[N-]C2=O)c3ccc4cc(NS(=O)(=O)C)ccc4c3

Molfile	Download MolFile
Canonical SMILES	COc1c(cc(cc1C(C)(C)C)N2C=CC(=O)NC2=O)c3ccc4cc(NS(=O)(=O)C)cc … Download SMILES

FDA Approves Epanova (omega-3-carboxylic acids) for the Treatment of Severe Hypertriglyceridemia

May 7, 2014 3:27 am / Leave a comment

FDA Approves Epanova (omega-3-carboxylic acids) for the Treatment of Severe Hypertriglyceridemia

Tuesday, 6 May 2014 — AstraZeneca today announced that the US Food and Drug Administration (FDA) has approved Epanova (omega-3-carboxylic acids) as an adjunct to diet to reduce triglyceride levels in adults with severe hypertriglyceridemia (triglyceride levels greater than or equal to 500 mg/dL).
Epanova is the first FDA approved prescription omega-3 in free fatty acid form. The dosage of Epanova is 2 grams (2 capsules) or 4 grams (4 capsules), making it the first prescription omega-3 to have a dosing option as few as two capsules once a day, with or without food.http://www.drugs.com/newdrugs/fda-approves-epanova-omega-3-carboxylic-acids-severe-hypertriglyceridemia-4038.html?utm_source=ddc&utm_medium=email&utm_campaign=Today%27s+news+summary+-+May+6%2C+2014 AT DRUGS.COM

old cut paste

LONDON, Sept. 18, 2013 – AstraZeneca today announced that the US Food and Drug Administration (FDA) has accepted for review a New Drug Application (NDA) for EpanovaTM, an investigational compound for the treatment for patients with severe hypertriglyceridaemia (triglyceride levels greater than or equal to 500mg/dL). The NDA submission for Epanova was filed by Omthera Pharmaceuticals, now a wholly-owned subsidiary of AstraZeneca, as a 505(b)(1) application in July 2013. The Prescription Drug User Fee Act (PDUFA) goal date for the FDA is 5 May 2014.http://www.pharmalive.com/fda-accepts-astrazeneca-nda-for-epanova

FDA Approves Zykadia, Ceritinib, LDK378 for ALK-Positive NSCLC

April 30, 2014 4:05 am / Leave a comment

Ceritinib (LDK378)

mw 558.14, C28H36ClN5O3S, CAS 1032900-25-6

NVP-LDK378, NVP-LDK378-NX

Novartis Ag innovator

5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl) phenyl)pyrimidine-2,4-diamine

5-chloro-N-(2-isopropoxy-5-methyl-4- (piperidin-4-ylphenyl)-N-2-(isopropylsulfonyl)phenyl)-2,4-diamine

5-Chloro-N2-[5-methyl-4-(piperidin-4-yl)-2-(propan-2-yloxy)phenyl]-N4-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine

LDK378 dihydrochloride

CAS No: 1380575-43-8

5-chloro-N-(2-isopropoxy-5-methyl-4- (piperidin-4-ylphenyl)-N-2-(isopropylsulfonyl)phenyl)-2,4-diamine di-hydrochloride salt.

LDK378 is a highly selective inhibitor of an important cancer target, anaplastic lymphoma kinase (ALK)

Ceritinib (LDK378) a selective inhibitor of the cancer target anaplastic lymphoma kinase (ALK), shows a marked clinical response in patients with ALK+ non-small cell lung cancer (NSCLC) during the 49th Annual Meeting of the American Society of Clinical Oncology (ASCO) on June 3, 2013. FDA designated LDK378 as Breakthrough Therapy in March, 2013. A regulatory application was submitted in January 2014 in the US for LDK378 (ceritinib). see current status………….

April 29, 2014

Acting 4 months ahead of schedule, the FDA has granted an accelerated approval to ceritinib (Zykadia; LDK378) as a treatment for patients with ALK-positive metastatic non-small cell lung cancer (NSCLC) following treatment with crizotinib (Xalkori), based on a single-arm clinical trial demonstrating a durable improvement in overall response rates (ORR).

The approval for the second-generation ALK inhibitor was supported by results from an analysis of 163 patients treated with single-agent ceritinib at 750 mg daily following progression on crizotinib. In these select patients, the ORR was 54.6% with a 7.4-month median duration of response, according to data submitted to the FDA by Novartis, the company developing the drug. Based on these findings, the FDA granted ceritinib a Breakthrough Therapy designation, Priority Review, and orphan product designation.

“Today’s approval illustrates how a greater understanding of the underlying molecular pathways of a disease can lead to the development of specific therapies aimed at these pathways,” Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a statement. “It also demonstrates the FDA’s commitment to working cooperatively with companies to expedite a drug’s development, review and approval, reflecting the promise of the breakthrough therapy designation program.”

In the study that was the basis for the approval, the primary endpoint was ORR by RECIST criteria with a secondary outcome measure of duration of response. Treatment with ceritinib resulted in an ORR of 54.6% by investigator assessment with a median duration of response of 7.4 months. By blinded independent central review, the ORR was 43.6% and the duration of response was 7.1 months.

Earlier this year, results from a dose escalation study that examined ceritinib in 130 patients who were untreated or refractory to crizotinib were published in the New England Journal of Medicine. In this analysis for patients who received doses of at least 400 mg (n = 114), the ORR was 58%. Patients who had progressed on crizotinib (n = 80) experienced an ORR of 56% and those who were crizotinib-naïve (n =34) had an ORR of 62%.

The median progression-free survival was 7.0 months and the median duration of response was 8.2 months (95% CI; 6.9-11.4). Additionally, responses were seen in patients with untreated metastatic brain lesions who progressed on prior therapy with crizotinib, the authors of the study noted.

The most frequent adverse events were nausea (82%), diarrhea (75%), vomiting (65%), fatigue (47%) and increased alanine aminotransferase levels (35%). These adverse events were generally mild and resolved when treatment stopped or the dose was reduced.

The most common grade 3 or 4 drug-related adverse events were increased alanine aminotransferase levels (21%), increased aspartate aminotransferase levels (11%), diarrhea (7%) and increased lipase levels (7%), all of which were reversible upon treatment discontinuation.

“Zykadia represents an important treatment option for ALK-positive NSCLC patients who relapse after starting initial therapy with crizotinib,” Alice Shaw, MD, PhD, of the Massachusetts General Hospital (MGH) Cancer Center, lead author of the report, said in a statement. “This approval will affect the way we manage and monitor patients with this type of lung cancer, as we will now be able to offer them the opportunity for continued treatment response with a new ALK inhibitor.”

Two phase III studies are enrolling patients to further explore the efficacy and safety of ceritinib in patients with ALK-positive NSCLC. These studies will likely act as confirmation for the accelerated approval. In the first, ceritinib will be compared with chemotherapy in untreated patients with ALK-rearranged NSCLC (NCT01828099). The second will compare ceritinib to chemotherapy in ALK-positive patients with NSCLC following progression on chemotherapy and crizotinib (NCT01828112).

“The approval of Zykadia less than three and a half years after the first patient entered our clinical trial exemplifies what is possible with a highly focused approach to drug development and strong collaboration,” Alessandro Riva, MD, president of Novartis Oncology ad interim and global head of Oncology Development and Medical Affairs, said in a statement. “The dedication of clinical investigators, patients, the FDA and others has enabled us to bring this medicine to patients in need as swiftly as possible.”

Chemical Synthesis of Ceritinib_LDK378-ALK inhibitor-Lung Cancer-Novartis

Nitration of 2-chloro-4-fluoro-1-methylbenzene with KNO3 in the presence of H2SO4 gives 1-chloro-5-fluoro-2-methyl-4-nitrobenzene , which upon condensation with isopropyl alcohol in the presence of Cs2CO3 in 2-PrOH at 60 °C yields 5-isopropoxy-2-methyl-4-nitrobenzene .

Suzuki coupling of chloride with 4-pyridineboronic acid in the presence of Pd2dba3, K3PO4 and SPhos in dioxane/water at 150 °C (microwave irradiation) provides 4-(5-isopropoxy-2-methyl-4-nitrophenyl)pyridine , which is then subjected to global reduction using H2 over PtO2 in the presence of TFA in AcOH to afford 2-isopropoxy-5-methyl-4-piperidin-4-ylaniline .

N-Protection of piperidine with Boc2O in the presence of Et3N in CH2Cl2 furnishes the corresponding carbamate (VIII), which upon Buchwald-Hartwig cross coupling with 2,5-dichloropyrimidine derivative (prepared by condensation of 2-(isopropylsulfonyl)aniline and 2,4,5-trichloropyrimidine in the presence of NaH in DMSO/DMF) in the presence of Pd(OAc)2, Xantphos and Cs2CO3 in THF affords Boc-protected ceritinib . Finally, removal of Boc-group in compound using TFA in CH2Cl2 furnishes the target compound ceritinib

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Anaplastic lymphoma kinase (ALK), a member of the insulin receptor superfamily of receptor tyrosine kinases, has been implicated in oncogenesis in hematopoietic and non- hematopoietic tumors. The aberrant expression of full-length ALK receptor proteins has been reported in neuroblastomas and glioblastomas; and ALK fusion proteins have occurred in anaplastic large cell lymphoma. The study of ALK fusion proteins has also raised the possibility of new therapeutic treatments for patients with ALK-positive malignancies. (Pulford et al., Cell. MoI. Life Sci. 61:2939-2953 (2004)).

Focal Adhesion Kinase (FAK) is a key enzyme in the integrin-mediated outside-in signal cascade (D. Schlaepfer et al., Prog Biophys MoI Biol 1999, 71, 43578). The trigger in the signal transduction cascade is the autophosphorylation of Y397. Phosphorylated Y397 is a SH2 docking site for Src family tyrosine kinases; the bound c-Src kinase phosphorylates other tyrosine residues in FAK. Among them, phsophorylated Y925 becomes a binding site for the SH2 site of Grb2 small adaptor protein. This direct binding of Grb2 to FAK is one of the key steps for the activation of down stream targets such as the Ras-ERK2/MAP kinase cascade.

Zeta-chain-associated protein kinase 70 (ZAP-70), a member of the protein tyrosine kinase family, is of potential prognostic importance in chronic lymphocytic leukemia (CLL). ZAP-70, known to be of importance in T and NK cell signaling but absent in normal peripheral B cells, is expressed in the majority of the poorer prognosis unmutated CLL and absent in most cases with mutated IgVH genes. ZAP-70 is also expressed in a minority of other B cell tumors. (Orchard et al., Leuk. Lymphoma 46:1689-98 (2005)). [0006] Insulin- like growth factor (IGF-I) signaling is highly implicated in cancer, with the IGF-I receptor (IGF-IR) as the predominating factor. IGR-IR is important for tumor transformation and survival of malignant cells, but is only partially involved in normal cell growth. Targeting of IGF-IR has been suggested to be a promising option for cancer therapy. (Larsson et al., Br. J. Cancer 92:2097-2101 (2005)).

Because of the emerging disease-related roles of ALK, FAK, ZAP-70 and IGF-IR, there is a continuing need for compounds which may be useful for treating and preventing a disease which responds to inhibition of ALK, FAK, ZAP-70 and/or IGF-IR

The compound 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2- (propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine, in the form of a free base, of formula

(I)

is an anaplastic lymphoma kinase (ALK) inhibitor, a member of the insulin receptor super family of receptor tyrosine kinases. Compound I was originally described in WO 2008/073687 Al as Example 7, compound 66. WO 2008/073687 Al , however, provides no information about crystalline forms of 5-

Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)- phenyl]-pyriniidine-2, 4-diamine or its corresponding salts. Crystalline forms of 5-Chloro-N2- (2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]- pyrimidine-2, 4-diamine have been discovered, which are useful in treating diseases which respond to inhibition of anaplastic lymphoma kinase activity, focal adhesion kinase (FAK), zeta- chain-associated protein kinase 70 (ZAP-70) insulin-like growth factor (IGF-1 or a

combination thereof. The crystalline forms exhibit new physical properties that may be exploited in order to obtain new pharmacological properties, and that may be utilized in the drug product development of 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2- (propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine.

…………………….

WO 2008073687

http://www.google.com/patents/WO2008073687A2?cl=en

Example 7

5-Chloro-N²-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N⁴-r2-(propane-2-sulfonyl)- phenvH-pyrimidine-2,4-diamine (66)

1 : 4-(5-Isopropoxv-2-methvl-4-nitro-phenyl)-pvridine

[0111] 4-Pyridineboronic acid (147 mg, 1.20 mmol, 1.1 equiv.) is dissolved in a 2:1 v/v mixture of dioxane and H₂O (15 mL) and N₂ is bubbled through for 5 minutes. Tris(dibenzylidene acetone)dipalladium (0) (100 mg, 0.109 mmol, 0.1 equiv.), 2- dicyclohexylphosphine-2′-6′-dimethoxy biphenyl (112 mg, 0.272 mmol, 0.25 equiv.), 1-chloro- 5-isopropoxy-2-methyl-4-nitro-benzene (Intermediate 4, 250 mg, 1.09 mmol, 1.0 equiv.) and K₃PO₄ (462 mg, 2.18 mmol, 2.0 equiv.) are added under a N₂ blanket. The reaction vessel is sealed and heated with microwave irradiation to 150 ⁰C for 20 min. After cooling to room temperature, the reaction is diluted with ethyl acetate and washed with 1 N aqueous NaOH (2x), the organic layer is then dried over Na₂SO₄ and filtered. After concentration, the crude product is purified by silica gel chromatography (gradient from hexanes to 30% ethyl acetate in hexanes) to give 4-(5-Isopropoxy-2-methyl-4-nitro-phenyl)-pyridine as a brown solid: ESMS m/z 273.1 (M + H⁺).

Steps 2 and 3 : 4-(4-Amino-5-isopropoxy-2-methyl-phenyl)-piperidine-l-carboxylic acid tert- butyl ester

[0112] 4-(5-Isopropoxy-2-methyl-4-nitro-phenyl)-pyridine from the previous step(438 mg, 1.61 mmol) dissolved in acetic acid (30 mL) is treated with TFA (0.24 mL, 3.22 mmol) and PtO₂ (176 mg, 40% w/w). The reaction mixture is vigorously stirred under 1 atm. H₂ for 36 hours. The reaction mixture is filtered and the filtrate is concentrated under vacuum. The resulting residue is diluted with ethyl acetate and washed with 1 N aqueous NaOH (2x), the organic layer is then dried over Na₂SO₄ and filtered. After concentration, the crude product (391 mg) is dissolved in anhydrous CH₂Cl₂ (30 mL). TEA is added (0.44 mL, 3.15, 2 equiv.) followed by Boc₂O (344 mg, 1.57 equiv, 1 equiv.). The reaction is stirred at room temperature for 30 min. The reaction is concentrated under vacuum. The resulting residue is purified by silica gel chromatography (gradient from hexanes to 30% ethyl acetate in hexanes) to give 4-(4-amino-5- isopropoxy-2-methyl-phenyl)-piperidine-l-carboxylic acid tert-butyl ester as a sticky foam: ESMS m/z 293.1 (M-?Bu+H)⁺.

Steps 4 and 5

[0113] 4-(4-Amino-5-isopropoxy-2-methyl-phenyl)-piperidine-l-carboxylic acid tert-butyl ester (170 mg, 0.488 mmol) from the previous step, (2,5-Dichloro-pyrimidin-4-yl)-[2-(propane- 2-sulfonyl)-phenyl]-amine (Intermediate 2, 169 mg, 0.488 mmol, 1 equiv.), xantphos (28 mg, 0.049 mmol, 0.1 equiv.), palladium acetate (5.5 mg, 0.024 mmol, 0.05 equiv.), and Cs₂CO₃ (477 mg, 1.46 mmol, 3 equiv.) are dissolved in anhydrous THF (6 mL). N₂ is bubbled through the reaction mixture for 5 minutes and then the reaction vessel is sealed and heated with microwave irradiation to 150 ⁰C for 20 min. The reaction is filtered and the filtrate concentrated under vacuum. After concentration, the crude product is purified by silica gel chromatography (gradient from hexanes to 30% ethyl acetate in hexanes) to give 4-(4-{5-chloro-4-[2-(propane-2- sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-5-isopropoxy-2-methyl-phenyl)-piperidine-l- carboxylic acid tert-butyl ester as a yellow film: ESMS m/z 658.3 (M + H⁺). This product (105 mg, 0.160 mmol) is dissolved in CH₂Cl₂ (3 mL) and treated with TFA (3 mL). After 45 min., the reaction is concentrated under vacuum. 1 N HCl in Et₂O (5 mL x 2) is added causing the product HCl salt to precipitate. The solvent is removed by decantation. The resulting 5- Chloro-N²-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N⁴-[2-(propane-2-sulfonyl)- phenyl]-pyrimidine-2,4-diamine (66) is dried under high vacuum, generating an off-white powder: ¹H NMR (400 MHz, DMSO-J₆+ trace D₂O) δ 8.32 (s, IH), 8.27 (d, IH), 7.88 (d, IH), 7.67 (dd, IH), 7.45 (dd, IH), 7.42 (s, IH), 6.79 (s, IH), 4.56-4.48 (m, IH), 3.49-3.32 (m, 3H), 3.10-2.91 (m, 3H), 2.09 (s, 3H), 1.89-1.77 (m, 4H), 1.22 (d, 6H), 1.13 (d, 6H); ESMS m/z 558.1 (M + H⁺).

Figure imgf000046_0001 66

……………………..

WO 2012082972

http://www.google.com/patents/WO2012082972A1

EXAMPLE 1

Preparation of Form A of 5-chloro-N-(2-isopropoxy-5-methyl-4-(piperidin-4-ylphenyl)-N-2- (isopropylsulfonyl phenyl)-2^-diamine

5-chloro-N-(2-isopropoxy-5-methyl-4-(piperidin-4-ylphenyl)-N-2-(isopropylsulfonyl)phenyl)- 2,4-diamine di-hydrochloride salt

The compound 2-isopropoxy-5-methyl-4-(piperdin-4-yl) aniline dihydrochloride (33.00 g, 85.25 mmol) and 2,5-dichloro-N-(2-(isopropyl sulfonyl )phenyl)pyrimidin-4-amine (32.53 g) was added to a 3 -necked 500-mL round-bottomed flask equipped with mechanical stirring, thermocouple, reflux condenser and N₂ inlet-outlet. A solvent, 2-propanol (255.0 g, 325 mL), was added and the mixture to heated to reflux at 82±2 °C and stirred for at least 14 hours. The mixture was cooled to 22±3 °C over 1 hour and stirred at 22±3 °C for 3 hours. The resulting solids were filtered and rinsed with 3 x 40 g (3 x 51 mL) of 2-propanol. The solids were dried at 50±5 °C/10 mbar for 16 hours to yield 44.63 g of 5-chloro-N-(2-isopropoxy-5-methyl-4- (piperidin-4-ylphenyl)-N-2-(isopropylsulfonyl)phenyl)-2,4-diamine di-hydrochloride salt. Chemical Purity (as determined by HPLC): 97.3%. Corrected yield: 71.6%. LOD = 11.60%. The dihydrochloride salt was recrystallized using acetone:water (10:l,v/v). Chemical Purity (as determined by HPLC): 98.8%.

…………….

J Med Chem 2013, 56(14): 5675

http://pubs.acs.org/doi/abs/10.1021/jm400402q

Synthesis of 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-ylphenyl)-N4-[2-(propane-2-sulfonyl)phenyl]pyrimidine-2,4-diamine 15b

4-(4-Amino-5-isopropoxy-2-methylphenyl)piperidine-1-carboxylic acid tert-butyl ester (13b, 170 mg, 0.488 mmol), (2,5-dichloropyrimidin-4-yl)-[2-(propane-2-sulfonyl)phenyl]amine (9a, 169 mg, 0.488 mmol, 1 equiv), Xantphos (28 mg, 0.049 mmol, 0.1 equiv), Pd(OAc)₂ (5.5 mg, 0.024 mmol, 0.05 equiv), and Cs₂CO₃ (477 mg, 1.46 mmol, 3 equiv) were dissolved in anhydrous THF (6 mL). N₂ was bubbled through the reaction mixture for 5 min, and then the reaction vessel was sealed and heated under microwave irradiation to 150 °C for 20 min. The mixture was filtered and the filtrate concentrated under vacuum. After concentration, the crude product was purified by silica gel chromatography (gradient from hexanes to 30% ethyl acetate in hexanes) to give 4-(4-{5-chloro-4-[2-(propane-2-sulfonyl)phenylamino]pyrimidin-2-ylamino}-5-isopropoxy-2-methylphenyl)piperidine-1-carboxylic acid tert-butyl ester as a yellow film (105 mg) which was directly used in the next step: ESMS m/z 658.3 (M + H⁺). This product (105 mg, 0.160 mmol) was dissolved in CH₂Cl₂ (3 mL) and treated with TFA (3 mL). After 45 min, the mixture was concentrated under vacuum. Then 1 N HCl in Et₂O (5 mL × 2) was added causing the product HCl salt to precipitate. The solvent was removed by decantation.

The resulting 5-chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-ylphenyl)-N4-[2-(propane-2-sulfonyl)phenyl]pyrimidine-2,4-diamine (15b) was dried under high vacuum, generating an off-white powder (101 mg, 35% yield):

¹H NMR (400 MHz, DMSO-d₆ + trace D₂O) δ 8.32 (s, 1H), 8.27 (d, 1H), 7.88 (d, 1H), 7.67 (dd, 1H), 7.45 (dd, 1H), 7.42 (s, 1H), 6.79 (s, 1H), 4.56–4.48 (m, 1H), 3.49–3.32 (m, 3H), 3.10–2.91 (m, 3H), 2.09 (s, 3H), 1.89–1.77 (m, 4H), 1.22 (d, 6H), 1.13 (d, 6H);

ESMS m/z 558.1 (M + H⁺).

Anal. Calcd for C₂₈H₃₆ClN₅O₃S: C, 60.25; H, 6.50; Cl, 6.35; N, 12.55; O, 8.60; S, 5.75. Found: C, 60.29; H, 6.45; N, 12.55 (analytical sample of free base).

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Organic Impurities in TR-701 FA Drug Substance
Impurity
‘Name’	Structure and Chemical Name

Rx600013 ‘Des-methyl TR- 701’
	dihydrogen ((5R)-3-{3-fluoro-4-[6-(2H-1,2,3,4-tetrazol-5-
	yl)-3-pyridinyl]phenyl}-2-oxo-1,3-oxazolan-5-yl)methyl
	phosphate

Rx600024 ‘Pyrophosphate’
	trihydrogen ((5R)-3-{3-fluoro-4-[6-(1-methyl-1H-1,2,3,4-
	tetraazol-5-yl)-3-pyridinyl]phenyl}-2-oxo-1,3-oxazolan-5-
	yl)methyl pyrophosphate

Rx600014 ‘Ring opened’
	dihydrogen 3-{3-fluoro-4-[6-(2-methyl-2H-1,2,3,4-tetraazol-5-
	yl)-3-pyridinyl]aniline}-2-hydroxypropyl phosphate

Rx600023 ‘Me-isomer’
	dihydrogen ((5R)-3-{3-fluoro-4-[6-(1-methyl-1H-1,2,3,4-
	tetraazol-5-yl)-3-pyridinyl]phenyl}-2-oxo-1,3-oxazolan-5-
	yl)methyl phosphate

Rx600025 ‘Overalkylated- phosphorylated impurity’
	(R)-1-((3-(3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-
	yl)pyridin-3-yl)phenyl)-2-oxooxazolidin-5-yl)methoxy)-3-
	hydroxypropan-2-yl dihydrogen phosphate;
	(R)-3-((3-(3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-
	yl)pyridin-3-yl)phenyl)-2-oxooxazolidin-5-yl)methoxy)-2-
	hydroxypropyl dihydrogen phosphate

Rx600020 ‘Dimer impurity’
	dihydrogen bis-O-O′-[(5R)-3-{3-fluoro-4-[6-(2-methyl-
	2H-1,2,3,4-tetrazol-5-yl)-3-pyridinyl]phenyl}-2-oxo-1,3-
	oxazolidin-5-yl]methyl pyrophosphate

Rx600026 “Chloro”
	(R)-5-(chloromethyl)-3-(3-fluoro-4-(6-(2-methyl-2H-
	tetrazol-5-yl)pyridin-3-yl)phenyl)oxazolidin-2-one

Rx600001 TR-700
	5R)-3-{3-Fluoro-4-[6-(2-methyl-2H-1,2,3,4-tetrazol-5-yl)-
	pyridin-3-yl]-phenyl}-5-hydroxymethyl-1,3-oxazolidin-2-one

Rx600022 ‘Bis phosphate’
	hydrogen bis-O-O′-[(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-1,2,3,4-
	tetrazol-5-yl)-3-pyridinyl]phenyl}-2-oxo-1,3-oxazolidin-5-yl]methyl
	phosphate

Rx600042
	3-{[(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-
	yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl]methoxy}-2-hydroxypropyl
	[(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-
	yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl]methyl hydrogen phosphate

Rx600043
	2-{[(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-
	yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl]methoxy}-1-hydroxyethyl
	[(5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-
	yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl]methyl hydrogen phosphate

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Dasabuvir sodium anhydrous RN: 1132940-11-4 UNII: R2M8F5TK9T

Methanesulfonamide, N-(6-(5-(3,4-dihydro-2,4-dioxo-1(2H)-pyrimidinyl)-3-(1,1-dimethylethyl)-2-methoxyphenyl)-2-naphthalenyl)-, sodium salt (1:1)

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Dasabuvir sodium anhydrous
RN: 1132940-11-4
UNII: R2M8F5TK9T