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Commentary Regarding new USP Chapters and for Particulate Matter Guidance

September 11, 2014 5:03 am / Leave a comment

DRUG REGULATORY AFFAIRS INTERNATIONAL

Commentary Regarding new USP Chapters and for Particulate Matter Guidance
There are new chapters in the USP regarding testing of subvisible particles. Chapter Subvisible Particulate Matter in Therapeutic Protein Injections <787> became official August 1, 2014. The informational chapter <1787> was developed to support chapter <787> and will be published in USP 38 in November and become official on May 1, 2015. Read more.

http://www.gmp-compliance.org/enews_4513_Commentary-Regarding-new-USP-Chapters–787–and–1787–for-Particulate-Matter-Guidance_8398,8427,9086,Z-PEM_n.html

During the current (2010-2015) USP Expert Committee cycle, the Dosage Forms Expert Committee has developed both new and revised general chapters that provide guidance on particulate matter content of injectable drug products. For visible particles, methods are based upon human detection sensitivity as described in Visible Particulates in Injections <790>, which applies to all sterile injectable dosage forms. For subvisible particle content, which is based upon instrumental determination, new particulate matter guidance has been established specifically for sterile injectable biotherapeutic products.

The new…

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IMATINIB

September 10, 2014 12:46 pm / 1 Comment on IMATINIB

Imatinib

CAS No:- [152459-95-5]

IUPAC Name:- 4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]benzamide

M. P.:- 211-213 °C

MW: 493.604

4-[(4-methylpiperazin-1-yl)methyl]-N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide

-[(4-methylpiperazin-1-yl)methyl]-N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide

N-(4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)-4-((4-methylpiperazin-1-
yl)methyl)benzamide

Imatinib (INN), marketed by Novartis as Gleevec (Canada, South Africa and the USA) or Glivec (Australia, Europe and Latin America), and sometimes referred to by its investigational name STI-571, is a tyrosine-kinase inhibitor used in the treatment of multiple cancers, most notably Philadelphia chromosome-positive (Ph⁺) chronic myelogenous leukemia (CML).^[1]

Like all tyrosine-kinase inhibitors, imatinib works by preventing a tyrosine kinase enzyme, in this case BCR-Abl, fromphosphorylating subsequent proteins and initiating the signalling cascade necessary for cancer growth and survival, thus preventing the growth of cancer cells and leading to their death by apoptosis.^[2] Because the BCR-Abl tyrosine kinase enzyme exists only in cancer cells and not in healthy cells, imatinib works as a form of targeted therapy—only cancer cells are killed through the drug’s action.^[3] In this regard, imatinib was one of the first cancer therapies to show the potential for such targeted action, and is often cited as a paradigm for research in cancer therapeutics.^[4]

Imatinib has been cited as the first of the exceptionally expensive cancer drugs, costing $92,000 a year. Doctors and patients complain that this is excessive, given that its development costs have been recovered many times over, and that the costs of synthesizing the drug are orders of magnitude lower. In the USA, the patent protecting the active principle will expire on 4 January 2015 while the patent protecting the beta crystal form of the active principal ingredient will expire on 23 May 2019.^[5]

The developers of imatinib were awarded the Lasker Award in 2009 and the Japan Prize in 2012.^[6]^[7]

bcr-abl kinase (green), which causes CML, inhibited by imatinib (red; small molecule).

Medical uses

Imatinib is used to treat chronic myelogenous leukemia (CML), gastrointestinal stromal tumors (GISTs) and a number of othermalignancies.

Chronic myelogenous leukemia

The U.S. Food and Drug Administration (FDA) has approved imatinib as first-line treatment for Philadelphia chromosome-positive CML, both in adults and children. The drug is approved in multiple Philadelphia chromosome-positive cases of CML, including after stem cell transplant, in blast crisis, and newly diagnosed.^[8]

Gastrointestinal stromal tumors

The FDA first granted approval for advanced GIST patients in 2002. On 1 February 2012, imatinib was approved for use after the surgical removal of KIT-positive tumors to help prevent recurrence.^[9] The drug is also approved in unresectable KIT-positive GISTs.^[8]

Other

The FDA has approved imatinib for use in adult patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), myelodysplastic/ myeloproliferative diseases associated with platelet-derived growth factor receptor gene rearrangements, aggressive systemic mastocytosis without or an unknown D816V c-KIT mutation, hypereosinophilic syndrome and/or chronic eosinophilic leukemia who have the FIP1L1-PDGFRα fusion kinase (CHIC2 allele deletion) or FIP1L1-PDGFRα fusion kinase negative or unknown, unresectable, recurrent and/or metastaticdermatofibrosarcoma protuberans.^[8] On 25 January 2013, Gleevec was approved for use in children with Ph+ ALL.^[10]

For treatment of progressive plexiform neurofibromas associated with neurofibromatosis type I, early research has shown potential for using the c-KIT tyrosine kinase blocking properties of imatinib.^[11]^[12]^[13]^[14]

Legal challenge to generics

In 2007, imatinib became a test case through which Novartis challenged India’s patent laws. A win for Novartis would make it harder for Indian companies to produce generic versions of drugs still manufactured under patent elsewhere in the world. Doctors Without Borders argues a change in law would make it impossible for Indian companies to produce cheap generic antiretrovirals (anti-HIV medication), thus making it impossible for Third World countries to buy these essential medicines.^[43] On 6 August 2007, the Madras High Court dismissed the writ petition filed by Novartis challenging the constitutionality of Section 3(d) of Indian Patent Act, and deferred to the World Trade Organization (WTO) forum to resolve the TRIPS compliance question. As of 2009 India has refused to grant patent exclusivity..

On April 01, 2013 Supreme Court of India dismissed the plea of Novartis for the grant of patent.

in germany

Mechanism of action

Imatinib
Drug mechanism
Crystallographic structure of tyrosine-protein kinase ABL (rainbow colored, N-terminus = blue, C-terminus = red) complexed with imatinib (spheres, carbon = white, oxygen = red, nitrogen = blue).^[31]
Therapeutic use	chronic myelogenous leukemia
Biological target	ABL, c-kit, PDGF-R
Mechanism of action	Tyrosine-kinase inhibitor
External links
ATC code	L01XE01
PDB ligand id	STI: PDBe, RCSB PDB
LIGPLOT	1iep

Imatinib is a 2-phenyl amino pyrimidine derivative that functions as a specific inhibitor of a number of tyrosine kinase enzymes. It occupies the TK active site, leading to a decrease in activity.

There are a large number of TK enzymes in the body, including the insulin receptor. Imatinib is specific for the TK domain inabl(the Abelson proto-oncogene), c-kit and PDGF-R (platelet-derived growth factorreceptor).

In chronic myelogenous leukemia, the Philadelphia chromosome leads to a fusion protein of abl with bcr(breakpoint cluster region), termed bcr-abl. As this is now aconstitutively active tyrosine kinase, imatinib is used to decrease bcr-abl activity.

The active sites of tyrosine kinases each have a binding site for ATP. The enzymatic activity catalyzed by a tyrosine kinase is the transfer of the terminal phosphate from ATP to tyrosine residues on its substrates, a process known as protein tyrosinephosphorylation. Imatinib works by binding close to the ATP binding site of bcr-abl, locking it in a closed or self-inhibited conformation, and therefore inhibiting the enzyme activity of the protein semi-competitively.^[32] This fact explains why many BCR-ABL mutations can cause resistance to imatinib by shifting its equilibrium toward the open or active conformation.^[33]

Imatinib is quite selective for bcr-abl – it does also inhibit other targets mentioned above (c-kit and PDGF-R), but no other knowntyrosine kinases. Imatinib also inhibits the abl protein of non-cancer cells but cells normally have additional redundant tyrosine kinases which allow them to continue to function even if abl tyrosine kinase is inhibited. Some tumor cells, however, have a dependence on bcr-abl.^[34] Inhibition of the bcr-abl tyrosine kinase also stimulates its entry in to the nucleus, where it is unable to perform any of its normal anti-apoptopic functions.^[35]

The Bcr-Abl pathway has many downstream pathways including the Ras/MapK pathway, which leads to increased proliferation due to increased growth factor-independent cell growth. It also affects the Src/Pax/Fak/Rac pathway. This affects the cytoskeleton, which leads to increased cell motility and decreased adhesion. The PI/PI3K/AKT/BCL-2 pathway is also affected. BCL-2 is responsible for keeping the mitochondria stable; this suppresses cell death by apoptosis and increases survival. The last pathway that Bcr-Abl affects is the JAK/STAT pathway, which is responsible for proliferation.^[36]

synthesis

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Imatinib is known as an inhibitor of protein-tyrosine kinase and is indicated for the treatment of chronic myeloid leukemia (CML). Imatinib also has potential for the treatment of various other cancers that express these kinase including acute lymphocyte leukemia and certain solid tumors. It can also be used for the treatment of atherosclerosis, thrombosis, restenosis, or fibrosis. Thus, imatinib can also be used for the treatment of non-malignant diseases. Imatinib is usually administered orally in the form of a suitable salt, e.g., in the form of imatinib mesylate.

The chemical name of Imatinib is 4-(4-methyl piperazine -1- methyl) -N-4-methyl-3-[4- (3- pyridyl) pyrimidine-2-amino] – benzamide and is represented by the following structural formula:

(Imatinib)

Imatinib Mesylate is an inhibitor of signal transduction (STI571) invented by Novartis AG after 7 years of hard work; it is the first inhibitor of cancer signal transduction ratified in the whole world. It is sold by Novartis as Gleevec capsules containing imatinib mesylate in amounts equivalent to 100 mg or 400 mg of imatinib free base.

Imatinib Mesylate is the rare drug in America, European Union and Japan. In May 10, 2001, it was ratified by American Food and Drug Administration (FDA) to treat the chronic myelogenous leukemia patients. EP0564409 (US5521 184) describes the process for the preparation of imatinib and the use thereof, especially as an anti tumour agent.

There are generally two synthetic routes for synthesis of Imatinib, suitable for the industrial production. One synthetic process as described in scheme-I comprises using 2-methyl-5-nitroaniline as the raw material which is reacted with cyanamide to obtain guanidine; cyclization reaction with 3-dimethylamino-l-(3-pyridyl)-2-propylene-l- ketone; reduction step of nitro to amine and condensation reaction with 4- (Chloromethyl)benzoyl chloride and N-methylpiperazidine to obtain Imatinib (WO 2004/108669). -I

Scheme-2 describes the successful process for the synthesis of Imatinib using 4-methyl-3- nitroanilines as the raw material, comprising reacting 4-methyl-3-nitroanilines with 4- (Chloromethyl)benzoyl chloride and N-methyl piperazidine in turns; followed by reduction of nitro group to amino group; then reaction with cyanamide to obtain guanidine; finally cyclization reaction with 3- dimethyl amino- 1 -(3- pyridyl)-2- propylene-1 -ketone to obtain Imatinib (WO 03/066613). The said PCT application discloses the use of 4-4-(methyl piperazin-l-ylmethyl)-benzoic acid methyl ester as one of the raw material but rest of the reactants are different from that of N-(5-amino -2- methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine in presence of trimethyl aluminium.

Scheme-2

Common feature of the processes for preparing imatinib according to (WO 2004/108669) and (WO03/066613) lies in use of cyanamide as a reagent. The main difference between the two routes is that the reaction sequence of cyclization of pyrimidine chain is different. Example 10 of PCT International Publication no. WO 2003/066613 is less applicable to industrial purposes. These include the reaction between N-(3-bromo-4-methyl-phenyl)-4- (4-methyl-piperazin-l -ylmethyl)-benzamide and 4-(3-pyridyl)-2-pyrimidineamine which uses a mixture of rac-BINAP (a phosphine oxide catalyst) and Pd₂ (dba)₃*CHCl₃. These catalysts are very expensive, therefore, their use is unfit for commercial production.

CN1630648A describes a process comprising reaction of 3- bromine-4- methyl aniline with 4-(4-methyl-piperazin- methyl) methyl benzoate in presence of trimethyl-Aluminum to obtain N-(4-methyl-3-bromobenzene)-4-(4-methyl-piperazin- 1 -methyl)-benzamide, which further reacts with 2-amino-4-(3-pyridyl)- pyrimidine in presence of palladium as catalyst to obtain Imatinib.

The drawback of the above process is the use of trimethyl-Aluminum, which is flammable and reacts severely when comes in contact with water.

CN101016293A describes another process using N-(4-methyl-3-3- aminophenyl)-4-(4- methyl-piperazin-1 -methyl)- benzamide as the raw material. The said raw material is reacted with 2-halogen-4-(3-pyridyl)- pyrimidine to obtain Imatinib.

The process disclosed in CN 101016293 A comprises use of halogenated agent, such as phosphorus oxychloride, which is used to synthesize 2-halogeno-4- methyl- (3-pyridyl) – pyridine is lachrymator and corrosive and has great influence to the surroundings. EP0564409 describes a coupling reaction between N-(5-amino -2-methylphenyl)-4-(3- pyridyl)-2-pyrimidine amine and 4-(4-methyl piperazin-l-ylmethyl)-benzoyl chloride in the presence of high quantity of pyridine to starting reactant amine N-(5-amino -2- methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine. The ratio of the pyridine to the said reactant is 138 which is equivalent to about 40 parts v/w. Use of such a large quantity of pyridine is unsafe as it is a toxic solvent according to ICH guidelines. The workup of the reaction comprises evaporation of the remaining pyridine and further processing, which finally involves chromatography for purification, which is highly undesirable on industrial scale because it is expensive and time consuming.

US2006/0149061 and US20060223817 also discloses a similar synthetic approach comprising the use of similar pyridine /starting amine ratio (140 equivalents which is equals about 41 parts v/w). The product obtained is purified by slurring in ethyl acetate.

WO2004/074502 describes a coupling reaction between N-(5-amino -2-methylphenyl)-4- (3-pyridyl)-2-pyrimidine amine and 4-(4-methyl piperazin-l-ylmethyl)-benzoyl chloride wherein solvent like dimethyl pharmamide , dimethyl acetamide, N-methyl pyrilidinone are used as solvents instead of pyridine. However the method described in this patent application lacks an advantage in that the coupling reaction produces the hydrohalide salt of imatinib, e.g. imatinib trihydrochloride monohydrate, which has to be treated with a base in order to afford the imatinib base, thus an extra step is required. Further, conventional methods for coupling N-(5-amino -2-methylphenyl)-4-(3-pyridyl)-2- pyrimidine amine require reaction with an acid halide, e.g. 4-(4-methyl piperazin-1- ylmethyl)-benzoyl chloride, which requires an additional production step that can involve harsh and/or toxic chlorinating agent.

WO2008/1 17298 describes a coupling reaction between N-(5-amino -2-methylphenyl)-4- (3-pyridyl)-2-pyrimidine amine and 4-(4-methyl piperazin-l-ylmethyl)-benzoyl chloride in presence of a base selected from potassium carbonate, sodium carbonate, potassium or sodium hydroxide. Use of potassium carbonate as base results into the formation of Imatinib dihydrochloride which ultimately requires an additional operation of neutralization by using excessive base to get imatinib.

WO2008/136010 describes a coupling reaction between N-(5-amino -2-methylphenyl)-4- (3-pyridyl)-2-pyrimidine amine and 4-(4-methyl piperazin-l-ylmethyl)-benzoyl chloride in presence of base potassium hydroxide resulting into 78.6% yield of crude imatinib base. Preparation of crude requires imatinib hydrochloride preparation during the workup which is then basified to get base in crude form. This also describes maleate salt preparation as mode of purification which is again basified to give pure Imatinib base.

US patent application 2004/0248918 discloses a different approach using N-(5-amino -2- methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine and 4-(2-chloromethyl)-benzoyl chloride as raw material. The reaction for the preparation of Imatinib is carried out in tetrahydrofuran as a reaction solvent and in the presence of pyridine as a base. However the method described in this patent application lacks an advantage as purification of the product requires column chromatography using chloroform: methanol (3: 1 v/v), which is not suitable purification method when performing the reaction on large scale, followed by crystallizati

US patent application 2008/0103305 discloses a process comprising reacting N-(5-amino -2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine or its alkyl derivative and an acid salt of 4-[(4-methyl-l-piperazinyl)-methyl] benzoyl derivative as given below in the scheme-3 using pyridine in an amount of about 2 to 10 volumes per gram of the said amine. However the drawback associated with this process is use of pyridine especially when reaction is performed on large scale. -3

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SYNTHESIS

Inverse synthetic analysis will be divided into four imatinib into fragment A has 1,3 – parents electrical, fragment B are 1,3 – parent nuclear, fragments A and B constitute a pyrimidine ring.

Compound 4 can be obtained in two ways, benzyl bromide 1 and secondary amines 2 by SN2 reaction, or the aldehyde 3 with a secondary amine 2 by reductive amination. Sodium cyanoborohydride electron withdrawing effect of the cyano group, thereby reducing the activity of the negative hydrogen, it may be present in acidic solution. Also in the acidic conditions of aldehydes and secondary amines imine positive ions, which is higher than the activity of aldehyde reduction.This is why the reductive amination reagent with inert negative and hydrogen under acidic conditions. 4 hydrolyzed ester with thionyl chloride into the acid chloride 5 . The reaction of aniline and cyanamide dinucleophile guanidine 7 . Compound 8 and DMF-DMA reaction electrophilic reagent parents 9 , 7 , and 9 ring closure under alkaline conditions to generate 10 . Finally, reduction, amidation, and a salt of imatinib mesylate generated.

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Org. Process Res. Dev., 2012, 16 (11), pp 1794–1804

DOI: 10.1021/op300212u

http://pubs.acs.org/doi/abs/10.1021/op300212u

An efficient, economic process has been developed for the production of imatinib with 99.99% purity and 50% overall yield from four steps. Formation and control of all possible impurities is described. The synthesis comprises the condensation of N-(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine with 4-(4-methylpiperazinomethyl)benzoyl chloride in isopropyl alcohol solvent in the presence of potassium carbonate to yield imatinib base.

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Org. Biomol. Chem., 2013,11, 1766-1800

DOI: 10.1039/C2OB27003J

http://pubs.rsc.org/en/content/articlelanding/2013/ob/c2ob27003j#!divAbstract

Imatinib (1), nilotinib (2) and dasatinib (3) are Bcr-Abl tyrosine kinase inhibitors approved for the treatment of chronic myelogenous leukemia (CML). This review collates information from the journal and patent literature to provide a comprehensive reference source of the different synthetic methods used to prepare the aforementioned active pharmaceutical ingredients (API’s).

Graphical abstract: The synthesis of Bcr-Abl inhibiting anticancer pharmaceutical agents imatinib, nilotinib and dasatinib

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Organic Process Research & Development, 12(3), 490-495. DOI: 10.1021/op700270nAs an example of research aimed at industrial production one involving imatinib. This cancer drug was one of the first offspring of rational drug design and if you believe the Wikipedia page hugely expensive despite its simple appearance (no stereocenters!). A group of Northwest University researchers set out to improve the existing Novartis procedure DOI and here is how they did it.

2-acetylpyridine (1) was alkylated with the acetal of N,N-dimethylformamide 2 to enamine 3. A pyrimidine ring in 5was formed with base and reagent guanidine nitrate 4 and nitrotoluene fragment 6 was added in a Ullmann-type reaction with CuI generating secondary amine 7. The nitro group was reduced by hydrazine / FeCl₃/C to the amine which was then converted to amide 8 with acid chloride 9. The final step is addition of piperazine 10 to form imatinib11.So is this procedure an improvement on the existing method and ready-made for industrial implementation? Surely they have eradicated the use of toxic cyanamide, cumbersome sodium metal and expensive palladium but they have also introduced equally toxic hydrazine and the harmful and explosive guanidine nitrate. As a further point of criticism the final step is demonstrated on a 0.5 gram scale. If the journal Organic Process Research & Development would live up to its standards the scale would at least be a kilogram.Liu, Y., Wang, C., Bai, Y., Han, N., Jiao, J., Qi, X. (2008). A Facile Total Synthesis of Imatinib Base and Its Analogues. Organic Process Research & Development, 12(3), 490-495. DOI: 10.1021/op700270n
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Tetrahedron Lett. 2007, 48, 3455. DOI: 10.1016/j.tetlet.2007.03.033

Angelo Carotti and his group from University of Bari have developed a solid-phase synthesis of Imatinib which acts as a selective tyrosine kinase inhibitor (Tetrahedron Lett. 2007, 48, 3455. DOI: 10.1016/j.tetlet.2007.03.033). By applying microwave heating in five steps of the synthesis (preparation of linker 1, nucleophilic substitution, reduction of the nitro group, formation of guanidine and final cyclization) the total process could be accelerated. Key steps were the guanylation of aniline 2 where a higher yield and purity of product 3 could be obtained under microwave irradiation, and the final cyclization to resin bound Imatinib where the reaction time could be reduced from 20 h to 50 min. Addiotionally, resin stability was ensured due to the shorter reaction time.

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http://www.google.com/patents/EP2509973A1?cl=en

process for the preparation of imatinib, which comprises the reaction of 4-Methyl-N-(4-pyridin-3-yl-pyrimidin-2-yl)- benzene-l,3-diamine (II) also referred as N-(5-amino -2-methylphenyl)-4-(3-pyridyl)-2- pyrimidine amine with 4-(4-Methyl-piperazin-l-ylmethyl)-benzoic acid ester (III) in the presence of a base in a suitable solvent to yield substantially pure imatinib base in about 90% yield.

R is C1-C4 alkyl group The preparation of 4-Methyl-N-(4-pyridin-3-yl-pyrimidin-2-yl)-benzene-l,3-diamine (II) and 4-(4-Methyl-piperazin-l-ylmethyl)-benzoic acid ester (III) may be carried out according to prior art methods.

Compound of formula (II) can be synthesized by the process disclosed in WO2004/ 108669 comprising

reacting 2-methyl-5-nitroaniline with 50% aqueous solution of cyanamide to obtain N-(2- Methyl-5-nitrophenyl)-guanidinium nitrate, which further reacted with 3-dimethylamino- l-pyridin-3-yI-propenone to yield (2-methyI-5-nitrophenyl)-(4-pyridin-3-yI-pyrimidin -2- yl)-amine, finally, reduction of nitro group to obtain compound of formula (Π).

Componds of formula (III) can be synthesized by the process disclosed in synthtic communications 2003, 3597

comprising reacting a-halogen-/?-toluinitrile or methanesulfonic acid 4-cyano-benzyl ester or toluene-4-sulfonic acid 4-cyano-benzyl ester with N-methylpiperazine, followed by hydrolysis of the cyano to acid which formed as dihydrochloride contain half crystalline hydrate, finally reaction with alcohol to obtain compound of formula (III).

The synthetic route for preparing imatinib according to the present invention is is given below

EXAMPLES

Example 1

To a solution of 4-Methyl-N-(4-pyridin-3-yl-pyrimidin-2-yl)-benzene-l,3-diamine (27.7g) and 4-(4-Methyl-piperazin-l-ylmethyl)-benzoic acid methyl ester (50g) in Tetrahydrofuran (250ml), a solution of sodium methylate (lOg) in methanol (10ml) was added. The reaction mixture was heated to reflux. After completion of the reaction solution was poured into ice-water and a large amount of solid precipitated, which was filtered and washed with water and dried to obtain Imatinib base (45g). Yield: 91%.

The spectral data is as follows:

Ή NMR ( 500M , DMSO ) δ : 10.2 (s, lH), 9.30 (s, 1H), 8.99 (s, 1H), 8.72 (d, J=4.0

Hz, 1H), 8.57 (s, 1H), 8.53 (s, 1H), 8.11 (s, 1H), 8.00 (s, 1H), 7.98 (s, 1H), 7.58-7.51 (m, 4H), 7.44 (d, J=4.3 Hz, 1H), 7.22 (d, J=8.1 Hz, 1H), 3.70 (s, 2H), 3.50-3.25 (m, 2H),

3.20-2.90 (m, 4H), 2.81 (s, 3H), 2.40 (s, 3H), 2.24 (s, 3H). ¹³C NMR (125M ,

DMSO ) δ : 164.9, 161.3, 161.1, 159.4, 150.8, 147.7, 137.7, 137.1, 134.9, 134.3, 132.3, 129.9, 129.1, 127.7, 127.6, 123.9, 117.2, 1 16.8, 107.5, 59.9, 52.1, 48.9, 42.2, 17.5.

MS (M⁺+l): 494.3

Example 2

To a solution of 4-Methyl-N-(4-pyridin-3-yl-pyrimidin-2-yl)-benzene-l,3-diamine (27.7g) and 4-(4-Methyl-piperazin-l-ylmethyl)-benzoic acid methyl ester (50g) in toluene (250ml), a solution of sodium ethoxide (20g) in methanol (10ml) was added. The reaction mixture was heated to reflux. After completion of the reaction, solution was poured into ice-water and a large amount of solid precipitated, which was filtered and washed with water and dried to obtain Imatinib base (44g). Yield: 91%.

Example 3

To a solution of potassium butoxide (250g) in methanol (1000ml), a solution of 4-Methyl- N-(4-pyridin-3-yl-pyrimidin-2-yl)-benzene-l,3-diamine (277g) and 4-(4-Methyl- piperazin-l-ylmethyl)-benzoic acid propyl ester (600g) in Tetrahydrofuran (2500ml) was added. The reaction mixture was stirred at room temperature. After completion of the reaction solution was poured into ice-water and a large amount of solid precipitated, which was filtered and washed with water and dried to obtain Imatinib base (450g). Yield: 91%. Example 4

To a solution of potassium butoxide (25kg) in ethanol (lOOLitre), a solution of 4-Methyl- N-(4-pyridin-3-yI-pyrimidin-2-yl)-benzene-l,3-diamine (27.7kg) and 4-(4-MethyI- piperazin-l-ylmethyl)-benzoic acid ethyl ester (50.0kg) in toluene (250Litre) was added. The reaction mixture was stirred at room temperature. After completion of reaction, solution was poured into ice-water and a large amount of solid precipitated, which was filtered and washed with water, and dried to obtain Imatinib base (40.0kg). Yield: 81%.

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FIGURE 2.

Synthesis of SKI696. (A) isopropanol/sodium hydroxide (a); iron/acetic acid/EtOH/water (b); triethyl amine/acetonitrile (c); 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride/N,N-dimethylaminopyridine/dimethylformamide (d); trifluoroacetic acid/dichloromethane (e); potassium carbonate/acetonitrile (f). (B) ¹⁸F-KF/Kryptofix/1,2-dichlorobenzene (g); dimethylformamide/acetonitrile (h).

http://jnm.snmjournals.org/content/52/8/1301/F2.expansion.html

………………………………….

http://www.beilstein-journals.org/bjoc/single/articleFullText.htm?publicId=1860-5397-9-265

In order to prepare the core heterocyclic unit a direct condensation between a 1,3-dicarbonyl compound 3.39 and an amidine or guanidine 3.40 is frequently employed (Scheme 36a). Alternatively, an amidine can be condensed with a vinylogous amide 3.41 resulting in the direct formation of 2,4-disubstituted pyrimidines. These condensations often require relatively harsh reaction conditions despite this they are of great value as they involve cheap or easily accessible materials and typically only form water as the principle byproduct.

A modification of the above pyrimidine synthesis has been applied in the generation of imatinib (3.36, Gleevec) which is Novartis’ tyrosine kinase inhibitor used for the treatment of chronic myeloic leukaemia. In a patented route the aldol product 3.47 undergoes a condensation reaction with guanidine 3.48 in basic media to give the 2-aminopyrimidine 3.49 (Scheme 37) [93]. After generating the functional pyrimidine core a hydrazine-mediated reduction of the nitro group in the side chain was conducted with Raney-Nickel as the catalyst. Amide formation with 4-chloromethylbenzoyl chloride (3.50) and a direct displacement of the benzylic chloride with N-methylpiperazine (1.118) complete this synthesis of imatinib in excellent overall yields.

Scheme 37: Synthesis of imatinib.

One noteworthy feature of this imatinib synthesis is that it is specifically designed for facile isolation of intermediates by precipitation due to their limited solubility in non-polar solvents [94]. Whilst this process was efficient in enabling the isolation of pure material after each step, it does not encourage telescoping of steps, which would in principal increase the overall efficiency of the process. Recently, similar approaches have been utilised in the academic environment using enabling techniques in a route to imatinib. For instance, our group has employed continuous flow synthesis methods to imatinib [95,96]. The route not only afforded imatinib but led to many previously inaccessible derivatives in an automated fashion within a single working day (Scheme 38). In addition, this particular sequence showcases the uses of scavenger resins for in-line purification as the synthesis progresses and features the use of a Buchwald–Hartwig amination in a late stage fragment coupling. While it was sufficient to access only small amounts of these structures (around 50 mg), these techniques are currently being adopted by several major pharmaceutical companies in order to enhance drug development and even manufacturing sequences.

Scheme 38: Flow synthesis of imatinib.

pick up ref from

http://www.beilstein-journals.org/bjoc/single/articleFullText.htm?publicId=1860-5397-9-265

…………………………………..

Imatinib is a tyrosine-kinase inhibitor used for the treatment of cancer. A key steps in its synthesis is the enamine formation highlighted in green below.

1) Show a mechanism for this transformation?

2) This particular enamine is rather stable. Comment on it relatively high stability? (i.e. What make it so stable?)

Imatinib Synthesis

……………………………………..

Org. Biomol. Chem., 2009,7, 5129-5136

DOI: 10.1039/B913333J

http://pubs.rsc.org/en/content/articlelanding/2009/ob/b913333j#!divAbstract

Protein kinases catalyze the phosphorylation of serine, threonine, tyrosine and histidine residues in proteins. Aberrant regulation of kinase activity has been implicated in many diseases including cancer. Thus development of new strategies for kinase inhibitor design remains an active area of research with direct relevance to drug development. Abelson (Abl)tyrosine kinase is one of the Src-family of tyrosine kinases and is directly implicated in Chronic Myelogenous Leukemia (CML). In this article, we have, for the first time, developed an efficient method for the construction of small molecule-based bisubstrate inhibitors of Abl kinase using click chemistry. Subsequent biochemical screenings revealed a set of moderately potentinhibitors, a few of which have comparable potency to Imatinib (an FDA-approved drug for treatment of chronic myeloid leukemia) against Abl.

Graphical abstract: Rapid synthesis of Abelson tyrosine kinase inhibitors using click chemistry

……………………………………

Medicine for Blood Cancer

‘Imitinef Mercilet’ is a medicine which cures blood cancer.
Its available free of cost at “Adyar Cancer Institute in Chennai”.
Create Awareness. It might help someone.Cancer Institute in Adyar, Chennai

‘Imitinef Mercilet’ is apparently an alternative spelling of the drug Imatinib mesylate which is used in the treatment of some forms of leukemia along with other types of cancer. Imatinib, often referred to a “Gleevec”, has proved to be an effective treatment for some forms of cancers. However, “blood cancer” is a generalized term for cancers that affect the blood, lymphatic system or bone marrow. The three types of blood cancer are listed as leukemia, lymphoma, and multiple myeloma. These three malignancies require quite different kinds of treatments. While drugs (including Imatinib), along with other treatments such as radiation can help to slow or even stop the progress of these cancers, there is currently no single drug treatment that can be said to actually cure all such cancers.

Category: Cancer
Address: East Canal Bank Road , Gandhi Nagar
Adyar, Chennai -600020
Landmark: Near Michael School
Phone: 044-24910754 044-24910754 ,
044-24911526 044-24911526 , 044-22350241

Imatinib is a small molecule selectively inhibiting specific tyrosine kinases that has emerged recently as a valuable treatment for patients with advanced GIST. The use of imatinib as monotherapy for the treatment of GIST has been described in PCT publication WO 02/34727, which is here incorporated by reference. However, it has been reported that primary resistance to imatinib is present in a population of patients, for example 13.7% of patients in one study. In addition, a number of patients acquire resistance to treatment with imatinib. More generally this resistance is partial with progression in some lesions, but continuing disease control in other lesions. Hence, these patients remain on imatinib treatment but with a clear need for additional or alternative therapy.

Imatinib is 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]-benzamide having the formula I

The preparation of imatinib and the use thereof, especially as an anti-tumour agent, are described in Example 21 of European patent application EP-A-0 564 409, which was published on 6 Oct. 1993, and in equivalent applications and patents in numerous other countries, e.g. in U.S. Pat. No. 5,521,184 and in Japanese patent 2706682

flow synthesis

The flow-based route required minimal manual intervention and was achieved despite poor solubility of many reaction components

21 January 2013Michael Parkin

http://www.rsc.org/chemistryworld/2013/01/flow-synthesis-anticancer-drug

UK chemists have used a combination of flow chemistry methods with solid-supported scavengers and reagents to synthesise the active pharmaceutical ingredient, imatinib, of the anticancer drug Gleevec. The method avoids the need for any manual handling of intermediates and allows the drug to be synthesised in high purity in less than a day.

Gleevec, developed by Novartis, is a tyrosine kinase inhibitor used for the treatment of chronic myeloid leukaemia and gastrointestinal stromal tumours.

READ ALL AT

http://www.rsc.org/chemistryworld/2013/01/flow-synthesis-anticancer-drug



IMATINIB

CREDIT

http://www.veomed.com/va041542042010

‘Wrapping’ Gleevec Fights Drug-Resistant Cancer, Study Shows

http://www.sciencedaily.com/releases/2007/05/070501115127.htm

The anti-cancer drug Gleevec® is far more effective against a drug-resistant strain of cancer when the drug wraps the target with a molecular bandage that seals out water from a critical area. This image shows the bandage (black box) on the modified version of the drug, WBZ-7. (Credit: Image courtesy of Rice University)

A new study in Cancer Research finds that the anti-cancer drug Gleevec® is far more effective against a drug-resistant strain of cancer when the drug wraps the target with a molecular bandage that seals out water from a critical area.

FIG 23.8 Optimization of imatinib as a chemotherapeutic agent. The discovery that 2-phenylaminopyrimidine inhibitors of PKC also inhibit the unrelated v-Abl oncogene turned attention to its potential use in the treatment of chronic myelogenous leukaemia. Starting with the 2-phenylaminopyrimidine backbone, addition of the benzamidine group increased activity against tyrosine kinases, the methyl group reduced its activity against PKC (so-called ‘ target hopping ’ ). Addition of a 3’-pyridyl group improved the activity in cellular assays. Subsequent addition of N -methylpiperazine increased water solubility and oral bioavailability, enabling the drug to survive the stomach and to enter the bloodstream.

……………………..

An automated flow-based synthesis of imatinib: the API of gleevec M.D. Hopkin, I.R. Baxendale, S.V. Ley, J.C.S. Chem. Commun.2010, 46, 2450-2452.

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External links

Imatinib

Title: Imatinib

CAS Registry Number: 152459-95-5

CAS Name: 4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]benzamide

Additional Names: N-[5-[4-(4-methylpiperazinomethyl)benzoylamido]-2-methylphenyl]-4-(3-pyridyl)-2-pyrimidineamine

Molecular Formula: C29H31N7O

Molecular Weight: 493.60

Percent Composition: C 70.57%, H 6.33%, N 19.86%, O 3.24%

Literature References: Tyrosine kinase inhibitor; highly specific for BCR-ABL, the enzyme associated with chronic myelogenous leukemia (CML) and certain forms of acute lymphoblastic leukemia (ALL). Also shown to inhibit the transmembrane receptor KIT and platelet-derived growth factor (PDGF) receptors. Prepn: J. Zimmermann, EP 564409; idem, US 5521184 (1993, 1996 both to Ciba-Geigy); idem et al., Bioorg. Med. Chem. Lett. 7, 187 (1997). Structural mechanism of ABL specificity: T. Schindler et al., Science 289, 1938 (2000). Activity vs KIT and PDGF receptor kinases: E. Buchdunger et al., J. Pharmacol. Exp. Ther. 295, 139 (2000). Clinical trial in CML: H. Kantarjian et al., N. Engl. J. Med. 346, 645 (2002); in gastrointestinal stromal tumors related to KIT: G. D. Demetri et al., ibid. 347, 472 (2002). Review of clinical experience: D. G. Savage, K. H. Antman, ibid. 346, 683-693 (2002); and pharmacology: V. K. Pindolia et al., Pharmacotherapy 22, 1249-1265 (2002); and development of therapeutic target: B. J. Druker, Adv. Cancer Res. 91, 1-30 (2004).

Properties: mp 211-213°. pKa1 8.07; pKa2 3.73; pKa3 2.56; pKa4 1.52.

Melting point: mp 211-213°

pKa: pKa1 8.07; pKa2 3.73; pKa3 2.56; pKa4 1.52

Derivative Type: Methanesulfonate

CAS Registry Number: 220127-57-1

Manufacturers’ Codes: STI-571; CGP-57148B

Trademarks: Gleevec (Novartis); Glivec (Novartis)

Molecular Formula: C29H31N7O.CH3SO3H

Molecular Weight: 589.71

Percent Composition: C 61.10%, H 5.98%, N 16.63%, O 10.85%, S 5.44%

Literature References: Prepn of crystalline form: J. Zimmermann et al., WO 9903854 (1999 to Novartis).

Properties: Occurs in 2 crystalline modifications. a-form, begins to melt at 226°; b-form, mp 217°. Lipophilic at pH 7.4. Soly in water: >100 g/l (pH 4.2); 49 mg/l (pH 7.4).

Melting point: mp 217°

Therap-Cat: Antineoplastic.

Keywords: Antineoplastic, Tyrosine Kinase Inhibitors, imatinib mesylate, GGP-57148B, STI-571, CGP-57148 (free base), Gleevec, Glivec, imatinib

IMATINIB BASE

http://www.rsc.org/suppdata/cc/c0/c001550d/c001550d.pdf

Mp 206 – 207 °C (lit.:1 207 – 210 °C);

1= 1 Y.‐F. Liu, C.‐L. Wang, Y.‐J. Bai, N. Han, J.‐P. Jiao and X.‐L. Qi, Org. Process Res. Dev., 2008, 12, 490.

IR νmax/cm-1 3275.0(w), 2928.5(w),
2796.5(w), 1645.9(m), 1586.0(m), 1575.1(s), 1554.0(m), 1531.5(s), 1510.3(m), 1478.1(m),
1448.9(s), 1416.7(m), 1377.7(m), 1352.2(m), 1334.8(m), 1325.6(m), 1308.8(m), 1290.3(s),
1261.1(m), 1204.3(m), 1164.1(m), 1141.7(m), 1124.6(w), 1102.6(m), 1089.2(w), 1052.0(w),
1024.4(w), 1010.0(m), 992.5(w), 968.3(w), 924.5(w), 886.2(w), 857.9(w), 850.3(w),
807.8(m), 795.7(s), 748.1(m), 703.2(m), 690.1(m), 670.7(m);

δH (d6-DMSO, 600 MHz) =
10.14 (1 H, s, NH), 9.26 (1 H, d, J = 1.5 Hz, 2H-pyridin-3-yl), 8.95 (1 H, s, NH), 8.66 (1 H, dd,
J = 4.8 and 1.2 Hz, 6H-pyridin-3-yl), 8.49 (1 H, d, J = 5.1 Hz, 6H-pyridin-2-amine), 8.46 (1 H,
ddd, J = 7.9, 1.5 and 1.2 Hz, 4H-pyridin-3-yl), 8.06 (1 H, d, J = 1.5 Hz, 3H-2-aminotoluene),
7.89 (2 H, d, J = 8.1 Hz, 2H-benzamide), 7.50 (1 H, dd, J = 7.9 and 4.8 Hz, 5H-pyridin-3-yl),
7.46 (1 H, dd, J = 8.3 and 1.5 Hz, 5H-2-aminotoluene), 7.42 – 7.40 (3 H, m, 3H-benzamide
and 5H-pyridin-2-amine), 7.18 (1 H, d, J = 8.3 Hz, 6H-2-aminotoluene), 3.51 (2 H, s, CH2),
2.50 – 2.20 (8 H, m, piperazine CH2), 2.20 (3 H, s, CCH3), 2.13 (3 H, s, NCH3);

δC (CDCl3,
150 MHz) = 165.42(C), 162.72(C), 160.57(C), 158.99(CH), 151.44(CH), 148.48(CH),
142.52(C), 137.77(C), 136.60(C), 134.92(CH), 133.88(C), 132.66(C), 130.75(CH),
129.28(CH), 127.00(CH), 124.23(C), 123.71(CH), 115.35(CH), 113.19(CH), 108.32(CH),
62.49(CH2), 55.07(CH2), 53.10(CH2), 45.98(CH3), 17.65(CH3);

Rf (MeOH) = 0.09; Rt 3.48,

M+H m/z = 494.2; HRMS calculated for C29H31N7ONa [M + Na]+, 516.2488; found 516.2491.

1H NMR

13 C NMR

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—

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

New Route to Paricalcitol

September 10, 2014 7:31 am / Leave a comment

thumbnail image: New Route to Paricalcitol

Synthesis offers potential routes to analogues of vitamin-D-based drug

Paricalcitol, an A-ring-modified 19-nor analogue of 1α,25-dihydroxyvitamin D₂, is currently used for the treatment and prevention of secondary hyperparathyroidism associated with chronic renal failure.

http://www.chemistryviews.org/details/ezine/6508291/New_Route_to_Paricalcitol.html

Zemplar; 131918-61-1; 19-Nor-1alpha,25-dihydroxyvitamin D2; Compound 49510; Paracalcin; Zemplar (TN); 19-Nor-1,25-(OH)2D2; CHEBI:7931

Molecular Formula: C₂₇H₄₄O₃ Molecular Weight: 416.63646

Abbott (Originator), Tetrionics (Bulk Supplier)

launched 1998

19-Nor-1alpha,25-dihydroxyvitamin D2

(1R,3R)-5-[(2E)-2-[(1R,3aS,7aR)-1-[(E,2R,5S)-6-hydroxy-5,6-dimethylhept-3-en-2-yl]-7a-methyl-2,3,3a,5,6,7-hexahydro-1H-inden-4-ylidene]ethylidene]cyclohexane-1,3-diol

For treatment of secondary hyperparathyroidism associated with chronic kidney disease (CKD) Stage 3 and 4

Paricalcitol (chemically it is 19-nor-1,25-(OH)₂-vitamin D₂. Marketed by Abbott Laboratories under the trade name Zemplar) is a drugused for the prevention and treatment of secondary hyperparathyroidism (excessive secretion of parathyroid hormone) associated withchronic renal failure. It is an analog of 1,25-dihydroxyergocalciferol, the active form of vitamin D₂ (Ergocalciferol).

Paricalcitol is a synthetic vitamin D analog. Paricalcitol has been used to reduce parathyroid hormone levels. Paricalcitol is indicated for the prevention and treatment of secondary hyperparathyroidism associated with chronic renal failure.

Medical uses

Its primary use in medicine is in the treatment of secondary hyperparathyroidism associated with chronic kidney disease.^[2] In three placebo-controlled studies, chronic renal failure patients treated with paricalcitol achieved a mean parathyroid hormone (PTH) reduction of 30% in six weeks. Additionally there was no difference in incidence of hypercalcemia or hyperphosphatemia when compared to placebo.^[3] A double-blind randomised study with 263 dialysis patients showed a significant advantage over calcitriol (also known as activated vitamin D₃; a similar molecule to 1,25-dihydroxyergocalciferol, adding a methyl group on C₂₄ and lacking a double-bond in the C₂₂ position). After 18 weeks, all patients in the paricalcitol group had reached the target parathormone level of 100 to 300 pg/ml, versus none in the calcitriol group.^[4] Combination therapy with paricalcitol and trandolapril has been found to reduce fibrosis inobstructive uropathy.^[5] Forty-eight week therapy with paricalcitol did not alter left ventricular mass index or improve certain measures of diastolic dysfunction in 227 patients with chronic kidney disease.^[6]

Patents

Country	Patent Number	Approved	Expires (estimated)
United States	6136799	1998-10-08	2018-10-08
United States	5246925	1995-04-17	2012-04-17

Mechanism of action

3D structure of paricalcitol

Like 1,25-dihydroxyergocalciferol, paricalcitol acts as an agonist for the vitamin D receptor and thus lowers the bloodparathyroid hormone level.^[1]

Pharmacokinetics

Within two hours after administering paricalcitol intravenous doses ranging from 0.04 to 0.24 µg/kg, concentrations of paricalcitol decreased rapidly; thereafter, concentrations of paricalcitol declined log-linearly. No accumulation of paricalcitol was observed with multiple dosing.^[9]

vitamin D is a fat-soluble vitamin. It is found in food, but also can be formed in the body after exposure to ultraviolet rays. Vitamin D is known to exist in several chemical forms, each with a different activity. Some forms are relatively inactive in the body, and have limited ability to function as a vitamin. The liver and kidney help convert vitamin D to its active hormone form. The major biologic function of vitamin D is to maintain normal blood levels of calcium and phosphorus. Vitamin D aids in the absorption of calcium, helping to form and maintain healthy bones.

The 19-nor vitamin D analogue, Paricalcitol (I), is characterized by the following formula:

In the synthesis of vitamin D analogues, a few approaches to obtain a desired active compound have been outlined previously. One of the methods is the Wittig-Homer attachment of a 19-nor A-ring phosphine oxide to a key intermediate bicyclic-ketone of the Windaus-Grundmann type, to obtain the desired Paricalcitol, as is shown for example in U.S. Pat. Nos. 5,281,731 and 5,086,191 of DeLuca.

The synthesis of Paricalcitol requires many synthetic steps which produce undesired by-products. Therefore, the final product may be contaminated not only with a by-product derived from the last synthetic step of the process but also with compounds that were formed in previous steps. In the United States, the Food and Drug Administration guidelines recommend that the amounts of some impurities be limited to less than 0.1 percent.

U.S. Pat. Nos. 5,281,731 and 5,086,191 of DeLuca disclose a purification process of Paricalcitol by using a HPLC preparative method.

As the unwanted products have almost the same structure as the final product, it may difficult to get a sufficiently pure drug substance, vitamin D analogue, using this route to purify the drug substance. Moreover, the high polarity of Paricalcitol makes it very difficult to purify by HPLC and to recover the solid product. Furthermore, HPLC preparative methods are generally not applicable for use on industrial scale. There remains a need in the art to provide a method of preparing the vitamin D analogue Paricalcitol in a sufficiently pure form which is applicable for use on an industrial scale.

Paricalcitol (chemical name: 19-nor-1α,3β,25-trihydroxy-9,10-secoergosta-5(Z),7(Z),22(E)-triene; Synonyms: 19-nor-1,25-dihydroxyvitamin D₂, Paracalcin) is a synthetic, biologically active vitamin D analog of calcitriol with modifications to the side chain (D2) and the A (19-nor) ring. Paricalcitol inhibits the secretion of parathyroids hormone (PTH) through binding to the vitamin D receptor (D. M. Robinson, L. J. Scott, Drugs, 2005, 65 (4), 559-576) and it is indicated for the prevention and treatment of secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD).

Paricalcitol is marketed under the name Zemplar®, which is available as a sterile, clear, colorless, aqueous solution for intravenous injection (each mL contains 2 microgram (2 μg) or 5 μg paricalcitol as active ingredient) or as soft gelatin capsules for oral administration containing 1 μg, 2 μg or 4 μg paricalcitol.

The molecular formula of paricalcitol is C₂₇H₄₄O₃which corresponds to a molecular weight of 416.65. It is a white, crystalline powder and has the following structural formula:

Historically, nor-vitamin D compounds were described in 1990 as a new class of vitamin D analogs wherein the exocyclic methylene group C(19) in ring A has been removed and replaced by two hydrogen atoms (see e.g. WO 90/10620). So far, two different routes have been discovered for the synthesis of such 19-nor-vitamin analogs which specifically may be used for the preparation of paricalcitol.

The first synthesis of paricalcitol is disclosed in WO 90/10620 (additional patents from patent family: EP patent no. 0 387 077, U.S. Pat. No. 5,237,110, U.S. Pat. No. 5,342,975, U.S. Pat. No. 5,587,497, U.S. Pat. No. 5,710,294 and U.S. Pat. No. 5,880,113) and generally described in Drugs of the Future, 1998, 23, 602-606.

Example 3 of WO 90/10620 provides the preparation of 1α,25-dihydroxy-19-nor-vitamin D₂(Scheme 1) by using experimental conditions analogous to the preparation of 1α,25-dihydroxy-19-nor-vitamin D₃. According to this description the starting material 25-hydroxyvitamin D2 is first converted to 1α,25-dihydroxy-3,5-cyclovitamin D₂(a2) using the procedures published by DeLuca et al. in U.S. Pat. No. 4,195,027 and Paaren et al. published in J. Org. Chem., 1980, 45, 3252. Acetylation of compound a2 followed by dihydroxylation of the exocyclic methylene group using osmium tetroxide in pyridine gives the 10,19-dihydroxy compound a4 which is converted with sodium metaperiodate (diol cleavage) to the 10-oxo-intermediate a5. Reduction of the 10-oxo group in a5 is carried out by treatment with sodium borohydride in a mixture of ethanol and water giving the corresponding 10-hydroxy derivative a6. Mesylation of the 10-hydroxy group in a6 (→a7) followed by reduction with lithium aluminium hydride in THF gives the 10-deoxy intermediate a8 wherein the 1-OAcyl group was simultaneously cleaved during the reduction step. Solvolysis (cycloreversion) of a8 by treatment with hot (55° C.) acetic acid results in the formation of two monoacetates (a9 and a10) which are separated and purified by using HPLC. Finally both monoacetates are saponified with aqueous potassium hydroxide in methanol yielding paricalcitol which is purified by HPLC.

The preparation of paricalcitol according to the method provided in WO 90/10620 has several drawbacks:

- (1) the starting material 25-hydroxyvitamin D2 is one of the major metabolites of vitamin D2 and not readily available in larger amounts. Additional efforts have to be made in order to synthesize the starting material in sufficient amounts resulting in a protractive and unattractive total synthesis of paricalcitol. Examples for the preparation of 25-hydroxyvitamin D2 are described e.g. in U.S. Pat. No. 4,448,721; WO 91/12240; Tetrahedron Letters, 1984, 25, 3347-3350; J. Org. Chem., 1984, 49, 2148-2151 and J. Org. Chem., 1986, 51, 1264-1269;
- (2) the use of highly toxic osmium tetroxide which requires special precaution for its handling;
- (3) use of HPLC for separation of isomers and purification of the final compound. As teached in WO 2007/011951 paricalcitol is difficult to purify by HPLC and as a preparative method HPLC is generally not applicable for use on industrial scale;
- (4) the yields for the preparation of paricalcitol are not described in WO 90/10620. Generally, the provided yields for the preparation of the analogue compound 1α,25-dihydroxy-19-nor-vitamin D3 are very low especially for the corresponding steps 7 to 11 (yield starting from 1α,25-dihydroxy-10-oxo-3,5-cyclo-19-nor-vitamin D3 1-acetate which is the vitamin D3 analogue to a5 in Scheme1: step 7: 63.4%, steps 8-10: 10.7%, step 11: 51.7%; overall yield starting with step 7: 3.5%).

Another strategy for synthesizing 19-nor vitamin D compounds is disclosed in EP 0 516 410 (and corresponding U.S. Pat. No. 5,281,731, U.S. Pat. No. 5,391,755, U.S. Pat. No. 5,486,636, U.S. Pat. No. 5,581,006, U.S. Pat. No. 5,597,932 and U.S. Pat. No. 5,616,759). The concept is based on condensing of a ring-A unit, as represented by structure b1 (Scheme 2), with a bicyclic ketone of the Windaus-Grundmann type, structure b2, to obtain 19-nor-vitamin D compound (b3).

Specific methods for synthesizing compounds of formula b1 are shown in Schemes 3, 4 and 5. According to Scheme 3, the route starts with the commercially available (1R,3R,4R,5R)(−)quinic acid (b4). Esterification of b4 with methanol followed by protection of the l- and 3-hydroxygroup using tert.-butyldimethylsilyl chloride (TBDMSCl) gives compound b5. Reduction of the ethyl ester in b5 yields b6 which is subjected to a diol cleavage giving compound b7. The 4-hydroxy group is protected as trimethylsilylether resulting in the formation of b8 which is further converted in a Peterson reaction with ethyl (trimethylsilyl)acetate before being deprotected with dilute acetic acid in tetrahydrofurane (THF). The resulting compound b9 is treated with 1,1-thiocarbonyldiimidazole to obtain b10. Subsequent reaction with tributyltin hydride in the presence of a radical initiator (AIBN) gives b11. Compound b11 is then reduced with DIBAH to the allylalcohol b12 which is then reacted with NCS and dimethyl sulfide giving the allylchloride b13. Finally the ring A synthon b14 is prepared by treatment of the allychloride b13 with lithium diphenylphosphide followed by oxidation with hydrogen peroxide.

In an alternative method for synthesizing the ring A unit (Scheme 3), the intermediate b5 can be also subjected to radical deoxygenation using analogues conditions as previously described, resulting in the formation of b16. Reduction of the ester (→b17), followed by diol cleavage (→b18) and Peterson reaction gives intermediate b11 which can be further processed to b14 as outlined in Scheme 3.

Another modification for the preparation is shown in Scheme 5. As described, b7 can be also subjected to the radical deoxygenation yielding intermediate b18 which can be further processed to b14 as depicted in Schemes 3 and 4.

In EP 0 516 411 (and its counterpart, U.S. Pat. No. 5,086,191) is disclosed the preparation of intermediates useful for the synthesis of 19-nor vitamin D compounds (Scheme 6). The key step is the condensation of compounds c1 which can be prepared in an analogous manner as previously described for e.g. b14 (Scheme 3) with compounds c2, resulting in compounds of formula c3.

EP 0 516 411 discloses that Grignard coupling of hydroxy-protected 3-hydroxy-3-methylbutylmagnesium bromide with compound c5 (Scheme 7) can give hydroxy-protected 1α,25-dihydroxy-19-nor vitamin D3 or coupling of the corresponding 22-aldehyde c3 (X¹=X²=TBDMS, R¹=—CHO) with 2,3-dimethylbutyl phenylsulphone can give after desulfonylation, 1α-hydroxy-19-norvitamin d2 in hydroxy-protected form.

An additional method for preparation of 1α-hydroxy-19-nor-vitamin D compounds is provided in EP 0 582 481 (and corresponding U.S. Pat. No. 5,430,196, U.S. Pat. No. 5,488,183, U.S. Pat. No. 5,525,745, U.S. Pat. No. 5,599,958, U.S. Pat. No. 5,616,744 and U.S. Pat. No. 5,856,536) (Scheme 8). Similar to the strategy as described above and shown in schemes 3 to 7, the basis for preparing 1α-hydroxy-19-nor-vitamin D compounds is an independent synthesis of ring A synthon and ring C/D synthon which are finally coupled resulting in vitamin analogs.

Thus the synthesis of 1α-hydroxy-19-nor-vitamin D compounds comprises the coupling of either the ketone d1 with the acetylenic derivatives d2 or ketone d4 with acetylenic derivatives d3, yielding compounds of formula d5. Partial reduction of the triple bond giving d6 followed by reduction using low-valent titanium reducing agents results in the formation of 7,8-cis and 7,8-trans-double bond isomers (d7). Compounds of formula d7 can be also obtained directly from d5 by reaction of d5 with a metal hydride/titanium reducing agent. The isomeric mixture of compounds of formula d7 may be separated by chromatography to obtain separately the 7,8-trans-isomer. The 7,8-cis-isomer of structure d7 can be isomerized to yield the corresponding 7,8-trans-isomer. Finally any protecting groups, if present, can be then removed to obtain 1α-hydroxy-19-nor-vitamin D compounds.

The main disadvantage of the strategies as shown in Schemes 3 to 8 is the fact that ring A as well as ring C/D of the vitamin D derivative has to be separately synthesized before coupling them to compounds like 1α-hydroxy-nor-vitamin D or a protected precursor thereof. According to literature procedure, the ring fragment C/D can be prepared from vitamin D2 by ozonolysis (see e.g. J. C. Hanekamp et al., Tetrahedron, 1992, 48, 9283-9294) from which the ring A is cleaved (and disposed). This fragment has then to be separately synthesized e.g. by using other sources or starting materials like quinic acid in up to 10 steps or more. Therefore such strategies for the total synthesis of 1α-hydroxy-nor-vitamin D compounds become protractive and unattractive for large scale and according to the procedures provided in these patents, the final compounds are obtained only in amounts of <10 mg and in most cases even <1 mg.

Paricalcitol is an active Vitamin D Analog. Paricalcitol is used for the treatment and prevention of secondary hyperparathyroidism associated with chronic kidney disease.

It has been shown to reduce parathyroid hormone levels by inhibiting its synthesis and secretion.

…………………………….

………………………………….

The 25-hydroxyvitamin D2 (I) is converted into the cyclovitamin D2 acetate (II) according to known methods. The dihydroxylation of the methylene group of (II) with OsO4 in pyridine gives vicinal diol (III), which is oxidized with NaIO4 yielding the ketonic cyclovitamin (IV). The reduction of the ketonic group of (IV) with NaBH4 in ethanol/water affords the corresponding hydroxy derivative (V), which is treated with mesyl chloride and triethylamine to give the mesylate (VI). The reduction of (VI) with LiAlH4 in THF yields the 19-nor-cyclovitamin D (VII), which is treated with hot acetic acid to afford both monoacetates (VIII) and (IX), separated by HPLC. Finally, both monoacetates (VIII) and (IX) are hydrolyzed with KOH in methanol.

…………………………

EXAMPLEShttp://www.google.com/patents/US20070149489



HPLC method:


Column:	Hypersyl Gold (250 × 4.6 5 μm)
Mobile phase:	(A) water (95%)
	(B) acetonitrile (5%)
Gradient:	From 0 to 10 min (A) isocraticaly
	From 10 to 30 min (B) increases from 0 to 55%
	From 30 to 40 min (A) isocraticaly
	From 30 to 40 min (B) increases from 55 to 100%
Detection:	252 nm
Flow:	2 mL/min
Detection limit:	0.02%

Example 1 Crystallization of Paricalcitol from Acetone

500 mg of Paricalcitol were dissolved in 75 ml of acetone in a sonicator at 28° C. over a period of 15 minutes. The clear solution was filtered through glass wool into another flask, and the solution was then concentrated by evaporation, until the volume was 57.5 ml acetone (control by weight). The solution was cooled to −18° C., and the temperature was maintained at −18° C. for 20 hours. The crystals were filtered and washed with 20 ml of cold (−18° C.) acetone, then dried at high vacuum in an oven at 28° C. for 22 hours to obtain a yield of 390 mg (purity of 98.54%).

………………………………………………………….

http://www.google.com/patents/US20110184199

FIG. 3 is a flow chart showing a detailed example for the synthesis of paricalcitol according to route A1.

FIG. 4 is a flow chart showing the general synthesis of paricalcitol according to route A1.

FIG. 5 is a flow chart showing a detailed example for the synthesis of paricalcitol according to route B1.

FIG. 6 is a flow chart showing the general synthesis of paricalcitol according to route B1.

FIG. 7 is a flow chart showing the general synthesis of paricalcitol using Julia olefination for installation of the side chain according to route B2.

FIG. 8 is a flow chart showing a detailed example for the synthesis of paricalcitol according to route C1.

FIG. 9 is a flow chart showing the general synthesis of paricalcitol according to route C1.

FIG. 10 is a flow chart showing the general synthesis of paricalcitol using Julia olefination for installation of the side chain according to route C2.

Example B11Process Step 12Deprotection of IM-A10b(I) and IM-A10b(II) to Paricalcitol

A mixture consisting of IM-A10b(I) and IM-A10b(II) (41 mg, HPLC purity 54.8%) was dissolved in 1M TBAF in THF (1.5 mL) at temperature 20-25° C. and stirred for 2 h. Then, the reaction mixture was diluted with MeOH (1.5 mL) and 2M aqueous NaOH (0.3 mL) was added. The mixture was stirred for another 2 h and monitored by TLC. Then AcOEt (20 mL) and saturated aqueous NaHCO₃solution (20 mL) were added and the phases separated. The organic phase was washed with brine (20 mL), dried over MgSO₄and concentrated under reduced pressure. The product was purified by column chromatography on silica gel (15 g), with mobile phase cyclohexane/AcOEt (100:0 to 92:8).

Yield 11 mg (81%).

In an additional purification, the product (Paricalcitol, 11 mg) was dissolved in acetone (1 mL) at 35-40° C. The solution was filtered and then cooled to −18° C. to initiate crystallization. The obtained slurry was stirred for 15 min at room temperature (20-25° C.) and again cooled to −18° C. for 3.5 h. The solid material was filtered off, washed with cold (−18° C.) acetone (0.25 mL) and dried in vacuo (6 mbar, 40° C.).

Yield of paricalcitol: 4 mg (36%, HPLC purity 98.3%)

Example C7Process Step 12Hydrolysis of IM-A11a to Paricalcitol

To a solution of IM-A11a(I) and IM-A11a(II) (5.24 g, HPLC-purity 94.2%) in EtOH (80 mL) was added at room temperature (20-25° C.) 2M aqueous NaOH solution (8 mL). The reaction mixture was stirred for 1 h 20 min (TLC monitoring), then EtOAc (8 mL) was added and the mixture was concentrated under reduced pressure to a volume of 40 mL whereupon the crystallization started. Water (50 mL) was added to the suspension and after stirring for 75 min at room temperature the solid was isolated by filtration (pH of the mother liquor measured 8-9). The wet product was slurried in EtOH/H₂O (24 g, 1:1) at room temperature, filtered, washed with EtOH/H₂O (5 mL, 1:1) and dried (40° C., 10 mbar).

Yield of paricalcitol: 4.26 g (89.5%, HPLC-purity 97.7%).

…………………………………………………..

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US7795459 *	Apr 28, 2009	Sep 14, 2010	Alphora Research Inc.	Paricalcitol purification
US20110137058 *	Feb 15, 2011	Jun 9, 2011	Formosa Laboratories, Inc.	Preparation of paricalcitol
DE102009013609A1	Mar 17, 2009	Nov 5, 2009	Formosa Laboratories, Inc.	Herstellung von Paricalcitol

References

“Zemplar (paricalcitol) dosing, indications, interactions, adverse effects, and more”. Medscape Reference. WebMD. Retrieved 26 January 2014.
Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3. edit
“Zemplar: Drug Information”
Schubert-Zsilavecz, M, Wurglics, M, Neue Arzneimittel 2005/2006 (in German).
Tan, X; He, W; Liu, Y (2009). “Combination therapy with paricalcitol and trandolapril reduces renal fibrosis in obstructive nephropathy”. Kidney international 76 (12): 1248–57.doi:10.1038/ki.2009.346. PMID 19759524.
Thadhani, R; Appelbaum, E; Pritchett, Y; Chang, Y; Wenger, J; Tamez, H; Bhan, I; Agarwal, R et al. (2012). “Vitamin D Therapy and Cardiac Structure and Function in Patients With Chronic Kidney Disease – The PRIMO Randomized Controlled Trial”. JAMA 307 (7): 674–684. doi:10.1001/jama.2012.120. PMID 22337679.
“PARICALCITOL capsule, liquid filled [Teva Pharmaceuticals USA Inc]” (PDF). DailyMed. Teva Pharmaceuticals USA Inc. September 2013. Retrieved 26 January 2014.
“Zemplar Soft Capsules 1 mcg – Summary of Product Characteristics”. electronic Medicines Compendium. AbbVie Limited. 15 April 2013. Retrieved 26 January 2014.
Rxlist: Zemplar
- Synthesis of 19-Nor-Vitamin D A-Ring Synthons via Ring-Closing Olefin Metathesis
  Yu Nagai, Tomoe Tanami, Junko Abe, Hazuki Nagai, Toru Hamamizu, Kaichiro Kominato, Keisuke Iida, Kazuo Nagasawa
  Asian J. Org. Chem. 2014.
  DOI: 10.1002/ajoc.201402109
Anchel Schwartz, Alexei Ploutno, Koby Wolfman, “Preparation of paricalcitol.” U.S. Patent US20070149489, issued June 28, 2007.US20070149489

Systematic (IUPAC) name
(1R,3R,7E,17β)-17-[(1R,2E,4S)-5-hydroxy-1,4,5-trimethylhex-2-en-1-yl]-9,10-secoestra-5,7-diene-1,3-diol
Clinical data
Trade names	Zemplar
AHFS/Drugs.com	monograph
MedlinePlus	a682335
Pregnancy cat.	AU: C US: C
Legal status	AU: Prescription Only (S4) CA: ℞-only UK: POM US: ℞-only
Routes	Oral, Intravenous
Pharmacokinetic data
Bioavailability	72%^[1]
Protein binding	99.8%^[1]
Metabolism	Hepatic^[1]
Half-life	14-20 hours^[1]
Excretion	Faeces (74%), urine (16%)^[1]
Identifiers
CAS number	131918-61-1
ATC code	H05 BX02
PubChem	CID 5281104
IUPHAR ligand	2791
DrugBank	DB00910
ChemSpider	4444552
UNII	6702D36OG5

ChEMBL	CHEMBL1200622
Synonyms	(1R,3S)-5-[2-[(1R,3aR,7aS)-1-[(2R,5S)-6-hydroxy-5,6-dimethyl-3E-hepten-2-yl]-7a-methyl-2,3,3a,5,6,7-hexahydro-1H-inden-4-ylidene]ethylidene]-cyclohexane-1,3-diol
Chemical data
Formula	C₂₇H₄₄O₃
Mol. mass	416.636 g/mol

more………….

Teva’s Asthma Drug ‘Significantly’ Improves Lung Function In Phase 3 Trials

September 9, 2014 8:45 am / Leave a comment

Reslizumab

CAS 241473-69-8

PETAH TIKVA (dpa-AFX) – Teva Pharmaceutical Industries Ltd. (TEVA) Monday said asthma patients with elevated eosinophils showed significant improvement in lung function and asthma control after being treated with reslizumab in final-stage studies of the anti-IL5 monoclonal antibody

read

http://www.finanznachrichten.de/nachrichten-2014-09/31346564-teva-s-asthma-drug-significantly-improves-lung-function-in-phase-3-trials-020.htm

Reslizumab is a humanized monoclonal antibody intended for the treatment of eosinophil-meditated inflammations of the airways, skinand gastrointestinal tract.^[1] As of September 2009, the drug is undergoing Phase II/III clinical trials.^[2]

Treatment of bronchial asthma as well as a pharmacological tool to elucidate the role of IL-5 in human eosinophilic diseases

References

Walsh, GM (2009). “Reslizumab, a humanized anti-IL-5 mAb for the treatment of eosinophil-mediated inflammatory conditions”. Current opinion in molecular therapeutics 11 (3): 329–36. PMID 19479666.
ClinicalTrials.gov

Albaconazole

September 9, 2014 4:02 am / Leave a comment

Chemical structure for albaconazole

Albaconazole

Also known as: UNII-YDW24Y8IAB; UR-9825; 187949-02-6; UR 9825, W-0027

Molecular Formula: C₂₀H₁₆ClF₂N₅O₂ Molecular Weight: 431.823146

(1R,2R)-7-chloro-3-[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]quinazolin-4(3H)-one

7-chloro-3-[(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1,2,4-triazol-1-yl)butan-2-yl]quinazolin-4-one

Albaconazole (UR-9825) is a triazole antifungal. It has potential broad-spectrum activity.

Albaconazole is a broad-spectrum antifungal agent being evaluated in phase II clinical trials by Stiefel for the oral treatment of fungal infections, including toenail fungus, distal onychomycosis and subungual onychomycosis. Early clinical trials for the treatment of tinea pedis have been completed. In September 2005, Uriach, originator of albaconazole, granted Stiefel exclusive rights to develop and market albaconazole on a worldwide basis. In November 2006, Uriach’s R&D pipeline was transferred to Palau Pharma, a newly-created spin-out company. Under the terms of the agreement with Stiefel, Palau retains rights as comarketing partner in some European countries. In August 2013, Palau Pharma granted worldwide rights to Actavis. A triazole, albaconazole, has shown potent activity against a broad range of organisms, including pathogens resistant to other antifungals, such as fluconazole or itraconazole. It will be developed as an oral and topical formulation, and is expected to be available to the medical community for a variety of dermatological indications and fungal infections, including vulvovaginal candidiasis.

Albaconazole
Systematic (IUPAC) name

7-Chloro-3-[(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1,2,4-triazol-1-yl)butan-2-yl]quinazolin-4-one
Clinical data

Identifiers
CAS number	187949-02-6
ATC code	None
PubChem	CID 208952
ChemSpider	181045
UNII	YDW24Y8IAB
KEGG	D09702
ChEMBL	CHEMBL298817
Chemical data
Formula	C₂₀H₁₆Cl F₂N₅O₂
Mol. mass	431.823146 g/mol

US6653475

11-26-2003

Method for preparing pyrimidone derivatives with antifungal activity

The condensation of the chiral oxazolidinone (I) with 2,4-difluorophenacyl bromide (II) by means of NaHMDS in THF/Et2 O gives the chiral oxirane (III), which is treated with LiOH and H2O2 to eliminate the chiral auxiliary, yielding the carboxylic acid (IV). The cleavage of the oxirane ring of (IV) with 1,2,4-triazole (V) and NaH in hot DMF affords the chiral hydroxyacid (VI), which is submitted to Curtius rearrangement by means of DPPA in hot pyridine to provide the chiral oxazolidinone (VII). The cleavage of the oxazolidinone ring of (VII) by means of refluxing aq. HCl gives the chiral aminoalcohol (VIII), which is condensed with 2-amino-4-chlorobenzoic acid (IX) by means of DCC and HOBt to yield the corresponding amide (X). Finally, this compound is cyclized to the target quinazolinone by reaction with triethyl orthoformate in hot dioxane/NMP.

EP 0783501; ES 2107376; ES 2120885; JP 1998508317; US 5807854; WO 9705130

…………………………………………..

The condensation of (R)-lactic acid (I) with morpholine (II) gives the corresponding morpholide (III), which is protected at the hydroxyl position with dihydropyran (IV) to yield the tetrahydropyranyl ether (V). The Grignard reaction of (V) with 2,4-difluorophenylmagnesium bromide (VI) affords the chiral 1-propanone (VII), which by a Corey’s diastereoselective epoxidation with trimethylsulfoxonium iodide is converted into the oxirane (VIII). The opening of the oxirane ring of (VIII) by means of 1,2,4-triazole (IX) and NaH provides the tertiary alcohol (X), which is treated with pyridine p-toluenesulfonate to give the deprotected diol (XI) as a (2R,3R) and (2R,3S) 4:1 diastereomeric mixture, from which the desired (2R,3R)-isomer (XII) was isolated by crystallization. The reaction of (XII) with Ms-Cl and TEA, followed by cyclization with NaOMe, yields the oxirane (XIII), which is finally condensed with 7-chloroquinazolin-4(3H)-one (XIV) by means of K2CO3 in hot NMP.

ES 2159488; WO 0166519

…………………………………………….

Alternatively, intermediate (XIII) can be obtained as follows: Heating of ethyl (S)-lactate (XIV) with morpholine affords amide (XVI), which then reacts with 3,4-dihydro-2H-pyran (A) in the presence of p-TsOH to give protected derivative (XVII). Grignard reaction between (XVII), bromo derivative (XVIII) and Mg turnings in THF yields protected ketone (XIX), which is treated with pyridinium p-toluenesulfonate (PPTS) (THP group removal) and reprotected by means of Tf2O and DIEA to give triflate derivative (XX). Conversion of (XX) into intermediate (XIII) is achieved by reaction with triazolone (VII) and NaH in THF.

Chem Pharm Bull 1993,41(6),1035-42

……………………………………

Alternatively, derivative (XXIX) can be obtained in an analogous way as its enantiomer (XIX). Diastereoselective epoxidation of (XXIX) with trimethylsulfoxonium iodide and NaH in DMSO provides oxirane (XXX) (3). THP group removal by means of PPTS in EtOH, followed by reaction with 3,5-dinitrobenzoyl chloride (XXXI) and NaHCO3 in CH2Cl2, yields a diastereomeric mixture from which dinitrobenzoate derivative (2R,3R)-(XXXII) is obtained by recrystallization (1). Hydrolysis of (2R,3R)-(XXXII) in MeOH by treatment with aqueous NaOH gives compound (2R,3R)-(XXXIII), which is converted into ester (2R,3S)-(XXXIV) by Mitsunobu reaction with benzoic acid, Ph3P and DEAD in THF. Subsequent debenzoylation of (2R,3S)-(XXXIV) with NaOMe in MeOH affords oxiranyl ethanol derivative (2R,3R)-(XXXV), which is first converted into its triflate derivative by means of Tf2O and DIEA in CH2Cl2, and then into triazolone derivative (2S,3R)-(XXXVI) by reaction with intermediate (VII) and NaH in CH2Cl2/DMF. Finally, oxirane derivative (2S,3R)-(XXXVI) reacts with triazole (XXVI) and NaH in DMF to furnish the desired product.

…………………………………………………..

ER-30346 is synthesized by thiazole ring formation of (2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)thiobutanamide (I) and 4-bromoacetylbenzonitrile (II) by means of reflux in methanol. The thioamide (I) is obtained with excellent yield from a chiral nitrile (III) by heating with diethyl dithiophosphate in aqueous medium.

…………………………………………….

The nitrile (III), a chiral key intermediate of this synthesis, can be obtained by two different synthetic routes as follows: Route-a: The key step of this route is ring opening reaction of the trisubstituted oxirane (VII) by cyanide anion leading to the nitrile (III). The chiral oxirane (VII) is synthesized from (R)-lactic acid derivatives as already reported. The reaction of (VII) with diethylaluminum cyanide in toluene or lithium cyanide in tetrahydrofuran gives the nitrile (III) with high yield without any epimerization reaction.

…………………………………………..

The nitrile (III), a chiral key intermediate of this synthesis, can be obtained by two different synthetic routes as follows: Route-b: The starting material of this route is methyl (S)-3-hydroxy-2-methylpropionate (VIII), which contains one additional carbon between the hydroxyl group and the 2-position carbon of (R)-lactate, the starting material of route-a. The hydroxyl group of (VIII) is protected by triphenylmethyl group. Then, 2,4-difluorophenyl moiety is introduced to give the ketone (X). Direct conversion of the ketone (X) to the oxirane (XIV) by dimethylsulfoxonium methylide, the same condition for compound (IV) in route-a, does not proceed. The oxirane (XIV) having desired stereochemistry is obtained via oxidation reaction. The ketone (X) is converted to the exomethylene (XI) by Wittig reaction. The stereoselective oxidation of (XI) is achieved by means of osmium tetroxide in the presence of 4-methylmorpholine N-oxide to give the diol (XII) in 58% yield after separation of its epimer by column chromatography. After methanesulfonylation of the primary alcohol of (XII), a triazole moiety is introduced and the triphenylmethyl group is deprotected. Then, the primary hydroxyl group of (XVI) is oxidized under Swern oxidation condition to give the aldehyde (XVII), which is converted to the chiral nitrile intermediate (III) by means of heating with hydroxylamine-O-sulfonic acid.

………………………………..

J. Med. Chem., 1998, 41 (11), pp 1869–1882

DOI: 10.1021/jm9707277

A series of azole antifungal agents featuring a quinazolinone nucleus have been subjected to studies of structure−activity relationships. In general, these compounds displayed higher in vitro activities against filamentous fungi and shorter half-lives than the structures described in our preceding paper. The most potent products in vitro carried a halogen (or an isostere) at the 7-position of the quinazolinone ring. Using a murine model of systemic candidosis, oral activity was found to be dependent on hydrophobicity, which, in turn, modulated the compound’s half-life. The 7-Cl derivative, (1R,2R)-7-chloro-3-[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]quinazolin-4(3H)-one (20, UR-9825), was selected for further testing due to its high in vitro activity, low toxicity, good pharmacokinetic profile, and ease of obtention. Compound 20 is the (1R,2R) isomer of four possible stereoisomers. The other three isomers were also prepared and tested. The enantiomer (1S,2S) and the (1R,2S) epimer were inactive, whereas the (1S,2R) epimer retained some activity. In vitro 20 was superior to fluconazole, itraconazole, SCH-42427, and TAK-187 and roughly similar to voriconazole and ER-30346. In vivo, 20 was only moderately active in a mouse model of systemic candidosis when administration was limited to the first day. This was attributed to its short half-life in that species (t_1/2 = 1 h po). Protection levels comparable to or higher than those of fluconazole, however, were observed in systemic candidosis models in rat and rabbit, where the half-life of the compound was found to be 6 and 9 h, respectively. Finally, 20 showed excellent protection levels in an immunocompromised rat model of disseminated aspergillosis. The compound showed low toxicity signs when administered to rats at 250 mg/kg qd or at 100 mg/kg bid during 28 days.

J Med Chem 1998,41(11),1869

http://pubs.acs.org/doi/abs/10.1021/jm9707277

(1R,2R)-7-Chloro-3-[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]quinazolin-4(3H)-one (20, UR-9825). Precipitated from EtOH/H₂O (66% yield from amine 11): white amorphous solid;

mp 93−110 °C (wide range);

IR (KBr) ν 1675, 1601, 1554, 1498 cm^-1;

¹H NMR (300 MHz, CDCl₃) 8.58 (s, 1H, NCH-N), 8.26 (d, J = 8.6, 1H, arom), 8.11 (d, J = 5.7, trace rotamer), 7.76 (s, 2H, triazol),

7.74 (d, J = 5.3, 1H, arom), 7.5 (m, 2H, arom), 7.10 (s, trace rotamer), 6.9−6.7 (m, 2H, arom),

5.91 (dq, J_d = 2, J_q = 7, 1H, MeCH), 5.54 (d, J = 2, 1H, OH),

5.15 (d, J = 14.2 1H, CH(H)), 4.9−4.7 (m, trace rotamer), 4.30 (d, trace rotamer), 3.99 (d, J = 14.2, 1H, CH(H)),

1.46 (d, J = 6.9, trace rotamer), 1.29 (d, J = 7, 3H, CHMe);

GC−MS 224 (Tr-CH₂COHAr, C₁₀H₈F₂N₃O), 208 (group N-ethylheterocycle, C₁₀H₉ClN₂O);

[α]_D −8.0° (c 1, CHCl₃).

Chiral HPLC (column, CicloBond SN 1; eluent, MeOH: Et₃NHOAc in H₂O at pH7 1:1; retention times: (S,S) (74) t_R 12.6 min; (R,R) (20) t_R 13.7 min). Area ratio: 0.01:99.99.

Anal. (C₂₀H₁₆ClF₂N₅O₂) C, H, N.

KEY
Albaconazole,UNII-YDW24Y8IAB, UR-9825, UR 9825, W-0027

Infinity and AbbVie partner to develop and commercialise Duvelisib for cancer… for the treatment of chronic lymphocytic leukemia

September 9, 2014 3:30 am / 3 Comments on Infinity and AbbVie partner to develop and commercialise Duvelisib for cancer… for the treatment of chronic lymphocytic leukemia

Figure imgf000008_0001

Duvelisib

Infinity and AbbVie partner to develop and commercialise duvelisib for cancer

INK 1197; IPI 145; 8-Chloro-2-phenyl-3-[(1S)-1-(9H-purin-6-ylamino)ethyl]-1(2H)-isoquinolinone

1(2H)-Isoquinolinone, 8-chloro-2-phenyl-3-((1S)-1-(9H-purin-6-ylamino)ethyl)-
8-Chloro-2-phenyl-3-((1S)-1-(7H-purin-6-ylamino)ethyl)isoquinolin-1(2H)-one

(S)-3-(l-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one

UNII-610V23S0JI; IPI-145; INK-1197;

Originator…….. Millennium Pharmaceuticals

Molecular Formula		C₂₂H₁₇ClN₆O
Molecular Weight		416.86
CAS Registry Number		1201438-56-3

Infinity Pharmaceuticals has partnered with AbbVie to develop and commercialise its duvelisib (IPI-145), an oral inhibitor of phosphoinositide-3-kinase (PI3K)-delta and PI3K-gamma, to treat patients with cancer.

Duvelisib has shown clinical activity against different blood cancers, such as indolent non-Hodgkin’s lymphoma (iNHL) and chronic lymphocytic leukemia (CLL).

AbbVie executive vice-president and chief scientific officer Michael Severino said: “We believe that duvelisib is a very promising investigational treatment based on clinical data showing activity in a broad range of blood cancers.”

http://www.pharmaceutical-technology.com/news/newsinfinity-abbvie-partner-develop-commercialise-duvelisib-cancer-4363381?WT.mc_id=DN_News

Duvelisib (IPI-145, INK-1197), an inhibitor of PI3K-delta and –gamma, originated at Takeda subsidiary Intellikine. It is now being developed by Infinity Pharmaceuticals, which began a phase III trial in November, following US and EU grant of orphan drug status for both CLL and small lymphocytic leukemia

INK-1197 is a dual phosphatidylinositol 3-Kinase delta (PI3Kdelta) and gamma (PI3Kgamma) inhibitor in phase III clinical development at Infinity Pharmaceuticals for the treatment of chronic lymphocytic leukemia and small lymphocytic lymphoma. The company is also carring phase II trials for the treatment of patients with mild asthma undergoing allergen challenge, for the treatment of rheumatoid arthritis and for the treatment of refractory indolent non-Hodgkin’s lymphoma. Phase I clinical trials for the treatment of advanced hematological malignancies (including T-cell lymphoma and mantle cell lymphoma) are currently under way.
IPI-145 is an oral inhibitor of phosphoinositide-3-kinase (PI3K)-delta and PI3K-gamma. The PI3K-delta and PI3K-gamma isoforms are preferentially expressed in leukocytes (white blood cells), where they have distinct and non-overlapping roles in key cellular functions, including cell proliferation, cell differentiation, cell migration and immunity. Targeting PI3K-delta and PI3K-gamma may provide multiple opportunities to develop differentiated therapies for the treatment of blood cancers and inflammatory diseases.
Licensee Infinity Pharmaceuticals is developing INK-1197. In 2014, Infinity licensed Abbvie for joint commercialization in the U.S. and exclusive commercialization elsewhere. Originator Millennium Pharmaceuticals had also been developing the compound; however, no recent development has been reported for this research. In 2013, orphan drug designations were assigned by the FDA and the EMA for the treatment of chronic lymphocytic leukemia, for the treatment of small lymphocytic lymphoma and for the treatment of follicular lymphoma.

currently enrolling patients DYNAMO™, a Phase 2 study designed to evaluate the activity and safety of IPI-145 in approximately 120 people with refractory indolent non-Hodgkin lymphoma (iNHL) and DUO™, a Phase 3 clinical study of IPI-145 in approximately 300 people with relapsed/refractory chronic lymphocytic leukemia (CLL). These studies are supported by Phase 1 data reported at the 2013 American Society of Hematology (ASH) Annual Meeting which showed that IPI-145 was well tolerated and clinically active in a broad range of malignancies, including iNHL and CLL. These studies are part of DUETTS™, a worldwide investigation of IPI-145 in blood cancers.

Chemical structure for Duvelisib

WO 2011008302

http://www.google.com/patents/WO2011008302A1?cl=en

Reaction Scheme 1

Reaction Scheme 2:

201 202 203

204 205

Reaction Scheme 3:

Reaction Scheme 4A:

Reaction Scheme 4B:

Example 14b: Synthesis of (S)-3-(l-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one (9)

(compound 4904)

Scheme 27b. The synthesis of (S)-3-(l-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one (9)

(compound 4904) is described.

[00493] The compound of Formula 4904 (compound 292 in Table 4) was synthesized using the synthetic transformations as described in Examples 12 and 14a, but 2-chloro-6-methyl benzoic acid (compound 4903) was used instead of 2, 6 ,dimethyl benzoic acid (compound 4403). By a similar method, compound 328 in Table 4 was synthesized using the synthetic transformations as described starting from the 2-chloro-6-methyl m-fluorobenzoic acid.

…………………………………….

http://www.google.com/patents/WO2012097000A1?cl=en OR http://www.google.com/patents/US8809349?cl=en

Formula (I):

(I),

or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In one embodiment, the method comprises any one, two, three, four, five, six, seven, or eight, or more of the following steps:

“Formula (I)” includes (S)-3-(l -(9H-purin-6-ylamino)ethyl)-8-chloro-2- phenylisoquinolin-l(2H)-one in its imide tautomer shown below as (1-1) and in its lactim tautomer shown below as (1-2):

(1-1)………………………………………………………………………………… (1-2)

[0055] FIG. 27 shows an FT-IR spectra of Polymorph Form C.

[0056] FIG. 28 shows a ‘H-NMR spectra of Polymorph Form C.

[0057] FIG. 29 shows a ¹³C-NMR spectra of Polymorph Form C.

Example 1

Synthesis of (S)-3-(l-aminoethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one

Example 1A

1 2

[00563] Compound 1 (6.00 kg) was treated with 1-hydroxybenzotriazole monohydrate (HOBt^»H₂0), triethylamine, Ν,Ο-dimethylhydroxylamine hydrochloride, and EDCI in dimethylacetamide (DMA) at

10 °C. The reaction was monitored by proton NMR and deemed complete after 2.6 hours, affording Compound 2 as a white solid in 95% yield. The R-enantiomer was not detected by proton NMR using (R)-(- ) -alpha-ace tylmandelic acid as a chiral-shift reagent.

[00564] Compound 3 (4.60 kg) was treated with p-toluenesulfonic acid monohydrate and 3,4-dihydro-2H- pyran (DHP) in ethyl acetate at 75 °C for 2.6 hours. The reaction was monitored by HPLC. Upon completion of the reaction, Compound 4 was obtained as a yellow solid in 80% yield with >99% (AUC) purity by HPLC analysis.

[00565] Compound 5 (3.30 kg) was treated with thionyl chloride and a catalytic amount of DMF in methylene chloride at 25 °C for five hours. The reaction was monitored by HPLC which indicated a 97.5% (AUC) conversion to compound 6. Compound 6 was treated in situ with aniline in methylene chloride at 25 °C for 15 hours. The reaction was monitored by HPLC and afforded Compound 7 as a brown solid in 81% yield with >99% (AUC) purity by HPLC analysis. [00566] Compound 2 was treated with 2.0 M isopropyl Grignard in THF at -20 °C. The resulting solution was added to Compound 7 (3.30 kg) pre -treated with 2.3 M n-hexyl lithium in tetrahydrofuran at -15 °C. The reaction was monitored by HPLC until a 99% (AUC) conversion to Compound 8 was observed.

Compound 8 was treated in situ with concentrated HC1 in isopropyl alcohol at 70 °C for eight hours. The reaction was monitored by HPLC and afforded Compound 9 as a brown solid in 85% yield with 98% (AUC) purity and 84% (AUC) ee by HPLC analysis.

Example ID

[00567] Compound 9 (3.40 kg) was treated with D-tartaric acid in methanol at 55 °C for 1-2 hours. The batch was filtered and treated with ammonium hydroxide in deionized (DI) water to afford enantiomerically enriched Compound 9 as a tan solid in 71% yield with >99% (AUC) purity and 91% (AUC) ee by HPLC analysis.

Example 2

Synthesis of (S)-3-(l-aminoethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one

Example 2A

[00568] To Compound 7 (20.1 g) was charged 100 mL of anhydrous THF. The resulting solution was cooled to about -10 °C and 80 mL of n-hexyl lithium (2.3 M in hexanes, 2.26 equiv.) was slowly added (e.g. , over about 20 min). The resulting solution was stirred at about -10 °C for about 20 min.

[00569] To Compound 2 (26.5 g; 1.39 equiv.) was charged 120 mL of anhydrous THF. The resulting mixture was cooled to about -10 °C and 60 mL of isopropyl magnesium chloride (2.0 M in THF, 1.47 equiv.) was slowly added (e.g. , over about 15-20 min). The resulting mixture was then stirred at about -10 °C for about 20 min. The mixture prepared from Compound 2 was added to the solution prepared from Compound 7 while maintaining the internal temperature between about -10 and about 0 °C. After the addition was complete (about 5 min), the cold bath was removed, and the resulting mixture was stirred at ambient temperature for about 1 h, then cooled. [00570] A solution of 100 mL of anisole and 33 mL of isobutyric acid (4.37 equiv.) was prepared. The anisole solution was cooled to an internal temperature of about -3 °C. The above reaction mixture was added to the anisole solution such that the internal temperature of the anisole solution was maintained at below about 5 °C. The ice bath was then removed (after about 15 min, the internal temperature was about 7 °C). To the mixture, 100 mL of 10 wt aqueous NaCl solution was rapidly added (the internal temperature increased from about 7 °C to about 15 °C). After stirring for about 30 min, the two phases were separated. The organic phase was washed with another 100 mL of 10 wt aqueous NaCl. The organic phase was transferred to a flask using 25 mL of anisole to facilitate the transfer. The anisole solution was then concentrated to 109 g. Then, 100 mL of anisole was added.

[00571] To the approximately 200 mL of anisole solution was added 50 mL of TFA (8 equiv.) while maintaining the internal temperature below about 45-50 °C. The resulting solution warmed to about 45-50 °C and stirred for about 15 hrs, then cooled to 20-25 °C. To this solution was added 300 mL of MTBE dropwise and then the resulting mixture was held at 20-25 °C for 1 h. The mixture was filtered, and the wet cake washed with approximately 50 mL of MTBE. The wet cake was conditioned on the filter for about 1 h under nitrogen. The wet cake was periodically mixed and re-smoothed during conditioning. The wet cake was then washed with 200 mL of MTBE. The wet cake was further conditioned for about 2 h (the wet cake was mixed and resmoothed after about 1.5 h). The wet cake was dried in a vacuum oven at about 40 °C for about 18 h to afford Compound 9^»TFA salt in about 97.3% purity (AUC), which had about 99.1 % S- enantiomer (e.g. , chiral purity of about 99.1 %).

[00572] Compound 9^»TFA salt (3 g) was suspended in 30 mL of EtOAc at about 20 °C. To the EtOAc suspension was added 4.5 mL (2.2 eq.) of a 14% aqueous ammonium hydroxide solution and the internal temperature decreased to about 17 °C. Water (5 mL) was added to the biphasic mixture. The biphasic mixture was stirred for 30 min. The mixing was stopped and the phases were allowed to separate. The aqueous phase was removed. To the organic phase (combined with 5 mL of EtOAc) was added 10 mL of 10% aqueous NaCl. The biphasic mixture was stirred for about 30 min. The aqueous phase was removed. The organic layer was concentrated to 9 g. To this EtOAc mixture was added 20 mL of i-PrOAc. The resulting mixture was concentrated to 14.8 g. With stirring, 10 mL of n-heptane was added dropwise. The suspension was stirred for about 30 min, then an additional 10 mL of n-heptane was added. The resulting suspension was stirred for 1 h. The suspension was filtered and the wet cake was washed with additional heptane. The wet cake was conditioned for 20 min under nitrogen, then dried in a vacuum oven at about 40 °C to afford Compound 9 free base in about 99.3% purity (AUC), which had about 99.2% S-enantiomer (e.g., chiral purity of about 99.2%).

Example 2B [00573] A mixture of Compound 7 (100 g, 0.407 mol, 1 wt) and THF (500 mL, 5 vol) was prepared and cooled to about 3 °C. n-Hexyllithium (2.3 M in hexanes, 400 mL, 0.920 mol, 2.26 equiv) was charged over about 110 minutes while maintaining the temperature below about 6 °C. The resulting solution was stirred at 0 ± 5 °C for about 30 minutes. Concurrently, a mixture of Compound 2 (126 g, 0.541 mol, 1.33 equiv) and THF (575 mL, 5.8 vol) was prepared. The resulting slurry was charged with isopropylmagnesium chloride (2.0 M in THF, 290 mL, 0.574 mol, 1.41 equiv) over about 85 minutes while maintaining the temperature below about 5 °C. The resulting mixture was stirred for about 35 minutes at 0 ± 5 °C. The Compound 2 magnesium salt mixture was transferred to the Compound 7 lithium salt mixture over about 1 hour while maintaining a temperature of 0 ± 5 °C. The solution was stirred for about 6 minutes upon completion of the transfer.

[00574] The solution was added to an about -5 °C stirring solution of isobutyric acid (165 mL, 1.78 mol, 4.37 equiv) in anisole (500 mL, 5 vol) over about 20 minutes during which time the temperature did not exceed about 6 °C. The resulting solution was stirred for about 40 minutes while being warmed to about 14 °C. Then, a 10% sodium chloride solution (500 mL, 5 vol) was rapidly added to the reaction. The temperature rose to about 21 °C. After agitating the mixture for about 6 minutes, the stirring was ceased and the lower aqueous layer was removed (about 700 mL). A second portion of 10% sodium chloride solution (500 mL, 5 vol) was added and the mixture was stirred for 5 minutes. Then, the stirring was ceased and the lower aqueous layer was removed. The volume of the organic layer was reduced by vacuum distillation to about 750 mL (7.5 vol).

[00575] Trifluoroacetic acid (250 mL, 3.26 mol, 8.0 equiv) was added and the resulting mixture was agitated at about 45 °C for about 15 hours. The mixture was cooled to about 35 °C and MTBE (1.5 L, 15 vol) was added over about 70 minutes. Upon completion of the addition, the mixture was agitated for about 45 minutes at about 25-30 °C. The solids were collected by vacuum filtration and conditioned under N₂ for about 20 hours to afford Compound 9*TFA salt in about 97.5% purity (AUC), which had a chiral purity of about 99.3%.

[00576] Compound 9^»TFA salt (100 g) was suspended EtOAc (1 L,10 vol) and 14% aqueous ammonia (250 mL, 2.5 vol). The mixture was agitated for about 30 minutes, then the lower aqueous layer was removed. A second portion of 14% aqueous ammonia (250 mL, 2.5 vol) was added to the organic layer. The mixture was stirred for 30 minutes, then the lower aqueous layer was removed. Isopropyl acetate (300 mL, 3 vol) was added, and the mixture was distilled under vacuum to 500 mL (5 vol) while periodically adding in additional isopropyl acetate (1 L, 10 vol).

[00577] Then, after vacuum-distilling to a volume of 600 mL (6 vol), heptanes (1.5 L, 15 vol) were added over about 110 minutes while maintaining a temperature between about 20 °C and about 30 °C. The resulting slurry was stirred for about 1 hour, then the solid was collected by vacuum filtration. The cake was washed with heptanes (330 mL, 3.3 vol) and conditioned for about 1 hour. The solid was dried in an about 45 °C vacuum oven for about 20 hours to afford Compound 9 free base in about 99.23% purity (AUC), which has a chiral purity of about 99.4%.

Example 3

Chiral Resolution of (S)-3-(l-aminoethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one (Compound 9)

[00578] In some instances, (S)-3-(l-aminoethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one (Compound 9) obtained by synthesis contained a minor amount of the corresponding (R)-isomer. Chiral resolution procedures were utilized to improve the enantiomeric purity of certain samples of (S)-3-(l-aminoethyl)-8- chloro-2-phenylisoquinolin- 1 (2H)-one.

[00579] In one experiment, Compound 9 (3.40 kg) was treated with D-tartaric acid in methanol at about 55 °C for about 1 to about 2 hours. The mixture was filtered and treated with ammonium hydroxide in deionized (DI) water to afford Compound 9 in greater than about 99% (AUC) purity, which had a chiral purity of about 91% (AUC).

[00580] In another procedure, MeOH (10 vol.) and Compound 9 (1 equiv.) were stirred at 55 ± 5 °C. D- Tartaric acid (0.95 equiv.) was charged. The mixture was held at 55 ± 5 °C for about 30 min and then cooled to about 20 to about 25 °C over about 3 h. The mixture was held for about 30 min and then filtered. The filter cake was washed with MeOH (2.5 vol.) and then conditioned. The cake was returned to the reactor and water (16 vol.) was charged. The mixture was stirred at 25 ± 5 °C. NH₄OH was then charged over about 1 h adjusting the pH to about 8 to about 9. The mixture was then filtered and the cake was washed with water (4 vol.) and then heptanes (4 vol.). The cake was conditioned and then vacuum dried at 45-50 °C to afford Compound 9 free base with a chiral purity of about 99.0%.

Example 4

Synthesis of (S)-3-(l-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one

[00581] A mixture of Compound 7 (1 equiv.) and anhydrous THF (5 vol.) was prepared. Separately, a mixture of Compound 2 (1.3 equiv.) and anhydrous THF (5 vol.) was prepared. Both mixtures were stirred for about 15 min at about 20 to about 25 °C and then cooled to -25 ± 15 °C. n-Hexyl lithium (2.05 equiv.) was added to the Compound 7 mixture, maintaining the temperature at > 5 °C. i-PrMgCl (1.33 equiv.) was added to the Compound 2 mixture, maintaining the temperature at > 5 °C. The Compound 2 mixture was transferred to the Compound 7 mixture under anhydrous conditions at 0 ± 5 °C. The resulting mixture was warmed to 20 ± 2 °C and held for about 1 h. Then, the reaction was cooled to -5 ± 5 °C, and 6 N HC1 (3.5 equiv.) was added to quench the reaction, maintaining temperature at below about 25 °C. The aqueous layer was drained, and the organic layer was distilled under reduced pressure until the volume was 2-3 volumes. IPA (3 vol.) was added and vacuum distillation was continued until the volume was 2-3 volumes. IPA (8 vol.) was added and the mixture temperature was adjusted to about 60 °C to about 75 °C. Cone. HC1 (1.5 vol.) was added and the mixture was subsequently held for 4 hours. The mixture was distilled under reduced pressure until the volume was 2.5-3.5 volumes. The mixture temperature was adjusted to 30 ± 10 °C. DI water (3 vol.) and DCM (7 vol.) were respectively added to the mixture. Then, NH₄OH was added to the mixture, adjusting the pH to about 7.5 to about 9. The temperature was adjusted to about 20 to about 25 °C. The layers were separated and the aqueous layer was washed with DCM (0.3 vol.). The combined DCM layers were distilled until the volume was 2 volumes. i-PrOAc (3 vol.) was added and vacuum distillation was continued until the volume was 3 volumes. The temperature was adjusted to about 15 to about 30 °C. Heptane (12 vol.) was charged to the organic layer, and the mixture was held for 30 min. The mixture was filtered and filter cake was washed with heptane (3 vol.). The cake was vacuum dried at about 45 °C afford Compound 9.

[00582] Then, MeOH (10 vol.) and Compound 9 (1 equiv.) were combined and stirred while the temperature was adjusted to 55 ± 5 °C. D-Tartaric acid (0.95 equiv.) was charged. The mixture was held at 55 ± 5 °C for about 30 min and then cooled to about 20 to about 25 °C over about 3 h. The mixture was held for 30 min and then filtered. The filter cake was washed with MeOH (2.5 vol.) and then conditioned. Water (16 vol.) was added to the cake and the mixture was stirred at 25 ± 5 °C. NH₄OH was charged over 1 h adjusting the pH to about 8 to about 9. The mixture was then filtered and the resulting cake washed with water (4 vol.) and then heptanes (4 vol.). The cake was conditioned and then vacuum dried at 45-50 °C to afford Compound 9.

[00583] To a mixture of i-PrOH (4 vol.) and Compound 9 (1 equiv.) was added Compound 4 (1.8 equiv.), Et₃N (2.5 equiv.) and i-PrOH (4 vol.). The mixture was agitated and the temperature was adjusted to 82 ± 5 °C. The mixture was held for 24 h. Then the mixture was cooled to about 20 to about 25 °C over about 2 h. The mixture was filtered and the cake was washed with i-PrOH (2 vol.), DI water (25 vol.) and n-heptane (2 vol.) respectively. The cake was conditioned and then vacuum dried at 50 ± 5 °C to afford Compound 10.

To a mixture of EtOH (2.5 vol.) and Compound 10 (1 equiv.) was added EtOH (2.5 vol.) and DI water (2 vol.). The mixture was agitated at about 20 to about 25 °C. Cone. HC1 (3.5 equiv.) was added and the temperature was adjusted to 35 ± 5 °C. The mixture was held for about 1.5 h. The mixture was cooled to 25 ± 5 °C and then polish filtered to a particulate free vessel. NH₄OH was added, adjusting the pH to about 8 to about 9. Crystal seeds of Form C of a compound of Formula (I) (0.3 wt ) were added to the mixture which was held for 30 minutes. DI water (13 vol.) was added over about 2 h. The mixture was held for 1 h and then filtered. The resulting cake was washed with DI water (4 vol.) and n-heptane (2 vol.) respectively. The cake was conditioned for about 24 h and then DCM (5 vol.) was added. This mixture was agitated for about 12 h at about 20 to about 25 °C. The mixture was filtered and the cake washed with DCM (1 vol.). The cake was conditioned for about 6 h. The cake was then vacuum-dried at 50 ± 5 °C. To the cake was added DI water (10 vol.), and i-PrOH (0.8 vol.) and the mixture was agitated at 25 ± 5 °C for about 6 h. An XRPD sample confirmed the compound of Formula (I) was Form C. The mixture was filtered and the cake was washed with DI water (5 vol.) followed by n-heptane (3 vol.). The cake was conditioned and then vacuum dried at 50 ± 5 °C to afford a compound of Formula (I) as polymorph Form C. Example 5

Synthesis of (S)-3-(l-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one

Example 5A

[00584] Compound 9 (2.39 kg) was treated with Compound 4 and triethylamine in isopropyl alcohol at 80 °C for 24 hours. The reaction was monitored by HPLC until completion, affording 8-chloro-2-phenyl-3- ((lS)-l-(9-(tetrahydro-2H^yran-2-yl)-9H^urin-6-ylamino)ethyl)isoquinolin-l(2H)-one (compound 10) as a tan solid in 94% yield with 98% (AUC) purity by HPLC analysis.

[00585] 8-Chloro-2-phenyl-3-((lS)-l-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-ylamino)ethyl)- isoquinolin-l(2H)-one (compound 10) (3.63 kg) was treated with HC1 in ethanol at 30 °C for 2.3 hours. The reaction was monitored by HPLC until completion, and afforded a compound of Formula (I) as a tan solid in 92% yield with >99% (AUC) purity and 90.9% (AUC) ee by HPLC analysis.

Example 5B

[00586] 3-(l-Aminoethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one (Compound 9) (0.72 mmol), 6-chloro- 9-(tetrahydro-2H-pyran-2-yl)-9H-purine (Compound 4) (344 mg, 1.44 mmol) and DIPEA

(279 mg, 2.16 mmol) were dissolved in «-BuOH (20 mL), and the resulting mixture was stirred at reflux for 16 h. The reaction mixture was concentrated in vacuo and purified by flash column chromatography on silica gel (eluting with 30% to 50% Hex/EA) to afford the product, 8-chloro-2-phenyl-3-((lS)-l-(9-(tetrahydro-2H- pyran-2-yl)-9H-purin-6-ylamino)ethyl)isoquinolin-l(2H)-one (Compound 10), as a white solid (60% yield). [00587] 8-Chloro-2-phenyl-3-((lS)-l-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-ylamino)ethyl)- isoquinolin-l(2H)-one (Compound 10) (0.42 mmol) was dissolved in HCl/EtOH (3 M, 5 mL), and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with saturated NaHC0₃ aqueous solution and the pH was adjusted to about 7-8. The mixture was extracted with CH₂C1₂ (50 mL x 3), dried over anhydrous Na₂S0₄, and filtered. The filtrate was concentrated in vacuo, and the residue was recrystallized from ethyl acetate and hexanes (1 : 1). The solid was collected by filtration and dried in vacuo to afford the product (S)-3-(l-(9H-purin-6-ylamino) ethyl)-8-chloro-2-phenylisoquinolin- l(2H)-one (Formula (I)) (90% yield) as a white solid as polymorph Form A.

Example 5C

[00588] 3-(l-Aminoethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one (Compound 9) and 6-chloro-9- (tetrahydro-2H-pyran-2-yl)-9H-purine (Compound 4) are combined in the presence of triethylamine and isopropyl alcohol. The reaction solution is heated at 82 °C for 24 hours to afford Compound 10. The intermediate compound 10 is treated with concentrated HCl and ethanol under aqueous conditions at 35 °C to remove the tetrahydropyranyl group to yield (S)-3-(l-(9H-purin-6-ylamino)ethyl)-8-chloro-2- phenylisoquinolin-l(2H)-one. Isolation/purification under aqueous conditions affords polymorph Form C.

Example 6

Synthesis of (S)-3-(l-(9H^urin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one

[00589] 3-(l-Aminoethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one (Compound 9) (150 g; 90% ee) and 6- chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (Compound 4) (216 g, 1.8 equiv) were charged to a round bottom flask followed by addition of IPA (1.2 L; 8 vol) and triethylamine (175 mL; 2.5 equiv). The resultant slurry was stirred at reflux for one day. Heptane (1.5 L; 10 vol) was added dropwise over two hours. The batch was then cooled to 0-5 °C, held for one hour and filtered. The cake was washed with heptane (450 mL; 3 vol) and returned to the reactor. IPA (300 mL; 2 vol) and water (2.25 L; 15 vol) were added and the resultant slurry stirred at 20-25 °C for three and half hours then filtered. The cake was washed with water (1.5 L; 10 vol) and heptane (450 mL; 3 vol) and then vacuum dried at 48 °C for two and half days to give 227 g (90.1 %) of the intermediate (Compound 10) as an off-white solid with >99% (AUC) purity and >94 ee (chiral HPLC). The ee was determined by converting a sample of the cake to the final product and analyzing it with chiral HPLC.

[00590] The intermediate (Compound 10) (200 g) was slurried in an ethanol (900 mL; 4.5 vol) / water (300 mL; 1.5 vol) mixture at 22 °C followed by addition of cone. HC1 (300 mL; 1.5 vol) and holding for one and half hours at 25-35 °C. Addition of HC1 resulted in complete dissolution of all solids producing a dark brown solution. Ammonium hydroxide (260 mL) was added adjusting the pH to 8-9. Product seeds of polymorph Form C (0.5 g) (Form A seeds can also be used) were then added and the batch which was held for ten minutes followed by addition of water (3 L; 15 vol) over two hours resulting in crystallization of the product. The batch was held for 3.5 hours at 20-25 °C and then filtered. The cake was washed with water (1 L; 5 vol) followed by heptane (800 mL; 4 vol) and vacuum dried at 52 °C for 23 hours to give 155.5 g (93.5%) of product with 99.6% (AUC) purity and 93.8% ee (chiral HPLC).

Example 7

-3-(l-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one

[00591] A mixtue of isopropanol (20.20 kg, 8 vol.), Compound 9 (3.17 kg, 9.04 mol, 1 eq.), Compound 4 (4.61 kg, 16.27 mol, 1.8 eq.) and triethylamine (2.62 kg, 20.02 mol, 2.4 eq.) was prepared and heated to an internal temperature of 82 ± 5 °C. The mixture was stirred at that temperature for an additional about 24 h. The temperature was adjusted to 20 ± 5 °C slowly over a period of about 2 h and the solids were isolated via vacuum filtration through a 24″ polypropylene table top filter equipped with a Sharkskin paper. The filter cake was rinsed sequentially with IPA (5.15 kg, 3 vol.), purified water (80.80 kg, 25 vol.) and n-heptane (4.30 kg, 2 vol.). The cake was further dried for about 4 days in vacuo at 50 ± 5 °C to afford Compound 10.

[00592] To a mixture of ethanol (17.7 kg, 5 vol.) and Compound 10 (4.45 kg, 8.88 mol. 1.0 eq.) was added purified water (8.94 kg, 2 vol.). To this mixture was slowly added concentrated HC1 (3.10 kg, 3.5 eq.) while maintaining the temperature below about 35 °C. The mixture was stirred at 30 ± 5 °C for about 1.5 h and HPLC analysis indicated the presence the compound of Formula (I) in 99.8% (AUC) purity with respect to compound 10.

[00593] Then, the compound of Formula (I) mixture was cooled to 25 ± 5 °C. The pH of the mixture was adjusted to about 8 using pre filtered ammonium hydroxide (1.90 kg). After stirring for about 15 min, Form C crystal seeds (13.88 g) were added. After stirring for about 15 min, purified water (58.0 kg, 13 vol.) was charged over a period of about 2 h. After stirring the mixture for 15 h at 25 ± 5 °C, the solids were isolated via vacuum filtration through a 24″ polypropylene table top filter equipped with a PTFE cloth over Sharkskin paper. The filter cake was rinsed with purified water (18.55 kg, 4 vol.) followed by pre -filtered n-heptane (6.10 kg, 2 vol.). After conditioning the filter cake for about 24 h, HPLC analysis of the filter cake indicated the presence the compound of Formula (I) in about 99.2% (AUC) purity.

[00594] To the filter cake was added dichloromethane (29.9 kg, 5 vol.) and the slurry was stirred at 25 ± 5 °C for about 24 h. The solids were isolated via vacuum filtration through a 24″ polypropylene table top filter equipped with a PTFE cloth over Sharkskin paper, and the filter cake was rinsed with DCM (6.10 kg, 1 vol.). After conditioning the filter cake for about 22 h, the filter cake was dried for about 2 days in vacuo at 50 ± 5 °C to afford the compound of Formula (I) in 99.6% (AUC) purity. The compound of Formula (I) was consistent with a Form A reference by XRPD.

[00595] To this solid was added purified water (44.6 kg, 10 vol.) and pre filtered 2-propanol (3.0 kg, 0.8 vol.). After stirring for about 6 h, a sample of the solids in the slurry was analyzed by XRPD and was consistent with a Form C reference. The solids were isolated via vacuum filtration through a 24″ polypropylene table top filter equipped with a PTFE cloth over Sharkskin paper, and the filter cake was rinsed with purified water (22.35 kg, 5 vol.) followed by pre filtered n-heptane (9.15 kg, 3 vol.). After conditioning the filter cake for about 18 h, the filter cake was dried in vacuo for about 5 days at 50 ± 5 °C.

[00596] This process afforded a compound of Formula (I) in about 99.6% (AUC) purity, and a chiral purity of greater than about 99% (AUC). An XRPD of the solid was consistent with a Form C reference standard. ^:H NMR (DMSO-<i₆) and IR of the product conformed with reference standard.

…………………………..

http://www.google.com/patents/US20140120083

In some embodiments, the compound has the following structure:

which is also referred to herein as Compound 292.

In some embodiments, a polymorph of a compound disclosed herein is used. Exemplary polymorphs are disclosed in U.S. Patent Publication No. 2012-0184568 (“the ‘568 publication”), which is hereby incorporated by reference in its entirety.

In one embodiment, the compound is Form A of Compound 292, as described in the ‘568 publication. In another embodiment, the compound is Form B of Compound 292, as described in the ‘568 publication. In yet another embodiment, the compound is Form C of Compound 292, as described in the ‘568 publication. In yet another embodiment, the compound is Form D of Compound 292, as described in the ‘568 publication. In yet another embodiment, the compound is Form E of Compound 292, as described in the ‘568 publication. In yet another embodiment, the compound is Form F of Compound 292, as described in the ‘568 publication. In yet another embodiment, the compound is Form G of Compound 292, as described in the ‘568 publication. In yet another embodiment, the compound is Form H of Compound 292, as described in the ‘568 publication. In yet another embodiment, the compound is Form I of Compound 292, as described in the ‘568 publication. In yet another embodiment, the compound is Form J of Compound 292, as described in the ‘568 publication.

In specific embodiments, provided herein is a crystalline monohydrate of the free base of Compound 292, as described, for example, in the ‘568 application. In specific embodiments, provided herein is a pharmaceutically acceptable form of Compound 292, which is a crystalline monohydrate of the free base of Compound 292, as described, for example, in the ‘568 application.

Any of the compounds (PI3K modulators) disclosed herein can be in the form of pharmaceutically acceptable salts, hydrates, solvates, chelates, non-covalent complexes, isomers, prodrugs, isotopically labeled derivatives, or mixtures thereof.

Chemical entities described herein can be synthesized according to exemplary methods disclosed in U.S. Patent Publication No. US 2009/0312319, International Patent Publication No. WO 2011/008302A1, and U.S. Patent Publication No. 2012-0184568, each of which is hereby incorporated by reference in its entirety, and/or according to methods known in the art.

……………………………………………

KEY Duvelisib, IPI-145, INK-1197, AbbVie, INFINITY, chronic lymphocytic leukemia, phase 3, orphan drug

WO2013088404A1	Dec 14, 2012	Jun 20, 2013	Novartis Ag	Use of inhibitors of the activity or function of PI3K
WO2014004470A1 *	Jun 25, 2013	Jan 3, 2014	Infinity Pharmaceuticals, Inc.	Treatment of lupus, fibrotic conditions, and inflammatory myopathies and other disorders using pi3 kinase inhibitors
WO2014072937A1	Nov 7, 2013	May 15, 2014	Rhizen Pharmaceuticals Sa	Pharmaceutical compositions containing a pde4 inhibitor and a pi3 delta or dual pi3 delta-gamma kinase inhibitor

US7449477 *	Nov 22, 2004	Nov 11, 2008	Eli Lilly And Company	7-phenyl-isoquinoline-5-sulfonylamino derivatives as inhibitors of akt (protein kinase B)
US20090312319 *	Jul 15, 2009	Dec 17, 2009	Intellikine	Certain chemical entities, compositions and methods
US20100168153 *	Nov 16, 2007	Jul 1, 2010	Novartis Ag	Salts and crystall forms of 2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-propionitrile

WO2013012915A1	Jul 18, 2012	Jan 24, 2013	Infinity Pharmaceuticals Inc.	Heterocyclic compounds and uses thereof
WO2013012918A1	Jul 18, 2012	Jan 24, 2013	Infinity Pharmaceuticals Inc.	Heterocyclic compounds and uses thereof
WO2013032591A1	Jul 18, 2012	Mar 7, 2013	Infinity Pharmaceuticals Inc.	Heterocyclic compounds and uses thereof
WO2013049332A1	Sep 27, 2012	Apr 4, 2013	Infinity Pharmaceuticals, Inc.	Inhibitors of monoacylglycerol lipase and methods of their use
WO2013088404A1	Dec 14, 2012	Jun 20, 2013	Novartis Ag	Use of inhibitors of the activity or function of PI3K
WO2013154878A1	Apr 3, 2013	Oct 17, 2013	Infinity Pharmaceuticals, Inc.	Heterocyclic compounds and uses thereof
WO2014004470A1 *	Jun 25, 2013	Jan 3, 2014	Infinity Pharmaceuticals, Inc.	Treatment of lupus, fibrotic conditions, and inflammatory myopathies and other disorders using pi3 kinase inhibitors
WO2014071105A1	Nov 1, 2013	May 8, 2014	Infinity Pharmaceuticals, Inc.	Treatment of rheumatoid arthritis and asthma using p13 kinase inhibitors
WO2014071109A1	Nov 1, 2013	May 8, 2014	Infinity Pharmaceuticals, Inc.	Treatment of cancers using pi3 kinase isoform modulators
WO2014072937A1	Nov 7, 2013	May 15, 2014	Rhizen Pharmaceuticals Sa	Pharmaceutical compositions containing a pde4 inhibitor and a pi3 delta or dual pi3 delta-gamma kinase inhibitor

WO2001081346A2	Apr 24, 2001	Nov 1, 2001	Icos Corp	Inhibitors of human phosphatidyl-inositol 3-kinase delta
US6800620	Jan 6, 2003	Oct 5, 2004	Icos	Contacting leukocytes, osteoclasts with an enzyme inhibitors, a 9h-purin-3h-quinazolin-4-one derivatives, treating bone-resorption disorder, antiproliferative agents treating leukemia cells
US20060276470 *	Aug 18, 2003	Dec 7, 2006	Jackson Shaun P	(+-)-7-Methyl-2-morpholin-4-yl-9-(1-phenylaminoethyl)-pyrido[1,2-a]pyrimidin-4-one, for example; selective inhibitors of phosphoinositide (PI) 3-kinase beta for use in anti-thrombotic therapy
US20080032960 *	Apr 4, 2007	Feb 7, 2008	Regents Of The University Of California	PI3 kinase antagonists

Tecadenoson…………Atrial Fibrillation

September 8, 2014 7:44 am / Leave a comment

Tecadenoson

CAS : 204512-90-3

N-[(3R)-Tetrahydro-3-furanyl]adenosine

(2R,3S,4R,5R)-2-(hydroxymethyl)-5-[6-[[(3R)-oxolan-3-yl]amino]purin-9-yl]oxolane-3,4-diol

N-(3-Tetrahydrofuranyl)-6-aminopurine riboside

Manufacturers’ Codes: CVT-510

UNII-GZ1X96601Z; AC1L4KMO;

Molecular Formula: C14H19N5O5

Molecular Weight: 337.33

Percent Composition: C 49.85%, H 5.68%, N 20.76%, O 23.71%

Therap-Cat: Antiarrhythmic.

clinical……..http://clinicaltrials.gov/search/intervention=Tecadenoson…phase 2…………gilead

Tecadenoson is a novel selective A1 adenosine receptor agonist that is currently being evaluated for the conversion of paroxysmal supraventricular tachycardia (PSVT) to sinus rhythm. It is being developed by CV Therapeutics, Inc.

Tecadenoson is an adenosine A1 agonist which had been in phase II clinical evaluation by Gilead Sciences for treatment of atrial fibrillation. The company was also conducting phase III clinical trials for the treatment of paroxysmal supraventricular tachycardia (PSVT); however, no recent developments have been reported for these indications.

Due to the fact that tecadenoson selectively stimulates the A1 receptor and slows electrical impulses in the heart’s conduction system without significantly stimulating the A2 receptor, the intravenous administration of CVT-510 may hold potential for rapid intervention in the control of atrial arrhythmias without lowering blood pressure.

The reaction of 3-tetrahydrofuroic acid (I) with diphenyl phosphoryl azide (DPPA) in refluxing dioxane gave the intermediate isocyanate (II), which was treated with benzyl alcohol (III) to yield carbamate (IV). Subsequent hydrogenolysis in the presence of Pd/C afforded racemic amine (V), which was resolved by treatment with S-(+)-10-camphorsulfonyl chloride (VI) in pyridine, followed by column chromatography and recrystallization from acetone of the resulting sulfonamide (VII). Then, hydrolysis in HCl-AcOH provided the S-amine (VIII). Condensation of amine (VIII) with 6-chloropurine riboside (IX) in the presence of triethylamine in refluxing MeOH furnished the title compound.

EP 0920438; EP 0992510; JP 2000501426; US 5789416; WO 9808855

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http://www.google.com/patents/WO2011123518A1?cl=en

CVT-510 (tecadenoson) has chemical structure (8 :

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http://www.google.co.in/patents/US6576619

Compound I can be prepared through reaction of the corresponding primary amino compound, R₁NH₂, through heating with commercially available 6-chloroadenosine in the appropriate solvent (e.g. n-butanol, dimethylformamide, and ethanol). The primary amino compound, R₁NH₂, is either commercially available or can be prepared as previously described (International Patent Application WO 98/08855).

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http://www.google.com/patents/WO1998008855A2?cl=en

EXAMPLE 1

The compounds of this invention may be prepared by conventional methods of organic chemistry. The reaction sequence outlined below, is a general method, useful for the preparation of compounds of this invention.

According to this method, oxacycloalkyl carboxylic acid is heated in a mixture of dioxane, diphenylphosphoryazide and triethylamine for 1 hour. To this mixture is added benzyl alcohol and the reaction is further heated over night to give intermediate compound 1. Compound 1 is dissolved in methanol. Next, concentrated HC1, Pd/C is added and the mixture is placed under hydrogen at 1 atm. The mixture is stirred overnight at room temperature and filtered. The residue is recrystallized to give intermediate compound 2. 6-chloropurine riboside is combined and the mixture is compound 2 dissolved in methanol and treated with triethylamine. The reaction is heated to 80° C for 30 hours. Isolation and purification leads to Compound 3.

EXAMPLE 2

Compounds of this invention prepared according to the method of Example 1 were tested in two functional models specific for adenosine A, receptor agonist function. The first was the A , receptor mediated inhibition of isoproterenol stimulated cAMP accumulation in DDT cells. The EC50 of each derivative is shown in Table I. Also shown in Table I is the ability of each derivative to stimulate cAMP production in PC 12 cells, a function of agonist stimulation of adenosine A₂ receptors. The ratio of the relative potency of each compound in stimulating either an A, receptor or an A₂ receptor effect is termed the selectivity of each compound for the A, receptor. As can be seen in Table I, each derivative is relatively selective as an A, receptor agonist. The use of measuring cAMP metabolism as an assay for adenosine A , receptor function has been previously described (Scammells, P., Baker, S., Belardinelli, L., and Olsson, R. , 1994, Substituted 1 ,3-dipropylxanthines as irreversible antagonists of A, adenosine receptors. J. Med. Chem 37: 2794-2712, 1994).

Table I

Compound R EC₅₀ (nM) EC_S, (nM) A,/A₂ A-/A, DDT cells PC 12 cells

I 4-arninopyran 12 970 0.012 80.0

II (±)-3-aminotetrahydrofuran 13 1400 0.0093 107.6

III (R)-3-aminotetrahydrofuran 1.08 448 0.0024 414

IV ( 1 )-caprolactam 161 181 0.889 1.12

V (S)-3-aminotetrahydrofuran 3.40 7680 0.00044 2258

Compounds were also tested in a whole organ model of A, receptor activation with respect to atrial and AV nodal function. In this model, guinea pig hearts are isolated and perfused with saline containing compound while atrial rate and AV nodal conduction time are assessed by electrographic measurement of atrial cycle length and AV intervals, as detailed in Belardinelli, L, Lu, J. Dennis, D. Martens, J, and Shryock J. (1994); The cardiac effects of a novel A,-adenosine receptor agonist in guinea pig isolated heart. J. Pharm. Exp. Therap. 271:1371-1382 (1994). As shown in Figure 1, each derivative was effective in slowing the atrial rate and prolonging the AV nodal conduction time of spontaneously beating hearts in a concentration-dependent manner, demonstrating efficacy as adenosine A, receptor agonists in the intact heart.

EXAMPLE 3

Preparation ofN-benzyloxycarbonyl-4-aminopyran.

A mixture of 4-pyranylcarboxylic acid (2.28 gm, 20 mmol), diphenylphosphorylazide (4.31 ml, 20 mmol), triethylamine (2.78 ml, 20 mmol) in dioxane (40 ml) was heated in a 100° C oil bath under dry nitrogen for 1 hour. Benzyl alcohol (2.7 ml, 26 mmol) was added, and heating was continued at 100° C for 22 hours. The mixture was cooled, filtered from a white precipitate and concentrated. The residue was dissolved in 2N HC1 and extracted twice with EtOAc. The extracts were washed with water, sodium bicarbonate, brine and then dried over MgSO4, and concentrated to an oil which solidified upon standing. The oil was chromatographed (30% to 60% EtO Ac/Hex) to give 1.85 g of a white solid (40%).

Preparation of 4-aminopyran.

N-benzyloxycarbonyl-4-aminopyran (1.85 gm, 7.87 mmol) was dissolved in MeOH (50 ml) along with cone. HC1 and Pd-C ( 10%, 300 mg). The vessel was charged with hydrogen at 1 atm and the mixture was allowed to stir for 18 hours at room temperature. The mixture was filtered through a pad of eelite and concentrated. The residue was co-evaporated twice with MeOH/EtOAc and recrystallized from MeOH/EtOAc to afford 980 mg (91 %) of white needles (mp 228-230° C).

Preparation of 6-(4-aminopyran)-purine riboside. A mixture of 6-chloropurine riboside (0.318 gm, 1. 1 mmol), 4-aminopyran-HCl

(0.220 mg,

1.6 mmol) and triethylamine (0.385 ml, 2.5 mmol) in methanol (10 ml) was heated to 80° C for 30 hours. The mixture was cooled, concentrated and the residue chromatographed (90: 10: 1, CH₂ Cl₂/MeOH/PrNH₂). The appropriate fractions were collected and recliromatographed using a chromatotron

(2 mm plate, 90: 10: 1, CH₂ Cl₂/MeOH/PrNH₂) to give an off white foam (0.37 gm, 95%).

EXAMPLE 4

Preparation of N-benzyloxycarbonyl-3-aminotetrahydrofuran. A mixture of 3-tetrahydrofuroic acid (3.5 gm, 30 mmol), diphenylphosphorylazide (6.82 ml, 32 mmol), triethylamine (5 ml, 36 mmol) in dioxane (35 ml) was stirred at RT for 20 min then heated in a 100° C oil bath under dry nitrogen for 2 hours. Benzyl alcohol (4.7 ml, 45 mmol) was added, and continued heating at 100° C for 22 hours. The mixture was cooled, filtered from a white precipitate and concentrated. The residue was dissolved in 2N HC1 and extracted twice using EtOAc. The extracts were washed with water, sodium bicarbonate, brine dried over MgSO₄, and then concentrated to an oil which solidifies upon standing. The oil was chromatographed (30% to 60% EtO Ac/Hex) to give 3.4 g of an oil (51

%).

Preparation of 3-aminotetrahydrofuran.

N-benzyloxycarbonyl-3-aminotetrahydrofuran (3.4 gm, 15 mmol) was dissolved in MeOH (50 ml) along with cone. HC1 and Pd-C (10%, 300 mg). The vessel was charged with hydrogen at 1 atm and the mixture was allowed to stir for 18 hours at room temperature. The mixture was filtered through a pad of celite and concentrated. The residue was co-evaporated two times with MeOH/EtOAc and recrystallized from MeOH/EtOAc to give 1.9 g of a yellow solid.

Preparation of 6-(3-aminotetrahydrofuranyl)purine riboside. A mixture of 6-chloropurine riboside (0.5 gm, 1.74 mmol), 3-aminotetrahydrofuran

(0.325 gm, 2.6 mmol) and triethylamine (0.73 ml, 5.22 mmol) in methanol (10 ml) was heated to 80° C for 40 hours. The mixture was cooled, and concentrated. The residue was filtered through a short column of silica gel eluting with 90/10/1 (CH₂Cl₂/MeOH/PrNH₂), the fractions containing the product were combined and concentrated. The residue was chromatorgraphed on the chromatotron (2 mm plate, 92.5/7.5/1 , CH₂CL₂/MeOH/P.NH₂). The resulting white solid was recrystallized from MeOH/EtOAc to give 0.27 gm of white crystals (mp 128-130° C).

EXAMPLE 5

Resolution of 3-arninotetrahydrofuran hydrochloride

A mixture of 3-aminotetrahydrofuran hydrochloride (0.5 gm, 4 mmol) and

(S)-(+)-10-camphorsulfonyl chloride (1.1 gm, 4.4 mmol) in pyridine (10 ml) was stirred for 4 hours at room temperature and then concentrated. The residue was dissolved in EtOAc and washed with 0.5N HC1, sodium bicarbonate and brine. The organic layer was dried over MgSO₄, filtered and concentrated to give 1. 17 g of a brown oil (97%) which was chromatographed on silica gel (25% to 70% EtOAc/Hex). The white solid obtained was repeatedly recrystallized from acetone and the crystals and supernatant pooled until an enhancement of greater than 90% by 1H NMR was acheived.

Preparation of 3-(S)-aminotetrahydrofuran hydrochloride.

The sulfonamide (170 mg, 0.56 mmol) was dissolved in cone. HCl/AcOH (2 mL each), stirred for 20 hours at room temperature, washed three times with CH₂C1₂ (10 ml) and concentrated to dryness to give 75 mg (qaunt ) of a white solid

Preparation of 6-(3-(S)-aminotetrahydrofuranyl)puπne riboside.

A mixture of 6-chloropurιne riboside (30 mg, 0.10 mmol),

3-(S)-amιnotetrahydrofuran hydrochloride (19 mg, 0.15 mmol) and triethylamine (45 ml, 0.32 mmol) in methanol

(0.5 ml) was heated to 80° C for 18 hours. The mixture was cooled, concentrated and chromatographed with 95/5 (CH₂Cl /MeOH) to give 8 mg (24%) of a white solid.

Literature References:

Selective adenosine A1-receptor agonist. Prepn: R. T. Lum et al., WO 9808855; eidem, US 5789416 (both 1998 to CV Therapeutics).

Clinical effect on AV nodal conduction: B. B. Lerman et al., J. Cardiovasc. Pharmacol. Ther. 6, 237 (2001).

Clinical evaluation in paroxysmal supraventricular tachycardia: E. N. Prystowsky et al., J. Am. Coll. Cardiol. 42, 1098 (2003); K. A. Ellenbogen et al., Circulation 111, 3202 (2005).

Review of pharmacology and clinical experience: A. Zaza, Curr. Opin. Invest. Drugs 3, 96-100 (2002); J. W. Cheung, B. B. Lerman, Cardiovasc. Drug Rev. 21, 277-292 (2003).

US7144871 *	19 Feb 2003	5 Dec 2006	Cv Therapeutics, Inc.	Partial and full agonists of A1 adenosine receptors
US7696181 *	24 Aug 2006	13 Apr 2010	Cv Therapeutics, Inc.	Partial and full agonists of A1 adenosine receptors

Keywords: Antiarrhythmic, Adenosine Receptor Agonist, Tecadenoson, CVT-510, CV Therapeutics

Tioconazole UK-20349 an antifungal agent

September 8, 2014 7:12 am / Leave a comment

Tioconazole;UK-20349;Trosyd;Trosyl;Vagistat-1

l-[2-(2-chloro-3-thienyl)methoxy]-2-(2,4- dichlorophenyl)ethyl]-lH-imidazole,

1-[2-(2-Chloro-3-thienylmethoxy)-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole

65899-73-2

Launched – 1983, Bristol-Myers Squibb

Trademarks: Fungibacid (Asche); Gyno-Trosyd (Pfizer); Trosyd (Pfizer); Trosyl (Pfizer); Vagistat (BMS); Zoniden (Irbi)

Molecular Formula: C16H13Cl3N2OS

Molecular Weight: 387.71

Percent Composition: C 49.57%, H 3.38%, Cl 27.43%, N 7.23%, O 4.13%, S 8.27%

Derivative Type: Hydrochloride

Molecular Formula: C16H13Cl3N2OS.HCl

Molecular Weight: 424.17

Percent Composition: C 45.31%, H 3.33%, Cl 33.43%, N 6.60%, O 3.77%, S 7.56%

Properties: Crystals, mp 168-170°.

Melting point: mp 168-170°

Therap-Cat: Antifungal (topical).

Tioconazole is an antifungal medication of the imidazole class used to treat infections caused by a fungus or yeast. It is marketed under the brand names Trosyd and Gyno-Trosyd (Pfizer). Tioconazole ointments serve to treat women’s vaginal yeast infections.^[1]They are available in one day doses, as opposed to the 7-day treatments more common in use in the past.

Tioconazole topical (skin) preparations are also available for ringworm, jock itch, athlete’s foot, and tinea versicolor or “sun fungus”.

Side effects

Side effects (for the women’s formulas) may include temporary burning/irritation of the vaginal area, moderate drowsiness, headachesimilar to a sinus headache, hives, and upper respiratory infection. These side effects may be only temporary, and do not normally interfere with the patient’s comfort enough to outweigh the end result.

Tioconazole
Systematic (IUPAC) name

(RS)-1-[2-[(2-Chloro-3-thienyl)methoxy]-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole
Clinical data
Trade names	Vagistat-1
AHFS/Drugs.com	monograph
Legal status	US: OTC
Routes	Topical
Identifiers
CAS number	65899-73-2
ATC code	D01AC07 G01AF08
PubChem	CID 5482
DrugBank	DB01007

KEGG	D00890

Synonyms	Thioconazole
Chemical data
Formula	C₁₆H₁₃Cl₃N₂O S
Mol. mass	387.711 g/mol

http://www.google.com/patents/EP0934279A1?cl=en

Imidazole derivatives, in particular, l-[2-(2-chloro-3-thienyl)methoxy]-2-(2,4- dichlorophenyl)ethyl]-lH-imidazole, commonly referred to as tioconazole, are known for their antifungal therapeutic properties. US 4,062,966 discloses a process for the preparation of l-aryl-2-(l -imidazolyl) alkyl ethers and thioethers which employs arylation of an appropriate 1 -aryl-2-(l -imidazolyl)alkanol or alkane thiol having the formula

wherein R^l to R⁴ are each H or C,^ alkyl, Ar is phenyl, or substituted phenyl wherein said substitutents are halogen, C,^ alkyl, C,_₆ alkoxy, thienyl, or halothienyl, and, Z is oxygen or sulfur. In accordance with US’966, the reaction comprises converting the alcohol or thiol in a suitable solvent to its alkali metal derivative by treatment with a strong base, such as an alkali metal amide or hydride, and reacting with the appropriate aralkyl halide ofthe formula

X-(CH₂)η-Y

where n is 1 or 2, Y is an aromatic heterocyclic group or substituted heterocyclic group, wherein substitutents are halogen, C,.₆ alkyl, or C,.₆ alkoxy atoms, thienyl or halothienyl group, and X is a halogen, preferably chlorine. Tetrahydrofuran (THF) is the preferred solvent taught in US ‘966. Reaction temperatures may range from about 0 °C to reflux temperature ofthe solvent and reaction times range from about 1 hour to about 24 hours. The product is isolated with water, extracted with ether, and may be purified as the free base or converted to a salt, e.g. the hydrochloride, and purified by recrystallization. A disadvantage ofthe process disclosed in US ‘966 is that THF is a peroxide generator which presents the potential for an explosion. From a commercial viewpoint, peroxide generators are not preferred due to the dangers associated therewith.

GB 1 522 848 discloses a process for the preparation of imidazoles useful as antifungal agents involving a labor intensive, multi-sequence reaction of an imidazole ether with a reactive ester. Like US ‘966, THF is employed presenting similar concerns in the synthesis ofthe desired imidazole product.

According to the Pharmaceutical Manufacturing Encyclopedia, tioconazole is prepared by dissolving l-(2,4-dichlorophenyl)-2-(l- imidazolyl)ethanol in THF and sodium hydride and heating to about 70 ^βC. The resulting mixture is then contacted with 2-chloro-3- chloromethylthiophene and heated to reflux (about 67 ^CC). The resulting product is filtered, saturated with hydrogen chloride, triturated and recrystallized to obtain the purified tioconazole hydrochloride product having a melting point of about 170 ^βC. This salt must then be freebased to form the product used in pharmaceutical formulations. This route, like those discussed above, also presents the dangers of a potential explosion. There is thus a continuing need for a commercially viable, synthetic route for the production of imidazoles, in particular tioconazole.

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see US 4062966

http://www.google.com/patents/US4062966

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References

Tioconazole, Mayo Clinic
References1:

Gymer, G.E.; DE 2619381 .

References2:

Hillier, K.; Blancafort, P.; Castaner, J.; Serradell, M.N.; Tioconazole. Drugs Fut 1980, 5, 10, 509.
Growth quantification and rapid drug susceptibility testing of uropathogenic Candida albicans by isothermal microcalorimetry
28th Congr Eur Assoc Urol (March 15-19, Milan) 2013, Abst 618
Difference in percutaneous absorption and intracutaneous distribution in guinea pigs among topical antifungal drugs (tioconazole solution, tioconazole cream, miconazole nitrate solution and bifonazole solution)
Biol Pharm Bull 2004, 27(9): 1428
A randomized comparison of the nail surface remainder of three nail lacquers containing amorolfine 5%, ciclopirox 8%, or tioconazole 28% in healthy volunteers
63rd Annu Meet Am Acad Dermatol (AAD) (February 18-22, New Orleans) 2005, Abst P1805

Literature References:

Antimycotic imidazole derivative. Prepn: G. E. Gymer, BE 841309; idem, (1976, 1977 both to Pfizer).

Antifungal spectrum: S. Jevons, Antimicrob. Agents Chemother. 15, 597 (1979); F. C. Odds, J. Antimicrob. Chemother. 6,749 (1980).

Pharmacology: M. S. Marriott et al., Dermatologica 166, Suppl. 1, 1 (l983).

Clinical trial in dermatomycosis: Y. M. Clayton et al., Clin. Exp. Dermatol. 7, 543 (1982). Series of articles on pharmacology and clinical efficacy in gynecological use:Gynak. Rundsch. 23, Suppl. 1, 1-60 (l983).

Fosravuconazole in phase 1 for the treatment of fungal infections.

September 8, 2014 4:16 am / Leave a comment

Fosravuconazole

Phosphoric acid 2(R)-[4-(4-cyanophenyl)thiazol-2-yl]-1(R)-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-ylmethyl)propyoxymethyl monoester

(2R,3R)-3-r4-(4-cyanophenyl)thiazol-2-yll-2-(2,4-difluorophenyl)- 1 -(1 H- 1 ,2,4- triazol-l-yl)-2-[(dihydrogen phosphonoxy)methoxylbutane

BEF-1224
BMS-379224
E-1224

Phosphoric acid 2(R)-[4-(4-cyanophenyl)thiazol-2-yl]-1(R)-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-ylmethyl)propyoxymethyl monoester bis(L-lysine) salt is used as drug

The azole antifungal agent E-1224 is a prodrug of ravuconazole. In 2009, originator Eisai licensed E-1224 to Drugs for Neglected Diseases Initiative for the treatment of American trypanosomiasis (Chagas disease) in Latin America and the Caribbean. DNDi was conducting phase II clinical trials with the prodrug for this indication, however, development of the compound has been discontinued due to lack of sustained efficacy. Ravuconazole was originally licensed by Eisai to Bristol-Myers Squibb (BMS). BMS developed the drug’s prodrug, referred to by BMS as BMS-379224. For strategic reasons, BMS did not pursue development of the compound. In 2010, E-1224 was licensed exclusively to Brain Factory for development, commercialization and sublicense in Japan for the treatment of fungal infections.

About Ravuconazole and Ravuconazole Prodrug
The compound on the left is ravuconazole; the compound on the right is the dihydrogen phosphonoxy methoxy derived ravuconazole prodrug which has improved solubility and bioavailability.

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WO 2001052852

http://www.google.com/patents/WO2001052852A1?cl=en

Triazole antifungal compounds are well known in the prior art. Of the several classes known, one particularly potent class contains a tertiary hydroxyl group. For example, U. S. Patent 5,648,372 discloses that (2R,3R)-3-[4-(4- cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)- 1 -( 1 H- 1 ,2,4-triazol- 1 -yl)- butan-2-ol has anti-fungal activity.

The utility of this class of compounds is limited by their low water solubility. For example, the solubility of the above triazole compound in water at pH 6.8 is 0.0006 mg/mL. This greatly impedes developing suitable parenteral dosage forms.

One method of addressing this problem was disclosed in European Patent Application 829478, where the water solubility of an azole antifungal agent was increased by attaching a linked amino-acid to the azole portion of the molecule

Alternatively, WO 97/28169 discloses that a phosphate moiety can be attached directly to the tertiary hydroxyl portion of the anti-fungal compound, e.g. the compound having the formula

U.S. Patent 5,707,977 and WO 95/19983 disclose water soluble prodrugs having the general formula

wherein X is OP(O)(OH)₂ or an easily hydrolyzable ester OC(O)RNR l’rR>2.

WO 95/17407 discloses water-soluble azole prodrugs of the general formula

wherein X is P(O)(OH)₂, C(O)-(CHR’)_n-OP(O)(OH)₂ or C(O)-(CHR’)_π

-(OCHR^,CHR¹)_mOR₂.

WO 96/38443 discloses water-soluble azole prodrugs of the general formula

U.S. Patent 5,883,097 discloses water-soluble amino acid azole prodrugs such as the glycine ester

The introduction of the phosphonooxymethyl moiety into hydroxyl containing drugs has been disclosed as a method to prepare water-soluble prodrugs of hydroxyl containing drugs.

European Patent Application 604910 discloses phosphonooxymethyl taxane derivatives of the general formula

wherein at least one of R^{1 ‘}, R^2″, R^3′, R^6′ or R^7′ is OCH₂OP(O)(OH)₂.

European Patent Application 639577 discloses phosphonooxymethyl taxane derivatives of the formula T-[OCH₂(OCH₂)_mOP(O)(OH)₂]_n wherein T is a taxane moiety bearing on the C13 carbon atom a substituted 3-amino-2- hydroxypropanoyloxy group; n is 1, 2 or 3; m is 0 or an integer from 1 to 6 inclusive, and pharmaceutically acceptable salts thereof. WO 99/38873 discloses O-phosphonooxymethyl ether prodrugs of a diaryl 1,3,4-oxadiazolone potassium channel opener.

Golik, J. et al, Bioorganic & Medicinal Chemistry Letters, 1996, 6:1837- 1842 discloses novel water soluble prodrugs of paclitaxel such as

EXAMPLE 1

(2R,3R)-3-r4-(4-cyanophenyl)thiazol-2-yll-2-(2,4-difluorophenyl)- 1 -(1 H- 1 ,2,4- triazol-l-yl)-2-[(dihydrogen phosphonoxy)methoxylbutane, sodium salt

(2R,3R)-3-r4-(4-cyanophenyl)thiazol-2-yll-2-(2,4-difluorophenyl)-l-(lH- 1 ,2,4-triazol- 1 -yl)-2-[(di-tert-butyl phosphonoxy)methoxy1butane

To a solution of (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4- difluorophenyl)-l-(lH-l,2,4-triazol-l-yl)butan-2-ol, II, (8.74 g, 20 mmol) in THF (40 mL) under a nitrogen atmosphere was added sodium hydride (0.80 g, 60% in oil, 20 mmol) at rt. The resulting mixture was stirred at rt for 0.25 h and then di- tert-butyl chloromethyl phosphate, III (10.3 g, 40 mmol) was added. The reaction mixture was heated at 50 °C for 16 h. The reaction mixture was then allowed to cool to rt and was concentrated under reduced pressure. The residue was dissolved in Et₂O and was washed with H₂O and brine. The organic layer was dried over MgSO₄ and was concentrated under reduced pressure to obtain 17.0 g of crude subtitled compound. IV, as a gum. A small portion of this crude compound was purified by reverse phase chromatography on C- 18. The column was eluted with 30% CH₃CN/H₂O, 38% CH₃CN/H₂O, 45% CH₃CN/H₂O and then 50% CH₃CN/Η₂O. The product containing fractions were concentrated under reduced pressure in order to remove CH₃CN. The resulting aqueous layer was then extracted with Et₂O. The Et O layers were washed with brine, dried and concentrated under reduced pressure to afford purified subtitled compound, IV, as a white solid. 1H NMR (300 MHz, CDC1₃): δ 8.35 (s, 1H), 7.98 (d, 2H, J=9), 7.76 (s, 1H), 7.71 (d, 2H, J=9), 7.63 (s, 1H), 7.36-7.27 (m, 1H), 6.86-6.78 (m, 2H), 5.53 (dd, 1H, J=28,6), 5.53 (dd, 1H, J=9,6), 5.17 (d, 1H, J=15), 5.03 (d, 1H, J=15), 4.01 (q, 1H, J=7), 1.47 (s, 9H), 1.45 (s, 9H), 1.37 (d, 3H, J=7). MS [ESI⁺ (M+H)⁺] 660.2 obs. B. (2R,3R)-3-r4-(4-cyanoρhenyl)thiazol-2-yll-2-(2,4-difluorophenyl)-l-(lH- 1 ,2,4-triazol-l-yl)-2-[(dihydrogen phosphonoxy)methoxy]butane, sodium saltdeprotection

The crude (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4- difluoropheny 1)- 1 -( 1 H- 1 ,2 ,4-triazol- 1 -y l)-2- [(di-tert-buty 1 phosphonoxy)methoxy]butane, IV, (17 g) was dissolved in CH C1 (100 mL). To this solution was added TFA (50 mL) and the reaction mixture was stirred at rt for 0.25 h. The reaction mixture was then concentrated under reduced pressure. To the residue was added H₂O (200 mL), Et₂O (100 mL) and EtOAc (100 mL). The pH of the aqueous layer was adjusted to 7.6 by addition of solid Na₂CO₃ and then the organic and aqueous layers were separated. The aqueous layer was then subjected to reverse phase chromatography on 400 g of C-18 eluted with H₂O to 5% CH₃CN/Η₂O. The product containing fractions were concentrated under reduced pressure, frozen and lyophilized to afford 1.5 g of the subtitled compound, I, as a white solid. (1.5 g, 12% over two steps). Η NMR (500 MHz, D₂O) δ 8.91 (s, IH), 7.92 (s, IH), 7.81 (d, 2H, J=8), 7.80 (s, IH), 7.77 (d, 2H, J=8), 7.21 (dd, IH, J=15,9), 6.99 (ddd, IH, J=9,9,2), 6.91 (ddd, IH, J=9,9,2), 5.35 (dd, IH, J=6,6), 5.29 (d, IH, J=15), 5.21 (dd, IH, J=6,6), 5.19 (d, IH, J=15), 3.86 (q, IH, J=7), and 1.35 (d, 3H, J=7); MS [(ESI^“ (M-HV 546.1]; Anal. Calcd for C23Hi8F₂N5θ5SιPι Na2/3.5 H₂O: C, 42.21 : H, 3.85: N, 10.70: Na, 7.03. Found: C, 42.32: H, 3.83: N, 10.60: Na, 7.04.

Di-tert-butyl chloromethyl phosphate, III:

Di-tert-butyl chloromethyl phosphate, III, may be made by any of the following methods.

Method 1

Silver di-t-butyl phosphate (6.34 g, 20 mmol), which was prepared by mixing di- t-butyl phosphate (obtained from di-t-butyl phosphite by the method of Zwierzak and Kluba, Tetrahedron, 1971 , 27, 3163) with one equivalent of silver carbonate in 50% aqueous acetonitrile and by lyophilizing to dryness, was placed together with chloroiodomethane (35 g, 200 mmol) in benzene and stirred at room temperature for 18 hrs. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residue was chromatographed on silica and eluted with 2:1 hexanes-ethyl acetate. Appropriate fractions were concentrated to dryness to obtain the subtitled compound III (3.7 g, 71% yield): H NMR (CDCI3) δ 5.63 (d, 2H, J=17), 1.51 (s, 18H); MS (MH⁺ = 259).

Method 2

Tetrabutylammonium di-t-butyl phosphate was prepared by dissolving di-t-butyl phosphate [ 20g, 94 mmol (obtained from di-t-butyl phosphite by the method of Zwierzak and Kluba, Tetrahedron, 1971, 27, 3163)] in methanolic tetrabutylammonium hydroxide (47 mL of 1M solution, 47 mmol). The reaction mixture had a temperature of 23 °C and pH of 4.33. The pH of the reaction mixture was adjusted to 6.5-7.0 by addition of methanolic tetrabutylammonium hydroxide (48 mL of 1M solution, 48 mmol) over 0.2 h. The reaction mixture was stirred for 0.5 h at approximately 26 °C and then was concentrated under reduced pressure at a bath temperature below 40 °C. The crude residue was azeotroped three times by adding toluene (3×100 mL) and then the mixture was concentrated under reduced pressure. The crude residue was then triturated in cold hexanes (0°C) for 1 h and then the solid was collected by filtration, washed with a minimum amount of cold hexanes and dried to give a first crop of tetrabutylammonium di-t-butyl phosphate as a white solid. (24. Og). The mother liquor was concentrated under reduced pressure and then triturated in cold hexanes (20 mL) for 1 h. The solid was collected by filtration, washed with a minimum amount of cold hexanes and dried to give a second crop of tetrabutylammonium di-t-butyl phosphate as a white solid. [(8.5g), 32.5g total (77%)]. A solution of tetrabutylammonium di-t-butyl phosphate (218 g, 480 mmol) in benzene (200 mL) was added dropwise to stirred chloroiodomethane (800g, 4535 mmol) over 1.5 h at rt. The reaction mixture was stirred an additional 1.5 h at rt and then was concentrated under reduced pressure. The oily residue was dissolved in Et₂O and filtered to remove white solids which had precipitated. The organic layer was washed with saturated NaHCO₃ and H O/brine (1/1). The organic layer was then dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield a red brown oil (320 g). The red brown oil was subjected to chromatography on silica gel (800g) eluted with 20% EtOAc/Hexanes, 25% EtOAc/Hexanes then 30% EtOAc/Hexanes. The product containing fractions were concentrated under reduced pressure to yield a golden oil. The oil was diluted with CH₂C1₂ (30 mL) , concentrated under reduced pressure and then dried under vacuum to yield the subtitled compound III (61.3g, 49% yield). 1H NMR (Benzene-d₆) δ 5.20 (2H, d, J=15), 1.22 (18H, s).

Method 3

Iodochloromethane (974 g, 402 mL, 5.53 mol) at 25°C was treated with tetrabutylammonium di-t-butylphosphate (250 g, 0.553 mol). The phosphate was added portion wise over 10 minutes. The heterogeneous mixture became a clear pink solution after approximately 15 minutes. The mixture was stirred for three hours, and the iodochloromethane was then removed by rotary evaporation with a bath temperature of <30°C. The residue was taken up in 1 L t-butyl methyl ether and stirred for 15 minutes to precipitate tetrabutylammonium iodide by-product. Tetrabutylammonium iodide was removed by vacuum filtration through a sintered glass funnel. The filtrate was concentrated by rotary evaporation to an oil which contained a 5:1 mixture of III and undesired dimer impurity

III”

The mixture can be purified by a silica gel chromatography to obtain III as pure compound in ~60% yield as an oil.

EXAMPLE 2

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-l-(lH-l,2,4- triazol- 1 -yl)-2- (dihydrogen phosphonoxy)methoxy]butane

A. An oven dried, 1L round-bottom flask equipped with a mechanical stirrer, nitrogen inlet adapter, pressure-equalizing addition funnel fitted with a rubber septum and temperature probe was charged with sodium hydride (2.89 g, 0.069 mol, 60%) and THF (50 mL). To this stirred suspension, (2R,3R)-3-[4-(4- cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)- 1 -( 1 H- 1 ,2,4-triazol- 1 -yl)butan- 2-ol, II, (10 g, 0.023 mol) in 30 mL of THF was added dropwise over 20 minutes at room temperature. After stirring for 45 minutes, a solution of iodine (2.99 g, 0.0115 mol) in THF (30 mL)) was added dropwise over 10 minutes followed by dropwise addition of compound di tert butylchloromethyl phosphate, III (13.29 g, 0.035 mol, -68% purity) over 15 minutes. The reaction mixture was stirred for 4 hours at about 41 °C to complete the reaction. The completion of the reaction was judged by in-process HPLC. The reaction mixture was poured into ice cold water (100 mL). The aqueous phase was separated and extracted with ethyl acetate (3 x 50 mL) and the combined organic extract was washed with 10% sodium thiosulfite (50 mL), water (50 mL), brine (50 mL), dried over magnesium sulfate and concentrated under reduced pressure to give pale yellow oil (22.8 g, In-process HPLC: ~ 97% pure). The crude product was used “as is” in step B.

B. To a round-bottom flask equipped with magnetic stirrer, cooling bath, pH probe and N₂ inlet-outlet was charged the product of Step A above (7.5 g) in CH₂C1₂ (23 mL) and cooled to 0 °C. To this stirred solution, trifluoroacetic acid (8.8 mL) was added slowly and stirred for 3 h to complete the reaction. The completion of the reaction was judged by in-process HPLC. The reaction mixture was poured into a cold solution of 2N NaOH (64 mL). The reaction mixture was extracted with t-butyl acetate (2 x 65 mL) to remove all the organic impurities. The aqueous layer containing the title product as bis sodium salt was treated with activated charcoal (10 g) and filtered through a bed of Celite. The clear filtrate was acidified with IN HC1 to pH 2.5. The free acid, the title product, was extracted into ethyl acetate (2 x 50 mL). The combined organic layer was washed with water, dried over MgSO₄₎ filtered, and the filtrate concentrated under reduced pressure to afford 3.39 g of crude title product.

EXAMPLE 3

Bis lysine salt of (2R,3R)-3-r4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4- difluorophenyl)- 1 -( 1 H- 1 ,2,4-triazol- 1 -yl)-2-[(dihydrogen phosphonoxy)methoxy]butane

The above obtained title product from Example 2 was dissolved in methanol (75 mL) and to this L-lysine (1.8 g) was added and heated at 60 °C for 4.5 h. The hot reaction mixture was filtered through a bed of Celite. The filtrate was concentrated to about 5 mL, mixed with ethanol (100 mL) and heated to 65 °C to crystallize the bis lysine salt. The salt was collected on a Buchner funnel and dried under vacuum to afford 3.71 g of the title compound as an off white crystalline solid.

About Eisai Co., Ltd.
Eisai Co., Ltd. is a research-based human health care (hhc) company that discovers, develops, and markets products throughout the world. Eisai focuses its efforts in three therapeutic areas: integrative neuroscience, including neurology and psychiatric medicines; integrative oncology, which encompasses oncotherapy and supportive-care treatments; and vascular and immunological reactions. Eisai contributes to the well-being of people around the world through a global network of research facilities, manufacturing sites and marketing subsidiaries. For more information about Eisai Co., Ltd., please visit http://www.eisai.co.jp/index-e.html.

ref

BMS-379224, a water-soluble prodrug of ravuconazole
42nd Intersci Conf Antimicrob Agents Chemother (ICAAC) (September 27-30, San Diego) 2002, Abst F-817

WO2000030655A1 *	Nov 17, 1999	Jun 2, 2000	Squibb Bristol Myers Co	Water soluble prodrugs of azole compounds

WO2006118351A1	May 1, 2006	Nov 9, 2006	Eisai Co Ltd	Mono-lysine salts of azole compounds
WO2012060448A1	Nov 4, 2011	May 10, 2012	Eisai R&D Management Co., Ltd.	Combined pharmaceutical composition as antifungal agent
CN101341160B	Dec 20, 2006	Jan 25, 2012	卫材R&D管理有限公司	Process for production of water-soluble azole prodrug
EP1345915A1 *	Oct 18, 2001	Sep 24, 2003	Bristol-Myers Squibb Company	Improved process for water soluble azole compounds
EP2291084A1 *	May 20, 2009	Mar 9, 2011	Neurogesx, Inc.	Carbonate prodrugs and methods of using the same
US7230023	Aug 20, 2003	Jun 12, 2007	Sankyo Company, Limited	Triazole compound containing a phosphonate group
US8735376	May 20, 2009	May 27, 2014	Acorda Therapeutics, Inc.	Carbonate prodrugs and methods of using the same

some animations

RAVUCONAZOLE

September 7, 2014 11:27 am / Leave a comment

Ravuconazole

BMS-207147, ER-30346

BMS 207147
ER 30346
Ravuconazole
UNII-95YH599JWV

CAS Registry Number: 182760-06-1

CAS Name: 4-[2-[(1R,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-thiazolyl]benzonitrile

Additional Names: (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol

(2R,3R)-3-i4-(4-cvanophenyl)thiazol-2-yl1-1 -(1 H-1 ,2,4-triazol-1 -yl)-2-(2,4-difluorophenyl)- butan-2-ol

[R-(R*,R*)]-4-[2-[2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-thiazolyl]benzonitrile
4-[2-[(1R,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-thiazolyl]benzonitrile

Molecular Formula: C22H17F2N5OS

Molecular Weight: 437.47

Percent Composition: C 60.40%, H 3.92%, F 8.69%, N 16.01%, O 3.66%, S 7.33%

Eisai (INNOVATOR)

poser

Properties: Colorless prisms from diisopropyl ether/n-hexane, mp 164-166°. [a]D24= -29.1° (c = 1.03 in methanol).

Melting point: mp 164-166°

Optical Rotation: [a]D24= -29.1° (c = 1.03 in methanol)

Therap-Cat: Antifungal.

http://www.google.com/patents/WO2011042827A1?cl=en…………m.p. 164-166^° C; [a]=-30^° (c=1 , methanol, 25^° C); NMR (CDCI3): 1 .23(3H, d, J=8 Hz), 4.09(1 H, q, J=8Hz), 4.26(1 H, d, J=14Hz), 4.92(1 H, d, J=14Hz), 5.75(1 H, s), 6.75- 6.85(2H, m), 7.45-7.54(2H, m), 7.62(1 H, s), 7.69(1 H, s), 7.75(1 H, d, J=8Hz), 7.86(1 H, s), 8.03(1 H,d,J=8Hz). The analytical data were identical with published (US5648372 and Chem. Pharm. Bull. 1998, 46, 623-630).

SEE……..http://orgspectroscopyint.blogspot.in/2015/03/ravuconazole.html

Ravuconazole (BMS-207147 and ER-30346) is a potent triazole antifungal, being developed by Bristol-Myers Squibb, that is currently in phase I/II clinical trials.^[1] The drug has a shown to have a similar spectrum of activity to voriconazole, with an increased half-life.^[2] However, ravuconazole has limited activity against species of Fusarium, Scedosporium, and Zygomycetes.^[3]^[4]

Ravuconazole
Systematic (IUPAC) name

4-[2-[(2R,3R)-3-(2,4-Difluorophenyl)-3-hydroxy-4-(1,2,4-triazol-1-yl)butan-2-yl]-1,3-thiazol-4-yl]benzonitrile
Clinical data
Legal status	PHASE 2 AS ON SEPT 2014
Identifiers
CAS number	182760-06-1
ATC code	None
PubChem	CID 467825


NIAID ChemDB	057176
Chemical data
Formula	C₂₂H₁₇F₂N₅O S
Mol. mass	437.465086 g/mol

Chemical structure for Ravuconazole

DRUG PROCESS…do not miss this

http://www.drugprocess.com/pdf/Isavuconazole_DPLA_ProcessSummary.pdf =++++++++++++++++++++++

…………………………………………………

Thiazole antifungals. III. Stereocontrolled synthesis of an optically active triazolymethyloxirane precursor to antifungal oxazolidine derivatives
Chem Pharm Bull 1991, 39(9): 2241

https://www.jstage.jst.go.jp/article/cpb1958/39/9/39_9_2241/_pdf

……………………………………………………

Optically active antifungal azoles. I. Synthesis and antifungal activity of (2R,3R)-2-(2,4-difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl)-2-butanol and its stereoisomers
Chem Pharm Bull 1993, 41(6): 1035

https://www.jstage.jst.go.jp/article/cpb1958/41/6/41_6_1035/_pdf

………………………………………………………….

A novel route for chiral synthesis of the triazole antifungal ER-30346
Chem Pharm Bull 1998, 46(7): 1125

https://www.jstage.jst.go.jp/article/cpb1958/46/7/46_7_1125/_pdf

……………………………………………………….

ER-30346 is synthesized by thiazole ring formation of (2R, 3R) -3- (2,4-difluorophenyl) -3-hydroxy-2-methyl-4- (1H-1,2,4-triazol-1-yl ) thiobutanamide (I) and 4-bromoacetylbenzonitrile (II) by means of reflux in methanol. The thioamide (I) is obtained with excellent yield from a chiral nitrile (III) by heating with diethyl dithiophosphate in aqueous medium.

Synthesis method

The nitrile (III), a chiral key intermediate of this synthesis, can be obtained by two different synthetic routes as follows: Route-a: The key step of this route is ring opening reaction of the trisubstituted oxirane (VII) by cyanide anion leading to the nitrile (III). The chiral oxirane (VII) is synthesized from (R) -lactic acid derivatives as already reported. The reaction of (VII) with diethylaluminum cyanide in toluene or lithium cyanide in tetrahydrofuran gives the nitrile (III) with high yield without any epimerization reaction.

The nitrile (III), a chiral key intermediate of this synthesis, can be obtained by two different synthetic routes as follows: Route-b: The starting material of this route is methyl (S) -3-hydroxy-2-methylpropionate (VIII ), which contains one additional carbon between the hydroxyl group and the 2-position carbon of (R) -lactate, the starting material of route-a. The hydroxyl group of (VIII) is protected by triphenylmethyl group. Then, 2,4 -difluorophenyl moiety is introduced to give the ketone (X). Direct conversion of the ketone (X) to the oxirane (XIV) by dimethylsulfoxonium methylide, the same condition for compound (IV) in route-a, does not proceed. The oxirane (XIV) having desired stereochemistry is obtained via oxidation reaction. The ketone (X) is converted to the exomethylene (XI) by Wittig reaction. The stereoselective oxidation of (XI) is achieved by means of osmium tetroxide in the presence of 4-methylmorpholine N-oxide to give the diol (XII) in 58% yield after separation of its epimer by column chromatography. After methanesulfonylation of the primary alcohol of (XII), a triazole moiety is introduced and the triphenylmethyl group is deprotected. Then, the primary hydroxyl group of (XVI) is oxidized under Swern oxidation condition to give the aldehyde (XVII), which is converted to the chiral nitrile intermediate (III) by means of heating with hydroxylamine-O-sulfonic acid.

The synthesis of (2S, 3S) -3- (2,4-difluorophenyl) -3-hydroxy-2-methyl-4- (1,2,4-triazol-1-yl) butyronitrile (XV), a key intermediate the synthesis of ER-30346 has been described: The tritylation of 3-hydroxy-2 (S) -methylpropionic acid methyl ester (I) with trityl chloride in hot pyridine gives the trityl ether (II), which is hydrolyzed with LiOH in H2O / THF / methanol yielding the free acid (III). The esterification of (III) with 2-mercaptopyridine (IV) by means of dicyclohexylcarbodiimide (DCC) in dichloromethane gives the thioester (V), which is treated with 2,4-difluorophenylmagnesium bromide (VI) in THF yielding the propiophenone (VII), which by treatment with methyltriphenylphosphonium bromide / NaH in THF is converted into the methylene derivative (VIII). The oxidation of (VIII) with OsO4 and N-methylmorpholine oxide in acetone affords, after column chromatography, the chiral diol (IX), which is monomesylated with mesyl chloride / triethylamine in dichlormethane giving the monoester (X). The reaction of (X) with 1,2,4-triazol (XI) and NaH in DMF yields (2R, 3S) -2- (2,4-difluorophenyl) -3-methyl-1- (1,2,4-triazol-1-yl) -4- (triphenylmethoxy) -2-butanol (XII), which is detritylated with p-toluenesulfonic acid in methanol affording the diol (XIII). The oxidation of (XIII) with oxalyl chloride / DMSO in dichloromethane gives the aldehyde (XIV), which is finally treated with hydroxylamine-O-sulfonic acid in water yielding the desired bytyronitrile intermediate (XV) already referenced.

http://www.google.com/patents/WO2011042827A1?cl=en

Example 1

(2R,3R)-3-i4-(4-cvanophenyl)thiazol-2-yl1-1 -(1 H-1 ,2,4-triazol-1 -yl)-2-(2,4-difluorophenyl)- butan-2-ol

To a solution of racemic 3-[4-(4-cyanophenyl)thiazol-2-yl]-1 -(1 H-1 ,2,4-triazol-1 -yl)-2-(2,4- difluorophenyl)-butan-2-ol (43.7 g) in acetone (800 ml) a solution of (1 R)-10- camphorsulfonic acid (23 g) in methanol (300 ml) was added and the mixture was heated under reflux until a clear solution was obtained. The solution was slowly cooled to rt, seeded with crystals of the title enantiomeric salt and let overnight. The solid was collected by filtration, washed with acetone and dried to provide (2R,3R)-3-[4-(4- cyanophenyl)thiazol-2-yl]-1 -(1 H-1 ,2,4-triazol-1 -yl)-2-(2,4-difluorophenyl)-butan-2-ol (1 R)- 10-camphorsulfonate as white solid. This crude salt was then taken up in methylenechloride (100 ml) and water (ca. 100 ml) and the mixture was basified with aqueous sodium hydroxide solution. The organic layer was separated and the aqueous phase washed twice with methylenechloride (50 ml) and combined. The organic phases were then washed twice with water (2×50 ml), dried with sodium sulfate, filtrated and the solvent removed under reduced pressure. The crude product was then mixed with isopropanol (ca. 150 ml), heated for 10 min, cooled to 0^° C and stirred for ca. 2 hrs. The product was collected, washed with isopropanol and dried under reduced pressure to provide the enantiomerically pure title compound (17.5 g, 41 % yield, 99.1 % ee); m.p. 164-166^° C; [a]=-30^° (c=1 , methanol, 25^° C); NMR (CDCI3): 1 .23(3H, d, J=8 Hz), 4.09(1 H, q, J=8Hz), 4.26(1 H, d, J=14Hz), 4.92(1 H, d, J=14Hz), 5.75(1 H, s), 6.75- 6.85(2H, m), 7.45-7.54(2H, m), 7.62(1 H, s), 7.69(1 H, s), 7.75(1 H, d, J=8Hz), 7.86(1 H, s), 8.03(1 H,d,J=8Hz). The analytical data were identical with published (US5648372 and Chem. Pharm. Bull. 1998, 46, 623-630).

…………………………

http://www.google.com/patents/WO1999045008A1?cl=en

Example 1

a) Preparation of (2R)-2′,5′-Difluoro-2-(3,4,5,6-tetrahydro-

2H-pyran-2-yloxy)-propiophenone A mixture of magnesium ( 7.25 g, 0.298 mol ) and iodine ( catalytic amount ) and l-bromo-2,5-difluorobenzene ( 20.0 g, 0.178 mol ) in THF ( 250ml ) was vigously stirred. The color of iodine was disappeared and the inner temperature rose up to 65°C. To this mixture was added additional l-bromo-2,5-difluorobenzene ( 30.0 g, 0.267 mol ) dropwise to maintain the inner temperature from 50 to 55°C over 45min. The resulting mixture was stirred at 55°C for 30min. then at r.t. for lhr. The – 21 –

mixture was cooled down to -5°C. To this mixture was added a solution of.4-[(2R)-2-(3,4,5,6-Tetrahydro-2H-pyran-2-yloxy)propionyl] morpholine ( 52.5 g, 0.216 mol ) in THF ( 150ml ) dropwise over 40min. And the resulting mixture was stirred at r.t. for 4hrs. The reaction mixture was cooled down to 5°C and saturated NH4C1 aq. ( 100ml ) was added carefully. The whole was diluted with H20 ( 600ml ) and extracted with EtOAc ( 400ml + 200ml x 2 ). The combined organic layer was dried over Na2S04 and concentrated in vacuo. The residue was chromatographed on silica gel ( n-hexane : EtOAc = 10 :1 ~ 5 : 1 ) to give (2R)-2′,5′- Difluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)-propiophenone (47.3 g,

81 % ) as pale yellow syrup.

Physical form : colorless oil; FAB-MS: m/z 271(M+H)⁺; Η-NMR(CDCl_;j): 1.42~1.90(9H,m),3.32~3.40(lHxl/2,m),3.69~3.77(lHxl/2,m),3.86~3.94 (lHxl/2,m),4.66(lHxl/2,t,J=3.6Hz),4.75(lHxl/2,t,J=3.6Hz),4.87(lHxl/2, q,J=6.6Hz),5.11(lHxl/2,q,J=6.9Hz),7.08~7.25(2H,m),7.49~7.55(lH,m).

b) Preparation of 2-(2,5-Difluorophenyl)-2-[(lR)-l-(3,4,5,6,- tetr ahy dro-2H-pyran-2-yloxy ) ethyl] oxir ane To a stirred mixture of NaH ( 60% in oil, 9.1g, 0.228mol ) in DMSO

(300ml ) was added portionwise trimethylsulfoxonium iodide ( 53.9g, 0.245 mol ) at the inner teperature with the range from 15°C to 18°C. over 20min. The ice bath was removed and the mixtuer was stirred at r.t. for 3hrs. The mixture was cooled down to 10°C. To this mixture was added a solution of (2R)-2′,5′-Difluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2- yloxy)-propiophenone ( 47.3 g , 0.175 mol ) in DMSO (150ml ) dropwise over 20min. The resulting mixture was stirred at r.t. for 4hrs. The reaction mixture was poured into ice-water ( 800ml ). The whole was extracted with EtOAc ( 400ml + 200ml x 2 ). The combined organic layer was washed with brine, dried over Na2S04 and concentrated in vacuo.

The residue was chromatograkkphed on silicagel ( n-hexane : EtOAc = – 22 –

8 : 1 ~ 5 : 1 ) to give 2-(2,5-Difluorophenyl)-2-[(lR)-l-(3,4,5,6,- tetrahydro-2H-pyran-2-yloxy)ethyl]oxirane (48.3 g, 97 % ). Physical form : pale yellow syrup, EI-MS: m/z 284 (M)⁺ ; ¹H-NMR(CDC1₃): 1.15(3Hxl/2,dd,J=6.6,1.3Hz), 1.24(3Hxl/2,dd, J=6.6,1.3Hz), 1.52-1.87 (6H,m),2.83~2,90(lH,m),3.07

(lHxl/2,d,J=5.3Hz),3.36(lHxl/2,d,J=5.6Hz), 3.48~3.56(lH,m),3.82~3.92 (lH,m),4.00~4.16(lH,m),4.73~4.92(lH,m), 6.96~7.02(lH,m),7.09~7.15 (lH,m).

c) Preparation of (3R)-2-(2,5-difluorophenyl)-3-(3,4,5,6- tetrahydro-2H-pyran-2-yloxy)-l-(lH-l,2,4-triazol-l-yl)-2-butanol

To a stirred suspension of NaH ( 60 % in oil, 21.0 g, 0.525 mol ) in DMF (300ml ) was added portionwise 1,2,4-triazole ( 43.3 g, 0.627 mol ) at the inner temperature from 2°C to 11°C over 30min. The resulting mixture was stirred at r.t. for l.δhrs. To this mixture was added a solution of 2-(2,5-Difluorophenyl)-2-[(lR)-l-(3,4,5,6-tetrahydro-2H- pyran-2-yloxy)ethyl]oxirane ( 48.3 g, 0.170 mol ) in DMF ( 50 ml ). The mixture was stirred at 60°C for lhr. and then at 65°C for 14hrs. The reaction mixture was cooled down to 10°C and then poured into ice- water (800 mL ). The resulting mixture was extracted with EtOAc

(400ml + 200ml x 2 ). The combined organic layer was dried over Na2S04 and concentrated in vacuo. The residue was chromatographed on silicagel ( n-hexane : EtOAc = 4 : 1 ~ 1 : 5 ) to give (3R)-2-(2,5- difluorophenyl)-3-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)-l-(lH-l,2,4- triazol-l-yl)-2-butanol ( 43.9 g, 73 % ) and recovered starting material

(13.2 g, 27 % ).

Physical form : colorless syrup ; FAB-MS: m/z 354 (M+H)⁺ ; Η- NMR(CDCl₃): 1.00(3Hxl/2,d,J=6.6Hz),1.13(3Hxl/2,d,J=6.6Hz), 1.42~1.88(6H,m),3.38~3.60 (lH,m),3.80~4.00(lH,m),4.32~5.02(5H,m),6.83~6.99 (2H,m),7.14-7.21

(lH,m),7.73(lHxl/2,s),7.74(lHxl/2,s),7.92(lHxl/2,s),7.95(lHxl/2,s). – 23 –

d) Preparation of (2R,3R)-2-(2,5-difluorophenyl)-l-(lH-l,2,4- triazol-l-yl)-2,3-butanediol

A mixture of (3R)-2-(2,5-difluorophenyl)-3-(3,4,5,6-tetrahydro-2H- pyran-2-yloxy)-l-(lH-l,2,4-triazol-l-yl)-2-butanol ( 43.9 g, 0.124 mol ) and PPTS ( 15.6 g, 62.1 mmol ) in EtOH ( 400ml ) was stirred at 55°C for 5hrs. The mixture was was evaporated to remove solvent down to 100ml. The residue was poured into ice-aqueous NaHC03 ( 500ml ). The whole was extracted with EtOAc ( 400ml + 200ml x 2 ). The combined organic layer was dried over Na2S04 and concentrated in vacuo. The residue was chromatographed on silicagel (CH2C12 : MeOH = 20 : 1) to give (2R,3R)-2-(2,5-difluorophenyl)-l-(lH-l,2,4-triazol-l-yl)-2,3- butanediol (18.0 g, 54 % ). Physical form : colorless syrup ; FAB-MS: m/z 270 (M+H)’ ; ‘H- NMR(CDC1₃): 0.99(3H,d,J=6.6Hz),2.61(lH,d,J=10.6Hz), 4.31-4.36

(lH,m),4.79,4.88

(2H,ABq,J=14.5Hz),4.84(lH,s),6.84~6.99(2H,m),7.13~7.19(lH,m),7.84(l H,s),7.85(lH,s).

e) Preparation of (2R,3S)-2-(2,5-Difluorophenyl)-3-methyl-2-

[ ( 1H- 1 ,2,4-triazol-l -yl) -methyl] -oxir ane

To a cold ( 0°C ) and stirred solution of (2R,3R)-2-(2,5-difluorophenyl)- l-(lH-l,2,4-triazol-l-yl)-2,3-butanediol ( 35.0 g, 0.130 mol ) and triethylamine ( 54.8 ml, 0.393 mol ) in CH2C12 ( 500ml ) was added a mesylchloride ( 12.1 ml, 0.156 mol ) dropwise over 5min. The resulting mixture was stirred at r.t. for l.δhrs. The reaction mixture was poured into ice-water ( 300ml ). The resulting mixture was shaken well and the organic layer was separated. The aqueous layer was further extracted with CH2C12 ( 150ml x 2 ). All the organic layers were combined, dried over Na2SO4 and concentrated in vacuo to give mesylate ( 46.7 g ) as crude syrup. The obtained mesylate was dissolved in MeOH ( 500ml ) – 24 –

and the solution was cooled down to 0°C. To this solution was added 28% NaOMe methanol solution (29.0 ml ). The mixture was stirred at 0°C for 50min. The reaction mixture was evaporated to reduce the volume of the solvent down to 150 ml. The residue was poured into ice- water ( 300ml ). The resulting mixture was extracted with ethylacetate (300ml + 200ml x 2 ). The combined organic layer was dried over Na.,S0 and concentrated in vacuo. The residue was cromatographed on silicagel (hexane : EtOAc = 1 : 3 ) to give (2R,3S)-2-(2,5-Difluorophenyl)- 3-methyl-2-[(lH-l,2,4-triazol-l-yl)-methyl]-oxirane (30.3 g, 93 %).

Physical form : white solid ; FAB-MS : m z 252 (M+H)⁺ ; ^]H- NMR(CDC1₃): 1.64(3H,d,J=5.6Hz),3.19(lH,q,J=5.6Hz),4.42,4.97 (2H,ABq,J=14.8Hz), 6.75~6.81(lH,m),6.89~7.01(2H,m),7.83(lH,s),7.98 UH,s).

f) Preparation of (2S,3R)-3-(2,5-Difluoro-phenyl)-3-hydroxy-

2-methyl-4-[l,2,4]triazol-l-yl-butyronitrile

A mixture of (2R,3S)-2-(2,5-Difluorophenyl)-3-methyl-2-[(lH-l,2,4- triazol-l-yl)-methyl]-oxirane ( 30.3 g, 0.121 mol ), trimethylsilylcyanide ( 65.0 ml ) and MgO ( 24.5 g ) in o-xylene ( 400 ml ) was stirred at 130°C for lOhrs. To this mixture was added additional trimethylsilylcyanide (20.0 ml ) and MgO ( 8.5 g ) and the resulting mixture was stirred at 130°C further for 6hrs. The reaction mixture was cooled down to r.t. The precipitate was filtered off and washed with CH2C12. The filtrate was concentrated in vacuo to give crude brown syrup.

This crude syrup was dissolved in THF ( 600ml ) and the solution was cooled down to 0°C. To this mixture was added 1.0 M tetra n- butylammoniumfluoride THF solution ( 133ml, 0.133 mol ) dropwise over 5min. The mixture was stirred at r.t. for 50min. The solvent was removed under reduced pressure down to 150ml. The residue was poured into ice-water ( 400ml ). The resulting mixture was extracted – 25 –

with EtOAc ( 300ml + 200ml x 2 ). The combined organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on silicagel ( n-hexane : EtOAc = 1 : 3 ) to give (2S,3R)-3-(2,5-Difluoro-phenyl)-3-hydroxy-2-methyl-4-[l,2_;4]triazol-l-yl- butyronitrile ( 30.5 g, 91 % ).

Physical form : colorless syrup ; FAB-MS : m/z 279 (M+H)⁺ ; Η- NMR(CDCl₃): 1.19(3H,d,J=7.3Hz),3.33(lH,q,J=7.3Hz),4.82,5.00 (2H,ABq,J=13.9Hz), 5.56(lH,brs),6.89~7.04(2H,m),7.12~7.19(lH,m),7.85(lH,s),7.86(lH,s).

g) Preparation of (2R,3R)-3-(2,5-Difluoro-phenyl)-3-hydroxy-

2-methyl-4- [ 1 ,2,4] triazol-1 -ylthiob tyramide

A mixture of (2S,3R)-3-(2,5-Difluoro-phenyl)-3-hydroxy-2-methyl-4- [l,2,4]triazol-l-yl-butyronitrile ( ³⁰–⁵ S> O.llOmol ), diethyldithio- phospate ( 235 ml ) and H2O ( 110 ml ) was stirre at 80°C for 2hrs. The reaction mixture was cooled down to r.t. n-Hexane ( 400ml ) and water (200 ml ) was added. The whole was shaken well and the aqueous layer was separated. The remaining organic layer was further extracted with H20 ( 100ml x 3 ). All the aqueous layer was combined. Cooled down to

0°C and neutralized and basified ( PH8 ) with NaHC03. This basic(PH8) aqueous layer was extracted with EtOAc ( 300ml + 100ml x 3 ). The combined organic layer was dried over Na2S04 and concentrated in vacuo to give dark brown syrup. By addition of CH2C12 ( 100ml ) to this crude syrup, precipitate was formed. The precipitate was filtered and washed with CH2C12-hexane ( 5 : 1 mixture ) to give (2R,3R)-3-(2,5-Difluoro-phenyl)-3-hydroxy-2-methyl-4-[l,2,4]triazol-l- ylthiobutyramide ( 19.2 g, 56 % ) as white powder. On the oter hand, the filtrate was concentrated in vacuo and the residue was chromatographed on silica gel ( Wako-gel C-300, CH2C12 : MeOH = 20 :

1 ) to give additional (2R,3R)-3-(2,5-Difluoro-phenyl)-3-hydroxy-2- – 26 –

methyl-4-[l,2,4]triazol-l-ylthiobutyramide ( 7.46 g, 22 % ) as pale brown amorphous powder.

Physical form : White solid ; FAB-MS : m/z 313 (M+H)⁺ ; ‘H-NMR (CDC1₃): 1.12(3H,d,J=7.3Hz),3.74(lH,q,J=7.3Hz), 4.55,5.12 (2H,ABq,J=14.5Hz), 5.84(lH,s),6.85~7.02(2H,m),7.15-7.22(lH,m),7.80

(1H,S),7.89(1H,S), 7.89(lH,brs),8.43(lH,brs).

h) Preparation of 4-{2-[(lR,2R)-2-(2,5-Difluoro-phenyl)-2- hydroxy-l-methyl-3-[l,2,4]triazol-l-yl-propyl]-thiazol-4-yl}- benzonitrile

A mixture of (2R,3R)-3-(2,5-Difluoro-phenyl)-3-hydroxy-2-methyl-4- [l,2,4]triazol-l-ylthiobutyramide ( 26.7 g, 85.4 mmol ) and a-bromo-4′- cyano-acetophenone ( 24.0 g, 0.107 mol ) in EtOH ( 500ml ) was refluxed for lhr. The reaction mixture was cooled down to r.t. And the solvent was removed under reduced pressure down to 150ml. The residue was poured into in to cold ( 0°C ) saturated NaHC03 aq. ( 400ml ). The resulting mixture was extracted with EtOAc ( 300ml + 150 ml x 2 ). The combined organic layer was washed with brine (200ml ), dried over Na2S04 and concentrated in vacuo. The residue was chromatographed on silica gel ( Wako-gel C-300, Hexane : EtOAc = 1 : 2 ) to give 4-{2-

[(lR,2R)-2-(2,5-Difluoro-phenyl)-2-hydroxy-l-methyl-3-[l,2,4]triazol-l- yl-propyl]-thiazol-4-yl}-benzonitrile ( 32.0 g, 86 % ).

Physical form : colorless heavy syrup ; ESI-MS : m/z 437 (M)⁺ ; ‘H-

NMR(CDCl₃): 1.25(3H,d,J=7.3Hz),4.12(lH,q,J=7.3Hz),4.26,4.96 (2H,Abq,J=14.5Hz), 5.75(lH,s),6.89~7.07(2H,m),7.23~7.29(lH,m),7.65

(lH,s),7.71(lH,s),7.75,8.02 (4H,Abq,J=8.6Hz),7.85(lH,s). – 27 –

i) Preparation of 4-{4-[(tert-Butoxycarbonyl-methyl-amino)- acetoxy]-3,5-dimethyl-benzyl}-l-[(2R,3R)-3-[4-(4-cyano-phenyl)- thiazol-2-yl]-2-(2,5-difluoro-phenyl)-2-hydroxy-butyl]-lH- [l,2,4]triazol-4-ium bromide A mixture of 22.7mg of 4-{2-[(lR,2R)-2-(2,5-Difluoro-phenyl)-2-hydroxy- l-methyl-3-[l,2,4]triazol-l-yl-propyl]-thiazol-4-yl}-benzonitrile and 25.0mg of 4-tert-butoxycarbonyl-methyl-aminoacetoxy-3,5-dimethyl- benzyl bromide in CH₃CN(1.5mL) was refluxed over 15hrs. The solvent was evaporated in vacuo and the residue was chromatographed on silica gel (Wakogel C-200, solvent:CH₂Cl MeOH=10/l) to give 4-{4-[(tert-

Butoxycarbonyl-methyl-amino)-acetoxy]-3,5-dimethyl-benzyl}-l- [(2R,3R)-3-[4-(4-cyano-phenyl)-thiazol-2-yl]-2-(2,5-difluoro-phenyl)-2- hydroxy-butyl]-lH-[l,2,4]triazol-4-ium bromide (36.0mg, 84% as colorless heavy syrup) ; FAB-MS : m/z 743 (M-Br)’ ; Η-NMR(CDC1_S): 1.23(3H,d,J=7.3Hz),

1.47(9H,s),2.14(6H,s),3.03(3H,s),4.15(lH,q,J=7.3Hz),4.25(2H,s), 4.98,5.16(2H,ABq,J=13.9Hz),5.39~5.54(2H,m),6.27(lH,s),6.89-7.07(4H, m),7.24~7.27(lH,m),7.58(lH,s),7.73,8.06(4H,ABq,J=8.58),8.07(lH,s),ll. 26 (lH,s).

j) Preparation of l-{(2R,3R)-3-[4-(4-cyano-phenyl)-thiazol-2-yl]- 2-(2,5-difluoro-phenyl)-2-hydroxy-butyl}-4-(3,5-dimethyl-4- methylaminoacetoxy-benzyl)-lH-[l,2,4]triazol-4-ium bromide To a solution of 36mg of 4-{4-[(tert-Butoxycarbonyl-methyl-amino)- acetoxy]-3,5-dimethyl-benzyl}-l-[(2R,3R)-3-[4-(4-cyano-phenyl)-thiazol-

2-yl]-2-(2,5-difluoro-phenyl)-2-hydroxy-butyl]-lH-[l,2,4]triazol-4-ium bromide in ethylacetate(2ml) was added dropwise 4N HC1 ethylacetate solution(lmL) and the mixture was stirred at r.t. for 4hrs.The precipitate was ^“filtered and washed with diethylether to give 1- {(2R,3R)-3-[4-(4-cyano-phenyl)-thiazol-2-yl]-2-(2,5-difluoro-phenyl)-2- hydroxy-butyl}-4-(3,5-dimethyl-4-methylaminoacetoxy-benzyl)-lH- – 28 –

[l,2,4]triazol-4-ium bromide (24.5mg, 74% as HC1 salt and as white solid) ;

FAB-MS : m/z 643 (M-Br)⁺ ; Η-NMR(DMSO-d): 1.19(3H,d,J=7.3Hz), 2.11(6H,s),2.64(3H,s),4.15(lH,q,J=7.3Hz),4.41(2H,s),4.74,5.04(2H,ABq,J =14.5Hz),5.40(2H,s),6.76(lH,brs),7.10(2H,s),7.20~7.38(2H,m), 7.94,8.21

(4H,ABq,J=8.25),8.45(lH,s),9.07(lH,s),9.50(lH,brs),10.17(lH,s).

………………………

http://www.google.co.in/patents/US5648372

http://www.google.co.in/patents/EP1394142A1

COMPD 21

2-(2,4-Difluorophenyl)-3-thioamide-1-(1H-1,2,4-triazol-1-yl)-2-butanol (the raw material 2) (156 mg) was dissolved in EtOH (2 ml), and 2-bromo-4′-cyanoacetophenone (the raw material 3) (224 mg) was added to the solution, followed by heating and refluxing for 1 hour. The liquid reaction mixture was neutralized with a saturated aqueous solution of NaHCO₃ and subjected to extraction with AcOEt. After the extract was washed with H₂O and then a saturated aqueous solution of NaCl and dried over MgSO₄, AcOEt was distilled out. The resultant residue was purified by chromatography on silica gel (SiO₂: 20 g, eluted with CH₂Cl₂ and then with 1% solution of MeOH in CH₂Cl₂), and then crystallized from IPE, thereby obtaining the intended compound (109 mg). Physical properties of this compound are described below.

mp:

196-197°C.

NMR:

δ solvent (CDCl₃)
1.23(3H,d,J=8.0Hz), 4.09(1H,q,J=8.0Hz), 4.26(1H,d,J=14.3Hz), 4.92(1H,d,J=14.3Hz), 5.74(1H,s), 6.78-6.85(2H,m), 7.48-7.54(1H,m), 7.64(1H,s), 7.69(1H,s), 7.75(1H,d,J=8.1Hz), 7.85(1H,s), 8.03(1H,d,J=8.1Hz).

MS:

MH⁺ = 438.

References

National Cancer Institute. Ravuconazole in Preventing Fungal Infections in Patients Undergoing Allogeneic Stem Cell Transplantation. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2010 Feb 18]. Available from:http://clinicaltrials.gov/ct2/show/NCT00064311?term=ravuconazole&spons_ex=Y&rank=1 NLM Identifier: NCT00064311.
The Aspergillus Website, Pasqualotto AC, Denning DW. Ravuconazole. Date accessed: 2010 Feb 18.
Pasqualotto AC, Thiele KO, Goldani LZ (2010). “Novel triazole antifungal drugs: focus on isavuconazole, ravuconazole and albaconazole”. Curr Opin Investig Drugs 11 (2): 165–74. PMID 20112166.
Pfaller, M. A.; Messer, S. A.; Hollis, R. J.; Jones, R. N.; Sentry Participants, Group (2002). “Antifungal Activities of Posaconazole, Ravuconazole, and Voriconazole Compared to Those of Itraconazole and Amphotericin B against 239 Clinical Isolates of Aspergillus spp. and Other Filamentous Fungi: Report from SENTRY Antimicrobial Surveillance Program, 2000”. Antimicrobial Agents and Chemotherapy46 (4): 1032. doi:10.1128/AAC.46.4.1032-1037.2002. PMC 127116. PMID 11897586.

Literature References:

Ergosterol biosynthesis inhibitor. Prepn (stereochemistry unspecified): T. Naito et al, EP 667346; eidem,US 5648372 (1995, 1997 both to Eisai); of optically acitve form: A. Tsuruoka et al., Chem. Pharm. Bull. 46, 623 (1998). Chiral synthesis: Y. Kaku et al., ibid. 1125.

In vitro comparative antifungal spectrum: J. C. Fung-Tomc et al., Antimicrob. Agents Chemother. 42, 313 1998. Antifungal activity in candidosis: K. V. Clemons, D. A. Stevens, ibid. 45, 3433 (2001); in aspergillosis: W. R. Kirkpatrick et al., J. Antimicrob. Chemother. 49, 353 (2002).

Clinical evaluation in onychomycosis: A. K. Gupta et al., J. Eur. Acad. Dermatol. Venereol. 19, 437 (2005).

Review of development and therapeutic potential: S. Arikan, J. H. Rex, Curr. Opin. Invest. Drugs 3, 555-561 (2002).

Extras you may need

moonwalk

http://www.google.com/patents/WO2011042827A1?cl=en

Scheme 1 :

The manufacturing process for Isavuconazole is similar: Since Isavuconazole differentiates from Ravuconazole by only another fluorine substitution on the aromatic ring (2,5- instead of 2,4-difluorophenyl), the identical synthesis has been used (US 6300353 from October 9, 2001 and Bioorg. & Med. Chem. Lett. 13, 191 (2003)). Consequently, also this manufacturing process, based on (R)-lactic acid, faces the same problems: to many steps, extremely low overall yield and in addition to US patent 6300353 claims even already known step as novel (claim 36).

Recent attempts to improve this concept as reported in WO 2007/062542 (Dec.1 , 2005), using less expensive, natural configured (S)-lactic acid, also failed: As already reported in US 6133485 and in US 2003/0236419, the second chiral center was formed from an optically active allyl alcohol prepared in a few steps from (S)-lactic acid. This allyl alcohol was subjected to Sharpless diastereoselective epoxidation providing first an opposite configured, epimeric epoxy alcohol which had to be then epimerized in an additional inversion step yielding finally the desired epoxy alcohol as the known precursor for Isavuconazole (US 6300353). It is obvious that this process using less expensive (S)- lactic acid makes the entire process with an inversion step even more complex than the original approach.

Elegant and more efficient process has been claimed in US 2004/0176432 from June 26, 2001 ) in which both chiral centers have been formed simultaneously, diastereo- and enantio-selectively pure in one single reaction step using chiral (R)-2-butynol as a chiral precursor in the presence of Pd(ll)-catalyst and diethyl zinc (Scheme 2).

Scheme 2:

Since water soluble, (R)-2-butynol is expensive, recently identical process has been published, in which instead of (R)-2-butynol less water soluble and therefore, less expensive (R)-4-phenyl-3-butyn-2-ol was used (Synthetic Commun. 39, 161 1 (2009)). Nevertheless, as incorrectly stated there, this process does not provide better diastereoselectivity than the original process using (R)-2-butynol: On the contrary disadvantage of this process is a very bad atom economy because huge phenyl group of (R)-4-phenyl-3-butyn-2-ol has to be “disposed” in oxidation step by the conversion of triple bond into carboxylic acid function.

……………………………

http://www.google.com/patents/WO2014023623A1?cl=en

The invention relates to a process for the manufacture of a

diastereomerically and enantiomerically enriched ester intermediate for isavuconazole or ravuconazole.

Isavuconazole and ravuconazole are triazole antifungal compounds. Processes for the manufacture of isavuconazole and ravuconazole were disclosed in patents WO99/45008, WO2007/062542 and WO03/002498 to Basilea. In WO2011/042827 a process for the manufacture of enantiomerically pure antifungal azoles such as ravuconazole and isavuconazole is disclosed, wherein a classical resolution of a racemic mixture is performed by the addition of an enantiopure chiral acid, then collection of the desired diastereomer followed by conversion of the salt into the enantiomerically pure form of the desired compound by treatment with a base or an ion-exchange resin. The disadvantages of using such classical resolution are that the chiral auxiliary needs to be applied in near stoichiometric amounts, and that additional process steps are required for recovery of these relatively high amounts of chiral reagent as well as for converting the salt into the free enantiopure product.

http://www.google.com/patents/US8076494

Reaction Scheme 1:

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‘Wrapping’ Gleevec Fights Drug-Resistant Cancer, Study Shows

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Paricalcitol is a synthetic vitamin D analog. Paricalcitol has been used to reduce parathyroid hormone levels. Paricalcitol is indicated for the prevention and treatment of secondary hyperparathyroidism associated with chronic renal failure.

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Albaconazole

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