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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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FDA approves first treatment Azedra (iobenguane I 131) for rare adrenal tumors


FDA approves first treatment for rare adrenal tumors

The U.S. Food and Drug Administration today approved Azedra (iobenguane I 131) injection for intravenous use for the treatment of adults and adolescents age 12 and older with rare tumors of the adrenal gland (pheochromocytoma or paraganglioma) that cannot be surgically removed (unresectable), have spread beyond the original tumor site and require systemic anticancer therapy. This is the first FDA-approved drug for this use.

July 30, 2018

Release

The U.S. Food and Drug Administration today approved Azedra (iobenguane I 131) injection for intravenous use for the treatment of adults and adolescents age 12 and older with rare tumors of the adrenal gland (pheochromocytoma or paraganglioma) that cannot be surgically removed (unresectable), have spread beyond the original tumor site and require systemic anticancer therapy. This is the first FDA-approved drug for this use.

“Many patients with these ultra-rare cancers can be treated with surgery or local therapies, but there are no effective systemic treatments for patients who experience tumor-related symptoms such as high blood pressure,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Patients will now have an approved therapy that has been shown to decrease the need for blood pressure medication and reduce tumor size in some patients.”

Pheochromocytomas are rare tumors of the adrenal glands. These glands are located right above the kidneys and make hormones including stress hormones called epinephrines and norepinephrines. Pheochromocytomas increase the production of these hormones, leading to hypertension (high blood pressure) and symptoms such as headaches, irritability, sweating, rapid heart rate, nausea, vomiting, weight loss, weakness, chest pain or anxiety. When this type of tumor occurs outside the adrenal gland, it is called a paraganglioma.

The efficacy of Azedra was shown in a single-arm, open-label, clinical trial in 68 patients that measured the number of patients who experienced a 50 percent or greater reduction of all antihypertensive medications lasting for at least six months. This endpoint was supported by the secondary endpoint, overall tumor response measured by traditional imaging criteria. The study met the primary endpoint, with 17 (25 percent) of the 68 evaluable patients experiencing a 50 percent or greater reduction of all antihypertensive medication for at least six months. Overall tumor response was achieved in 15 (22 percent) of the patients studied.

The most common severe side effects reported by patients receiving Azedra in clinical trials included low levels of white blood cells (lymphopenia), abnormally low count of a type of white blood cells (neutropenia), low blood platelet count (thrombocytopenia), fatigue, anemia, increased international normalized ratio (a laboratory test which measures blood clotting), nausea, dizziness, hypertension and vomiting.

As it is a radioactive therapeutic agent, Azedra includes a warning about radiation exposure to patients and family members, which should be minimized while the patient is receiving Azedra. The risk of radiation exposure is greater in pediatric patients. Other warnings and precautions include a risk of lower levels of blood cells (myelosuppression), underactive thyroid, elevations in blood pressure, renal failure or kidney injury and inflammation of lung tissue (pneumonitis). Myelodysplastic syndrome and acute leukemias, which are cancers of the blood and bone marrow, were observed in patients who received Azedra, and the magnitude of this risk will continue to be studied. Azedra can cause harm to a developing fetus; women should be advised of the potential risk to the fetus and to use effective contraception after receiving Azedra. Radiation exposure associated with Azedra may cause infertility in males and females.

The FDA granted this application Fast TrackBreakthrough Therapy and Priority Review designations. Azedra also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted the approval of Azedra to Progenics Pharmaceuticals, Inc.

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm615155.htm?utm_campaign=07302018_PR_treatment%20for%20rare%20adrenal%20tumors&utm_medium=email&utm_source=Eloqua

/////////////// Azedra, iobenguane I 131, fda 2018, Progenics Pharmaceuticals, Fast TrackBreakthrough Therapy,  Priority Review, orphan drug,
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Fostamatinib, фостаматиниб , وستاماتينيب , 福他替尼 , ホスタマチニブジナトリウム水和物


Fostamatinib.svgChemSpider 2D Image | Fostamatinib | C23H26FN6O9PFostamatinib.png

Fostamatinib

  • Molecular FormulaC23H26FN6O9P
  • Average mass580.459 Da
SQ8A3S5101
TAVALISSE [Trade name]
фостаматиниб [Russian] [INN]
فوستاماتينيب [Arabic] [INN]
福他替尼 [Chinese] [INN]
[6-({5-Fluoro-2-[(3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl}amino)-2,2-dimethyl-3-oxo-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl]methyl dihydrogen phosphate[ACD/IUPAC Name]
2H-Pyrido[3,2-b]-1,4-oxazin-3(4H)-one, 6-[[5-fluoro-2-[(3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl]amino]-2,2-dimethyl-4-[(phosphonooxy)methyl]-[ACD/Index Name]
901119-35-5[RN]
9022
Image result for fostamatinib disodium hexahydrateImage result for fostamatinib disodium hexahydrate

Fostamatinib disodium hexahydrate

ホスタマチニブジナトリウム水和物

INGREDIENT UNII CAS
Fostamatinib disodium 86EEZ49YVB 914295-16-2
Molecular Formula: C23H36FN6Na2O15P
Molecular Weight: 732.52 g/mol

TAVALISSE™
(fostamatinib disodium hexahydrate) Tablets, for Oral Use

DESCRIPTION

Fostamatinib is a tyrosine kinase inhibitor. TAVALISSE is formulated with the disodium hexahydrate salt of fostamatinib, a phosphate prodrug that converts to its pharmacologically active metabolite, R406, in vivo.

The chemical name for fostamatinib disodium hexahydrate is disodium (6-[[5-fluoro-2-(3,4,5trimethoxyanilino) pyrimidin-4-yl]amino]-2,2-dimethyl-3-oxo-pyrido[3,2-b][1,4]oxazin-4-yl)methyl phosphate hexahydrate. The molecular formula is C23H24FN6Na2O9P·6H2O, and the molecular weight is 732.52. The structural formula is:

TAVALISSE™ (fostamatinib disodium hexahydrate) Structural Formula Illustration

Fostamatinib disodium is a white to off-white powder that is practically insoluble in pH 1.2 aqueous buffer, slightly soluble in water, and soluble in methanol.

Each TAVALISSE oral tablet contains 100 mg or 150 mg fostamatinib, equivalent to 126.2 mg or 189.3 mg fostamatinib disodium hexahydrate, respectively.

The inactive ingredients in the tablet core are mannitol, sodium bicarbonate, sodium starch glycolate, povidone, and magnesium stearate. The inactive ingredients in the film coating are polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, talc, iron oxide yellow, and iron oxide red.

Image result for fostamatinib disodium hexahydrate

Fostamatinib, sold under the brand name Tavalisse, is a medication approved by the U.S. Food and Drug Administration since 2018 for the treatment of chronic immune thrombocytopenia (ITP). The drug is administered orally as a disodium hexahydrate salt, and is a prodrug of the active compound tamatinib (R-406),[1] which is an inhibitor of the enzyme spleen tyrosine kinase (Syk),[2] hence it is an syk inhibitor.

Fostamatinib has been investigated for the treatment and basic science of Rheumatoid Arthritis and Immune Thrombocytopenic Purpura (ITP). It was approved on April 17, 2018 under the trade name Tavalisse for use in ITP [8]. Fostamatinib has also been granted orphan drug status by the FDA [8].

Fostamatinib is indicated for use in the treatment of chronic immune thrombocytopenia (ITP) in patients who have had insufficient response to previous therapy [Label].

Syk is a protein tyrosine kinase associated with various inflammatory cells, including macrophages, which are presumed to be the cells responsible for ITP platelet clearance.[3] When FcγRs I, IIA, and IIIA bind to their ligands, the receptor complex becomes activated and triggers the phosphorylation of the immunoreceptor-activating motifs (ITAMs). This leads to various genes becoming activated, which causes a cytoskeletal rearrangement that mediates phagocytosis in cells of the monocyte/macrophage lineage. Because Syk plays an important role in FcγR-mediated signal transduction and inflammatory propagation, it is considered a good target for the inhibition of various autoimmune conditions, including rheumatoid arthritis and lymphoma.

Clinical trials

Fostamatinib has been in clinical trials for rheumatoid arthritisautoimmune thrombocytopeniaautoimmune hemolytic anemiaIgA nephropathy, and lymphoma.[1][4]

The investigation of fostamatinib began with studies involving the treatment of mouse models with cytopenia. Mice were used to measure the effectiveness of R788, a small molecule prodrug of the biologically active R406, a Syk inhibitor. In animal models, treatment with R406/R788 was shown to be safe and effective in reducing inflammation and joint damage in immune-mediated rheumatoid arthritis. The models responded favorably to treatment so the study progressed to Phase 2 trials involving humans. Human studies have shown that R788 has good oral bioavailability, biologic activity, is well tolerated, and does not exhibit collagen or ADP-induced platelet aggregation. In NCT00706342, 16 adults with chronic ITP were entered into an open-label, single-arm cohort dose-escalation trials beginning with 75 mg and rising to 175 mg twice a day. The dose was increased until a persistent response was evident, toxicity was reached, or 175 mg twice a day was met. 8 patients achieved persistent responses with platelet counts greater than 50,000 mm3/L on more than 67% of their visits. 3 of these patients had not persistently responded to thrombopoietic agents. 4 others had nonsustained responses. Mean peak platelet count exceeded 100,000 mm3/L in these 12 patients. Toxicity was evidenced primarily in GI-related side effects, notable diarrhea, urgency, and vomiting. 2 patients developed transaminitis.[5]

Rheumatoid arthritis

A phase II study of rheumatoid arthritis patients failing to respond to a biologic agent showed little efficacy as compared to placebo, but the drug was well tolerated. In patients with high inflammatory burden, measured by levels of C-reactive proteinACR20 was achieved by a significantly higher portion of those in the fostamatinib group (42%) versus the placebo group (26%).[6]

Autoimmune thrombocytopenia

Immune thrombocytopenic purpura (ITP) is an autoimmune disease where the immune system attacks and destroys platelets in the blood, causing abnormally low platelet counts. It is characterized by the antibody-mediated destruction of platelets. Patients with ITP have accelerated clearance of circulating IgG-coated platelets via Fcγ receptor-bearing macrophages in the spleen and liver, leading to different levels of thrombocytopenia and variable degrees of mucocutaneous bleeding.[7] Recent studies of ITP pathophysiology suggest decreased platelet production may also be an important component of the thrombocytopenia. Many patients exhibit responses to established therapies, including corticosteroids, IV immunoglobulin, anti-D, splenectomy, and rituximab. However, there are a significant minority of patients who retain persistently low platelet counts despite treatment. These patients are consistently at risk of intracranial hemorrhage and other bleeding complications. Several thrombopoiesis-stimulating therapies including eltrombopag and AMG 531 are being investigated to help combat low platelet counts in ITP patients. Rigel reported results from two Phase III clinical trials for fostamatinib as an ITP treatment in August and October 2016. The study is the second Phase 3, multi-center, randomized, double-blind, placebo controlled, study of fostamatinib disodium in the treatment of persistent/chronic immune thrombocytopenic purpura that Rigel has conducted. Primary outcome measures are defined as a stable platelet response by the end of the study (week 24) of at least 50,000/µL on at least 4 of the 6 visits between weeks 14-24. Participants received either a placebo, 100 mg, or 150 mg of the drug in the morning and evening for 24 full weeks. The first study, FIT 1 (047) met the primary endpoint in a statistically significant manner, with 18% of patients hitting the 50,000 platelets/µL of blood and no patients receiving the placebo meeting that criteria. As of June 2016, the open-label, long term extension study (049) is currently tracking 118 patients who opted to receive fostamatinib after completing either study 047 or 048.[8]

Autoimmune hemolytic anemia

Approval for treatment of autoimmune hemolytic anemia (AIHA) is in Stage 1 of Phase II trials. This study is a Phase 2, multi-center, open label, Simon two-stage study to evaluate the safety and efficacy of fostamatinib disodium in the treatment of warm antibody autoimmune hemolytic anemia. Primary outcome measures examined include a hemoglobin response measured by levels higher than 10 g/dL and 2 g/dL higher than the baseline hemoglobin. Responses were studied for a period of 12 weeks and for a dose of 150 mg in the morning and evening. The study began in April 2016 and is estimated to conclude in September 2017. The study is currently recruiting participants from U.S. states including Arizona, California, D.C., Massachusetts, New York, North Carolina, and Texas. Subjects must have had a diagnosis of primary or secondary warm antibody AIHA, and must have failed at least 1 prior treatment regimen for AIHA. Subjects cannot have a platelet count less than 30,000/µL, have AIHA secondary to autoimmune disease, have uncontrolled or poorly controlled hypertension, or have cold antibody AIHA, cold agglutinin syndrome, mixed type AIHA, or paroxysmal cold hemoglobinuria.[9]

Immunoglobulin A nephropathy

Fostamatinib as a treatment for IgA nephropathy (IgAN) is in Phase II trials, which will conclude at the end of 2016. IgAN is a chronic autoimmune disease associated with inflammation in the kidneys that reduces their ability to successfully filter blood. There are currently no disease-targeted therapies for IgAN. Participants are currently being recruited from the US, Austria, Germany, Hong Kong, Taiwan, and the UK. Patients must be between 18 and 70 years old, have renal biopsy findings consistent with IgA nephropathy, have been treated with an Angiotensin Converting Enzyme inhibitor (ACEi) and/or an Angiotensin II Receptor Blocker (ARB) for at least 90 days at the maximum approved dose, have a proteinuria > 1 gm/day at diagnosis of IgA nephropathy and a level > 0.5 gm/day at the second screening visit, and a blood pressure controlled to ≤ 1302/80 with angiotensin blockade. Eligible candidates cannot have recently used cyclophosphamide, mycophenolate mofetil, azathioprine, Rituximab, or > 15 mg/day of prednisone or any other corticosteroid equivalent. The study investigates whether fostamatinib is a safe and effective treatment for IgAN. It is a Phase 2, multi-center, randomized, double-blind, ascending-dose, placebo-controlled clinical study. Primary outcome measures include the mean change in proteinuria as measured by spot urine protein/creatinine ratio (sPCR). Effects were evaluated for 100 mg, 150 mg, and placebo formulations taken twice daily by mouth for 24 weeks. The study began in October 2014 and is expected to complete by June 2017.[10]

Synthesis

PATENTS

https://patents.google.com/patent/WO2008064274A1/en14

Suitable active 2,4-pyrimidinediamine compounds are described, for example, in U.S. application Serial No. 10/355,543 filed January 31 , 2003 (US2004/0029902A1), international application Serial No. PCT/US03/03022 filed January 31, 2003 (WO 03/063794), U.S. application Serial No. 10/631,029 filed July 29, 2003 (US 2005/0028212), international application Serial No. PCT/US03/24087 (WO2004/014382), U.S. application Serial No. 10/903,263 filed July 30, 2004 (US2005/0234049), and international application Serial No.
PCT/US2004/24716 (WO 2005/016893), the disclosures of which are incorporated herein by reference. In such 2,4-pyrimidinediamine compounds, the progroup(s) Rp can be attached to any available primary or secondary amine, including, for example, the N2 nitrogen atom of the 2,4-pyrimidinediamine moiety, the N4 nitrogen atom of the 2,4-pyrimidinediamine moiety, and/or a primary or secondary nitrogen atom included in a substituent on the 2,4-pyrimidinediamine compound. The use of phosphate-containing progroups Rp is especially useful for 2,4-pyrimidinediamine compounds that exhibit poor water solubility under physiological conditions (for example, solubilities of less than about 10 μg/ml). While not intending to be bound by any theory of operation, it is believed that the phosphate-containing progroups aid the solubility of the underlying active 2,4-pyrimidinediamine compound, which in turn increases its bioavailability when administered orally. It is believed that the phosphate progroups Rp are metabolized by phosphatase enzymes found in the digestive tract, permitting uptake of the underlying active drug.

[0024] It has been discovered that the water solubility and oral bioavailability of a particular biologically active 2,4-pyrimidinediamine compound, illustrated below (Compound 1), increased dramatically when formulated to include a progroup Rp of the formula -CH2-O-P(O)(OH)2 at the ring nitrogen atom highlighted with the asterisk (Compound 4):

Compound 4

EXAMPLES

1. Synthesis of Prodrug Compound 4

1.1 N4-(2,2-dimethyl-4-[(di-tert-butyl phosphonoxy)methyl]-3- oxo-5-pyrido[l,4]oxazin-6-yl)-5-fluoro-N2-(3,4,5- trimethoxyphenyl)-2,4-pyrimidinediamine (Compound 3)

4 days

[0260] N4-(2,2-dimethyl-3-oxo-4H-5-pyrido[l,4]oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine (1, 1.0 g, 2.12 mmol), Cs2CO3 (1.0 g, 3.07 mmol) and di-tert-butyl chloromethyl phosphate (2, 0.67 g, 2.59 mmol) in acetone (20 mL) was stirred at room temperature under nitrogen atmosphere. Progress of the reaction was monitored by LC/MS. Crude reaction mixture displayed three product peaks with close retention times with M++H 693 (minor-1), 693 (major; 3) and 477 (minor-2) besides starting material (Compound 1). Upon stirring the contents for 4 days (70% consumption), the reaction mixture was concentrated and diluted with water. The resultant pale yellow precipitate formed was collected by filtration and dried. The crude solid was purified by silica gel (pretreated with 10%NEt3/CH2Cl2 followed by eluting with hexanes) column chromatography by gradient elution with 70% EtOAc / hexanes-100% EtOAc). The fractions containing Compound 1 and M++H 693 were collected and concentrated. The resulting crude white solid was subjected to repurifϊcation in the similar manner as described previously but by eluting with 30%-50%-75%-100% EtOAc/hexanes. The major product peak with M++H 693 was collected as a white solid (270 mg, 18%) and was characterized as N4-(2,2-dimethyl-4-[(di-tert-butyl phosphonoxy)methyl]-3-oxo-5-pyrido[l,4]oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine (Compound 3). 1H NMR (DMSO-d6): δ 9.21 (s, IH), 9.17 (s, IH), 8.16 (d, IH, J = 2.6 Hz), 7.76 (d, IH, J = 8.5 Hz), 7.44 (d, IH, J = 8.5 Hz), 7.02 (s, 2H), 5.78 (d, IH, J3PH = 6.1 Hz), 3.64 (s, 6H), 3.58 (s, 3H), 1.45 (s, 6H), 1.33 (s, 9H). LCMS: ret. time: 14.70 min.; purity: 95%; MS (m/e): 693 (MH+). 31P NMR (DMSO-d6): -11.36.

1.2. N4-(2,2-dimethyl-4-[(dihydrogen phosphonoxy)methyl]-3- oxo-5-pyrido[l,4]oxazin-6-yl)-5-fluoro-N2-(3,4,5- trimethoxyphenyl)-2,4-pyrimidinediamine (Compound 4)

[0261] Trifluoroacetic acid (1.5 mL) was added dropwise as a neat for 5 min to N4-(2,2-dimethyl-4-[(di-tert-butyl phosphonoxy)methyl]-3-oxo-5-pyrido[l,4]oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine (Compound 3, 120 mg, 0.173 mmol ) dissolved in CH2Cl2 (10 mL) at 00C under nitrogen atmosphere. The contents were allowed to stir for 1.5 h. Progress of the reaction mixture was monitored by LC/MS. After complete consumption of the starting material, reaction mixture was concentrated, dried and triturated with ether. The ethereal layer was decanted and dried to provide the crude solid. LC/MS analysis of the crude displayed three peaks with M++H 581, 471 and 501. The peak corresponding to M++H 581 was collected by preparative HPLC chromatographic purification. The fractions were lyophilised and dried to provide 53 mg (52%) of off white fluffy solid and characterized as N4-(2,2-dimethyl-4-[(dihydrogen phosphonoxy)methyl]-3-oxo-5-pyrido[ 1 ,4]oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine (Compound 4). 1H NMR (DMSO-d6): δ 9.21 (br s, 2H), 8.16 (d, IH, J = 2.6 Hz), 7.93 (d, IH, J = 8.5 Hz), 7.39 (d, IH, J = 8.5 Hz), 7.05 (s, 2H), 5.79 (d, IH, J3PH = 6.6 Hz), 3.67 (s, 6H), 3.59 (s, 3H), 1.44 (s, 6H). LCMS: ret. time: 8.52 min.; purity: 95%; MS (m/e): 581 (MH+). 31P NMR (DMSO-d6): -2.17.

2. Alternative Synthesis of Prodrug Compound 4
[0262] An alternative method of synthesizing prodrug Compound 4 which alleviates the need for column chromatography and HPLC purification is provided below.

2.1 Synthesis of N4-(2,2-dimethyl-4- [(di-tert-butyl
phosphonoxy)methyl] -3-oxo-5-pyrido [ 1 ,4] oxazin-6-yl)-5- fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine
(Compound 3)

rt
92% conversion

majoπminor 6.5:1

[0263] N4-(2,2-dimethyl-3-oxo-4H-5-pyrido[l,4]oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine (Compound 1, 19.73 g, 41.97 mmol),
Cs2CO3 (15.04 g, 46.16 mmol) and di-tert-butyl chloromethyl phosphate (13.0 g, 50.38 mmol) in DMF (100 mL) was stirred at room temperature under nitrogen atmosphere. Progress of the reaction was monitored by in process LC/MS. Crude reaction mixture displayed two product peaks (ratio 1 :6.5) with close retention times displaying M++H 693 (minor) and 693 (major) besides starting material (Compound 1). Initial yellow reaction mixture turned to olive green as the reaction progressed. Workup was carried out as follows 1). Upon stirring the contents for 30 h (92% consumption), reaction mixture was poured onto ice-water (400 mL) and stirred the contents by adding brine solution (200 mL). Fine yellow tan solid formed was filtered, washed with water and dried overnight.
2). The solid (35 g) was dissolved in MTBE (500 mL) and washed with water (40OmL). Aqueous layer was extracted with MTBE (2 X 350 mL) till the absence of UV on TLC. Combined organic layers were dried over anhydrous Na2SO4 and decanted.
Note: step 2 can be done directly, however, DMF extraction back into solution leads to difficulty in the crystallization step.
3). The dark red clear solution was subjected to 10 g of activated charcoal treatment, heated to boil and filtered.
4). The dark red clear solution was concentrated by normal heating to 400 mL of its volume and left for crystallization. The solid crystallized as granules was filtered, crushed the granules to powder, washed with MTBE (400 mL) and dried under high vacuum. See step 7 for the workup of mother liquor. Weight of the solid: 17 g; purity: 90% (Compound 3), 6.26% (Compound 1), 1.8% (minor M+ 693).
5). At this stage solid was taken in 500 ml of ethyl ether and heated to boil. Cooled and filtered to remove undissolved material. Filtrate was concentrated.
6). Above concentrate was subjected to crystallization in MTBE (300 mL).

The white solid formed was filtered, washed with MTBE (100 mL) and dried under high vacuum to provide the desired N4-(2,2-dimethyl-4-[(di-tert-butyl
phosphonoxy)methyl]-3-oxo-5-pyrido[l,4]oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine (Compound 3) in 97% purity. 1H NMR (DMSO-d6): δ 9.21 (s, IH), 9.17 (s, IH), 8.16 (d, IH, J = 2.6 Hz), 7.76 (d, IH, J = 8.5 Hz), 7.44 (d, IH, J = 8.5 Hz), 7.02 (s, 2H), 5.78 (d, IH, J3PH = 6.1 Hz), 3.64 (s, 6H), 3.58 (s, 3H), 1.45 (s, 6H), 1.33 (s, 9H). LCMS: ret. time: 14.70 min.; purity: 95%; MS (m/e): 693 (MH+). 31P NMR (DMSO-d6): -11.36. Weight of the solid: 15.64 g (yield: 55%); purity: 97% (Compound 3), 3% (Compound 1).
7). The mother liquor was concentrated and steps 5 and 6 were repeated to provide Compound 3.

2.2. Synthesis of N4-(2,2-dimethyl-4-[(dihydrogen
phosphonoxy)methyl] -3-oxo-5-pyrido [ 1 ,4] oxazin-6-yl)-5- fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine
(Compound 4)
[0264] N4-(2,2-dimethyl-4-[(di-tert-butyl phosphonoxy)methyl]-3-oxo-5-pyrido[l,4]oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine (Compound 3); (15.0 g, 21.67 mmol) dissolved in AcOH:H20 (225 niL, 4:1) was heated at 65 0C (oil bath temp). The progress of the reaction was monitored by in process LC/MS. The reaction mixture transformed to faint tan white solid after Ih of heating. At this point most of Compound 3 converted to mono des t-butyl product. After 3h of heating, consumption of SM and complete conversion of intermediate (mono des t-butylated) to product was observed.
[0265] Reaction mixture was cooled, poured onto ice-water (200 mL), stirred for 20 min and filtered. The clear white filter cake was washed with water (600 ml) and acetone (200 mL) successively, dried for 2h followed by drying under high vacuum over P2O5 in a desiccator. Weight of the solid: 12.70 g; purity: 97% (Compound 3) and 3% (Compound 1) 1H NMR indicated acetic acid presence (1 :1)
[0266] To remove acetic acid, the solid was taken in acetonitrile (300 mL) and concentrated by rotovap vacuum. This process was repeated 2 times with acetonitrile and toluene (3 X 300 mL). The solid obtained was dried under high vacuum at 50 OC. [0267] Finally, the solid was taken in acetone (400 mL), filtered and dried to provide solid N4-(2,2-dimethyl-4-[(dihydrogen phosphonoxy)methyl]-3-oxo-5-pyrido[l,4]oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine (Compound 4). 1H NMR (DMSO-d6): δ 9.21 (br s, 2H), 8.16 (d, IH, J = 2.6 Hz), 7.93 (d, IH, J = 8.5 Hz), 7.39 (d, IH, J = 8.5 Hz), 7.05 (s, 2H), 5.79 (d, IH, J3PH = 6.6 Hz), 3.67 (s, 6H), 3.59 (s, 3H), 1.44 (s, 6H). LCMS: ret. time: 8.52 min.; purity: 95%; MS (m/e): 581 (MH+). 31P NMR (DMSO-d6): -2.17.

3. Synthesis of N4-(2,2-dimethyl-4-[(dihydrogen phosphonoxy)methyl]-3-oxo- 5-pyrido[l,4]oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4- pyrimidinediamine mono calcium salt (Prodrug Salt 6)

[0268] Aqueous (10 niL) NaHCO3 (0.17 g, 2.02 mmol) solution was added dropwise to a suspension of N4-(2,2-dimethyl-4-[(dihydrogen phosphonoxy)methyl]-3-oxo-5-pyrido[l,4]oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine (0.5 g, 0.86 mmol) in water (5 mL) at room temperature while stirring the contents. The clear solution formed was treated with aqueous (10 mL) CaCl2 (0.11 g in 10 mL water, 0.99 mmol) n a dropwise manner at room temperature. The addition resulted in the precipitation of a white solid from reaction mixture. Upon completion of addition, the contents were stirred for a period of 30 min, filtered, washed with water (40 mL) and dried. The clear white solid was taken in water (30 mL) and heated on a stir plate to boil. The solution was cooled, filtered and dried. The white solid collected and further dried under high vacuo at 80 0C for 32 h to provide 0.41 g (83%) of solid N4-(2,2-dimethyl-4-[(dihydrogen phosphonoxy)methyl]-3-oxo-5-pyrido[ 1 ,4]oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine mono calcium salt (Prodrug Salt 6).
[0269] Ca(OAc)2 may also used in place Of CaCl2 in this preparation.

4. Synthesis of N4-(2,2-dimethyl-4-[(dihydrogen phosphonoxy)methyl]-3-oxo- 5-pyrido[l,4]oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4- pyrimidinediamine disodium salt hexahydrate and monosodium salt
hydrate

[0270] A round-bottomed flask was charged with 10.00 g N4-(2,2-dimethyl-4-[(dihydrogen phosphonoxy)methyl]-3-oxo-5-pyrido[ 1 ,4]oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine (Compound 4) and 140 mL water into a round bottom flask to form a slurry having a pH between 3.6 and 3.7. The pH was adjusted to in the range of 9.3 to 10.3 by addition of 1 M aqueous NaOH, initially forming a turbid solution, which returned to a suspension upon prolonged stirring. The mixture was heated at reflux, then the turbid solution was hot filtered through filter paper. The solid collected in the filter paper was rinsed with 10 mL hot water.
Isopropanol (75 mL) was added to the filtrate, yielding a clear solution, which was allowed to cool to room temperature over about 1.5 hours with stirring, during which time a solid precipitated. The precipitate was collected by filtration, rinsed with 47 mL isopropanol, and taken up in 73 mL acetone to form a slurry, which was stirred for 1.5 hours at room temperature. The solid was again collected by filtration and rinsed with 18 mL acetone, then dried at about 40 0C under vacuum until substantially all isopropanol and acetone was removed (i.e., below 0.5 wt% each). The product was exposed to air at about 40% relative humidity and room temperature until the water content stabilized at about 15% by Karl Fisher titration, yielding 8.18 g of the title compound. 1H NMR (D2O): δ 7.67 (d, IH, J = 3.8 Hz), 7.49 (d, IH, J = 8.8 Hz), 6.87 (d, IH, J = 8.8 Hz), 6.50 (s, 2H), 5.52 (d, IH, J3PH = 2.0 Hz), 3.53 (s, 3H), 3.47 (s, 6H), 1.32 (s, 6H). 31P NMR (D2O): 2.75. The prodrug salt hydrate was obtained as a pure-white, highly crystalline material. Microscopic investigation indicated that the crystallites are plate-like with a particle size of less than 10 μm. Polarized light microscopy revealed birefringence corroborating the crystalline nature of the hydrate. [0271] The monosodium salt can be prepared from N4-(2,2-dimethyl-4-[(dihydrogen phosphonoxy)methyl]-3-oxo-5-pyrido[l,4]oxazin-6-yl)-5-fiuoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine and sodium hydroxide by a proper pH control; pH of 5-5.5 results in predominantly the formation of monosodium salt.

References

  1. Jump up to:a b S.P. McAdoo; F.W.K. Tam (2011). “Fostamatinib Disodium”. Drugs of the Future36 (4): 273–280.
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Fostamatinib
Fostamatinib.svg
Clinical data
Trade names Tavalisse
Synonyms Fostamatinib disodium hexahydrate, tamatinib fosdium, R-788, NSC-745942, R-935788
MedlinePlus a618025
Pregnancy
category
  • US: C (Risk not ruled out)
Routes of
administration
by mouth
Legal status
Legal status
Pharmacokinetic data
Bioavailability 55% (tamatinib metabolite)
Protein binding 98% (tamatinib metabolite)
Metabolism Gut (ALP to tamatinib)
Liver (tamatinib metabolite by CYP3A4UGT1A9)
Elimination half-life 15 hours
Excretion faecal (80%), urine (20%)
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ECHA InfoCard 100.125.771 Edit this at Wikidata
Chemical and physical data
Formula C23H26FN6O9P
Molar mass 580.47 g/mol
3D model (JSmol)

Fostamatinib

structure depiction
    1. FDA Orange Book Patents

      FDA Orange Book Patents: 1 of 14 (FDA Orange Book Patent ID)
      Patent 7989448
      Expiration Jun 12, 2026
      Applicant RIGEL PHARMS INC
      Drug Application
      1. N209299 (Prescription Drug: TAVALISSE. Ingredients: FOSTAMATINIB DISODIUM)
      2. N209299 (Prescription Drug: TAVALISSE. Ingredients: FOSTAMATINIB DISODIUM)
      FDA Orange Book Patents: 2 of 14 (FDA Orange Book Patent ID)
      Patent 8163902
      Expiration Jun 17, 2026
      Applicant RIGEL PHARMS INC
      Drug Application
      1. N209299 (Prescription Drug: TAVALISSE. Ingredients: FOSTAMATINIB DISODIUM)
      2. N209299 (Prescription Drug: TAVALISSE. Ingredients: FOSTAMATINIB DISODIUM)
      FDA Orange Book Patents: 3 of 14 (FDA Orange Book Patent ID)
      Patent 9737554
      Expiration Jan 19, 2026
      Applicant RIGEL PHARMS INC
      Drug Application
      1. N209299 (Prescription Drug: TAVALISSE. Ingredients: FOSTAMATINIB DISODIUM)
      2. N209299 (Prescription Drug: TAVALISSE. Ingredients: FOSTAMATINIB DISODIUM)
      FDA Orange Book Patents: 4 of 14 (FDA Orange Book Patent ID)
      Patent 7449458
      Expiration Sep 4, 2026
      Applicant RIGEL PHARMS INC
      Drug Application
      1. N209299 (Prescription Drug: TAVALISSE. Ingredients: FOSTAMATINIB DISODIUM)
      2. N209299 (Prescription Drug: TAVALISSE. Ingredients: FOSTAMATINIB DISODIUM)
      FDA Orange Book Patents: 5 of 14 (FDA Orange Book Patent ID)
      Patent 8211889
      Expiration Jan 19, 2026
      Applicant RIGEL PHARMS INC
      Drug Application
      1. N209299 (Prescription Drug: TAVALISSE. Ingredients: FOSTAMATINIB DISODIUM)
      2. N209299 (Prescription Drug: TAVALISSE. Ingredients: FOSTAMATINIB DISODIUM)
      FDA Orange Book Patents: 6 of 14 (FDA Orange Book Patent ID)
      Patent 8263122
      Expiration Nov 24, 2030
      Applicant RIGEL PHARMS INC
      Drug Application
      1. N209299 (Prescription Drug: TAVALISSE. Ingredients: FOSTAMATINIB DISODIUM)
      2. N209299 (Prescription Drug: TAVALISSE. Ingredients: FOSTAMATINIB DISODIUM)
      FDA Orange Book Patents: 7 of 14 (FDA Orange Book Patent ID)
      Patent 8445485
      Expiration Jun 17, 2026
      Applicant RIGEL PHARMS INC
      Drug Application
      1. N209299 (Prescription Drug: TAVALISSE. Ingredients: FOSTAMATINIB DISODIUM)
      2. N209299 (Prescription Drug: TAVALISSE. Ingredients: FOSTAMATINIB DISODIUM)
      FDA Orange Book Patents: 8 of 14 (FDA Orange Book Patent ID)
      Patent 8652492
      Expiration Nov 6, 2028
      Applicant RIGEL PHARMS INC
      Drug Application
      1. N209299 (Prescription Drug: TAVALISSE. Ingredients: FOSTAMATINIB DISODIUM)
      2. N209299 (Prescription Drug: TAVALISSE. Ingredients: FOSTAMATINIB DISODIUM)
      FDA Orange Book Patents: 9 of 14 (FDA Orange Book Patent ID)
      Patent 8771648
      Expiration Jul 27, 2032
      Applicant RIGEL PHARMS INC
      Drug Application
      1. N209299 (Prescription Drug: TAVALISSE. Ingredients: FOSTAMATINIB DISODIUM)
      2. N209299 (Prescription Drug: TAVALISSE. Ingredients: FOSTAMATINIB DISODIUM)
      FDA Orange Book Patents: 10 of 14 (FDA Orange Book Patent ID)
      Patent 8912170
      Expiration Jun 17, 2026
      Applicant RIGEL PHARMS INC
      Drug Application
      1. N209299 (Prescription Drug: TAVALISSE. Ingredients: FOSTAMATINIB DISODIUM)
      2. N209299 (Prescription Drug: TAVALISSE. Ingredients: FOSTAMATINIB DISODIUM)
      FDA Orange Book Patents: 11 of 14 (FDA Orange Book Patent ID)
      Patent 8951504
      Expiration Jul 27, 2032
      Applicant RIGEL PHARMS INC
      Drug Application
      1. N209299 (Prescription Drug: TAVALISSE. Ingredients: FOSTAMATINIB DISODIUM)
      2. N209299 (Prescription Drug: TAVALISSE. Ingredients: FOSTAMATINIB DISODIUM)
      FDA Orange Book Patents: 12 of 14 (FDA Orange Book Patent ID)
      Patent 9266912
      Expiration Jan 19, 2026
      Applicant RIGEL PHARMS INC
      Drug Application
      1. N209299 (Prescription Drug: TAVALISSE. Ingredients: FOSTAMATINIB DISODIUM)
      2. N209299 (Prescription Drug: TAVALISSE. Ingredients: FOSTAMATINIB DISODIUM)
      FDA Orange Book Patents: 13 of 14 (FDA Orange Book Patent ID)
      Patent 9283238
      Expiration Jun 17, 2026
      Applicant RIGEL PHARMS INC
      Drug Application
      1. N209299 (Prescription Drug: TAVALISSE. Ingredients: FOSTAMATINIB DISODIUM)
      2. N209299 (Prescription Drug: TAVALISSE. Ingredients: FOSTAMATINIB DISODIUM)
      FDA Orange Book Patents: 14 of 14 (FDA Orange Book Patent ID)
      Patent 7538108
      Expiration Mar 28, 2026
      Applicant RIGEL PHARMS INC
      Drug Application
      1. N209299 (Prescription Drug: TAVALISSE. Ingredients: FOSTAMATINIB DISODIUM)
      2. N209299 (Prescription Drug: TAVALISSE. Ingredients: FOSTAMATINIB DISODIUM)

///////////SQ8A3S5101, TAVALISSE ,  фостаматиниб , وستاماتينيب 福他替尼 , FDA 2018, fostamatinib disodium hexahydrate, fostamatinib , ホスタマチニブジナトリウム水和物

COC1=CC(NC2=NC=C(F)C(NC3=NC4=C(OC(C)(C)C(=O)N4COP(O)(O)=O)C=C3)=N2)=CC(OC)=C1OC

TAFENOQUINE タフェノキン


Tafenoquine(RS)-Tafenoquin Structural Formula V1.svg

ChemSpider 2D Image | Tafenoquine | C24H28F3N3O3

Tafenoquine

タフェノキン

N-[2,6-dimethoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy]quinolin-8-yl]pentane-1,4-diamine

1,4-Pentanediamine, N4-[2,6-dimethoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy]-8-quinolinyl]-
106635-80-7 [RN]
262P8GS9L9
7835
N4-{2,6-Dimethoxy-4-methyl-5-[3-(trifluormethyl)phenoxy]-8-chinolinyl}-1,4-pentandiamin
WR-238605, WR 238605, cas no 106635-80-7, Tafenoquine succinate, Etaquine, SB-252263, WR-238605
N(4)-(2,6-Dimethoxy-4-methyl-5-((3-trifluoromethyl)phenoxy)-8-quinolinyl)-1,4-pentanediamine
Molecular Formula: C24H28F3N3O3
Molecular Weight: 463.49263

Medicines for Malaria Venture
Walter Reed Army Institute (Originator)

PATENT  US 4617394

Synonyms

  • Etaquine[5]
  • WR 238605 [5]
  • SB-252263

New Drug Application (NDA): 210795
Company: GLAXOSMITHKLINE

FDA approved on July 20, 2018

FDA

Orphan

This new drug application provides for the use of KRINTAFEL (tafenoquine) tablets for the radical cure (prevention of relapse) of Plasmodium vivax malaria in patients aged 16 years and older who are receiving appropriate antimalarial therapy for acute P. vivax infection….https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2018/210795Orig1s000Ltr.pdf

Tafenoquine under the commercial name of Krintafel is an 8-aminoquinoline drug manufactured by GlaxoSmithKline that is being investigated as a potential treatment for malaria, as well as for malaria prevention.[2][3]

The proposed indication for tafenoquine is for treatment of the hypnozoite stages of Plasmodium vivax and Plasmodium ovale that are responsible for relapse of these malaria species even when the blood stages are successfully cleared. This is only now achieved by administration of daily primaquine for 14 days. The main advantage of tafenoquine is that it has a long half-life (2–3 weeks) and therefore a single treatment may be sufficient to clear hypnozoites. The shorter regimen has been described as an advantage.[4]

Like primaquine, tafenoquine causes hemolysis in people with G6PD deficiency.[2] Indeed, the long half-life of tafenoquine suggests that particular care should be taken to ensure that individuals with severe G6PD deficiency do not receive the drug.

The dose of tafenoquine has not been firmly established, but for the treatment of Plasmodium vivax malaria, a dose of 800 mg over three days has been used.[5]

Image result for TAFENOQUINE IR

In 2018 United States Food and Drug Administration (FDA) approved single dose tafenoquine for the radical cure (prevention of relapse) of Plasmodium vivax malaria[6].

Tafenoquine is used for the treatment and prevention of relapse of Vivax malaria in patients 16 years and older. Tafenoquine is not indicated to treat acute vivax malaria.[1]

Malaria is a disease that remains to occur in many tropical countries. Vivax malaria, caused by Plasmodium vivax, is known to be less virulent and seldom causes death. However, it causes a substantive illness-related burden in endemic areas and it is known to present dormant forms in the hepatocytes named hypnozoites which can remain dormant for weeks or even months. This dormant form produces ongoing relapses

FDA Approves Tafenoquine, First New P VivaxMalaria Treatment in 60 Years

JUL 23, 2018

The US Food and Drug Administration (FDA) has approved, under Priority Review, GlaxoSmithKline (GSK)’s tafenoquine (Krintafel), which is the first single-dose medicine for the prevention of  Plasmodium vivax (P vivax) malaria relapse in patients over the age of 16 years who are receiving antimalarial therapy. This is the first drug to be approved for the treatment of P vivax in over 60 years.

“[The] approval of Krintafel, the first new treatment for Plasmodium vivax malaria in over 60 years, is a significant milestone for people living with this type of relapsing malaria.” Hal Barron, MD, chief scientific officer and president of research and development of  GSK, said in the announcement, “Together with our partner, Medicines for Malaria Venture (MMV), we believe Krintafel will be an important medicine for patients with malaria and contribute to the ongoing effort to eradicate this disease.”

Tafenoquine is an 8-aminoquinoline derivative with activity against all stages of the P vivax lifecycle, including hypnozoites. It was first synthesized by scientists at the Walter Reed Army Institute of Research in 1978, and in 2008, GSK entered into a collaboration with MMV, to develop tafenoquine as an anti-relapse medicine.

After an infected mosquito bite, the P vivax parasite infects the blood and causes an acute malaria episode and can also lie dormant in the liver (in a form known as hypnozoite) from where it periodically reactivates to cause relapses, which can occur weeks, months, or years after the onset of the initial infection. The dormant liver forms cannot be readily treated with most anti-malarial treatments. Primaquine, an 8-aminoquinolone, has been the only FDA-approved medicine that targeted the dormant liver stage to prevent relapse; however, effectiveness only occurs after 14 days and the treatment has shown to have poor compliance.

“The US FDA’s approval of Krintafel is a major milestone and a significant contribution towards global efforts to eradicate malaria,” commented David Reddy, PhD, chief executive officer of MMV in a recent statement, “The world has waited decades for a new medicine to counter P vivax malaria relapse. Today, we can say the wait is over. Moreover, as the first ever single-dose for this indication, Krintafel will help improve patient compliance.”

Approval for tafenoquine was granted based on the efficacy and safety data gleaned from a comprehensive global clinical development program for P vivaxprevention of relapse which has been designed by GSK and MMV in agreement with the FDA. The program consisted of 13 studies assessing the safety of a 300 mg single-dose of tafenoquine, including 3 double-blind studies referred to as DETECTIVE Parts 1 and 2 and GATHER.

With the approval of tafenoquine, GSK has also been awarded a tropical disease priority review voucher by the FDA. Additionally, GSK is waiting for a decision from Australian Therapeutics Good Administration regarding the regulatory submission for the drug.

P vivax malaria has caused around 8.5 million clinical infections each year, primarily in South Asia, South-East Asia, Latin America, and the Horn of Africa, a peninsula in East Africa. Symptoms include fever, chills, vomiting, malaise, headache and muscle pain, and can lead to death in severe cases.

Tafenoquine should not be administered to: patients who have glucose-6-phosphate dehydrogenase (G6PD) deficiency or have not been tested for G6PD deficiency, patients who are breastfeeding a child known to have G6PD deficiency or one that has not been tested for G6PD deficiency, or patients who are allergic to tafenoquine or any of the ingredients in tafenoquine or who have had an allergic reaction to similar medicines containing 8-aminoquinolines

Stereochemistry

Tafenoquine contains a stereocenter and consists of two enantiomers. This is a mixture of (R) – and the (S) – Form:

Enantiomers of tafenoquine
(R)-Tafenoquin Structural Formula V1.svg
(R)-Form
(S)-Tafenoquin Structural Formula V1.svg
(S)-Form

CLIP

US 4431807

Nitration of 1,2-dimethoxybenzene (XXIX) with HNO3/AcOH gives 4,5-dimethoxy-1,2-dinitrobenzene (XXX), which is treated with ammonia in hot methanol to yield 4,5-dimethoxy-2-nitroaniline (XXXI). Cyclization of compound (XXXI) with buten-2-one (XXXII) by means of H3PO4 and H3AsO4 affords 5,6-dimethoxy-4-methyl-8-nitroquinoline (XXXIII), which is selectively mono-demethylated by means of HCl in ethanol to provide 5-hydroxy-6-methoxy-4-methyl-8-nitroquinoline (XXXIV). Reaction of quinoline (XXXIV) with POCl3 gives the corresponding 5-chloro derivative (XXXV), which is condensed with 3-(trifluoromethyl)phenol (IV) by means of KOH to yield the diaryl ether (XXXVI). Finally, the nitro group of (XXXVI) is reduced by means of H2 over PtO2 in THF or H2 over Raney nickel.

Nitration of 2-fluoroanisole (XXXVII) with HNO3/Ac2O gives 3-fluoro-4-methoxynitrobenzene (XXXVIII), which is reduced to the corresponding aniline (XXXIX) with SnCl2/HCl. Reaction of compound (XXXIX) with Ac2O yields the acetanilide (XL), which is nitrated with HNO3 to afford 5-fluoro-4-methoxy-2-nitroacetanilide (XLI). Hydrolysis of (XLI) with NaOH provides 5-fluoro-4-methoxy-2-nitroaniline (XLII), which is cyclized with buten-2-one (XXXII) by means of As2O5 and H3PO4 to furnish 5-fluoro-6-methoxy-4-methyl-8-nitroquinoline (XLIII). Condensation of quinoline (XLIII) with 3-(trifluoromethyl)phenol (IV) by means of K2CO3 gives the diaryl ether (XXXIV), which is finally reduced by means of H2 over PtO2 in THF.

CLIP

US 4617394

Reaction of 8-amino-6-methoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy]quinoline (XIV) with phthalic anhydride (XV) affords the phthalimido derivative (XVI), which is oxidized with MCPBA to yield the quinoline N-oxide (XVII). Treatment of compound (XVII) with neutral alumina gives the quinolone derivative (XVIII), which by reaction with POCl3 in refluxing CHCl3 provides the 2-chloroquinoline derivative (XIX). Alternatively, reaction of the quinoline N-oxide (XVII) with POCl3 as before also gives the 2-chloroquinoline derivative (XIX) The removal of the phthalimido group of compound (XIX) by means of hydrazine in refluxing ethanol gives the chlorinated aminoquinoline (XX), which is finally treated with MeONa in hot DMF.

CLIP

US 6479660; WO 9713753

Chlorination of 6-methoxy-4-methylquinolin-2(1H)-one (I) with SO2Cl2 in hot acetic acid gives the 5-chloro derivative (II), which is nitrated with HNO3 in H2SO4 to yield the 8-nitroquinolinone (III). Condensation of compound (III) with 3-(trifluoromethyl)phenol (IV) by means of KOH in NMP provides the diaryl ether (V), which is treated with refluxing POCl3 to afford the 2-chloroquinoline (VI). Reaction of compound (VI) with MeONa in refluxing methanol results in the 2,6-dimethoxyquinoline derivative (VII), which is reduced with hydrazine over Pd/C to give the 8-aminoquinoline derivative (VIII). Condensation of aminoquinoline (VIII) with N-(4-iodopentyl)phthalimide (IX) by means of diisopropylamine in hot NMP yields the phthalimido precursor (X), which is finally cleaved with hydrazine in refluxing ethanol.

Reaction of 1,4-dibromopentane (XI) with potassium phthalimide (XII) gives N-(4-bromopentyl)phthalimide (XIII), which is then treated with NaI in refluxing acetone.

Reaction of 4-methoxyaniline (XXI) with ethyl acetoacetate (XXII) by means of triethanolamine in refluxing xylene gives the acetoacetanilide (XXIII), which is cyclized by means of hot triethanolamine and H2SO4 to yield 6-methoxy-4-methylquinolin-2(1H)-one (I), which is treated with refluxing POCl3 to provide 2-chloro-6-methoxy-4-methylquinoline (XXIV). Reaction of compound (XXIV) with SO2Cl2 in hot AcOH affords 2,5-dichloro-6-methoxy-4-methylquinoline (XXV), which is treated with MeONa in refluxing methanol to furnish 5-chloro-2,6-dimethoxy-4-methylquinoline (XXVI). Alternatively, the reaction of compound (XXIV) with MeONa as before gives 2,6-dimethoxy-4-methylquinoline (XXVII), which is treated with SO2Cl2 in hot AcOH to give the already described 5-chloro-2,6-dimethoxy-4-methylquinoline (XXVI). Nitration of compound (XXVI) with KNO3 and P2O5 gives the 8-nitroquinoline derivative (XXVIII), which is condensed with 3-(trifluoromethyl)phenol (IV) by means of KOH in hot NMP to yield the diaryl ether (VII). Finally, the nitro group of compound (VII) is reduced with hydrazine over Pd/C.

PAPER

http://pubs.rsc.org/en/Content/ArticleLanding/2017/RA/C7RA04867J#!divAbstract

An antimalarial drug, tafenoquine, as a fluorescent receptor for ratiometric detection of hypochlorite

 Author affiliations

Abstract

Tafenoquine (TQ), a fluorescent antimalarial drug, was used as a receptor for the fluorometric detection of hypochlorite (OCl). TQ itself exhibits a strong fluorescence at 476 nm, but OCl-selective cyclization of its pentan-1,4-diamine moiety creates a blue-shifted fluorescence at 361 nm. This ratiometric response facilitates rapid, selective, and sensitive detection of OCl in aqueous media with physiological pH. This response is also applicable to a simple test kit analysis and allows fluorometric OCl imaging in living cells.

Graphical abstract: An antimalarial drug, tafenoquine, as a fluorescent receptor for ratiometric detection of hypochlorite

1 H NMR (300 MHz, CDCl3, TMS) d (ppm): 7.32 (q, 1H, J ¼ 18 Hz), 7.21 (d, 1H, J ¼ 6 Hz), 7.07 (s, 1H), 6.94 (d, 1H, J ¼ 6 Hz), 6.64 (s, 1H), 6.50 (s, 1H), 5.84 (d, 1H, J ¼ 6 Hz), 4.00 (s, 3H), 3.79 (s, 3H), 3.66 (s, 1H), 2.78 (d, 2H, J ¼ 6 Hz), 2.55 (s, 3H), 1.69 (dd, 6H, J ¼ 6 Hz, J ¼ 9 Hz), 1.35 (d, 3H, J ¼ 6 Hz).

13C NMR (100 MHz, CDCl3, TMS) d (ppm): 159.64, 148.961, 146.339, 142.010, 132.085, 131.760, 131.007, 129.968, 126.917, 125.344, 122.636, 120.681, 118.006, 115.256, 112.052, 94.996, 56.989, 52.870, 48.446, 42.248, 34.439, 30.130, 23.103, 20.833.

MS (m/z): M+ calcd for C24H28F3N3O3: 463.2083; found (ESI): 464.17 (M + H)+ .

PAPER

J Med Chem 1989,32(8),1728-32

https://pubs.acs.org/doi/pdf/10.1021/jm00128a010

Synthesis of the intermediate diazepinone (IV) is accomplished by a one-pot synthesis. Condensation of 2-chloro-3-aminopyridine (I) with the anthranilic ester (II) is effected in the presence of potassium tert-butoxide as a catalyst. The resulting anthranilic amide (III) is cyclized under the influence of catalytic amounts of sulfuric acid. Treatment of (IV) with chloroacetylchloride in toluene yields the corresponding choroacetamide (V). The side chain of AQ-RA 741 is prepared starting from 4-picoline, which is alkylated by reaction with 3-(diethylamino)propylchloride in the presence of n-butyllithium. Hydrogenation of (VIII) using platinum dioxide as a catalyst furnishes the diamine (IX), which is coupled with (V) in the presence of catalytic amounts of sodium iodide in acetone leading to AQ-RA 741 as its free base.

Image result for tafenoquine DRUG FUTURE

Image result for tafenoquine DRUG FUTURE

CLIP

Image result for TAFENOQUINE IR

Image result for TAFENOQUINE IR

References

  1. Jump up to:a b Peters W (1999). “The evolution of tafenoquine–antimalarial for a new millennium?”J R Soc Med92 (7): 345–352. PMC 1297286Freely accessiblePMID 10615272.
  2. Jump up to:a b Shanks GD, Oloo AJ, Aleman GM, et al. (2001). “A New Primaquine Analogue, Tafenoquine (WR 238605), for prophylaxis against Plasmodium falciparum malaria”. Clin Infect Dis33 (12): 1968–74. doi:10.1086/324081JSTOR 4482936PMID 11700577.
  3. Jump up^ Lell B, Faucher JF, Missinou MA, et al. (2000). “Malaria chemoprophylaxis with tafenoquine: a randomised study”. Lancet355 (9220): 2041–5. doi:10.1016/S0140-6736(00)02352-7PMID 10885356.
  4. Jump up^ Elmes NJ, Nasveld PE, Kitchener SJ, Kocisko DA, Edstein MD (November 2008). “The efficacy and tolerability of three different regimens of tafenoquine versus primaquine for post-exposure prophylaxis of Plasmodium vivax malaria in the Southwest Pacific”Transactions of the Royal Society of Tropical Medicine and Hygiene102 (11): 1095–101. doi:10.1016/j.trstmh.2008.04.024PMID 18541280.
  5. Jump up^ Nasveld P, Kitchener S (2005). “Treatment of acute vivax malaria with tafenoquine”. Trans R Soc Trop Med Hyg99 (1): 2–5. doi:10.1016/j.trstmh.2004.01.013PMID 15550254.
  6. Jump up^ “Drugs@FDA: FDA Approved Drug Products”http://www.accessdata.fda.gov. Retrieved 2018-07-23.
  1.  Shanks GD, Oloo AJ, Aleman GM et al. (2001). “A New Primaquine Analogue, Tafenoquine (WR 238605), for prophylaxis against Plasmodium falciparum malaria”. Clin Infect Dis 33 (12): 1968–74. doi:10.1086/324081JSTOR 4482936.PMID 11700577.
  2. Lell B, Faucher JF, Missinou MA et al. (2000). “Malaria chemoprophylaxis with tafenoquine: a randomised study”.Lancet 355 (9220): 2041–5. doi:10.1016/S0140-6736(00)02352-7PMID 10885356.
  3.  Elmes NJ, Nasveld PE, Kitchener SJ, Kocisko DA, Edstein MD (November 2008). “The efficacy and tolerability of three different regimens of tafenoquine versus primaquine for post-exposure prophylaxis of Plasmodium vivax malaria in the Southwest Pacific”Transactions of the Royal Society of Tropical Medicine and Hygiene 102 (11): 1095–101.doi:10.1016/j.trstmh.2008.04.024PMID 18541280.
  4.  Nasvelda P, Kitchener S. (2005). “Treatment of acute vivax malaria with tafenoquine”. Trans R Soc Trop Med Hyg 99 (1): 2–5. doi:10.1016/j.trstmh.2004.01.013PMID 15550254.
  5.  Peters W (1999). “The evolution of tafenoquine–antimalarial for a new millennium?”. J R Soc Med 92 (7): 345–352.PMID 10615272.
  6. J Med Chem 1982,25(9),1094
8-3-2007
Methods and compositions for treating diseases associated with pathogenic proteins
12-6-2006
Process for the preparation of quinoline derivatives
3-14-2002
PROCESS FOR THE PREPARATION OF ANTI-MALARIAL DRUGS
4-2-1998
MULTIDENTATE METAL COMPLEXES AND METHODS OF MAKING AND USING THEREOF
4-18-1997
PROCESS FOR THE PREPARATION OF ANTI-MALARIAL DRUGS
12-20-1996
MULTIDENTATE METAL COMPLEXES AND METHODS OF MAKING AND USING THEREOF
12-15-1993
Use of interferon and a substance with an antimalarial activity for the treatment of malaria infections
10-15-1986
4-methyl-5-(unsubstituted and substituted phenoxy)-2,6-dimethoxy-8-(aminoalkylamino) quinolines
Title: Tafenoquine
CAS Registry Number: 106635-80-7
CAS Name: N4[2,6-Dimethoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy]-8-quinolinyl]-1,4-pentanediamine
Additional Names: 8-[(4-amino-1-methylbutyl)amino]-2,6-dimethoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy]quinoline
Manufacturers’ Codes: WR-238605
Molecular Formula: C24H28F3N3O3
Molecular Weight: 463.49
Percent Composition: C 62.19%, H 6.09%, F 12.30%, N 9.07%, O 10.36%
Literature References: Analog of primaquine, q.v. Prepn: P. Blumbergs, M. P. LaMontagne, US 4617394 (1986 to U.S. Sec. Army); M. P. LaMontagne et al., J. Med. Chem. 32, 1728 (1989). HPLC determn in blood and plasma: D. A. Kocisko et al., Ther. Drug Monit. 22, 184 (2000). Metabolism: O. R. Idowu et al., Drug Metab. Dispos. 23, 1 (1995). Clinical pharmacokinetics: M. D. Edstein et al., Br. J. Pharmacol. 52, 663 (2001). Clinical evaluation in prevention of malaria relapse: D. S. Walsh et al., J. Infect. Dis. 180, 1282 (1999); in malaria prophylaxis: B. Lell et al., Lancet 355, 2041 (2000); B. R. Hale et al., Clin. Infect. Dis. 36, 541 (2003).
Derivative Type: Succinate
CAS Registry Number: 106635-81-8
Trademarks: Etaquine (GSK)
Molecular Formula: C24H28F3N3O3.C4H6O4
Molecular Weight: 581.58
Percent Composition: C 57.83%, H 5.89%, F 9.80%, N 7.23%, O 19.26%
Properties: Crystals from acetonitrile, mp 146-149°. LD50 in male, female rats (mg/kg): 102, 71 i.p.; 429, 416 orally (LaMontagne).
Melting point: mp 146-149°
Toxicity data: LD50 in male, female rats (mg/kg): 102, 71 i.p.; 429, 416 orally (LaMontagne)
Therap-Cat: Antimalarial.
Keywords: Antimalarial.
Tafenoquine
(RS)-Tafenoquin Structural Formula V1.svg
Clinical data
Synonyms Etaquine,[1] WR 238605,[1] SB-252263
ATC code
  • none
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
NIAID ChemDB
Chemical and physical data
Formula C24H28F3N3O3
Molar mass 463.493 g/mol
3D model (JSmol)

OLD CLIP

April 28, 2014
GlaxoSmithKline (GSK) and Medicines for Malaria Venture (MMV) announced the start of a Phase 3 global program to evaluate the efficacy and safety of tafenoquine, an investigational medicine which is being developed for the treatment and relapse prevention (radical cure) of Plasmodium vivax (P. vivax) malaria.

P. vivax malaria, a form of the disease caused by one of several species of Plasmodium parasites known to infect humans, occurs primarily in South and South East Asia, Latin America and the horn of Africa. Severe anemia, malnutrition and respiratory distress are among the most serious consequences described to be caused by the infection.

The Phase 3 program includes two randomized, double-blind treatment studies to investigate tafenoquine in adult patients with P. vivax malaria. The DETECTIVE study (TAF112582) aims to evaluate the efficacy, safety and tolerability of tafenoquine as a radical cure for P. vivax malaria, co-administered with chloroquine, a blood stage anti-malarial treatment. The GATHER study (TAF116564) aims to assess the incidence of hemolysis and safety and efficacy of tafenoquine compared to primaquine, the only approved treatment currently available for the radical cure of P. vivax malaria.

Tafenoquine is not yet approved or licensed for use anywhere in the world.

“P. vivax malaria can affect people of all ages and is particularly insidious because it has the potential to remain dormant within the body in excess of a year, and causes some patients to experience repeated episodes of illness after the first mosquito bite,” said Nicholas Cammack, head, Tres Cantos Medicines Development Center for Diseases of the Developing World.  “Our investigation of tafenoquine for the treatment of P. vivax malaria is part of GSK’s efforts to tackle the global burden of malaria. Working with our partners, including MMV, we are determined to stop malaria in all its forms.”

“One of the big challenges we face in tackling malaria is to have new medicines to prevent relapse, caused by dormant forms of P. vivax,” said Dr. Timothy Wells, MMV’s chief scientific officer. “The Phase 3 program is designed to build upon the promising results of the Phase 2b study which showed that treatment with tafenoquine prevented relapses. If successful, tafenoquine has the potential to become a major contributor to malaria elimination. It’s a great privilege to be working with GSK on this project; they have a clear commitment to changing the face of public health in the countries in which we are working.”

/////////////Tafenoquine, タフェノキン , Orphan, FDA 2018,  KRINTAFEL, Priority Review, GlaxoSmithKline
COC1=CC(C)=C2C(OC3=CC=CC(=C3)C(F)(F)F)=C(OC)C=C(NC(C)CCCN)C2=N1

Umeclidinium bromide, ウメクリジニウム臭化物


Umeclidinium bromide.svg

ChemSpider 2D Image | Umeclidinium bromide | C29H34BrNO2Umeclidinium bromide.png

Umeclidinium bromide

GSK-573719A, ウメクリジニウム臭化物

  • Molecular FormulaC29H34BrNO2
  • Average mass508.490 Da
1-[2-(Benzyloxy)ethyl]-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane bromide
1-Azoniabicyclo[2.2.2]octane, 4-(hydroxydiphenylmethyl)-1-[2-(phenylmethoxy)ethyl]-, bromide (1:1)
diphenyl-[1-(2-phenylmethoxyethyl)-1-azoniabicyclo[2.2.2]octan-4-yl]methanol;bromide
7AN603V4JV
869113-09-7 [RN]
9551
GSK573719A; UNII-7AN603V4JV

Umeclidinium bromide (trade name Incruse Ellipta) is a long-acting muscarinic antagonist approved for the maintenance treatment of chronic obstructive pulmonary disease (COPD).[1] It is also approved for this indication in combination with vilanterol (as umeclidinium bromide/vilanterol).[2][3]

In the 2014, the drug was also approved in the E.U. and in the U.S. for the maintenance treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD). It was launched in the U.K. in October 2014 and in the U.S. in January 2015. In Japan, the product candidate was approved in 2015 as monotherapy for the maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD) and launched on October in the same year.

Image result for umeclidinium bromide synthesis

Umeclidinium bromide (Ellipta)
Umeclidinium bromide is a long-acting muscarinic acetylcholine antagonist developed by GlaxoSmithKline and approved by the US FDA at the end of 2013 for use in combination with vilanterol, a b2 agonist, for the treatment of chronic obstructive pulmonary disease.269 Due to umeclidinium’s poor oral bioavailability, the drug is administrated by inhalation as dry powder.269

The most likely scale preparation of the drug is described in Scheme .270
Commercially available ethyl isonipecotate (278) was alkylated with 1-bromo-2-chloroethane in the presence of K2CO3 in acetone to give ethyl 1-(2-chloroethyl)piperidine-4-carboxylate (279). This material was then treated with lithium diisopropylamine (LDA) in THF to affect a transannular substitution reaction resulting in the cyclized quinuclidine 280 in 96% yield.270 Excess of phenyllithium was added to ester 280 in THF starting at low temperature then gradually warming to room temperature to give tertiary alcohol 281 in 61% yield. Amine 281 was finally alkylated with benzyl 2-bromoethyl ether (282) in MeCN/CHCl3 at elevated temperatures
to afford umeclidinium bromide (XXXV) in 69% yield.

269. Tal-Singer, R.; Cahn, A.; Mehta, R.; Preece, A.; Crater, G.; Kelleher, D.;Pouliquen, I. J. Eur. J. Pharmacol. 2013, 701, 40.
270. Laine, D. I.; McCleland, B.; Thomas, S.; Neipp, C.; Underwood, B.; Dufour, J.;Widdowson, K. L.; Palovich, M. R.; Blaney, F. E.; Foley, J. J.; Webb, E. F.;Luttmann, M. A.; Burman, M.; Belmonte, K.; Salmon, M. J. Med. Chem. 2009, 52, 2493.

FDA

https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/203975Orig1s000ChemR.pdf

1-[2-(benzyloxy)ethyl]-4-(hydroxydiphenylmethyl)-1-azoniabicyclo[2.2.2]octane bromide

PATENT

https://patents.google.com/patent/CN105461710A/en

umeclidinium bromide prepared patent US7439393, US RE44874, US 7488827, US 7498440, US7361787 and the like using phenyllithium prepared by reaction of intermediate 4 – [(diphenyl) hydroxymethyl] azabicyclo [2.2.2 ] octane.Specific methods: azabicyclo [2.2.2] octane-nucleophilic addition reaction with 4-carboxylate-fold amount of 2.02-2.5 phenyllithium occurs, the reaction temperature is controlled to -78 ° 0_15 ° C ο lithium Reagents expensive, difficult to store, use of harsh conditions, relatively high cost.

 Example 1

Phenyl magnesium chloride: Under nitrogen atmosphere to 55g (2.3mol) of metallic magnesium sandpaper lit with 3 L of tetrahydrofuran was added dropwise 215g (1.91mol) chlorobenzene, micro-thermal reaction proceeds, controlled dropping, the reaction was kept boiling, dropwise for about 1.5 hours, after the dropping was heated slightly under reflux for 30min. Cool reserve.

[0008] Example 2

Phenyl magnesium bromide: The under argon 50.4g (2.lmol) sandpaper lit magnesium metal with 4.2 liters of anhydrous ethyl ether was added a solution of 300g (1.91mol) of bromobenzene, was added an iodine initiator, electrical hair fever reaction proceeds, controlled dropping, the reaction was kept boiling, about 1.5 hours dropwise was added dropwise to a gentle reflux heated 30min. Cool reserve.

[0009] Example 3

Preparation of crude product: azabicyclo [2.2.2] octane-4-carboxylate (135g, 0.736mo 1) was dissolved in 3L of tetrahydrofuran, under nitrogen, was cooled to -5~0 ° C, was added dropwise 300g preparation of benzyl bromide Grignard reagent. After incubation -5~0 ° C stirred for 1 hour (progress of the reaction was monitored by TLC sample). Adding 50ml of water quenching. Liquid separation, the aqueous phase was extracted twice with 500ml of tetrahydrofuran, and the combined organic phases were washed with water, dried and filtered. The solvent was partially removed under reduced pressure, the balance maintaining approximately 1L, the residue was stirred overnight at 20 ° C crystallization.Filtered, washed (petroleum ether 2 X 200 ml), the filter cake was dried at 40 ° C in vacuo to give a yellowish white crystals 121.2 g, yield 54.2%.

[0010] Example 4

Preparation of crude product: azabicyclo [2.2.2] octane-4-carboxylate (18.3g, 0.lOmo 1) was dissolved in 3L of tetrahydrofuran, under nitrogen, was cooled to 0~5 ° C, was added dropwise 0.25 mol phenyl magnesium chloride. After incubation 0~5 ° C stirred for 1 hour (progress of the reaction was monitored by TLC sample) o quenched with 10ml of water was added. Liquid separation, the aqueous phase was extracted twice with 100ml of tetrahydrofuran, and the combined organic phases were washed with water, dried and filtered. The solvent was partially removed under reduced pressure, the balance maintaining approximately 50mL, the residue was stirred overnight at 20 ° C crystallization.Filtered, washed (petroleum ether 2X20 ml), the filter cake was dried at 40 ° C in vacuo to give a yellowish white crystals 14.63 g, yield 48.1%.

[0011] Example 5

Preparation of crude product: azabicyclo [2.2.2] octane-4-carboxylate (18.38,0.1011101) ^ 31 was dissolved in tetrahydrofuran, under nitrogen, was cooled to 5~15 ° C, was added dropwise 0.30 mol of benzene bromide. After incubation 5~15 ° C stirred for 1 hour (progress of the reaction was monitored by TLC sample) o quenched with 10ml of water was added. Liquid separation, the aqueous phase was extracted twice with 100ml of tetrahydrofuran, and the combined organic phases were washed with water, dried and filtered. The solvent was partially removed under reduced pressure, the balance maintaining approximately 50mL, the residue was stirred overnight at 20 ° C crystallization.Filtered, washed (petroleum ether 2 X 20 ml), the filter cake was dried at 40 ° C in vacuo to yield 13.80 g of yellow-white crystals, yield 47.1%.

[0012] Example 6

Umeclidinium bromide purification: 100g crude product was dissolved in 320ml of water to 80 ° C a mixture of 640ml of acetone, add 5g active carbon, and filtered.The filtrate was cooled to 25 ° C, for 1 hour. Within 1 to 2 hours and cooled to 0~5 ° C for 3 hours. The filter cake with chilled 1: 2 acetone – washed twice with water (2x20ml). The filter cake was dried in vacuo at 60 ° C to give white crystalline solid (92 g, yield 92%). Purity (HPLC normalization method) 99.25%.

[0013] Example 7

Umeclidinium bromide purification: 100g crude product was dissolved in 180ml water at 50 ° C a mixture of 360ml of acetone, add 5g active carbon, and filtered.The filtrate was ~ 2 hours to 25 ° C, for 1 hour. Within 1 to 2 hours cooled to 0 ° C and left overnight protection. The filter cake with chilled 1: 2 acetone – washed twice with water (2x20ml). The filter cake was dried at 60 ° C in vacuo to give fine (98.3 g, yield 98.3%). Purity (HPLC normalization method) 97.75%.

PATENT

https://patents.google.com/patent/WO2014027045A1

International Patent Publication Number WO 2005/104745 (Glaxo Group Limited), filed 27th April 2005, discloses muscarinic acetylcholine receptor antagonists. In particular, WO 2005/104745 discloses 4- [hydroxy(diphenyl)methyl]-l-{2-[(phenylmethyl)oxy]ethyl}-l-azoniabicyclo[2.2.2]octane bromide, of formula (I), and a process for the preparation of this compound (Example 84):

Figure imgf000002_0001

4-[Hydroxy(diphenyl)methyl]-l-{2-[(phenylmethyl)oxy]ethyl}-l-azoniabicyclo[2.2.2]octane bromide may also be referred to as umeclidinium bromide.

International Patent Publication Number WO 2011/029896 (Glaxo Group Limited), filed 10th September 2010, discloses an alternative preparation for an early intermediate, ethyl-l-azabicyclo[2.2.2] octane-4-carboxylate, in the multi-step synthesis of umeclidinium bromide.

There exists a need for an alternative process for the preparation of umeclidinium bromide. In particular, a process that offers advantages over those previously disclosed in WO 2005/104745 and WO 2011/029896 is desired. Advantages may include, but are not limited to, improvements in safety, control (i.e of final product form and physical characteristics), yield, operability, handling, scalability, and efficiency.

Summary of the Invention

The present invention provides, in a first aspect, a process for the preparation of umeclidinium bromide, which comprises: a) reacting ((2-bromoethoxy)methyl)benzene, of formula (II)

Figure imgf000003_0001

in a dipolar aprotic solvent with a boiling point greater than about 90°C or an alcohol with a boiling point greater than about 80°C; and optionally

b) re-crystallising the product of step (a).

The present invention is further directed to intermediates used in the preparation of the compound of formula (III), and hence of umeclidinium bromide. The process disclosed herein provides a number of advantages over prior art processes of WO 2005/104745 and WO 2011/029896.

PATENT

EP 3248970

FORM A B AND AMORPHOUS

https://patents.google.com/patent/EP3248970A1/en

The invention relates to novel solid forms of umeclidinium bromide (I), chemically 1-[2-(benzyloxy)ethyl]-4-(hydroxydiphenylmethyl)-1-azabicyclo[2.2.2]octane bromide. In particular, to its novel crystalline forms, identified as form A and form B, as well as to an amorphous form, and to their characterization by means of analytic methods. The invention further relates to methods of their preparation and their use for the preparation of umeclidinium bromide in the API quality.

Figure imgb0001

Umeclidinium bromide is indicated as an inhalation anticholinergic drug with an ultra-long-term effect in cooperating patients with the diagnosis of COPD (chronic obstructive pulmonary disease). COPD is defined as a preventable and treatable disease that is characterized by a persistent obstruction of air flow in the bronchi (bronchial obstruction), which usually progresses and is related to an intensified inflammatory response of the airways to harmful particles or gases. The main goal of the treatment of COPD is an improvement of the current control, i.e. elimination of symptoms, improvement of toleration of physical effort, improvement of the health condition and reduction of future risks, i.e. prevention and treatment of exacerbations, prevention of progression of the disease and mortality reduction

The structure of umeclidinium bromide, 1-[2-(benzyloxy)ethyl]-4-(hydroxydiphenylmethyl)-1-azabicyklo[2.2.2]octane bromide, is first mentioned in the general patent application WO2005009362 of 2003 .

Preparation of umeclidinium bromide is first disclosed in the patent EP 1 740 177B ( WO2005104745 ), where two methods (A and B) are mentioned, differing in the final processing and the product yield (method B included in Scheme 1). There, the last steps of the synthesis are described, the product being described by means of EI-MS, 1H NMR and elementary analysis. There is no information concerning the chemical purity or polymorphic form.

Figure imgb0002
Another preparation method of umeclidinium bromide is disclosed in the patent application WO 2014027045 , where three forms are also described (identified as forms 1 to 3), prepared using a method that is different from the procedure disclosed in the patent EP 1 740 177B .
    • Example 5

Preparation of the amorphous form of umeclidinium bromide

1-[2-(benzyloxy)ethyl]-4-(hydroxydiphenylmethyl)-1-azabicyclo[2.2.2]octane bromide (100 mg, 0.197 mmol, purity UPLC 98.89%) is dissolved at the temperature of 25°C in a water: tert-butanol mixture in the volume ratio of 6:4 (total 70 ml). The clear solution is freeze-dried (a bath with a mixture of dry ice and ethanol, -70°C) and lyophilized (vacuum: 1.8 Pa for 72 h). An amorphous form of umeclidinium bromide was obtained (100 mg). This amorphous form was confirmed with DSC and X-ray powder diffraction. The X-ray powder diffraction pattern is shown in Fig. 8 and the DSC record in Fig. 9.

PAPER

Synthetic Communications  An International Journal for Rapid Communication of Synthetic Organic Chemistry , Volume 48, 2018 – Issue 9, Convenient new synthesis of umeclidinium bromide

Pages 995-1000 | Received 05 Mar 2017, Accepted author version posted online: 10 Jul 2017, Published online: 10 Jul 2017

Umeclidinium bromide, a drug used for chronic obstructive pulmonary disease, is synthesized through a new intermediate of phenyl(quinuclidin-4-yl)methanone. This novel method with simple operation flow and cheap reagents, makes it suitable for scale up. The overall four-step process provides umeclidinium bromide in 29% yield and the purity up to 99.83%. The X-ray crystal structure of the drug molecule was first reported.

External links

References

  1. Jump up to:a b “Incruse Ellipta (umeclidinium inhalation powder) for Oral Inhalation Use. Full Prescribing Information” (PDF). GlaxoSmithKline, Research Triangle Park, NC 27709. Retrieved 22 February 2016.
  2. Jump up^ Feldman, GJ; Edin, A (2013). “The combination of umeclidinium bromide and vilanterol in the management of chronic obstructive pulmonary disease: Current evidence and future prospects”. Therapeutic advances in respiratory disease7 (6): 311–9. doi:10.1177/1753465813499789PMID 24004659.
  3. Jump up^ “FDA Approves Umeclidinium and Vilanterol Combo for COPD”. Medscape. December 18, 2013.
Umeclidinium bromide
Umeclidinium bromide.svg
Clinical data
Trade names Incruse Ellipta
Synonyms GSK573719A
License data
Pregnancy
category
  • US: C (Risk not ruled out)
Routes of
administration
Inhalation (DPI)
ATC code
Legal status
Legal status
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Protein binding ~89%[1]
Metabolism Hepatic (CYP2D6)
Elimination half-life 11 hours
Excretion Feces (58%) and urine(22%)
Identifiers
CAS Number
PubChem CID
ChemSpider
KEGG
ChEBI
ECHA InfoCard 100.166.375 Edit this at Wikidata
Chemical and physical data
Formula C29H34BrNO2
Molar mass 508.49 g/mol
3D model (JSmol)

//////////////Umeclidinium bromide, Incruse Ellipta, ウメクリジニウム臭化物 , GSK573719A,  UNII-7AN603V4JV, FDA 2014

C1C[N+]2(CCC1(CC2)C(C3=CC=CC=C3)(C4=CC=CC=C4)O)CCOCC5=CC=CC=C5.[Br-]

Synthesis

FDA Orange Book Patents: 1 of 15 (FDA Orange Book Patent ID)
Patent 9750726
Expiration Nov 29, 2030
Applicant GLAXOSMITHKLINE
Drug Application
  1. N203975 (Prescription Drug: ANORO ELLIPTA. Ingredients: UMECLIDINIUM BROMIDE
  2. VILANTEROL TRIFENATATE)
FDA Orange Book Patents: 2 of 15 (FDA Orange Book Patent ID)
Patent 6759398
Expiration Aug 3, 2021
Applicant GLAXOSMITHKLINE
Drug Application
  1. N209482 (Prescription Drug: TRELEGY ELLIPTA. Ingredients: FLUTICASONE FUROATE
  2. UMECLIDINIUM BROMIDE
  3. VILANTEROL TRIFENATATE)
FDA Orange Book Patents: 3 of 15 (FDA Orange Book Patent ID)
Patent 7439393
Expiration May 21, 2025
Applicant GLAXOSMITHKLINE
Drug Application
  1. N203975 (Prescription Drug: ANORO ELLIPTA. Ingredients: UMECLIDINIUM BROMIDE
  2. VILANTEROL TRIFENATATE)
FDA Orange Book Patents: 4 of 15 (FDA Orange Book Patent ID)
Patent 7629335
Expiration Aug 3, 2021
Applicant GLAXOSMITHKLINE
Drug Application
  1. N209482 (Prescription Drug: TRELEGY ELLIPTA. Ingredients: FLUTICASONE FUROATE
  2. UMECLIDINIUM BROMIDE
  3. VILANTEROL TRIFENATATE)
FDA Orange Book Patents: 5 of 15 (FDA Orange Book Patent ID)
Patent 7776895
Expiration Sep 11, 2022
Applicant GLAXOSMITHKLINE
Drug Application
  1. N209482 (Prescription Drug: TRELEGY ELLIPTA. Ingredients: FLUTICASONE FUROATE
  2. UMECLIDINIUM BROMIDE
  3. VILANTEROL TRIFENATATE)
FDA Orange Book Patents: 6 of 15 (FDA Orange Book Patent ID)
Patent 8161968
Expiration Feb 5, 2028
Applicant GLAXOSMITHKLINE
Drug Application
  1. N209482 (Prescription Drug: TRELEGY ELLIPTA. Ingredients: FLUTICASONE FUROATE
  2. UMECLIDINIUM BROMIDE
  3. VILANTEROL TRIFENATATE)
FDA Orange Book Patents: 7 of 15 (FDA Orange Book Patent ID)
Patent 8201556
Expiration Feb 5, 2029
Applicant GLAXO GRP ENGLAND
Drug Application N205382 (Prescription Drug: INCRUSE ELLIPTA . Ingredients: UMECLIDINIUM BROMIDE)
FDA Orange Book Patents: 8 of 15 (FDA Orange Book Patent ID)
Patent 6537983
Expiration Aug 3, 2021
Applicant GLAXOSMITHKLINE
Drug Application
  1. N209482 (Prescription Drug: TRELEGY ELLIPTA. Ingredients: FLUTICASONE FUROATE
  2. UMECLIDINIUM BROMIDE
  3. VILANTEROL TRIFENATATE)
FDA Orange Book Patents: 9 of 15 (FDA Orange Book Patent ID)
Patent 7498440
Expiration Apr 27, 2025
Applicant GLAXOSMITHKLINE
Drug Application
  1. N209482 (Prescription Drug: TRELEGY ELLIPTA. Ingredients: FLUTICASONE FUROATE
  2. UMECLIDINIUM BROMIDE
  3. VILANTEROL TRIFENATATE)
FDA Orange Book Patents: 10 of 15 (FDA Orange Book Patent ID)
Patent 7488827
Expiration Dec 18, 2027
Applicant GLAXOSMITHKLINE
Drug Application
  1. N203975 (Prescription Drug: ANORO ELLIPTA. Ingredients: UMECLIDINIUM BROMIDE
  2. VILANTEROL TRIFENATATE)
FDA Orange Book Patents: 11 of 15 (FDA Orange Book Patent ID)
Patent 8183257
Expiration Jul 27, 2025
Applicant GLAXOSMITHKLINE
Drug Application
  1. N209482 (Prescription Drug: TRELEGY ELLIPTA. Ingredients: FLUTICASONE FUROATE
  2. UMECLIDINIUM BROMIDE
  3. VILANTEROL TRIFENATATE)
FDA Orange Book Patents: 12 of 15 (FDA Orange Book Patent ID)
Patent 6878698
Expiration Aug 3, 2021
Applicant GLAXOSMITHKLINE
Drug Application
  1. N209482 (Prescription Drug: TRELEGY ELLIPTA. Ingredients: FLUTICASONE FUROATE
  2. UMECLIDINIUM BROMIDE
  3. VILANTEROL TRIFENATATE)
FDA Orange Book Patents: 13 of 15 (FDA Orange Book Patent ID)
Patent 8511304
Expiration Jun 14, 2027
Applicant GLAXOSMITHKLINE
Drug Application
  1. N209482 (Prescription Drug: TRELEGY ELLIPTA. Ingredients: FLUTICASONE FUROATE
  2. UMECLIDINIUM BROMIDE
  3. VILANTEROL TRIFENATATE)
FDA Orange Book Patents: 14 of 15 (FDA Orange Book Patent ID)
Patent RE44874
Expiration Mar 23, 2023
Applicant GLAXOSMITHKLINE
Drug Application
  1. N209482 (Prescription Drug: TRELEGY ELLIPTA. Ingredients: FLUTICASONE FUROATE
  2. UMECLIDINIUM BROMIDE
  3. VILANTEROL TRIFENATATE)
FDA Orange Book Patents: 15 of 15 (FDA Orange Book Patent ID)
Patent 8309572
Expiration Apr 27, 2025
Applicant GLAXOSMITHKLINE
Drug Application
  1. N209482 (Prescription Drug: TRELEGY ELLIPTA. Ingredients: FLUTICASONE FUROATE
  2. UMECLIDINIUM BROMIDE
  3. VILANTEROL TRIFENATATE)

Vilanterol trifenatate, ビランテロールトリフェニル酢酸塩


Vilanterol trifenatate.pngThumb

ThumbImage result for Vilanterol Trifenatate

str1

Vilanterol trifenatate, ビランテロールトリフェニル酢酸塩

ビランテロールトリフェナテート

UNII-40AHO2C6DG; GW642444M; CAS 503070-58-4

free form, 503068-34-6

HY-14300ACS-1679

444
642444
GSK-642444
GW-642444
GW-642444M

4-[(1R)-2-[6-[2-[(2,6-dichlorophenyl)methoxy]ethoxy]hexylamino]-1-hydroxyethyl]-2-(hydroxymethyl)phenol;2,2,2-triphenylacetic acid

1,3-Benzenedimethanol, α1-[[[6-[2-[(2,6-dichlorophenyl)methoxy]ethoxy]hexyl]amino]methyl]-4-hydroxy-, (α1R)-
4-{(1R)-2-[(6-{2-[(2,6-Dichlorbenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol
Molecular Formula: C44H49Cl2NO7
Molecular Weight: 774.776 g/mol

4-[(1R)-2-({6-[(2-{[(2,6-Dichlorophenyl)methyl]oxy}ethyl)oxy]hexyl}-amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol Acetate Salt

J. Med. Chem.201053 (11), pp 4522–4530
DOI: 10.1021/jm100326d

white crystalline solid: mp (DSC) 131.9−134.2 °C, [α]D 20 −14.6 (c 1.034 in MeOH). MS ES +ve m/z 289, 486/488 (M + H)+1H NMR δ (500 MHz, CD3OD) 7.47 (2H, m), 7.38 (8H, m), 7.28 (6H, tt, J 7.1, 1.8 Hz), 7.22 (4H, m), 6.86 (1H, d, J 7.9 Hz), 4.94 (1H, dd, J 9.7, 4.6 Hz), 4.91 (2H, s), 4.74 (2H, s), 3.79 (2H, m), 3.69 (2H, m), 3.56 (2H, t, J 6.1 Hz), 3.10 (2H, m), 2.99 (2H, m), 1.72 (2H, m), 1.65 (2H, m), 1.45 (4H, m). 13C NMR δ (125 MHz, CD3OD) 180.1, 156.2, 147.7, 140.3, 137.9, 134.5, 133.0, 131.9, 131.6, 129.6, 128.9, 128.1, 127.1, 127.0, 126.7, 116.0, 72.1, 71.4, 71.3, 71.1, 70.1, 68.4, 60.9, 55.4, 48.9, 30.5, 27.4, 27.1, 26.8. Anal. found: C, H, N, Cl.

Vilanterol is a selective long-acting beta2-adrenergic agonist (LABA) with inherent 24-hour activity for once daily treatment of COPD and asthma. Its pharmacological effect is attributable to stimulation of intracellular adenylyl cyclase which catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3′,5′-adenosine monophosphate (cAMP). Increases in cyclic AMP are associated with relaxation of bronchial smooth muscle and inhibition of release of hypersensitivity mediators from mast cells in the lungs.

Vilanterol is approved for use in several combination products such as with fluticasone furoate under the tradename Breo Ellipta and in combination with umeclidinium bromide as Anoro Ellipta. Approved by the FDA in 2013, use of Breo Ellipta is indicated for the long-term, once-daily maintenance treatment of airflow obstruction in patients with COPD, including chronic bronchitis and emphysema. It is also indicated for once-daily maintenance treatment of asthma in patients aged 18 or older with reversible obstructive airways disease.

Vilanterol is approved for use in several combination products such as with fluticasone furoate under the tradename Breo Ellipta and in combination with umeclidinium bromide as Anoro Ellipta. Approved by the FDA in 2013, use of Breo Ellipta is indicated for the long-term, once-daily maintenance treatment of airflow obstruction in patients with COPD, including chronic bronchitis and emphysema. It is also indicated for once-daily maintenance treatment of asthma in patients aged 18 or older with reversible obstructive airways disease.

Vilanterol (INNUSAN) is an ultra-long-acting β2 adrenoreceptor agonist (ultra-LABA), which was approved in May 2013 in combination with fluticasone furoate for sale as Breo Ellipta by GlaxoSmithKline for the treatment of chronic obstructive pulmonary disease (COPD).[1]

Vilanterol is available in following combinations:

The other active component of BREO ELLIPTA is vilanterol trifenatate, a LABA with the chemical name triphenylacetic acid-4-{(1R)-2-[(6-{2-[2,6-dicholorobenzyl)oxy]ethoxy} hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol (1:1) and the following chemical structure:

Vilanterol trifenatate - Structural Formula Illustration

Vilanterol trifenatate is a white powder with a molecular weight of 774.8, and the empirical formula is C24H33Cl2NO5•C20H16O2. It is practically insoluble in water.

Image result for Vilanterol Trifenatate

https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/203975Orig1s000ChemR.pdf

PATENT

WO 2003024439

https://patents.google.com/patent/WO2003024439A1/ru

PAPER

 Journal of Medicinal Chemistry (2010), 53(11), 4522-4530

Abstract Image

A series of saligenin β2 adrenoceptor agonist antedrugs having high clearance were prepared by reacting a protected saligenin oxazolidinone with protected hydroxyethoxyalkoxyalkyl bromides, followed by removal of the hydroxy-protecting group, alkylation, and final deprotection. The compounds were screened for β2, β1, and β3 agonist activity in CHO cells. The onset and duration of action in vitro of selected compounds were assessed on isolated superfused guinea pig trachea. Compound 13f had high potency, selectivity, fast onset, and long duration of action in vitro and was found to have long duration in vivo, low oral bioavailability in the rat, and to be rapidly metabolized. Crystalline salts of 13f (vilanterol) were identified that had suitable properties for inhaled administration. A proposed binding mode for 13f to the β2-receptor is presented.

Synthesis and Structure−Activity Relationships of Long-acting β2Adrenergic Receptor Agonists Incorporating Metabolic Inactivation: An Antedrug Approach

 Departments of Medicinal Chemistry
 Respiratory Biology
§ Computational Structural Chemistry
 Drug Metabolism and Pharmacokinetics
Respiratory CEDD, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom
 Synthetic Chemistry, GlaxoSmithKline, Old Powder Mills, Near Leigh, Tonbridge, Kent TN11 9AN, United Kingdom
J. Med. Chem.201053 (11), pp 4522–4530
DOI: 10.1021/jm100326d
*To whom correspondence should be addressed. Phone: (+44)1438 762883. Fax: (+44)1438 768302. E-mail: pan.a.procopiou@gsk.com

4-[(1R)-2-({6-[(2-{[(2,6-Dichlorophenyl)methyl]oxy}ethyl)oxy]hexyl}-amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol (13f) Triphenylacetate Salt

Triphenylacetic acid (1.81 g, 6.28 mmol) was added to a solution of 4-((R)-2-{6-[2-(2,6-dichlorobenzyloxy)-ethoxy]-hexylamino}-1-hydroxyethyl)-2-hydroxymethyl-phenol (95% pure; 3.28 g, 6.41 mmol) in EtOH (20 mL), and the mixture heated to 80 °C to obtain a solution. The mixture was allowed to cool to ambient temperature, and the resulting product filtered, washed with a little ethanol, then dried in vacuo at 50 °C to afford 13f-triphenylacetate salt (4.3 g, 88%) as a white crystalline solid: mp (DSC) 131.9−134.2 °C, [α]D20 −14.6 (c 1.034 in MeOH). MS ES +ve m/z 289, 486/488 (M + H)+1H NMR δ (500 MHz, CD3OD) 7.47 (2H, m), 7.38 (8H, m), 7.28 (6H, tt, J 7.1, 1.8 Hz), 7.22 (4H, m), 6.86 (1H, d, J 7.9 Hz), 4.94 (1H, dd, J 9.7, 4.6 Hz), 4.91 (2H, s), 4.74 (2H, s), 3.79 (2H, m), 3.69 (2H, m), 3.56 (2H, t, J 6.1 Hz), 3.10 (2H, m), 2.99 (2H, m), 1.72 (2H, m), 1.65 (2H, m), 1.45 (4H, m). 13C NMR δ (125 MHz, CD3OD) 180.1, 156.2, 147.7, 140.3, 137.9, 134.5, 133.0, 131.9, 131.6, 129.6, 128.9, 128.1, 127.1, 127.0, 126.7, 116.0, 72.1, 71.4, 71.3, 71.1, 70.1, 68.4, 60.9, 55.4, 48.9, 30.5, 27.4, 27.1, 26.8. Anal. found: C, H, N, Cl.
Patent
CN 103923058

β 2- adrenergic receptor agonist is most widely used in clinical treatment of asthma and chronic obstructive pulmonary disease drugs. Currently available on the market β2_ adrenoceptor agonists longest duration of action of 12 hours, which resulted in the need twice daily dosing. Over the last decade, the development of high potency, high selectivity, rapid onset, long duration of action, is administered once daily β2- adrenoreceptor agonists caused great concern in the pharmaceutical industry. Triflate vilanterol by Glaxo Group Limited to develop a new type of ultra-long-acting β 2- adrenergic receptor agonist, on 18 December 2013 by the US FDA clearance to market its drugs name Anoro Ellipta0

vilanterol chemical name is 4 – {(lR) -2 – [(6- {2 _ [(2,6- dichlorobenzyl) oxy] ethoxy} hexyl) amino] -1 – hydroxyethyl} -2_ (hydroxymethyl) phenol, having the formula as follows:

Figure CN103923058AD00031

At present the synthesis of chiral vilanterol reported mainly in the following two ways:

1, and references J.Med.Chem.2010,53,4522-4530 Patent W02003024439, synthetic routes such as

under:

Figure CN103923058AD00032

1.2, and references J.Med.Chem.2010,53,4522-4530 Patent W02003024439, synthetic routes such as

under:

Figure CN103923058AD00041

Two or more routes are carried over a key intermediate in the alkylation of the amine compound X and then deprotecting to give the target compound I. Use of highly toxic chiral oxazaborolidine key intermediate in the process for preparing a compound X as a catalyst is expensive, and serious environmental pollution can not be recycled, high production costs; while boron reducing agent used in the process alkoxy – tetrahydrofuran solution of dimethyl sulfide have high reactivity shortcomings need to use special equipment. Further, throughout the synthesis process used in amounts of sodium hydride, sodium hydride in the reaction process will emit a lot of heat, and the use of sodium hydride and stored under harsh conditions, there are security risks in industrial production, is not suitable for industrial production.

Laurus Labs Limited was improved synthesis process described above, Patent W02014041565, which scheme is as follows:

Figure CN103923058AD00042

While this synthesis will replace potassium t-butoxide, sodium hydride, to reduce the security risks in industrial production, but the process for preparing a key intermediate compound using X is still toxic as chiral oxazaborolidine catalyst, and environmental pollution high production cost issues remain unresolved.

An epoxy compound IV (preparation described in Bioorganic & Medicinal Chemistry Letters, 23 (5), 2013,1548-1552 and Patent CN101684074A) amine VI with a chiral auxiliary to give the chiral compound V.

Figure CN103923058AD00043

Wherein the amine is a chiral auxiliary or S- S- phenylethylamine naphthylethyl amine, amine chiral auxiliary used has S- (a) – methylbenzylamine, (S) -2_ A -1-phenylethylamine, S – (-) _ N- benzyl-1-phenylethylamine, S – (-) – l_ (l- naphthyl) ethylamine

Example a

(R) -1- (2,2- dimethyl–4H- benzo [d] [I, 3] dioxin-6-yl) _2_ (⑶-1- phenyl-ethylamino) ethanol, and the step of preparing a salt of I): 2, 2- dimethyl-6- ethylene prepared -4H- benzo [d] [I, 3] dioxane (compound of formula IV) burning

Was added to a three neck round bottom flask, 12.8 g of 2-bromo-1- (2,2-dimethyl -4H-1,3- benzodioxin-6-yl) (Compound of formula II) ethanone and 100 ml of methanol, stirred and dissolved it was cooled to -10 ° C, followed by the slow addition of 2.4 g of sodium borohydride addition was completed, the reaction at room temperature for 90 minutes. Was added to the reaction mixture quenched with 50 ml aqueous ammonium chloride solution, stirred and concentrated to remove most of the methanol for 10 minutes, then extracted with 50 ml of methylene chloride, the aqueous phase was repeatedly extracted three times with 50 ml dichloromethane and the combined organic phases . The organic phase was washed with 20 ml of distilled water and once with 20 ml of saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated. Then a mixture of tetrahydrofuran and methanol in this step the resulting compound (about 12 g) was dissolved in a total volume of 200 ml (volume ratio of tetrahydrofuran to methanol is 1: 1), 20.8 g of potassium carbonate was added, and the reaction at room temperature for 18 hour. The reaction was concentrated to remove most of the organic solvent, 100 ml of distilled water was added to the concentrate, and then 60 ml of methylene chloride was separated out and the aqueous phase repeatedly extracted three times with 30 ml of methylene chloride, the organic phase was washed with 20 ml of distilled water once with 20 ml saturated brine once, dried over anhydrous sodium sulfate, and concentrated to give a white solid. Compound IV obtained in this step without further purification was used directly in the next reaction.

. [0012] Step 2): (R) -1- (2, 2 ~ _ methyl -4H- benzo [d] [I, 3] dioxo TK 6-yl) -2 – ((S preparation) -1-phenyl-ethylamino) ethanol

The 8.24 g of the epoxy compound IV dissolved in 30 ml dimethyl sulfoxide at room temperature was slowly added 5.8 g S- (a) – methylbenzylamine, and then controlling the reaction temperature at 60 ° C 3 hours, by TLC monitoring the reaction is complete. Wait until the reaction mixture was cooled, added to 90 ml saturated aqueous sodium bicarbonate, and extracted with ethyl acetate (3 x 50 mL), the organic phase was dried over anhydrous sodium sulfate, then filtered and concentrated to give (R) -1- (2, 2-methyl–4H- benzo [d] [1,3] dioxin-6-yl) -2 – ((S) -1- phenylethyl) ethanol The crude product was 10.3 g, yield rate of 73%. The crude product obtained in this step without further purification was used directly in the next salt-forming reaction. [0013] 1H-NMR (500 MHz, CDCl3) δ 1.27 (d, J = 12.2 Hz, 3H), 1.49 (s, 6H), 2.94 (dd, J = 24.8 and 11.4 Hz, 1H), 3.21 (dd, J = 24.8 and 11.4 Hz, 1H), 4.32-4.39 (m, 1H), 4.59 (s, 2H), 4.84 – 4.89 (m, 1H), 6.82 (d, J = 15.0 Hz, 1H), 7.06 (d , J = 3.1 Hz, 1H), 7.25 – 7.35 (m, 6H).

[0014] LC-MS: m / z = 328.1 (C20H25NO3 + H +).

[0015] Chiral HPLC: R- configuration: 96.4%, S- configuration: 3.6%.

[0016] Step 3) (! R) -1- (2,2- dimethyl-benzo -41- [(1] [1,3] dioxin-6-yl) -2 – (( preparation of different salts of 1-phenyl-ethylamino) ethanol 5)

Step 2) The obtained crude product was equally divided into four parts, each of 20 ml of methanol are added to the solvent, stirring at 40 ° C under conditions to dissolve and camphorsulfonic acid were added to a solution of four parts, methanesulfonic acid , oxalic acid and benzoic acid is added in an amount of 1.5 equivalent of the crude product, after the addition was complete, stirring was continued for 2 hours, allowed to stand overnight and cooled at 0 ° C, filtered, to give the corresponding salt. The results shown in the following table.

Figure CN103923058AD00061

[0017] Second Embodiment

(R) -1- (2,2- dimethyl–4H- benzo [d] [I, 3] dioxane _6_ yl) _2_ (⑶-2- methoxy-1-phenyl ethanol and salts thereof ethylamino)

Step I): (R) -1- (2, 2- dimethyl -4H- benzo [d] [I, 3] dioxin-6-yl) ~ 2 ~ (⑶-2- methoxy preparation of 1-phenyl-ethylamino) ethanol

The method of preparation of a Compound IV The procedure of Example I) the same embodiment.

[0018] The epoxy compound IV was added 8.24 g to 50 ml of acetonitrile solvent, stirring and dissolved slowly added

9.06 g S-2- methoxy-1-phenylethylamine, followed by stirring at 80 ° C for 6 hours. After completion of the reaction was monitored by TLC, the reaction mixture was concentrated. 30 ml of saturated aqueous sodium bicarbonate, and extracted with ethyl acetate (3×30 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give (R) -1- (2, 2- dimethyl -4H- benzo [d] [1,3] dioxin-6-yl) -2 – ((S) -2_ gas-methoxy-1-phenylethyl-yl) ethanol 9.8 g crude was wide, wide rate of 68%. The crude product obtained in this step without further purification was used directly in the next salt-forming reaction.

[0019] 1H-NMR (500 MHz, CDCl3) δ 1.49 (s, 6H), 2.98 – 3.21 (m, 2H), 3.34 (s, 3H), 3.55 – 3.80 (m, 2H), 4.02 (dd, J = 12.4 and 2.3 Hz, 1H), 4.59 (s, 2H), 4.86 – 4.88 (m, 1H), 6.82 (d, J = 7.5 Hz, 1H), 7.06 (d, J = 1.4 Hz, 1H), 7.28 –

7.37 (m, 6H).

[0020] LC-MS: m / z = 358.0 (C21H27NO4 + H +).

[0021] Chiral HPLC: R- configuration: 97.1%, S- configuration: 2.9%.

[0022] Step 2) 😦 R) -l_ (2,2- dimethyl–4H- benzo [d] [l, 3] dioxin-6-yl) -2 – ((S) _2 preparation of different salts methoxy-1-phenyl-ethylamino) ethanol –

The procedure of Example I) thus-obtained crude product is equally divided into four parts, each mixed solvent was added 25 ml of ethanol and water (Vis: V # 1: 1) and stirred at 60 ° C under conditions so dissolved, then four solutions are each selected fumaric acid, malic acid, maleic acid and tartaric acid, acid is added in an amount 1.2 equivalents of crude product, after the addition was complete, stirring continued for 2 hours, allowed to stand between 5 ° C cooled overnight and filtered to give the corresponding salt. The results shown in the following table.

Figure CN103923058AD00071

[0023] Example three

(R) -2- (benzyl ((S) -1-phenylethyl) amino) -1- (2, 2 – dimethyl – -4H- benzo [d] [I, 3] dioxane ethanol and salts of 6-yl)

Step I): (R) _2_ (benzyl ((S) -1-phenylethyl) atmosphere yl) -1- (2, 2 – dimethyl – -4H- benzo [d] [I, 3] preparation dioxin-6-yl) ethanol

The method of preparation of a Compound IV The procedure of Example I) the same embodiment.

[0024] 8.24 g of the epoxy compound IV were added to 50 ml of tetrahydrofuran solvent, and stirred to dissolve slowly added

10.97 g (i) S-benzyl-1-N- phenethylamine, the reaction was refluxed for 4 hours, the reaction was complete by TLC monitoring. Wait until the reaction solution was cooled, 30 ml of saturated aqueous ammonium chloride was added, stirred at room temperature for 10 minutes, then add 3 g of sodium chloride, stirring was continued for 30 minutes standing layer, the aqueous phase was extracted with ethyl acetate (3×30 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give (R) -2_ (benzyl ((S) -1-phenylethyl) amino) -1- (2, 2 – dimethyl -4H- benzo [d] [1,3] dioxin-6-yl) ethanol The crude product was 9.3 g, 56% yield. The crude product obtained in this step without further purification was used directly in the next salt-forming reaction.

[0025] 1H-NMR (500 MHz, CDCl3) δ 1.27 (d, J = 12.4 Hz, 3H), 1.49 (s, 6H), 2.78 – 3.21 (m, 2H), 3.46 (s, 1H), 4.00 – 4.08 (m, 2H), 4.59 (s, 2H), 4.85 – 4.88 (m, 1H), 6.81 (d, J = 14.9 Hz, 1H), 7.05 – 7.37 (m, 12H).

[0026] LC-MS: m / z = 418.1 (C27H31NO3 + H +).

[0027] Chiral HPLC: R- configuration: 95.8%, S- configuration: 4.2%.

[0028] Step 2): (R) _2- (benzyl ((S) -1-phenylethyl) gas-yl) -1- (2, 2 – dimethyl – -4H- benzo [d] [ preparation I 3] dioxin-6-yl) ethanol of different salts

A mixed solvent of water -.V The procedure of Example I embodiment) of the obtained crude product was equally divided into four parts, each of which shall propanol and 30 ml of water is 3: 2) at 80 ° C for dissolution while stirring, and then was added to four parts, respectively, fumaric acid, citric acid, maleic acid and tartaric acid, the acid is added in an amount 1.2 equivalents of crude product, after the addition was complete, stirring continued for 2 hours, allowed to stand at 5 ° C for cooling overnight and filtered, to give the corresponding salt. The results shown in the following table.

Figure CN103923058AD00081

[0029] Fourth Embodiment

(R) -1- (2,2- dimethyl–4Η- benzo [d] [I, 3] dioxane _6_-yl) -2- (S) -1- (naphthyl _1_ yl) ethanol and salts thereof ethylamino)

Step I): (R) -1- (2,2_ dimethyl -4H- benzo [d] [1,3] dioxin-6-yl) -2_

Preparation (S) _1_ (naphthalen-1-yl) ethylamino) ethanol Preparation of Compound IV in a procedure as in Example I) the same embodiment.

[0030] The 8.24 g of the epoxy compound IV were added to 40 ml _2_ N- methyl pyrrolidone was slowly added with stirring so that after dissolution 9.58 g S – (-) – 1- (1- naphthyl) ethylamine, temperature was controlled at 100 ° C for 6 hours, the reaction was complete by TLC monitoring. After the reaction was cooled, 60 ml of saturated aqueous sodium bicarbonate, and extracted with ethyl acetate (3X 50 ml), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give 00-1- (2,2-bis methyl-4! l-benzo [d] [l, 3] dioxin-6-yl) -2- (S) -1- (naphthalen-1-yl) ethylamino) ethanol The crude product 9.5 g, yield 63%. The crude product obtained in this step without further purification was used directly in the next salt-forming reaction.

[0031] 1H NMR (500 MHz, CDCl3) δ 1.40 (d, J = 11.9 Hz, 3H), 1.49 (s, 6H), 2.95 (dd, J = 24.7 and 11.0 Hz, 1H), 3.21 (dd, J = 24.9 and 11.0 Hz, 1H), 4.59 (s, 2H), 4.89 – 4.95 (m, 2H), 6.80 – 8.01 (m, I OH).

[0032] LC-MS: m / z = 378.2 (C24H27NO3 + H +).

[0033] Chiral HPLC: R- configuration: 97.8%, S- configuration: 2.3%.

[0034] Step 2): (R) -l_ (2,2- dimethyl–4H- benzo [d] [1,3] dioxin-6-yl) -2- (S) -1 preparation of (naphthalene-1-yl) ethylamino) ethanol salt of different –

The procedure of Example I embodiment) of the obtained crude product was equally divided into four parts, each of which shall solvent was added 25 ml of butanol was stirred at 80 ° C for the condition to be dissolved and then the mixture was four respective selection naphthalenesulfonic acid, camphorsulfonic acid, methanesulfonic acid and benzoic acid treatment, acid is added in an amount 1.5 equivalents crude product, after completion, stirring was continued for 2 hours, allowed to stand overnight and cooled at 0 ° C, filtered, to give the corresponding salt. The results shown in the following table.

Figure CN103923058AD00082

[0035] Embodiment V

(S) – (2- (tert-butoxy quasi-yl) ((R) -2- (2, 2- dimethyl-benzo [d] [I, 3] dioxin-6-yl) – 2 preparation amino) phenylacetate -2_ their salts light ~ ethyl)

The I step) (2S) – Preparation of [(tert-butoxycarbonyl) amino] (phenyl) acetate Patent Documents US8455514 and CN102120724A prepared (2S) according to – [(tert-butoxycarbonyl) amino] (phenyl) acetic acid methyl ester.

[0036] 1H-NMR (500 MHz, CDCl3) δ 1.42 (s, 9H), 3.67 (s, 3H), 6.19 (s, 1H), 7.20 – 7.38 (m, 5H).

[0037] Step 2): (S) – (2- (tert-butoxy quasi-yl) ((R) -2- (2,2- dimethyl-benzo [d] [I, 3] dioxane ) -2-6-yl) -2-hydroxyethyl) aminophenyl acetate

The 8.24 g of the epoxy compound IV were added to 30 ml of dimethyl sulfoxide, added slowly with stirring to dissolve after

12.72 g (2S) – [(tert-butoxycarbonyl) amino] (phenyl) acetate, the reaction temperature is controlled at 70 ° C 4 h, monitoring by TLC the reaction was complete. Wait until the reaction solution was cooled, added 60 mL of saturated aqueous sodium bicarbonate, and extracted with ethyl acetate (3 x 50 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give (S) – (2- (tert oxycarbonyl group) ((R) -2- (2, 2- dimethyl-benzo [d] [l, 3] dioxin-6-yl) -2-hydroxyethyl) amino) phenyl _2_ acetate The crude product was 11.2 g, yield 59%. The crude product obtained in this step without further purification was used directly in the next salt-forming reaction.

[0038] 1H-NMR (500 MHz, CDCl3) δ 1.42 (s, 9H), 1.49 (s, 6H), 3.48 (dd, J = 23.7and 7.5 Hz, 1H), 3.67 (s, 3H), 3.78 ( dd, J = 24.8 and 7.6 Hz, 1H), 4.59 (s, 2H), 5.52 – 5.55 (m, 1H), 6.41 (s, 1H), 6.80 – 7.32 (m, 8H).

[0039] LC-MS: m / z = 472.1 (C26H33NO7 + H +).

[0040] Chiral HPLC: R- configuration: 96.1%, S- configuration: 4.0%.

[0041] Step 3) (S) – (2_ (tert quasi-yl) ((R) _2_ (2,2_-dimethyl-benzo [d] [1,3] dioxin-6-yl) preparation of amino group) of different salts of methyl-2-phenyl-2-hydroxyethyl)

Step 2) The obtained crude product was equally divided into four parts, each solvent were added 20 ml of methanol was stirred at 40 ° C under conditions to dissolve, then the mixture was four respective selection acid, hydrochloric acid, naphthalenesulfonic acid, and methanesulfonic acid treatment, acid is added in an amount 1.5 equivalents crude product, after completion, stirring was continued for 2 hours, allowed to stand overnight and cooled at 0 ° C, filtered, to give the corresponding salt. The results shown in the following table.

Figure CN103923058AD00091
PATENT
W02014041565

Vilanterol is chemically described as 4-{(lR)-2-[6-{2-(2, 6-dichlorobenzyl) oxy] ethoxy} hexyl) amino]- l-hydroxyethyl}-2-(hydroxymethyl) phenol as represented by Formula I.

Figure imgf000002_0001

Formula I The compound 4-{(lR)-2-[(6-{2-[(2,6-dicUorobenzyl)oxy]emoxy}hexyl)amino]-l- hydroxy ethyl} -2-(hydroxymethyl)phenol is specifically described in WO2003/024439, as are pharmaceutically acceptable salts thereof, in particular the acetate, triphenylacetate, a-phenylcinnamate, 1-naphthoate and (R)-mandelate salts. More specifically the preferred pharmaceutically acceptable salt is triphenylacetate salt.

The PCT publication WO 2003/024439, the corresponding US equivalent US 7,361,787 (herein after the ‘787 patent) and J.Med.Chem, 2010, 53, 4522-4530 discloses the process for preparation of vilanterol along with pharmaceutically acceptable salt. The ‘787 patent reaction sequence is schematically represented as follows:

Figure imgf000003_0001

The process described in the ‘787 patent uses alcoholic solvent during the acetonide cleavage of Formula XIV, which tends to result in the formation of the corresponding ether impurities. This requires repetitive purifications, which can be tedious to practice during scale up process. Moreover the dibromo hexane used in the process contains the corresponding 1, 5-dibromo alkanes which tends to react in the same sequential manner to generate the corresponding analogues, which requires repetitive purifications to separate out from the final API. The ‘787 patent imply the use of column chromatographic procedures which are not feasible on the commercial scale.

The ‘787 patent further elucidates the process for preparing (5R)-5-(2, 2-dimethyl-4H-l,

Figure imgf000003_0002

isomeric impurities for the chiral intermediate would carry forward during the process 2013/000556

which results in the formation of various isomeric impurities which are difficult to separate and need more tedious procedures. Moreover reagents like sodium hydride are difficult to handle during the scale up process as it tends to generate high exothermicity, which can affect the yield and purity of the said compound.

The purity and the yield of vilanterol trifenatate as per the disclosed process are not satisfactory and also the said process involves chromatography techniques to isolate the intermediate compounds. The said techniques are tedious, labor intensive, time consuming process not suitable for industrial scale and which in turn result to an increase in the manufacturing cost. Moreover the said process involves the use of vilanterol trifenatate which degrades to form certain impurities and results in the formation of the final compound with a lesser purity.

In view of intrinsic fragility there is a need in the art to develop a simple, industrially feasible and scalable process for the synthesis of vilanterol that would avoid the aforementioned difficulties. Moreover it becomes necessary to prepare highly chiral pure oxazolidinone intermediate to prepare chirally pure vilanterol.

Examplel2: Preparation of 4-((R)-2-{6-[2-(2, 6-Dichlorobenzyloxy)-ethoxy]- hexylamino}-l-hydroxy ethyl)-2-hydroxymethyI-phenol (I-Vilanterol)

Compound XTV (1.0 eqt) was dissolved in acetone (10V) under nitrogen at ambient temperature. The reaction mass was cooled to 0-5°C and 0.5N HCl (12V) was added slowly. The reaction mass was allowed to stir for completion over one hour period. The reaction mass was diluted with dichloromethane and water, followed by addition of saturated sodium bicarbonate solution (lOv) at 0-5°C. The organic layer was separated then washed successively with water/saturated brine and dried over sodium sulfate the solution was concentrated to dryness under vacuum to obtain the residue, followed by column chromatography (MeOH-DCM as eluent). The pure fractions were concentrated under vacuum to afford the title compound as pale yellow color oil.

Yield: 77%; purity by HPLC: 99.15%; Chiral purity: R-isomer: 99.97%; S-isomer: 0.03%

Examplel3: Preparation of 4-((R)-2-{6-[2-(2, 6-Dichlorobenzyloxy)-ethoxy]- hexylamino}-l-hydroxy ethyI)-2-hydroxymethyl-phenol triphenyl acetate (IA: Vilanterol trifenatate)

Triphenyl acetic acid (l.Oeqt) was added to a solution of compound I (l.Oeqt) in acetone (20V) at ambient temperature and the mixture heated to 50-55°C to obtain a homogenous solution. The mixture was allowed to cool to ambient temperature; the resultant product was filtered, washed with chilled acetone, dried under vacuum at 50°C to afford the title compound as a white solid.

Yield: 69%; purity by HPLC: 99.79%; chiral purity-R-isomer: 99.96%; S-isomer: 0.049%

Patent
CN 102120724
Patent
CN 104744270
PATENT
CN 104744271
Patent

β 2- adrenergic receptor agonist is most widely used in clinical treatment of asthma and chronic obstructive pulmonary disease drugs. Currently available on the market β 2- adrenoreceptor agonist longest duration of action of 12 hours, which resulted in the need twice daily dosing. Over the last decade, the development of high potency, high selectivity, rapid onset, long duration of action, once daily dosing of β 2- adrenoreceptor agonists caused great concern in the pharmaceutical industry. Three acid vilanterol by Glaxo Group Limited development of a new Ultralente β 2- adrenergic receptor agonists, having bronchodilatory action.

[0003] vilanterol chemical name is 4 – {(lR) -2 – [(6- {2 – [(2,6- dichlorobenzyl) oxy] ethoxy} hexyl) amino] – 1-hydroxyethyl} -2_ (hydroxymethyl) phenol, having the formula as follows:

Figure CN105646285AD00041

[0005] vilanterol synthetic routes are:

Figure CN105646285AD00042

[0007] (5R) -5- (2, 2- dimethyl -4H-1,3- benzodioxin-6-yl) -1,3-oxazolidin-2-one was prepared an important intermediate Whelan Castro. The synthesis of this intermediate are currently two main ways:

[0008] 1: Reference Laurus Labs Limited published patent W02014041565, its main synthetic routes are as follows:

[0009]

Figure CN105646285AD00051

[0010] obvious drawback of this method, the starting material is 4-bromo-2-hydroxymethyl-phenol, expensive, the next two steps harsh reaction conditions, where low temperature -75 ° C, and the yield rate is not high. Obviously not suitable for large-scale industrial production.

[0011] 2: Reference J. Med Chem 2010, 53, 4522-4530, and patent W02003024439, scheme is as follows:

Figure CN105646285AD00052

[0013]

Figure CN105646285AD00061

The route salicylaldehyde as raw material, the final seven-step synthesis intermediates, but the reaction step, 2-bromo-1- (2,2-dimethyl -4H-1,3- benzodioxin en-6-yl) ethanone di-t-butyl imine and a dicarboxylic acid, a lower yield, only 58%; while the imine dicarboxylate and cesium carbonate expensive, more cost high; the next step and also acidolysis out a tert-butoxycarbonyl group, relatively low utilization atoms.

Synthetic Route [0046] The reaction is as follows:

[0047]

Figure CN105646285AD00091

Preparation of 5- (2-bromoacetyl) -2-hydroxyphenyl 4-carbaldehyde: [0048] Example 1

[0049] Under nitrogen, the ice bath, the aluminum trichloride 164g (5eq) dispersed into 600mL (20-fold amount) in DCM was slowly added dropwise bromoacetyl bromide 99. 4g (2eq), 20min After completion of the dropwise addition, the temperature warmed to room temperature, the reaction LH, salicylaldehyde to this mixture was added dropwise 30g, 20min dropwise addition, dropwise, the reaction overnight at 35 ° C. To the reaction mixture was added ice-water, the organic layer was separated, washed with water, dried and concentrated to dryness in vacuo.With DCM and recrystallized from n-hexane, the product was filtered to give 36. 5g, about 61% yield. 4 bandit 1 (4001 hold, 0)? (: 13): Sll.52 (s, lH), 9.99 (s, lH), 8.30 (s, lH), 8.17 (d, lH, J = 8Hz), 7.10 (d, lH, J = 8Hz), 4.39 (s, 2H); MS (-ESI) m / z 240 [MH]

– 5 -phenyl-1-one Preparation of 2-bromo-1- [4-hydroxy-3- (hydroxymethyl): [0050] Example 2

[0051] 40. 0g of the compound 4 dissolved in 400mL of acetic acid (10 times the amount), under ice-cooling, sodium borohydride was added portionwise 6. 8g (1. leq), was added stirred at rt for lh, TLC showed the reaction complete.Concentrated in vacuo to remove most of acetic acid, diluted with water and neutralized with sodium bicarbonate, extracted with EA, the organic phase washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to crude off-white powder did. After laundering refluxed with DCM to give a white powder 32g, 80% yield.

[0052] ^ NMR (400MHz, DMS0-d6): δ 10. 53 (s, 1H), 7. 99 (s, 1H), 7. 79 (d, 1H, J = 8Hz), 6.87 (d, lH , J = 8Hz), 4.75 (s, 2H), 4.50 (s, 2H); MS (+ ESI) m / z 267 [m + Na] +

[0053] Example 3: 2-amino-1- [4-hydroxy-3- (hydroxymethyl) – phenyl-1-one hydrochloride (6)

[0054] 10. 0g of the compound 5 was added to 200mL of ethyl acetate, was added hexamethylenetetramine (1. leq) 6. 2g, room temperature lh, TLC showed complete reaction. After filtration the filter cake was dried in vacuo as a white powder 15. 6g.The above white powder was dissolved in 150mL of ethanol, concentrated hydrochloric acid (5eq) 17. 5mL, room temperature overnight, the reaction was concentrated to dryness in vacuo to give an off-white powder 16. 0g (mixture) administered directly in the next step.

[0055] ^ NMR (400MHz, DMS0-d6): δ 10. 89 (s, 1H), 8. 40 (s, 2H), 7. 98 (d, 1H, J = 2Hz), 7 · 70 (dd , 1H, J = 8Hz and 2Hz), 7 · 02 (d, 1H, J = 8Hz), 4 · 49 (s, 2H), 4 · 43 (s, 2H); MS (+ ESI) m / z 182 [M + H] +

Preparation of 2- (3-hydroxymethyl-4-hydroxyphenyl) -2-carbonyl-ethyl carbamate ⑵ of: [0056] Example 4

[0057] The product from the previous step, compound 6 (hydrochloride) 16. 0g added to 150mL of THF and 150mL water was added 20. 6gNaHC03 (5eq), dissolved 30mL THF was added dropwise to a solution of 9. 8g Boc20, 20min After dropping. Reaction at room temperature lh, TLC showed complete reaction. Water was added, extracted with EA, the organic phase was washed successively with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to a crude solid powder did, then after 1-2 times the amount of reflux in DCM starched white powder 8. 7g, two step yield 76%.

[0058] ^ NMRQOOMHz, DMS0-d6):.. Δ 10. 35 (dr, 1H), 7 94 (s, 1H), 7 75 (d, 1H, J = 8Hz), 6 · 95 (t, 1H , J = 4Hz), 6 · 85 (t, 1H, J = 8Hz), 4 · 49 (s, 2H), 4 · 35 (d, 1H, J = 4Hz), L 39 (s, 9H); MS (ES +) m / z 304 [m + Na] +

[0059] Example 5: 2- (2,2-dimethyl -4H-1,3- benzodioxin-6-yl) -2-carbonyl-ethyl carbamate (7 ) preparation of

[0060] 7. 0g of the compound 2 was dissolved in 70mL of DCM (10-fold amount) was added a catalytic amount of p-toluenesulfonic acid (0. 05eq), was added dropwise 2-dimethoxyethane at reflux propane (2eq) was dissolved in 2-fold amount of DCM, 40min addition was complete, the reaction lh, TLC showed complete reaction. The reaction mixture was washed with saturated NaHC (V Sin three times, the organic phase was dried over anhydrous sodium sulfate, and concentrated in vacuo to give a yellow oil. Of isopropyl ether and recrystallized from n-heptane to obtain a white powder 6. 7g, 83% yield.

[0061] iHNMRGOOMHz, CDC13):. Δ 7. 77 (dd, 1H, J = 8Hz and 2Hz), 7 65 (s, 1H), 6 86 (d, 1H, J = 8Hz), 5 51 (.. dr, 1H), 4 87 (s, 2H), 4 56 (d, 2H, J = 4Hz), 1 56 (s, 6H), 1 47 (s, 9H);…. MS (ES +) m / z 344 [M + Na] +

[0062] Example 6: (2R) -2- (2, 2- dimethyl -4H-1,3- benzodioxin-6-yl) -2-hydroxyethyl carbamate butyl ester (8)

[0063] The catalyst was added 0. 78mL to 10mL of anhydrous THF under nitrogen was added dropwise BH3 ice bath. THF, 20min addition was complete. Was added dropwise under ice-cooling 2. 5g of compound 7 was dissolved in 20mL of anhydrous THF, 50min dropwise addition, reaction was warmed to room temperature 0. 5h, TLC indicated complete reaction. After quenched with methanol under ice-cooling the reaction, the reaction solution was concentrated in vacuo, water was added, extracted with EA, the organic phase washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give a pale yellow oil 2. 8g. After petroleum ether starched white powder 2. 2g, 88% yield.

[0064] iHNMRGOOMHz, CDC13):… Δ 7. 13 (dd, 1H, J = 8Hz and 2Hz), 6 99 (s, 1H), 6 79 (d, 1H, J = 8Hz), 4 92 ( dr, 1H), 4. 71-4. 74 (m, 1H), 3. 42 (d, 1H, J = 12Hz), 3. 20-3. 25 (m, 1H), 1.53 (s, 6H) , 1.44 (s, 9H); MS (+ ESI) m / z 346 [m + Na] +

[0065] Example 7: (5R) -5- (2, 2- dimethyl -4H-1,3- benzodioxin-6-yl) -1, 3 oxazolidin -2 – preparation of ⑴ -one

[0066] Under nitrogen, 8 dissolved in 15mL of DMF 1. 8g compound, at 10-15 ° C, potassium tert-butoxide was added 0. 7g (l. Leq), After completion of the reaction at room temperature lh, TLC the reaction was complete. Ice water was added, a white solid was precipitated, stirring at room temperature after 3h, filtered off with suction, the filter cake was dried to obtain a white powder l.Og, 72% yield (purity 99.6%, ee 99.2%).

[0067] iHNMRGOOMHz, CDC13): δ 7. 15 (dd, 1H, J = 8Hz and 4Hz), 7 · 02 (s, 1H), 6 · 83 (d, 1H, J = 8Hz), 6.09 (br, lH), 5.52 (t, lH, J = 8Hz), 4.84 (s, 2H), 3.92 (t, lH, J = 8Hz), 3.53 (t, lH, J = 8Hz), 1.53 (s, 6H); MS (+ ESI) m / z 250 [m + H] +.

PATENT

https://patents.google.com/patent/WO2017001907A1/en

onverting the formed alcohol, preferably Compound II, to Vilanterol trifenatate, according to the below scheme:

Figure imgf000013_0001
Figure imgf000013_0002

timarate

Figure imgf000013_0003

VII L-tait rate

Figure imgf000013_0004
Figure imgf000013_0005

Example 16: Vilanterol base

Compound VII (5 g, obtained by procedure in Example 10) was dissolved in 5 EtOH (50 mL), followed by addition of 1M HCI solution (50 mL). The mixture was

stirred at room temp, for 90 minutes. Afterwards, pH of the mixture was adjusted to

~9 by addition of 20 % K2C03 solution (25 mL). The mixture was then extracted to dichloromethane (100 mL). Organic phase was washed with water (2 x 25 mL), dried over MgS04 and evaporated to dryness. The residue was purified by column 10 chromatography, elution with mixture of dichloromethane/ethanol/ammonia (50/8/1 ) to give title compound as brownish slightly yellowish oil .

Example 17: Vilanterol trifenatate

Vilanterol base (0.620 g) was dissolved in EtOH (6 mL). Triphenylacetic acid

(0.370 g) was added and the mixture was heated to 50° C and stirred at the same 15 temp, for 15 min. The mixture was then cooled to room temp., followed by cooling in ice-water bath for 90 minutes. The formed suspension was filtered, the filtration cake was washed with cold EtOH and dried at room temp, overnight.

Example 18: Preparation of Vilanterol base 20

( l/ )-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-l-(2,2-dimethyl- 4H-l,3-benzodioxin-6-yl)ethanol (15.5 g, obtained according to the procedure in US

2005/0075394, Example 77(iv)) was dissolved in EtOH (50 mL), followed by addition of 1M HCI solution (50 mL). The mixture was stirred at room temperature for 90 minutes.

Afterwards, the pH of the mixture was adjusted to ~9 by addition of 20 % K2C03 25 solution (25 mL). The mixture was then extracted to dichloromethane ( 100 mL). The organic phase was washed with water (2 x 25 mL), dried over MgS04 and evaporated to dryness.

The crude vilanterol base ( 14.5 g, 90.9 % purity) was dissolved in

dichloromethane and the solution was loaded on a column packed with 300 g Diol-silica 30 in dichloromethane. The column was eluted with dichloromethane with gradient of ethanol (2 – 20 %) . The chromatographic fractions were monitored by TLC. The

fractions containing relatively pure vilanterol were joined and evaporated to dryness, obtaining 11.0 g of vilanterol with purity 97.1 %.

Example 21: Preparation of Vilanterol L-tartrate

EtOH (700 mL) was mixed with 1 M aq. HCI acid (700 mL), the formed mixture 25 was cooled to 5 °C, followed by addition of compound VII L-tartrate ( 100 g, obtained by procedure in Example 15). The mixture was stirred at 5 °C for 15 hours. Afterwards, DCM (500 mL) was added, the mixture was cooled to 0 °C and aq. Solution of K2C03 ( 130g of K2C03 in 200 mL of water) was then added drop wise to the stirred reaction mixture until pH 9 – 9.5 was obtained. Temp, during the addition was kept below 5 °C. 30 The water phase was separated, and extracted with additional DCM (300 mL).

Combined organic extracts were warmed to temp. 20-25 °C and washed with water (2 x 500 mL), 1% brine (500 mL) and 24% brine (500 mL). Afterwards, organic extract was mixed with solution of L-Tartaric acid (26.6 g) in EtOH (210 mL). The mixture was stirred for 10 min. at temp. 20-25°C and then heated by setting the temp, of the 35 reactor jacket to 40°C. All DCM solvent was distilled off under vacuum to residual approximate 350 mL. The mixture was then cooled to 25°C, followed by addition of

EtOAc ( 1.5 L) . The mixture was stirred at 20-25 °C for 1 hour then cooled to -5 °C and stirred overnight. The product was separated by filtration, washed with cold EtOAc and dried under inert gas and room temp. Isolated yield 85%, chemical purity 99.8%, 5 optical purity 99.93%. The sample was analyzed by PXRD, the PXRD pattern is

presented in Figure 5.

Example 22: Preparation of Vilanterol trifenatate

Dichloromethane (256 mL) was mixed with water (256 mL), the formed mixture was cooled to 0 °C, followed by addition of Vilanterol L-tartrate (32 g, obtained by 10 procedure in Example 21 ) and EtOH (64 mL). Afterwards, 25% aq. solution of ammonia (34 mL) was then added drop wise to the stirred mixture. Temp, during the addition was kept below 5 °C. The water phase was separated, and extracted with additional

DCM (128 mL) . Combined organic extracts were warmed to temp. 20-25 °C mixed with MTBE (220 mL), EtOH (64 mL). The obtained mixture was then washed with water (3 x 15 220 mL). Afterwards, the obtained organic extract was mixed with triphenylacetic acid ( 14.5 g) and stirred until complete dissolution at temp. 20-25°C. Then EtOH (96 mL) was added and the mixture was heated by setting the temp, of the reactor jacket to

40°C. Part of DCM solvent was distilled off under vacuum to residual approximate volume 220 mL, The mixture was then cooled to 25°C, followed by addition of MTBE 20 (256 mL). The mixture was stirred at 20-25 °C for 1 hour then cooled to -5 °C and for additional 2 hours. The product was separated by filtration, washed with cold MTBE and dried under inert gas and room temp. Isolated yield 93%, chemical purity 99.8%, optical purity 99.93%.

CN102480971A *2009-09-042012-05-30葛兰素史密丝克莱恩有限责任公司Chemical compounds
WO2013183656A1 *2012-06-042013-12-12大日本住友製薬株式会社Conjugate of g-protein coupled receptor binding ligand and nucleic acid molecule
WO2014041565A2 *2012-09-132014-03-20Laurus Labs Private LimitedAn improved process for the preparation of vilanterol and intermediates thereof
CN103923058A *2014-05-062014-07-16上海鼎雅药物化学科技有限公司Method for synthesizing vilanterol intermediate and salt thereof
CN105646285A *2014-12-022016-06-08上海医药工业研究院Vilanterol intermediate, preparation method and application thereof
WO2017001907A12015-06-292017-01-05Teva Pharmaceuticals International Gmbh

References

  1. Harrell AW, Siederer SK, Bal J, Patel NH, Young GC, Felgate CC, Pearce SJ, Roberts AD, Beaumont C, Emmons AJ, Pereira AI, Kempsford RD: Metabolism and disposition of vilanterol, a long-acting beta(2)-adrenoceptor agonist for inhalation use in humans. Drug Metab Dispos. 2013 Jan;41(1):89-100. doi: 10.1124/dmd.112.048603. Epub 2012 Oct 4. [PubMed:23043183]
  2. Spyratos D, Sichletidis L: Umeclidinium bromide/vilanterol combination in the treatment of chronic obstructive pulmonary disease: a review. Ther Clin Risk Manag. 2015 Mar 25;11:481-7. doi: 10.2147/TCRM.S67491. eCollection 2015. [PubMed:25848294]
 
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/////////////Vilanterol trifenatate, HY-14300ACS-1679, fda 2013, Breo Ellipta,  Relvar Ellipta, 444 , 642444 , GSK-642444  , GW-642444  , GW-642444M , ビランテロール  , ビランテロールトリフェニル酢酸塩 , ビランテロールトリフェナテート

C1=CC=C(C=C1)C(C2=CC=CC=C2)(C3=CC=CC=C3)C(=O)O.C1=CC(=C(C(=C1)Cl)COCCOCCCCCCNCC(C2=CC(=C(C=C2)O)CO)O)Cl

Ivosidenib,  ивосидениб , إيفوزيدينيب , 艾伏尼布 , 


Ivosidenib.svg

Ivosidenib

AG-120; TIBSOVO
FDA approves first targeted treatment Tibsovo (ivosidenib) for patients with relapsed or refractory acute myeloid leukemia who have a certain genetic mutation
The U.S. Food and Drug Administration today approved Tibsovo (ivosidenib) tablets for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) who have a specific genetic mutation. This is the first drug in its class (IDH1 inhibitors) and is approved for use with an FDA-approved companion diagnostic used to detect specific mutations in the IDH1 gene in patients with AML.
“Tibsovo is a targeted therapy that fills an unmet need for patients with relapsed or refractory AML who have an IDH1 mutation,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “The use of Tibsovo is associated with a complete remission in some patients and a reduction in the need for both red cell and platelet transfusions.”

July 20, 2018

Release

The U.S. Food and Drug Administration today approved Tibsovo (ivosidenib) tablets for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) who have a specific genetic mutation. This is the first drug in its class (IDH1 inhibitors) and is approved for use with an FDA-approved companion diagnostic used to detect specific mutations in the IDH1 gene in patients with AML.

“Tibsovo is a targeted therapy that fills an unmet need for patients with relapsed or refractory AML who have an IDH1 mutation,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “The use of Tibsovo is associated with a complete remission in some patients and a reduction in the need for both red cell and platelet transfusions.”

AML is a rapidly progressing cancer that forms in the bone marrow and results in an increased number of abnormal white blood cells in the bloodstream and bone marrow. The National Cancer Institute at the National Institutes of Health estimates that approximately 19,520 people will be diagnosed with AML this year; approximately 10,670 patients with AML will die of the disease in 2018.

Tibsovo is an isocitrate dehydrogenase-1 inhibitor that works by decreasing abnormal production of the oncometabolite 2-hydroxyglutarate (2-HG), leading to differentiation of malignant cells. If the IDH1 mutation is detected in blood or bone marrow samples using an FDA-approved test, the patient may be eligible for treatment with Tibsovo. Today the agency also approved the RealTime IDH1 Assay, a companion diagnostic that can be used to detect this mutation.

The efficacy of Tibsovo was studied in a single-arm trial of 174 adult patients with relapsed or refractory AML with an IDH1 mutation. The trial measured the percentage of patients with no evidence of disease and full recovery of blood counts after treatment (complete remission or CR), as well as patients with no evidence of disease and partial recovery of blood counts after treatment (complete remission with partial hematologic recovery or CRh). With a median follow-up of 8.3 months, 32.8 percent of patients experienced a CR orCRh that lasted a median 8.2 months. Of the 110 patients who required transfusions of blood or platelets due to AML at the start of the study, 37 percent went at least 56 days without requiring a transfusion after treatment with Tibsovo.

Common side effects of Tibsovo include fatigue, increase in white blood cells, joint pain, diarrhea, shortness of breath, swelling in the arms or legs, nausea, pain or sores in the mouth or throat, irregular heartbeat (QT prolongation), rash, fever, cough and constipation. Women who are breastfeeding should not take Tibsovo because it may cause harm to a newborn baby.

Tibsovo must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks. The prescribing information for Tibsovo includes a boxed warning that an adverse reaction known as differentiation syndrome can occur and can be fatal if not treated. Signs and symptoms of differentiation syndrome may include fever, difficulty breathing (dyspnea), acute respiratory distress, inflammation in the lungs (radiographic pulmonary infiltrates), fluid around the lungs or heart (pleural or pericardial effusions), rapid weight gain, swelling (peripheral edema) or liver (hepatic), kidney (renal) or multi-organ dysfunction. At first suspicion of symptoms, doctors should treat patients with corticosteroids and monitor patients closely until symptoms go away.

Other serious warnings include a QT prolongation, which can be life-threatening. Electrical activity of the heart should be tested with an electrocardiogram during treatment. Guillain-Barré syndrome, a rare neurological disorder in which the body’s immune system mistakenly attacks part of its peripheral nervous system, has happened in people treated with Tibsovo, so patients should be monitored for nervous system problems.

The FDA granted this application Fast Track and Priority Review designations. Tibsovo also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted the approval of Tibsovo to Agios Pharmaceuticals, Inc. The FDA granted the approval of the RealTime IDH1 Assay to Abbott Laboratories.

ChemSpider 2D Image | ivosidenib | C28H22ClF3N6O3

ivosidenib

  • Molecular FormulaC28H22ClF3N6O3
  • Average mass582.961 Da
1448347-49-6 [RN]
2-Pyrrolidinecarboxamide, N-[(1S)-1-(2-chlorophenyl)-2-[(3,3-difluorocyclobutyl)amino]-2-oxoethyl]-1-(4-cyano-2-pyridinyl)-N-(5-fluoro-3-pyridinyl)-5-oxo-, (2S)-
AG-120
UNII:Q2PCN8MAM6
ивосидениб [Russian] [INN]
إيفوزيدينيب [Arabic] [INN]
艾伏尼布 [Chinese] [INN]

Ivosidenib is an experimental drug for treatment of cancer. It is a small molecule inhibitor of IDH1, which is mutated in several forms of cancer. The drug is being developed by Agios Pharmaceuticals and is in phase III clinical trials. The FDA awarded orphan drug statusfor acute myeloid leukemia and cholangiocarcinoma.[1][better source needed]

It is in a phase III clinical trial for acute myeloid leukemia (AML) with an IDH1 mutation and a phase III clinical trial for cholangiocarcinoma with an IDH1 mutation.[2]

  • OriginatorAgios Pharmaceuticals
  • DeveloperAbbVie; Agios Pharmaceuticals; University of Texas M. D. Anderson Cancer Center
  • ClassAntineoplastics; Cyclobutanes; Nitriles; Pyridines; Pyrrolidines; Small molecules
  • Mechanism of ActionIsocitrate dehydrogenase 1 inhibitors
  • Orphan Drug StatusYes – Acute myeloid leukaemia; Cholangiocarcinoma
  • New Molecular EntityYes

Highest Development Phases

  • PreregistrationAcute myeloid leukaemia
  • Phase IIICholangiocarcinoma
  • Phase IGlioma; Myelodysplastic syndromes; Solid tumours

Most Recent Events

  • 28 Jun 2018Massachusetts General Hospital and Agios Pharmaceuticals plan a phase I trial for Acute myeloid leukaemia; Myelodysplastic syndromes and Chronic myelomonocytic leukaemia (Maintenance therapy) in USA (NCT03564821)
  • 26 Jun 2018Ivosidenib licensed to CStone Pharmaceuticals in China, Hong Kong, Macau and Taiwan
  • 14 Jun 2018Efficacy and adverse events data from a phase I trial in Acute myeloid leukaemia presented at the 23rd Congress of the European Haematology Association (EHA-2018)
Ivosidenib
Ivosidenib.svg
Clinical data
Routes of
administration
Oral
ATC code
  • None
Legal status
Legal status
  • Investigational
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
Formula C28H22ClF3N6O3
Molar mass 582.97 g·mol−1
3D model (JSmol)
///////////////Tibsovo, ivosidenib, fda 2018,  Fast Track, Priority Review ,  Orphan Drug designation, UNII:Q2PCN8MAM6, ивосидениб , إيفوزيدينيب , 艾伏尼布 ,

BMS-978587


str1

str1

Ido-IN-4.pngFigure imgf000059_0001

BMS-978587

Molecular Formula: C26H35N3O3 CAS 1629125-65-0
Molecular Weight: 437.582

US9675571   PATENT

Inventor James Aaron Balog Audris Huang Bin Chen Libing Chen Steven P. Seitz Amy C. Hart Jay A. Markwalder

AssigneeBristol-Myers Squibb Co Priority date 2013-03-15

IDO-IN-4; 1629125-65-0; SCHEMBL17456163; AKOS030526622; ZINC521836543; CS-5086

(1R,2S)-2-[4-(Di-isobutylamino)-3-(3-(p-tolyl)ureido)phenyl] Cyclopropanecarboxylic Acid

(1R,2S)-2-[4-[bis(2-methylpropyl)amino]-3-[(4-methylphenyl)carbamoylamino]phenyl]cyclopropane-1-carboxylic acid

(lR,2S)-2-(4-(diisobutylamino)-3-(3-(p- tolyl)ureido)phenyl)cyclopropanecarboxylic acid

BMS-978587 was discovered and developed within Bristol-Myers Squibb as a potent small molecule IDO inhibitor

Tryptophan is an amino acid which is essential for cell proliferation and survival. Indoleamine-2,3-dioxygenase is a heme-containing intracellular enzyme that catalyzes the first and rate-determining step in the degradation of the essential amino acid L-tryptophan to N-formyl-kynurenine. N-formyl-kynurenine is then metabolized by mutliple steps to eventually produce nicotinamide adenine dinucleotide (NAD+). Tryptophan catabolites produced from N-formyl-kynurenine, such as kynurenine, are known to be preferentially cytotoxic to T-cells. Thus an overexpression of IDO can lead to increased tolerance in the tumor microenvironment. IDO overexpression has been shown to be an independent prognostic factor for decreased survival in patients with melanoma, pancreatic, colorectal and endometrial cancers among others. Moreover, IDO has been found to be implicated in neurologic and psychiatric disorders including mood idsorders as well as other chronic diseases characterized by IDO activation and tryptophan depletiion, such as viral infections, for example AIDS, Alzheimer’s disease, cancers including T-cell leukemia and colon cancer, autimmune diseases, diseases of the eye such as cataracts, bacterial infections such as Lyme disease, and streptococcal infections.

Accordingly, an agent which is safe and effective in inhibiting production of IDO would be a most welcomed addition to the physician’s armamentarium

SYNTHESIS

 

PATENT

https://patents.google.com/patent/US9675571

Figure US09675571-20170613-C00026

Figure US09675571-20170613-C00027

Example 1 Method A Enantiomer 1 and Enantiomer 2 Enantiomer 1: (1R,2S)-2-(4-(diisobutylamino)-3-(3-(p-tolyl)ureido)phenyl)cyclopropanecarboxylic acid

Figure US09675571-20170613-C00039

PATENT

WO2014/150677

https://patents.google.com/patent/WO2014150677A1/en

Example 1- Method A

Enantiomer 1 and Enantiomer 2

Enantiomer 1 : (lR,2S)-2-(4-(diisobutylamino)-3-(3-(p- tolyl)ureido)phenyl)cyclopropanecarboxylic acid

Figure imgf000059_0001

Enantiomer 2: (lS,2R)-2-(4-(diisobutylamino)-3-(3-(p- tolyl)ureido)phenyl)cyclopropanecarboxylic acid

Figure imgf000060_0001

1A. 4-bromo-N,N-diisobutyl-2-nitroaniline

4-bromo-l-fluoro-2 -nitrobenzene (7 g, 31.8 mmol) and diisobutylamine (12.23 ml, 70.0 mmol) were heated at 130 °C for 3 h. It was then cooled to RT, purification via flash chromatography gave 1A (bright red solid, 8.19 g, 24.88 mmol, 78 % yield) LC-MS Anal. Calc’d for Ci4H2iBrN202 328.08, found [M+3] 331.03, Tr = 2.63 min (Method A).

IB. N,N-diisobutyl-2-nitro-4-vinylaniline

To a solution of 1 A (1 g, 3.04 mmol) in ethanol (15.00 mL) and toluene (5 mL) (sonication to break up the solid) was added 2,4,6-trivinyl- 1 ,3 ,5 ,2,4,6-trioxatriborinane pyridine complex (0.589 g, 3.64 mmol) followed by K3PO4 (1.289 g, 6.07 mmol) and water (2.000 mL). The reaction mixture was purged with Argon for 2 min and then Pd (PPh3)4(0.351 g, 0.304 mmol) was added. It was then heated at 80 °C in an oil bath for 8 h. LC-MS indicated completion. It was diluted with EtOAc (10 mL) and water (5 mL) and filtered through a pad of Celite, rinsed with EtOAc (2×30 mL). Aqueous layer was further extracted with EtOAc (2×30 mL), the combined extracts were washed with water, brine, dried over MgS04, filtered and concentrated. Purification via fiash chromatography gave IB (orange oil, 800 mg, 2.89 mmol, 95 % yield). LC-MS Anal. Calc’d for

Ci6H24N202 276.18, found [M+H] 277.34, Tr = 2.41 min (Method A). 1H NMR

(400MHz, CHLOROFORM-d) δ 7.73 (d, J=2.2 Hz, 1H), 7.44 (dd, J=8.8, 2.2 Hz, 1H), 7.08 (d, J=8.6 Hz, 1H), 6.60 (dd, J=17.5, 10.9 Hz, 1H), 5.63 (dd, J=17.6, 0.4 Hz, 1H), 5.20 (d, J=11.2 Hz, 1H), 3.00 – 2.89 (m, 4H), 1.99 – 1.85 (m, 2H), 0.84 (d, J=6.6 Hz, 12H) IC. Racemic (lR,2S)-ethyl 2-(4-(diisobutylamino)-3 nitrophenyl)

cyclopropanecarboxylate

To a solution of IB (800 mg, 2.61 mmol) in DCM (15 mL) was added rhodium(II) acetate dimer (230 mg, 0.521 mmol) followed by a slow addition of a solution of ethyl diazoacetate (0.811 mL, 7.82 mmol) in CH2CI2 (5.00 mL) over a period of 2 h via a syringe pump. The reaction mixture turned into a dark red solution and it was stirred at RT for extra 1 h. LC-MS indicated the appearance of two peaks with the desired molecular mass, the solvent was removed in vacuo and purification via flash

chromatography gave 1C (cis isomer) (yellow oil, 220 mg, 0.607 mmol, 23.30 % yield) and trans isomer (yellow oil, 300 mg, 0.828 mmol, 31.8 % yield). LC-MS Anal. Calc’d for C20H30N2O4 362.22, found [M+H] 363.27, Tr = 2.34 min (cis), 2.42 min (trans) (Method A), cis isomer: 1H NMR (400MHz, CHLOROFORM-d) δ 7.62 (d, J=1.8 Hz, 1H), 7.30 – 7.25 (m, 1H), 7.02 (d, J=8.6 Hz, 1H), 3.95 – 3.86 (m, 2H), 2.89 (d, J=7.3 Hz, 4H), 2.53 – 2.44 (m, 1H), 2.07 (ddd, J=9.2, 7.9, 5.7 Hz, 1H), 1.87 (dquin, J=13.5, 6.8 Hz, 2H), 1.67 (dt, J=7.3, 5.5 Hz, 1H), 1.37 – 1.30 (m, 1H), 0.99 (t, J=7.0 Hz, 3H), 0.82 (d, J=6.6 Hz, 12H) trans isomer: 1H NMR (400MHz, CHLOROFORM-d) δ 7.43 (d, J=2.2 Hz, 1H), 7.17 – 7.11 (m, 1H), 7.08 – 7.03 (m, 1H), 4.18 (q, J=7.3 Hz, 2H), 2.89 (d, J=7.3 Hz, 4H), 2.46 (ddd, J=9.2, 6.4, 4.2 Hz, 1H), 1.94 – 1.80 (m, 3H), 1.62 – 1.54 (m, 1H), 1.34 – 1.23 (m, 4H), 0.83 (d, J=6.6 Hz, 12H)

ID. Racemic (lR,2S)-ethyl 2-(3-amino-4-(diisobutylamino)phenyl) cyclopropanecarboxylate

To a stirred solution of 1C (cis isomer) (220 mg, 0.607 mmol) in EtOAc (6 mL) was added palladium on carbon (64.6 mg, 0.061 mmol) and the suspension was hydrogenated (1 atm, balloon) at RT for 1 h. LC-MS indicated completion. The suspension was filtered through a pad of Celite and the filter cake was rinsed with EtOAc (2×30 mL). Combined filtrate and rinses were evaporated in vacuo. Purification via flash chromatography gave ID (light yellow oil, 140 mg, 0.421 mmol, 69.4 % yield). LC-MS Anal. Calc’d for C20H32N2O2 332.25, found [M+H] 333.34, Tr= 2.22 min (Method A). 1H NMR (400MHz, CHLOROFORM-d) δ 6.95 (d, J=8.1 Hz, 1H), 6.65 (d, J=2.0 Hz, 1H), 6.64 – 6.59 (m, 1H), 4.06 (s, 2H), 3.87 (qd, J=7.1, 0.9 Hz, 2H), 2.56 (d, J=7.0 Hz, 4H), 2.47 (q, J=8.6 Hz, IH), 2.01 (ddd, J=9.4, 7.8, 5.7 Hz, IH), 1.78 – 1.61 (m, 3H), 1.24 (ddd, J=8.6, 7.9, 5.1 Hz, IH), 0.92 (t, J=7.2 Hz, 3H), 0.89 (dd, J=6.6, 0.9 Hz, 12H)

Racemic example 1. Racemic (lR,2S)-2-(4-(diisobutylamino)-3-(3-(p- tolyl)ureido)phenyl)cyclopropanecarboxylic acid

To a solution of ID (140 mg, 0.421 mmol) in THF (4mL) was added 1- isocyanato-4-methylbenzene (0.079 mL, 0.632 mmol). The resulting solution was stirred at RT for 3 h. LC-MS indicated completion. The reaction mixture was concentrated and used without purification in the next step. The crude ester (180 mg, 0.387 mmol) was dissolved in THF (4 mL), NaOH (IN aqueous) (1.160 mL, 1.160 mmol) was added. Then MeOH (1 mL) was added to dissolve the precipitate and it turned into a clear yellow solution. After 60 h, reaction was complete by LC-MS. Most MeOH and THF was removed in vacuo and the crude was diluted with 2 mL of water, the pH was adjusted to ca. 2 using IN aqueous HC1. The aqueous phase was then extracted with EtOAc (3×10 mL) and the combined organic phase was washed with brine, dried over Na2S04 and concentrated. Purification via flash chromatography gave racemic example 1 (yellow foam, 110 mg, 0.251 mmol, 65.0 % yield), LC-MS Anal. Calc’d for CzeHssNsOs 437.27, found [M+H] 438.29, Tr = 4.22 min (Method A). 1H NMR (400MHz, CHLOROFORM- d) δ 10.15 (br. s., IH), 7.42 – 7.35 (m, 3H), 7.22 – 7.14 (m, 2H), 7.10 (d, J=8.1 Hz, 2H), 3.22 (d, J=6.6 Hz, 4H), 2.54 (q, J=8.6 Hz, IH), 2.31 (s, 3H), 2.16 – 1.98 (m, 3H), 1.61 (dt, J=7.3, 5.6 Hz, IH), 1.40 (td, J=8.3, 5.3 Hz, IH), 1.01 (br. s., 12H)

Example 1, Enantiomer 1 and Enantiomer 2. Chiral separation of racemic example 1 (Method H) gave enantiomer 1 Tr = 9.042 min (Method J). [a]24 D = -11.11 (c 7.02 mg/mL, MeOH) and enantiomer 2 Tr = 10.400 min (Method J). [a]24 D = + 11.17 (c 7.02 mg/mL, MeOH) as single enantiomers. Absolute stereochemistry was confirmed in example 1 method B.

Enantiomer 1 : LC-MS Anal. Calc’d for C26H35N3O3 437.27, found [M+H] 438.25, Tr= 4.19 min (Method A). 1H NMR (400MHz, CHLOROFORM-d) δ 8.12 (d, J=1.3 Hz, IH), 7.97 (s, IH), 7.20 (d, J=8.4 Hz, 2H), 7.14 – 7.07 (m, 2H), 7.02 (t, J=7.7 Hz, 2H),

6.89 (dd, J=8.1, 1.5 Hz, IH), 2.60 (q, J=8.6 Hz, IH), 2.50 (d, J=7.0 Hz, 4H), 2.32 (s, 3H), 2.13 – 2.04 (m, 1H), 1.71 – 1.55 (m, 3H), 1.35 (td, J=8.3, 5.1 Hz, 1H), 0.76 (dd, J=6.6, 2.2 Hz, 12H)

Enantiomer 2: LC-MS Anal. Calc’d for C26H35N3O3 437.27, found [M+H] 438.24, Tr= 4.18 min (Method A). 1H NMR (400MHz, CHLOROFORM-d) δ 8.11 (d, J=1.5 Hz, 1H), 7.96 (s, 1H), 7.23 – 7.16 (m, 2H), 7.13 – 7.07 (m, 2H), 7.05 – 6.98 (m, 2H), 6.89 (dd, J=8.3, 1.7 Hz, 1H), 2.59 (q, J=8.7 Hz, 1H), 2.49 (d, J=7.3 Hz, 4H), 2.32 (s, 3H), 2.12 – 2.03 (m, 1H), 1.70 – 1.53 (m, 3H), 1.34 (td, J=8.2, 5.0 Hz, 1H), 0.75 (dd, J=6.6, 2.0 Hz, 12H) Example 1 – Method B

Enantiomer 1 and Enantiomer 2

Enantiomer 2: (lS,2R)-2-(4-(diisobutylamino)-3-(3-(p- tolyl)ureido)phenyl)cyclopropanecarboxylic acid

Figure imgf000063_0001

IE. 4-(5,5-dimethyl-l,3,2-dioxaborinan-2-yl)-N,N-diisobutyl-2-nitroaniline

1A (10 g, 30.4 mmol), 5,5,5′,5′-tetramethyl-2,2′-bi(l,3,2-dioxaborinane) (7.55 g, 33.4 mmol), PdCl2(dppf)- CH2C12 adduct (0.556 g, 0.759 mmol) and potassium acetate

(8.94 g, 91 mmol) were combined in a round bottom flask, and DMSO (100 mL) was added. It was vacuated and back-filled with N2 three times, then heated at 80 °C for 8 h. Reaction was complete by LC-MS. Cooled to RT and passed through a short plug of silica gel, rinsed with a mixture of Hexane/EtOAc (5: 1) (3×100 mL). After removing the solvent in vacuo, purification via flash chromatography gave IE (orange oil, 9 g, 22.36 mmol, 73.6 % yield), LC-MS Anal. Calc’d for C19H31BN2O4 362.24, found [M+H] 295.18 (mass of boronic acid), Tr = 3.65 min (Method A). 1H NMR (400MHz,

CHLOROFORM-d) δ 8.13 (d, J=1.8 Hz, 1H), 7.73 (dd, J=8.4, 1.5 Hz, 1H), 7.04 (d, J=8.6 Hz, 1H), 3.75 (s, 4H), 3.00 – 2.92 (m, 4H), 1.93 (dquin, J=13.5, 6.8 Hz, 2H), 1.02 (s, 6H), 0.93 – 0.79 (m, 12H)

IF. (lS,2R)-ethyl 2-(4-(diisobutylamino)-3-nitrophenyl)

cyclopropanecarboxylate

To IE (9 g, 22.36 mmol) in a 500 mL round bottom flask was added 1,4-dioxane (60 mL). After it was dissolved, cesium carbonate (15.30 g, 47.0 mmol) was added. To the suspension was then added water (30 mL) slowly. It became an homogeneous solution. Enantiopure (lR,2R)-ethyl 2-iodocyclopropanecarboxylate (5.90 g, 24.59 mmol) (For synthesis see Organic Process Research & Development 2004, 8, 353-359 ) was then added. The resulting mixture was purged with nitrogen for 25 min. Then PdCl2(dppf)-

CH2C12 adduct (1.824 g, 2.236 mmol) was added. The reaction mixture was purged with nitrogen for another 10 min. It became dark brown colored solution. This mixture was then stirred under nitrogen at 87 °C for 22 h. LC-MS indicated product formation and depletion of starting material. It was then cooled to RT. After removing solvent under reduced pressure, it was diluted with EtOAc (50 mL) and water (50 mL). Organic layer was separated and the aqueous layer was further extracted with EtOAc (3x 30 mL). The combined organic layers were washed with brine, dried over MgS04, filtered and concentrated. Purification via flash chromatography gave IF (dark orange oil, 3.2 g, 8.83 mmol, 39.5 % yield), LC-MS Anal. Calc’d for C20H30N2O4 362.22, found [M+H] 363.3, Tr = 3.89 min (Method A). 1H NMR (400MHz, CHLOROFORM-d) 57.65 – 7.60 (m, 1H), 7.29 (d, J=2.2 Hz, 1H), 7.02 (d, J=8.6 Hz, 1H), 3.95 – 3.84 (m, 2H), 2.89 (d, J=7.3 Hz, 4H), 2.48 (q, J=8.6 Hz, 1H), 2.07 (ddd, J=9.2, 7.9, 5.7 Hz, 1H), 1.87 (dquin, J=13.5, 6.8 Hz, 2H), 1.67 (dt, J=7.3, 5.5 Hz, 1H), 1.38 – 1.28 (m, 1H), 0.99 (t, J=7.2 Hz, 3H), 0.82 (d, J=6.6 Hz, 12H

IG. (lS,2R)-ethyl 2-(3-amino-4-(diisobutylamino)phenyl)

cyclopropanecarboxylate

To a stirred solution of IF (5.5 g, 15.17 mmol) in EtOAc (150 mL) was added palladium on carbon (1.615 g, 1.517 mmol) and the suspension was hydrogenated (1 atm, balloon) for 1.5 h. LC-MS indicated completion. The suspension was filtered through a pad of Celite and the filter cake was rinsed with EtOAc (2×50 mL). Combined filtrate and rinses were concentrated under reduced pressure. Purification via flash chromatography gave 1G (yellow oil, 4.5 g, 13.53 mmol, 89 % yield). LC-MS Anal. Calc’d for

C20H32N2O2 332.25, found [M+H] 333.06, Tr = 2.88 min (Method A). 1H NMR

(400MHz, CHLOROFORM-d) δ 6.95 (d, J=7.9 Hz, 1H), 6.68 – 6.58 (m, 2H), 4.06 (s, 2H), 3.93 – 3.81 (m, 2H), 2.57 (d, J=7.3 Hz, 4H), 2.47 (q, J=8.6 Hz, 1H), 2.01 (ddd, J=9.4, 7.8, 5.5 Hz, 1H), 1.78 – 1.59 (m, 3H), 1.30 – 1.18 (m, 1H), 0.92 (t, J=7.2 Hz, 3H), 0.89 (dd, J=6.6, 0.9 Hz, 12H)

Example 1 enantiomer 2 was prepared following the reduction, urea formation and basic saponification procedures in racemic example 1 method A except that saponification was carried out at 50 °C for 8 h instead of at RT. Chiral analytical analysis verified it was enantiomer 2 Tr = 10.646 min (Method J). Absolute stereochemistry was confirmed by referring to reference: Organic Process Research & Development 2004, 8, 353-359.

Enantiomer 1 Method B: (lR,2S)-2-(4-(diisobutylamino)-3

tolyl)ureido)phenyl)cyclopropanecarboxylic acid

Figure imgf000065_0001

1H. Single enantiomer (lR,2S)-ethyl 2-(3-amino-4-(diisobutylamino)phenyl) cyclopropanecarboxylate

1H was prepared following procedures in example 1 enantiomer 2 method B utilizing enantiopure (l S,2S)-ethyl 2-iodocyclopropanecarboxylate. This was obtained through chiral resolution modifying the procedure in Organic Process Research & Development 2004, 8, 353-359, using (i?)-(+)-N-benzyl-a-methylbenzylamine instead of (S)-(-)-N-benzyl-a-methylbenzylamine). LC-MS Anal. Calc’d for C20H32N2O2 332.25, found [M+H] 333.06, Tr = 2.88 min (Method A). 1H NMR (400MHz, CHLOROFORM- d) δ 6.95 (d, J=7.9 Hz, 1H), 6.68 – 6.58 (m, 2H), 4.06 (s, 2H), 3.93 – 3.81 (m, 2H), 2.57 (d, J=7.3 Hz, 4H), 2.47 (q, J=8.6 Hz, 1H), 2.01 (ddd, J=9.4, 7.8, 5.5 Hz, 1H), 1.78 – 1.59 (m, 3H), 1.30 – 1.18 (m, 1H), 0.92 (t, J=7.2 Hz, 3H), 0.89 (dd, J=6.6, 0.9 Hz, 12H).

Note: 1H was also made through chiral separation (Method I) of racemic (1R,2S)- ethyl 2-(3-amino-4-(diisobutylamino)phenyl)cyclopropanecarboxylate. Chiral analytical analysis (Method K) showed 1H as a single enantiomer (99 % ee).

Example 1 enantiomer 1 was prepared following the reduction, urea formation and basic saponification procedures in racemic example 1 method A using 1H except that saponification was carried out at 50 °C for 8 h instead of at RT. Chiral analytical analysis verified it was enantiomer 1 with 97.8% ee (Method J).

Example 1 – Method C

Enantiomer 1

(lR,2S)-2-(4-(diisobutylamino)-3-(3-(p-tolyl)ureido)phenyl)cyclopropanecarboxylic acid

Figure imgf000066_0001

II. Diastereomer 1: (R)-4-benzyl-3-((lR,2S)-2-(4-(diisobutylamino)-3- nitrophenyl)cyclopropanecarbonyl)oxazolidin-2-one

Diastereomer 2: (R)-4-benzyl-3-((l S,2R)-2-(4-(diisobutylamino)-3- nitrophenyl)cyclopropanecarbonyl)oxazolidin-2-one: 1C (1.2 g, 3.31 mmol) was dissolved in THF (20 mL), NaOH (IN aqueous) (8.28 mL, 8.28 mmol) was added. Saw precipitate formed, then MeOH (5.00 mL) was added and it turned into a clear yellow solution. The reaction was monitored by LC-MS. After 24 h, reaction was complete. Most MeOH and THF was removed in vacuo and the crude was diluted with 10 mL of water, the pH was adjusted to ca. 2 using IN aqueous HC1. The aqueous phase was then extracted with EtOAc (3×30 mL) and the combined organic phase was washed with brine, dried over Na2S04 , filtered and concentrated to give 1.1 g of desired acid as an orange foam. This was used without purification in the subsequent step. To a solution of the crude acid from the previous step (1132 mg, 3.39 mmol) in THF (15 mL) cooled in an ice-water bath was added N-methylmorpholine (0.447 mL, 4.06 mmol) followed by slow addition of pivaloyl chloride (0.500 mL, 4.06 mmol). After stirring in an ice-water bath for 30 min, the reaction mixture was then cooled to -78 °C. In a separate reaction flask, ftBuLi (1.354 mL, 3.39 mmol) was added dropwise to a solution of (R)-4- benzyloxazolidin-2-one (600 mg, 3.39 mmol) in THF (15.00 mL). After 45 min at -78 °C, the solution was cannulated into the -78 °C anhydride mixture. After 30 min, the cooling bath was removed and the solution was allowed to warm to RT. After 1 h, LC-MS indicated completion. The reaction was quenched by addition of saturated aqueous NH4C1. The solution was then partitioned between EtOAc and water. The organic phase was further extracted with EtOAc (2×30 mL). The combined organic extracts were washed with water, brine, dried over MgS04, filtered and concentrated. Purification via flash chromatography gave II Diastereomer 1 (yellow oil, 600 mg, 1.216 mmol, 35.9 % yield). Diastereomer 2 (yellow oil, 450 mg, 0.912 mmol, 26.9 % yield) LC-MS Anal. Calc’d for C28H35N305 493.26, found: [M+H] 494.23, Tr = 5.26 min (Diastereomer 1). Tr = 5.25 min (Diastereomer 2) (Method A). Diastereomer 1 : 1H NMR (400MHz,

CHLOROFORM-d) δ 7.56 (d, J=1.8 Hz, 1H), 7.35 – 7.23 (m, 4H), 7.18 – 7.12 (m, 2H), 7.03 (d, J=8.8 Hz, 1H), 4.37 (ddt, J=9.6, 7.3, 3.6 Hz, 1H), 4.11 – 4.06 (m, 2H), 3.48 – 3.40 (m, 1H), 3.22 (dd, J=13.4, 3.5 Hz, 1H), 2.89 (d, J=7.3 Hz, 4H), 2.77 – 2.66 (m, 2H), 1.97 – 1.81 (m, 3H), 1.52 – 1.44 (m, 1H), 0.82 (d, J=6.6 Hz, 12H); Diastereomer 2: 1H NMR (400MHz, CHLOROFORM-d) δ 7.62 (d, J=2.0 Hz, 1H), 7.36 – 7.19 (m, 4H), 7.09 – 6.97 (m, 3H), 4.45 (ddt, J=10.2, 7.2, 3.0 Hz, 1H), 4.14 – 4.05 (m, 2H), 3.45 – 3.36 (m, 1H), 2.80 (d, J=7.3 Hz, 4H), 2.52 (dd, J=13.3, 3.2 Hz, 1H), 2.19 (dd, J=13.2, 10.3 Hz, 1H), 2.03 (dt, J=7.2, 5.8 Hz, 1H), 1.72 (dquin, J=13.4, 6.8 Hz, 2H), 1.45 (ddd, J=8.3, 7.3, 5.3 Hz, 1H), 0.64 (dd, J=6.6, 2.0 Hz, 12H) 1 J. (lR,2S)-methyl 2-(4-(diisobutylamino)-3-nitrophenyl)

cyclopropanecarboxylate

To a solution of II Diastereomer 1 (460 mg, 0.932 mmol) in THF (6mL) at 0 °C was added hydrogen peroxide (0.228 mL, 3.73 mmol). Then a solution of lithium hydroxide monohydrate (44.6 mg, 1.864 mmol) in water (2.000 mL) was added to the cold THF solution and stirred for 6 h. LC-MS indicated completion, then 2 mL of saturated aqueous Na2S03 was added followed by 3 mL of saturated aqueous NaHC03. The mixture was concentrated to remove most of the THF. The solution was then diluted with 5 mL of water. The aqueous solution was acidified with 1 N aqueous HC1 and extracted with EtOAc (3×20 mL). The combined organic extracts was washed with water, brine, dried over MgS04, filtered and concentrated to give 300 mg acid. To a solution of the crude acid from previous step (300 mg, 0.897 mmol) in MeOH (10 mL) was added 6 drops of concentrated H2SO4. The resulting solution was stirred at 50 °C for 6 h. After LC-MS indicated completion, solvent was removed under reduced pressure. It was then diluted with 5 mL of water, the aqueous layer was then extracted with EtOAc (3×20 mL) and the combined organic extracts were washed with water, brine, dried with Na2S04, filtered and concentrated. Purification via flash chromatography gave 1J (orange oil, 260 mg, 0.746 mmol, 83 % yield). LC-MS Anal. Calc’d for Ci9H28N204 348.20, found:

[M+H] 349.31 , Tr = 3.87 min (Method A). 1H NMR (400MHz, CHLOROFORM-d) δ

7.66 – 7.61 (m, 1H), 7.31 – 7.25 (m, 1H), 7.04 (d, J=8.8 Hz, 1H), 3.47 (s, 3H), 2.90 (d, J=7.3 Hz, 4H), 2.54 – 2.44 (m, 1H), 2.14 – 2.04 (m, 1H), 1.89 (dquin, J=13.5, 6.8 Hz, 2H),

1.67 (dt, J=7.5, 5.5 Hz, 1H), 1.42 – 1.31 (m, 1H), 0.83 (dd, J=6.6, 1.1 Hz, 12H)

IK. (lR,2S)-methyl 2-(3-amino-4-(diisobutylamino)phenyl)

cyclopropanecarboxylate

To a stirred solution of 1 J (100 mg, 0.287 mmol) in EtOAc (5mL) was added palladium on carbon (30.5 mg, 0.029 mmol) and the suspension was hydrogenated (1 atm, balloon) for 2 h. LC-MS indicated completion. The suspension was filtered through a pad of Celite and the filter cake was rinsed with EtOAc (20 mL). Combined filtrate and rinses were concentrated. Purification via flash chromatography gave IK (yellow oil, 90 mg, 0.287 mmol, 99 % yield). LC-MS Anal. Calc’d for Ci9H3oN202 318.23, found:

[M+H] 319.31 , Tr = 2.72 min (Method A). 1H NMR (400MHz, CHLOROFORM-d) δ 6.95 (d, J=8.1 Hz, 1H), 6.65 (d, J=1.8 Hz, 1H), 6.60 (dd, J=8.1 , 1.5 Hz, 1H), 4.08 (br. s., 2H), 3.42 (s, 3H), 2.58 (d, J=7.0 Hz, 4H), 2.52 – 2.42 (m, 1H), 2.09 – 1.98 (m, 1H), 1.79 – 1.59 (m, 3H), 1.32 – 1.22 (m, 1H), 0.94 – 0.84 (m, 12H)

Enantiomer 1 was prepared following the urea formation and saponification procedure in racemic example 1 method A. Chiral analytical analysis verified it was enantiomer 1 with 98.1% ee (Method J).

Example 1 – Method C Enantiomer 2

(lS,2R)-2-(4-(diisobutylamino)-3-(3-(p-tolyl)ureido)phenyl)cyclopropanecarboxylic acid

Figure imgf000069_0001

Example 1 Enantiomer 2 was prepared following the procedure for Example 1 enantiomer 1 method C using diastereomer 2 instead of diastereomer 1. Chiral analytical analysis verified it was enantiomer 2 with 94.0% ee (Method J).

PAPER

https://pubs.acs.org/doi/10.1021/acs.oprd.8b00171

Development of a Scalable Synthesis of BMS-978587 Featuring a Stereospecific Suzuki Coupling of a Cyclopropane Carboxylic Acid

 Chemical Development and API SupplyBiocon Bristol-Myers Squibb Research and Development CenterBiocon Park, Jigani Link Road, Bommasandra IV, Bangalore-560099, India
 Chemical and Synthetic DevelopmentBristol-Myers Squibb, 1 Squibb Drive, New Brunswick, New Jersey 08903, United States
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.8b00171
*E-mail: vaidy@bms.com.
Abstract Image

A modified synthetic route to BMS-978587 was developed featuring a chemoselective nitro reduction and a stereospecific Suzuki coupling as the key bond formation steps. A systematic evaluation of the reaction conditions led to the identification of a robust catalyst/ligand/base combination to reproducibly effect the Suzuki reaction on large scale. The modified route avoided several challenges with the original synthesis and furnished the API in high overall yield and purity without recourse to chromatography.

(1R,2S)-2-[4-(Di-isobutylamino)-3-(3-(p-tolyl)ureido)phenyl] Cyclopropanecarboxylic Acid (1)

………… afford 1 as a white solid (510 g, 99.05 HPLC area % purity, 96.0% potency, 60% yield; Pd content: <10 ppm).
1H NMR (300 MHz, DMSO-d6) 11.83 (br s, 1H), 9.30 (s, 1H), 7.90 (d, 1H, J = 1.5 Hz), 7.82 (s, 1H), 7.35–7.37 (d, 2H, J = 8.1 Hz), 7.06–7.10 (q, 3H, J = 2.1, 6.3, and 2.1 Hz), 6.78–6.80 (t, 1H, J = 6.3 and 1.8 Hz), 2.50–2.72 (m, 4H), 2.25 (s, 3H), 1.934–2.01 (m, 1H), 1.59–1.65 (m, 2H), 1.20–1.41 (m, 2H), 0.81(m, 13H);
13C NMR (100 MHz, DMSO-d6) 172.2, 153.0, 139.0, 137.8, 135.2, 133.1, 131.2, 129.6, 123.0, 122.1, 121.4, 119.4, 63.6, 26.3, 25.3, 21.9, 21.6, 20.8, 11.4.
HRMS (ESI) m/zcalcd for C26H36N3O3 [M + H]+ 438.2757, found 438.2714.

REF

(a) Balog, J. A.Huang, A.Chen, B.Chen, L.Seitz, P.Hart, A. C.Markwalder, J. A. Preparation of cycloalkylaryl amide compounds as indoleamine 2,3-dioxygenase and therapeutic uses thereof, PCT Int. Appl. 2014WO 2014150677A1 20140925.

(b) Balog, J. A.Cherney, E. C.Guo, W.Huang, A.Markwalder, J. A.Seitz, S. P.Shan, W.Williams, D. K.Murugesan, N.Nara, S.Jethanand; Preparation of benzenediamine derivatives as inhibitors of indoleamine 2,3-dioxygenase for the treatment of cancer, PCT Int. Appl. 2016WO 2016161269A1 20161006.

(c) Markwalder, J. A.Seitz, S. P.Hart, A.Nation, A.Balog, A.Vite, G.Borzilleri, R.Jure-Kunkel, M.Chen, B.Chen, L.Newitt, J.Lu, H.Abell, L.Lin, T.-A.Covello, K.Hunt, J.D’Arienzo, C.Fargnoli, J.Ranasinghe, A.Traeger, S. C. Manuscript in preparation.
D
Swift, E. C.Jarvo, E. R. Asymmetric transition metal-catalyzed cross-coupling reactions for the construction of tertiary stereocentersTetrahedron 2013695799– 5817DOI: 10.1016/j.tet.2013.05.001
E
Proceedings of the National Academy of Sciences of the United States of America2018vol. 115  13p. 3249 – 3254

////////////BMS-978587, IDO-IN-4, 1629125-65-0,  CS-5086, BMS978587, BMS 978587

OC(=O)[C@@H]3C[C@@H]3c2cc(NC(=O)Nc1ccc(C)cc1)c(cc2)N(CC(C)C)CC(C)C

FDA approves first cancer drug Kisqali (ribociclib) through new oncology review pilot that enables greater development efficiency FDA expands the use of breast cancer drug


FDA approves first cancer drug through new oncology review pilot that enables greater development efficiency FDA expands the use of breast cancer drug

The U.S. Food and Drug Administration today approved Kisqali (ribociclib) in combination with an aromatase inhibitor for the treatment of pre/perimenopausal or postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer, as initial endocrine-based therapy. The FDA also approved Kisqali in combination with fulvestrant for the treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer, as initial endocrine based therapy or following disease progression on endocrine therapy.

July 18, 2018

Release

The U.S. Food and Drug Administration today approved Kisqali (ribociclib) in combination with an aromatase inhibitor for the treatment of pre/perimenopausal or postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer, as initial endocrine-based therapy. The FDA also approved Kisqali in combination with fulvestrant for the treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer, as initial endocrine based therapy or following disease progression on endocrine therapy.

This is the first approval that FDA has granted as a part of two new pilot programs announced earlier this year that collectively aim to make the development and review of cancer drugs more efficient, while improving FDA’s rigorous standard for evaluating efficacy and safety. With this real-time review, the FDA was able to start evaluating the clinical data as soon as the trial results become available, enabling FDA to be ready to approve the new indication upon filing of a formal application with the Agency.

The first new program, called Real-Time Oncology Review, allows for the FDA to review much of the data earlier, after the clinical trial results become available and the database is locked, before the information is formally submitted to the FDA. This allows the FDA to begin its analysis of the data earlier, and provide feedback to the sponsor on how they can most effectively analyze the data to answer key regulatory questions. The pilot focuses on early submission of data that are the most relevant to assessing safety and effectiveness of the product. Then, when the sponsor submits the application with the FDA, the review team will already be familiar with the data and in a better position to conduct a more efficient, timely, and thorough review.

The second program is a new templated Assessment Aid that the applicant uses to organize its submission into a structured format to facilitate FDA’s review of the application. By using a structured template, the FDA is able to layer its assessment into the same file submitted by the sponsor, allowing this annotated application to serve as the document that contains the FDA review. This voluntary submission form provides for a more streamlined approach to reviewing data and illustrating FDA’s analysis. It allows for drug reviewers to focus on the key benefit-risk and labeling issues rather than administrative issues.

“With this approval, we’ve demonstrated some of the benefits of the new programs that we’re piloting for our review of cancer drugs, to improve regulatory efficiency while enhancing the process for evaluating the data submitted to us. This shows that, with smart policy approaches, we can gain efficiency while also improving the rigor of our process. These new programs were designed to reduce some of the administrative issues that can add to the time and cost of the review process, including the staffing burdens on the FDA. For example, by analyzing data earlier in the process, before formal submission to the FDA, and evaluating submissions in a structured template, we can make it easier to identify earlier when applications are missing key analysis or information that can delay reviews,” said FDA Commissioner Scott Gottlieb, M.D. “With today’s approval, the FDA used these new approaches to allow the review team to start analyzing data before the actual submission of the application and help guide the sponsor’s analysis of the top-line data to tease out the most relevant information. This enabled our approval less than one month after the June 28 submission date and several months ahead of the goal date.”

These new processes are good for patients, good for health care providers, good for product developers, and good for the FDA, by allowing our staff to have more time to engage with product developers and focus on the key aspects of drug reviews. We can improve efficiency and solidify our gold standard for review.”

Currently the two pilot programs are being used for supplemental applications for already-approved cancer drugs and could later be expanded to original drugs and biologics.

Kisqali was first approved in March 2017 for use with an AI to treat HR-positive, HER2-negative breast cancer in post-menopausal women whose cancer is advanced or has spread to other parts of the body.

“The approval adds a new treatment choice for patients with breast cancer,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “We are committed to continuing to bring more treatment options to patients.”

Breast cancer is the most common form of cancer in the United States. The National Cancer Institute at the National Institutes of Health estimates approximately 266,120 women will be diagnosed with breast cancer this year and 40,920 will die of the disease. Approximately 72 percent of patients with breast cancer have tumors that are HR-positive and HER2-negative.

The efficacy of Kisqali in combination with an AI for pre/perimenopausal women was demonstrated in a clinical trial of 495 participants who received either Kisqali and an AI or placebo and an AI. All pre- or peri-menopausal patients on this study received ovarian suppression with goserelin. The trial measured progression-free survival (PFS), which is generally the amount of time after the start of this treatment during which the cancer does not substantially grow and the patient is alive. PFS was longer for patients taking Kisqali plus an AI (median PFS of 27.5 months) compared to patients who received placebo plus an AI (median PFS of 13.8 months).

The efficacy of Kisqali in combination with fulvestrant in treating advanced or metastatic breast cancer was demonstrated in a clinical trial that included 726 participants who received either Kisqali and fulvestrant or placebo and fulvestrant. The trial measured PFS, which was longer for patients taking Kisqali plus fulvestrant (median PFS of 20.5 months) compared to patients who received placebo plus fulvestrant (median PFS of 12.8 months).

The common side effects of Kisqali are infections, abnormally low count of a type of white blood cell (neutropenia), a reduction in the number of white cells in the blood (leukopenia), headache, cough, nausea, fatigue, diarrhea, vomiting, constipation, hair loss and rash.

Warnings include the risk of a heart problem known as QT prolongation that can cause an abnormal heartbeat and may lead to death, serious liver problems, low white blood cell counts that may result in infections that may be severe, and fetal harm.

The FDA granted Priority Review and Breakthrough Therapy designation for this indication.

The FDA granted this approval to Novartis Pharmaceuticals Corporation.

Mercaptamine bitartrate, システアミン , меркаптамин , 巯乙胺


Cysteamine bitartrate.pngImage result for mercaptamine bitartrate

Image result for mercaptamine bitartrate

Mercaptamine bitartrate

2-aminoethanethiol;2,3-dihydroxybutanedioic acid

Molecular Formula: C6H13NO6S
Molecular Weight: 227.231 g/mol

Cystagon; Cysteamine – Mylan/Orphan Europe; Cysteamine bitartrate

Procysbi; CYSTEAMINE BITARTRATE; 27761-19-9; CHEBI:50386; (+/-)-Tartaric Acid

INGREDIENT UNII CAS
Cysteamine Bitartrate QO84GZ3TST 27761-19-9
Cysteamine Hydrochloride IF1B771SVB 156-57-0

Cysteamine bitartrate is a mercaptoethylamine compound that is endogenously derived from the COENZYME A degradative pathway. The fact that cysteamine is readily transported into LYSOSOMES where it reacts with CYSTINE to form cysteine-cysteamine disulfide and CYSTEINE has led to its use in CYSTINE DEPLETING AGENTS for the treatment of CYSTINOSIS.

Cysteamine Bitartrate is an aminothiol salt used in the treatment of nephropathic cystinosis. Cysteamine bitartrate enters the cell and reacts with cystine producing cysteineand cysteinecysteamine mixed disulfide compound, both of which, unlike cystine, can pass through the lysosomal membrane. This prevents the accumulation of cystinecrystals in the lysosomes of patients with cystinosis, which can cause considerable damage and eventual destruction of the cells, particularly in the kidneys. (NCI05)

Cysteamine is a simple aminothiol molecule that is used to treat nephropathic cystinosis, due to its ability to decrease the markedly elevated and toxic levels of intracellular cystine that occur in this disease and cause its major complications. Cysteamine has been associated with serum enzyme elevations when given intravenously in high doses, but it has not been shown to cause clinically apparent acute liver injury.

Given intravenously or orally to treat radiation sickness. The bitartrate salts (Cystagon® and Procysbi) have been used for the oral treatment of nephropathic cystinosis and cystinurea. The hydrochloride salt (Cystaran™) is indicated for the treatment of corneal cystine crystal accumulation in cystinosis patients.

  • OriginatorMylan
  • DeveloperAlphapharm; Mylan
  • ClassMercaptoethylamines; Small molecules; Sulfhydryl compounds
  • Mechanism of ActionGlutathione synthase stimulants

Highest Development Phases

  • MarketedNephropathic cystinosis
  • DiscontinuedUnspecified

Most Recent Events

  • 09 Apr 2018Mercaptamine bitartrate licensed to Recordati worldwide
  • 26 Oct 2017Chemical structure information added
  • 31 Dec 2008Mercaptamine bitartrate oral is still in phase II/III trials for Undefined indication in European Union

DESCRIPTION: CYSTAGON® (cysteamine bitartrate) Capsules for oral administration, contain cysteamine bitartrate, a cystine depleting agent which lowers the cystine content of cells in patients with cystinosis, an inherited defect of lysosomal transport. CYSTAGON® is the bitartrate salt of cysteamine, an aminothiol, beta-mercaptoethylamine. Cysteamine bitartrate is a highly water soluble white powder with a molecular weight of 227 and the molecular formula C2H7NS · C4H6O6. It has the following chemical structure:

str1

Cysteamine is a medication intended for a number of indications, and approved by the FDA to treat cystinosis.

It is stable aminothiol, i.e., an organic compound containing both an amine and a thiol functional groups. Cysteamine is a white, water-soluble solid. It is often used as salts of the ammonium derivative [HSCH2CH2NH3]+[1] including the hydrochloride, phosphocysteamine, and bitartrate.[2]

Cysteamine molecule is biosynthesized in mammals, including humans, by the degradation of coenzyme A. The intermedia pantetheineis broken down into cysteamine and pantothenic acid.[2] It is the biosynthetic precursor to the neurotransmitter hypotaurine.[3][4]

Medical uses

Cysteamine is used to treat cystinosis. It is available by mouth (capsule and extended release capsule) and in eye drops.[5][6][7][8][9]

Adverse effects

Topical use

The most important adverse effect related to topical use might be skin irritation.

Oral use

The label for oral formulations of cysteamine carry warnings about symptoms similar to Ehlers-Danlos syndrome, severe skin rashes, ulcers or bleeding in the stomach and intestines, central nervous symptoms including seizures, lethargy, somnolence, depression, and encephalopathy, low white blood cell levelselevated alkaline phosphatase, and idiopathic intracranial hypertension that can cause headache, tinnitus, dizziness, nausea, double or blurry vision, loss of vision, and pain behind the eye or pain with eye movement.[6]

The main side effects are Ehlers-Danlos syndrome, severe skin rashes, ulcers or bleeding in the stomach and intestines, central nervous symptoms, low white blood cell levelselevated alkaline phosphatase, and idiopathic intracranial hypertension (IIH). IIH can cause headache, ringing in the ears, dizziness, nausea, blurry vision, loss of vision, and pain behind the eye or with eye movement.

Additional adverse effects of oral cysteamine include bad breath, skin odor, vomiting, nausea, stomach pain, diarrhea, and loss of appetite.[6]

The drug is in pregnancy category C; the risks of cysteamine to a fetus are not known but it harms babies in animal models at doses less than those given to people.[7][8]

For eye drops, the most common adverse effects are sensitivity to light, redness, and eye pain, headache, and visual field defects.[8]

Interactions

There are no drug interactions for normal capsules or eye drops,[7][8] but the extended release capsules should not be taken with drugs that affect stomach acid like proton pump inhibitors or with alcohol, as they can cause the drug to be released too quickly.[6] It doesn’t inhibit any cytochrome P450 enzymes.[6]

Pharmacology

People with cystinosis lack a functioning transporter (cystinosin) which transports cystine from the lysosome to the cytosol. This ultimately leads to buildup of cystine in lysosomes, where it crystallizes and damages cells.[5] Cysteamine enters lysosomes and converts cystine into cysteine and cysteine-cysteamine mixed disulfide, both of which can exit the lysosome.[6]

Biological function

Cysteamine also promotes the transport of L-cysteine into cells, that can be further used to synthesize glutathione, which is one of the most potent intracellular antioxidants.[4]

Cysteamine is used as a drug for the treatment of cystinosis; it removes cystine that builds up in cells of people with the disease.[10]

History

First evidence regarding the therapeutic effect of cysteamine on cystinosis dates back to 1950s. Cysteamine was first approved as a drug for cystinosis in the US in 1994.[6] An extended release form was approved in 2013.[11]

Society and culture

It is approved by FDA and EMA.[5][6]

In 2013, the regular capsule of cysteamine cost about $8,000 per year; the extended release form that was introduced that year was priced at $250,000 per year.[11]

Research

It was studied in in vitro and animal models for radiation protection in the 1950s, and in similar models from the 1970s onwards for sickle cell anemia, effects on growth, its ability to modulate the immune system, and as a possible inhibitor of HIV.[2]

In the 1970s it was tested in clinical trials for Paracetamol toxicity which it failed, and in clinical trials for systemic lupus erythematosus in the 1990s and early 2000s, which it also failed.[2]

Clinical trials in Huntington’s disease were begun in the 1990s and were ongoing as of 2015.[2][12]

As of 2013 it was in clinical trials for Parkinson’s diseasemalaria, radiation sickness, neurodegenerative disorders, neuropsychiatric disorders, and cancer treatment.[10][2]

It has been studied in clinical trials for pediatric nonalcoholic fatty liver disease[13]

Horizon Pharma , following the acquisition of Raptor Pharmaceuticals (previously through its Bennu Pharmaceuticals subsidiary, and following its acquisition of Encode Pharmaceuticals , which licensed the drug from the University of California )) has developed and launched DR Cysteamine (EC Cysteamine; Procysbi), a methyl-CpG binding protein 2 (MECP2) gene modulating, oral delayed-release (DR), enteric-coated (EC), bitartrate salt formulation of mercaptamine (cysteamine).

PRODUCT PATENT, WO2007089670 ,

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2007089670

hold SPC protection in most of the EU states until September 2028, and expire in the US in July 2037. In July 2018, the US FDA’s Orange Book was seen to list a patent covering product ( US8026284 and US9173851 ) of cysteamine bitartrate, that is due to expire in September 2027 and December 2034, respectively.

Cystinosis is a rare, autosomal recessive disease caused by intra-lysosomal accumulation of the amino acid cystine within various tissues, including the spleen, liver, lymph nodes, kidney, bone marrow, and eyes. Nephropathic cystinosis is associated with kidney failure that
necessitates kidney transplantation. To date, the only specific treatment for nephropathic cystinosis is the sulfhydryl agent, cysteamine. Cysteamine has been shown to lower intracellular cystine levels, thereby reducing the rate of progression of kidney failure in children.
[0004] Cysteamine, through a mechanism of increased gastrin and gastric acid production, is ulcerogenic. When administered orally to children with cystinosis, cysteamine has also been shown to cause a 3 -fold increase in gastric acid production and a 50% rise of serum gastrin levels. As a consequence, subjects that use cysteamine suffer
gastrointestinal (GI) symptoms and are often unable to take cysteamine regularly or at full dose .

[0005] To achieve sustained reduction of leukocyte cystine levels, patients are normally required to take oral cysteamine every 6 hours, which invariably means having to awaken from sleep. However, when a single dose of
cysteamine was administered intravenously the leukocyte cystine level remained suppressed for more than 24 hours, possibly because plasma cysteamine concentrations were higher and achieved more rapidly than when the drug is administered orally. Regular intravenous administration of cysteamine would not be practical. Accordingly, there is a need for formulations and delivery methods that would result in higher plasma, and thus intracellular, concentration as well as decrease the number of daily doses and therefore improve the quality of life for patients.

PATENT

US-20180193292

Process for the preparation of cysteamine bitartrate . Represents the first patenting to be seen from Lupin Limited on cysteamine bitartrate.

Cysteamine bitartrate (I) is a cystine depleting agent which lower the cystine content of cells in patients with cystinosis, an inherited defect of lysosomal transport, it is indicated for the management of nephropathic cystinosis in children and adults. Cysteamine bitartrate (I) is simplest stable aminothiol salt and has the following structural formula:

 The application WO 2014204881 provides pharmaceutical composition of cysteamine bitrate and another application WO 2007089670 provides method of administrating cysteamine and pharmaceutically salts and method of treatment thereof.

Examples

1. Preparation of Cysteamine Bitartrate.

 A mixture of ethanol (1000 ml), butylated hydroxy anisole (1 g) and cysteamine hydrochloride (100 g) was stirred and cooled to 5 to 10° C. To this mixture a solution of ethanol (500 ml) and sodium hydroxide (352 g) was added over a period of 30 minutes.
The mixture was stirred at a temperature of 10 to 15° C. for 45 minutes. The mixture was filtered through celite. The filtrate was added to a mixture of ethanol (1250 ml), butylated hydroxy anisole (1 g) and L-(+)-tartaric acid (132 g) at a temperature of 55-60° C. The reaction mixture was stirred at 70-75° C. for 45 minutes. The mixture was cooled to 20-30° C. The solid was filtered, washed with ethanol and dried under vacuum.

2. Purification of Cysteamine Bitartrate.

A mixture of cysteamine bitartrate (100 g) and ethanol (5000 ml) was heated to a temperature of 77-82° C. The solution was filtered and the filtrate was cooled to 20 to 30° C. and stirred for 40 minutes. The solid was filtered, washed with ethanol and dried under vacuum. Yield: 80 g; HPLC purity: 99.90%.

3. Preparation of Crystalline Form L1 of Cysteamine Bitartrate.

A mixture of cysteamine bitartrate (50 g) and methanol (600 ml) was heated to a temperature of 35-45° C. The solution was filtered and the filtrate was cooled to 5 to 10° C. Cysteamine bitartrate (0.25 g) seed material was added to the filtrate. The slurry was cooled to −5 to −25° C. and stirred for 40 minutes. The solid was filtered, washed with precooled methanol and dried under vacuum. Yield: 40 g. Cysteamine bitartrate with X-ray powder diffraction pattern as depicted in FIG. 1 was obtained.

4. Preparation of Crystalline Form L2 of Cysteamine Bitartrate.

A mixture of cysteamine bitartrate (50 g), butylated hydroxy anisole (1.3 g) and methanol (600 ml) was heated to a temperature of 35-45° C. The solution was filtered and the filtrate was cooled to 5 to 10° C. Cysteamine bitartrate (0.25 g) seed material was added to the filtrate. The slurry was cooled to −25 to −30° C. and stirred for 40 minutes. The solid was filtered, washed with precooled methanol and the solid was dried under 800-900 mm/Hg of vacuum at 35-40° C. for 5 hours. Yield: 40 g. Cysteamine bitartrate with X-ray powder diffraction pattern as depicted in FIG. 2 was obtained.

PATENT

WO 2014204881

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014204881

PATENTS
EP3308773A1 *2016-10-112018-04-18Recordati Industria Chimica E Farmaceutica SPAFormulations of cysteamine and cysteamine derivatives
Family To Family Citations
JP2016523364A *2013-06-172016-08-08ラプター ファーマシューティカルズ インコーポレイテッドシステアミン組成物の分析方法
WO2017087532A1 *2015-11-162017-05-26The Regents Of The University Of CaliforniaMethods of treating non-alcoholic steatohepatitis (nash) using cysteamine compounds
WO2017157922A12016-03-182017-09-21Recordati Industria Chimica E Farmaceutica S.P.A.Prolonged release pharmaceutical composition comprising cysteamine or salt thereof, 
KR20167000255A2014-06-17서방성 시스테아민 비드 투약 형태
JP2016521489A2014-06-17
CN 2014800346472014-06-17延迟释放型半胱胺珠粒调配物,以及其制备及使用方法
EP201408131322014-06-17Delayed release cysteamine bead formulation
CA 29147702014-06-17Delayed release cysteamine bead formulation, and methods of making and using same

References

  1. Jump up^ Reid, E. Emmet (1958). Organic Chemistry of Bivalent Sulfur1. New York: Chemical Publishing Company, Inc. pp. 398–399.
  2. Jump up to:a b c d e f Besouw, M; Masereeuw, R; van den Heuvel, L; Levtchenko, E (August 2013). “Cysteamine: an old drug with new potential”. Drug Discovery Today18 (15–16): 785–92. doi:10.1016/j.drudis.2013.02.003PMID 23416144.
  3. Jump up^ Singer, Thomas P (1975). “Oxidative Metabolism of Cysteine and Cystine”. In Greenberg, David M. Metabolic pathways Vol. 7. Metabolism of sulfur compounds (3rd ed.). New York: Academic Press. p. 545. ISBN 9780323162081.
  4. Jump up to:a b Besouw, Martine; Masereeuw, Rosalinde; van den Heuvel, Lambert; Levtchenko, Elena (August 2013). “Cysteamine: an old drug with new potential”. Drug Discovery Today18(15–16): 785–792. doi:10.1016/j.drudis.2013.02.003ISSN 1878-5832PMID 23416144.
  5. Jump up to:a b c Nesterova, Galina; Gahl, William A. (October 6, 2016). “Cystinosis”GeneReviews. University of Washington, Seattle.
  6. Jump up to:a b c d e f g h “US Label: Cysteamine bitartrate delayed-release capsules” (PDF). FDA. August 2015.
  7. Jump up to:a b c “US Label: Cysteamine bitartrate capsules” (PDF). FDA. June 2007.
  8. Jump up to:a b c d “US Label: Cysteamine ophthalmic solution” (PDF). FDA. October 2012.
  9. Jump up^ Shams, F; Livingstone, I; Oladiwura, D; Ramaesh, K (10 October 2014). “Treatment of corneal cystine crystal accumulation in patients with cystinosis”Clinical ophthalmology (Auckland, N.Z.)8: 2077–84. doi:10.2147/OPTH.S36626PMC 4199850Freely accessiblePMID 25336909.
  10. Jump up to:a b Besouw, Martine; Masereeuw, Rosalinde; van den Heuvel, Lambert; Levtchenko, Elena (August 2013). “Cysteamine: an old drug with new potential”Drug Discovery Today18(15–16): 785–792. doi:10.1016/j.drudis.2013.02.003ISSN 1878-5832PMID 23416144.
  11. Jump up to:a b Pollack, Andrew (30 April 2013). “F.D.A. Approves Raptor Drug for Form of Cystinosis”The New York Times.
  12. Jump up^ Shannon, KM; Fraint, A (15 September 2015). “Therapeutic advances in Huntington’s Disease”. Movement disorders : official journal of the Movement Disorder Society30 (11): 1539–46. doi:10.1002/mds.26331PMID 26226924.
  13. Jump up^ Mitchel, EB; Lavine, JE (November 2014). “Review article: the management of paediatric nonalcoholic fatty liver disease”Alimentary pharmacology & therapeutics40 (10): 1155–70. doi:10.1111/apt.12972PMID 25267322.
ysteamine
Cysteamine-2D-skeletal.png
Cysteamine 3D ball.png

Skeletal formula (top)
Ball-and-stick model of the cysteamine
Clinical data
Synonyms 2-Aminoethanethiol
β-Mercaptoethylamine
2-Mercaptoethylamine
Decarboxycysteine
Thioethanolamine
Mercaptamine
License data
Identifiers
CAS Number
PubChemCID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.000.421 Edit this at Wikidata
Chemical and physical data
Formula C2H7NS
Molar mass 77.15 g·mol−1
Melting point 95 to 97 °C (203 to 207 °F)
Title: Cysteamine
CAS Registry Number: 60-23-1
CAS Name: 2-Aminoethanethiol
Additional Names: mercaptamine; b-mercaptoethylamine; 2-aminoethyl mercaptan; thioethanolamine; decarboxycysteine; MEA; mercamine
Manufacturers’ Codes: L-1573
Trademarks: Becaptan (Labaz); Lambratene (formerly) (Cilag Italiano)
Molecular Formula: C2H7NS
Molecular Weight: 77.15
Percent Composition: C 31.14%, H 9.15%, N 18.16%, S 41.56%
Line Formula: HSCH2CH2NH2
Literature References: A sulfhydryl compound with a variety of biological effects. Prepn: Gabriel, Leupold, Ber. 31, 2837 (1898); Knorr, Rössler, ibid. 36, 1281 (1903); Mills, Jr., Bogart, J. Am. Chem. Soc. 62, 1173 (1940); Wenker, ibid. 57, 2328 (1935); D. A. Shirley, Preparation of Organic Intermediates (Wiley, New York, 1951) p 189. Use in treatment of paracetamol (acetaminophen) poisoning: L. F. Prescott et al., Lancet 2, 109 (1976); A. L. Harris, Br. Med. J. 284, 825 (1982). Effects in nephropathic cystinosis: M. Yudkoff et al., N. Engl. J. Med. 304, 141 (1981). Radioprotective effects: R. P. Bird, Radiat. Res. 72, 290 (1980); C. J. Koch, R. L. Howell, ibid. 87, 265 (1981). Cysteamine has been shown to be a duodenal ulcerogen in rats: H. Selye, S. Szabo, Nature 244,458 (1973); S. Szabo, Am. J. Pathol. 93, 273 (1978); P. Kirkegaard et al., Scand. J. Gastroenterol. 15, 621 (1980). Review: S. Szabo, Lab. Invest. 51, 121 (1984). It has also been found to deplete somatostatin concentration: S. Szabo, S. Reichlein, Endocrinology 109, 2255 (1981); S. M. Sagar et al., J. Neurosci. 2, 225 (1982). In pituitary tissue, cysteamine is a potent depletor of prolactin concentrations in vivo and in vitro: W. J. Millard et al., Science 217, 452 (1982). Toxicity studies: E. Beccari et al.,Arzneim.-Forsch. 5, 421 (1955); D. L. Klayman et al., J. Med. Chem. 12, 510 (1969); P. K. Srivastava, L. Field, ibid. 18, 798 (1975).
Properties: Crystals by sublimation in vacuo. Disagreeable odor. mp 97-98.5°. Oxidizes to cystamine on standing in air. Freely sol in water, alkaline reaction. LD50 in mice (mg/kg): 625 orally; 250 i.p. (Klayman); (Srivastava, Field).
Melting point: mp 97-98.5°
Toxicity data: LD50 in mice (mg/kg): 625 orally; 250 i.p. (Klayman); (Srivastava, Field)
Derivative Type: Hydrochloride
Molecular Formula: C2H7NS.HCl
Molecular Weight: 113.61
Percent Composition: C 21.14%, H 7.10%, N 12.33%, S 28.22%, Cl 31.21%
Properties: Crystals from alc, mp 70.2-70.7°. Sol in water, alcohol. LD50 (cg/kg): 23.19 i.p. in rats; 14.95 i.v. in rabbits (Beccari).
Melting point: mp 70.2-70.7°
Toxicity data: LD50 (cg/kg): 23.19 i.p. in rats; 14.95 i.v. in rabbits (Beccari)
Use: Experimentally as a radioprotective agent and to produce acute and chronic duodenal ulcers in rats.
Therap-Cat: Antidote to acetaminophen.
Keywords: Antidote (Acetaminophen Poisoning)

///////////Mercaptamine bitartrate, Cystagon, Cysteamine,  Cysteamine bitartrate, Mercaptamine,, システアミン , меркаптамин ,  巯乙胺

C(CS)N.C(C(C(=O)O)O)(C(=O)O)O

National award to Anthony Melvin Crasto for contribution to Pharma society from Times Network for Excellence in HEALTHCARE) | 5th July, 2018 | Taj Lands End, Mumbai, India


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DR ANTHONY MEVIN CRASTO Conferred prestigious individual national award at function for contribution to Pharma society from Times Network, National Awards for Marketing Excellence ( For Excellence in HEALTHCARE) | 5th July, 2018 | Taj Lands End, Mumbai India

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////////////National award,  contribution to Pharma society, Times Network, Excellence in HEALTHCARE,  5th July, 2018, Taj Lands End, Mumbai,  India, ANTHONY CRASTO

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