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DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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FDA approves Odactra for house dust mite allergies
March 1, 2017
Release
The U.S. Food and Drug Administration today approved Odactra, the first allergen extract to be administered under the tongue (sublingually) to treat house dust mite (HDM)-induced nasal inflammation (allergic rhinitis), with or without eye inflammation (conjunctivitis), in people 18 through 65 years of age.
“House dust mite allergic disease can negatively impact a person’s quality of life,” said Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research. “The approval of Odactra provides patients an alternative treatment to allergy shots to help address their symptoms.”
House dust mite allergies are a reaction to tiny bugs that are commonly found in house dust. Dust mites, close relatives of ticks and spiders, are too small to be seen without a microscope. They are found in bedding, upholstered furniture and carpeting. Individuals with house dust mite allergies may experience a cough, runny nose, nasal itching, nasal congestion, sneezing, and itchy and watery eyes.
Odactra exposes patients to house dust mite allergens, gradually training the immune system in order to reduce the frequency and severity of nasal and eye allergy symptoms. It is a once-daily tablet, taken year round, that rapidly dissolves after it is placed under the tongue. The first dose is taken under the supervision of a health care professional with experience in the diagnosis and treatment of allergic diseases. The patient is to be observed for at least 30 minutes for potential adverse reactions. Provided the first dose is well tolerated, patients can then take Odactra at home. It can take about eight to 14 weeks of daily dosing after initiation of Odactra for the patient to begin to experience a noticeable benefit.
The safety and efficacy of Odactra was evaluated in studies conducted in the United States, Canada and Europe, involving approximately 2,500 people. Some participants received Odactra, while others received a placebo pill. Participants reported their symptoms and the need to use symptom-relieving allergy medications. During treatment, participants taking Odactra experienced a 16 to 18 percent reduction in symptoms and the need for additional medications compared to those who received a placebo.
The most commonly reported adverse reactions were nausea, itching in the ears and mouth, and swelling of the lips and tongue. The prescribing information includes a boxed warning that severe allergic reactions, some of which can be life-threatening, can occur. As with other FDA-approved allergen extracts administered sublingually, patients receiving Odactra should be prescribed auto-injectable epinephrine. Odactra also has a Medication Guide for distribution to the patient.
Odactra is manufactured for Merck, Sharp & Dohme Corp., (a subsidiary of Merck and Co., Inc., Whitehouse Station, N.J.) by Catalent Pharma Solutions Limited, United Kingdom.
(sublingually) to treat house dust mite (HDM)-induced nasal inflammation (allergic rhinitis), with or without eye inflammation (conjunctivitis), in people 18 through 65 years of age
/////////////Odactra, Merck, Sharp & Dohme Corp, Catalent Pharma Solutions Limited, United Kingdom, FDA 2017, approves, house dust mite allergies
Award for me, 100 Most Impactful Health care Leaders, Global listing
At award function for my award “100 Most Impactful Health care Leaders Global listing”, conferred on me at Taj lands end, Mumbai, India on 14 Feb 2014 by World Health Wellness congress and awards
FDA approves Xermelo (telotristat ethyl) for carcinoid syndrome diarrhea
Telotristat ethyl
Molecular Formula, C27-H26-Cl-F3-N6-O3,
Molecular Weight, 574.9884,
RN: 1033805-22-9
UNII: 8G388563M
LX 1032
(2S)-2-Amino-3-[4-[2-amino-6-[[(1R)-1-[4-chloro-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoroethyl]oxy]pyrimidin-4-yl]phenyl]propionic acid ethyl ester
Ethyl-4-(2-amino-6-{(1R)-1-[4-chlor-2-(3-methyl-1H-pyrazol-1-yl)phenyl]-2,2,2-trifluorethoxy}-4-pyrimidinyl)-L-phenylalaninat
CAS: 1137608-69-5 (etiprate), LX 1606
Chemical Formula: C36H35ClF3N7O6
Molecular Weight: 754.16
- LX 1032 hippurate
- LX 1606
Carcinoid syndrome is a cluster of symptoms sometimes seen in people with carcinoid tumors. These tumors are rare, and often slow-growing. Most carcinoid tumors are found in the gastrointestinal tract. Carcinoid syndrome occurs in less than 10 percent of patients with carcinoid tumors, usually after the tumor has spread to the liver. The tumors in these patients release excess amounts of the hormone serotonin, resulting in diarrhea. Complications of uncontrolled diarrhea include weight loss, malnutrition, dehydration, and electrolyte imbalance.
“Today’s approval will provide patients whose carcinoid syndrome diarrhea is not adequately controlled with another treatment option,” said Julie Beitz, M.D., director of the Office of Drug Evaluation III in the FDA’s Center for Drug Evaluation and Research.
Xermelo, in a regimen with SSA therapy, is approved in tablet form to be taken orally three times daily with food. Xermelo inhibits the production of serotonin by carcinoid tumors and reduces the frequency of carcinoid syndrome diarrhea.
The safety and efficacy of Xermelo were established in a 12-week, double-blind, placebo-controlled trial in 90 adult participants with well-differentiated metastatic neuroendocrine tumors and carcinoid syndrome diarrhea. These patients were having between four to 12 daily bowel movements despite the use of SSA at a stable dose for at least three months. Participants remained on their SSA treatment, and were randomized to add placebo or treatment with Xermelo three times daily. Those receiving Xermelo added on to their SSA treatment experienced a greater reduction in average bowel movement frequency than those on SSA and placebo. Specifically, 33 percent of participants randomized to add Xermelo on to SSA experienced an average reduction of two bowel movements per day compared to 4 percent of patients randomized to add placebo on to SSA.
The most common side effects of Xermelo include nausea, headache, increased levels of the liver enzyme gamma-glutamyl transferase, depression, accumulation of fluid causing swelling (peripheral edema), flatulence, decreased appetite and fever. Xermelo may cause constipation, and the risk of developing constipation may be increased in patients whose bowel movement frequency is less than four bowel movements per day. Patients treated with a higher than recommended dosage of Xermelo developed severe constipation in clinical trials. One patient required hospitalization and two other patients developed complications of either intestinal perforation or intestinal obstruction. Patients should be monitored for severe constipation. If a patient experiences severe constipation or severe, persistent or worsening abdominal pain, they should discontinue Xermelo and contact their healthcare provider.
The FDA granted this application fast track designation and priority review. The drug also received orphan drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.
Xermelo is manufactured by Woodlands, Texas-based Lexicon Pharmaceuticals, Inc.
SYNTHESIS…….WO 2011100285
5.67. Synthesis of (S)-2-Amino-3-[4-(2-amino-6-{R-l-[4-chloro-2-(3-methyl-pyrazol-l-yll- phenyll-2,2,2-trifluoro-ethoxy)-pyrimidin-4-yl)-phenyll-propionic acid ethyl ester
The title compound was prepared stepwise, as described below:
Step 1: Synthesis of l-(2-bromo-4-chloro-phenyl)-2,2,2-trifluoro-ethanone. To a 500 ml 2 necked RB flask containing anhydrous methanol (300 ml) was added thionyl chloride (29.2 ml, 400 mmol) dropwise at 0-5°C (ice water bath) over 10 minutes. The ice water bath was removed, and 2-bromo-4-chloro-benzoic acid (25 g, 106 mmol) was added. The mixture was heated to mild reflux for 12h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was concentrated. Crude product was dissolved in dichloromethane (DCM, 250 ml), washed with water (50 ml), sat. aq. NaHC03 (50 ml), brine (50 ml), dried over sodium sulfate, and concentrated to give the 2- bromo-4-chloro-benzoic acid methyl ester (26 g, 99 %), which was directly used in the following step.
2-Bromo-4-chloro-benzoic acid methyl ester (12.4 g, 50 mmol) in toluene (200 ml) was cooled to -70°C, and trifluoromethyl trimethyl silane (13 ml, 70 mmol) was added.
Tetrabutylamonium fluoride (1M, 2.5 ml) was added dropwise, and the mixture was allowed to warm to room temperature over 4h, after which it was stirred for 10 hours at room temperature. The reaction mixture was concentrated to give the crude [l-(2-bromo-4-chloro-phenyl)-2,2,2-trifluoro-l-methoxy-ethoxy]-trimethyl-silane. The crude intermediate was dissolved in methanol (100 ml) and 6N HCI (100 ml) was added. The mixture was kept at 45-50°C for 12h. Methanol was removed, and the crude was extracted with dichloromethane (200 ml). The combined DCM layer was washed with water (50 ml), NaHC03 (50 ml), brine (50 ml), and dried over sodium sulfate. Removal of solvent gave a crude product, which was purified by ISCO column chromatography, using 1-2% ethyl acetate in hexane as solvent, to afford l-(2-bromo-4-chloro-phenyl)-2,2,2-trifluoro-ethanone (10 g, 70%). !H-NMR (300 MHz, CDC ): δ (ppm) 7.50 (d,lH), 7.65(d,lH), 7.80(s,lH).
Step 2: Synthesis of R-l-(2-bromo-4-chloro-phenyl)-2,2,2-trifluoro-ethanol. To catechol borane (1M in THF 280 ml, 280 mmol) in a 2L 3-necked RB flask was added S-2-methyl-CBS oxazaborolidine (7.76 g, 28 mmol) under nitrogen, and the resulting mixture was stirred at room temperature for 20 min. The reaction mixture was cooled to -78°C (dry ice/acetone bath), and 1-(2-bromo-4-chloro-phenyl)-2,2,2-trifluoro-ethanone (40 g, 139 mmol) in THF (400 ml) was added dropwise over 2 hours. The reaction mixture was allowed to warm to -36°C, and was stirred at that temperature for 24 hours, and further stirred at -32 °C for another 24h. 3N NaOH (250 ml) was added, and the cooling bath was replaced by ice-water bath. Then 30 % hydrogen peroxide in water (250 ml) was added dropwise over 30 minutes. The ice water bath was removed, and the mixture was stirred at room temperature for 4 hours. The organic layer was separated, concentrated and re-dissolved in ether (200 ml). The aqueous layer was extracted with ether (2 x 200 ml). The combined organic layers were washed with IN aq. NaOH (4 x 100 ml), brine, and dried over sodium sulfate. Removal of solvent gave crude product which was purified by column chromatography using 2 to 5% ethyl acetate in hexane as solvent to give desired alcohol 36.2 g (90 %, e.e. >95%). The alcohol (36.2 g) was crystallized from hexane (80 ml) to obtain R-l-(2-bromo-4-chloro-phenyl)-2,2,2-trifluoro-ethanol 28.2 g (70 %; 99-100 % e.e.). !H-NMR (400 MHz, CDCIs) δ (ppm) 5.48 (m, 1H), 7.40 (d, 1H), 7.61 (d, 2H).
Step 3: Synthesis of R-l-[4-chloro-2-(3-methyl-pyrazol-l-yl)-phenyll-2.2.2-trifluoro-ethanol. R-l-(2-bromo-4-chloro-phenyl)-2,2,2-trifluoro-ethanol (15.65 g, 54.06 mmol), 3-methylpyrazole (5.33 g, 65 mmol), Cul (2.06 g, 10.8 mmol), 2CO3 (15.7 g, 113.5 mmol), (lR,2R)-N,N’-dimethyl-cyclohexane-l,2-diamine (1.54 g, 10.8 mmol) and toluene (80 ml) were combined in a 250 ml pressure tube and heated to 130°C (oil bath temperature) for 12 hours. The reaction mixture was diluted with ethyl acetate and washed with H2O (4 x 100 ml), brine, and dried over sodium sulfate. Removal of solvent gave a crude product, which was purified by ISCO column chromatography using 5-10 % ethyl acetate in hexane as solvent to get R-l-[4-chloro-2-(3-methyl-pyrazol-l-yl)-phenyl]-2,2,2-trifluoro-ethanol (13.5 g; 86 %). i-H-NMR (400 MHz, CDC ): δ (ppm) 2.30(s, 3H), 4.90(m, 1H), 6.20(s, 1H), 6.84(d, 1H), 7.20(s, 1H), 7.30(d, 1H), 7.50(d, 1H).
Step 4: Synthesis of (S)-2-Amino-3- 4-(2-amino-6-fR-l-[4-chloro-2-(3-methyl-pyrazol-l-yl)-phenyll^^^-trifluoro-ethoxyl-pyrimidin^-yll-phenvD-propionic acid ethyl ester. R-l-[4-chloro-2-(3-methyl-pyrazol-l-yl)-phenyl]-2,2,2-trifluoro-ethanol (17.78 g, 61.17 mmol), (S)-3-[4-(2-amino-6-chloro-pyrimidine-4-yl)-phenyl]-2-tert-butoxycarbonylamino-propionic acid (20.03 g, 51 mmol), 1,4-dioxane (250 ml), and CS2CO3 (79.5 g, 244 mmol) were combined in a 3-necked 500 ml RB flask and heated to 100°C (oil bath temperature) for 12-24 hours. The progress of reaction was monitored by LCMS. After the completion of the reaction, the mixture was cooled to 60°C, and water (250 ml) and THF (400 ml) were added. The organic layer was separated and washed with brine (150 ml). The solvent was removed to give crude BOC protected product, which was taken in THF (400 ml), 3N HCI (200 ml). The mixture was heated at 35-40 °C for 12 hours. THF was removed in vacuo. The remaining aqueous layer was extracted with isopropyl acetate (2x 100 ml) and concentrated separately to recover the unreacted alcohol (3.5 g). Traces of remaining organic solvent were removed from the aqueous fraction under vacuum.
To a 1L beaker equipped with a temperature controller and pH meter, was added H3PO4 (40 ml, 85 % in water) and water (300 ml) then 50 % NaOH in water to adjust pH to 6.15. The temperature was raised to 58 °C and the above acidic aqueous solution was added dropwise into the buffer with simultaneous addition of 50 % NaOH solution in water so that the pH was maintained between 6.1 to 6.3. Upon completion of addition, precipitated solid was filtered and washed with hot water (50-60°C) (2 x 200 ml) and dried to give crude (S)-2-amino-3-[4-(2-amino-6-[R-l-[4-chloro-2-(3-methyl-pyrazol-l-yl)-phenyl]-2,2,2-trifluoro-ethoxy}-pyrimidin-4-yl)-phenyl}^ propionic acid (26.8 g; 95 %). LCMS and HPLC analysis indicated the compound purity was about 96-97 %.
To anhydrous ethanol (400 ml) was added SOC (22 ml, 306 mmol) dropwise at 0-5°C.
Crude acid (26.8 ) from the above reaction was added. The ice water bath was removed, and the reaction mixture was heated at 40-45°C for 6-12 hours. After the reaction was completed, ethanol was removed in vacuo. To the residue was added ice water (300 ml), and extracted with isopropyl acetate (2 x 100 ml). The aqueous solution was neutralized with saturated Na2C03 to adjust the pH to 6.5. The solution was extracted with ethyl acetate (2 x 300 ml). The combined ethyl acetate layer was washed with brine and concentrated to give 24 g of crude ester (HPLC purity of 96-97 %). The crude ester was then purified by ISCO column chromatography using 5 % ethanol in DCM as solvent to give (S)-2-amino-3-[4-(2-amino-6-{R-l-[4-chloro-2-(3-methyl-pyrazol-l-yl)-phenyl]-2,2,2-trifluoro-ethoxy}-pyrimidin-4-yl)-phenyl}-propionic acid ethyl ester (20.5g; 70 %; HPLC purity of 98 %). LCMS M+l = 575. !H-NMR (400 MHz, CDsOD): δ (ppm) 1.10 (t, 3H), 2.25 (s, 3H), 2.85 (m, 2H), 3.65 (m, IH), 4.00 (q, 2H), 6.35 (s, IH), 6.60 (s, IH), 6.90 (m, IH), 7.18 (d, 2H), 7.45 (m, 2H), 7.70 (d, IH), 7.85 (m, 3H).
SYNTHESIS OF INTERMEDIATE
WO 2009048864
https://google.com/patents/WO2009048864A1?cl=en
6.15. Preparation of 6SV3-(4-(2-Amino-6-chloropyrimidin-4-yl)phenyl)-2- (fert-butoxycarbonylamino)propanoic Acid Using the Lithium Salt of (S)-2-(te^-butoxycarbonylamino)-3-(4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)propanoic Acid
During preparation of compound 7, the isolation of the free acid can be optionally omitted. Thus, an aqueous solution of the lithium salt of compound 7 in 100 ml water, prepared from 5.0 g of Boc-Tyr-OMe (4, 17 mmol), was mixed 2-amino-4,6- dichloropyrimidine (3.3 g, 1.2 eq), potassium bicarbonate (5.0 g, 3 eq), bis(triphenylphosphine)palladium(II) dichloride (60 mg, 0.5 mol%), and 100 ml ethanol. The resulting mixture was heated at 700C for 5 hours. Additional 2-amino-4,6- dichloropyrimidine (1.1 g, 0.4 eq) was added and heating was continued at 7O0C for an additional 2 hours. HPLC analysis showed about 94% conversion. Upon cooling and filtration, the filtrate was analyzed by HPLC against a standard solution of compound 8. The assay indicated 3.9 g compound 8 was contained in the solution (59% yield from compound 4).
6.16. Alternative Procedure for Preparation of (S)-3-(4-f2-Amino-6- chloropyrimidin-4-yl)phenyl)-2-(fe^-butoxycarbonylamino)propanoic Acid Using Potassium Carbonate as Base
The boronic acid compound 11 (Ryscor Science, Inc., North Carolina, 1.0 g, 4.8 mmol) and potassium carbonate (1.32 g, 2 eq) were mixed in aqueous ethanol (15 ml ethanol and 8 ml water). Di-ter£-butyldicarbonate (1.25 g, 1.2 eq) was added in one portion. After 30 minutes agitation at room temperature, HPLC analysis showed complete consumption of the starting compound 11. The 2-amino-4,6- dichloropyrimidine (1.18 g, 1.5 eq) and the catalyst bis(triphenylphosphine)palladium(II) dichloride (34 mg, 1 mol%) were added and the resulting mixture was heated at 65-700C for 3 hours. HPLC analysis showed complete consumption of compound 12. After concentration and filtration, HPLC analysis of the resulting aqueous solution against a standard solution of compound 8 showed 1.26 g compound 8 (67% yield).
6.17. Alternative procedure for preparation of (5)-3-(4-(2-Amino-6-
The boronic acid compound 11 (10 g, 48 mmol) and potassium bicarbonate (14.4 g, 3 eq) were mixed in aqueous ethanol (250 ml ethanol and 50 ml water). Oi-tert- butyldicarbonate (12.5 g, 1.2 eq) was added in one portion. HPLC analysis indicated that the reaction was not complete after overnight stirring at room temperature. Potassium carbonate (6.6 g, 1.0 eq) and additional di-te/t-butyldicarbonate (3.1 g, 0.3 eq) were added. After 2.5 hours agitation at room temperature, HPLC analysis showed complete consumption of the starting compound 11. The 2-amino-4,6-dichloropyrimidine (11.8 g, 1.5 eq) and the catalyst bis(triphenylphosphine)-palladium(II) dichloride (0.34 g, 1 mol%” were added and the resulting mixture was heated at 75-8O0C for 2 hours. HPLC analysis showed complete consumption of compound 12. The mixture was concentrated under reduced pressure and filtered. The filtrate was washed with ethyl acetate (200 ml) and diluted with 3 : 1 THF/MTBE (120 ml). This mixture was acidified to pH about 2.4 by 6 N hydrochloric acid. The organic layer was washed with brine and concentrated under reduced pressure. The residue was precipitated in isopropanol, filtered, and dried at 500C under vacuum to give compound 8 as an off-white solid (9.0 g, 48% yield). Purity: 92.9% by HPLC analysis. Concentration of the mother liquor yielded and additional 2.2 g off-white powder (12% yield). Purity: 93.6% by HPLC analysis
PATENT
https://www.google.com/patents/WO2013059146A1?cl=en
This invention is directed to solid pharmaceutical dosage forms in which an active pharmaceutical ingredient (API) is (S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-l-(4-chloro-2-(3- methyl-lH-pyrazol-l-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate
(telotristat):
or a pharmaceutically acceptable salt thereof. The compound, its salts and crystalline forms can be obtained by methods known in the art. See, e.g., U.S. patent no. 7,709,493.
PATENT
http://www.google.co.in/patents/WO2008073933A2?cl=en
6.19. Synthesis of (S)-2-Amino-3-r4-q-amino-6-{R-l-r4-chloro-2-(3-methyl- Pyrazol-l-yl)-phenyll-2,2,2-trifluoro-ethoxy}-pyrimidin-4-yl)-phenyll- propionic acid ethyl ester
The title compound was prepared stepwise, as described below: Step 1 : Synthesis of l-(2-bromo-4-chloro-phenyl)-2,2,2-trifluoro-ethanone. To a 500 ml 2 necked RB flask containing anhydrous methanol (300 ml) was added thionyl chloride (29.2 ml, 400 mmol) dropwise at 0-50C (ice water bath) over 10 min. The ice water bath was removed, and 2-bromo-4-chloro-benzoic acid (25 g, 106 mmol) was added. The mixture was heated to mild reflux for 12h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was concentrated. Crude product was dissolved in dichloromethane (DCM, 250 ml), washed with water (50 ml), sat. aq. NaHCO3 (50 ml), brine (50 ml), dried over sodium sulfate, and concentrated to give the 2- bromo-4-chloro-benzoic acid methyl ester (26 g, 99 %), which was directly used in the following step.
2-Bromo-4-chloro-benzoic acid methyl ester (12.4 g, 50 mmol) in toluene (200 ml) was cooled to -700C, and trifluoromethyl trimethyl silane (13 ml, 70 mmol) was added. Tetrabutylamonium fluoride (IM, 2.5 ml) was added dropwise, and the mixture was allowed to warm to room temperature over 4h, after which it was stirred for 1Oh at room temperature. The reaction mixture was concentrated to give the crude [l-(2-bromo-4-chloro-phenyl)-2,2,2- trifluoro-l-methoxy-ethoxy]-trimethyl-silane. The crude intermediate was dissolved in methanol (100 ml) and 6N HCl (100 ml) was added. The mixture was kept at 45-500C for 12h. Methanol was removed, and the crude was extracted with dichloromethane (200 ml). The combined DCM layer was washed with water (50 ml), NaHCO3 (50 ml), brine (50 ml), and dried over sodium sulfate. Removal of solvent gave a crude product, which was purified by ISCO column chromatography, using 1-2% ethyl acetate in hexane as solvent, to afford 1- (2-bromo-4-chloro-phenyl)-2,2,2-trifluoro-ethanone (10 g, 70%). 1H-NMR (300 MHz, CDCl3): δ (ppm) 7.50 (d,lH), 7.65(d,lH), 7.80(s,lH).
Step 2: Synthesis of R-l-(2-bromo-4-chloro-phenyl)-2,2,2-trifluoro-ethanol. To catechol borane (IM in THF 280 ml, 280 mmol) in a 2L 3-necked RB flask was added S-2- methyl-CBS oxazaborolidine (7.76 g, 28 mmol) under nitrogen, and the resulting mixture was stirred at room temperature for 20 min. The reaction mixture was cooled to -78°C (dry ice/acetone bath), and l-(2-bromo-4-chloro-phenyl)-2,2,2-trifluoro-ethanone (40 g, 139 mmol) in THF (400 ml) was added dropwise over 2h. The reaction mixture was allowed to warm to -36°C, and was stirred at that temperature for 24 h, and further stirred at -32°C for another 24h. 3N NaOH (250 ml) was added, and the cooling bath was replaced by ice-water bath. Then 30 % hydrogen peroxide in water (250 ml) was added dropwise over 30 minutes. The ice water bath was removed, and the mixture was stirred at room temperature for 4h. The organic layer was separated, concentrated and re-dissolved in ether (200 ml). The aqueous layer was extracted with ether (2 x 200 ml). The combined organic layers were washed with IN aq. NaOH (4 x 100 ml), brine, and dried over sodium sulfate. Removal of solvent gave crude product which was purified by column chromatography using 2 to 5% ethyl acetate in hexane as solvent to give desired alcohol 36.2 g (90 %, e.e. >95%). The alcohol (36.2 g) was crystallized from hexane (80 ml) to obtain R-l-(2-bromo-4-chloro- phenyl)-2,2,2-trifiuoro-ethanol 28.2 g (70 %; 99-100 % e.e.). 1H-NMR (400 MHz, CDCl3) δ (ppm) 5.48 (m, IH), 7.40 (d, IH), 7.61 (d, 2H). Step 3: Synthesis of R-l-r4-chloro-2-(3-methyl-pyrazol-l-vπ-phenyl1-2.2.2-trifluoro- ethanol. R-l-(2-bromo-4-chloro-phenyl)-2,2,2-trifluoro-ethanol (15.65g, 54.06 mmol), 3- methylpyrazole (5.33 g, 65 mmol), CuI (2.06 g, 10.8 mmol), K2CO3 (15.7 g, 113.5 mmol), (lR,2R)-N,N’-dimethyl-cyclohexane-l,2-diamine (1.54 g, 10.8 mmol) and toluene (80 ml) were combined in a 250 ml pressure tube and heated to 1300C (oil bath temperature) for 12 h. The reaction mixture was diluted with ethyl acetate and washed with H2O (4 x 100 ml), brine, and dried over sodium sulfate. Removal of solvent gave a crude product, which was purified by ISCO column chromatography using 5-10 % ethyl acetate in hexane as solvent to get R-I- [4-chloro-2-(3-methyl-pyrazol-l-yl)-phenyl]-2,2,2-trifluoro-ethanol (13.5 g; 86 %). 1H-NMR (400 MHz, CDCl3): δ (ppm) 2.30(s, 3H), 4.90(m, IH), 6.20(s, IH), 6.84(d, IH), 7.20(s, IH), 7.30(d, IH), 7.50(d, IH).
Step 4: Synthesis of (S)-2-Amino-3- r4-(2-amino-6- (R-I- r4-chloro-2-(3-methyl- pyrazol- 1 -ylVphenyl~|-2,2.,2-trifluoro-ethoxy| -pyrimidin-4-yl)-phenyU -propionic acid ethyl ester. R-l-[4-chloro-2-(3-methyl-pyrazol-l-yl)-phenyl]-2,2,2-trifluoro-ethanol (17.78 g, 61.17 mmol), (S)-3-[4-(2-amino-6-chloro-pyrimidine-4-yl)-phenyl]-2-tert- butoxycarbonylamino-propionic acid (20.03 g, 51 mmol), 1,4-dioxane (250 ml), and Cs2CO3 (79.5 g, 244 mmol) were combined in a 3-necked 500 ml RB flask and heated to 1000C (oil bath temperature) for 12-24 h. The progress of reaction was monitored by LCMS. After the completion of the reaction, the mixture was cooled to 600C, and water (250 ml) and THF (400 ml) were added. The organic layer was separated and washed with brine (150 ml). The solvent was removed to give crude BOC protected product, which was taken in THF (400 ml), 3N HCl (200 ml). The mixture was heated at 35-400C for 12h. THF was removed in vacuo. The remaining aqueous layer was extracted with isopropyl acetate (2x 100 ml) and concentrated separately to recover the unreacted alcohol (3.5 g). Traces of remaining organic solvent were removed from the aqueous fraction under vacuum.
To a IL beaker equipped with a temperature controller and pH meter, was added H3PO4 (40 ml, 85 % in water) and water (300 ml) then 50 % NaOH in water to adjust pH to 6.15. The temperature was raised to 58°C and the above acidic aqueous solution was added dropwise into the buffer with simultaneous addition of 50 % NaOH solution in water so that the pH was maintained between 6.1 to 6.3. Upon completion of addition, precipitated solid was filtered and washed with hot water (50-600C) (2 x 200 ml) and dried to give crude (S)-2- amino-3-[4-(2-amino-6-{R-l-[4-chloro-2-(3-methyl-pyrazol-l-yl)-phenyl]-2,2,2-trifluoro- ethoxy}-pyrimidin-4-yl)-phenyl} -propionic acid (26.8 g; 95 %). LCMS and HPLC analysis indicated the compound purity was about 96-97 %. To anhydrous ethanol (400 ml) was added SOCl2 (22 ml, 306 mmol) dropwise at 0-
5°C. Crude acid (26.8 g ) from the above reaction was added. The ice water bath was removed, and the reaction mixture was heated at 40-450C for 6-12h. After the reaction was completed, ethanol was removed in vacuo. To the residue was added ice water (300 ml), and extracted with isopropyl acetate (2 x 100 ml). The aqueous solution was neutralized with saturated Na2CO3 to adjust the pH to 6.5. The solution was extracted with ethyl acetate (2 x 300 ml). The combined ethyl acetate layer was washed with brine and concentrated to give 24 g of crude ester (HPLC purity of 96-97 %). The crude ester was then purified by ISCO column chromatography using 5 % ethanol in DCM as solvent to give (S)-2-amino-3-[4-(2- amino-6- (R- 1 -[4-chloro-2-(3-methyl-pyrazol- 1 -yl)-phenyl]-2,2,2-trifluoro-ethoxy} – pyrimidin-4-yl)-phenyl} -propionic acid ethyl ester (20.5g; 70 %; HPLC purity of 98 %). LCMS M+l = 575. 1H-NMR (400 MHz, CD3OD): δ (ppm) 1.10 (t, 3H), 2.25 (s, 3H), 2.85 (m, 2H), 3.65 (m, IH), 4.00 (q, 2H), 6.35 (s, IH), 6.60 (s, IH), 6.90 (m, IH), 7.18 (d, 2H), 7.45 (m, 2H), 7.70 (d, IH), 7.85 (m, 3H).
PATENT
WO 2011056916
https://www.google.com/patents/WO2011056916A1?cl=en
PATENT
WO 2010065333
CLIP,……..PL CHECK ERROR
REFERENCES
Kulke, M.H.; Hoersch, D.; Caplin, M.E.; et al.
Telotristat ethyl, a tryptophan hydroxylase inhibitor for the treatment of carcinoid syndrome
J Clin Oncol 2017, 35(1): 14
| WO2010056992A1 * | Nov 13, 2009 | May 20, 2010 | The Trustees Of Columbia University In The City Of New York | Methods of preventing and treating low bone mass diseases |
| US7709493 | May 20, 2009 | May 4, 2010 | Lexicon Pharmaceuticals, Inc. | 4-phenyl-6-(2,2,2-trifluoro-1-phenylethoxy)pyrimidine-based compounds and methods of their use |
| US20090088447 * | Sep 25, 2008 | Apr 2, 2009 | Bednarz Mark S | Solid forms of (s)-ethyl 2-amino-3-(4-(2-amino-6-((r)-1-(4-chloro-2-(3-methyl-1h-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-pyrimidin-4-yl)phenyl)propanoate and methods of their use |
| Citing Patent | Filing date | Publication date | Applicant | Title |
|---|---|---|---|---|
| US9199994 | Sep 5, 2014 | Dec 1, 2015 | Karos Pharmaceuticals, Inc. | Spirocyclic compounds as tryptophan hydroxylase inhibitors |
| US9512122 | Sep 1, 2015 | Dec 6, 2016 | Karos Pharmaceuticals, Inc. | Spirocyclic compounds as tryptophan hydroxylase inhibitors |
///////////telotristat ethyl, fast track designation,priority review,orphan drug designation, Xermelo , Woodlands, Texas-based, Lexicon Pharmaceuticals, Inc, fda 2017, LX 1606, LX 1032
O=C(OCC)[C@@H](N)Cc1ccc(cc1)c2cc(nc(N)n2)O[C@H](c3ccc(Cl)cc3n4ccc(C)n4)C(F)(F)F
O=C(OCC)[C@@H](N)CC1=CC=C(C2=NC(N)=NC(O[C@H](C3=CC=C(Cl)C=C3N4N=C(C)C=C4)C(F)(F)F)=C2)C=C1.O=C(O)CNC(C5=CC=CC=C5)=O
Tradipitant, традипитант , تراديبيتانت , 曲地匹坦 ,
Tradipitant
VLY-686, LY686017
- Molecular Formula C28H16ClF6N5O
- Average mass 587.903 Da
PHASE 2, Gastroparesis; Pruritus
FDA 2025, APPROVALS 2025, 12/30/2025, To treat vomiting associated with motion
pyridine-containing NK-1 receptor antagonist ie tradipitant, useful for treating anxiety, pruritus and alcoholism.
Vanda Pharmaceuticals, under license from Eli Lilly, was developing tradipitant, a NK1 antagonist, for treating anxiety disorder, pruritus and alcohol dependence. The company was also investigating the drug for treating gastroparesis. In February 2017, tradipitant was reported to be in phase 2 clinical development for treating anxiety and pruritus.
- Originator Eli Lilly
- Developer Eli Lilly; National Institute on Alcohol Abuse and Alcoholism; Vanda Pharmaceuticals
- Class Antipruritics; Anxiolytics; Chlorobenzenes; Pyridines; Small molecules; Triazoles
- Mechanism of Action Neurokinin 1 receptor antagonists; Substance P inhibitors
Highest Development Phases
- Phase II Gastroparesis; Pruritus
- Discontinued Alcoholism; Social phobia
- The drug had been in phase II clinical trials at Lilly and the National Institute on Alcohol Abuse and Alcoholism for the treatment of alcoholism; however, no recent development has been reported for this research.
- A phase II clinical trial for the treatment of social phobia has been completed by Lilly.
PATENT WO 2003091226
SYNTHESIS
Condensation of 2-chloropyridine with thiophenol in the presence of K2CO3 in DMF at 110ºC yields sulfide intermediate,
which is then oxidized by means of NaOCl in AcOH to give 2-(benzenesulfonyl)pyridine.
This is treated with (iPr)2NH and n-BuLi in THF at -60 to -70°C and subsequently couples with 2-chlorobenzaldehyde in THF at -60 to -70°C to furnish (2-(phenylsulfonyl)pyridin-3-yl)-(2-chlorophenyl)methanone.
Ketone couples with the enolate of 4-acetylpyridine (formed by treating 4-acetylpyridine (VII) with t-BuOK in DMSO) in the presence of LiOH in DMSO and subsequently is treated with PhCOOH in iPrOAc to give rise to pyridine benzoate derivative.
This finally couples with 1-azidomethyl-3,5-bistrifluoromethylbenzene (obtained by treating 3,5-bis(trifluoromethyl)benzylchloride with NaN3 ini DMSO) in the presence of K2CO3 in t-BuOH to afford the title compound Tradipitant.
Tradipitant (VLY-686 or LY686017) is an experimental drug that is a neurokinin 1 antagonist. It works by blocking substance P, a small signaling molecule. Originally, this compound was owned by Eli Lilly and named LY686017. VLY-686 was purchased by Vanda Pharmaceuticals from Eli Lilly and Company in 2012.[1] Vanda Pharmaceuticals is a U.S. pharmaceutical company that as of November 2015 only has 3 drugs in their product pipeline: tasimelteon, VLY-686, and iloperidone.[2]
Tachykinins are a family of peptides that are widely distributed in both the central and peripheral nervous systems. These peptides exert a number of biological effects through actions at tachykinin receptors. To date, three such receptors have been characterized, including the NK-1 , NK-2, and NK-3 subtypes of tachykinin receptor.
The role of the NK-1 receptor subtype in numerous disorders of the central nervous system and the periphery has been thoroughly demonstrated in the art. For instance, NK-1 receptors are believed to play a role in depression, anxiety, and central regulation of various autonomic, as well as cardiovascular and respiratory functions. NK- 1 receptors in the spinal cord are believed to play a role in pain transmission, especially the pain associated with migraine and arthritis. In the periphery, NK-1 receptor activation has been implicated in numerous disorders, including various inflammatory disorders, asthma, and disorders of the gastrointestinal and genitourinary tract.
There is an increasingly wide recognition that selective NK-1 receptor antagonists would prove useful in the treatment of many diseases of the central nervous system and the periphery. While many of these disorders are being treated by new medicines, there are still many shortcomings associated with existing treatments. For example, the newest class of anti-depressants, selective serotonin reuptake inhibitors (SSRIs), are increasingly prescribed for the treatment of depression; however, SSRIs have numerous side effects, including nausea, insomnia, anxiety, and sexual dysfunction. This could significantly affect patient compliance rate. As another example, current treatments for chemotherapy- induced nausea and emesis, such as the 5-HT3receptor antagonists, are ineffective in managing delayed emesis. The development of NK-1 receptor antagonists will therefore greatly enhance the ability to treat such disorders more effectively. Thus, the present invention provides a class of potent, non-peptide NK-1 receptor antagonists, compositions comprising these compounds, and methods of using the compounds.
Indications
Pruritus
It is being investigated by Vanda Pharmaceuticals for chronic pruritus (itchiness) in atopic dermatitis. In March 2015, Vanda announced positive results from a Phase II proof of concept study.[3] A proof of concept study is done in early stage clinical trials after there have been promising preclinical results. It provides preliminary evidence that the drug is active in humans and has some efficacy.[4]
Alcoholism
VLY-686 reduced alcohol craving in recently detoxified alcoholic patients as measured by the Alcohol Urge Questionnaire.[5] In a placebo controlled clinical trial of recently detoxified alcoholic patients, VLY-686 significantly reduced alcohol craving as measured by the Alcohol Urge Questionnaire. It also reduced the cortisol increase seen after a stress test compared to placebo. The dose given was 50 mg per day.
Social anxiety disorder
In a 12-week randomized trial of LY68017 in 189 patients with social anxiety disorder, 50 mg of LY68017 did not provide any statistically significant improvement over placebo.[6]
PATENT
WO03091226,
https://www.google.com/patents/WO2003091226A1?cl=en
PATENT
The compound {2-[l-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-lH-[l,2,3]triazol-4-yl]- pyridin-3-yl}-(2-chlorophenyl)-methanone, depicted below as the compound of Formula I, was first described in PCT published application WO2003/091226.
(I)
Because the compound of Formula I is an antagonist of the NK-I subtype of tachykinin receptor, it is useful for the treatment of disorders associated with an excess of tachykinins. Such disorders include depression, including major depressive disorder; anxiety, including generalized anxiety disorder, panic disorder, obsessive compulsive disorder, and social phobia or social anxiety disorder; schizophrenia and other psychotic disorders, including bipolar disorder; neurodegenerative disorders such as dementia, including senile dementia of the Alzheimer’s type or Alzheimer’s disease; disorders of bladder function such as bladder detrusor hyper-reflexia and incontinence, including urge incontinence; emesis, including chemotherapy-induced nausea and acute or delayed emesis; pain or nociception; disorders associated with blood pressure, such as hypertension; disorders of blood flow caused by vasodilation and vasospastic diseases, such as angina, migraine, and Reynaud’s disease; hot flushes; acute and chronic obstructive airway diseases such as adult respiratory distress syndrome, bronchopneumonia, bronchospasm, chronic bronchitis, drivercough, and asthma; inflammatory diseases such as inflammatory bowel disease; gastrointestinal disorders or diseases associated with the neuronal control of viscera such as ulcerative colitis, Crohn’s disease, functional dyspepsia, and irritable bowel syndrome (including constipation-predominant, diarrhea- -?-
predominant, and mixed irritable bowel syndrome); and cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria, and other eczematoid dermatitis.
In PCT published application, WO2005/042515, novel crystalline forms of the compound of Formula I, identified as Form IV and Form V, are identified. Also described in WO2005/042515 is a process for preparation of the compound of Formula I, comprising reacting (2-chlorophenyl)-[2-(2- hydroxy-2-pyridin-4-yl-vinyl)pyridin-3-yl]methanone or a phosphate salt thereof with l-azidomethyl-3,5- bistrifluoromethylbenzene in the presence of a suitable base and a solvent. Use of this procedure results in several shortcomings for synthesis on a commercial scale. For example, use of the solvent DMSO, with (2- chlorophenyl)-[2-(2-hydroxy-2-pyridin-4-yl-vinyl)pyridin-3-yl]methanone phosphate, requires a complex work-up that has a propensity to emulsify. This process also requires extraction with CH2CI2, the use of which is discouraged due to its potential as an occupational carcinogen, as well as the use of MgSC>4 and acid-washed carbon, which can generate large volumes of waste on a commercial scale. Conducting the reaction with (2-chlorophenyl)-[2-(2-hydroxy-2-pyridin-4-yl-vinyl)pyridin-3-yl]methanone in isopropyl alcohol, as also described in WO2005/042515, is also undesirable due to the need to incorporate a free base step. Furthermore, variable levels of residual l-azidomethyl-3,5-bistrifluoromethylbenzene, a known mutagen, are obtained from use of the procedures described in WO2005/042515.
An improved process for preparing the compound of Formula I would control the level of 1- azidomethyl-3,5-bistrifluoromethylbenzene impurity, and improve the yield. We have discovered that use of the novel salt, (2-chlorophenyl)-[2-(2-hydroxy-2-pyridin-4-yl-vinyl)pyridin-3-yl]methanone benzoate, as well as use of tert-butanol as the reaction solvent, improves reaction times and final yield, and decreases impurities in the final product. In addition, a novel process for the preparation of (2-chlorophenyl)- [2-(2- hydroxy-2-pyridin-4-yl-vinyl)pyridin-3-yl]methanone benzoate, in which a pre-formed enolate of 4-acetyl pyridine is added to (2-phenylsulfonyl-pyridine-3-yl)-(2-chlorophenyl)methanone, results in an overall improved yield and improved purity, and is useful on a commercial scale.
EXAMPLES
Example 1 {2-[l-(3,5-bistrifluoromethylbenzyl)-5-pyridin-4-yl-lH-[l,2,3]triazol-4-yl]-pyridin-3-yl}-(2-chlorophenyl)- methanone (Form IV)
Suspend (2-chlorophenyl)-[2-(2-hydroxy-2-pyridin-4-yl-vinyl)pyridin-3-yl] methanone benzoate (204.7 g; 1.04 equiv; 445 mmoles) in t-butanol (614 mL) and treat the slurry with potassium carbonate (124.2 g; 898.6 mmoles). Heat to 7O0C with mechanical stirring for 1 hour. Add l-azidomethyl-3,5- bistrifluoromethylbenzene (115.6 g; 1.00 equiv; 429.4 mmoles) in a single portion, then heat the mixture to reflux. A circulating bath is used to maintain a condenser temperature of 3O0C. After 18 hours at reflux, HPLC reveals that the reaction is complete (<2% l-azidomethyl-3,5-bistrifluoromethylbenzene remaining). The mixture is cooled to 7O0C, isopropanol (818 mL) is added, then the mixture is stirred at 7O0C for 1 hour. The mixture is filtered, and the waste filter cake is rinsed with isopropanol (409 mL). The combined filtrate and washes are transferred to a reactor, and the mechanically stirred contents are heated to 7O0C. To the dark purple solution, water (1.84 L) is added slowly over 35 minutes. The solution is cooled to 6O0C, then stirred for 1 hour, during which time a thin precipitate forms. The mixture is slowly cooled to RT, then the solid is filtered, washed with 1 : 1 isopropanol/water (614 mL), subsequently washed with isopropanol (410 mL), then dried in vacuo at 450C to produce 200.3 g of crude {2-[l-(3,5- bistrifluoromethylbenzyl)-5-pyridin-4-yl-lH-[l,2,3]triazol-4-yl]-pyridin-3-yl}-(2-chlorophenyl)-methanone as a white solid. Crude {2-[l-(3,5-bistrifluoromethylbenzyl)-5-pyridin-4-yl-lH-[l,2,3]triazol-4-yl]-pyridin- 3-yl}-(2-chlorophenyl)-methanone (200.3 g) and isopropyl acetate (600 mL) are charged to a 5L 3-neck jacketed flask, then the contents heated to 750C. After dissolution is achieved, the vessel contents are cooled to 550C, then the solution polish filtered through a 5 micron filter, and the filter rinsed with a volume of isopropyl acetate (200 mL). After the polish filtration operation is complete, the filtrates are combined, and the vessel contents are adjusted to 5O0C. After stirring for at least 15 minutes at 5O0C, 0.21 grams of {2-[l-(3,5-bistrifluoromethylbenzyl)-5-pyridin-4-yl-lH-[l,2,3]triazol-4-yl]-pyridin-3-yl}-(2- chlorophenyl)-methanone Form IV seed (d90 = 40 microns) is added, and the mixture stirred at 5O0C for at least 2 h. Heptanes (1.90 L) are then added over at least 2 h. After the heptanes addition is completed, the slurry is stirred for an hour at 5O0C, cooled to 230C at a rate less then 2O0C per hour, then aged at 230C for an hour prior to isolation. The mixture is then filtered in portions through the bottom outlet valve in the reactor into a 600 mL filter. The resulting wetcake is washed portionwise with a solution containing heptanes (420 mL) and isopropyl acetate (180 mL), which is passed directly through the 5L crystallization vessel. The wetcake is blown dry for 5 minutes with nitrogen, then transferred to a 500 mL plastic bottle. The product is dried at 5O0C for 4 h. to produce 190.3g of pure {2-[l-(3,5- bistrifluoromethylbenzyl)-5-pyridin-4-yl-lH-[l,2,3]triazol-4-yl]-pyridin-3-yl}-(2-chlorophenyl)- methanone, Form IV in 75.0% yield with 100% purity, as determined by HPLC analysis. Particle size is reduced via pin or jet mill. 1H NMR (400 MHz, CDCl3): 5.46 (s, 2H); 7.19 (m, 5H); 7.36 (dd, IH, J = 4.9, 7.8); 7.45 (s, 2H); 7.59 (m, IH); 7.83 (s, IH); 7.93 (dd, IH, J = 1.5, 7.8); 8.56 (dd, IH, J= 1.5, 4.9); 8.70 (d, 2H, J= 5.9).
Preparation 1-A (2-chlorophenyl)-[2-(2-hydroxy-2-pyridin-4-yl-vinyl)pyridin-3-yl]methanone benzoate Charge powdered KOfBu (221.1 g, 1.93 moles, 1.40 eq.) to Reactor A, then charge DMSO (2 L) at
250C over 10 min. The KOfBu/DMSO solution is stirred for 30 min at 230C, then a solution of 4-acetyl pyridine (92 mL, 2.07 moles, 1.50 eq) in DMSO (250 mL) is prepared in reactor B. The contents of reactor B are added to Reactor A over 10 minutes, then the Reactor A enolate solution is stirred at 230C for Ih. In a separate 12-L flask (Reactor C), solid LiOH (84.26 g, 3.45 moles, 2.0 eq) is poured into a mixture of (2- phenylsulfonyl-pyridin-3-yl)-(2-chlorophenyl)methanone (500.0 g, 1.34 moles, 1.0 eq) and DMSO (2L), with stirring, at 230C. The enolate solution in reactor A is then added to Reactor C over a period of at least 15 minutes, and the red suspension warmed to 4O0C. The reaction is stirred for 3h, after which time HPLC analysis reveals less than 2% (2-phenylsulfonyl-pyridin-3-yl)-(2-chlorophenyl)methanone. Toluene (2.5 L) is charged, and the reactor temperature cooled to 3O0C. The mixture is quenched by addition of glacial acetic acid (316 mL, 5.52 moles, 4.0 eq), followed by 10 % NaCl (2.5 L). The biphasic mixture is transferred to a 22-L bottom-outlet Morton flask, and the aqueous layer is removed. The aqueous layer is then extracted with toluene (750 mL). The combined organic layers are washed with 10 % NaCl (750 mL), then concentrated to 4 volumes and transferred to a 12-L Morton flask and rinsed with isopropyl acetate (4 vol, 2 L). The opaque amber solution is warmed to 75 degrees to 750C over 40 min. Benzoic acid (171. Ig, 1.34 moles, 1.0 eq) is dissolved in hot isopropyl acetate (1.5 L), and charged to the crude free base solution over at least 30 min. The crude solution containing benzoate salt is stirred for 0.5 h at 750C then cooled to 23 0C. When solids are first observed, the cooling is stopped and the mixture is aged for an hour at the temperature at which crystals are first observed. Alternatively, if seed crystal is available, the mixture may be seeded with (2-chlorophenyl)-[2-(2-hydroxy-2-pyridin-4-yl-vinyl)pyridin-3-yl]methanone benzoate (2.25g) at 750C, followed by stirring for 0.5 h at 750C, then cooling to 230C over at least 1.5 h. The mixture is then cooled to <5 0C, then filtered through paper on a 24cm single-plate filter. The filtercake is then rinsed with cold z‘-PrOAc (750 mL) to produce granular crystals of bright orange-red color. The wet solid is dried at 550C to produce 527.3 g (83% yield) with 99.9% purity. (2-chlorophenyl)-[2-(2-hydroxy-2- pyridin-4-yl-vinyl)pyridin-3-yl]methanone benzoate. Anal. Calcd. for C26Hi9N2ClO4: C, 68.05; H, 4.17; N, 7.13. Found: C, 67.89; H, 4.15; N 6.05. HRMS: calcd for C19H13ClN2O2, 336.0666; found 336.0673.
The synthesis of(2-chlorophenyl)-[2-(2-hydroxy-2-pyridin-4-yl-vinyl)pyridin-3-yl]methanone benzoate proceeds optimally when the potassium enolate of 4-acetyl pyridine is pre-formed using KOfBu in DMSO. Pre-formation of the enolate allows the SNAR (nucleophilic aromatic substitution) reaction to be performed between room temperature and 4O0C, which minimizes the amount of degradation. Under these conditions, the SNAR is highly regioselective, resulting in a ratio of approximately 95:5 preferential C – acylation. In all cases, less polar solvents such as THF or toluene, or co-solvents of these solvents mixed with DMSO, results in a substantial increase of acylation at the oxygen in the SNAR, and leads to a lower yield of product. This is a substantial improvement over the procedures described in WO2005/042515 for synthesis of the free base or the phosphate salt, in which the SNAR is performed at 60-700C, resulting in a substantial increase in chemical impurity. Using the conditions described in WO2005/042515, when scaled to 2kg, results in maximum yields of 55%, with sub-optimal potency. In comparison, the improved conditions described herein can be run reproducibly from 0.4 to 2kg scale to give yields of 77-83%, with >99% purity. In addition, the reaction can be held overnight at 4O0C with minimal degradation, whereas holding the reaction for 1 h past completion at 60-70°C results in substantial aromatized impurity. The reaction may also be performed using sodium tert-amylate as the base, in combination with an aprotic solvent, such as DMSO or DMF.
The title compound exists as a mixture of tautomers and geometric isomers. It is understood that each of these forms is encompassed within the scope of the invention.
Preparation 1-B
(2-chlorophenyl)-[2-(2-hydroxy-2-pyridin-4-yl-vinyl)pyridin-3-yl]methanone toluate The procedure described in Preparation 1-A is followed, with the following exception. Solid toluic acid (1.0 eq) is added to the crude free base solution at 550C, then the solution cooled to 45 0C. The solution is stirred for one hour at 45 0C, then slowly cooled to 23 0C. When solids are first observed, the cooling is stopped and the mixture is aged for an hour at the temperature at which crystals are first observed. Alternatively, if seed crystal is available, the mixture may be seeded, aged for 3 h at 450C , then cooled to O0C over 4 h. The isolation slurry is filtered, and the wetcake washed with MeOH (3 volumes). The wetcake is dried at 5O0C to provide 14.0 g (76.4%) of (2-chlorophenyl)-[2-(2-hydroxy-2-pyridin-4-yl- vinyl)pyridin-3-yl]methanone toluate as a light red powder.
As with the benzoate salt, the toluate salt can also exist as a mixture of tautomers and geometric isomers, each of which is encompassed within the scope of the invention. (2-chlorophenyl)-[2-(2-hydroxy- 2-pyridin-4-yl-vinyl)pyridin-3-yl]methanone toluate . 13C NMR (125 MHz,DMS0-d6) δ 194.5, 167.8, 167.4, 155.5, 150.7 (2C), 147.4, 144.0, 143.4, 142.7, 138.6, 133.0, 130.8, 130.7, 130.5, 129.8(2C), 129.5(2C), 128.5, 128.0, 127.9, 119.9 (2C), 118.6, 92.6, 21.5.
Preparation 1-C
(2-phenylsulfonyl-pyridin-3-yl)-(2-chlorophenyl)methanone
A solution of 1.3 eq of diisopropylamine (based on 2-benzenesulfonyl pyridine) in 5 volumes of THF in a mechanically stirred 3 -necked flask is cooled to -70 to -75 0C. To this solution is added 1.05 eq of w-butyllithium (1.6M in hexanes) at such a rate as to maintain the temperature below -6O0C. The light yellow solution is stirred at -60 to -70 0C for 30 minutes. Once the temperature has cooled back down to – 60 to -650C, 1.0 eq of 2-benzene-sulfonyl pyridine, as a solution in 3 volumes of THF, is added at the fastest rate that will maintain the reaction temperature under -6O0C. A yellow suspension forms during the addition that becomes yellow-orange upon longer stirring. This mixture is stirred for 3 hours at -60 to – 750C, and then 1.06 eq of 2-chlorobenzaldehyde, as a solution in 1 volume of THF, is added dropwise at a sufficient rate to keep the temperature under -55 0C. The suspension gradually turns orange-red, thins out, and then becomes a clear red solution. The reaction mixture is allowed to stir at -60 to -7O0C for 1 hour, 3N aqueous HCl (7 volumes) is added over 20-30 minutes, and the temperature is allowed to exotherm to 0-100C. The color largely disappears, leaving a biphasic yellow solution. The solution is warmed to at least 1O0C, the layers are separated, and the aqueous layer is back-extracted with 10 volumes of ethyl acetate. The combined organic layers are washed with 10 volumes of saturated sodium bicarbonate solution and concentrated to about 2 volumes. Ethyl acetate (10 volumes) is added, and the solution is once again concentrated to 2 volumes. The thick solution is allowed to stand overnight and is taken to the next step with no purification of the crude alcohol intermediate. The crude alcohol intermediate is transferred to a 3 -necked flask with enough ethyl acetate to make the total solution about 10 volumes. The yellow solution is treated with 3.2 volumes of 10% aqueous (w/w) potassium bromide, followed by 0.07 eq of 2,2,6,6-Tetramethylpiperidine-N-oxide (TEMPO). The orange mixture is cooled to 0-50C and treated with a solution of 1.25 eq of sodium bicarbonate in 12% w/w sodium hypochlorite (9 volumes) and 5 volumes of water over 30-60 minutes while allowing the temperature to exotherm to a maximum of 2O0C. The mixture turns dark brown during the addition, but becomes yellow, and a thick precipitate forms. The biphasic light yellow mixture is allowed to stir at ambient temperature for 1-3 hours, at which time the reaction is generally completed. The biphasic mixture is cooled to 0-50C and stirred for 3 hours at that temperature. The solid is filtered off, washed with 4 volumes of cold ethyl acetate, followed by 4 volumes of water, and dried in vacuo at 450C to constant weight. Typical yield is 80-83% with a purity of greater than 98%. 1H NMR (600 MHz, CDCl3-^) δ ppm 7.38 (td, ./=7.52, 1.28 Hz, 1 H) 7.47 (dd, ./=7.80, 1.30 Hz, 1 H) 7.51 (td, ./=7.79, 1.60 Hz, 1 H) 7.51 (t, ./=7.89 Hz, 2 H) 7.50 – 7.54 (m, J=7.75, 4.63 Hz, 1 H) 7.60 (t, J=7.43 Hz, 1 H) 7.73 (dd, J=7.75, 1.60 Hz, 1 H) 7.81 (dd, J=7.79, 1.56 Hz, 1 H) 8.00 (dd, ./=8.44, 1.10 Hz, 2 H) 8.76 (dd, ./=4.63, 1.61 Hz, 1 H).
Preparation 1-D 1 -azidomethyl-3,5-bistrifluoromethyl-benzene
Sodium azide (74.3 g, 1.14 mol) is suspended in water (125 mL), then DMSO (625 mL) is added. After stirring for 30 minutes, a solution consisting of 3,5-Bis(trifluoromethyl)benzyl chloride (255.3 g, 0.97 moles) and DMSO (500 mL) is added over 30 minutes. (The 3,5-Bis(trifluoromethyl)benzyl chloride is heated to 350C to liquefy prior to dispensing (MP = 30-320C)). The benzyl chloride feed vessel is rinsed with DMSO (50 mL) into the sodium azide solution, the mixture is heated to 4O0C, and then maintained for an hour at 4O0C, then cooled to 230C.
In Process Analysis: A drop of the reaction mixture is dissolved in d6-DMSO and the relative intensities of the methylene signals are integrated (NMR verified as a 0.35% limit test for 3,5- Bis(trifluoromethyl)benzyl Chloride). Work-up: After the mixture reaches 230C , it is diluted with heptanes (1500 mL), then water (1000 mL) is added, and the mixture exotherms to 350C against a jacket setpoint of 230C. The aqueous layer is removed (-2200 mL), then the organic layer (approximately 1700 mL) is washed with water (2 X 750 mL). The combined aqueous layers (-3700 mL) are analyzed and discarded.
The solvent is then partially removed via vacuum distillation with a jacket set point of 850C, pot temperature of 60-650C and distillate head temperature of 50-550C to produce 485g (94.5% yield) of 51 Wt% solution title compound as a clear liquid. Heptanes can be either further removed by vacuum distillation or wiped film evaporation technology. 1H NMR (400 MHz, CDCl3): 4.58 (s, 2H); 7.81 (s, 2H); 7.90 (s, IH).
Preparation 1-E 2-benzene-sulfonyl pyridine Charge 2-chloropyridine (75 mL, 790 mmol), thiophenol (90 mL, 852 mmol), and DMF (450 mL) to a 2L flask. Add K2CO3 (134.6 g, 962 mmol), then heat to HO0C and stir for 18 hours. Filter the mixture, then rinse the waste cake with DMF (195 mL). The combined crude sulfide solution and rinses are transferred to a 5-L flask, and the waste filtercake is discarded. Glacial acetic acid (57 mL, 995 mmol) is added to the filtrate, then the solution is heated to 4O0C, and 13 wt % NaOCl solution (850 mL, 1.7 mol) is added over 2 hours. After the reaction is complete, water (150 mL) is added, then the pH of the mixture adjusted to 9 with 20 % (w/v) NaOH solution (250 mL). The resulting slurry is cooled to <5 0C, stirred for 1.5 h, then filtered, and the cake washed with water (3 x 200 mL). The product wetcake is dried in a 550C vacuum oven to provide 2-benzene-sulfonyl pyridine (149 g, 676 mmol) in 86 % yield: 1H NMR (500 MHz, CDCl3) δ 8.66 (d, J = 5.5 Hz, IH), 8.19 (d, J = 1.1 Hz, IH), 8.05 (m, 2H), 7.92 (ddd, J= 9.3, 7.7, 1.6 Hz, IH), 7.60 (m, IH), 7.54 (m, 2H), 7.44 (m, IH); IR (KBr) 788, 984, 1124, 1166, 1306, 1424, 1446, 1575, 3085 cm“1; MS (TOF) mlz 220.0439 (220.0427 calcd for C11H10NO2S, MH); Anal, calcd for C11H9NO2S: C, 60.26; H, 4.14; N, 6.39; S, 14.62. Found: C, 60.40; H, 4.02; N, 6.40; S, 14.76.
As noted above, use of the improved process of the present invention results in an improved habit of the crystalline Form IV compound of Formula I. The improved habit reduces surface area of the crystal, improves the filtration, and washing, and improves the efficiency of azide mutagen rejection. These improvements are described in greater detail below.
In patent application WO2005/042515, the polish filtration is carried out in 7 volumes (L/kg) of isopropanol near its boiling point (65-83 0C), a process that is difficult and hazardous to execute in commercial manufacturing because of the high risk of crystallization on the filter and/or vessel transfer lines due to supersaturation. In the preferred crystallization solvent, isopropyl acetate, the polish filtration is conducted in four volumes of isopropyl acetate at temperatures from 45 to 55 0C. This temperature range is 35 to 45 0C lower than the boiling point of isopropyl acetate, which provides a key safety advantage.
PATENT
PATENT
WO 2017031215
EXAMPLES
Example 1: Preparation of Compound (I) via Negishi Coupling Route
Example 1 provides a scheme including preparations 1A-1D, described below, for the synthesis of the compound of Formula (I) and intermediates used in the route. An overview of the scheme is as follows:
80 on ma s ale
Example 1A: Preparation of Compound (I)
Zinc dust (200 mg, 3.06 mmol) combined with 2.0 mL of dimethylformamide was treated with 0.010 mL of 1,2-dibromoethane and heated to 65°C for 3 minutes. The mixture was cooled to ambient temperature and treated with 0.010 mL of trimethylsilyl chloride. After 5 minutes, 1.26 mL of 1M zinc chloride in diethyl ether was added to the mixture followed by Compound (Ila) (600 mg, 1.20 mmol). The mixture was heated to 65°C and further treated with 0.020 mL each of 1,2-dibromoethane and trimethylsilyl chloride. After 2.5 hours, via HPLC chromatogram, the reaction showed some formation of the zincate and was allowed to stir at ambient temperature for 16 hours. At this time
tetrakis(triphenylphosphine)palladium(0) (70 mg, 0.06 mmol), Compound (Ilia) (357 mg, 1.20 mmol) were added to the reaction and the mixture heated to 65°C. HPLC analysis showed the formation of Compound (I) in the reaction.
IB: Preparation of Comp
To a solution of Compound (IV) (8.00 g, 18 mmol) in 40 mL of 1,2-dichloroethane was added a solution of iodine monochloride (10.7 g, 65.9 mmol) in 40 mL of 1,2-dichloroethane resulting in a slurry. The slurry was heated to 75°C for 4 hours then cooled to ambient temperature. The solids were collected by filtration, washed with heptane, then combined with 90 mL of ethyl acetate and 80 mL of saturated sodium thiosulfate solution. The organic phase was washed with saturated sodium chloride solution and dried with sodium sulfate. The mixture was concentrated to yield 7.80 g (87%) of Compound (Ila) as a yellow solid. The product could be further purified by silica gel chromatography. Thus 2.0 g of yellow solid was dissolved in dichloromethane and charged onto a silica gel column. The product was eluted using tert-butyl methyl ether to provide 1.87 g (93% recovery) of Compound (Ila) as a white powder. Analytical data: Iodine monochloride complex: ¾ NMR (500 MHz, DMSO-de) δ 8.80 (2 H), 8.05 (1 H), 7.77 (2 H), 7.59 (2 H), 5.86 (2 H).
Uncomplexed: ¾ NMR (500 MHz, DMSO-de) δ 8.71 (2 H), 8.03 (1 H), 7.74 (2 H), 7.44 (2 H), 5.86 (2 H).
It was observed that the iodination proceeded smoothly as a suspension in 1,2-dichloroethane with IC1 (4.0 equiv) at 75°C. An ICl-Compound (Ila) complex was initially isolated by filtration. Compound (Ila) was then obtained in approximately 85% yield by treatment of the ICl-Compound (Ila) complex with sodium thiosulfate. This protocol provided a viable means of isolation of Compound (Ila) without the use of DMF.
Example 1C: Preparation of silyl substituted triazole (Compound IV)
A mixture of Compound (V) (8.07 g, 30.0 mmol) and Compound (VI) (5.12 g, 29.2 mmol) was heated to 100°C for 18 hours. To the mixture was added 40 mL of heptane and the reaction was allowed to cool with rapid stirring. After 1 hour the solids were collected by filtration and washed with heptane then dried to 9.30 g (72%) of Compound (IV) as a tan solid. Analytical data: ¾ NMR (500 MHz, DMSO-de) δ 8.66 (2 H), 8.04 (1 H), 7.67 (2 H), 7.32 (2 H), 5.72 (2 H), 0.08 (9 H).
It was further found that combining Compound (V) and Compound (VI) (neat) and heating at 95 – 105°C afforded a 92: 8 mixture of regioisomers as shown below:
Crystallization of the mixture from heptane afforded Compound (IV) in 62-72% yield, thus obviating the need for chromatography to isolate Compound (IV).
Example ID: Preparation of starting material Compound (VI)
Zinc bromide (502 g, 2.23 mole) was added in approximately 100 g portions to 2.0 L of tetrahydrofuran cooled to between 0 and 10°C. To this cooled solution was added 4-bromopyridine hydrochloride (200 g, 1.02 mol), triphenylphosphine (54 g, 0.206 mol), and palladium (II) chloride (9.00 g, 0.0508 mol). Triethylamine (813 g, 8.03 mol) was then added at a rate to maintain the reaction temperature at less than 10°C, and finally
trimethylsilylacetylene (202 g, 2.05 mol) was added. The mixture was heated to 60°C for 4.5 hours. The reaction was cooled to -5°C and combined with 2.0 L of hexanes and treated with 2 L of 7.4 M NH4OH. Some solids were formed and were removed as much as possible with the aqueous phase. The organic phase was again washed with 2.0 L of 7.4 M NH4OH, followed by 2 washes with 500 mL of water, neutralized with 1.7 L of 3 M hydrochloric acid, dried with sodium sulfate, and concentrate to a thick slurry. The slurry was combined with 1.0 L of hexanes to give a precipitate. The precipitate was removed by filtration and the filtrate was concentrated to 209 g of dark oil. The product was purified by distillation (0.2 torr, 68°C) to give 172 g (96%) of Compound (VI) as colorless oil. Analytical data: ¾ NMR (500 MHz, DMDO-de) δ 8.57 (2 H), 7.40 (2 H), 0.23 (9 H).
EXAMPLE 2 – Preparation of Compound (Ilia)
Example 2 provides a morpholine amide route for the synthesis of Compound (Ilia). In this approach, morpholine amide (Compound VII) was prepared from 2-chlorobenzoyl chloride (Preparation 2A). Metallation of 2-bromopyridine with LDA (1.09 equiv.) in THF at -70°C followed by addition of (Compound VII) afforded Compound (Ilia) in 37% yield after crystallization from IP A/heptane (Preparation 2B). This sequence provides a direct route to Compound (Ilia), and a means to isolate Compound (Ilia) without the use of
chromatography. Compound (Ilia) may then be used to form Compound (I) as shown in Example 1A above (Preparation 2C).
Preparation 2A: Preparation of Compound (VII)
Toluene (1.5 L) was added to Compound (IX) (150 g, 0.86 mol) and cooled to 10°C. Morpholine (82 mL, 0.94 mol) was added to the clear solution over 10 minutes. The resulting white slurry was stirred for 20 minutes then pyridine (92 mL, 1.2 mol) was added dropwise over 20 minutes. The cloudy white mixture was stirred in a cold bath for 1 hour. Water (600 mL) was added in a single portion and the cold bath removed. The mixture was stirred for 20 minutes and the layers are separated. The organic layer was washed with a mixture of 1 N HC1 and water (2: 1, 500 mL:250 mL). The pH of the aqueous layer was ~ 2. The organic layer was washed with a mixture of saturated NaHCCb and water (1 : 1, 100 mL: 100 mL). The pH of the aqueous layer was ~ 9. The layers were separated. The organic layer was concentrated in vacuo to an oil. The oil was dissolved in IPA (70 mL) and heated at 60°C for 30 min. The clear solution was allowed to cool to 30°C, then heptane (700 mL, 4.7 v) was added dropwise. The resulting slurry was stirred at RT for 2 hours then cooled to 0°C for 1 hour. The slurry was filtered at RT, washed with heptane then dried under vacuum at 30°C overnight. Compound (VII) (156.2 g, 81%) was obtained as a white solid. Analytical data: ¾ NMR (500 MHz, CDCh) δ 7.42-7.40 (m, 1 H), 7.35-7.29 (m, 3 H), 3.91-3.87 (m, 1 H), 3.80-3.76 (m, 3 H), 3.71 (ddd, J= 11.5, 6.8, 3.3 Hz, 1 H), 3.60 (ddd, J = 11.2, 6.4, 3.4 Hz, 1 H), 3.28 (ddd, J= 13.4, 6.3, 3.2 Hz, 1 H), 3.22 (ddd, J= 13.7, 6.8, 3.3 Hz, 1 H); LRMS (ES+) calcd for CnHi3F6ClN02 (M+H)+ 226.1, found 225.9 m/z.
Preparation 2B: Preparation of Compound (Ilia)
THF (75 mL) was added to diisopropyl amine (4.9 mL, 34.8 mmol) and cooled to a
temperature of -70°C under N2 atmosphere. 2.5 M w-BuLi in hexanes (13.9 mL, 34.8 mmol) was added in a single portion (a 30-40°C exotherm) to the clear solution and cooled back to -70°C. Compound (VIII) (5.0 g, 31.6 mmol) was added neat to the LDA solution (a 2 to 5°C exotherm) followed by a THF (10 mL) rinse, keeping T< -65°C. This clear yellow solution was stirred at -70°C for 15 min. Compound (VII) (7.1 g, 31.6 mmol) in THF (30 mL) was added keeping T< -65°C. The resulting clear orange solution was stirred at -70°C for 3 hours. MeOH (3 mL) was added to quench reaction mixture and the cold bath was removed. 5 N HC1 (25 mL) was added to the reaction solution. MTBE (25 mL) was added, and the layers were separated. The organic layer was washed with water (25 mL X 2). The organic layer was dried over MgS04 and filtered. The organic layer was concentrated in vacuo to an orange oil. The oil was dissolved in IPA (15 mL, 3 vol) at ambient temperature. Heptane (25 mL) was added dropwise and the resulting slurry was stirred at RT for 1 hour. The slurry was cooled to 0°C for 1 hour and filtered. The filter cake was rinsed with chilled heptane (20 mL) and dried under vacuum at 30°C overnight. Compound (Ilia) (4.25 g, 45%) was obtained as a yellow solid.
Several reactions were run at different temperatures and with different addition rates of Compound (VII). If the reaction temperature was maintained below -65°C and Compound (VII) was added in <5 min, it was found that the reaction worked well. If the temperature was increased and/or the addition time of Compound (VII) was increased, then yields suffered, and the work-up was complicated by emulsions.
Preparation 2C: Preparation of Compound (I)
Compound (Ilia) may then reacted with Compound (Ila) to produce Compound (I) as shown in Preparation 1A.
EXAMPLE 3
Example 3 describes a new route for the synthesis of an intermediate free base, which may be used to form Compound (I) as described further below.
Example 3A: Preparation of starting material (Compound X) from 2-Chloronicotinonitrile
A mixture of NaH (40.0 g, 1 mol, 60% dispersion in mineral oil) and 2-chloronicotinonitrile (69.3 g, 500 mmol) in THF (1 L) was heated to reflux. A solution of 4-acetylpyridine (60.6 g, 500 mmol) in THF (400 mL) was added over a period of 40 min. The resulting dark brown mixture was stirred at reflux for ~ 2 h. The heating mantle was then removed, and AcOH (58 mL, 1 mol) was added. EtOAc (1 L) and H2O (1 L) were then added, and the layers were separated. The organic layer was concentrated to afford an oily solid. CH3CN (500 mL) was added, and the mixture was stirred for 30 min. H2O (1 L) was then added. The mixture was stirred for 1 h then filtered. The solid was rinsed with 2: 1
CH3CN-H2O (900 mL) and hexanes (400 mL) then dried under vacuum at 45°C overnight to afford 61.4 g (55% yield) of Compound (X) as yellow solid. Compound (X) exists as an approximate 95:5 enol-ketone mixture in CDCI3. Analytical data for enol: IR (CHCI3): 3024, 2973, 2229, 1631, 1597, 1579, 1550, 1497; ¾ NMR (500 MHz, CDCI3) δ 8.69 (dd, J= 4.4,
1.7 Hz, 2H), 8.55 (dd, J = 5.2, 1.8 Hz, 1H), 7.97 (dd, J= 7.9, 1.8 Hz, 1H), 7.70 (dd, J= 4.6, 1.5 Hz, 2H, 7.17 (dd, J = 7.8, 5.0 Hz, 1H), 6.59 (s, 1H); LRMS (ES+) calcd for C13H10N3O (M+H)+ 224.1, found 224.0 m/z.
Preparation 3B: Preparation of Compound (XI)
Preparation 3B(1):
(X) (XI)
Compound (XI) may be prepared using Compound (X).
Preparation 3B(2):
Alternatively, the following procedure for the conversion of nitrile into an acid which may also yield compound (XI). A mixture of Compound (X) (1 eq) and NaOH (1.5 eq) in 1 : 1 fhO-EtOH (3.5 mL/g of Compound (X)) was heated at 65°C overnight. The reaction mixture was cooled to RT then added to CH2C12 (12.5 mL/g of Compound (X)) and H20 (12.5 mL/g of Compound (X)). Cone. HC1 (2.5 mL/g of Compound (X)) was then added, and the layers were separated. The aqueous layer was extracted with CH2CI2 (10 mL/g of Compound (X)). The combined organic extracts were washed with H2O (12.5 ml/g of Compound (X)), dried (MgS04), filtered and concentrated to afford Compound (XI).
Preparation 3C
Compound Compound (XI) may then be converted into a Stage C intermediate free base, with observed 87% conversion in Grignard reaction as shown above. A complete synthesis route for Com ound (I) starting from compound Compound (XI) is depicted below.
Detailed experimental procedures for the synthesis of benzoate salt and final step are given in
International Patent Application Publication WO 2008/079600 Al .
References
- “Company Overview of Eli Lilly & Co., Worldwide License to Develop and Commercialize VLY-686”. Bloomberg Business. Retrieved 16 November 2015.
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- “Vanda Pharmaceuticals Announces Tradipitant Phase II Proof of Concept Study Results for Chronic Pruritus in Atopic Dermatitis”. PR Newswire. Retrieved 16 November 2015.
- Schmidt, B (2006). “Proof of principle studies”. Epilepsy Res. 68 (1): 48–52. doi:10.1016/j.eplepsyres.2005.09.019. PMID 16377153.
- George, DT; Gilman, J; Hersh, J; et al. (2008). “Neurokinin 1 receptor antagonism as a possible therapy for alcoholism.”. Science. 6: 1536–1539. doi:10.2147/SAR.S70350. PMC 4567173
. PMID 26379454. - Tauscher, J; Kielbasa, W; Iyengar, S; et al. (2010). “Development of the 2nd generation neurokinin-1 receptor antagonist LY686017 for social anxiety disorder”. European Neuropsychopharmacology. 20 (2): 80–87. doi:10.1016/j.euroneuro.2009.10.005. PMID 20018493.
George, D.T.; Gilman, J.; Hersh, J.; Thorsell, A.; Herion, D.; Geyer, C.; Peng, X.; Kielbasa, W.; Rawlings, R.; Brandt, J.E.; Gehlert, D.R.; Tauscher, J.T.; Hunt, S.P.; Hommer, D.; Heilig, M. Neurokinin 1 receptor antagonism as a possible therapy for alcoholism, Science 2008, 319(5869): 1536
Gackenheimer, S.L.; Gehlert, D.R.In vitro and in vivo autoradiography of the NK-1 antagonist (3H)-LY686017 in guinea pig brain39th Annu Meet Soc Neurosci (October 17-21, Chicago) 2009, Abst 418.16
Tonnoscj, K.; Zopey, R.; Labus, J.S.; Naliboff, B.D.; Mayer, E.A.
The effect of chronic neurokinin-1 receptor antagonism on sympathetic nervous system activity in irritable bowel syndrome (IBS) Dig Dis Week (DDW) (May 30-June 4, Chicago) 2009, Abst T1261
Kopach, M.E.; Kobierski, M.E.; Coffey, D.S.; et al.
Process development and pilot-plant synthesis of (2-chlorophenyl)[2-(phenylsulfonyl)pyridin-3-yl]methanone
Org Process Res Dev 2010, 14(5): 1229
| Patent ID | Patent Title | Submitted Date | Granted Date |
|---|---|---|---|
| US2016060250 | NOVEL INTERMEDIATE AND PROCESS USEFUL IN THE PREPARATION OF -(2-CHLOROPHENYL)-METHANONE | 2015-11-10 | 2016-03-03 |
| US2015320866 | PHARMACEUTICAL COMPOSITION COMPRISING ANTIEMETIC COMPOUNDS AND POLYORTHOESTER | 2013-12-13 | 2015-11-12 |
| US2014206877 | NOVEL INTERMEDIATE AND PROCESS USEFUL IN THE PREPARATION OF -(2-CHLOROPHENYL)-METHANONE | 2014-03-27 | 2014-07-24 |
| US2012225904 | New 7-Phenyl-[1, 2, 4]triazolo[4, 3-a]Pyridin-3(2H)-One Derivatives | 2010-11-09 | 2012-09-06 |
| US2010056795 | NOVEL INTERMEDIATE AND PROCESS USEFUL IN THE PREPARATION OF -(2-CHLOROPHENYL)-METHANONE | 2010-03-04 | |
| US7381826 | Crystalline forms of {2-[1-(3, 5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1, 2, 3]triazol-4-yl]-pyridin-3-yl}-(2-chlorophenyl)-methanone | 2007-04-05 | 2008-06-03 |
| US7320994 | Triazole derivatives as tachykinin receptor antagonists | 2005-10-27 | 2008-01-22 |
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| Legal status | |
|---|---|
| Legal status |
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| Identifiers | |
| CAS Number | |
| PubChem CID | |
| ChemSpider | |
| Chemical and physical data | |
| Formula | C28H16ClF6N5O |
| Molar mass | 587.90 g/mol |
| 3D model (Jmol) | |
Tradipitant
Tradipitant is being evaluated in a Phase II study in treatment resistant pruritus in atopic dermatitis.
Tradipitant is an NK-1 receptor antagonist licensed from Eli Lilly in 2012. Tradipitant has demonstrated proof-of-concept in alcohol dependence in a study published by the NIH1. In that study tradipitant was shown to reduce alcohol cravings and voluntary alcohol consumption among patients with alcohol dependence. NK-1R antagonists have been evaluated in a number of indications including chemotherapy-induced nausea and vomiting (CINV), post-operative nausea and vomiting (PONV), alcohol dependence, anxiety, depression, and pruritus.
The NK-1R is expressed throughout different tissues of the body, with major activity found in neuronal tissue. Substance P (SP) and NK-1R interactions in neuronal tissue regulate neurogenic inflammation locally and the pain perception pathway through the central nervous system. Other tissues, including endothelial cells and immune cells, have also exhibited SP and NK-1R activity2. The activation of NK-1R by the natural ligand SP is involved in numerous physiological processes, including the perception of pain, behavioral stressors, cravings, and the processes of nausea and vomiting1,2,3. An inappropriate over-expression of SP either in nervous tissue or peripherally could result in pathological conditions such as substance dependence, anxiety, nausea/vomiting, and pruritus1,2,3,4. An NK-1R antagonist may possess the ability to reduce this over-stimulation of the NK-1R, and as a result address the underlying pathophysiology of the symptoms in these conditions.
References
- George DT, Gilman J, Hersh J, Thorsell A, Herion D, Geyer C, Peng X, Keilbasa W, Rawlings R, Brandt JE, Gehlert DR, Tauscher JT, Hunt SP, Hommer D, Heilig M. Neurokinin 1 receptor antagonism as a possible therapy for alcoholism. Science. 2008; 319(5869):1536-9
- Almeida TA, Rojo J, Nieto PM, Pinto FM, Hernandez M, et al. Tachykinins and tachykinin receptors: structure and activity relationships. Current Medicinal Chemistry. 2004;11:2045-2081.
- Hargreaves R, Ferreira JC, Hughes D, Brands J, Hale J, Mattson B, Mill S. Development of aprepitant, the first neurokinin-1 receptor antagonist for the prevention of chemotherapy-induced nausea and vomiting. Annals of the New York Academy of Sciences. 2011; 1222:40-48.
- Stander S, Weisshaar E, Luger A. Neurophysiological and neurochemical basis of modern pruritus treatment. Experimental Dermatology. 2007;17:161-69.
///////////////////tradipitant, PHASE 2, VLY-686, LY686017, традипитант , تراديبيتانت , 曲地匹坦 , VANDA, ELI LILLY, Gastroparesis Pruritus, FDA 2025, APPROVALS 2025, vomiting associated with motion
Zydus Cadila to launch India’s 1st Tetravalent Inactivated Influenza vaccine – VaxiFlu – 4
Zydus Cadila to launch India’s 1st Tetravalent Inactivated Influenza vaccine – VaxiFlu – 4
Ahmedabad, February 24, 2017
Zydus Cadila, a research-driven, global healthcare provider has received approvals from the Drug Controller General of India (DCGI), Central Drugs Standard Control Organization (CDSCO) and the Central Drug Laboratory (CDL) to market the Tetravalent Inactivated Influenza vaccine for seasonal flu, VaxiFlu – 4. With this, Zydus Cadila will become the first Indian pharma company and second in the world to launch a Tetravalent Inactivated Influenza vaccine. The vaccine provides protection from the four influenza viruses- H1N1, H3N2, Type B (Brisbane) and Type B (Phuket).
VaxiFlu – 4 will be marketed by Zydus Vaxxicare – a division of the group focussing on preventives. The Tetravalent Inactivated Influenza vaccine has been developed at the Vaccine Technology Centre (VTC) in Ahmedabad which has proven capabilities in researching, developing, and manufacturing of safe and efficacious vaccines. The group was also the first to indigenously develop, manufacture and launch India’s first vaccine against H1N1 – Vaxiflu-S.
VTC further plans to develop a wide spectrum of vaccines against bacterial, viral and protozoal infections and has a robust pipeline of vaccines like Pentavalent (DTP-Hib-HepB), Conjugated Typhoid Vaccine, HPV, MMRV, Malaria and Hepatitis B vaccines. The group also markets the anti-rabies vaccine and the typhoid vaccine.
Speaking on the development Mr. Pankaj R. Patel, Chairman and Managing Director, Zydus Cadila said, “Disease prevention is the key to public health in both the developing and the developed world and vaccines have the potential to improve the quality of life in both spectrums. In countries such as India, there is a pressing need for low cost, high quality vaccines that can address healthcare challenges. With the launch of vaccines like VaxiFlu – 4 we are serving the cause of public health and meeting the twin challenge of affordability and accessibility.”
Influenza, or the “flu” as it is commonly called, is an infection of the respiratory tract. It is a dreaded disease and the morbidity and mortality rates associated with influenza are especially high during pandemics. Annually it is estimated that it attacks 5-10% of adults and 20-30% of children globally and causes significant levels of illness, hospitalization and death. In India, the 2009 swine flu pandemic infected more than 10 million people and resulted in more than 18000 deaths worldwide.
The last major outbreak in India occurred in 2015 with more than 33000 registered cases of influenza and over 2000 deaths. There are different strains of influenza viruses that infect human beings, the predominant ones being influenza A and influenza B. The common subtypes of influenza A found in general circulation amongst people are H1N1 (which was responsible for the devastating swine flu pandemic) and H3N2.
The subtypes of influenza B commonly found in circulation are influenza B (Brisbane – Victoria lineage) and influenza B (Phuket – Yamagata lineage). Vaccination against influenza is the most effective way to protect oneself against the dangers of influenza. Majority of the influenza vaccines available in India are inactivated trivalent influenza vaccines.
These vaccines provide protection against 2 strains of influenza A and 1 strain of influenza B. Protection against only 1 subtype of influenza B often leads to a vaccine mismatch i.e. the antigen of influenza B present in the trivalent vaccine may not match the influenza B subtype circulating during the season, leading to suboptimal protection. A quadrivalent vaccine, by virtue of having a comprehensive coverage against 2 strains of both influenza A and influenza B, provides a broader protection and significantly reduces the risk of vaccine mismatch. Vaxiflu – 4 is the first quadrivalent influenza vaccine in india.
About Zydus Zydus Cadila is an innovative, global pharmaceutical company that discovers, develops, manufactures and markets a broad range of healthcare therapies, including small molecule drugs, biologic therapeutics and vaccines. The group employs over 19,500 people worldwide, including 1200 scientists engaged in R & D, and is dedicated to creating healthier communities globally. For more information, please visit http://www.zyduscadila.com
Zydus’ vaccine research programme The Vaccine Technology Centre (VTC) is the vaccine research centre of the Zydus Group. The group has two state-of-the-art R & D Centers, one located in Catania, Italy and the other in Ahmedabad, in the western part of India. The goup has been developing vaccines for the basic vaccine programmes such as Diphtheria, Pertussis, Tetanus, Haemophilus Influenzae type B, Hepatitis B, Measles, Mumps, Rubella, Varicella, Influenza and Typhoid fever. In addition, it is developing new vaccines such as Human Papilloma Virus, Leishmaniasis, Malaria, Haemorrhagic Congo Fever, Ebola and Japanese Encephalitis.
Ref
Zydus Cadila to launch India’s 1st Tetravalent Inactivated Influenza vaccine – VaxiFlu – 4 Read more: https://goo.gl/xuSTfK #ZydusAnnouncement
///////////Zydus Cadila, Tetravalent Inactivated, Influenza vaccine, VaxiFlu – 4
Zydus receives approval from USFDA to initiate Phase II clinical studies of Saroglitazar Magnesium in patients with Primary Biliary Cholangitis (PBC)
Zydus receives approval from USFDA to initiate Phase II clinical studies of Saroglitazar Magnesium in patients with Primary Biliary Cholangitis (PBC) Read more: https://goo.gl/eugRnZ #ZydusAnnouncement
Ahmedabad, India, February 23, 2017
Zydus Cadila, a research-driven, global healthcare provider, today announced that the USFDA has approved the group’s plans to initiate a Phase 2 clinical trial of Saroglitazar Magnesium (Mg) in patients with Primary Biliary Cholangitis (PBC) of the liver. This randomized, double-blind Phase 2 trial will evaluate Saroglitazar Magnesium 2mg and 4 mg Vs. Placebo.
Speaking on the development, Mr. Pankaj R. Patel, Chairman and Managing Director, Zydus Cadila said, “We are very thankful to the USFDA for their timely and useful feedback on the clinical trial designs of Saroglitazar Mg in patients with Primary Biliary Cholangitis (PBC). This development underlines our commitment to bridging unmet healthcare needs with innovative therapies.”
Primary Biliary Cholangitis (PBC) is a liver disease, caused due to progressive destruction of the bile ducts in the liver which leads to reduction of bile flow – a condition referred to as cholestasis. PBC is often discovered incidentally due to abnormal results on routine liver blood tests. Progression of PBC leads to symptoms of cirrhosis like yellowing of the skin, swelling of legs and feet (edema), ascites, internal bleeding (varices) and thinning of the bones (osteoporosis). The buildup of toxic bile in the liver leads to liver inflammation and fibrosis which can progress to cirrhosis. People with cirrhosis are at increased risk of hepatocellular carcinoma or liver cancer, which is a leading cause of liver transplants or death.
With an increasing number of people being affected by PBC which can lead to progressive cholestasis and even turn fatal, there is a pressing need to develop therapies which help to achieve an adequate reduction in alkaline phosphotase (ALP) or bilirubin and bring in better tolerance and efficacy.
About Lipaglyn™ Lipaglyn™ is a prescription drug authorized for sale in India only. Lipaglyn™ was launched in India during Sept 2013 for the treatment of Hypertriglyceridemia and Diabetic Dyslipidemia in Patients with Type 2 Diabetes not controlled by statins. Saroglitazar Mg is an investigational new drug with the USFDA, and is currently under clinical investigation for three significant unmet medical needs in the United States – Primary Biliary Cholangitis (PBC), Non-alcoholic Steatohepatitis (NASH) and Severe Hypertriglyceridemia (TG>500).
About Zydus Zydus Cadila is an innovative, global healthcare provider that discovers, develops, manufactures and markets a broad range of healthcare therapies, including small molecule drugs, biologic therapeutics and vaccines. The group employs over 19,500 people worldwide, including 1200 scientists engaged in R & D, and is dedicated to creating healthier communities globally. For more information, please visit http://www.zyduscadila.com
http://zyduscadila.com/wp-content/uploads/2017/02/USFDA-approval-for-clinical-trial-of-Saro-Mg.pdf
Saroglitazar magnesium
CAS: 1639792-20-3
Molecular Formula, 2C25-H28-N-O4-S.Mg,
Molecular Weight, 901.4354
Magnesium, bis((alphaS)-alpha-(ethoxy-kappaO)-4-(2-(2-methyl-5-(4-(methylthio)phenyl)-1H-pyrrol-1-yl)ethoxy)benzenepropanoato-kappaO)-, (T-4)-
(2S)-2-Ethoxy-3-(4-(2-(2-methyl-5-(4-(methylsulfanyl)phenyl)-1H-pyrrol-1-yl(ethoxy)phenyl)propanoic acid, magnesium salt (2:1)
DR RANJIT DESAI
ZYDUS
//////////Zydus, USFDA, Phase II, clinical studies, Saroglitazar Magnesium, Primary Biliary Cholangitis, (PBC)
[Mg+2].CCO[C@@H](Cc1ccc(OCCn2c(C)ccc2c3ccc(SC)cc3)cc1)C(=O)[O-].CCO[C@@H](Cc4ccc(OCCn5c(C)ccc5c6ccc(SC)cc6)cc4)C(=O)[O-]
AZD 8931, Sapitinib,
AZD 8931, Sapitinib, SAPATINIB
PHASE 2, at AstraZeneca for the treatment of non-small cell lung cancer.
CAS 848942-61-0,
MF C23H25ClFN5O3, MW 473.9,
pan-EGFR/pan-erbB inhibitor
4-[[4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxy-6-quinazolinyl]oxy]-N-methyl-1-piperidineacetamide
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[[1-(N-methylcarbamoylmethyl)piperidin-4-yl] oxy]quinazoline
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[[1-(N-methylcarbamoylmethyl)piperidin-4-yl]oxy]quinazoline
2-[4-[4-(3-Chloro-2-fluoro-anilino)-7-methoxy-quinazolin-6-yl]oxy-1-piperidyl]-N-methyl-acetamide
AZD8931 is an oral, equipotent inhibitor of ErbB1, ErbB2 and ErbB3 receptor signaling.
WO 2005028469
| Inventors | Robert Hugh Bradbury, Laurent Francois Andre Hennequin, Bernard Christophe Barlaam, |
| Applicant | Astrazeneca Ab, Astrazeneca Uk Limited |
Deregulation of the HER receptor family, comprising four related receptor tyrosine kinases (EGFR, HER2, HER3, and HER4), promotes proliferation, invasion, and tumor cell survival.Such deregulation has been observed in many human cancers, including lung, head and neck, and breast. Numerous small molecules have been investigated for inhibition of tyrosine kinases with the aminoquinazoline motif coming to the forefront as a privileged scaffold. Three of the clinically available treatments, gefitinib (1),lapatinib (2), and erlotinib (3),as well as the candidate drug dacomitinib (4), contain this arrangement
Figure 1. Structure of gefitinib (1), lapatinib (2), erlotinib (3), dacomitinib (4), and AZD8931 (5).
SYNTHESIS
PATENT
https://www.google.com/patents/WO2005028469A1?cl=en
PAPER
The first radiosynthesis of [11C]AZD8931 as a new potential PET agent for imaging of EGFR, HER2 and HER3 signaling
Bioorganic & Medicinal Chemistry Letters (2014), 24, (18), 4455-4459.
Synthesis of the reference standard AZD8931 (11a)
Reagents and conditions: (a) SnCl2·H2O, concd HCl; (b) formamide, 168–170 °C; (c) l-methionine, methanesulfonic acid, 120 °C; (d) Ac2O, pyridine, DMAP, 100 °C; (e) POCl3, DEA, 100 °C; (f) 3-chloro-2-fluoroaniline, i-PrOH, refluxing; (g) conc. NH3, MeOH; (h) (1) Boc2O, CH2Cl2, dioxane; (2) methanesulfonyl chloride, Et3N, CH2Cl2; (i) Compound 8, CsF, DMA, 85 °C; (j) TFA; (k) Compound 11a: 2-chloro-N-methylacetamide, KI, K2CO3, CH3CN, refluxing; compound
PAPER
Discovery of AZD8931, an Equipotent, Reversible Inhibitor of Signaling by EGFR, HER2, and HER3 Receptors
ACS Medicinal Chemistry Letters (2013), 4, (8), 742-746.
Discovery of AZD8931, an Equipotent, Reversible Inhibitor of Signaling by EGFR, HER2, and HER3 Receptors
Deregulation of HER family signaling promotes proliferation and tumor cell survival and has been described in many human cancers. Simultaneous, equipotent inhibition of EGFR-, HER2-, and HER3-mediated signaling may be of clinical utility in cancer settings where the selective EGFR or HER2 therapeutic agents are ineffective or only modestly active. We describe the discovery of AZD8931 (2), an equipotent, reversible inhibitor of EGFR-, HER2-, and HER3-mediated signaling and the structure–activity relationships within this series. Docking studies based on a model of the HER2 kinase domain helped rationalize the increased HER2 activity seen with the methyl acetamide side chain present in AZD8931. AZD8931 exhibited good pharmacokinetics in preclinical species and showed superior activity in the LoVo tumor growth efficacy model compared to close analogues. AZD8931 is currently being evaluated in human clinical trials for the treatment of cancer.
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-{[1-(N-methylcarbamoylmethyl)piperidin-4-yl]oxy}quinazoline
(2). 2 as a white solid (60%).1H NMR (CDCl3):
δ 1.98 (m, 2H), 2.08 (m, 2H), 2.46 (m, 2H), 2.85 (m, 2H), 2.87 (d, 3H), 3.07 (s, 2H), 4.02 (s, 3H), 4.49 (m, 1H),
7.16 (m, 4H), 7.31 (m, 2H), 8.49 (m, 1H), 8.71 (s, 1H). MS-ESI m/z MH+ 474 [MH]+. Anal.
(C23H25ClFN5O3
.0.21 H2O) C, H, N. Found C, 57.88; H, 5.45; N, 14.67; Requires C, 57.83; H, 5.36; N, 14.66%.
PATENT
Compound (I) is disclosed in International Patent Application Publication number WO2005/028469 as Example 1 therein and is of the structure:
Compound (I)
Compound (I) is an erbB receptor tyrosine kinase inhibitor, in particular compound (I) is a potent inhibitor of EGFR and erbB2 receptor tyrosine kinases. Compound (I) also inhibits erbB3 mediated signalling through the inhibition of phosphorylation of erbB3 following ligand stimulated EGFR/erbB3 and/or erbB2/erbB3 heterodimerisation. Compound (I) is expected to be useful in the treatment of hyperproliferative disorders such as cancer.
WO 03/082831 discloses the preparation of various 4-(3-chloro-2- fluoroanilino)quinazo lines. However, compound (I) is not disclosed therein.
WO2005/028469 discloses as Example 1 therein the preparation of compound (I) as follows: 2-Chloro-N-methylacetamide (32 mg, 0.3 mmol) was added to a mixture of
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(piperidin-4-yl)oxy]quinazoline (120 mg, 0.3 mmol), potassium iodide (16 mg, 0.1 mmol), and potassium carbonate (50 mg, 0.36 mmol) in acetonitrile (5 ml). The mixture was heated at reflux for one hour. After evaporation of the solvents under vacuum, the residue was taken up in dichloromethane. The organic solution was washed with water and brine, dried over magnesium sulfate. After evaporation of the solvents under vacuum, the residue was purified by chromatography on silica gel (eluant: 1% to 2% 7 N methanolic ammonia in dichloromethane) to give compound (I).
Scheme 1 :
Example 1 : Preparation of 4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-{[l-(N- methylcarbamoylmethyl)piperidin-4-yl]oxy } quinazoline (Compound (I)).
Compound (I) was prepared according to the scheme shown below:
Compound (III) Compound (IV)
Compound (V)
Compound (I)Compound (II)
Step 1. Preparation of tert-butyl 4-(5-cyano-2-methoxyphenoxy)piperidine-l- carboxylate (Intermediate 2). 3-hydroxy-4-methoxybenzonitrile (Compound (X), 6.00 g, 39.62 mmole), tert-butyl (4-methanesulfonyloxy)piperidine-l-carboxylate (16.6 g, 59.44 mmoles) (Chemical & Pharmaceutical Bulletin 2001, 49(7), 822-829); and potassium carbonate (6.71 g, 47.55 mmoles) were suspended in isopropanol (78.98 g) and the mixture was heated at reflux with stirring. Additional tert-butyl (4-methanesulfonyloxy)piperidine-l- carboxylate (2.08 g, 7.43 mmoles) was added to push the reaction to completion. The mixture was then cooled and quenched by the addition of water (100.47 g). Seeding with intermediate 2 followed by cooling to 00C resulted in a crystalline product, which was isolated by filtration. The filter cake was washed with a mixture of water (8.86 g) and isopropanol (6.97 g), followed by water (23.64 g) and then dried to give Intermediate 2 (10.75 g, 80% yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.39 (s, 9 H) 1.48 (m, 2 H) 1.88 (m, 2 H) 3.13 (m, 2 H) 3.67 (m, 2 H) 3.83 (s, 3 H) 4.56 (tt, J=8.1, 3.8 Hz, 1 H) 7.13 (d, J=8.4 Hz, 1 H) 7.42 (dd, J=8.4, 1.9 Hz, 1 H) 7.51 (d, J=1.9 Hz, 1 H); Mass Spectrum: m/z (M + H)+ 333.1. Step 2. Preparation of 4-methoxy-3-(piperidin-4-yloxy)benzonitrile (Compound
(VI)). Intermediate 2 (39.31 g, 118.26 mmoles) was suspended in ethanol (155.53 g) and heated to 40 0C. To this slurry was slowly added HCl (46.61 g, 573.04 mmoles). The mixture was heated to 60 0C and held for 3 hours. The reaction mixture was cooled to 200C and seed was charged initiating crystallisation. The resulting solid was isolated by filtration at 00C, washed twice with ethanol (62.21 g) and then dried to give compound (VI) as the hydrochloride salt (29.84 g, 77% yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.84 (m, 2 H) 2.09 (m, 2 H) 3.02 (ddd, J=12.7, 8.9, 3.4 Hz, 2 H) 3.20 (m, 2 H) 3.84 (s, 3 H) 4.63 (tt, J=7.7, 3.6 Hz, 1 H) 7.15 (d, J=8.5 Hz, 1 H) 7.45 (dd, J=8.5, 1.9 Hz, 1 H) 7.56 (d, J=1.9 Hz, 1 H) 9.16 (br. s, 2 H); Mass Spectrum: m/z (M + H)+ 233.2. Step 3. Preparation of 2-[4-(5-cyano-2-methoxyphenoxy)piperidin-l-yl]-JV- methylacetamide (Compound (V)). Compound (VI) (28.36 g, 95.82 mmoles), 2-chloro-N- methylacetamide (12.37 g, 114.98 mmoles) and potassium carbonate (33.11 g, 239.55 mmoles) were suspended in acetonitrile (161.36 g). The reaction mixture was heated at reflux for 3 hours. The reaction mixture was cooled to 200C and water (386.26 g) was charged. The reaction was heated to 75°C and the volume reduced by distillation. Upon cooling crystallisation occurred. The resulting solid was isolated by filtration, washed twice with water (77.25 g and 128.75 g) and then dried to give compound (V) (27.95 g, 94% yield); 1H NMR (400 MHz, DMSO-J6) δ ppm 1.68 (m, 2 H) 1.91 (m, 2 H) 2.29 (m, 2 H) 2.61 (d, J=4.7 Hz, 3 H) 2.67 (m, 2 H) 2.88 (s, 2 H) 3.83 (s, 3 H) 4.41 (tt, J=8.3, 4.0 Hz, 1 H) 7.11 (d, J=8.4 Hz, 1 H) 7.40 (dd, J=8.4, 1.9 Hz, 1 H) 7.47 (d, J=I.9 Hz, 1 H) 7.68 (q, J=4.7 Hz, 1 H); Mass Spectrum: m/z (M + H)+ 304.2.
Step 4. Preparation of 2-[4-(5-cyano-2-methoxy-4-nitrophenoxy)piperidin-l-yl]-N- methylacetamide (Compound (IV)). Compound (V) (8.78 g, 26.11 mmoles) was suspended in acetic acid (22.82 g, 364.87 mmoles) and the resulting reaction mixture cooled to 5°C. To this was added sulfuric acid (23.64 g, 234.95 mmoles) maintaining the reaction temperature below 300C. To the resulting solution was added nitric acid (2.40 g, 26.63 mmoles). The reaction mixture was then heated to 35°C and held for 3 hours. Additional nitric acid (117 mg, 1.31 mmoles) and sulphuric acid (1.31 g 13.1 mmoles) were charged and the reaction mixture was heated at 35°C for 30 minutes. The solution was cooled to 200C and quenched with aqueous ammonia (92.45 g 1.36 moles), resulting in an increase in temperature to 500C. To the resulting slurry was added, propionitrile (61.58 g 1.12 moles) and water (19 g). The reaction mixture was heated to 80 0C resulting in a clear solution, which upon settling gave two layers. The bottom layer was removed. The reaction mixture was cooled to 20 0C resulting in a thick slurry. The solid was isolated by filtration, washed with propionitrile (6.16 g 112.0 mmoles) and dried to afford compound (IV) (7.44 g, 82% yield); 1H NMR (400 MHz, DMSO-de) δ ppm 1.72 (m, 2 H) 1.97 (m, 2 H) 2.35 (m, 2 H) 2.61 (d, J=4.7 Hz, 3 H) 2.66 (m, 2 H) 2.90 (s, 2 H) 3.96 (s, 3 H) 4.73 (tt, J=8.4, 4.0 Hz, 1 H) 7.71 (q, J=4.7 Hz, 1 H) 7.82 (s, 1 H) 7.86 (s, 1 H). Mass Spectrum: m/z (M + H)+ 349.2
Step 5. Preparation of 2-[4-(4-amino-5-cyano-2-methoxyphenoxy)piperidin-l-yl]-N- methylacetamide (Compound (III)). Compound (IV) (7.42 g, 19.38 mmoles) was suspended in water (44.52 g) and methanol (5.35 g). To this was added sodium dithionite (11.91 g, 58.15 mmoles) and the resulting reaction mixture was heated to 600C. To the reaction mixture was added hydrochloric acid (46.98 g, 463.89 mmoles)), resulting in a solution, which was held at 60 0C for 3 hours. The reaction mixture was then allowed to cool to 20 0C. Aqueous sodium hydroxide (15.51 g 182.2 mmoles) was charged followed by 2-methyltetrahydrofuran (58.0 g). The reaction mixture was heated to 60 0C, which upon settling gave two layers and the lower aqueous layer was discarded. The volume of the reaction mixture was reduced by vacuum distillation and methyl tert-butyl ether (18.54 g) was added to give a slurry which was cooled to 10 0C. and then the solid was collected by filtration. The solid was washed with 2- methyltetrahydrofuran (5.8 g) and dried to give compound (III) (5.4 g, 78% yield); 1H NMR (400 MHz, DMSO-de) δ ppm 1.62 (m, 2 H) 1.82 (m, 2 H) 2.20 (m, 2 H) 2.60 (d, J=4.7 Hz, 3 H) 2.65 (m, 2 H) 2.86 (s, 2 H) 3.72 (s, 3 H) 4.00 (tt, J=8.3, 4.0 Hz, 1 H) 5.66 (br. s, 2 H) 6.39 (s, 1 H) 6.94 (s, 1 H) 7.65 (q, J=4.7 Hz, 1 H). Mass Spectrum: m/z (M + H)+ 319.2.
Step 6. Preparation of 2-[4-(5-cyano-4-{[(dimethylamino)methylene]amino}-2- methoxyphenoxy)piperidin-l-yl]-Λ/-methylacetamide (Compound (H)). Compound (III) (18.21 g, 52.05 mmoles) was suspended in 2-methyltetrahydrofuran (99.62 g). To this was added acetic acid (162.79 mg), and N,N-dimethylformamide dimethyl acetal (DMA) (8.63 g, 70.27 mmoles) and the resulting reaction mixture was heated at 76 0C for 16 hrs. Additional N,N-dimethylformamide dimethyl acetal (639.41 mg, 5.20 mmoles) was added to the reaction mixture to ensure the reaction completed. The reaction mixture was cooled to 300C during which time crystallisation occurred. The resulting solid was isolated by filtration, washed with 2-methyltetrahydrofuran (14.23 g) and dried to afford compound (II) (19.53 g, 97% yield); 1H NMR (400 MHz, DMSO-J6) δ ppm 1.65 (m, 2 H) 1.86 (m, 2 H) 2.24 (m, 2 H) 2.60 (d, J=4.7 Hz, 3 H) 2.66 (m, 2 H) 2.87 (s, 2 H) 2.95 (s, 3 H) 3.04 (s, 3 H) 3.81 (s, 3 H) 4.19 (tt, J=8.2, 3.8 Hz, 1 H) 6.72 (s, 1 H) 7.15 (s, 1 H) 7.67 (q, J=4.7 Hz, 1 H) 7.90 (s, 1 H); Mass Spectrum: m/z (M + H)+ 374.2.
Step 7. Preparation of compound (I). 2-[4-(5-cyano-4-
{ [(dimethylamino)methylene] amino } -2-methoxyphenoxy)piperidin- 1 -yl] -JV-methylacetamide (compound (II), 7.00 g, 17.71 mmoles), was suspended in methoxybenzene (35.8 g). Acetic acid (16.6 g) was charged and to the resulting solution was added 3-chloro-2-fluoroaniline (2.71 g, 18.07 mmoles). The reaction mixture was heated at 90 0C for 20 hours then cooled to 200C. Water (37.04 g) was charged to the reaction mixture, and the organic layer discarded. To the resulting aqueous mixture was charged isopropanol (39.00 g), followed by aqueous ammonia (20.79 g, 25%). The reaction mixture was heated to 30 0C and seeded with compound (I), which induced crystallisation. The reaction was then cooled to 00C and the product isolated by filtration. The filter cake was washed twice with a mixture of water (7.28 g) and isopropanol (4.68 g), then dried to afford the compound (I) (5.65 g, 55% yield); 1H NMR (400 MHz, DMSO-J6) δ ppm 1.79 (m, 2 H) 2.04 (m, 2 H) 2.38 (m, 2 H) 2.62 (d, J=4.5 Hz, 3 H) 2.74 (m, 2 H) 2.94 (s, 2 H) 3.93 (s, 3 H) 4.56 (tt, J=8.1, 3.8 Hz, 1 H) 7.21 (s, 1 H) 7.28 (m, 1 H) 7.50 (m, 2 H) 7.73 (q, J=4.5 Hz, 1 H) 7.81 (s, 1 H) 8.36 (s, 1 H) 9.56 (br.s, 1 H); Mass Spectrum: m/z (M + H)+ 474.2, 476.2.
Example 2: Preparation of 4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-{[l-(N- methylcarbamoylmethyl)piperidin-4-yl]oxy } quinazoline (Compound (I)). Compound (I) was prepared according to the scheme shown below:
Compound (III) Compound (IV)
Compound (V)
Compound (Xl)
Compound (I)
Steps 1, 2, 3 and 4 as set forth in Example 1.
Step 5, alternate 1. Preparation of compound (III). 2-[4-(5-Cyano-2-methoxy-4- nitrophenoxy)piperidin-l-yl]-N-methylacetamide (compound (IV), 15.00 g, 42.50 mmoles) was suspended in water (90.00 g) and methanol (59.38 g). To this was added sodium dithionite (30.47 g, 148.75 mmoles) and water (90.00 g), the resulting reaction mixture was heated to 30 0C and held for 2 hrs. To the reaction mixture was added hydrochloric acid (27.98 g, 276.25 mmoles)), resulting in a solution, which was held at 600C for 2 hours. Aqueous sodium hydroxide (30.60 g 382.49 mmoles) was added followed by a line wash of water (30.00 g). The reaction mixture was cooled to 25°C to give a slurry which was collected by filtration. The solid was washed with water (30.00 g) and dried to give compound (III) (13.50 g, 82% yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.62 (m, 2 H) 1.82 (m, 2 H) 2.20 (m, 2 H) 2.60 (d, J=4.7 Hz, 3 H) 2.65 (m, 2 H) 2.86 (s, 2 H) 3.72 (s, 3 H) 4.00 (tt, J=8.3, 4.0 Hz, 1 H) 5.66 (br. s, 2 H) 6.39 (s, 1 H) 6.94 (s, 1 H) 7.65 (q, J=4.7 Hz, 1 H). Mass Spectrum: m/z (M+H)+ 319.2.
Step 5, alternate 2. Preparation of compound (III). Compound (IV) (8.00 g, 22.67 mmoles) and 1% platinum + 2 % vanadium catalyst on carbon (1.23 g, 0.023 mmoles) were suspended in Acetonitrile (94.00 g). The reaction mixture was hydrogenated at a pressure of 3 Bar G and at a temperature of 35°C for 3 hrs. Once complete, the reaction mixture was filtered to remove the catalyst which is washed with acetonitrile (31.33 g). The volume of the reaction mixture was reduced by vacuum distillation to give a slurry which was cooled to 00C and then the solid was collected by filtration. The solid was washed with acetonitrile (12.53 g) and dried to give compound (III) (5.88 g, 78% yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.62 (m, 2 H) 1.82 (m, 2 H) 2.20 (m, 2 H) 2.60 (d, J=4.7 Hz, 3 H) 2.65 (m, 2 H) 2.86 (s, 2 H) 3.72 (s, 3 H) 4.00 (tt, J=8.3, 4.0 Hz, 1 H) 5.66 (br. s, 2 H) 6.39 (s, 1 H) 6.94 (s, 1 H) 7.65 (q, J=4.7 Hz, 1 H). Mass Spectrum: m/z (M+H)+ 319.2.
Step 6. Preparation of N, ΛT-bis(3-chloro-2-fluorophenyl)imidoformamide (compound (XI)). 3-chloro-2-fluroaniline (51.21 g, 341.22 mmoles) was suspended in cyclohexane (87.07 g). To this ethyl orthoformate (22.28 g, 150.32 mmoles) and acetic acid (0.94 g, 15.03 mmoles) were added. The resulting reaction mixture was heated, with stirring, to 48°C for 12 hours. Following this the reaction mixture was cooled to 200C over 12 hours and the solid product was isolated by filtration. The filter cake was washed with cylcohexane (26.12 g) and dried in vacuo at 40 0C to give compound (XI) as a white crystalline product (33.95 g, 93% yield); IH NMR Spectrum (400 MHz, DMSO-d6) δ ppm 7.14 (t, 2 H) 7.22 (m, 2 H) 8.14 (s, 1 H), 9,98 (s, 1 H); Mass Spectrum (by GC-MS EI): m/z (M+) 300.0.
Step 7, alternate 1 : Preparation of compound (I). 2-[4-(4-Amino-5-cyano-2- methoxyphenoxy)piperidin-l-yl]-N-methylacetamide (compound (III)) (10 g, 29.84 mmol) and TV, ΛT-bis(3-chloro-2-fluorophenyl)imidoformamide (compound (XI)) (11.46 g, 37.3 mmol) were suspended in 2-methyltetrahydrofuran (30.4 ml) and heated to 800C. To this yellow suspension was added acetic acid (7.6 ml, 127.33 mmol) and the resulting solution was heated to 92°C for 6 hours. 2-methyltetrahydrofuran (66.5 ml) and water (28.5 ml) were added and mixture was cooled to 550C before adding 50%w/w sodium hydroxide (7 ml, 131.29 mmol) resulting in a temperature rise to 63°C. The temperature was raised further to 69°C and after settling the aqueous phase was discarded. The organic phase was washed with water (3 x 20 ml) and each aqueous phase was discarded after settling. 2- methyltetrahydrofuran (100 ml, 997 mmol) was added and the volume reduced by distillation. Seed was added to induce crystallisation and the resulting mixture was cooled to 15°C. The crystalline form was initially obtained following a spontaneous crystallisation from the experiment as described. The resulting solid was isolated by filtration, washed twice with 2- methyltetrahydrofuran (19 ml) and dried under vacuum at 400C to yield compound (I) as a white solid (12.14 g, 95%). 1H NMR (400 MHz, DMSO-J6) δ ppm 1.12 (d, J= 6Hz, 1.3H), 1.26 -1.36 (m, 0.4H), 1.75-1.97 (m, 3.3H), 2.02-2.15 (m, 2H), 2.35-2.44 (m, 2H), 2.64 (d, J= 4.7Hz, 3H), 2.72-2.80 (m, 2H), 2.95 (s, 2H), 3.52-3.59 (m, 0.4H), 3.72-3.87 (m, 0.86H), 3.95 (s, 3H), 4.53-4.63 (m, IH), 7.22 (s, IH), 7.29 (dt J= IHz J= 8Hz, IH), 7.51 (dt J= 7.4Hz, J= 18Hz, 2H), 7.71-7.77 (m, IH), 7.82 (s, IH), 8.37 (s, IH), 9.57 (s, IH). Mass Spectrum: m/z (M+H)+ 474.0. The NMR data above includes signals for the 2-methyltetrahydrofuran solvent which is present in a 0.43 molar equivalence. The signals pertaining to the solvent are at δ ppm shifts of 1.12, 1.26-1.36, 3.52-3.59 and 3.72-3.87. The cluster at 1.75-1.93 contains signals for the solvent and the parent compound. The XRPD for this compound is shown in Figure 2.
Step 7, alternate 2. Preparation of compound (I). Compound (III) (15 g, 44.76 mmol) and compound (XI) (17.19 g, 55.95 mmol) were suspended in 2-methyltetrahydrofuran (45.6 ml) and heated to 83°C. To this yellow suspension was added acetic acid (11.4 ml, 190.99 mmol) and the resulting solution was heated to 92°C for 3 Vi hours. 2-methyltetrahydrofuran (105 ml) and water (50 ml) were added and mixture was cooled to 49°C before adding 50%w/w sodium hydroxide (10.74 ml, 201.4 mmol), resulting in a temperature rise to 62°C. The temperature was maintained at 62°C and after settling the aqueous phase was discarded. The organic phase was washed with water (3 x 30 ml) and each aqueous phase was discarded after settling. The mixture was cooled to 15°C and seed was added to induce crystallisation. The crystalline form was initially obtained following a spontaneous crystallisation from the experiment as described. The resulting solid was isolated by filtration, washed twice with 2- methyltetrahydrofuran (21 ml) and dried under vacuum at 400C to yield compound (I) as a white solid (20.12 g, 95%). 1H NMR (400 MHz, DMSO-J6) δ ppm 1.75-1.86 (m, 2H), 2.02- 2.15 (m, 2H), 2.35-2.44 (m, 2H), 2.64 (d, J= 4.7Hz, 3H), 2.72-2.80 (m, 2H), 2.95 (s, 2H), 3.95 (s, 3H), 4.53-4.63 (m, IH), 7.22 (s, IH), 7.29 (dt J= IHz J= 8Hz, IH), 7.51 (dt J= 7.4Hz, J= 18Hz, 2H), 7.71-7.77 (m, IH), 7.82 (s, IH), 8.37 (s, IH), 9.57 (s, IH). Mass Spectrum: m/z (M+H)+ 474.0. The XRPD for this compound is shown in Figure 3.
Step 7, alternate 3. Preparation of compound (I). Compound (III) (15.1 g, 45.06 mmol) and compound (XI) (17.31 g, 56.32 mmol) were suspended in 2-methyltetrahydrofuran (46 ml) and heated to 800C. To this yellow suspension was added acetic acid (12 ml, 458 mmol) and the resulting solution was heated to 92° C for 7 hours. 2-methyltetrahydrofuran (100 ml) and water (43 ml) were added and mixture was cooled to 59°C before adding 50%w/w sodium hydroxide (11 ml, 207 mmol), resulting in a temperature rise to 71.5°C. The temperature was adjusted to 69°C and the aqueous phase was discarded after settling. The organic phase was washed with water (2 x 43 ml) and each aqueous phase was discarded after settling. 2-methyltetrahydrofuran (72 ml) was removed by distillation at atmospheric pressure and was replaced by addition of isopropyl alcohol (72 ml). A further 72 ml of solvent was removed by distillation at atmospheric pressure and replaced by isopropyl alcohol (72 ml). Seed was added to induce crystallisation and the resulting mixture was cooled to 15°C. The solid was isolated by filtration, washed twice with isopropylalcohol (32 ml) and dried under vacuum at 400C to yield compound (I) as a white solid (20.86 g, 87%). 1H NMR (400 MHz, DMSO-J6) δ ppm 1.04 (d, J= 6Hz, 6H),1.75-1.88 (m, 2H), 2.02-2.15 (m, 2H), 2.35-2.44 (m, 2H), 2.64 (d, J= 4.7Hz, 3H), 2.72-2.80 (m, 2H), 2.95 (s, 2H), 3.73-3.84 (m, IH), 3.95 (s, 3H), 4.34 (d, J = 4.2Hz, IH), 4.53-4.63 (m, IH), 7.22 (s, IH), 7.29 (dt J= IHz J= 8Hz, IH), 7.51 (dt J= 7Hz, J= 18Hz, 2H), 7.71-7.77 (m, IH), 7.82 (s, IH), 8.37 (s, IH), 9.57 (s, IH). Mass Spectrum: m/z (M+H)+ 474.0. The NMR data include signals for 1 mole equivalent isopropanol present. The XRPD for this compound is shown in Figure 4.
Example 3. Preparation of 4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-{[l-(N- methylcarbamoylmethyl)piperidin-4-yl]oxy } quinazoline di- [(2E)-but-2-enedioate] (compound (I) difumarate salt). Compound (I) difumarate salt was prepared according to the scheme shown below:
Compound (III) Compound (IV) Compound (V)
Compound (Xl)
Difumarate Compound (I)
Steps 1, 2, 3, 4, 5 and 6 were performed as set forth in Example 2. Step 7. Preparation of compound (I) difumarate salt. Compound (III) (17.90 mmoles) and N, ΛT-bis(3-chloro-2-fluorophenyl)imidoformamide (compound (XI)) (7.04 g, 23.27 mmoles) were suspended in tert-butyl alcohol (88.95 g). To this suspension fumaric acid (10.39 g, 89.52 mmoles) was added and the mixture was heated to 800C, with stirring, for 2.5 hrs. Water (11.40 g, 632.80 mmoles) was charged and the reaction continued for a further 21.5 hrs. The reaction was cooled to 200C over 12 hours, during which time crystallisation occurred. The resulting solid was isolated by filtration and was washed with a mixture of water (1.00) and tert-butyl alcohol (7.80 g) followed by a wash with a mixture of water (0.50 g) and tert-butyl alcohol (7.30 g). The solid was dried in vacuo at 40 0C to give compound (I) difumarate salt (8.17 g, 61.40%) as a mustard yellow powder; 1H NMR (400 MHz, DMSO- dβ) δ ppm 1.83 (m, 2 H, broad) 2.07 (m, 2 H, broad) 2.64 (d, J=5.0 Hz, 3 H) 2.80 (m, 2 H, broad) 3.03 (s, 2 H) 3.94 (s, 3 H) 4.58 (m, 1 H) 6.63 (s, 4 H) 7.22 (s, 1 H) 7.29 (td, J=8.5, 1.0 Hz, 1 H) 7.51 (m, 2 H) 7.82 (m, 2 H) 8.37 (s, 1 H); Mass Spectrum: m/z (M+H)+ 474.0. Example 4. Preparation of 4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-{[l-(N- methylcarbamoylmethyl)piperidin-4-yl]oxy}quinazoline (compound (I)).
Compound (I) was prepared according to the scheme shown below:
Compound (III) Compound (IV)
Compound (V)
Compound (XII)
Compound (I)
Steps 1, 2, 3, 4 and 5 were performed as set forth in Example 2.
Step 6. Preparation of N’-(3-chloro-2-fluoro-phenyl)-N,N-dimethyl-formamidine (compound (XII)). 3-chloro-2-fluroaniline (5.30 g, 35.29 mmoles) was dissolved in 2- methyltetrahydrofuran (52.94 g). To this N,N-dimethylformamide dimethyl acetal (6.07 g, 49.41 mmoles) and acetic acid (0.11 g, 1.76 mmoles) were added. The resulting reaction mixture was heated, with stirring, to 76 0C for 3 hours. Following this the solvent was removed in vacuo at 400C to give compound (XII) as a yellow oil (6.60 g, 93% yield); IH NMR Spectrum (400 MHz, DMSO-d6) δ ppm 2.74 (s, 0.29H), 2.89 (s, 0.31H), 2.94 (s, 2.75H), 3.03 (s, 2.66H), 3.34 (br s, 0.70H), 5.48 (s, 0.06H) 6.91-7.10 (m, 3H), 7.79 (s, 1 H), 7.96 (s, 1 H). The NMR data above includes signals for N,N-dimethylformamide dimethyl acetal which is present in a 0.06 molar equivalence. The signals pertaining to N5N- dimethylformamide dimethyl acetal are at δ ppm shifts of 3.75, and 6.90-6.95. The signal at δ ppm 3.35 is due to residual water. Mass Spectrum (by LCMS EI): m/z (M+H)+ 201.2. Step 7: Preparation of compound (I). 2-[4-(4-Amino-5-cyano-2- methoxyphenoxy)piperidin-l-yl]-N-methylacetamide (compound (III)) (0.50 g, 1.45 mmol) and N’-(3-chloro-2-fluoro-phenyl)-N,N-dimethyl-formamidine (compound (XII)) (0.32 g, 1.52 mmol) were suspended in methoxybenzene (3.1 ml). To this yellow suspension was added acetic acid (1.52 ml, 25.51 mmol) and the resulting solution was heated to 90 0C for 14 hours. The reaction mixture was cooled to 20 0C and water (2.58 mL) was added. The organic layer was removed and the aqueous layer washed with methoxybenzene (1.4 mL). Ethanol (2.45 mL) and ammonia (1.94 ml, 25.55 mmoles) were added to the aqueous layer. The solution was heated to 900C resulting in the loss of some ethanol by evaporation. The solution was cooled to 40 0C. Seed was added to induce crystallisation and the resulting mixture was cooled to 20 0C. The solid was isolated by filtration to yield compound (I) as a white solid (0.61 g, 73% yield). IH NMR (400 MHz, DMSO-d6) δ ppm 1.75-1.87 (m, 2H), 2.02-2.15 (m, 2H), 2.35-2.44 (m, 2H), 2.64 (d, J= 4.8Hz, 3H), 2.72-2.80 (m, 2H), 2.95 (s, 2H), 3.35 (s, 5.4H), 3.75 (s, 1.3H), 3.95 (s, 3H), 4.58 (hept., J=4.0Hz, IH), 6.90-6.95 (m, 1.3H), 7.23 (s, 1.8H), 7.26-7.34 (m, IH), 7.45-7.58 (m 2H), 7.72-7.78 (m, IH), 7.83 (s, IH), 8.38 (s, IH), 9.58 (s, IH). The NMR data above includes signals for the methoxybenzene solvent which is present in a 0.40 molar equivalence. The signals pertaining to the solvent are at δ ppm shifts of 3.75, and 6.90-6.95. The cluster at 7.26-7.34 contains signals for the solvent and the parent compound. The signal at δ ppm 3.35 is due to residual water. Mass Spectrum: m/z (M + H)+ 474.0, 476.0. Example 5. Preparation of compound (I) difumarate Form A – 2-[4-({4-[(3-Chloro-2- fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidin-l-yl]-N-methylacetamide di- [(2E)-but-2-enedioate] Form A. A solution of fumaric acid (2.7 g, 23.22 mmol) in methanol (95 ml) was added to a mixture of 2-[4-({4-[(3-Chloro-2-fluorophenyl)amino]-7- methoxyquinazolin-6-yl}oxy)piperidin-l-yl]-N-methylacetamide (compound (I)) (5.62 g at 89% w/w, 10.55 mmol) in isopropanol (100 ml) maintaining the temperature >65°C. The mixture was heated at reflux for one hour before clarification. The reaction mixture was cooled to 300C over 90 minutes and held for 30 minutes to establish crystallisation. The reaction was cooled to 00C over 2 hours and held for 1 hour before isolation by filtration. The filter cake was washed twice with cold isopropanol (2 x 10 ml) and dried in vacuo at 500C to give the title compound as a white solid (5.84 g, 78%); 1H NMR Spectrum: (DMSO) 1.85 (m, IH), 2.08 (m, IH), 2.50 (m, IH), 2.66 (d, 3H), 2.83 (m, IH), 3.05 (s, 2H), 3.96 (s, 3H), 4.58 (m, IH), 6.64 (s, 4H), 7.23 (s, IH), 7.28 (m, IH), 7.46 (ddd, IH), 7.55 (m, IH), 7.70 (broad q, IH), 7.85 (s, IH), 8.38 (s, IH).
Example 6. Preparation of compound (I) difumarate Form A: 2-[4-({4-[(3-Chloro-2- fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidin-l-yl]-N-methylacetamide di- [(2E)-but-2-enedioate] Form A. A solution of fumaric acid (1.4 kg, 12.1 mol) in methanol (26.6 kg) was added to a mixture of 2-[4-({4-[(3-chloro-2-fluorophenyl)amino]-7- methoxyquinazolin-6-yl}oxy)piperidin-l-yl]-N-methylacetamide (2.93 kg, 84.8% w/w, 5.24 mol) in isopropanol (39 kg) maintaining the temperature >65°C. A line wash of methanol (3.6 kg) was charged. The mixture was heated at reflux for one hour before clarification, followed by a line wash of methanol (7 kg). The reaction mixture was distilled at atmospheric pressure to remove 47 kg of distillates. Isopropanol (15.8 kg was added and the reaction mixture distilled to remove 15.6 kg of distillates. Crystallisation occurred during the distillation. Isopropanol (21 kg) was added and the reaction cooled to 00C over 8 hours and held for 1 hour before isolation by filtration. The filter cake was washed with cold 50:50 isopropanol:MeOH (4 kg) followed by cold isopropanol (4 kg) and dried in vacuo at 500C to give the title compound as a white solid (3.64 kg, 98%); 1H NMR Spectrum: (DMSO) 1.85 (m, IH), 2.08 (m, IH), 2.50 (m, IH), 2.66 (d, 3H), 2.83 (m, IH), 3.05 (s, 2H), 3.96 (s, 3H), 4.58 (m, IH), 6.64 (s, 4H), 7.23 (s, IH), 7.28 (m, IH), 7.46 (ddd, IH), 7.55 (m, IH), 7.70 (broad q, IH), 7.85 (s, IH), 8.38 (s, IH).
Example 7. Preparation of compound (I) difumarate Form A: 2-[4-({4-[(3-Chloro-2- fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidin-l-yl]-N-methylacetamide di- [(2E)-but-2-enedioate] Form A. 2-[4-({4-[(3-Chloro-2-fluorophenyl)amino]-7- methoxyquinazolin-6-yl}oxy)piperidin-l-yl]-N-methylacetamide (compound (I)) (60.19 g at 88% w/w, 111.8 mmol) was dissolved in ethyl acetate (1550 ml). The solution was clarified by filtration and the filter washed with ethyl acetate (53 ml). The solution was cooled to 400C. A clarified solution of fumaric acid (26.60 g, 257.0 mmol) in isopropanol (408 ml) was then added over 1 hour. The filter used to clarify the fumaric acid solution was then washed with isopropanol (37 ml). After holding for 1 hour at 400C the reaction was cooled to 200C over 1 hour. The reaction mixture was held for 13.5 hours before isolating the product by filtration. The filter cake was washed twice with ethyl acetate (82 ml) : isopropanol (24 ml) and then dried in vacuo at 400C to give the title compound as a white solid (72.32 g, 90%); 1H NMR Spectrum: (DMSO) 1.85 (m, IH), 2.08 (m, IH), 2.50 (m, IH), 2.66 (d, 3H), 2.83 (m, IH), 3.05 (s, 2H), 3.96 (s, 3H), 4.58 (m, IH), 6.64 (s, 4H), 7.23 (s, IH), 7.28 (m, IH), 7.46 (ddd, IH), 7.55 (m, IH), 7.70 (broad q, IH), 7.85 (s, IH), 8.38 (s, IH). Example 8. Preparation of compound (I) difumarate Form A: 2-[4-({4-[(3-Chloro-2- fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidin-l-yl]-N-methylacetamide di- [(2E)-but-2-enedioate] Form A. 2-[4-({4-[(3-Chloro-2-fluorophenyl)amino]-7- methoxyquinazolin-6-yl}oxy)piperidin-l-yl]-N-methylacetamide (compound (I)) (2.75 g at assumed 100% w/w, 5.80 mmol) was dissolved in ethyl acetate (94 ml) and isopropanol (14 ml). The solution was distilled such that 25.2 ml of distillates were collected. The solution was cooled to 400C. A clarified solution of fumaric acid (1.38 g, 11.90 mmol) in isopropanol (21 ml) was then added over 1 hour. Compound (I) difumarate Form A seed was added (3.7 mg, 5.3 μmol). The filter used to clarify the fumaric acid solution was then washed with isopropanol (2 ml). After holding for 1 hour at 400C the reaction was cooled to 200C over 2 hours. The reaction mixture was held for 15 hours before isolating the product by filtration. The filter cake was washed twice with ethyl acetate (4.3 ml): isopropanol (1.2 ml) and then dried in vacuo at 400C to give the title compound as a white solid (72.32 g, 90%); 1H NMR Spectrum: (DMSO) 1.85 (m, IH), 2.08 (m, IH), 2.50 (m, IH), 2.66 (d, 3H), 2.83 (m, IH), 3.05 (s, 2H), 3.96 (s, 3H), 4.58 (m, IH), 6.64 (s, 4H), 7.23 (s, IH), 7.28 (m, IH), 7.46 (ddd, IH), 7.55 (m, IH), 7.70 (broad q, IH), 7.85 (s, IH), 8.38 (s, IH).
Example 9. Preparation of compound (I) difumarate Form A: 2-[4-({4-[(3-Chloro-2- fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidin-l-yl]-N-methylacetamide di- [(2E)-but-2-enedioate] Form A. 2-[4-({4-[(3-Chloro-2-fluorophenyl)amino]-7- methoxyquinazolin-6-yl}oxy)piperidin-l-yl]-N-methylacetamide (compound (I)) (1 g, 1.86 mmoles) and fumaric acid (0.44 g, 3.81 mmoles) were suspended in water (4.4 g) and heated to 85°C. The reaction mixture was cooled to 600C at l°C/minute and compound (I) Form A seed was added when the temperature was 77°C. The resulting solid was isolated by filtration, washed twice with acetone (0.7O g per wash) and dried in a vacuum oven at 400C to afford the title compound (0.89 g, 68% yield), IH NMR (400 MHz, DMSO-d6) d ppm 1.84 (m, 2 H) 2.08 (m, 2 H) 2.55 (m, 2 H) 2.63 (d, J=4.7 Hz, 3 H) 2.86 (m, 2 H) 3.12 (s, 2 H) 3.93 (s, 3 H) 4.59 (tt, J=7.8, 3.7 Hz, 1 H) 6.62 (s, 4 H) 7.21 (s, 1 H) 7.27 (td, J=8.1, 1.3 Hz, 1 H) 7.49 (m, 2 H) 7.86 (m, 2 H) 8.36 (s, 1 H) 9.63 (br. s., 1 H). Compound (I) difumarate Form A is a free flowing powder.
PAPER
http://pubs.acs.org/doi/abs/10.1021/acs.oprd.6b00412
The Development of a Dimroth Rearrangement Route to AZD8931
, Kay Boardman‡, Oliver Cunningham‡, Matthew Evans‡, Martin F. Jones‡§, Kirsty Millard‡, Raquel Rozada-Sanchez‡, Yvonne Sawyer†, Paul Siedlecki‡, and Brian Whitlock‡
Recently, the aminoquinazoline motif has been highly prevalent in anticancer pharmaceutical compounds. Synthetic methods are required to make this structure on a multikilo scale and in high purity. The initial route to aminoquinazoline AZD8931 suffered from the formation of late-stage impurities. To avoid these impurities, a new high-yielding Dimroth rearrangement approach to the aminoquinazoline core of AZD8931 was developed. Assessment of route options on a gram scale demonstrated that the Dimroth rearrangement is a viable approach. The processes were then evolved for large-scale production with learning from a kilo campaign and two plant-scale manufactures. Identification of key process impurities offers an insight into the mechanisms of the Dimroth rearrangement as well as the hydrogenation of a key intermediate. The final processes were operated on a 30 kg scale delivering the target AZD8931 in 41% overall yield.
2-[4-[4-(3-chloro-2-fluoro-anilino)-7-methoxy-quinazolin-6-yl]oxy-1-piperidyl]-N-methyl-acetamide IPA solvate (5) as a white solid (38.1 kg, 84.2% yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.81 (m, 2 H), 2.06 (m, 2 H), 2.39 (m, 2 H), 2.63 (d, J = 4.7 Hz, 3 H), 2.75 (m, 2 H), 2.95 (s, 2 H), 3.94 (s, 3 H), 4.57 (Dt, J = 8.1, 4.2 Hz, 1 H), 7.22 (s, 1 H), 7.29 (t, J = 8.0 Hz, 1 H), 7.51 (m, 2 H), 7.74 (br d, J = 4.6 Hz, 1 H), 7.83 (s, 1 H), 8.37 (s, 1 H), 9.58 (br.s, 1 H); m/Z ES+ 474.2 [MH]+; HRMS found [MH]+ = 474.1706, C23H25ClFN5O3 requires [MH]+ = 474.1630; Assay (QNMR) 97.5 wt %/wt.
1H NMR PREDICT
13C NMR PREDICT
| CHEMICAL & PHARMACEUTICAL BULLETIN, vol. 49, no. 7, 2001, pages 822 – 829 |
| Citing Patent | Filing date | Publication date | Applicant | Title |
|---|---|---|---|---|
| WO2013051883A3 * | Oct 5, 2012 | Jun 6, 2013 | Hanmi Science Co., Ltd. | Method for preparing 1-(4-(4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)piperidin-1-yl)-prop-2-en-1-one hydrochloride and intermediates used therein |
| US8859767 | Oct 5, 2012 | Oct 14, 2014 | Hanmi Science Co., Ltd | Method for preparing 1-(4-(4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)piperidin-1-yl)-prop-2-en-1-one hydrochloride and intermediates used therein |
////////////////AZD 8931, Sapitinib, pan-EGFR, pan-erbB inhibitor, SAPATINIB, PHASE 2, 848942-61-0
CNC(=O)CN1CCC(CC1)OC2=C(C=C3C(=C2)C(=NC=N3)NC4=C(C(=CC=C4)Cl)F)OC
“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This article is a compilation for educational purposes only.
P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent
1-Amino-3-ethyl-5-nitratemethyladamantane hydrochloride (MN-05)
1-Amino-3-ethyl-5-nitratemethyladamantane hydrochloride (MN-05)
Med. Chem. Commun., 2017, 8,135-147
A series of memantine nitrate derivatives, as dual functional compounds with neuroprotective and vasodilatory activity for neurodegenerative diseases, was designed and synthesized
Synthesis and biological evaluation of memantine nitrates as a potential treatment for neurodegenerative diseases
E-mail: yxy0723@163.com, zaijunzhang@163.com
Fax: +86 20 8522 4766
Tel: +86 20 8522 5030
A series of memantine nitrate derivatives, as dual functional compounds with neuroprotective and vasodilatory activity for neurodegenerative diseases, was designed and synthesized. These compounds combined the memantine skeleton and a nitrate moiety, and thus inhibited the N-methyl-D-aspartic acid receptor and released NO in the central nervous system. The biological evaluation results revealed that the new memantine nitrates were effective in protecting neurons against glutamate-induced injury in vitro. Moreover, memantine nitrates dilated aortic rings against phenylephrine-induced contraction. The structure–activity relationships of neuroprotection and vasodilation were both analyzed. In further studies, compound MN-05 significantly protected cortical neurons by inhibiting Ca2+ influx, reducing free radical production and maintaining the mitochondrial membrane potential. Further research on MN-05 is warranted.
1-Amino-3-ethyl-5-nitratemethyladamantane hydrochloride (MN-05).
Compound MN- 05 was synthesized using a similar method to that as described for synthesis of compound MN-01 from compound 16. White solid, 65.5% yield. ESI-MS: m/z 255.1 [M + H]+ .
1H NMR (300 MHz, DMSO-d6) δ 0.75-0.80 (t, J = 7.5 Hz, 3H, CH3), 1.16-1.24 (q, J = 7.5 Hz, 2H, CH2), 1.24-1.25 (m, 2H), 1.30-1.39 (m, 2H), 1.43 (s, 2H), 1.45-1.57 (dd, J = 12 Hz, 6 Hz, 2H), 1.57-1.63 (dd, J = 12 Hz, 6 Hz, 2H), 1.71 (s, 2H), 2.23 (m, 1H, CH), 4.30 (s, 2H, CH2O), 8.21 (s, 3H, NH2HCl).
13C NMR (75 MHz, DMSO-d6) δ 7.4, 28.6, 34.5, 35.0, 36.8, 40.3, 41.6, 43.9, 52.3, 80.9. Anal. Calcd for C13H23N2O3Cl·0.3 H2O: C, 52.72%; H, 8.03%; N, 9.46%. Found: C, 52.72%; H, 7.92%; N, 9.51%
“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This article is a compilation for educational purposes only.
P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent
Deflazacort
Deflazacort
- CAS 14484-47-0
- Molecular Formula C25H31NO6
- Average mass 441.517 Da
- 5’βH-Pregna-1,4-dieno[17,16-d]oxazole-3,20-dione, 11β,21-dihydroxy-2′-methyl-, 21-acetate (8CI)
- (11β,16β)-21-(Acetyloxy)-11-hydroxy-2′-methyl-5’H-pregna-1,4-dieno[17,16-d]oxazole-3,20-dione
- 2H-Naphth[2′,1′:4,5]indeno[1,2-d]oxazole, 5’H-pregna-1,4-dieno[17,16-d]oxazole-3,20-dione deriv.
- Azacort
- Azacortinol
- Calcort
- DL 458IT
- Deflan
| Optical Rotatory Power | +62.3 ° | Conc: 0.5 g/100mL; Solv: chloroform (67-66-3); Wavlength: 589.3 nm |
…………..REF, “Drugs – Synonyms and Properties” data were obtained from Ashgate Publishing Co. (US)Hoechst Marion Roussel (now Aventis Pharma) has developed and launched Deflazacort (Dezacor; Flantadin; Lantadin; Calcort) a systemic corticosteroid developed for the treatment of a variety of inflammatory conditions .
In March 1990, the drug was approved in Spain, and by January 2013, the drug had been launched by FAES Farma . By the end of 1999, the product had been launched in Germany, Italy, Belgium, Switzerland and South Korea
Deflazacort is a corticosteroid first launched in 1985 by Guidotti in Europe for the oral treatment of allergic asthma, rheumatoid arthritis, arthritis, and skin allergy.
In 2017, an oral formulation developed at Marathon Pharmaceuticals was approved by the FDA for the treatment of Duchenne’s muscular dystrophy in patients 5 years of age and older.
Deflazacort (trade name Emflaza or Calcort among others) is a glucocorticoid used as an anti-inflammatory and immunosuppressant.
In 2013, orphan drug designation in the U.S. was assigned to the compound for the treatment of Duchenne’s muscular dystrophy. In 2015, additional orphan drug designation in the U.S. was assigned for the treatment of pediatric juvenile idiopathic arthritis (JIA) excluding systemic JIA.
Also in 2015, deflazacort was granted fast track and rare pediatric disease designations in the U.S. for the treatment of Duchenne’s muscular dystrophy.
| Deflazacort is a glucocorticoid used as an anti-inflammatory and immunosuppressant. It was approved in February, 2017 by the FDA for use in treatment of Duchenne muscular dystrophy (trade name Emflaza). |
- Aventis Pharma (Originator), Lepetit (Originator), Guidotti (Licensee), Shire Laboratories (Licensee)
February 9, 2017 FDA approved
The U.S. Food and Drug Administration today approved Emflaza (deflazacort) tablets and oral suspension to treat patients age 5 years and older with Duchenne muscular dystrophy (DMD), a rare genetic disorder that causes progressive muscle deterioration and weakness. Emflaza is a corticosteroid that works by decreasing inflammation and reducing the activity of the immune system.
Corticosteroids are commonly used to treat DMD across the world. This is the first FDA approval of any corticosteroid to treat DMD and the first approval of deflazacort for any use in the United States.
“This is the first treatment approved for a wide range of patients with Duchenne muscular dystrophy,” said Billy Dunn, M.D., director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. “We hope that this treatment option will benefit many patients with DMD.”
DMD is the most common type of muscular dystrophy. DMD is caused by an absence of dystrophin, a protein that helps keep muscle cells intact. The first symptoms are usually seen between 3 and 5 years of age and worsen over time. The disease often occurs in people without a known family history of the condition and primarily affects boys, but in rare cases it can affect girls. DMD occurs in about one of every 3,600 male infants worldwide.
People with DMD progressively lose the ability to perform activities independently and often require use of a wheelchair by their early teens. As the disease progresses, life-threatening heart and respiratory conditions can occur. Patients typically succumb to the disease in their 20s or 30s; however, disease severity and life expectancy vary.
The effectiveness of deflazacort was shown in a clinical study of 196 male patients who were 5 to 15 years old at the beginning of the trial with documented mutation of the dystrophin gene and onset of weakness before age 5. At week 12, patients taking deflazacort had improvements in a clinical assessment of muscle strength across a number of muscles compared to those taking a placebo. An overall stability in average muscle strength was maintained through the end of study at week 52 in the deflazacort-treated patients. In another trial with 29 male patients that lasted 104 weeks, deflazacort demonstrated a numerical advantage over placebo on an assessment of average muscle strength. In addition, although not statistically controlled for multiple comparisons, patients on deflazacort appeared to lose the ability to walk later than those treated with placebo.
The side effects caused by Emflaza are similar to those experienced with other corticosteroids. The most common side effects include facial puffiness (Cushingoid appearance), weight gain, increased appetite, upper respiratory tract infection, cough, extraordinary daytime urinary frequency (pollakiuria), unwanted hair growth (hirsutism) and excessive fat around the stomach (central obesity).
Other side effects that are less common include problems with endocrine function, increased susceptibility to infection, elevation in blood pressure, risk of gastrointestinal perforation, serious skin rashes, behavioral and mood changes, decrease in the density of the bones and vision problems such as cataracts. Patients receiving immunosuppressive doses of corticosteroids should not be given live or live attenuated vaccines.
The FDA granted this application fast track designation and priority review. The drug also received orphan drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.
The sponsor is receiving a rare pediatric disease priority review voucher under a program intended to encourage development of new drugs and biologics for the prevention and treatment of rare pediatric diseases. A voucher can be redeemed by a sponsor at a later date to receive priority review of a subsequent marketing application for a different product. This is the ninth rare pediatric disease priority review voucher issued by the FDA since the program began.
Emflaza is marketed by Marathon Pharmaceuticals of Northbrook, Illinois.
Medical uses
The manufacturer lists the following uses for deflazacort:[1]
- Acute interstitial nephritis
- Anaphylaxis
- Asthma
- Autoimmune haemolytic anaemia
- Bullous pemphigoid
- Mixed connective tissue disease (other than systemic sclerosis)
- Crohn’s disease
- Dermatomyositis
- Idiopathic thrombocytopenic purpura
- Juvenile chronic arthritis
- Severe hypersensitivity reactions
- Immunosuppression in transplantation
- Acute and lymphatic leukaemia
- Malignant lymphoma
- Multiple myeloma
- Rheumatoid arthritis
- Polymyalgia rheumatica
- Nephrotic syndrome
- Pemphigus
- Polyarteritis nodosa
- Pyoderma gangrenosum
- Sarcoidosis
- Systemic lupus erythematosus
- Ulcerative colitis
In the United States, deflazacort is only FDA-approved for the treatment of Duchenne muscular dystrophy in people over the age of 5.
Adverse effects
Deflazacort carries the risks common to all corticosteroids, including immune suppression, decreased bone density, and endocrine insufficiency. In clinical trials, the most common side effects (>10% above placebo) were Cushing’s-like appearance, weight gain, and increased appetite.[2]
Pharmacology
Mechanism of action
Deflazacort is an inactive prodrug which is metabolized rapidly to the active drug 21-desacetyldeflazacort.[3]
Relative potency
Deflazacort’s potency is around 70–90% that of prednisone.[4] A 2017 review found its activity of 7.5 mg of deflazacort is approximately equivalent to 25 mg cortisone, 20 mg hydrocortisone, 5 mg of prednisolone or prednisone, 4 mg of methylprednisolone or triamcinolone, or 0.75 mg of betamethasone or dexamethasone. The review noted that the drug has a high therapeutic index, being used at initial oral doses ranging from 6 to 90 mg, and probably requires a 50% higher dose to induce the same demineralizing effect as prednisolone. Thus it has “a smaller impact on calcium metabolism than any other synthetic corticosteroid, and therefore shows a lower risk of growth rate retardation in children and of osteoporosis” in the elderly, and comparatively small effects on carbohydrate metabolism, sodium retention, and hypokalemia.[5]
History
In January 2015, the FDA granted fast track status to Marathon Pharmaceuticals to pursue approval of deflazacort as a potential treatment for Duchenne muscular dystrophy, a rare, “progressive and fatal disease” that affects boys.[6] Although deflazacort was approved by the FDA for use in treatment of Duchenne muscular dystrophy on February 9, 2017,[7][8] Marathon CEO announced on February 13, 2017 that the launch of deflazacort (Emflaza) would be delayed amidst controversy over the steep price Marathon was asking for the drug – $89,000-a-year. In Canada the same drug can be purchased for around $1 per tablet.[9] Marathon has said that Emflaza is estimated to cost $89,000/year which is “roughly 70 times” more than it would cost overseas.[10] Deflazacort is sold in the United Kingdom under the trade name Calcort;[4] in Brazil as Cortax, Decortil, and Deflanil; in India as Moaid, Zenflav, Defolet, DFZ, Decotaz, and DefZot; in Bangladesh as Xalcort; in Panama as Zamen; Spain as Zamene; and in Honduras as Flezacor.[11]
SYNTHESIS
Worlddrugtracker drew this
1 Protection of the keto groups in pregna-1,4-diene derivative with NH2NHCOOMe using HCOOH, yields the corresponding methyl ester.
2 Cleavage of epoxide with NH3 in DMAc/DMF gives amino-alcohol,
3 which on esterification with acetic anhydride in the presence of AcOH furnishes acetate.
4 Cyclization of amine using NaOH, Na2CO3 or K2CO3 produces oxazoline derivative ,
5 which is finally deprotected with HCl to afford Deflazacort
SYNTHESIS FROM CHEMDRUG
The cyclization of 17alpha-azido-3beta,16alpha-acetoxy-5alpha-pregnane-11,20-dione (I) by hydrogenation with H2 over Pt in methanol, followed by a treatment with 10% HCl gives 3beta-hydroxy-5alpha-pregnane-11,20-dione-[17alpha,16alpha-d]-2′-methyloxazoline (II), which is converted into the semicarbazone (III) by treatment with semicarbazide hydrochloride (A) and pyridine in refluxing methanol. The reduction of one ketonic group of (III) with NaBH4 in refluxing ethanol yields the dihydroxy-semicarbazone (IV), which is hydrolyzed with 10% HCl in refluxing methanol to afford the ketodiol (V). The oxidation of (V) with cyclohexanone and aluminum isopropoxide in refluxing toluene gives 11beta-hydroxy-5alpha-pregnane-3,20-dione-[17alpha,16alpha-d]-2′-methyloxazoline (VI). The dehydrogenation of (VI) by treatment with Br2 in dioxane-acetic acid, followed by treatment with Li2CO3 in DMF at 140 C yields the corresponding 1,4-diene derivative (VII). Finally, the reaction of (VII) with I2 by means of azobisisobutyronitrile in CH2Cl2 affords the corresponding 21-iodo compound, which is then acetylated with triethylammonium acetate in refluxing acetone.
The monoacetylation of (V) with acetic anhydride and pyridine at 100 C gives the 3-acetoxy-11-hydroxy compound (IX), which is dehydrated by treatment with methanesulfonyl chloride and then with sodium acetate yielding 3beta-acetoxy-5alpha-pregn-9(11)-ene-20-one-[17alpha,16alpha-d]-2′-methyloxazoline (X). The hydrolysis of (X) with KOH in refluxing methanol affords the corresponding hydroxy compound (XI), which is acetoxylated by treatment with I2 and AZBN as before giving the iodo derivative (XII), and then with triethylammonium acetate also as before, yielding 3beta-hydroxy-21-acetoxy-5alpha-pregn-9(11)-ene-20-one-[17alpha,16alpha-d]-2′-methyloxazoline (XIII). The oxidation of (XIII) with CrO3 in acetone yields the 3,20-diketone (XIV), which by treatment with Br2 and Li2CO3 as before is dehydrogenated affording the 1,4,9(11)-pregnatriene (XV). Finally, the reaction of (XV) with N-bromoacetamide in THF yields 9alpha-bromo-11beta-hydroxy-21-acetoxy-5alpha-pregna-1,4-dieno-3,20-dione-[17alpha,16alpha-d]-2′-methyloxazoline (XVI), which is then debrominated by reaction with chromous acetate and butanethiol in DMSO.
PAPER
Journal of Medicinal Chemistry (1967), 10(5), 799-802
Steroids Possessing Nitrogen Atoms. III. Synthesis of New Highly Active Corticoids. [17α,16α,-d]Oxazolino Steroids
PATENT
CN 105622713
PATENT CN 106008660
MACHINE TRANSLATED FROM CHINESE may seem funny
Description of the drawings
[0007] Figure 1 is a map of the traditional method of the combination process;
Figure 2 is a two-step method of the present invention.
detailed description
[0008] In order to more easily illustrate the gist and spirit of the present invention, the following examples illustrate:
Example 1
A: Preparation of hydroxylamine
In a 100 ml three-necked flask, 20 g of 16 (17) a-epoxy prednisolone, 30 ml of DMF, 300 ml of chloroform was added and incubated at 30-35 ° C with 8 g of ammonia gas at 1-2 atmospheres Reaction 16 ~ 20 hours, TLC detection reaction end point, after the reaction, the vacuum exhaust ammonia gas, add 3x100ml saturated brine washing 3 times, plus 10ml pure water washing times, then, under reduced pressure to chloroform to dry, add 200ml Ethyl acetate, Ig activated carbon, stirring reflux 60-90 minutes, cooling to 50-55 degrees, hot filter, l-2ml ethyl acetate washing carbon, combined filtrate and lotion, and then below 500C concentrated under pressure 95 % Of ethyl acetate, the system cooled to -5-0 ° C, stirring crystallization 2 ~ 3 hours, filter, 0.5-lml ethyl acetate washing, lotion and filtrate combined sets of approved; filter cake below 70 ° C Drying, get hydroxylamine 18.2g, HPLC content of 99.2%, weight loss of 91%.
[0009] B: Preparation of terracavir
Add 10 g of hydroxylamine, 150 ml of glacial acetic acid and 150 ml of acetic anhydride in a 100 ml three-necked flask. Add 5 g of concentrated sulfuric acid under stirring at room temperature. The reaction was carried out at 30-35 ° C for 12-16 hours. TLC confirmed the end of the reaction. Add 500ml of pure water, and adjust the pH of 7.5.5 with liquid alkali, cool to 10 ~ 15 ° C, stirring crystallization 2-3 hours, filtration, washing to neutral, combined filtrate and lotion, pretreated into Waste water treatment tank, filter cake below 70 V drying, Texaco can be special crude 112.5g, HPLC content of 98.2%, the yield of 112.5% ο the above terracotta crude dissolved in 800ml of alcohol, add 5g activated carbon, Decolorization 1-1.5 hours, hot filter, 10ml alcohol detergent cake, lotion and filtrate combined, atmospheric pressure recovery of about 90% of the alcohol, and then cooled to -5-0 ° C, frozen crystal 2-3 hours, Filtration, filter cake with 4-5ml alcohol washing, 70 ° C below drying, digoxin special product 89.2g, melting point 255.5-256.0 degrees, HPLC content of 99.7%, yield 89.2%. The mother liquor is recycled with solvent and crude.
[0010] Example II
A: Preparation of hydroxylamine
In a 100 ml three-necked flask, 20 g of 16 (17) a-epoxy prednisolone, 120 ml of toluene was added and incubated at 30-35 ° C with 8 g of ammonia and 16 to 20 at atmospheric pressure The reaction was carried out in the presence of 3 x 50 ml of saturated brine and 50 ml of pure water was added. Then, the toluene was dried under reduced pressure to dryness, and 200 ml of ethyl acetate, Ig activated carbon was added, and the mixture was stirred. Reflux 60-90 minutes, cool to 50-55 ° C, hot filter, l2ml ethyl acetate wash carbon, combined filtrate and lotion, and then below 500C under reduced pressure 95% ethyl acetate, the system cooling To 5-0C, stirring crystallization 2 ~ 3 hours, filter, 0.5-lml ethyl acetate washing, lotion and filtrate combined sets of the next batch; filter cake 70 ° C below drying, hydroxylamine 18.0g, HPLC content 99.1%, 90% by weight.
[0011] B: Preparation of terracavir
Add 10 g of hydroxylamine, 500 ml of chloroform and 150 ml of acetic anhydride in a 100 ml three-necked flask, add 5 g of p-toluenesulfonic acid under stirring at room temperature, and incubate at 30-35 ° C for 12-16 hours. TLC confirms the reaction end, After the addition of 500ml of pure water, and with the liquid alkali pH 7.55, down to 10 ~ 15 ° C, stirring 0.5_1 hours, separate the water layer, washed to neutral, combined with water and lotion, pretreated into Waste water treatment tank, organic layer under reduced pressure concentrated chloroform to near dry, adding 200ml hexane, reflux 0.5-1 hours, slowly cooling to -5 ~ O0C, stirring crystallization 2-3 hours, filter, filter cake with 4-5ml Alcohol washing, the filtrate and lotion combined apply to the next batch, the filter cake below 70 ° C drying, Texaco can crude 110.5g, HPLC content of 98.4%, the yield of 110.5%. The above-mentioned diltiazem crude product dissolved in 800ml alcohol, add 5g activated carbon, temperature reflux bleaching 1-1.5 hours, hot filter, 10ml alcohol washing cake, lotion and filtrate combined, atmospheric pressure recovery of about 90% of the alcohol And then cooled to -500C, frozen crystallization for 2-3 hours, filtration, filter cake with 4-5ml alcohol washing, 70 ° C the following drying, digester can special products 88.6g, melting point 255.0-256.0 degrees, HPLC content of 99.5%, the yield of 88.6%. The mother liquor is recycled with solvent and crude.
[0012] Example 3
A: Preparation of hydroxylamine
Add 20 g of 16 (17) a-epoxy prednisolone to 120 ml of ethanol in a 100 ml three-necked flask and incubate at 30-35 ° C with stirring to give Sg ammonia at 16 to 20 hours , TLC test reaction end point, after the reaction, vacuum exhaust ammonia gas, concentrated ethanol to the near dry, cooling, adding 300ml chloroform, stirring dissolved residue, and then add 3x100ml saturated brine washing, plus 10ml pure water washing, washing And then concentrated to reduce the chloroform to dry, add 200ml of ethyl acetate, Ig activated carbon, stirring reflux 60-90 minutes, cooling to 50-55 ° C, hot filter, l2ml ethyl acetate washing carbon, combined filtrate and lotion And then concentrated below 50 ° C to 95% ethyl acetate under reduced pressure. The system was cooled to -5-0 0C, stirred for 2 to 3 hours, filtered, 0.5-l of ethyl acetate, washed and filtrate The filter cake was dried at 70 ° C, 18.6 g of hydroxylamine, 99.5% of HPLC, and 93% by weight.
[0013] B: Preparation of terracavir
In a 100ml three-necked flask, add 10g of hydroxylamine, 500ml toluene, 150ml acetic anhydride, stirring at room temperature by adding 5g concentrated sulfuric acid, insulation at 30-35 degrees stirring reaction 12-16 hours, TLC confirmed the end of the reaction, after the reaction, Add 500ml of pure water, and liquid pH adjustment pH 7.5, cooling to 1 ~ 15 ° C, stirring 0.5-1 hours, the water layer, washed to neutral, combined with water and lotion, pretreated into the wastewater The cells were dried and the organic layer was concentrated to dryness under reduced pressure. 200 ml of hexane was added and refluxed
0.5-1 hours, slowly cool to -5 ~ O0C, stirring crystallization 2-3 hours, filtration, filter cake with 4-5ml hexane, the filtrate and lotion combined apply to the next batch, filter cake below 70 ° C Drying, digoxin crude 112.5g, HPLC content of 97.4%, the yield of 112,5% ο will be the above terracotta crude dissolved in 800ml of alcohol, add 5g activated carbon, heating reflux bleaching 1-1.5 hours, while Hot filter, 10ml alcohol detergent cake, lotion and filtrate combined, atmospheric pressure recovery of about 90% of the alcohol, and then cooled to -500C, frozen crystallization for 2-3 hours, filter, filter cake with 4-5ml alcohol Washing, 70 ° C below the dry, Diges can special products 86.2g, melting point 255.5-256.0 degrees, HPLC content of 99.8%, the yield of 86.2%. The mother liquor is recycled with solvent and crude.
PATENT
https://www.google.com/patents/CN101418032A?cl=en
Example 1
21- bromo -ll (3- hydroxy – pregna–l, 4- diene -3, 20-dione [170, 16o-d] -2′- methyl-oxazoline (4) Preparation:
A dry fitted with a thermometer, a reflux condenser, magnetically stirred flask was added 250mL three compound (2) (19.17 g; Fw: 383.48; 50 mmol), N- bromosuccinimide (9.79 g; Fw: 178.00; 55 mmol), 150 ml of ether; then ammonium acetate (0.39 g; Fw: 77.08; 0.005 mmol) added to the system. System continues to stir at 20 ° C 0.5 h, the reaction is complete. After completion of the reaction was filtered to remove the white precipitate cake was washed with 50 mL of dichloromethane, and the combined organic Xiangde pale yellow clear liquid, the solvent was evaporated under reduced pressure to give a pale yellow solid 21.27 g, yield: 92%, HPLC content of greater than 95%.
Example 2
21- bromo -lip- hydroxy – pregna–l, 4- diene -3, 20-dione [17 “16o-d] -2′- methyl-oxazoline (4) Preparation:
A dry fitted with a thermometer, a reflux condenser, magnetically stirred flask were added sequentially 250mL three compound (2) (19.17 g; Fw: 383.48; 50 mmol), N- bromosuccinimide (9.79 g; Fw : 178.00; 55 mmol), 150 ml of toluene; then ammonium acetate (0.39 g; Fw: 77.08; 0.005 mmol) added to the system. System continues to stir at 110 ° C 5 h, the reaction is complete. After completion of the reaction was cooled to room temperature, the white precipitate was removed by filtration cake was washed with 50 mL of dichloromethane, and the combined organic Xiangde pale yellow clear liquid, concentrated under reduced pressure to remove the solvent to give a pale yellow solid 19.65 g, yield: 85%, HPLC content greater than 95%.
Example 3
21 Jie bromo -11 – hydroxy – pregna-1,4-diene -3, 20-dione [17a, 16o-d] -2′- methyl-oxazoline (4) Preparation:
A dry fitted with a thermometer, a reflux condenser, magnetically stirred flask were added sequentially 250mL three compound (2) (19.17 g; Fw: 383.48; 50 mmol), 1,3- dibromo-5,5-dimethyl- Hein (35.74 g; Fw: 285.94; 125 mmol), 150 ml of ether; then ammonium acetate (0.39 g; Fw: 77.08; 0.005 mmol) added to the system. System Stirring was continued at reflux for 3 h, the reaction was completed. After completion of the reaction a white precipitate was removed by filtration and the cake was washed with 50 mL of diethyl ether, and the combined organic Xiangde pale yellow clear liquid, concentrated under reduced pressure to remove the solvent to give a pale yellow solid 16.18 g, yield: 70%, HPLC content greater than 92%.
Example 4
21- bromo -11 Jie – hydroxy – pregna-1,4-diene -3, 20- dione [17c, 16o-d] -2′- methyl-oxazoline (4) Preparation:
A dry fitted with a thermometer, a reflux condenser, magnetically stirred flask were added sequentially 250mL three compound (2) (19.17 g; Fw: 383.48; 50 mmol), 1,3- dibromo-5,5-dimethyl- Hein (35.74 g; Fw: 285.94; 125 mmol), 150 ml dichloromethane; followed by ammonium acetate (0.039 g; Fw: 77.08; 0.0005 mmol) added to the system. System Stirring was continued at reflux for 24 h, the reaction was completed. After completion of the reaction a white precipitate was removed by filtration and the cake was washed with 50 mL of diethyl ether, and the combined organic Xiangde pale yellow clear liquid, concentrated under reduced pressure to remove the solvent to give a pale yellow solid 16.41 g, yield: 71%, HPLC content of greater than 92. / 0.
Example 5
Deflazacort Preparation:
In a nitrogen-filled dry fitted with a thermometer, magnetic stirring and a reflux condenser 100 mL three-necked flask was charged with Compound (4) (11.56 g; Fw: 462.38; 25 mmol), followed by addition of sodium acetate (8.20g; Fw: 82.03; lOOmmol), 50 mL methanol was added to the system.
Then tetrabutylammonium bromide (O. 81g; Fw: 322.38; 2.5 mmol). Warmed to 50 ° C with stirring
48 h. Until after the completion of the reaction was cooled to room temperature. After completion of the reaction, temperature of the system was cooled to room temperature, the system was supplemented with chloroform 50mL, filtered, and the filter cake was washed with small amount of chloroform and then to confirm that no product was dissolved, and the combined organic phases, the organic phase washed with 10% aqueous sodium carbonate paint 3 times, saturated sodium chloride once. The organic phase was dried over anhydrous sodium sulfate, the inorganic salt was removed to give a pale yellow liquid, was concentrated to dryness, purified ethyl acetate to give the product 9.93g, yield 90%, HPLC content> 990/0.
Example 6
Deflazacort Preparation –
In a nitrogen-filled dry fitted with a thermometer, magnetic stirring and a reflux condenser 100 mL three-necked flask was charged with Compound (4) (11.56 g; Fw: 462.38; 25 mmol), followed by addition of anhydrous potassium acetate (3.68g; Fw: 98.14; 37.5 mmol), 50 mL acetone was added to the system. Followed by tetrabutylammonium iodide (0.10g; Fw: 369.37; 0.25 mmol). Heated to reflux with stirring 2h. Until after the completion of the reaction was cooled to room temperature. After completion of the reaction, temperature of the system was cooled to room temperature, the system was supplemented with chloroform 50mL, filtered, and the filter cake was washed with small amount of chloroform and then to confirm that no product was dissolved, and the combined organic phases, the organic phase was washed 3 times with 10% aqueous sodium carbonate , washed once with saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate, the inorganic salt was removed to give a pale yellow liquid, was concentrated to dryness, ethyl acetate was purified to give the product 10.93 g, yield 99%, HPLC content> 99%.
Example 7
Deflazacort Preparation:
In a nitrogen-filled dry fitted with a thermometer, magnetic stirring and a reflux condenser 100 mL three-necked flask was charged with Compound (4) (11.56 g; Fw: 462.38; 25 mmol), followed by addition of anhydrous potassium acetate (3.68g; Fw: 98.14; 37.5 mmol), 50 mL acetonitrile was added to the system. Followed by tetrabutylammonium iodide (0.10g; Fw: 369.37; 0.25 mmol). Heated to reflux with stirring 2h. Until after the completion of the reaction was cooled to room temperature. After completion of the reaction, temperature of the system was cooled to room temperature, the system was supplemented with chloroform 50mL, filtered, and the filter cake was washed with small amount of chloroform and then to confirm that no product was dissolved, and the combined organic phases, the organic phase was washed 3 times with 10% aqueous sodium carbonate , washed once with saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate, the inorganic salt was removed to give a pale yellow liquid, was concentrated to dryness, ethyl acetate was purified to give the product 10.93 g, yield 99%, HPLC content> 99%.
Example 8
Deflazacort Preparation:
In a nitrogen-filled dry fitted with a thermometer, magnetic stirring and a reflux condenser 100 mL three-necked flask was charged with Compound (4) (11.56 g; Fw: 462.38; 25 mmol), followed by addition of anhydrous potassium acetate (2.45g; Fw: 98.14; 25 mmol), the N, N- dimethylformamide, 50 mL added to the system. Followed by tetrabutylammonium iodide (O.IO g; Fw: 369.37; 0.25 mmol). Warmed to 120. C stirring 2h. Until after the completion of the reaction was cooled to room temperature. After completion of the reaction, temperature of the system was cooled to room temperature, the system was supplemented with chloroform 50mL, filtered, and the filter cake was washed with small amount of chloroform and then to confirm that no product was dissolved, and the combined organic phases, the organic phase was washed 3 times with 10% aqueous sodium carbonate , washed once with saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate, the inorganic salt was removed to give a pale yellow liquid, was concentrated to dryness, ethyl acetate was purified to give the product 10.93 g, yield 99%, HPLC content> 99o / q.
PATENT
https://www.google.com/patents/WO1997021722A1?cl=zh
compound (llβ,16β)-21-(acetyloxy)-11- hydroxy-2 ‘ -methyl-5 ‘H-pregna-1, -dieno[17 , 16-d Joxazole- 3,20-dione, also known, and hereinafter referred to, with the INN (International Nonproprietary Name) deflazacort. Deflazacort is represented by the following formula I
Deflazacort is employed in therapy aince some years as a calcium-sparing corticoid agent. This compound belongs to the more general class of pregneno-oxazolines, for which anti-inflammatory, glucocorticoid and hormone-like pharmacological activities are reported. Examples of compounds of the above class, comprising deflazacort, are disclosed in US 3413286, where deflazacort is referred to as llβ-21-dihydroxy-2 ‘ -methyl-5 ‘ βH-pregna-1,4-dieno.17 , 16- d]oxazole-3,20-dione 21-acetate.
According to the process disclosed by US 3413286, deflazacort is obtained from 5-pregnane-3β-ol-ll , 20- dione-2 ‘-methyloxazoline by 2 , -dibromination with Br2– dioxane, heating the product in the presence of LiBr- iC03 for obtaining the 1,4-diene, and converting this latter into the 21-iodo and then into the desired 21- acetyloxy compound. By hydrolysis of deflazacort, the llβ-21-dihydroxy-2 ‘ -methyl-5 ‘βH-pregna-1, -dieno[ 17 , 16- d-]oxazoline-3, 20-dione of formula II is obtained:
The compound of formula II is preferably obtained according to a fermentation process disclosed in
EP-B-322630; in said patent, the compound of formula II is referred to as llβ-21-dihydroxy-2 ‘-methyl-5 ‘ βH- pregna-1,4-dieno[17,16-d-]oxazoline-3,20-dione.
The present invention provides a new advantageous single-step process for obtaining deflazacort, by acetylation of the compound of formula II.
CLIP
tructure of deflazacort and its forced degradation product (A), chromatogram plot of standard deflazacort (B), contour plot of deflazacort (C). Deflazacort was found to be a stable drug under stress condition such as thermal, neutral and oxidative condition. However, the forceddegradation study on deflazacort showed that the drug degraded under alkaline, acid and photolytic conditions.
Mass fragmentation pathway for degradant product of deflazacort.
PATENT
Example 1: Protective reaction To the reaction flask was added 20 g of 1,4-diene-11? -hydroxy-16,17-epoxy_3,20-dione pregnone (Formula I) 20% of the aqueous solution of glacial acetic acid 300g, stirring 5 minutes, temperature 10 ° C ~ 15 ° C, adding ethyl carbazate 14g, temperature control 30 ° C reaction 6 hours; TLC detection reaction is complete, cooling to 0 ° C ~ 5 ° C for 2 hours, until dry, washed to neutral; 60 ° C vacuum dry to dry creatures 20. 5g; on P, oxazoline ring reaction The above protective products into the reaction bottle, add 41ml Of the DMAC dissolved, temperature 25 ~ 30 ° C, access to ammonia, to keep the reaction bottle micro-positive pressure, the reaction of 32 hours, atmospheric pressure exhaust ammonia and then decompression pumping ammonia for 30 minutes; 5 ° C, temperature 5 ~ 0 ° C by adding 5ml glacial acetic acid, then add 21ml acetic anhydride, heated to 35 ° C reaction 4 hours, the sample to confirm the reaction completely; slowly add 5% sodium hydroxide solution 610ml and heated to 60 ~ 70 ° C reaction 2 hours; point plate to confirm the end of the reaction, cooling to 50 ° C, half an hour by adding refined concentrated hydrochloric acid 40ml, insulation 50 ~ 55 ° C reaction 10 hours; to the end of the reaction temperature to room temperature, chloroform Extraction, drying and filtration, concentration of at least a small amount of solvent, ethyl acetate entrained twice, leaving a small amount of solvent, frozen crystallization filter high purity [17a, 16a-d] terfu Kete intermediate. Example 2: Protective reaction 20 g of 1,4-diene-l1-la-hydroxy-16,17-epoxy_3,20_dione progestin (Formula I) was added to the reaction flask and 15% Formic acid solution 300g, stirring for 5 minutes, temperature 10 ~ 15 ° C, adding methyl carbazate 12g, temperature control 30 ° C reaction 5 hours to test the end of the reaction, cooling to O ~ 5 ° C stirring 2 hours crystallization, Suction to dry, washed to neutral; 60 ° C vacuum drying to dry protection of 20g; on P, oxazoline ring reaction The protection of the reaction into the reaction flask, add 30ml of DMF dissolved, temperature control 25 ~ 30 ° C, access to ammonia, keep the reaction bottle in the micro-positive pressure, reaction 30 hours, atmospheric pressure exhaust ammonia and then decompression pumping ammonia for 30 minutes, ice water cooled to 5 ° C, temperature 5 ~ 10 ° C add 5ml of glacial acetic acid, then add 20ml acetic anhydride, heated to 30 ° C reaction for 5 hours to confirm the reaction is complete; slowly add 20% sodium carbonate aqueous solution 500ml and heated to 60 ~ 70 ° C reaction 4 hours, the point plate to confirm the reaction The temperature of 55 ~ 60 ° C for 10 hours; to be the end of the reaction temperature to room temperature, chloroform extraction, drying and filtration, concentration of a small amount of solvent, acetic acid isopropyl The ester was entrained twice, leaving a small amount of solvent, frozen and crystallized to obtain high purity [17a, 16a-d] oxazoline residues. [0024] Example 3: Protective reaction 20 g of I, 4-diene-16,17-epoxy-3,11,20-triketone pregnone (Formula I) was added to the reaction flask and 20% Formic acid solution 300g, stirring for 5 minutes, temperature 10 ~ 15 ° C, adding hydrazine carbamate 15g, temperature control 30 ° C reaction 5 hours to test the end of the reaction, cooling to O ~ 5 ° C stirring 2 hours crystallization, To the dry, washed to neutral; 60 ° C vacuum drying to dry protection of 22g; on P, oxazoline ring reaction of the protection of the reaction into the bottle, add 30ml of DMAC dissolved temperature control 35 ~ 40 ° C, access to ammonia, keep the reaction bottle in the micro-positive pressure, reaction 40 hours, atmospheric pressure exhaust ammonia and then decompression pumping ammonia for 30 minutes, ice water cooling to 5 ° C, temperature 5 ~ 10 ° C add 5ml of glacial acetic acid, then add 20ml acetic anhydride, heated to 40 ° C reaction 5 hours to confirm the reaction is complete; slowly add 20% potassium carbonate aqueous solution 500ml and heated to 60 ~ 70 ° C reaction 7 hours, the point plate to confirm the reaction The temperature of the reaction to the end of the temperature to room temperature, chloroform extraction, drying filter, concentrated to a small amount of solvent, acetic acid isopropyl The ester was entrained twice, leaving a small amount of solvent, frozen and crystallized to obtain high purity [17a, 16a-d] oxazoline residues.
PATENT
xample 1
[0028] A 30 g 16, 17 α- epoxy – pregn -20- substituting methyl hydrazine -3-acetyl-1,4-diene, 11- dione (a) and 150 mL of chloroform and 15 mLDMF mixed, pressure reactor, stirring ammonia gas to the reactor pressure to 0.15 MPa (during ventilation control the reaction temperature at 10-15 ° C), 30 ° C heat reaction, TLC track the progress of the reaction. Completion of the reaction, the material was transferred to a glass reaction flask, the temperature of the material to be reduced to below 10 ° C, add acetic acid adjusted to pH 5 to 6, the solvent was removed under reduced pressure; reaction flask was added 30 mL of acetic acid, 30 g of acetic anhydride, The reaction temperature was controlled at 30 ° C, the reaction 6 hours, the reaction mixture was poured into cold 500 mL10% sodium hydroxide solution, stirred for 1 hour, filtration to give product 30.6 g, 102% mass yield, product by HPLC , a purity of 95.2%.
[0029] Example 2
[0030] A 30 g 16, 17 α- epoxy – pregn -20- substituting methyl hydrazine -3-acetyl-1,4-diene, 11- dione (a) and 150 mL of chloroform and 30 mL of pyridine were mixed, added pressure reactor, stirring ammonia gas to the reactor pressure to 0. 15 MPa (during ventilation control the reaction temperature at 10~15 ° C), 15 ° C heat reaction, TLC track the progress of the reaction. Completion of the reaction, the material was transferred to a glass reaction flask, the temperature of the material to be reduced to below 10 ° C, add acetic acid adjusted to pH 5 to 6, the solvent was removed under reduced pressure; reaction flask was added 30 mL of acetic acid, 30 g of acetic anhydride, The reaction temperature was controlled at 30 ° C, the reaction 6 hours, the reaction mixture was poured into cold 500 mL10% sodium hydroxide solution, stirred for 1 hour, filtration to give product 28.6 g, yield 95% by mass, product by HPLC , a purity of 94.8%.
[0031] Example 3
[0032] A 30 g 16, 17 α- epoxy – pregn -20- substituting methyl hydrazine -3-acetyl-1,4-diene, 11- dione (a) and 150 mL of chloroform and 30 mLDMF mixed, pressure reactor, stirring ammonia gas to the reactor pressure to 0.15 MPa (during ventilation control the reaction temperature at 10~15 ° C), 40 ° C heat reaction, TLC track the progress of the reaction.Completion of the reaction, the material was transferred to a glass reaction flask, the temperature of the material to be reduced to below 10 ° C, add acetic acid adjusted to pH 5 to 6, the solvent was removed under reduced pressure; reaction flask was added 30 mL of acetic acid, 30 g of acetic anhydride, The reaction temperature was controlled at 30 ° C, the reaction for 6 hours. The reaction mixture was poured into cold 500 mL10% sodium hydroxide solution, stirred for 1 hour, filtration to give the product 31.2 g, yield 104% quality products by HPLC , a purity of 95.4%.
[0033] Example 4
[0034] A 30 g 16, 17 α- epoxy – pregn -20- substituting methyl hydrazine -3-acetyl-1,4-diene, 11- dione (a) and 150 mL of chloroform and 30 mLDMF mixed, pressure reactor, stirring ammonia gas to the reactor pressure to 0.5 MPa (during ventilation control the reaction temperature at 10~15 ° C), 40 ° C heat reaction, TLC track the progress of the reaction. Completion of the reaction, the material was transferred to a glass reaction flask, the temperature of the material to be reduced to below 10 ° C, add acetic acid adjusted to pH 5 to 6, the solvent was removed under reduced pressure; reaction flask was added 30 mL of acetic acid, 30 g of acetic anhydride, The reaction temperature was controlled at 30 ° C, the reaction 6 hours, the reaction mixture was poured into cold 500 mL10% sodium hydroxide solution, stirred for 1 hour, filtration to give the product 31. I g, 102% mass yield, product by by HPLC, the purity was 95.2%.
[0035] Example 5
[0036] A 30 g 16, 17 α- epoxy – pregn -20- substituting methyl hydrazine -3-acetyl-1,4-diene, 11- dione (a) and 150 mL of chloroform and 30 mLDMF mixed, pressure reactor, stirring ammonia gas to the reactor pressure to 0.15 MPa (during ventilation control the reaction temperature at 10~15 ° C), 40 ° C heat reaction, TLC track the progress of the reaction. Completion of the reaction, the material was transferred to a glass reaction flask, the temperature of the material to be reduced to below 10 ° C, add acetic acid adjusted to pH 5 to 6, the solvent was removed under reduced pressure; reaction flask was added 60 mL of acetic acid, 15 g of acetic anhydride, The reaction temperature was controlled at 30 ° C, the reaction 6 hours, the reaction mixture was poured into cold 500 mL10% sodium hydroxide solution, stirred for 1 hour, filtration to give the product 29. 5 g, yield 98% by mass, the product of by HPLC, purity of 95%.
[0037] Example 6
[0038] A 30 g 16, 17 α- epoxy – pregn -20- substituting methyl hydrazine -3-acetyl-1,4-diene, 11- dione (a) and 150 mL of chloroform and 30 mLDMF mixed, pressure reactor, stirring ammonia gas to the reactor pressure to 0.15 MPa (during ventilation control the reaction temperature at 10~15 ° C), 40 ° C heat reaction, TLC track the progress of the reaction. The reaction was complete, the material was transferred to a glass reaction flask until the material temperature drops below 10 ° C, plus acetic acid to adjust the pH to 5 to 6, the solvent was removed under reduced pressure; the reaction flask was added 30 mL of acetic acid, 30 g of maleic dianhydride, the reaction temperature was controlled at 30 ° C, the reaction 6 hours, the reaction mixture was poured into cold 500 mL10% sodium hydroxide solution, stirred for 1 hour, filtration to give the product 30 g, 100% mass yield, product by HPLC purity of 95.2%.
[0039] Example 7
[0040] A 30 g 16, 17 α- epoxy – pregn -20- substituting methyl hydrazine -3-acetyl-1,4-diene, 11- dione (a) and 150 mL of chloroform and 30 mLDMF mixed, pressure reactor, stirring ammonia gas to the reactor pressure to 0.15 MPa (during ventilation control the reaction temperature at 10~15 ° C), 40 ° C heat reaction, TLC track the progress of the reaction. Completion of the reaction, the material was transferred to a glass reaction flask, the temperature of the material to be reduced to below 10 ° C, add acetic acid adjusted to pH 5 to 6, the solvent was removed under reduced pressure; reaction flask was added 30 mL of acetic acid, 30 g of propionic anhydride, The reaction temperature was controlled at 30 ° C, the reaction for 6 hours. The reaction mixture was poured into cold 500 mL10% sodium hydroxide solution, stirred for 1 hour, filtration to give the product 27.6 g, 92% yield of quality products by HPLC , a purity of 93.5%.
[0041] Example 8
[0042] A 30 g 16, 17 α- epoxy – pregn -20- substituting methyl hydrazine -3-acetyl-1,4-diene, 11- dione (a) and 150 mL of chloroform and 30 mLDMF mixed, pressure reactor, stirring ammonia gas to the reactor pressure to 0.15 MPa (during ventilation control the reaction temperature at 10~15 ° C), 40 ° C heat reaction, TLC track the progress of the reaction. Completion of the reaction, the material was transferred to a glass reaction flask, the temperature of the material to be reduced to below 10 ° C, add acetic acid adjusted to pH 5 to 6, the solvent was removed under reduced pressure; reaction flask was added 30 mL of acetic acid, 30 g of acetic anhydride, The reaction temperature is controlled at 50 ° C, the reaction for 6 hours. The reaction mixture was poured into cold 500 mL10% sodium hydroxide solution, stirred for 1 hour, filtration to give the product 29.8 g, 99% yield of quality products by HPLC , a purity of 94.8%.
References
- Jump up^ “Refla: deflazacort” (PDF).
- Jump up^http://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208684s000,208685s000lbl.pdf
- Jump up^ Möllmann, H; Hochhaus, G; Rohatagi, S; Barth, J; Derendorf, H (1995). “Pharmacokinetic/pharmacodynamic evaluation of deflazacort in comparison to methylprednisolone and prednisolone”. Pharmaceutical Research. 12 (7): 1096–100. PMID 7494809.
- ^ Jump up to:a b “Calcort”. electronic Medicines Compendium. June 11, 2008. Retrieved on October 28, 2008.
- Jump up^ Luca Parente (2017). “Deflazacort: therapeutic index, relative potency and equivalent doses versus other corticosteroids”. BMC Pharmacol Toxicol. doi:10.1186/s40360-016-0111-8.
- Jump up^ Ellen Jean Hirst (January 19, 2015), Duchenne muscular dystrophy drug could get OK for U.S. sales in 2016, The Chicago Tribune, retrieved February 13, 2017,
has been shown to prolong lives … a progressive and fatal disease that has no drug treatment available in the US
- Jump up^ “FDA approves drug to treat Duchenne muscular dystrophy”. http://www.fda.gov. 2017-02-09. Retrieved 2017-02-10.
- Jump up^ “Marathon Pharmaceuticals to Charge $89,000 for Muscular Dystrophy Drug”. http://www.wsj.com. 2017-02-10. Retrieved 2017-02-10.
- Jump up^ Clifton Sy Mukherjee (February 10, 2017). “Brainstorm Health Daily”. Retrieved February 13, 2017.
- Jump up^ Joseph Walker and Susan Pulliam (February 13, 2017), Marathon Pharmaceuticals to Charge $89,000 for Muscular Dystrophy Drug After 70-Fold Increase, The Wall Street Journal, retrieved February 13, 2017,
FDA-approved deflazacort treats rare type of disease affecting boys
- Jump up^ “Substâncias: DEFLAZACORT” (in Portuguese). Centralx. 2008. Retrieved on October 28, 2008.
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|
| Clinical data | |
|---|---|
| Trade names | Emflaza, Calcort, others |
| AHFS/Drugs.com | International Drug Names |
| Routes of administration |
By mouth |
| ATC code | |
| Legal status | |
| Legal status |
|
| Pharmacokinetic data | |
| Protein binding | 40% |
| Metabolism | By plasma esterases, to active metabolite |
| Biological half-life | 1.1–1.9 hours (metabolite) |
| Excretion | Renal (70%) and fecal (30%) |
| Identifiers | |
| CAS Number | |
| PubChem CID | |
| DrugBank | |
| ChemSpider | |
| UNII | |
| KEGG | |
| ChEMBL | |
| ECHA InfoCard | 100.034.969 |
| Chemical and physical data | |
| Formula | C25H31NO6 |
| Molar mass | 441.517 g/mol |
| 3D model (Jmol) | |
| CN102746358A * | Apr 22, 2011 | Oct 24, 2012 | 天津金耀集团有限公司 | Novel technology for synthesis of pregnane 21-bit bromide |
| CN102746358B * | Apr 22, 2011 | Feb 10, 2016 | 天津金耀集团有限公司 | 一种合成孕甾21位溴化物的工艺 |
| CN102936274A * | Nov 12, 2012 | Feb 20, 2013 | 浙江仙居君业药业有限公司 | Preparation method for [17alpha, 16alpha-d] methyl oxazoline |
| CN102936274B * | Nov 12, 2012 | Apr 1, 2015 | 江西君业生物制药有限公司 | Preparation method for [17alpha, 16alpha-d] methyl oxazoline |
///////FDA 2017, Emflaza, Calcort, Deflazacort, orphan drug designation, FAST TRACK
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FDA approves new psoriasis drug Siliq (brodalumab)
FDA approves new psoriasis drug
The U.S. Food and Drug Administration today approved Siliq (brodalumab) to treat adults with moderate-to-severe plaque psoriasis. Siliq is administered as an injection.
For Immediate Release
February 15, 2017
Release
The U.S. Food and Drug Administration today approved Siliq (brodalumab) to treat adults with moderate-to-severe plaque psoriasis. Siliq is administered as an injection.
Siliq is intended for patients who are candidates for systemic therapy (treatment using substances that travel through the bloodstream, after being taken by mouth or injected) or phototherapy (ultraviolet light treatment) and have failed to respond, or have stopped responding to other systemic therapies.
“Moderate-to-severe plaque psoriasis can cause significant skin irritation and discomfort for patients, and today’s approval provides patients with another treatment option for their psoriasis,” said Julie Beitz, M.D., director of the Office of Drug Evaluation III in the FDA’s Center for Drug Evaluation and Research. “Patients and their health care providers should discuss the benefits and risks of Siliq before considering treatment.”
Psoriasis is a skin condition that causes patches of skin redness and flaking. Psoriasis is an autoimmune disorder that occurs more commonly in patients with a family history of the disease, and most often begins in people between the ages of 15 and 35. The most common form of psoriasis is plaque psoriasis, in which patients develop thick, red skin with flaky, silver-white scales.
Siliq’s active ingredient (brodalumab) binds to a protein that causes inflammation, inhibiting the inflammatory response that plays a role in the development of plaque psoriasis.
Siliq’s safety and efficacy were established in three randomized, placebo-controlled clinical trials with a total of 4,373 adult participants with moderate-to-severe plaque psoriasis who were candidates for systemic therapy or phototherapy. More patients treated with Siliq compared to placebo had skin that was clear or almost clear, as assessed by scoring of the extent, nature and severity of psoriatic changes of the skin.
Suicidal ideation and behavior, including completed suicides, have occurred in patients treated with Siliq during clinical trials. Siliq users with a history of suicidality or depression had an increased incidence of suicidal ideation and behavior compared to users without this history. A causal association between treatment with Siliq and increased risk of suicidal ideation and behavior has not been established.
Because of the observed risk of suicidal ideation and behavior, the labeling for Siliq includes a Boxed Warning and the drug is only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Siliq REMS Program. Notable requirements of the Siliq REMS Program include the following:
- Prescribers must be certified with the program and counsel patients about this risk. Patients with new or worsening symptoms of depression or suicidality should be referred to a mental health professional, as appropriate.
- Patients must sign a Patient-Prescriber Agreement Form and be made aware of the need to seek medical attention should they experience new or worsening suicidal thoughts or behavior, feelings of depression, anxiety or other mood changes.
- Pharmacies must be certified with the program and must only dispense to patients who are authorized to receive Siliq.
Siliq is also approved with a Medication Guide to inform patients of the risk of suicidal ideation and behavior, and that because Siliq is a medication that affects the immune system, patients may have a greater risk of getting an infection, or an allergic or autoimmune condition. Patients with Crohn’s disease should not use Siliq. Health care providers should also evaluate patients for tuberculosis (TB) infection prior to initiating treatment with Siliq. Health care providers should not administer Siliq to patients with active TB infection, and should avoid immunizations with live vaccines in patients being treated with Siliq.
The most common adverse reactions reported with the use of Siliq include joint pain (arthralgia), headache, fatigue, diarrhea, throat pain (oropharyngeal pain), nausea, muscle pain (myalgia), injection site reactions, influenza, low white blood cell count (neutropenia) and fungal (tinea) infections.
Siliq is marketed by Bridgewater, New Jersey-based Valeant Pharmaceuticals.
New Drug Approvals 