New Drug Approvals

MYSELF

DR ANTHONY MELVIN CRASTO Ph.D ( ICT, Mumbai) , INDIA 36Yrs Exp. in the feld of Organic Chemistry,Working for AFRICURE PHARMA as ADVISOR earlier with GLENMARK PHARMA at Navi Mumbai, INDIA. Serving chemists around the world. Helping them with websites on Chemistry.Million hits on google, NO ADVERTISEMENTS , ACADEMIC , NON COMMERCIAL SITE, world acclamation from industry, academia, drug authorities for websites, blogs and educational contribution, ........amcrasto@gmail.com..........+91 9323115463, Skype amcrasto64

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with AFRICURE PHARMA, ROW2TECH, NIPER-G, Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Govt. of India as ADVISOR, earlier assignment was with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 32 PLUS year tenure till date Feb 2023, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 38 lakh plus views on New Drug Approvals Blog in 227 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc He has total of 32 International and Indian awards

Verified Services

View Full Profile →

Medicinal Chemistry International: NARLAPREVIR

December 30, 2013 1:08 am / Leave a comment

Medicinal Chemistry International: NARLAPREVIR

WANT TO KNOW ABOUT VIR SERIES CLICK

click

http://drugsynthesisint.blogspot.in/p/vir-series-hep-c-virus-22.html

AND

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

NARLAPREVIR

An antiviral agent that inhibits hepatitis C virus NS3 protease.

M.Wt: 707.96
Formula: C36H61N5O7S

CAS No.: 865466-24-6

SCH 900518;SCH900518;SCH-900518

3-Azabicyclo[3.1.0]hexane-2-carboxamide, N-[(1S)-1-[2-(cyclopropylamino)-2-
oxoacetyl]pentyl]-3-[(2S)-2-[[[[1-[[(1,1-dimethylethyl)sulfonyl]methyl]cyclohexyl]
amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-, (1R,2S,5S)-

2. (1R,2S,5S)-N-{(1S)-1-[2-(cyclopropylamino)-2-oxoacetyl]pentyl}-3-[(2S)-2-{[(1-{[(1,1-
dimethylethyl)sulfonyl]methyl}cyclohexyl)carbamoyl]amino}-3,3-dimethylbutanoyl]-6,6-
dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide

3. (1R,2S,5S)-3-{N-[({1-[(tert-butylsulfonyl)methyl]cyclohexyl}amino)carbonyl]-3-methyl-L-
valyl}-N-{(1S)-1-[(cyclopropylamino)(oxo)acetyl]pentyl}-6,6-dimethyl-3-
azabicyco[3.1.0]hexane-2-carboxamide

Narlaprevir is a potent, Second Generation HCV NS3 Serine Protease Inhibitor.Narlaprevir is useful for Antiviral

Merck & Co. (Originator)

SCH-900518 had been in phase II clinical trials by Merck & Co. for the treatment of genotype 1 chronic hepatitis C; however, no recent development has been reported for this indication.

A potent oral inhibitor of HCV NS3 protease, SCH-900518 disrupts hepatitis C virus (HCV) polyprotein processing. When added to the current standard of care (SOC), peginterferon-alfa plus ribavirin, SCH-900518 is likely to increase the proportion of patients achieving undetectable HCV-RNA levels and sustained virologic response (SVR).

In 2012, the product was licensed by Merck & Co. to R-Pharm in Russia and the Commonwealth of Independent States (CIS) for the development and commercialization as treatment of hepatitis C (HCV)

PATENTS

WO 2011014494

WO 2010068714

(1 R,5S)-N-[1 (S)-[2-(cyclopropylamino)-1 ,2-dioxoethyl]pentyl]-3-[2(S)- [[[[1-[[1.¹-di^methylethyl)sulfonyl]methyl]cyclohexyl]amino]carbonyl]amino]-3,3- dimethyl-1-oxobutyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2(S)-carboxamide.

Identification of any publication in this section or any section of this application is not an admission that such publication is prior art to the present invention.

The compound of Formula I is generically and specifically disclosed in

Published U.S. Patent No.2007/0042968, published February 22, 2007 (the ‘968 publication), incorporated herein by reference.

Processes suitable for making the compound of Formula I are generally described in the ‘968 publication. In particular, the ‘968 publication discusses preparing a sulfone carbamate compound, for example, the compound of Formula 837 comprising a cyclic sulfone substituent (paragraphs [0395] through [0403]). The following reaction scheme describes the procedure:

The process disclosed in the ‘968 publication produces the intermediate alcohol in step S7 as a mixture of diastereomers at the hydroxyl group; while this chiral center is lost in the final step of the disclosed process, the alcohol intermediate as a mixture of isomers cannot be crystallized and required a volumetrically inefficient precipitative isolation that did not remove any impurities

,………………………………………………………………………………………………………………………

WO2011014494A1

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

US20120178942

Preparation of Compound VIJ

LDA was made by slowly charging n-butyl lithium (2.5 M, 159 kg) to diisopropyl amine (60 kg) dissolved in THF (252 kg), keeping the temperature at about −20° C., followed by agitation at this temperature for about 30 min. To this solution was charged cyclohexane carboxylic acid, methyl ester (70 kg), keeping the temperature below −10° C. The mixture was agitated at this temperature for about 2 h. To the resulting enolate was charged TMSCI (64.4 kg). The mixture was agitated at −10 to −20° C. for about 30 min, and then heated to about 25° C. and held at this temperature to allow for conversion to the silylenol ether Compound VIH. The reaction mixture was solvent exchanged to n-heptane under vacuum, keeping the temperature below 50° C., resulting in the precipitation of solids. The solids were filtered and washed with n-heptane, and the wash was combined with the n-heptane reaction mixture. The n-heptane mixture of Compound VIH was concentrated under vacuum and diluted with CH₂Cl₂.

In a separate reactor was charged CH₂Cl₂(461 kg) and anhydrous ZnBr₂(14.5 kg). The temperature of the zinc slurry was adjusted to about 20° C. To the zinc slurry was simultaneously charged the solution of Compound VIH and 2-chloromethylsulfanyl-2-methyl-propane (63.1 kg, ref: Bioorg. Med. Chem. Lett, 1996, 6, 2053-2058), keeping the temperature below 45° C. After complete addition, the mixture was agitated for about 1.5 h at 35 to 45° C., after which the reaction mixture was cooled to 10 to 15° C. A solution of dilute aqueous HCl was then charged, keeping the temperature between 0 and 15° C., followed by a separation of the aqueous and organic layers (desired compound in organic layer). The organic layer was washed with aqueous NaHCO₃and water. The organic layer was solvent exchanged to methanol by vacuum distillation, keeping the temperature below 35° C., and kept as a solution in methanol for further processing to Compound VIK. Active Yield of Compound VIJ=69.7 kg (molar yield=57.9%).

Preparation of Compound VIK

To a fresh reactor was charged Compound VIJ (99.8 kg active in a methanol solution), water (270 kg), NaOH (70 kg), and methanol (603 kg). The mixture was heated to −70° C. and agitated at this temperature for about 16 h. Upon conversion to the sodium salt of Compound VIK, the reaction mixture was concentrated under vacuum, keeping the temperature below 55° C., and then cooled to about 25° C. Water and MTBE were then charged, agitiated, and the layers were separated (product in the aqueous layer). The product-containing aqueous layer was further washed with MTBE.

CH₂Cl₂was charged to the aqueous layer and the temperature was adjusted to ˜10° C. The resultant mixture was acidified to a pH of about 1.5 with HCl, agitated, settled, and separated (the compound was in the organic layer). The aqueous layer was extracted with CH₂Cl₂, and the combined organic layers were stored as a CH₂Cl₂solution for further processing to Compound VID. Active yield of Compound VIK=92.7 kg (molar yield=98.5 kg). MS Calculated: 230.13; MS Found (ES−, M−H): 229.11.

Preparation of Compound VID

To a reactor was charged water (952 kg), Oxone® (92.7 kg), and Compound VIK (92.7 kg active as a solution in CH₂Cl₂). The reaction mixture was agitated for about 24 h at a temperature of about 15° C., during which time Compound VIK oxidized to sulfone Compound VID. The excess Oxone® was quenched with aqueous Na₂S₂O₅, the reaction mixture was settled and the layers separated; the aqueous layer was back-extracted with CH₂Cl₂, and the combined product-containing organic layers were washed with water.

The resultant solution was then concentrated under vacuum. To precipitate Compound VID, n-heptane was charged, and the resulting slurry was agitated for about 60 min at a temperature of about 30° C. The reaction mixture was filtered, and the wet cake was washed with n-heptane. The wet cake was redissolved in CH₂Cl₂, followed by the addition of n-heptane. The resultant solution was then concentrated under vacuum, keeping the temperature below 35° C., to allow for product precipitation. The resultant solution was cooled to about 0° C. and agitated at this temperature for about 1 h. The solution was filtered, the wet cake was washed with n-heptane, and dried under vacuum at about 45° C. to yield 68.7 kg Compound VID (molar yield=65.7%). MS Calculated: 262.37; MS Found (ES−, M−H): 261.09

Preparation of Compound VI

To a reactor was charged Compound VID (68.4 kg), toluene (531 kg), and Et₃N (31 kg). The reaction mixture was atmospherically refluxed under Dean-Stark conditions to remove water (target KF <0.05%). The reaction temperature was adjusted to 80° C., DPPA (73.4 kg) was charged over 7 h, and the mixture was agitated for an additional 2 h. After conversion to isocyanate Compound VIE via the azide, the reaction mixture was cooled to about 0 to 5° C. and quenched with aqueous NaHCO₃. The resultant mixture was agitated, settled and the layers were separated. The aqueous layer was extracted with toluene, and the combined isocyante Compound VIE organic layers were washed with water.

In a separate vessel was charged L-tert- Leucine (L-Tle, 30.8 kg), water (270 kg), and Et₃N (60 kg). While keeping the temperature at about 5° C., the toluene solution of Compound VIE was transferred to the solution of L-Tle. The reaction mixture was stirred at 0 to 5° C. for about 5 h, at which time the mixture was heated to 15 to 20° C. and agitated at this temperature for 2 h to allow for conversion to urea Compound VI.

The reaction was quenched by the addition of aqueous NaOH, keeping the temperature between 0 and 25° C. The reaction mixture was separated, and the organic layer was extracted with water. The combined Compound VI-containing aqueous layers were washed with toluene, and acidified to pH 2 by the addition of HCl, at which time the product precipitated from solution. The reaction mixture was filtered, washed with water and dried under vacuum at 65 to 70° C. to yield 79.7 kg crude Compound VI (molar yield 52.7%). MS Calculated: 390.54; MS Found (ES−, M−H): 389.20.

Compound VI is further purified by slurrying in CH₃CN at reflux (about 80° C.), followed by cooling to RT. Typical recovery is 94%, with an increase in purity from about 80% to 99%.

Preparation of Compound Va

To a reactor was charged Compound VI (87.6 kg), Compound VII-1 (48.2 kg), HOBt (6 kg) and CH₃CN (615 kg). The reaction mixture was cooled to about 5° C., and NMM (35 kg) and EDCi (53.4 kg) were charged. The reaction was heated to 20 to 25° C. for about 1 h, and then to 35 to 40° C., at which time water was charged to crystallize Compound Va. The reaction mixture was cooled to 5° C. and held at this temperature for about 4 h. Compound Va was filtered and washed with water. XRD data for the hydrated polymorph of Va is as follows:

The Compound Va wet cake was charged to a fresh vessel and was dissolved in ethyl acetate at 25 to 30° C. The solution was washed with an aqueous HCl solution, aqueous K₂CO₃solution, and brine. The solution was then concentrated under vacuum, keeping the temperature between 35 to 50° C. Additional ethyl acetate was charged, and the solution was heated to 65 to 70° C. While keeping the temperature at 65 to 70° C., n-heptane was charged, followed by cooling the resultant solution to 0 to 5° C. Compound Va was filtered and washed with an ethyl acetate/n-heptane mix.

The wet cake was dried under vacuum between 55 to 60° C. to yield 96.6 kg crystalline Compound Va (molar yield 79.2%). MS Calculated: 541.32; MS Found (ES+, M+H): 542.35.

Preparation of Compound IUB

Pyridine (92 L) was charged to the reactor and was cooled to 5° C. To the cooled pyridine was slowly charged malonic acid (48.5 kg) and valeraldehyde (59 L), keeping the temperature below 25° C. The reaction was stirred between 25 to 35° C. for at least 60 h. After this time, H₂SO₄was charged to acidify, keeping the temperature below 30° C. The reaction mixture was then extracted into MTBE. The organic layer was washed with water. In a separate reactor was charged water and NaOH. The MTBE solution was charged to the NaOH solution, keeping the temperature below 25° C., and the desired material was extracted into the basic layer. The basic layer was separated and the organic layer was discarded. MTBE was charged, the mixture was agitated, settled, and separated, and the organic layer was discarded. To the resultant solution (aqueous layer) was charged water and H₂SO₄to acidify, keeping the temperature between 10 to 15° C. To the acidified mixture was charged MTBE, keeping the temperature below 25° C. The resultant solution was agitated, settled, and separated, and the aqueous layer was discarded. The product-containing organic layer was washed with water and was concentrated under vacuum, keeping the temperature below 70° C., to yield 45.4 kg Compound IIIB (molar yield=76.2%) as an oil. Compound Reference: Concellon, J. M.; Concellon, C J. Org. Chem., 2006, 71, 1728-1731

Preparation of Compound IIIC

To a pressure vessel was charged Compound IIIB (9.1 kg), heptane (9 L), and H₂SO₄(0.5 kg). The pressure vessel was sealed and isobutylene (13.7 kg) was charged, keeping the temperature between 19 to 25° C. The reaction mixture was agitated at this temperature for about 18 h. The pressure was released, and a solution of K₂CO₃was charged to the reaction mixture, which was agitated and settled, and the bottom aqueous layer was then separated. The resultant organic solution was washed with water and distilled under vacuum (temp below 45° C.) to yield 13.5 kg Compound IIIC (molar yield=88.3%) as a yellow oil.

Preparation of Compound IIID

To a reactor capable of maintaining a temperature of −60° C. was charged (S)-benzyl-1-phenyl ethylamine (18 kg) and THF (75 L). The reaction mixture was cooled to −60° C. To the mixture was charged n-hexyl lithium (42 L of 2.3 M in heptane) while maintaining a temperature of −65 to −55° C., followed by a 30 min agitation within this temperature range. To the in situ-formed lithium amide was charged Compound IIIC over 1 h, keeping the temperature between −65 to −55° C. . The reaction mixture was agitated at this temperature for 30 min to allow for conversion to the enolate intermediate. To the resultant reaction mixture was charged (+)-camphorsulfonyl oxaziridine (24 kg) as a solid, over a period of 2 h, keeping the temperature between −65 to −55° C. . The mixture was agitated at this temperature for 4 h.

The resultant reaction mixture was quenched by the addition of acetic acid (8 kg), keeping the temperature between −60 to −40° C. The mixture was warmed to 20 to 25° C., then charged into a separate reactor containing heptane. The resultant mixture was concentrated under vacuum, keeping the temperature below 35° C. Heptane and water were charged to the reaction mixture, and the precipitated solids were removed by filtration (the desired compound is in the supernatant). The cake was washed with heptane and this wash was combined with the supernatant. The heptane/water solution was agitated, settled, and separated to remove the aqueous layer. An aqueous solution of H₂SO₄was charged, and the mixture was agitated, settled, and separated. The heptane layer was washed with a solution of K₂CO₃.

The heptane layer was concentrated under reduced pressure, keeping the temperature below 45° C., and the resulting oil was diluted in toluene, yielding 27.1 kg (active) of Compound IIID (molar yield=81.0%). MS Calculated: 411.28; MS Found (ES+, M+H): 412.22.

A similar procedure for this step was reported in: Beevers, R, et al, Bioorg. Med. Chem. Lett. 2002, 12, 641-643.

Preparation of Compound IDE

Toluene (324 L) and a toluene solution of Compound IIID (54.2 kg active) was charged to the reactor. TFA (86.8 kg) was charged over about 1.5 h, keeping the temperature below 50° C. The reaction mixture was agitated for 24 h at 50° C. The reaction mixture was cooled to 15° C. and water was charged. NaOH was slowly charged, keeping the temperature below 20° C., to adjust the batch to a pH between 5.0 and 6.0. The reaction mixture was agitated, settled, and separated; the aqueous layer was discarded. The organic layer was concentrated under vacuum, keeping the temperature below 40° C., and the resulting acid intermediate (an oil), was dissolved in 2-MeTHF.

In a separate reactor, 2-MeTHF (250 L), HOBt (35.2 kg), and EDCi-HCl (38.0 kg) were charged and the mixture was adjusted to a temperature between 0 to 10° C. DIPEA (27.2 kg) was charged, keeping the mixture within this temperature range. The mixture was agitated for 5 min, followed by the addition of cyclopropyl amine (11.4 kg), keeping the temperature between 0 to 10° C.

To this solution was charged the 2-MeTHF/ acid intermediate solution, keeping the resultant solution between 0 to 10° C. The resultant mixture was heated to 25 to 35° C., and was agitated at this temperature for about 4 h. The reaction mixture was cooled to about 20° C., and was washed with aqueous citric acid, aqueous K₂CO₃, and water. The solvent was exchanged to n-heptane, and the desired compound was crystallized from a mix of n-heptane and toluene by cooling to 0° C. The crystalline product was filtered, washed with n-heptane, and dried to yield 37.1 kg Compound IIIE (molar yield=70.7%). MS Calculated: 394.26; MS Found (ES+, M+H): 395.22.

Preparation of Compound III

To a pressure reactor was charged acetic acid (1.1 kg), methanol (55 kg), and Compound IIIE (10.9 kg). In a separate vessel, Pd/C (50% water wet, 0.5 kg) was suspended in methanol (5 kg). The Pd/C suspension was transferred to the solution containing Compound IIIE. The resultant mixture was pressurized to 80 psi with hydrogen, and agitated at 60° C. for 7 h. The reaction mixture was then purged with nitrogen, and the Pd/C catalyst was filtered off. The resultant solution was concentrated under vacuum and adjusted to about 20° C. MTBE was charged, and the resultant solution was brought to reflux. Concentrated HCl (3 L) was charged and the product was crystallized by cooling the reaction mixture to about 3° C. The desired compound was filtered, washed with MTBE, and dried under vacuum, keeping the temperature below 40° C. to yield 5.5 kg Compound III (molar yield=83.0%). MS Calculated (free base): 200.15; MS Found (ES+, M+H): 201.12.

Preparation of Compound II

Compound Va (119.3 kg) was dissolved in 2-MeTHF (720 kg) and water (180 kg). To this solution was charged 50% NaOH (21.4 kg) while maintaining a temperature between 20 and 30° C. The reaction mixture was then agitated for about 7 h at a temperature between 50 and 60° C. The reaction mixture was cooled to a temperature between 20 and 30° C.

The pH of the reaction mixture was adjusted to 1.5-3.0 with dilute phosphoric acid, maintaining a temperature between 20 and 30° C. The resultant mixture was agitated for 10 min, settled for 30 min, and the bottom aqueous layer was separated and removed. The top organic layer was washed with water, followed by concentration by atmospheric distillation.

The concentrated solution was solvent exchanged to CH₃CN by continuous atmospheric distillation, and crystallized by cooling to 0° C. The crystalline product was filtered, washed with CH₃CN, and dried under vacuum at a temperature between 45 and 55° C. to yield 97.9 kg Compound II (molar yield=83.7%). MS Calculated: 527.30; MS Found (ES+, M+H): 528.29.

Preparation of Compound IV

Compound II (21.1 kg), Compound III (9.9 kg), HOBt (3.2 kg) and EDCi (11.2 kg) were charged to the vessel, followed by CH₃CN (63 kg), ethyl acetate (20 kg) and water (1.5 kg). The reaction mixture was agitated and the heterogeneous mixture was cooled to −5 to +5° C. DIPEA (11.2 kg) was charged to the reaction mixture, maintaining a temperature between −5 to +5° C. and the mixture was agitated at a temperature of −5 to +5° C. for 1 h. The resultant reaction mixture was warmed to 20 to 30° C. and agitated for 2 to 3 h.

The resultant product was extracted with aqueous HCl, aqueous K₂CO₃, and water.

The desired product was crystallized from ethyl acetate by cooling from reflux (78° C.) to about 0° C. The crystalline product was filtered and dried at 30° C. under vacuum to yield 23.1 kg Compound IV (molar yield=81.3%). MS Calculated: 709.44; MS Found (ES+, M+H): 710.47.

Preparation of Compound I

Compound IV (22.5 kg), TEMPO (5 kg), NaOAc (45 kg), methyl acetate (68 L), MTBE (158 L), water (23 L) and acetic acid (22.5 L) were charged to the reactor. The reaction mixture was stirred at 20-30° C. to allow for dissolution of the solids, and was then cooled to 5-15° C. NaOCl solution (1.4 molar equivalents) was charged to the reaction mixture, keeping the temperature at about 10° C. After complete addition of NaOCl, the reaction mixture was agitated at 10° C. for 2 h.

The reaction was quenched by washing with a buffered sodium ascorbate/HCl aqueous solution, followed by a water wash.

The reaction mixture was solvent exchanged to acetone under vacuum, keeping the temperature below 20° C.; the desired product was crystallized by the addition of water, and dried under vacuum, keeping the temperature below 40° C. to yield 18.6 kg Compound I (molar yield=82.7%). MS Calculated: 707.43: MS Found (ES+, M+H): 708.44.

WANT TO KNOW ABOUT VIR SERIES CLICK

click

http://drugsynthesisint.blogspot.in/p/vir-series-hep-c-virus-22.html

AND

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

Medicinal Chemistry International: ROXADUSTAT

December 29, 2013 9:20 am / 1 Comment on Medicinal Chemistry International: ROXADUSTAT

Medicinal Chemistry International: ROXADUSTAT

Medicinal Chemistry International

December 29, 2013 9:19 am / Leave a comment

Medicinal Chemistry International

World Drug Tracker: Degarelix …NICE backs Ferring’s Firmagon for prostate cancer subgroup

December 29, 2013 4:59 am / Leave a comment

World Drug Tracker: Degarelix …NICE backs Ferring’s Firmagon for prostate cancer subgroup

TAVABOROLE, AN 2690, 他伐硼罗 Таваборол تافابورول

December 29, 2013 3:14 am / 2 Comments on TAVABOROLE, AN 2690, 他伐硼罗 Таваборол تافابورول

TAVABOROLE

AN 2690
AN-2690
AN2690
UNII-K124A4EUQ3

5-Fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole

5-Fluoro-2,1-benzoxaborol-1(3H)-ol;

1,3-Dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole

MOLECULAR FORMULA C7H6BFO2

MOLECULAR WEIGHT 151.9

SPONSOR Anacor Pharmaceuticals, Inc.

CAS REGISTRY NUMBER 174671-46-6 Fine

Mp 118-120° C…..US20070265226

¹H NMR (300 MHz, DMSO-d₆) δ (ppm) 4.95 (s, 2H), 7.15 (m, 1H), 7.24 (dd, J=9.7, 1.8 Hz, 1H), 7.74 (dd, J=8.2, 6.2 Hz, 1H), 9.22 (s, 1H)

FDA APPROVED JULY 2 2014………..“FDA Approves Anacor Pharmaceuticals’ KERYDIN™ (Tavaborole) Topical Solution, 5% for the Treatment of Onychomycosis of the Toenails”. Market Watch. July 8, 2014.

Has antifungal activity.

The US Food and Drug Administration (FDA) 2014 JULY 8 ratified the Anacor’s Kerydin (5% Tavaborole solution) for the topical treatment of nail fungal infections. Tavaboroleindications of toenail fungus Trichophyton rubrum or Trichophyton rubrum infections.Instructions recommended once a day for toenail infections, treatment for 48 weeks, on the recommendation of Anacor, and do not need to nail debridement.

I tis an oxaborole antifungal used topically, as a 5% w/w solution, for the treatment of onychomycosis of the toenails due to Trichophyton rubrumor T. mentagrophytes. It is applied to the affected toenail once daily for 48 weeks.

Ingrowing toenails and application site reactions including exfoliation, erythema, and dermatitis have been reported during use. Stock market

1H NMR FROM NET

CLICK ON IMAGE FOR CLEAR VIEW

COSY NMR PREDICT

Tavaborole (AN2690, trade name Kerydin) is a topical antifungal medication for the treatment of onychomycosis, a fungal infectionof the nail and nail bed. Tavaborole began its Phase 3 trials in December 2010^[1] and was approved in July 2014.^[2] Tavaborole inhibits an essential fungal enzyme, Leucyl-tRNA synthetase, or LeuRS, required for protein synthesis. The inhibition of protein synthesis leads to termination of cell growth and cell death, eliminating the fungal infection. No treatment-related systemic side effects were observed in any of its clinical trials. Passing

Tavaborole is the first oxygen boron used to treat toenail infections dioxolane (oxaborole) antifungal agents, located in Palo Alto, Anacor focuses on boron-based drug development and production, according to the latest news, Tavaborole future also be used to infect fingernails. Wedbush Securities analyst predicts that next year the drug sales in the United States for $ 16 million, by 2021 will reach peak sales of $ 347 million.

Gram-negative bacteria cause approximately 70% of the infections in intensive care units. A growing number of bacterial isolates responsible for these infections are resistant to currently available antibiotics and to many in development. Most agents under development are modifications of existing drug classes, which only partially overcome existing resistance mechanisms. Therefore, new classes of Gram-negative antibacterials with truly novel modes of action are needed to circumvent these existing resistance mechanisms. We have previously identified a new a way to inhibit an aminoacyl-tRNA synthetase, leucyl-tRNA synthetase (LeuRS), in fungi via the oxaborole tRNA trapping (OBORT) mechanism. Irrigation

Herein, we show how we have modified the OBORT mechanism using a structure-guided approach to develop a new boron-based antibiotic class, the benzoxaboroles, which inhibit bacterial leucyl-tRNA synthetase and have activity against Gram-negative bacteria by largely evading the main efflux mechanisms in Escherichia coli and Pseudomonas aeruginosa. The lead analogue, is active against Gram-negative bacteria, including Enterobacteriaceaebearing NDM-1 and KPC carbapenemases, as well as P. aeruginosa. This novel boron-based antibacterial, has good mouse pharmacokinetics and was efficacious against E. coli and P. aeruginosa in murine thigh infection models, which suggest that this novel class of antibacterials has the potential to address this unmet medical need.

Anacor continued development on that drug, tavaborole, and filed for FDA approval in July. The FDA will review the phase 3 trial data and issue a decision on July 29, 2014.

If approved, Anacor hopes tavaborole’s ability to clear onychomycosis in 10% of treated patients will be enough to win market share away from generic Lamisil and generic topical Pentac. While Lamisil cleared the fungus in 38% of patients, it’s been associated with rare cases of liver failure. And Pentac requires frequent debridement of the nail and only clears the fungus in 5.5% to 8.5% of patients.

Tavaborole is a novel, topical antifungal medication being developed for the topical treatment of onychomycosis, a nail fungus infection, which affects seven to ten percent of the U.S. population. Early studies show AN-2690 penetrates the nail effectively and has robust activity against dermatophytes, which cause onychomycosis.

1H NMR PREDICT You do not buy

……………………………………………………………………………

13 C NMR PREDICT Stock market

ARTICLE Grab spaces

July 18, 2013

Anacor Pharmaceuticals to Present Pivotal Phase 3 Data of Tavaborole for the Topical Treatment of Toenail Onychomycosis
Abstract Accepted for Oral Presentation at the 2013 American Podiatric Medical Association Annual Scientific Meeting

PALO ALTO, Calif.–(BUSINESS WIRE)– Anacor Pharmaceuticals (NASDAQ:ANAC) announced today that its abstract “Pivotal Phase 3 Safety and Efficacy Results of Tavaborole (Formerly AN2690), a Novel Boron-Based Molecule for the Topical Treatment of Toenail Onychomycosis” was accepted for oral presentation at the 2013 APMA Annual Scientific Meeting (The National) to be held in Las Vegas, Nevada. Max Weisfeld, DPM, will present the data from tavaborole’s Phase 3 studies on Monday, July 22, 2013 during the Evidence-Based Medicine and Oral Abstracts session.

As announced earlier this year, tavaborole achieved statistically significant and clinically meaningful results on all primary and secondary endpoints in two Phase 3 pivotal studies without concomitant debridement. Anacor is seeking approval for tavaborole from the Food and Drug Administration (FDA) and will file a New Drug Application imminently. Currently, there is only one FDA-approved topical treatment for onychomycosis, a fungal infection of the nail and nail bed, which affects approximately 35 million people in the United States. Mildew

“I’m impressed with tavaborole’s safety and efficacy data. There is no FDA-approved topical treatment for onychomycosis with tavaborole’s range of efficacy and ability to penetrate the nail to reach the site of the infection,” said Dr. Weisfeld. “Tavaborole’s Phase 3 results demonstrate its ability to clear the nail and eliminate the infection which is important to both patients and the physicians who treat them. In addition, tavaborole is easy to apply and dries quickly which makes it convenient for patients to use.”

“We are pleased to present these positive data at the APMA’s Annual Scientific Meeting, the leading annual meeting of podiatrists. As we seek FDAapproval for tavaborole, we look forward to developing relationships with podiatrists to potentially offer them a new treatment option for the large number of patients who seek treatment for onychomycosis,” said David Perry, Chief Executive Officer of Anacor Pharmaceuticals.

About the Studies

Anacor conducted two separate Phase 3 studies of tavaborole on patients with distal subungual onychomycosis affecting 20 to 60 percent of the target great toenail. Approximately 600 patients aged 18 years and older with no upper age limit (the oldest subject was 88 years old) were enrolled in each study and randomized two-to-one to receive either tavaborole or the vehicle control. Patients were instructed to apply tavaborole solution or the vehicle to the toenail once daily for 48 weeks.

A copy of the presentation will be available on Anacor’s website following the oral session.

About Anacor Pharmaceuticals

Anacor is a biopharmaceutical company focused on discovering, developing and commercializing novel small-molecule therapeutics derived from its boron chemistry platform. Anacor has discovered eight compounds that are currently in development. Its two lead product candidates are topically administered dermatologic compounds — tavaborole, a topical antifungal for the treatment of onychomycosis, and AN2728, a topical anti-inflammatory PDE-4 inhibitor for the treatment of atopic dermatitis and psoriasis. In addition to its two lead programs, Anacor has discovered three other wholly-owned clinical product candidates — AN2718 and AN2898, which are backup compounds to tavaborole and AN2728, respectively, and AN3365 an antibiotic for the treatment of infections caused by Gram-negative bacteria. We have discovered three other compounds that we have out-licensed for further development — two compounds for the treatment of animal health indications that are licensed to Eli Lilly and Company and AN5568, also referred to as SCYX-7158, for human African trypanosomiasis (HAT, or sleeping sickness), which is licensed to Drugs for Neglected Diseases initiative, or DNDi. We also have a pipeline of other internally discovered topical and systemic boron-based compounds in development. For more information, visit http://www.anacor.com.

Patents

WO 1995033754

WO 2004009578….

WO 2006089067

WO 2008025543

…………………………..

SYNTHESIS

APX1

Stock market

Reference:

ELI LILLY AND COMPANY Patent: WO2004/9578 A2, 2004 ; Location in patent: Page 36-37 ; WO 2004/009578 A2

APX1

PATENT

Anacor Pharmaceuticals Patent: US2007/265226 A1, 2007 ; Location in patent: Page/Page column 59 ;

http://www.google.com/patents/US20070265226

1,3-Dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborole (19b)

To a solution of 5b (73.2 g, 293 mmol) in dry THF (400 mL) was added n-butyllithium (1.6 M in hexanes; 200 mL) over 45 min at −78° C. under nitrogen atmosphere. Anion precipitated. After 5 min, (i-PrO)₃B (76.0 mL, 330 mmol) was added over 10 min, and the mixture was allowed to warm to room temperature over 1.5 h. Water and 6 N HCl (55 mL) were added, and the solvent was removed under reduced pressure to about a half volume. The mixture was poured into ethyl acetate and water. The organic layer was washed with brine and dried over anhydrous Na₂SO₄. The solvent was removed under reduced pressure. To a solution of the residue in tetrahydrofuran (360 mL) was added 6 N HCl (90 mL), and the mixture was stirred at 30° C. overnight. The solvent was removed under reduced pressure to about a half volume. The mixture was poured into ethyl acetate and water. The organic layer was washed with brine and dried over anhydrous Na₂SO₄. The solvent was removed under reduced pressure, and the residue was treated with i-Pr₂O/hexane to give 19b (26.9 g, 60%) as a white powder:

mp 118-120° C.;

¹H NMR (300 MHz, DMSO-d₆) δ (ppm) 4.95 (s, 2H), 7.15 (m, 1H), 7.24 (dd, J=9.7, 1.8 Hz, 1H), 7.74 (dd, J=8.2, 6.2 Hz, 1H), 9.22 (s, 1H);

ESI-MS m/z 151 (M−H)⁻;

HPLC purity 97.8%; Anal (C₇H₆BFO₂) C, H.

Stock market

…………………

Gunasekera, Dinara S.; Gerold, Dennis J.; Aalderks, Nathan S.; Chandra, J. Subash; Maanu, Christiana A.; Kiprof, Paul; Zhdankin, Viktor V.; Reddy, M. Venkat Ram Tetrahedron, 2007 , vol. 63, # 38 p. 9401 – 9405

…………………….

Baker, Stephen J.; Zhang, Yong-Kang; Akama, Tsutomu; Lau, Agnes; Zhou, Huchen; Hernandez, Vincent; Mao, Weimin; Alley; Sanders, Virginia; Plattner, Jacob J. Journal of Medicinal Chemistry, 2006 , vol. 49, # 15 p. 4447 – 4450

………………..

Ding, Charles Z.; Zhang, Yong-Kang; Li, Xianfeng; Liu, Yang; Zhang, Suoming; Zhou, Yasheen; Plattner, Jacob J.; Baker, Stephen J.; Liu, Liang; Duan, Maosheng; Jarvest, Richard L.; Ji, Jingjing; Kazmierski, Wieslaw M.; Tallant, Matthew D.; Wright, Lois L.; Smith, Gary K.; Crosby, Renae M.; Wang, Amy A.; Ni, Zhi-Jie; Zou, Wuxin; Wright, Jon Bioorganic and Medicinal Chemistry Letters, 2010 , vol. 20, # 24 p. 7317 – 7322

…………..

PATENT

US20050261277

PREPARATION 13 5-Fluoro-3H-benzo[c][1,2)oxaborol-1-ol

Figure US20050261277A1-20051124-C00027
Dissolve 1-bromo-2-(1-ethoxy-ethoxymethyl)-4-fluoro-benzene(5.4 g, 19.5 mmol) in dry THF (100 mL) and cool to −78° C. under nitrogen. Add butyl lithium (2.5M in Hexanes, 10.2 mL, 25.4 mmol) dropwise at −78° C. Upon complete addition, stir the reaction at −78° C. for 10 minutes and then add trimethyl borate (4.4 mL, 39 mmol) and warm the reaction to room temperature. Pour the reaction into 1N HCl (100 mL) and stir for 1 hour. Extract the biphasic mixture with ether three times. Dry the combined organic layers with sodium sulfate, filter and concentrate in vacuo. Triturate the oily residue with cold hexanes to yield 2.1 g (70%) of the title compoud as a white solid.

1H NMR (d6-DMSO)

9.18 (s, 1H),

7.70 (dd, J=8.2, 5.8 Hz, 1H),

7.20 (dd, J=9.5, 2.7 Hz, 1H),

7.11 (m, 1H), 4.92 (s, 1H).

…………………

SEE

http://jpet.aspetjournals.org/content/early/2012/11/28/jpet.112.200030.full.pdf

………………………………..

SEE Top

Discovery of a new boron-containing antifungal agent, 5-fluoro-1,3-dihydro-1-hydroxy-2,1- benzoxaborole (AN2690), for the potential treatment of onychomycosis.

Baker SJ, Zhang YK, Akama T, Lau A, Zhou H, Hernandez V, Mao W, Alley MR, Sanders V, Plattner JJ.

J Med Chem. 2006 Jul 27;49(15):4447-50.

Boron-containing inhibitors of synthetases.

Baker SJ, Tomsho JW, Benkovic SJ.

Chem Soc Rev. 2011 Aug;40(8):4279-85. doi: 10.1039/c0cs00131g. Epub 2011 Feb 7. Review.

Benzoxaborole antimalarial agents. Part 2: Discovery of fluoro-substituted 7-(2-carboxyethyl)-1,3-dihydro-1-hydroxy-2,1-benzoxaboroles.

Zhang YK, Plattner JJ, Freund YR, Easom EE, Zhou Y, Ye L, Zhou H, Waterson D, Gamo FJ, Sanz LM, Ge M, Li Z, Li L, Wang H, Cui H.

Bioorg Med Chem Lett. 2012 Feb 1;22(3):1299-307. doi: 10.1016/j.bmcl.2011.12.096. Epub 2011 Dec 28.

Tavaborole Market Opportunity

Anacor is developing tavaborole specifically to address the current limitations of existing treatment options for onychomycosis. This includes designed leaps forward in both the potential safety and efficacy profile aimed to make the drug a best-in-class therapy. Additionally, management has used the company’s expertise in medicinal chemistry to improve delivery of the compound through the nail plate to the nail bed, the site of onychomycosis infection. For example, preclinical studies indicate that tavaborole is able to penetrate the nail plate 250 times more effectively than ciclopirox.

Tavaborole novel mechanism of action inhibits an essential fungal enzyme, leucyl transfer RNA synthetase, or LeuRS required for protein synthesis. The inhibition of protein synthesis leads to termination of cell growth and cell death, eliminating the fungal infection.

Likewise, the topical dosing was designed to eliminate systemic absorption. Previous preclinical and clinical data shows topical treatment with tavaborole resulted in little or no detectable levels of drug in the blood or urine. No treatment related systemic side effects have been observed in any clinical trials to date. Safety data from the company’s studies to date was recently presented at the 100th National APMA meeting in Washington, DC.

Anacor’s topical solution currently in two phase III trials for onychomycosis. Phase II data with tavaborole suggests efficacy superior to ciclopirox with little to no systemic exposure.

Data from an open-label phase 2 program with tavaborole showed 50% patients using a 7.5% solution saw 2 mm clear nail growth and negative fungal cultures after six months. Roughly 25% of the patients saw 5 mm clear nail growth and negative fungal cultures after six months.

Anacor and partner Merck (NYSE:MRK) met with the U.S. FDA in 2009 to discuss the phase II data. Merck has since returned the rights to tavaborole to Anacor. The original deal was with Schering-Plough in 2007. Merck most likely felt as though tavaborole clashed with existing products or did not have peak sales potential large enough to continue the partnership with Anacor. We see tavaborole as a specialty promoted product, into podiatrists and dermatologists. For a company like Anacor, it’s an attractive first product.

Anacor’s first phase III trial completed enrollment in November 2011. The second phase III trial completed enrollment in December 2011. Data from these trials are expected around the middle of January 2013. Data from the second study is expected six weeks later. Given the positive phase II data noted above, we think odds favor a positive outcome. A benchmark for the trial is the efficacy of Lamisil, which is a complete cure rate of around 35% to 40%, and a mycological cure of around 70% after a typical course of treatment.

I note that on Anacor’s third quarter conference call management noted that they are pleased with the conduct of the trial to date. Specifically, the compliance rate appears to better than management had expected. The trial was designed with a 20% drop-out rate. It looks as though the drop-out rate is only around 13%, at a minimum suggestive of good safety and tolerability, but potentially also a sign that the drug is working.

I see onychomycosis as a significant market opportunity for Anacor. An estimated 35 million Americans have nail fungus, with about 95% of the infections in the toenail. With efficacy similar to Lamisil, we think Anacor can capture 20% of the market. With a price per course of treatment at around $1,200, I think peak sales of tavaborole are $500 million.

Conclusion

I’ll note two more important pieces of information for investors. Firstly, besides optimism for tavaborole, Anacor has apipeline of anti-infectant drugs. For this article I discussed only tavaborole. A second article can be dedicated entirely to AN2728 for the treatment of psoriasis and atopic dermatitis. Anacor also has an animal health collaboration with Eli Lilly (NYSE:LLY).

The second important thing to note is Anacor’s cash position. The company reported financial results on November 7, 2012. The company held $36.6 million in cash on the balance sheet as of September 30, 2012. However, in October 2012, the company completed an underwritten public offering of 4.0 million shares of common stock at $6.00 per share to raise net proceeds of $22.7 million. I view the current cash position as sufficient to report data from both phase 3 trials and, if positive, file the new drug application (NDA) around the middle of 2013.

With phase 3 data expected in less than two months, good prior evidence of both safety and efficacy, and a solid cash position, I think Anacor could be an attractive investment at today’s price. The stock is down meaningfully over the past month and investors can buy sizably below the October offering.

SYNTHESIS

References

Clinical trial number NCT01270971 at ClinicalTrials.gov
“FDA Approves Anacor Pharmaceuticals’ KERYDIN™ (Tavaborole) Topical Solution, 5% for the Treatment of Onychomycosis of the Toenails”. Market Watch. July 8, 2014.
http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204427s000lbl.pdf
http://www.molbase.com/en/hnmr_174671-46-6-moldata-1568017.html#tabs

Tavaborole
Systematic (IUPAC) name


5-Fluoro-2,1-benzoxaborol-1(3H)-ol
Clinical data
Trade names	Kerydin
Legal status	℞ (Prescription only)
Routes of administration	Topical use only
Identifiers
CAS Registry Number	174671-46-6
ATC code	None
PubChem	CID: 11499245
ChemSpider	9674047
Synonyms	AN2690
Chemical data
Formula	C₇H₆B F O₂
Molecular mass	151.93 g/mol

Fine Stock market

Stock market

NMR PREDICT

H-NMR spectral analysis

CAS NO. 174671-46-6, 5-fluoro-1-hydroxy-3H-2,1-benzoxaborole H-NMR spectral analysis

C-NMR spectral analysis

CAS NO. 174671-46-6, 5-fluoro-1-hydroxy-3H-2,1-benzoxaborole C-NMR spectral analysis

GSK2251052

BIG TEAM Hernandez, front row, fifth from left, poses during a research meeting at Naeja’s headquarters. Anacor

BIG TEAM Hernandez, front row, fifth from left, poses during a research meeting at Naeja’s headquarters.

Anacor Pharmaceuticals is out to change that. The Palo Alto, Calif.-based biotechnology company is developing a family of boron-containing small-molecule drugs. And with the assistance of Naeja Pharmaceutical, a Canadian contract research organization, Anacor has licensed one of those molecules to GlaxoSmithKline and taken another one into Phase III clinical trials.

Anacor was founded in 2002 to develop technology created by Lucy Shapiro, a Stanford University bacterial geneticist, and Stephen J. Benkovic, a Pennsylvania State University organic chemist. Through a long-standing scientific collaboration, the two researchers had discovered boron-containing compounds that inhibited specific bacterial targets………..https://pubs.acs.org/cen/coverstory/89/8912cover3.html

UPDATED………….

Click to access NMR.pdf

mp 118-120….http://www.syninnova.com/catalog/product/SL-264

Click to access HPLC.pdf

antifugal AN2690 by Anacor

Tavaborole inhibits an essential fungal enzyme, Leucyl-tRNA synthetase, or LeuRS, required for protein synthesis.
Minimum Inhibitory Concentration: 1, 1, 0.5, 0.25, and 0.25 μg/mL for T.rubrum, T.mentagrophytes, C.albicans, C.neoformans, A.fumigatus, respectivley.

AN2690 is a new boron-containing antifungal agent for the potential treatment of onychomycosis. Onychomycosis is caused mainly by dermatophytes, a class of fungus that dwells on skin, hair, and nails and is the cause of other cutaneous fungal infections such as athlete’s foot.

In vitro: AN2690 showed the most active against fungi and especially against the dermatophytes T. rubrum and T. mentagrophytes, the primary fungal pathogens causing onychomycosis. In addition, AN2690 was identified as having a unique profile of in vitro antidermatophyte activity, maintenance of this activity in the presence of keratin, and exceedingly good penetration of human nails [1].

Ex vivo: AN2690 was found to have superior penetration compared to ciclopirox, and achieves levels within and under the nail plate that suggest it has the potential to be an effective topical treatment for onychomycosis [2].

Clinical trial: The efficacy of tavaborole as a topical treatment for onychomycosis has been evaluated in two identical randomised, double-blind phase III studies, NCT01270971 (301) and NCT01302119 (302), enrolling 593 and 601 patients, respectively. Completely or almost clear nail and negative mycology was achieved in 15.3 and 17.9 % of tavaborole recipients compared with 1.5 and 3.9 % of vehicle recipients [3]

References:
[1] Baker SJ, Zhang YK, Akama T, Lau A, Zhou H, Hernandez V, Mao W, Alley MR, Sanders V, Plattner JJ. Discovery of a new boron-containing antifungal agent, 5-fluoro-1,3-dihydro-1-hydroxy-2,1- benzoxaborole (AN2690), for the potential treatment of onychomycosis. J Med Chem. 2006;49(15):4447-50.
[2] Hui X, Baker SJ, Wester RC, Barbadillo S, Cashmore AK, Sanders V, Hold KM, Akama T, Zhang YK, Plattner JJ, Maibach HI. In Vitro penetration of a novel oxaborole antifungal (AN2690) into the human nail plate. J Pharm Sci. 2007;96(10):2622-31.
[3] Markham A. Tavaborole: first global approval. Drugs. 2014;74(13):1555-8.

UPDATE

http://www.google.im/patents/EP1976536A2?cl=en

EXAMPLE 23

Alternative Preparation of 4 from 3

A 22.0 L 3-neck flask was equipped with a stir motor, N₂ inlet, addition funnel, heating mantle, and condenser. The flask was charged with 3500 g (17.1 moi) of 2-bromo-5-fluorobenzyl alcohol followed by the addition of 3556 g of tetrahydrofuran and 16.4 g (0.17 mol) of methanesulfonic acid. Next, 400 g (4.7 mol) of 3,4-dihydro-2H-pyran was added at 10⁰C. This step is exothermic so no additional charges should be made until exotherm subsides. The temperature was increased to 27°C, stirred for 15 min and then charged with 400 g (4.7 mol) of 3,4-dihydro-2H- pyran at 24⁰C. Again the temperature increased (24°C to 38⁰C). The mixture was stirred for 15 min. Once the exotherm subsided, the flask was again charged with 40Og (4.7 mol) of 3,4-dihydro-2H-pyran at 35⁰C. The temperature again increased to 47⁰C over a 20 min period. Once the exotherm subsided, the mixture was stirred for 15 min. Finally the remaining 400 g (4.7 mol) of 3,4-dihydro-2H-pyran was added at 44⁰C. The temperature increased to 51⁰C. After stirring for one hour, a sample was removed to check for removal of starting material. Upon reaction completion, contents were cooled to 20 ± 5 ⁰C.

EXAMPLE 24

Alternative Preparation of 5 from 4

To a 22.0 L 3-neck flask equipped with a stir motor, N₂ inlet, addition funnel, cooling bath, and condenser was charged 436 g (17.96 mol) of magnesium turnings. 5334 g of tetrahydrofuran was then added followed by 291 g (0.51 mol) of diisobutylaluminum hydride (DIBAL) (25%wt) in toluene. The mixture was stirred for 60 min at 20 ± 5 ⁰C. Some gas evolution was seen. Next, 260-430 g -3-5% (by weight if solution of 4 was dropped to drums) of 4 in THF was added. The mixture was stirred for 15-30 min at which time a slight exotherm should be seen (ΔT = 10- 15⁰C). Once the exotherm was observed, the reaction mixture was cooled to 5 ± 5 ⁰C. To this mixture, the remaining 8.22-8.39 kg of 4 in THF was added at a rate such that the temperature was kept below 30⁰C (t = 3h). The reaction was stirred at 20-25 ⁰C for 30 min, at which time an aliquot was removed, quench with 3 N HCl (10 mL), and analyzed.

Upon completion, the contents were cooled to -25 ± 5°C. A solution of trimethylborate in THF was prepared by mixing 2665 g (25.7 mol) of trimethyl borate and 6666 g of tetrahydrofuran. This solution can be prepared in a drum with stirring. [0618] Next, the 9331 g of trimethyl borate in THF was added at a rate such that the temperature was kept between -35 and -20 °C (t = 2.5h). The mixture became very thick so THF was added. After stirring at -25 ± 5°C for 10 min, 50 mL aliquot was removed, quenched with 25 mL of 3N HCl, and submitted for CoR. Stirring continued at -25 ± 5⁰C for Ih, and then the mixture was allowed to warm to ambient temperature, where it was stirred for at least 12h. Pull two samples (one at 6h and the other at 12h).

Results:

¹H-NMR (300 MHz, DMSO-d₆) δ (ppm) 1.45-1.75 (m, 6H), 3.53 (s, 6H), 3.45 (m, IH), 3.75 (m, IH), 4.69 (t, J=3 Hz, IH), 4.97 (d, J=14.1 Hz, IH), 5.14 (d, J=14.1 Hz, IH), 7.03 ((td, J=8.4, 2.7 Hz, IH), 7.24 (dd, J=10.8, 2.1 Hz, IH), 7.89 (t, J=7.8 Hz, IH), 8.76 (s, IH).

EXAMPLE 25

Alternative Preparation of I from 5

To the reaction mixture above was added 5.3 kg of USP water. After stirring for 30 min, the mixture was charged 5.3 kg of acetic acid. Gas evolution was seen. After stirring for 30 min, an aliquot was removed for analysis. Mixture was then heated to reflux for 36-48 hours. During the reflux period, 12-13 L of THF were removed.

When the reaction was complete, the contents were cooled by the reactor to <40°C by setting jacket and by charging 10.5 kg of USP water. THF was removed until distillate did not remain. Contents of the reactor were transferred to Rosenmund filter dryer and allowed to cool to 20 ± 5°C. Reactor was rinsed with water, filtered, and then washed again with 10.5 kg of USP water. The flask was charged with 10.5 kg of 10% ACN in water (v/v) and agitated for Ih. After filtering, the cake was washed with 10.5 kg of 10% ACN in water (v/v), and then charged with 10.5 kg 10% ACN in water (v/v). The contents were agitated for Ih. The contents were subsequently washed with 10.5 kg of USP water, charged with 7.0 L of 5% Methyl t- Butyl Ether (MTBE)/Heptane (v/v), agitated for Ih, filtered, charged with 7.0 L of 5% MTBE/Heptanes (v/v) and again agitated for Ih. After filtering, the contents were charged again with 7.0 L of heptane and filtered. Solids were dried at <45°C to constant weight. Solids were recrystallized from toluene :heptane 75:25.

see full series on boroles

http://apisynthesisint.blogspot.in/p/borole-compds.html

do not miss out

see full series on boroles

http://apisynthesisint.blogspot.in/p/borole-compds.html

do not miss out

Fine

///////

Medicinal Chemistry International

December 29, 2013 2:59 am / Leave a comment

Medicinal Chemistry International

Vedroprevir

December 29, 2013 1:40 am / Leave a comment

Vedroprevir

GS 9451, GS-9451, 1098189-15-1 USAN ZZ-81

VEDROPREVIR THERAPEUTIC CLAIM Treatment of hepatitis C

CHEMICAL NAMES 1. Cyclopropanecarboxylic acid, N-[[(1α,3β,5α)-bicyclo[3.1.0]hex-3- yloxy]carbonyl]-3-methyl-L-valyl-(4R)-4-[[8-chloro-2-[2-[(1-methylethyl)amino]- 4-thiazolyl]-7-[2-(4-morpholinyl)ethoxy]-4-quinolinyl]oxy]-L-prolyl-1-amino-2- ethyl-, (1R,2R)-

2. N-{[(1R,3r,5S)-bicyclo[3.1.0]hex-3-yloxy]carbonyl}-3-methyl-L-valyl-(4R)-4-[(8- chloro-2-{2-[(1-methylethyl)amino]thiazol-4-yl}-7-[2-(morpholin-4- yl)ethoxy]quinolin-4-yl)oxy]-L-prolyl-(1R,2R)-1-amino-2- ethylcyclopropanecarboxylic acid

MOLECULAR FORMULA C45H60ClN7O9S

MOLECULAR WEIGHT 910.5 daltons

SPONSOR Gilead Sciences, Inc.

CODE DESIGNATION GS-9451

CAS REGISTRY NUMBER1098189-15-1

WHO NUMBER9745

GS-9451 is a NS3 protease inhibitor in phase II clinical trials at Gilead for the oral treatment of hepatitis C.

…………………………………………………………………………

Discovery of GS-9451: An acid inhibitor of the hepatitis C virus NS3/4A protease Bioorg Med Chem Lett 2012, 22(7): 2629 ……………………………………………………………

PATENTS WO 2012087596 WO 2009005676 WO 2013106631 WO2013101550 ……………………….

WO2012087596A1 Compound 3 can be prepared using synthetic methods and intermediates like those described in USSN 12/215,605 (US 20090257978 A1). Compound 3 can also be prepared described in the following Example. Example 3: Preparation of Compound 3

Compound 315 (12 g, 13 mmol) was dissolved in THF (200 ml), LiOH (11g, 260 mmol) in H₂0 (200 ml) was added, followed by MeOH (200 ml). The mixture was kept stirring at room temperature for 20 hours. Upon completion of the reaction, 4 N HCI in H₂0 was added to adjust pH to 7 at 0 °C. The mixture was extracted with EtOAc (2 x 400 ml). The combined organic layer was washed with brine, dried (Na₂S0₄) and concentrated in vacuo to give compound 3 as a yellow solid (11 g, 93%). LC/MS = 911.52(M⁺+1 ). ¹H NMR (300MHz, CD₃OD)57.95 (d, 1H), 7.90 (s, 1H), 7.48 (s, 1H), 7.31 (d, 1H), 5.42 (s, 1H), 4.37 (dd, 1H), 4.20 (m, 2H), 3.83-3.56 (m, 7H), 3.50 (m, 2H), 3.39 (m, 2H), 2.45 (m, 1H), 2.27(m, 1H), 1.62 (m, 2H), 1.50 (m, 1H), 1.33 (m, 2H), 1.18 (m, 1H), 1.05 (m, 8H), 0.90 (m, 3H), 0.76 (m, 11H), 0.14-0.04 (m, 2H) The intermediate compound 315 was prepared as follows.

301 302 a. Preparation of compound 301. To a dry, argon purged three-neck round bottom flask (1000 mL) were added anhydrous dichloromethane (100 mL) and Et₂Zn (28 mL, 273 mmol) at 0 °C. (CAUTION: Source of argon can not be from needle. Use appropriate glass adapter only. A second bubbler can also be attached to the flask to prevent excessive pressure build up.) Cyclopenten-3-ol (10.0 mL, 119 mmol) was then added dropwise (large quantity of ethane gas was produced) to the flask and the reaction mixture was allowed to stir until the evolution of gas had ceased. Diiodomethane (22 mL, 242 mmol) was then added dropwise over a period of 30 minutes. The reaction was allowed to warm to room temperature and continued to stir overnight under a positive flow of argon, at which point TLC analysis had indicated complete disappearance of the starting alcohol. The reaction was then diluted with CH₂CI₂ and quenched with 2M HCI (white precipitate should be completely dissolved). The biphasic mixture was poured into a separatory funnel and the organic layer was collected. The solvent was removed under reduced pressure until 100 mL of material containing compound 301 remained. b. Preparation of compound 302. Anhydrous dichloromethane (525 mL) was added to the flask followed by the dropwise addition of triethylamine (34 mL, 245 mmol). The reaction continued to stir at room temperature under a positive flow of nitrogen at which point, disuccinimidylcarbonate (40.7 g, 159 mmol) was added to the flask portion wise. The reaction was allowed to stir until TLC analysis indicated complete disappearance of the starting material (2-3 days). Upon completion, the reaction mixture was quenched with 1 M HCI (200 mL x 2) and washed with H₂0 (200 mL x 2). The desired material was extracted using CH₂CI₂and the combined organic layers were dried using anhydrous MgS0 and passed through a silica plug. The solvent was removed under reduced pressure and the crude material was purified using flash chromatography (R_f = 0.33, 1 :1 Hex/EtOAc) to provide compound 302 (22 g, 75%): ¹H NMR (300 MHz, CDCI₃): δ 5. 24 (t, 1 H), 3.82 (s, 4H), 2.24 (m, 2H), 2.03 (d, 2H), 1.38 (m, 2H), 0.48 (m, 1 H), 0.40 (m, 1 H).

c. Preparation of compound 304. N-i-Boc-cis-4-Hydroxy-L-Proline methyl ester 303 (100.0 g, 407.7 mmol) and DABCO (1.5eq, 68.6g, 61 1.6 mmol) were dissolved in anhydrous toluene (200 mL) in a 2 L three necked round bottom flask with a mechanical stirrer and an addition funnel. After cooling the solution to 0 °C under N₂, A solution of 4-Bromo-benzenesulfonyl chloride (1.3eq, 135.6g, 530.0 mmol) in 300 mL of toluene was added through addition funnel over 60 minutes. The reaction mixture was stirred and warmed to room temperature overnight (16 hours). The mixture was slowly poured into 2L 1 M Na₂C0₃ (aq.), and the product was extracted with EtOAc (2L). After the organic phase was washed by 0.5 N HCI (2L), H₂0 (1 L), and brine (1 L), it was dried (MgS0₄), concentrated to give 195.45 g of a yellow oily brosylate product. To a solution of the above brosylate (407.7 mmol) in dichloromethane (300 mL) was slowly added 4.0 M HCI in dioxane (500 mL, 5eq) and the resulting solution was allowed to stir at room temperature for 2 hours. After ether (500mL) was added to the reaction mixture, the mixture was stirred for 15 minutes and the white precipitate was collected by filtration. The solid was washed with ether and hexane and then dried under vacuum overnight to obtain 153.0 g of the HCI amine salt of compound 304, 381.8 mmol, in 94% yield for two steps. d. Preparation of compound 305. To a solution of Boc-fert-butyl-glycine (97.0g, 420.0 mmol) in DMF (200mL) and DCM (200mL) were added HATU (217.76g, 572.7 mmol) and Hunig’s base (126 mL, 1 145.4 mmol) at room temperature. After the mixture was stirred for 20 minutes at room temperature, a solution of the previous HCI salt (153.0 g, 381.8 mmol) and Hunig’s base (126 mL, 1 145.4 mmol) in DMF (200mL) and dichloromethane (200mL) was added to the above acid mixture in one portion. The reaction mixture was stirred at room temperature for 3h, with monitoring by LCMS. The reaction mixture was concentrated to remove dichloromethane under reduced pressure and the white solid that formed was filtered off. The remaining DMF solution was diluted with ethyl acetate (1 L), washed successively with 3% LiCI (aq) (3x650mL), sat’d NH₄CI (2x500mL), 0.5N HCI (aq) (2x600ml_), brine (500ml_), sat’d NaHC0₃ (3x500mL), and brine (500mL). The resulting organic fraction was dried (MgS0₄) and concentrated to afford compound 305 (111g). e. Preparation of compound 306. To a solution of the methyl ester 305 (120 g, 207.8 mmol) in THF (300 ml_), MeOH (75 mL) was added a solution of LiOH (26.18 g, 623.4 mmol) in H₂0 (150 ml_). The solution was allowed to stir at room temperature for 4 hours. The mixture was cooled in an ice-bath while acidifying with 3N HCI to pH about 5.5, stirred for 10minut.es, and the resulting white solids were collected by filtration. The solids were washed with more water, ether and hexane. The solids were dried under vacuum at 40°C overnight to give 95.78g (82%) of the acid 306. f. Preparation of compound 307. To a solution of the carboxylic acid 306 (81.4 g, 144.27 mmol) in DMF (200ml_) and dichloromethane (200mL) was added HATU (82.3g, 216.4 mmol) and Hunig’s base (47.5 mL, 432.8 mmol) at room temperature. After the mixture was stirred for 20 minutes at room temperature, a solution of amine (158.7 mmol) and Hunig’s base (47.5 mL, 1145.4 mmol) in DMF (200mL) and dichloromethane (200mL) was added to the above acid mixture in one portion. The reaction mixture was stirred at room temperature for 3 hours and monitored by LCMS. After the mixture was concentrated under reduced pressure to remove dichloromethane, the white solids that formed were filtered off. The remaining DMF solution was diluted with ethyl acetate (600mL) and successively washed with 3% LiCI (aq) (2x550mL), sat’d NH₄CI (500mL), 1 N HCI (aq) (500mL), sat’d NaHC0₃(500mL), and brine (300mL). The resulting organic fraction was dried (Na₂S0₄) and concentrated to afford compound 307 (111 g). g. Preparation of compound 308. Compound 307 was dissolved in 4N HCI in dioxane (300 mL) at room temperature and stirred for 2 hours. It was then concentrated under vacuum, and co-evaporated with dichloromethane (2 x 200mL) to dryness. The residue was dissolved in EtOAc (600mL) and sat’d aq. NaHC0₃ (1 L). It was stirred vigorously. After 10 minutes, carbonic acid bicyclo[3.1.0]hex-3-yl ester 2,5-dioxo-pyrrolidin-1-yl ester 302 (41.4 g, 173.1 mmol) was added in one portion. After the resulting mixture was stirred for another 30 minutes, the organic layer was collected and washed with brine (500mL), dried (Na₂S0₄), and concentrated. The crude product was purified by flash chromatography on silica gel with ethyl acetate/hexane to afford 94.44 g (92%) of compound 308.

h. Preparation of compound 310.1-(2-Amino-3-chloro-4-hydroxy-phenyl)-ethanone 309 (70.7 g, 354 mmol) was stirred in 48% aq. HBr (500 mL) at 110 °C for 72 hours. After the mixture was cooled to 0 °C with stirring, the solids were filtered and washed with water. The resulting solids were triturated with a saturated NaHC0₃ solution (-350 mL), filtered, washed with water, and dried under vacuum to give – 40 g (61%) of crude 310 as a dark brown solid. LC/MS = 186 (M⁺+1). i. Preparation of compound 311. 1-(2-Amino-3-chloro-4-hydroxy-phenyl)-ethanone 310 (40 g, 215 mmol) was dissolved in DMF (360 ml). Cesium carbonate (140 g, 430 mmol) was added, followed by bromoacetaldehyde dimethyl acetal (54.5 g, 323 mmol). The mixture was then vigorously stirred at 65 °C for 24 hours. Upon cooling to room temperature, EtOAc (1 L) and H₂0 (1 L) were added to the mixture. The organic layer was extracted with EtOAc (1 x 400 ml). The combined organic layer was washed with aqueous 3% LiCI solution (2 x 1 L), brine, dried (Na₂S0₄) and concentrated in vacuo. The residue was purified by silica gel chromatography to give compound 311 as a white solid (39 g, 67%). j. Preparation of compound 312. To a mixture of 1-[2-Amino-3-chloro-4-(2,2-dimethoxy-ethoxy)-phenyl]-ethanone 311 ( 13 g, 47.5 mmol) and isopropylaminothiazole-4-carboxylic acid hydrobromide (12.64 g, 47.5 mmol) in pyridine (150 ml) was slowly added phosphorus oxychloride (9.47 g, 61.8 mmol) at -40 °C. The mixture was then stirred at 0 °C for 4 hours. Upon completion of the reaction, H₂0 (30 ml) was added dropwise to the mixture. The mixture was then stirred at 0 °C for another 15 minutes. The mixture was concentrated in vacuo. The residue was diluted with EtOAc, washed with a sat. NaHC0₃ aqueous solution. The organic layer was dried (Na₂S0₄) and concentrated in vacuo. The residue was dissolved in CH₂CI₂, hexanes were added slowly to the solution, and a yellow solid started to crash out. More hexanes were added until not much product was left in the mother liquid to provide compound 312 (18 g, 85%). k. Preparation of compound 313. 2-lsopropylamino-thiazole-4-carboxylic acid [6-acetyl-2-chloro-3-(2,2-dimethoxy-ethoxy)- phenyl]-amide 312 (18 g, 40.7 mmol) was suspended in toluene (400 ml). NaH (2.4 g, 61 mmol) was added to the vigorously stirred mixture while monitoring H₂evolution. The mixture became a clear solution during heating to reflux. The reaction was complete after refluxing for 3 hours. The mixture was cooled to room temperature. A solution of AcOH (69.2 mmol) in H₂0 (3 vol) was added to the mixture. After vigorous agitation for 1 hour at 0 °C, the solids were collected by filtration, rinsed forward with H₂0. The wet cake was dried under high vacuum to a constant weight to provide compound 313 ( 5 g, 86%). I. Preparation of compound 314. To a mixture of brosylate intermediate 303 (15 g, 35 mmol) and compound 313 (27.5 g, 38.5 mmol) in NMP (200 ml) was added cesium carbonate (25.1 g, 77 mmol). The mixture was stirred at 65 °C for 5 hours. The reaction was cooled to room temperature and EtOAc (600 ml) and an aqueous solution of 3% LiCI (600 ml) were added to the mixture. The organic layer was washed with aqueous 3% LiCI (1 x 600 ml), brine, dried (Na₂S0₄) and concentrated in vacuo. The residue was purified by silica gel chromatography to give the desired methyl ester as a yellow solid (23.6 g, 75%). LC/MS = 900. 1 3(M⁺+ 1 ) . m. Preparation of compound 315. Methyl ester 314 (23.6 g, 26 mmol) was dissolved in glacial acetic acid (200 ml), 1.4 N HCI in H₂0 (75 ml) was added to the solution. The mixture was stirred at 60 °C for 1 hour. Upon completion of the reaction, the mixture was concentrated to remove the solvents, coevaporated with toluene (x 2) to remove residual acetic acid. The residue was then dissolved in EtOAc (500 ml) and sat. NaHC0₃ aqueous solution (enough to neutralize the mixture) while monitoring C0₂ evolution. The organic layer was washed with brine, dried (Na₂S0₄) and concentrated in vacuo. The residue was further dried under high vacuum for 1 h and used as is for the next step. The crude was dissolved in CH₂CI₂ (360 ml), morpholine (3.4 g, 39 mmol) and sodium triacetoxyborohydride (7.2 g, 34 mmol) were added to the mixture at 0 °C. Then glacial acetic acid (0.47 g, 7.8 mmol) was added dropwise to the mixture. The reaction was complete in 10 minutes at 0 °C. Sat. NaHC0₃ aqueous solution was added to quench the reaction. After stirring for another 20 minutes, the organic layer was washed with brine, dried (Na₂S0₄) and concentrated in vacuo. The residue was purified by silica gel chromatography to give the desired amine product 315 as a yellow solid (12 g, 50%). LC/MS = 924.63(M⁺+ 1 )

Preparation of 8-chloro-4-hydroxy-7-methoxyquinoline-2-carboxylic acid 215. To a solution of methyl 8-chloro-4-hydroxy-7-methoxyquinoline-2-carboxylate 214 (36.5g, 0.145 mol) in a mixture of 1 :1 of MeOH: THF (160 mL total) was added a solution of LiOH (30.5 g, 0.725 mol) in H₂0 (80 mL). The mixture was stirred at room temperature for an hour when LCMS analysis showed complete conversion to the carboxylic acid. The reaction was worked up by removal of the volatiles and adjusting the pH of the solution to 6 using aqueous 6N HCI. The resulted gummy residue was filtered and dried on the lyophilizer for 2 days to provide 34.4 g (99.6 %) of compound 215 as a white solid. El MS (mlz) 253.9 [M+H]. j. Preparation of 2-(2-diazo-l-oxo)-8-chloro-7-methoxyquinolin-4-yl isobutyl carbonate 216. To a solution of 8-chloro-4-hydroxy-7-methoxyquinoline-2-carboxylic acid 215 (10.2 g, 0.04 mol) in THF (400 mL) was added triethyl amine (12.3 mL, 0.088 mol) and /-Butylchloroformate (11.6 mL, 0.088 mol) at 0°C under an argon atmosphere. The mixture was stirred at 0°C for 1 hour when LCMS analysis demonstrated completion of the reaction to provide the desired mixed anhydride. El MS (mlz) 454.0 [M+H]. To the reaction mixture of the anhydride was added a 1 M solution of diazomethane (121 mL, 0.121 mol) in diethyl ether via a plastic funnel at 0°C. This mixture was allowed to stir while warming up to room temperature for additional 2 hours. Analysis of the mixture by LCMS demonstrated completion of the reaction. The septum was removed and the reaction was stirred for additional 20 minutes before removal of the solvent. The residue was dried further under high vacuum to provide compound 216, which was carried on to the next step. El MS (m/z) 377.9 [M+H]. k. Preparation of 8-chloro-2-(2-(isopropylamino)thiazol-4-yl)-7-methoxyquinoiin-4-ol 207. To a cooled solution of 2-(2-diazo-l-oxo)-8-chloro-7-methoxyquinolin-4-yl isobutyl carbonate 216 (15.2 g, 0.040 mol) at 0°C in THF (268 mL) was added 48% HBr (23 mL, 0.201 mol) slowly over 15 minutes. The solution was stirred at 0°C for an additional 40 minutes when LCMS analysis demonstrated complete reaction. The reaction was worked up by addition of aqueous 1 N NaOH (180 mL) at 0° C to adjust the pH of the aqueous layer to 9. The layers were separated and the aqueous layer was washed with EtOAc (2 x 200 mL). Combined organic extracts were washed with brine and dried over MgS04. The solvent was removed in vacuo to provide 17.7 g of a yellow solid. El MS (m/z) 4³¹.9 [M+H]. The solution of the bromoketone obtained from the previous reaction was suspended in i-propanol (270 mL) and isopropylisourea (9.4 g, 0.080 mol). The reaction mixture was heated at 72 °C for 32 hours. LCMS analysis of the reaction demonstrated complete conversion to the desired- product. The reaction was allowed to cool to room temperature to allow for the product to precipitate out of the solution. The reaction was further cooled to 0°C for 12 hours before filtration. The filtrate was washed with ether and dried on lyopholizer to provide 8.03 g of compound 207 as an orange solid. ¹H NMR (500 MHz, CDCI₃): δ 8.21 (d, J= 9 Hz, 1 H), 7.74 (s, 1 H), 7.44 (d, J= 10Hz), 1 H), 7.07 (s, 1 H), 4.05 (s, 3H), 3.92 (pentet, J=6 Hz, 1 H), 1.25 (d, J= 7 Hz, 6H): El MS (m/z) 350.0 [M+H].

WANT TO KNOW ABOUT VIR SERIES CLICK

click

http://drugsynthesisint.blogspot.in/p/vir-series-hep-c-virus-22.html

AND

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

Medicinal Chemistry International: NARLAPREVIR

December 28, 2013 11:40 am / Leave a comment

Medicinal Chemistry International: NARLAPREVIR

TOLVAPTAN

December 28, 2013 6:15 am / Leave a comment

TOLVAPTAN

的合成

N-(4-{[(5R)-7-chloro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]carbonyl}-3-methylphenyl)-2-methylbenzamide

Formula	C₂₆H₂₅ClN₂O₃
Mol. mass	448.941 g/mol

150683-30-0 CAS NO

+ form 331947-66-1 Rform

OPC-41061

Otsuka…..innovator

UPDATE 2022

Tolvaptan sodium phosphate, Samtasu,

トルバプタンリン酸エステルナトリウム

2022/3/28 JAPAN PPROVED

Formula	C26H24ClN2O6P. 2Na
CAS
Mol weight	572.8849

Tolvaptan sodium phosphate (JAN).png

Tolvaptan sodium phosphate

disodium;[(5R)-7-chloro-1-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-2,3,4,5-tetrahydro-1-benzazepin-5-yl] phosphate

European Medicines Agency (EMA) Accepts Otsuka’s Marketing Authorisation Application (MAA) for Tolvaptan, an Investigational Compound for Autosomal Dominant Polycystic Kidney Disease (ADPKD)

•Tolvaptan was discovered by Otsuka in Japan and, if approved by the EMA, would become the first pharmaceutical therapy in Europe for patients with ADPKD
•ADPKD is an inherited genetic disease that causes cyst growth in the kidneys, which gradually impairs their functioning. There is no current pharmaceutical treatment option
•Otsuka’s development of tolvaptan as a treatment for ADPKD illustrates the company’s commitment to address significant patient needs for diseases that traditionally have not been a priority for the pharmaceutical industry

TOKYO–(BUSINESS WIRE)–Otsuka Pharmaceutical Co., Ltd. announced today that the European Medicines Agency (EMA) has accepted the submission of a marketing authorisation application (MAA) for the potential approval of tolvaptan for the treatment of autosomal dominant polycystic kidney disease (ADPKD). Phase III clinical trial results that form the basis of the regulatory filing were published in the New England Journal of Medicine.

http://www.pharmalive.com/ema-accepts-otsukas-maa-for-tolvaptan

Tolvaptan is a selective vasopressin V2-receptor antagonist with an affinity for the V2-receptor that is 1.8 times that of native arginine vasopressin (AVP).

Tolvaptan is (±)-4′-[(7-chloro-2,3,4,5-tetrahydro-5-hydroxy-1H-1-benzazepin-1-yl) carbonyl]-otolu-m-toluidide. The empirical formula is C₂₆H₂₅ClN₂O₃. Molecular weight is 448.94. The chemical structure is:

SAMSCA® (tolvaptan) Structural Formula Illustration

SAMSCA tablets for oral use contain 15 mg or 30 mg of tolvaptan. Inactive ingredients include corn starch, hydroxypropyl cellulose, lactose monohydrate, low-substituted hydroxypropyl cellulose, magnesium stearate and microcrystalline cellulose and FD&C Blue No. 2 Aluminum Lake as colorant.

SEE NEW UPDATE AT END OF PAGE

Tolvaptan (INN), also known as OPC-41061, is a selective, competitive vasopressin receptor 2 antagonist used to treat hyponatremia (low blood sodium levels) associated withcongestive heart failure, cirrhosis, and the syndrome of inappropriate antidiuretic hormone(SIADH). Tolvaptan was approved by the U.S. Food and Drug Administration (FDA) on May 19, 2009, and is sold by Otsuka Pharmaceutical Co. under the trade name Samsca and in India is manufactured & sold by MSN laboratories Ltd. under the trade name Tolvat & Tolsama.

ChemSpider 2D Image | Tolvaptan | C26H25ClN2O3

Tolvaptan is also in fast-track clinical trials[2] for polycystic kidney disease. In a 2004 trial, tolvaptan, when administered with traditional diuretics, was noted to increase excretion of excess fluids and improve blood sodium levels in patients with heart failure without producing side effects such as hypotension (low blood pressure) or hypokalemia(decreased blood levels of potassium) and without having an adverse effect on kidney function.[3] In a recently published trial (TEMPO 3:4 ClinicalTrials.gov number, NCT00428948) the study met its primary and secondary end points. Tolvaptan, when given at an average dose of 95 mg per day over a 3-year period, slowed the usual increase in kidney volume by 50% compared to placebo (2.80% per year versus 5.51% per year, respectively, p<0.001) and reduced the decline in kidney function when compared with that of placebo-treated patients by approximately 30% (reciprocal serum creatinine, -2.61 versus -3.81 (mg/mL)-1 per year, p <0.001)[4]

Tolvaptan was first approved by the U.S. Food and Drug Administration (FDA) on May 19, 2009, then approved by the European Medicines Agency (EMA) on August 3, 2009 and approved by Pharmaceuticals and Medical Devices Agency of Japan on Feb 4, 2013. It was developed and marketed as Samsca^® by Otsuka in the US, DE and JP.

UPDATED

Tolvaptan is a selective vasopressin V₂-receptor antagonist with an affinity for the V₂-receptor that is 1.8 times that of native arginine vasopressin (AVP) and that is 29 times greater than for the V_1a-receptor. When taken orally, 15 to 60 mg doses of tolvaptan antagonize the effect of vasopressin and cause an increase in urine water excretion that results in an increase in free water clearance (aquaresis), a decrease in urine osmolality, and a resulting increase in serum sodium concentrations. It is indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia [serum sodium < 125 mEq/L or less marked hyponatremia that is symptomatic and has resisted correction with fluid restriction], including patients with heart failure, cirrhosis, and syndrome of inappropriate antidiuretic hormone (SIADH).

Samsca^® is available as tablet for oral use, containing 7.5 mg/15 mg/30 mg of free Tolvaptan. The recommended starting dose is 15 mg once daily and it may be increased at intervals ≥ 24 hr to 30 mg once daily, and to a maximum of 60 mg once daily as needed to raise serum sodium.

PATENT NUMBER	PEDIATRIC EXTENSION	APPROVED	EXPIRES (ESTIMATED)
US5258510	No	1993-11-02	2010-11-02
US5753677	No	1998-05-19	2020-05-19
US8501730	No	2013-08-06	2026-09-01
US5972882	No	1999-10-26	2018-12-14
US10905694	No	2021-02-02	2030-04-07

Synthesis Reference

Bandi Parthasaradhi Reddy, “PROCESS FOR PREPARING TOLVAPTAN INTERMEDIATES.” U.S. Patent US20130190490, issued July 25, 2013.

US20130190490

Route 1

Reference：1. US5258510A.

Route 2

Reference：1. Bio. Med. Chemistry 2006, 14, 6165–6173.

Route 3

Reference：1. Bio. Med. Chem. Lett. 2007, 17, 6455–6458.

Route 4

Reference：1. CN102060769B.

Route 5

Reference：1. Org. Lett. 2014, 16, 6041−6043.

Route 6

Reference：1. Bio. Med. Chem. 1999, 7, 1743-1754.

2. WO2007026971A2.

SYN

Chemical synthesis:[5]

Tolvaptan is chemically, N-[4-[(7-chloro-2,3,4,5-tetrahydro-5-hydroxy1H-1-benzazepin-1-yl)carbonyl]-3-methylphenyl]-2-methylbenzamide. Tolvaptan is represented by the following structure:

Tolvaptan, also known as OPC-41061, is a selective, competitive arginine vasopressin receptor 2 antagonist used to treat hyponatremia (low blood sodium levels) associated with congestive heart failure, cirrhosis, and the syndrome of inappropriate antidiuretic hormone (SIADH). Tolvaptan is sold by Otsuka Pharmaceutical Co. under the trade name Samsca.

Tolvaptan and its process for preparation were disclosed in U.S. Pat. No. 5,258,510.

Processes for the preparation of 7-chloro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one, 7-chloro-1-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine and 7-chloro-1-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine were reported in Bioorganic & medicinal chemistry 7 (1999), 1743-1754. According to the journal, 7-chloro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one can be prepared by reacting 7-chloro-4-ethoxycarbonyl-5-oxo-N-p-toluenesufonyl-2,3,4,5-tetrahydro-1H-1-benzazepine with acetic acid in the presence of hydrochloric acid and water to obtain 7-chloro-5-oxo-2,3,4,5-tetrahydro-1-p-toluenesulfonyl-1H-1-benzazepine, and then reacted with polyphospholic acid. According to the journal, 7-chloro-1-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine can be prepared by reacting 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine with 2-methyl-4-nitobenzoyl chloride in the presence of triethylamine.

According to the journal, 7-chloro-1-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine can be prepared by reacting 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine with 2-methylbenzoylchloride in the presence of triethylamine.

PCT publication no. WO 2007/026971 disclosed a process for the preparation oftolvaptan can be prepared by the reduction of 7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one with sodium borohydride.

7-Chloro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one is a key intermediate for the preparation of tolvaptan.

Biooganic and Medicinal Chemistry I (2007) 6455-6458, Biooganic andMedicinal Chemistry 14 (2000) 2493-2495 reported in the literature of the intermediate 2 – carboxylic acid -5 – (2 – methyl-benzoylamino) toluene synthesis method,

5-Chloro-2-nitrobenzoic acid (I) was converted into methyl ester (II) using dimethyl sulfate and K2CO3 in acetone. The nitro group of (II) was then reduced with SnCl2 to afford aniline (III), which was protected as the p-toluenesulfonamide (IV) with tosyl chloride in pyridine. Alkylation of (IV) with ethyl 4-bromobutyrate (V) yielded diester (VI). Subsequent Dieckmann cyclization of (VI) in the presence of potassium tert-butoxide provided benzazepinone (VIIa-b) as a mixture of ethyl and methyl esters, which was decarboxylated to (VIII) by heating with HCl in AcOH. Deprotection of the tosyl group of (VIII) was carried out in hot polyphosphoric acid. The resulting benzazepinone (IX) was condensed with 2-methyl-4-nitrobenzoyl chloride (X) to give amide (XI). After reduction of the nitro group of (XI) to the corresponding aniline (XII), condensation with 2-methylbenzoyl chloride (XIII) provided diamide (XIV). Finally, ketone reduction in (XIV) by means of NaBH4 led to the target compound.

……………………………………….

PATENT

CN102382053A Figure CN102382053AD00031

……………………………………………..

PATENT

CN102060769

Synthesis of Intermediate III: 1.

Example

2-methyl-4-nitrobenzoic acid (available from Alfa Aesar Tianjin Chemical Co., purity> 99%, 25g,

0.14mol) was added to a 250ml reaction flask, is reacted with thionyl chloride under reflux conditions for 3h, thionyl chloride was distilled off under reduced pressure to give 2-methyl-4-nitrobenzoyl chloride (26.Sg, light yellow oily liquid), without purification, was used directly in the next step.

Intermediate II (20g, 0.1moI) and 2_ methyl _4_ nitrobenzoylchloride (22.4g, 0.llmol) was added to a 250ml reaction flask. Dichloromethane (50ml), cooled to ice bath with stirring to dissolve O~5 ° C, was slowly added dropwise N- methylmorpholine (11.2g, 0.llmol), Bi dropwise with stirring while, at room temperature the reaction 4h. TLC [developing solvent: ethyl acetate – petroleum ether (I: I), hereinafter] is displayed after completion of the reaction, saturated aqueous sodium bicarbonate (20ml), stirred for lOmin, filtered, the filter cake with dichloromethane (15ml X 2 ) washing. The filtrate and washings were combined, washed with saturated sodium chloride solution (30ml X 3), dried over anhydrous sodium sulfate and filtered. The filtrate under reduced pressure to recover the solvent, the residue was recrystallized from anhydrous methanol to give a white powder 111 (27.5g, 75.2%), mp 154.8 ~155.6 ° C. Purity 97.9% (HPLC normalization method).

Synthesis of Intermediate IV:

Intermediate III (10g, 28mmol) was added to a 250ml reaction flask, concentrated hydrochloric acid (40ml) and ethanol (50ml), with stirring, was slowly added dropwise stannous chloride (20g, 88mmol) in ethanol (40ml) . Bi room temperature drops 5h. After TLC showed completion of the reaction, ethanol was distilled off under reduced pressure to about 70ml, the residue was -10 ° C -0 ° C allowed to stand overnight to cool. Filtered, and the filter cake was washed with water poured into water (40ml) in. Plus 20% sodium hydroxide solution (approximately 60ml) was adjusted to pH 9. Filtered, washed with ethanol and recrystallized to give a pale yellow powdered solid IV (6.3g, 68.7%), mp 190.4~191.1 ° C. Purity 97.2% (HPLC normalization method).

Synthesis of intermediate V:

Intermediate IV (5g, 15mmol) and triethylamine (2.3g, 23mmol) was added followed by IOOml reaction flask was added dichloromethane (30ml), stir until dissolved. Solution of o-methylbenzoyl chloride (2.8g, 18mmol), dropwise at room temperature completion of the reaction Ih0 TLC showed the reaction was complete was poured into ice-water (about 40ml) in, (20ml X 3) and extracted with dichloromethane, the combined organic phases, and saturated sodium chloride solution successively (25ml X 3), dried over anhydrous sodium sulfate and filtered with 5% hydrochloric acid (25ml X 3). The filtrate under reduced pressure to recover the solvent (about 50ml), dried over anhydrous methanol residue – petroleum ether (2: 1) and recrystallized to give white crystals of Intermediate V (6.2g, 90.9%), mp 121.1 ~123.6 ° C. Purity 98.6% (HPLC normalization method).

Synthesis of tolvaptan: Example 4

Intermediate V (5g, Ilmmol) IOOml added to the reaction flask, was added anhydrous methanol (25ml), stirred and then added portionwise sodium borohydride (0.65g, 17mmol) to the reaction mixture, addition was complete the reaction at room temperature lh. After TLC showed the reaction was complete, the methanol recovered under reduced pressure (approximately 20ml), the residue was added methylene chloride (25ml), (25mlX3) and washed with saturated sodium chloride solution. Anhydrous sodium sulfate and filtered, and the filtrate under reduced pressure to recover the solvent, the residue with absolute methanol – petroleum ether (2: 1) and recrystallized tolvaptan white crystals (4.85g, 96.6%), mp 220.1~221.5 ° C. Purity 99.2% (HPLC normalization method). ES1-HRMS (C26H25C1N203, m / z) found (calc): 447.1476 (447.1481) [MH] – “

…………..

PATENT

http://www.google.com/patents/WO2012046244A1?cl=en

Tolvaptan is chemically, N-[4-[(7-chloro-2,3,4,5-tetrahydro-5-hydroxylH-l- benzazepin- 1 -yl)carbonyl]-3-methylphenyl]-2-methylbenzamide. Tolvaptan is represented by the following structure:

Tolvaptan and its process for preparation were disclosed in U.S. patent no. 5,258,510. Processes for the preparation of 7-chloro-2,3,4,5-tetrahydro-lH-l-benzazepin-5- one, 7-chloro-l-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-lH-l-benzazepine and 7-chloro- 1 -[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5- tetrahydro-lH-l-benzazepine were reported in Bioorganic & medicinal chemistry 7 (1999), 1743-1754. According to the journal, 7-chloro-2,3,4,5-tetrahydro-lH-l- benzazepin-5-one can be prepared by reacting 7-chloro-4-ethoxycarbonyl-5-oxo-N-p- toluenesufonyl-2,3,4,5-tetrahydro-lH-l-benzazepine with acetic acid in the presence of hydrochloric acid and water to obtain 7-chloro-5-oxo-2,3,4,5-tetrahydro-l-p- toluenesulfonyl-lH-l-benzazepine, and then reacted with polyphospholic acid.

According to the journal, 7-chloro- 1 -(2 -methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5- tetrahydro-lH-l-benzazepine can be prepared by reacting 7-chloro-5-oxo-2,3,4,5- tetrahydro-lH-l-benzazepine with 2-methyl-4-nitobenzoyl chloride in the presence of triethylamine.

According to the journal, 7-chloro- l-[2-methyl-4-[(2- methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro-lH-l-benzazepine can be prepared by reacting l-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro- lH-l-benzazepine with 2-methylbenzoylchloride in the presence of triethylamine.

PCT publication no. WO 2007/026971 disclosed a process for the preparation of tolvaptan can be prepared by the reduction of 7-chloro- l-[2-methyl-4-(2- methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-l-benzazepin-5-one with sodium borohydride.

7-Chloro-2,3,4,5-tetrahydro-lH-l-benzazepin-5-one is a key intermediate for the preparation of tolvaptan.

SYNTHESIS CONSTRUCTION

Reference example 1 :

Preparation of methyl 5-chloro-2-nitrobenzoate

Potassium carbonate (515 gm) was added to a solution of 5-chloro-2-nitro benzoic acid (500 gm) in acetone (2750 ml) at room temperature. Dimethyl sulphate (306.5 gm) was added to the reaction mixture slowly and heated to reflux for 30 minutes. The reaction mass was filtered and then concentrated to obtain a residual mass. The residual mass was poured to the ice water and extracted with methylene chloride. The solvent was distilled off under reduced pressure to obtain a residual solid of methyl 5- chloro-2-nitrobenzoate (534 gm). Reference example 2:

Preparation of methyl 2-amino-5-chlorobenzoate

A mixture of methyl 5-chloro-2-nitrobenzoate (534 gm) as obtained in reference example 1 and concentrated hydrochloric acid (2250 ml) was added to ethyl acetate (1120 ml). To the reaction mixture was added a solution of tin chloride (1680 gm) in ethyl acetate (2250 ml). The reaction mass was stirred for 16 hours at room temperature and then poured to the ice water. The pH of the reaction mass was adjusted to 8.0 to 9.0 with aqueous sodium hydroxide solution (2650 ml). The separated aqueous layer was extracted with ethyl acetate and then concentrated to obtain a residual solid of methyl 2- amino-5-chlorobenzoate (345 gm). Reference example 3:

Preparation of methyl 5-chIoro-2-(N-p-toluenesulfonyl)aminobenzoate

To a solution of methyl-2-amino-5-chloro benzoate (345 gm) as obtained in reference example 2 in pyridine (1725 ml) was added p-toluenesulfonyl chloride (425 gm). The reaction mixture was stirred for 2 hours at room temperature and poured to the ice water. The separated solid was filtered and dried to obtain 585 gm of methyl 5- chloro-2-(N-p-toluenesulfonyl)aminobenzoate.

Reference example 4:

Preparation of methyl 5-chloro-2-[N-(3-ethoxycarbonyI)propyI-N-p- toluenesulfonyl] aminobenzoate

Methyl 5-chloro-2-(N-p-toluenesulfonyl)aminobenzoate (585 gm) as obtained in reference example 3, ethyl-4-bromo butyrate (369.6 gm) and potassium carbonate (664 gm) in dimethylformamide (4400 ml) were added at room temperature. The contents were heated to 120°C and maintained for 2 hours. The reaction mass was poured into water and filtered. The solid obtained was dried to give 726 gm of methyl 5-chloro-2-[N- (3 -ethoxycarbonyl)propyl-N-p-toluenesulfonyl] aminobenzoate.

Reference example 5:

Preparation of 7-chloro-4-ethoxycarbonyI-5-oxo-N-p-toluenesufonyl-2,3,4,5- tetrahydro-lH-l-benzazepine

To a heated mixture of potassium tetrabutoxide (363 gm) in toluene (1000 ml) at 70°C was added portion wise methyl 5-chloro-2-[N-(3-ethoxycarbonyl)propyl-N-p- toluenesulfonyl]aminobenzoate (726 gm) as obtained in reference example 4. The contents were heated to reflux and maintained for 30 minutes. The reaction mass was then cooled to room temperature and then poured to the ice water. The layers were separated and the aqueous layer was extracted with toluene. The solvent was distilled off under reduced pressure to obtain a residual solid of 7-chloro-4-ethoxycarbonyl-5-oxo-N- p-toluenesufonyl-2,3,4,5-tetrahydro-lH-l-benzazepine (455 gm).

Example 1:

Preparation of 7-chIoro-5-oxo-2,3,4,5-tetrahydro-lH-l-benzazepine

7-Chloro-4-ethoxycarbonyl-5-oxo-N-p-toluenesufonyl-2,3,4,5-tetrahydro- 1 H- 1 – benzazepine (455 gm) as obtained in reference example 5 was added to aqueous sulfuric acid (80%, 2275 ml). The contents heated to 75°C and maintained for 2 hours. The reaction mass was then cooled to room temperature and then poured to the ice water. The pH of the reaction mass was adjusted to 7.5 to 8.0 with sodium hydroxide solution (2575 ml). The solid obtained was collected by filtration and dried to give 160 gm of 7- chloro-5-oxo-2,3 ,4,5-tetrahydro- 1 H- 1 -benzazepine.

Example 2:

Preparation of 7-chIoro-l-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-lH-l- benzazepine

7-Chloro-5-oxo-2,3,4,5-tetrahydro-lH-l -benzazepine (160 gm) as obtained in example 1 was dissolved in methylene dichloride (480 ml) and then added aqueous sodium bicarbonate solution (20%, 68.75 gm). The reaction mixture was then cooled to 0 to 5°C and then added 2-methyl-4-nitrobenzoylchloride (180 gm) slowly. The pH of the reaction mass was adjusted to 7.0 to 8.0 with aqueous sodium bicarbonate solution (170 ml). The layers were separated and the aqueous layer was extracted with methylene chloride. The solvent was distilled off under reduced pressure to obtain a residual mass. To the residual mass was dissolved in isopropyl alcohol (7300 ml) and maintained for 2 hours at reflux temperature. The separated solid was filtered and dried to obtain 250 gm of 7-chloro-l-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-lH-l-benzazepine. Example 3:

Preparation of l-(4-amino-2-methylbenzoyl)-7-chIoro-5-oxo-2,3,4,5-tetrahydro-lH- 1-benzazepine

7-Chloro- 1 -(2-methyl-4-nitrobenzoyl)-5-oxo-2,3 ,4,5-tetrahydro- 1 H- 1 – benzazepine (250 gm) as obtained in example 2 was dissolved in methanol (575 ml) and then added a solution of tin chloride (630 gm) in methanol (1130 ml). The reaction mixture was stirred for 16 hours at room temperature and then poured to the ice water. The pH of the reaction mass was adjusted to 8.0 to 9.0 with sodium hydroxide solution (1250 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate. The solvent was distilled off under vacuum to obtain a residual solid of l-(4- amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro- 1 H- 1 -benzazepine (185 gm).

Example 4:

Preparation of 7-chloro-l-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-dxo- 2,3,4,5-tetrahydro-lH-l-benzazepine

1 -(4-Amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3 ,4,5-tetrahydro- 1 H- 1 – benzazepine (185 gm) as obtained in example 3 was dissolved in methylene chloride (4000 ml) and then added sodium bicarbonate solution (10%, 47.3 gm). The reaction mass was cooled to 0 to 5°C and then added 2-methyl benzoyl chloride (95.7 gm) slowly. -The pH of the reaction mass was adjusted to 7.0 to 8.0 with aqueous sodium bicarbonate solution (120 ml). The separated aqueous layer was extracted with methylene chloride and then concentrated to obtain a residual solid of 7-chloro-l-[2- methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro- 1 H- 1 – benzazepine (185 gm). Example 5:

Preparation of tolvaptan

7-Chloro- 1 -[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5- tetrahydro-lH-1 -benzazepine (63 gm) as obtained in example 4 was dissolved in methanol (570 ml) and then added sodium borohydride (2.07 gm) at room temperature. The reaction mass was stirred for 1 hour and pH of the reaction mass was adjusted to 6.0 to 7.0 with hydrochloric acid solution (1%, 630 ml). The separated solid was filtered and dried to obtain 57 gm of tolvaptan.

……………….

Process used to prepare Tolvaptan involves condensing 7-chloro-1, 2, 3, 4-tetrahydro-benzo[b]azepin-5-one with 2-methyl, 4-nitro benzoyl chloride, followed by reduction using SnCl2/HCl catalyst resulting in amine which is then condensed with o-toluoyl chloride followed by reduction with sodium borohydride to give Tolvaptan

///////////

AS ON DEC2021 3,491,869 VIEWS ON BLOG WORLDREACH AVAILABLEFOR YOUR ADVERTISEMENT

join me on Linkedin

Anthony Melvin Crasto Ph.D – India | LinkedIn

join me on Researchgate

RESEARCHGATE

This image has an empty alt attribute; its file name is research.jpg

join me on Facebook

Anthony Melvin Crasto Dr. | Facebook

join me on twitter

Anthony Melvin Crasto Dr. | twitter

+919321316780 call whatsaapp

EMAIL. amcrasto@amcrasto

/////////////////////////////////////////////////////////////////////////////

SYN 1

Synthetic Reference

Cordero-Vargas, Alejandro; Quiclet-Sire, Beatrice; Zard, Samir Z. A flexible approach for the preparation of substituted benzazepines: Application to the synthesis of tolvaptan. Bioorganic & Medicinal Chemistry. Volume 14. Issue 18. Pages 6165-6173. 2006.

SYN 2

Synthetic Reference

Torisawa, Yasuhiro; Abe, Kaoru; Muguruma, Yasuaki; Fujita, Shigekazu; Ogawa, Hidenori; Utsumi, Naoto; Miyake, Masahiro. Process for preparation of benzoylaminobenzoylbenzazepinones by reaction of benzazepinones with benzoylaminophenyl halides in the presence of carbonylating agents. Assignee Otsuka Pharmaceutical Co.,

SYN 3

Synthetic Reference

Zard, Samir; Cordero Vargas, Alejandro; Sire, Beatrice. Improved process for the preparation of benzazepines and their derivatives. Assignee Centre National de la Recherche Scientifique CNRS, Fr.; Ecole Polytechnique. FR 2867187. (2005).

SYN 4

Synthetic Reference

Gao, Junlong; Li, Peng; Liu, Kai; Guo, Dapeng. Method for preparing high-purity Tolvaptan intermediate. Assignee Jiangsu Hengrui Medicine Co., Ltd., Peop. Rep. China. CN 108503586. (2018).

SYN 5

Synthetic Reference

Han, Shin; Jeon, Seong Hyeon; Lee, Shin Yoon. Improved method for preparing synthetic intermediates for tolvaptan. Assignee Hexa Pharmatec Co., Ltd., S. Korea. JP 2018012690. (2018).

SYN 6

Synthetic Reference

Guo, Xinfu; Wang, Qiang; Liu, Zhaoguo; Wang, Zhipeng. Preparation method of tolvaptan. Assignee Tianjin Taipu Pharmaceutical Co., Ltd., Peop. Rep. China. CN 106883175. (2017).

SYN 7

Synthetic Reference

Lixin, Juanzi; Li, Jianzhi; Ma, Xilai; Chi, Wangzhou; Liu, Hai; Hu, Xuhua; Zheng, Xiaoli; Zhai, Zhijun; Li, Jianxun. Process for the preparation of tolvaptan. Assignee Shanghai Tianci International Pharmaceutical Co., Ltd., Peop. Rep. China. CN 105753735. (2016).

STR8

Synthetic Reference

Patel, Dhaval J.; Shah, Tejas C.; Singh, Manoj Kumar. A process for the preparation of tolvaptan. Assignee Cadila Healthcare Limited, India. IN 2012MU01559. (2014).

STR9

Synthetic Reference

Sethi, Madhuresh Kumar; Rawat, Vijendrasingh; Thirunavukarasu, Jayaprakash; Yerramala, Raja Krishna; Kumar, Anish. Improved process for the preparation of tolvaptan. Assignee Matrix Laboratories Ltd., India. IN 2011CH01303. (2013).

/////////////////////

Title: Tolvaptan
CAS Registry Number: 150683-30-0
CAS Name: N-[4-[(7-Chloro-2,3,4,5-tetrahydro-5-hydroxy-1H-1-benzazepin-1-yl)carbonyl]-3-methylphenyl]-2-methylbenzamide
Additional Names: 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine
Manufacturers’ Codes: OPC-41061
Molecular Formula: C26H25ClN2O3
Molecular Weight: 448.94
Percent Composition: C 69.56%, H 5.61%, Cl 7.90%, N 6.24%, O 10.69%
Literature References: Nonpeptide arginine vasopressin V2 receptor antagonist. Prepn: H. Ogawa et al., WO 9105549; eidem, US 5258510 (1991, 1993 both to Otsuka); K. Kondo et al., Bioorg. Med. Chem. 7, 1743 (1999). Pharmacology: Y. Yamamura et al., J. Pharmacol. Exp. Ther. 287, 860 (1998). Clinical trial in heart failure: M. Gheorghiade et al., J. Am. Med. Assoc. 291, 1963 (2004).
Properties: Colorless prisms, mp 225.9°.
Melting point: mp 225.9°
Therap-Cat: In treatment of congestive heart failure.
Keywords: Vasopressin Receptor Antagonist.

Shoaf S, Elizari M, Wang Z, et al. (2005). “Tolvaptan administration does not affect steady state amiodarone concentrations in patients with cardiac arrhythmias”. J Cardiovasc Pharmacol Ther 10 (3): 165–71. doi:10.1177/107424840501000304. PMID 16211205.
Otsuka Maryland Research Institute, Inc.
Gheorghiade M, Gattis W, O’Connor C, et al. (2004). “Effects of tolvaptan, a vasopressin antagonist, in patients hospitalized with worsening heart failure: a randomized controlled trial”. JAMA 291 (16): 1963–71. doi:10.1001/jama.291.16.1963. PMID 15113814.
(2012) Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease
Kondo, K.; Ogawa, H.; Yamashita, H.; Miyamoto, H.; Tanaka, M.; Nakaya, K.; Kitano, K.; Yamamura, Y.; Nakamura, S.; Onogawa, T.; et al.; Bioor. Med. Chem. 1999, 7, 1743.
http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm350185.htm?source=govdelivery

Gheorghiade M, Niazi I, Ouyang J et al. (2003). “Vasopressin V2-receptor blockade with tolvaptan in patients with chronic heart failure: results from a double-blind, randomized trial”. Circulation 107 (21): 2690–6. doi:10.1161/01.CIR.0000070422.41439.04.PMID 12742979.

G. R. Belum, V. R. Belum, S. K. Chaitanya Arudra, and B. S. N. Reddy, “The Jarisch-Herxheimer reaction: revisited,” Travel Medicine and Infectious Disease, vol. 11, no. 4, pp. 231–237, 2013.
H. D. Zmily, S. Daifallah, and J. K. Ghali, “Tolvaptan, hyponatremia, and heart failure,” International Journal of Nephrology and Renovascular Disease, vol. 4, pp. 57–71, 2011.
M. N. Ferguson, “Novel agents for the treatment of hyponatremia: a review of conivaptan and tolvaptan,” Cardiology in Review, vol. 18, no. 6, pp. 313–321, 2010.
H. Ogawa, H. Miyamoto, K. Kondo, et al., US5258510, 1993.
K. Kondo, H. Ogawa, H. Yamashita et al., “7-Chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5- tetrahydro-1H-1-benzazepine (OPC-41061): a potent, orally active nonpeptide arginine vasopressin V2 receptor antagonist,” Bioorganic and Medicinal Chemistry, vol. 7, no. 8, pp. 1743–1754, 1999.

WO2012046244A1 *	Aug 23, 2011	Apr 12, 2012	Hetero Research Foundation	Process for preparing tolvaptan intermediates
CN102060769A *	Dec 20, 2010	May 18, 2011	天津药物研究院	Preparation method of tolvaptan
CN102060769B	Dec 20, 2010	Sep 18, 2013	天津药物研究院	Preparation method of tolvaptan
US9024015	Aug 23, 2011	May 5, 2015	Hetero Research Foundation	Process for preparing tolvaptan intermediates

Cited Patent	Filing date	Publication date	Applicant	Title
CN101817783A	May 12, 2010	Sep 1, 2010	天津泰普药品科技发展有限公司	Method for preparing tolvaptan intermediate
WO2007026971A2	Sep 1, 2006	Mar 8, 2007	Otsuka Pharma Co Ltd	Process for preparing benzazepine compounds or salts thereof

Reference
1		Cordero-Vargas, Alejandro
2		Kondo, Kazumi et al.7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoyl-amino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine (OPC-41061): A potent, orally active nonpeptide arginine vasopressin V2 receptor antagonist.《Bioorganic & Medicinal Chemistry》.1999,1743-1757.
3		Quiclet-Sire, Beatrice
4		Torisawa, Yasuhiro et al.Aminocarbonylation route to tolvaptan.《Bioorganic & Medicinal Chemistry Letters》.2007,6455-6458.
5		Zard, Samir Z.A flexible approach for the preparation of substituted benzazepines: Application to the synthesis of tolvaptan.《Bioorganic & Medicinal Chemistry》.2006,6165-6173.

///////////////

CC1=CC=CC=C1C(=O)NC2=CC(=C(C=C2)C(=O)N3CCCC(C4=C3C=CC(=C4)Cl)OP(=O)([O-])[O-])C.[Na+].[Na+]

////////////UPDATE 2022

Tolvaptan
Clinical data


Trade names	Samsca, Jinarc, Jynarque, others
Other names	OPC-41061
AHFS/Drugs.com	Monograph
MedlinePlus	a609033
License data	EU EMA: by INN US DailyMed: Tolvaptan US FDA: Tolvaptan
Pregnancy category	UK: Contraindicated
Routes of administration	By mouth
ATC code	C03XA01 (WHO)
Legal status
Legal status	UK: POM (Prescription only) ^[1]^[2] US: ℞-only ^[3]^[4] EU: Rx-only ^[5]^[6]
Pharmacokinetic data
Bioavailability	Unknown (40% absorbed)
Protein binding	99%
Metabolism	Liver (CYP3A4-mediated)^[7]
Elimination half-life	12 hours (terminal)
Identifiers
show IUPAC name
CAS Number	150683-30-0
PubChem CID	216237
IUPHAR/BPS	2226
DrugBank	DB06212
ChemSpider	187438
UNII	21G72T1950
KEGG	D01213
ChEMBL	ChEMBL344159
CompTox Dashboard (EPA)	DTXSID3048780
ECHA InfoCard	100.219.212
Chemical and physical data
Formula	C₂₆H₂₅ClN₂O₃
Molar mass	448.95 g·mol⁻¹
3D model (JSmol)	Interactive image
show SMILES
show InChI
(what is this?) (verify)

Tolvaptan, sold under the brand name Samsca among others, is an aquaretic drug that functions as a selective, competitive vasopressin receptor 2 (V₂) antagonist used to treat hyponatremia (low blood sodium levels) associated with congestive heart failure, cirrhosis, and the syndrome of inappropriate antidiuretic hormone (SIADH). Tolvaptan was approved by the U.S. Food and Drug Administration (FDA) on May 19, 2009, and is sold by Otsuka Pharmaceutical Co. under the trade name Samsca.^[8] Tolvaptan, as Jynarque, was granted approval for medical use in the United States in April 2018.^[9]

The U.S. Food and Drug Administration (FDA) granted tolvaptan a fast track designation for clinical trials investigating its use for the treatment of polycystic kidney disease.^[10] The FDA granted Jynarque an orphan drug designation in April 2012, for the treatment of autosomal dominant polycystic kidney disease.^[11]

Tolvaptan is available as a generic medication.^[12]

Medical uses

Tolvaptan (Samsca) is indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia.^[13]

Tolvaptan (Jynarque) is indicated to slow kidney function decline in adults at risk of rapidly progressing autosomal dominant polycystic kidney disease (ADPKD).^[14]

Side effects

The FDA has determined that tolvaptan should not be used for longer than 30 days and should not be used in patients with underlying liver disease because it can cause liver injury, potentially leading to liver failure.^[15] When using to treat hyponatremia, it may cause too rapid correction of hyponatremia resulting in fatal osmotic demyelination syndrome.^[16]

Pharmacology

Tolvaptan is a selective vasopressin V₂ receptor antagonist.^[13]^[14]

Chemistry

Tolvaptan is a racemate, a 1:1 mixture of the following two enantiomers:^[17]

Enantiomers of tolvaptan
(R)-Tolvaptan CAS number: 331947-66-1	(S)-Tolvaptan CAS number: 331947-44-5

References

^ “Samsca 15 mg tablets – Summary of Product Characteristics (SmPC)”. (emc). Retrieved 14 December 2020.
^ “Jinarc 15 mg tablets – Summary of Product Characteristics (SmPC)”. (emc). 21 April 2020. Retrieved 14 December 2020.
^ “Jynarque- tolvaptan kit Jynarque- tolvaptan tablet”. DailyMed. 31 March 2020. Retrieved 14 December 2020.
^ “Samsca- tolvaptan tablet”. DailyMed. 26 October 2020. Retrieved 14 December 2020.
^ “Samsca EPAR”. European Medicines Agency (EMA). Retrieved 14 December 2020.
^ “Jinarc EPAR”. European Medicines Agency (EMA). Retrieved 14 December 2020.
^ Shoaf S, Elizari M, Wang Z, et al. (2005). “Tolvaptan administration does not affect steady state amiodarone concentrations in patients with cardiac arrhythmias”. J Cardiovasc Pharmacol Ther. 10 (3): 165–71. doi:10.1177/107424840501000304. PMID 16211205. S2CID 39158242.
^ “Drug Approval Package: Samsca (Tolvaptan) Tablets NDA #022275”. U.S. Food and Drug Administration (FDA). 21 July 2009. Retrieved 15 August 2020. Lay summary (PDF). {{cite web}}: Cite uses deprecated parameter |lay-url= (help)
^ “Drug Approval Package: Jynarque (tolvaptan)”. U.S. Food and Drug Administration (FDA). 8 June 2018. Retrieved 15 August 2020.
^ “Otsuka Maryland Research Institute, Inc. Granted Fast Track Designation For Tolvaptan In PKD”. Medical News Today. Healthline Media UK Ltd. Retrieved 6 December 2018.
^ “Tolvaptan Orphan Drug Designations and Approvals”. U.S. Food and Drug Administration (FDA). 6 April 2012. Retrieved 15 August 2020.
^ “Drugs@FDA: FDA-Approved Drugs”. U.S. Food and Drug Administration (FDA). Retrieved 15 August 2020.
^ Jump up to:^a ^b “Samsca- tolvaptan tablet”. DailyMed. 28 May 2019. Retrieved 15 August 2020.
^ Jump up to:^a ^b “Jynarque- tolvaptan kit Jynarque- tolvaptan tablet”. DailyMed. 31 March 2020. Retrieved 15 August 2020.
^ “U.S. Food and Drug Administration.” Samsca (Tolvaptan): Drug Safety Communication. N.p., 30 Apr. 2013. Web. 1 June 2014. <http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm350185.htm>^{[dead link]}
^ Goodman & Gilman’s the pharmacological basis of therapeutics. Brunton, Laurence L, Knollmann, Björn C, Hilal-Dandan, Randa (Thirteenth ed.). New York. 5 December 2017. ISBN 9781259584732. OCLC 994570810.
^ Rote Liste Service GmbH (Hrsg.): Rote Liste 2017 – Arzneimittelverzeichnis für Deutschland (einschließlich EU-Zulassungen und bestimmter Medizinprodukte). Rote Liste Service GmbH, Frankfurt/Main, 2017, Aufl. 57, ISBN 978-3-946057-10-9, S. 222.

External links

“Tolvaptan”. Drug Information Portal. U.S. National Library of Medicine.

Synthesis

Fugure 1: Synthesis of Tolvaptan

NEW DRUG APPROVALS

HELP TO MAINTAIN THIS BLOG SUBSCRIPTION

$10.00

Title: Tolvaptan

CAS Registry Number: 150683-30-0

CAS Name: N-[4-[(7-Chloro-2,3,4,5-tetrahydro-5-hydroxy-1H-1-benzazepin-1-yl)carbonyl]-3-methylphenyl]-2-methylbenzamide

Additional Names: 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine

Manufacturers’ Codes: OPC-41061

Molecular Formula: C26H25ClN2O3

Molecular Weight: 448.94

Percent Composition: C 69.56%, H 5.61%, Cl 7.90%, N 6.24%, O 10.69%

Literature References: Nonpeptide arginine vasopressin V2 receptor antagonist. Prepn: H. Ogawa et al., WO 9105549; eidem, US 5258510 (1991, 1993 both to Otsuka); K. Kondo et al., Bioorg. Med. Chem. 7, 1743 (1999). Pharmacology: Y. Yamamura et al., J. Pharmacol. Exp. Ther. 287, 860 (1998). Clinical trial in heart failure: M. Gheorghiade et al., J. Am. Med. Assoc. 291, 1963 (2004).

Properties: Colorless prisms, mp 225.9°.

Melting point: mp 225.9°

Therap-Cat: In treatment of congestive heart failure.

Keywords: Vasopressin Receptor Antagonist.

Medicinal Chemistry International: DELDEPREVIR (NECEPREVIR)

December 27, 2013 12:00 pm / Leave a comment

Medicinal Chemistry International: DELDEPREVIR (NECEPREVIR)

WANT TO KNOW ABOUT VIR SERIES CLICK

click

http://drugsynthesisint.blogspot.in/p/vir-series-hep-c-virus-22.html

AND

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

DELDEPREVIR OR NECEPREVIR

deldeprevir,

ACH-0142684, ACH-2684

HCV NS3 PR

USAN (YY-152) DELDEPREVIR

THERAPEUTIC CLAIM Treatment of Hepatitis C
CHEMICAL NAMES
1. Cyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a(5H)-carboxamide, N-
(cyclopropylsulfonyl)-6-[2-(3,3-difluoro-1-piperidinyl)-2-oxoethyl]-
1,2,3,6,7,8,9,10,11,13a,14,15,16,16a-tetradecahydro-2-[[7-methoxy-8-methyl-2-[4-(1-
methylethyl)-2-thiazolyl]-4-quinolinyl]oxy]-5,16-dioxo-, (2R,6R,12Z,13aS,14aR,16aS)-
2. (2R,6R,12Z,13aS,14aR,16aS)-N-(cyclopropylsulfonyl)-6-[2-(3,3-difluoropiperidin-1-yl)-
2-oxoethyl]-2-({7-methoxy-8-methyl-2-[4-(1-methylethyl)thiazol-2-yl]quinolin-4-yl}oxy)-
5,16-dioxo-1,2,3,6,7,8,9,10,11,13a,14,15,16,16atetradecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a(5H)-
carboxamide

MOLECULAR FORMULA C45H56F2N6O8S2
MOLECULAR WEIGHT 911.1
SPONSOR Achillion Pharmaceuticals, Inc.
CODE DESIGNATION ACH-0142684, ACH-2684
CAS REGISTRY NUMBER 1229626-28-1
WHO NUMBER 9600
NOTE: This adoption statement replaces adoption N12/17 and the name neceprevir is hereby rescinded.

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

deldeprevir-sodium

DELDEPREVIR SODIUM

USAN (yy-153) DELDEPREVIR SODIUM

THERAPEUTIC CLAIM Treatment of Hepatitis C

CHEMICAL NAMES

1. Cyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a(5H)-carboxamide, N-
(cyclopropylsulfonyl)-6-[2-(3,3-difluoro-1-piperidinyl)-2-oxoethyl]-
1,2,3,6,7,8,9,10,11,13a,14,15,16,16a-tetradecahydro-2-[[7-methoxy-8-methyl-2-[4-(1-
methylethyl)-2-thiazolyl]-4-quinolinyl]oxy]-5,16-dioxo-, sodium salt (1:1),
(2R,6R,12Z,13aS,14aR,16aS)-

2. Sodium (cyclopropylsulfonyl){[(2R,6R,12Z,13aS,14aR,16aS)-6-[2-(3,3-difluoropiperidin-
1-yl)-2-oxoethyl]-2-({7-methoxy-8-methyl-2-[4-(1-methylethyl)thiazol-2-yl]quinolin-4-
yl}oxy)-5,16-dioxo-1,2,3,6,7,8,9,10,11,13a,14,15,16,16a-
tetradecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-14a(5H)-
yl]formyl]azanide

MOLECULAR FORMULA C45H55F2N6NaO8S2

MOLECULAR WEIGHT 933.1

SPONSOR Achillion Pharmaceuticals, Inc.

CODE DESIGNATION ACH-0142684.Na, ACH-2684.Na

CAS REGISTRY NUMBER 1298053-61-8

NOTE: This adoption statement replaces adoption N12/18 and the name neceprevir sodium

is hereby rescinded.

ACH-2684 is a HCV NS3 protease inhibitor in phase I clinical development at Achillion for the oral treatment of chronic hepatitis C genotype 1 and 3.

WO 2010068761
US 2010152103

COMPD 133

(2R,6R,14aR,16aS,Z)- N-(cyclopropylsulfonyl)- 6-(2-(3,3-difluoropiperidin- 1-yl)-2-oxoethyl)-2- (2-(2-isopropylthiazol- 4-yl)-7-methoxy-8- methylquinolin-4- yloxy)-5,16-dioxo- 1,2,3,5,6,7,8,9,10,11, 13a,14,14a,15,16,16a- hexadecahydrocyclopropa [e]pyrrolo[1,2- a][1,4] diazacyclopentadecine- 14a-carboxamide

https://www.google.co.in/patents/US20100152103?pg=PA1&dq=US+2010152103&hl=en&sa=X&ei=1ma9Utq-C4mxrgeu54G4DA&ved=0CDcQ6AEwAA

picture animation

click

http://drugsynthesisint.blogspot.in/p/vir-series-hep-c-virus-22.html

AND

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

Latest Posts

Danifexor
Danifexor CAS 2648738-68-3 MF C29H20Cl2N2O5 MW547.386 6-[6-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]naphthalen-2-yl]oxypyridine-3-carboxylic acid 3-Pyridinecarboxylic acid, 6-[[6-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methoxy]-2-naphthalenyl]oxy]- farnesoid X receptor agonist, TUU8G1CX9O, HEC 96719, ASC42 Danifexor is an investigational drug that acts…
Dabogratinib
Dabogratinib CAS 2800223-30-5 MF C25H24Cl2N6O3S, 559.5 g/mol 5-[(1R)-1-(3,5-dichloro-4-pyridinyl)ethoxy]-3-[6-(2-methylsulfonyl-2,6-diazaspiro[3.3]heptan-6-yl)-3-pyridinyl]-1H-indazole (R)-5-(1-(3,5-Dichloropyridin-4-yl)ethoxy)-3-(6-(6-(methylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-1H-indazole [6-(5-{5-[(1R)-1-(3,5-dichloropyridin-4-yl)ethoxy]-1H-indazol-3-yl}pyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl](methyl)-λ6sulfanedioneTYRA-300fibroblast growth factor receptor inhibitor, antineoplastic, TYRA-300, TYRA 300, A1AV2, FH245S2JZJ Dabogratinib (TYRA-300) is an orally active, highly…
Colfosceril miristate
Colfosceril miristate CAS 18194-24-6 MF C36H72NO8P MW677.9325 1,2 Dimyristoyl glycero 3 phosphorylcholine (2R)-2,3-bis(tetradecanoyloxy)propyl 2-(trimethylazaniumyl)ethyl phosphatesurfactant replacement, DIMYRISTOYL LECITHIN, Dimyristoyllecithin, DMCP, DMPC Colfosceril miristate (1,2-dimyristoyl-sn-glycero-3-phosphocholine or…
Claturafenib
Claturafenib CAS 2754408-94-9 MF C18H15Cl2F2N5O3S MW490.3 g/mol N-[2-chloro-3-[(5-chloro-3-methyl-4-oxoquinazolin-6-yl)amino]-4-fluorophenyl]-3-fluoroazetidine-1-sulfonamide N-{2-chloro-3-[(5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino]-4-fluorophenyl}-3-fluoroazetidine-1-sulfonamideB-Raf (BRAF) inhibitor, antineoplastic, PF-07799933, PF 07799933, ARRY440, ARRY 440, PC35M52J8T Claturafenib (development code PF-07799933) is an investigational cancer drug currently…
Cirtociclib
Cirtociclib CAS 2888704-84-3 MF C15H17F2N7O2 MW365.34 g/mol N-[3-(difluoromethoxy)-1H-pyrazol-5-yl]-1-(oxan-4-ylmethyl)pyrazolo[3,4-b]pyrazin-6-amine N-[5-(difluoromethoxy)-1H-pyrazol-3-yl]-1-[(oxan-4-yl)methyl]-1H-pyrazolo[3,4-b]pyrazin-6-aminecyclin-dependent kinase inhibitor, antineoplastic, BLU-222, BLU 222, BLU 170298, U93X72ED47, CDK2 Inhibitor BLU-222 Cirtociclib (also known as BLU-222) is an…
Ceperognastat
Ceperognastat CAS 2241514-56-5 MF C16H22FN5O3S MW383.4 g/mol Acetamide, N-(4-fluoro-5-(((2S,4S)-2-methyl-4-((5-methyl-1,2,4-oxadiazol-3-yl)methoxy)-1-piperidinyl)methyl)-2-thiazolyl)- N-[4-fluoro-5-({(2S,4S)-2-methyl-4-[(5-methyl-1,2,4-oxadiazol-3-yl)methoxy]piperidin-1-yl}methyl)-1,3-thiazol-2-yl]acetamideO-GlcNAcase (OGA) enzyme inhibitor, LY3372689, LY3372689, U0SGP6ZX2V Ceperognastat (LY3372689) is a drug candidate molecule under investigation to treat…
Cendifensine
Cendifensine CAS 1034048-49-1 MF C14H17Cl2NO MW286.2 g/mol Methanone, (3,4-dichlorophenyl)[(3S)-3-propyl-3-pyrrolidinyl]- (3,4-dichlorophenyl)[(3S)-3-propylpyrrolidin-3-yl]methanonemonoamine reuptake inhibitor, NOE-115, NOE 115, N4U2JR8GCX, Cendifensine (INNTooltip International Nonproprietary Name) is a monoamine reuptake inhibitor (MRI)[1] related to the amphetamines and cathinones which…
Catadegbrutinib
Catadegbrutinib CAS 2736508-60-2 MF C47H54N12O4 MW851.0 g/mol 1,2,4-Oxadiazole-5-carboxamide, 3-(1,1-dimethylethyl)-N-[(1R)-1-[2-methyl-4-[6-[6-[4-[[1-[4-(tetrahydro-2,4-dioxo-1(2H)-pyrimidinyl)phenyl]-4-piperidinyl]methyl]-1-piperazinyl]-3-pyridinyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]phenyl]ethyl]- 3-tert-butyl-N-[(1R)-1-[4-[6-[6-[4-[[1-[4-(2,4-dioxo-1,3-diazinan-1-yl)phenyl]piperidin-4-yl]methyl]piperazin-1-yl]-3-pyridinyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-methylphenyl]ethyl]-1,2,4-oxadiazole-5-carboxamide 3-tert-butyl-N-{(1R)-1-[13-methyl-82,84-dioxo-27H-2(4,6)-pyrrolo[2,3-d]pyrimidina-8(1)-[1,3]diazinana-4(1,4)-piperazina3(5,2)-pyridina-6(4,1)-piperidina-1(1),7(1,4)-dibenzenaoctaphan-14-yl]ethyl}-1,2,4-oxadiazole-5-carboxamideBruton tyrosine kinase degrader, antineoplastic, BGB-16673, BGB 16673, PF6GPZ4DYT, BTK-IN-29, Tacabrutideg Catadegbrutinib (BGB-16673) is an orally active,…
Bretisilocin
Bretisilocin CAS2698331-35-8 MF C13H17FN2 MW220.29 g/mol N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethan-1-amineserotonin (5-HT2A) receptor agonist, GM-2505, GM 2505, 5-Fluoro-N-methyl-N-ethyltryptamine, 5F-MET, 5-F-MET, 5-Fluoro-MET, DS425RQ8SX Bretisilocin, also known by its developmental code name GM-2505 and…
Blixeprodil
Blixeprodil CAS 2881017-49-6 MF C13H16FNO MW 221.27 g/mol Cyclohexanone, 2-(4-fluorophenyl)-2-(methylamino)-, (2R)- (2R)-2-(4-fluorophenyl)-2-(methylamino)cyclohexan-1-oneN-methyl-D-aspartate (NMDA) receptor antagonist, GM-1020, GM1020, (R)-4-Fluorodeschloroketamine, (R)-4-FDCK, (R)-4FDCK, S2MGG2PC5K Blixeprodil,[5] also known by its developmental…

DISCLAIMER

I , Dr A.M.Crasto is writing this blog to share the knowledge/views, after reading Scientific Journals/Articles/News Articles/Wikipedia. My views/comments are based on the results /conclusions by the authors(researchers). I do mention either the link or reference of the article(s) in my blog and hope those interested can read for details. I am briefly summarising the remarks or conclusions of the authors (researchers). If one believe that their intellectual property right /copyright is infringed by any content on this blog, please contact or leave message at below email address amcrasto@gmail.com. It will be removed ASAP

Blog at WordPress.com.

No.	Major Technical Classification	Publication No.	Patent No.	Legal Status	Filling Date	Estimated Expiry Date
1	Preparation	CN1051038A	CN1027505C	Granted/expired	1990/10/19	2010/10/19
2	Preparation	CN1107146A	CN1048484C	Granted/expired	1990/10/19	2010/10/19
3	Formulation	CN1091288A		Withdrawn	1993/7/2
4	Uses	CN1120810A		Withdrawn	1994/2/22
5	Uses	CN1700919A	CN100577171C	Granted	2004/2/23	2024/2/23
6	Preparation	CN101273017A	CN101273017B	Granted	2006/9/1	2026/9/1
7	Preparation	CN102219741A	CN102219741B	Granted	2006/9/1	2026/9/1
8	Preparation	CN102746229A	CN102746229B	Granted	2006/9/1	2026/9/1
9	Preparation	CN101967107A	CN101967107B	Granted	2006/9/1	2026/9/1
10	Formulation	CN101340882A	CN101340882B	Granted	2006/12/21	2026/12/21
11	Formula	CN101346390A	CN101346390B	Granted	2006/12/22	2026/12/22
12	Combination	CN101808517A		Examination	2008/5/12
13	Combination	CN103550233A		Examination	2008/5/12
14	Formulation	CN103463095A		Examination	2008/6/20
15	Formulation	CN101686941A		Examination	2008/6/20
16	Formulation	CN103989644A		Examination	2008/6/20
17	Formula	CN101687805A		Refusal	2008/6/26
18	Formula	CN103342679A		Examination	2008/6/26
19	Formula	CN103342680A		Examination	2008/6/26
20	Formulation	CN101854920A	CN101854920B	Granted	2008/9/26	2028/9/26
21	Formulation	CN102143738A		Examination	2009/8/26
22	Formula	CN102753530A	CN102753530B	Examination	2010/10/25	2030/10/25
23	Others	CN104447555A		Examination	2010/10/25
24	Combination	CN104334176A		Publication	2013/5/30

	shivkr2 on SPSR Excellence Award 2025 – S…
	Bonkasaurus on Infigratinib phosphate
	PALOVAROTENE \| ORGAN… on Palovarotene
	Pfizer just purchase… on Temanogrel
	Pfizer To Cash In On… on Temanogrel
	VÍDEOS – A Pfizer ac… on Temanogrel
	Pfizer Bought Arena… on Temanogrel
	Pfizer va profita de… on Temanogrel
	Pfizer to Cash In on… on Temanogrel
	Pfizer tocmai a achi… on Temanogrel
	Pfizer just purchase… on Temanogrel
	Pfizer just purchase… on Temanogrel
	Tanya A on Dasotraline, ダソトラリン
	Julia Chernus on RIDINILAZOLE
	Adv.Siji Antony Kera… on Myself Anthony Crasto up for g…

SEARCH THIS BLOG

FLAGS AND HITS

Meta

Pages

Archives

Categories

MYSELF

Follow Blog via Email

Verified Services

Recent Posts

SEARCH THIS BLOG

Share this:

Share this:

Share this:

Share this:

Reference:

References

Share this:

Share this:

Share this:

Share this:

的合成

Synthesis Reference

AS ON DEC2021 3,491,869 VIEWS ON BLOG WORLDREACH AVAILABLEFOR YOUR ADVERTISEMENT

Anthony Melvin Crasto Dr. | Facebook

Synthetic Reference

Synthetic Reference

Synthetic Reference

Synthetic Reference

Synthetic Reference

Synthetic Reference

Synthetic Reference

Synthetic Reference

Synthetic Reference

Medical uses

Side effects

Pharmacology

Chemistry

References

Further reading

External links

Synthesis

Share this:

Share this:

Post navigation

SEARCH THIS BLOG

DR ANTHONY MELVIN CRASTO

Meta

Follow Blog via Email

ORGANIC SPECTROSCOPY

Latest Posts

Pages

feedjit

Recent Comments

DISCLAIMER

SEARCH THIS BLOG

SEARCH THIS BLOG

FLAGS AND HITS

Follow Blog via Email