US20100210868A1 - Process for obtaining pure oseltamivir - Google Patents

Process for obtaining pure oseltamivir Download PDF

Info

Publication number
US20100210868A1
US20100210868A1 US12/701,739 US70173910A US2010210868A1 US 20100210868 A1 US20100210868 A1 US 20100210868A1 US 70173910 A US70173910 A US 70173910A US 2010210868 A1 US2010210868 A1 US 2010210868A1
Authority
US
United States
Prior art keywords
oseltamivir
free base
solvent
crystalline
oseltamivir free
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US12/701,739
Inventor
Bandi Parthasaradhi Reddy
Kura Rathnakar Reddy
Rapolu Raji Reddy
Dasari Muralidhara Reddy
Kesireddy Subash Chander Reddy
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hetero Drugs Ltd
Original Assignee
Hetero Drugs Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hetero Drugs Ltd filed Critical Hetero Drugs Ltd
Priority to US12/701,739 priority Critical patent/US20100210868A1/en
Assigned to HETERO DRUGS LIMITED (R&D) reassignment HETERO DRUGS LIMITED (R&D) ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MURALIDHARA REDDY, DASARI, PARTHASARADHI REDDY, BANDI, RAJI REDDY, RAPOLU, RATHNAKAR REDDY, KURA, SUBASH CHANDER REDDY, KESIREDDY
Publication of US20100210868A1 publication Critical patent/US20100210868A1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/22—Separation; Purification; Stabilisation; Use of additives
    • C07C231/24—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

  • the present invention provides a process for obtaining highly pure crystalline form of oseltamivir free base.
  • the present invention also provides a process for preparation of oseltamivir phosphate in high purity.
  • Oseltamivir chemically Ethyl (3R,4R,5S)-4-(acetylamino)-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate is a orally active inhibitor of influenza virus neuraminidase.
  • Oseltamivir is represented by the following structure:
  • Oseltamivir free base obtained by these processes are not satisfactory from purity point of view and there is a need for a process for obtaining consistently reproducible pure crystalline oseltamivir free base.
  • One object of the present invention is to provide a process for preparation of highly pure crystalline oseltamivir free base that can be used to obtain pharmaceutically acceptable salts of oseltamivir in high purity.
  • Another object of the present invention is to provide a process for preparation of oseltamivir phosphate in high purity.
  • a process for isolation of pure crystalline oseltamivir free base comprises suspending or dissolving impure or non-crystalline oseltamivir free base in a hydrocarbon solvent and then isolating crystals to obtain oseltamivir free base in well defined crystalline form.
  • the crystalline oseltamivir free base obtained by the process as described in the present invention is characterized by an x-ray powder diffraction spectrum having peaks expressed as 20 at about 4.8, 5.2, 6.9, 8.7, 9.9, 10.5, 11.9, 13.0, 14.5, 17.2, 17.3, 18.4, 18.6, 19.9, 21.0, 21.3, 22.2, 22.5, 23.9 and 24.7 degrees as shown in FIG. 1 .
  • Preferable hydrocarbon solvent is selected from the group consisting of n-hexane, n-heptane, cyclohexane, toluene, xylene and a mixture thereof. More preferable hydrocarbon solvent is n-heptane, toluene or a mixture thereof.
  • the suspension is stirred for at least 30 minutes at below boiling temperature of the solvent used, more preferably for 1 hour to 4 hours at 15-60° C. and still more preferably for 1 hour to 3 hours at 20-40° C.
  • the isolation of the crystalline oseltamivir free base may be carried out by usually known methods such as filtration or centrifugation.
  • the isolation may, if required, be carried out by cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution or a combination thereof.
  • a process for preparation of pure oseltamivir phosphate comprises by contacting a solution or suspension of an organic acid addition salt of oseltamivir with a solution of phosphoric acid in an alcoholic solvent and then isolating pure oseltamivir phosphate from the solution.
  • the solution or suspension of the organic acid addition salt of oseltamivir used in the above process is prepared by dissolving or suspending the organic acid addition salt of oseltamivir in a ketonic solvent or an alcoholic solvent or a mixture thereof.
  • ketonic solvent is selected from the group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl isopropyl ketone, methyl tert-butyl ketone and more preferable ketonic solvent is acetone;
  • preferable alcoholic solvent is selected from the group consisting of methanol, ethanol, isopropyl alcohol, tert-butyl alcohol and more preferable alcoholic solvent is ethanol.
  • the organic acid addition salt of oseltamivir is prepared by dissolving oseltamivir free base in an ester solvent or a ketonic solvent, adding an organic acid to the solution and then isolating organic acid addition salt of oseltamivir from the solution.
  • Preferable ester solvent is selected from the group consisting of ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate and more preferable ester solvent is ethyl acetate;
  • preferable ketonic solvent is selected from the group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl isopropyl ketone, methyl tert-butyl ketone and more preferable ketonic solvent is acetone.
  • Preferable organic acid is selected from the group consisting of tartaric acid, dibenzoyl tartaric acid, di-p-toluoyl tartaric acid, 10-camphorsulfonic acid, lactic acid, malic acid, mandelic acid, citric acid, fumaric acid, maleic acid, succinic acid, methane sulfonic acid and p-toluenesulfonic acid. More preferable organic acid is tartaric acid.
  • the process ensures the high purity oseltamivir.
  • the process of the invention has the advantage that oseltamivir phosphate obtained has the better purity than when prepared by usual method of converting oseltamivir free base directly to oseltamivir phosphate by using phosphoric acid.
  • the process of the invention has also the advantage in that oseltamivir phosphate obtained has the better purity than when prepared by neutralizing a salt of oseltamivir, isolating oseltamivir free base and converting the free base to oseltamivir phosphate.
  • FIG. 1 is a x-ray powder diffraction spectrum of crystalline oseltamivir free base obtained in example 1.
  • x-Ray powder diffraction spectrum was measured on a Bruker axs D8 advance x-ray powder diffractometer having a Copper-K ⁇ radiation. Approximately 500 mg of sample was gently flattened on a sample holder and scanned from 2 to 50 degrees two-theta, at 0.03 degrees two-theta per step and a step time of 0.5 seconds. The sample was simply placed on the sample holder. The sample was rotated at 30 rpm at a voltage 40 KV and current 35 mA.
  • Oseltamivir phosphate (20 gm, HPLC purity: 97%) is stirred with water (100 ml) and methylene chloride (100 ml) for 10 minutes at 25-30° C. and then pH of the mass is adjusted to 9-10 with liquor ammonia. Separated the layers, the organic layer is subjected to carbon treatment and filtered on hiflo bed. Washed the hiflo bed with methylene chloride (20 ml) and then distilled the organic layer under vacuum at 40° C. to give 16.5 gm of oseltamivir free base as a residue.
  • step-(a) To the residue obtained in step-(a) is added n-heptane (100 ml) and stirred for 1 hour at 25-30° C. Filtered the solid and dried to give 13 gm of pure oseltamivir free base (HPLC Purity: 99.2%, Melting Range: 102.5-103.9° C.).
  • Tartaric acid (5 gm) is added to the solution of oseltamivir free base (9 gm, HPLC purity: 95.8%) in ethyl acetate (50 ml) at 25-30° C., the contents are heated to 50° C. and then slowly cooled to 30° C. in 1 hour. Filtered the solid, washed with 70 ml of ethyl acetate and dried to yield 13 gm of oseltamivir tartrate (H PLC purity: 97.2%).
  • Oseltamivir tartrate (13 gm, obtained in example 3) is added to acetone (150 ml) at 25-30° C., the solution of H 3 PO 4 (3.5 gm) in 40 ml of ethanol is added to the contents and then stirred for 1 hour 30 minutes at 25-30° C. Filtered the solid, washed with 30 ml of acetone and dried to yield 6.5 gm of oseltamivir phosphate (HPLC purity: 99.8%).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The present invention provides a process for obtaining highly pure crystalline form of oseltamivir free base, thus, for example, suspending or dissolving impure or non-crystalline oseltamivir free base in a hydrocarbon solvent and then isolating crystals to obtain oseltamivir free base in well defined crystalline form. The present invention also provides a process for preparation of oseltamivir phosphate in high purity.

Description

    FIELD OF THE INVENTION
  • The present invention provides a process for obtaining highly pure crystalline form of oseltamivir free base. The present invention also provides a process for preparation of oseltamivir phosphate in high purity.
    • BACKGROUND OF THE INVENTION
  • U.S. Pat. No. 5,763,483, which is herein incorporated by reference, disclosed carbocyclic compounds and pharmaceutically acceptable salts thereof. Among them Oseltamivir, chemically Ethyl (3R,4R,5S)-4-(acetylamino)-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate is a orally active inhibitor of influenza virus neuraminidase. Oseltamivir is represented by the following structure:
  • Figure US20100210868A1-20100819-C00001
  • Various processes for preparation of oseltamivir and its pharmaceutically acceptable salts were disclosed, for example, in U.S. Pat. No. 5,763,483, J. Org. Chem., Vol. 63, No. 13, 1998 (page: 4545-4550), J. Amer. Chem. Soc., Vol. 115, No. 4, 1997 (Page: 681-690), U.S. Pat. No. 5,952,375, PCT Publication No. WO 98/07685 and PCT Publication No. WO 99/44185.
  • PCT Publication No. WO 98/07685 described in example 11 that crystalline oseltamivir free base is obtained by concentrating reaction mass containing oseltamivir free base to obtain oseltamivir free base as a foam, which is solidified on standing. It has been found that the process described in WO 98/07685 does not produce the well-defined crystalline form of oseltamivir free in a consistently reproducible manner.
  • Oseltamivir free base obtained by these processes are not satisfactory from purity point of view and there is a need for a process for obtaining consistently reproducible pure crystalline oseltamivir free base.
  • One object of the present invention is to provide a process for preparation of highly pure crystalline oseltamivir free base that can be used to obtain pharmaceutically acceptable salts of oseltamivir in high purity.
  • Another object of the present invention is to provide a process for preparation of oseltamivir phosphate in high purity.
    • DETAILED DESCRIPTION OF THE INVENTION
  • According to one aspect of the present invention, there is provided a process for isolation of pure crystalline oseltamivir free base, the said process comprises suspending or dissolving impure or non-crystalline oseltamivir free base in a hydrocarbon solvent and then isolating crystals to obtain oseltamivir free base in well defined crystalline form.
  • The crystalline oseltamivir free base obtained by the process as described in the present invention is characterized by an x-ray powder diffraction spectrum having peaks expressed as 20 at about 4.8, 5.2, 6.9, 8.7, 9.9, 10.5, 11.9, 13.0, 14.5, 17.2, 17.3, 18.4, 18.6, 19.9, 21.0, 21.3, 22.2, 22.5, 23.9 and 24.7 degrees as shown in FIG. 1.
  • Preferable hydrocarbon solvent is selected from the group consisting of n-hexane, n-heptane, cyclohexane, toluene, xylene and a mixture thereof. More preferable hydrocarbon solvent is n-heptane, toluene or a mixture thereof.
  • Preferably the suspension is stirred for at least 30 minutes at below boiling temperature of the solvent used, more preferably for 1 hour to 4 hours at 15-60° C. and still more preferably for 1 hour to 3 hours at 20-40° C.
  • The isolation of the crystalline oseltamivir free base may be carried out by usually known methods such as filtration or centrifugation.
  • The isolation may, if required, be carried out by cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution or a combination thereof.
  • According to another aspect of the present invention, there is provided a process for preparation of pure oseltamivir phosphate, the said process comprises by contacting a solution or suspension of an organic acid addition salt of oseltamivir with a solution of phosphoric acid in an alcoholic solvent and then isolating pure oseltamivir phosphate from the solution.
  • The solution or suspension of the organic acid addition salt of oseltamivir used in the above process is prepared by dissolving or suspending the organic acid addition salt of oseltamivir in a ketonic solvent or an alcoholic solvent or a mixture thereof.
  • Preferable ketonic solvent is selected from the group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl isopropyl ketone, methyl tert-butyl ketone and more preferable ketonic solvent is acetone; preferable alcoholic solvent is selected from the group consisting of methanol, ethanol, isopropyl alcohol, tert-butyl alcohol and more preferable alcoholic solvent is ethanol.
  • The organic acid addition salt of oseltamivir is prepared by dissolving oseltamivir free base in an ester solvent or a ketonic solvent, adding an organic acid to the solution and then isolating organic acid addition salt of oseltamivir from the solution.
  • Preferable ester solvent is selected from the group consisting of ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate and more preferable ester solvent is ethyl acetate; preferable ketonic solvent is selected from the group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl isopropyl ketone, methyl tert-butyl ketone and more preferable ketonic solvent is acetone.
  • Preferable organic acid is selected from the group consisting of tartaric acid, dibenzoyl tartaric acid, di-p-toluoyl tartaric acid, 10-camphorsulfonic acid, lactic acid, malic acid, mandelic acid, citric acid, fumaric acid, maleic acid, succinic acid, methane sulfonic acid and p-toluenesulfonic acid. More preferable organic acid is tartaric acid.
  • The process ensures the high purity oseltamivir. The process of the invention has the advantage that oseltamivir phosphate obtained has the better purity than when prepared by usual method of converting oseltamivir free base directly to oseltamivir phosphate by using phosphoric acid. The process of the invention has also the advantage in that oseltamivir phosphate obtained has the better purity than when prepared by neutralizing a salt of oseltamivir, isolating oseltamivir free base and converting the free base to oseltamivir phosphate.
  • ‘Impure’ in the specification refers to having HPLC purity 98% or less and ‘pure’ refers to having HPLC purity more than 98%.
    • BRIEF DESCRIPTION OF THE DRAWINGS
  • FIG. 1 is a x-ray powder diffraction spectrum of crystalline oseltamivir free base obtained in example 1.
  • x-Ray powder diffraction spectrum was measured on a Bruker axs D8 advance x-ray powder diffractometer having a Copper-Kα radiation. Approximately 500 mg of sample was gently flattened on a sample holder and scanned from 2 to 50 degrees two-theta, at 0.03 degrees two-theta per step and a step time of 0.5 seconds. The sample was simply placed on the sample holder. The sample was rotated at 30 rpm at a voltage 40 KV and current 35 mA.
  • The invention will now be further described by the following non-limiting examples.
    • Example 1 Step-(a):
  • Oseltamivir phosphate (20 gm, HPLC purity: 97%) is stirred with water (100 ml) and methylene chloride (100 ml) for 10 minutes at 25-30° C. and then pH of the mass is adjusted to 9-10 with liquor ammonia. Separated the layers, the organic layer is subjected to carbon treatment and filtered on hiflo bed. Washed the hiflo bed with methylene chloride (20 ml) and then distilled the organic layer under vacuum at 40° C. to give 16.5 gm of oseltamivir free base as a residue.
    • Step-(b):
  • To the residue obtained in step-(a) is added n-heptane (100 ml) and stirred for 1 hour at 25-30° C. Filtered the solid and dried to give 13 gm of pure oseltamivir free base (HPLC Purity: 99.2%, Melting Range: 102.5-103.9° C.).
    • Example 2
  • The residue (5 gm, obtained as per the process described in step-(a) of example 1) is dissolved in toluene (10 ml), n-heptane (70 ml) is slowly added to the solution for 30 minutes to 1 hour at 20-30° C. and then stirred for 2 hours at 20-30° C. Filtered the solid, washed with n-heptane (20 ml) and dried to yield pure oseltamivir free base (HPLC Purity: 99.3%).
    • Example 3
  • Tartaric acid (5 gm) is added to the solution of oseltamivir free base (9 gm, HPLC purity: 95.8%) in ethyl acetate (50 ml) at 25-30° C., the contents are heated to 50° C. and then slowly cooled to 30° C. in 1 hour. Filtered the solid, washed with 70 ml of ethyl acetate and dried to yield 13 gm of oseltamivir tartrate (H PLC purity: 97.2%).
    • Example 4
  • Oseltamivir tartrate (13 gm, obtained in example 3) is added to acetone (150 ml) at 25-30° C., the solution of H3PO4 (3.5 gm) in 40 ml of ethanol is added to the contents and then stirred for 1 hour 30 minutes at 25-30° C. Filtered the solid, washed with 30 ml of acetone and dried to yield 6.5 gm of oseltamivir phosphate (HPLC purity: 99.8%).

Claims (8)

1. A process for isolation of pure crystalline oseltamivir free base, which comprises suspending or dissolving impure or non-crystalline oseltamivir free base in a hydrocarbon solvent and then isolating crystals to obtain oseltamivir free base in well defined crystalline form.
2. The process as claimed in claim 1, wherein the hydrocarbon solvent is selected from the group consisting of n-hexane, n-heptane, cyclohexane, toluene, xylene and a mixture thereof.
3. The process as claimed in claim 2, wherein the hydrocarbon solvent is n-heptane, toluene or a mixture thereof.
4. The process as claimed in claim 1, wherein the suspension is stirred for at least 30 minutes at below boiling temperature of the solvent used.
5. The process as claimed in claim 4, wherein the suspension is stirred for 1 hour to 4 hours at 15-60° C.
6. The process as claimed in claim 5, wherein the suspension is stirred for 1 hour to 3 hours at 20-40° C.
7. The process as claimed in claim 1, wherein the isolation of the crystalline oseltamivir free base is carried out by filtration or centrifugation.
8. The process as claimed in claim 1, wherein the isolation of the crystalline oseltamivir free base is carried out by cooling, seeding, partial removal of the solvent from the solution or by adding an anti-solvent to the solution; or a combination thereof.
US12/701,739 2006-01-02 2010-02-08 Process for obtaining pure oseltamivir Abandoned US20100210868A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US12/701,739 US20100210868A1 (en) 2006-01-02 2010-02-08 Process for obtaining pure oseltamivir

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
INPCT/IN06/00001 2006-01-02
PCT/IN2006/000001 WO2007077570A1 (en) 2006-01-02 2006-01-02 Process for obtaining pure oseltamivir
US71977307A 2007-05-21 2007-05-21
US12/701,739 US20100210868A1 (en) 2006-01-02 2010-02-08 Process for obtaining pure oseltamivir

Related Parent Applications (2)

Application Number Title Priority Date Filing Date
PCT/IN2006/000001 Division WO2007077570A1 (en) 2006-01-02 2006-01-02 Process for obtaining pure oseltamivir
US71977307A Division 2006-01-02 2007-05-21

Publications (1)

Publication Number Publication Date
US20100210868A1 true US20100210868A1 (en) 2010-08-19

Family

ID=38227956

Family Applications (2)

Application Number Title Priority Date Filing Date
US11/719,773 Expired - Fee Related US7732632B2 (en) 2006-01-02 2006-01-02 Process for obtaining pure oseltamivir
US12/701,739 Abandoned US20100210868A1 (en) 2006-01-02 2010-02-08 Process for obtaining pure oseltamivir

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US11/719,773 Expired - Fee Related US7732632B2 (en) 2006-01-02 2006-01-02 Process for obtaining pure oseltamivir

Country Status (3)

Country Link
US (2) US7732632B2 (en)
EP (1) EP1968934A4 (en)
WO (1) WO2007077570A1 (en)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8334319B2 (en) * 2008-01-04 2012-12-18 Roche Palo Alto Llc Polymorphic forms of oseltamivir phosphate
RU2639158C1 (en) * 2016-07-01 2017-12-20 Общество с ограниченной ответственностью Научно-производственный центр "Химические технологии" Ethyl (3s,4r,5s)-4-acetamido-5-amino-3-(1-ethyl propoxy) cyclohex-1-en-1-carboxylate etoxy succinate as anti-viral drug and method for its production
WO2019245974A1 (en) 2018-06-21 2019-12-26 Genentech, Inc. Solid forms of 3-((1r,3r)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2h-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol and processes for preparing fused tricyclic compounds comprising a substituted phenyl or pyridinyl moiety, including methods of their use
CN114920662A (en) * 2022-04-29 2022-08-19 天方药业有限公司 Method for recycling oseltamivir phosphate mother liquor

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040180933A1 (en) * 2003-03-13 2004-09-16 Brown Jack D. Process for preparing 1,2-diamino compounds

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE69711395T2 (en) * 1996-08-23 2002-11-07 Gilead Sciences Inc METHOD FOR PRODUCING CYCLOHEXEN-CARBOXYLATE DERIVATIVES

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040180933A1 (en) * 2003-03-13 2004-09-16 Brown Jack D. Process for preparing 1,2-diamino compounds

Also Published As

Publication number Publication date
EP1968934A4 (en) 2014-02-26
US20090149670A1 (en) 2009-06-11
WO2007077570A1 (en) 2007-07-12
US7732632B2 (en) 2010-06-08
EP1968934A1 (en) 2008-09-17

Similar Documents

Publication Publication Date Title
KR101391132B1 (en) Crystalline minocycline base and processes for its preparation
US9828380B2 (en) Efficient method for the preparation of tofacitinib citrate
US20100210868A1 (en) Process for obtaining pure oseltamivir
JP2021105003A (en) Process for preparing polymorph and quinazolinyl derivative
WO2008084494A1 (en) Novel polymorphic forms of carvedilol dihydrogen phosphate and process for preparing the same
US9624207B2 (en) Polymorphs of azilsartan medoxomil
US20090076288A1 (en) Process for isolation of desired isomers of nebivolol intermediates
WO2016174685A1 (en) Process for the enantiomeric resolution of apremilast intermediates
JP2011516519A (en) Polymorph of argatroban monohydrate and its synthesis
CN107531744B (en) Novel crystal form of obeticholic acid and preparation method thereof
EP2094693B1 (en) A method for the preparation of solifenacin
EP1789412B1 (en) Crystalline alfuzosin base
US20100305328A1 (en) Process for preparation of piperidine carboxylic acid
JP2005120024A (en) Method for producing 4'-cyano-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methyl-3'-trifluoromethylpropionanilide
JP4594938B2 (en) Method for preparing gabapentin
US7932415B2 (en) Process for manufacturing entacapone
WO2007127396A1 (en) Process for the synthesis of (+) and (-) -1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane
JP5952748B2 (en) Novel crystalline form of phthaloyl amlodipine and process for producing high purity amlodipine besylate using the same
WO2009001367A2 (en) Novel crystalline forms of atovaquone
US6495711B2 (en) Process for preparing (-)-(1S, 4R) N-protected 4-amino-2-cyclopentene-1-carboxylate esters
WO2012147020A1 (en) An improved process for the preparation of frovatriptan
EP3594210B1 (en) Lubiprostone crystals and methods for preparing the same
WO2006108910A1 (en) Detomidine hydrochloride crystallization method
KR101392993B1 (en) A preparing method of chiral 1,4-thiazepin phenyl butanoate compound
WO2013080221A2 (en) Process for alvimopan

Legal Events

Date Code Title Description
AS Assignment

Owner name: HETERO DRUGS LIMITED (R&D), INDIA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:PARTHASARADHI REDDY, BANDI;RATHNAKAR REDDY, KURA;RAJI REDDY, RAPOLU;AND OTHERS;REEL/FRAME:023910/0540

Effective date: 20070523

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO PAY ISSUE FEE