WO2010071558A1 - New process for the preparation of 1- [5- (3-chloro-phenyl) - isooxazol-3-yl] -ethanone and (r) -1- [5- (3-chloro-phenyl) - isooxazol-3-yl] -ethanol - Google Patents
New process for the preparation of 1- [5- (3-chloro-phenyl) - isooxazol-3-yl] -ethanone and (r) -1- [5- (3-chloro-phenyl) - isooxazol-3-yl] -ethanol Download PDFInfo
- Publication number
- WO2010071558A1 WO2010071558A1 PCT/SE2009/051405 SE2009051405W WO2010071558A1 WO 2010071558 A1 WO2010071558 A1 WO 2010071558A1 SE 2009051405 W SE2009051405 W SE 2009051405W WO 2010071558 A1 WO2010071558 A1 WO 2010071558A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- solvent
- process according
- chloro
- phenyl
- isoxazol
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D261/18—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
Definitions
- the present invention relates to a new process for large-scale production of l-[5-(3-chloro- phenyl)-isoxazole-3-yl]-ethanone and, optionally, (R)-l-[5-(3-chloro-phenyl)-isoxazole-3- yl]-ethanol. These compounds are useful as intermediates for manufacturing pharmaceutically active larger compounds.
- 4-(5- ⁇ (IR)- 1 -[5-(3-chlorophenyl) isoxazol-3-yl] ethoxy ⁇ -4-methyl-4H- 1 ,2,4-triazol-3-yl) pyridine is an antagonist of the mGluR5 receptor. Accordingly, this compound is expected to be well suited for treatment of mGluR5 -mediated disorders, such as acute and chronic neurological and psychiatric disorders, gastrointestinal disorders and chronic and acute pain disorders. This and similar compounds are disclosed in WO, Al, 2007/040982.
- the present invention provides a process for the preparation of the compound l-[5-(3- chloro-phenyl)-isoxazol-3-yl]-ethanone of the formula
- Ci_i 2 alkyl relates to a linear or branched alkyl group comprising 1 - 12 carbon atoms, such as but not limited to, methyl, ethyl, n-propyl, i- propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, neo-pentyl, n-hexyl or i-hexyl, t-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl and n-dodecyl.
- the solvent is selected from the group of aromatic hydrocarbons, such as toluene, and ortho-, meta- and para-xylene, as well as ethers such as 2-methyl tetrahydrofuran, tetrahydrofuran, diethyl ether, tert-butyl methyl ether or mixtures thereof.
- the reagent CH3MgX may be charged to the reaction as a solution in a solvent such as toluene, tetrahydrofuran, 2-methyl tetrahydrofuran or mixtures thereof.
- the reaction between said ethyl 5-(3-chlorophenyl)-isoxazole-3-carboxylate and said CH 3 MgX is carried out in the presence of a tertiary amine, such as triethyl amine.
- a tertiary amine such as triethyl amine.
- other tertiary aliphatic amines, linear or branched, such as tri-N-butylamine or N- alkylpiperidines, may be considered.
- reaction mixture and surplus of said CH 3 MgX is quenched by adding an acid aqueous solution, such as 6 M HCl.
- organic reaction mixture after removal of said acid aqueous mixture is treated with an aqueous base such as sodium hydroxide.
- the present invention also provides a process for preparing (R)- 1 - [5 -(3 -chloro-phenyl)-isoxazol-3 -yl]-ethanol.
- this compound may be prepared by a process comprising the steps of:
- step iv) recovering (R)-l-[5-(3-chloro-phenyl)-isoxazol-3-yl]-ethanol from the reaction.
- l-[5-(3-chloro-phenyl)-isoxazol-3-yl]-ethanone dissolved in said second solvent is added to the solution obtained in step ii), during a time period of up to 4h.
- the borane in step ii) is borane dimethyl sulfide.
- Alternative borane sources such as borane tetrahydrofuran, borane triethylamine and borane JV,iV-diethylaniline complexes may be used in the process.
- the solvent is tetrahydrofuran, 2-methyl tetrahydrofuran or toluene.
- an excess of borane is quenched by adding an alcohol, such as methanol, after completion of formation of (R)-l-[5-(3-chloro-phenyl)-isoxazol-3-yl]-ethanol.
- an alcohol such as methanol
- (R)-l-[5-(3-chloro-phenyl)-isoxazol-3-yl]-ethanol is recovered by crystallization.
- a suitable solvent or solvent mixture for the crystallization of (R)-l-[5-(3-chloro-phenyl)-isoxazol-3-yl]-ethanol may be selected from the group of aromatic hydrocarbons such as toluene and xylenes, ethers such as 2-methyl tetrahydrofuran, tetrahydrofuran, diethyl ether and tert-butyl methyl ether, alkanes such as n-heptane and cyclohexan, polar aprotic solvents such as dimethylsulfoxide, dimethylformamide as single crystallization solvent or in any combination with or without water present.
- (R)-l-[5-(3-chloro-phenyl)-isoxazol-3-yl]-ethanol may be prepared by an enzymatic process involving the use of a stereospecif ⁇ c alcohol dehydrogenase capable of catalyzing formation of (R)-l-[5-(3-chloro-phenyl)-isoxazol-3-yl]-ethanol together with a suitable co-factor selected from the group of NADH and NADPH, comprising the steps of:
- a suitable reaction medium for the reaction may be a buffered aqueous solution containing an alcohol such as 2-propanol.
- Said buffered aqueous solution may be a triethanolamine buffer having a pH within the range of 7.0 - 8.5.
- suitable alcohol dehydrogenases include IEP 0x29 and IEP 0x58, which are manufactured by IEP GmbH, DE and obtainable from DSM Pharmaceutical Products, Geleen, NL.
- said co- factor is NADH.
- (R)-l-[5-(3-chloro-phenyl)-isoxazol-3-yl]-ethanol may be recovered from the reaction medium by extraction with ethyl acetate, recovering the organic phase and evaporating the solvent.
- (R)-l-[5-(3-chloro-phenyl)-isoxazol-3-yl]-ethanol may be recovered from the reaction medium by extraction with methyl tert-butyl ether, recovering the organic phase and crystallizing the product from a mixture of methyl tert- butyl ether and n-heptane.
- (R)-l-[5-(3-chloro-phenyl)-isoxazol-3-yl]-ethanol may be prepared by an asymmetric hydrogenation comprising the steps of:
- (R)-l-[5-(3-chloro-phenyl)-isoxazol-3-yl]-ethanol may be prepared by an asymmetric transfer hydrogenation comprising the steps of:
- (R)-l-[5-(3-chloro-phenyl)-isoxazol-3-yl]-ethanol may be prepared by a dynamic kinetic resolution comprising the steps of:
- one embodiment of the present invention relates to a process for producing 1 -[5-(3-chloro-phenyl)-isoxazole-3-yl]-ethanone.
- Still an embodiment of the invention is directed to a process for making (R)- 1- [5 -(3- chloro-phenyl)-isoxazole-3-yl]-ethanol.
- step a-c of the manufacturing process a compound of formula IV is prepared.
- step a compound I is reacted with a compound of formula VII VII where R is a linear or branched Ci -C ⁇ alkyl; in the presence of a solvent and a base, particularly an alkoxide base, to (after quench and acidic work-up) give a compound of formula II where R is a linear or branched Ci-i 2 alkyl;
- the compound of formula V may be exposed to an alcohol dehydrogenase together with an appropriate co-factor in a suitable reaction medium in order to produce a compound of formula VI.
- the compound of formula V may be exposed to a transition metal based catalyst in presence of a strong base and hydrogen gas to produce a compound of formula VI.
- the compound of formula V may be exposed to a transition metal based catalyst in the presence of
- the compound of formula V may be reduced to a racemic mixture of VI by adding a reducing agent such as sodium borohydride to a suitable reaction media followed by enzymatic resolution by a lipase in the presence of an acyl donor, such as vinyl acetate.
- a reducing agent such as sodium borohydride
- an acyl donor such as vinyl acetate
- the resulting ester may be cleaved off using a basic reagent such as lithium hydroxide, providing a compound of formula VI.
- reaction steps a) b) and c) may be performed in a solvent.
- Suitable solvents are alcohols such as ethanol, methanol and 2-propanol and ethers such as tetrahydrofuran and 2-methyl tetrahydrofuran.
- the total amount of solvents used in process steps a-c may vary in the range of from about 2-100 (v/w) volume parts per weight of starting material (compound I), particularly in the range from 6-30 (v/w) volume parts per weight of starting material.
- a suitable base may be an alkoxide base such as sodium ethoxide or sodium methoxide.
- alkoxide base such as sodium ethoxide or sodium methoxide.
- the temperature for step a-c may be in the range of from about 0 0 C -100 0 C, particularly in the range of from 50-80 0 C.
- the temperature for step d) should be in the range of from about -10 0 C -50 0 C, particularly in the range of from -5°C -20 0 C.
- the temperature for step e) should be in the range of from about -10 0 C -50 0 C.
- Example 2 Preparation of ethyl S-O-chlorophenyD-isoxazole-S-carboxylate via 4-(3- chloro-phenyl)-2-r(E)-hvdroximinol-4-oxobutyric acid ethyl ester
- the organic phase was further evaporated to dryness and the residue was dissolved in 245 rnL toluene.
- the temperature was adjusted to 20 0 C after which crystallization was initiated by addition of 0.2 g II (seed crystals).
- the crystallization mixture was kept for 30 min after which 492 mL n-heptane was added as anti-solvent over 6h.
- the crystallization mixture was then chilled from 20 to 0 0 C over 6h.
- the crystals were then filtered off and washed with (i) 165 mL n-heptane -toluene 2/1 and (ii) 165 mL n-heptane.
- the crystals were finally dried at 40 0 C under reduced pressure. 66.4 g product corresponding to an isolated yield of 80% was isolated. Enantiomeric excess was determined to >98%.
- Example 6 Catalytic enantioselective transfer hydrogenation of l-[5-Chloro-phenyl)- isoxazol-3-yll-ethanone to give (R)-l-r5-(3-Chloro-phenyl)-isoxazol-3-yll-ethanol.
- reaction was then sampled showing a virtually complete conversion of starting material to (R)-l-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-ethanol in 95.4% enantio selectivity.
- the reaction mixture was then diluted with 35 mL toluene and extracted with 2x35 mL water. The organic layer was further concentrated by evaporation under reduced pressure. The residue was purified by crystallization from a mixture of toluene and n- heptane. Finally, the crystals were isolated by filtration, washed with n-heptane and dried under reduced pressure at 40 0 C.
- the mixtures were agitated at room temp, for 30 minutes to generate the active catalysts. Then 200 ⁇ L of the hydride donor (Et 3 N/HCOOH 5:8 molar ratio) was added followed by 500 ⁇ L of a solution of the ketone in THF (40mg/mL) to all vials. The mixtures were then agitated for 2 hours at 25°C. The mixtures were then sampled (20 ⁇ L) and diluted with iPrOH 500 ⁇ L + heptane 500 ⁇ L.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
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Priority Applications (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2009801513651A CN102256950A (en) | 2008-12-18 | 2009-12-11 | New process for the preparation of 1- [5- (3-chloro-phenyl) - isooxazol-3-yl] -ethanone and (r) -1- [5- (3-chloro-phenyl) - isooxazol-3-yl] -ethanol |
EP09833722A EP2379514A4 (en) | 2008-12-18 | 2009-12-11 | New process for the preparation of 1- [5- (3-chloro-phenyl) - isooxazol-3-yl]-ethanone and (r) -1- [5- (3-chloro-phenyl) - isooxazol-3-yl]-ethanol |
MX2011005982A MX2011005982A (en) | 2008-12-18 | 2009-12-11 | New process for the preparation of 1- [5- (3-chloro-phenyl) - isooxazol-3-yl] -ethanone and (r) -1- [5- (3-chloro-phenyl) - isooxazol-3-yl] -ethanol. |
JP2011542061A JP2012512867A (en) | 2008-12-18 | 2009-12-11 | Of 1- [5- (3-chloro-phenyl) -isoxazol-3-yl] -ethanone and (R) -1- [5- (3-chloro-phenyl) -isoxazol-3-yl] -ethanol New manufacturing method |
AU2009327566A AU2009327566A1 (en) | 2008-12-18 | 2009-12-11 | New process for the preparation of 1- [5- (3-chloro-phenyl) - isooxazol-3-yl] -ethanone and (R) -1- [5- (3-chloro-phenyl) - isooxazol-3-yl] -ethanol |
US13/140,565 US20110313172A1 (en) | 2008-12-18 | 2009-12-11 | Process for the preparation of 1-[5-(3-chloro-phenyl)-isooxazol-3-yl]-ethanone and (r)-1-[5-(3-chloro-phenyl)-isooxazol-3-yl]-ethanol |
SG2011036076A SG171755A1 (en) | 2008-12-18 | 2009-12-11 | New process for the preparation of 1- [5- (3-chloro-phenyl) - isooxazol-3-yl] -ethanone and (r) -1- [5- (3-chloro-phenyl) - isooxazol-3-yl] -ethanol |
CA2747507A CA2747507A1 (en) | 2008-12-18 | 2009-12-11 | New process for the preparation of 1- [5-(3-chloro-phenyl)-isooxazol-3-yl]-ethanone and (r)-1-[5-(3-chloro-phenyl)-isooxazol-3-yl]-ethanol |
BRPI0923053A BRPI0923053A2 (en) | 2008-12-18 | 2009-12-11 | process for preparing a compound |
IL213037A IL213037A0 (en) | 2008-12-18 | 2011-05-19 | New process for the preparation of 1-[5-(3-chloro-phenyl)-isooxazol-3-yl]-ethanone and (r)-1-[5-(3-chloro-phenyl)-isooxazol-3-yl]-ethanol |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US13874108P | 2008-12-18 | 2008-12-18 | |
US61/138,741 | 2008-12-18 |
Publications (1)
Publication Number | Publication Date |
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WO2010071558A1 true WO2010071558A1 (en) | 2010-06-24 |
Family
ID=42269019
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/SE2009/051405 WO2010071558A1 (en) | 2008-12-18 | 2009-12-11 | New process for the preparation of 1- [5- (3-chloro-phenyl) - isooxazol-3-yl] -ethanone and (r) -1- [5- (3-chloro-phenyl) - isooxazol-3-yl] -ethanol |
Country Status (12)
Country | Link |
---|---|
US (1) | US20110313172A1 (en) |
EP (1) | EP2379514A4 (en) |
JP (1) | JP2012512867A (en) |
KR (1) | KR20110101164A (en) |
CN (1) | CN102256950A (en) |
AU (1) | AU2009327566A1 (en) |
BR (1) | BRPI0923053A2 (en) |
CA (1) | CA2747507A1 (en) |
IL (1) | IL213037A0 (en) |
MX (1) | MX2011005982A (en) |
SG (1) | SG171755A1 (en) |
WO (1) | WO2010071558A1 (en) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004014881A2 (en) * | 2002-08-09 | 2004-02-19 | Astra Zeneca Ab | '1,2,4'oxadiazoles as modulators of metabotropic glutamate receptor-5 |
WO2007040982A1 (en) * | 2005-09-29 | 2007-04-12 | Astrazeneca Ab | 5- (phenylisoxazolylethoxy) -triazol- 3 -yl substituted pyridine compounds for the treatment of neurological, psychiatric or pain disorders |
US20070259895A1 (en) * | 2006-05-05 | 2007-11-08 | Astrazeneca Ab | MGluR5 modulators VI |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TW200808800A (en) * | 2006-05-05 | 2008-02-16 | Astrazeneca Ab | MGluR5 modulators V |
TW200821305A (en) * | 2006-10-05 | 2008-05-16 | Astrazeneca Ab | MGluR5 modulators |
-
2009
- 2009-12-11 WO PCT/SE2009/051405 patent/WO2010071558A1/en active Application Filing
- 2009-12-11 KR KR1020117014043A patent/KR20110101164A/en not_active Application Discontinuation
- 2009-12-11 EP EP09833722A patent/EP2379514A4/en not_active Withdrawn
- 2009-12-11 US US13/140,565 patent/US20110313172A1/en not_active Abandoned
- 2009-12-11 BR BRPI0923053A patent/BRPI0923053A2/en not_active IP Right Cessation
- 2009-12-11 MX MX2011005982A patent/MX2011005982A/en unknown
- 2009-12-11 CN CN2009801513651A patent/CN102256950A/en active Pending
- 2009-12-11 SG SG2011036076A patent/SG171755A1/en unknown
- 2009-12-11 JP JP2011542061A patent/JP2012512867A/en active Pending
- 2009-12-11 CA CA2747507A patent/CA2747507A1/en not_active Abandoned
- 2009-12-11 AU AU2009327566A patent/AU2009327566A1/en not_active Abandoned
-
2011
- 2011-05-19 IL IL213037A patent/IL213037A0/en unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004014881A2 (en) * | 2002-08-09 | 2004-02-19 | Astra Zeneca Ab | '1,2,4'oxadiazoles as modulators of metabotropic glutamate receptor-5 |
WO2007040982A1 (en) * | 2005-09-29 | 2007-04-12 | Astrazeneca Ab | 5- (phenylisoxazolylethoxy) -triazol- 3 -yl substituted pyridine compounds for the treatment of neurological, psychiatric or pain disorders |
US20070259895A1 (en) * | 2006-05-05 | 2007-11-08 | Astrazeneca Ab | MGluR5 modulators VI |
Non-Patent Citations (5)
Title |
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ITOH, KEN-ICHI ET AL: "Biocatalytic asymmetric reduction of 3-acetylisoxazoles", TETRAHEDRON: ASYMMETRY, vol. 16, 2005, pages 1403 - 1408, XP004807206 * |
QUALLICH G.J. ET AL: "Enantioselective oxazaborolidine reduction of ketones containing heteroatoms", TETRAHEDRON LETTERS, vol. 34, no. 5, 1993, pages 785 - 788, XP003011604 * |
RICHTER H.G.F. ET AL: "Synthesis and biological evaluation of novel hexahydro-pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazines as potent and selective 5-HT2c receptor agonists", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 16, 2006, pages 1207 - 1211, XP025106321 * |
SANI M. ET AL: "Total synthesis of Tubulysins U and V", ANGEW. CHEM. INT. ED., vol. 46, 2007, pages 3526 - 3529, XP002505479 * |
See also references of EP2379514A4 * |
Also Published As
Publication number | Publication date |
---|---|
EP2379514A4 (en) | 2012-06-13 |
AU2009327566A1 (en) | 2010-06-24 |
MX2011005982A (en) | 2011-06-27 |
SG171755A1 (en) | 2011-07-28 |
JP2012512867A (en) | 2012-06-07 |
CN102256950A (en) | 2011-11-23 |
CA2747507A1 (en) | 2010-06-24 |
KR20110101164A (en) | 2011-09-15 |
US20110313172A1 (en) | 2011-12-22 |
EP2379514A1 (en) | 2011-10-26 |
IL213037A0 (en) | 2011-07-31 |
BRPI0923053A2 (en) | 2017-06-06 |
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