US10385006B2 - Process for the preparation of amino alcohol derivatives or salts thereof - Google Patents
Process for the preparation of amino alcohol derivatives or salts thereof Download PDFInfo
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- US10385006B2 US10385006B2 US15/518,498 US201515518498A US10385006B2 US 10385006 B2 US10385006 B2 US 10385006B2 US 201515518498 A US201515518498 A US 201515518498A US 10385006 B2 US10385006 B2 US 10385006B2
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- AZSQSUWXVPHQLM-QLAFRAKWSA-N NC1=NC2=C(N=CN2C2C=C[C@@H](CO)C2)C(NC2CC2)=N1.NC1=NC2=C(N=CN2C2C=C[C@@H](CO)C2)C(NC2CC2)=N1.O=S(=O)(O)O Chemical compound NC1=NC2=C(N=CN2C2C=C[C@@H](CO)C2)C(NC2CC2)=N1.NC1=NC2=C(N=CN2C2C=C[C@@H](CO)C2)C(NC2CC2)=N1.O=S(=O)(O)O AZSQSUWXVPHQLM-QLAFRAKWSA-N 0.000 description 2
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/10—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/42—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C215/44—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton bound to carbon atoms of the same ring or condensed ring system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/16—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/10—Systems containing only non-condensed rings with a five-membered ring the ring being unsaturated
Definitions
- the present invention relates to a process for the preparation of amino alcohol derivatives or salts thereof.
- the present invention relates to process for the preparation of amino alcohol derivatives or salts thereof which may be used as intermediates in the preparation of HIV reverse transcriptase inhibitors, more preferably Carbovir and Abacavir.
- the present invention more specifically relates to a process for the preparation of (1S,4R)-4-amino-2-cyclopentene-1-methanol of Formula IIIa.
- the present invention also specifically relates to process for the preparation of Abacavir sulfate of Formula II using compound of Formula IIIa prepared according to the process of the present invention.
- AIDS Acquired immune deficiency syndrome
- HBV human immunodeficiency virus
- ABT 3′-azido-3′-deoxythymidine
- Carbocyclic nucleosides are structural analogs to nucleosides in which the furanose oxygen is replaced by a methylene group. Similar to native nucleosides, carbocyclic nucleosides can behave as inhibitors of the enzymes. However, because carbocyclic nucleosides lack the labile glycosidic linkage between heterocycle and sugar of native nucleosides, they are not susceptible to hydrolysis by phosphorylases or phosphotransferases.
- Carbocyclic nucleosides have been the subject of extensive investigation because of the variety of biological properties displayed by these compounds. Of particular interest is the potential of carbocyclic nucleosides for use in antiviral, antitumor and anticancer chemotherapeutic applications. Perhaps the best known examples of such carbocyclic nucleosides are Abacavir and Carbovir, both of which show great promise as anti-HIV agents.
- Carbovir has been reported as the first carbocylic nucleoside analogue, with potent anti-HIV activity in vitro; its discovery provided a base for the synthesis of other carbocyclic analogues.
- the first synthesis of Carbovir has been accomplished in 1990 by Vince et al., as a racemic mixture of two enantiomers. Afterwards, a chemoenzymatic synthesis of both enantiomers of Carbovir, has been reported.
- the natural ( ⁇ )-enantiomer of Carbovir is primarily responsible for the antiviral activity.
- Chemically Carbovir is represented as 2-Amino-9-[(1R,4S)-4-(hydroxymethyl)-2-cyclopenten-1-yl]-1,9-dihydro-6H-purin-6-one and structurally as shown below:
- Abacavir sulphate having the brand name ZIAGEN®, is a synthetic carbocyclic nucleoside analogue with inhibitory activity against HIV-1.
- the chemical name of Abacavir sulfate is (1S,cis)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol sulfate (salt) (2:1).
- Abacavir sulfate is the enantiomer with 1S, 4R absolute configuration on the cyclopentene ring. It has a molecular formula of (C 14 H 18 N 6 O) 2 .H 2 SO 4 and a molecular weight of 670.76 daltons. It has the following structural formula:
- U.S. Pat. No. 5,034,394 discloses a process for the preparation of (1S,4R)-4-amino-2-cyclopentene-1-methanol dibenzoyl-D-tartrate which comprises reaction of racemic 2-azabicyclo[2.2.1]hept-5-en-3-one with hydrogenchloride in methanol to give ( ⁇ )cis-methyl-4-amino-2-cyclopentene-1-carboxylate hydrochloride which on reduction with DIBAL-H in hexane gave racemic 4-amino-2-cyclopentene-1-methanol which is further subjected to resolution with dibenzoyl-D-tartaric acid to give (1S,4R)-4-amino-2-cyclopentene-1-methanol dibenzoyl-D-tartrate.
- the process is shown in the scheme given below:
- U.S. Pat. No. 6,448,402 discloses a process for the preparation of compound of (1S,4R)-4-amino-2-cyclopentene-1-methanol D-hydrogen tartrate which comprises resolution of racemic 1-amino-4-(hydroxymethyl)-2-cyclopentene with D( ⁇ )-tartaric acid in methanol at reflux temperature followed by cooling to 20° C. for about 2 hours gave crystals of compound of (1S,4R)-4-amino-2-cyclopentene-1-methanol D-hydrogen tartrate, Racemic 1-amino 1 (hydroxymethyl)-2-cyclopentene is prepared in turn by reduction of 2-azabicyclo[2.2.1]hept-5-en-3-one using lithium borohydride. The process is shown in the scheme given below:
- U.S. Pat. No. 6,495,711 discloses a process for the preparation of compound of (1S,4R)-4-amino-2-cyclopentene-1-methanol L-hydrogen tartrate which comprises resolution of racemic reacting racemic 2-azabicyclo[2.2.1]hept-5-en-3-one with methanol in the presence of HCl gas followed by resolution of the obtained compound with L(+)-tartaric acid in water, addition of triethylamine and then workup resulted in crystals of (1S,4R)-methyl-4-amino-2-cyclopentene carboxylate L-hydrogen tartrate.
- the process is shown in the scheme given below:
- Nucleosides, Nucleotides & Nucleic acid, 19(1&2), 297-327, 2000 discloses a process for the preparation of (1S,4R)-4-amino-2-cyclopentene-1-methanoldibenzoyl-D-tartrate which comprises reduction of tosylate salt of 4-amino-2-cyclopentene-1-carboxylate using lithium aluminium hydride in THF to give racemic 4-amino-2-cyclopentene-1-methanol followed by resolution of the same with dibenzoyl-D-tartaric acid in ethanol and acetonitrile to give (1S,4R)-4-amino-2-cyclopentene-1-methanol dibenzoyl-D-tartrate.
- the process is shown in the scheme given below:
- the main objective of the present invention is to provide a process which is safe on industrial scale for the preparation of (1S,4R)-4-amino-2-cyclopentene-1-methanol salt of Formula IIIa.
- Another objective of the present invention is to provide a commercially viable process for the preparation of compound of Formula IIIa through intermediate compound of Formula IVa.
- Yet another objective of the present invention is to provide industrially safe and commercially viable process for the preparation of compound of (1S,4R)-4-amino-2-cyclopentene-1-methanol D-hydrogen tartrate of Formula IIIb.
- Yet another objective of the present invention of is to provide a process for the preparation of Carbovir and Abacavir using (1S,4R)-4-amino-2-cyclopentene-1-methanol salt prepared according to the process of the present invention.
- Yet another objective of the present invention provides an improved process for the preparation of (1S,4R)-4-amino-2-cyclopentene-1-methanol of Formula III.
- Yet another objective of the present invention provides an improved process for the preparation of (1S,4R)-methyl-4-amino-2-cyclopentene carboxylate L-hydrogen tartrate of Formula IVb.
- Yet another objective of the present invention provides an improved process for the preparation of (1S,4R)-methyl-4-amino-2-cyclopentene carboxylate of Formula IV.
- the present invention provides an improved process for the preparation of (1S,4R)-4-amino-2-cyclopentene-1-methanol salt of Formula IIIa
- Another embodiment of the present invention provides an improved process for the preparation of (1S,4R)-4-amino-2-cyclopentene-1-methanol salt of Formula IIIa
- the present invention provides an improved process for the preparation of (1S,4R)-4-amino-2-cyclopentene-1-methanol of Formula III
- the present invention provides an improved process for the preparation of (1S,4R)-4-amino-2-cyclopentene-1-methanol of Formula III,
- step iii) reduction of the compound obtained in step i) using a suitable reducing agent in a solvent
- the present invention provides an improved process for the preparation of (1S,4R)-4-amino-2-cyclopentene-1-methanol of Formula III
- step ii) reduction of the compound obtained in step i) using sodium borohydride in 2-butanol, iii) resolution of compound obtained in step ii) using D-tartaric acid in methanol and iv) converting the compound obtained in step iii) to compound of Formula III.
- the present invention provides an improved process for the preparation of (1S,4R)-4-amino-2-cyclopentene-1-methanol D-hydrogen tartrate of Formula IIIb which comprises the steps of
- the present invention provides an improved process for the preparation of (1S,4R)-4-amino-2-cyclopentene-1-methanol D-hydrogen tartrate of Formula IIIb which comprises the steps of
- the present invention provides an improved process for the preparation of (1S,4R)-4-amino-2-cyclopentene-1-methanol D-hydrogen tartrate of Formula IIIb which comprises the steps of
- the present invention provides an improved process for the preparation of (1S,4R)-4-amino-2-cyclopentene-1-methanol D-hydrogen tartrate of Formula IIIb which comprises the steps of:
- R is halogen selected from chloro, fluoro, bromo, iodo; with compound of Formula IIIa
- R is halogen selected from chloro, fluoro, bromo, iodo; ii) cyclization of compound of Formula VI in the presence of triethyl orthoformate to give compound of Formula VII,
- R is halogen selected from chloro, fluoro, bromo, iodo, iii) conversion of compound of Formula VII to compound of Formula I or II where in R is OH and cyclopropylamine respectively.
- the present invention provides an improved process for the preparation of (1S,4R)-4-amino-2-cyclopentene-1-methanol of Formula III
- Suitable base used in the hydrolysis is selected from alkali metal hydroxides such as sodium hydroxide, lithium hydroxide or potassium hydroxide, or alkali metal carbonates such as caesium carbonate, sodium carbonate or potassium carbonate, or alkoxides such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, the base optionally being present in aqueous solution.
- alkali metal hydroxides such as sodium hydroxide, lithium hydroxide or potassium hydroxide
- alkali metal carbonates such as caesium carbonate, sodium carbonate or potassium carbonate
- alkoxides such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide
- Suitable reducing agents are selected from metal hydrides such as boron reagents like sodium borohydride, lithium borohydride, zinc borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium cyanoborohydride and the like or aluminum reagents like diisobutylaluminum hydride, aluminum hydride, lithium aluminum hydride and the like.
- metal hydrides such as boron reagents like sodium borohydride, lithium borohydride, zinc borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium cyanoborohydride and the like or aluminum reagents like diisobutylaluminum hydride, aluminum hydride, lithium aluminum hydride and the like.
- Suitable solvents used in reduction are selected from solvents that are inert to the reaction.
- solvents include alcohols such as methanol, ethanol, propanol, butanol and the like or aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene and the like or aliphatic hydrocarbons such as heptane, hexane and the like or halogenated hydrocarbons such as chloroform, dichloromethane and the like or ethers such as diethyl ether, tetrahydrofuran, dioxane and the like and or mixtures thereof.
- alcohols such as methanol, ethanol, propanol, butanol and the like
- aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene and the like or aliphatic hydrocarbons such as heptane, hexane and the like or halogenated hydrocarbons such as chlor
- Chiral acid used for resolution are selected from acids having D-configuration such as malic acid, mandelic acid, 2-chloromandelic, 3-chloromandelic, 4-chloromandelic acid, tartaric acid, diacetyl tartaric acid, di-p-anisolyl tartaric acid, dibenzoyl tartaric acid, ditoluoyl tartaric acid, camphorsulfonic acid.
- Suitable solvents used in resolution are selected from alcohols such as methanol, ethanol, isopropanol, butanol, 1,2-dimethoxy ethanol, 2-methoxy ethanol, 2-ethoxy ethanol and ethylene glycol; ethers such as diethyl ether, 1,4-dioxane, dimethoxy ethane, DIPE, MTBE, THF, 2-methyl tetrahydrofuran and aprotic polar solvents such as DMF, DMSO, DMA and or mixtures thereof.
- alcohols such as methanol, ethanol, isopropanol, butanol, 1,2-dimethoxy ethanol, 2-methoxy ethanol, 2-ethoxy ethanol and ethylene glycol
- ethers such as diethyl ether, 1,4-dioxane, dimethoxy ethane, DIPE, MTBE, THF, 2-methyl tetrahydrofuran and aprotic polar solvents such as
- R is halogen selected from chloro, fluoro, bromo, iodo; with compound of Formula IIIa
- R is halogen selected from chloro, fluoro, bromo, iodo; ii) cyclization of compound of Formula VI in the presence of triethyl orthoformate to give compound of Formula VII,
- R is halogen selected from chloro, fluoro, bromo, iodo; iii) conversion of compound of Formula VII to compound of Formula I or II where in R is OH and cyclopropylamine respectively.
- Suitable base used in step i) is selected from organic bases such as triethylamine, tributylamine, N-methylmorpholine, N,N-diisopropylethylamine, N-methylpyrrolidine, pyridine, 4-(N,N-dimethylamino) pyridine, morpholine, imidazole, 2-methylimidazole, 4-methylimidazole, or the like; inorganic bases such as alkali metal hydrides like lithium hydride, sodium hydride, potassium hydride, or the like; sodamide; n-butyl lithium; lithium diisopropylamide; alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, or cesium hydroxide; alkaline metal hydroxides, such as aluminum hydroxide, magnesium hydroxide, calcium hydroxide, or the like; alkali metal carbonates, such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, or the like;
- Suitable solvents used in step i) is selected from water; alcohols, such as for example, methanol, ethanol, propanol, butanol, pentanol, isopropyl alcohol, 2-butanol, ethylene glycol, glycerol, or the like; esters, such as for example, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like; aromatic hydrocarbons, such as for example, toluene, xylene, chlorobenzene, tetralin, or the like; nitriles, such as for example, acetonitrile, propionitrile, or the like; or any mixtures thereof.
- alcohols such as for example, methanol, ethanol, propanol, butanol, pen
- vince lactum (0.9163 mol) in methanol at room temperature and stirred for 30 min. Distilled out methanol completely. Allowed to cool to room temperature, then water and L-(+)-tartaric acid (0.5496 mol) was added. Adjusted the pH to 4.4-4.5 with triethylamine and maintained for about 5-6 hrs at RT. Filtered and washed with methanol to obtain pure compound.
- N-[2-amino-4-chloro-6-[[(1R,4S)-4-(hydroxymethyl)-2-cyclopenten-1-yl]amino]-5-pyrimidinyl]formamide (0.3527 mol) was added to trietyl orthoformate (4.2 mol) and hydrochloride acid at 10-15° C. Maintained for 24 hrs at room temperature. Filtered the mass and purified in methanol.
- Example 17 Preparation of ⁇ (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]cyclopent-2-en-1-yl ⁇ methanol
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Abstract
Description
in the presence of a base.
ii) reduction of the compound obtained in step i) using a suitable reducing agent in a solvent,
iii) resolution of compound obtained in step ii) using a chiral acid with D-configuration in a solvent and
iv) isolating compound of Formula IIIa.
using a suitable reducing agent in the presence of a base and in a solvent,
iii) resolution of compound obtained in step i) using a chiral acid with D-configuration in a solvent and
iv) isolating compound of Formula IIIa.
using a suitable reducing agent in the presence of a base and in a solvent to compound of Formula III or its salts.
in the presence of a base,
ii) reduction of the compound obtained in step i) using a suitable reducing agent in a solvent,
iii) resolution of compound obtained in step ii) using a chiral acid with D-configuration in a solvent and
iv) converting the compound obtained in step iii) to compound of Formula III.
in the presence of sodium hydroxide.
ii) reduction of the compound obtained in step i) using sodium borohydride in 2-butanol,
iii) resolution of compound obtained in step ii) using D-tartaric acid in methanol and
iv) converting the compound obtained in step iii) to compound of Formula III.
in the presence of a base,
ii) reduction of the compound obtained in step i) using a suitable reducing agent in a solvent,
iii) resolution of compound obtained in step ii) using a chiral acid with D-configuration in a solvent and
iv) isolating compound of Formula IIIb.
in the presence of sodium hydroxide,
ii) reduction of the compound obtained in step i) using sodium borohydride in 2-butanol,
iii) resolution of compound obtained in step ii) using D-tartaric acid in methanol and
iv) isolating compound of Formula IIIb.
with alcohol in the presence of an acid followed by resolution using a chiral acid with L-configuration to give (1S,4R)-methyl-4-amino-2-cyclopentene carboxylate of Formula IVa,
ii) hydrolysis of compound of formula IVa in the presence of a base,
iii) reduction of the compound obtained in step ii) using a suitable reducing agent in a solvent,
iv) resolution of compound obtained in step iii) using a chiral acid with D-configuration in a solvent and
v) isolating compound of Formula IIIb.
with methanol in the presence of dry HCl gas followed by resolution with L-(+)-tartaric acid in water in the presence of triethylamine give (1S,4R)-methyl-4-amino-2-cyclopentene carboxylate L-hydrogen tartrate of Formula IVb,
ii) hydrolysis of compound of formula IVb in the presence of sodium hydroxide,
iii) reduction of the compound obtained in step ii) using sodium borohydride in 2-butanol,
iv) resolution of compound obtained in step iii) using D-tartaric acid in methanol and
v) isolating compound of Formula IIIb.
wherein R is halogen selected from chloro, fluoro, bromo, iodo;
ii) cyclization of compound of Formula VI in the presence of triethyl orthoformate to give compound of Formula VII,
wherein R is halogen selected from chloro, fluoro, bromo, iodo,
iii) conversion of compound of Formula VII to compound of Formula I or II where in R is OH and cyclopropylamine respectively.
wherein R is halogen selected from chloro, fluoro, bromo, iodo;
ii) cyclization of compound of Formula VI in the presence of triethyl orthoformate to give compound of Formula VII,
wherein R is halogen selected from chloro, fluoro, bromo, iodo;
iii) conversion of compound of Formula VII to compound of Formula I or II where in R is OH and cyclopropylamine respectively.
Claims (8)
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PCT/IB2015/058243 WO2016067182A2 (en) | 2014-10-27 | 2015-10-26 | Process for the preparation of amino alcohol derivatives or salts thereof |
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US10385006B2 true US10385006B2 (en) | 2019-08-20 |
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CN111484418B (en) * | 2020-04-30 | 2021-03-19 | 安徽红杉生物医药科技有限公司 | Preparation method of 4-amino-2-cyclopentene-1-methanol hydrochloride |
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US5034394A (en) * | 1988-06-27 | 1991-07-23 | Burroughs Wellcome Co. | Therapeutic nucleosides |
US6448402B2 (en) | 1997-11-27 | 2002-09-10 | Lonza Ag | Process for the preparation of aminoalcohol derivatives and their further conversion to (1R, 4S)-4-((2-amino-6-chloro-5-formamido-4-pyrimidinyl)-amino)-2-cyclopentenyl-1-methanol |
US6495711B2 (en) * | 1999-06-28 | 2002-12-17 | Biocryst Pharmaceuticals Inc. | Process for preparing (-)-(1S, 4R) N-protected 4-amino-2-cyclopentene-1-carboxylate esters |
-
2015
- 2015-10-26 US US15/518,498 patent/US10385006B2/en not_active Expired - Fee Related
- 2015-10-26 WO PCT/IB2015/058243 patent/WO2016067182A2/en unknown
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US5034394A (en) * | 1988-06-27 | 1991-07-23 | Burroughs Wellcome Co. | Therapeutic nucleosides |
US6448402B2 (en) | 1997-11-27 | 2002-09-10 | Lonza Ag | Process for the preparation of aminoalcohol derivatives and their further conversion to (1R, 4S)-4-((2-amino-6-chloro-5-formamido-4-pyrimidinyl)-amino)-2-cyclopentenyl-1-methanol |
US6723868B1 (en) * | 1997-11-27 | 2004-04-20 | Lonza Ag | Process for the preparation of aminoalcohol derivatives and their further conversion to (1R,4S)-4-((2-amino-6-chloro-5-formamido-4-pyrimidinyl)-amino)-2-cyclopentenyl-1-methanol |
US6495711B2 (en) * | 1999-06-28 | 2002-12-17 | Biocryst Pharmaceuticals Inc. | Process for preparing (-)-(1S, 4R) N-protected 4-amino-2-cyclopentene-1-carboxylate esters |
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Eliel et al, Stereochemistry of Organic Compounds, Chemical Separation of Enantiomers Via Diastereomers, 1994, John Wiley & Sons, New York, pp. 322-381. (Year: 1994). * |
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WO2016067182A3 (en) | 2016-06-23 |
US20170233329A1 (en) | 2017-08-17 |
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