WO1999055898A1 - Enzymatic resolvation for obtaining a (-)-3,4-trans-diarylchroman - Google Patents

Enzymatic resolvation for obtaining a (-)-3,4-trans-diarylchroman Download PDF

Info

Publication number
WO1999055898A1
WO1999055898A1 PCT/DK1999/000231 DK9900231W WO9955898A1 WO 1999055898 A1 WO1999055898 A1 WO 1999055898A1 DK 9900231 W DK9900231 W DK 9900231W WO 9955898 A1 WO9955898 A1 WO 9955898A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
salt
alkyl
process according
Prior art date
Application number
PCT/DK1999/000231
Other languages
French (fr)
Inventor
Søren LEHMANN
Original Assignee
Novo Nordisk A/S
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 Novo Nordisk A/S filed Critical Novo Nordisk A/S
Priority to JP2000546041A priority Critical patent/JP2002512807A/en
Priority to EP99915517A priority patent/EP1073762A1/en
Priority to AU34077/99A priority patent/AU3407799A/en
Publication of WO1999055898A1 publication Critical patent/WO1999055898A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
    • C12P41/003—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions
    • C12P41/004—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions by esterification of alcohol- or thiol groups in the enantiomers or the inverse reaction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/74—Benzo[b]pyrans, hydrogenated in the carbocyclic ring
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/02—Oxygen as only ring hetero atoms
    • C12P17/06—Oxygen as only ring hetero atoms containing a six-membered hetero ring, e.g. fluorescein

Definitions

  • the present invention relates to a new process for the preparation of (-)-3,4-trans- compounds involving an enzymatic hydrolysis.
  • U.S. Pat. No. 5,280,040 discloses a class of 3,4-diaryichromans and their salts useful in the treatment of bone loss.
  • PCT/DK96/00014 discloses that these compounds are useful in the treatment of hyperlipoproteinaemia, hypertriglyceridaemia, hyperlipidaemia, or hypercholesterolaemia or arteriosclerosis or for anticoagulative treatment.
  • PCT/DK96/00015 discloses that these compounds are useful in the treatment of gynaecological disorders, such as endometriosis, dysfunctional bleedings, endometriai cancer, polycystic ovarian syndrome and anovulatoric bleeding and for the induction of endometriai thinning.
  • the compounds are also known to have useful effects on gynaecomastia, obesity, vasodilation (respectively from PCT/DK96/00012, PCT/DK96/00011 , and PCT/DK96/00013) and furthermore on e.g. Alzheimers disease (PCT/DK96/00010).
  • One object of the present invention is therefore to provide a new process involving an enzy- matic resolution step for the preparation of (-)-3,4-trans enantiomers of compounds of formula I which process is adaptable to large scale manufacture, provide good yields and high purity and reduce the cost of manufacture.
  • the present invention concerns a process for the preparation of (-)-3,4-trans-compounds of the formula I
  • R 1 and R 4 are individually hydrogen, C 1-6 alkyl or C 1-6 alkoxy
  • R 5 is -0-(CH 2 ) n -NR 6 R 7 wherein n is an integer in the range of 1 to 6 and R 6 and R 7 independently are C 1-6 alkyl or R 6 and R 7 together with the N atom is a saturated or unsaturated 5- or 6- membered heterocyclic group containing one or two heteroatom(s) which heterocyclic group is optionally substituted with C 1-6 alkyl
  • R 2 and R 3 are individually hydrogen or C 1-6 alkyl; or a salt thereof, which comprises
  • R 1 , R 2 , R 3 and R 4 are as defined above with an agent of formula R- CO-X, wherein R is C 1-12 alkyl, optionally substituted with C 1-6 alkyl, C ⁇ alkoxy, hetaryl or aryl or C 1-12 alkoxy, optionally substituted with C 1-6 alkyl, C 1-6 alkoxy, hetaryl or aryl, and X is a leaving group, thereby providing a cis-racemate of a compound of formula VI tf (VI)
  • step a The above process may also be carried out by starting with a trans-racemate in step a), thus the process comprises
  • R 1 , R 2 , R 3 and R 4 are as defined above with an agent of formula R- CO-X, wherein R is C ⁇ alkyl, optionally substituted with C ⁇ alkyl, C ⁇ alkoxy, hetaryl or aryl or C 1-12 alkoxy, optionally substituted with C 1-6 alkyl, C ⁇ alkoxy, hetaryl or aryl, and X is a leaving group, thereby providing a trans-racemate of a compound of formula III o
  • R , R 3 and R 4 are as defined above,
  • the invention concerns a process for the preparation of (3R,4S)-cis- compounds of the formula VII
  • R 1 and R 4 are individually hydrogen, C 1-6 alkyl or C 1-6 alkoxy, and R 2 and R 3 are individually hydrogen or C ⁇ alkyl; or a salt thereof, which comprises
  • R is C 1-12 alkyl, optionally substituted with C 1-6 alkyl, C,. 6 alkoxy, hetaryl or aryl or C ⁇ alkoxy, optionally substituted with C ⁇ alkyl, C.,. 6 alkoxy, hetaryl or aryl, and R 1 , R 2 , R 3 and R 4 are as defined above, with an enzyme having lipase activity, thereby providing a mixture comprising a compound of formula Via
  • the invention concerns a process for the preparation of (3R,4R)-trans- compounds of the formula IV
  • R 1 and R 4 are individually hydrogen, C 1-6 alkyl or C ⁇ alkoxy, and R 2 and R 3 are indi- vidually hydrogen or C h alky!; or a salt thereof, which comprises 1 1 a) treating a trans-racemate of formula
  • R is C 1-12 alkyl, optionally substituted with C 1-6 alkyl, C ⁇ alkoxy, hetaryl or aryl or C ⁇ alkoxy, optionally substituted with C 1-6 alkyl, C ⁇ alkoxy, hetaryl or aryl, and R 1 , R 2 , R 3 and R 4 are as defined above, with an enzyme having lipase activity, thereby providing a mixture comprising a compound of formula Ilia
  • Preferred compounds of formula I are those in which R 1 is C ⁇ alkoxy, especially methoxy.
  • R 2 and R 3 preferably are the same and C 1-6 alkyl, especially methyl;
  • R 4 is preferably hydrogen;
  • R 5 is preferably -0-(CH 2 ) n -NR 6 R 7 wherein n is 2 and R 6 and R 7 together with the N atom is a saturated or unsaturated 5- or 6- membered heterocyclic group containing one or two heteroatom(s) and optionally substituted with C 1-6 alkyl.
  • R 1 is in the 7-position and is C ⁇ alkoxy, particularly methoxy; each of R 2 and R 3 is methyl, R 4 is hydrogen, and R 5 is in the 4-position and is 2-(pyrrolidin- 1-yl)ethoxy.
  • Preferred compounds of formula IV and VII are those in which R 1 is C ⁇ alkoxy, especially methoxy.
  • R 2 and R 3 preferably are the same and C 1-6 alkyl, especially methyl; R 4 is preferably hydrogen.
  • R 1 is in the 7-position and is C ⁇ alkoxy, particularly methoxy; each of R 2 and R 3 is methyl, R 4 is hydrogen, and the hydroxy group is in the 4-position.
  • a preferred embodiment of the invention provides a process for the preparation of ( - ) - 3R,4R- trans - 7-methoxy-2,2-dimethyl-3-phenyl-4- ⁇ 4-[2-(pyrrolidin-1- yl)ethoxy]phenyl ⁇ chromane, herein referred to as levormeloxifene, or a salt thereof prepared from 3,4-cis-(+/-)-4-hydroxyphenyl-7-methoxy-2,2-dimethyl-3-phenylchromane or a salt thereof.
  • R is C 1-12 alkyl or C 1-12 alkoxy.
  • R is C ⁇ alkyl, such as C,. 6 alkyl, e.g. methyl, ethyl or pentyl.
  • X is a halogen or a group of formula -0-CO-C 1-6 alkyl, such as chloro or -0-CO-CH 3 .
  • the enzyme is a lipase.
  • suitable lipases are Candida antartica lipase B, Lipozyme, Humicola, Pseudomonas cepasia, Candida cylindracea, Pig liver esterase and Pig pancreas lipase.
  • Y is a halogen, such as chloro.
  • the strong base in an aprotic solvent is potassium hydroxide in dimethylsulfoxide and toluene, or potassium t-butoxide in N- methylpyrrolidine and toluene.
  • Trans-racemate of formula (1) is treated with an acylating agent, such as an agent of formula R-CO-X, wherein R is C ⁇ alkyl, optionally substituted with C 1-6 alkyl, C ⁇ alkoxy, hetaryl or aryl or C ⁇ alkoxy, optionally substituted with C 1-6 alkyl, C ⁇ alkoxy, hetaryl or aryl, and X is a leaving group, thereby obtaining the protected trans-racemate of formula (2).
  • the trans- isomers of formula (1) are commercially available or may be prepared according to well defined procedures disclosed in the prior art starting from commercially available starting compounds.
  • trans-isomers of formula (1) may be prepared from the corresponding cis-isomers (6), illustrated in scheme 2 below, by treating the cis-isomers (6) with a base in an organic solvent, e.g. potassium hydroxide in toluene and dimethylsulfoxide, and working up in a suitable manner, e.g. by treatment with hydrochloric acid and filtering off the product, thereby obtaining the trans-isomers of formula (1).
  • the trans-isomers of formula (2) are then treated with an enzyme having lipase activity, e.g.
  • Candida antartica lipase B Lipozyme, Humicola, Pseudomonas cepasia, Candida cylindracea, Pig liver esterase and Pig pancreas lipase
  • a suitable solvent such as an organic solvent, e.g. n-hexane, n-heptane, acetoni- tril, methanol or ethanol, or an aqueous/organic solvent mixture, e.g. water/n-hexane or wa- ter/n-heptane, and at a suitable temperature within the range from about 0-50 °C.
  • Such enzymatic treatment results in hydrolysis of one of the enantiomers, thus obtaining a mixture of either (3a) and (3) or a mixture of (4) and (4a). If the mixture of (3) and (3a) is obtained, then the mixture is separated in a well known manner to obtain compound (3). If the mixture of (4) and (4a) is obtained, then (4) is isolated and hydrolysed in a well known manner to obtain compound (3).
  • the compound of formula (3) is then treated with an alkylating agent, such as an agent of formula Y-R 5 wherein R 5 and Y are as defined above, e.g. chloroethylpyrrolidine, thereby obtaining a compound of formula (5).
  • an alkylating agent such as an agent of formula Y-R 5 wherein R 5 and Y are as defined above, e.g. chloroethylpyrrolidine
  • Cis-racemate of formula (6) is treated with an acylating agent, such as an agent of formula R-CO-X, wherein R is C ⁇ alkyl, optionally substituted with C 1-6 alkyl, C ⁇ alkoxy, hetaryl or aryl or C ⁇ alkoxy, optionally substituted with C ⁇ alkyl, C ⁇ profession 6 alkoxy, hetaryl or aryl, and X is a leaving group, thereby obtaining the protected cis-racemate of formula (7).
  • the cis-isomers of formula (6) are commercially available or may be prepared according to well defined procedures disclosed in the prior art starting from commercially available starting compounds.
  • the cis-isomers of formula (7) are then treated with an enzyme having lipase activity, e.g. Candida antartica lipase B, Lipozyme, Humicola, Pseudomonas cepasia, Candida cylindra- cea, Pig liver esterase and Pig pancreas lipase, in a suitable solvent, such as an organic solvent, e.g. n-hexane, n-heptane, acetonitril, methanol or ethanol, or an aqueous/organic solvent mixture, e.g. water/n-hexane or water/n-heptane, and at a suitable temperature within the range from about 0-50 °C.
  • a suitable solvent such as an organic solvent, e.g. n-hexane, n-heptane, acetonitril, methanol or ethanol, or an aqueous/organic solvent mixture, e.g. water/
  • Such enzymatic treatment results in hydrolysis of one of the enantiomers, thus obtaining a mixture of either (8a) and (8) or a mixture of (9) and (9a). If the mixture of (8) and (8a) is obtained, then the mixture is separated in a well known manner to obtain compound (8). If the mixture of (9) and (9a) is obtained, then (9) is isolated and hydrolysed in a well known manner to obtain compound (8).
  • the compound of formula (8) is then treated with an alkylating agent, such as an agent of formula Y-R 5 wherein R 5 and Y are as defined above, e.g. chloroethylpyrrolidine, thereby obtaining a compound of formula (10).
  • an alkylating agent such as an agent of formula Y-R 5 wherein R 5 and Y are as defined above, e.g. chloroethylpyrrolidine
  • the compound (10) is then treated with a strong base in an aprotic solvent, e.g. potassium hydroxide in dimethylsulfoxide, thereby obtaining a compound of formula (5).
  • a strong base e.g. potassium hydroxide in dimethylsulfoxide
  • the (-)-3R,4R- trans-7-methoxy-2,2-dimethyl-3-phenyl- 4- ⁇ 4-[2-(pyrrolidin-1-yl)ethoxy]phenyl ⁇ chromane is isolated as the hydrogen fumarate salt.
  • the C 1-12 -alkyl, C ⁇ -alkyl or C M -alkyl groups specified above are intended to include those alkyl groups of the designated length in either a linear or branched or cyclic configuration.
  • Examples of linear alkyl are methyl, ethyl, n-propyl, n-butyl, pentyl, n-amyl, hexyl, n-hexyl and the like.
  • Examples of branched alkyl are isopropyl, sec-butyl, tert-butyl, 2-ethylbutyl, 2,3-dimethylbutyl, isopentyi, sec-amyl, and isohexyl.
  • Examples of cyclic alkyl are C ⁇ -cycloalkyl such as cyclo- propyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • the C 1-12 -alkoxy, C 1-6 -alkoxy or C ⁇ -alkoxy groups specified above are intended to include those alkoxy groups of the designated length in either a linear or branched or cyclic configura- tion.
  • linear alkoxy are methoxy, ethoxy, propoxy, butoxy, pentoxy, and hexoxy.
  • branched alkoxy are isopropoxy, sec-butoxy, tert-butoxy, isopentoxy, and iso- hexoxy.
  • Examples of cyclic alkoxy are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cy- clohexyloxy.
  • aryl is intended to include monovalent carbocyclic aromatic ring moieties, being either monocyclic, bicyclic or polycyclic, e.g. selected from the group consisting of phenyl and naphthyl, optionally substituted with one or more C 1-6 -alkyl, C 1-6 -alkoxy, halogen, amino or aryl.
  • heterocyclic aromatic ring moieties being either monocyclic, bicyclic or polycyclic, e.g. selected from the group consisting of pyridyl, 1-H-tetrazol-5-yl, thiazolyl, imidazolyl, indolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, quinolinyl, pyrazinyl, or isothiazolyl, optionally substituted by one or more C 1-6 -alkyl, C 1-6 -alkoxy, halogen, amino or aryl.
  • heteroatom(s) preferably are selected among N, O, or S such as e.g., piperidine, pyrrolidine, N-methylpiperazine or morpholine.
  • Halogen includes chloro, fluoro, bromo and iodo.
  • hydrolyzing agent in step c) is normally used a weak base such as e.g. aqueous ammonia, sodium carbonate, potassium carbonate or the like, or an enzyme having lipase activity.
  • a weak base such as e.g. aqueous ammonia, sodium carbonate, potassium carbonate or the like, or an enzyme having lipase activity.
  • strong bases for the rearrangement may be used potassium hydroxide, sodium hydroxide, metal alkoxides, such as sodium methoxide, sodium ethoxide or potassium t-butoxide , sodium hydride, alkyllithiums such as n-butyllithium and sec-butyllithium; methal amides, such as sodium amide, magnesium diisopropylamide and lithium diisopropylamide or the like.
  • the preferred strong bases are potassium hydroxide and potassium t-butoxide.
  • the treatment with the strong base is normally carried out by heating the mixture, preferably at 80 - 110 °C.
  • the preferred aprotic solvents are dimethylsulfoxide (DMSO), dimethylformamide (DMF), N- methylpyrrolidone (NMP) and toluene or combinations thereof.
  • DMSO dimethylsulfoxide
  • DMF dimethylformamide
  • NMP N- methylpyrrolidone
  • toluene or combinations thereof.
  • the combination NMP and toluene is preferred.
  • the combination toluene and DMSO is another preferred.
  • the term "leaving group” (as used in connection with X and Y) is in- tended to comprise any suitable group within the definition of leaving groups as defined in Advanced Organic Chemistry, by J. March, "Reactions, Mechanisms and Structures", 4. Ed., page 205, and includes e.g. a halogen or an acid residue e.g. a group of formula -O-CO-C ! . 12 alkyl.
  • enzyme having lipase activity is intended to mean any hy- drolase or lipase as comprised in EC 3.11.1.3, and any modification thereof, which modification have retained the hydrolysing ability of the enzyme.
  • the enzyme having lipase activity may be derived by means involving the use of a microorganism or by recombinant means.
  • the compounds of formulas I, II, III, Ilia, lllb, IV, IVa, V, VI, Via, Vlb, VII, Vila, and Vlll may be prepared in the form of salts thereof e.g. pharmaceutically acceptable salts, especially acid-addition salts, including salts of organic acids and mineral acids.
  • pharmaceutically acceptable salts especially acid-addition salts, including salts of organic acids and mineral acids.
  • salts include salts of organic acids such as formic acid, fumaric acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, succinic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid and the like.
  • Suitable inorganic acid-addition salts include salts of hydrochloric, hydrobromic, sulphuric and phosphoric acids and the like.
  • the acid addition salts may be obtained from the free base in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent e.g. by crystallisation. 20
  • the starting compound for the process e.i. the cis-racemate of formula (V) or the trans- racemate of formula (II) may be prepared according to known methods, such as those disclosed in Ray et al., J JVIed Chem 19 (1976), 276 - 279.
  • Example 8 cis-3R.4S-7-Methoxy -3-phenyl 4- ⁇ 4-[2-(pyrrolidin-1 -yl)ethoxy]phenyl ⁇ chromane.
  • the product was dissolved in acetone (20ml) and refluxed overnight with potassium carbonate and chloroethylpyrrolidine hydrochloride (300mg).
  • the reaction mixture was partitioned 23 between water and toluene. The organic phase was separated, dried over potassium carbonate and evaporated to an oil.
  • the mixture was stirred until ail salts have dissolved.
  • the aqueous phase was separated and extracted with another portion of toluene (65 ml).
  • the combined organic phase was washed with water (3x130 ml).
  • the organic phase was dried by removal of water in an azeotropic distillation.
  • the mix- ture was heated to reflux while water was distilled from the mixture. The reflux was maintained for 6 hours.
  • the reaction mixture was cooled down to room temperature, water ( 200 ml) was added and the mixture stirred until all the salt was dissolved.
  • the aqueous phase was separated and extracted with another portion of toluene (135 ml).
  • the organic phases were pooled washed with water (2x200 ml) and evaporated to an oil.
  • the oil was dissolved in ethanol (135 ml) at 40 °C and mixed with a solution of fumaric acid (9.1 g) in ethanol (265 ml) at 40 - 60 °C. The mixture was stirred for 2 hours at ambient temperature and then for 1 hour at 0 °C. The crystals were filtered off and dried.
  • Cis-3R,4S-4-(4-Hydroxyphenyl)-7-methoxy-3-phenylchromane was isolated from cis-3S,4R- 4-(4-acetoxyphenyl)-7-methoxy-3-phenylchromane in the hydrolysis mixture by crystallisation at -18 °C.
  • the CE system was: 5 mM sulfobuthylether-beta-cyclodextrin in 75 mM fosphate buffer, pH 2.5.
  • the capillary was 83.5 cm long and with 50 ⁇ m internal diameter.
  • the conditions were - 20 kV/-35 ⁇ A, 30°C and samples were injected for 3.0 seconds with 50 mBar. 10 ⁇ l samples were taken from the reaction mixture and dilluted in 300 ⁇ l acetonitrile plus 300 ⁇ l fosphate buffer.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Wood Science & Technology (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Zoology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Rheumatology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Genetics & Genomics (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Medicinal Chemistry (AREA)
  • Biochemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Analytical Chemistry (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrane Compounds (AREA)

Abstract

The invention relates to a process for the preparation of (-)-3,4-trans-compounds involving an enzymatic hydrolysis. These compounds and their salts are useful in the treatment of bone loss, hyperlipoproteinaemia, hypertriglyceridaemia, hyperlipidaemia, or hypercholesterolaemia or arteriosclerosis or in anticoagulative treatment.

Description

Enzymatic resolvation for obtaining a (-)-3,4-trans-diarylchroman
FIELD OF INVENTION
The present invention relates to a new process for the preparation of (-)-3,4-trans- compounds involving an enzymatic hydrolysis.
BACKGROUND OF THE INVENTION
U.S. Pat. No. 5,280,040 discloses a class of 3,4-diaryichromans and their salts useful in the treatment of bone loss. Furthermore, PCT/DK96/00014 discloses that these compounds are useful in the treatment of hyperlipoproteinaemia, hypertriglyceridaemia, hyperlipidaemia, or hypercholesterolaemia or arteriosclerosis or for anticoagulative treatment. PCT/DK96/00015 discloses that these compounds are useful in the treatment of gynaecological disorders, such as endometriosis, dysfunctional bleedings, endometriai cancer, polycystic ovarian syndrome and anovulatoric bleeding and for the induction of endometriai thinning. The compounds are also known to have useful effects on gynaecomastia, obesity, vasodilation (respectively from PCT/DK96/00012, PCT/DK96/00011 , and PCT/DK96/00013) and furthermore on e.g. Alzheimers disease (PCT/DK96/00010).
A process for the preparation of ( +,- ) -3,4-trans diarylchromanes is described in U.S. Pat. No. 3,822,287 and by Suprabhat Ray et al. in J.Med.Chem.19,276 (1976). The ( +,- ) -3,4-trans- isomer is obtained by conversion of the ( +,- ) -3,4-cis-isomer by means of an organometallic base-catalyzed rearrangement as described in US Patent Specification No. 3,822,287.
The resolvation of ( +,- ) - 3,4-trans-7-methoxy-2,2-dimethyl-3-phenyl-4-{4-[2-(pyrrolidin-1- yl)ethoxy]phenyl}chromane in its optical antipodes is described in U.S. Pat. No. 4,447,622. According to this process the ( +,- )- 3,4- trans-7-methoxy-2,2-dimethyl-3-phenyl-4-{4-[2- (pyrrolidin-1-yl)ethoxy]phenyl}chromane is reacted with di-p-toluoyl-l-tartaric acid monohy- drate in a protic solvent, the reaction mixture is subjected to fractional crystallization and the crystalline salt is subjected to alkaline hydrolysis to produce the desired enantiomer. 2 Example 1 of U.S. Pat. No. 4,447,622 describes the preparation of the (-)-3,4-trans enantiomer, shown by the following formula :
Figure imgf000004_0001
When using the process disclosed in U.S. Pat. No. 4,447,622 the desired (-)-3,4-trans enan- tiomer is only obtained with a low chiral purity, less than 80% ee (enantiomeric excess) after the first crystallization. In order to improve the chiral purity the enantiomer has to be crystallized several times.
One object of the present invention is therefore to provide a new process involving an enzy- matic resolution step for the preparation of (-)-3,4-trans enantiomers of compounds of formula I which process is adaptable to large scale manufacture, provide good yields and high purity and reduce the cost of manufacture.
DESCRIPTION OF THIS INVENTION.
The present invention concerns a process for the preparation of (-)-3,4-trans-compounds of the formula I
Figure imgf000005_0001
wherein R1 and R4 are individually hydrogen, C1-6alkyl or C1-6alkoxy, R5 is -0-(CH2)n-NR6R7 wherein n is an integer in the range of 1 to 6 and R6 and R7 independently are C1-6alkyl or R6 and R7 together with the N atom is a saturated or unsaturated 5- or 6- membered heterocyclic group containing one or two heteroatom(s) which heterocyclic group is optionally substituted with C1-6alkyl; and R2 and R3 are individually hydrogen or C1-6alkyl; or a salt thereof, which comprises
a) treating a cis-racemate of a compound of formula V
(V)
Figure imgf000005_0002
or a salt thereof, wherein R1, R2 , R3 and R4 are as defined above with an agent of formula R- CO-X, wherein R is C1-12alkyl, optionally substituted with C1-6alkyl, C^alkoxy, hetaryl or aryl or C1-12alkoxy, optionally substituted with C1-6alkyl, C1-6alkoxy, hetaryl or aryl, and X is a leaving group, thereby providing a cis-racemate of a compound of formula VI tf (VI)
Figure imgf000006_0001
or a salt thereof, wherein R, R , R , R and R are as defined above,
b) treating said cis-racemate of formula VI with an enzyme having lipase activity, thereby providing a mixture comprising a compound of formula Via
(Via)
Figure imgf000006_0002
or a salt thereof, and a compound of formula VII
OH
(VII)
Figure imgf000006_0003
or a salt thereof; or a mixture comprising a compound of formula Vlb (Vlb)
Figure imgf000007_0001
or a salt thereof, and a compound of formula Vila
OH
R (Vila)
Figure imgf000007_0002
or a salt thereof,
c) separating said mixture of compound Via and VII or said mixture of compound Vlb and Vila, thereby obtaining a compound of formula VII or a compound of formula Vlb, which compound Vlb is then hydrolyzed to said compound of formula VII,
d) treating said compound of formula VII or a salt thereof, with an agent of formula Y-R5 wherein Y is a leaving group, thereby providing a compound of formula VIII
(VIII)
Figure imgf000007_0003
or a salt thereof, e) treating said compound of formula VIII or a salt thereof with a strong base in an aprotic solvent, thereby obtaining said compound of formula I or a salt thereof.
The above process may also be carried out by starting with a trans-racemate in step a), thus the process comprises
a) treating a trans-racemate of a compound of formula II
(II)
Figure imgf000008_0001
or a salt thereof, wherein R1, R2 , R3 and R4 are as defined above with an agent of formula R- CO-X, wherein R is C^^alkyl, optionally substituted with C^alkyl, C^alkoxy, hetaryl or aryl or C1-12alkoxy, optionally substituted with C1-6alkyl, C^alkoxy, hetaryl or aryl, and X is a leaving group, thereby providing a trans-racemate of a compound of formula III o
(III)
Figure imgf000008_0002
or a salt thereof, wherein R , R , R3 and R4 are as defined above,
b) treating said trans-racemate of formula III with an enzyme having lipase activity, thereby providing a mixture comprising a compound of formula Ilia R« (Ilia)
Figure imgf000009_0001
or a salt thereof, and a compound of formula IV
OH
FT (IV)
Figure imgf000009_0002
or a salt thereof; or a mixture comprising a compound of formula lllb o
R4 (lllb)
Figure imgf000009_0003
or a salt thereof, and a compound of formula IVa FT (IVa)
Figure imgf000010_0001
or a salt thereof,
c) separating said mixture of compound Ilia and IV or said mixture of compound lllb and IVa, thereby obtaining a compound of formula IV or a compound of formula lllb, which compound lllb is then hydrolyzed to said compound of formula IV,
d) treating said compound of formula IV with an agent of formula Y-R5 wherein Y is a leaving group, thereby obtaining the compound of formula I or a salt thereof.
In another aspect the invention concerns a process for the preparation of (3R,4S)-cis- compounds of the formula VII
(VII)
Figure imgf000010_0002
wherein R1 and R4 are individually hydrogen, C1-6alkyl or C1-6alkoxy, and R2 and R3 are individually hydrogen or C^alkyl; or a salt thereof, which comprises
a) treating a cis-racemate of formula VI (VI)
Figure imgf000011_0001
or a salt thereof, wherein R is C1-12alkyl, optionally substituted with C1-6alkyl, C,.6alkoxy, hetaryl or aryl or C^^alkoxy, optionally substituted with C^alkyl, C.,.6alkoxy, hetaryl or aryl, and R1, R2 , R3 and R4 are as defined above, with an enzyme having lipase activity, thereby providing a mixture comprising a compound of formula Via
(Via)
Figure imgf000011_0002
or a salt thereof, and a compound of formula VII OH
R (VII)
Figure imgf000011_0003
or a salt thereof; or a mixture comprising a compound of formula Vlb 10
(Vlb)
Figure imgf000012_0001
or a salt thereof, and a compound of formula Vila
OH
R (Vila)
Figure imgf000012_0002
or a salt thereof,
b) separating said mixture of compound Via and VII or said mixture of compound Vlb and Vila, thereby obtaining a compound of formula VII or a compound of formula Vlb, which compound Vlb is then hydrolyzed to said compound of formula VII.
In a further aspect the invention concerns a process for the preparation of (3R,4R)-trans- compounds of the formula IV
R (IV)
Figure imgf000012_0003
wherein R1 and R4 are individually hydrogen, C1-6alkyl or C^alkoxy, and R2 and R3 are indi- vidually hydrogen or Chalky!; or a salt thereof, which comprises 1 1 a) treating a trans-racemate of formula
(III)
Figure imgf000013_0001
or a salt thereof, wherein R is C1-12alkyl, optionally substituted with C1-6alkyl, C^alkoxy, hetaryl or aryl or C^^alkoxy, optionally substituted with C1-6alkyl, C^alkoxy, hetaryl or aryl, and R1, R2 , R3 and R4 are as defined above, with an enzyme having lipase activity, thereby providing a mixture comprising a compound of formula Ilia
(Ilia)
Figure imgf000013_0002
or a salt thereof, and a compound of formula IV
OH
(iv)
Figure imgf000013_0003
or a salt thereof; or a mixture comprising a compound of formula lllb 12
(lllb)
Figure imgf000014_0001
or a salt thereof, and a compound of formula IVa OH
(IVa)
Figure imgf000014_0002
or a salt thereof,
b) separating said mixture of compound Ilia and IV or said mixture of compound lllb and IVa, thereby obtaining a compound of formula IV or a compound of formula lllb, which compound lllb is then hydrolyzed to said compound of formula IV, or a salt thereof.
Preferred compounds of formula I are those in which R1 is C^alkoxy, especially methoxy. Furthermore, R2 and R3 preferably are the same and C1-6alkyl, especially methyl; R4 is preferably hydrogen; and R5 is preferably -0-(CH2)n-NR6R7 wherein n is 2 and R6 and R7 together with the N atom is a saturated or unsaturated 5- or 6- membered heterocyclic group containing one or two heteroatom(s) and optionally substituted with C1-6alkyl. Within particularly preferred embodiments, R1 is in the 7-position and is C^alkoxy, particularly methoxy; each of R2 and R3 is methyl, R4 is hydrogen, and R5 is in the 4-position and is 2-(pyrrolidin- 1-yl)ethoxy. 13 Preferred compounds of formula IV and VII are those in which R1 is C^alkoxy, especially methoxy. Furthermore, R2 and R3 preferably are the same and C1-6alkyl, especially methyl; R4 is preferably hydrogen. Within particularly preferred embodiments, R1 is in the 7-position and is C^alkoxy, particularly methoxy; each of R2 and R3 is methyl, R4 is hydrogen, and the hydroxy group is in the 4-position.
A preferred embodiment of the invention provides a process for the preparation of ( - ) - 3R,4R- trans - 7-methoxy-2,2-dimethyl-3-phenyl-4-{4-[2-(pyrrolidin-1- yl)ethoxy]phenyl}chromane, herein referred to as levormeloxifene, or a salt thereof prepared from 3,4-cis-(+/-)-4-hydroxyphenyl-7-methoxy-2,2-dimethyl-3-phenylchromane or a salt thereof.
In one embodiment of the above process according to the invention in the agent of formula R-CO-X, R is C1-12alkyl or C1-12alkoxy. In a particular embodiment R is C^alkyl, such as C,. 6alkyl, e.g. methyl, ethyl or pentyl. In another embodiment X is a halogen or a group of formula -0-CO-C1-6alkyl, such as chloro or -0-CO-CH3.
In another embodiment of the present process the enzyme is a lipase. In particular suitable lipases are Candida antartica lipase B, Lipozyme, Humicola, Pseudomonas cepasia, Candida cylindracea, Pig liver esterase and Pig pancreas lipase.
In a further embodiment of the present process in the agent of formula Y-R5, Y is a halogen, such as chloro.
In a still further embodiment of the present process the strong base in an aprotic solvent is potassium hydroxide in dimethylsulfoxide and toluene, or potassium t-butoxide in N- methylpyrrolidine and toluene.
The stereoselective rearrangement of the (-)-3,4-cis enantiomer of formula VIII to the corre- sponding (-)-3,4-trans enatiomer of formula I is possible without any loss of chiral purity. 14 By the process disclosed in US Patent Specification No. 4,447,622 the (-)-3,4-trans enantiomer is only obtained in a chiral purity above 80% ee (enantiomeric excess) by crystallization several times.
The process of the invention is illustrated in the following schemes 1 and 2, wherein the synthesis of levormeloxifene (5) involves an enzymatic resolution step which overcomes a number of problems associated with a purely chemical resolution step.
Scheme 1
trans-isomers
(1)
Figure imgf000016_0001
C? 1 C7 I
Figure imgf000016_0002
Figure imgf000016_0003
(5) (5) 15 Trans-racemate of formula (1) is treated with an acylating agent, such as an agent of formula R-CO-X, wherein R is C^alkyl, optionally substituted with C1-6alkyl, C^alkoxy, hetaryl or aryl or C^^alkoxy, optionally substituted with C1-6alkyl, C^alkoxy, hetaryl or aryl, and X is a leaving group, thereby obtaining the protected trans-racemate of formula (2). The trans- isomers of formula (1) are commercially available or may be prepared according to well defined procedures disclosed in the prior art starting from commercially available starting compounds. Moreover, trans-isomers of formula (1) may be prepared from the corresponding cis-isomers (6), illustrated in scheme 2 below, by treating the cis-isomers (6) with a base in an organic solvent, e.g. potassium hydroxide in toluene and dimethylsulfoxide, and working up in a suitable manner, e.g. by treatment with hydrochloric acid and filtering off the product, thereby obtaining the trans-isomers of formula (1). The trans-isomers of formula (2) are then treated with an enzyme having lipase activity, e.g. Candida antartica lipase B, Lipozyme, Humicola, Pseudomonas cepasia, Candida cylindracea, Pig liver esterase and Pig pancreas lipase, in a suitable solvent, such as an organic solvent, e.g. n-hexane, n-heptane, acetoni- tril, methanol or ethanol, or an aqueous/organic solvent mixture, e.g. water/n-hexane or wa- ter/n-heptane, and at a suitable temperature within the range from about 0-50 °C. Such enzymatic treatment results in hydrolysis of one of the enantiomers, thus obtaining a mixture of either (3a) and (3) or a mixture of (4) and (4a). If the mixture of (3) and (3a) is obtained, then the mixture is separated in a well known manner to obtain compound (3). If the mixture of (4) and (4a) is obtained, then (4) is isolated and hydrolysed in a well known manner to obtain compound (3). The compound of formula (3) is then treated with an alkylating agent, such as an agent of formula Y-R5 wherein R5 and Y are as defined above, e.g. chloroethylpyrrolidine, thereby obtaining a compound of formula (5). One way to carry out the alkylating step is described in Ray et al. J. Med. Chem. 19, p. 276-279 (1976).
16
Scheme 2
Figure imgf000018_0001
Figure imgf000018_0002
(5) 17 Cis-racemate of formula (6) is treated with an acylating agent, such as an agent of formula R-CO-X, wherein R is C^^alkyl, optionally substituted with C1-6alkyl, C^alkoxy, hetaryl or aryl or C^^alkoxy, optionally substituted with C^alkyl, Cι„6alkoxy, hetaryl or aryl, and X is a leaving group, thereby obtaining the protected cis-racemate of formula (7). The cis-isomers of formula (6) are commercially available or may be prepared according to well defined procedures disclosed in the prior art starting from commercially available starting compounds. The cis-isomers of formula (7) are then treated with an enzyme having lipase activity, e.g. Candida antartica lipase B, Lipozyme, Humicola, Pseudomonas cepasia, Candida cylindra- cea, Pig liver esterase and Pig pancreas lipase, in a suitable solvent, such as an organic solvent, e.g. n-hexane, n-heptane, acetonitril, methanol or ethanol, or an aqueous/organic solvent mixture, e.g. water/n-hexane or water/n-heptane, and at a suitable temperature within the range from about 0-50 °C. Such enzymatic treatment results in hydrolysis of one of the enantiomers, thus obtaining a mixture of either (8a) and (8) or a mixture of (9) and (9a). If the mixture of (8) and (8a) is obtained, then the mixture is separated in a well known manner to obtain compound (8). If the mixture of (9) and (9a) is obtained, then (9) is isolated and hydrolysed in a well known manner to obtain compound (8). The compound of formula (8) is then treated with an alkylating agent, such as an agent of formula Y-R5 wherein R5 and Y are as defined above, e.g. chloroethylpyrrolidine, thereby obtaining a compound of formula (10). The compound (10) is then treated with a strong base in an aprotic solvent, e.g. potassium hydroxide in dimethylsulfoxide, thereby obtaining a compound of formula (5). One way to carry out the alkylating step is described in Ray et al. J. Med. Chem. 19, p. 276-279 (1976).
In scemes 1 and 2 above, the compounds of formulas (1), (2), (3), (3a), (4), (4a), (5), (6), (7), (8), (8a), (9), (9a) and (10) are shown for the purpose of illustrating the present process, and should by no means limit the invention in any aspect.
In a particularly preferred embodiment the (-)-3R,4R- trans-7-methoxy-2,2-dimethyl-3-phenyl- 4-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}chromane is isolated as the hydrogen fumarate salt.
In the above structural formulas and throughout the present specification, the following terms have the indicated meanings: 18 The C1-12-alkyl, C^-alkyl or CM-alkyl groups specified above are intended to include those alkyl groups of the designated length in either a linear or branched or cyclic configuration. Examples of linear alkyl are methyl, ethyl, n-propyl, n-butyl, pentyl, n-amyl, hexyl, n-hexyl and the like. Examples of branched alkyl are isopropyl, sec-butyl, tert-butyl, 2-ethylbutyl, 2,3-dimethylbutyl, isopentyi, sec-amyl, and isohexyl. Examples of cyclic alkyl are C^-cycloalkyl such as cyclo- propyl, cyclobutyl, cyclopentyl and cyclohexyl.
The C1-12-alkoxy, C1-6-alkoxy or C^-alkoxy groups specified above are intended to include those alkoxy groups of the designated length in either a linear or branched or cyclic configura- tion. Examples of linear alkoxy are methoxy, ethoxy, propoxy, butoxy, pentoxy, and hexoxy. Examples of branched alkoxy are isopropoxy, sec-butoxy, tert-butoxy, isopentoxy, and iso- hexoxy. Examples of cyclic alkoxy are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cy- clohexyloxy.
In the present context, the term "aryl" is intended to include monovalent carbocyclic aromatic ring moieties, being either monocyclic, bicyclic or polycyclic, e.g. selected from the group consisting of phenyl and naphthyl, optionally substituted with one or more C1-6-alkyl, C1-6-alkoxy, halogen, amino or aryl.
In the present context, the term "hetaryl" is intended to include monovalent heterocyclic aromatic ring moieties, being either monocyclic, bicyclic or polycyclic, e.g. selected from the group consisting of pyridyl, 1-H-tetrazol-5-yl, thiazolyl, imidazolyl, indolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, quinolinyl, pyrazinyl, or isothiazolyl, optionally substituted by one or more C1-6-alkyl, C1-6-alkoxy, halogen, amino or aryl.
Herein, the term "5- or 6- membered heterocyclic group containing one or two hetero atom(s)" include groups wherein the heteroatom(s) preferably are selected among N, O, or S such as e.g., piperidine, pyrrolidine, N-methylpiperazine or morpholine.
"Halogen" includes chloro, fluoro, bromo and iodo.
As hydrolyzing agent in step c) is normally used a weak base such as e.g. aqueous ammonia, sodium carbonate, potassium carbonate or the like, or an enzyme having lipase activity. 19 As strong bases for the rearrangement may be used potassium hydroxide, sodium hydroxide, metal alkoxides, such as sodium methoxide, sodium ethoxide or potassium t-butoxide , sodium hydride, alkyllithiums such as n-butyllithium and sec-butyllithium; methal amides, such as sodium amide, magnesium diisopropylamide and lithium diisopropylamide or the like. The preferred strong bases are potassium hydroxide and potassium t-butoxide.
The treatment with the strong base is normally carried out by heating the mixture, preferably at 80 - 110 °C.
The preferred aprotic solvents are dimethylsulfoxide (DMSO), dimethylformamide (DMF), N- methylpyrrolidone (NMP) and toluene or combinations thereof. The combination NMP and toluene is preferred. The combination toluene and DMSO is another preferred.
In the present context, the term "leaving group" (as used in connection with X and Y) is in- tended to comprise any suitable group within the definition of leaving groups as defined in Advanced Organic Chemistry, by J. March, "Reactions, Mechanisms and Structures", 4. Ed., page 205, and includes e.g. a halogen or an acid residue e.g. a group of formula -O-CO-C!. 12alkyl.
In the present context, the term "enzyme having lipase activity" is intended to mean any hy- drolase or lipase as comprised in EC 3.11.1.3, and any modification thereof, which modification have retained the hydrolysing ability of the enzyme. The enzyme having lipase activity may be derived by means involving the use of a microorganism or by recombinant means.
Within the present invention, the compounds of formulas I, II, III, Ilia, lllb, IV, IVa, V, VI, Via, Vlb, VII, Vila, and Vlll may be prepared in the form of salts thereof e.g. pharmaceutically acceptable salts, especially acid-addition salts, including salts of organic acids and mineral acids. Examples of such salts include salts of organic acids such as formic acid, fumaric acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, succinic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid and the like. Suitable inorganic acid-addition salts include salts of hydrochloric, hydrobromic, sulphuric and phosphoric acids and the like. The acid addition salts may be obtained from the free base in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent e.g. by crystallisation. 20
The starting compound for the process, e.i. the cis-racemate of formula (V) or the trans- racemate of formula (II) may be prepared according to known methods, such as those disclosed in Ray et al., J JVIed Chem 19 (1976), 276 - 279.
Further embodiments of the present process may be provided by any possible combination of any one of the above embodiments.
The process of the invention is described in greater detail in the following non-limitative ex- amples.
Example 1 trans-(+/-)-4-Hydroxyphenyl- 7-methoxy-2,2-dimethyl-3-phenylchromane
cis-(+/-)-4-Hydroxyphenyl-7-methoxy-2,2-dimethyl-3-phenylchromane (50 g) was refluxed in a mixture of toluene (500 ml), dimethylsulfoxide(100 ml) and potassium hydroxide (20 g) for 12 hours. The reflux was carried out with a condenser equipped with a water trap for removing water from the reaction mixture during the process. The reaction mixture was poured into diluted hydrochloric acid (500 ml 1 M). The product was filtered off and dried. Yield 48.6 g (97 %), m.p. = 267 °C.
The identity of the product was verified by 1 H-NMR.
Example 2 cis-(+/-)-4-Acetoxyphenyl- 7-methoxy-2.2-dimethyl-3-phenylchromane
cis-(+/-)-4-Hydroxyphenyl- 7-methoxy-2,2-dimethyl-3-phenylchromane (3.6g) was dissolved in acetic anhydride (10.8g). Triethylamine (1.45g) was added and the mixture stirred at ambient temperature for 3 hours. The mixture was evaporated in vacuum. The residue was partitioned between water (100 ml) and ethyl acetate ( 200 ml). The organic phase was sepa- rated washed with 1M sodium hydroxide, brine and dried over sodium sulphate evaporated and the residue crystallised from a mixture of water (10 ml) and ethanol (30ml). Yield 3.6 g ( 89 %). M.p.= 121.5 - 123 °C.
The identity of the product was verified by 1 H-NMR and Mass Spectroscopy. 21 Example 3. cis-(+ -4-Hexanoyloxyphenyl-7-methoxy-2.2-dimethyl-3-phenylchromane
cis-(+/-)-4-Hydroxyphenyl- 7-methoxy-2,2-dimethyl-3-phenylchromane (7.2g) was dissolved in tetrahydrofuran (20ml). Triethylamine (8ml) and hexanoyl chloride (5.4g) was added and the mixture stirred at ambient temperature overnight. The mixture was poured into water and extracted with ethyl acetate (100ml). The organic phase was separated and washed with 10 % sodium bicarbonate solution and dried over sodium sulphate. The organic extract was evaporated to an heavy oil. Yield 6 g ( 75 %).
The identity of the product was verified by 1 H-NMR.
Example 4. cis-(+/-)-4-Ethoxycarbonyloxyphenyl-7-methoxy-2.2-dimethyl-3-phenylchromane
cis-(+/-)-4-Hydroxyphenyl- 7-methoxy-2,2-dimethyl-3-phenylchromane (7.2g) was dissolved in tetrahydrofuran (20ml). Triethylamine (4.2ml) and ethyl chloroformate (3.8 ml) was added and the mixture stirred at ambient temperature overnight. The mixture was poured into ice water and extracted with ethyl acetate (100ml). The organic phase was separated and washed with brine and dried over sodium sulphate. The organic extract was evaporated and crystallised from ethanol. Yield 7.2 g( 96 %). M.p. = 112 °C
The identity of the product was verified by 1 H-NMR.
Example 5. trans-(+/-)-4-Acetoxyphenyl- 7-methoxy-2,2-dimethyl-3-phenylchromane
trans-(+/-)-4-Hydroxyphenyl- 7-methoxy-2,2-dimethyl-3-phenylchromane ( 3.6g) was dissolved in acetic anhydride (20ml). Triethylamine (4ml) was added and the mixture stirred at ambient temperature overnight. The mixture was evaporated in vacuum. The residue was stirred with water (100 ml). The solid was filtered off and recrystallised from ethanol water. Yield 5.2 g ( 76 %). M.p.= 192 °C.
The identity of the product was verified by "Η-NMR. 22 Example 6. trans-(+ -4-Hexanoyloxyphenyl-7-methoxy-2.2-dimethyl-3-phenylchromane
trans-(+/-)-4-Hydroxyphenyl- 7-methoxy-2,2-dimethyl-3-phenylchromane (7.2g) was dissol- ved in tetrahydrofuran (20ml). Triethylamine (8ml) and hexanoyl chloride (5.4g) was added and the mixture stirred at ambient temperature overnight. The mixture was poured into water and extracted with ethyl acetate (100ml). The organic phase was separated and washed with 10 % sodium bicarbonate solution and dried over sodium sulphate. The organic extract was evaporated to an heavy oil and crystallised from light petroleum. Yield 5.5g ( 69 %).M.p. = 95 °C
The identity of the product was verified by 1 H-NMR.
Example 7. trans-(+/-)-4-Ethoxycarbonyloxyphenyl-7-methoxy-2.2-dimethyl-3-phenylchromane
trans-(+/-)-4-Hydroxyphenyl- 7-methoxy-2,2-dimethyl-3-phenylchromane (7.2g) was dissolved in tetrahydrofuran (30ml). Triethylamine (4.2ml) and ethyl chloroformate (3.8 ml) was added and the mixture stirred at ambient temperature overnight. The mixture was poured into ice water and extracted with ethyl acetate (100ml). The organic phase was separated and washed with brine and dried over sodium sulphate. The organic extract was evaporated and crystallised from ethanol. Yield 7.4 g( 99 %). M.p. = 150 °C
The identity of the product was verified by 1 H-NMR.
Example 8 cis-3R.4S-7-Methoxy -3-phenyl 4-{4-[2-(pyrrolidin-1 -yl)ethoxy]phenyl}chromane.
cis-3R,4S-4-(4-Hydroxyphenyl)-7-methoxy-3-phenylchromane synthesised in an enzymatic hydrolysis of cis-(+/-)-4-acetoxyphenyl-7-methoxy-2,2-dimethyl-3-phenylchromane (500mg) in hexane was isolated from cis-3S,4R-4-(4-acetoxyphenyl)-7-methoxy-3-phenylchromane in the hydrolysis mixture by crystallisation at -18 °C.
The product was dissolved in acetone (20ml) and refluxed overnight with potassium carbonate and chloroethylpyrrolidine hydrochloride (300mg). The reaction mixture was partitioned 23 between water and toluene. The organic phase was separated, dried over potassium carbonate and evaporated to an oil.
The product was identified on HPCE as cis-3R,4S-7-methoxy -3-phenyl 4-{4-[2-(pyrrolidin-1- yl)ethoxy]phenyl}chromane which is the precursor to levormeloxifene.
Example 9
(-)-trans-7-Methoxy-2.2-dimethyl-3-phenyl-4-{4-[2-(pyrrolidin-1-yhethoxy]phenyl}chromane hydrogenfumarate
(-)-cis-7-Methoxy-2,2-dimethyl-3-phenyl-4-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}chromane (-)- O,0'-ditoluoyltartrate (66.3 g) (or the basic compound: (-)-cis-7-Methoxy-2,2-dimethyl-3- phenyl-4-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}chromane in an amount corresponding to the chiral (-)-0,0'-ditoluoyltartrate salt) was suspended in a mixture of toluene (330 ml), water (265 ml) and sodium carbonate (20.8 g). The mixture was stirred until ail salts have dissolved. The aqueous phase was separated and extracted with another portion of toluene (65 ml). The combined organic phase was washed with water (3x130 ml). The organic phase was dried by removal of water in an azeotropic distillation. To the dry toluene solution was added dimethylsulfoxide (66 ml) and finely grinded potassium hydroxide (15.4 g). The mix- ture was heated to reflux while water was distilled from the mixture. The reflux was maintained for 6 hours. The reaction mixture was cooled down to room temperature, water ( 200 ml) was added and the mixture stirred until all the salt was dissolved. The aqueous phase was separated and extracted with another portion of toluene (135 ml). The organic phases were pooled washed with water (2x200 ml) and evaporated to an oil. The oil was dissolved in ethanol (135 ml) at 40 °C and mixed with a solution of fumaric acid (9.1 g) in ethanol (265 ml) at 40 - 60 °C. The mixture was stirred for 2 hours at ambient temperature and then for 1 hour at 0 °C. The crystals were filtered off and dried.
By Chiral HPLC the enantiomeric purity was determined to be better than 99.5 % and the identity to be hydrogen fumarate salt of levormeloxifene, i.e. the minus enantiomer of the racemic compound Centchroman. Chiral HPLC system: Column: Chiradex 5 , 250x4 mm(Merck). Eluent: 70 % methanol/buffer (0.25 % triethylammonium acetate, pH = 5.2). Yield 43 g (85 %), m.p. 220 °C with slight decomposition. The structure of the compound was verified by "Η-NMR and elemental analysis. 24 Example 10 Cis-3R,4S-4-(4-Hydroxyphenyl)-7-methoxy-3-phenylchromane
500 mg cis-(+/-)-4-acetoxyphenyl-7-methoxy-2,2-dimethyl-3-phenylchromane dissolved in 200 ml n-hexane was added to 50 ml buffer/enzyme suspension consisting of 550 mg Candida cyiindracea Lipase (EC3.1.1.3, 2.3 U/mg, Fluka) and 50 ml 50 mM fosphate buffer pH 7.0. The suspension was stirred with a magnet (450 rounds/minute) for 206 minuttes. The organic phase was dryed with magnesium sulphate. Chiral CE analysis showed that the conversion was app. 60 % with an ee = 69 % for the title product.
Cis-3R,4S-4-(4-Hydroxyphenyl)-7-methoxy-3-phenylchromane was isolated from cis-3S,4R- 4-(4-acetoxyphenyl)-7-methoxy-3-phenylchromane in the hydrolysis mixture by crystallisation at -18 °C.
The CE system was: 5 mM sulfobuthylether-beta-cyclodextrin in 75 mM fosphate buffer, pH 2.5. The capillary was 83.5 cm long and with 50 μm internal diameter. The conditions were - 20 kV/-35 μA, 30°C and samples were injected for 3.0 seconds with 50 mBar. 10 μl samples were taken from the reaction mixture and dilluted in 300 μl acetonitrile plus 300 μl fosphate buffer.

Claims

25 CLAIMS:
A process for the preparation of (-)-3,4-trans-compounds of the formula I
FT
(I)
Figure imgf000027_0001
wherein R1 and R4 are individually hydrogen, C^alkyl or C^alkoxy, R5 is -0-(CH2)n-NR6R7 wherein n is an integer in the range of 1 to 6 and R6 and R7 independently are C1-6alkyl or R6 and R7 together with the N atom is a saturated or unsaturated 5- or 6- membered heterocyclic group containing one or two heteroatom(s) which heterocyclic group is optionally substituted with C1-6alkyl; and R2 and R3 are individually hydrogen or C1-6alkyl; or a salt thereof, which comprises
a) treating a cis-racemate of a compound of formula V
(V)
Figure imgf000027_0002
or a salt thereof, wherein R\ R2 , R3 and R4 are as defined above with an agent of formula R- CO-X, wherein R is C1-12alkyl, optionally substituted with C1-6alkyl, C1-6alkoxy, hetaryl or aryl or C^^alkoxy, optionally substituted with C1-6alkyl, C1-6alkoxy, hetaryl or aryl, and X is a leaving group, thereby providing a cis-racemate of a compound of formula VI 26
(VI)
Figure imgf000028_0001
or a salt thereof, wherein R, R , R , R and R4 are as defined above,
b) treating said cis-racemate of formula VI with an enzyme having lipase activity, thereby providing a mixture comprising a compound of formula Via o
(Via)
Figure imgf000028_0002
or a salt thereof, and a compound of formula VII
OH
(VII)
Figure imgf000028_0003
or a salt thereof; or a mixture comprising a compound of formula Vlb 27
(Vlb)
Figure imgf000029_0001
or a salt thereof, and a compound of formula Vila OH
(Vila)
Figure imgf000029_0002
or a salt thereof,
c) separating said mixture of compound Via and VII or said mixture of compound Vlb and Vila, thereby obtaining a compound of formula VII or a compound of formula Vlb, which compound Vlb is then hydrolyzed to said compound of formula VII,
d) treating said compound of formula VII or a salt thereof, with an agent of formula Y-R5 wherein Y is a leaving group, thereby providing a compound of formula VIII
(VIM)
Figure imgf000029_0003
or a salt thereof, 28 e) treating said compound of formula VIII or a salt thereof with a strong base in an aprotic solvent, thereby obtaining said compound of formula I or a salt thereof.
2. A process for the preparation of (-)-3,4-trans-compounds of the formula I
Figure imgf000030_0001
wherein R1 and R4 are individually hydrogen, C^alkyl or C^alkoxy, R5 is -0-(CH2)n-NR6R7 wherein n is an integer in the range of 1 to 6 and R6 and R7 independently are C^alkyl or R6 and R7 together with the N atom is a saturated or unsaturated 5- or 6- membered heterocyclic group containing one or two heteroatom(s) which heterocyclic group is optionally substituted with C1-6alkyl; and R2 and R3 are individually hydrogen or C1-6alkyl; or a salt thereof, which comprises
a) treating a trans-racemate of a compound of formula II
(ll)
Figure imgf000030_0002
or a salt thereof, wherein R1, R2 , R3 and R4 are as defined above with an agent of formula R- CO-X, wherein R is C1-12alkyl, optionally substituted with C1-6alkyl, C^alkoxy, hetaryl or aryl or C1-12alkoxy, optionally substituted with C1-6alkyl, C^alkoxy, hetaryl or aryl, and X is a leaving group, thereby providing a trans-racemate of a compound of formula III 29
(III)
Figure imgf000031_0001
or a salt thereof, wherein R1, R2 , R3 and R4 are as defined above,
b) treating said trans-racemate of formula III with an enzyme having lipase activity, thereby providing a mixture comprising a compound of formula Ilia
R (Ilia)
Figure imgf000031_0002
or a salt thereof, and a compound of formula IV
OH
(IV)
Figure imgf000031_0003
or a salt thereof; or a mixture comprising a compound of formula lllb 30
(lllb)
Figure imgf000032_0001
or a salt thereof, and a compound of formula IVa OH
(IVa)
Figure imgf000032_0002
or a salt thereof,
c) separating said mixture of compound Ilia and IV or said mixture of compound lllb and IVa, thereby obtaining a compound of formula IV or a compound of formula 1Mb, which compound lllb is then hydrolyzed to said compound of formula IV,
d) treating said compound of formula IV with an agent of formula Y-R5 wherein Y is a leaving group, thereby obtaining the compound of formula I or a salt thereof.
3. The process according to claim 1 or 2, wherein R1 is C,.6alkoxy, R2 and R3 are the same and are C^alkyl, R4 is hydrogen and R5 is -O-(CH2)n-NR6R7 wherein n is 2 and R6 and R7 together with the N atom is a saturated or unsaturated 5- or 6- membered heterocyclic group containing one or two heteroatom(s) and optionally substituted with C1-6alkyl.
4. The process according to any one of claims 1-3 wherein R1 is in the 7-position and R5 is in the 4-position.
5. The process according to any one of claims 1-4 wherein R1 is methoxy . 31
6. The process according to any one of claims 1-5 wherein R2 is methyl.
7. The process according to any one of claims 1-6 wherein R3 is methyl.
8. The process according to any one of claims 1-7 wherein R4 is hydrogen.
9. The process according to any one of claims 1-8 wherein R5 is pyrrolidinoethoxy.
10. The process according to any one of claims 1-9 wherein in said agent of formula R- CO-X, R is C1-12alkyl or C^^alkoxy, and X is a halogen or a -O-CO-C^alkyl.
11. The process according to any one of claims 1-10 wherein said enzyme is a lipase.
12. The process according to any one of claims 1-11 wherein in said agent of formula Y-R5, Y is a halogen.
13. The process according to any one of claims 1-12 wherein said strong base in an aprotic solvent is potassium hydroxide in dimethylsulfoxide and toluene, or potassium t- butoxide in N-methylpyrrolidine and toluene.
14. A process for the preparation of (3R,4S)-cis-compounds of the formula VII
R (VII)
Figure imgf000033_0001
wherein R1 and R4 are individually hydrogen, C1-6alkyl or C.,.6alkoxy, and R2 and R3 are individually hydrogen or C1-6alkyl; or a salt thereof, which comprises
a) treating a cis-racemate of a compound of formula V 32
(V)
Figure imgf000034_0001
or a salt thereof, wherein R1, R2 , R3 and R4 are as defined above with an agent of formula R- CO-X, wherein R is C1-12alkyl, optionally substituted with C1-6alkyl, C1-6alkoxy, hetaryl or aryl or C1-12alkoxy, optionally substituted with C1-6alkyl, C1-6alkoxy, hetaryl or aryl, and X is a leaving group, thereby providing a cis-racemate of a compound of formula VI
(VI)
Figure imgf000034_0002
or a salt thereof, wherein R, R1, R2 , R3 and R4 are as defined above,
b) treating said cis-racemate of formula VI with an enzyme having lipase activity, thereby providing a mixture comprising a compound of formula Via
(Via)
Figure imgf000034_0003
or a salt thereof, and a compound of formula VII 33
(VII)
Figure imgf000035_0001
or a salt thereof; or a mixture comprising a compound of formula Vlb o
(Vlb)
Figure imgf000035_0002
or a salt thereof, and a compound of formula Vila
OH
(Vila)
Figure imgf000035_0003
or a salt thereof,
c) separating said mixture of compound Via and VII or said mixture of compound Vlb and Vila, thereby obtaining a compound of formula VII or a compound of formula Vlb, which compound Vlb is then hydrolyzed to said compound of formula VII.
15. The process according to claim 14 further comprising the step of treating said compound of formula VII or a salt thereof, with an agent of formula Y-R5 wherein Y is a leaving group and R5 is -O-(CH2)n-NR6R7 wherein n is an integer in the range of 1 to 6 and R6 and 34 R7 independently are C1-6alkyl or R6 and R7 together with the N atom is a saturated or unsaturated 5- or 6- membered heterocyclic group containing one or two heteroatom(s) which heterocyclic group is optionally substituted with C1-6alkyl, thereby providing a compound of formula VIII
(VIII)
Figure imgf000036_0001
or a salt thereof.
16. The process according to claim 15 wherein in said agent of formula Y-R5, Y is a halogen.
17. The process according to claim 15 or 16 wherein R5 is pyrrolidinoethoxy.
18. The process according to claim 15 further comprising the step of treating said compound of formula VIII or a salt thereof with a strong base in an aprotic solvent, thereby ob- taining said compound of formula I or a salt thereof.
19. The process according to claim 18 wherein said strong base in an aprotic solvent is potassium hydroxide in dimethylsulfoxide and toluene, or potassium t-butoxide in N- methylpyrrolidine and toluene.
20. The process according to claim 14, wherein R1 is C^alkoxy, R2 and R3 are the same and are C1-6alkyl and R4 is hydrogen.
21. The process according to any one of claims 14 or 20 wherein R1 is in the 7-position and the hydroxy group is in the 4-position.
22. The process according to any one of claims 14, 20 or 21 wherein R1 is methoxy . 35
23. The process according to any one of claims 14, 20, 21 or 22 wherein R2 is methyl.
24. The process according to any one of claims 14, 20, 21 , 22 or 23 wherein R3 is methyl.
25. The process according to any one of claims 14, 20, 21 , 22, 23 or 24 wherein R4 is hydrogen.
26. The process according to any one of claims 14, 20, 21 , 22, 23, 24 or 25 wherein in said agent of formula R-CO-X, R is C1-12alkyl or C^^alkoxy, and X is a halogen or a -O-CO-
C^alkyl.
27. The process according to any one of claims 14, 20, 21 , 22, 23, 24, 25 or 26 wherein said enzyme is a lipase.
28. A process for the preparation of (3R,4R)-trans-compounds of the formula IV
(iv)
Figure imgf000037_0001
wherein R1 and R4 are individually hydrogen, C1-6alkyl or C^alkoxy, and R2 and R3 are indi- vidually hydrogen or Chalky!; or a salt thereof, which comprises
a) treating a trans-racemate of a compound of formula II 36
(II)
Figure imgf000038_0001
or a salt thereof, wherein R1, R2 , R3 and R4 are as defined above with an agent of formula R- CO-X, wherein R is C1-12alkyl, optionally substituted with C^alkyl, C╬╣.6alkoxy, hetaryl or aryl or C1-12alkoxy, optionally substituted with C1-6alkyl, C^alkoxy, hetaryl or aryl, and X is a leaving group, thereby providing a trans-racemate of a compound of formula III
(III)
Figure imgf000038_0002
or a salt thereof, wherein R\ R , R3 and R4 are as defined above,
b) treating said trans-racemate of formula III with an enzyme having lipase activity, thereby providing a mixture comprising a compound of formula Ilia
(Ilia)
Figure imgf000038_0003
or a salt thereof, and a compound of formula IV 37
(IV)
Figure imgf000039_0001
or a salt thereof; or a mixture comprising a compound of formula lllb o
(lllb)
Figure imgf000039_0002
or a salt thereof, and a compound of formula IVa
OH
(IVa)
Figure imgf000039_0003
or a salt thereof,
c) separating said mixture of compound Ilia and IV or said mixture of compound lllb and IVa, thereby obtaining a compound of formula IV or a compound of formula lllb, which compound lllb is then hydrolyzed to said compound of formula IV, or a salt thereof.
29. The process according to claim 28 further comprising the step of treating said compound of formula IV with an agent of formula Y-R5 wherein R5 is -O-(CH2)n-NR6R7 wherein n is an integer in the range of 1 to 6 and R6 and R7 independently are C.,.6alkyl or R6 and R7 38 together with the N atom is a saturated or unsaturated 5- or 6- membered heterocyclic group containing one or two heteroatom(s) which heterocyclic group is optionally substituted with C1-6alkyl and Y is a leaving group, thereby obtaining the compound of formula I or a salt thereof.
30. The process according to claim 29 wherein in said agent of formula Y-R5, Y is a halogen.
31. The process according to any one of claims 29 or 30 wherein R5 is pyrrolidinoet- hoxy.
32. The process according to claim 28, wherein R1 is C^alkoxy, R2 and R3 are the same and are C^aikyl and R4 is hydrogen.
33. The process according to any one of claims 28 or 32 wherein R1 is in the 7-position and the hydroxy group is in the 4-position.
34. The process according to any one of claims 28, 32 or 33 wherein R1 is methoxy .
35. The process according to any one of claims 28, 32, 33 or 34 wherein R2 is methyl.
36. The process according to any one of claims 28, 32, 33, 34 or 35 wherein R3 is methyl.
37. The process according to any one of claims 28, 32, 33, 34, 35 or 36 wherein R4 is hydrogen.
38. The process according to any one of claims 28, 32, 33, 34, 35, 36 or 37 wherein in said agent of formula R-CO-X, R is C1-12alkyl or C^^alkoxy, and X is a halogen or a -O-CO- C^alkyl.
39. The process according to any one of claims 28, 32, 33, 34, 35, 36, 37 or 38 wherein said enzyme is a lipase.
PCT/DK1999/000231 1998-04-28 1999-04-27 Enzymatic resolvation for obtaining a (-)-3,4-trans-diarylchroman WO1999055898A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP2000546041A JP2002512807A (en) 1998-04-28 1999-04-27 (-)-3.4 Enzymatic resolution to obtain trans-diarylchromans
EP99915517A EP1073762A1 (en) 1998-04-28 1999-04-27 Enzymatic resolvation for obtaining a (-)-3,4-trans-diarylchroman
AU34077/99A AU3407799A (en) 1998-04-28 1999-04-27 Enzymatic resolvation for obtaining a (-)-3,4-trans-diarylchroman

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DK0579/98 1998-04-28
DK57998 1998-04-28

Publications (1)

Publication Number Publication Date
WO1999055898A1 true WO1999055898A1 (en) 1999-11-04

Family

ID=8095166

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/DK1999/000231 WO1999055898A1 (en) 1998-04-28 1999-04-27 Enzymatic resolvation for obtaining a (-)-3,4-trans-diarylchroman

Country Status (4)

Country Link
EP (1) EP1073762A1 (en)
JP (1) JP2002512807A (en)
AU (1) AU3407799A (en)
WO (1) WO1999055898A1 (en)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005035517A1 (en) * 2003-10-14 2005-04-21 Council Of Scientific And Industrial Research (3r, 4r)-trans-3,4-diarylchroman derivatives with estrogenic activity
US7601855B2 (en) 2004-09-21 2009-10-13 Novogen Research Pty Ltd Substituted chroman derivatives, medicaments and use in therapy
US8080675B2 (en) 2004-09-21 2011-12-20 Marshall Edwards, Inc. Chroman derivatives, medicaments and use in therapy
US9663484B2 (en) 2010-11-01 2017-05-30 Mei Pharma, Inc. Isoflavonoid compounds and methods for the treatment of cancer
US10980774B2 (en) 2015-02-02 2021-04-20 Mei Pharma, Inc. Combination therapies

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4447622A (en) * 1981-09-22 1984-05-08 Council Of Scientific And Industrial Research Rafi Marg Preparation of l- and d-isomers of dl-3,4-trans-2,2-disubstituted-3,4-diarylchromans and derivatives thereof
US5089637A (en) * 1990-03-21 1992-02-18 Pfizer Inc. Process and intermediates for 2r-benzyl-chroman-6-carbaldehyde
JPH0767690A (en) * 1993-09-03 1995-03-14 Amano Pharmaceut Co Ltd Production of coumarone derivative
JPH0884598A (en) * 1994-09-16 1996-04-02 Kuraray Co Ltd Method for producing optically active chromane compound

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4447622A (en) * 1981-09-22 1984-05-08 Council Of Scientific And Industrial Research Rafi Marg Preparation of l- and d-isomers of dl-3,4-trans-2,2-disubstituted-3,4-diarylchromans and derivatives thereof
US5089637A (en) * 1990-03-21 1992-02-18 Pfizer Inc. Process and intermediates for 2r-benzyl-chroman-6-carbaldehyde
JPH0767690A (en) * 1993-09-03 1995-03-14 Amano Pharmaceut Co Ltd Production of coumarone derivative
JPH0884598A (en) * 1994-09-16 1996-04-02 Kuraray Co Ltd Method for producing optically active chromane compound

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005035517A1 (en) * 2003-10-14 2005-04-21 Council Of Scientific And Industrial Research (3r, 4r)-trans-3,4-diarylchroman derivatives with estrogenic activity
US9198895B2 (en) 2004-09-21 2015-12-01 Mei Pharma, Inc. Chroman derivatives, medicaments and use in therapy
US8084628B2 (en) 2004-09-21 2011-12-27 Marshall Edwards, Inc. Substituted chroman derivatives, medicaments and use in therapy
US9381186B2 (en) 2004-09-21 2016-07-05 Mei Pharma, Inc. Substituted chroman derivatives, medicaments and use in therapy
US8461361B2 (en) 2004-09-21 2013-06-11 Marshall Edwards, Inc. Chroman derivatives, medicaments and use in therapy
US8697891B2 (en) 2004-09-21 2014-04-15 Marshall Edwards, Inc. Substituted chroman derivatives, medicaments and use in therapy
US8957109B2 (en) 2004-09-21 2015-02-17 Mei Pharma, Inc. Chroman derivatives, medicaments and use in therapy
US9138478B2 (en) 2004-09-21 2015-09-22 Mei Pharma, Inc. Substituted chroman derivatives, medicaments and use in therapy
US7601855B2 (en) 2004-09-21 2009-10-13 Novogen Research Pty Ltd Substituted chroman derivatives, medicaments and use in therapy
US8080675B2 (en) 2004-09-21 2011-12-20 Marshall Edwards, Inc. Chroman derivatives, medicaments and use in therapy
US11723893B2 (en) 2010-11-01 2023-08-15 Mei Pharma, Inc. Isoflavonoid compositions and methods for the treatment of cancer
US9708283B2 (en) 2010-11-01 2017-07-18 Mei Pharma, Inc. Isoflavonoid compositions and methods for the treatment of cancer
US9981936B2 (en) 2010-11-01 2018-05-29 Mei Pharma, Inc. Isoflavonoid compositions and methods for the treatment of cancer
US10105346B2 (en) 2010-11-01 2018-10-23 Mei Pharma, Inc. Isoflavonoid compounds and methods for the treatment of cancer
US10369132B2 (en) 2010-11-01 2019-08-06 Mei Pharma, Inc. Isoflavonoid compositions and methods for the treatment of cancer
US10973799B2 (en) 2010-11-01 2021-04-13 Mei Pharma, Inc. Isoflavonoid compositions and methods for the treatment of cancer
US11583514B2 (en) 2010-11-01 2023-02-21 Mei Pharma, Inc. Isoflavonoid compounds and methods for the treatment of cancer
US9663484B2 (en) 2010-11-01 2017-05-30 Mei Pharma, Inc. Isoflavonoid compounds and methods for the treatment of cancer
US10980774B2 (en) 2015-02-02 2021-04-20 Mei Pharma, Inc. Combination therapies

Also Published As

Publication number Publication date
EP1073762A1 (en) 2001-02-07
AU3407799A (en) 1999-11-16
JP2002512807A (en) 2002-05-08

Similar Documents

Publication Publication Date Title
JP5006499B2 (en) Method for producing 2- (6-substituted-1,3-dioxan-4-yl) acetic acid derivative
EP0864569B1 (en) Process for manufacturing simvastatin from lovastatin or mevinolinic acid
WO1998018770A1 (en) A process for the preparation of (-)-3,4-trans-diarylchromans
KR20220084102A (en) Acyloxy of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid Method for preparing methyl ester
KR100669823B1 (en) Process for Preparing 2-4-Chlorobenzoylamino-3-[21?- quinolinon-4-yl]propionic acid and intermediate thereof
SK282909B6 (en) Key intermediates in the manufacture of simvastatin
EP1073762A1 (en) Enzymatic resolvation for obtaining a (-)-3,4-trans-diarylchroman
JP4142444B2 (en) Method for producing 2-azetidinone derivative
RU2124506C1 (en) Method of stereoselective synthesis of heterobicyclic alcohol enantiomer, pure alcohol enantiomer, method of synthesis of piperazine derivative
US6184005B1 (en) Enzymatic resolvation for obtaining a (−)-3,4-trans-diarylchroman
JPH04234871A (en) Process for preparing 2r-benzylchroman-6- carbaldehyde and intermediate therefor
JP4783998B2 (en) Preparation of (3R, 5S) -7-substituted-3,5-dihydroxyhept-6-enoic acid
AU2001230192B2 (en) Method for the enzymatic resolution of the racemates of aminomethyl-aryl-cyclohexanol derivatives
KR20010066863A (en) Process for producing erythro-3-amino-hydroxybutyric acid derivatives
US7067305B2 (en) Enzymatic process for the resolution for enantiomeric mixtures of β-lactams
US5925771A (en) Process for the preparation of (-)-3,4-trans-diarylchromans
KR19980069782A (en) Methods for preparing simvastatin from lovastatin or mesylonic acid
JP2007521801A (en) Method for producing stereoisomerically enhanced amine
KR20070076549A (en) Processes for the preparations of optically active cyclopentenones and cyclopentenones prepared therefrom
US5661014A (en) Chiral compounds and their resolution synthesis using enantioselective esterases
US5070022A (en) Enzymic process for preparing leukotriene antagonists
HU213569B (en) Enzymatic process for the stereoselective preparation of a heterobicyclic alcohol enantiomer
JP2002533327A (en) Use of an alkyl ester of 3- (3,4-dihalophenyl) -2,6-dioxopiperidine-3-propionic acid as an intermediate
JPH0466471B2 (en)

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SL SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 1999915517

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: KR

WWP Wipo information: published in national office

Ref document number: 1999915517

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

NENP Non-entry into the national phase

Ref country code: CA

WWW Wipo information: withdrawn in national office

Ref document number: 1999915517

Country of ref document: EP