WO1999002513A1 - Preparation of diaryl-benzopyrans - Google Patents

Preparation of diaryl-benzopyrans Download PDF

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Publication number
WO1999002513A1
WO1999002513A1 PCT/DK1998/000302 DK9800302W WO9902513A1 WO 1999002513 A1 WO1999002513 A1 WO 1999002513A1 DK 9800302 W DK9800302 W DK 9800302W WO 9902513 A1 WO9902513 A1 WO 9902513A1
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Prior art keywords
optically active
acid
diaryl
phenyl
carbon atoms
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Application number
PCT/DK1998/000302
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French (fr)
Inventor
Kanchan Hajela
Jaya Pandey
Janak Dulari Dhar
Suprabhat Ray
Virender Mohan Labroo
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Novo Nordisk A/S
Central Drug Research Institute
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Application filed by Novo Nordisk A/S, Central Drug Research Institute filed Critical Novo Nordisk A/S
Priority to AU81024/98A priority Critical patent/AU8102498A/en
Publication of WO1999002513A1 publication Critical patent/WO1999002513A1/en

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    • 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
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/60—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with aryl radicals attached in position 2

Definitions

  • This invention relates to a process for the preparation of optically active 2,3- diaryl-2H-1-benzopyrans and its derivatives useful as contraceptives.
  • the present invention particularly relates to the resolution of d- and l-enantiomers of dl-2,3-diaryl- 2H-1-benzopyrans and its derivatives of the general formula 1 of the drawing accompanying this specification wherein R and R 2 which may be the same or different are each H, OH, linear or branched chain alkyl or alkoxy of 1 to 17 carbon atoms, linear or branched chain acyloxy of 2 to 18 carbon atoms or a halide group and R 3 is a tertiary amino alkoxy group such as O(CH 2 ) n NR 4 R 5 wherein R 4 and R 5 are the same or different, linear or branched chain alkyl substituents of 1-18 carbon atoms or a cy- clised ring containing 2-10 carbon atoms containing the N atom
  • 2,3-Diaryl-2H-1-benzopyrans have recently emerged as a novel group of non-steroidal compounds which are anti-estrogenic and possess significant activity against egg implantation and breast cancer (see Kapil et al., U.S. Pat. No. 5,254,568 dt. Oct. 19, 1993; Saeed et al., J. Med. Chem., 33, 3210-3216, 1990; Sharma et al., J. Med. Chem., 33, 3216-3222, 3222-3229, 1990).
  • the main object of the present invention is to provide a process for the preparation of optically active 2,3-diaryl-2H-1-benzopyrans and its derivatives into optically active d- and l-enantiomers, useful as contraceptives.
  • Another object of the present invention is to provide a simple and high yield process for the preparation of optically active isomers from the racemic mixture.
  • the present invention provides a process for the preparation of optically active 2,3-diaryl-2H-1-benzopyrans and its derivatives which comprises reacting a racemic 2,3-diaryl-2H-1-benzopyran derivative of general formula 1 of the drawing accompanying this specification wherein R 1 and R 2 which may be the same or different are each H, OH, linear or branched chain alkyl or alkoxy of 1 to 17 carbon atoms, linear or branched chain acyloxy of 2 to 18 carbon atoms or a halide group and R 3 is a tertiary amino alkoxy group such as O(CH 2 ) n NR 4 R 5 wherein R 4 and R 5 are the same or different, linear or branched chain alkyl substituents of 1-18 carbon atoms or a cyclised ring containing 2-10 carbon atoms containing the N atom with an optically active acid in a protic solvent for a period of 0.5 to 12 hrs., evaporating the excess
  • R 1 being H or (ii) R 1 and R 2 each being an acyl, alkyl, alkoxy or a halide group and R 3 is preferably a 2- piperidinoethoxy group.
  • the optically active acid used may be di-p-toluoyl-l-tartaric acid, di-p-toluoyl-d-tartaric acid, dibenzoyl-l-tartaric acid, dibenzoyl-d-tartaric acid, (1 S)-(+)-10-camphorsulphonic acid, (1 R)-(-)-10- camphorsulphonic acid.
  • the protic solvent used may be such as methanol, ethanol, isopropanol.
  • the enantiomers of a chiral drug can differ in their biological activity, pharmacokinetically and/or pharmacodynamically, there is considerable interest in the resolution of such molecules into their pure enantiomeric forms.
  • 3-diaryl-2H-1 -benzopyran and its derivatives evince potent anti-estrogenic, anti-implantation, anti-breast cancer, anti-osteoporosis and serum cholesterol lowering activities, the applicants have effected additional research by effecting the resolution of racemic compound into its optically active laevo (I) and dextro (d) isomeric forms.
  • the achieved compounds particularly the l-isomers exhibit increased anti-implantation an antiestrogenic activities over the known dl-isomer.
  • the novel l-2-(4-(2-(1 -piperidino)ethoxy)phenyl)-3-phenyl-2H-1 -benzopyran was found to be two fold more active as an antifertility agent in female albino rats as compared to the corresponding dl-compound in a single day post-coital oral administration schedule.
  • the corresponding d-enantiomer was found to be inactive as an antifertility agent at an equivalent dose.
  • Example III d-2-(4-(2-(1 -Piperidino)ethoxy)pheny l)-3-pheny I-2H-1 -benzopyran di-p-toluoy l-d- tartrate dl-2-(4-(2-(1-Piperidino)ethoxy)phenyl)-3-phenyl-2H-1 -benzopyran of the general formula 1 (411 mg) and di-p-toluoyl-d-tartararic acid monohydrate in 1 :1 equivalent molar ratio were dissolved by warming in distilled ethanol and the mixture stirred for 3 hrs.
  • Example V l_2-(4-(2-( 1 -Piperidino)ethoxy)phenyl-3-(4-methoxypheny l)-2H-1 -benzopyran di- p-toiouiyl-l-tartrate dl-2-(4-(2-(1 -Piperidino)ethoxy)phenyl-3-(4-methoxyphenyl)-2H-1 -benzopyran of the general formula I and di-p-toloulyl-l-tartaric acid in 1 :1 equivalent molar ratio were dissolved by warming in distilled ethanol and the mixture stirred for 3 hrs.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The present invention relates to a process for the preparation of optically active 2,3-diaryl-2H-1-benzopyrans. The compouds are useful in the prevention or treatment of estrogen related diseases or syndromes.

Description

Preparation of diaryl-benzopyrans
This invention relates to a process for the preparation of optically active 2,3- diaryl-2H-1-benzopyrans and its derivatives useful as contraceptives. The present invention particularly relates to the resolution of d- and l-enantiomers of dl-2,3-diaryl- 2H-1-benzopyrans and its derivatives of the general formula 1 of the drawing accompanying this specification wherein R and R2 which may be the same or different are each H, OH, linear or branched chain alkyl or alkoxy of 1 to 17 carbon atoms, linear or branched chain acyloxy of 2 to 18 carbon atoms or a halide group and R3 is a tertiary amino alkoxy group such as O(CH2)nNR4R5 wherein R4 and R5 are the same or different, linear or branched chain alkyl substituents of 1-18 carbon atoms or a cy- clised ring containing 2-10 carbon atoms containing the N atom, useful as contraceptives, in the treatment and prophylaxis of breast cancer, osteoporosis, hypercho- lesteremia, endometriosis, vasoconstriction and endometrial disorders.
2,3-Diaryl-2H-1-benzopyrans have recently emerged as a novel group of non-steroidal compounds which are anti-estrogenic and possess significant activity against egg implantation and breast cancer (see Kapil et al., U.S. Pat. No. 5,254,568 dt. Oct. 19, 1993; Saeed et al., J. Med. Chem., 33, 3210-3216, 1990; Sharma et al., J. Med. Chem., 33, 3216-3222, 3222-3229, 1990). They have also been shown to be effective in the treatment of bone loss due to osteoporosis and other conditions, including post-menopausal osteoporosis and glucocorticoid-related osteoporosis, Paget's disease, hyperparathyroidism, hypercalcemia of malignancy and other conditions characterised by excessive rates of bone resorption and/or decreased rates of bone formation (see Labroo et al., U.S. Pat. No. 5,389,646 dt. Feb. 14, 1995). Further, they are also useful for lowering serum cholesterol (see Eli Lilly & Company, Eur. Pat. No. 0,652,006 A1 dt. Nov. 2, 1994). Indian Patent Appl. Nos. 173335, 173336, 173337 and 1141/DEL/91 describe the process for the preparation of dl-2,3- diaryl-2H-1-benzopyran and derivatives thereof. The main object of the present invention is to provide a process for the preparation of optically active 2,3-diaryl-2H-1-benzopyrans and its derivatives into optically active d- and l-enantiomers, useful as contraceptives.
Another object of the present invention is to provide a simple and high yield process for the preparation of optically active isomers from the racemic mixture.
Accordingly, the present invention provides a process for the preparation of optically active 2,3-diaryl-2H-1-benzopyrans and its derivatives which comprises reacting a racemic 2,3-diaryl-2H-1-benzopyran derivative of general formula 1 of the drawing accompanying this specification wherein R1 and R2 which may be the same or different are each H, OH, linear or branched chain alkyl or alkoxy of 1 to 17 carbon atoms, linear or branched chain acyloxy of 2 to 18 carbon atoms or a halide group and R3 is a tertiary amino alkoxy group such as O(CH2)nNR4R5 wherein R4 and R5 are the same or different, linear or branched chain alkyl substituents of 1-18 carbon atoms or a cyclised ring containing 2-10 carbon atoms containing the N atom with an optically active acid in a protic solvent for a period of 0.5 to 12 hrs., evaporating the excess solvent from the reaction mixture to obtain the compound of general formula 2 wherein R\ R2 and R3 are the same as stated above and X denotes an optically active acid anion, subjecting the said compound of formula 2 to alkaline hydrolysis by known methods to obtain the desired optically active compound. In one preferred embodiment R1 and R2 are each independently H, OH or
C^-alkoxy. Other preferred embodiments include (i) R1 being H or (ii) R1 and R2 each being an acyl, alkyl, alkoxy or a halide group and R3 is preferably a 2- piperidinoethoxy group.
In another embodiment of the present invention the optically active acid used may be di-p-toluoyl-l-tartaric acid, di-p-toluoyl-d-tartaric acid, dibenzoyl-l-tartaric acid, dibenzoyl-d-tartaric acid, (1 S)-(+)-10-camphorsulphonic acid, (1 R)-(-)-10- camphorsulphonic acid.
In still another embodiment of the invention the protic solvent used may be such as methanol, ethanol, isopropanol. With the increasing appreciation that the enantiomers of a chiral drug can differ in their biological activity, pharmacokinetically and/or pharmacodynamically, there is considerable interest in the resolution of such molecules into their pure enantiomeric forms. As 2, 3-diaryl-2H-1 -benzopyran and its derivatives evince potent anti-estrogenic, anti-implantation, anti-breast cancer, anti-osteoporosis and serum cholesterol lowering activities, the applicants have effected additional research by effecting the resolution of racemic compound into its optically active laevo (I) and dextro (d) isomeric forms. The achieved compounds particularly the l-isomers exhibit increased anti-implantation an antiestrogenic activities over the known dl-isomer.
The novel l-2-(4-(2-(1 -piperidino)ethoxy)phenyl)-3-phenyl-2H-1 -benzopyran was found to be two fold more active as an antifertility agent in female albino rats as compared to the corresponding dl-compound in a single day post-coital oral administration schedule. The corresponding d-enantiomer was found to be inactive as an antifertility agent at an equivalent dose.
The process of the present invention is described herein below with reference to examples which are illustrative only and should not be construed to limit the scope of the present invention in any manner.
Example I
l-2-(4-(2-(1-Piperidino)ethoxy)phenyl)-3-phenyl-2H-1 -benzopyran di-p-toluoyl-l- tartrate dl-2-(4-(2-(1 -piperidino)ethoxy)phenyl)-3-phenyl-2H-1 -benzopyran of the general formula 1 (411 mg) and di-p-toluoyl-l-tartaric acid in 1:1 equivalent molar ratio were dissolved by warming in distilled ethanol and the mixture stirred for 3 hrs. Excess of ethanol was removed and the residue allowed to stand overnight to get the crystals of l-2-(4-(2-(1 -piperidino)ethoxy)phenyl)-3-phenyl-2H-1 -benzopyran di-p-toluoyl-l- tartrate, m.p.126°C, [α]20 D= -72.2 (c 1 in EtOH), yield, 120 mg.
Example II
l-2-(4-(2-(1 -Piperidino)ethoxy)phenyl)-3-phenyl-2H-1 -benzopyran The l-2-(4-(2-(1 -piperidino)ethoxy)phenyl)-3-phenyl-2H-1 -benzopyran di-p-toluoyl-l- tartrate salt (100 mg) obtained from example I was hydrolysed by dissolving it in ethyl acetate and treating it with aqueous alkali (10% NaOH). The organic layer was washed with water to neutral, dried over anhydrous sodium sulphate and concen- trated to yield colorless crystalline l-2-(4-(2-(1-piperidino)ethoxy)phenyl)-3-phenyl-2H- 1 -benzopyran, m.p.75°C, [α]20 D= -34.3 (c 1 in EtOH), yield, 48 mg.
Example III d-2-(4-(2-(1 -Piperidino)ethoxy)pheny l)-3-pheny I-2H-1 -benzopyran di-p-toluoy l-d- tartrate dl-2-(4-(2-(1-Piperidino)ethoxy)phenyl)-3-phenyl-2H-1 -benzopyran of the general formula 1 (411 mg) and di-p-toluoyl-d-tartararic acid monohydrate in 1 :1 equivalent molar ratio were dissolved by warming in distilled ethanol and the mixture stirred for 3 hrs. Excess of ethanol was removed and the residue allowed to stand overnight to get crystals of pure d-2-(4-(2-(1 -piperidino)ethoxy)phenyl)-3-phenyl-2H-1 -benzopyran di-p-toluoyl-d-tartrate as colorless solid, m.p. 132°C, [α]20 D= +72.2 (c 1 in EtOH), yield, 105 mg.
Example IV
d-2-(4-(2-(1-Piperidino)ethoxy)phenyl)-3-phenyl-2H-1-benzopyran
The d-2-(4-(2-(1 -piperidino)ethoxy)phenyl)-3-phenyl-2H-1 -benzopyran di-p-toluoyl-d- tartrate salt (100 mg) obtained from example III was hydrolysed by dissolving the salt in ethyl acetate and treating it with aqueous alkali (10% NaOH). The organic layer was washed with water to neutral, dried over anhydrous sodium sulphate and concentrated to yield colorless crystalline d-2-(4-(2-(1-piperidino)ethoxy)phenyl)-3- phenyl-2H-1 -benzopyran, m.p. 69°C, [α] 0 D= +34.3 (c 1 in EtOH), yield, 45 mg.
Example V l_2-(4-(2-( 1 -Piperidino)ethoxy)phenyl-3-(4-methoxypheny l)-2H-1 -benzopyran di- p-toiouiyl-l-tartrate dl-2-(4-(2-(1 -Piperidino)ethoxy)phenyl-3-(4-methoxyphenyl)-2H-1 -benzopyran of the general formula I and di-p-toloulyl-l-tartaric acid in 1 :1 equivalent molar ratio were dissolved by warming in distilled ethanol and the mixture stirred for 3 hrs. Excess of ethanol was removed and the residue allowed to stand overnight to get the crystals of /-2-(4-(2-(1 -piperidino)ethoxy)phenyl-3-(4-methoxyphenyl)-2H-1 -benzopyran di-p- toloulyl-i-tartrate, m.p.122°C, [α]20 D= -83.9 (c 1 in EtOH).
Example VI
l-2-(4-(2-(1-Piperidino)et oxy)phenyl-3-(4-methoxyphenyl)-2H-1 -benzopyran
The l-2-(4-(2-(1 -piperidino)ethoxy)phenyl-3-(4-methoxyphenyl)-2H-1 -benzopyran di- p-toloulyl-l-tartrate salt obtained from example V was hydrolysed by dissolving it in ethyl acetate and treating it with aqueous alkali. The organic layer was washed with water to neutral, dried over anhydrous sodium sulphate and concentrated to yield colorless crystalline l-2-(4-(2-(1 -piperidino)ethoxy)phenyl-3-(4-methoxyphenyl)-2H-1 - benzopyran, m.p. 92°C, [α]20 D= -40.3 (c 1 in EtOH).
Example VII
d-2-(4-(2-(1 -Piperidino)ethoxy)phenyl-3-(4-methoxyphenyl)-2H-1 -benzopyran di- p-toloulyi-d-tartrate dl-2-(4-(2-(1 -Piperidino)ethoxy)phenyl-3-(4-methoxyphenyl)-2H-1 -benzopyran and di- p-toioulyl-d-tartaric acid monohydrate in 1 :1 equivalent molar ratio were dissolved in ethanol and the mixture stirred for 3 hrs. Excess of ethanol was removed and the residue allowed to stand overnight to get crystals of pure d-2-(4-(2-(1- piperidino)ethoxy)phenyl-3-(4-methoxyphenyl)-2H-1-benzopyran di-p-toloulyl-d- tartrate as colorless solid, m.p. 128°C, [α]20 D= +83.9 (c 1 in EtOH).
Example VIII d-2-(4-(2-(1-Piperidino)ethoxy)phenyl-3-(4-methoxyphenyl)-2H-1-benzopyran
The d-2-(4-(2-(1 -piperidino)ethoxy)phenyl-3-(4-methoxyphenyl)-2H-1 -benzopyran di- p-toloulyl-d-tartrate salt obtained from example VII was hydrolysed by dissolving the salt in ethyl acetate and treating it with aqueous alkali. The organic layer was washed with water to neutral, dried over anhydrous sodium sulphate and concentrated to yield colorless crystals, m.p. 89°C, [α]20 D= +40.3 (c 1 in EtOH).

Claims

Claims
1. A process for the preparation of optically active 2,3-diaryl-2H-1-benzopyrans and its derivatives which comprises reacting a racemic 2,3-diaryl-2H-1 benzopyrene derivative of general formula 1 of the drawing accompanying this specification wherein R1 and R2 which may be the same or different are each H, OH, linear or branched chain alkyl or alkoxy of 1 to 17 carbon atoms, linear or branched chain acyloxy of 2 to 18 carbon atoms or a halide group and R3 is a tertiary amino alkoxy group such as O(CH2)nNR4R5 wherein R4 and R5 are the same or different, linear or branched chain alkyl substituents of 1-18 carbon atoms or a cyclised ring containing 2-10 carbon atoms containing the N atom with an optically active acid in a protic solvent for a period of 0.5 to 12 hrs., evaporating the excess solvent from the reaction mixture to obtain the compound of general formula 2 wherein R\ R2 and R3 are the same as stated above and X denotes an optically active acid anion, subjecting the said compound of general formula 2 to alkaline hydrolysis by known methods to obtain the desired optically active compound.
2. A process as claimed in claim 1 wherein the optically active acid used in the invention is such as di-p-toluoyl-l-tartaric acid, di-p-toluoyl-d-tartaric acid, di-benzoyl- l-tartaric acid, di-benzoyl-d-tartaric acid, (1S)-(+)-10-camphorsulphonic acid, (1 R)- (-)-IO-camphorsulphonic acid.
3. A process as claimed in claims 1 and 2 wherein the protic solvent used for the reaction is, such as methanol, ethanol, propanol or the like.
4. A process as claimed in claims 1 to 3 wherein the alkali used for the hydrolysis is, such as NaOH, KOH or an organic base.
5. A process for the preparation of optically active 2,3-diaryl-2H-1-benzopyrans and its derivatives of the general formula 1 shown in the drawing accompanying this specification as described herein above with reference to the examples.
PCT/DK1998/000302 1997-07-09 1998-07-02 Preparation of diaryl-benzopyrans WO1999002513A1 (en)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6312738B1 (en) * 1997-07-11 2001-11-06 Neem Extracts Pty. Ltd. Azadirachtin extraction process
JP2002522533A (en) * 1998-08-14 2002-07-23 シェーリング コーポレイション Enantioselective synthesis
WO2008134923A1 (en) * 2007-04-28 2008-11-13 Zhejiang Nexchem Pharmaceutical Co., Ltd A preparation method of thiol derivative as side chain intermediate for synthesis of carbapenem derivative
US8703810B2 (en) 2010-06-10 2014-04-22 Seragon Pharmaceuticals, Inc. Estrogen receptor modulators and uses thereof
US9187460B2 (en) 2011-12-14 2015-11-17 Seragon Pharmaceuticals, Inc. Estrogen receptor modulators and uses thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5254568A (en) * 1990-08-09 1993-10-19 Council Of Scientific & Industrial Research Benzopyrans as antiestrogenic agents
WO1996026201A1 (en) * 1995-02-21 1996-08-29 Endorecherche, Inc. Benzopyran-containing compounds and method for their use

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5254568A (en) * 1990-08-09 1993-10-19 Council Of Scientific & Industrial Research Benzopyrans as antiestrogenic agents
WO1996026201A1 (en) * 1995-02-21 1996-08-29 Endorecherche, Inc. Benzopyran-containing compounds and method for their use

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6312738B1 (en) * 1997-07-11 2001-11-06 Neem Extracts Pty. Ltd. Azadirachtin extraction process
JP2002522533A (en) * 1998-08-14 2002-07-23 シェーリング コーポレイション Enantioselective synthesis
WO2008134923A1 (en) * 2007-04-28 2008-11-13 Zhejiang Nexchem Pharmaceutical Co., Ltd A preparation method of thiol derivative as side chain intermediate for synthesis of carbapenem derivative
US8703810B2 (en) 2010-06-10 2014-04-22 Seragon Pharmaceuticals, Inc. Estrogen receptor modulators and uses thereof
US9078871B2 (en) 2010-06-10 2015-07-14 Seragon Pharmaceuticals, Inc. Estrogen receptor modulators and uses thereof
US9187460B2 (en) 2011-12-14 2015-11-17 Seragon Pharmaceuticals, Inc. Estrogen receptor modulators and uses thereof
US9193714B2 (en) 2011-12-14 2015-11-24 Seragon Pharmaceuticals, Inc. Fluorinated estrogen receptor modulators and uses thereof

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