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Enantioeletive synthesis of nonsteroidal antiestrogen

A technology of diastereomers and compounds, applied in the field of anti-estrogen formula I or XIV compound, enantioselective synthesis method, can solve the problems of unsuitable industrial production scale and high cost

Inactive Publication Date: 2004-04-21
MERCK & CO INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, what is disclosed in these documents is a laboratory-scale synthetic method, which includes several steps with relatively high cost, and is not suitable for actual industrial production scale.

Method used

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  • Enantioeletive synthesis of nonsteroidal antiestrogen
  • Enantioeletive synthesis of nonsteroidal antiestrogen
  • Enantioeletive synthesis of nonsteroidal antiestrogen

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0067] Embodiment 1 (step A)

[0068] 2'-Hydroxy-4'-tetrahydropyranyloxy-2-(4"-tetrahydropyranyloxyphenyl)acetophenone

[0069] preparation of

[0070]

[0071] method

[0072] 1. In a 500ml three-necked round bottom flask equipped with a mechanical stirrer, thermometer, nitrogen inlet and condenser, add 2',4'-dihydroxy-2-(4"-hydroxyphenyl)acetophenone (48.85 g, 0.2 mol), 3,4-dihydropyran (Aldrich, 91.24 ml, 1.0 mol) and ethyl acetate (Fisher, 90 ml).

[0073] 2. Add p-toluenesulfonic acid monohydrate "p-tsa" (MCB, 30.4 mg, 0.16 mmol) and blanket the reaction with nitrogen. At this point an exothermic reaction occurred, with the temperature rising from 21°C to about 55°C in about 5 minutes.

[0074] 3. The above reaction was stirred for about 3 hours until conversion of starting material to product was complete. The progress of the reaction can be monitored by TLC or HPLC.

[0075] 4. When the reaction was complete, triethylamine (Aldrich, 1.4...

Embodiment 2

[0081] Embodiment 2 (steps B&C)

[0082] (±)-trans 2-(4”-[2-piperidinylethoxy]phenyl)-3-(4’-tetrahydropyranyloxybenzene

[0083] Base)-7-tetrahydropyranyloxy-2,3-dihydro-4H-1-benzopyran-4-one preparation

[0084]

[0085] method

[0086] 1. Into a 500 ml three necked round bottom flask equipped with a mechanical stirrer, thermometer, nitrogen inlet and condenser (with receiving device such as a Dean-Stark trap), add 4-(2'-piperidinylethoxy ) benzaldehyde (36.75 g, 0.158 mol) and 160 ml of (±)-2-butanol (from Fischer Scientific).

[0087] 2. Add 2'-hydroxy-4'-tetrahydropyranyloxy-(4-tetrahydropyranyloxy-phenyl)acetophenone (61.87g, 0.15mol) prepared according to Example 1, Piperidine (Aldrich, 99% pure, 4.26 g, 0.05 mol) and diazabicyclo[5,4,0]undec-7-ene ("DBU') (from Aldrich, 97%, 7.61 g, 0.05mol), and then cover the reactant with dry nitrogen.

[0088] 3. The resulting reaction mixture was heated to reflux (98° C.) with stirring at atmospheric pressure.

[0089] 4....

Embodiment 3

[0095] Example 3 (steps D and E)

[0096] (2R,S)-7-Hydroxy-3-(4’-hydroxyphenyl)-4-methyl-2-(4”-[2-piperidinylethoxy]

[0097] Phenyl)-2H-1-benzopyran

[0098] Preparation of (S)-(+)-camsylate

[0099]

[0100] method

[0101] 1. Into a 1 L three-neck round bottom flask equipped with a mechanical stirrer, thermometer, nitrogen inlet and addition funnel, add (±)-trans-2-(4”-[2-piperidinyl from Example 2 Ethoxy]phenyl)-3-(4'-tetrahydropyranyloxyphenyl)-7-tetrahydropyranyloxy-2,3-dihydro-4H-1-benzopyran -4-Kone (50.0 g, 0.0796 mol).

[0102] 2. Add tert-butyl methyl ether (250ml) and blanket the reaction with dry nitrogen.

[0103] 3. Cool the resulting suspension to 0°C with stirring.

[0104] 4. A solution of 8% methyllithium in diethoxymethane (75.1 ml, 0.263 mol, 3.3 equiv) was added to the flask over a period of 30 minutes while maintaining the temperature of the reaction mixture below 5°C.

[0105] 5. The reaction mixtu...

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Abstract

The present invention provides a short practical commercial process for the efficient enantioselective synthesis of the non-steroidal antiestrogen of formula (I) or (XIV) or a pharmaceutically acceptable salt thereof.

Description

technical field [0001] The present invention relates to a brief and efficient enantioselective synthesis of an orally active antiestrogenic compound of formula I or XIV or a pharmaceutically acceptable salt thereof [0002] Background technique [0003] Formula I compound, namely (S)-7-hydroxyl-3-(4'-hydroxyphenyl)-4-methyl-2-(4"-[2''-(1-piperidino)-ethoxy Base] phenyl)-2H-benzopyran-4', the synthesis method of 7-bistrimethyl acetate and its antiestrogenic activity in J. Med Chem., 1997, 40 , 2117-2122 were introduced. See also U.S. Patent Nos. 5,395,842 and 5,407,947 and J. Med. Chem., 1990, 33 , 3216-3222. However, all of the synthetic methods disclosed in these documents are laboratory-scale synthesis methods, which include several steps with relatively high cost, and are not suitable for actual industrial production scale. [0004] Therefore, there is a need for short, efficient, enantioselective syntheses suitable for large-scale productio...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D311/04A61K31/352A61P5/32C07B57/00C07B61/00C07D311/26C07D311/60
CPCC07D311/26C07D311/60A61P5/32
Inventor R·W·德拉佩尔R·V·伊耶尔Y·卢E·J·瓦特尔
Owner MERCK & CO INC
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