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Method for synthesizing 1R,2R,3R-substituted cyclopentanone compound

A synthesis method and compound technology, which is applied in the field of synthesis of 1R, 2R, 3R-substituted cyclopentanone compounds, can solve the problems of low diastereoselectivity, difficulty in industrialization, and low purity of products, and achieve diastereometry. High selectivity, easy reaction control, and high product purity

Inactive Publication Date: 2018-09-07
GUANGZHOU KAIMO BIOTECH CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In the document J.Am.Chem.SOC.1988,110,4718-4126, the synthesis process of alprostadil is described, and the preparation of its intermediate 1R, 2R-alkyl substituted-3R-alkoxy substituted cyclopentanone is obtained from The yield is very low, the diastereoselectivity is low, the product purity is not high, it is difficult to realize industrialization

Method used

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  • Method for synthesizing 1R,2R,3R-substituted cyclopentanone compound
  • Method for synthesizing 1R,2R,3R-substituted cyclopentanone compound
  • Method for synthesizing 1R,2R,3R-substituted cyclopentanone compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] The synthesis of embodiment 1 prostaglandin E1 (compound 5b)

[0042]

[0043] (1) Synthesis of compound 3b

[0044]

[0045] Under the protection of argon, cuprous iodide (0.50g, 5.65mmol) was added to a dry round bottom flask, tetrahydrofuran (3ml) was added, it was cooled to -78°C, tert-butyllithium was added dropwise Alkane solution (4.2ml, 6.78mmol), stirred for 2h, and slowly heated to 40°C for 30 minutes to obtain the first reaction solution, which was set aside.

[0046] Under the protection of argon at -78°C, add n-butyl lithium in n-hexane (4.2ml, 6.78mmol) dropwise to a solution of compound 2b (2.08g, 5.65mmol) in tetrahydrofuran (3ml), and stir at -78°C 2 hours; then slowly add the first reaction solution dropwise into the reaction system, react at -78°C for 2 hours, then raise the temperature to 40°C and react for 30 minutes, then cool down to -78°C to obtain the second reaction solution, ready for use .

[0047]Under the protection of argon at -78...

Embodiment 2

[0054] Synthesis of Example 2 Limatoprost Analog (Compound 5c)

[0055]

[0056] (1) Synthesis of compound 3c

[0057]

[0058] Replace 2b in Example 1 with 2c, and its synthesis method is the same as step (1) in Example 1. Yield, 82%. 1 HNMR (CDCl 3 ,400MHz):5.68(dd,J=15.6and 5.2Hz,1H),5.55(dd,J=15.6,7.6Hz,1H),4.15-4.05(m,2H),3.68(s,3H),2.65( dd, J=18.4and 6.8Hz, 1H), 2.46(m, 1H), 2.28(t, J=7.6Hz, 2H), 2.21(dd, J=18.4and 8.0Hz, 1H), 1.93(m, 2H ), 1.63–1.26(m,17H), 0.91-0.89(m,24H), 0.01(s,12H). MS (m / z): 642 (M+1). de>96%.

[0059] (2) Synthesis of compound 4c

[0060]

[0061] Use 3c to replace 3b in Example 1, and its synthesis method is the same as step (2) in Example 1. Yield, 95%. 1 HNMR (CDCl 3 ,400MHz):5.67(dd,J=15.6and 5.2Hz,1H),5.54(dd,J=15.6,7.6Hz,1H),4.15-4.05(m,2H),2.63(dd,J=18.4and 6.8 Hz, 1H), 2.45(m, 1H), 2.27(t, J=7.6Hz, 2H), 2.20(dd, J=18.4and 8.0Hz, 1H), 1.92(m, 2H), 1.62–1.26(m ,17H),0.91-0.89(m,24H),0.01(s,12H). MS (m / z): 628 (M+1). ...

Embodiment 3

[0065] Synthesis of embodiment 3 misoprostol analog (compound 5d)

[0066]

[0067] (1) Synthesis of compound 3d

[0068]

[0069] Replace 2b in Example 1 with 2d, and its synthesis method is the same as step (1) in Example 1. Yield, 82%. 1 HNMR (CDCl 3 ,400MHz):5.58(dd,J=15.0and 5.2Hz,1H),5.49(dd,J=15.0,7.2Hz,1H),4.11-4.00(m,2H),3.65(s,3H),2.60( dd, J=17.6and 6.8Hz, 1H), 2.43(m, 1H), 2.24(t, J=7.6Hz, 2H), 2.18(dd, J=17.6and 8.0Hz, 1H), 1.91(m, 2H ), 1.59–1.23(m,16H), 0.88-0.90(m,24H), 0.01(s,12H). MS (m / z): 628 (M+1). de>96%.

[0070] (2) Synthesis of compound 4d

[0071]

[0072] Replace 3b in Example 1 with 3d, and its synthesis method is the same as step (2) in Example 1. Yield, 96%. 1 HNMR (CDCl 3 ,400MHz):5.57(dd,J=15.0and 5.2Hz,1H),5.48(dd,J=15.0,7.2Hz,1H),4.10-4.00(m,2H),2.60(dd,J=17.6and 6.8 Hz, 1H), 2.42(m, 1H), 2.23(t, J=7.6Hz, 2H), 2.17(dd, J=17.6and 8.0Hz, 1H), 1.90(m, 2H), 1.57–1.23(m ,16H),0.87-0.90(m,24H),0.01(s,12H). MS (m / z): 628 (M+1). ...

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Abstract

The invention relates to a method for synthesizing a 1R,2R,3R-substituted cyclopentanone compound. The method comprises: carrying out a reaction on a compound 1 and a halogenated alkane in an organicsolvent under the actions of a strong alkali and a cuprous salt to obtain a compound 3, carrying out ester hydrolysis on the compound 3 under the action of an alkali or pancreatin, and carrying out deprotection by using a fluorine reagent to obtain the product. According to the present invention, the synthesis method has characteristics of high yield, high product purity, good diastereoselectivity, easy reaction control and simple post-treatment, is suitable for industrial production, and can synthesize high-purity and high-yield alprostadil, lubiprostone, and the analogs of misoprostol and limaprost. The compound 1 is defined in the specification.

Description

technical field [0001] The invention relates to the fields of organic synthesis and medicinal chemistry, in particular to a method for synthesizing 1R, 2R, 3R-substituted cyclopentanone compounds. Background technique [0002] Alprostadil, also known as prostaglandin E1, is one of the natural prostaglandins. Prostaglandins exist in most mammalian tissues, and their basic structure is a 20-carbon fatty acid containing a cyclopentane and two fatty side chains. According to the position of the double bond and the substituent on the cyclopentane, it can be divided into several types, mainly including four types such as E / F / A / B. Each class has different subtypes with a wide range of biological effects. Among them, prostaglandin E1 has the functions of dilating blood vessels, improving microcirculation disorders, inhibiting platelet aggregation, and preventing thrombosis and arteriosclerosis. In the document J.Am.Chem.SOC.1988,110,4718-4126, the synthesis process of alprostadil...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D311/94C07C51/367C07C59/90
Inventor 李铁旦李阳
Owner GUANGZHOU KAIMO BIOTECH CO LTD
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