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Preparation method of trans-1,3-dihydroxy-cyclobutane-1-carboxylic acid

A technology of trimethylsilyl cyanide and methyl, which is applied in the field of synthesis of pharmaceutical intermediates, can solve the problems of no literature reports on synthetic methods, and achieve the effects of rapid preparation, mild reaction conditions, and easy operation

Active Publication Date: 2018-12-28
NANJING FURUN KAIDE BIOLOGICAL PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Usually optically active compounds have wider applications in drug design, and there are currently no reports in the literature on the synthesis of trans 1,3-dihydroxycyclobutane-1-carboxylic acid

Method used

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  • Preparation method of trans-1,3-dihydroxy-cyclobutane-1-carboxylic acid
  • Preparation method of trans-1,3-dihydroxy-cyclobutane-1-carboxylic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038]

[0039] Preparation of compound III

[0040] Compound II (80.00g, 0.454mol, 1.0eq.) was dissolved in 600mL THF, and K 2 CO 3 (75.32g, 0.545mol, 1.2eq.) and TMSCN (54.05g, 0.545mol, 1.2eq.), reacted at 20°C for 3h, TLC detected that the reaction was complete, filtered, and the filtrate was concentrated to obtain compound III as a red liquid 120.0g, yield : 96.0%. (ESI-TOF) m / z: [M+H] + calcd for C 15 h 21 NO 2 Si: 275; found: 276.

[0041] Preparation of Compound IV-1

[0042] Compound III (104.11g, 0.378mol, 1.0eq.) was dissolved in 500mL MeOH, and SOCl was added dropwise under ice-cooling 2 (80.90g, 0.684mol, 1.8eq.), the temperature was controlled below 35°C, after dropping, heated to reflux at 55°C for 3h, a large amount of solids were formed. TLC detects that the reaction is complete. Methanol was concentrated, 500 mL of tertiary methyl ether was added, filtered, the filtrate was washed with water, dried, and concentrated to obtain 80.0 g of compound I...

Embodiment 2

[0060]

[0061] Preparation of Compound III

[0062] Compound II (80.00g, 0.454mol, 1.0eq.) was dissolved in 600mL THF, and Na 2 CO 3 (24.06g, 0.227mol, 0.5eq.) and TMSCN (45.04g, 0.454mol, 1.0eq.), reacted at 20°C for 3h, TLC detected that the reaction was complete, filtered, and the filtrate was concentrated to obtain compound III as a red liquid 112.5g, yield : 90.0%. (ESI-TOF) m / z: [M+H] + calcd for C 15 h 21 NO 2 Si: 275; found: 276.

[0063] Preparation of Compound IV-2

[0064] Compound III (100.1g, 0.363mol, 1.0eq.) was dissolved in 500mL EtOH, and concentrated sulfuric acid (3.56g, 0.0363mol, 0.1eq.) was added dropwise under ice-cooling. Refluxing at 55°C for 4h, a large amount of solids were formed. TLC detects that the reaction is complete. Concentrate methanol, add 500 mL of tertiary methyl ether, filter, wash the filtrate with water, dry, and concentrate to obtain 78.3 g of compound IV-2 as a brown liquid, yield: 87%. (ESI-TOF) m / z: [M+H] + calcd fo...

Embodiment 3

[0082]

[0083] Preparation of compound III

[0084] Compound II (80.00g, 0.454mol, 1.0eq.) was dissolved in 1000mL of acetonitrile, cesium carbonate (295.8g, 0.908mol, 2.0eq.) and TMSCN (90.07g, 0.908mol, 2.0eq.) were added, at 20°C After reacting for 3 hours, TLC detected that the reaction was complete, filtered, and the filtrate was concentrated to obtain 112.5 g of compound III as a red liquid, with a yield of 90.0%. (ESI-TOF) m / z: [M+H] + calcd for C 15 h 21 NO 2 Si: 275; found: 276.

[0085] Preparation of Compound IV-1

[0086] Compound III (102.1g, 0.370mol, 1.0eq.) was dissolved in 500mL of methanol, and SOCl was added dropwise under ice-cooling 2 (132.32g, 1.11mol, 3.0eq.), the temperature was controlled below 35°C, after dropping, heated to reflux at 55°C for 5h, a large amount of solids were formed. TLC detects that the reaction is complete. Concentrate methanol, add 500 mL of tertiary methyl ether, filter, wash the filtrate with water, dry, and concentrat...

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Abstract

The invention discloses a preparation method of trans-1,3-dihydroxy-cyclobutane-1-carboxylic acid and mainly solves the technical problem of absence of a synthetic process of trans-1,3-dihydroxy-cyclobutane-1-carboxylic acid. The method comprises the following steps: a compound II (3-(benzyloxy) cyclobutanone) is taken as a raw material and subjected to a reaction with trimethylsilyl cyanide, anda compound III is generated; cyano groups of the compound III are subjected to alcoholysis, and a compound IV is generated; a compound V is generated by hydrolysis; the compound V is subjected to recrystallization separation, and a cis-compound VI is obtained; a compound VII is generated from the compound VI by esterification; hydroxy groups in the compound VII are protected by tert-butyldimethylsilyl chloride, and a compound VIII is generated; the compound VIII is subjected to benzyl protecting group removal, and a compound IX is obtained; the compound IX and p-nitrobenzoic acid are subjectedto Mitsunobu reaction, a compound X is generated, p-nitrobenzoyl groups are removed, a compound XI is obtained, and hydroxy configuration is inverted; the compound I (trans-1,3-dihydroxy-cyclobutane-1-carboxylic acid) is obtained finally by hydrolysis.

Description

technical field [0001] The invention relates to the field of synthesis of pharmaceutical intermediates, in particular to a preparation method of trans-1,3-dihydroxycyclobutane-1-carboxylic acid and intermediates thereof. Background technique [0002] 1-Hydroxycyclobutane-1-carboxylic acid derivatives are an important class of pharmaceutical intermediates, which can be used to synthesize drugs with thrombin inhibitor activity, and play a very important role in pharmaceutical synthesis. Patent WO1998011094A1 International Publication reports that 1,3-dihydroxycyclobutane-1-carboxylic acid can be used to prepare benzamidine derivatives substituted by cyclic hydroxycarboxylic acid derivatives for use as anticoagulants. Generally, optically active compounds have wider applications in drug design, and there is no literature report on the synthesis method of trans 1,3-dihydroxycyclobutane-1-carboxylic acid. Therefore, it is necessary to develop a synthetic route with easy-to-obtai...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C62/08C07C51/09C07C51/353C07F7/18C07C69/757C07C67/22
CPCC07B2200/07C07C51/09C07C51/353C07C67/22C07C2601/04C07C69/757C07C62/08Y02P20/55
Inventor 练华文刘贵华
Owner NANJING FURUN KAIDE BIOLOGICAL PHARMA CO LTD
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