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Preparation method of 2-diethylamino-1-methylethyl-7-cyclohexyl-7-oxoheptanoate

A technology of methylethyl and diethylamino, which is applied in the field of chemical drug synthesis, can solve the problems of low content and inability to obtain, and achieves the effects of simple processing and convenient and easy-to-obtain products.

Active Publication Date: 2017-10-24
SHANGHAI INST OF PHARMA IND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The research on related substances is very important. In the gas chromatography GC analysis of the crude product of rosivirin, it was found that there was an unknown impurity at the position of retention time 44.976min.

Method used

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  • Preparation method of 2-diethylamino-1-methylethyl-7-cyclohexyl-7-oxoheptanoate
  • Preparation method of 2-diethylamino-1-methylethyl-7-cyclohexyl-7-oxoheptanoate
  • Preparation method of 2-diethylamino-1-methylethyl-7-cyclohexyl-7-oxoheptanoate

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Experimental program
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specific Embodiment approach

[0038] step 1) , cyclic ester 4 Preparation of:

[0039] First add m-chloroperoxybenzoic acid into the reaction flask, then add the solvent dichloromethane, stir in an ice bath to cool down, drop to -5°C~5°C, add cycloheptanone dropwise, after the dropwise addition, heat up to 25°C~ 40°C, continue to stir for 5-10 days, after the reaction, add saturated sodium thiosulfate aqueous solution to quench, after quenching, wash with saturated sodium bicarbonate aqueous solution several times, then wash with saturated brine, and dry over anhydrous magnesium sulfate , concentrated to obtain the crude compound 4, which was passed through the column to obtain compound 4. In step 1), the reaction temperature is preferably 25°C (room temperature), and the reaction time is preferably 7 days.

[0040] step 2) ,alcohol 7 Preparation of:

[0041]Add compound 4, N,O-dimethylhydroxylamine hydrochloride, and dichloromethane as a solvent to the reaction flask in sequence, cool down...

Embodiment 1

[0049] Embodiment one: the preparation of cyclic ester 4

[0050] First add 85% m-CPBA (95g, 0.55mol, 1.8eq) and dichloromethane (1000ml) into a 2L reaction flask in turn, cool down in an ice bath and stir, and when the temperature of the reaction system reaches 0°C, start to add cyclic Heptanone (34g, 0.31mol), the temperature of the system remained basically unchanged during the dropwise addition, the ice bath was removed after the dropwise addition, and the stirring was continued at room temperature (25°C), and the reaction was carried out for 7 days, during which the reaction solution changed from transparent to white turbid. Add saturated sodium thiosulfate solution to quench, add 10% sodium bicarbonate aqueous solution to wash several times after quenching, saturated brine, dry the organic layer, filter, concentrate to obtain compound 4 crude product, and then obtain compound 4 through column chromatography ( 19.5g), yield 50.2%. [M+H] + =129

[0051] 1 H-NMR (400MHz...

Embodiment 2

[0052] Embodiment two: the preparation of alcohol 7

[0053] Add compound 4 (0.64g, 5mmol), N, O-dimethylhydroxylamine hydrochloride (0.4875g, 5mmol, 1eq), dichloromethane (20ml) into the reaction flask in turn, stir and cool down in an ice-salt bath, when the system When the temperature reached -3~-4°C, 2M THF solution of isopropylmagnesium chloride (5.5ml, 11mmol, 2.2eq) was added dropwise. After the dropwise addition, a golden yellow liquid was obtained, and the stirring was continued at low temperature for 1h. After the completion of the reaction was monitored by pointing the plate, slowly add 1M THF solution of cyclohexane magnesium bromide (15ml, 15mmol, 3eq) dropwise. The temperature of the system was kept at -3.5°C. Aqueous solution (10ml) was quenched, washed twice with saturated aqueous sodium bicarbonate solution, washed twice with water, the organic layer was dried, filtered, concentrated to give 1.72g of yellow oil, 0.2g of alcohol 7 was obtained by column chromat...

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Abstract

The invention provides a compound 2-diethylamino-1-methylethyl-7-cyclohexyl-7-oxo-heptanoate (1) and a synthesis method thereof. The compound 1 adopts a structural formula as shown in the specification. The invention further provides the application of the compound 1 as an impurity reference substance for monitoring synthesis of an active pharmaceutical ingredient of rociverine. By taking cycloheptanone as a starting material, the compound 1 is synthesized through a four-step reaction; the obtained product is simple in posttreatment of each step, the product is convenient and easy to obtain, the compound 1 is suitable for being synthesized on a large scale, and a relevant substance or the impurity reference substance are provided for quality research on the synthesis of the active pharmaceutical ingredient of the rociverine.

Description

technical field [0001] The invention belongs to the field of chemical drug synthesis, and in particular relates to a preparation method of 2-diethylamino-1-methylethyl-7-cyclohexyl-7-oxo-heptanoate, a related substance of rosiverine. Background technique [0002] Rociverine, chemical name 2-diethylamino-1-methylethyl-cis-1-hydroxy[dicyclohexyl]-2-carboxylate, molecular formula C 20 h 37 NO 3 , the trade name is Liraton. As an antispasmodic analgesic, it has a unique dual mechanism of action. On the one hand, it has a direct smooth muscle relaxation effect, and on the other hand, it also has an anticholinergic effect; it is suitable for antispasmodic, analgesic, and dynamic dystocia in the genitourinary tract and biliary tract. , puerperium uterine contraction pain and dysmenorrhea. Its structural formula is as follows: [0003] [0004] The literature mainly reports two synthetic routes of rosiverine. [0005] The synthetic route reported in the patent GB1167386 is:...

Claims

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Application Information

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IPC IPC(8): C07C219/10C07C213/02C07C49/82C07C45/57
CPCC07C45/57C07C49/82C07C51/16C07C213/02C07D313/18C07C219/10C07C59/353
Inventor 陈施伟韩强郭晔堃钟静芬
Owner SHANGHAI INST OF PHARMA IND
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