Tert-butyl carbamate derivative and preparation method and application thereof

A technology of isobutyl chloroformate and serine, applied in the fields of organic chemistry and medicinal chemistry, can solve problems such as large loss, great difficulty, environmental pollution and the like

Active Publication Date: 2011-04-20
ZHEJIANG JIUZHOU PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0028] The technical problem that this route exists is: (1) first carry out alkylation reaction (synthesis of compound 5), then carry out condensation reaction (synthesis of compound 4), in the alkylation reaction process, the carboxyl of compound 5 is easily by Esterification will cause more by-products in the reaction process, more impurities and more difficult to remove; and compound 5 is an oily substance, which is not separated, which is unfavorable for the synthesis of compound 4 and lacosamide in terms of yield and quality control. Repeating this patent, the yield of compound 4 is 77%; (2) using dichloromethane as a solvent, the loss in the recovery process is relatively large, the general recovery rate is 60% to 70%, and the environmental pollution is relatively large
(3) In the aftertreatment process of intermediate compound 5, a large amount of by-product sodium citrate has not been recovered with citric acid to regulate the pH value of the system; if it is recovered, it will be difficult; direct discharge will cause certain pollution to the environment
In short, this synthetic route does not conform to the currently advocated "green synthesis" route (i.e. chemical synthesis with low toxicity and low pollution).

Method used

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  • Tert-butyl carbamate derivative and preparation method and application thereof
  • Tert-butyl carbamate derivative and preparation method and application thereof
  • Tert-butyl carbamate derivative and preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] 29.48g benzylamine was dissolved in 50g anhydrous ethyl acetate to prepare a solution for use. In a 1000ml four-necked round bottom flask, 51.3g of compound 6 (N-BOC-D-serine) was dissolved in 400ml of anhydrous ethyl acetate, the temperature was lowered to -10℃, and 27.83g of N-methylmorpholine and 37.59g isobutyl chloroformate. After the addition is complete, continue the reaction at -15~-10°C for 2 hours. Then add dropwise the ethyl acetate solution of benzylamine that has been prepared. After the dropwise addition is completed, the temperature is raised to 10-15°C and reacted for 2 hours. After the reaction is completed, add water, extract the phases, wash the organic phase with dilute hydrochloric acid and brine, evaporate the solvent under reduced pressure, crystallize with hexane / ethyl acetate = 8 / 1, and dry to obtain 66.3 g of the product with a yield of 90.2% .

[0066] The structure data is as follows: 1H NMR (400MHz, DMSO- ) ppm: 1.38 (s, 9H), 3.58 (m, 2H), ...

Embodiment 2

[0068] 34.84g benzylamine was dissolved in 60g anhydrous ethyl acetate to prepare a solution for use. In a 1000ml four-necked round bottom flask, 51.3g of compound 6 (N-BOC-D-serine) was dissolved in 400ml of anhydrous ethyl acetate, the temperature was lowered to -20℃, and 32.99g of N-methylmorpholine and 44.42g isobutyl chloroformate. After the addition is complete, continue the reaction at -15~-10°C for 2 hours. Then add dropwise the ethyl acetate solution of benzylamine that has been prepared. After the dropwise addition is completed, the temperature is raised to 15-20°C and reacted for 2 hours. After the reaction is complete, add water, extract the phases, wash the organic phase with dilute hydrochloric acid and brine, evaporate the solvent under reduced pressure, crystallize with hexane / ethyl acetate = 8 / 1, and dry to obtain 66.9 g of product with a yield of 91.0% .

Embodiment 3

[0070] 40.20 g benzylamine was dissolved in 70 g anhydrous ethyl acetate to prepare a solution for use. In a 1000ml four-necked round bottom flask, 51.3g of compound 6 (N-BOC-D-serine) was dissolved in 400ml of anhydrous ethyl acetate, the temperature was reduced to 0℃, and 38.06g of N-methylmorpholine and 51.25 were added dropwise successively. g Isobutyl chloroformate. After the dropwise addition is completed, continue the reaction at 0-5°C for 2 hours. Then add dropwise the ethyl acetate solution of benzylamine that has been prepared. After the dropwise addition is completed, the temperature is raised to 10-15°C and reacted for 2 hours. After the reaction is complete, add water, extract the phases, wash the organic phase with dilute hydrochloric acid and brine, evaporate the solvent under reduced pressure, crystallize with hexane / ethyl acetate = 8 / 1, and dry to obtain 68.4 g of product with a yield of 93.1% .

[0071] Compound 4, the synthesis of (R)-2-(amino-Boc)-N-benzyl-...

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Abstract

The invention relates to a synthetic intermediate of lacosamide and a preparation method and application thereof. In the method, a compound shown as a formula I is prepared by condensing a compound 6; the compound shown as the formula I is a novel intermediate compound for synthesizing the lacosamide; (R)-2-(amino-Boc)-N-benzyl-3-methoxyl propionamide (compound 4) can be conveniently prepared from the compound shown as the formula I through alkylation reaction; and the (R)-2-(amino-Boc)-N-benzyl-3-methoxyl propionamide is another important intermediate for synthesizing the lacosamide. The related chemical reaction formulas are shown in the specifications.

Description

Technical field [0001] The invention relates to the fields of organic chemistry and medicinal chemistry. Specifically, the invention relates to a tert-butyl carbamate derivative and a preparation method and application thereof. Background technique [0002] A tert-butyl carbamate derivative with the structure shown in formula 1: [0003] [0004] The group -Boc is specifically: tert-butoxycarbonyl, namely: [0005] [0006] Note: The following structural formula and the group -Boc appearing in the text are the same as this definition. [0007] The chemical name of compound 1 is: [1-(hydroxymethyl)-2-carbonyl-2-[(phenylmethyl)amino]ethyl]-carbamic acid tert-butyl ester ([1-hydroxymethyl)-2-oxo -2-[(phenylmethyl)amino]ethyl]-carbamic acid tertbutyl ester), the CAS number is 934169-87-6, the synthesis process is shown in the figure below (reference: Indian journal of chemistry (Indian journal of chemistry), 1994, 33 :445-450): [0008] [0009] The reported yield was 81.6%. [0010] At p...

Claims

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Application Information

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IPC IPC(8): C07C271/18C07C269/04C07C269/06C07C237/22C07C231/14
Inventor 吴立猛张现毅林雅群徐明东车大庆
Owner ZHEJIANG JIUZHOU PHARM CO LTD
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