Tert-butyl carbamate derivative and preparation method and application thereof

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...

Examples

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-...

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...

Examples

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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