Synthesis method of Fmoc-O-tert-butyl-L-threoninol

A synthetic method and technology of threonine alcohol, applied in chemical instruments and methods, preparation of organic compounds, preparation of carbamic acid derivatives, etc., can solve the problems of high risk, high cost, low yield, etc., and achieve increased yield , low cost and high yield

Inactive Publication Date: 2017-05-10
GL BIOCHEM SHANGHAI
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  • Description
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  • Application Information

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Problems solved by technology

[0003] The object of the present invention is to improve a kind of synthetic method of Fmoc-O-tert-butyl-L-threoninol, mainly solve Fmoc-thr (tbu)-oh in sodium borohydride reduction process, the reaction temperature requirement is strict, and productive rate is low , high cost, high risk and technical problems

Method used

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  • Synthesis method of Fmoc-O-tert-butyl-L-threoninol
  • Synthesis method of Fmoc-O-tert-butyl-L-threoninol
  • Synthesis method of Fmoc-O-tert-butyl-L-threoninol

Examples

Experimental program
Comparison scheme
Effect test

experiment example 1

[0023] 1. Add 70g of L-threonine and 500ml of methanol to a 1000ml three-neck flask, control the temperature below 0°C, and add 64ml of thionyl chloride dropwise. After the dropwise addition, the mixture was heated to reflux for 4 hours. Distilled to dryness under reduced pressure at 55°C to obtain 100 g of L-threonine methyl ester hydrochloride oil. Calculate next step reaction with productive rate 100%;

[0024] 2. In a 2L beaker, add 100g of L-threonine methyl ester hydrochloride, 600ml of water, adjust the pH to alkaline with sodium bicarbonate, add 110 g of z-cl dropwise and adjust it with 2moc / l sodium hydroxide The pH reacts at 8-9. After the reaction, add 1L of ethyl acetate for extraction, wash with 500ml of water, wash with 500ml of saturated brine, dry with 100g of anhydrous sodium sulfate, filter with suction, distill under reduced pressure until solid precipitates, add 600Ml of petroleum ether for crystallization, filter with suction, and dry to obtain z-thr -o...

experiment example 2

[0030] Experimental example 2: 1-4 steps are the same and will not be repeated.

[0031] 5. Put 130g of z-thr(tbu)-oh into a 2L three-necked flask, add 1300ml of tetrahydrofuran, T<0°C, add dropwise 42.5g of N-methylmorpholine, 45.6g of ethyl chloroformate, 15.8g of sodium borohydride g / 139ml (3mol / l) water. After reacting overnight, add ethyl acetate 800Ml for extraction. Wash with 300ml of water, 300ml of saturated brine, and dry with 100g of anhydrous sodium sulfate. Suction filtration, concentrated under reduced pressure to obtain 96g of product, yield 78.5%;

[0032] 6. Add 96g of Z-thr(tbu)-o to a 1L three-necked flask, add 800ML of methanol, 8.3g of 5% palladium carbon, and pass through hydrogen to react. After the reaction is completed, filter with suction and concentrate to dryness under reduced pressure to obtain H-thr( tbu)-ol 54g, calculates with the next reaction of productive rate 100%;

[0033] 7. In a 2L beaker, add 54g of H-thr(tbu)-ol, 300ml of water, 500...

experiment example 3

[0034] Experimental Example 3: Steps 1-4 are the same and will not be repeated

[0035] 5. Put 130g of z-thr(tbu)-oh into a 2L three-necked flask, add 1300ml of tetrahydrofuran, T<0°C, add dropwise 42.5g of N-methylmorpholine, 45.6g of ethyl chloroformate, 15.8g of sodium borohydride g / 83.5ml (5mol / l) water. After reacting overnight, add ethyl acetate 800Ml for extraction. Wash with 300ml of water, 300ml of saturated brine, and dry with 100g of anhydrous sodium sulfate. Suction filtration, concentrated under reduced pressure to obtain product 92g yield 74.7%;

[0036] 6. Add 92g of Z-thr(tbu)-o to a 1L three-necked flask, add 800ML of methanol, 8.3g of 5% palladium carbon, and pass through hydrogen to react. After the reaction is completed, filter with suction, and concentrate to dryness under reduced pressure to obtain H-thr( tbu)-ol 53g is calculated with the next step reaction of productive rate 100%;

[0037] 7. In a 2L beaker, add H-thr(tbu)-ol 53g, water 300ml, aceto...

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Abstract

The present invention relates to a synthesis method of Fmoc-O-tert-butyl-L-threoninol, and mainly solves the technical problems that in a process of Fmoc-thr(tbu)-oh reduction by sodium borohydride, the reaction temperature is strictly required and a FMoc protecting group is decomposed, resulting in low yield and high cost. The synthesis method of the invention comprises the following steps: a. L-threonine reacts with thionyl chloride to form L-threonine methyl ester hydrochloride; b. the L-threonine methyl ester hydrochloride under the action of sodium hydroxide is reacted with benzyl chloroformate to produce z-thr-ome; c. the Z-thr-ome reacts with introduced isobutene in the presence of methylene chloride and concentrated sulfuric acid, and alkali adjustment treatment is carried out to obtain z-thr (tbu)-ome; d. in the presence of acetone and water, the Z-thr(tbu)-ome is saponified with added alkali to obtain z-thr(tbu)-oh; e. the Z-thr(tbu)-oh is reduced to z-thr(tbu)-ol by sodium borohydride in tetrahydrofuran; f. the z-thr(tbu)-ol is hydrogenated in methanol to obtain H-thr(tbu)-ol; and g. N-(9-fluorenylmethoxycarbonyloxy)succinimide is added to the H-thr(tbu)-ol to obtain the Fmoc-O-tert-butyl -L-threoninol.

Description

technical field [0001] The invention relates to a synthesis method of Fmoc-O-tert-butyl-L-threoninol. Background technique [0002] The existing N-fluorenylmethoxycarbonyl-O-tert-butyl-L-4-hydroxyproline synthesis method is generally: a. L-threonine is reacted with thionyl chloride to obtain L-threonine methyl ester hydrochloride Salt. b. L-threonine methyl ester hydrochloride was reacted with benzyl chloroformate under the action of sodium hydroxide to obtain z-thr-ome c. In the presence of dichloromethane and concentrated sulfuric acid, Z-thr-ome is passed through isobutene for reaction to obtain z-thr(tbu)-ome. d. In the presence of acetone and water, Z-thr(tbu)-ome is saponified by adding alkali to obtain z-thr(tbu)-oh. e. Hydrogenation of z-thr(tbu)-oh in methanol gives H-thr(tbu)-oH. F. Addition of H-thr(tbu)-oH to fluorenylmethoxycarbonyl succinimide gives Fmoc-O-tert-butyl-L-threonine. G Fmoc-O-tert-butyl-L-threonine was reduced in methanol solution of sodium...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C269/00C07C271/16
CPCY02P20/55C07C269/00C07C271/16
Inventor 刘浩徐红岩
Owner GL BIOCHEM SHANGHAI
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