CN108794335A - A method of di-tert-butyl dicarbonate is synthesized using phase transfer catalysis process - Google Patents

Abstract

The invention discloses a method for synthesizing di-tert-butyl dicarbonate by adopting a phase transfer catalysis method, belonging to the technical field of organic synthesis technology. Use triphosgene, tert-butanol, etc. as raw materials to synthesize di-tert-butyl dicarbonate under the conditions of adding alkali and phase transfer catalyst, avoiding the use of dangerous phosgene as raw materials, mild reaction conditions, and greatly shortening the reaction time. Greater application value.

Description

A kind of method adopting phase-transfer catalytic method to synthesize di-tert-butyl dicarbonate

technical field

The invention belongs to the technical field of organic synthesis technology, and relates to a new method for synthesizing di-tert-butyl dicarbonate by using a phase transfer catalyst.

Background technique

Di-tert-butyl dicarbonate is a new type of amino acid protective agent, which is safer, more economical, more efficient and easier to control than traditional protective agents (such as benzyl chloroformate, etc.). It is widely used in the synthesis of various products such as medicine, protein and peptide synthesis, and biochemistry. Di-tert-butyl dicarbonate has the advantages of low price, good reactivity, and simple post-treatment. The reaction by-products are carbon dioxide and tert-butanol, which will not cause new pollution.

The existing preparation methods of di-tert-butyl dicarbonate include: taking metal potassium salt or sodium salt of mono-tert-butyl carbonate as raw material, reacting with aromatic or aliphatic sulfonyl chloride to generate di-tert-butyl dicarbonate and other routes. This method produces di-tert-butyl dicarbonate, the amount of aromatic or aliphatic sulfonyl chloride is large, and the reaction yield is not high, and the product purification is difficult.

In addition, Japanese Patent JP Hei 4-356445 discloses a synthesis method of di-tert-butyl dicarbonate, using sodium tert-butoxide as raw material, n-hexane as solvent, introducing CO ₂ and adding 1,4-diazo ring Octane (DABCO) is used as a catalyst, and phosgene is introduced to react, and then the product is obtained by acid washing and alkali elution solvent. The catalyst of this method is expensive, and the industrialization prospect is not ideal. Chinese patent 200610117788 discloses another method for synthesizing di-tert-butyl dicarbonate, using sodium tert-butoxide as a raw material, using toluene or heptane as a solvent, introducing CO ₂ After adding an organic base catalyst and a crown ether interface catalyst, Liquid diphosgene dissolved in toluene was dropped into the reaction. After the reaction, acid wash, alkali wash and water wash, and solvent removal to obtain di-tert-butyl dicarbonate product. This method uses an expensive crown ether catalyst, and the operation is complicated, the amount of waste water is large, and industrial production is relatively difficult.

The present invention adopts the phase-transfer catalytic method to synthesize di-tert-butyl dicarbonate, which avoids the use of metal alkali and _CO2 , and the operation is more convenient, and the present invention uses triphosgene instead of phosgene, and the reaction is safer. The improved synthesis of tert-butyl ester provides an important way.

Contents of the invention

The present invention aims at the deficiencies that exist above, and the technical scheme that the invention adopts is:

A method for synthesizing di-tert-butyl dicarbonate by phase transfer catalysis The technical field is carried out according to the following steps:

(1) Taking tert-butanol and triphosgene as raw materials, adding additives and phase transfer catalysts, and synthesizing di-tert-butyl dicarbonate in a batch reactor.

(2) At -5°C to 10°C, put tert-butanol-n-hexane solution and a certain amount of additives into the reactor, mix and stir evenly, and slowly add triphosgene-n-hexane solution dropwise, and keep warm to continue the reaction , Sampling analysis, lye absorbs tail gas. After the reaction was completed, the water bath was removed, washed with ice-soda water to neutrality, and the hydrogen chloride and excess phosgene in the product were pumped out. Put a phase transfer catalyst into the above reaction solution, stir it magnetically, slowly add the alkali solution dropwise, control the temperature at 0°C to 10°C, and keep it warm. The reaction solution was washed with dilute hydrochloric acid and water to neutrality, separated, and the organic layer was dried with anhydrous calcium chloride, and part of the solvent was spun off. Crystallize below 0°C for 20-40 hours, centrifuge after crystallization to obtain di-tert-butyl dicarbonate with a content of about 99% and a yield of 65-72%.

Wherein the carbonylating agent described in step (1) is triphosgene, and the molar ratio of triphosgene to tert-butanol is (0.75-3.0):1, preferably (1.50-3.0):1.

Wherein the auxiliary agent described in step (1) is a kind of in triethylamine, NNNN-tetramethylethylenediamine, pyridine. The amount used is 0.5% to 3% of the mole number of triphosgene, and the preferred molar ratio is 1% to 2%.

Wherein the alkali described in step (2) is sodium hydroxide, potassium hydroxide etc., and the concentration of its aqueous solution is 15%～70%. The preferred concentration is 30% to 50%.

The reaction temperature described therein is -5°C to 10°C, preferably the reaction temperature is 0 to 8°C.

Wherein the phase-transfer catalyst described in step (1) preferably selects the one in tetrabutylammonium bromide, tetraalkyltrimethylammonium chloride, cetyltrimethylammonium chloride, and phase-transfer catalyst is alkali The dosage is 1% to 5% (wt.).

The invention has the advantages of simple process, easy operation, wide application range, flexible production and high yield. It is safer to use triphosgene instead of phosgene as carbonylation reagent.

Description of drawings

Fig. 1 is the process flow chart of synthesizing di-tert-butyl dicarbonate by interphase transfer catalytic method of the present invention.

Detailed ways

The present invention will be described in detail below in conjunction with the examples, but the following examples are only preferred embodiments of the present invention, and the scope of protection of the present invention is not limited thereto, and any person familiar with the technical field of the present invention is within the technical scope disclosed in the present invention Within the technical scheme of the present invention and its inventive concept, any equivalent substitution or change shall be covered within the protection scope of the present invention.

Example 1

(1) Carbonylation reaction: put 4g of triethylamine, 100g of tert-butanol and 15ml of n-hexane into the reaction kettle, stir, and keep the temperature at -5°C in an ice-water bath. After mixing evenly, slowly add triphosgene-n-hexane solution (0.84mol/L) dropwise for 400min. After the dropwise addition, keep warm and continue the reaction. During the keep warm process, take samples for analysis every 3min, and the lye absorbs the tail gas. After the reaction was completed, the water bath was removed, washed with ice-alkali water until neutral, and pumped for 20 minutes to remove hydrogen chloride and excess phosgene in the product.

(2) Add 1.2 g of polyethylene glycol 4000 into the above reaction solution, stir it magnetically, slowly add NaOH aqueous solution (3mol/L) dropwise for 300 min, control the temperature at 10°C, and keep it warm for 20 min. The reaction solution was washed with dilute hydrochloric acid and water to neutrality, separated, and the organic layer was dried with anhydrous calcium chloride, and part of the solvent was spun off. Crystallize below 0°C for 20 hours, centrifuge after crystallization to obtain 70 g of di-tert-butyl dicarbonate. Content 99%, yield 72%.

Example 2

(1) Carbonylation reaction: put 3.2g of N,N,N,N tetramethylethylenediamine, 100g of tert-butanol and 15ml of n-hexane into the reaction kettle, stir, and keep the temperature at 3°C in an ice-water bath. After mixing evenly, slowly add triphosgene-n-hexane solution (0.68mol/L) dropwise for 400min. After the dropwise addition, keep warm to continue the reaction. During the keep warm process, take samples for analysis every 3min, and the lye absorbs the tail gas. After the reaction was completed, the water bath was removed, washed with ice-alkali water until neutral, and pumped for 20 minutes to remove hydrogen chloride and excess phosgene in the product.

(2) Put 0.8 g of polyethylene glycol 6000 into the above reaction solution, stir it magnetically, slowly add NaOH aqueous solution (2.8 mol/L) dropwise for 300 min, control the temperature at 15°C, and keep it warm for 20 min. The reaction solution was washed with dilute hydrochloric acid and water to neutrality, separated, and the organic layer was dried with anhydrous calcium chloride, and part of the solvent was spun off. Crystallize at below 0°C for 25h, and centrifuge after crystallization to obtain 65g of di-tert-butyl dicarbonate. Content 99%, yield 67%.

Example 3

(1) Carbonylation reaction: put 2.8g of pyridine, 100g of tert-butanol and 15ml of n-hexane into the reaction kettle, stir, and keep the temperature at 0°C in an ice-water bath. After mixing evenly, slowly add triphosgene-n-hexane solution (0.60mol/L) dropwise for 400min, keep warm to continue the reaction after the dropwise addition, take samples for analysis every 3min during the keep warm process, and the lye absorbs the tail gas. After the reaction was completed, the water bath was removed, washed with ice-alkali water until neutral, and pumped for 20 minutes to remove hydrogen chloride and excess phosgene in the product.

(2) Put 0.5 g of tetrabutylammonium chloride into the above reaction solution, stir it magnetically, slowly add NaOH aqueous solution (2.6 mol/L) dropwise for 300 min, control the temperature at 15° C., and keep it warm for 20 min. The reaction solution was washed with dilute hydrochloric acid and water to neutrality, separated, and the organic layer was dried with anhydrous calcium chloride, and part of the solvent was spun off. Crystallize at below 5°C for 26h, and centrifuge after crystallization to obtain 66g of di-tert-butyl dicarbonate. Content 99%, yield 65%.

Example 4

(1) Carbonylation reaction: put 2.5g of diethylenetriamine, 100g of tert-butanol and 15ml of n-hexane into the reaction kettle, stir, and keep the temperature in an ice-water bath at 5°C. After mixing evenly, slowly add triphosgene-n-hexane solution (0.57mol/L) dropwise for 400 minutes. After the dropwise addition, keep warm to continue the reaction. During the keep warm process, take samples for analysis every 3 minutes, and the lye absorbs the tail gas. After the reaction was completed, the water bath was removed, washed with ice-alkali water until neutral, and pumped for 20 minutes to remove hydrogen chloride and excess phosgene in the product.

(2) Add 0.35 g tetradecyl trimethyl sodium chloride into the above reaction solution, stir magnetically, slowly add NaOH aqueous solution (2.4 mol/L) dropwise for 300 min, control the temperature at 30° C., and keep warm for 20 min. The reaction solution was washed with dilute hydrochloric acid and water to neutrality, separated, and the organic layer was dried with anhydrous calcium chloride, and part of the solvent was spun off. Crystallize at below 5°C for 28h, and centrifuge after crystallization to obtain 68g of di-tert-butyl dicarbonate. Content 99%, yield 67%.

Example 5

(1) Carbonylation reaction: put 2.2 g of polyacetate polyamine, 100 g of tert-butanol and 15 ml of n-hexane into the reaction kettle, stir, and keep the temperature at 5° C. in an ice-water bath. After mixing evenly, slowly add triphosgene-n-hexane solution (0.52mol/L) dropwise for 400 minutes, keep warm to continue the reaction after the dropwise addition, take samples for analysis every 3 minutes during the keep warm process, and the lye absorbs tail gas. After the reaction was completed, the water bath was removed, washed with ice-alkali water until neutral, and pumped for 20 minutes to remove hydrogen chloride and excess phosgene in the product.

(2) Add 0.32 g of cetyltrimethylammonium chloride into the above reaction solution, stir it magnetically, slowly add KOH aqueous solution (2.0 mol/L) dropwise for 300 minutes, control the temperature at 21° C., and keep it warm for 20 minutes. The reaction solution was washed with dilute hydrochloric acid and water to neutrality, separated, and the organic layer was dried with anhydrous calcium chloride, and part of the solvent was spun off. Crystallize at below 5°C for 32h, and centrifuge after crystallization to obtain 63g of di-tert-butyl dicarbonate. Content 99%, yield 61%.

Example 6

(1) Carbonylation reaction: put 2g of diethylenetetramine, 100g of tert-butanol and 15ml of n-hexane into the reaction kettle, stir, and keep the temperature at 5°C in an ice-water bath. After mixing evenly, slowly add triphosgene-n-hexane solution (0.5mol/L) dropwise for 400 minutes, keep warm to continue the reaction after the dropwise addition, take samples for analysis every 3 minutes during the keep warm process, and the lye absorbs tail gas. After the reaction was completed, the water bath was removed, washed with ice-alkali water until neutral, and pumped for 20 minutes to remove hydrogen chloride and excess phosgene in the product.

(2) Put 0.3g of benzyltrimethylammonium chloride into the above reaction solution, stir it magnetically, slowly add KOH aqueous solution (1.8mol/L) dropwise for 300min, control the temperature at 10°C-30°C, and keep it warm for 20min. The reaction solution was washed with dilute hydrochloric acid and water to neutrality, separated, and the organic layer was dried with anhydrous calcium chloride, and part of the solvent was spun off. Crystallize at below 5°C for 34h, and centrifuge after crystallization to obtain 68g of di-tert-butyl dicarbonate. Content 99%, yield 70%.

Example 7

(1) Carbonylation reaction: put 1.6g of N,N,N,N-tetraethylethylenediamine, 100g of tert-butanol and 15ml of n-hexane into the reaction kettle, stir, and keep the temperature in an ice-water bath at 8°C. After mixing evenly, slowly add triphosgene-n-hexane solution (0.42mol/L) dropwise for 400 minutes, keep warm to continue the reaction after the dropwise addition, take samples for analysis every 3 minutes during the keep warm process, and the lye absorbs tail gas. After the reaction was completed, the water bath was removed, washed with ice-alkali water until neutral, and pumped for 20 minutes to remove hydrogen chloride and excess phosgene in the product.

(2) Put 0.28g tetrabutylammonium bromide into the above reaction solution, stir it magnetically, slowly add KOH aqueous solution (1.5mol/L) dropwise for 300min, control the temperature at 10°C-30°C, and keep it warm for 20min. The reaction solution was washed with dilute hydrochloric acid and water to neutrality, separated, and the organic layer was dried with anhydrous calcium chloride, and part of the solvent was spun off. Crystallize at below 8°C for 36h, and centrifuge after crystallization to obtain 62g of di-tert-butyl dicarbonate. Content 99%, yield 65%.

Example 8

(1) Carbonylation reaction: 1 g of DMF, 100 g of tert-butanol and 15 ml of n-hexane were put into the reaction kettle, stirred, and the temperature was kept at 10° C. in an ice-water bath. After mixing evenly, slowly add triphosgene-n-hexane solution (0.40mol/L) dropwise for 400min, keep warm to continue the reaction after dropwise addition, take samples for analysis every 3min during the keep warm process, and the lye absorbs tail gas. After the reaction was completed, the water bath was removed, washed with ice-alkali water until neutral, and pumped for 20 minutes to remove hydrogen chloride and excess phosgene in the product.

(2) Put 0.26 g of benzyltrimethylammonium chloride into the above reaction solution, stir it magnetically, slowly add KOH aqueous solution (1mol/L) dropwise for 300 minutes, control the temperature at 23° C., and keep it warm for 20 minutes. The reaction solution was washed with dilute hydrochloric acid and water to neutrality, separated, and the organic layer was dried with anhydrous calcium chloride, and part of the solvent was spun off. Crystallize below 10°C for 40 hours, and centrifuge after crystallization to obtain 68 g of di-tert-butyl dicarbonate. Content 99%, yield 70%.

Claims (7)

1. it is a kind of using phase transfer catalysis process synthesize di-tert-butyl dicarbonate method, it is characterised in that as steps described below into Row：

(1) using the tert-butyl alcohol, triphosgene as raw material, addition auxiliary agent, phase transfer catalyst synthesize two carbon in batch tank reactor Sour di tert butyl carbonate；

(2) equal by being mixed in the tert-butyl alcohol-hexane solution and a certain amount of auxiliary agent input reaction kettle at -5 DEG C~10 DEG C It is even, and triphosgene-hexane solution is slowly added dropwise, heat preservation is added dropwise, and the reaction was continued, and sampling analysis, lye absorbs tail gas；Instead It should finish and remove water-bath, ice buck is washed till neutrality, and water pump pumps hydrogen chloride and extra phosgene in product；It is thrown in above-mentioned reaction solution Enter phase transfer catalyst, aqueous slkali is slowly added dropwise in magnetic agitation, and temperature is controlled at 0 DEG C~10 DEG C, heat preservation；Dilute hydrochloric acid, clear is used in combination Water washing reaction solution to neutrality, liquid separation dries organic layer with anhydrous calcium chloride, and rotation removes partial solvent；In 0 DEG C of following crystallization 20~ 40h, crystallization finish centrifugation, obtain di-tert-butyl dicarbonate, content 99% or so, yield 65~72%.

2. a kind of method synthesizing di-tert-butyl dicarbonate using phase transfer catalysis process according to claim 1, feature It is the carbonylation agent described in wherein step (1) for triphosgene, the molar ratio of triphosgene and the tert-butyl alcohol is (0.75~3.0)： 1。

3. a kind of method synthesizing di-tert-butyl dicarbonate using phase transfer catalysis process according to claim 1, feature It is that wherein step (1) triphosgene and the molar ratio of the tert-butyl alcohol are (1.50~3.0)：1.

4. a kind of method synthesizing di-tert-butyl dicarbonate using phase transfer catalysis process according to claim 1, feature It is that the auxiliary agent described in wherein step (1) is one kind in triethylamine, NNNN- tetramethylethylenediamines, pyridine；Its dosage is three light The 0.5%~3% of the molal quantity of gas.

5. a kind of method synthesizing di-tert-butyl dicarbonate using phase transfer catalysis process according to claim 1, feature It is that the dosage of the auxiliary agent described in wherein step (1) is the 1%~2% of the molal quantity of triphosgene.

6. a kind of method synthesizing di-tert-butyl dicarbonate using phase transfer catalysis process according to claim 1, feature It is that the alkali described in wherein step (2) is sodium hydroxide, potassium hydroxide etc., concentration of aqueous solution is 15%~70%；It is preferred that dense Degree is 30%~50%.

7. a kind of method synthesizing di-tert-butyl dicarbonate using phase transfer catalysis process according to claim 1, feature It is that the wherein described reaction temperature is -5 DEG C~10 DEG C, preferable reaction temperature is 0~8 DEG C.