阅读说明：本技术 一种r-3-氨基正丁醇的精制工艺 (Refining process of R-3-amino n-butanol ) 是由 张�荣 吴德全 于 2020-12-17 设计创作，主要内容包括：本发明公开一种R-3-氨基正丁醇的精制工艺,属于有机化工技术领域。本发明的R-3-氨基正丁醇精制工艺,先采用4-羟基-2-丁酮和盐酸羟胺进行肟化反应,再将肟化物进行氢化,之后通过加入L-苹果酸形成拆分盐,再利用无水乙醇进行精制、游离后,即可得到高光学纯度的R-3-氨基正丁醇。本发明的精制工艺成本低廉、环境友好,更利于工业化生产。(The invention discloses a refining process of R-3-amino n-butanol, belonging to the technical field of organic chemical industry. The R-3-amino n-butanol refining process includes oximation reaction of 4-hydroxy-2-butanone and hydroxylamine hydrochloride, hydrogenation of oximation product, addition of L-malic acid to form split salt, refining with anhydrous alcohol and dissociation to obtain high optical purity R-3-amino n-butanol. The refining process has low cost and environmental protection, and is more beneficial to industrial production.)

1. A refining process of R-3-amino n-butanol is characterized by comprising the following steps:

step 1, reacting 4-hydroxy-2-butanone with hydroxylamine hydrochloride under alkaline condition to obtain oxime compound

Step 2, in the presence of Raney nickel, the oxime compound obtained in the step 1 is hydrogenated, so that hydride is obtained

Step 3, adding L-malic acid into hydride to form a split salt, refining the split salt by absolute ethyl alcohol, and dissociating to obtain R-3-amino n-butanol

2. The refining process of claim 1, wherein: in the step 1, the reaction temperature is 5-10 ℃.

3. The refining process of claim 1, wherein: in the step 2, the reaction temperature is 30 ℃.

4. The refining process of claim 1, wherein: in the step 3, L-malic acid is added into hydride and reacts at 20 ℃ to form a resolved salt.

Technical Field

The invention belongs to the technical field of organic chemical industry, and particularly relates to a refining process of R-3-amino n-butanol.

Background

The R-3-aminobutanol with optical activity is a key intermediate of a plurality of chiral drugs, such as antitumor drugs 4-methyl cyclophosphamide, beta-lactam, anti-AIDS drugs dorzolavir and the like. Compared with the existing anti-AIDS medicaments, the doramevir serving as an anti-AIDS integrase inhibitor has improved safety, does not need to be combined with medicament promoters, and has very strong medicament resistance. As a key intermediate of the chiral six-membered ring of the doriravir, the optical purity and the price of the R-3-aminobutanol have important influence on the quality and the production cost of the doriravir.

At present, the production of R-3-aminobutanol is mainly carried out by a chemical synthesis method, one method is to obtain chirally pure 3-aminobutanol by adopting a kinetic resolution method, but the chemical resolution method has the defects of low yield, high consumption of a resolving agent, harsh reaction conditions and the like. The other method is to use chiral compound as the starting material and obtain chirally pure 3-amino n-butanol through multi-step reaction of D-alanine or R-phenylethylamine.

Disclosure of Invention

Aiming at the defects of the prior art, the invention aims to provide a refining process of R-3-amino n-butanol.

In order to achieve the above purpose, the solution of the invention is:

a refining process of R-3-amino n-butanol comprises the following steps:

step 1, reacting 4-hydroxy-2-butanone with hydroxylamine hydrochloride under alkaline condition to obtain oxime compound

Step 2, in the presence of Raney nickel, the oxime compound obtained in the step 1 is hydrogenated, so that hydride is obtained

Step 3, adding L-malic acid into hydride to form a split salt, refining the split salt by absolute ethyl alcohol, and dissociating to obtain R-3-amino n-butanol

Further, the reaction temperature in step 1 is 5-10 ℃.

Further, the reaction temperature in step 2 was 30 ℃.

Further, the addition of L-malic acid to the hydride in step 3 was followed by stirring at 20 ℃ to form a resolved salt.

After the scheme is adopted, the R-3-amino n-butanol refining process firstly adopts 4-hydroxy-2-butanone and hydroxylamine hydrochloride to carry out oximation reaction, then carries out hydrogenation on oximation products, then adds L-malic acid to form split salt, and then carries out refining and dissociation by using absolute ethyl alcohol to obtain the R-3-amino n-butanol with high optical purity. The refining process has low cost and environmental protection, and is more beneficial to industrial production.

Detailed Description

The present invention is described in further detail below with reference to specific examples, but the present invention should not be construed as being limited thereto. Modifications or substitutions to methods, procedures, or conditions of the invention may be made without departing from the spirit and scope of the invention. The experimental methods and reagents of the formulations not specified in the examples are in accordance with the conventional conditions in the art.

Example 1

The R-3-amino n-butanol refining process of the invention comprises the following reaction processes:

the specific process is as follows:

step 1: oximation reaction

The feeding ratio is as follows:

the process flow is as follows:

1. adding 4-hydroxy-2-butanone, 95% ethanol and hydroxylamine hydrochloride into a 500 ml four-mouth bottle, stirring and dissolving, and cooling to 5 ℃ in ice water bath.

2. Adding 40% sodium hydroxide solution into the dropping funnel, dropping alkali liquor when the temperature of the reaction flask is reduced to 5 ℃, controlling the temperature of the reaction flask between 5 and 10 ℃, and dropping for 1 to 2 hours.

3. After dropping, the reaction is carried out for 4 hours at the temperature of 5-10 ℃, the filtration is carried out, and the mixed solution of ethanol and water is distilled off under reduced pressure at the temperature of 50 ℃.

4. When the distillate is very little, adding 20 ml of absolute ethyl alcohol and distilling once (removing water), at this time, some salt is separated out, adding 50 ml of absolute ethyl alcohol and shaking up, filtering to remove salt, and distilling the filtrate to be thick.

Steaming at 5.50 ℃ until the weight is not reduced basically, 30 g of pale yellow viscous oil is obtained, and the gas phase purity is 89.7%.

Step 2, hydrogenation reaction

The feeding ratio is as follows:

the process flow is as follows:

1. a250 ml autoclave was charged with an oximate and anhydrous ethanol, the contents of which were about 15 g of Raney nickel, and the autoclave was charged and then the atmosphere in the autoclave was replaced with argon under reduced pressure three times.

2. Introducing hydrogen into the autoclave, replacing argon in the autoclave for three times under the condition of keeping the pressure of 0.5M, increasing the pressure to 0.5M for reaction, keeping the temperature of the autoclave at 30 ℃, reacting under the condition of stirring speed of 30 revolutions, and stopping the reaction when the pressure is not changed greatly, wherein the reaction time is about 12 hours.

3. And after the reaction is finished, releasing the pressure to normal pressure, replacing the argon environment, opening the hydrogenation kettle, and performing suction filtration on the hydrogenated liquid to obtain a light yellow hydrogenated material.

The solvent in the hydrogenate was evaporated at 4.40 deg.C (water must be evaporated) and taken up once in the dry state with 10 ml of absolute ethanol to give 26 g of oil with a gas phase purity of 88%.

Step 3, resolution and dissociation

The feeding ratio is as follows:

the process flow is as follows:

salt-forming refining of chiral acid

1. Adding 250 ml of absolute ethyl alcohol into the hydrogenated liquid, if salt precipitation exists, carrying out suction filtration on a small amount of nickel powder, covering a funnel with a small amount of 2 g of diatomite, cooling the obtained filtrate by using ice water to 5-10 ℃, adding 75 g of L-malic acid 5 times in 20 minutes, stirring in the ice water to completely dissolve the solid L-malic acid, stirring for half an hour at room temperature, adding 0.1 g of splitting salt seed crystal, stirring for 10 hours at 20 ℃ for crystallization, and precipitating a large amount of white solid in about 1-2 hours.

2. Cooling to about 5-10 ℃ by using ice bath, preserving the heat for 1 hour, and performing suction filtration to obtain the split salt. Chiral purity 84.95%.

3. Splitting salt I, adding the split salt I into a single-mouth bottle, adding 200 ml of absolute ethyl alcohol, heating to 50-60 ℃, heating to dissolve, reducing the temperature to 35-40 ℃ for 1 hour, adding 0.1 g of seed crystal, stirring for 2 hours under heat preservation, reducing the temperature to 20-25 ℃ for 1 hour, preserving the heat for 1 hour, reducing the temperature to 5-10 ℃, stirring for 1 hour under heat preservation, and filtering to obtain a refined product with chiral purity of 96.29%.

4. Splitting the salt II, adding the first refined product into a single-mouth bottle, adding 150 ml of absolute ethyl alcohol, heating to raise the temperature to dissolve the first refined product (about 60-70 ℃), reducing the temperature to 35-40 ℃ within 1 hour, adding 0.1 g of seed crystal, keeping the temperature and stirring for 2 hours, reducing the temperature to 20-25 ℃ within 1 hour, keeping the temperature for 1 hour, reducing the temperature to 5-10 ℃, keeping the temperature and stirring for 1 hour, and performing suction filtration to obtain the second refined product with the chiral purity of 99.11%.

5. Splitting the salt III essence, adding the second refined product into a single-mouth bottle, adding 150 ml of absolute ethyl alcohol, heating to raise the temperature to dissolve the salt III essence (about 70 ℃), reducing the temperature to 40 ℃ within 1 hour, adding 0.1 g of seed crystal, keeping the temperature and stirring for 2 hours, reducing the temperature to 20-25 ℃ within 1 hour, keeping the temperature for 1 hour, reducing the temperature to 5-10 ℃, keeping the temperature and stirring for 1 hour, and performing suction filtration to obtain the third refined product with the chiral purity of 99.85%. Enantiomer 0.15%.

6. Splitting the salt four essence, adding the three essence into a single-mouth bottle, adding 150 ml of absolute ethyl alcohol, heating to raise the temperature to dissolve the three essence clearly (about 75 ℃), reducing the temperature to 45 ℃ within 1 hour, adding 0.1 g of seed crystal, keeping the temperature and stirring for 2 hours, reducing the temperature to 20-25 ℃ within 1 hour, keeping the temperature for 1 hour, reducing the temperature to 5-10 ℃, keeping the temperature and stirring for 1 hour, and performing suction filtration to obtain the three essence with the chiral purity of 99.96%. Enantiomer 0.04%. Vacuum drying at 45 ℃ gave 35 g of the resolved salt.

(II) dissociation

1. Adding 69 g of 20% sodium hydroxide solution into a single-mouth bottle, and adding 35 g of resolving salt (without heat release) in three batches at 10-20 ℃ in a water bath under stirring for about 10 min;

2. stirring at 20 + -5 deg.C until the solid is substantially dissolved (about half an hour), leaving a very small amount of solid undissolved;

3. adding 50 ml of isopropanol, stirring for 10 minutes, separating liquid, standing for 20 minutes, basically separating, collecting an upper isopropanol layer, and separating a lower layer into the just single-mouth bottle;

4. adding 50 ml of isopropanol into the single-mouth bottle, stirring for 10 minutes, separating, standing for 20 minutes, layering after a clear interface, and combining isopropanol layers; no product was detected on the water ply layer.

Concentrating an isopropanol layer at 5.40 degrees (no material is brought out during isopropanol distillation), adding 10 ml of isopropanol with primary water after concentrating and drying, concentrating for half an hour by using a material water pump, pumping out residual water, and transferring to an oil pump for reduced pressure distillation after the water content is measured to be less than 1%;

6. distilling the liquid to be distilled under high vacuum of an oil pump (the vacuum degree of the oil pump is 60pa), firstly, at room temperature, not starting condensation circulation, pulling away a small amount of residual solvent and a small amount of water, after 20 minutes, starting condensed water and then heating. Slowly heating to 90 ℃, condensing the effluent at the temperature of minus 15 ℃ of an ice maker, distilling to obtain the distillate at the temperature of 60 ℃, and obtaining the colorless product of 12.9g (the molar yield of the free distillation in the step is 92.3%).

The detection shows that the GC purity of the obtained product is more than 99 percent, the maximum impurity is less than 0.5 percent, the water content is less than 1 percent, and the chirality is 99.90 percent.

The R-3-amino n-butanol refining process includes oximation reaction of 4-hydroxy-2-butanone and hydroxylamine hydrochloride, hydrogenation of oximation product, addition of L-malic acid to form split salt, refining with anhydrous alcohol and dissociation to obtain high optical purity R-3-amino n-butanol. The refining process has low cost and environmental protection, and is more beneficial to industrial production.

The above embodiments are only for illustrating the technical idea of the present invention, and the protection scope of the present invention is not limited thereby, and any modifications made on the basis of the technical scheme according to the technical idea of the present invention fall within the protection scope of the present invention.