阅读说明：本技术 一种三水多西他赛生产工艺 (Production process of docetaxel trihydrate ) 是由 葛月兰 文佺佺 王旭阳 于 2020-07-02 设计创作，主要内容包括：本发明涉及三水多西他赛生产技术领域,且公开了一种三水多西他赛生产工艺,包括以下步骤：S1：加热溶解,将10份无水多西他赛溶解于30-60份的丙酮中,然后进行搅拌,搅拌的同时进行加热；S2：冷却混合,在丙酮彻底溶解后对其进行冷却,直到溶液冷却到26-32℃之间后加入100-150份的醇,然后进行搅拌混合；S3：加水,向得到的混合溶液中加入50-70份的水,然后混合搅拌15-20分钟,静置60-80分钟,得到新的混合物。本发明使得经过初步提纯后的原料能够在大量的溶解液下再次反映,除去杂质,提高其除杂效率,能够充分的使其冷却,防止温度过高影响浆体的形成。(The invention relates to the technical field of docetaxel trihydrate production, and discloses a docetaxel trihydrate production process, which comprises the following steps: s1: heating for dissolving, dissolving 10 parts of anhydrous docetaxel in 30-60 parts of acetone, stirring, and heating while stirring; s2: cooling and mixing, namely cooling the acetone after the acetone is completely dissolved until the solution is cooled to 26-32 ℃, adding 100-150 parts of alcohol, and then stirring and mixing; s3: adding water, adding 50-70 parts of water into the obtained mixed solution, mixing and stirring for 15-20 minutes, and standing for 60-80 minutes to obtain a new mixture. The method ensures that the raw materials after primary purification can be reflected again under a large amount of dissolved solution, removes impurities, improves the impurity removal efficiency, can fully cool the raw materials, and prevents the formation of slurry caused by overhigh temperature.)

1. A production process of docetaxel trihydrate is characterized by comprising the following steps:

s1: heating for dissolving, dissolving 10 parts of anhydrous docetaxel in 30-60 parts of acetone, stirring, and heating while stirring;

s2: cooling and mixing, namely cooling the acetone after the acetone is completely dissolved until the solution is cooled to 26-32 ℃, adding 100-150 parts of alcohol, and then stirring and mixing;

s3: adding water, adding 50-70 parts of water into the obtained mixed solution, mixing and stirring for 15-20 minutes, and standing for 60-80 minutes to obtain a new mixture;

s4: cooling again, cooling the mixture after adding water to about 10-30 ℃ to obtain slurry;

s5: filtering, washing and drying the slurry to obtain docetaxel trihydrate;

s6: preliminary purification, dissolving the obtained docetaxel trihydrate in 10 parts to 40 to 60 parts of ethyl acetate for 10 to 20 minutes, filtering, concentrating under vacuum to produce a residue, then adding 20 to 44 parts of dichloromethane to dissolve the residue, and purifying the solution by chromatography using acetone and n-heptane as eluents, concentrating the purified solution under vacuum, and filtering to obtain docetaxel trihydrate;

s7: performing secondary purification, namely adding 80-120 parts of ethyl acetate, 50-90 parts of dichloromethane and 2-10 parts of acetic acid solution into the docetaxel trihydrate obtained by the primary purification for dissolving, and stirring at a high speed during dissolving;

s8: and (3) crystallizing, adding 30-60 parts of alkane in the stirring process for secondary purification, generating crystals after adding, and then performing suction filtration and vacuum drying on the generated crystals to obtain a secondary purified product of the docetaxel trihydrate.

2. The process of claim 1, wherein the drying temperature in S6 is 35-38 ℃, the drying time is 5-8 hours, and the pressure is 700-860Pa, which can be obtained by experiment.

3. The process of claim 1, wherein 10 parts of anhydrous docetaxel is dissolved in 30-60 parts of acetone and stirred at 40-52 ℃ for 10-25 minutes in S1.

4. The process of claim 3, wherein the alcohol added in S2 is ethanol or methanol, and the mixture is stirred and mixed for 20-40 min and then left for 20-30 min.

5. The process of claim 1, wherein the cooling temperature of the S4 is controlled to be 10-30 ℃.

6. The process of claim 5, wherein the alkane added in the S8 crystallization process is one or more of pentane, hexane and heptane, and can be freely combined, and the crystallization is performed with suction filtration, and the crystals after suction filtration are rapidly washed with water and then vacuum-dried.

7. The process of claim 1, wherein the second purification in S7 is performed by heating while stirring, and the temperature is controlled at 26-32 ℃.

8. The process of claim 3, wherein the docetaxel trihydrate is dissolved in S6 and S8 and then filtered through a microporous polytetrafluoroethylene membrane.

Technical Field

The invention relates to the technical field of docetaxel trihydrate production, in particular to a production process of docetaxel trihydrate.

Background

Docetaxel (chemical name is (2R,3S) -3-tert-butyloxycarbonylamino-2-hydroxy-3-phenylpropanoic acid (4-acetoxyl-2 alpha-benzoyloxy-5 beta, 20-epoxy-1, 7 beta, 10 beta-trihydroxy-9-oxotaxane-11-ene-13 alpha) ester) is a semisynthetic anticancer drug obtained by chemical synthesis of a main taxane core extract (called 10-deacetylbaccatin or 10-DAB) in taxus chinensis, and is more and more recognized by people due to excellent anticancer performance. Researches show that the anticancer performance of docetaxel is superior to that of paclitaxel, and the toxic and side effects are lower, so that docetaxel is more and more widely applied, but docetaxel compounds are more, and docetaxel trihydrate is one of the docetaxel compounds.

The general docetaxel trihydrate is produced by taking anhydrous docetaxel as a raw material during production, and the steps of dissolving, filtering, drying and the like are generally needed in the production process, but the purity of the docetaxel trihydrate produced by the general process is too low to meet the requirements of people.

Disclosure of Invention

Technical problem to be solved

Aiming at the defects of the prior art, the invention provides a production process of docetaxel trihydrate, which mainly solves the problem that docetaxel trihydrate produced by the existing process has too low purity and cannot meet the requirements of people.

(II) technical scheme

In order to achieve the purpose, the invention provides the following technical scheme:

a production process of docetaxel trihydrate comprises the following steps:

s1: heating for dissolving, dissolving 10 parts of anhydrous docetaxel in 30-60 parts of acetone, stirring, and heating while stirring;

s2: cooling and mixing, namely cooling the acetone after the acetone is completely dissolved until the solution is cooled to 26-32 ℃, adding 100-150 parts of alcohol, and then stirring and mixing;

s3: adding water, adding 50-70 parts of water into the obtained mixed solution, mixing and stirring for 15-20 minutes, and standing for 60-80 minutes to obtain a new mixture;

s4: cooling again, cooling the mixture after adding water to about 10-30 ℃ to obtain slurry;

s5: filtering, washing and drying the slurry to obtain docetaxel trihydrate;

s6: preliminary purification, dissolving the obtained docetaxel trihydrate in 10 parts to 40 to 60 parts of ethyl acetate for 10 to 20 minutes, filtering, concentrating under vacuum to produce a residue, then adding 20 to 44 parts of dichloromethane to dissolve the residue, and purifying the solution by chromatography using acetone and n-heptane as eluents, concentrating the purified solution under vacuum, and filtering to obtain docetaxel trihydrate;

s7: performing secondary purification, namely adding 80-120 parts of ethyl acetate, 50-90 parts of dichloromethane and 2-10 parts of acetic acid solution into the docetaxel trihydrate obtained by the primary purification for dissolving, and stirring at a high speed during dissolving;

s8: and (3) crystallizing, adding 30-60 parts of alkane in the stirring process for secondary purification, generating crystals after adding, and then performing suction filtration and vacuum drying on the generated crystals to obtain a secondary purified product of the docetaxel trihydrate.

Further, in the step S6, when vacuum drying is performed, the drying temperature is ensured to be between 35 and 38 ℃, the drying time is ensured to be between 5 and 8 hours, and the pressure is ensured to be between 700 and 860 Pa.

Based on the scheme, 10 parts of anhydrous docetaxel is dissolved in 30-60 parts of acetone in S1, the stirring time is controlled to be 10-25 minutes, and the heating temperature is controlled to be 40-52 ℃.

In a still further embodiment of the present invention, the alcohol added in S2 may be ethanol or methanol, and after stirring and mixing, the raw materials are dissolved for 20 to 40 minutes, and then left to stand for 20 to 30 minutes, and the dissolution time is controlled sufficiently to dissolve the raw materials.

Further, the cooling temperature in the cooling in the S4 is controlled to be between 10 and 30 ℃.

On the basis of the scheme, the alkane added in the S8 crystallization process is one or more of pentane, hexane and heptane, can be freely combined, and is subjected to suction filtration after crystallization is generated, the crystals after suction filtration are quickly washed by water, and then are subjected to vacuum drying after washing.

In a further scheme of the invention, when the secondary purification is carried out in S7, heating is carried out while stirring is carried out, and the temperature is controlled to be 26-32 ℃.

Further, docetaxel trihydrate is dissolved in the S6 and S8, and then is filtered through a polytetrafluoroethylene microporous membrane.

(III) advantageous effects

Compared with the prior art, the invention provides a production process of docetaxel trihydrate, which has the following beneficial effects:

1. through twice purification operation, can improve the purity of docetaxel trihydrate greatly, in the purification of secondary moreover, the quantity of ethyl acetate and dichloromethane all exceeds for the first time, can make the raw materials after preliminary purification reflect once more under a large amount of dissolving liquids like this, gets rid of impurity, improves its edulcoration efficiency.

2. In the S1, the raw material can be dissolved to the maximum extent at the set temperature, the dissolving and filling degree of the raw material can be ensured by accurately controlling the time, and the raw material can be sufficiently dried at the set temperature, time and pressure during vacuum drying, so that the drying efficiency is improved.

3. The cooling temperature is controlled between 10 ℃ and 30 ℃ when the S4 is cooled, so that the slurry can be sufficiently cooled, the phenomenon that the slurry is formed due to overhigh temperature is prevented, and impurities cannot be sufficiently separated out due to overhigh temperature to affect the subsequent filtering work.

4. The docetaxel trihydrate is dissolved and then filtered by a polytetrafluoroethylene microporous membrane, and a crude product is filtered by the polytetrafluoroethylene microporous membrane, so that zinc ions introduced in a synthesis process are effectively removed, and the generation of 10-carbonyl docetaxel in a subsequent drying process is avoided.

Drawings

Fig. 1 is a schematic flow structure diagram of a production process of docetaxel trihydrate provided by the invention.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.