阅读说明：本技术 一种卡培他滨中间体的工业大生产方法 (Industrial large-scale production method of capecitabine intermediate ) 是由 龙在华 刘玲玲 于 2020-06-23 设计创作，主要内容包括：发明提出一种卡培他滨中间体的工业大生产方法,采用甲醇核丙酮同时加入的一锅煮的生产方法,节省能源、生产周期较短及提高收率的制备方法；采用在二甲亚砜或者吡咯烷酮中加入乙酸乙酯等低沸点溶剂进行回流冷却带走热量的方法；设计采用一边水解一边蒸馏的生产方法,把水解产生的甲醇及丙酮蒸馏出来,不断减少水中的甲醇及丙酮,使反应向K3进行,反应完全彻底的制备方法。(The invention provides an industrial large-scale production method of a capecitabine intermediate, which adopts a one-pot production method of adding methanol and nuclear acetone simultaneously, saves energy, has shorter production period and improves the yield; a method of adding low boiling point solvents such as ethyl acetate and the like into dimethyl sulfoxide or pyrrolidone for reflux cooling to take away heat is adopted; the preparation method is designed by adopting a production method of hydrolyzing and distilling at the same time, and the methanol and the acetone generated by hydrolysis are distilled out, so that the methanol and the acetone in water are continuously reduced, the reaction is carried out to K3, and the reaction is completely and completely carried out.)

1. An industrial mass production method of a capecitabine intermediate comprises the following specific technical scheme:

synthesis of Step1, K0:

putting measured methanol and acetone into a reaction kettle, starting the reaction kettle to stir, cooling jacket chilled water to 0-5 ℃, and slowly adding measured concentrated sulfuric acid; adding D-ribose into a reaction kettle, keeping the temperature in the reaction kettle for reaction for 3-8 hours, heating the temperature in the reaction kettle to 20-28 ℃, stirring for reaction for 20-28 hours, cooling, and then dropwise adding a sodium hydroxide solution; concentrating in vacuum to obtain dry solvent, adding water and dichloromethane solvent, stirring for layering, and concentrating the obtained organic phase in a distillation kettle to obtain product K0;

synthesis of Step2, K1:

adding the measured K0, triethylamine, 4-dimethylaminopyridine and dichloromethane into a reaction kettle; starting cold salt water to reduce the temperature in the reaction kettle to 10-20 ℃; slowly adding p-toluenesulfonyl chloride in batches, keeping the temperature in the reaction kettle at 10-20 ℃, preserving the temperature for 10-30 ℃ after the addition, reacting for 2-3 hours, and finishing the reaction; carrying out acid washing and alkali washing on the obtained material; standing and layering; putting the obtained organic phase in a desolventizing kettle to evaporate the solvent to dryness; adding dimethyl sulfoxide and ethyl acetate solvent for dissolving to obtain a product K1;

synthesis of Step3, K2:

adding metered sodium borohydride, dimethyl sulfoxide and ethyl acetate into a reaction kettle; starting the reaction kettle to stir and jacket steam; slowly dropwise adding K1, and controlling the temperature in the reaction kettle to be 80-95 ℃; after the dropwise addition is finished, carrying out heat preservation reaction for 2-4 hours; pumping the reaction solution into a hydrolysis kettle in which tap water is added in advance, stirring, and adding dichloromethane for extraction and layering; concentrating the organic phase to dryness to obtain a product K2;

synthesis of Step4, K3:

adding the metered water and K2 into a hydrolysis reaction kettle; adding concentrated sulfuric acid, opening steam to raise the temperature in the reaction kettle to 80-90 ℃, and carrying out heat preservation reaction for 2-4 hours; slowly opening vacuum, keeping micro-vacuum distillation of the reaction kettle at-0.01 Mpa-0.03 Mpa, keeping the temperature of the reaction kettle at 60-90 ℃, and reacting while distilling until the reaction is finished; slowly adjusting the pH value to be neutral by using 10% liquid alkali solution; vacuum concentrating water under reduced pressure; evaporating to dryness until no flow occurs to obtain a product K3;

synthesis of Step5, K4:

adding metered dichloromethane and triethylamine into a reaction kettle, adding dimethylaminopyridine, and cooling; adding the concentrated K3 into a reaction kettle while the solution is hot; slowly dropwise adding a metered acetic anhydride solvent in the elevated tank, keeping the temperature in the reaction kettle within 10-20 ℃, keeping the temperature for reacting for 2-4 hours after dropwise adding, and finishing the reaction; slowly adding water into the reaction kettle, standing and layering; then sequentially carrying out acid washing, alkali washing, drying and decoloring, filtering and concentrating to dryness on the obtained organic phase, adding isopropanol, cooling the boiled salt water to 0-3 ℃, crystallizing for 2-4 hours, and carrying out centrifugal filtration to obtain a product K4;

the K0 is 1-methyl-2, 3-diisopropylene-D-ribose, the K1 is 1-methyl-2, 3-diisopropylene-5-p-toluenesulfonate-D-ribose, the K2 is 1-methyl-2, 3-diisopropylene-5-deoxy-D-ribose, the K3 is 5-deoxy-D-ribose, and the K4 is 1,2, 3-tri-O-acetyl-5-deoxy-D-ribose.

2. The method for the industrial mass production of a capecitabine intermediate according to claim 1, wherein: step1 the NaOH solution is at pH > 8.

3. The method for the industrial mass production of a capecitabine intermediate according to claim 1, wherein: the isopropylidene protection method of the K0 in the Step1 is one of acetone and 2, 2-dimethoxypropane.

4. The method for the industrial mass production of a capecitabine intermediate according to claim 1, wherein: step3 is to add one of the low boiling point solvents of ethyl acetate, toluene and cyclohexane to the reduction of K2 to carry out reflux cooling to remove heat.

5. The method for the industrial mass production of a capecitabine intermediate according to claim 1, wherein: step4 in the hydrolysis of K3, the distillation method is replaced by a method of diluting methanol and acetone with a larger amount of water to break the reaction equilibrium.

6. The method for the industrial mass production of a capecitabine intermediate according to claim 1, wherein: and Step1, before feeding, the reaction tank needs to be dried and anhydrous, and the measured methanol and acetone are simultaneously put into the reaction kettle.

7. The method for the industrial mass production of a capecitabine intermediate according to claim 1, wherein: in the Step of Step3, the reaction tank needs to be dried and anhydrous before feeding.

8. The method for the industrial mass production of a capecitabine intermediate according to claim 1, wherein: the inside of the reaction tank must be ensured to be clean before the Step4 feeding.

Technical Field

The invention relates to the field of pharmaceutical chemistry, in particular to an industrial mass production method of an antitumor drug capecitabine intermediate.

Background

Capecitabine (capecitabine) is a prodrug of 5-fluorouracil (5-FU) developed by Roche, Switzerland, is a nucleoside anticancer drug and is mainly used for treating breast cancer and rectal cancer, 1,2, 3-tri-O-acetyl-5-deoxy-D-ribose (hereinafter, abbreviated as K4), and K4 is an important intermediate in the synthesis process. There are two main synthetic methods for K4: the first method is to take inosine as raw material, iodinate and hydrogenate 5-hydroxyl, and remove hypoxanthine by acetylation of 2 'and 3' hydroxyl to obtain K4 with a total yield of about 30%; the second method is to take D-ribose as raw material, and obtain K4 through methylation, isopropylidene protection, 5-hydroxyl p-toluene sulfo protection, reduction, hydrolysis and acetylation, and the total yield is about 58%. The comprehensive cost is low, the second method is economical and suitable for industrial production, and the specific route is shown in a reaction route chart.

For the synthesis of K4, many reports exist, but the methylation and isopropylidene protection method of 1-methyl-2, 3-diisopropylidene-D-ribose (hereinafter referred to as K0) in the reports is carried out step by step, methanol is added firstly, after reaction for a period of time, acetone is added for continuous reaction, so that the actual production time is longer, the power consumption is higher, the operation is complicated, and the yield of the product K0 is low in the industrial production process. The research aims to overcome the problems, and designs a preparation method which adopts the production method of adding methanol and nuclear acetone simultaneously, saves energy, has shorter production period and improves yield.

For the synthesis of K4, many reports exist, but in the reported reduction of 1-methyl-2, 3-diisopropylidene-5-deoxy-D-ribose (hereinafter referred to as K2), sodium borohydride or potassium borohydride is directly used in a solvent of dimethyl sulfoxide or pyrrolidone, and during actual production, because the reaction is violent, the heat release amount is huge, the production is difficult to control, and the material is easy to wash, so that safety accidents are caused. The purpose of the research is to overcome the problems, and the problems are successfully solved by adopting a method of adding a low-boiling-point solvent such as ethyl acetate and the like into dimethyl sulfoxide for reflux cooling to take away heat.

For the synthesis of K4, many reports exist, but in the reported hydrolysis process of 5-deoxy-D-ribose (hereinafter referred to as K3), since the reaction is a hydrolysis equilibrium reaction, methanol and acetone hydrolyzed from the raw material K2 easily react with the generated K3 under the catalysis of acid and are converted into K2 to reach the reaction equilibrium, the reaction is not thorough in the industrial production process, and the product yield is low, and the impurity content of the finished product K4 is high, and the quality is poor. The present inventors have devised a preparation method in which methanol and acetone produced by hydrolysis are distilled out by a production method in which hydrolysis is carried out while distillation is carried out, and the reaction proceeds to K3 by continuously reducing methanol and acetone in water, thereby completely completing the reaction.

The prior production has the following problems

(1) For the synthesis of K4, many reports exist, but the methylation and isopropylidene protection methods of K0 in the reports are carried out step by step, methanol is added firstly, after reaction is carried out for a period of time, acetone is added for continuous reaction, so that the actual production time is long, the power consumption is large, the operation is complicated, and the yield of the product K0 is low in the industrial production process.

(2) For the synthesis of K4, many reports exist, but sodium borohydride or potassium borohydride is directly used in dimethyl sulfoxide or pyrrolidone in the reported reduction of K2, and the actual production is severe in reaction, large in heat release amount, difficult to control production, easy to flush and cause safety accidents.

(3) For the synthesis of K4, many reports exist, but in the reported hydrolysis process of K3, since the reaction is a hydrolysis equilibrium reaction, methanol and acetone hydrolyzed from raw material K2 easily react with the generated K3 under the catalysis of acid, and then are converted into K2 to reach the reaction equilibrium, so that in the industrial production process, the reaction is not thorough, the product yield is low, and the impurity content of the finished product K4 is high, and the quality is poor.

Disclosure of Invention

Aiming at the situation, the invention adopts a one-pot production method of simultaneously adding methanol and nuclear acetone, saves energy, has shorter production period and improves the yield, thus solving the problem 1; the method of adding low boiling point solvents such as ethyl acetate and the like into dimethyl sulfoxide for reflux cooling to take away heat is adopted, and the problem 2 is successfully solved; the preparation method which adopts a production method of hydrolyzing and distilling simultaneously is designed to distill methanol and acetone generated by hydrolysis, continuously reduce the methanol and the acetone in water, and lead the reaction to be carried out to K3, thus solving the problem 3.

In order to achieve the purpose, the invention provides an industrial mass production method which is low in production cost, beneficial to industrial production and capable of safely and efficiently preparing K4 capecitabine intermediate, and the specific technical scheme is as follows:

synthesis of Step1, K0:

putting measured methanol and acetone into a reaction kettle, starting the reaction kettle to stir, cooling jacket chilled water to 0-5 ℃, and slowly adding measured concentrated sulfuric acid; adding D-ribose into a reaction kettle, keeping the temperature in the reaction kettle for reaction for 3-8 hours, heating the temperature in the reaction kettle to 20-28 ℃, stirring for reaction for 20-28 hours, cooling, and then dropwise adding a sodium hydroxide solution; vacuum concentrating to dry solvent, adding water and dichloromethane solvent, stirring for layering, and concentrating the obtained organic phase in a distillation kettle to dryness to obtain product K0.

Synthesis of Step2, K1:

adding the measured K0, triethylamine, 4-dimethylaminopyridine and dichloromethane into a reaction kettle; starting cold salt water to reduce the temperature in the reaction kettle to 10-20 ℃; slowly adding p-toluenesulfonyl chloride in batches, keeping the temperature in the reaction kettle at 10-20 ℃, preserving the temperature for 10-30 ℃ after the addition, reacting for 2-3 hours, and finishing the reaction; carrying out acid washing and alkali washing on the obtained material; standing and layering; putting the obtained organic phase in a desolventizing kettle to evaporate the solvent to dryness; adding dimethyl sulfoxide and ethyl acetate solvent to dissolve to obtain the product K1.

Synthesis of Step3, K2:

adding metered sodium borohydride, dimethyl sulfoxide and ethyl acetate into a reaction kettle; starting the reaction kettle to stir and jacket steam; slowly dropwise adding K1, and controlling the temperature in the reaction kettle to be 80-95 ℃; after the dropwise addition is finished, carrying out heat preservation reaction for 2-4 hours; pumping the reaction solution into a hydrolysis kettle in which tap water is added in advance, stirring, and adding dichloromethane for extraction and layering; the organic phase was concentrated to dryness to give product K2.

Synthesis of Step4, K3:

adding the metered water and K2 into a hydrolysis reaction kettle; adding concentrated sulfuric acid, opening steam to raise the temperature in the reaction kettle to 80-90 ℃, and carrying out heat preservation reaction for 2-4 hours; slowly opening vacuum, keeping micro-vacuum distillation of the reaction kettle at-0.01 Mpa-0.03 Mpa, keeping the temperature of the reaction kettle at 60-90 ℃, and reacting while distilling until the reaction is finished; slowly adjusting the pH value to be neutral by using 10% liquid alkali solution; vacuum concentrating water under reduced pressure; the mixture was evaporated to dryness until no flow occurred to obtain K3.

Synthesis of Step5, K4:

adding metered dichloromethane and triethylamine into a reaction kettle, adding dimethylaminopyridine, and cooling; adding the concentrated K3 into a reaction kettle while the solution is hot; slowly dropwise adding a metered acetic anhydride solvent in the elevated tank, keeping the temperature in the reaction kettle within 10-20 ℃, keeping the temperature for reacting for 2-4 hours after dropwise adding, and finishing the reaction; slowly adding water into the reaction kettle, standing and layering; and then the obtained organic phase is subjected to acid washing and alkali washing, drying and decoloring, filtering and concentrating to be dry, isopropanol is added, boiled salt water is cooled to 0-3 ℃, crystallization is carried out for 2-4 hours, and centrifugal filtration is carried out to obtain a product K4.

The K0 is 1-methyl-2, 3-diisopropylene-D-ribose, the K1 is 1-methyl-2, 3-diisopropylene-5-p-toluenesulfonate-D-ribose, the K2 is 1-methyl-2, 3-diisopropylene-5-deoxy-D-ribose, the K3 is 5-deoxy-D-ribose, and the K4 is 1,2, 3-tri-O-acetyl-5-deoxy-D-ribose.

Further, Step1 shows that the sodium hydroxide solution has a pH > 8.

Further, the isopropylidene protection method of K0 in Step1 is one of acetone and 2, 2-dimethoxypropane, and acetone is preferred because acetone is cheap.

Further, in the reduction of K2 in Step3, a method of adding one of low boiling point solvents such as ethyl acetate, toluene and cyclohexane into dimethyl sulfoxide for reflux cooling to take away heat is adopted, all the solvents which can be refluxed and do not react with sodium borohydride can solve the problem of violent heat release, and the preferable method is that the ethyl acetate flows back and forth to cool to take away huge heat generated by the reaction.

Further, Step4 is to distill or remove methanol and acetone generated during the hydrolysis process of K3, such as diluting methanol and acetone with more water, and breaking the equilibrium of the reaction, preferably, the methanol and acetone are removed by slight vacuum distillation.

Further, in the Step of Step1, before feeding, the reaction tank needs to be dried and anhydrous, and the measured methanol and acetone are simultaneously put into the reaction kettle.

Furthermore, the reaction tank needs to be dried and anhydrous before the Step3 is fed.

Further, the inside of the reaction tank must be ensured to be clean before feeding in Step 4.

Due to the implementation of the technical scheme, compared with the prior art, the invention has the following advantages:

(1) the preparation method adopts the method of simultaneously adding and boiling the K0 methyl and isopropylidene, saves energy, has shorter production period and improves yield.

(2) In the reduction of K2, a method of adding a low-boiling point solvent into dimethyl sulfoxide for reflux cooling to take away heat generated by the reaction is adopted, and the problem that the violent heat release of the reaction cannot be controlled is successfully solved.

(3) In the hydrolysis process of K3, methanol and acetone generated by the reaction are taken away by distillation, the reaction balance is destroyed, the methanol and the acetone in water are continuously reduced, the reaction is carried out to K3, and the K2 reaction is completely carried out.

Drawings

FIG. 1 is a synthetic scheme for K0 in example 1.

FIG. 2 is a synthetic scheme for K1 in example 1.

FIG. 3 is a synthetic scheme for K2 in example 1.

FIG. 4 is a synthetic scheme for K3 in example 1.

FIG. 5 is a synthetic scheme for K4 in example 1.

Detailed Description

The invention will be further described with reference to specific embodiments and drawings.

The specific technical scheme is as follows:

synthesis of Step1, K0:

adding 750kg of measured methanol and 380kg of measured acetone into a reaction kettle, starting the reaction kettle to stir, cooling jacket chilled water to 0-5 ℃, and slowly adding measured concentrated sulfuric acid. Adding 300 kgD-ribose into a reaction kettle, and keeping the temperature in the reaction kettle for reaction for 5 hours; and (3) heating the temperature in the kettle to 20-28 ℃, stirring for reaction for 24 hours, and cooling and dripping sodium hydroxide solution with the pH value of more than 8. Vacuum concentrating to dry solvent, adding 300kg of water and 600kg of dichloromethane solvent, stirring for layering, and concentrating the organic phase in a distillation kettle to dryness to obtain the product 350kgK 0.

Synthesis of Step2, K1:

adding 210kg of K0, 150kg of triethylamine, 6kg of 4-dimethylaminopyridine and 630kg of dichloromethane into a reaction kettle; starting cold saline water to reduce the temperature in the reaction kettle to 10-20 ℃; slowly adding 240kg of p-toluenesulfonyl chloride in batches, keeping the temperature in the reaction kettle at 10-20 ℃, preserving the temperature at 10-30 ℃ after the addition, reacting for 2-3 hours, and finishing the reaction; respectively carrying out acid washing, alkali washing and standing layering on the materials; separating the organic phase into desolventizing kettles and evaporating the solvent to dryness; under stirring, 60kg of dimethyl sulfoxide and 300kg of ethyl acetate solvent are added for dissolution, and the subsequent reaction is carried out dropwise.

Synthesis of Step3, K2:

adding 60kg of sodium borohydride, 300kg of dimethyl sulfoxide and 150kg of ethyl acetate into a reaction kettle; starting the reaction kettle to stir and jacket steam to enable the solvent in the reaction kettle to flow back; slowly dripping a K1 solution in a high-level tank, and controlling the temperature in the reaction kettle to be 80-93 ℃; after the dropwise addition, the reaction is carried out for 3 hours under the condition of heat preservation; adding the reaction solution into a hydrolysis kettle which is added with 2000kg of tap water in advance, stirring for 30 minutes, and adding 800kg of dichloromethane for extraction and layering; the organic phase was concentrated to dryness to give 170kgK 2.

Synthesis of Step4, K3:

adding 1500kg of water and 150kg of K2 into a hydrolysis reaction kettle; adding 5kg of concentrated sulfuric acid, starting steam to raise the temperature in the reaction kettle to 80-90 ℃, and carrying out heat preservation reaction for 3 hours; slowly starting vacuum, keeping micro-vacuum distillation of the reaction kettle at-0.01 Mpa-0.03 Mpa, keeping the temperature of the reaction kettle at 60-90 ℃, and reacting while distilling until the reaction is finished; slowly adjusting pH to neutral with 10% liquid alkali solution, and vacuum concentrating water under reduced pressure; the mixture was evaporated to dryness until no flow, and the mixture was weighed while hot, and was ready for the K4 reaction.

Synthesis of Step5, K4:

putting 600kg of dichloromethane and 300kg of triethylamine into a reaction kettle, adding 1kg of 4-dimethylaminopyridine, and cooling; adding the concentrated K3 into a reaction kettle while the solution is hot; slowly dropwise adding a metered acetic anhydride solvent in the elevated tank, keeping the temperature in the reaction kettle within 10-20 ℃, and after dropwise adding, keeping the temperature to react for 2 hours to finish the reaction; slowly adding 500kg of water into a reaction kettle, standing and layering; and then sequentially carrying out acid washing, alkali washing, drying and decoloring, filtering and concentrating the obtained organic phase to dryness, then adding 200kg of isopropanol, simultaneously boiling brine, cooling to 0-3 ℃, then crystallizing for 2 hours, and then centrifuging and carrying out spin filtration to obtain a product 150kgK 4.

The K0 is 1-methyl-2, 3-diisopropylene-D-ribose, the K1 is 1-methyl-2, 3-diisopropylene-5-p-toluenesulfonate-D-ribose, the K2 is 1-methyl-2, 3-diisopropylene-5-deoxy-D-ribose, the K3 is 5-deoxy-D-ribose, and the K4 is 1,2, 3-tri-O-acetyl-5-deoxy-D-ribose.

The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.