CN111646953A

CN111646953A - Novel method for synthesizing ritonavir

Info

Publication number: CN111646953A
Application number: CN202010324610.2A
Authority: CN
Inventors: 侯鹏翼; 涂福荣
Original assignee: Xiamen Weijia Pharmaceutical Co ltd
Current assignee: Xiamen Weijia Pharmaceutical Co ltd
Priority date: 2020-04-23
Filing date: 2020-04-23
Publication date: 2020-09-11

Abstract

A novel method for synthesizing ritonavir, which relates to the field of pharmaceutical chemistry,

it includes: adding pivaloyl chloride into the intermediate V at the temperature of between 5 ℃ below zero and 10 ℃, then dripping organic base, keeping the temperature in the reaction kettle at the temperature of between 5 ℃ below zero and 10 ℃, stirring for reaction for T1 time, then adding 4-dimethylaminopyridine, stirring for T2 time, finally adding dichloromethane solution of the intermediate VI, heating the reaction temperature to between 25 ℃ and 35 ℃, and stirring until the reaction is finished. The invention changes common industrial raw materials and reagents into the method, is suitable for industrial mass production, and obtains the product with the yield of more than 85 percent and the purity of more than 99.5 percent through simple purification.

Description

Novel method for synthesizing ritonavir

Technical Field

The invention relates to the field of pharmaceutical chemistry, and in particular relates to a novel method for synthesizing ritonavir.

Background

Ritonavir has been synthesized in a few ways as reported to date, the main synthetic method being the condensation of two key intermediate structures, N- ((N-methyl-N- ((2-isopropyl-4-thiazolyl) methyl) amino) formyl) -L-valine and (2S, 3S, 5S) -5- (tert-butoxycarbonylamino) -2- (N-5-thiazolyl-methoxycarbonyl) amino-1, 6-diphenyl-3-hydroxyhexane. The two fragments are structurally as follows:

1.1N- ((N-methyl-N- ((2-isopropyl-4-thiazolyl) methyl) amino) formyl) -L-valine methyl ester (carboxylic acid intermediate) and 1.2(2S, 3S, 5S) -5-amino-2- (N-5-thiazolyl-methoxycarbonyl) amino-1, 6-diphenyl-3-hydroxyhexane (amino intermediate), the existing process for the condensation of the two fragments is reported as follows:

1) yapei WO9414436, formerly Yazhi corporation, which uses 1-ethyl- (3-dimethylaminopropyl) carbodiimide (EDC) as a condensing agent and 1-Hydroxybenzotriazole (HOBT) as a weak base for condensation; the method uses EDC and HOBt as reagents, which are expensive and have high production cost. The introduction of byproducts into the reaction reagent is more, and the post-treatment and purification are more complicated; is not beneficial to ensuring the product quality.

Another patent, Yapeh, of the same company as the original research, US5567823, reported the condensation of isobutyl chloroformate with N-hydroxysuccinimide under N-methylmorpholine. The isobutyl chloroformate and N-hydroxysuccinimide have relatively high price, the product yield of the method is only 70 percent, the industrial production cost is high, the reaction process has high requirement on the water content of the system, and the industrial production condition has high requirement.

2) Northeast pharmaceutical patents CN106749084 and CN106749085 respectively report that 2- (7-azabenzotriazole) -N, N' -tetramethylurea Hexafluorophosphate (HATU) and Diisopropylcarbodiimide (DIC) are used as condensing agents to perform condensation reaction. The reaction solvent chloroform has high toxicity and is not beneficial to the production safety; the reagents butanone and butyl acetate are not common solvents, which increases the difficulty of industrial mass production. The reaction byproducts of tetramethylurea, phosphorus-containing salts and the like are complicated in post-treatment and purification, and are not beneficial to ensuring the product quality.

In a word, the ritonavir synthesis process has the defects of expensive reaction reagent, low reaction yield and difficulty in controlling the process large production cost; the reaction conditions are harsh, the operation is complicated, and the control of the product quality is not facilitated.

Disclosure of Invention

In the field of production of chemical bulk drugs, the synthesis method which is originally feasible in a laboratory research stage, a small trial process stage or a Chinese process stage often has problems such as excessive impurity content, low purity, low yield and the like during industrial scale-up production; in addition, reagents available in laboratory research phase, pilot process phase or chinese process phase are not necessarily feasible in industrial production, and such examples are well known in the pharmaceutical drug substance preparation field. The same problem exists in the process of industrially preparing and synthesizing ritonavir, and the preparation method reported in the prior art is not suitable for industrial production.

Therefore, the technical problem to be solved by the invention is to provide a novel method for synthesizing ritonavir, which is suitable for industrial production.

In order to solve the problems in the prior art, the invention adopts the following technical scheme:

a novel method for synthesizing ritonavir,

it includes: adding pivaloyl chloride into the intermediate V at the temperature of between 5 ℃ below zero and 10 ℃, then dripping organic base, keeping the temperature in the reaction kettle at the temperature of between 5 ℃ below zero and 10 ℃, stirring for reaction for T1 time, then adding 4-dimethylaminopyridine, stirring for T2 time, finally adding dichloromethane solution of the intermediate VI, heating the reaction temperature to between 25 ℃ and 35 ℃, and stirring until the reaction is finished.

In some embodiments, the organic base is selected from one or more of triethylamine, N-Diisopropylethylamine (DIEPA), N-methylmorpholine, pyridine, and 1, 8-diazabicycloundec-7-ene (DBU); in some embodiments, the organic base is triethylamine.

In some embodiments, the T1 time is greater than 0.5 hours, preferably greater than 1 hour, and in certain embodiments from 1 to 2 hours. In some embodiments, the T2 time is 0.5 hour.

The invention has the advantages that:

the pivaloyl chloride, 4-dimethylamino pyridine, dichloromethane and organic base are combined in the reaction, so that the reaction activation stage of the intermediate V and the pivaloyl chloride can be ensured, and the carboxylic acid is completely activated; pivaloyl chloride is added into the intermediate V, then organic base and 4-dimethylamino pyridine are added dropwise, and finally dichloromethane solution of the intermediate VI is added. In addition, other materials are added into the materials during the process of adding the materials at proper intervals of T1 and T2, so that the yield and the purity of the reaction are improved. Due to the adoption of the technical scheme, the invention has the following beneficial effects:

1) common industrial raw materials and reagents are changed, so that the method is suitable for industrial mass production;

2) the reaction reagent by-product is liquid at normal temperature, the post-treatment and the product purification are easy, and the product quality can be well controlled;

3) the price of the reaction raw material reagent is proper, which is beneficial to the control of the production cost;

4) the reaction condition is simple, the operation is convenient, and the improvement of large-scale production capacity is facilitated;

5) the yield is more than 85 percent and the purity is more than 99.7 percent through simple purification.

Drawings

Figure 1 shows a high performance liquid chromatography assay profile of the finished ritonavir product prepared in example 1 of the present invention.

Detailed Description

In order to make the technical solutions of the present invention better understood by those skilled in the art, the following further discloses some non-limiting examples to further explain the present invention in detail.

EXAMPLE 1A novel Process for the Synthesis of ritonavir

Vacuumizing a reaction kettle R101, breaking the nitrogen, adding 1500kg of dichloromethane and 165kg of intermediate V into the kettle under the protection of the nitrogen, starting stirring, and cooling to 5 +/-5 ℃; adding 58.0kg of pivaloyl chloride into a kettle; after the addition, the temperature of the reaction kettle R101 is kept at 5 +/-5 ℃, and 50.0g of triethylamine is dropwise added into the kettle through a high-level tank V101-I; after dripping, keeping the temperature in the reaction kettle at 5 +/-5 ℃, and stirring for reaction for 1-2 hours; 12.0kg of 4-Dimethylaminopyridine (DMAP) was added to the kettle and stirred for 30 minutes, followed by the addition of a solution of intermediate VI in dichloromethane (183.0g in 500 kg); after the addition, raising the temperature in the kettle to 30 +/-5 ℃, and stirring for reaction for 8-10 hours; sampling and detecting the intermediate VI by HPLC to completely react.

Method for post-treating ritonavir reaction solution

Keeping the temperature in the reaction kettle at 20 +/-5 ℃, slowly adding 5% sodium hydroxide aqueous solution (500kg), stirring for 30 minutes, and standing for 30 minutes; transferring the lower organic phase to a reaction kettle R102, and transferring the upper water layer to a storage tank;

adding a 5% sodium hydroxide aqueous solution (500kg) into the R102 kettle, stirring for 30 minutes, standing for 30 minutes, transferring a lower organic phase to the reaction kettle R101, and combining an upper water layer to a storage tank;

adding 1M dilute hydrochloric acid solution (60kg industrial hydrochloric acid is dissolved in 500kg water) into an R101 kettle, stirring for 30 minutes, standing for 30 minutes, and separating out a water layer; transferring the lower organic phase to a reaction kettle R103;

keeping the temperature in the reaction kettle R103 less than 50 ℃, and starting reduced pressure distillation to recover dichloromethane until no fraction exists;

adding 180kg of ethyl acetate into the reaction kettle R103, continuously keeping the temperature in the reaction kettle R102 less than 50 ℃, and distilling the ethyl acetate under reduced pressure until no fraction exists basically;

adding 1000.0kg of ethyl acetate into a reaction kettle R103, raising the temperature in the kettle to 45 +/-5 ℃, stirring until the temperature is completely dissolved, then adding 100kg of anhydrous sodium sulfate and 20kg of active carbon, raising the temperature in the kettle to 65 +/-5 ℃, and stirring for decoloring for 30 minutes;

and (3) preserving the heat of the materials in the reaction kettle R103 at 65 +/-5 ℃, filtering the materials through a filter press, washing the kettle wall of the reaction kettle R103 and a filter cake with 80.0kg of ethyl acetate, and transferring the filtrate into the reaction kettle R201 in a clean area.

Keeping the temperature in the reaction kettle R201 at 65 +/-5 ℃, adding 800kg of n-heptane, and stirring for 30 minutes under heat preservation;

reducing the temperature in the reaction kettle R201 to 35 +/-5 ℃ within 4-5 hours, separating out solids, and stirring for 1 hour under the condition of heat preservation;

continuously reducing the temperature in the reaction kettle R201 to 15 +/-5 ℃, and keeping the temperature and stirring for 1 hour;

putting the materials in the reaction kettle R201 into a centrifugal machine for spin-filtering, and leaching 40kg of mixed solution of 23kg of ethyl acetate and 17kg of normal heptane;

putting the solid wet product into a double cone, controlling the temperature to be 50 +/-5 ℃, drying under reduced pressure, cooling to be 25 +/-5 ℃, discharging and packaging to obtain 260 kg-280 kg of finished ritonavir, wherein the yield is more than 85%, the purity is 99.795%, and the details are shown in figure 1.

The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A novel method for synthesizing ritonavir,

2. The novel process for the synthesis of ritonavir as claimed in claim 1, wherein the organic base is one or more of triethylamine, N-diisopropylethylamine, N-methylmorpholine, pyridine and 1, 8-diazabicycloundec-7-ene.

3. The novel process for the synthesis of ritonavir as claimed in claim 2, wherein the organic base is triethylamine.

4. The novel process for the synthesis of ritonavir as claimed in claim 1, wherein the time T1 is 0.5 hours or more and the time T2 is within 1.0 hour.

5. The novel process for the synthesis of ritonavir as claimed in claim 4, wherein the time T1 is 1-2 hours and the time T2 is 0.5 hours.

6. A novel process for the synthesis of ritonavir as claimed in claim 1 comprising: adding organic base into the intermediate V at the temperature of between 5 ℃ below zero and 10 ℃, then dripping pivaloyl chloride, keeping the temperature in the reaction kettle at the temperature of between 5 ℃ below zero and 10 ℃, stirring for reaction for T1 time, then adding 4-dimethylaminopyridine, stirring for T2 time, finally adding the dichloromethane solution of the intermediate VI, heating the reaction temperature to between 25 and 35 ℃, and stirring until the reaction is finished.