CN109082450B - Method for producing sitagliptin free base by using continuous flow technology - Google Patents
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Abstract
The invention discloses a method for producing sitagliptin free alkali by using a continuous flow technology, which comprises the steps of respectively dissolving a reaction substrate and an enzyme reduction system in an organic solvent, pumping a material solution into a microchannel reactor by using a feeding pump, and fully mixing, wherein the feeding ratio of the substrate solution to the enzyme reduction system solution is 1: 1-1: 3, the reaction temperature is 40-50 ℃, and the retention time is 30-120 mins; meanwhile, a small amount of raw materials which are not completely reacted in the post-treatment kettle are prepared into a solution through concentration and enrichment and then return to a reaction system again, so that the utilization rate of the raw materials is improved to the maximum extent, and the continuous production of the sitagliptin free alkali enzymatic reaction is realized. The method has the advantages of high yield, less side reactions, simple operation, great improvement on production efficiency and capability of quickly, stably and continuously obtaining the sitagliptin free base intermediate.
Description
Technical Field
The invention relates to application of a continuous flow technology in sitagliptin enzymatic reaction, belonging to the technical field of medicine preparation.
Background
The traditional chemical pharmaceutical industry always depends on intermittent production, the amplification effect needs to be considered and the influence of strong heat release high-temperature conditions needs to be avoided, usually, a typical periodic production needs several weeks, the production belongs to labor-intensive industry, and the quality of products produced in each batch is different, so that the traditional intermittent production mode always faces the pressure of all aspects such as quality, cost, safety, environmental protection and the like.
In recent years, flow chemistry techniques typified by microchannel reactors have been developed. The micro channel structure of the microchannel reactor has higher specific surface area, better mixing, mass transfer and heat transfer efficiency than a kettle reactor, and has the obvious advantages of short reaction time, high conversion rate, high yield, small occupied area and the like by accurately controlling the reaction through controlling the process parameters such as mixing degree, temperature, pressure, residence time and the like.
Because the microchannel continuous production mode is safe, stable, intuitive and high in selectivity, the pharmaceutical industry has started to develop a new process of complex chiral drugs by using a continuous flow synthesis method and gradually accepts the concept of continuous production, and many large pharmaceutical enterprises around the world are adopting the continuous production mode and are changing in leading industries, including the FDA in the united states, and all large pharmaceutical enterprises are also always encouraged to adopt the continuous flow process for drug production.
Sitagliptin phosphate (Sitagliptin phosphate) is the first dipeptidyl peptidase (DPP-IV) inhibitor developed by Merck corporation in the united states, approved by FDA to be marketed in 10 months in 2006, approved by the national food and drug administration to be marketed in china in 11 months 6 days in 2009, with trade names: jienowei (Januvia). The sitagliptin phosphate is mainly used for treating type II diabetes, has obvious hypoglycemic effect when being used alone or being used together with metformin and pioglitazone, is safe to take, has good tolerance and few adverse reactions, and has great market demand.
Sitagliptin phosphate has the following structure:
the American Merck company is in the leading position of innovation in the synthesis process, a plurality of process routes are successively proposed, the latest generation of process can refer to international patent WO2005003135 and Chinese granted patent CN103608355B, and for the chiral amination reduction part, a traditional chemical metal catalysis method is replaced by biological enzyme catalysis, and the process routes are summarized as follows:
researches show that compared with the traditional metal catalyst, the biological enzymatic reaction has obvious advantages in the aspects of controlling chiral purity and reaction impurities due to stronger specificity and selectivity, but has the characteristics of long reaction time (usually more than 24 hours), incomplete conversion, higher by-product and lower yield (usually 75-80%), and meanwhile, the enzymatic activity is reduced easily, the yield is low, the production cost is higher, and the development of the enzymatic process is restricted due to long-time reaction. Therefore, the development of a more efficient, energy-saving and low-cost production method has important practical significance.
Disclosure of Invention
The invention aims to improve the conversion rate and the production efficiency of sitagliptin enzymatic reaction by using a micro-channel continuous flow technology, realize continuous production and save cost. The product obtained by the process has good stability, high purity, convenient process operation, high productivity, solvent and cost saving, and is suitable for large-scale production.
The technical scheme adopted by the invention is as follows:
a method for producing sitagliptin free alkali by using a continuous flow technology comprises the steps of respectively dissolving a reaction substrate and an enzyme reduction system in an organic solvent, pumping a material solution into a microchannel reactor by using a feeding pump, and fully mixing, wherein the feeding ratio of the substrate solution to the enzyme reduction system solution is 1: 1-1: 3, the reaction temperature is 40-50 ℃, and the retention time is 30-120 mins; meanwhile, a small amount of raw materials which are not completely reacted in the post-treatment kettle are prepared into solution to be returned to the reaction system again through concentration and enrichment, so that the utilization rate of the raw materials is improved to the maximum extent, the continuous production of the sitagliptin free alkali enzymatic reaction is realized,
wherein, the reaction substrates are: (2Z) -4-oxo-4- [3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7- (8H) -yl ] -1- (2,4, 5-trifluorophenyl) butan-2-one, the structural formula of which is shown in the specification
The pH control range of the DMSO solution of the prepared enzyme reduction system is 8.0-9.0. The specific composition and mass relationship of the enzyme reduction system is m [ isopropylamine ]]: m [ concentrated hydrochloric acid]: m [ GB71# enzyme]：m[PLP]：m[DMSO]:m[H2O]＝1.6～2.0:1.4～1.8:
4.5～6.0:0.01～0.02:8～12:6～10。
The enzyme is specifically Escherichia coli cell sap, and the active component is transaminase ATA117 with trade name GB71# enzyme.
The feeding flow ratio of the substrate solution to the enzyme reduction system solution is 1: 2.
The feeding flow rate range of the substrate solution is 2-10 mL/min, and the feeding flow rate range of the enzyme reduction system is 2-30 mL/min.
The microchannel reaction was carried out at a reaction temperature of 45 ℃.
The residence time of the microchannel reaction was 50 mins.
The material of the selected microchannel reactor is silicon carbide ceramics, stainless steel and special glass.
The inner diameter range of the channel of the selected micro-channel reactor is 50-3000 μm. The channel types are a variety of variable channels (including hearts, diamonds, etc.) and plug flow packing tubes.
The micro-channel technology continuous production method for sitagliptin enzymatic reaction researched by the invention is reported for the first time.
The technical principle adopted by the invention is as follows: the microchannel reactor has a micro channel structure and a higher specific surface area, has better mixing, mass transfer and heat transfer efficiency than a kettle reactor, accurately controls the reaction by controlling the technological parameters such as mixing degree, temperature, pressure, residence time and the like, has the obvious advantages of short reaction time, high conversion rate, high yield, small occupied area and the like, and can realize the continuous production of sitagliptin enzymatic reaction.
The reaction principle adopted by the invention is as follows:
the continuous production process flow chart of enzymatic reaction is shown in figure 1, a reaction substrate and an enzyme reduction system are respectively dissolved in an organic solution, a material solution is pumped into a microchannel reactor by using a feeding pump to be fully mixed, comparative experiments under different process conditions are designed, the reaction conversion rate is detected by sampling HPLC (high performance liquid chromatography) at the outlet of the reactor, the influence of the material feeding ratio, the reaction temperature and the retention time on the reaction conversion rate is respectively inspected, the productivity is evaluated, and the optimal process conditions of the microchannel reactor are obtained by screening: the feeding ratio of the substrate solution to the enzyme reduction system solution is 1:2, the reaction temperature is 45 ℃, and the retention time is 50 mins; meanwhile, a small amount of raw materials which are not completely reacted in the post-treatment kettle are prepared into a solution through multiple concentration and enrichment and then return to a reaction system again, so that the utilization rate of the raw materials is improved to the maximum extent, and the continuous production of the sitagliptin free alkali enzymatic reaction is realized.
Wherein the concentration and enrichment of the small amount of raw materials which are not completely reacted are as follows: distilling the raw material extract phase in a reaction kettle under reduced pressure to remove the solvent, controlling the internal temperature to be less than 50 ℃ to obtain oily concentrated solution, and preparing the oily concentrated solution into DMSO solution with the mass fraction of 38-42%.
The selected reaction organic solvent is DMSO or DMF strong polar solvent.
The selected extraction organic solvent is one or more of ethyl acetate, isopropyl acetate, methyl tert-butyl ether, normal hexane and normal heptane, and the extraction solvent can be repeatedly utilized to enrich the raw materials for many times.
The specific example provides a preparation method of a starting material solution, which comprises the following steps:
preparing a substrate solution: 5.0Kg of Compound 1 was dissolved in 8.0Kg of DMSO, and the resulting solution was heated and stirred.
Preparing an enzyme reduction system solution: dissolving 1.8Kg of isopropylamine in 4.0Kg of water to prepare a solution, adding 1.5Kg of concentrated hydrochloric acid to adjust the pH to 9.0, adding 10.0Kg of DMSO, 4.0Kg of water and 0.01Kg of coenzyme (PLP) to obtain a yellow clear solution, adding hydrochloric acid to adjust the pH to 9.0, adding 5.0Kg of GB71# enzyme, and uniformly stirring for later use, wherein the pH control range of the DMSO solution is 8.0-9.0.
Wherein the feeding ratio of the substrate solution for carrying out the microchannel reaction to the enzyme reduction system solution is 1: 1-1: 3. The feeding flow rate range of the substrate solution is 2-10 mL/min, and the feeding flow rate range of the DMSO solution of the enzyme reduction system is 2-30 mL/min.
The specific example provides related parameters and specifications of a microchannel reactor as follows: Si-C material of 200-1000 μm, liquid holdup of 750mL, made in China.
The specific example provides a HPLC detection method, 1mL of sample is taken at the outlet of a microchannel reactor, 1 drop of dilute hydrochloric acid is added for acidification, the reaction conversion rate is detected by HPLC, and if the conversion rate is more than 95.0%, the reaction meets the requirement.
The specific screening process of the optimal process parameter conditions of the microchannel reactor comprises the following steps: and designing a contrast experiment, detecting the reaction conversion rate by adopting HPLC, respectively inspecting the influence of the material feeding ratio, the reaction temperature and the retention time on the conversion rate, and comprehensively evaluating the productivity to obtain the optimal process condition. The method comprises the following specific steps:
the correlation calculation formula:
the residence time and the substrate flow rate satisfy the following relationship: t is V/(a + b), unit: min;
v, liquid holdup (ml), a, substrate flow rate (ml/min), b, reductase system flow rate (ml/min)
The substrate consumption per day and the substrate flow rate satisfy the following relationship: g ═ 60 × 24 × Ma×a)/(1000×Va) The unit: kg;
Maquality (Kg) of substrate in the prepared substrate solution, Va: volume of substrate solution prepared (L)
Description of the drawings: the reaction temperature range of the microchannel reactor is determined to be narrow according to the suitable temperature range of the reductase activity of 40-50 ℃, and the influence is small. The median value of 45 ℃ was chosen here as the optimum reaction temperature, and the reaction temperature was no longer investigated separately.
(1) The influence of different feed ratios on the reaction conversion was examined at a reaction temperature of 45 ℃ and a residence time of 50mins, and the results are shown in Table 1.
TABLE 1 Effect of different feed ratios on reaction conversion
The experimental results show that: under the condition that the reaction temperature and the residence time are the same, the feeding ratio determines the flow rate of the substrate, when the feeding ratio is 1:3, the flow rate of the substrate is minimum, although the conversion rate can meet the requirement (more than 95.0 percent), the consumption of the substrate per day is minimum, and the production efficiency is influenced; at a feed ratio of 1:1, the substrate flow rate was maximized, and although the productivity could be ensured, the amount of reductase was insufficient, resulting in incomplete conversion of the reaction. Therefore, a feed ratio of 1:2 is the optimum condition under which the conversion rate of the reaction and the single-day productivity of the reactor are both desirable.
(2) The effect of residence time at different substrate flow rates on the conversion of the reaction was examined at a reaction temperature of 45 ℃ and a feed ratio of 1:2, and the results are shown in Table 2.
TABLE 2 influence of residence time on the conversion of the reaction
The experimental results show that: under the condition that the reaction temperature and the feeding ratio are the same, the length of the retention time depends on the flow velocity of the substrate, the smaller the flow velocity of the substrate is, the longer the retention time is, although the conversion rate can meet the requirement (more than 95.0%), the single-day consumption of the substrate is too small, and the production efficiency is influenced; the smaller the residence time, the higher the substrate flow rate, and the productivity can be ensured, but the reaction time is not enough, and the conversion is incomplete. Therefore, the substrate flow rate a of 5.0ml/min is the optimum condition, and the conversion rate of the reaction and the single-day productivity of the reactor are both ideal.
In summary, the optimal reaction conditions are: the reaction temperature is 45 ℃, the feeding flow ratio of the substrate solution to the enzyme reduction system solution is 1:2, and the retention time is 50 mins. Example 2 demonstrates that the conversion range for the microchannel reactor under this process condition is: 96.2 to 97.8 percent, realizes continuous reaction for 24 hours, theoretically produces 3.0Kg of product every day, and actually obtains 2.7Kg, the yield is 90.0 percent, and the purity is 99.3 percent.
The process conditions are different from different production requirements in terms of different microchannel reactors, and specific parameters are different. Relevant process parameters such as material feeding ratio, reaction temperature, residence time and the like are adjusted according to actual conditions, so that continuous and stable optimal process conditions can be obtained.
Has the advantages that: the continuous production method for preparing the sitagliptin free base intermediate has the advantages of high conversion rate, less side reaction, convenient operation, high product yield, solvent saving, occupied area saving, great improvement on production efficiency and contribution to industrialization, and DMSO, the ester solvent and alkane or naphthenic hydrocarbon used by the method belong to three types of solvents with low toxicity in organic solvents, and the sitagliptin free base intermediate can be quickly, stably and continuously obtained.
Drawings
FIG. 1: a continuous production process flow diagram of enzymatic reaction;
FIG. 2: sampling HPLC spectrogram of sitagliptin enzymatic reaction;
FIG. 3: HPLC chromatogram of sitagliptin free base intermediate.
Detailed Description
The following examples are intended to further clarify and fully illustrate the present invention, and are intended to be only partial examples, not all examples, and should not be construed as limiting the scope of the present invention, and modifications and adaptations thereof based on non-invasive results may occur to those skilled in the relevant art and are within the scope of the present invention.
The enzyme is Escherichia coli cell sap, and its active component is transaminase ATA117, with trade name of GB71# enzyme, and is from Jiangsu American Biotechnology Ltd.
Example 1
Adding 50.0g of 2,4, 5-trifluorophenylacetic acid, 40.0g of isopropylidene malonate, 0.25g of dimethylaminopyridine and 240g of acetonitrile into a 1000L jacketed reaction kettle, cooling to 0-5 ℃, dropwise adding 72.0g N, N-diisopropylethylamine, obviously releasing heat, controlling the temperature to be not more than 25 ℃, cooling to 0-10 ℃ after dropwise adding, dropwise adding 42.3g of pivaloyl chloride, controlling the temperature to be not more than 20 ℃, and adding 3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazine hydrochloride once after dropwise adding. Heating the reaction to 60-65 ℃, reacting for 6 hours, sampling, monitoring the completion of the reaction, cooling to 0-5 ℃, slowly dropwise adding 240g of 3% sodium hydroxide solution, generating a large amount of precipitate, performing suction filtration, pulping and washing a filter cake with 20% acetonitrile-water solution (150mL x 2), and drying to obtain 92.8g of a product (compound 1), wherein the yield is 86.8% and the purity is 99.1%.
Example 2
Preparing a substrate solution: 5.0Kg of Compound 1 was dissolved in 8.0Kg of DMSO, and the resulting solution was heated and stirred.
Preparing an enzyme reduction system solution: dissolving 1.8Kg of isopropylamine in 4.0Kg of water to prepare a solution, adding 1.5Kg of concentrated hydrochloric acid to adjust the pH to 9.0, adding 10.0Kg of DMSO, 4.0Kg of water and 0.01Kg of coenzyme (PLP) to obtain a yellow clear solution, adding hydrochloric acid to adjust the pH to 9.0, adding 5.0Kg of GB71# enzyme, and stirring uniformly for later use.
Micro-channel reaction: the method comprises the following steps of setting a jacket temperature of 45 ℃ and a substrate solution feeding pump flow of 5mL/min in a microchannel reactor (made of Si-C materials, 200-1000 mu m, made in China, and 750mL of liquid holdup), setting the substrate solution feeding pump flow of 10mL/min, setting a feeding ratio of 1:2 and a retention time of 50mins, and fully mixing and reacting the two materials in the reactor.
Samples were taken at the reactor outlet for HPLC detection. The specific operation is as follows: sampling 1mL at the outlet of the microchannel reactor, adding 1 drop of dilute hydrochloric acid for acidification, and detecting the reaction conversion rate by HPLC, wherein if the conversion rate is more than 95.0 percent, the reaction meets the requirement. Actual multiple detection results: the conversion rate is 96.2-97.8%.
The outlet end of the reactor is connected with a reaction kettle to collect reaction liquid (the first batch is intermittent, and the subsequent batches are continuously operated), hydrochloric acid and diatomite are added for stirring and filtering, filtrate is transferred into an extraction kettle, residual substrate and impurities are extracted by ethyl acetate (concentrated and enriched for multiple times, dissolved by a solvent and then transferred back to a substrate solution), a water phase is transferred into the next reaction kettle, sodium hydroxide is added for alkali adjustment, products are extracted by ethyl acetate, reduced pressure distillation, crystallization and centrifugation are carried out, and sitagliptin free alkali is obtained. The continuous reaction is realized for 24 hours, 3.0Kg of product is theoretically produced every day under the process condition, 2.7Kg of product is actually obtained, the yield is 90.0%, and the purity is 99.3%.
It is to be noted that: according to different production requirements, different microchannel reactors are selected, parameters such as liquid holdup, feed ratio, reaction temperature, residence time and the like are different, and optimal process conditions need to be formed by debugging for many times according to actual conditions.
Claims (8)
1. A method for producing sitagliptin free base by using a continuous flow technology, which is characterized by comprising the following steps: respectively dissolving a reaction substrate and an enzyme reduction system in an organic solvent, pumping a material solution into a microchannel reactor by using a feeding pump, and fully mixing, wherein the feeding ratio of the substrate solution to the enzyme reduction system solution is 1: 1-1: 3, the reaction temperature is 40-50 ℃, and the retention time is 30-120 mins; meanwhile, a small amount of raw materials which are not completely reacted in the post-treatment kettle are prepared into solution to be returned to the reaction system again through concentration and enrichment, so that the utilization rate of the raw materials is improved to the maximum extent, the continuous production of the sitagliptin free alkali enzymatic reaction is realized,
wherein, the reaction substrates are: (2Z) -4-oxo-4- [3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7- (8H) -yl ] -1- (2,4, 5-trifluorophenyl) butan-2-one;
the composition and mass relationship of each substance in the enzyme reduction system are m [ isopropylamine ]]: m [ concentrated hydrochloric acid]: m [ enzyme]：m[PLP]：m[DMSO]: m[H2O]=1.6~2.0:1.4~1.8:4.5~6.0:0.01~0.02:8~12:6~10；
The feeding flow rate range of the substrate solution is 2-10 mL/min, and the feeding flow rate range of the enzyme reduction system is 2-30 mL/min.
2. The process for the production of sitagliptin free base using continuous flow technology according to claim 1, characterized in that: the reaction organic solvent is DMSO or DMF.
3. The process for the production of sitagliptin free base using continuous flow technology according to claim 1, characterized in that: the feeding flow ratio of the substrate solution to the enzyme reduction system solution is 1: 2.
4. The process for the production of sitagliptin free base using continuous flow technology according to claim 1, characterized in that: the microchannel reaction was carried out at a reaction temperature of 45 ℃.
5. The process for the production of sitagliptin free base using continuous flow technology according to claim 1, characterized in that: the residence time of the microchannel reaction was 50 mins.
6. The process for the production of sitagliptin free base using continuous flow technology according to claim 1, characterized in that: the material of the selected microchannel reactor is silicon carbide ceramics, stainless steel and special glass.
7. The process for the production of sitagliptin free base using continuous flow technology according to claim 1, characterized in that: the inner diameter range of the selected micro-channel reactor is 50-3000 mu m, and the channel types are various variable channels and plug flow filler pipelines.
8. The process for the production of sitagliptin free base using continuous flow technology according to claim 1, characterized in that: the enzyme is transaminase, and the pH value of the DMSO solution in the enzyme reduction system is controlled to be 8.0-9.0.
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