CN109082450A - A method of applying continuous Flow Technique production Xi Gelieting free alkali - Google Patents
A method of applying continuous Flow Technique production Xi Gelieting free alkali Download PDFInfo
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Abstract
The invention discloses a kind of methods for applying continuous Flow Technique production Xi Gelieting free alkali, reaction substrate and enzyme reduction system are dissolved in organic solvent respectively, use feed pump, material solution is pumped into micro passage reaction and is sufficiently mixed, the charge ratio of substrate solution and enzyme reduction system solution is 1:1 ~ 1:3, reaction temperature is 40 ~ 50 DEG C, 30 ~ 120mins of residence time；Meanwhile by unreacted in post-processing kettle, completely a small amount of raw material is configured to solution and is come back in reaction system by enrichment method, is maximized and is improved raw material availability, realizes the continuous production of Xi Gelieting free alkali enzymatic reaction.This method high income, side reaction is few, easy to operate, and production efficiency is greatly improved, can fast and stable be continuously available Xi Gelieting free alkali intermediate.
Description
Technical field
The present invention relates to a kind of application of continuous Flow Technique in Xi Gelieting enzymatic reaction, belong to pharmaceutical formulation techniques neck
Domain.
Background technique
Traditional chemical industry pharmaceutical industry is produced by intermittent mode all the time, is needed in view of enlarge-effect and is avoided
The influence of some strongly exothermic hot conditions, usual one typical interim production need several weeks, belong to labor-intensive production,
And the product quality that every batch of is produced has differences, therefore traditional batch production method is faced with always quality, cost, peace
Entirely, the pressure of the various aspects such as environmental protection.
In recent years, it comes into being by the flowing chemical technology of representative of micro passage reaction.Micro passage reaction is small
Channel design specific surface area with higher has better mixing, mass transfer, heat transfer efficiency than tank reactor, passes through control
The technological parameters such as mixability, temperature, pressure, residence time have the reaction time short the accurate control of reaction, high conversion rate,
High income, the small equal clear superiorities of occupied area.
Because microchannel continuous production mode is safe and stable, intuitive, selectivity is higher, pharmaceutical industry has begun benefit
The new process of complicated chiral drug is developed with continuous flow synthetic method and gradually receives the concept of continuous production, and the whole world is many greatly
Type pharmacy corporation is using continuous production mode and is also encouraging major medicine always in guidance industry transformation, including U.S. FDA
Enterprise carries out drug production using continuous flow process.
Phosphoric acid Xi Gelieting (Sitagliptin phosphate) is first two peptidyl of Merck company of U.S. exploitation
Peptase (DPP-IV) inhibitor is ratified to list in October, 2006 by FDA, 6 Nikkei state food drug November in 2009 prison
Management board's approval is superintended and directed in Discussion on Chinese Listed, trade name: Jie Nuowei (Januvia).Phosphoric acid Xi Gelieting is mainly used for treating II type sugar
Urine disease, is applied alone or has shared apparent blood sugar reducing function with melbine, Pioglitazone, and take safety, tolerance is good, no
Good reaction is few, has the great market demand.
Phosphoric acid Xi Gelieting structure is as follows:
Merck company of the U.S. is constantly in innovation leading position on synthesis technology, successively proposes a plurality of process route,
The technique of latest generation can refer to international monopoly WO2005003135 and Chinese granted patent CN103608355B, for Chiral Amine
Change reduction part, use biological enzyme and replace traditional chemical metal catalyzed process, process route is summarized as follows:
The study found that compared to conventional metals catalyst, biological enzymatic reaction due to stronger specificity and selectivity,
It has a clear superiority in terms of control chiral purity and reaction impurities, it is still, long (usually for 24 hours more than) there is also the reaction time, turn
Change not exclusively, by-product is higher, yield relatively low (the characteristics of usual 75~80%), while prolonged reaction be easy to cause enzyme activity
Property reduce, production capacity it is low, production cost is higher, restrict enzymatic process development.Therefore, it develops a kind of more efficient, energy saving, low
The production method of cost has important practical significance.
Summary of the invention
The purpose of the present invention is utilizing the continuous Flow Technique in microchannel, conversion ratio and the production of Xi Gelieting enzymatic reaction are improved
Efficiency realizes continuous production, save the cost.The product stability that this technique obtains is good, and purity is high, technological operation is convenient, produces
Can be high, solvent and cost are saved, large-scale production is suitble to.
The technical solution adopted by the present invention are as follows:
A method of continuous Flow Technique production Xi Gelieting free alkali is applied, reaction substrate and enzyme reduction system are distinguished
Dissolution in organic solvent, using feed pump, material solution is pumped into micro passage reaction and is sufficiently mixed, substrate solution and enzyme
The charge ratio of reduction system solution is 1:1~1:3, and reaction temperature is 40~50 DEG C, 30~120mins of residence time；Meanwhile it will
Post-processing unreacted in kettle, completely a small amount of raw material is configured to solution and is come back in reaction system by enrichment method, maximum
Change and improve raw material availability, realizes the continuous production of Xi Gelieting free alkali enzymatic reaction,
Wherein, reaction substrate are as follows: (2Z) -4- oxo -4- [3- (trifluoromethyl) -5,6- dihydro-[1,2,4] triazol [4,
3-a] pyrazine -7- (8H)-yl] -1- (2,4,5- trifluorophenyl) butyl- 2- ketone, structural formula is as follows
The pH control range of the DMSO solution of the enzyme reduction system configured is 8.0~9.0.Specific group of enzyme reduction system
At and relationship between quality be 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.
Enzyme used is specially a kind of Bacillus coli cells liquid, and active constituent is transaminase ATA117, trade name GB71# enzyme.
The feed rate ratio of substrate solution and enzyme reduction system solution is 1:2.
The feed flow rate range of substrate solution is 2~10mL/min, the feed flow rate range of enzyme reduction system is 2~
30mL/min。
Carrying out the reaction temperature that microchannel plate is answered is 45 DEG C.
The residence time that microchannel plate is answered is 50mins.
The material of selected micro passage reaction is silicon carbide ceramics, stainless steel, special glass.
The channel internal diameter range of selected micro passage reaction is 50 μm~3000 μm.Channel type be it is a variety of can be flexible
Road (including cardioid, diamond shape etc.) and plug flow loading pipe road.
The microchannel continuous production method for the Xi Gelieting enzymatic reaction that the present invention studies is to report for the first time.
The technical principle that the present invention uses are as follows: micro passage reaction has small channel design and higher specific surface
Product has better mixing, mass transfer, heat transfer efficiency than tank reactor, when by control mixability, temperature, pressure, stop
Between equal technological parameters to the accurate control of reaction, have the reaction time short, high conversion rate, high income, occupied area is small equal obvious excellent
The continuous production of Xi Gelieting enzymatic reaction may be implemented in gesture.
The reaction principle that the present invention uses are as follows:
The continuous production process figure of enzymatic reaction of the invention is as shown in Figure 1, by reaction substrate and enzyme Reduction Body
System is dissolved in organic solution respectively, using feed pump, material solution is pumped into micro passage reaction and is sufficiently mixed, and design is not
With the comparative experiments under process conditions, HPLC is sampled by reactor outlet and detects reaction conversion ratio, investigates material charging respectively
Than, the influence of reaction temperature, residence time to reaction conversion ratio, and production capacity is assessed, screening obtains the optimal of micro passage reaction
Process conditions: the charge ratio of substrate solution and enzyme reduction system solution is 1:2, and reaction temperature is 45 DEG C, residence time 50mins；
Meanwhile completely a small amount of raw material is configured to solution and comes back to reaction by multiple enrichment method by unreacted in post-processing kettle
It in system, maximizes and improves raw material availability, realize the continuous production of Xi Gelieting free alkali enzymatic reaction.
The wherein enrichment method of the complete a small amount of raw material of the unreacted are as follows: raw material abstraction mutually steam in a kettle by decompression
Solvent is removed in distillation, control in 50 DEG C of < of temperature, obtain oily concentrate, then be configured to mass fraction 38%~42% DMSO it is molten
Liquid.
Selected reaction organic solvent is DMSO or DMF class intensive polar solvent.
Selected extraction organic solvent is ethyl acetate, isopropyl acetate, methyl tertiary butyl ether(MTBE), n-hexane, normal heptane
One or more of, extractant can be recycled, multiple rich material.
Specific example provides a kind of preparation method of starting material solution:
Substrate solution is prepared: 5.0Kg compound 1 is dissolved in 8.0Kg DMSO, heating stirring dissolved clarification.
Enzyme reduction system solution is prepared: 1.8Kg isopropylamine, which is dissolved in 4.0Kg water, is configured to solution, adds 1.5Kg concentrated hydrochloric acid tune
PH=9.0 is saved, 10.0Kg DMSO, 4.0Kg water is added, 0.01Kg coenzyme (PLP) obtains yellow clear solution, then plus hydrochloric acid adjusting
PH=9.0 adds 5.0Kg GB71# enzyme, stirs evenly spare, and the pH control range of DMSO solution is 8.0~9.0.
The charge ratio of substrate solution and enzyme reduction system solution that wherein the progress microchannel plate is answered is 1:1~1:3.
The feed flow rate range of substrate solution is 2~10mL/min, the feed flow rate range of the DMSO solution of enzyme reduction system is 2~
30mL/min。
Wherein specific example provides the relevant parameter and specification of a kind of micro passage reaction are as follows: Si-C material, 200~
It is 1000 μm, liquid holdup 750mL, domestic.
Wherein specific example provides a kind of method of HPLC detection: sampling 1mL in micro passage reaction exit, adds 1
Dilute hydrochloric acid acidification is dripped, HPLC detects reaction conversion ratio, if conversion ratio > 95.0%, reaction meets the requirements.
The wherein specific screening process of the optimal procedure parameters condition of the micro passage reaction are as follows: comparison of design is real
It tests, reaction conversion ratio is detected using HPLC, investigate the influence of material charge ratio, reaction temperature, residence time to conversion ratio respectively,
Comprehensive assessment production capacity, obtains Optimal technique process.It is specific as follows:
Relevant calculation formula:
Residence time and substrate flow velocity meet following relationship: t=V/ (a+b), unit: min；
V: liquid holdup (ml), a: substrate flow velocity (ml/min), b: reduction enzyme system flow velocity (ml/min)
The consumption of substrate odd-numbered day meets following relationship: G=(60 × 24 × M with substrate flow velocitya×a)/(1000×Va), unit:
Kg；
Ma: the substrate solution indsole amount of substance (Kg) of preparation, Va: the volume (L) of the substrate solution of preparation
Illustrate: 40~50 DEG C of temperature range for being suitable for according to reductase activity determine the reaction temperature of micro passage reaction
It is relatively narrow to spend range, influences less.45 DEG C of median are chosen herein and is used as peak optimization reaction temperature, and no longer reaction temperature is individually examined
It examines.
(1) under the conditions of 45 DEG C of reaction temperature, residence time 50mins, the shadow that different feeds compare reaction conversion ratio is investigated
It rings, the results are shown in Table 1.
The influence of 1 different feeds of table comparison reaction conversion ratio
According to the experimental results: under reaction temperature and residence time identical situation, charging ratio determines substrate flow velocity
Size, when charge ratio is 1:3, substrate flow velocity is minimum, although conversion ratio can satisfy requirement (> 95.0%), substrate list
Daily consumption is minimum, influences production efficiency；And charge ratio is when being 1:1, substrate flow velocity is maximum, although can guarantee production capacity, also
The amount of protoenzyme is insufficient, causes reaction conversion incomplete.Therefore, it is optimal conditions that charge ratio, which is 1:2, under this feed conditions, instead
The odd-numbered day production capacity of the conversion ratio and reactor answered is ideal.
(2) under the conditions of 45 DEG C of reaction temperature, charge ratio 1:2, the residence time under different substrate flow velocitys is investigated to reaction
The influence of conversion ratio, the results are shown in Table 2.
Influence of 2 residence time of table to reaction conversion ratio
According to the experimental results: under reaction temperature and the identical situation of charge ratio, the length of residence time depends on substrate
The size of flow velocity, substrate flow velocity is smaller, then the residence time is longer, although conversion ratio can satisfy requirement (> 95.0%), bottom
The consumption of object odd-numbered day is too small, influences production efficiency；And the residence time is smaller, substrate flow velocity is big, anti-although can guarantee production capacity
Between seasonable not enough, conversion is incomplete.Therefore, substrate flow velocity a=5.0ml/min is optimal conditions, under this flow conditions, reaction
Conversion ratio and reactor odd-numbered day production capacity it is ideal.
In conclusion optimal reaction condition are as follows: reaction temperature is 45 DEG C, substrate solution and enzyme reduction system solution into
Expect that flow-rate ratio is 1:2, residence time 50mins.The proof of embodiment 2, the conversion ratio model of micro passage reaction under this process condition
Enclosing is: 96.2%~97.8%, realize that serialization is reacted for 24 hours, theory output 3.0Kg product, actually obtains 2.7Kg daily, receives
Rate 90.0%, purity 99.3%.
The process conditions select different micro passage reactions for different production requirements, and design parameter has
Difference.Adjust material charge ratio, reaction temperature, the related process parameters such as residence time according to the actual situation, can obtain it is continuous,
Stable Optimal technique process.
The utility model has the advantages that the present invention prepares the continuous production method high conversion rate of Xi Gelieting free alkali intermediate, it is secondary anti-
It should lack, easy to operate, product yield is high, and solvent and occupied area are saved, production efficiency is greatlyd improve, is conducive to industrialize,
Used DMSO, esters solvent and alkane or cycloalkane are the three classes solvents for belonging to hypotoxicity in organic solvent, and energy
Enough fast and stables are continuously available Xi Gelieting free alkali intermediate.
Detailed description of the invention
Fig. 1: the continuous production process figure of enzymatic reaction；
Fig. 2: Xi Gelieting enzymatic reaction samples HPLC spectrogram；
Fig. 3: Xi Gelieting free alkali intermediate HPLC spectrogram.
Specific embodiment
Following embodiment is further clearly and completely to illustrate the present invention, and only section Example, is not all of implementation
Example is understood not to the limitation protected to the present invention, and the technical staff of relevant art is on without creative performance basis
Modifications of the present invention and adjustment belong to the content that the present invention protects.
Enzyme used is a kind of Bacillus coli cells liquid, and active constituent is transaminase ATA117, trade name GB71# enzyme, source
In Jiangsu Mei Ke Biotechnology Co., Ltd.
Embodiment 1
Addition 2,4, the 5- trifluoro benzene acetic acid of 50.0g into 1000L jacket reactor, 40.0g malonic acid ring Asia isopropyl ester,
0.25g dimethylamino naphthyridine and 240g acetonitrile are cooled to 0~5 DEG C, and 72.0g n,N-diisopropylethylamine is added dropwise, and heat release is obvious,
It controls temperature and is no more than 25 DEG C, be added dropwise and be cooled to 0~10 DEG C, 42.3g pivaloyl chloride is added dropwise, control temperature is no more than 20
DEG C, it drips and is added at one time 3- (trifluoromethyl) -5,6,7,8- tetrahydros-[1,2,4] triazol [4,3-a] pyrazine hydrochloride.
Reaction is warming up to 60~65 DEG C, is reacted 6 hours, sampling monitoring reaction is completed, and is cooled to 0~5 DEG C, 240g 3% is slowly added dropwise
Sodium hydroxide solution has a large amount of precipitatings to generate, filters, and 20% acetonitrile-aqueous solution of filter cake is beaten washing (150mL*2), drying
It obtains 92.8g product (compound 1), yield 86.8%, purity 99.1%.
Embodiment 2
Substrate solution is prepared: 5.0Kg compound 1 is dissolved in 8.0Kg DMSO, heating stirring dissolved clarification.
Enzyme reduction system solution is prepared: 1.8Kg isopropylamine, which is dissolved in 4.0Kg water, is configured to solution, adds 1.5Kg concentrated hydrochloric acid tune
PH=9.0 is saved, 10.0Kg DMSO, 4.0Kg water is added, 0.01Kg coenzyme (PLP) obtains yellow clear solution, then plus hydrochloric acid adjusting
PH=9.0 adds 5.0Kg GB71# enzyme, stirs evenly spare.
Microchannel plate is answered: micro passage reaction (Si-C material, 200~1000 μm, domestic, liquid holdup 750mL), setting folder
Sleeving temperature is 45 DEG C, sets substrate solution charging pump discharge as 5mL/min, sets substrate solution charging pump discharge as 10mL/
Min, charge ratio 1:2, residence time 50mins, the two are sufficiently mixed reaction in reactor.
In reactor exit sampling HPLC detection.Concrete operations are as follows: sample 1mL in micro passage reaction exit, add 1
Dilute hydrochloric acid acidification is dripped, HPLC detects reaction conversion ratio, if conversion ratio > 95.0%, reaction meets the requirements.Practical repeated detection
As a result: conversion ratio 96.2%~97.8%.
Reactor outlet end connects reaction kettle and collects reaction solution (first is interval, and subsequent batches realize continuous operation),
Add hydrochloric acid, diatomite stirring, filtering, filtrate is transferred in extraction kettle, and remaining substrate and impurity (repeatedly concentration is extracted with ethyl acetate
Enrichment, solvent dissolution, then go back in substrate solution), water phase is transferred to adding sodium hydroxide alkali tune in next reaction kettle, ethyl acetate extraction
Product is taken, is evaporated under reduced pressure, crystallization, centrifugation obtains Xi Gelieting free alkali.Realize that serialization is reacted for 24 hours, under process conditions daily
Theoretical output 3.0Kg product actually obtains 2.7Kg, yield 90.0%, purity 99.3%.
It may be noted that: according to different production requirements, select different micro passage reactions, liquid holdup, charge ratio, reaction
The parameters such as temperature, residence time have difference, and optimal process conditions need according to the actual situation repeatedly debugging formation, the present invention
Embodiment, provide some parameter data, be not particularly suited for all microchannel plates and answer working condition.
Claims (10)
1. a kind of method for applying continuous Flow Technique production Xi Gelieting free alkali, it is characterised in that: also by reaction substrate and enzyme
Substance system dissolves in organic solvent respectively, using feed pump, material solution is pumped into micro passage reaction and is sufficiently mixed, bottom
The charge ratio of object solution and enzyme reduction system solution is 1:1 ~ 1:3, and reaction temperature is 40 ~ 50 DEG C, 30 ~ 120mins of residence time；
Meanwhile completely a small amount of raw material is configured to solution and comes back to reaction system by enrichment method by unreacted in post-processing kettle
In, it maximizes and improves raw material availability, realize the continuous production of Xi Gelieting free alkali enzymatic reaction,
Wherein, reaction substrate are as follows: (2Z) -4- oxo -4- [3- (trifluoromethyl) -5,6- dihydro-[1,2,4] triazol [4,3-a]
Pyrazine -7- (8H)-yl] -1- (2,4,5- trifluorophenyl) butyl- 2- ketone.
2. the method for the continuous Flow Technique production Xi Gelieting free alkali of application according to claim 1, it is characterised in that: institute
The reaction organic solvent stated is DMSO or DMF.
3. the method for the continuous Flow Technique production Xi Gelieting free alkali of application according to claim 1, it is characterised in that: institute
Stating each material composition and relationship between quality in enzyme reduction system is 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。
4. the method for the continuous Flow Technique production Xi Gelieting free alkali of application according to claim 1, it is characterised in that: bottom
The feed rate ratio of object solution and enzyme reduction system solution is 1:2.
5. the method for the continuous Flow Technique production Xi Gelieting free alkali of application according to claim 1, it is characterised in that: bottom
The feed flow rate range of object solution is 2 ~ 10mL/min, and the feed flow rate range of enzyme reduction system is 2 ~ 30mL/min.
6. the method for the continuous Flow Technique production Xi Gelieting free alkali of application according to claim 1, it is characterised in that: into
The reaction temperature that row microchannel plate is answered is 45 DEG C.
7. the method for the continuous Flow Technique production Xi Gelieting free alkali of application according to claim 1, it is characterised in that: micro-
The residence time of pathway reaction is 50mins.
8. the method for the continuous Flow Technique production Xi Gelieting free alkali of application according to claim 1, it is characterised in that: institute
The material of the micro passage reaction of selection is silicon carbide ceramics, stainless steel, special glass.
9. the method for the continuous Flow Technique production Xi Gelieting free alkali of application according to claim 1, it is characterised in that: institute
The channel internal diameter range of the micro passage reaction of selection is 50 μm ~ 3000 μm, and channel type is a variety of changeable channels and plug flow
Filler pipeline.
10. the method for the continuous Flow Technique production Xi Gelieting free alkali of application according to claim 1, it is characterised in that:
The enzyme is transaminase, and the pH control of DMSO solution is 8.0 ~ 9.0 in the enzyme reduction system.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110106130A (en) * | 2019-05-23 | 2019-08-09 | 浙江工业大学 | A kind of transaminase-coenzyme co-immobilization engineering bacteria cell and application |
| CN112375801A (en) * | 2020-10-22 | 2021-02-19 | 复旦大学 | Micro-reaction system and method for continuously preparing (R) -3-hydroxy-5-hexenoic acid ester by using same |
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| CN106834376A (en) * | 2017-01-05 | 2017-06-13 | 湖北省宏源药业科技股份有限公司 | A kind of method of Enzyme catalyzed synthesis Xi Gelieting |
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| CN106834376A (en) * | 2017-01-05 | 2017-06-13 | 湖北省宏源药业科技股份有限公司 | A kind of method of Enzyme catalyzed synthesis Xi Gelieting |
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| WOLF.DIETER FESSNER和TUORLEIF ANTHONSEN主编: "《现代生物催化 高立体选择及环境友好的反应》", 1 June 2016 * |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110106130A (en) * | 2019-05-23 | 2019-08-09 | 浙江工业大学 | A kind of transaminase-coenzyme co-immobilization engineering bacteria cell and application |
| CN112375801A (en) * | 2020-10-22 | 2021-02-19 | 复旦大学 | Micro-reaction system and method for continuously preparing (R) -3-hydroxy-5-hexenoic acid ester by using same |
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