CN109897874A - A method of preparing chiral isoquinolinecarboxylic acid - Google Patents

A method of preparing chiral isoquinolinecarboxylic acid Download PDF

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Publication number
CN109897874A
CN109897874A CN201910226159.8A CN201910226159A CN109897874A CN 109897874 A CN109897874 A CN 109897874A CN 201910226159 A CN201910226159 A CN 201910226159A CN 109897874 A CN109897874 A CN 109897874A
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reaction
value
solution
default
immo
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CN201910226159.8A
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Inventor
吴坚平
汤灵娇
詹晓
杨立荣
钱明心
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SUZHOU TONGLI BIOMEDICAL CO Ltd
Zhejiang University ZJU
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SUZHOU TONGLI BIOMEDICAL CO Ltd
Zhejiang University ZJU
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Priority to CN201910226159.8A priority Critical patent/CN109897874A/en
Publication of CN109897874A publication Critical patent/CN109897874A/en
Priority to PCT/CN2020/080300 priority patent/WO2020192560A1/en
Priority to DE212020000228.2U priority patent/DE212020000228U1/en
Pending legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y301/00—Hydrolases acting on ester bonds (3.1)
    • C12Y301/01—Carboxylic ester hydrolases (3.1.1)
    • C12Y301/01003—Triacylglycerol lipase (3.1.1.3)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/10—Nitrogen as only ring hetero atom
    • C12P17/12—Nitrogen as only ring hetero atom containing a six-membered hetero ring

Abstract

The invention discloses a kind of methods for preparing chiral isoquinolinecarboxylic acid (I), it include: to make the racemic modification of compound I in water phase buffer solution, react compound shown in production (I) under candida antarctica lipase B catalysis, carry out the reaction under default pH value always, the default pH value is 7.8-8.2；The features such as the method for the present invention reaction condition is mild, stereoselectivity is strong, reaction efficiency is high, technique is relatively easy has industrial applications prospect.

Description

A method of preparing chiral isoquinolinecarboxylic acid
Technical field
The invention belongs to biocatalysis technology fields, and in particular to a method of prepare chiral isoquinolinecarboxylic acid.
Background technique
Tetrahydroisoquinoline (THIQ) skeleton is the weight of a variety of drugs such as tributidine, coscopin, quinapril and praziquantel Want construction module.Novel THIQ therapeutic agent receives increasingly due to having specific anticancer activity, anti-inflammatory effect and immunocompetence More concerns, for example, (R) -1- methyl -6,7- dihydroxy -1,2,3,4- tetrahydroisoquinolines and 1- methyl-1,2,3,4- tetrahydros are different Quinoline is the important intermediate for synthesizing Parkinson's disease new therapeutic agent.As a kind of non-natural bicyclic amino acid, 1,2,3,4- tetra- Hydrogen isoquinoline -1- carboxylic acid (1-TIC) can be used for developing biologically active peptide, such as the antibacterial peptide for congenital immunity protection (AMPs).In addition, the phenylalanine synthesis farnesyl transferase inhibitor that 1-TIC alternative structure is similar, for developing cancer The new tool for the treatment of.Currently, there are no the report for closing into (R) -1-TIC.
Summary of the invention
It is an object of the invention to overcome the deficiencies of the prior art and provide the method for improved preparation (R) -1-TIC a kind of, The features such as this method reaction condition is mild, stereoselectivity is strong, reaction efficiency is high, technique is relatively easy has industrial applications Prospect.
To achieve the above object, the technical solution adopted by the present invention is as follows:
A method of (R) -1-TIC (I) is prepared,
The described method includes: make the racemic modification of 1-TIC ester in water phase buffer solution, in antarctic candidia lipase Compound shown in lower reaction production (I) of B catalysis, carries out the reaction under default pH value always, the default pH value is 7.8-8.2。
Some preferred aspects according to the present invention, it is molten the method also includes detecting reaction before the reaction and in reaction process The step of liquid pH value, it is molten to adjust reaction by addition pH adjusting agent when the pH value detected is lower than the default pH value Liquid pH value is always the default pH value.
In certain specific embodiments of the invention, the pH adjusting agent be ammonium hydroxide, alkali metal hydroxide or its Aqueous solution.
One according to the present invention specific and preferred aspect, the pH adjusting agent are 20wt%~35wt% ammonium hydroxide.
Another specific aspect according to the present invention, the pH adjusting agent are the water-soluble of sodium hydroxide or potassium hydroxide Liquid.
Some preferred aspects according to the present invention carry out the reaction at 20-35 DEG C of temperature.Preferably, make described Reaction carries out at 25-32 DEG C of temperature.It is highly preferred that carrying out the reaction at 28-32 DEG C of temperature.Above-mentioned reaction temperature Setting, can significantly shorten the reaction time, and avoid enzyme to cause catalytic performance to decline due to impregnating, being swollen, can also mention The space-time yield of height reaction, while can avoid energy consumption problem brought by low-temp reaction in the prior art.
Some preferred aspects according to the present invention, the water phase buffer solution are water phase ammonium acetate buffer.
Some preferred aspects according to the present invention, the candida antarctica lipase B use immobilised enzymes dosage form.
Some preferred aspects according to the present invention, the candida antarctica lipase B are to cure selected from Suzhou with power biology The lipase QLlip-9 of medicine Co., Ltd, Suzhou are public with the Novozyme 435 of power biological medicine Co., Ltd, the peculiar limit of drift Lay The Immo 8285 of department, Immo plus of Piao Laite Co., Ltd, Piao Laite Co., Ltd D5544 Buddhist monk section biological medicine One of SZ-PLE-100 (CAL-B)-IMMO of (Shanghai) Co., Ltd. or a variety of combinations.The selection of above-mentioned lipase is not Preferable catalytic effect (showing catalytic efficiency and selectivity etc.) only may be implemented, while repetition benefit can also be recycled With enzyme after the recovery still is able to the effects for having fabulous, and catalytic capability is held essentially constant, and greatly reduces enzyme Usage amount has greatly saved cost.
It is further preferred that the candida antarctica lipase B is selected from Suzhou with power biological medicine Co., Ltd Lipase QLlip-9.
Some preferred aspects according to the present invention, the racemic of the candida antarctica lipase B and the 1-TIC ester The mass ratio 1:1.8-2.2 that feeds intake of body.
Some preferred aspects according to the present invention, the specific embodiment of the method are as follows: weigh the outer of 1-TIC ester respectively Then the racemic modification of 1-TIC ester is added in water phase ammonium acetate buffer, obtains by raceme, candida antarctica lipase B Then substrate solution, the pH value for adjusting substrate solution using pH adjusting agent are added into substrate solution and weigh to default pH value Candida antarctica lipase B obtain reaction solution, react reaction solution under preset temperature, production (I) shownization Object is closed, controlling the pH value of reaction solution by addition pH adjusting agent during the reaction is always default pH value；
Wherein, the candida antarctica lipase B is lipase QLlip- of the Suzhou with power biological medicine Co., Ltd 9, Suzhou is the same as the Novozyme 435 of power biological medicine Co., Ltd, the Immo 8285 of Piao Laite Co., Ltd, the drift peculiar limit of Lay Immo plus of company, D5544 or Shang Ke biological medicine (Shanghai) Co., Ltd. of Piao Laite Co., Ltd SZ-PLE-100 (CAL-B)-IMMO, the preset temperature are 28-32 DEG C.
Due to the implementation of above technical scheme, compared with prior art, the present invention has the following advantages:
Present invention discover that carrying out under substantially invariable certain ph environment by controlling reaction, (R) -1- can be efficiently prepared TIC, selectivity is good, and high income, the time converted completely greatly shortens, and reaction condition is mild, and throughput rate height (reaches 0.24g·(h·gEnzyme)-1More than), e.e. in the product being preparedp>=99%[e.e.p=(R acid product amount-S acid product amount) ÷ (R acid product amount+S acid product amount) × 100%], and technique is relatively easy.
Specific embodiment
Above scheme is described further below in conjunction with specific embodiment；It should be understood that these embodiments are for illustrating The basic principles, principal features and advantages of the present invention, and the present invention is not by the scope limitation of following embodiment；It is used in embodiment Implementation condition further adjustment can be done according to specific requirement, the implementation condition being not specified is usually the item in routine experiment Part.
In following, unless otherwise specified, all raw materials are substantially from conventional method that is commercially available or passing through this field It is prepared；QLlip-9 is purchased from Suzhou with power biological medicine Co., Ltd, and Novozyme 435 is purchased from Suzhou with power biological medicine Co., Ltd, SZ-PLE-100 (CAL-B)-IMMO are purchased from Shang Ke biological medicine (Shanghai) Co., Ltd..
The preparation of embodiment 1 (R) -1-TIC with separate
(R) preparation of -1-TIC:
The preparation of substrate solution: the 1-TIC ester of 10g/L is prepared with the water phase ammonium acetate buffer (pH=8.0) of 0.1M Racemic modification solution simultaneously adjusts the initial pH value of solution to 8.0 with 30% ammonium hydroxide.
Prepared substrate solution 300mL is transferred to round-bottomed flask, external constant temperature heated water bath pot, into substrate solution Addition QLlip-9 is 5g/L up to the content of QLlip-9, and 6h is reacted at 30 DEG C, passes through 30% ammonia of addition during the reaction The pH value that water adjusts reaction solution is about 8.0 always.Reaction terminates, and taking a certain amount of hydrochloric acid to adjust reaction solution is highly acid, with Reaction is terminated, reaction solution is fully transferred to volumetric flask, with mobile phase constant volume, dilutes certain multiple, then have machine filter through micropore Film filtering finally carries out analysis detection using high performance liquid chromatograph, and [(residual substrate amount ÷ is anti-at the end of 1- reacts for conversion ratio Amount of substrate when should start) × 100%] it is greater than 99%, e.e.p[(R acid product amount-S acid product amount) ÷ (R acid product amount+S Acid product amount) × 100%] it is 96.20%.
(R) separation of -1-TIC:
By the reaction solution in aforementioned preparation process after reaction by filtering QLlip-9 particle and reaction solution point It opens, reaction solution concentrated by rotary evaporation at 60 DEG C, the crystal being precipitated in the process is placed in 50 DEG C of drying, finally obtains dry (R) -1- TIC crystal, separation yield [separation yield=claim to obtain product quality ÷ theoretical product quality × 100%, theoretical product quality=bottom Amount of substance ÷ 241.5 × 177] it is 81.06%, optical purity is greater than 99%.
The preparation of embodiment 2 (R) -1-TIC with separate
(R) preparation of -1-TIC:
The preparation of substrate solution: the 1-TIC ester of 10g/L is prepared with the water phase ammonium acetate buffer (pH=8.0) of 0.1M Racemic modification solution simultaneously adjusts the initial pH value of solution to 8.0 with 30% ammonium hydroxide.
Prepared substrate solution 1000mL is transferred to reaction vessel, external constant temperature heated water bath pot, to substrate solution Middle addition QLlip-9 is 5g/L up to the content of QLlip-9, and 6h is reacted at 30 DEG C, passes through addition 30% during the reaction The pH value that ammonium hydroxide adjusts reaction solution is about 8.0 always.Reaction terminates, and taking a certain amount of hydrochloric acid to adjust reaction solution is highly acid, To terminate reaction, reaction solution is fully transferred to volumetric flask, with mobile phase constant volume, dilutes certain multiple, then organic through micropore Membrane filtration finally carries out analysis detection, conversion ratio [(residual substrate amount ÷ at the end of 1- reacts using high performance liquid chromatograph Amount of substrate when reaction starts) × 100%] it is greater than 99%, e.e.p[(R acid product amount-S acid product amount) ÷ (R acid product amount + S acid product amount) × 100%] it is 96.21%.
(R) separation of -1-TIC:
By the reaction solution in aforementioned preparation process after reaction by filtering QLlip-9 particle and reaction solution point It opens, reaction solution concentrated by rotary evaporation at 60 DEG C, the crystal being precipitated in the process is placed in 50 DEG C of drying, finally obtains dry (R) -1- TIC crystal, separation yield [separation yield=claim to obtain product quality ÷ theoretical product quality × 100%, theoretical product quality=bottom Amount of substance ÷ 241.5 × 177] it is 80.27%, optical purity is greater than 99%.
The preparation of embodiment 3 (R) -1-TIC with separate
(R) preparation of -1-TIC:
The preparation of substrate solution: the 1-TIC ester of 10g/L is prepared with the water phase ammonium acetate buffer (pH=8.0) of 0.1M Racemic modification solution simultaneously adjusts the initial pH value of solution to 8.0 with 30% ammonium hydroxide.
Prepared substrate solution 20000mL is transferred in reaction vessel, the external insulation jacket of stirred reactor, the bottom of to QLlip-9 is added in object solution until the content of QLlip-9 is 5g/L, 6h is reacted at 30 DEG C, during the reaction by adding Add 30% ammonium hydroxide to adjust the pH value of reaction solution is about 8.0 always.Reaction terminates, and it is strong for taking a certain amount of hydrochloric acid to adjust reaction solution Reaction solution is fully transferred to volumetric flask to terminate reaction by acidity, with mobile phase constant volume, dilutes certain multiple, then through micropore Organic membrane filtration finally carries out analysis detection, conversion ratio [(residual substrate at the end of 1- reacts using high performance liquid chromatograph Measure amount of substrate when ÷ reaction starts) × 100%] it is greater than 99%, e.e.p[(R acid produces (R acid product amount-S acid product amount) ÷ Object amount+S acid product amount) × 100%] it is 96.16%.
(R) separation of -1-TIC:
By the reaction solution in aforementioned preparation process after reaction by filtering QLlip-9 particle and reaction solution point It opens, reaction solution concentrated by rotary evaporation at 60 DEG C, the crystal being precipitated in the process is placed in 50 DEG C of drying, finally obtains dry (R) -1- TIC crystal, separation yield [separation yield=claim to obtain product quality ÷ theoretical product quality × 100%, theoretical product quality=bottom Amount of substance ÷ 241.5 × 177] it is 80.18%, optical purity is greater than 99%.
The preparation of embodiment 4 (R) -1-TIC with separate
(R) preparation of -1-TIC:
The preparation of substrate solution: the 1-TIC ester of 9.5g/L is prepared with the water phase ammonium acetate buffer (pH=8.0) of 0.1M Racemic modification solution simultaneously adjusts the initial pH value of solution to 7.9 with 30% ammonium hydroxide.
Prepared substrate solution 300mL is transferred in reaction vessel, external constant temperature heated water bath pot, to substrate solution Middle addition Novozyme 435 is 5g/L up to the content of Novozyme 435, and 6h is reacted at 32 DEG C, is led to during the reaction Crossing 30% ammonium hydroxide of addition and adjusting the pH value of reaction solution is about 7.9 always.Reaction terminates, and a certain amount of hydrochloric acid is taken to adjust reaction solution Reaction solution is fully transferred to volumetric flask to terminate reaction for highly acid, with mobile phase constant volume, dilutes certain multiple, then pass through The organic membrane filtration of micropore finally carries out analysis detection using high performance liquid chromatograph, and [(1- is remaining at the end of reacting for conversion ratio Amount of substrate when amount of substrate ÷ reaction starts) × 100%] it is greater than 99%, e.e.p[(R acid product amount-S acid product amount) ÷ (R Acid product amount+S acid product amount) × 100%] it is 96.04%.
(R) separation of -1-TIC:
By the reaction solution in aforementioned preparation process after reaction by filter by 435 particle of Novozyme with react Solution separates, and reaction solution concentrated by rotary evaporation at 60 DEG C, the crystal being precipitated in the process is placed in 50 DEG C of drying, finally obtains dry (R) -1-TIC crystal, separation yield [separation yield=claim to obtain product quality ÷ theoretical product quality × 100%, theoretical product matter Amount=substrate quality ÷ 241.5 × 177] it is 80.14%, optical purity is greater than 99%.
The preparation of embodiment 5 (R) -1-TIC with separate
(R) preparation of -1-TIC:
The preparation of substrate solution: the 1-TIC ester of 10.5g/L is prepared with the water phase ammonium acetate buffer (pH=8.0) of 0.1M Racemic modification solution and adjust the initial pH value of solution to 8.1 with 30% ammonium hydroxide.
Prepared substrate solution 20000mL is transferred in reaction vessel, external constant temperature heated water bath pot is molten to substrate SZ-PLE-100 (CAL-B)-IMMO is added in liquid until the content of SZ-PLE-100 (CAL-B)-IMMO is 5g/L, at 28 DEG C 6h is reacted, is always about during the reaction 8.1 by the pH value that 30% ammonium hydroxide of addition adjusts reaction solution.Reaction terminates, and takes It is that reaction solution is fully transferred to volumetric flask, uses mobile phase by highly acid to terminate reaction that a certain amount of hydrochloric acid, which adjusts reaction solution, Constant volume, dilution certain multiple, then through the organic membrane filtration of micropore, analysis detection finally is carried out using high performance liquid chromatograph, turn Rate [(amount of substrate when residual substrate amount ÷ reaction starts at the end of 1- reacts) × 100%] is greater than 99%, e.e.p【(R Acid product amount-S acid product amount) ÷ (R acid product amount+S acid product amount) × 100%] it is 95.89%.
(R) separation of -1-TIC:
By the reaction solution in aforementioned preparation process after reaction by filtering SZ-PLE-100 (CAL-B)-IMMO Particle is separated with reaction solution, reaction solution concentrated by rotary evaporation at 60 DEG C, and the crystal being precipitated in the process is placed in 50 DEG C of drying, finally Obtain dry (R) -1-TIC crystal, separation yield [separation yield=claim to obtain product quality ÷ theoretical product quality × 100%, Theoretical product quality=substrate quality ÷ 241.5 × 177] it is 79.85%, optical purity is greater than 99%.
The above embodiments merely illustrate the technical concept and features of the present invention, and its object is to allow person skilled in the art Scholar cans understand the content of the present invention and implement it accordingly, and it is not intended to limit the scope of the present invention.It is all according to the present invention Equivalent change or modification made by Spirit Essence, should be covered by the protection scope of the present invention.

Claims (10)

1. a kind of method for preparing chiral isoquinolinecarboxylic acid (I),
The described method includes: making the racemic modification of isoquinolinecarboxylic acid's ester in water phase buffer solution, in antarctic candida fat Compound shown in lower reaction production (I) of enzyme B catalysis, which is characterized in that carry out the reaction under default pH value always, institute Stating default pH value is 7.8-8.2.
2. the method according to claim 1, wherein the method also includes examining before the reaction and in reaction process The step of surveying reacting solution pH value is adjusted when the pH value detected is lower than the default pH value by addition pH adjusting agent Saving reacting solution pH value is always the default pH value.
3. according to the method described in claim 2, it is characterized in that, the pH adjusting agent is ammonium hydroxide, alkali metal hydroxide Or its aqueous solution.
4. the method according to claim 1, wherein carrying out the reaction at 20-35 DEG C of temperature.
5. the method according to claim 1, wherein the water phase buffer solution is water phase ammonium acetate buffer.
6. the method according to claim 1, wherein the candida antarctica lipase B uses immobilised enzymes Dosage form.
7. method according to claim 1 or 6, which is characterized in that the candida antarctica lipase B is selected from Suzhou Novozyme 435, drift with the lipase QLlip-9 of power biological medicine Co., Ltd, Suzhou with power biological medicine Co., Ltd The Immo 8285 of Lai Te Co., Ltd, Immo plus of Piao Laite Co., Ltd, Piao Laite Co., Ltd D5544 Buddhist monk section One of SZ-PLE-100 (CAL-B)-IMMO of biological medicine (Shanghai) Co., Ltd. or a variety of combinations.
8. the method according to the description of claim 7 is characterized in that the candida antarctica lipase B is same selected from Suzhou The lipase QLlip-9 of power biological medicine Co., Ltd.
9. the method according to claim 1, wherein the candida antarctica lipase B and the isoquinolin The mass ratio 1: 1.8-2.2 that feeds intake of the racemic modification of carboxylate.
10. the method according to claim 1, wherein the specific embodiment of the method are as follows: weigh respectively different Then water phase is added in the racemic modification of isoquinolinecarboxylic acid's ester by racemic modification, the candida antarctica lipase B of quinoline carboxylic ester In ammonium acetate buffer, substrate solution is obtained, the pH value of substrate solution is adjusted to the default pH value, so using pH adjusting agent Weighed candida antarctica lipase B is added in backward substrate solution and obtains reaction solution, makes reaction solution in preset temperature Lower reaction, compound shown in production (I) are begun by the pH value that addition pH adjusting agent controls reaction solution during the reaction It is eventually the default pH value；
Wherein, the candida antarctica lipase B be Suzhou with power biological medicine Co., Ltd lipase QLlip-9, Soviet Union State is the same as the Novozyme 435 of power biological medicine Co., Ltd, the Immo 8285 of Piao Laite Co., Ltd, Piao Laite Co., Ltd Immo plus, Piao Laite Co., Ltd D5544 or Shang Ke biological medicine (Shanghai) Co., Ltd. SZ-PLE-100 (CAL-B)-IMMO, the preset temperature are 28-32 DEG C.
CN201910226159.8A 2019-03-25 2019-03-25 A method of preparing chiral isoquinolinecarboxylic acid Pending CN109897874A (en)

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PCT/CN2020/080300 WO2020192560A1 (en) 2019-03-25 2020-03-20 Chiral isoquinoline carboxylic acid and preparation method thereof
DE212020000228.2U DE212020000228U1 (en) 2019-03-25 2020-03-20 A chiral isoquinoline carboxylic acid

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WO2020192560A1 (en) * 2019-03-25 2020-10-01 苏州同力生物医药有限公司 Chiral isoquinoline carboxylic acid and preparation method thereof
CN112481344A (en) * 2019-09-11 2021-03-12 苏州同力生物医药有限公司 Preparation method of (R) -1,2,3, 4-tetrahydroisoquinoline-1-carboxylic acid and derivatives thereof
WO2021047566A1 (en) * 2019-09-11 2021-03-18 苏州同力生物医药有限公司 Preparation method for (r)-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid, derivative thereof and levo-praziquantel
CN114341362A (en) * 2019-09-11 2022-04-12 苏州同力生物医药有限公司 (R) -1,2,3, 4-tetrahydroisoquinoline-1-carboxylic acid and derivatives thereof and preparation method of levo-praziquantel
CN112481344B (en) * 2019-09-11 2024-02-02 苏州同力生物医药有限公司 Preparation method of (R) -1,2,3, 4-tetrahydroisoquinoline-1-carboxylic acid and derivative thereof
CN114341362B (en) * 2019-09-11 2024-02-02 苏州同力生物医药有限公司 Preparation method of (R) -1,2,3, 4-tetrahydroisoquinoline-1-carboxylic acid and derivative thereof, and levopraziquantel

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