CN111118073B - Method for synthesizing intermediate of ezetimivir by enzyme method - Google Patents
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Abstract
The invention provides an enzymatic synthesis method of a key intermediate (formula 6) of the ribavirin, which comprises the step of carrying out a catalytic reaction on a substrate, namely formula 5 by using lipase to obtain a compound shown in a formula 6:
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a synthetic method of a piretavir intermediate.
Background
Viral hepatitis type c, abbreviated as hepatitis c and hepatitis c, is a viral hepatitis caused by infection with Hepatitis C Virus (HCV). According to the statistics of the world health organization, the infection rate of HCV is about 3 percent globally, about 1.8 million people are estimated to be infected with HCV, and about 3.5 ten thousand new cases of hepatitis C are generated every year. Hepatitis c is a global epidemic that can lead to chronic inflammatory necrosis and fibrosis of the liver, and some patients can develop cirrhosis and even hepatocellular carcinoma (HCC).
DAA (direct-acting antiviral agents) micromolecular hepatitis C drugs refer to micromolecular drugs for directly resisting hepatitis C virus. The nonstructural proteins NS3/4A, NS5B and NS5A of hepatitis C virus are the major target of DAA. The NS3/4A serine protease is involved in multiple site cleavage and cleavage of HCV viral polypeptide chains, NS5B encodes RNA polymerase during HCV replication, and NS5A replication complex protein plays an important role during viral replication and assembly. DAA blocks HCV intrahepatic replication from different stages by inhibiting these important viral proteins in the HCV life cycle and thus exerts antiviral effects.
A series of DAA small molecule hepatitis c drugs have been developed against NS3/4A, NS5B and NS5A, respectively, such as Telaprevir, Boceprevir, cimetivir (Simeprevir), anappivir (Asunaprevir), Sofosbuvir (Sofosbuvir), and the like. Although these DAA small molecule hepatitis c drugs hold promise for refractory hepatitis c patients, they still face many challenges, such as high production costs, increased resistance, decreased tolerance, increased side effects, etc.
Cimicavir, shown by the following structure (formula 1), is a novel HCV NS5A protease inhibitor:
in the prior art, WO2014019344 discloses a chemical synthesis route of the ezetimivir, and the chemical synthesis has certain limitations and low selectivity. Further research into enzymatic synthesis of entetavir may provide additional options for enzymatic synthesis of entetavir.
Disclosure of Invention
The invention provides an improved synthesis method of the ezetimivir and a synthesis method of a key intermediate (the following formula 6) of the ezetimivir, wherein the synthesis method has the advantages of good selectivity, mild reaction conditions and the like, and can greatly reduce the production cost of the ezetimivir compound:
(wherein R is C1-C6 alkyl).
In a first aspect, the invention provides a synthesis method of etavir, which comprises a step of carrying out a catalytic reaction on a substrate by using lipase to obtain a compound shown as a formula 6, wherein the substrate is a diester compound shown as a formula 5:
wherein R is C1-C6 alkyl;
wherein R is C1-C6 alkyl.
Preferably, the synthesis method of the ribavirin comprises the following steps:
(1) converting the starting compound represented by formula 2 into a diester compound represented by the following formula 5:
wherein R is C1-C6 alkyl;
(2) carrying out catalytic reaction on the diester compound shown in the formula 5 obtained in the step (1) by using high-selectivity lipase to obtain a compound shown in a formula 6 (key intermediate of the isometrivir):
wherein R is C1-C6 alkyl; and
(3) preparing a target compound, namely the intended compound, namely the ribavirin, on the basis of the compound shown in the formula 6;
preferably, the synthesis method of the ribavirin comprises the following steps:
(1) carrying out catalytic reaction on diester shown in formula 5 by using high-selectivity lipase to obtain a compound shown in formula 6 (key intermediate):
wherein R is C1-C6 alkyl; and
(2) the objective compound of the Cimetavir is generated on the basis of the compound shown in the formula 6.
Preferably, R in formula 6 and formula 5 is methyl or ethyl.
Preferably, the compound represented by formula 2 is converted into the diester compound represented by formula 5 using an acid anhydride.
Preferably, the anhydrides are acetic anhydride and propionic anhydride, preferably propionic anhydride.
Preferably, the high selectivity lipase is Candida Antarctica Lipase B (CALB).
Preferably, the CALB lipase can be expressed from escherichia coli, yeast, mold, and the like. Preferably, the CALB lipase may be in the form of whole cells of escherichia coli, crushed liquid of escherichia coli, yeast, fermentation supernatant of mold, freeze-dried/spray-dried enzyme powder.
Preferably, the product is further purified after step (3), thereby obtaining the compound represented by formula 6 in high purity.
Preferably, the reaction temperature in the catalytic reaction is less than or equal to 50 ℃, and preferably, the temperature is 30-50 ℃.
Preferably, the substrate concentration is from 30g/L to 50g/L, preferably, the substrate concentration is 40 g/L.
Preferably, the organic solvent in the catalytic reaction is selected from methyl tert-butyl ether (MTBE), DMSO, methanol, acetone, acetonitrile, toluene. Preferably, the organic solvent is methyl tert-butyl ether (MTBE).
Preferably, the proportion of the organic solvent in the catalytic reaction is 5-20% (v/v). Preferably, the organic solvent is present in a proportion of 10% (v/v).
Preferably, the amount of enzyme in the catalytic reaction is 5g/L to 15 g/L. Preferably, the amount of enzyme in the catalytic reaction is 10 g/L.
Preferably, the dosage of the lipase is 1/4-1 time of the dosage of the substrate.
Preferably, the reaction time of the reaction system is 6h-24 h. Preferably, the reaction time of the reaction system is 18 h.
In a second aspect, the present invention provides a method for synthesizing a key intermediate (formula 6) of etavir, the method comprising performing a catalytic reaction on a substrate with lipase to obtain a compound represented by formula 6, wherein the substrate is a diester compound represented by formula 5:
(wherein R is C1-C6 alkyl),
(wherein, R is C1-C6 alkyl).
Preferably, the synthesis method of the key intermediate (formula 6) of the ribavirin comprises the following steps:
(1) converting the starting compound represented by formula 2 into a diester compound represented by formula 5:
wherein R is C1-C6 alkyl;
(2) hydrolyzing the diester compound shown in the formula 5 obtained in the step (1) into a compound shown in a formula 6 (key intermediate of the isometrivir) by using high-selectivity lipase:
wherein R is C1-C6 alkyl.
Preferably, R in formula 6 and formula 5 is methyl or ethyl.
Preferably, the compound represented by formula 2 is converted into the diester compound represented by formula 5 using an acid anhydride.
Preferably, the anhydrides are acetic anhydride and propionic anhydride, preferably propionic anhydride.
Preferably, the high selectivity lipase is Candida Antarctica Lipase B (CALB).
Preferably, the CALB lipase can be expressed from escherichia coli, yeast, mold, and the like. Preferably, the CALB lipase may be in the form of whole cells of escherichia coli, crushed liquid of escherichia coli, yeast, fermentation supernatant of mold, freeze-dried/spray-dried enzyme powder.
Preferably, the product is further purified after step (3), thereby obtaining the compound of formula 6 in high purity.
Preferably, the reaction temperature in the catalytic reaction is less than or equal to 50 ℃, and preferably, the reaction temperature in the catalytic reaction is 30-50 ℃.
Preferably, the substrate concentration is from 30g/L to 50g/L, preferably, the substrate concentration is 40 g/L.
Preferably, the organic solvent in the catalytic reaction is selected from methyl tert-butyl ether (MTBE), DMSO, methanol, acetone, acetonitrile, toluene. Preferably, the organic solvent is methyl tert-butyl ether (MTBE).
Preferably, the proportion of the organic solvent in the catalytic reaction is 5-20% (v/v). Preferably, the organic solvent is present in a proportion of 10% (v/v).
Preferably, the amount of enzyme in the catalytic reaction is 5g/L to 15 g/L. Preferably, the amount of enzyme in the catalytic reaction is 10 g/L.
Preferably, the dosage of the lipase is 1/4-1 time of the dosage of the substrate.
Preferably, the reaction time in the catalytic reaction is between 6h and 24 h. Preferably, the reaction time in the catalytic reaction is 18 h.
The present invention unexpectedly found that highly selective lipases, in particular Candida Antarctica Lipase B (CALB), are capable of hydrolyzing diester compounds of formula 5 to yield key intermediates of iracetavir of formula 6, wherein the proportion of the opposite product of formula 4 below is less than 2%, thereby solving the problem of producing unwanted chiral opposite products:
(wherein, R is C1-C6 alkyl)
The conversion rate and the selectivity of diester hydrolysis in the method are both more than 95%, and compared with the method, the target intermediate product (formula 6) and the chiral opposite product (formula 4) in the chemical synthesis respectively account for about 50%, so that the enzymatic method has the advantages of simple operation, less pollution, good selectivity, mild reaction conditions and the like compared with the chemical synthesis method.
The noun explains:
lipases (Lipase, E.C.1.1.3), also known as Triacylglycerol acyl hydrolase (Triacylglycerol acyl hydrolase), are hydrolases that catalyze the hydrolysis of ester bonds of triglycerides to produce glycerol and fatty acids, and are widely found in various animals, plants and microorganisms, with the most diverse lipases being found in microorganisms such as Aspergillus, Rhizopus, Mucor, etc. Lipase (EC 3.1.1.3) is a biocatalyst for hydrolysis of triacylglycerol, has high chemical, regio-and stereoselectivity, and can catalyze various reactions such as synthesis, decomposition, ester exchange and the like of ester compounds, so that the lipase is widely applied to industries such as food, cosmetics, chemical industry, pharmacy and the like. Candida Antarctica Lipase B (CALB) is an excellent lipase and has strong catalytic activity in both aqueous and organic phases. Due to the special active center structure, CALB does not show interface activity but has strong stereoselectivity and wide substrate specificity, so that the CALB can be widely applied to the fields of chiral compound resolution, organic synthesis, medical intermediate preparation and the like.
The ee value, enantiomeric composition of a compound sample can be described in terms of "enantiomeric excess (enantiomeric excess)" or "e.e.%. It represents the excess of one enantiomer over the other, usually expressed as a percentage.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The following are preferred embodiments of the present invention, and the present invention is not limited to the following preferred embodiments. It should be noted that various changes and modifications based on the inventive concept herein will occur to those skilled in the art and are intended to be included within the scope of the present invention. The reagents used are not indicated by the manufacturer, and are all conventional products commercially available.
Example 1
1g of CALB lipase powder (commercially available) was dissolved in 90mL of phosphate buffer (100mM, pH 7.4) to obtain an enzyme solution. 4g of the diester (compound of formula 5, wherein R is ethyl) was dissolved in methyl tert-butyl ether (MTBE) to give a final volume of 10mL of the substrate solution. The 10mL of substrate solution was added to the enzyme solution to obtain an enzyme reaction system. And (3) adding condensation reflux to the enzyme reaction system (reducing the loss of the organic solvent), magnetically stirring at 40 ℃ for 18h, extracting the reaction solution by dichloromethane after the substrate is completely converted, and detecting a reaction product by HPLC (high performance liquid chromatography), wherein the reaction conversion rate of the monoester B is 98% and the ee value is 95% as shown by an HPLC detection result.
Examples 2 to 6
The conditions were the same as in example 1 except that the solvent in the enzyme reaction system was changed, and the results of HPLC measurements are shown in Table 1 below:
table 1: influence of solvent on the reaction
As can be seen from the results in Table 1, when the substrate concentration was 40g/L, the enzyme amount was 10g/L, the organic solvent amount was 10% (v/v), and the reaction was carried out at 40 ℃ for 18 hours, the conversion and ee value of the reaction were optimum when methyl tert-butyl ether (MTBE) was used as the organic solvent, and therefore, methyl tert-butyl ether (MTBE) was the most suitable solvent in the present invention.
Examples 7 to 10
The conditions were the same as in example 1 except that the reaction temperature was changed, and the results of HPLC measurements are shown in Table 2 below:
table 2: influence of temperature on the reaction
As can be seen from the results in Table 2, when the substrate concentration was 40g/L, the enzyme amount was 10g/L, MTBE was an organic solvent (10% v/v), the reaction was carried out for 18 hours, and the reaction temperature was 40 ℃ because the conversion rate was optimum, the optimum reaction temperature in the present invention was 40 ℃.
Examples 11 to 12
The conditions were the same as in example 1 except that the organic solvent ratio was changed, and the results of HPLC measurements are shown in Table 3 below:
table 3: influence of organic solvent content on reaction
As can be seen from the results in Table 3, when the substrate concentration was 40g/L, the enzyme amount was 10g/L, methyl tert-butyl ether (MTBE) was used as the organic solvent, and the reaction was carried out at 40 ℃ for 18 hours with the organic solvent content of 10%, the conversion rate and the ee value were the most preferable, so that the organic solvent content of 10% was the most preferable in the present invention.
Examples 13 to 14
The conditions were the same as in example 1 except that the substrate concentration was changed, and the results of HPLC measurements are shown in Table 4 below:
table 4: effect of substrate concentration on the reaction
As can be seen from the results in Table 4, when the enzyme amount was 10g/L and methyl tert-butyl ether (MTBE) was used as an organic solvent (10% v/v in amount) and reacted at 40 ℃ for 18 hours, the maximum substrate concentration of the reaction was 40g/L (substrate conversion was substantially complete), so that the optimum substrate concentration in the present invention was 40 g/L.
Examples 15 to 16
The conditions were the same as in example 1 except that the amount of enzyme was changed, and the results of HPLC measurements are shown in Table 5 below:
table 5: influence of the amount of enzyme on the reaction
The results in Table 5 show that, when methyl tert-butyl ether (MTBE) was used as an organic solvent (10% v/v) at 40 ℃ for 18 hours at a substrate concentration of 40g/L, the minimum enzyme amount was 10g/L (substrate conversion was substantially complete), and therefore, the optimum enzyme amount in the present invention was 10 g/L.
Examples 17 to 19
The conditions were the same as in example 1 except that the reaction time was changed, and the results of HPLC measurements are shown in Table 6 below:
table 6: influence of reaction time on the reaction
As can be seen from the results in Table 6, the substrate concentration was 40g/L, the enzyme amount was 10g/L, methyl tert-butyl ether (MTBE) was used as an organic solvent (10% v/v in amount), the conversion of the substrate was substantially complete at 40 ℃ and the reaction time was 18 hours, so that the optimum reaction time in the present invention was 18 hours.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (19)
1. A method for synthesizing the ribavirin, which comprises the steps of carrying out a catalytic reaction on a substrate shown in a formula 5 by using high-selectivity lipase to obtain a compound shown in a formula 6, and preparing the ribavirin on the basis of the compound shown in the formula 6:
wherein R is methyl or ethyl,
wherein the high-selectivity lipase is candida antarctica lipase B.
2. A method for synthesizing a compound represented by formula 6, the method comprising catalyzing a substrate represented by formula 5 with a high-selectivity lipase to obtain a compound represented by formula 6:
wherein R is methyl or ethyl,
wherein the high-selectivity lipase is candida antarctica lipase B.
3. The synthesis process according to claim 1 or 2, wherein said Candida antarctica lipase B is obtained by expression in Escherichia coli, yeast or mold.
4. The synthesis method according to claim 3, wherein the Candida antarctica lipase B is in the form of whole cells of Escherichia coli, crushed liquid of Escherichia coli, fermentation supernatant of yeast and mold, and freeze-dried or spray-dried enzyme powder.
5. The synthesis method according to claim 1 or 2, further purifying the product after hydrolyzing the diester compound of formula 5 to the compound of formula 6 using a high selectivity lipase, thereby obtaining the compound of formula 6 with high purity.
6. The synthesis process according to claim 1 or 2, wherein the reaction temperature in the catalytic reaction is 50 ℃ or less.
7. The synthesis process according to claim 6, wherein the reaction temperature in the catalytic reaction is from 30 ℃ to 50 ℃.
8. The synthesis method according to claim 1 or 2, wherein the substrate concentration is from 30g/L to 50 g/L.
9. The synthesis according to claim 8, wherein the concentration of the substrate is 40 g/L.
10. The synthesis process according to claim 1 or 2, wherein the organic solvent in the catalytic reaction is selected from the group consisting of methyl tert-butyl ether, DMSO, methanol, acetone, acetonitrile and toluene.
11. The synthesis process according to claim 10, wherein the organic solvent in the catalytic reaction is methyl tert-butyl ether.
12. The synthesis process according to claim 1 or 2, wherein the proportion of organic solvent in the catalytic reaction is between 5% and 20% (v/v).
13. A synthesis method according to claim 12, wherein the proportion of organic solvent in the catalytic reaction is 10% (v/v).
14. The synthesis method according to claim 1 or 2, wherein the amount of the enzyme of the high-selectivity lipase in the catalytic reaction is 5g/L to 15 g/L.
15. The synthesis method according to claim 14, wherein the amount of the enzyme of the high selectivity lipase in the catalytic reaction is 10 g/L.
16. The synthetic method according to claim 14, wherein the amount of the high selectivity lipase used in the catalytic reaction is 1/4-1 times of the amount of the substrate used.
17. The synthesis process according to claim 1 or 2, wherein the reaction time of the catalytic reaction is between 6h and 24 h.
18. A synthesis method according to claim 17, wherein the reaction time of the catalytic reaction is 18 h.
19. The synthesis method according to claim 2, wherein the compound represented by formula 6 is used as a synthesis intermediate of ribavirin.
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