CN109748893B - Method for preparing gemcitabine intermediate by using chiral catalyst - Google Patents
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Abstract
The invention relates to a method for preparing gemcitabine intermediate by using chiral catalyst, belonging to the technical field of synthesis of drug intermediates. In order to solve the problem of poor reaction stereoselectivity, a method for preparing gemcitabine intermediate by using chiral catalyst is provided, which comprises the steps of carrying out condensation reaction on R-glyceraldehyde acetonide and difluoro halogenated ethyl acetate in an inert organic solvent under the common catalysis of active zinc powder and-amino alcohol ligand to obtain corresponding intermediate; and then carrying out deprotection and lactonization treatment on the intermediate, and reacting the intermediate with benzoyl chloride in the presence of an acid-binding agent to obtain a corresponding gemcitabine intermediate. The product obtained by the method has an ee value of over 98 percent, the erythro product content is high, and the obtained product does not need to be refined and can be directly used for the subsequent reaction.
Description
Technical Field
The invention relates to a method for preparing gemcitabine intermediate by using chiral catalyst, belonging to the technical field of synthesis of drug intermediates.
Background
Gemcitabine is a pyrimidine nucleoside antimetabolite antitumor drug developed by American Gift company, can interfere the synthesis of nucleic acid to prevent cancer cells from producing DNA or RNA, finally stops the growth of the cancer cells and leads the cancer cells to die, and has better inhibiting effect on human leucocytes, certain murine solid tumors and human tumor xenografts.
2-deoxy-2, 2-D-erythro-pentofurano-1-ulose-3, 5-dibenzoate as a key intermediate of gemcitabine, at present, R-glyceraldehyde acetonide and ethyl difluorobromoacetate are mainly used as raw materials, zinc powder is added for initiation reaction to obtain ethyl 2, 2-difluoro-D-threo-3-hydroxy- (2, 2-dimethyl-1, 3-dioxolane-4-yl) propionate and ethyl 2, 2-difluoro-D-erythro-3-hydroxy- (2, 2-dimethyl-1, 3-dioxolane-4-yl) propionate, the selectivity is poor due to the adoption of the zinc powder, the content of erythro is too low, and the ratio of threo to erythro is 1: about 3, which is equivalent to that the content of erythro is 65-70 percent, directly and continuously reacts with acid for deprotection and lactonization to obtain 2-deoxy-2, 2-difluoro-1-O-ribose, and then the 2-deoxy-2, 2-difluoro-1-O-ribose reacts with benzoyl chloride to obtain the corresponding product 2-deoxy-2, 2-D-erythro-pentofuranose-1-ketone-3, 5-dibenzoate, the content of which is only 75-80 percent and is lower. For example, Chinese patent (publication No. CN102617678B) discloses a method for preparing gemcitabine hydrochloride, which specifically relates to the preparation of 2-deoxy-2, 2-D-erythro-pentofuranose-1-ulose-3, 5-dibenzoate, wherein R-glyceraldehyde acetonide and ethyl difluorobromoacetate are used as raw materials, and the gemcitabine hydrochloride is prepared by a Rerormatsky reaction, deprotection, lactonization and dibenzoylation. Although threo and erythro are not clearly separated by the Rerormatsky reaction, the yield reaches about 60 percent, which also indicates that the selectivity requirements on threo and erythro cannot be very good when the zinc powder is used for activation reaction, and the erythro content is too low. Therefore, in order to obtain a qualified product, a solvent is added for refining again, the byproduct 2-deoxy-2, 2-D-threo-pentofuranose-1-ulose-3, 5-dibenzoate in the preparation process of the intermediate is removed by refining, so that the cost of raw and auxiliary materials is increased, and the separated byproduct is treated as solid waste to pollute the environment.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a method for preparing gemcitabine intermediate by using chiral catalyst, and solves the problems of how to improve the stereoselectivity of the reaction, realize high erythro configuration conversion and high content and high yield of the product.
The object of the present invention is achieved by the following technical solution, a method for preparing gemcitabine intermediate using chiral catalyst, comprising the steps of:
A. under the co-catalysis of active zinc powder and an amino alcohol ligand, carrying out condensation reaction on a compound R-glyceraldehyde acetonide and difluoro halogenated ethyl acetate in a formula I in an inert organic solvent to obtain a corresponding intermediate compound in a formula II;
B. then carrying out deprotection and lactonization treatment on the intermediate compound shown in the formula II to obtain a corresponding compound shown in the formula III;
C. reacting the compound shown in the formula III with benzoyl chloride in the presence of an acid-binding agent to obtain a corresponding gemcitabine intermediate compound shown in the formula IV;
the active zinc powder can generate an organic zinc reagent with ethyl difluorobromoacetate, but the formed organic zinc reagent is in a linear structure, has relatively low reaction activity and is not beneficial to the stereoselectivity (chiral selectivity) of product configuration. The addition of the amino alcohol ligand can act on the organic zinc reagent, the linear structure of the organic zinc reagent is converted into the structural characteristic similar to a tetrahedron, so that the bond sequence between zinc and carbon bonds can be reduced, the nucleophilic performance of the organic zinc reagent is improved, the stereoselectivity of the reaction is controlled, the overall reaction activity of the zinc reagent is also improved, the asymmetric addition reaction can be more effectively carried out through the synergistic action of the zinc powder and the amino alcohol ligand, the formed product has the effects that the ee value is higher than 98 percent, the content of the erythro product is high, the obtained product does not need to be refined, the product is directly applied to subsequent deprotection and lactonization treatment, the corresponding product is obtained through sulfonylation, and the use cost and the energy consumption loss of the raw material are reduced. Meanwhile, the catalytic system can also make the reaction condition milder, is beneficial to reducing the generation of byproducts, is easy to operate and is more beneficial to being suitable for industrial production.
In the above method for preparing gemcitabine intermediate using chiral catalyst, preferably, the formula of the-amino alcohol ligand in step a is as follows:
wherein R is1And R2Each independently selected from methyl, ethyl or n-propyl. Preferably, R is1And R2Are the same substituent groups. Can better form the structural characteristic similar to a tetrahedron, further reduce the bond sequence between zinc-carbon bonds, increase the nucleophilic performance, improve the stereoselectivity of asymmetric reaction, realize the effect of high erythro product purity and ensure that the ee value purity of the product reaches more than 99 percent. Even more preferably, R is1And R2Are all methyl.
In the above method for preparing gemcitabine intermediate using chiral catalyst, preferably, the mass ratio of the active zinc powder and the — amino alcohol ligand in step a is 1: 0.01 to 0.03. The conversion of the formed organic zinc structure can be promoted only by adding a small amount of amino alcohol ligand, the stereoselectivity can be effectively improved, and the purity effect of the ee value can be ensured.
In the above method for preparing gemcitabine intermediate using chiral catalyst, preferably, the difluorohaloacetic acid ethyl ester is selected from difluorochloroacetic acid ethyl ester or difluorobromoacetic acid ethyl ester. The difluorochloroacetic acid ethyl ester is preferably adopted, because bromide ions are not easy to carry out biochemical treatment, a large amount of waste liquid is easy to cause, and the difluorochloroacetic acid ethyl ester is adopted, so that the waste liquid formed in the reaction process is easier to carry out biochemical treatment, and the environmental pollution is reduced.
In the above process for preparing gemcitabine intermediate using chiral catalyst, preferably, the molar ratio of the compound i, R-glyceraldehyde acetonide and active zinc powder in step a is 1: 1.05 to 2.0. The method not only can reduce the waste of raw materials, ensure the reaction to be more sufficient, improve the conversion rate and reduce the influence on the purity of the product caused by insufficient reaction of the raw materials.
In the above method for preparing gemcitabine intermediate using chiral catalyst, preferably, the inert organic solvent in step a is one or more selected from tetrahydrofuran, toluene, dichloromethane and ethyl acetate.
In the above method for preparing gemcitabine intermediate using chiral catalyst, the temperature of the reaction in step a is preferably-5 to 10 ℃. By adopting the catalytic system, the catalytic activity of the organic zinc can be better improved, the reaction can be carried out at a lower temperature, the reaction does not need to be carried out in a high-temperature reflux state, the operation safety is improved, the formation of byproducts can be further reduced, and the product purity is improved.
In the above method for preparing gemcitabine intermediate using chiral catalyst, preferably, the method further comprises adding acid to the reaction solution to quench the reaction solution after the condensation reaction in step a is completed. The reaction quenching is stopped by adding acid, which is beneficial to reducing the generation of byproducts in the post-treatment process and further ensuring the purity of the product.
In the above method for preparing gemcitabine intermediate using chiral catalyst, preferably, the deprotection and lactone internal treatment in step B are specifically:
and mixing and dissolving the intermediate compound shown in the formula II and an alcohol solvent, adding inorganic strong acid and water, and heating to react under a reflux condition. Because the purity content of the product of the previous reaction can reach a higher level, the product can be directly used for the reaction, the content and the purity effect of the formed product can be effectively ensured, the operation process is greatly reduced, and the operation is easier. As a still further preference, the strong inorganic acid is selected from trifluoroacetic acid, concentrated hydrochloric acid or concentrated sulfuric acid; the alcohol solvent is selected from one or more of methanol, ethanol and propanol.
In the above method for preparing gemcitabine intermediate using chiral catalyst, preferably, the acid scavenger in step C is selected from organic bases, such as pyridine, triethylamine or DMAP. More preferably, the acid-binding agent is a mixture of pyridine and DMAP, so that the reaction can be better carried out.
In the above method for preparing gemcitabine intermediate using chiral catalyst, preferably, the reaction in step C is carried out in an alcoholic solvent, where the alcoholic solvent may be a lower alcoholic solvent, such as methanol, ethanol or propanol, etc. The method can also ensure that the reaction is carried out in a reflux state in an alcohol solvent system, is favorable for ensuring the reaction to be more sufficient, more effectively ensures the conversion rate, and has higher level of the overall yield.
The reaction process of the method for preparing gemcitabine intermediate using chiral catalyst of the present invention may be represented by the following reaction equation:
in summary, compared with the prior art, the invention has the following advantages:
the addition of the amino alcohol ligand can act on the formed organic zinc reagent, and the linear structure of the organic zinc reagent is converted into the structural characteristic similar to a tetrahedron, so that the bond sequence between zinc and carbon bonds can be reduced, the nucleophilic performance of the organic zinc reagent is improved, the stereoselectivity of the reaction is controlled, and the overall reaction activity of the zinc reagent is also improved.
Detailed Description
The technical solution of the present invention is further specifically described below by way of specific examples, but the present invention is not limited to these examples.
Example 1
The amino alcohol ligands in this example are as follows:
wherein R is1And R2Likewise, all are methyl.
Adding 100g of tetrahydrofuran solvent, 15g of zinc powder and 0.3g of amino alcohol ligand into a clean reactor, stirring and cooling to 0 ℃, and then beginning to dropwise add a mixed solution of R-glyceraldehyde acetonide and ethyl difluorobromoacetate, wherein the weight ratio of the R-glyceraldehyde acetonide to the ethyl difluorobromoacetate is 23 g: 35g of a soybean milk powder; and controlling the temperature to be 0-5 ℃ in the dripping process, continuously controlling the temperature to be 0-5 ℃ after dripping is finished, carrying out heat preservation condensation reaction for 2 hours, detecting by TLC, quenching by dripping hydrochloric acid with the concentration of 5% after the reaction is finished, stopping dripping when the pH value of the reaction solution is adjusted to 5-6, and then standing for layering. Collecting an organic layer, washing the organic layer with a saturated sodium bicarbonate solution until the pH value is 7-8, standing the organic layer for layering, and collecting the organic layer; then, the collected organic layer was subjected to distillation under reduced pressure to remove the solvent, and after completion of concentration, 43.6g of ethyl 2, 2-difluoro-D-erythro-3-hydroxy- (2, 2-dimethyl-1, 3-dioxolan-4-yl) propionate, a compound of formula ii, was obtained in a yield of 97.0% and a content of 98.5%, which corresponds to an ee value of 98.5% or more in purity, and this intermediate product was used in the next reaction without purification.
Adding 150g of methanol, 40g of ethyl 2, 2-difluoro-D-erythro-3-hydroxy- (2, 2-dimethyl-1, 3-dioxolane-4-yl) propionate, 5g of trifluoroacetic acid and 10g of water into another clean reactor, heating to slowly raise the temperature to a reflux state, carrying out heat preservation reaction for 12 hours, carrying out reduced pressure distillation, cooling to about 20 ℃ after concentration is finished, adding 180g of ethyl acetate into the reactor, stirring and dissolving uniformly, then adding 20g of pyridine and 2g of DMAP, beginning to dropwise add 45g of benzoyl chloride, controlling the temperature to be below 20 ℃ in the dropwise adding process, finishing dropwise adding, slowly raising the temperature to reflux, carrying out heat preservation for 12 hours, cooling to 0 ℃ after heat preservation is finished, controlling the temperature to be 0-5 ℃, carrying out suction filtration, carrying out reduced pressure distillation on filtrate, when a large amount of solid is separated out, the distillation is stopped, the temperature is reduced, when the temperature is reduced to 0-5 ℃, the filtration is carried out, 58g of the solid product, namely the compound 2-deoxy-2, 2-D-erythro-pentofuranose-1-ketone-3, 5-dibenzoate, of the formula IV is obtained, the yield is 98.0%, and the content is 99.5%.
Example 2
The amino alcohol ligands in this example are as follows:
wherein R is1And R2Likewise, all are methyl.
Adding 120g of tetrahydrofuran solvent, 20g of zinc powder and 0.5g of amino alcohol ligand into a clean reactor, stirring and cooling to 0 ℃, and then beginning to dropwise add a mixed solution of R-glyceraldehyde acetonide and ethyl difluorobromoacetate, wherein the weight ratio of the R-glyceraldehyde acetonide to the ethyl difluorobromoacetate is 23 g: 35g of a soybean milk powder; and controlling the temperature to be 0-5 ℃ in the dripping process, continuously controlling the temperature to be-5-0 ℃ after dripping is finished, carrying out heat preservation condensation reaction for 2 hours, detecting by TLC, quenching by dripping hydrochloric acid with the concentration of 5% after the reaction is finished, stopping dripping when the pH value of the reaction solution is adjusted to be 5-6, and then standing for layering. Collecting an organic layer, washing the organic layer with a saturated sodium bicarbonate solution until the pH value is 7-8, standing the organic layer for layering, and collecting the organic layer; then, the collected organic layer was subjected to distillation under reduced pressure to remove the solvent, and after completion of concentration, 44g of ethyl 2, 2-difluoro-D-erythro-3-hydroxy- (2, 2-dimethyl-1, 3-dioxolan-4-yl) propionate, a compound of formula ii, was obtained in a yield of 98.0% and a content of 99.1%, which corresponds to an ee value of purity of 99.1% or more, and this intermediate product was used in the next reaction without purification.
Adding 200g of methanol, 40g of ethyl 2, 2-difluoro-D-erythro-3-hydroxy- (2, 2-dimethyl-1, 3-dioxolane-4-yl) propionate, 7g of concentrated sulfuric acid and 15g of water into another clean reactor, heating to slowly raise the temperature to a reflux state for carrying out heat preservation reaction for 14 hours, carrying out reduced pressure distillation, cooling to about 20 ℃ after concentration is finished, adding 200g of ethyl acetate into the reactor, stirring and dissolving uniformly, then adding 25g of pyridine and 1.5g of DMAP, beginning to dropwise add 45g of benzoyl chloride, controlling the temperature to be below 20 ℃ in the dropwise adding process, finishing dropwise add, slowly raising the temperature to reflux for carrying out heat preservation for 12 hours, cooling to 0 ℃ after heat preservation is finished, controlling the temperature to be 0-5 ℃, carrying out suction filtration, carrying out reduced pressure distillation on filtrate, when a large amount of solid is separated out, the distillation is stopped, the temperature is reduced, when the temperature is reduced to 0-5 ℃, the filtration is carried out, 57.4g of the solid product, namely the compound 2-deoxy-2, 2-D-erythro-pentofuranose-1-ketone-3, 5-dibenzoate, of the formula IV is obtained, the yield is 97.5%, and the content is 99.6%.
Example 3
The amino alcohol ligands in this example are as follows:
wherein R is1And R2Likewise, all are methyl.
Adding 150g of tetrahydrofuran solvent, 22g of zinc powder and 0.9g of amino alcohol ligand into a clean reactor, stirring and cooling to 0 ℃, and then beginning to dropwise add a mixed solution of R-glyceraldehyde acetonide and ethyl difluorobromoacetate, wherein the weight ratio of the R-glyceraldehyde acetonide to the ethyl difluorobromoacetate is 23 g: 35g of a soybean milk powder; and (3) controlling the temperature to be 0-5 ℃ in the dripping process, continuously controlling the temperature to be-5-0 ℃ after dripping is finished, carrying out heat preservation condensation reaction for 2 hours, finishing TLC detection reaction, dripping sulfuric acid for quenching after the reaction is finished, stopping dripping when the pH value of the reaction solution is adjusted to 5-6, and then standing for layering. Collecting an organic layer, washing the organic layer with a saturated sodium bicarbonate solution until the pH value is 7-8, standing the organic layer for layering, and collecting the organic layer; then, the collected organic layer was distilled under reduced pressure to remove the solvent, and after concentration, 44.5g of ethyl 2, 2-difluoro-D-erythro-3-hydroxy- (2, 2-dimethyl-1, 3-dioxolan-4-yl) propionate, a compound of formula ii, was obtained in a yield of 99% and a content of 99.5%, which corresponds to an ee value of purity of 99.5% or more, and this intermediate product was used in the next reaction without purification.
Adding 250g of absolute ethyl alcohol, 40g of ethyl 2, 2-difluoro-D-erythro-3-hydroxy- (2, 2-dimethyl-1, 3-dioxolane-4-yl) propionate and 18g of concentrated hydrochloric acid into another clean reactor, heating slowly to reflux state, carrying out heat preservation reaction for 12 hours, carrying out reduced pressure distillation, cooling to about 20 ℃ after concentration is finished, adding 250g of ethyl acetate into the reactor, stirring and dissolving uniformly, then adding 23g of pyridine and 1.7g of DMAP, beginning to dropwise add 45g of benzoyl chloride, controlling the temperature to be below 20 ℃ in the dropwise adding process, finishing dropwise adding, slowly heating to reflux, carrying out heat preservation for 12 hours, cooling to 0 ℃ after heat preservation is finished, controlling the temperature to be 0-5 ℃, carrying out suction filtration, carrying out reduced pressure distillation on filtrate, when a large amount of solid is separated out, the distillation is stopped, the temperature is reduced, when the temperature is reduced to 0-5 ℃, the filtration is carried out, 58.3g of the solid product, namely the compound 2-deoxy-2, 2-D-erythro-pentofuranose-1-ketone-3, 5-dibenzoate, of the formula IV is obtained, the yield is 98.5%, and the content is 99.7%.
Example 4
The amino alcohol ligands in this example are as follows:
wherein R is1And R2The same applies to ethyl.
Adding 120g of dichloromethane solvent, 12g of zinc powder and 0.36g of amino alcohol ligand into a clean reactor, stirring and cooling to 5 ℃, and then beginning to dropwise add a mixed solution of R-glyceraldehyde acetonide and ethyl difluorobromoacetate, wherein the weight ratio of the R-glyceraldehyde acetonide to the ethyl difluorobromoacetate is 23 g: 37g of a soybean milk powder; and controlling the temperature to be 5-10 ℃ in the dripping process, continuously controlling the temperature to be 5-10 ℃ after dripping is finished, carrying out heat preservation condensation reaction for 1.0 hour, detecting by TLC (thin layer chromatography), quenching by dripping hydrochloric acid with the concentration of 5% after the reaction is finished, stopping dripping when the pH value of the reaction solution is adjusted to 5-6, and then standing for layering. Collecting an organic layer, washing the organic layer with a saturated sodium bicarbonate solution until the pH value is 7-8, standing the organic layer for layering, and collecting the organic layer; then, the collected organic layer was subjected to distillation under reduced pressure to remove the solvent, and after completion of concentration, 43.6g of ethyl 2, 2-difluoro-D-erythro-3-hydroxy- (2, 2-dimethyl-1, 3-dioxolan-4-yl) propionate, a compound of formula ii, was obtained in a yield of 97.9% and a content of 98.8%, which corresponds to an ee value of 98.8% or more in purity, and this intermediate product was used in the next reaction without purification.
The specific preparation of the following compound of formula IV, 2-deoxy-2, 2-D-erythro-pentofurano-1-ulose-3, 5-dibenzoate, is identical to that of example 1 and is not repeated here.
Example 5
The amino alcohol ligands in this example are as follows:
wherein R is1And R2The same applies to ethyl.
Adding 120g of toluene solvent, 18g of zinc powder and 0.18g of amino alcohol ligand into a clean reactor, stirring and cooling to 5 ℃, and then, beginning to dropwise add a mixed solution of R-glyceraldehyde acetonide and ethyl difluorochloroacetate, wherein 23g of R-glyceraldehyde acetonide and 30g of ethyl difluorochloroacetate; and controlling the temperature to be below 0 ℃ in the dripping process, continuously controlling the temperature to be between-5 and 0 ℃ after dripping is finished, carrying out heat preservation condensation reaction for 2.0 hours, detecting by TLC, quenching by dripping hydrochloric acid with the concentration of 5% after the reaction is finished, stopping dripping when the pH value of the reaction solution is adjusted to be between 5 and 6, and then standing for layering. Collecting an organic layer, washing the organic layer with a saturated sodium carbonate aqueous solution until the pH value is 7-8, standing the organic layer for layering, and collecting the organic layer; then, the collected organic layer was subjected to distillation under reduced pressure to remove the solvent, and after completion of concentration, 44.2g of ethyl 2, 2-difluoro-D-erythro-3-hydroxy- (2, 2-dimethyl-1, 3-dioxolan-4-yl) propionate, a compound of formula ii, was obtained in a yield of 98.3% and a content of 99.2%, which corresponds to an ee value of purity of 99.2% or more, and this intermediate product was used in the next reaction without purification.
The specific preparation of the following compound of formula IV, 2-deoxy-2, 2-D-erythro-pentofurano-1-ulose-3, 5-dibenzoate, is identical to that of example 1 and is not repeated here.
Example 6
The amino alcohol ligands in this example are as follows:
wherein R is1And R2The same applies to the n-propyl group.
Adding 180g of tetrahydrofuran solvent, 20g of zinc powder and 0.4g of amino alcohol ligand into a clean reactor, stirring and cooling to 5 ℃, and then, beginning to dropwise add a mixed solution of R-glyceraldehyde acetonide and ethyl difluorochloroacetate, wherein the mixed solution comprises 23g of R-glyceraldehyde acetonide and 32g of ethyl difluorochloroacetate; and controlling the temperature to be below 0 ℃ in the dripping process, continuously controlling the temperature to be between-5 and 0 ℃ after dripping is finished, carrying out heat preservation condensation reaction for 2.0 hours, detecting by TLC, quenching by dripping hydrochloric acid with the concentration of 5% after the reaction is finished, stopping dripping when the pH value of the reaction solution is adjusted to be between 5 and 6, and then standing for layering. Collecting an organic layer, washing the organic layer with a saturated sodium carbonate aqueous solution until the pH value is 7-8, standing the organic layer for layering, and collecting the organic layer; then, the collected organic layer was subjected to distillation under reduced pressure to remove the solvent, and after completion of concentration, 43.9g of ethyl 2, 2-difluoro-D-erythro-3-hydroxy- (2, 2-dimethyl-1, 3-dioxolan-4-yl) propionate, a compound of formula ii, was obtained in 97.8% yield with a content of 98.8%, which corresponds to an ee value of 98.8% in purity, and this intermediate product was used in the next reaction without purification.
The specific preparation of the following compound of formula IV, 2-deoxy-2, 2-D-erythro-pentofurano-1-ulose-3, 5-dibenzoate, is identical to that of example 1 and is not repeated here.
The specific embodiments described herein are merely illustrative of the spirit of the invention. Various modifications or additions may be made to the described embodiments or alternatives may be employed by those skilled in the art without departing from the spirit or ambit of the invention as defined in the appended claims.
While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.
Claims (9)
1. A method for preparing a gemcitabine intermediate using a chiral catalyst, comprising the steps of:
A. under the co-catalysis of active zinc powder and an amino alcohol ligand, carrying out condensation reaction on a compound R-glyceraldehyde acetonide and difluoro halogenated ethyl acetate in a formula I in an inert organic solvent to obtain a corresponding intermediate compound in a formula II;
the structural formula of the amino alcohol ligand is shown as follows:
wherein R is1And R2Each independently selected from methyl, ethyl or n-propyl;
B. then carrying out deprotection and lactonization treatment on the intermediate compound shown in the formula II to obtain a corresponding compound shown in the formula III;
C. reacting the compound shown in the formula III with benzoyl chloride in the presence of an acid-binding agent to obtain a corresponding erythro product gemcitabine intermediate compound shown in the formula IV;
2. the method for preparing gemcitabine intermediate using chiral catalyst as claimed in claim 1, wherein the mass ratio of the active zinc powder and the amino alcohol ligand in step a is 1: 0.01 to 0.03.
3. The method for preparing gemcitabine intermediate using chiral catalyst as claimed in claim 1 or 2, wherein the difluorohaloacetic acid ethyl ester is selected from difluorochloroacetic acid ethyl ester or difluorobromoacetic acid ethyl ester.
4. The process for preparing gemcitabine intermediate using chiral catalyst as claimed in claim 1 or 2, wherein the molar ratio of R-glyceraldehyde acetonide to zinc powder in step a is 1: 1.05 to 2.0.
5. The method for preparing gemcitabine intermediate using chiral catalyst as claimed in claim 1 or 2, wherein the inert organic solvent in step a is one or more selected from tetrahydrofuran, toluene, dichloromethane and ethyl acetate.
6. The method for preparing gemcitabine intermediate using chiral catalyst as claimed in claim 1 or 2, wherein the condensation reaction in step a is carried out at a temperature of-5 ℃ to 10 ℃.
7. The method for preparing gemcitabine intermediate using a chiral catalyst as claimed in claim 1 or 2, wherein the step a further comprises adding an acid to the reaction solution to perform a quenching treatment after the condensation reaction is completed.
8. The method for preparing gemcitabine intermediate using chiral catalyst as claimed in claim 1 or 2, wherein the deprotection and lactonization process in step B is specifically:
and mixing and dissolving the intermediate compound shown in the formula II and an alcohol solvent, adding strong acid and water, and heating to react under a reflux condition.
9. The process for preparing gemcitabine intermediate using chiral catalyst as claimed in claim 8, wherein the strong acid is selected from trifluoroacetic acid, concentrated hydrochloric acid or concentrated sulfuric acid; the alcohol solvent is selected from one or more of methanol, ethanol and propanol.
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