CN113717996B - Biosynthesis method of 2-deoxy-2, 2-difluoro-3, 5-dibenzoyl-D-ribofuranose - Google Patents
Biosynthesis method of 2-deoxy-2, 2-difluoro-3, 5-dibenzoyl-D-ribofuranose Download PDFInfo
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Abstract
The invention relates to a biosynthesis method of 2-deoxy-2, 2-difluoro-3, 5-dibenzoyl-D-ribofuranose, belonging to the technical field of pharmaceutical intermediates. In order to solve the problems of long synthetic route and large pollution, a biosynthesis method of 2-deoxy-2, 2-difluoro-3, 5-dibenzoyl-D-ribofuranose is provided, which comprises the step of carrying out enzyme catalytic reaction on a compound 2-deoxy-2, 2-difluoropentosan-1-one-3, 5-dibenzoate of a formula II in an alcohol solvent under the catalytic action of a catalytic amount of CIR enzyme to generate a product compound 2-deoxy-2, 2-difluoro-3, 5-dibenzoyl-D-ribofuranose of the formula I. The invention has the advantages of high product yield and high purity, the product yield reaches more than 98 percent, and the purity reaches more than 96 percent. Less environmental pollution.
Description
Technical Field
The invention relates to a biosynthesis method of 2-deoxy-2, 2-difluoro-3, 5-dibenzoyl-D-ribofuranose, belonging to the technical field of pharmaceutical intermediates.
Background
Gemcitabine hydrochloride is a cell cycle specific antimetabolite, and mainly acts on tumor cells in the DNA synthesis stage, namely S-stage cells, under certain conditions, the gemcitabine hydrochloride can prevent the progress of the G1 stage to the S stage, and has obvious cytotoxic activity on various cultured human and mouse tumors.
The synthesis of gemcitabine hydrochloride reported in the prior literature is mainly to use 2-deoxy-2, 2-difluoro-3, 5-dibenzoyl-D-ribofuranose as an intermediate of gemcitabine, and further synthesize the final product of gemcitabine hydrochloride. The catalyst is prepared by using 2-deoxy-2, 2-difluoropentose-1-ketone-3, 5-dibenzoate as a raw material and carrying out palladium-carbon catalytic hydrogenation reduction. The palladium-carbon catalyst adopted in the synthesis method is high in price, the process hazard in the hydrogenation reaction process is high, and the obtained product is low in yield and purity and is not suitable for industrial production.
The method also uses 2-deoxidized-2, 2-difluoro pentose-1-ketone 3, 5-dibenzoate as raw material, adopts lithium aluminum hydride or red aluminum to carry out reduction reaction to obtain corresponding products, and the lithium aluminum hydride or red aluminum adopted in the method is inflammable and explosive, the process is dangerous, the method is not suitable for industrial production, and the waste water produced by post-treatment is not well treated, and the environment is polluted.
It can be seen that the synthesis of 2-deoxy-2, 2-difluoro-3, 5-dibenzoyl-D-ribofuranose is mainly performed by chemical method, and the risk is high and the environmental pollution is large. Therefore, finding a new synthetic route is of great importance.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention provides a biosynthesis method of 2-deoxy-2, 2-difluoro-3, 5-dibenzoyl-D-ribofuranose, which solves the technical problem of how to provide a new synthesis route which can reduce pollution and has high product yield.
The invention aims at realizing the following technical scheme, namely a biosynthesis method of 2-deoxidization-2, 2-difluoro-3, 5-dibenzoyl-D-ribofuranose, which is characterized by comprising the following steps:
in an alcohol solvent, carrying out enzyme catalytic reaction on a compound 2-deoxidized-2, 2-difluoro pentose-1-ketone-3, 5-dibenzoate of a formula II under the catalytic action of a catalytic amount of CIR enzyme to generate a compound 2-deoxidized-2, 2-difluoro-3, 5-dibenzoyl-D-ribofuranose of a formula I;
the protein sequence of the CIR enzyme is shown as SEQ ID NO. 1.
The synthesis is carried out by adopting an enzymatic method, and a specific CIR enzyme with a protein sequence shown in SEQ ID NO.1 is adopted, so that raw material 2-deoxidization-2, 2-difluoro pentose-1-ketone-3, 5-dibenzoyl benzoate can be effectively subjected to enzyme catalysis to enable ketocarbonyl in a molecular structure to be efficiently reduced and converted into hydroxyl, and then the hydroxyl can be converted into a corresponding product 2-deoxidization-2, 2-difluoro-3, 5-dibenzoyl-D-ribofuranose, and the method has the advantages of high conversion efficiency, high product yield and high purity. And a hydrogenation reduction mode with high palladium carbon and potential safety hazard is not needed. Meanwhile, the method is carried out under an alcohol solvent system, so that the reaction is mild, the post-treatment is easy to operate, a large amount of waste liquid and the like cannot be generated after the reaction is finished, the pollution to the environment is reduced, the production operation is greatly simplified, and the method is easy for industrial production.
In the above-mentioned biosynthesis method of 2-deoxy-2, 2-difluoro-3, 5-dibenzoyl-D-ribofuranose, it is preferable that the added amount of the CIR enzyme is 10% to 25% by weight of the 2-deoxy-2, 2-difluoropentofuranose-1-on-3, 5-dibenzoate of the compound of formula ii. The method can more effectively realize the carbonyl conversion in the catalytic reduction raw material, better avoid the generation of other byproducts, and have better requirements on the generation yield and purity quality, so that the yield of the product reaches more than 98 percent and the purity reaches more than 99 percent. As a further preference, the CIR enzyme is added in an amount of 18 to 20% by weight of the 2-deoxy-2, 2-difluoropentofuranose-1-on-3, 5-dibenzoate of the compound of formula II.
In the above-mentioned biosynthesis method of 2-deoxy-2, 2-difluoro-3, 5-dibenzoyl-D-ribofuranose, the temperature of the enzymatic reaction is preferably 20℃to 30 ℃. By adopting the CIR enzyme with the protein sequence for enzyme catalysis, the reaction can be performed mildly, the efficient reaction can be promoted under the condition of lower reaction temperature, the reaction is mild, the generation of impurities is reduced, and the purity and quality requirements of the product are further ensured.
In the biosynthesis method of the 2-deoxy-2, 2-difluoro-3, 5-dibenzoyl-D-ribofuranose, the alcohol solvent has the advantages of low toxicity and high safety. Preferably, the alcohol solvent is selected from one or more of ethanol, propanol and isopropanol. Can ensure that the reaction is mild, and the solvent is easy to recycle, thereby being beneficial to reducing the production cost.
In the above biosynthesis method of 2-deoxy-2, 2-difluoro-3, 5-dibenzoyl-D-ribofuranose, filtering after the enzyme-catalyzed reaction is completed, and distilling the collected filtrate to remove the solvent. The enzyme catalytic reduction and the alcohol solvent system are adopted for reaction, so that the yield and purity quality of the product can be effectively ensured, and the corresponding product can be obtained by removing residual particles in the enzyme and the system through filtration and directly removing the solvent. The refining treatment is not needed, the effect of ensuring the yield and the purity of the product is better realized, and the production operation is greatly reduced.
In the above-mentioned biosynthesis method of 2-deoxy-2, 2-difluoro-3, 5-dibenzoyl-D-ribofuranose, the temperature of the distillation treatment is controlled to 50℃or lower. The influence of the too high temperature of the distillation process on the product can be better ensured, and the effect of ensuring the purity and quality of the product is better realized.
The biosynthesis method of 2-deoxy-2, 2-difluoro-3, 5-dibenzoyl-D-ribofuranose of the invention can be represented by the following chemical reaction equation:
in summary, compared with the prior art, the invention has the following advantages:
by adopting a specific CIR enzyme with the protein sequence shown in SEQ ID NO.1 and an alcohol solvent system, the method has the advantages of high raw material conversion rate, high product yield and high purity. The method has the advantages that the reaction is mild, the post-treatment is easy to operate, a large amount of waste liquid and the like are not generated after the reaction is finished, the hydrogenation reduction mode with high palladium-carbon and potential safety hazard is not needed, the environmental pollution is reduced, the production operation is greatly simplified, the industrial production is easy, the final product yield reaches more than 98%, and the purity reaches more than 96%.
Detailed Description
The technical scheme of the present invention will be further specifically described by means of specific examples, but the present invention is not limited to these examples.
Example 1
Adding 50g of isopropanol solvent and 25g of 2-deoxy-2, 2-difluoropentose-1-one 3, 5-dibenzoate and 5g of CIR enzyme with a protein sequence shown as SEQ ID NO.1 into a clean reaction bottle, then carrying out heat preservation reaction for 5h under the condition that the reaction temperature is controlled to be 20-25 ℃, carrying out pressure filtration after the reaction is finished, collecting filtrate, carrying out reduced pressure distillation to remove the solvent in the reaction solution, heating by adopting a water bath in the reduced pressure distillation process and controlling the temperature to be below 50 ℃ to obtain 24.8g of the corresponding gemcitabine intermediate 2-deoxy-2, 2-difluoro-3, 5-dibenzoyl-D-ribofuranose, wherein the yield is 98.8%, and the content of liquid phase (HPLC) is 96.5%.
Example 2
50g of isopropanol solvent and 25g of 2-deoxy-2, 2-difluoropentose-1-one 3, 5-dibenzoate and 2.5g of CIR enzyme are added into a clean reaction bottle, the protein sequence of the CIR enzyme is shown as SEQ ID NO.1, then, the reaction temperature is controlled to be 25-30 ℃ for carrying out heat preservation reaction for 6 hours, after the reaction is finished, filter pressing is carried out, filtrate is collected, the obtained filtrate is subjected to reduced pressure distillation to remove the solvent in the reaction liquid, water bath heating is adopted in the reduced pressure distillation process, the temperature is controlled to be below 50 ℃ to obtain 24.7g of the corresponding gemcitabine intermediate 2-deoxy-2, 2-difluoro-3, 5-dibenzoyl-D-ribofuranose, the yield is 98.5%, and the content of liquid phase (HPLC) is 96.1%.
Example 3
80g of isopropanol solvent and 25g of 2-deoxy-2, 2-difluoropentose-1-one 3, 5-dibenzoate and 4.5g of CIR enzyme are added into a clean reaction bottle, the protein sequence of the CIR enzyme is shown as SEQ ID NO.1, then, the reaction temperature is controlled to be 20-25 ℃ for carrying out heat preservation reaction for 5 hours, after the reaction is finished, filter pressing is carried out, the filtrate is collected, the obtained filtrate is subjected to reduced pressure distillation to remove the solvent in the reaction liquid, water bath heating is adopted in the reduced pressure distillation process, the temperature is controlled to be lower than 50 ℃ to obtain 24.85g of the corresponding gemcitabine intermediate 2-deoxy-2, 2-difluoro-3, 5-dibenzoyl-D-ribofuranose, the yield is 99%, and the liquid phase (HPLC) content is 98.5%.
Example 4
50g of absolute ethanol solvent and 25g of 2-deoxy-2, 2-difluoropentose-1-one 3, 5-dibenzoate and 4g of CIR enzyme are added into a clean reaction bottle, the protein sequence of the CIR enzyme is shown as SEQ ID NO.1, then, the reaction is carried out for 6 hours under the condition of controlling the temperature to be 25-28 ℃, after the reaction is finished, filter pressing is carried out, the filtrate is collected, the obtained filtrate is subjected to reduced pressure distillation to remove the solvent in the reaction liquid, water bath heating is adopted in the reduced pressure distillation process, the temperature is controlled below 50 ℃, and the corresponding gemcitabine intermediate 2-deoxy-2, 2-difluoro-3, 5-dibenzoyl-D-ribofuranose is obtained, the yield is 98%, and the content of liquid phase (HPLC) is 98.4%.
Example 5
Adding 80g of absolute ethanol solvent and 25g of 2-deoxy-2, 2-difluoropentose-1-ketone 3, 5-dibenzoate and 6.25g of CIR enzyme with a protein sequence shown as SEQ ID NO.1 into a clean reaction bottle, then carrying out heat preservation reaction for 4 hours at a temperature of 20-25 ℃, after the reaction is finished, carrying out pressure filtration, collecting filtrate, carrying out reduced pressure distillation to remove the solvent in the reaction liquid, heating in a water bath in a reduced pressure distillation process, controlling the temperature below 50 ℃ to obtain 24.7g of the corresponding gemcitabine intermediate 2-deoxy-2, 2-difluoro-3, 5-dibenzoyl-D-ribofuranose, wherein the yield is 98.3%, and the content of liquid phase (HPLC) is 98.2%.
The specific embodiments described herein are offered by way of illustration only. Those skilled in the art may make various modifications or additions to the described embodiments or substitutions thereof without departing from the spirit of the invention or exceeding the scope of the invention as defined in the accompanying 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.
Sequence listing
<110> Jiangsu eight huge pharmaceutical industry Co., ltd
<120> a biosynthesis method of 2-deoxy-2, 2-difluoro-3, 5-dibenzoyl-D-ribofuranose
<160> 1
<170> SIPOSequenceListing 1.0
<210> 1
<211> 263
<212> PRT
<213> CIR enzyme (EC 1.1.1.184)
<400> 1
Met Pro Leu Glu Met Thr Ile Ala Leu Asn Asn Val Val Ala Val Val
1 5 10 15
Thr Gly Ala Ala Gly Gly Ile Gly Arg Glu Leu Val Lys Ala Met Lys
20 25 30
Ala Ala Asn Ala Ile Val Ile Ala Thr Asp Met Ala Pro Ser Ala Asp
35 40 45
Val Glu Gly Ala Asp His Tyr Leu Gln His Asp Val Thr Ser Glu Ala
50 55 60
Gly Trp Lys Ala Val Ala Ala Leu Ala Gln Glu Lys Tyr Gly Arg Val
65 70 75 80
Asp Ala Leu Val His Asn Ala Gly Ile Ser Leu Val Thr Lys Phe Glu
85 90 95
Asp Thr Pro Leu Ser Asp Phe His Arg Val Asn Thr Val Asn Val Asp
100 105 110
Ser Ile Ile Ile Gly Thr Gln Val Leu Leu Pro Leu Leu Lys Glu Gly
115 120 125
Gly Lys Ala Arg Ala Gly Gly Ala Ser Val Val Asn Phe Ser Ser Val
130 135 140
Gly Gly Leu Arg Gly Ala Ala Phe Asn Ala Ala Tyr Cys Thr Ser Lys
145 150 155 160
Ala Ala Val Lys Met Leu Ser Lys Cys Leu Gly Ala Glu Phe Ala Ala
165 170 175
Leu Gly Tyr Asn Ile Arg Val Asn Ser Val His Pro Gly Gly Ile Asp
180 185 190
Thr Pro Met Leu Gly Ser Ile Met Asp Lys Tyr Val Glu Leu Gly Ala
195 200 205
Ala Pro Ser Arg Glu Val Ala Gln Ala Ala Met Glu Met Arg His Pro
210 215 220
Ile Gly Arg Met Gly Arg Pro Ala Glu Met Gly Gly Gly Val Val Tyr
225 230 235 240
Leu Cys Ser Asp Ala Ala Ser Phe Val Thr Cys Thr Glu Phe Val Met
245 250 255
Asp Gly Gly Phe Ser Gln Val
260
Claims (7)
1. A method for biosynthesis of 2-deoxy-2, 2-difluoro-3, 5-dibenzoyl-D-ribofuranose, comprising the steps of:
in an alcohol solvent, carrying out enzyme catalytic reaction on a compound 2-deoxidized-2, 2-difluoro pentose-1-ketone-3, 5-dibenzoate of a formula II under the catalytic action of a catalytic amount of CIR enzyme to generate a compound 2-deoxidized-2, 2-difluoro-3, 5-dibenzoyl-D-ribofuranose of a formula I;
the protein sequence of the CIR enzyme is shown as SEQ ID NO. 1.
2. The method for biosynthesis of 2-deoxy-2, 2-difluoro-3, 5-dibenzoyl-D-ribofuranose according to claim 1, wherein the CIR enzyme is added in an amount of from 10% to 25% by weight of the 2-deoxy-2, 2-difluoropentofuranose-1-on-3, 5-dibenzoate of the compound of formula ii.
3. The method for biosynthesis of 2-deoxy-2, 2-difluoro-3, 5-dibenzoyl-D-ribofuranose according to claim 2, wherein the CIR enzyme is added in an amount of 18% to 20% by weight of the 2-deoxy-2, 2-difluoropentofuranose-1-keto-3, 5-dibenzoate of the compound of formula ii.
4. The method for biosynthesis of 2-deoxy-2, 2-difluoro-3, 5-dibenzoyl-D-ribofuranose according to claim 1, wherein the temperature of the enzyme-catalyzed reaction is from 20 ℃ to 30 ℃.
5. The method for biosynthesis of 2-deoxy-2, 2-difluoro-3, 5-dibenzoyl-D-ribofuranose according to claim 1 or 2 or 3 or 4, wherein the alcoholic solvent is selected from one or more of ethanol, propanol and isopropanol.
6. The method for biosynthesis of 2-deoxy-2, 2-difluoro-3, 5-dibenzoyl-D-ribofuranose according to claim 1, 2, 3 or 4, wherein the enzyme-catalyzed reaction is completed further comprising filtering, and distilling the collected filtrate to remove the solvent.
7. The method for biosynthesis of 2-deoxy-2, 2-difluoro-3, 5-dibenzoyl-D-ribofuranose according to claim 6, wherein the temperature of the distillation treatment is controlled below 50 ℃.
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Patent Citations (4)
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| CN102482648A (en) * | 2009-06-22 | 2012-05-30 | 科德克希思公司 | Ketoreductase-mediated stereoselective route to alpha chloroalcohols |
| CN108300743A (en) * | 2018-02-06 | 2018-07-20 | 江苏八巨药业有限公司 | The Biocatalysis method of one kind (R) -2- chloro- 1- (the fluoro- benzodihydropyran -2- bases of 6-) -1- ethyl alcohol |
| CN112852769A (en) * | 2020-08-14 | 2021-05-28 | 中国科学院天津工业生物技术研究所 | Method for preparing (S) -1- (2-methoxy-3-bromophenyl) ethanol |
| CN112225767A (en) * | 2020-12-10 | 2021-01-15 | 苏州华鑫医药科技有限公司 | High-selectivity synthesis method of gemcitabine intermediate |
Non-Patent Citations (1)
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| Chou, T. S. et al.Stereospecific synthesis of 2-deoxy-2,2-difluororibonolactone and its use in the preparation of 2'-deoxy-2',2'-difluoro-β-D-ribofuranosyl pyrimidine nucleosides: the key role of selective crystallization.Synthesis .1992,第6卷565-570. * |
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