CN111253348A - Preparation method of 2,3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone - Google Patents
Preparation method of 2,3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone Download PDFInfo
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- CN111253348A CN111253348A CN202010153517.XA CN202010153517A CN111253348A CN 111253348 A CN111253348 A CN 111253348A CN 202010153517 A CN202010153517 A CN 202010153517A CN 111253348 A CN111253348 A CN 111253348A
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- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/32—Oxygen atoms
- C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
Abstract
The invention provides a preparation method of 2,3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone, in the preparation method, sodium bromide/TEMPO is used as a catalyst creatively in an oxidation step, sodium hypochlorite is used as an oxidant, the generation of a large amount of high-concentration acidic wastewater and dimethyl sulfide in a post-treatment step is avoided, a crystallization mode is used for purification in the post-treatment step, the purification by silica gel chromatography is avoided, the production process is simpler to operate, the preparation method is more environment-friendly, and the generation of system impurities is reduced.
Description
Technical Field
The invention belongs to improvement of a preparation method of a drug intermediate, and particularly relates to a preparation method of 2,3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone.
Background
The 2,3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone is an important biological medicine intermediate and can be widely applied to the synthesis of various medicines. The molecular weight is small, the structure is unique, various downstream products can be derived, one of the purposes is that the derivative can be used as a key intermediate to synthesize the Reidesivir, the Reidesivir (Remdesivir) is a potential drug for treating the novel coronavirus at present, and the clinical test application of the Reidesivir is officially accepted by the drug approval Center (CDE) of the Chinese drug administration of 2020.2.2 days.
Regarding 2,3, 5-tribenzyloxy-D-ribono-1, 4-lactone, the synthetic route in the prior art is as follows, namely, taking D-ribose 1 as a raw material, and obtaining a final product 5 through simple upper protection, hydrolysis and oxidation reactions.
For the last oxidation step, CN103052631B reported the use of DMSO/Ac2O as an oxidizing agent and purification by silica gel chromatography is required in the post-treatment step.
The method can cause a large amount of high-concentration acidic wastewater and dimethyl sulfide with unpleasant odor to be generated in the large-scale production process, a large amount of silica gel and eluent are required to be used in the post-treatment step, a large amount of waste solvent and waste silica gel are generated, the method is not environment-friendly in the amplification production process, and 1% of ethyl ester impurity 6 of raw materials and 2% of ring-opening impurity 7 of products are observed in a reaction system.
The invention is to improve the process of the oxidation step in the preparation process of the 2,3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone on the basis of the technical problems.
Disclosure of Invention
The invention aims to solve the problems in the prior art and provides an improved preparation method of 2,3, 5-tribenzyloxy-D-ribono-1, 4-lactone, in the preparation method, sodium bromide/TEMPO is used as a catalyst in an oxidation step creatively, sodium hypochlorite is used as an oxidant, the generation of a large amount of high-concentration acidic wastewater and dimethyl sulfide in a post-treatment step is avoided, a crystallization mode is used for purification in the post-treatment step, the purification by a silica gel chromatography is avoided, the production process is simpler to operate and more environment-friendly, and the generation of system impurities is reduced.
A preparation method of 2,3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone comprises an oxidation step of oxidizing an intermediate 4 into a target product 5 by using sodium bromide and TEMPO as catalysts.
Further, the solvent used in the oxidation step is one or a combination of several of dichloromethane, dichloroethane, chloroform and tetrahydrofuran, wherein chloroform belongs to a country control solvent, the toxicity is high, tetrahydrofuran has an influence on the yield of a target product, and dichloroethane has a high toxicity, so dichloromethane with low toxicity and environmental friendliness is preferred.
Further, the volume mass ratio of the solvent used in the oxidation step to the intermediate 4 is (4-6): 1.
Further, the oxidizing agent used in the oxidation step is hypochlorite/TEMPO, Dess-Martin, DMSO/Ac2One or a combination of more of O, pyridinium chlorochromate and 2-iodoxybenzoic acid, Dess-Martin and 2-iodoxybenzoic acid oxidants are expensive, DMSO/Ac2The O oxidation system generates dimethyl sulfide, so that the environment is not friendly; pyridinium chlorochromate oxidation systems are complex to operate and produce chromium-containing waste solids, are environmentally friendly, and are therefore preferably hypochlorite and more preferably sodium hypochlorite.
Further, the mass ratio of the 10% sodium hypochlorite aqueous solution to the intermediate 4 in the oxidation step is 1 (3-4), and the addition temperature of the sodium hypochlorite aqueous solution is 0-10 ℃, and preferably 0-5 ℃.
Further, the mass ratio of the catalyst to the intermediate 4 in the oxidation step is 20 (0.5-1.5).
Further, the mass ratio of the catalyst sodium bromide to TEMPO in the oxidation step is (1-2): 1.
Namely, the present invention discloses the following oxidation step.
In addition, the preparation method of the 2,3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone further comprises a post-treatment step of purification in a crystallization mode.
Further, the crystallization reagent in the post-treatment step is one or a combination of more of acetone, n-hexane, toluene, methyl tertiary ether, petroleum ether, ethyl acetate and dichloromethane, wherein the petroleum ether, ethyl acetate and dichloromethane can cause the problems of insufficient product purity and difficult removal of solvent coating; acetone and toluene as crystallization reagents can obtain high-purity products with high yield, but the two solvents belong to easily prepared toxic chemicals and are not suitable for production and use; the methyl tert-ether and n-hexane system can solve the above problems, and therefore, the crystallization reagent is preferably methyl tert-ether and n-hexane.
Furthermore, the volume ratio of the methyl tertiary ether to the n-hexane is 1 (1-2).
The preparation method of the 2,3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone has the following beneficial effects:
(1) the 2,3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone is easy to hydrolyze under high-temperature acidic and strong-alkaline conditions due to the characteristic of an ester group, sodium bromide/TEMPO is used as a catalyst in the oxidation step, sodium hypochlorite is used as an oxidant, the oxidation process is milder, a large amount of high-concentration acidic wastewater in the post-treatment step is avoided, impurities caused by hydrolysis of a target product are avoided, and the yield of the oxidation step is improved;
(2) in the oxidation step, sodium bromide/TEMPO is used as a catalyst, sodium hypochlorite is used as an oxidant, the generation of dimethyl sulfide in the prior art is avoided, the oxidation process is environment-friendly, the operation is simple, the synthesis condition cost is low, and the production amplification is more favorable;
(3) the method effectively improves the yield from the intermediate 4 to the target product 5 by matching the oxidation step (sodium bromide/TEMPO is used as a catalyst, and sodium hypochlorite is used as an oxidant) with the crystallization purification step and optimizing the parameters of each step through a large number of experiments, and the method is applied to amplification production, so that the impurity 6 and the impurity 7 cannot be generated, and the yield is as high as 94.5%.
Drawings
FIG. 1 is a nuclear magnetic spectrum of a target product 5 of example 12 of the present invention.
Detailed Description
Unless defined otherwise, technical terms used in the following examples have the same meanings as commonly understood by one of ordinary skill in the art to which the present invention belongs. The test reagents used in the following examples, unless otherwise specified, are all conventional biochemical reagents; the experimental methods are conventional methods unless otherwise specified. The present invention will be described in detail with reference to examples.
Example 1
Adding 20g of the intermediate 4 into a four-neck bottle, adding 200mL of dichloromethane, adding 4.5g of DMSO, cooling to-70-80 ℃, controlling the temperature to-70-80 ℃, dropwise adding 7.9g of oxalyl chloride, keeping the temperature for 0.5h after dropwise adding, controlling the temperature to-70-80 ℃, dropwise adding 14.5g of triethylamine, keeping the temperature and stirring for 0.5h after dropwise adding, returning the system to-10-20 ℃, adding 100mL of water, continuing to return to 10-20 ℃ for liquid separation, washing the organic phase twice with 100mL of 0.5N hydrochloric acid, discarding the water phase, washing the organic phase once with 100mL of 5% sodium bicarbonate water solution, washing with 100mL of 20% sodium chloride water solution, drying the organic phase with anhydrous sodium sulfate, concentrating to no fraction, adding 40mL of methyl tert-ether and 60mL of n-hexane, cooling to 0-5 ℃, stirring for crystallization for 2-4h, filtering, and drying a filter cake at 20-30 ℃ to obtain 17.8g of a product.
The method has the advantages that the ethyl ester impurity 6 of the raw material and the ring-opening impurity 7 of the product are not contained, the yield is high, the operation is complex, a large amount of high-concentration wastewater is also generated, carbon monoxide/carbon dioxide and dimethyl sulfide with unpleasant odor are generated in the production process, the method is not environment-friendly, and the low-temperature operation causes that the production does not have economy.
Example 2
Adding 20g of the intermediate 4 into a four-neck bottle, adding 200mL of dichloromethane, controlling the temperature to be 20-30 ℃, adding 15.4g of 100-200 mesh silica gel and 15.4g of PCC (pyridinium chlorochromate), stirring for 8-12h, tracking until the raw materials are less than or equal to 0.5%, filtering, leaching a filter cake with 100mL of dichloromethane, washing a filtrate once with 100mL of water, washing once with 100mL of 5% sodium bicarbonate aqueous solution, washing with 100mL of 20% sodium chloride aqueous solution, drying an organic phase with anhydrous sodium sulfate, concentrating until no fraction is formed, adding 40mL of methyl tert-ether and 60mL of n-hexane, cooling to 0-5 ℃, stirring for crystallization for 2-4h, filtering, and drying the filter cake at 20-30 ℃ to obtain 18.2g of a product.
The method is simple to operate, does not contain the ethyl ester impurity 6 of the raw material and the ring-opening impurity 7 of the product, has high yield, but can generate a large amount of chromium-containing waste solids in the process of production amplification, and is not environment-friendly.
Example 3
Adding 20g of the intermediate 4 into a four-mouth bottle, adding 120mL of acetonitrile, controlling the temperature to be 20-30 ℃, adding 20g of 2-iodoxybenzoic acid, stirring for 8-12h, tracking until the raw material is less than or equal to 0.5%, filtering, leaching a filter cake with 200mL of ethyl acetate, washing a filtrate with 100mL of water, washing a filtrate with 100mL of 5% sodium bicarbonate aqueous solution, washing with 100mL of 20% sodium chloride aqueous solution, drying an organic phase with anhydrous sodium sulfate, concentrating to obtain a non-distillate, adding 40mL of methyl tert-ether and 60mL of n-hexane, cooling to 0-5 ℃, stirring for 2-4h, filtering, and drying the filter cake at 20-30 ℃ to obtain 16.2g of a product.
The method is simple to operate, does not contain the ethyl ester impurity 6 of the raw material and the ring-opening impurity 7 of the product, but has high material cost, and is not suitable for large-scale production and use.
Example 4
Adding 20g of the intermediate 4 into a four-mouth bottle, adding 120mL of tetrahydrofuran, controlling the temperature to be 20-30 ℃, adding 0.5g of sodium bromide and 0.4g of TEMPO, dropwise adding 71g (2eq) of 10% sodium hypochlorite aqueous solution at 0-5 ℃, stirring for 4h to track 1.3% of the remainder of the intermediate 4, adding 100mL of ethyl acetate, separating, washing an organic phase twice by using 40mL of 10% sodium thiosulfate aqueous solution, washing once by using 40mL of saturated sodium chloride aqueous solution, drying the organic phase by using anhydrous sodium sulfate, concentrating to obtain no fraction, adding 40mL of methyl tertiary ether and 60mL of n-hexane, cooling to 0-5 ℃, stirring for crystallization for 2-4h, filtering, and drying a filter cake at 20-30 ℃ to obtain 15.1g of a product.
The method is simple to operate and has the characteristic of environmental friendliness, but the product yield is low due to the reduction of the conversion efficiency of the raw materials, the production cost is increased due to the introduction of ethyl acetate for auxiliary extraction, and the method is not suitable for large-scale production.
Example 5
Adding 20g of the intermediate 4 into a four-mouth bottle, adding 100mL of dichloromethane, adding under the stirring condition, adding 0.5g of sodium bromide and 0.4g of TEMPO, dropwise adding 71g (2eq) of 10% sodium hypochlorite aqueous solution at 0-5 ℃, stirring for 2h until the intermediate 4 is less than or equal to 0.5%, separating, washing an organic phase twice with 40mL of 10% sodium thiosulfate aqueous solution, washing once with 40mL of saturated sodium chloride aqueous solution, drying the organic phase with anhydrous sodium sulfate, concentrating until no fraction is produced, adding 40mL of methyl tert-ether and 60mL of n-hexane, cooling to 0-5 ℃, stirring for crystallization for 2-4h, filtering, and drying a filter cake at 20-30 ℃ to obtain 19g of a product.
The method is simple to operate, has the characteristic of environmental friendliness, is low in production cost, does not contain product ring-opening impurities 7, avoids the use of acetic anhydride, does not produce raw material ethyl ester impurities 6, is high in yield of 95%, and is used for amplifying production and thoroughly investigating process parameters.
Example 6
Adding 20g of the intermediate 4 into a four-mouth bottle, adding 100mL of dichloromethane, adding under the stirring condition, adding 1.0g of sodium bromide and 0.4g of TEMPO, dropwise adding 71g (2eq) of 10% sodium hypochlorite aqueous solution at 0-5 ℃, stirring for 2h until the intermediate 4 is less than or equal to 0.5%, separating, washing an organic phase twice with 40mL of 10% sodium thiosulfate aqueous solution, washing once with 40mL of saturated sodium chloride aqueous solution, drying the organic phase with anhydrous sodium sulfate, concentrating until no fraction is produced, adding 40mL of methyl tert-ether and 60mL of n-hexane, cooling to 0-5 ℃, stirring for crystallization for 2-4h, filtering, and drying a filter cake at 20-30 ℃ to obtain 19g of a product.
The scheme increases the using amount of the sodium bromide, and has no obvious change and promotion on the yield of the reaction.
Example 7
Adding 20g of the intermediate 4 into a four-mouth bottle, adding 100mL of dichloromethane, adding under the stirring condition, adding 0.5g of sodium bromide and 0.4g of TEMPO, dropwise adding 100g of 10% sodium hypochlorite aqueous solution at 0-5 ℃, stirring for 2h until the intermediate 4 is less than or equal to 0.5%, separating, washing an organic phase twice with 40mL of 10% sodium thiosulfate aqueous solution, washing once with 40mL of saturated sodium chloride aqueous solution, drying the organic phase with anhydrous sodium sulfate, concentrating until no fraction is obtained, adding 40mL of methyl tert-ether and 60mL of n-hexane, cooling to 0-5 ℃, stirring for crystallization for 2-4h, filtering, and drying a filter cake at 20-30 ℃ to obtain 18.9g of a product.
The scheme increases the using amount of sodium hypochlorite, and has no obvious change and promotion on the yield of the reaction.
Example 8
Adding 20g of the intermediate 4 into a four-mouth bottle, adding 100mL of dichloromethane, adding under the stirring condition, adding 0.5g of sodium bromide and 0.8g of TEMPO, dropwise adding 71g (2eq) of 10% sodium hypochlorite aqueous solution at 0-5 ℃, stirring for 2h until the intermediate 4 is less than or equal to 0.5%, separating, washing an organic phase twice with 40mL of 10% sodium thiosulfate aqueous solution, washing once with 40mL of saturated sodium chloride aqueous solution, drying the organic phase with anhydrous sodium sulfate, concentrating until no fraction is produced, adding 40mL of methyl tert-ether and 60mL of n-hexane, cooling to 0-5 ℃, stirring for crystallization for 2-4h, filtering, and drying a filter cake at 20-30 ℃ to obtain 19g of a product.
The scheme increases the consumption of TEMPO, and has no obvious change and improvement on the yield of the reaction.
Example 9
Adding 20g of the intermediate 4 into a four-mouth bottle, adding 100mL of dichloromethane, adding under stirring, adding 0.5g of sodium bromide and 0.8g of TEMPO, dropwise adding 71g (2eq) of 10% sodium hypochlorite aqueous solution at 0-5 ℃, stirring for 2h until the intermediate 4 is less than or equal to 0.5%, separating, washing an organic phase twice with 40mL of 10% sodium thiosulfate aqueous solution, washing once with 40mL of saturated sodium chloride aqueous solution, drying the organic phase with anhydrous sodium sulfate, concentrating until no fraction is produced, adding 100mL of n-hexane, cooling to 0-5 ℃, stirring for crystallization for 2-4h, filtering, layering a system, and no obvious solid is separated out.
The crystallization solvent uses a single solvent of n-hexane, which is not feasible.
Example 10
Adding 20g of intermediate 4 into a four-mouth bottle, adding 100mL of dichloromethane, adding under stirring, adding 0.5g of sodium bromide and 0.8g of TEMPO, dropwise adding 71g (2eq) of 10% sodium hypochlorite aqueous solution at 0-5 ℃, stirring for 2h until the intermediate 4 is less than or equal to 0.5%, separating, washing an organic phase twice with 40mL of 10% sodium thiosulfate aqueous solution, washing once with 40mL of saturated sodium chloride aqueous solution, drying the organic phase with anhydrous sodium sulfate, concentrating until no fraction is produced, adding 40mL of methyl tert-butyl ether, cooling to 0-5 ℃, stirring for crystallization for 2-4h, filtering, drying at 20-30 ℃, and adding 8.2g of product
The crystallization solvent uses a single solvent, namely methyl tert-butyl ether, and has the advantages of good solubility, low yield and impracticability, and the crystallization solvent uses methyl tert-butyl ether: n-hexane volume ratio of 40: the condition of 60 is optimal.
Example 11
Adding 20g of the intermediate 4 into a four-mouth bottle, adding 100mL of dichloromethane, adding under the stirring condition, adding 0.5g of sodium bromide and 0.4g of TEMPO, dropwise adding 71g (2eq) of 10% sodium hypochlorite aqueous solution at 20-25 ℃, stirring for 2h until the intermediate 4 is less than or equal to 0.5%, separating, washing an organic phase twice with 40mL of 10% sodium thiosulfate aqueous solution, washing once with 40mL of saturated sodium chloride aqueous solution, drying the organic phase with anhydrous sodium sulfate, concentrating until no fraction is produced, adding 40mL of methyl tert-ether and 60mL of n-hexane, cooling to 0-5 ℃, stirring for crystallization for 2-4h, filtering, and drying a filter cake at 20-30 ℃ to obtain 18.6g of a product.
About 1% of the product ring-opened impurity 7 was observed during the treatment in this scheme, so the dropping conditions of the sodium hypochlorite aqueous solution at 0-5 ℃ in example 5 were more excellent.
Example 12
Adding 22Kg of intermediate 4 into a reaction kettle, adding 88L of dichloromethane, adding 0.55Kg of sodium bromide and 0.44Kg of TEMPO under the stirring condition, cooling to 0-5 ℃, controlling the temperature to 0-5 ℃, dropwise adding 78.1Kg of 10% sodium hypochlorite aqueous solution into the reaction kettle, keeping the temperature and stirring for 2h until the intermediate 4 is less than or equal to 0.5%, separating the system, washing the organic phase twice with 45L of 10% sodium thiosulfate aqueous solution, washing once with 45L of saturated sodium chloride aqueous solution, drying the organic phase with anhydrous sodium sulfate, concentrating until no fraction is produced, adding 44L of methyl tertiary ether and 66L of n-hexane, cooling to 0-5 ℃, stirring and crystallizing for 4-12h, filtering, and drying the solid at 20-30 ℃ to obtain 20.8Kg of product.
The scheme of the embodiment is a final test experiment, and the product yield reaches 94.5 percent.
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 (10)
1. A preparation method of 2,3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone is characterized by comprising an oxidation step of oxidizing an intermediate 4 into a target product 5 by taking sodium bromide and TEMPO as catalysts;
2. the preparation method of 2,3, 5-tribenzyloxy-D-ribono-1, 4-lactone according to claim 1, wherein the solvent used in the oxidation step is one or more of dichloromethane, dichloroethane, chloroform and tetrahydrofuran, and preferably dichloromethane.
3. The method for preparing 2,3, 5-tribenzyloxy-D-ribono-1, 4-lactone according to claim 1 or 2, wherein the volume-to-mass ratio of the solvent used in the oxidation step to the intermediate 4 is (4-6): 1.
4. The method for preparing 2,3, 5-tribenzyloxy-D-ribono-1, 4-lactone according to claim 1, wherein the oxidant used in the oxidation step is one or more of hypochlorite, Dess-Martin, TEMPO, 2-iodoxybenzoic acid, DMSO, pyridinium chlorochromate, and preferably hypochlorite.
5. The method for preparing 2,3, 5-tribenzyloxy-D-ribonic acid-1, 4-lactone according to claim 1 or 4, wherein the mass ratio of 10% sodium hypochlorite aqueous solution to intermediate 4 in the oxidation step is 1 (3-4), and the addition temperature of the sodium hypochlorite aqueous solution is 0-10 ℃.
6. The method for preparing 2,3, 5-tribenzyloxy-D-ribono-1, 4-lactone according to claim 1, wherein the mass ratio of the catalyst to the intermediate 4 in the oxidation step is 20 (0.5-1.5).
7. The method for preparing 2,3, 5-tribenzyloxy-D-ribono-1, 4-lactone according to claim 1 or 6, wherein the mass ratio of sodium bromide to TEMPO as catalyst in the oxidation step is (1-2): 1.
8. The process for preparing 2,3, 5-tribenzyloxy-D-ribono-1, 4-lactone according to claims 1-7, characterized by further comprising a post-treatment step of purification by crystallization.
9. The preparation method of 2,3, 5-tribenzyloxy-D-ribono-1, 4-lactone according to claim 8, wherein the crystallization reagent in the post-treatment step is one or more of acetone, n-hexane, toluene, methyl tert-ether, petroleum ether, ethyl acetate and dichloromethane, preferably the crystallization reagent is methyl tert-ether and n-hexane.
10. The preparation method of 2,3, 5-tribenzyloxy-D-ribono-1, 4-lactone according to claim 9, wherein the volume ratio of methyl tert-ether to n-hexane is 1 (1-2).
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| WO2017202365A1 (en) * | 2016-05-25 | 2017-11-30 | 四川海思科制药有限公司 | Preparation method for trifluoromethyl-substituted pyran derivative |
| CN108285438A (en) * | 2018-01-18 | 2018-07-17 | 上海仁实医药科技有限公司 | A kind of synthesis technology of benzyl ribonolactone |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2017202365A1 (en) * | 2016-05-25 | 2017-11-30 | 四川海思科制药有限公司 | Preparation method for trifluoromethyl-substituted pyran derivative |
| CN108285438A (en) * | 2018-01-18 | 2018-07-17 | 上海仁实医药科技有限公司 | A kind of synthesis technology of benzyl ribonolactone |
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Application publication date: 20200609 |