A method for synthesizing prostaglandin intermediate (3R, Z)-7-(3-hydroxy-5-oxocyclopent-1-yl)-5-heptenoic acid isopropyl ester

Abstract

The present application relates to the field of drug synthesis technology, and in particular to a method for synthesizing a prostaglandin intermediate (3R,Z)-7-(3-hydroxy-5-oxocyclopentyl-1-yl)-5-heptenoic acid isopropyl ester, comprising the following steps: compound B is selectively acetylated to the R configuration by enzyme 1 to generate a mixture; the mixture is subjected to a Mitsunobu reaction to obtain a mixture of compounds C and E; the mixture of compounds C and E uses enzyme 2 as a catalyst, and selectively hydrolyzes the mixture of compounds C and E (R configuration) in an alcohol-containing system to obtain a prostaglandin intermediate; the enzyme 2 is a powdered hydrolase, an immobilized hydrolase, a powdered lipase or an immobilized lipase. The present application provides a method for synthesizing a prostaglandin intermediate in a simple and efficient manner, shortening the reaction steps, simplifying the production operation, avoiding the duplication of the process, avoiding the generation of impurities that are difficult to remove, improving production efficiency, and reducing production costs.

Description

Technical Field

[0001] The present application relates to the technical field of drug synthesis, and in particular to a method for synthesizing a prostaglandin intermediate (3R, Z)-7-(3-hydroxy-5-oxocyclopent-1-yl)-5-heptenoic acid isopropyl ester. Background Art

[0002] Bimatoprost and travoprost are both a class of highly effective intraocular pressure-lowering drugs developed and manufactured by Allergan, an American company. They are unique in pharmacology and have a strong intraocular pressure-lowering effect.

[0003] The prostaglandin intermediate (3R, Z)-7-(3-hydroxy-5-oxocyclopent-1-yl)-5-heptenoic acid isopropyl ester (intermediate A) is the key to the preparation of drugs bimatoprost and travoprost. The method disclosed in patent CN102056887B can produce prostaglandin intermediate A, but more impurities will be produced in the reaction, and the impurities will increase with the extension of the reaction time. The impurities and the impurities derived from them are very difficult to remove during the purification process. It is necessary to control the reaction to terminate the reaction immediately after the reaction is completed, which is very unfavorable for large-scale production. At the same time, in order to meet the requirements for raw material chirality control, the ee value of prostaglandin intermediate A needs to reach more than 99%, and the process needs to perform enzyme splitting reaction and guanidine hydrolysis reaction again, which leads to lengthy process, low efficiency and high cost. Summary of the invention

[0004] In order to solve the problems of lengthy process steps and impurity generation, the present application provides a method for synthesizing a prostaglandin intermediate (3R, Z)-7-(3-hydroxy-5-oxocyclopent-1-yl)-5-heptenoic acid isopropyl ester.

[0005] The present application provides a method for synthesizing a prostaglandin intermediate (3R, Z)-7-(3-hydroxy-5-oxocyclopent-1-yl)-5-heptenoic acid isopropyl ester, which adopts the following technical scheme: A method for synthesizing a prostaglandin intermediate (3R, Z)-7-(3-hydroxy-5-oxocyclopent-1-yl)-5-heptenoic acid isopropyl ester comprises the following steps: S1, compound B is selectively acetylated to the R configuration using an acylating agent catalyzed by enzyme 1 to generate a mixture; the mixture is subjected to Mitsunobu reaction to obtain a mixture of compounds C and E; S2, using enzyme 2 as a catalyst, selectively alcoholyzing the mixture of compounds C and E (R configuration) in an alcohol-containing system to obtain a prostaglandin intermediate; The enzyme 1 is powdered lipase or immobilized lipase, powdered hydrolase or immobilized hydrolase.

[0006] The enzyme 2 is powdered hydrolase or immobilized hydrolase, powdered lipase or immobilized lipase.

[0007] The enzyme 1 and the enzyme 2 may be the same or different. In the acylation reaction reagent, the alcohol may be acylated into an ester; in the alcohol or water, the ester may be esterified (or transesterified) or hydrolyzed.

[0008] The compound B is prepared according to the method reported in CN102056887B and the literature Julian PH et al. Org. Process Res. Dev., 2012, 16, 1905-1916, specifically as follows: Furfural reacts with an allyl metal reagent, a protecting reagent, a hydroxylating reagent and a cleaving reagent in sequence to obtain compound 3; the aldehyde group of compound 3 reacts with ylide to generate compound 4; compound 4 is deprotected to obtain compound 5; compound 5 is esterified to obtain compound 8 after salt formation and crystallization to remove the trans isomer; compound 8 is rearranged to obtain racemic compound B (the following reaction route).

[0009] Synthesis route of compound B By adopting the above technical scheme, the compound B of the present application is selectively acetylated to the R configuration by enzyme catalysis, and the unreacted S configuration is subjected to a light-nobu reaction to flip the configuration to obtain a formylated product of the R configuration, and then a prostaglandin intermediate with an ee value of more than 99% can be obtained by using enzyme 2, while avoiding the generation of impurities. The present application provides a simple and efficient method for synthesizing the prostaglandin intermediate A, shortening the reaction steps, simplifying the production operation, avoiding the repetition of the process, avoiding the generation of impurities that are difficult to remove, improving production efficiency, and reducing production costs.

[0010] In a specific feasible technical solution, the enzyme 1 is the brand Amano lipase PS, and the enzyme 2 is the brand Amano hydrolase CES L-3.

[0011] In a specific embodiment, in S2, the amount of the enzyme 2 is 1%-150% by weight of the mixture of compounds C and E.

[0012] By adopting the above technical solution, the enzyme participates in the reaction process as a catalyst. Under certain reaction conditions, the amount of enzyme has a direct effect on the reaction rate. As the amount of enzyme continues to increase, the reaction rate will also increase. After reaching a certain threshold, the reaction active points between the reactants and the enzyme reach saturation, and the reaction rate can no longer be increased. By affecting the reaction rate, it also affects the conversion rate and yield of the product.

[0013] In a specific embodiment, in S2, the alcohol in the alcohol-containing system is one or more of methanol, ethanol, isopropanol, and n-butanol, preferably isopropanol.

[0014] By adopting the above technical solution, isopropanol is a polar solvent that can mix freely with water and has good solubility for lipophilic substances. In particular, when preparing intermediates for synthetic drugs, isopropanol is used as a solvent or reaction medium to participate in the synthesis and purification of the drugs, thereby ensuring the safety and effectiveness of the drugs.

[0015] In a specific embodiment, in S2, the volume mass ratio of the mixture of the alcohol and compounds C and E is 2-50 ml:1 g.

[0016] In a specific embodiment, in S2, the volume mass ratio of the mixture of the alcohol and compounds C and E is 3-10 ml:1 g.

[0017] By adopting the above technical scheme, the solvent plays an important role in the chemical synthesis reaction process, which can not only provide a reaction medium, but also adjust the reaction rate and selectivity. Correctly selecting the solvent and controlling the dosage have an important influence on the reaction results. The amount of solvent used in chemical synthesis reactions is usually large, occupying a part of the entire reaction system. Reasonable control of the amount of solvent can reduce costs and improve economic benefits; the waste generated in synthetic chemical reactions usually contains a large amount of unreacted solvent, which pollutes the environment. Controlling the amount of solvent helps to reduce waste emissions and reduce environmental pollution; excessive and insufficient solvents may affect the effect of the reaction. Too much solvent may cause excessive dilution of the reaction, reducing the reaction rate and selectivity. Therefore, correctly controlling the amount of solvent can improve the reaction effect, reduce costs, and reduce environmental pollution.

[0018] In a specific embodiment, in S2, the reaction temperature is 10-70°C.

[0019] In a specific embodiment, in S2, the reaction temperature is 20-40°C.

[0020] By adopting the above technical solution, in chemical reactions, temperature is an important factor affecting the rate of chemical reactions. An increase in temperature usually accelerates the rate of reaction, while a decrease in temperature slows down the reaction rate. An increase in temperature accelerates the reaction rate, but too high a temperature may lead to an unfavorable reaction. Selecting a suitable temperature range can optimize the reaction conditions and product quality.

[0021] In a specific embodiment, S2 also includes a post-processing purification process, specifically: after the reaction is complete, the enzyme 2 is removed by cooling and filtering, and the mother liquor is concentrated to obtain the product.

[0022] In a specific embodiment, in S2, the post-treatment purification process further comprises separating the mixture of unreacted compounds C and E from the product obtained by concentrating the mother liquor by column chromatography to obtain a prostaglandin intermediate A with a purity greater than 99% and an ee value greater than 99%.

[0023] By adopting the above technical solution, the operation is simple and the purity of the product is further improved.

[0024] In summary, this application has the following beneficial technical effects: 1. The present application utilizes a one-step enzymatic esterification reaction, which has a simple process, improves the purity of the prostaglandin intermediate A, and reduces the generation of impurities; 2. This application improves the utilization rate of raw materials and reduces the occurrence of side reactions by controlling the parameters of each process step during the process, thus facilitating subsequent separation and purification; 3. The reaction process of the present application has good stability and strong tolerance, and there is no obvious impurity generation and growth when the reaction time is extended. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 This is the H NMR spectrum of the prostaglandin intermediate A prepared in Example 1 of the present application.

[0026] Figure 2 This is the NMR mass spectrum of the prostaglandin intermediate A prepared in Example 1 of the present application. DETAILED DESCRIPTION

[0027] The present application is further described in detail below through examples.

[0028] All raw materials in the examples are commercially available. Example

[0029] Example 1 This embodiment discloses a method for synthesizing a prostaglandin intermediate A, comprising the following steps: S1, compound B is selectively acetylated to the R configuration by enzyme 1 to generate a mixture (compound C + compound D); the mixture is subjected to Mitsunobu reaction to obtain a mixture of compounds C and E; The reaction equation in S1 is as follows: Note: For the detailed process of S1, please refer to paragraphs

[0127] -

[0197] of patent CN102056887B, which will not be described in detail here; S2, under nitrogen protection, a mixture of compounds C and E (69.6 mg, 0.23 mmol), Amano hydrolase CES L-3 (35 mg, 50% w / w) and isopropanol (3.5 ml, 50 times volume, stirred at 30°C for 27 hours, the raw material remaining 1.6%, filtered, the mother liquor was concentrated to dryness to obtain prostaglandin intermediate A with a purity of 96.5%, an ee value of 99.2% and a yield of 93%; its H NMR spectrum is as follows Figure 1 As shown, the NMR carbon spectrum is as follows Figure 2 shown.

[0030] The reaction equation in S2 is as follows:

[0031] Example 2 This embodiment is basically the same as embodiment 1, except that in S2, a mixture of compounds C and E (1 g, 3.3 mmol), Amano hydrolase CES L-3 (0.5 g, 50% w / w) and isopropanol (5 mL, 5 volumes) were added to the reaction bottle under nitrogen protection, and the mixture was stirred at 40° C. for 20 hours. The raw material remained at 4.9%. The mixture was filtered and the mother liquor was concentrated to dryness to obtain a prostaglandin intermediate A with a purity of 91.8%, an ee value of 99.6% and a yield of 89%.

[0032] Example 3 This embodiment is basically the same as embodiment 1, except that in S2, a mixture of compounds C and E (2 g, 6.6 mmol), Amano hydrolase CES L-3 (1 g, 50% w / w) and isopropanol (10 mL, 5 volumes) were added to a reaction bottle under nitrogen protection, and stirred at 40° C. for 20 hours. The raw material remained 8.4%. After cooling to 20° C., the mixture was filtered and the mother liquor was concentrated to dryness to generate a prostaglandin intermediate with a purity of 90.7% and an ee value of 99.6%. The prostaglandin intermediate A with a yield of 85%, a purity of 99.5% and an ee value of 99.6% was obtained by purification by silica gel column chromatography (eluent: ethyl acetate / n-heptane = 1 / 3).

[0033] Example 4 This embodiment is basically the same as embodiment 1, except that in S2, a mixture of compounds C and E (1 g, 3.3 mmol), Amano hydrolase CES L-3 (0.5 g, 50% w / w) and isopropanol (5 mL, 5 volumes) were added to the reaction bottle under nitrogen protection, and stirred at 50° C. for 20 hours. The raw materials remained 10.8%. After cooling to 20° C., the mother liquor was filtered and concentrated to dryness to generate a prostaglandin intermediate with a purity of 86.2% and an ee value of 99.5%. The prostaglandin intermediate A with a yield of 81%, a purity of 99.1% and an ee value of 99.5% was obtained by purification by silica gel column chromatography (eluent: ethyl acetate / n-heptane = 1 / 3).

[0034] Example 5 This embodiment is basically the same as embodiment 1, except that in S2, a mixture of compounds C and E (1 g, 3.3 mmol), Amano hydrolase CES L-3 (0.5 g, 50% w / w) and isopropanol (5 mL, 5 volumes) were added to the reaction bottle under nitrogen protection, and the mixture was stirred at 60° C. for 20 hours. The raw materials remained at 4.2%. After cooling to 20° C., the mixture was filtered and the mother liquor was concentrated to dryness to generate a prostaglandin intermediate with a purity of 92.6% and an ee value of 99.3%. The prostaglandin intermediate A with a yield of 86%, a purity of 99.2% and an ee value of 99.3% was obtained by purification by silica gel column chromatography (eluent: ethyl acetate / n-heptane = 1 / 3).

[0035] Comparative Example Comparative Example 1 The prostaglandin intermediate A of this comparative example is the compound (R)-8b in patent CN102056887B, see

[0127] -

[0202] for details. The racemic intermediate B is obtained in this method, and the R configuration is selectively acetylated by enzyme catalysis, and the unreacted S configuration is subjected to a light-nobu reaction to flip the configuration to obtain a formylated product of the R configuration, and guanidine is used to deacylate the acetylated and formylated mixture to obtain a prostaglandin intermediate, and its ee value is about 94%. In the deacylation reaction, more impurities will be produced, such as generating more than 2% impurity F and more than 4% impurity G, and the impurities will increase with the extension of the reaction time. Impurity F and its derived impurities are very difficult to remove during the purification process, and the reaction needs to be controlled to terminate the reaction immediately after the reaction is completed, which is very unfavorable for large-scale production. In order to meet the requirements for raw material chirality control, the ee value of the prostaglandin intermediate A needs to reach more than 99%, and the process needs to perform enzyme resolution reaction and guanidine hydrolysis reaction again, which leads to lengthy process, low efficiency and high cost.

[0036] The guanidine hydrolysis degradation impurities and related derivatives F and G are shown in the figure below: By comparison, it is found that the present application provides a simple and efficient method for synthesizing prostaglandin intermediate A, which shortens the reaction steps, simplifies the production operation, avoids process duplication, avoids the generation of difficult-to-remove impurities, improves production efficiency, and reduces production costs. Specifically, it has the following advantages: 1. Reduce the generation of impurities, including avoiding the generation of impurity F and the generation of impurity G not exceeding 1%.

[0037] 2. The reaction process has good stability and strong tolerance, and there is no obvious impurity generation and growth when the reaction time is extended.

[0038] 3. The one-step enzymatic esterification reaction replaces the original three-step reaction, which simplifies the process and improves economic benefits. The conversion rate is not less than 90%; the separation yield of this one-step reaction is more than 80%, which is more than 10% higher than the original three-step reaction total yield of about 70%.

[0039] This specific embodiment is merely an explanation of the present application and is not a limitation of the present application. After reading this specification, those skilled in the art may make modifications to the present embodiment without any creative contribution as needed, but such modifications are protected by the patent law as long as they are within the scope of the claims of the present application.

Claims

1. A method for synthesizing a prostaglandin intermediate (3R, Z)-7-(3-hydroxy-5-oxocyclopent-1-yl)-5-heptenoic acid isopropyl ester, characterized in that: The following steps are involved: S1, compound B is selectively acetylated to the R configuration by enzyme 1 to generate a mixture; the mixture is subjected to Mitsunobu reaction to obtain a mixture of compounds C and E; S2, using enzyme 2 as a catalyst, the mixture of compounds C and E is selectively hydrolyzed (R configuration) in an alcohol-containing system to obtain a prostaglandin intermediate A; The enzyme 2 is powdered hydrolase, immobilized hydrolase, powdered lipase or immobilized lipase.

2. The method for synthesizing the prostaglandin intermediate (3R, Z)-7-(3-hydroxy-5-oxocyclopent-1-yl)-5-heptenoic acid isopropyl ester according to claim 1, characterized in that: In S2, the amount of the enzyme 2 is 1%-150% by weight of the mixture of compounds C and E.

3. The method for synthesizing the prostaglandin intermediate (3R, Z)-7-(3-hydroxy-5-oxocyclopent-1-yl)-5-heptenoic acid isopropyl ester according to claim 1, characterized in that: In S2, the alcohol in the alcohol-containing system is one or more of methanol, ethanol, isopropanol, and n-butanol.

4. The method for synthesizing the prostaglandin intermediate (3R, Z)-7-(3-hydroxy-5-oxocyclopent-1-yl)-5-heptenoic acid isopropyl ester according to claim 1, characterized in that: In S2, the volume mass ratio of the mixture of the alcohol and compounds C and E is 2-50 ml:1 g.

5. The method for synthesizing the prostaglandin intermediate (3R, Z)-7-(3-hydroxy-5-oxocyclopent-1-yl)-5-heptenoic acid isopropyl ester according to claim 4, characterized in that: The volume mass ratio of the mixture of the alcohol and compounds C and E is 3-10 ml:1 g.

6. The method for synthesizing the prostaglandin intermediate (3R, Z)-7-(3-hydroxy-5-oxocyclopent-1-yl)-5-heptenoic acid isopropyl ester according to claim 1, characterized in that: In the step S2, the reaction temperature is 10-70°C.

7. The method for synthesizing the prostaglandin intermediate (3R, Z)-7-(3-hydroxy-5-oxocyclopent-1-yl)-5-heptenoic acid isopropyl ester according to claim 6, characterized in that: The reaction temperature is 20-40°C.

8. The method for synthesizing the prostaglandin intermediate (3R, Z)-7-(3-hydroxy-5-oxocyclopent-1-yl)-5-heptenoic acid isopropyl ester according to claim 1, characterized in that: The S2 also includes a post-processing purification process, specifically: after the reaction is complete, the enzyme 2 is removed by cooling and filtering, and the mother liquor is concentrated to obtain the product.

9. The method for synthesizing the prostaglandin intermediate (3R, Z)-7-(3-hydroxy-5-oxocyclopent-1-yl)-5-heptenoic acid isopropyl ester according to claim 8, characterized in that: The post-treatment purification process also includes separating the mixture of unreacted compounds C and E from the product obtained by concentrating the mother liquor through column chromatography to obtain a prostaglandin intermediate with a purity greater than 99% and an ee value greater than 99%.

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