CN105985303B - Preparation method of anticoagulant, intermediate and preparation method thereof - Google Patents
Preparation method of anticoagulant, intermediate and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a preparation method of an anticoagulantIntermediates and methods of making the same. The invention provides a preparation method of a vallapachol sulfate intermediate IV, which comprises the following steps: and (3) carrying out oxidation reaction on the compound III and an oxidant in an organic solvent to obtain the intermediate IV of the valapasha sulfate. The preparation method has the advantages of simple operation, mild reaction conditions, high reaction conversion rate, high yield, high purity of the prepared product, low production cost, simple post-treatment and suitability for industrial production.
Description
Technical Field
The invention relates to a preparation method of an anticoagulant, an intermediate and a preparation method thereof.
Background
8-Riemershadong anticoagulant Zontity (vorapaxar) was approved by FDA in 2014, and the cardiovascular drug vorapaxar sulfate was formally marketed. Vorapaxar is a pioneering (first-in-class) protease activated receptor 1(PAR-1) antagonist, is an antiplatelet agent, and aims to reduce the platelet aggregation tendency and inhibit the formation of blood clotting clots. Researchers have found that Vorapaxar, when used in patients suffering a heart attack or in patients with a blockage in a leg artery, significantly reduces the risk of further heart attacks, stroke, cardiovascular death and the need for surgery in the patient. Another cardiovascular disease drug, Tredaptive, in the eastern siler, has been previously denied by the FDA. To date, moraxedon has invested $ 80 million in developing vorapaxar, which now also receives permission to prevent relapse in patients with primary heart disease.
In the prior art, the preparation of the valaparsat sulfate mainly comprises the following two routes:
(1) the earliest patents on Vorapaxa sulfate were the ones filed in 1998 by Schering Corporation (US 6063847A:)
The method takes a compound 44 protected by ethylene glycol as a raw material, and obtains a target compound 50 through coupling, D-A ring closure reaction, reduction from acid to aldehyde and final coupling again, wherein the specific synthetic route is as follows:
in the above process, the original inventor adopted a one-pot process for the two-step reaction of converting acid 48 to aldehyde 49.
The method has long steps and low yield of key steps, wherein the synthesis method adopts tin hydride to reduce acyl chloride to prepare the compound 49, a large amount of thionyl chloride is used in the process of the method, and then tetrabutyltin hydride is adopted to obtain the aldehyde 49 under the action of metal palladium, so the method is not suitable for large-scale industrial production; in addition, the tributyl tin hydride is a toxic reagent, has a large toxic effect on human bodies and the environment, and is not suitable for large-scale production.
(2) There are also patent routes filed by Schering Corporation in 2006: WO2006/076415(PCT/US2006/000954), which reports that target compound 11 is obtained by using chiral alkynol as a raw material through a D-A reaction, an isomerization reaction and a coupling reaction, and the specific synthetic route is shown as follows:
in the above method, the original inventor adopts a method of palladium carbon reduction to convert acid 14 into aldehyde 15, and the yield reported in the literature is 66%. However, according to the method of this document, we have tried a method from acid 14 to key intermediate 15, but the yield is low, about 10%, the reaction conditions are severe, special equipment is required, the raw materials are expensive, and the post-treatment is complicated, so this method is not suitable for mass production.
In conclusion, both Pd high pressure hydrogenation and Bu high pressure hydrogenation are used3The key intermediate aldehyde cannot be obtained ideally by the SnH mode. Thus, there is a need in the art for a new class of acids to aldehydesTo solve the technical problem.
Disclosure of Invention
The invention aims to solve the technical problems that the preparation method of the anticoagulant, the intermediate and the preparation method thereof are provided in order to overcome the defects that the preparation method of the anticoagulant from the fatty carboxylic acid to the fatty aldehyde, which is a key step in the preparation method of the anticoagulant, is complicated in steps, large in toxicity of used reagents, dangerous in operation, serious in environmental pollution, low in yield, not suitable for industrial production and the like in the prior art. The preparation method has the advantages of simple operation, mild reaction conditions, high reaction conversion rate, high yield, high purity of the prepared product, low production cost, simple post-treatment and suitability for industrial production.
The invention provides a preparation method of a vallapachol sulfate intermediate IV, which comprises the following steps: in an organic solvent, carrying out oxidation reaction on the compound III and an oxidant to obtain a valapasha sulfate intermediate IV;
the preparation method of the vorapaxate sulfate intermediate IV can be a conventional method in the field of such oxidation reactions, and the following reaction methods and conditions are particularly preferred in the present invention:
in the preparation method of the valaparsat sulfate intermediate IV, the organic solvent is preferably a halogenated hydrocarbon solvent; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent is preferably dichloromethane.
In the preparation method of the intermediate IV of valapaxate sulfate, the volume-to-mass ratio of the organic solvent to the compound III is preferably 1mL/g to 100mL/g, and more preferably 5mL/g to 50 mL/g.
In the preparation method of the intermediate IV of the valapasha sulfate, the oxidizing agent is preferably oxalyl chloride and dimethyl sulfoxide or pyridinium chlorochromate (PCC).
In the preparation method of the valapasha sulfate intermediate IV, the molar ratio of the oxidant to the compound III is preferably 1-6. When the oxidizing agent is pyridinium chlorochromate (PCC), the molar ratio of the oxidizing agent to the compound III is further preferably 5 to 6. When the oxidant is the combination of oxalyl chloride and dimethyl sulfoxide, the molar ratio of the oxalyl chloride to the compound III is further preferably 1-2; the molar ratio of the dimethyl sulfoxide to the oxalyl chloride is preferably 1-3, and more preferably 1-2.
In the preparation method of the valapasha sulfate intermediate IV, the temperature of the oxidation reaction is preferably-80-40 ℃; when the oxidizing agent is a combination of oxalyl chloride and dimethyl sulfoxide, the temperature of the oxidation reaction is more preferably from-80 ℃ to-60 ℃, and when the oxidizing agent is pyridinium chlorochromate (PCC), the temperature of the oxidation reaction is more preferably from 0 ℃ to 40 ℃, and still more preferably from 15 ℃ to 30 ℃.
In the preparation method of the intermediate IV, the progress of the oxidation reaction can be monitored by a conventional monitoring method in the field (such as TLC, HPLC or NMR), and the end point of the reaction is generally the disappearance of the compound III, and the time of the oxidation reaction is preferably 30 minutes to 3 hours.
The preparation method of the vallappa sul-hydrate intermediate IV is preferably carried out in the presence of a protective gas, and when the preparation method of the vallappa sul-hydrate intermediate IV is carried out in the presence of the protective gas, the protective gas is preferably one or more of nitrogen, helium, argon, neon, krypton and xenon, and further preferably nitrogen and/or argon.
In the preparation method of the intermediate IV of the valapasha sulfate, when the oxidizing agent is pyridinium chlorochromate (PCC), the oxidation reaction preferably adopts the following steps: the solution of compound III and an organic solvent is added dropwise to a mixed solution of pyridinium chlorochromate (PCC) and an organic solvent. Preferably, silica gel is added to the reaction system, and the mass ratio of the silica gel to the pyridinium chlorochromate (PCC) is preferably 2:1 to 1:2, and more preferably 1:1 to 1: 1.5. The dropping speed is based on the temperature of the reaction system not exceeding 30 ℃.
In the preparation method of the intermediate IV of the valapasha sulfate, when the oxidizing agent is pyridinium chlorochromate (PCC), the oxidation reaction preferably adopts the following post-treatment steps: and after the reaction is finished, filtering, washing, drying and concentrating to obtain the purified intermediate IV of the vallapachol sulfate (the HPLC purity is more than 98%). The filtration, washing, drying and concentration can be carried out by methods and conditions conventional in the art for such procedures. The filtration is preferably carried out by using kieselguhr as a pad. The washing is preferably carried out with 1N hydrochloric acid, water, saturated sodium bicarbonate, or saturated brine. The drying is preferably carried out using anhydrous sodium sulfate.
In the preparation method of the intermediate IV of the valapasha sulfate, when the oxidant is the combination of oxalyl chloride and dimethyl sulfoxide, the oxidation reaction preferably comprises the following steps: and (3) dropwise adding a solution formed by dimethyl sulfoxide and an organic solvent into a solution formed by oxalyl chloride and the organic solvent at the temperature of-70 to-80 ℃, reacting for 30 minutes to 1 hour, and then dropwise adding a solution formed by a compound III and the organic solvent, and carrying out oxidation reaction to obtain the intermediate IV of the valapasha sulfate. The dropping speed is preferably such that the temperature of the reaction system does not exceed-60 ℃. The oxidation reaction preferably comprises the following post-treatment steps, after the reaction is finished, adding alkali to quench the reaction, adding water, extracting, washing, concentrating to obtain a crude product, and recrystallizing to obtain the purified compound IV. The molar ratio of the base to the compound III is preferably 3-8, and more preferably 4-6. The extraction is preferably carried out by adopting a halogenated hydrocarbon solvent, and the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent is preferably dichloromethane. The washing is preferably carried out by washing with hydrochloric acid having a molar concentration of 2N to a pH of 3-4 and then washing with saturated brine. The recrystallization preferably adopts a mixed solvent of an ester solvent and an alkane solvent, the ester solvent is preferably ethyl acetate, and the alkane solvent is preferably n-heptane.
The preparation method of the vallappa sulfate intermediate IV further comprises the following steps: in an organic solvent, carrying out reduction reaction on a compound II and a reducing agent to obtain a compound III;
in the preparation method of the compound III, the organic solvent can be a conventional organic solvent for reduction reaction in the field, and an ether solvent and/or an alcohol solvent are particularly preferred in the invention; the ether solvent is preferably tetrahydrofuran, and the alcohol solvent is preferably n-butanol.
In the method for producing the compound III, the volume-to-mass ratio of the organic solvent to the compound II is preferably 1mL/g to 100mL/g, and more preferably 20mL/g to 50 mL/g.
In the preparation method of the compound III, the reducing agent can be sodium borohydride, zinc borohydride and tri-C1～C4One or more of lithium aluminum alkoxyhydrides, preferably tri-C1～C4Lithium aluminum alkoxide hydride, said tri-C1～C4Lithium aluminum alkoxyhydride such as lithium trimethoxy aluminum hydride, lithium triethoxy aluminum hydride, lithium tripropoxy aluminum hydride, lithium triisopropoxy aluminum hydride, lithium tributoxy aluminum hydride, lithium triisobutoxy aluminum hydride or lithium tri-tert-butoxy aluminum hydride, preferably lithium tri-tert-butoxy aluminum hydride.
In the present invention, said tri-C1～C4The lithium aluminum alkoxide hydride can be the conventional commercial tri-C in the art1～C4The alkoxy lithium aluminum hydride reagent can also be prepared by mixing lithium aluminum hydride with 2-3 times of molar amount of C1～C4Alkyl alcohol is reacted to obtain.
In the preparation method of the compound III, the molar ratio of the reducing agent to the compound II is preferably 1 to 5, and more preferably 1 to 2.5.
In the preparation method of the compound III, the temperature of the reduction reaction may be a conventional temperature in the art, and is preferably 0 to 10 ℃ in the present invention.
In the preparation method of the compound III, the progress of the reduction reaction can be monitored by a conventional monitoring method in the art (e.g., TLC, HPLC, or NMR), and generally the end point of the reaction is the disappearance of the compound II, and the time of the reduction reaction is preferably 30 minutes to 3 hours.
The preparation method of the compound III is preferably performed in the presence of a protective gas, and when the preparation method of the compound III is performed in the presence of a protective gas, the protective gas is preferably one or more of nitrogen, helium, argon, neon, krypton, and xenon, and further preferably nitrogen and/or argon.
The preparation method of the compound III preferably comprises the following post-treatment steps: after the reaction is finished, adding ice water, adjusting the pH value to 2-3 by hydrochloric acid, extracting, washing, drying and concentrating to obtain a crude compound III, and recrystallizing to obtain a purified compound III. The extraction, washing, drying, concentration and recrystallization can be carried out using methods and conditions conventional in the art for such procedures. The solvent adopted for extraction is preferably an ester solvent, and the ester solvent is preferably ethyl acetate. The washing is preferably carried out by washing with a saturated aqueous sodium bicarbonate solution and a saturated brine in this order. The solvent used for recrystallization is preferably a mixed solvent of an ester solvent and an alkane solvent, the ester solvent is preferably ethyl acetate, and the alkane solvent is preferably n-heptane.
The preparation method of the vallappa sulfate intermediate IV further comprises the following steps: in an organic solvent, in the presence of a catalyst, carrying out chlorination reaction on a compound I and a chlorinating agent to obtain a compound II;
the preparation method of the compound II can adopt the conventional method of the chlorination reaction in the field, and the following reaction method and conditions are particularly preferred in the invention:
in the preparation method of the compound II, the organic solvent is preferably a halogenated hydrocarbon solvent; the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent is preferably dichloromethane.
In the method for producing the compound II, the volume-to-mass ratio of the organic solvent to the compound I is preferably 1mL/g to 100mL/g, and more preferably 5mL/g to 30 mL/g.
In the preparation method of the compound II, the chlorinating agent is preferably oxalyl chloride.
In the method for preparing the compound II, the molar ratio of the chlorinating agent to the compound I is preferably 1-5, and more preferably 2.5-3.5.
In the preparation method of the compound II, the catalyst is preferably N, N-dimethylformamide.
In the method for producing the compound II, the molar ratio of the catalyst to the compound I is preferably 0.001 to 0.1, and more preferably 0.005 to 0.01.
In the method for producing the compound II, the temperature of the chlorination reaction is preferably 20 to 30 ℃.
In the preparation method of the compound II, the progress of the chlorination reaction can be monitored by a conventional monitoring method in the field (such as TLC, HPLC or NMR), and the end point of the reaction is generally the disappearance of the compound I, and the time of the chlorination reaction is preferably 30 minutes to 3 hours.
In the process for producing the compound II, the chlorination reaction is preferably carried out without further purification by removing the solvent after the completion of the reaction.
The preparation method of the intermediate IV of the valapasha sulfate preferably adopts the following synthetic route:
the invention also provides a preparation method of the Vorapaxar sulfate shown as the formula V, which comprises the following steps: carrying out Wittig reaction on the intermediate IV of the vallappa sulfate and phospholipid VI in an organic solvent in the presence of alkali to obtain vallappa sulfate V shown as a formula V;
the preparation process of vorlappa sulphate as shown in formula V may be a conventional process in the art for such wittig reactions, and the following reaction processes and conditions are particularly preferred in the present invention:
in the preparation method of the voraparsat sulfate shown in the formula V, the organic solvent is preferably an ether solvent, and the ether solvent is preferably tetrahydrofuran.
In the preparation method of the vallappa sudoxa sulfate shown in the formula V, the volume-to-mass ratio of the organic solvent to the vallappa sudoxa sulfate intermediate IV is preferably 1 mL/g-100 mL/g, and more preferably 10 mL/g-50 mL/g.
In the preparation method of the vallappa sulfate shown in the formula V, the base is preferably an organic base, and the organic base is preferably Lithium Diisopropylamide (LDA).
In the preparation method of the vallappa sudoxa sulfate shown as the formula V, the molar ratio of the alkali to the vallappa sudoxa sulfate intermediate IV is preferably 1-5, and more preferably 3-4.
In the preparation method of the vorapaxate sulfate shown in the formula V, the molar ratio of the phospholipid VI to the vorapaxate sulfate intermediate IV is preferably 1-5, and more preferably 2-3.
In the preparation method of the vallappa sulfate shown as the formula V, the vallappa sulfate intermediate IV is preferably prepared by adopting the method;
in said process for preparing voraparsat sulphate, as represented by formula V, said wittig reaction is preferably carried out at a temperature of-20 ℃ to-10 ℃.
In said preparation process of the vorapaxate sulfate represented by formula V, the progress of said wittig reaction can be monitored by conventional monitoring methods in the art (e.g. TLC, HPLC or NMR), generally taking the time when the vorapaxate sulfate intermediate IV disappears as the end point of the reaction, and said time of wittig reaction is preferably 30 minutes to 4 hours.
The preparation method of the vallappa sulfate shown in the formula V is preferably carried out in the presence of a protective gas, and when the preparation method of the vallappa sulfate shown in the formula V is carried out in the presence of the protective gas, the protective gas is preferably one or more of nitrogen, helium, argon, neon, krypton and xenon, and further preferably nitrogen and/or argon.
The preparation method of the Vorapaxar sulfate shown as the formula V preferably comprises the following steps: and (3) dropwise adding alkali into a solution formed by phospholipid VI and an organic solvent at the temperature of between 20 ℃ below zero and 10 ℃ below zero, reacting for 1 to 2 hours, dropwise adding a solution formed by the intermediate IV of the vallappa sulfate and the organic solvent into the reaction system, and reacting for 1 to 2 hours to obtain the vallappa sulfate shown in the formula V.
The preparation method of the Vorapaxar sulfate shown as the formula V preferably adopts the following post-treatment steps: and after the reaction is finished, adding water to quench the reaction, adjusting the pH value to 6-7 by hydrochloric acid, extracting, washing, drying, concentrating, and performing column chromatography to obtain the vallapachol sulfate shown in the formula V. The extraction, washing, drying, concentration and column chromatography may be carried out using methods and conditions conventional in the art for such procedures. The solvent adopted for extraction is preferably an ester solvent, and the ester solvent is preferably ethyl acetate. The washing is preferably carried out by washing with a saturated saline solution in this order.
The vallappa sulfate shown in the formula V is preferably prepared by the following route:
the invention also provides a compound III, the structure of which is shown as follows:
the invention also provides a preparation method of the compound III, which comprises the following steps: in an organic solvent, carrying out reduction reaction on the compound II and a reducing agent to obtain a compound III;
wherein each reaction condition is as described above.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
In the invention, the room temperature refers to the ambient temperature and is 10-35 ℃.
The positive progress effects of the invention are as follows: the preparation method has the advantages of simple operation, mild reaction conditions, high reaction conversion rate, high yield, high purity of the prepared product, low production cost, simple post-treatment and suitability for industrial production.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
EXAMPLE 1 preparation of Compound II
A250 mL three-necked flask was charged with 3.5g of the solid starting compound I, followed by 70mL of dichloromethane to completely dissolve the compound, followed by 0.017mL of N, N-Dimethylformamide (DMF), nitrogen (N)2Under protection), stirring.
Then 4g of oxalyl chloride was added dropwise to the reaction system, after the addition was completed, the temperature was raised to 30 ℃ and stirring was continued at that temperature for 30 minutes, and the starting material was completely disappeared by TLC detection. The reaction was stopped, and the reaction system was directly evaporated to dryness under reduced pressure to give a pale yellow solid compound II3.2g. The reaction was carried out without purification in the next step with a yield of 100%.
EXAMPLE 2 preparation of Compound II
A2500 mL three-necked flask was charged with 200g of the solid starting compound I, followed by 1500mL of methylene chloride to completely dissolve the compound, and then 1mL of N, N-Dimethylformamide (DMF), nitrogen (N) was added2) Stirring under protection.
Then, 200g of oxalyl chloride was added dropwise to the reaction system, and after the addition was completed, the temperature was raised to 30 ℃ and stirring was continued at that temperature for 30 minutes, and the starting material was completely disappeared by TLC detection. The reaction was stopped, and the reaction system was directly evaporated to dryness under reduced pressure to give 210g of a pale yellow solid compound II. The reaction was carried out without purification in the next step with a yield of 100%.
EXAMPLE 3 preparation of Compound III
A250 mL three-necked flask was charged with 3.2g of the pale yellow solid Compound II, followed by 80mL of Tetrahydrofuran (THF) to dissolve it completely, and nitrogen (N)2) Cooled to 0 ℃ under protection. 10mL of Zn (BH) 2M were then added to the reaction in portions4)2Keeping the temperature of the reaction system not more than 10 ℃, continuously stirring the reaction system for 30 minutes at about 10 ℃ after the addition is finished, and detecting by TLC to finish the reaction.
10mL of ice water was added, 2N hydrochloric acid was added dropwise to adjust the pH of the reaction system to 2-3, the layers were separated, and the aqueous phase was extracted twice with Ethyl Acetate (EA) until the aqueous phase was free of the product. The organic phases were combined, washed successively with a saturated solution of sodium hydrogencarbonate and saturated brine, dried over anhydrous sodium sulfate, concentrated and recrystallized from Ethyl Acetate (EA)/n-heptane to give 0.9g of compound III as a white solid in 31% yield and 93% purity by HPLC.
EXAMPLE 4 preparation of Compound III
A250 mL three-necked flask was taken, and 3.25g of a pale yellow solid compound II was added, followed by 80mL of THF to completely dissolve it, and nitrogen (N) was added2) Cooled to 0 ℃ under protection. Then adding NaBH into the reaction system in batches40.5g, keeping the temperature of the reaction system not more than 10 ℃, continuously stirring at about 10 ℃ for reaction for 30 minutes after the addition, and detecting by TLC to finish the reaction.
10mL of ice water was added, 2N hydrochloric acid was added dropwise to adjust the pH of the reaction system to 2-3, the layers were separated, and the aqueous phase was extracted twice with Ethyl Acetate (EA) until the aqueous phase was free of the product. The organic phases were combined, washed successively with a saturated solution of sodium hydrogencarbonate and saturated brine, dried over anhydrous sodium sulfate, concentrated and recrystallized from Ethyl Acetate (EA)/n-heptane to give 0.615g of compound III as a white solid in 23% yield and 90% purity by HPLC.
EXAMPLE 5 preparation of Compound III
A250 mL three-necked flask was charged with 3.25g of the pale yellow solid compound II, followed by 80mL of THF and 1.5g of N-butanol to complete dissolution, and nitrogen (N) was added2) Cooled to 0 ℃ under protection. Then 380mg of lithium aluminum hydride is added into the reaction system in batches, the temperature of the reaction system is kept not to exceed 10 ℃, after the addition is finished, the reaction is continuously stirred at about 10 ℃ for 30 minutes, and the TLC detection is carried out, thus the reaction is finished.
10mL of ice water was added, 2N hydrochloric acid was added dropwise to adjust the pH of the reaction system to 2-3, the layers were separated, and the aqueous phase was extracted twice with Ethyl Acetate (EA) until the aqueous phase was free of the product. The organic phases were combined, washed successively with a saturated solution of sodium hydrogencarbonate and saturated brine, dried over anhydrous sodium sulfate, concentrated and recrystallized from Ethyl Acetate (EA)/n-heptane to give 1.38g of compound III as a white solid in 46% yield and 90% purity by HPLC.
EXAMPLE 6 preparation of Compound III
A250 mL three-necked flask was charged with 3.2g of the pale yellow solid Compound II, followed by 80mL of THF to dissolve it completely, and nitrogen (N)2) Cooled to 0 ℃ under protection.
And then adding 4.5g of lithium aluminum tri-tert-butoxyhydride into the reaction system in batches, keeping the temperature of the reaction system not to exceed 10 ℃, continuing stirring at about 10 ℃ for reaction for 30 minutes after the addition, and detecting by TLC (thin layer chromatography) to finish the reaction.
10mL of ice water was added, 2N hydrochloric acid was added dropwise to adjust the pH of the reaction system to 2-3, the layers were separated, and the aqueous phase was extracted twice with Ethyl Acetate (EA) until the aqueous phase was free of the product. The organic phases were combined, washed successively with a saturated solution of sodium hydrogencarbonate and saturated brine, dried over anhydrous sodium sulfate, concentrated and recrystallized from Ethyl Acetate (EA)/n-heptane to give 2.7g of compound III as a white solid in 93% yield and 95% purity by HPLC.
EXAMPLE 7 preparation of Vorapasol sulfate intermediate IV
A250 mL three-necked flask was charged with 9g of pyridinium chlorochromate (PCC) and 9g of silica gel, stirred well, and then charged with 80mL of methylene chloride and nitrogen (N)2) Stirring was carried out at 25 ℃ under an atmosphere.
Then, 2.4g of Compound III dissolved in 20mL of Dichloromethane (DCM) was added dropwise to the reaction system. The dropping speed is based on the temperature of the reaction system not exceeding 30 ℃, after the adding is finished, the reaction is continuously stirred for 30 minutes at the temperature, the TLC detection is carried out, and the reaction is finished.
Celite was filtered through a pad, the filtrate was washed with 100mL of Dichloromethane (DCM), the organic phases were combined, washed successively with 1N hydrochloric acid, water, saturated sodium bicarbonate, saturated brine each time, dried over anhydrous sodium sulfate, and concentrated to give worapaxar sulfate intermediate IV as a pale yellow solid 2.3g, yield 96%, HPLC purity 98%.
EXAMPLE 8 preparation of Vorapaxar sulfate intermediate IV
A5 liter three-necked flask equipped with a mechanical stirrer and a dry ice cooling device was charged with 132g of oxalyl chloride and 1200mL of methylene chloride, nitrogen (N)2) Under protection, the mixture was stirred, cooled to-70 ℃ or lower, and then 162g of a mixture of dimethyl sulfoxide (DMSO) and 100mL of dichloromethane was added dropwise thereto. The dropping speed is based on keeping the temperature of the system not to exceed minus 60 ℃, after the dropping is finished, the stirring reaction is continued for 30 minutes at the temperature, and then 170g of the compound III is dropped into the mixture to be dissolved into 200mL of dichloromethane solution, and the dropping speed is based on keeping the temperature of the system not to exceed minus 60 ℃. After the addition was complete, the reaction was stirred at this temperature for a further 1 hour.
Then, 262.6g of triethylamine is dripped into the mixture to quench the reaction, after the addition is finished, the cooling device is taken away, the temperature is slowly raised to 0 ℃, 2 liters of water is added, the mixture is kept stand for layering, the water phase is extracted once by 200mL of dichloromethane, the organic phases are combined, washed sequentially by 2N hydrochloric acid until the pH value is 3-4, then washed once by water and saturated saline water respectively, dried by anhydrous sodium sulfate and concentrated to obtain a crude product, the crude product is dissolved by ethyl acetate, and N-heptane is dripped for recrystallization to obtain a wet product, and the wet product is dried to obtain 165g of pale gray solid intermediate IV of the vallapacha sulfate, the yield is 97%, and the HPLC purity is 98%.
Example 9 preparation of Vorapasol sulfate represented by formula V
A250 mL three-necked flask was charged with 4g of phospholipid VI and 40mL of Tetrahydrofuran (THF), nitrogen (N)2) Cooling to-20 ℃ under an atmosphere. Then, 9.3mL of 2M Lithium Diisopropylamide (LDA) was added dropwise to the reaction system. After the addition was complete, the reaction was allowed to continue stirring at this temperature for 1.5 hours.
Then, 2.0g of the intermediate IV of voraparsat sulfate was added dropwise to the reaction system in 20mL of THF mixture, and the reaction was allowed to continue stirring at that temperature for 1 hour. TLC detection, the material disappeared.
The cooling device was removed, the temperature was raised to 0 ℃ and 40mL of water was added to quench the reaction. Adjusting pH to 6-7 with 2N hydrochloric acid, layering, extracting the water phase twice with Ethyl Acetate (EA), combining the organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating, and passing through a column to obtain light yellow solid, i.e. 2.5g of Vorapasol sulfate shown in formula V, with the yield of 80%, the HPLC purity of 99.3% and the chiral HPLC purity of 99.8%.
Comparative example 1 the procedure for the preparation of compound 49 from compound 48 in patent US6063847A was repeated
The specific operation is as follows (US 6063847A):
intermediate 48(1g, 3.2mmol) was dissolved in 20mL of toluene and 1.25mL of LOCl was added2The mixed solution is stirred and heated to 80 ℃, and is continuously heated and stirred for 16 hours. The combined solution was concentrated in vacuo and the remaining gum was dissolved in 16mL of toluene, stirred and cooled to 0 ℃. 186mgPd (Ph) was added first3P)4Followed by dropwise addition of Bu3SnH (1.3ml, 4.8 mmol). The mixed solution was stirred for 3 hours, followed by column chromatography to give 450mg of intermediate 49 (yield 48%).
Comparative example 2 the reaction procedure for the preparation of aldehydes from acids in the patent (WO2006/076564A1 or PCT/US2006/001208) was repeated
The specific operation is as follows: (taken from WO2006/076564A1 or PCT/US2006/001208)
A three-necked flask equipped with a stirrer, thermometer and nitrogen balloon was prepared, a solution of crude product 14 (containing 3.1g of product 14, about 30mL in volume) was added, and anhydrous 0.005mL of dmf was added. After stirring for 5 minutes, 1.22mL of oxalyl chloride was slowly added dropwise with temperature control at 15-25 ℃. Stirring was continued for 1h after the addition, and the progress of the reaction was monitored by NMR.
After the reaction is finished, the reaction solution is at low temperature under vacuum (<Concentrated to 13.5mL at 30 ℃ and the remaining oxalyl chloride was taken up in toluene (31.5mL × 2)<50 ℃) twice, 6.8ml of solution are finally obtained. The reaction solution was cooled to 15-25 ℃ and then 16ml of THF, 2.2ml of 2, 6-lutidine, were added. 5% Pd/C (0.90g) by mass (said mass% is the mass of palladium in the total mass of the palladium on carbon reagent) is added, followed by 100psiH2And stirring for 16 hours at the temperature of 20-25 ℃.
After the reaction, the reaction solution was filtered through celite, washed with a large amount of THF solvent, hydrogenator and catalyst, and the filtrate was filtered again in the same manner. The combined filtrates were concentrated to 31.5mL in vacuo at 25 ℃. 15.8mL of MTBE (methyl tert-butyl ether) and 15.8mL of a 10% by mass aqueous phosphoric acid solution (the mass percentage refers to the mass percentage of phosphoric acid to the total mass of the aqueous phosphoric acid solution) were added to remove 2, 6-lutidine, and the temperature was controlled at 10 ℃. Residual phosphoric acid in the organic phase was removed by washing with a sodium bicarbonate solution at 2% by mass (the mass percentage is the mass of sodium bicarbonate in the total mass of the sodium bicarbonate solution), and washed with brine. After the solvent was concentrated to 9ml, 31.5ml of isopropyl alcohol was added, the mixture was concentrated to 6.8ml, and the remainder was heated to 50 ℃ to prepare crystals. 6.8ml of n-heptane were slowly added and the temperature was maintained at 50 ℃. Then slowly reducing the temperature (the cooling time is at least 2.5h) to 25 ℃. 3.4mL of n-heptane was slowly added to control the temperature to 25 ℃ and then allowed to stand for at least 20 hours after further cooling to 20 ℃. Filtration, washing (25% by volume of a mixed solvent of isopropyl alcohol and n-heptane, the volume percentage being a ratio of the volume of isopropyl alcohol to the volume of the mixed solvent of isopropyl alcohol and n-heptane), and drying gave 1.95g of compound 15. (yield 66%)
Comparative example 3 the preparation of compound IV according to the invention was carried out by the method of patent US6063847A
Intermediate Compound I (3.2mmol) was dissolved in 20mL of toluene and 1.25mL of LOCl was added2The mixed solution is stirred and heated to 80 ℃, and is continuously heated and stirred for 16 hours. The combined solution was concentrated in vacuo and the remaining gum was dissolved in 16mL of toluene, stirred and cooled to 0 ℃. 186mgPd (Ph) was added first3P)4Followed by dropwise addition of Bu3SnH (1.3ml, 4.8 mmol). The mixed solution was stirred for 3 hours, followed by column chromatography to give 450mg of intermediate aldehyde IV (yield: 48%).
Comparative example 4 Compounds IV according to the invention are prepared by the methods of the patents (WO2006/076564A1 or PCT/US2006/001208)
A three-necked flask equipped with a stirrer, thermometer and nitrogen balloon was prepared, a solution of crude intermediate compound I (containing 31g of intermediate compound I, approximately 300ml in volume) was added, and anhydrous 0.05ml of dmf was added. After stirring for 5 minutes, 12.2mL of oxalyl chloride were slowly added dropwise with temperature control at 15-25 ℃. Stirring was continued for 1h after the addition, and the progress of the reaction was monitored by NMR.
After the reaction is finished, the reaction solution is at low temperature under vacuum (<Concentrated to 135ml at 30 ℃ and the remaining oxalyl chloride is taken up in toluene (315ml × 2)<50 ℃) twice, 68ml of solution are finally obtained. The reaction was cooled to 15-25 ℃ and then 160mL of HF, 22mL of 2, 6-lutidine was added. 5% Pd/C (9.0g) was added followed by 100psiH2Stirring for 16h at the temperature of 20-25 ℃.
After the reaction, the reaction solution was filtered through celite, washed with a large amount of THF solvent and the solid catalyst, and the filtrate was filtered again in the same manner. The combined filtrates were concentrated to 315mL in vacuo at 25 ℃. 158mL of TBE and 158mL of 10% aqueous phosphoric acid were added to remove 2, 6-lutidine, and the temperature was controlled at 10 ℃. The residual phosphoric acid in the organic phase was removed by washing with 2% sodium bicarbonate solution and washed with brine. After the solvent was concentrated to 90mL, 315mL of isopropanol was added, the mixture was concentrated to 68mL, and the remainder was heated to 50 ℃ to prepare crystals. 68mL of n-heptane were added slowly and the temperature was maintained at 50 ℃. Then slowly reducing the temperature (the cooling time is at least 2.5h) to 25 ℃. Then 34ml of n-heptane was slowly added to control the temperature to 25 ℃ and then further cooled to 20 ℃ and left to stand for at least 20 h. Filtration, washing (25% by volume of a mixed solvent of isopropyl alcohol and n-heptane, the volume percentage being a ratio of the volume of isopropyl alcohol to the volume of the mixed solvent of isopropyl alcohol and n-heptane), and drying gave 3.5g of the intermediate aldehyde compound IV. (yield 11%).
Claims (10)
1. A preparation method of a valapasha sulfate intermediate IV is characterized by comprising the following steps: step 1: in an organic solvent, carrying out reduction reaction on a compound II and a reducing agent to obtain a compound III, wherein the reducing agent is lithium aluminum tri-tert-butoxyhydride; the organic solvent is an ether solvent; the molar ratio of the reducing agent to the compound II is 1-2.5;
step 2: in an organic solvent, carrying out oxidation reaction on the compound III obtained in the step 1 and an oxidant to obtain a valapasha sulfate intermediate IV;
the oxidant is the combination of oxalyl chloride and dimethyl sulfoxide or pyridinium chlorochromate; the organic solvent is a chlorinated hydrocarbon solvent;
when the oxidant is a combination of oxalyl chloride and dimethyl sulfoxide, the oxidation reaction comprises the following steps: dropwise adding a solution formed by dimethyl sulfoxide and an organic solvent into a solution formed by oxalyl chloride and the organic solvent at the temperature of-70 to-80 ℃, reacting for 30 minutes to 1 hour, dropwise adding a solution formed by a compound III and the organic solvent, and carrying out oxidation reaction to obtain a valapasha sulfate intermediate IV; the molar ratio of the oxalyl chloride to the compound III is 1-2, and the molar ratio of the dimethyl sulfoxide to the oxalyl chloride is 1-3;
when the oxidant is pyridinium chlorochromate, the oxidation reaction adopts the following steps: dropwise adding a solution formed by the compound III and an organic solvent into a mixed solution formed by pyridinium chlorochromate and the organic solvent; the molar ratio of the oxidant to the compound III is 5-6; silica gel is added in the oxidation reaction;
2. the process for the preparation of vorapaxae sulfate intermediate IV as claimed in claim 1, wherein: in the preparation method of the valaparsat sulfate intermediate IV, the volume-to-mass ratio of the organic solvent to the compound III is 1-100 mL/g;
and/or the presence of a gas in the gas,
the preparation method of the intermediate IV of the valapasha sulfate is carried out in the presence of protective gas; and/or the presence of a gas in the gas,
in the preparation method of the intermediate IV of the valapasha sulfate, when the oxidant is pyridinium chlorochromate, the oxidation reaction adopts the following post-treatment steps: after the reaction is finished, filtering, washing, drying and concentrating to obtain a purified intermediate IV of the valapasha sulfate;
and/or the presence of a gas in the gas,
in the preparation method of the intermediate IV of the valapasha sulfate, when the oxidant is the combination of oxalyl chloride and dimethyl sulfoxide, the oxidation reaction comprises the following post-treatment steps, after the reaction is finished, alkali is added for quenching reaction, water is added, extraction, washing and concentration are carried out, so as to obtain a crude product, and the crude product is recrystallized to obtain the purified compound IV.
3. The process for the preparation of vorapaxae sulfate intermediate IV as claimed in claim 2, wherein: in the preparation method of the intermediate IV of the valapasha sulfate,
the volume-mass ratio of the organic solvent to the compound III is 5 mL/g-50 mL/g;
and/or the presence of a gas in the gas,
in the preparation method of the intermediate IV of the valapasha sulfate, when the oxidant is pyridinium chlorochromate, the temperature of the oxidation reaction is 0-40 ℃;
and/or the presence of a gas in the gas,
when the preparation method of the vallappa sand sulfate intermediate IV is carried out in the presence of a protective gas, the protective gas is one or more of nitrogen, helium, argon, neon, krypton and xenon;
and/or the presence of a gas in the gas,
in the preparation method of the intermediate IV of the valapasha sulfate, when the oxidant is the combination of oxalyl chloride and dimethyl sulfoxide, the molar ratio of the alkali to the compound III in the post-treatment step of the oxidation reaction is 3-8.
4. The process for the preparation of vorapaxae sulfate intermediate IV as claimed in claim 1, wherein: in the preparation method of the intermediate IV of the valapasha sulfate, the volume-mass ratio of the organic solvent to the compound II is 1 mL/g-100 mL/g;
and/or the presence of a gas in the gas,
in the preparation method of the compound III, the temperature of the reduction reaction is 0-10 ℃;
and/or the presence of a gas in the gas,
in the preparation method of the compound III, the reduction reaction time is 30 minutes to 3 hours;
and/or the presence of a gas in the gas,
the preparation method of the compound III is carried out in the presence of protective gas;
and/or the presence of a gas in the gas,
the preparation method of the compound III comprises the following post-treatment steps: after the reaction is finished, adding ice water, adjusting the pH value to 2-3 by hydrochloric acid, extracting, washing, drying and concentrating to obtain a crude compound III, and recrystallizing to obtain a purified compound III.
5. The process for the preparation of vorapaxae sulfate intermediate IV as claimed in claim 4, wherein:
in the preparation method of the compound III, the ether solvent is tetrahydrofuran;
and/or the presence of a gas in the gas,
in the preparation method of the intermediate IV of the valapasha sulfate, the volume-mass ratio of the organic solvent to the compound II is 20 mL/g-50 mL/g;
and/or the presence of a gas in the gas,
when the preparation method of the compound III is carried out in the presence of a protective gas, the protective gas is one or more of nitrogen, helium, argon, neon, krypton and xenon;
and/or the presence of a gas in the gas,
in the post-treatment step of the compound III, the solvent adopted for extraction is an ester solvent;
and/or the presence of a gas in the gas,
in the post-treatment step of the compound III, the washing is sequentially carried out by using a saturated sodium bicarbonate aqueous solution and a saturated saline solution;
and/or the presence of a gas in the gas,
in the post-treatment step of the compound III, the solvent adopted by recrystallization is a mixed solvent of an ester solvent and an alkane solvent.
6. The process for the preparation of vorapaxae sulfate intermediate IV as claimed in claim 1, wherein: the preparation method of the vallappa sulfate intermediate IV further comprises the following steps: in an organic solvent, in the presence of a catalyst, carrying out chlorination reaction on a compound I and a chlorinating agent to obtain a compound II;
7. the process for the preparation of vorapaxae sulfate intermediate IV as claimed in claim 6, wherein: in the preparation method of the compound II, the organic solvent is a halogenated hydrocarbon solvent;
and/or the presence of a gas in the gas,
in the preparation method of the compound II, the volume-mass ratio of the organic solvent to the compound I is 1 mL/g-100 mL/g;
and/or the presence of a gas in the gas,
in the preparation method of the compound II, the chlorinating agent is oxalyl chloride;
and/or the presence of a gas in the gas,
in the preparation method of the compound II, the molar ratio of the chlorinating reagent to the compound I is 1-5;
and/or the presence of a gas in the gas,
in the preparation method of the compound II, the catalyst is N, N-dimethylformamide;
and/or the presence of a gas in the gas,
in the preparation method of the compound II, the molar ratio of the catalyst to the compound I is 0.001-0.1;
and/or the presence of a gas in the gas,
in the preparation method of the compound II, the temperature of the chlorination reaction is 20-30 ℃;
and/or the presence of a gas in the gas,
in the preparation method of the compound II, the chlorination reaction is carried out for 30 minutes to 3 hours;
and/or the presence of a gas in the gas,
in the preparation method of the compound II, the solvent is removed after the chlorination reaction is finished, and the next reaction is directly carried out without further purification.
8. The process for the preparation of vorapaxae sulfate intermediate IV as claimed in claim 7, wherein: in the preparation method of the compound II, the halogenated hydrocarbon solvent is a chlorinated hydrocarbon solvent;
and/or the presence of a gas in the gas,
in the preparation method of the compound II, the volume-to-mass ratio of the organic solvent to the compound I is 5mL/g to 30 mL/g;
and/or the presence of a gas in the gas,
in the preparation method of the compound II, the molar ratio of the chlorinating reagent to the compound I is 2.5-3.5;
and/or the presence of a gas in the gas,
in the preparation method of the compound II, the molar ratio of the catalyst to the compound I is 0.005-0.01.
9. A preparation method of Vorapaxar sulfate shown as a formula V is characterized by comprising the following steps: after the compound IV is prepared by the preparation method according to any one of claims 1 to 8, performing wittig reaction between the compound IV and phospholipid VI in an organic solvent in the presence of a base to obtain vorapaxa sulfate V shown in formula V; wherein the molar ratio of the phospholipid VI to the intermediate IV of the valaparsat sulfate is 2-3;
10. the process for the preparation of voraparsat sulfate according to claim 9, wherein:
in the preparation method of the Vorapaxar sulfate shown in the formula V, the organic solvent is an ether solvent;
and/or the presence of a gas in the gas,
in the preparation method of the Vorapaxar sulfate shown in the formula V, the volume-to-mass ratio of the organic solvent to the compound IV is 1 mL/g-100 mL/g;
and/or the presence of a gas in the gas,
in the preparation method of the Vorapaxar sulfate shown as the formula V, the alkali is organic alkali;
and/or the presence of a gas in the gas,
in the preparation method of the Vorapaxar sulfate shown as the formula V, the molar ratio of the alkali to the compound IV is 1-5;
and/or the presence of a gas in the gas,
in the preparation method of the Volaparsa sulfate as shown in the formula V, the temperature of the Wittig reaction is-20 ℃ to-10 ℃;
and/or the presence of a gas in the gas,
in the preparation method of the Volaparsa sulfate as shown in the formula V, the Wittig reaction time is 30 minutes to 4 hours;
and/or the presence of a gas in the gas,
the preparation method of the Vorapaxar sulfate shown in the formula V is carried out in the presence of protective gas;
and/or the presence of a gas in the gas,
the preparation method of the Vorapaxar sulfate shown as the formula V comprises the following steps: dropwise adding alkali into a solution formed by phospholipid and an organic solvent at the temperature of minus 20-minus 10 ℃, reacting for 1-2 hours, dropwise adding a solution formed by a compound IV and the organic solvent into the reaction system, and reacting for 1-2 hours to obtain the valapasha sulfate shown in the formula V;
and/or the presence of a gas in the gas,
the preparation method of the Vorapaxar sulfate shown as the formula V adopts the following post-treatment steps: and after the reaction is finished, adding water to quench the reaction, adjusting the pH value to 6-7 by hydrochloric acid, extracting, washing, drying, concentrating, and performing column chromatography to obtain the vallapachol sulfate shown in the formula V.
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| CN108947947A (en) * | 2017-05-17 | 2018-12-07 | 北京新领先医药科技发展有限公司 | A kind of preparation method of Walla pa sand intermediate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US6063847A (en) * | 1997-11-25 | 2000-05-16 | Schering Corporation | Thrombin receptor antagonists |
| CN101137647A (en) * | 2005-01-14 | 2008-03-05 | 先灵公司 | Synthesis of himbacine analogs |
| CN101553484A (en) * | 2006-10-04 | 2009-10-07 | 先灵公司 | Thrombin receptor antagonists based on the modified tricyclic unit of himbacine |
| CN105777681A (en) * | 2014-12-17 | 2016-07-20 | 博瑞生物医药（苏州）股份有限公司 | Preparation methods of himbacine analogue and intermediate thereof |
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| ATE378330T1 (en) * | 2002-04-16 | 2007-11-15 | Schering Corp | TRICYCLIC THROMBIN RECEPTOR ANTAGONISTS |
| PL2206697T3 (en) * | 2005-01-14 | 2012-03-30 | Merck Sharp & Dohme | Exo- and diastereo-selective syntheses of himbacine analogs |
| US8153664B2 (en) * | 2006-10-04 | 2012-04-10 | Schering Corporation | Bicyclic and tricyclic derivatives as thrombin receptor antagonists |
| EP2991994B1 (en) * | 2013-05-01 | 2018-08-15 | Vitae Pharmaceuticals, Inc. | Thiazolopyrrolidine inhibitors of ror-gamma |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US6063847A (en) * | 1997-11-25 | 2000-05-16 | Schering Corporation | Thrombin receptor antagonists |
| CN101137647A (en) * | 2005-01-14 | 2008-03-05 | 先灵公司 | Synthesis of himbacine analogs |
| CN101553484A (en) * | 2006-10-04 | 2009-10-07 | 先灵公司 | Thrombin receptor antagonists based on the modified tricyclic unit of himbacine |
| CN105777681A (en) * | 2014-12-17 | 2016-07-20 | 博瑞生物医药（苏州）股份有限公司 | Preparation methods of himbacine analogue and intermediate thereof |
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