CN111116530A - Method for synthesizing beraprost - Google Patents
Method for synthesizing beraprost Download PDFInfo
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- CN111116530A CN111116530A CN201911160052.4A CN201911160052A CN111116530A CN 111116530 A CN111116530 A CN 111116530A CN 201911160052 A CN201911160052 A CN 201911160052A CN 111116530 A CN111116530 A CN 111116530A
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
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Abstract
The invention relates to a method for synthesizing beraprost, which comprises the following steps: taking the intermediate I as an initial raw material, carrying out selective primary alcohol oxidation and Witting reaction to obtain an intermediate V, reducing and purifying the intermediate V by column chromatography to obtain an intermediate IV, and hydrolyzing the intermediate IV to obtain the beraprost. According to the synthesis method, two hydroxyls of the intermediate I are selectively oxidized, so that the use of a hydroxyl protecting reagent is avoided; the oxidation step avoids the ultralow temperature (-60 to-80 ℃) reaction and the use of a reagent DCC with larger toxicity; the reduction step avoids the use of diisobutylaluminum hydride; the synthetic method greatly reduces the process operation units, shortens the reaction steps, reduces the discharge of three wastes, and has more efficient and environment-friendly reaction; the content of the beraprost main peak prepared by the method is more than 99.0 percent, and the total process yield is more than 26 percent. The invention provides a synthesis method which is more beneficial to industrial production.
Description
Technical Field
The field belongs to the field of compound preparation, and particularly relates to a synthetic method of beraprost.
Technical Field
Beraprost sodium (trade name Dorner) belongs to prostacyclin derivatives, and is an antiplatelet drug developed by Toray, eastern corporation of japan. Beraprost (Beraprost) was approved in japan as a drug for chronic arterial occlusion in 1992 and is marketed in japan. Beraprost in the form of racemate has been approved by FDA in the united states for the treatment of Pulmonary Arterial Hypertension (PAH) into phase ii clinical, and beraprost sodium sustained-release tablets (carreoad LA) of eastern corporation (Toray) and anstai corporation (Astellas, formerly Yamanouchi) were approved in japan for the treatment of PAH as the 1 st sustained-release agent in prostacyclin-based drugs in 2007.
The synthesis process of the beraprost bulk drug relates to 9-10 steps of synthesis steps, and the total yield is less than 1%. Particularly, beraprost has 6 chiral centers, the research and control of chiral impurities have great difficulty, and only raw material medicines imported from Japan and Hungary are in China due to high research technical barriers, so that no enterprise is produced in China. Therefore, the research and development of the effective preparation method of the beraprost and the intermediate thereof have very important significance and value.
Patents EP463162a1, US5202447 and the literature heterocyles, 2000,53,1085-; tetrahedron,1999,55,2449-2474 reported synthetic methods for the preparation of beraprost and its intermediates, the synthetic route is shown in scheme 1. The method takes an intermediate I (3a,8 b-cis-dihydro-3H-5, 7-dibromocyclopentadien [ b ] benzofuran) as a raw material, primary hydroxyl groups are protected by trityl or tert-butyldimethylsilane, secondary hydroxyl acetyl groups are protected by secondary hydroxyl groups, trityl protection is removed by HCl/MeOH, and the intermediate II is obtained by three-step continuous reaction. And (3) carrying out oxidation and Witting reactions on the intermediate II to obtain an intermediate III, and carrying out reduction, resolution and deprotection to obtain an intermediate IV. Finally, hydrolyzing the ester group of the intermediate IV to obtain the beraprost.
The synthetic route has the following defects: the synthetic route involves multiple operations of protecting group application and protecting group removal, and the operation is complicated. The process produces a large amount of waste liquid, for example, acetyl needs to be removed after reduction, and acetic acid is used for quenching after the reaction is finished to produce more acetate waste. DCC (dicyclohexylcarbodiimide) used in the oxidation reaction is highly toxic, and a urea derivative produced as a by-product of the reaction is difficult to remove from the system. In addition, the total yield is low, and the production cost is high.
Patent CN100347265C reports another way to synthesize beraprost sodium, as shown in the way 2, the way uses intermediate I as the starting material, protects hydroxyl group by triethylchlorosilane, selectively oxidizes primary hydroxyl group by Swern oxidation under oxalyl chloride and DMSO, then makes Witting reaction with side chain, removes hydroxyl protecting group under the action of concentrated hydrochloric acid, reduces carbonyl group under the action of diisobutylaluminum hydride (DIBAH) and 2, 6-di-tert-butyl-p-cresol (BHT), hydrolyzes under alkaline environment, and gets beraprost.
The reaction route has the following disadvantages: the protecting group on the secondary hydroxyl is removed before reduction, and the two steps of reactions of Swern oxidation and reduction need ultralow temperature reaction at-60 to-80 ℃. Diisobutylaluminum hydride (DIBAH) is used in the reduction step, and the reagent reacts violently in water to generate flammable and explosive hydrogen and isobutane, so that great potential safety hazard exists. In addition, the route involves anhydrous and anaerobic operation in many places, and the requirement on equipment conditions is high. The industrial production is difficult to realize.
Disclosure of Invention
In view of the above-mentioned deficiencies in the prior art, the present invention provides a method for preparing synthetic beraprost. The method takes an intermediate I as an initial raw material, a key intermediate V is obtained through selective primary alcohol oxidation reaction and Witting reaction, an intermediate IV is obtained through reduction and column chromatography purification of the intermediate V, and the beraprost is obtained after the intermediate IV is hydrolyzed. The synthetic route is as follows (scheme 3):
the intermediate I: methyl 4- ((1S,2R,3aS,8bS) -2-hydroxy-1- (hydroxymethyl) -2,3,3a,8 b-tetrahydro-1H-cyclopenta [ b ] benzofuran-5-yl) butanoate and enantiomers thereof.
An intermediate V: methyl 4- ((1R,2R,3aS,8bS) -2-hydroxy-1- ((E) -4-methyl-3-oxooct-1-en-6-yn-1-yl) -2,3,3a,8 b-tetrahydro-1H-cyclopenta [ b ] benzofuran-5-yl) butyrate and enantiomers thereof.
Intermediate IV: methyl 4- ((1R,2R,3aS,8bS) -2-hydroxy-1- ((3R, E) -3-hydroxy-4-methyloct-1-en-6-yn-1-yl) -2,3,3a,8 b-tetrahydro-1H-cyclopenta [ b ] benzofuran-5-yl) butanoate and enantiomers thereof.
The method comprises the following specific steps:
step (1)
Selective oxidation of hydroxyl groups: in dichloromethane: adding an intermediate I, TEMPO and an oxidant into a mixed solvent of N, N-dimethylacetamide (in a volume ratio of 300:1), stirring at a certain temperature, completely reacting, and removing the solvent to obtain crude methyl 4- ((1R,2R,3aS,8bS) -1-formyl-2-hydroxy-2, 3,3a,8 b-tetrahydro-1H-cyclopenta [ b ] benzofuran-5-yl) butyrate and an enantiomer thereof, and dissolving the crude methyl 4- ((1R,2R,3aS,8bS) -1-formyl-hydroxy-2, 3, 8 a-tetrahydro-1H-cyclopenta [ b ] benzofuran-5;
preparation of Witting reagent: adding tetrahydrofuran and alkali into the other reaction bottle, stirring uniformly, cooling to a certain temperature, dissolving a side chain in the tetrahydrofuran, dropwise adding into the reaction bottle, and stirring for a period of time under heat preservation to prepare the phosphorus ylide;
witting reaction: dropwise adding a crude solution of 4- ((1R,2R,3aS,8bS) -1-formyl-2-hydroxy-2, 3,3a,8 b-tetrahydro-1H-cyclopenta [ b ] benzofuran-5-yl) methyl butyrate and an enantiomer thereof into the reaction bottle, stirring and reacting for a period of time at a certain temperature, adding a small amount of acetic acid to adjust the solution to be neutral, distilling out the solvent, adding ethyl acetate and water, stirring and layering, extracting a water layer with ethyl acetate, combining organic phases, washing for 2 times with a salt solution, drying, filtering, and distilling out the solvent to obtain a crude intermediate V; standing to separate out a solid, adding a mixed solvent of ethyl acetate and n-hexane, pulping at a certain temperature, filtering and drying to obtain an intermediate V;
step (2)
Dissolving the intermediate V in a solvent 1, adding a catalyst, adding a reducing agent at a certain temperature, stirring until the reaction is complete, adding a saturated sodium bicarbonate solution, stirring and filtering, adding ethyl acetate and water, stirring and layering, extracting a water layer with ethyl acetate, combining organic layers, drying, filtering, evaporating the solvent to dryness, and performing column chromatography separation and purification on the residue with ethyl acetate/petroleum ether as a mobile phase to obtain a pure intermediate IV;
step (3)
Dissolving the intermediate IV in a solvent 2, adding a 1N NaOH solution, stirring at a certain temperature until the raw materials react completely, evaporating the solvent to dryness, adding water, adjusting the pH to 4 by using 1N HCl, extracting the water phase by using ethyl acetate for 3 times, combining organic phases, washing by using water and a saturated sodium chloride solution, drying, and evaporating to dryness to obtain the beraprost.
The method of the invention has the following optimized process conditions and material dosage ratio in each step:
in the selective oxidation step in the step (1), the molar ratio of TEMPO to the intermediate I is (0.05-0.1): 1;
in the selective oxidation step in the step (1), the oxidant is one of diacetoxyiodobenzene, a NaClO/NaBr mixed solution and sodium hypobromite, and the molar ratio of the oxidant to the intermediate I is (0.5-2): 1;
in the selective oxidation step in the step (1), the reaction temperature is 25-35 ℃;
in the step of preparing the Witting reagent in the step (1), the alkali is one or a combination of sodium methoxide, sodium ethoxide, potassium tert-butoxide and sodium hydride in any proportion, and the molar ratio of the alkali to the intermediate I is (0.7-2): 1; the reaction temperature is-10-30 ℃, and the reaction time is 30-120 minutes;
in the Witting reaction step in the step (1), the molar ratio of the phosphorus ylide to the intermediate I is (0.7-2) to 1; the reaction temperature is 5-65 ℃, and the reaction time is 2-8 hours;
in the step (2), the solvent 1 is one or a combination of methanol and dimethyl sulfoxide in any proportion, and the mass ratio of the solvent 1 to the intermediate V is (4-15): 1;
the catalyst in the step (2) is CeCl3·7H2O (cerium chloride heptahydrate), SmCl3·6H2One of O (samarium chloride hexahydrate), wherein the molar ratio of the catalyst to the intermediate V is (0.5-2.5): 1;
in the step (2), the reducing agent is one of sodium borohydride and potassium borohydride, and the molar ratio of the reducing agent to the intermediate V is (0.5-2.5): 1;
the reaction temperature in the step (2) is-20 ℃, and the reaction time is 5-30 minutes;
in the step (3), the solvent 2 is one of methanol, ethanol, acetone and THF, and the mass ratio of the solvent 2 to the intermediate IV is (4-15): 1;
in the step (3), the volume-to-mass ratio of the 1N NaOH solution to the intermediate IV is (5-40): 1.
compared with the prior art, the invention has the following improved innovation points:
the invention adopts a new synthesis method, two hydroxyls of the intermediate I are selectively oxidized and then directly subjected to Witting reaction to be connected into a side chain, and two-step protection of the hydroxyls and two subsequent deprotection reactions are avoided.
Has the advantages that:
1. the invention adopts a new synthesis method to selectively oxidize two hydroxyls of the intermediate I, thereby avoiding the use of hydroxyl protecting reagents such as triphenylchloromethane, acetic anhydride, pyridine and the like, reducing the discharge of three wastes, and having more efficient and environment-friendly reaction; meanwhile, ultralow temperature reaction (-60 to-80 ℃) and the use of diisobutyl aluminum hydride and a reagent DCC with higher toxicity are avoided, and reference is provided for the amplification production.
2. The invention greatly reduces unit operation in the process, shortens reaction steps and obviously shortens reaction time; the yield is greatly improved from 9.8 percent reported in literature to more than 26 percent, and the method is more beneficial to industrial amplification production.
3. The invention provides a method for efficiently preparing beraprost intermediate V, IV.
Detailed Description
The present invention is further described in the following detailed description, which is for the purpose of illustration only, and the scope of the invention is not limited to these examples, and it will be understood by those skilled in the art that various equivalent substitutions and modifications may be made within the scope of the invention.
The following examples are given to illustrate the invention in detail, but not to limit the patent.
The first embodiment is as follows: synthesis of intermediate V
Adding 15g of intermediate I, a mixed solution of dichloromethane and N, N-dimethylacetamide (300:1), TEMPO and diacetyloxyiodobenzene into a reaction bottle, wherein the mass ratio of a solution of the mixed solution of dichloromethane and N, N-dimethylacetamide (300:1) to the intermediate I is 20:1, the molar ratio of TEMPO to the intermediate I is 0.05:1, the molar ratio of diacetyloxyiodobenzene to the intermediate I is 1.2:1, reacting at 30-35 ℃ for 5 hours, completely reacting, evaporating the solvent and generated acetic acid to obtain crude 4- ((1R,2R,3aS,8bS) -1-formyl-2-hydroxy-2, 3,3a,8 b-tetrahydro-1H-cyclopenta [ b ] benzofuran-5-yl) methyl butyrate and an enantiomer thereof, dissolving with dried tetrahydrofuran, wherein the mass ratio of the tetrahydrofuran to the intermediate I is 3:1 for later use;
adding dried tetrahydrofuran and sodium hydride into another reaction bottle, wherein the mass ratio of the tetrahydrofuran to the intermediate I is 10:1, the molar ratio of the sodium hydride to the intermediate I is 1.1:1, uniformly stirring, cooling to 0-5 ℃, dissolving a side chain into the tetrahydrofuran, the molar ratio of the side chain to the intermediate I is 1.1:2, the mass ratio of the tetrahydrofuran to the side chain is 3:1, dropwise adding the mixture into the reaction bottle, stirring for 1 hour under heat preservation, dropwise adding the tetrahydrofuran solution of the crude product of the 4- ((1R,2R,3aS,8bS) -1-formyl-2-hydroxy-2, 3,3a,8 b-tetrahydro-1H-cyclopenta [ b ] benzofuran-5-yl) methyl butyrate and the enantiomer thereof into the reaction bottle, dropwise adding, stirring for 6 hours under 25-35 ℃, adding a small amount of acetic acid to adjust to neutrality, evaporating the solvent, adding ethyl acetate and water, stirring for layering, extracting the water layer with ethyl acetate, combining the organic phases, washing with salt water for 2 times, drying, filtering, evaporating the solvent to obtain an intermediate V crude product, standing to precipitate a solid, and adding ethyl acetate: and n-hexane is 1:10, the mass ratio of the solvent to the intermediate I is 5:1, the intermediate I is pulped at 5 ℃, filtered and dried to obtain 14.57g of the intermediate V, the yield is 72.5%, and the purity is 98.7%.
Example two: synthesis of intermediate V
Adding 15g of intermediate I, a mixed solution of dichloromethane and N, N-dimethylacetamide (300:1), TEMPO, a 5% NaClO solution and NaBr into a reaction bottle, wherein the mass ratio of the mixed solution of dichloromethane and N, N-dimethylacetamide (300:1) to the intermediate I is 10:1, the molar ratio of TEMPO to the intermediate I is 0.05:1, the molar ratio of NaClO to the intermediate I is 1.2:1, the molar ratio of NaBr to the intermediate I is 0.2:1, the reaction is carried out for 6 hours at 25-30 ℃, completely reacting, distilling out an organic solvent, extracting an aqueous phase for 2 times by using ethyl acetate, combining organic phases, drying, filtering and carrying out rotary evaporation to obtain 4- ((1R,2R,3aS,8bS) -1-formyl-2-hydroxy-2, 3,3a,8 b-tetrahydro-1H-cyclopenta [ b ] benzofuran-5-yl) methyl butyrate and an enantiomer thereof, dissolving with dried tetrahydrofuran, wherein the mass ratio of the tetrahydrofuran to the intermediate I is 5:1 for later use;
adding dried tetrahydrofuran and potassium tert-butoxide into another reaction bottle, wherein the mass ratio of the tetrahydrofuran to the intermediate I is 8:1, the molar ratio of the potassium tert-butoxide to the intermediate I is 1.3:1, stirring uniformly, cooling to 0-5 ℃, dissolving a side chain in the tetrahydrofuran, the molar ratio of the side chain to the intermediate I is 1.3:1, the mass ratio of the tetrahydrofuran to the side chain is 3:1, dropwise adding the mixture into the reaction bottle, stirring for 2 hours under heat preservation, dropwise adding the tetrahydrofuran solution of the crude product of the 4- ((1R,2R,3aS,8bS) -1-formyl-2-hydroxy-2, 3,3a,8 b-tetrahydro-1H-cyclopenta [ b ] benzofuran-5-yl) methyl butyrate and the enantiomer thereof into the reaction bottle, dropwise adding, stirring for 5 hours at 25-35 ℃, adding a small amount of acetic acid to adjust to neutrality, evaporating the solvent, adding ethyl acetate and water, stirring for layering, extracting the water layer with ethyl acetate, combining the organic phases, washing with salt water for 2 times, drying, filtering, evaporating the solvent to obtain an intermediate V crude product, standing to precipitate a solid, and adding ethyl acetate: n-hexane 1:10, the mass ratio of the solvent to the intermediate I is 5:1, pulping is carried out at 5 ℃, filtering and drying are carried out, 15.52g of the intermediate V is obtained, the yield is 77.2 percent, and the purity is 99.1 percent;
example three: synthesis of intermediate V
Adding 15g of intermediate I, a mixed solution of dichloromethane and N, N-dimethylacetamide (300:1), TEMPO and diacetyloxyiodobenzene into a reaction bottle, wherein the mass ratio of the mixed solution of dichloromethane and N, N-dimethylacetamide (300:1) to the intermediate I is 20:1, the molar ratio of TEMPO to the intermediate I is 0.1:1, the molar ratio of diacetyloxyiodobenzene to the intermediate I is 1.1:1, and the reaction is completed at 25-30 ℃ for 5 hours, evaporating the solvent and the generated acetic acid to obtain a crude product of methyl 4- ((1R,2R,3aS,8bS) -1-formyl-2-hydroxy-2, 3,3a,8 b-tetrahydro-1H-cyclopenta [ b ] benzofuran-5-yl) butyrate and an enantiomer thereof, dissolving the crude product with tetrahydrofuran, the mass ratio of tetrahydrofuran to the intermediate I is 3:1 for later use;
adding dried tetrahydrofuran and sodium hydride into another reaction bottle, wherein the mass ratio of the tetrahydrofuran to the intermediate I is 6:1, the molar ratio of the sodium hydride to the intermediate I is 1.5:1, stirring uniformly, cooling to 0-5 ℃, dissolving a side chain into the tetrahydrofuran, the molar ratio of the side chain to the intermediate I is 1.5:1, and the mass ratio of the tetrahydrofuran to the side chain is 3:1, dropwise adding the mixture into the reaction bottle, stirring for hours while keeping the temperature, dropwise adding the tetrahydrofuran solution of the crude product of the 4- ((1R,2R,3aS,8bS) -1-formyl-2-hydroxy-2, 3,3a,8 b-tetrahydro-1H-cyclopenta [ b ] benzofuran-5-yl) methyl butyrate and the enantiomer thereof into the reaction bottle, dropwise adding, stirring for 6 hours while keeping the temperature at 25-35 ℃, adding a small amount of acetic acid to adjust to neutrality, evaporating the solvent, adding ethyl acetate and water, stirring for layering, extracting the water layer with ethyl acetate, combining the organic phases, washing with salt water for 2 times, drying, filtering, evaporating the solvent to obtain an intermediate V crude product, standing to precipitate a solid, and adding ethyl acetate: n-hexane is 1:10, the mass ratio of the solvent to the intermediate I is 5:1, 5 ℃, the intermediate V is pulped, filtered and dried to obtain 16.80g of the intermediate V, the yield is 83.6 percent, and the purity is 99.3 percent;
example four: synthesis of intermediate IV
Dissolving 13g of crude intermediate V in dimethyl sulfoxide, adding samarium chloride hexahydrate, wherein the mass ratio of the solvent dimethyl sulfoxide to the intermediate V is 10:1, the molar ratio of the samarium chloride hexahydrate to the intermediate V is 1:1, cooling to 0 ℃, adding potassium borohydride, wherein the molar ratio of the potassium borohydride to the intermediate V is 1.1:1, stirring for 10 minutes, completing the reaction, adding a saturated sodium bicarbonate solution, stirring, filtering, adding ethyl acetate and water, stirring, layering, extracting a water layer with ethyl acetate, combining organic layers, drying, filtering, evaporating the solvent to dryness, and performing chromatographic separation and purification on the residue with a mobile phase column of ethyl acetate/petroleum ether (1: 3) to obtain 5.26g of pure intermediate IV, wherein the yield is 40.3% and the purity is 99.6%.
Example five: synthesis of intermediate IV
Dissolving 13g of crude intermediate V in methanol, adding cerium chloride heptahydrate, wherein the mass ratio of the solvent methanol to the intermediate V is 10:1, the molar ratio of the cerium chloride heptahydrate to the intermediate V is 1:1, cooling to 10 ℃, adding sodium borohydride, the molar ratio of the sodium borohydride to the intermediate V is 1.3:1, stirring for 10 minutes to complete reaction, adding a saturated sodium bicarbonate solution, stirring, filtering, adding ethyl acetate and water, stirring, layering, extracting a water layer with ethyl acetate, combining organic layers, drying, filtering, evaporating the solvent to dryness, and performing chromatographic separation and purification on the residue with a mobile phase column of ethyl acetate/petroleum ether (1: 3) to obtain 5.64g of pure intermediate IV, wherein the yield is 43.2%, and the purity is 99.6%.
Example six: synthesis of beraprost
Dissolving 4.5g of intermediate IV in methanol, adding a 1N NaOH solution, wherein the mass ratio of the methanol to the intermediate IV is 6:1, the mass ratio of the volume of the 1N NaOH solution to the intermediate IV is 5:1, stirring the mixture at 30-35 ℃ until the raw materials completely react, distilling the methanol out, adding water, adjusting the pH to 4 by using 1N HCl, extracting the water phase by using ethyl acetate for 3 times, combining the organic phases, washing the organic phases by using water and a saturated sodium chloride solution, drying the organic phases, and evaporating the solvent to dryness to obtain 3.88g of beraprost, wherein the yield is 89.2 percent and the purity is 99.3 percent.
Example seven: synthesis of beraprost
Dissolving 4.5g of intermediate IV in THF, adding a 1N NaOH solution, wherein the mass ratio of the THF to the intermediate IV is 5:1, the mass ratio of the volume of the 1N NaOH solution to the intermediate IV is 6:1, stirring to ensure that the raw materials completely react, distilling out methanol, adding water, adjusting the pH to 4 by using 1N HCl, extracting the water phase by using ethyl acetate for 3 times, combining the organic phases, washing by using water and a saturated sodium chloride solution, drying, and evaporating the solvent to dryness to obtain 4.01g of beraprost, wherein the yield is 92.3%, and the purity is 99.2%.
The total yield range of the process of the invention is as follows: 26.1 to 33.3 percent.
Comparative example one (reference: Tetrahedron,1999,55,2449-2474)
Synthesis of intermediate II
Intermediate I (5g,16.3mmol) was dissolved in 50mL THF, triethylamine (7.5mL,54mmol) and triphenylchloromethane (7g,25mmol) were added to the solution, the solution was stirred at room temperature for 24 hours, triethylamine (2mL,14mmol) and triphenylchloromethane (2g,7mmol) were added, and the mixture was stirred for 14 hours. Acetic anhydride (13.8mL,0.146mol) and pyridine (10.6mL,0.131mol) were added to the reaction, and the mixture was stirred for 14 hours. The reaction was cooled in an ice-water bath, adjusted to pH 1 with 3.7N HCI/MeOH solution (55mL), stirred for 4 h, and quenched with NaHCO under ice-water bath3(23.2g) adjusting the pH to 6, evaporating the solvent, dissolving the residue in ethyl acetate, filtering, rinsing the filter cake with ethyl acetate, washing the filtrate with water, extracting the aqueous phase with ethyl acetate for 3 times, combining the organic phases, washing with saturated sodium chloride solution, drying, and concentrating to obtain 4.4g of an intermediate II with a yield of 78%.
Synthesis of intermediate III
To a reaction flask, 10mL of benzene, intermediate II (200mg,0.574mmol), dry DMSO (10mL), dry pyridine (0.3mL,3.7mmol), trifluoroacetic acid (0.18mL,2.4 mmol), DCC (453mg,2.20mmol) were added, the reaction solution was stirred at room temperature for 14 hours, filtered, and the filtrate was concentrated to give a crude aldehyde intermediate, which was dissolved in 5mL of ethylene glycol dimethyl ether.
Dissolving a side chain (918mg,4.13mmol) in ethylene glycol dimethyl ether (10mL), dropwise adding the side chain solution into an ethylene glycol dimethyl ether solution of sodium hydride (3.6mmol), stirring at room temperature for 30 minutes, then adding the ethylene glycol dimethyl ether solution of the aldehyde intermediate prepared above into a reaction bottle, stirring at room temperature for 30 minutes, adjusting the pH of the mixed solution to 7 with acetic acid, concentrating the reaction solution, adding 10mL of a solution of petroleum ether and ethyl ether at a ratio of 1:1, filtering the generated solid, concentrating the filtrate to obtain 800mg of oil, and purifying by using cyclohexane and ethyl acetate column chromatography to obtain Ш 150mg of the intermediate, wherein the yield is 59.1%.
Synthesis of intermediate IV
Intermediate Ш (2.09g,4.73mmol), CeCl3·7H20(1.76g,4.73mmol), dissolved in 20mL of methanol, cooled to 0 ℃, added with sodium borohydride (89.5mg,2.37mmol), stirred for 10 minutes, added with 10mL saturated sodium bicarbonate solution and 50mL ethyl acetate, filtered to remove insoluble matter, the filter cake washed with ethyl acetate, the filtrate separated, the aqueous phase extracted with ethyl acetate, the organic phase combined and washed with brine, dried, concentrated to give an oil.
To the oil was added dry methanol (5mL), followed by addition of a solution of sodium methoxide (0.26g,4.73mmol) in methanol (15mL), the reaction was stirred for 7.5 hours, the pH was adjusted to 7 with acetic acid, 20mL of water was added to the reaction, the reaction was extracted with ethyl acetate (50mL × 2), the organic phases were combined, washed with brine, dried and concentrated to give an oily product, which was subjected to column chromatography using cyclohexane and ethyl acetate to give 0.64g of intermediate IV in 34% yield.
Synthesis of beraprost
Dissolving the intermediate IV (50mg,0.124mmol) in 5mL of methanol, adding 1mL of 1N NaOH solution, stirring the reaction solution for 14 hours, concentrating the reaction solution, adjusting the pH to 4 with 1N HCl solution in ice-water bath, extracting the mixture with ethyl acetate (5 mL. times.3), combining the organic phases, washing the organic phase with water and saline water successively, drying and concentrating to obtain a product, and recrystallizing the product with ethyl acetate and N-hexane to obtain 30mg of a pure product with the yield of 62.5%.
The total yield of the process is as follows: 9.8 percent.
Comparative example II (reference: patent CN 100347265C):
1.84g (6mmol) are dissolved in 10ml pyridine, stirred and dissolved, added2.35ml (14mmol) triethylsilane chloride were added and stirring was continued for 30 minutes. The reaction mixture was then poured into a mixture of 50ml of water and 20ml of hexane. The aqueous phase was extracted with hexane (2 x 10ml) and the combined hexane solutions were extracted with 1M NaHSO4Aqueous solution 30ml, water 30ml, 1M NaHCO3The solution was washed with 30ml, 2x 30ml water, followed by a saturated NaCl solution. The hexane solution is treated with Na2SO4Drying for 1 hour followed by concentration gave 3.08g of a colorless oil ready for use in 96% yield.
0.27ml (3mmol) of oxalyl chloride is dissolved in 3ml of dichloromethane, the mixture is cooled to-60 ℃ and 0.44ml (6.2mmol) of dimethyl sulfoxide dissolved in 3ml of dichloromethane solution is added dropwise to this solution at-60 ℃ and, after stirring for 5 minutes, 1.07g of the oil obtained in the preceding step dissolved in 2ml of dichloromethane are added to the mixture, the mixture is warmed to + -35 ℃ and stirred at this temperature for 30 minutes. The reaction mixture was cooled to-60 ℃ and 1.42ml (10mmol) triethylamine was added, the mixture was stirred at room temperature for 15 minutes and 10ml water and 10M NaHSO were added47ml of aqueous solution. The aqueous phase is extracted 2 times with 5ml of dichloromethane and the combined organic phases are extracted with 1M NaHCO3The aqueous solution 10ml, 10ml water, 10ml saturated NaCl solution were washed and the organic phase was Na-washed2SO4Drying and vacuum concentration gave the crude aldehyde as a yellow oil which was used directly in the next reaction.
92mg of sodium hydride (60%) (2.3mmol) were suspended in 2ml of toluene at 15 ℃ under nitrogen. To this mixture was added 0.51ml (2.2mmol) of side chain dissolved in 1ml of toluene, and the mixture was heated at 15 ℃ for 20 minutes, then at-10 ℃ to 0.83g (2mmol) of crude aldehyde (dissolved in 2ml of toluene); a solution containing a sodium phosphate salt was added dropwise. After stirring for 2 hours, 10ml of water and 1M NaHSO were added42ml of aqueous solution was added to the reaction mixture and stirred for 2 minutes. The aqueous phase is extracted 2 times with 5ml of toluene, the combined toluene solutions are extracted with 10ml of water, 1M NaHCO3Aqueous solution, 10ml water and 10ml saturated NaCl solution. The solution is passed through Na2SO4Drying and vacuum concentrating to obtain crude product of monosilane-ketene and yellow oily matter. Directly used for the next reaction.
1.2g (2mmol) of crude silylenone are dissolved in 20ml of methanol, to which 0.15ml (1.8 mmol) are addedl) concentrated hydrochloric acid. The mixture was stirred at 25 ℃ for 5 minutes, to which 0.16g (1.9mmol) of solid NaHCO was added3The mixture was then over-ridden at 25 ℃ for 10 minutes, then concentrated in vacuo, the residue was dissolved in toluene, the inorganic salts were filtered off and the solution was concentrated. Purifying the obtained crude product by column chromatography to obtain crude ketene and a gray yellow oily substance.
5.14g (22mol) of 2, 6-di-tert-butyl-p-cresol are dissolved in 50ml of distilled toluene under nitrogen. 1.55g (11mmol) of diisobutylaluminum hydride dissolved in 8ml of distilled toluene was dropped into the above solution. The reaction mixture was stirred at 0 ℃ for 1 hour, then cooled to-78 ℃ and added slowly dropwise to 0.45g (1.1mmol) of ketene in 4ml of distilled toluene at-78 ℃ to the diisobutylaluminum hydride, 2, 6-di-tert-butyl-p-cresol reagent, and the reaction mixture was stirred at 50 ℃ overnight and then quenched with 27ml of 2M aqueous hydrochloric acid. After stirring for 30 minutes the phases were separated, the aqueous phase was washed 2 times with 15ml of toluene and the combined organic phases were washed with 20ml of saturated NaCl solution, 1M NaHCO315ml of aqueous solution and 2X20ml saturated NaCl solution. The organic phase is passed through Na2SO4Drying, vacuum concentrating, and purifying by column chromatography to obtain intermediate IV 0.25g with yield 55%.
0.246g (0.6mmol) of intermediate IV was dissolved in 1ml of methanol, 1ml of a 1M aqueous solution of sodium hydroxide was slowly added dropwise thereto, and after stirring for 1 hour, methanol was distilled off from the reaction mixture in vacuo. The aqueous residue is diluted with 10ml of water, extracted with methyl-tert-butyl ether, the combined organic phases are washed with saturated NaCl solution and Na2SO4Drying, concentrating, and crystallizing the concentrated residue with ethyl acetate-hexane mixture. 0.21g of beraprost is obtained, colorless crystals are obtained, and the yield is 87%.
The total yield of the process is as follows: 25.2 percent.
Comparison summary of yield and product quality
TABLE 1 comparison summary of yields and product quality for the inventive and comparative processes
| Contrast item | Number of reaction steps | Total process yield range (%) | Purity of main peak of product (peak area normalization method) |
| The invention | 3 | 26.1％～33.3％ | >99.0％ |
| Comparative example 1 | 4 | 9.8％ | No report to guide |
| Comparative example No. two | 6 | 25.2％ | No report to guide |
Claims (9)
1. A synthetic method of a beraprost intermediate V is characterized in that an intermediate I is used as a starting raw material, and the intermediate V is obtained through selective oxidation reaction and Witting reaction, wherein the reaction formula is as follows:
the specific step (1) is as follows:
selective oxidation of hydroxyl groups: in dichloromethane: adding an intermediate I, TEMPO and an oxidant into a mixed solvent of N, N-dimethylacetamide (in a volume ratio of 300:1), stirring at a certain temperature, completely reacting, and removing the solvent to obtain crude methyl 4- ((1R,2R,3aS,8bS) -1-formyl-2-hydroxy-2, 3,3a,8 b-tetrahydro-1H-cyclopenta [ b ] benzofuran-5-yl) butyrate and an enantiomer thereof, and dissolving the crude methyl 4- ((1R,2R,3aS,8bS) -1-formyl-hydroxy-2, 3, 8 a-tetrahydro-1H-cyclopenta [ b ] benzofuran-5;
witting reaction: adding phosphorus ylide into another reaction bottle, dropwise adding a crude solution of 4- ((1R,2R,3aS,8bS) -1-formyl-2-hydroxy-2, 3,3a,8 b-tetrahydro-1H-cyclopenta [ b ] benzofuran-5-yl) methyl butyrate and an enantiomer thereof, stirring and reacting for a period of time at a certain temperature, adding a small amount of acetic acid to adjust the solution to be neutral, distilling out the solvent, adding ethyl acetate and water, stirring and layering, extracting a water layer with ethyl acetate, combining organic phases, washing for 2 times with saline, drying, filtering, and distilling out the solvent to obtain a crude intermediate V; standing to separate out a solid, adding a mixed solvent of ethyl acetate and n-hexane, pulping at a certain temperature, filtering and drying to obtain an intermediate V.
2. The synthesis method according to claim 1, wherein in the step (1) of selective oxidation, the molar ratio of TEMPO to the intermediate I is (0.05-0.1): 1; the oxidant is one of diacetoxyiodobenzene, NaClO/NaBr mixed solution and sodium hypobromite, and the molar ratio of the oxidant to the intermediate I is (0.5-2): 1; the reaction temperature is 25-35 ℃.
3. The synthesis method as claimed in claim 1, wherein in the step (1) of Witting reaction, the molar ratio of the phosphorus ylide to the intermediate I is (0.7-2): 1; the reaction temperature is 5-65 ℃, and the reaction time is 2-8 hours.
4. The synthesis method as claimed in claim 1, wherein in the step (1) of Witting reaction, the preparation method of the phosphorus ylide comprises the following steps: adding tetrahydrofuran and alkali into a reaction bottle, stirring uniformly, cooling to a certain temperature, dissolving a side chain in the tetrahydrofuran, dropwise adding into the reaction bottle, and stirring for a period of time under heat preservation to obtain the catalyst.
5. The synthesis method according to claim 4, wherein in the preparation process of the phosphorus ylide, the base is one or a combination of sodium methoxide, sodium ethoxide, potassium tert-butoxide and sodium hydride in any proportion, and the molar ratio of the base to the intermediate I is (0.7-2): 1; the reaction temperature is-10 to 30 ℃, and the reaction time is 30 to 120 minutes.
6. The synthesis method according to claim 1, wherein the intermediate V prepared in step (1) is used for synthesizing beraprost, and the reaction formula is as follows:
7. the method of claim 6, wherein the step of synthesizing beraprost comprises:
step (2): dissolving the intermediate V obtained in the step (1) in a solvent 1, adding a catalyst, adding a reducing agent at a certain temperature, stirring until the reaction is complete, adding a saturated sodium bicarbonate solution, stirring and filtering, adding ethyl acetate and water, stirring and layering, extracting a water layer with ethyl acetate, combining organic layers, drying, filtering, evaporating the solvent to dryness, and performing column chromatography separation and purification on the residue with ethyl acetate/petroleum ether as a mobile phase to obtain an intermediate IV;
and (3): dissolving the intermediate IV in a solvent 2, adding a 1N NaOH solution, stirring at a certain temperature until the raw materials react completely, evaporating the solvent to dryness, adding water, adjusting the pH to 4 by using 1N HCl, extracting the water phase by using ethyl acetate for 3 times, combining organic phases, washing by using water and a saturated sodium chloride solution, drying, and evaporating to dryness to obtain the beraprost.
8. The synthesis method according to claim 7, wherein in the step (2), the solvent 1 is one or a combination of methanol and dimethyl sulfoxide in any proportion, and the mass ratio of the solvent 1 to the intermediate V is (4-15): 1; the catalyst is CeCl3·7H2O、SmCl3·6H2O, the molar ratio of the catalyst to the intermediate V is (0.5-2.5): 1; the reducing agent is one of sodium borohydride and potassium borohydride, and the molar ratio of the reducing agent to the intermediate V is (0.5-2.5): 1; the reaction temperature is-20 ℃, and the reaction time is 5-30 minutes.
9. The synthesis method according to claim 7, wherein the solvent 2 in the step (3) is one of methanol, ethanol, acetone and THF, and the mass ratio of the solvent 2 to the intermediate IV is (4-15): 1; in the step (3), the volume-to-mass ratio of the 1N NaOH solution to the intermediate IV is (5-40): 1.
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| CN112778254A (en) * | 2020-12-31 | 2021-05-11 | 南京栖云高活医药科技有限公司 | Synthetic method of cyclopenta [ b ] benzofuran-5-sodium butyrate |
| CN115872962A (en) * | 2023-01-06 | 2023-03-31 | 成都硕德药业有限公司 | Beraprost sodium intermediate and preparation method thereof |
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