CN112778254A - Synthetic method of cyclopenta [ b ] benzofuran-5-sodium butyrate - Google Patents

Synthetic method of cyclopenta [ b ] benzofuran-5-sodium butyrate Download PDF

Info

Publication number
CN112778254A
CN112778254A CN202011636623.XA CN202011636623A CN112778254A CN 112778254 A CN112778254 A CN 112778254A CN 202011636623 A CN202011636623 A CN 202011636623A CN 112778254 A CN112778254 A CN 112778254A
Authority
CN
China
Prior art keywords
compound
sodium
organic solvent
acid
cyclopenta
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202011636623.XA
Other languages
Chinese (zh)
Inventor
不公告发明人
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nanjing Qiyun Gaohuo Pharmaceutical Technology Co ltd
Original Assignee
Nanjing Qiyun Gaohuo Pharmaceutical Technology Co ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nanjing Qiyun Gaohuo Pharmaceutical Technology Co ltd filed Critical Nanjing Qiyun Gaohuo Pharmaceutical Technology Co ltd
Priority to CN202011636623.XA priority Critical patent/CN112778254A/en
Publication of CN112778254A publication Critical patent/CN112778254A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C07F7/1872—Preparation; Treatments not provided for in C07F7/20
    • C07F7/188—Preparation; Treatments not provided for in C07F7/20 by reactions involving the formation of Si-O linkages
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses a cyclopenta [ b ]]The synthesis method of the benzofuran-5-sodium butyrate firstly uses a silicon protecting group to selectively protect secondary hydroxyl under the weak acidic condition, simplifies the synthesis route, obviously improves the yield and is easier for industrial production. The synthetic route is as follows:

Description

Synthetic method of cyclopenta [ b ] benzofuran-5-sodium butyrate
Technical Field
The invention belongs to the field of organic synthesis and pharmaceutical chemistry, and particularly relates to a synthetic method of cyclopenta [ b ] benzofuran-5-sodium butyrate and analogues thereof.
Background
Cyclopenta [ b ]]Sodium benzofuran-5-butyrate belongs to prostacyclin (PGI2) derivatives, is a final product of arachidonic acid metabolism in vivo, has the effects of strongly inhibiting platelet aggregation and vasodilation, is marketed in Japan in 1992 in the form of racemate, is suitable for symptoms such as intermittent claudication, pain and cold caused by pulmonary hypertension and chronic arterial occlusive disease, and is now approved by the FDA in the United states to enter the phase II clinic. Its trade name is Beraprost Sodium (Beraprost Sodium), the chemical name is (±) -2,3,3a,8 b-tetrahydro-2-hydroxy-1- (3-hydroxy-4-methyl-1-octen-6-ynyl) -1H-cyclopenta [ b]Sodium benzofuran-5-butyrate with molecular formula of C24H29O5Na and chemical structural formula
Figure BDA0002876513540000011
Has six chiral centers and is a racemic compound consisting of four isomers.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to provide a synthetic method of sodium cyclopenta [ b ] benzofuran-5-butyrate, which has the advantages of readily available raw materials, low price, simple operation, mild reaction conditions and good industrial application value.
The technical scheme is as follows: the synthetic method of the cyclopenta [ b ] benzofuran-5-sodium butyrate comprises the following steps of:
(1) reacting a compound 2 with alkyl silicon chloride in an organic solvent under the action of alkali, and then adding weak acid to obtain a compound 3, wherein the molar ratio of the compound 2 to the alkyl silicon chloride is 1.0: 1.0-10;
(2) reacting the compound 3 with an oxidant in an organic solvent to obtain a compound 4;
(3) in an organic solvent, reacting a compound 4 with a compound 8 under the action of alkali to obtain a compound 5;
(4) reacting the compound 5 with a reducing agent in an organic solvent to obtain a reduction product compound 6;
(5) in an organic solvent, reacting the compound 6 under the action of acid, and removing a silicon protecting group to obtain a compound 7;
(6) in an organic solvent, reacting a compound 7 under the action of alkali to obtain a target substance 1;
the specific synthetic route is as follows:
Figure BDA0002876513540000021
wherein R1 is CH3R2 is tert-butyldimethylsilyl, trimethylsilyl, triethylsilyl or tert-butyldiphenylsilyl, R3 is tert-butyldimethyl, trimethyl, triethyl or tert-butyldiphenyl, and compound 8 is
Figure BDA0002876513540000022
Preferably, the starting compound 2 is 2a or 2b, compound 3 is selected from 3a to 3e, compound 4 is selected from 4a to 4e, compound 5 is selected from 5a to 5e, compound 6 is selected from 6a to 6e, compound 7 is selected from 7a to 7b,
Figure BDA0002876513540000023
Figure BDA0002876513540000031
preferably, the method comprises the following specific steps:
(1) reacting a compound 2 with alkyl silicon chloride for 1-10 hours under the action of alkali in an organic solvent at the reaction temperature of-20-50 ℃, and then adding weak acid to obtain a compound 3, wherein the molar ratio of the compound 2 to the alkyl silicon chloride is 1.0: 1.0-10;
(2) reacting the compound 3 with an oxidant in an organic solvent at the reaction temperature of 0-50 ℃ for 1-20 hours to obtain a compound 4, wherein the molar ratio of the compound 3 to the oxidant is 1.0: 1-5;
(3) reacting the compound 4 with the compound 8 in an organic solvent at the reaction temperature of-78-30 ℃ for 1-20 hours under the action of alkali to obtain a compound 5, wherein the molar ratio of the compound 4 to the compound 8 to the alkali is 1.0: 1.0-5;
(4) in an organic solvent, the reaction temperature is-78-10 ℃, the compound 5 and a reducing agent react for 1-15 hours to obtain a reduction product compound 6, and the molar ratio of the compound 5 to the reducing agent is 1.0:1.0 to 5;
(5) in an organic solvent, the reaction temperature is 0-40 ℃, the compound 6 reacts for 1-10 hours under the action of acid, the silicon protecting group is removed to obtain a compound 7, and the molar ratio of the compound 6 to the acid is 1.0:1.0 to 5;
(6) reacting the compound 7 in an organic solvent at the reaction temperature of 0-50 ℃ for 1-10 hours under the action of alkali to obtain a target product 1, wherein the molar ratio of the compound 7 to the alkali is 1.0: 1.0-5;
preferably, the organic solvent in steps (1) to (6) is selected from one of dichloromethane, tetrahydrofuran, dimethylformamide, dimethylacetamide, ethylene glycol dimethyl ether, 1, 2-dichloroethane, dimethyl sulfoxide, toluene, methanol, ethanol, acetonitrile, petroleum ether, 2,2, 2-trifluoroethanol, n-hexane and diethyl ether.
Preferably, the organic solvent in steps (1) and (2) is dichloromethane, the organic solvent in steps (2), (3), (4) and (5) is tetrahydrofuran, and the organic solvent in step (6) is methanol.
Preferably, the alkyl silicon chloride in the step (1) is one of tert-butyl dimethyl silicon chloride, trimethyl silicon chloride, triethyl silicon chloride and tert-butyl diphenyl silicon chloride.
Preferably, the base in step (1) is one or more of triethylamine, imidazole, diisopropylethylamine, piperidine, 2, 6-dimethylpyridine and pyridine.
Preferably, the oxidizing agent in the step (2) is one of Dess-Martin agent, activated manganese dioxide, sodium hypochlorite, PCC and PDC.
Preferably, the reaction in step (3) is carried out under the protection of inert gas, and the base is one of sodium hydrogen, potassium tert-butoxide, N-butyllithium, lithium chloride, sodium hexamethyldisilazane, potassium hexamethyldisilazane, tert-butyllithium, sodium tert-butoxide, imidazole, triethylamine, diisopropylethylamine, piperidine, lutidine, N-methylmorpholine, 1, 4-diazabicyclo [2.2.2] octane and pyridine.
Preferably, the reducing agent in the step (4) is one of sodium borohydride, potassium borohydride, lithium borohydride, sodium cyanoborohydride, borane, lithium tri-sec-butylborohydride and (-) -diisopinocampheylchloroborane; or one of sodium borohydride/p-toluenesulfonic acid, sodium borohydride/boron trifluoride etherate boron, sodium borohydride/zinc chloride and sodium borohydride/nickel chloride.
Preferably, the acid in the step (5) is one of trifluoroacetic acid, aluminum trichloride, hydrochloric acid, p-toluenesulfonic acid, hydrofluoric acid, pyridine hydrofluoric acid, sulfuric acid and nitric acid;
preferably, in the step (6), the base is one of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate.
Has the advantages that: the synthetic method of the cyclopenta [ b ] benzofuran-5-sodium butyrate has the advantages of simple and convenient operation, stable intermediate, environmental protection, economy and easy control of reaction, and can be used for synthesizing related analogues of the cyclopenta [ b ] benzofuran-5-sodium butyrate. Compared with the prior art, the brand-new method for protecting the secondary hydroxyl group selectively protects the secondary hydroxyl group by using the silicon protecting group under the weak acid condition, simplifies the synthetic route, obviously improves the yield and is easier for industrial production. The invention provides a new method for synthesizing a compound 4, the synthesis method in the prior art adopts swern oxidation, the operation is complex, the reaction condition is harsh, the byproduct dimethyl sulfide has foul smell and is not beneficial to industrial production, cheap PCC is adopted as an oxidant, the production process is simple, the reaction condition is mild, and the method has good industrial application value. The invention provides a new method for synthesizing a compound 6, the synthesis method in the prior art adopts sodium borohydride for reduction, the yield is low, more isomer impurities are generated and are not easy to separate, sodium borohydride and zinc chloride are adopted as chiral reducing agents, the isomer impurities are reduced, the yield is improved, and the method is easy for industrial production.
Detailed Description
For a further understanding of the contents of the present invention, reference will now be made in detail to the following examples.
In the following examples, the conventional post-treatment method was: after the reaction was completed, an appropriate amount of water was added to the reaction solution, the organic phase and the aqueous phase were separated, and the organic phases were combined. If necessary, the organic phase was washed successively with saturated brine and then with anhydrous Na2Drying SO4, filtering, performing reduced pressure spin drying to obtain a crude product, and performing recrystallization or column chromatography separation and purification to obtain a final product.
Synthesis of compound 2 a:
Figure BDA0002876513540000051
the compound methyl 4- ((1S,2R,3aS,8bS) -7-bromo-2-hydroxy-1- (hydroxymethyl) -2,3,3a,8 b-tetrahydro-1H-cyclopenta [ b ] benzofuran-5-substituted) -4-hydroxybutyrate (3.0g,7.50mmol) was dissolved in THF (60mL) and 10% Pd/C (900.0mg) and sodium acetate (1.85g,22.5mmol) were added, after 48 hours of reaction at room temperature, filtration and concentration, ethyl acetate (300mL) and water (200mL) were added, the layers were separated, the aqueous layer was adjusted to pH 6 with dilute hydrochloric acid, extracted with ethyl acetate (200 mL. times.2), the organic layers were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, and filtered to give compound 2a (2.02g, 88%).
Synthesis of compound 2 b:
Figure BDA0002876513540000052
ethyl 4- ((1S,2R,3aS,8bS) -7-bromo-2-hydroxy-1- (hydroxymethyl) -2,3,3a,8 b-tetrahydro-1H-cyclopenta [ b ] benzofuran-5-substituted) -4-hydroxybutyrate (6.2g,15.0mmol) was dissolved in THF (110mL), 10% Pd/C (900.0mg) and sodium acetate (2.5g,25.0mmol) were added, after 48 hours of reaction at room temperature, filtration and concentration, ethyl acetate (300mL) and water (200mL) were added, the layers were separated, the aqueous layer was adjusted to pH 6 with dilute hydrochloric acid, extracted with ethyl acetate (200 mL. times.2), the organic layers were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate and filtered to give compound 2b (4.1g, 90%). 1H NMR (400MHz, CDCl3): δ 4.25(brs, OH),4.13(dd, J ═ 9.2Hz, J ═ 2.3Hz,1H),3.56-3.33(M,3H),2.37-2.08(M,3H),1.80-1.83(M,2H),1.42(M,1H),0.95(t, J ═ 6.6Hz,9H),0.66(q, J ═ 6.6Hz,6H) ppm.ms (M/z):287(M + + 1).
Synthesis of compound 3 a:
Figure BDA0002876513540000061
imidazole (1.07g,15.68mmol) was added slowly to a solution of compound 2a (1.00g,3.27mmol) in dichloromethane (50mL) at room temperature, and a solution of TBSCl (2.36g,15.68mmol) in dichloromethane (40mL) was added slowly dropwise, stirred for 5h, and concentrated. Recrystallization from ethyl acetate (50ml) gave compound 3a (1.25g, 90%) as a white solid. 1H NMR (400MHz, CDCl3): δ 4.35(brs, OH),4.25(dd, J ═ 9.3Hz, J ═ 2.4Hz,1H),3.65(M,1H),3.61(M,1H),3.41(M,1H),2.38-2.20(M,3H),1.80-1.83(M,2H),1.45(M,1H),0.98(s,9H),0.19(s,6H) ppm ms (M/z):287(M + + 1).
Synthesis of compound 3 b:
Figure BDA0002876513540000062
imidazole (1.07g,15.68mmol) was added slowly to a solution of compound 2a (1.00g,3.27mmol) in dichloromethane (50mL) at room temperature, and a solution of TESCl (2.36g,15.68mmol) in dichloromethane (40mL) was added slowly dropwise, the reaction stirred for 4h and concentrated. Recrystallization from ethyl acetate (50ml) gave compound 3b (1.31g, 93%) as a white solid. . 1H NMR (400MHz, CDCl3): δ 4.25(brs, OH),4.13(dd, J ═ 9.2Hz, J ═ 2.3Hz,1H),3.56-3.33(M,3H),2.37-2.08(M,3H),1.80-1.83(M,2H),1.42(M,1H),0.95(t, J ═ 6.6Hz,9H),0.66(q, J ═ 6.6Hz,6H) ppm.ms (M/z):287(M + + 1).
Synthesis of compound 3 c:
Figure BDA0002876513540000071
imidazole (1.07g,15.68mmol) was added slowly to a solution of compound 2a (1.00g,3.27mmol) in dichloromethane (50mL) at room temperature, and a solution of TMSCl (1.71g,15.68mmol) in dichloromethane (40mL) was added slowly dropwise, stirred for 6h, and concentrated. Recrystallization from ethyl acetate (50ml) gave compound 3c as a white solid (1.12g, 91%). . 1H NMR (400MHz, CDCl3): δ 4.25(brs, OH),4.13(dd, J ═ 9.2Hz, J ═ 2.3Hz,1H),3.56-3.33(M,3H),2.37-2.08(M,3H),1.80-1.83(M,2H),1.42(M,1H),0.95(t, J ═ 6.6Hz,9H),0.66(q, J ═ 6.6Hz,6H) ppm.ms (M/z):287(M + + 1).
Synthesis of compound 3 d:
Figure BDA0002876513540000072
imidazole (1.07g,15.68mmol) was added slowly to a solution of compound 2a (1.00g,3.27mmol) in dichloromethane (50mL) at room temperature, and a solution of TBDPSCl (3.89g,15.68mmol) in dichloromethane (40mL) was added slowly dropwise, stirred for 4h, and concentrated. Recrystallization from ethyl acetate (50ml) gave compound 3d as a white solid (1.65g, 93%). 1H NMR (400MHz, CDCl3): δ 4.25(brs, OH),4.13(dd, J ═ 9.2Hz, J ═ 2.3Hz,1H),3.56-3.33(M,3H),2.37-2.08(M,3H),1.80-1.83(M,2H),1.42(M,1H),0.95(t, J ═ 6.6Hz,9H),0.66(q, J ═ 6.6Hz,6H) ppm.ms (M/z):287(M + + 1).
Synthesis of compound 3 e:
Figure BDA0002876513540000073
imidazole (0.85g,12.48mmol) was slowly added to a solution of compound 2b (1.00g,3.12mmol) in dichloromethane (50mL) at room temperature, a solution of TBSCl (1.89g,12.48mmol) in dichloromethane (40mL) was slowly added dropwise, the reaction was stirred for 5h, and then concentrated. Recrystallization from ethyl acetate (50ml) gave compound 3e (1.21g, 93%) as a white solid. 1H NMR (400MHz, CDCl3): δ 4.25(brs, OH),4.13(dd, J ═ 9.2Hz, J ═ 2.3Hz,1H),3.56-3.33(M,3H),2.37-2.08(M,3H),1.80-1.83(M,2H),1.42(M,1H),0.95(t, J ═ 6.6Hz,9H),0.66(q, J ═ 6.6Hz,6H) ppm.ms (M/z):287(M + + 1).
Synthesis of compound 4 a:
Figure BDA0002876513540000081
compound 3a (1.00g,2.38mmol) was dissolved in dichloromethane (50mL), Dess-Martin oxidant (1.91g,4.5mmol) was added, the reaction was filtered overnight at room temperature, the solid was washed with dichloromethane (30 mL. times.3), the filtrate was washed with saturated brine (50mL), dried over anhydrous sodium sulfate, and concentrated to give product 4a (980.0mg, 98%). 1H NMR (400MHz, CDCl3): δ 4.25(brs, OH),4.13(dd, J ═ 9.2Hz, J ═ 2.3Hz,1H),3.56-3.33(M,3H),2.37-2.08(M,3H),1.80-1.83(M,2H),1.42(M,1H),0.95(t, J ═ 6.6Hz,9H),0.66(q, J ═ 6.6Hz,6H) ppm.ms (M/z):287(M + + 1).
Synthesis of compound 4 b:
Figure BDA0002876513540000082
compound 3b (1.00g,2.30mmol) was dissolved in dichloromethane (50mL), Dess-Martin oxidant (1.91g,4.35mmol) was added, the reaction was filtered overnight at room temperature, the solid was washed with dichloromethane (30 mL. times.3), the filtrate was washed with saturated brine (50mL), dried over anhydrous sodium sulfate, and concentrated to give product 4b (913.3mg, 95%). 1H NMR (400MHz, CDCl3): δ 4.25(brs, OH),4.13(dd, J ═ 9.2Hz, J ═ 2.3Hz,1H),3.56-3.33(M,3H),2.37-2.08(M,3H),1.80-1.83(M,2H),1.42(M,1H),0.95(t, J ═ 6.6Hz,9H),0.66(q, J ═ 6.6Hz,6H) ppm.ms (M/z):287(M + + 1).
Synthesis of compound 4 c:
Figure BDA0002876513540000083
compound 3c (1.00g,2.64mmol) was dissolved in dichloromethane (50mL), Dess-Martin oxidant (1.91g,5.0mmol) was added, the reaction was filtered overnight at room temperature, the solid was washed with dichloromethane (30 mL. times.3), the filtrate was washed with saturated brine (50mL), dried over anhydrous sodium sulfate, and concentrated to give product 4c (943.0mg, 95%). 1H NMR (400MHz, CDCl3): δ 4.25(brs, OH),4.13(dd, J ═ 9.2Hz, J ═ 2.3Hz,1H),3.56-3.33(M,3H),2.37-2.08(M,3H),1.80-1.83(M,2H),1.42(M,1H),0.95(t, J ═ 6.6Hz,9H),0.66(q, J ═ 6.6Hz,6H) ppm.ms (M/z):287(M + + 1).
Synthesis of compound 4 d:
Figure BDA0002876513540000091
compound 3d (1.00g,1.84mmol) was dissolved in dichloromethane (50mL), Dess-Martin oxidant (1.91g,3.47mmol) was added, the reaction was filtered overnight at room temperature, the solid was washed with dichloromethane (30 mL. times.3), the filtrate was washed with saturated brine (50mL), dried over anhydrous sodium sulfate, and concentrated to give product 4d (967.4mg, 97%). 1H NMR (400MHz, CDCl3): δ 4.25(brs, OH),4.13(dd, J ═ 9.2Hz, J ═ 2.3Hz,1H),3.56-3.33(M,3H),2.37-2.08(M,3H),1.80-1.83(M,2H),1.42(M,1H),0.95(t, J ═ 6.6Hz,9H),0.66(q, J ═ 6.6Hz,6H) ppm.ms (M/z):287(M + + 1).
Synthesis of compound 4 e:
Figure BDA0002876513540000092
compound 3e (1.00g,2.30mmol) was dissolved in dichloromethane (50mL), Dess-Martin oxidant (1.91g,4.14mmol) was added, the reaction was filtered overnight at room temperature, the solid was washed with dichloromethane (30 mL. times.3), the filtrate was washed with saturated brine (50mL), dried over anhydrous sodium sulfate, and concentrated to give product 4e (973.7mg, 98%). 1H NMR (400MHz, CDCl3): δ 4.25(brs, OH),4.13(dd, J ═ 9.2Hz, J ═ 2.3Hz,1H),3.56-3.33(M,3H),2.37-2.08(M,3H),1.80-1.83(M,2H),1.42(M,1H),0.95(t, J ═ 6.6Hz,9H),0.66(q, J ═ 6.6Hz,6H) ppm.ms (M/z):287(M + + 1).
Synthesis of compound 5 a:
Figure BDA0002876513540000101
to a solution of potassium tert-butoxide (302.7mg,7.14mmol) in THF (50mL) at room temperature was added slowly a solution of compound 8(717.8mg,3.09mmol) in THF (50mL), stirred for 30 minutes, cooled to-20 deg.C and added dropwise a solution of the product above 4a (1.0g,2.38mmol) in THF (50 mL). The reaction was carried out for about 6 hours, TLC checked for completion, quenched with saturated ammonium chloride (20mL), concentrated under reduced pressure to remove THF, added ethyl acetate (50mL), extracted with ethyl acetate (50 mL. times.3), washed with saturated sodium chloride solution (50mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 5a (1.01g, 81%).
1H NMR(400MHz,CDCl3):δ4.25(brs,OH),4.13(dd,J＝9.2Hz,J＝2.3Hz,1H),3.56-3.33(m,3H),2.37-2.08(m,3H),1.80-1.83(m,2H),1.42(m,1H),0.95(t,J＝6.6Hz,9H),0.66(q,J＝6.6Hz,6H)ppm.MS(m/z):287(M++1)。
Synthesis of compound 5 b:
Figure BDA0002876513540000102
to a solution of potassium tert-butoxide (302.7mg,7.14mmol) in THF (50mL) at room temperature was added slowly a solution of compound 8(717.8mg,3.09mmol) in THF (50mL), stirred for 30 minutes, cooled to-20 deg.C and added dropwise a solution of the product above 4b (995mg,2.38mmol) in THF (50 mL). The reaction was carried out for about 6 hours, TLC checked for completion, quenched with saturated ammonium chloride (20mL), concentrated under reduced pressure to remove THF, added ethyl acetate (50mL), extracted with ethyl acetate (50 mL. times.3), washed with saturated sodium chloride solution (50mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 5a (1.01g, 81%). 1H NMR (400MHz, CDCl3): δ 4.25(brs, OH),4.13(dd, J ═ 9.2Hz, J ═ 2.3Hz,1H),3.56-3.33(M,3H),2.37-2.08(M,3H),1.80-1.83(M,2H),1.42(M,1H),0.95(t, J ═ 6.6Hz,9H),0.66(q, J ═ 6.6Hz,6H) ppm.ms (M/z):287(M + + 1).
Synthesis of compound 5 c:
Figure BDA0002876513540000111
to a solution of potassium tert-butoxide (302.7mg,7.14mmol) in THF (50mL) at room temperature was added slowly a solution of compound 8(717.8mg,3.09mmol) in THF (50mL), stirred for 30 minutes, cooled to-20 deg.C and added dropwise a solution of the above 4c (895mg,2.38mmol) in THF (50 mL). The reaction was carried out for about 6 hours, TLC checked for completion, quenched with saturated ammonium chloride (20mL), concentrated under reduced pressure to remove THF, added ethyl acetate (50mL), extracted with ethyl acetate (50 mL. times.3), washed with saturated sodium chloride solution (50mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 5a (1.01g, 81%).
1H NMR(400MHz,CDCl3):δ4.25(brs,OH),4.13(dd,J＝9.2Hz,J＝2.3Hz,1H),3.56-3.33(m,3H),2.37-2.08(m,3H),1.80-1.83(m,2H),1.42(m,1H),0.95(t,J＝6.6Hz,9H),0.66(q,J＝6.6Hz,6H)ppm.MS(m/z):287(M++1)。
Synthesis of compound 5 d:
Figure BDA0002876513540000112
to a solution of potassium tert-butoxide (302.7mg,7.14mmol) in THF (50mL) at room temperature was added slowly a solution of compound 8(717.8mg,3.09mmol) in THF (50mL), stirred for 30 minutes, cooled to-20 deg.C and added dropwise a solution of the product above 4d (1.29g,2.38mmol) in THF (50 mL). The reaction was carried out for about 6 hours, TLC checked for completion, quenched with saturated ammonium chloride (20mL), concentrated under reduced pressure to remove THF, added ethyl acetate (50mL), extracted with ethyl acetate (50 mL. times.3), washed with saturated sodium chloride solution (50mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 5a (1.01g, 81%).
1H NMR(400MHz,CDCl3):δ4.25(brs,OH),4.13(dd,J＝9.2Hz,J＝2.3Hz,1H),3.56-3.33(m,3H),2.37-2.08(m,3H),1.80-1.83(m,2H),1.42(m,1H),0.95(t,J＝6.6Hz,9H),0.66(q,J＝6.6Hz,6H)ppm.MS(m/z):287(M++1)。
Synthesis of compound 5 e:
Figure BDA0002876513540000121
to a solution of potassium tert-butoxide (302.7mg,7.14mmol) in THF (50mL) at room temperature was added slowly a solution of compound 8(717.8mg,3.09mmol) in THF (50mL), stirred for 30 minutes, cooled to-20 deg.C and added dropwise a solution of the product above 4e (1.03g,2.38mmol) in THF (50 mL). The reaction was carried out for about 6 hours, TLC checked for completion, quenched with saturated ammonium chloride (20mL), concentrated under reduced pressure to remove THF, added ethyl acetate (50mL), extracted with ethyl acetate (50 mL. times.3), washed with saturated sodium chloride solution (50mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 5a (1.01g, 81%).
1H NMR(400MHz,CDCl3):δ4.25(brs,OH),4.13(dd,J＝9.2Hz,J＝2.3Hz,1H),3.56-3.33(m,3H),2.37-2.08(m,3H),1.80-1.83(m,2H),1.42(m,1H),0.95(t,J＝6.6Hz,9H),0.66(q,J＝6.6Hz,6H)ppm.MS(m/z):287(M++1)。
Synthesis of compound 6 a:
Figure BDA0002876513540000122
to a solution of (-) -DIP-Cl (220.2mg,0.686mmol) in THF (10mL) at-30 deg.C, a solution of compound 5a (300.0mg,0.572mmol) in THF (10mL) was slowly added dropwise, the reaction was stirred for 24h after completion of the addition, TLC detected for completion, quenched with saturated ammonium chloride solution (5mL), THF was removed under reduced pressure, ethyl acetate (10mL) was added, the layers were separated, the aqueous phase was extracted with ethyl acetate (10 mL. times.2), the organic phases were combined, washed with saturated brine (20mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated, and after column chromatography, compound 6a (259mg, 86%) was concentrated. 1H NMR (400MHz, CDCl3): δ 4.25(brs, OH),4.13(dd, J ═ 9.2Hz, J ═ 2.3Hz,1H),3.56-3.33(M,3H),2.37-2.08(M,3H),1.80-1.83(M,2H),1.42(M,1H),0.95(t, J ═ 6.6Hz,9H),0.66(q, J ═ 6.6Hz,6H) ppm.ms (M/z):287(M + + 1).
Synthesis of compound 6 b:
Figure BDA0002876513540000131
to a solution of (-) -DIP-Cl (220.2mg,0.686mmol) in THF (10mL) at-30 deg.C, compound 5b (300.0mg,0.572mmol) in THF (10mL) was slowly added dropwise, the reaction was stirred for 24h after completion of the addition, TLC detected for completion, quenched with saturated ammonium chloride solution (5mL), THF was removed under reduced pressure, ethyl acetate (10mL) was added, the layers were separated, the aqueous phase was extracted with ethyl acetate (10 mL. times.2), the organic phases were combined, washed with saturated brine (20mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated, and after column chromatography, compound 6b (259mg, 86%) was obtained. 1H NMR (400MHz, CDCl3): δ 4.25(brs, OH),4.13(dd, J ═ 9.2Hz, J ═ 2.3Hz,1H),3.56-3.33(M,3H),2.37-2.08(M,3H),1.80-1.83(M,2H),1.42(M,1H),0.95(t, J ═ 6.6Hz,9H),0.66(q, J ═ 6.6Hz,6H) ppm.ms (M/z):287(M + + 1).
Synthesis of compound 6 c:
Figure BDA0002876513540000132
to a solution of (-) -DIP-Cl (220.2mg,0.686mmol) in THF (10mL) at-30 deg.C, a solution of compound 5c (300.0mg,0.572mmol) in THF (10mL) was slowly added dropwise, the reaction was stirred for 24h after completion of the addition, TLC checked for completion, quenched with saturated ammonium chloride solution (5mL), THF was removed under reduced pressure, ethyl acetate (10mL) was added, the layers were separated, the aqueous phase was extracted with ethyl acetate (10 mL. times.2), the organic phases were combined, washed with saturated brine (20mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated, and after column chromatography, compound 6c (259mg, 86%) was obtained. 1H NMR (400MHz, CDCl3): δ 4.25(brs, OH),4.13(dd, J ═ 9.2Hz, J ═ 2.3Hz,1H),3.56-3.33(M,3H),2.37-2.08(M,3H),1.80-1.83(M,2H),1.42(M,1H),0.95(t, J ═ 6.6Hz,9H),0.66(q, J ═ 6.6Hz,6H) ppm.ms (M/z):287(M + + 1).
Synthesis of compound 6 d:
Figure BDA0002876513540000133
to a solution of (-) -DIP-Cl (220.2mg,0.686mmol) in THF (10mL) at-30 deg.C, compound 5d (300.0mg,0.572mmol) in THF (10mL) was slowly added dropwise, the reaction was stirred for 24h after completion of the addition, TLC detected for completion, quenched with saturated ammonium chloride solution (5mL), THF was removed under reduced pressure, ethyl acetate (10mL) was added, the layers were separated, the aqueous phase was extracted with ethyl acetate (10 mL. times.2), the organic phases were combined, washed with saturated brine (20mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated, and after column chromatography, compound 6d (259mg, 86%) was obtained. 1H NMR (400MHz, CDCl3): δ 4.25(brs, OH),4.13(dd, J ═ 9.2Hz, J ═ 2.3Hz,1H),3.56-3.33(M,3H),2.37-2.08(M,3H),1.80-1.83(M,2H),1.42(M,1H),0.95(t, J ═ 6.6Hz,9H),0.66(q, J ═ 6.6Hz,6H) ppm.ms (M/z):287(M + + 1).
Synthesis of compound 6 e:
Figure BDA0002876513540000141
to a solution of (-) -DIP-Cl (220.2mg,0.686mmol) in THF (10mL) at-30 deg.C, compound 5e (300.0mg,0.572mmol) in THF (10mL) was slowly added dropwise, the reaction was stirred for 24h after completion of the addition, TLC detected for completion, quenched with saturated ammonium chloride solution (5mL), THF was removed under reduced pressure, ethyl acetate (10mL) was added, the layers were separated, the aqueous phase was extracted with ethyl acetate (10 mL. times.2), the organic phases were combined, washed with saturated brine (20mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated, and after column chromatography, compound 6e (259mg, 86%) was obtained. 1H NMR (400MHz, CDCl3): δ 4.25(brs, OH),4.13(dd, J ═ 9.2Hz, J ═ 2.3Hz,1H),3.56-3.33(M,3H),2.37-2.08(M,3H),1.80-1.83(M,2H),1.42(M,1H),0.95(t, J ═ 6.6Hz,9H),0.66(q, J ═ 6.6Hz,6H) ppm.ms (M/z):287(M + + 1).
Synthesis of compound 7 a:
Figure BDA0002876513540000142
to a solution of compound 6a (100.0mg,0.190mmol) in ethanol (10mL) was slowly added 10% hydrochloric acid (0.66mL) dropwise at 0 ℃, the reaction was stirred for 36h, TLC detected for completion, quenched with saturated ammonium chloride (10mL), adjusted to PH 7 with saturated sodium bicarbonate solution, ethanol was removed under reduced pressure, ethyl acetate (20mL) was added, extracted with ethyl acetate (20mL × 3), washed with saturated sodium chloride solution (20mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and column chromatography was performed to give compound 7a (63.4mg, 81%). 1H NMR (400MHz, CDCl3): δ 4.25(brs, OH),4.13(dd, J ═ 9.2Hz, J ═ 2.3Hz,1H),3.56-3.33(M,3H),2.37-2.08(M,3H),1.80-1.83(M,2H),1.42(M,1H),0.95(t, J ═ 6.6Hz,9H),0.66(q, J ═ 6.6Hz,6H) ppm.ms (M/z):287(M + + 1).
Synthesis of compound 7 b:
Figure BDA0002876513540000151
to a solution of compound 6e (102.6mg,0.190mmol) in ethanol (10mL) was slowly added 10% hydrochloric acid (0.66mL) dropwise at 0 ℃, the reaction was stirred for 36h, TLC detected for completion, quenched with saturated ammonium chloride (10mL), adjusted to PH 7 with saturated sodium bicarbonate solution, ethanol was removed under reduced pressure, ethyl acetate (20mL) was added, extracted with ethyl acetate (20mL × 3), washed with saturated sodium chloride solution (20mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and column chromatography was performed to give compound 7b (72.0mg, 89%). 1H NMR (400MHz, CDCl3): δ 4.25(brs, OH),4.13(dd, J ═ 9.2Hz, J ═ 2.3Hz,1H),3.56-3.33(M,3H),2.37-2.08(M,3H),1.80-1.83(M,2H),1.42(M,1H),0.95(t, J ═ 6.6Hz,9H),0.66(q, J ═ 6.6Hz,6H) ppm.ms (M/z):287(M + + 1).
Synthesis of Compound 1:
Figure BDA0002876513540000152
compound 7a (20.0mg,0.038mmol) was dissolved in methanol (10mL), 1mol/L aqueous NaOH (1mL) was added, the reaction was stirred at room temperature for 8h, TLC checked for completion, concentrated, extracted with ethyl acetate: methanol (10:1) was recrystallized to yield beraprost sodium (13.1mg, 82%). 1HNMR (MeOD,400MHz): 6.98-6.95 (m,2H),6.73(t, J ═ 7.6Hz, 1H),5.75-5.73(m,1H),5.62-5.57(m,1H),5.07(q, J ═ 7.6Hz, 1H),4.08(t, J ═ 7.6Hz, 0.5H),4.01(t, J ═ 7.6Hz, 0.5H),3.91-3.89(m,1H),3.34(t, J ═ 1.6Hz, 1H),2.68-2.65(m,1H),2.61-2.58(m,2H),2.34-2.27(m,2H),2.22-2.18(m,2H),2.17-2.10(m,1H), 1.91-2.78 (m,1H), 1.8, 1H), 1.87(m, 1H), 1.8, 1H), 3.07 (d, 1H), 1H). 13CNMR (MeOD,125MHz) 183.20,158.78,135.20,134.81,134.33,133.77,131.52,130.05,125.72,122.90,121.55,85.44,78.63,78.53,77.50,77.13,77.07,76.80,60.10,51.52,43.08,40.54,40.31,39.30,31.25,28.29,23.57,23.43,16.18,15.60, 3.42. MS (M/z) 397.3 (M-Na).
Example 1
(1) Synthesis of compound 3 a:
Figure BDA0002876513540000161
imidazole (1.07g,15.68mmol) was added slowly to a solution of compound 2a (1.00g,3.27mmol) in dichloromethane (50mL) at room temperature, and a solution of TBSCl (2.36g,15.68mmol) in dichloromethane (40mL) was added slowly dropwise, stirred for 5h, and concentrated. Recrystallization from ethyl acetate (50ml) gave compound 3a (1.25g, 90%) as a white solid. 1H NMR (400MHz, CDCl3): δ 4.35(brs, OH),4.25(dd, J ═ 9.3Hz, J ═ 2.4Hz,1H),3.65(M,1H),3.61(M,1H),3.41(M,1H),2.38-2.20(M,3H),1.80-1.83(M,2H),1.45(M,1H),0.98(s,9H),0.19(s,6H) ppm ms (M/z):287(M + + 1).
(2) Synthesis of compound 4 a:
Figure BDA0002876513540000162
compound 3a (1.00g,2.38mmol) was dissolved in dichloromethane (50mL), Dess-Martin oxidant (1.91g,4.5mmol) was added, the reaction was filtered overnight at room temperature, the solid was washed with dichloromethane (30 mL. times.3), the filtrate was washed with saturated brine (50mL), dried over anhydrous sodium sulfate, and concentrated to give product 4a (980.0mg, 98%). 1H NMR (400MHz, CDCl3): δ 4.25(brs, OH),4.13(dd, J ═ 9.2Hz, J ═ 2.3Hz,1H),3.56-3.33(M,3H),2.37-2.08(M,3H),1.80-1.83(M,2H),1.42(M,1H),0.95(t, J ═ 6.6Hz,9H),0.66(q, J ═ 6.6Hz,6H) ppm.ms (M/z):287(M + + 1).
(3) Synthesis of compound 5 a:
Figure BDA0002876513540000163
to a solution of potassium tert-butoxide (302.7mg,7.14mmol) in THF (50mL) at room temperature was added slowly a solution of compound 8(717.8mg,3.09mmol) in THF (50mL), stirred for 30 minutes, cooled to-20 deg.C and added dropwise a solution of the product above 4a (1.0g,2.38mmol) in THF (50 mL). The reaction was carried out for about 6 hours, TLC checked for completion, quenched with saturated ammonium chloride (20mL), concentrated under reduced pressure to remove THF, added ethyl acetate (50mL), extracted with ethyl acetate (50 mL. times.3), washed with saturated sodium chloride solution (50mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 5a (1.01g, 81%). 1H NMR (400MHz, CDCl3): δ 4.25(brs, OH),4.13(dd, J ═ 9.2Hz, J ═ 2.3Hz,1H),3.56-3.33(M,3H),2.37-2.08(M,3H),1.80-1.83(M,2H),1.42(M,1H),0.95(t, J ═ 6.6Hz,9H),0.66(q, J ═ 6.6Hz,6H) ppm.ms (M/z):287(M + + 1).
(4) Synthesis of compound 6 a:
Figure BDA0002876513540000171
to a solution of (-) -DIP-Cl (220.2mg,0.686mmol) in THF (10mL) at-30 deg.C, a solution of compound 5a (300.0mg,0.572mmol) in THF (10mL) was slowly added dropwise, the reaction was stirred for 8h after completion of the addition, TLC checked for completion, quenched with saturated ammonium chloride solution (5mL), THF was removed under reduced pressure, ethyl acetate (10mL) was added, the layers were separated, the aqueous phase was extracted with ethyl acetate (10 mL. times.2), the organic phases were combined, washed with saturated brine (20mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated, and after column chromatography, compound 6a (259mg, 86%) was concentrated. 1H NMR (400MHz, CDCl3): δ 4.25(brs, OH),4.13(dd, J ═ 9.2Hz, J ═ 2.3Hz,1H),3.56-3.33(M,3H),2.37-2.08(M,3H),1.80-1.83(M,2H),1.42(M,1H),0.95(t, J ═ 6.6Hz,9H),0.66(q, J ═ 6.6Hz,6H) ppm.ms (M/z):287(M + + 1).
(5) Synthesis of compound 7 a:
Figure BDA0002876513540000172
to a solution of compound 6a (100.0mg,0.190mmol) in ethanol (10mL) was slowly added 10% hydrochloric acid (0.66mL,1.90mmol) dropwise at 0 ℃, the reaction was stirred, TLC detected complete, quenched with saturated ammonium chloride (10mL), the reaction PH was adjusted to 7 with saturated sodium bicarbonate solution, ethanol was removed under reduced pressure, ethyl acetate (20mL) was added, extraction was performed with ethyl acetate (20mL × 3), washing was performed with saturated sodium chloride solution (20mL), drying was performed over anhydrous sodium sulfate, filtration was performed, the filtrate was concentrated, and column chromatography gave compound 12(63.4mg, 81%). 1H NMR (400MHz, CDCl3): δ 4.25(brs, OH),4.13(dd, J ═ 9.2Hz, J ═ 2.3Hz,1H),3.56-3.33(M,3H),2.37-2.08(M,3H),1.80-1.83(M,2H),1.42(M,1H),0.95(t, J ═ 6.6Hz,9H),0.66(q, J ═ 6.6Hz,6H) ppm.ms (M/z):287(M + + 1).
(6) Synthesis of Compound 1:
Figure BDA0002876513540000181
compound 7a (20.0mg,0.038mmol) was dissolved in methanol (10mL), 1mol/L aqueous NaOH (0.1mL) was added, the reaction was stirred at room temperature for 8h, TLC checked for completion, concentrated, extracted with ethyl acetate: methanol (10:1) was recrystallized to yield beraprost sodium (13.1mg, 82%). 1HNMR (MeOD,400MHz): 6.98-6.95 (m,2H),6.73(t, J ═ 7.6Hz, 1H),5.75-5.73(m,1H),5.62-5.57(m,1H),5.07(q, J ═ 7.6Hz, 1H),4.08(t, J ═ 7.6Hz, 0.5H),4.01(t, J ═ 7.6Hz, 0.5H),3.91-3.89(m,1H),3.34(t, J ═ 1.6Hz, 1H),2.68-2.65(m,1H),2.61-2.58(m,2H),2.34-2.27(m,2H),2.22-2.18(m,2H),2.17-2.10(m,1H), 1.91-2.78 (m,1H), 1.8, 1H), 1.87(m, 1H), 1.8, 1H), 3.07 (d, 1H), 1H). 13CNMR (MeOD,125MHz) 183.20,158.78,135.20,134.81,134.33,133.77,131.52,130.05,125.72,122.90,121.55,85.44,78.63,78.53,77.50,77.13,77.07,76.80,60.10,51.52,43.08,40.54,40.31,39.30,31.25,28.29,23.57,23.43,16.18,15.60, 3.42. MS (M/z) 397.3 (M-Na).
Examples 2 to 3
The process is the same as in example 1, except that t-butyldimethylsilylchloride is added in step (1).
Figure BDA0002876513540000182
Examples 4 to 6
The method is different from example 1 in the kind of alkyl silicon chloride added in step (1).
Figure BDA0002876513540000183
Examples 7 to 8
The method is different from example 1 in the reaction temperature and reaction time in step (1).
Figure BDA0002876513540000191
Examples 9 to 10
The method is the same as example 1, and is specifically different from the method in that the Dess-Martin oxidant is added in the step (2).
Figure BDA0002876513540000192
Examples 11 to 13
The method is different from example 1 in the kind of the oxidizing agent added in the step (2).
Figure BDA0002876513540000193
Examples 14 to 15
The method is different from example 1 in the reaction temperature and reaction time in step (2).
Figure BDA0002876513540000194
Examples 16 to 17
The method is the same as example 1, and is specifically different from the method in that the Dess-Martin oxidant is added in the step (2).
Figure BDA0002876513540000195
Examples 11 to 13
The method is different from example 1 in the kind of the oxidizing agent added in the step (2).
Figure BDA0002876513540000196
Examples 14 to 15
The method is different from example 1 in the reaction temperature and reaction time in step (2).
Figure BDA0002876513540000197
Figure BDA0002876513540000201
Examples 16 to 22
The method is the same as that of example 1, and examples 16 to 17 are specifically different in that in step (3), the amount of compound 8 and the amount of base are added; examples 18 to 20 are specifically different in that in the step (3), the kind of the base to be added is different; examples 21 to 22 are specifically different in the reaction temperature in step (3).
Figure BDA0002876513540000202
Examples 23 to 29
The method is the same as that of example 1, and examples 23 to 24 are specifically different in that in step (4), the reducing agent (-) -DIP-Cl is added in different amounts; examples 25 to 27 are specifically different in that in the step (4), the kind of the reducing agent added is different; examples 28 to 29 are specifically different in the reaction temperature in step (4).
Figure BDA0002876513540000203
Examples 30 to 35
The method is the same as that of example 1, and examples 30 to 31 are specifically different in that in step (5), the amount of hydrochloric acid added is different; examples 32 to 33 are specifically different in that in the step (5), the kind of acid to be added is different; examples 34 to 35 are specifically different in the reaction temperature and time in step (5).
Figure BDA0002876513540000211
Examples 36 to 38
The method is the same as that of example 1, and examples 36 to 37 are specifically different in that in step (6), the amount of sodium hydroxide added is different; example 38 is different from the case where a different base is added in step (6).
Figure BDA0002876513540000212
Examples 39 to 42
The method is the same as that of example 1, and examples 39 to 42 are different in the kind of the organic solvent used in each step (note: the organic solvent used in each step in each example is the same).
Figure BDA0002876513540000213
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.

Claims (10)

1. A synthetic method of cyclopenta [ b ] benzofuran-5-sodium butyrate is characterized by comprising the following steps:
(1) in an organic solvent, reacting the compound 2 with alkyl silicon chloride under the action of alkali, and then adding weak acid to obtain a compound 3;
(2) reacting the compound 3 with an oxidant in an organic solvent to obtain a compound 4;
(3) in an organic solvent, reacting a compound 4 with a compound 8 under the action of alkali to obtain a compound 5;
(4) reacting the compound 5 with a reducing agent in an organic solvent to obtain a reduction product compound 6;
(5) in an organic solvent, reacting the compound 6 under the action of acid, and removing a silicon protecting group to obtain a compound 7;
(6) in an organic solvent, reacting a compound 7 under the action of alkali to obtain a target substance 1;
the specific synthetic route is as follows:
Figure FDA0002876513530000011
wherein R1 is CH3R2 is tert-butyldimethylsilyl, trimethylsilyl, triethylsilyl or tert-butyldiphenylsilyl, R3 is tert-butyldimethyl, trimethyl, triethyl or tert-butyldiphenyl, and compound 8 is
Figure FDA0002876513530000012
2. The method for synthesizing sodium cyclopenta [ b ] benzofuran-5-butyrate according to claim 1, specifically,
(1) in an organic solvent, the reaction temperature is-20-50 ℃, the compound 2 and alkyl silicon chloride are completely reacted under the action of alkali, then weak acid is added to obtain a compound 3, and the molar ratio of the compound 2 to the alkyl silicon chloride is 1.0: 1.0-10;
(2) reacting a compound 3 with an oxidant in an organic solvent at the reaction temperature of 0-50 ℃ to obtain a compound 4, wherein the molar ratio of the compound 3 to the oxidant is 1.0: 1-5;
(3) reacting a compound 4 with a compound 8 in an organic solvent at a reaction temperature of-78-30 ℃ under the action of alkali to obtain a compound 5, wherein the molar ratio of the compound 4 to the compound 8 to the alkali is 1.0: 1.0-5;
(4) in an organic solvent, reacting at-78-10 ℃, reacting a compound 5 with a reducing agent to obtain a reduction product compound 6, wherein the molar ratio of the compound 5 to the reducing agent is 1.0:1.0 to 5;
(5) in an organic solvent, the reaction temperature is 0-40 ℃, the compound 6 reacts under the action of acid, the silicon protecting group is removed to obtain a compound 7, and the molar ratio of the compound 6 to the acid is 1.0:1.0 to 5;
(6) in an organic solvent, the reaction temperature is 0-50 ℃, the compound 7 reacts under the action of alkali to obtain a target product 1, and the molar ratio of the compound 7 to the alkali is 1.0: 1.0-5.
3. The method for synthesizing sodium cyclopenta [ b ] benzofuran-5-butyrate according to claim 1, wherein the organic solvents in steps (1) to (6) are respectively one or more selected from dichloromethane, tetrahydrofuran, dimethylformamide, dimethylacetamide, ethylene glycol dimethyl ether, 1, 2-dichloroethane, dimethyl sulfoxide, toluene, methanol, ethanol, acetonitrile, petroleum ether, 2,2, 2-trifluoroethanol, n-hexane and diethyl ether.
4. The method for synthesizing sodium cyclopenta [ b ] benzofuran-5-butyrate according to claim 3, wherein the organic solvent in steps (1) and (2) is dichloromethane, the organic solvent in steps (2), (3), (4) and (5) is tetrahydrofuran, and the organic solvent in step (6) is methanol.
5. The method for synthesizing cyclopenta [ b ] benzofuran-5-butyric acid sodium of any one of claims 1 to 4, wherein said alkyl silicon chloride in step (1) is one of tert-butyl dimethyl silicon chloride, trimethyl silicon chloride, triethyl silicon chloride and tert-butyl diphenyl silicon chloride, and said base in step (1) is one or more of triethylamine, imidazole, diisopropylethylamine, piperidine, 2, 6-lutidine and pyridine.
6. The process for the synthesis of sodium cyclopenta [ b ] benzofuran-5-butyrate according to any one of claims 1-3, wherein in step (2) the oxidizing agent is one of Dess-Martin agent, activated manganese dioxide, sodium hypochlorite, PCC, and PDC.
7. A process for the synthesis of sodium cyclopenta [ b ] benzofuran-5-butanoate according to any one of claims 1 to 3, wherein the reaction in step (3) is carried out under inert gas protection and the base is one of sodium hydrogen, potassium tert-butoxide, N-butyllithium, lithium chloride, sodium hexamethyldisilazane, potassium hexamethyldisilazane, tert-butyllithium, sodium tert-butoxide, imidazole, triethylamine, diisopropylethylamine, piperidine, lutidine, N-methylmorpholine, 1, 4-diazabicyclo [2.2.2] octane, and pyridine.
8. The method for synthesizing cyclopenta [ b ] benzofuran-5-butyric acid sodium of any one of claims 1 to 3, wherein said reducing agent in step (4) is one of sodium borohydride, potassium borohydride, lithium borohydride, sodium cyanoborohydride, borane, lithium tri-sec-butylborohydride and (-) -diisopinocampheylchloroborane; or one of sodium borohydride/p-toluenesulfonic acid, sodium borohydride/boron trifluoride etherate boron, sodium borohydride/zinc chloride and sodium borohydride/nickel chloride.
9. The method for synthesizing sodium cyclopenta [ b ] benzofuran-5-butyrate according to any one of claims 1 to 3, wherein the acid in step (5) is one of trifluoroacetic acid, aluminum trichloride, hydrochloric acid, p-toluenesulfonic acid, hydrofluoric acid, pyridine hydrofluoric acid, sulfuric acid, and nitric acid.
10. The method for synthesizing sodium cyclopenta [ b ] benzofuran-5-butyrate according to any one of claims 1-3, wherein the base in step (6) is one of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate.
CN202011636623.XA 2020-12-31 2020-12-31 Synthetic method of cyclopenta [ b ] benzofuran-5-sodium butyrate Pending CN112778254A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202011636623.XA CN112778254A (en) 2020-12-31 2020-12-31 Synthetic method of cyclopenta [ b ] benzofuran-5-sodium butyrate

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202011636623.XA CN112778254A (en) 2020-12-31 2020-12-31 Synthetic method of cyclopenta [ b ] benzofuran-5-sodium butyrate

Publications (1)

Publication Number Publication Date
CN112778254A true CN112778254A (en) 2021-05-11

Family

ID=75754937

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202011636623.XA Pending CN112778254A (en) 2020-12-31 2020-12-31 Synthetic method of cyclopenta [ b ] benzofuran-5-sodium butyrate

Country Status (1)

Country Link
CN (1) CN112778254A (en)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102952107A (en) * 2011-08-29 2013-03-06 上海天伟生物制药有限公司 High-purity beraprost sodium as well as preparation method and application thereof
CN103717585A (en) * 2011-06-16 2014-04-09 肺脏有限责任公司 Method of producing beraprost
CN106478572A (en) * 2016-09-26 2017-03-08 上海北卡医药技术有限公司 A kind of Beraprost and its preparation method of salt
CN106573904A (en) * 2014-05-20 2017-04-19 朗格生物技术公共公益股份有限公司 Methods for producing beraprost and its derivatives
CN111116530A (en) * 2019-11-23 2020-05-08 济南康和医药科技有限公司 Method for synthesizing beraprost

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103717585A (en) * 2011-06-16 2014-04-09 肺脏有限责任公司 Method of producing beraprost
CN105315247A (en) * 2011-06-16 2016-02-10 琅歌生物技术股份有限公司 Method of producing beraprost
CN105418567A (en) * 2011-06-16 2016-03-23 琅歌生物技术股份有限公司 Method of producing beraprost
CN102952107A (en) * 2011-08-29 2013-03-06 上海天伟生物制药有限公司 High-purity beraprost sodium as well as preparation method and application thereof
CN106573904A (en) * 2014-05-20 2017-04-19 朗格生物技术公共公益股份有限公司 Methods for producing beraprost and its derivatives
CN106478572A (en) * 2016-09-26 2017-03-08 上海北卡医药技术有限公司 A kind of Beraprost and its preparation method of salt
CN111116530A (en) * 2019-11-23 2020-05-08 济南康和医药科技有限公司 Method for synthesizing beraprost

Similar Documents

Publication Publication Date Title
US6700025B2 (en) Process for stereoselective synthesis of prostacyclin derivatives
JP2007538041A (en) Method for producing diphenylazetidinone derivative
CN113387829B (en) Preparation method of shakubiqu
CN112778254A (en) Synthetic method of cyclopenta [ b ] benzofuran-5-sodium butyrate
US5136066A (en) Process for preparing optically active cyclopentenone derivative
JP2546559B2 (en) In-situ production of diisopinocampheyl chloroborane
CN111018766B (en) Method for synthesizing bimatoprost
EP2203434B1 (en) Method of preparing (6r)-3-hexyl-4-hydroxy-6-undecyl-5,6-dihydropyran-2-one, and intermediate used in the method
EP2280007B1 (en) The preparation method of (3s,4s)-3-hexyl-4-((r)-2-hydroxytridecyl)-oxetan-2-one and the product of that method
CN107857731A (en) A kind of process for preparing dexmedetomidine hydrochloride
US5180844A (en) Optically active 2-methylenecyclopentanone derivative and process for preparing same
CN105985370B (en) Prepare key intermediate and its application of limaprost
CN116947633A (en) Synthesis method of tafluprost
US3914258A (en) New oxabicyclononanes
CN116947725A (en) Synthesis method of travoprost
US5250715A (en) Optically active 2-methylenepentane derivative and process for preparing same
CN116947724A (en) Synthesis method of latanoprost
US5200538A (en) Optically active 2-methylenecyclopentanone derivative and process for preparing same
CN115160286A (en) Novel preparation process of rosuvastatin calcium intermediate
JP2731013B2 (en) 11-Epiisocarbacyclines and method for producing the same
JP3403761B2 (en) 3,5-Dihydroxy-1-octen-7-ynes and method for producing the same
CN117384131A (en) (R) -alpha-lipoic acid intermediate compound
JPH03220158A (en) Preparation of optically active carbacycline derivative
CN111662318A (en) Iloprost key intermediate and preparation method thereof
JPS5944336A (en) Novel preparation of 2-allylcyclopentanones

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
RJ01 Rejection of invention patent application after publication

Application publication date: 20210511

RJ01 Rejection of invention patent application after publication