CN113493430A - Intermediate of beraprost and salt thereof and preparation method thereof - Google Patents

Intermediate of beraprost and salt thereof and preparation method thereof Download PDF

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CN113493430A
CN113493430A CN202010194363.9A CN202010194363A CN113493430A CN 113493430 A CN113493430 A CN 113493430A CN 202010194363 A CN202010194363 A CN 202010194363A CN 113493430 A CN113493430 A CN 113493430A
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张富尧
李火明
官程波
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Jiangxi Kerui Pharmaceutical Co.,Ltd.
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Selection Bioscience LLC
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    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
    • 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
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    • Y02P20/00—Technologies relating to chemical industry
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    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention discloses an intermediate of beraprost and beraprost salt and a preparation method thereof, and the preparation method has the advantages of mild reaction conditions, high selectivity, easiness in purification, low synthesis cost and the like, and is suitable for large-scale production.

Description

Intermediate of beraprost and salt thereof and preparation method thereof
Technical Field
The invention relates to an intermediate of beraprost and a salt thereof and a preparation method thereof.
Background
Beraprost sodium was developed by Toray corporation of Japan and is a racemic compound containing four stereoisomers. Due to the introduction of a benzene ring structure, the chemical property of the beraprost is more stable, and the beraprost is the first oral prostaglandin medicine. It was marketed in japan in 4 months 1992 for the treatment of chronic arterial occlusions. Its sustained release tablet was approved in japan in 2007 for the treatment of pulmonary hypertension disease. Is marketed under the trade name of Dener in China and is used for improving symptoms such as ulcer, intermittent claudication, pain and cold caused by chronic arterial occlusive disease. Clinical trials for the treatment of pulmonary hypertension and vascular diseases (other than renal disease) are currently being conducted in north america and europe.
The existing methods for synthesizing beraprost and its salts are generally carried out by intermediate compounds as shown in formula A, as shown in patents US5202447, CN1537107, CN1680351, CN103509044, CN103717585, CN105315247, CN105418567, CN106478572, CN106573904, CN106632372, CN107325122, CN108463457, CN 109305986. On the one hand, the synthesis of this intermediate is a tedious route, and on the other hand, intermediate a needs to be converted into intermediate B to be able to introduce the side chain via HWE reaction. However, before the selective oxidation of the primary alcohol of the compound shown in formula a, complicated protection-deprotection steps such as selective primary alcohol protection-secondary alcohol protection-primary alcohol protecting group removal-primary alcohol oxidation and the like are required, which increases the complexity of the operation and the length of the synthetic route.
Patents US9388154 and KR101777633 directly synthesize intermediate B to prepare beraprost without intermediate a. However, ester groups belong to groups with poor stability to alkali, and alkali conditions need to be intentionally avoided in the synthesis process.
Figure BDA0002417047500000011
In the process of synthesizing beraprost, although the use of the two intermediates is avoided, the patent US7345181 requires the preparation of a very complex copper-lithium reagent (as shown in formula C), which poses a challenge to the stable scale-up of the route.
Figure BDA0002417047500000012
In view of the foregoing, there is a need in the art to develop a simple, highly selective, high-yield, low-cost beraprost intermediate and beraprost synthetic route for the large-scale preparation of beraprost sodium.
Disclosure of Invention
The invention aims to provide an intermediate of beraprost and a salt thereof and a preparation method thereof.
Aiming at the current situations of complicated synthesis steps, long routes and low yield of the existing beraprost and the salt thereof, the invention provides beraprost intermediates shown in formulas II, IV, VIII, IX, XI and the like which are derived by Weinreb amide or analogues thereof, a preparation method thereof, and a synthesis method for synthesizing the beraprost and the salt thereof from the intermediates. The method has the advantages of mild reaction conditions, simple operation, high selectivity, good stability of the intermediate under acidic or alkaline conditions, less generated by-products, simple and convenient purification and low cost, and is suitable for large-scale production of beraprost and beraprost salt shown in the formula I.
The invention provides a compound shown as a formula II,
Figure BDA0002417047500000021
wherein R is1Is hydrogen or a hydroxy protecting group;
R2and R3Independently selected from C1-C6Alkyl or aryl.
In a preferred embodiment of the present invention, the compound of formula II is a compound of formula II wherein R is1Is hydrogen or a hydroxy protecting group; r2And R3And may independently be methyl, ethyl, propyl, isopropyl, phenyl or benzyl.
In a more preferred embodiment of the present invention, the compound of formula II is shown wherein R is1Hydrogen, acetyl, benzoyl or tert-butyldimethylsilyl; r2And R3And may independently be methyl, ethyl, propyl, isopropyl, phenyl or benzyl.
In a more preferred embodiment of the present invention, the compound of formula II is shown wherein R is1Hydrogen, acetyl, benzoyl or tert-butyldimethylsilyl; r2And R3Independently a methyl group.
In a more preferred embodiment of the present invention, the compound of formula II is shown wherein R is1Is hydrogen or acetyl; r2And R3Independently a methyl group.
The invention also provides a preparation method of beraprost and beraprost salt shown as the formula I, which comprises the following steps: carrying out hydrolysis reaction on the compound shown in the formula II to obtain a compound shown in the formula I;
Figure BDA0002417047500000031
wherein R is1Is hydrogen or a hydroxy protecting group;
R2and R3Independently selected from C1-C6Alkyl or aryl.
In a preferred embodiment of the invention, in the preparation method of beraprost shown in the formula I and the salt thereof, R is1Is hydrogen or a hydroxy protecting group; r2And R3And may independently be methyl, ethyl, propyl, isopropyl, phenyl or benzyl.
In a more preferred embodiment of the present invention, in the preparation method of beraprost and its salt represented by formula I, R is1Can be hydrogen, acetyl, benzoyl or tert-butyl dimethyl silicon base; r2And R3And may independently be methyl, ethyl, propyl, isopropyl, phenyl or benzyl.
In a more preferred embodiment of the present invention, in the preparation method of beraprost and its salt represented by formula I, R is1Can be hydrogen, acetyl, benzoyl or tert-butyl dimethyl silicon base; r2And R3Independently a methyl group.
In a more preferred embodiment of the present invention, in the preparation method of beraprost and its salt represented by formula I, R is1Can be hydrogen or acetyl; r2And R3Independently a methyl group.
In a preferred embodiment of the present invention, in the method for preparing beraprost and its salt represented by formula I, the hydrolysis reaction is performed under alkaline conditions.
In a preferred embodiment of the present invention, the method for preparing beraprost and its salt represented by formula I comprises the following steps:
and dissolving the compound II in an organic solvent, adding alkali, reacting at 0-100 ℃, stirring for 2-24 hours, and performing TLC (thin layer chromatography) to show that the raw material is completely converted, quenching and post-treating to obtain the compound I.
In a more preferred embodiment of the present invention, in the method for preparing beraprost and its salt represented by formula I, the organic solvent may be a solvent conventional in the art for such reactions, and may also be one or more of methanol, ethanol, isopropanol, tert-butanol, tetrahydrofuran, dimethylsulfoxide, and N, N-dimethylformamide.
In a more preferred embodiment of the present invention, in the method for preparing beraprost and its salt represented by formula I, the base is one or more selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate.
The invention also provides a preparation method of the compound shown in the formula IIA, which comprises the following steps: carrying out deprotection reaction on the compound shown in the formula IIB to obtain a compound shown in the formula IIA;
Figure BDA0002417047500000041
wherein R is4Is a hydroxy protecting group;
R2and R3Independently selected from C1-C6Alkyl or aryl.
In a preferred embodiment of the present invention, in the preparation method of the compound represented by formula IIA, R is4Is a hydroxy protecting group; r2And R3And may independently be methyl, ethyl, propyl, isopropyl, phenyl or benzyl.
In a more preferred embodiment of the present invention, in the preparation method of the compound represented by formula IIA, R is4Is a hydroxy protecting group; r2And R3And may independently be methyl, ethyl, propyl, isopropyl, phenyl or benzyl.
In a more preferred embodiment of the present invention, in the preparation method of the compound represented by formula IIA, R is4Can be acetyl, benzoyl, tert-butyl dimethyl silicon base; r2And R3Independently a methyl group.
In a more preferred embodiment of the present invention, in the preparation method of the compound represented by formula IIA, R is4Can be acetyl; r2And R3Independently a methyl group.
In a preferred embodiment of the present invention, in the preparation method of the compound represented by formula IIA, the deprotection reaction is preferably performed under acidic or basic conditions.
In a preferred embodiment of the present invention, the method for preparing the compound represented by formula IIA can comprise the following steps:
dissolving the compound IIB in an organic solvent, adding acid or alkali, reacting at-20-50 ℃, stirring for 10 min-24 h, performing TLC to show that the raw material is completely converted, quenching, and performing post-treatment to obtain the compound IIA.
In a more preferred embodiment of the present invention, in the preparation method of the compound represented by formula IIA, the organic solvent may be a solvent conventional in the art, and may also be one or more of methanol, ethanol, isopropanol, tert-butanol, tetrahydrofuran, dimethylsulfoxide, and N, N-dimethylformamide.
In a more preferred embodiment of the present invention, in the preparation method of the compound represented by formula IIA, the base is selected from one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and tetrabutylammonium fluoride.
In a more preferred embodiment of the present invention, in the preparation method of the compound represented by formula IIA, the acid is selected from one or more of hydrochloric acid, sulfuric acid, and hydrofluoric acid.
The invention also provides a preparation method of the compound shown in the formula II, which comprises the following steps: carrying out reduction reaction on the compound shown in the formula III to obtain the compound shown in the formula II;
Figure BDA0002417047500000051
wherein R is1Is hydrogen or a hydroxy protecting group;
R2and R3Independently selected from C1-C6Alkyl or aryl.
In a preferred embodiment of the present invention, in the preparation method of the compound represented by the formula II, R is1Is hydrogen or a hydroxy protecting group; r2And R3And may independently be methyl, ethyl, propyl, isopropyl, phenyl or benzyl.
In a more preferred embodiment of the present invention, in the preparation method of the compound represented by the formula II, R is1Can be hydrogen, acetyl, benzoyl or tert-butyl dimethyl silicon base; r2And R3And may independently be methyl, ethyl, propyl, isopropyl, phenyl or benzyl.
In a more preferred embodiment of the present invention, in the preparation method of the compound represented by the formula II, R is1Can be hydrogen, acetyl, benzoyl or tert-butyl dimethyl silicon base; r2And R3Independently a methyl group.
In a more preferred embodiment of the present invention, in the preparation method of the compound represented by the formula II, R is1Can be hydrogen or acetyl; r2And R3Independently a methyl group.
In a preferred embodiment of the present invention, the preparation method of the compound represented by formula II may comprise the following steps:
and (3) dissolving the compound III in an organic solvent at the temperature of-78-50 ℃, adding a reducing agent, reacting, stirring for 30 min-16 h at the temperature of-78-50 ℃, and performing TLC (thin layer chromatography) to show that the raw material is completely converted, quenching and post-treating to obtain a compound II.
In a more preferred embodiment of the present invention, in the preparation method of the compound represented by formula II, the organic solvent may be a conventional solvent in the reaction in the field, and may also be one or more of methanol, ethanol, isopropanol, tert-butanol, tetrahydrofuran, toluene, and dichloromethane.
In a more preferred embodiment of the present invention, in the preparation method of the compound represented by formula II, the reducing agent is selected from one or more of sodium borohydride, sodium borohydride-cerium trichloride, DIBAL-H in n-hexane solution, CBS reducing agent.
The invention provides a compound shown as a formula III,
Figure BDA0002417047500000061
wherein R is1Is hydrogen or a hydroxy protecting group;
R2and R3Independently selected from C1-C6Alkyl or aryl.
In a preferred embodiment of the present invention, the compound of formula III is a compound of formula III wherein R is1Is hydrogen or a hydroxy protecting group; r2And R3And may independently be methyl, ethyl, propyl, isopropyl, phenyl or benzyl.
In a more preferred embodiment of the present invention, the compound of formula III is a compound of formula III wherein R1Hydrogen, acetyl, benzoyl or tert-butyldimethylsilyl; r2And R3And may independently be methyl, ethyl, propyl, isopropyl, phenyl or benzyl.
In a more preferred embodiment of the present invention, the compound of formula III is a compound of formula III wherein R1Hydrogen, acetyl, benzoyl or tert-butyldimethylsilyl; r2And R3Independently a methyl group.
In a more preferred embodiment of the present invention, the compound of formula III is a compound of formula III wherein R1Is hydrogen or acetyl; r2And R3Independently a methyl group.
The invention also provides a preparation method of the compound shown in the formula III, which comprises the following steps:
Figure BDA0002417047500000062
wherein R is1Is hydrogen or a hydroxy protecting group;
R2and R3Independently selected from C1-C6An alkyl or aryl group;
R5is C1-C6An alkyl group.
In a preferred embodiment of the present invention, in the preparation method of the compound represented by the formula III, R is1Is hydrogen or a hydroxy protecting group; r2And R3Can be independently methyl, ethyl, propyl, isopropylPhenyl or benzyl; r5And may be methyl or ethyl.
In a more preferred embodiment of the present invention, in the preparation method of the compound represented by the formula III, R is1Can be hydrogen, acetyl, benzoyl or tert-butyl dimethyl silicon base; r2And R3May independently be methyl, ethyl, propyl, isopropyl, phenyl or benzyl; r5And may be methyl or ethyl.
In a more preferred embodiment of the present invention, in the preparation method of the compound represented by the formula III, R is1Can be hydrogen, acetyl, benzoyl or tert-butyl dimethyl silicon base; r2And R3Independently is methyl; r5And may be methyl or ethyl.
In a more preferred embodiment of the present invention, in the preparation method of the compound represented by the formula III, R is1Can be hydrogen or acetyl; r2And R3Independently is methyl; r5And may be methyl or ethyl.
In a preferred embodiment of the present invention, the preparation method of the compound represented by formula III can comprise the following steps:
adding an organic solvent into a mixture of the compound IV and the compound V for dissolving, adding alkali at the temperature of-20-30 ℃, reacting, stirring for 1-16 h at the temperature of 0-50 ℃, and performing TLC (thin layer chromatography) to show that the raw materials are completely converted, quenching and post-treating to obtain a compound III.
In a more preferred embodiment of the present invention, in the preparation method of the compound represented by formula III, the organic solvent may be a conventional solvent in the reaction in the field, and may also be one or more of acetonitrile, ethyl acetate, dimethyl sulfoxide, N-dimethylformamide, tetrahydrofuran, toluene, and dichloromethane.
In a more preferred embodiment of the present invention, in the preparation method of the compound represented by formula III, the base is selected from one or more of triethylamine, diisopropylethylamine, lithium hydroxide, potassium carbonate, 2, 6-dimethylpyridine, and pyridine.
The invention also provides a compound shown as the formula IV,
Figure BDA0002417047500000071
wherein R is1Is hydrogen or a hydroxy protecting group;
R2and R3Independently selected from C1-C6Alkyl or aryl.
In a preferred embodiment of the present invention, the compound of formula IV is a compound of formula IV wherein R is1Is hydrogen or a hydroxy protecting group; r2And R3And may independently be methyl, ethyl, propyl, isopropyl, phenyl or benzyl.
In a more preferred embodiment of the present invention, the compound of formula IV is one wherein R is1Hydrogen, acetyl, benzoyl or tert-butyldimethylsilyl; r2And R3And may independently be methyl, ethyl, propyl, isopropyl, phenyl or benzyl.
In a more preferred embodiment of the present invention, the compound of formula IV is one wherein R is1Hydrogen, acetyl, benzoyl or tert-butyldimethylsilyl; r2And R3Independently a methyl group.
In a more preferred embodiment of the present invention, the compound of formula IV is one wherein R is1Is hydrogen or acetyl; r2And R3Independently a methyl group.
The invention also provides a preparation method A of the compound shown in the formula IV, which comprises the following steps: carrying out ozonization reaction on a compound shown as a formula VII to obtain a compound shown as a formula IV;
Figure BDA0002417047500000081
wherein R is1Is hydrogen or a hydroxy protecting group;
R2and R3Independently selected from C1-C6Alkyl or aryl.
In a preferred embodiment of the present invention, in the preparation method A of the compound shown in the formula IV, R is1Is hydrogen or a hydroxy protecting group; r2And R3And may independently be methyl, ethyl, propyl, isopropyl, phenyl or benzyl.
In a more preferred embodiment of the present invention, in the preparation method A of the compound shown in formula IV, R is1Can be hydrogen, acetyl, benzoyl or tert-butyl dimethyl silicon base; r2And R3And may independently be methyl, ethyl, propyl, isopropyl, phenyl or benzyl.
In a more preferred embodiment of the present invention, in the preparation method A of the compound shown in formula IV, R is1Can be hydrogen, acetyl, benzoyl or tert-butyl dimethyl silicon base; r2And R3Independently a methyl group.
In a more preferred embodiment of the present invention, in the preparation method A of the compound shown in formula IV, R is1Can be hydrogen or acetyl; r2And R3Independently a methyl group.
In a preferred embodiment of the present invention, the preparation method a of the compound shown in formula IV can comprise the following steps:
dissolving a compound VII in an organic solvent at the temperature of-78 to-40 ℃, introducing ozone, stirring for 30min to 3h at the temperature of-78 to-40 ℃ for reaction, enabling the color of the solution to turn blue, continuously adding a reducing agent into the reaction solution, stirring for 1 to 5h at room temperature for reaction, and obtaining a compound IV after TLC shows that the intermediate is completely converted and is quenched and post-treated.
In a more preferred embodiment of the present invention, in the preparation method a of the compound represented by formula IV, the organic solvent may be a conventional solvent in the reaction in the field, and may also be one or more of dichloromethane, n-heptane, isopropanol, and ethyl acetate.
In a more preferred embodiment of the present invention, in the preparation method a of the compound represented by formula IV, the reducing agent is selected from one or more of triphenylphosphine, dimethyl sulfide, zinc powder, and dithiodipropionic acid
The invention also provides a preparation method B of the compound shown in the formula IV, which comprises the following steps:
1) carrying out dihydroxylation reaction on the compound shown as the formula VII to obtain a compound shown as the formula VI;
2) carrying out oxidation reaction on the compound shown as the formula VI to obtain the compound shown as the formula IV;
Figure BDA0002417047500000091
wherein R is1Is hydrogen or a hydroxy protecting group;
R2and R3Independently selected from C1-C6Alkyl or aryl.
In a preferred embodiment of the present invention, in the preparation method B of the compound shown in the formula IV, R is1Is hydrogen or a hydroxy protecting group; r2And R3And may independently be methyl, ethyl, propyl, isopropyl, phenyl or benzyl.
In a more preferred embodiment of the present invention, in the preparation method B of the compound shown in the formula IV, R is1Can be hydrogen, acetyl, benzoyl or tert-butyl dimethyl silicon base; r2And R3And may independently be methyl, ethyl, propyl, isopropyl, phenyl or benzyl.
In a more preferred embodiment of the present invention, in the preparation method B of the compound shown in the formula IV, R is1Can be hydrogen, acetyl, benzoyl or tert-butyl dimethyl silicon base; r2And R3Independently a methyl group.
In a more preferred embodiment of the present invention, in the preparation method B of the compound shown in the formula IV, R is1Can be hydrogen or acetyl; r2And R3Independently a methyl group.
In a preferred embodiment of the invention, in the preparation method B of the compound represented by the formula IV, the reagent used in the dihydroxylation reaction is selected from one or more of an osmium reagent, a manganese reagent and a ruthenium reagent;
in a preferred embodiment of the invention, in the preparation method B of the compound shown in formula IV, the oxidizing reaction uses an oxidizing agent selected from one or more of sodium periodate and lead acetate.
In a preferred embodiment of the present invention, the preparation method B of the compound shown in formula IV can comprise the following steps:
1) dissolving a compound VII in an organic solvent and water, adding a dihydroxylation reagent, reacting at 0-50 ℃, stirring for 1-16 h, performing TLC (thin layer chromatography) to show that the raw materials are completely converted, quenching and extracting, and purifying a concentrated solution to obtain a compound VI, or directly using the compound VI in the next reaction without purification;
2) dissolving the compound VI in an organic solvent and water, adding an oxidant, reacting at 25 ℃ for 1-6 h, performing TLC (thin layer chromatography) to show that the raw materials are completely converted, quenching, extracting, and purifying the concentrated solution to obtain a compound IV, or directly using the compound IV in the next reaction without purification.
In a more preferred embodiment of the present invention, in the preparation method B of the compound represented by formula IV, the organic solvent may be a conventional solvent in the reaction in the field, and may also be one or more of acetonitrile, tetrahydrofuran, acetone, tert-butanol, and methanol.
In a more preferred embodiment of the present invention, in the preparation method B of the compound represented by formula IV, the dihydroxylation reagent is preferably one or more of osmium tetraoxide-NMO, potassium osmate-potassium ferricyanide, ruthenium trichloride and potassium permanganate.
In a more preferred embodiment of the present invention, in the preparation method B of the compound represented by formula IV, the oxidizing agent is preferably sodium periodate.
The invention also provides a compound shown as the formula VI,
Figure BDA0002417047500000101
wherein R is1Is hydrogen or a hydroxy protecting group;
R2and R3Independently selected from C1-C6Alkyl or aryl.
In a preferred embodiment of the present invention, the compound of formula VI, wherein R is1Is hydrogen or a hydroxy protecting group; r2And R3And may independently be methyl, ethyl, propyl, isopropyl, phenyl or benzyl.
In a more preferred embodiment of the present invention, the compound of formula VI wherein R is1Hydrogen, acetyl, benzoyl or tert-butyldimethylsilyl; r2And R3And may independently be methyl, ethyl, propyl, isopropyl, phenyl or benzyl.
In a more preferred embodiment of the present invention, the compound of formula VI wherein R is1Hydrogen, acetyl, benzoyl or tert-butyldimethylsilyl; r2And R3Independently a methyl group.
In a more preferred embodiment of the present invention, the compound of formula VI wherein R is1Is hydrogen or acetyl; r2And R3Independently a methyl group.
The invention also provides a preparation method of the compound shown in the formula VI, which comprises the following steps: carrying out dihydroxylation reaction on the compound shown as the formula VII to obtain the compound shown as the formula VI;
Figure BDA0002417047500000111
wherein R is1Is hydrogen or a hydroxy protecting group;
R2and R3Independently selected from C1-C6Alkyl or aryl.
In a preferred embodiment of the present invention, in the preparation method of the compound represented by the formula VI, R is1Is hydrogen or a hydroxy protecting group; r2And R3And may independently be methyl, ethyl, propyl, isopropyl, phenyl or benzyl.
In a more preferred embodiment of the present invention, in the preparation method of the compound represented by the formula VI, R is1Can be hydrogen, acetyl, benzoyl or tert-butyl dimethyl silicon base; r2And R3And may independently be methyl, ethyl, propyl, isopropyl, phenyl or benzyl.
In a more preferred embodiment of the present invention, in the preparation method of the compound represented by the formula VI, R is1Can be hydrogen, acetyl, benzoyl or tert-butyl dimethyl silicon base; r2And R3Independently a methyl group.
In a more preferred embodiment of the present invention, in the preparation method of the compound represented by the formula VI, R is1Can be hydrogen or acetyl; r2And R3Independently a methyl group.
In a preferred embodiment of the present invention, in the preparation method of the compound represented by formula IV, the reagent for the dihydroxylation reaction is selected from one or more of osmium reagent, manganese reagent and ruthenium reagent;
in a preferred embodiment of the present invention, the preparation method of the compound represented by the formula VI can comprise the following steps:
dissolving the compound VII in an organic solvent and water, adding a dihydroxylation reagent, reacting at 0-50 ℃, stirring for 1-16 h, and performing TLC (thin layer chromatography) to show that the raw material is completely converted, quenching and post-treating to obtain a compound VI.
In a more preferred embodiment of the present invention, in the preparation method of the compound represented by formula IV, the organic solvent may be a conventional solvent in the reaction in the field, and may also be one or more of acetonitrile, tetrahydrofuran, acetone, tert-butanol, and methanol.
In a more preferred embodiment of the present invention, in the preparation method of the compound represented by formula IV, the dihydroxylation reagent is selected from one or more of osmium tetroxide-NMO, potassium osmate-potassium ferricyanide, ruthenium trichloride and potassium permanganate.
The invention also provides a compound shown as the formula VII,
Figure BDA0002417047500000121
wherein R is1Is hydrogen or a hydroxy protecting group;
R2and R3Independently selected from C1-C6Alkyl or aryl.
In a preferred embodiment of the present invention, the compound of formula VII is shown in which R is1Is hydrogen or a hydroxy protecting group; r2And R3And may independently be methyl, ethyl, propyl, isopropyl, phenyl or benzyl.
In a more preferred embodiment of the present invention, the compound of formula VII is shown wherein R is1Hydrogen, acetyl, benzoyl or tert-butyldimethylsilyl; r2And R3And may independently be methyl, ethyl, propyl, isopropyl, phenyl or benzyl.
In a more preferred embodiment of the present invention, the compound of formula VII is shown wherein R is1Hydrogen, acetyl, benzoyl or tert-butyldimethylsilyl; r2And R3Independently a methyl group.
In a more preferred embodiment of the present invention, the compound of formula VII is shown wherein R is1Is hydrogen or acetyl; r2And R3Independently a methyl group.
The invention also provides a preparation method of the compound shown in the formula VII, which comprises the following steps: carrying out double bond shift reaction on the compound shown as the formula VIII to obtain the compound shown as the formula VII;
Figure BDA0002417047500000122
wherein R is1Is hydrogen or a hydroxy protecting group;
R2and R3Independently selected from C1-C6Alkyl or aryl.
One preferred of the present inventionIn one embodiment, the process for preparing a compound of formula VII, wherein R is1Is hydrogen or a hydroxy protecting group; r2And R3And may independently be methyl, ethyl, propyl, isopropyl, phenyl or benzyl.
In a more preferred embodiment of the present invention, in the preparation method of the compound represented by the formula VII, R is1Can be hydrogen, acetyl, benzoyl or tert-butyl dimethyl silicon base; r2And R3And may independently be methyl, ethyl, propyl, isopropyl, phenyl or benzyl.
In a more preferred embodiment of the present invention, in the preparation method of the compound represented by the formula VII, R is1Can be hydrogen, acetyl, benzoyl or tert-butyl dimethyl silicon base; r2And R3Independently a methyl group.
In a more preferred embodiment of the present invention, in the preparation method of the compound represented by the formula VII, R is1Can be hydrogen or acetyl; r2And R3Independently a methyl group.
In a preferred embodiment of the present invention, in the preparation method of the compound represented by the formula VII, the reagent used in the double bond shift reaction is a noble metal catalyst.
In a preferred embodiment of the present invention, the preparation method of the compound represented by formula VII may comprise the following steps:
and adding an organic solvent into the mixture of the compound VIII and the noble metal catalyst for dissolving, reacting at 80-110 ℃, stirring for 1-10 h, performing TLC (thin layer chromatography) to show that the raw material is completely converted, quenching at room temperature, and performing post-treatment to obtain a compound VII.
In a more preferred embodiment of the present invention, in the preparation method of the compound represented by the formula VII, the noble metal catalyst is selected from RuHCl (CO) (PPh)3)3，PdCl2(MeCN)2，PdCl2(PhCN)2，Pd(OAc)2，RhCl3，RuCl3One or more of (a).
In a more preferred embodiment of the present invention, in the preparation method of the compound represented by formula VII, the organic solvent may be a conventional solvent for such reactions in the art, and may also be one or more of toluene, tetrahydrofuran, acetonitrile, dimethylsulfoxide, N-dimethylformamide, and xylene.
The invention also provides a compound shown as the formula VIII,
Figure BDA0002417047500000131
wherein R is1Is hydrogen or a hydroxy protecting group;
R2and R3Independently selected from C1-C6Alkyl or aryl.
In a preferred embodiment of the present invention, the compound of formula VIII is a compound of formula VIII, wherein R is1Is hydrogen or a hydroxy protecting group; r2And R3And may independently be methyl, ethyl, propyl, isopropyl, phenyl or benzyl.
In a more preferred embodiment of the present invention, the compound of formula VIII is a compound of formula VIII, wherein R1Hydrogen, acetyl, benzoyl or tert-butyldimethylsilyl; r2And R3And may independently be methyl, ethyl, propyl, isopropyl, phenyl or benzyl.
In a more preferred embodiment of the present invention, the compound of formula VIII is a compound of formula VIII, wherein R1Hydrogen, acetyl, benzoyl or tert-butyldimethylsilyl; r2And R3Independently a methyl group.
In a more preferred embodiment of the present invention, the compound of formula VIII is a compound of formula VIII, wherein R1Is hydrogen or acetyl; r2And R3Independently a methyl group.
The invention also provides a preparation method of the compound shown in the formula VIII, which comprises the following steps: carrying out cyclization reaction on a compound shown as a formula IX to obtain the compound shown as a formula VIII;
Figure BDA0002417047500000141
wherein R is1Is hydrogen or a hydroxy protecting group;
R2and R3Independently selected from C1-C6An alkyl or aryl group;
x is halogen or a leaving group.
In a preferred embodiment of the present invention, in the preparation method of the compound represented by the formula VIII, R is1Is hydrogen or a hydroxy protecting group; r2And R3May independently be methyl, ethyl, propyl, isopropyl, phenyl or benzyl; x can be chlorine, bromine or iodine.
In a more preferred embodiment of the present invention, in the preparation method of the compound represented by the formula VIII, R is1Can be hydrogen, acetyl, benzoyl or tert-butyl dimethyl silicon base; r2And R3May independently be methyl, ethyl, propyl, isopropyl, phenyl or benzyl; x may be bromine or iodine.
In a more preferred embodiment of the present invention, in the preparation method of the compound represented by the formula VIII, R is1Can be hydrogen, acetyl, benzoyl or tert-butyl dimethyl silicon base; r2And R3Independently is methyl; x may be bromine or iodine.
In a more preferred embodiment of the present invention, in the preparation method of the compound represented by the formula VIII, R is1Can be hydrogen or acetyl; r2And R3Independently is methyl; x is bromine.
In a preferred embodiment of the present invention, in the preparation method of the compound represented by formula VIII, the cyclization reaction is preferably performed under the action of a radical initiator and an allyl tin reagent.
In a preferred embodiment of the present invention, in the preparation method of the compound represented by formula VIII, the radical initiator used in the cyclization reaction is AIBN.
In a preferred embodiment of the present invention, the preparation method of the compound represented by formula VIII can comprise the following steps:
and dissolving a mixture of the compound IX, an allyl tin reagent and AIBN in an organic solvent, reacting at 60-110 ℃, stirring for 1-6 h, displaying complete conversion of raw materials by TLC, quenching, and performing post-treatment to obtain the compound VIII.
In a more preferred embodiment of the present invention, in the preparation method of the compound represented by formula VIII, the organic solvent may be a conventional solvent for such reactions in the art, and may also be one or more of toluene, tetrahydrofuran, and xylene.
In a more preferred embodiment of the present invention, in the preparation method of the compound represented by formula VIII, the allyl tin reagent is allyl tributyltin.
The invention also provides a compound shown as the formula IX,
Figure BDA0002417047500000151
wherein R is1Is hydrogen or a hydroxy protecting group;
R2and R3Independently selected from C1-C6An alkyl or aryl group;
x is halogen or a leaving group.
In a preferred embodiment of the present invention, the compound of formula IX is shown wherein R is1Is hydrogen or a hydroxy protecting group; r2And R3May independently be methyl, ethyl, propyl, isopropyl, phenyl or benzyl; x can be chlorine, bromine or iodine.
In a more preferred embodiment of the present invention, the compound of formula IX is shown wherein R is1Hydrogen, acetyl, benzoyl or tert-butyldimethylsilyl; r2And R3May independently be methyl, ethyl, propyl, isopropyl, phenyl or benzyl; x can be chlorine, bromine or iodine.
In a more preferred embodiment of the present invention, the compound of formula IX is shown wherein R is1Is hydrogen, acetyl, benzoyl or tert-butyldimethylSilicon-based; r2And R3Independently is methyl; x may be bromine or iodine.
In a more preferred embodiment of the present invention, the compound of formula IX is shown wherein R is1Is hydrogen or acetyl; r2And R3Independently is methyl; x is bromine.
The invention also provides a preparation method of the compound shown in the formula IXA, which comprises the following steps: carrying out coupling reaction on a compound shown as a formula XI and a compound shown as a formula XII to obtain a compound shown as a formula IXA;
the reaction equation is as follows:
Figure BDA0002417047500000161
wherein R is2And R3Independently selected from C1-C6An alkyl or aryl group;
x is halogen or a leaving group.
In a preferred embodiment of the present invention, in the preparation method of the compound represented by the formula IXA, R is2And R3May independently be methyl, ethyl, propyl, isopropyl, phenyl or benzyl; x can be chlorine, bromine or iodine.
In a more preferred embodiment of the present invention, in the preparation method of the compound represented by the formula IXA, R is2And R3Independently is methyl; x may be bromine or iodine.
In a more preferred embodiment of the present invention, in the preparation method of the compound represented by the formula IXA, R is2And R3Independently is methyl; x is bromine.
In a preferred embodiment of the invention, in the preparation method of the compound shown in the formula IXA, the reagent for the coupling reaction is a palladium catalyst;
in a preferred embodiment of the present invention, the preparation method of the compound represented by the formula IXA comprises the following steps:
and (3) dissolving a mixture of a compound XI and a palladium catalyst in an organic solvent, adding an epoxy compound XII at-10-50 ℃, continuously stirring at the temperature for 30 min-4 h for reaction, and performing TLC (thin layer chromatography) to show that the raw material is completely converted, quenching and post-treating to obtain a compound IXA.
In a more preferred embodiment of the present invention, the palladium catalyst is selected from Pd in the preparation method of the compound represented by the formula IXA2(dba)3Palladium acetate, Pd (PPh)3)4And palladium chloride.
In a more preferred embodiment of the present invention, in the preparation method of the compound represented by the formula IXA, the organic solvent may be a conventional solvent in the reaction in the field, and may also be one or more of toluene, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, xylene, and dichloromethane.
The invention also provides a preparation method of the compound shown as the formula IXB, which comprises the following steps: carrying out hydroxyl protection reaction on a compound shown as a formula IXA to obtain a compound shown as a formula IXB;
Figure BDA0002417047500000171
wherein R is2And R3Independently selected from C1-C6An alkyl or aryl group;
R4is a hydroxyl protecting group.
In a preferred embodiment of the present invention, in the preparation method of the compound represented by the formula IXB, R is4Is a hydroxy protecting group; r2And R3May independently be methyl, ethyl, propyl, isopropyl, phenyl or benzyl; x can be chlorine, bromine or iodine.
In a more preferred embodiment of the present invention, in the preparation method of the compound represented by the formula IXB, R is4Acetyl, benzoyl or tert-butyl dimethyl silicon base; r2And R3May independently be methyl, ethyl, propyl, isopropyl, phenyl or benzyl; x may be bromine or iodine.
In a more preferred embodiment of the present invention, in the preparation method of the compound represented by the formula IXB, R is4Acetyl, benzoyl or tert-butyl dimethyl silicon base; r2And R3Independently is methyl; x may be bromine or iodine.
In a more preferred embodiment of the present invention, in the preparation method of the compound represented by the formula IXB, R is4Is acetyl; r2And R3Independently is methyl; x is bromine.
In a preferred embodiment of the present invention, the method for preparing the compound represented by formula IXB comprises the following steps:
dissolving a mixture of a compound IXA and alkali in an organic solvent, adding a hydroxyl protective reagent into the organic solvent at the temperature of minus 30-50 ℃, continuously stirring for 30 min-6 h at the temperature of minus 30-50 ℃ for reaction, and performing TLC (thin layer chromatography) to show that the raw materials are completely converted, quenching and post-treating to obtain a compound IXB.
In a more preferred embodiment of the present invention, in the method for preparing the compound represented by the formula IXB, the base is selected from one or more of triethylamine, diisopropylethylamine, DMAP, pyridine, 2, 6-dimethylpyridine, LDA, and sodium hydride.
In a more preferred embodiment of the present invention, in the preparation method of the compound represented by the formula IXB, the organic solvent may be a conventional solvent for such reactions in the field, and may also be one or more of dichloromethane, tetrahydrofuran, ethyl acetate, acetonitrile, toluene, dimethyl sulfoxide, and N, N-dimethylformamide.
In a more preferred embodiment of the present invention, in the method for preparing the compound represented by the formula IXB, the hydroxyl protecting reagent is selected from one or more of acetyl chloride, acetic anhydride, benzoyl chloride, benzoic anhydride, TBSCl, and TBSOTf.
The invention also provides a compound shown as the formula XI,
Figure BDA0002417047500000181
wherein，R2And R3Independently selected from C1-C6An alkyl or aryl group;
x is halogen or a leaving group.
In a preferred embodiment of the present invention, the compound of formula XI is a compound of formula XI, wherein R is2And R3May independently be methyl, ethyl, propyl, isopropyl, phenyl or benzyl; x can be chlorine, bromine or iodine.
In a more preferred embodiment of the present invention, the compound of formula XI is a compound of formula XI, wherein R is2And R3Independently is methyl; x may be bromine or iodine.
In a more preferred embodiment of the present invention, the compound of formula XI is a compound of formula XI, wherein R is2And R3Independently is methyl; x is bromine.
The invention also provides a preparation method C of the compound shown in the formula XI, which comprises the following steps:
1) carrying out Bayer-Villiger oxidation reaction on the compound shown in the formula XVI to obtain a compound shown in a formula XV;
2) carrying out ring-opening reaction on a compound shown as a formula XV and N, O-disubstituted hydroxylamine or salt thereof to obtain a compound shown as a formula XIII;
3) performing halogenation reaction on a compound shown in a formula XIII to obtain a compound shown in a formula XI;
Figure BDA0002417047500000182
wherein R is2And R3Independently selected from C1-C6An alkyl or aryl group;
x is halogen or a leaving group.
In a preferred embodiment of the present invention, in the preparation process C of the compound represented by the formula XI, R is2And R3May independently be methyl, ethyl, propyl, isopropyl, phenyl or benzyl; x can be chlorine, bromine or iodine.
A more preferred embodiment of the present inventionIn the preparation method C of the compound shown as the formula XI, R is2And R3Independently is methyl; x may be bromine or iodine.
In a more preferred embodiment of the present invention, in the process C for preparing the compound represented by formula XI, R is2And R3Independently is methyl; x may be bromine.
In a preferred embodiment of the invention, in the preparation method C of the compound represented by formula XI, the oxidation reagent is m-chloroperoxybenzoic acid (mCPBA);
in a preferred embodiment of the present invention, in the preparation method C of the compound represented by the formula XI, the ring-opening reaction is performed under alkaline conditions;
in a preferred embodiment of the present invention, the process C for preparing a compound of formula XI comprises the following steps:
dissolving a compound XIII in an organic solvent, adding alkali, adding a halogenating reagent at 0-50 ℃, continuously stirring for 3-16 h at the temperature for reaction, and performing TLC (thin layer chromatography) to show that the raw material is completely converted, quenching and post-treating to obtain a compound XI.
In a more preferred embodiment of the present invention, in the preparation method C of the compound represented by the formula XI, the halogenating agent is selected from I2、Br2One or more of dibromohydantoin, NIS, NBS and NCS.
In a more preferred embodiment of the present invention, in the preparation method C of the compound represented by formula XI, the organic solvent may be a conventional solvent in the reaction in this field, and may also be one or more of dichloromethane and carbon tetrachloride.
In a more preferred embodiment of the present invention, in the preparation method C of the compound represented by formula XI, the base is selected from one or more of diethylamine, triethylamine, diisopropylamine, diisopropylethylamine, pyridine, potassium carbonate and sodium carbonate.
The invention also provides a preparation method D of the compound shown in the formula XI, which comprises the following steps:
1) carrying out Bayer-Villiger oxidation reaction on the compound shown in the formula XVII to obtain a compound shown in a formula XIV;
2) carrying out a ring-opening reaction on a compound shown as a formula XIV to obtain a compound shown as a formula XI;
Figure BDA0002417047500000191
wherein R is2And R3Independently selected from C1-C6An alkyl or aryl group;
x is halogen or a leaving group.
In a preferred embodiment of the present invention, in the preparation process D of the compound represented by the formula XI, R is2And R3May independently be methyl, ethyl, propyl, isopropyl, phenyl or benzyl; x can be chlorine, bromine or iodine.
In a more preferred embodiment of the present invention, in the process D for preparing the compound represented by formula XI, R is2And R3Independently is methyl; x may be bromine or iodine.
In a more preferred embodiment of the present invention, in the process D for preparing the compound represented by formula XI, R is2And R3Independently is methyl; x may be bromine.
In a preferred embodiment of the invention, in the preparation method D of the compound represented by formula XI, the oxidizing agent of the oxidation reaction is m-chloroperoxybenzoic acid (mCPBA);
in a preferred embodiment of the present invention, in the preparation method D of the compound represented by the formula XI, the ring-opening reaction is performed under alkaline conditions;
in a preferred embodiment of the present invention, the process D for preparing a compound of formula XI comprises the following steps:
dissolving a compound XIV and N, O-disubstituted hydroxylamine hydrochloride in an organic solvent, adding alkali, reacting at 25-70 ℃, stirring for 2-16 h, and performing Thin Layer Chromatography (TLC) to show that the raw materials are completely converted, quenching and post-treating to obtain a compound XI.
In a more preferred embodiment of the present invention, in the preparation method D of the compound represented by formula XI, the base used in the basic condition is selected from one or more of pyridine, triethylamine, DMAP, and 2, 6-lutidine.
In a more preferred embodiment of the present invention, in the preparation method D of the compound represented by formula XI, the organic solvent may be a conventional solvent in the reaction in the art, and may also be one or more of dimethylsulfoxide, acetonitrile, and tetrahydrofuran.
The invention also provides a preparation method E of beraprost and beraprost salt shown as the formula I, which comprises the following steps:
Figure BDA0002417047500000211
wherein R is2And R3Independently selected from C1-C6An alkyl or aryl group;
R4is a hydroxy protecting group;
R5is C1-C6An alkyl group;
x is halogen or a leaving group.
In a preferred embodiment of the invention, in the synthesis method E of beraprost and its salt shown in formula I, R is4Is a hydroxy protecting group; r2And R3May independently be methyl, ethyl, propyl, isopropyl, phenyl or benzyl; r5Is methyl or ethyl; x can be chlorine, bromine or iodine.
In a more preferred embodiment of the present invention, in the method for synthesizing beraprost and its salt represented by formula I, R is4Can be acetyl, benzoyl or tert-butyl dimethyl silicon base; r2And R3May independently be methyl, ethyl, propyl, isopropyl, phenyl or benzyl; r5Is methyl or ethyl; x can be chlorine, bromine or iodine.
In a more preferred embodiment of the present invention, in the method for synthesizing beraprost and its salt represented by formula I, R is4Can be acetyl, benzoyl or tert-butyl dimethyl silicon base; r2And R3Independently is methyl; r5Is methyl or ethyl; x may be bromine or iodine.
In a more preferred embodiment of the present invention, in the method for synthesizing beraprost and its salt represented by formula I, R is4Is acetyl; r2And R3Independently is methyl; r5Is ethyl; x is bromine.
In a preferred embodiment of the present invention, in the method E for synthesizing beraprost and its salt represented by formula I, the reaction conditions in each step are as described above, and the method comprises the following steps:
1) carrying out coupling reaction on a compound shown as a formula XI and a compound shown as a formula XII to obtain a compound shown as a formula IXA; the coupling reaction is preferably carried out under the action of a palladium catalyst; the palladium catalyst is preferably palladium tetratriphenylphosphine and Pd2(dba)3One or more of palladium acetate and palladium chloride;
2) carrying out hydroxyl protection reaction on the compound shown in the formula IXA to obtain a compound shown in the formula IXB; the hydroxyl protection reaction is preferably carried out under alkaline conditions; the alkali adopted in the alkaline condition is preferably one or more of triethylamine, diisopropylethylamine, DMAP, pyridine, 2, 6-dimethylpyridine, LDA and sodium hydride; the hydroxyl protecting reagent is preferably one or more of acetyl chloride, acetic anhydride, benzoyl chloride, benzoic anhydride, TBSCl and TBSOTf;
3) carrying out cyclization reaction on the compound shown in the formula IXB to obtain a compound shown in a formula VIIIB; the cyclization reaction is preferably carried out under the action of a free radical initiator and an allyl tin reagent;
4) carrying out double bond shift reaction on the compound shown in the formula VIIIB to obtain a compound shown in a formula VIIB; the reagent for the double bond shift reaction is preferably a noble metal catalyst; the noble metal catalyst is preferably RuHCl (CO) (PPh)3)3，PdCl2(MeCN)2，PdCl2(PhCN)2，Pd(OAc)2，RhCl3，RuCl3One or more of;
5) carrying out dihydroxylation reaction on the compound shown in the formula VIIB to obtain a compound shown in a formula VIB; the reagent for the dihydroxylation reaction is preferably an osmium reagent, a manganese reagent or a ruthenium reagent; the dihydroxylation reagent is more preferably one or more of osmium tetroxide-NMO, potassium osmate-potassium ferricyanide, ruthenium trichloride and potassium permanganate;
6) carrying out oxidation reaction on the compound shown as the formula VIB to obtain a compound shown as a formula IVB; the reagent for the oxidation reaction is preferably sodium periodate;
or carrying out ozonization reaction on the compound shown in the formula VIIB to obtain a compound shown in the formula IVB in one step;
7) reacting a compound shown in a formula IVB with a compound shown in a formula V through HWE to obtain a compound shown in IIIB; the HWE reaction is preferably carried out under basic conditions; the base is preferably one or more of triethylamine, diisopropylethylamine, lithium hydroxide, potassium carbonate, 2, 6-dimethylpyridine or pyridine;
8) carrying out reduction reaction on the compound shown in the formula IIIB to obtain a compound shown in the formula IIB; the reducing agent is preferably one or more of sodium borohydride, sodium borohydride-cerium trichloride, a normal hexane solution of DIBAL-H or a CBS reducing agent;
9) carrying out deprotection reaction on the compound shown in the formula IIB to obtain a compound shown in the formula IIA; the deprotection reaction is preferably carried out under acidic or basic conditions; the alkali adopted in the alkaline condition is preferably one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and tetrabutylammonium fluoride; the acid adopted in the acidic condition is preferably one or more of hydrochloric acid, sulfuric acid and hydrofluoric acid;
10) carrying out hydrolysis reaction on a compound shown in a formula IIA or a compound shown in a formula IIB to obtain a compound shown in a formula I; the hydrolysis reaction is preferably carried out under alkaline conditions; the alkali adopted in the alkaline condition is preferably one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate;
in a preferred embodiment of the invention, the compound shown in the formula IIB is subjected to hydrolysis reaction to obtain the compound shown in the formula I in one step.
In a more preferred embodiment of the present invention, in the method for synthesizing beraprost and its salt represented by formula I, R is2And R3Independently is methyl; r4Is a hydroxy protecting group; r5Preferably methyl, ethyl; x is bromine or iodine.
The invention also provides a preparation method F of beraprost and beraprost salt shown as the formula I, which comprises the following steps:
Figure BDA0002417047500000241
wherein R is2And R3Independently selected from C1-C6An alkyl or aryl group;
R5is C1-C6An alkyl group;
x is halogen or a leaving group.
In a preferred embodiment of the invention, in the synthesis method F of beraprost and its salt shown in formula I, R is2And R3May independently be methyl, ethyl, propyl, isopropyl, phenyl or benzyl; r5Is methyl or ethyl; x can be chlorine, bromine or iodine.
In a more preferred embodiment of the present invention, in the method F for synthesizing beraprost and its salt represented by formula I, R is2And R3Independently is methyl; r5Is methyl or ethyl; x may be bromine or iodine.
In a more preferred embodiment of the present invention, in the method F for synthesizing beraprost and its salt represented by formula I, R is2And R3Independently is methyl; r5Is ethyl; x is bromine.
In a preferred embodiment of the present invention, the method F for synthesizing beraprost and its salt represented by formula I, wherein the reaction conditions in each step are as described above, may comprise the following steps:
1) reacting a compound of formula XI andcarrying out coupling reaction on the compound shown in the formula XII to obtain a compound shown in a formula IXA; the coupling reaction is preferably carried out under the action of a palladium catalyst; the palladium catalyst is preferably palladium tetratriphenylphosphine and Pd2(dba)3One or more of palladium acetate and palladium chloride;
2) carrying out cyclization reaction on a compound shown in a formula IXA to obtain a compound shown in a formula VIIIA; the cyclization reaction is preferably carried out under the action of a free radical initiator and an allyl tin reagent;
3) carrying out double bond shift reaction on the compound shown in the formula VIIIA to obtain a compound shown in the formula VIIA; the reagent for the double bond shift reaction is preferably a noble metal catalyst; the noble metal catalyst is preferably RuHCl (CO) (PPh)3)3，PdCl2(MeCN)2，PdCl2(PhCN)2，Pd(OAc)2，RhCl3，RuCl3One or more of;
4) carrying out dihydroxylation reaction on the compound shown in the formula VIIA to obtain a compound shown in the formula VIA; the reagent for the dihydroxylation reaction is preferably an osmium reagent, a manganese reagent or a ruthenium reagent; the reagent of the dihydroxylation reaction is more preferably one or more of osmium tetroxide-NMO, potassium osmate-potassium ferricyanide, ruthenium trichloride and potassium permanganate;
5) carrying out oxidation reaction on a compound shown in a formula VIA to obtain a compound shown in a formula IVA; the reagent for the oxidation reaction is preferably sodium periodate;
or carrying out ozonization reaction on the compound shown in the formula VIIA to obtain a compound shown in the formula IVA in one step;
6) reacting a compound shown in formula IVA with a compound shown in formula V through HWE to obtain a compound shown in IIIA; the HWE reaction is preferably carried out under basic conditions; the alkali adopted in the alkaline condition is preferably one or more of triethylamine, diisopropylethylamine, lithium hydroxide and pyridine;
7) carrying out reduction reaction on the compound shown in the formula IIIA to obtain a compound shown in the formula IIA; the reducing agent adopted in the reduction reaction is preferably one or more of sodium borohydride, sodium borohydride-cerium trichloride, a normal hexane solution of DIBAL-H or a CBS (Corey-Bakshi-Shibata) reducing agent;
8) carrying out hydrolysis reaction on the compound shown in the formula IIA to obtain a compound shown in a formula I; the hydrolysis reaction is preferably carried out under alkaline conditions; the alkali adopted in the alkaline condition is preferably one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate;
in a preferred embodiment of the present invention, in the method F for synthesizing beraprost and its salt represented by formula I, no protecting group is required in the synthetic route.
In a more preferred embodiment of the present invention, in the method for synthesizing beraprost and its salt represented by formula I, R is2And R3Independently is methyl; r5Is methyl or ethyl; x is bromine or iodine.
If available, the intermediate of beraprost of formula II and its salt can also be prepared in a shorter route using a portion of the products of the above reaction steps; intermediates for beraprost of formula II and salts thereof can be prepared, for example, by purchasing intermediates of formula IV, VIII, IX, XI as described above and then following the procedures provided in the above-described process.
The synthesis of N, O-disubstituted hydroxylamines can be found in the literature: J.chem.Soc.Perkin Trans.II 1987, 1125-1128; amer. chem.j.1913,50,457; tetrahedron Lett.2002,43,4369-4371.
The synthesis of compound XVII can be found in the literature: j.am.chem.soc.2015,137, 5346-5354; chem.2005,70, 596-; chem.2003,68, 10195-.
For the synthesis of compound V, reference may be made to the patents: CN 106573904A.
The invention also provides a method for preparing the beraprost shown as the formula I and the salt thereof, the method firstly prepares the compounds shown as the formula II, the formula IV, the formula VIII, the formula IX and the formula XI according to the method provided by the invention, and then prepares the beraprost shown as the formula I and the salt thereof or the analogue thereof through the compounds shown as the formula II, the formula IV, the formula VIII, the formula IX or the formula XI according to the known method.
The invention also provides a compound shown in II, IV, VIII, IX or XI for preparing beraprost and its salt or its analogue.
The terms used in the present invention have the following meanings, unless otherwise specified.
"alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 10 carbon atoms. Non-limiting examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. Alkyl groups may be substituted or unsubstituted, and when substituted, C1-C6 alkyl refers to a saturated aliphatic hydrocarbon group containing 1 to 6 carbon atoms in the main chain, and substituents on the branches may be substituted at any available point of attachment, preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkyloxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio or oxo.
"aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, more preferably phenyl and naphthyl, most preferably phenyl. The aryl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, or heterocycloalkylthio.
The hydroxyl protecting groups of the present invention are known in the artSuitable Groups for hydroxyl protection are described in the literature ("Protective Groups in Organic Synthesis", 5)Th Ed.T.W.Greene&P.g.m.wuts). By way of example, the hydroxyl protecting group may preferably be (C)1-10Alkyl or aryl)3Silane groups, for example: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl and the like; may be C1-10Alkyl or substituted alkyl, for example: methyl, t-butyl, allyl, benzyl, methoxymethyl, ethoxyethyl, 2-Tetrahydropyranyl (THP), etc.; may be (C)1-10Alkyl or aryl) acyl groups, such as: formyl, acetyl, benzoyl and the like; may be (C)1-6Alkyl or C6-10Aryl) sulfonyl; or (C)1-6Alkoxy or C6-10Aryloxy) carbonyl.
Leaving groups of the present invention are chemical groups well known in the art that are readily substituted with chemical groups that need to be introduced. Such leaving groups include, but are not limited to, halogen (e.g., chloro, bromo, iodo), sulfonyloxy, optionally substituted alkylsulfonyloxy (e.g., methanesulfonyloxy, trifluoromethanesulfonyloxy), optionally substituted arylsulfonyloxy (e.g., p-methylphenylsulfonyloxy, nitrophenylsulfonyloxy), and the like.
As used herein, "quenching" refers to the act of terminating the reaction by the addition of a reagent. Generally, water can act as a quenching agent for most organic reactions, and for common types of reactions, there are also common quenching agents familiar to those of ordinary skill in the art. For example, basic reaction systems are typically quenched with acidic reagents, including, by way of example and not limitation, saturated aqueous ammonium chloride solutions, dilute mineral acid solutions (e.g., 1N hydrochloric acid), organic acids (e.g., acetic acid); the acidic reaction system is typically quenched with an alkaline reagent, which illustratively includes, but is not limited to, saturated aqueous sodium bicarbonate solution, saturated aqueous sodium carbonate solution; the oxidation reaction system is typically quenched with a reducing agent, which illustratively includes, but is not limited to, sodium thiosulfate, sodium sulfite, sodium bisulfite.
The post-treatment used in the present invention includes extraction and purification steps. The extraction step, which often occurs after the quenching step, refers to the process of transferring the bulk of the organic to the organic phase by shaking the aqueous phase with a water immiscible organic solvent, including, but not limited to, ethyl acetate, methylene chloride, toluene, petroleum ether, n-hexane, methyl t-butyl ether, 2-methyltetrahydrofuran, by way of example. The purification step refers to a means of refining the crude product by physical separation means, and illustratively, purification means include, but are not limited to, extraction, distillation, rectification, recrystallization, column chromatography, high performance liquid chromatography preparation.
Abbreviation table:
Figure BDA0002417047500000271
Figure BDA0002417047500000281
Detailed Description
The present invention will be explained in detail below with reference to specific examples so that those skilled in the art can more fully understand the present invention, and the specific examples are only for illustrating the technical scheme of the present invention and do not limit the present invention in any way.
The following table is a structural formula of the compound referred to in the examples:
Figure BDA0002417047500000282
Figure BDA0002417047500000291
Figure BDA0002417047500000301
Figure BDA0002417047500000311
Figure BDA0002417047500000321
Figure BDA0002417047500000331
Figure BDA0002417047500000341
example 1: preparation of Compound XV
To a solution of compound XVI (100g, 685mmol, 1eq.) in DCM (300mL) was added mCPBA (166g), the reaction was stirred at 25 ℃ for 36h, TLC showed complete conversion of starting material. The reaction was quenched by addition of saturated aqueous sodium bisulfite solution, extracted with dichloromethane, and concentrated to give crude compound XV (105g), which was used in the next reaction without purification.
MS(ESI)m/z:163(M+H+)。
Examples 2 to 3 Synthesis of Compounds of formula XIV
Example 2: preparation of Compound XIVa
To a solution of compound XVIIa (30g, 133.8mmol, 1eq.) in DCM (300mL) was added mCPBA (75g), the reaction was stirred at 25 ℃ for 48h, TLC showed complete conversion of the starting material. The reaction was quenched by the addition of saturated aqueous sodium bisulfite solution, extracted with dichloromethane, and concentrated to give crude compound XIVa (30.6g), which was used in the next reaction without purification.
MS(ESI)m/z:241,243(M+H+)。
Example 3: preparation of Compound XIVb
To a solution of compound xviiib (10g, 36.7mmol, 1eq.) in DCM (100mL) was added mCPBA (20g) and the reaction was stirred at 60 degrees for 24h, TLC showed complete conversion of starting material. The reaction was quenched by addition of a saturated aqueous solution of sodium hydrogensulfite, extracted with dichloromethane, and then concentrated and purified to obtain compound XIVb (9.8 g).
MS(ESI)m/z:289(M+H+)。
Examples 4 to 7 are syntheses of compounds represented by formula XIII
Example 4: preparation of Compound XIIIa
To a solution of compound XV (30g, 184.7mmol, 1eq.) in THF (300mL) was added pyridine (52.6g) and N, O-dimethylhydroxylamine hydrochloride (32.4g), reacted at 25 ℃ for 16h and TLC showed complete conversion of the starting material. Adding saturated NH4The reaction was quenched with Cl solution, extracted with ethyl acetate, and the concentrate was purified by column chromatography to give Compound XIIIa (33.7 g).
MS(ESI)m/z:224(M+H+)。
1H NMR(400MHz,Chloroform-d)δ7.16–7.09(m,1H),7.05(dd,J＝7.5,1.7Hz,1H),6.91(dd,J＝8.0,1.2Hz,1H),6.83–6.76(m,1H),3.70(s,3H),3.25(s,3H),2.63(dd,J＝8.8,6.7Hz,2H),2.53(t,J＝6.0Hz,2H),1.92–1.81(m,2H).
Example 5: preparation of Compound XIIIb
To a solution of compound XV (11g, 68.4mmol, 1eq.) in THF (100mL) was added pyridine (19.5g) and N, O-diethylhydroxylamine hydrochloride (14g), reacted at 50 ℃ for 8 hours and TLC showed complete conversion of the starting material. Adding saturated NH4The reaction was quenched with Cl solution, extracted with ethyl acetate, and the concentrate was purified by column chromatography to give Compound XIIIb (12.7 g).
MS(ESI)m/z:252(M+H+)。
Example 6: preparation of Compound XIIic
To a solution of compound XV (11g, 68.4mmol, 1eq.) in acetonitrile (100mL) was added pyridine (19.5g) and N-ethyl-O-methylhydroxylamine hydrochloride (15g), reacted at 60 ℃ for 16h and TLC showed complete conversion of the starting material. Adding saturated NH4The reaction was quenched with Cl solution, extracted with ethyl acetate, and the concentrate was purified by column chromatography to give Compound XIIIC (13.5 g).
MS(ESI)m/z:238(M+H+)。
Example 7: preparation of Compound XIIId
To a solution of compound XV (11g, 68.4mmol, 1eq.) in tetrahydrofuran (100mL) was addedPyridine (19.5g) and N, O-dibenzylhydroxylamine hydrochloride (19g) were added and reacted at 40 ℃ for 16 hours, and TLC showed complete conversion of the starting material. Adding saturated NH4The reaction was quenched with Cl solution, extracted with ethyl acetate, and the concentrate was purified by column chromatography to give Compound XIIId (13.1 g).
MS(ESI)m/z:376(M+H+)。
Examples 8 to 17 Synthesis of Compounds represented by the formula XI
Example 8: preparation of Compound XIa
To a solution of compound XIIIa (8g, 35.8mmol) in DCM (240mL) was added diisopropylamine (3.6g), NBS (6.5g) was added at 0-5 deg.C, the reaction was stirred at this temperature for 3h, and TLC showed complete conversion of the starting material. Water was added to quench the reaction, and after extraction with methylene chloride, the concentrate was purified by column chromatography to give Compound XIa (6.6 g).
MS(ESI)m/z:302,304(M+H+)。
1HNMR(400MHz,CDCl3):δ7.83(brs,1H),7.34(dd,J＝8.0,1.6Hz,1H),7.03(dd,J＝7.5,1.5Hz,1H),6.69(t,J＝7.7Hz,1H),3.69(s,3H),3.22(s,3H),2.74–2.64(m,2H),2.51(t,J＝6.6Hz,2H),1.95–1.82(m,2H).
Example 9: preparation of Compound XIa
To a solution of compound XIVa (6g, 24.9mmol) in THF (60mL) was added pyridine (8.2g) and N, O-dimethylhydroxylamine hydrochloride (5.12g), the reaction was stirred at 25 ℃ for 16h and TLC showed complete conversion of the starting material. The reaction was quenched by addition of saturated ammonium chloride solution, extracted with ethyl acetate, and the concentrate was purified by column chromatography to give compound XIa (6.03 g).
MS(ESI)m/z:302,304(M+H+)。
1HNMR(400MHz,CDCl3):δ7.83(brs,1H),7.34(dd,J＝8.0,1.6Hz,1H),7.03(dd,J＝7.5,1.5Hz,1H),6.69(t,J＝7.7Hz,1H),3.69(s,3H),3.22(s,3H),2.74–2.64(m,2H),2.51(t,J＝6.6Hz,2H),1.95–1.82(m,2H).
Example 10: preparation of Compound XIb
To compound XIIIa (6g, 26.87mmol) was added carbon tetrachloride (90mL) solution triethylamine (1.37g) and, at 30 deg.C, NIS (6.05g) was added and the reaction was stirred at this temperature for a further 16h, TLC showed complete conversion of the starting material. Water was added to quench the reaction, and after extraction with methylene chloride, the concentrate was purified by column chromatography to give compound XIb (5.32 g).
MS(ESI)m/z:350(M+H+)。
1HNMR(400MHz,CDCl3):δ8.60(brs,1H),7.57(dd,J＝8.0,1.6Hz,1H),7.03(dd,J＝7.5,1.6Hz,1H),6.55(t,J＝7.5Hz,1H),3.70(s,3H),3.23(s,3H),2.66(t,J＝7.5Hz,2H),2.53(t,J＝6.6Hz,2H),1.95–1.82(m,2H).
Example 11: preparation of Compound XIb
To a solution of compound XIVb (6g, 20.8mmol, 1eq.) in dimethylsulfoxide (60mL) was added triethylamine (11.2g) and N, O-dimethylhydroxylamine hydrochloride (4.75g), the reaction was stirred at 60 ℃ for 4h and TLC showed complete conversion of the starting material. The reaction was quenched by addition of saturated ammonium chloride solution, extracted with ethyl acetate, and the concentrate was purified by column chromatography to give compound XIb (5.86 g).
MS(ESI)m/z:350(M+H+)。
1HNMR(400MHz,CDCl3):δ8.60(brs,1H),7.57(dd,J＝8.0,1.6Hz,1H),7.03(dd,J＝7.5,1.6Hz,1H),6.55(t,J＝7.5Hz,1H),3.70(s,3H),3.23(s,3H),2.66(t,J＝7.5Hz,2H),2.53(t,J＝6.6Hz,2H),1.95–1.82(m,2H).
Example 12: preparation of Compound XIc
To a solution of compound XIIIb (8g, 31.9mmol, 1eq.) in DCM (160mL) was added diisopropylamine (3.3g), and Br was added at 25 deg.C2(5.6g), the reaction was continued to stir at this temperature for 5h and TLC showed complete conversion of starting material. Water was added to quench the reaction, and after extraction with methylene chloride, the concentrate was purified by column chromatography to give Compound XIc (7.2 g).
MS(ESI)m/z:330,332(M+H+)。
Example 13: preparation of Compound XId
DMAP (8.9g) and N, O-dipropylhydroxylamine hydrochloride (7.2g) were added to a solution of compound XIVa (6g, 24.9mmol) in THF (60mL) and the reaction stirred at 70 ℃ for 2h, TLC indicating complete conversion of the starting material. The reaction was quenched by addition of saturated ammonium chloride solution, extracted with ethyl acetate, and the concentrate was purified by column chromatography to give Compound XId (6.2 g).
MS(ESI)m/z:358,360(M+H+)。
Example 14: preparation of Compound XIe
To a solution of compound XIVa (6g, 24.9mmol) in THF (60mL) was added DMAP (8.9g) and N, O-diisopropylhydroxylamine hydrochloride (8.1g), the reaction was stirred at 50 ℃ for 6h and TLC showed complete conversion of the starting material. The reaction was quenched by addition of saturated ammonium chloride solution, extracted with ethyl acetate, and the concentrate was purified by column chromatography to give XIe (6.7 g).
MS(ESI)m/z:358,360(M+H+)。
Example 15: preparation of Compound XIf
To a solution of compound XIIIC (8g, 22.0mmol) in DCM (200mL) was added diethylamine (2.6g), and NCS (5.3g) was added at 50 deg.C, the reaction was stirred at that temperature for an additional 3h, and TLC indicated complete conversion of the starting material. Water was added to quench the reaction, and after extraction with methylene chloride, the concentrate was purified by column chromatography to give XIf (6.2 g).
MS(ESI)m/z:272,274(M+H+)。
Example 16: preparation of Compound XIg
To a solution of compound XIIId (8g, 21.3mmol) in DCM (200mL) was added diisopropylamine (2.5g), dibromohydantoin (10.8g) was added at 20 deg.C, the reaction was stirred at this temperature for an additional 16h, and TLC indicated complete conversion of the starting material. Water was added to quench the reaction, and after extraction with methylene chloride, the concentrate was purified by column chromatography to give XIg (6.6 g).
MS(ESI)m/z:454,456(M+H+)。
Example 17: preparation of Compound XIh
To a solution of compound XIVa (6g, 24.9mmol) in acetonitrile (60mL) was added 2, 6-lutidine (8.5g) and N-phenyl-O-methylhydroxylamine hydrochloride (8.9g), the reaction was stirred at 60 ℃ for 12h and TLC showed complete conversion of the starting material. The reaction was quenched by addition of saturated ammonium chloride solution, extracted with ethyl acetate, and the concentrate was purified by column chromatography to give XIh (6.7 g).
MS(ESI)m/z:364,366(M+H+)。
Examples 18 to 31 Synthesis of Compounds represented by the formula IX
Example 18: preparation of the Compound IXAa
To a mixture of compound XIa (6g, 18.5mmol, 1eq.) and tetratriphenylphosphine palladium (460mg) was added THF (60mL) to dissolve. Epoxide XII (4.5g) was added at 25 ℃ and the reaction was stirred for a further 30min at this temperature, after which TLC showed complete conversion of the starting material. The reaction was quenched with water, extracted with ethyl acetate, and the concentrate was purified by column chromatography to give compound IXAa (6.05 g).
MS(ESI)m/z:384,386(M+H+)。
1HNMR(400MHz,CDCl3):δ7.42(dd,J＝8.0,1.5Hz,1H),7.14(dd,J＝7.5,1.5Hz,1H),6.92(t,J＝7.5Hz,1H),6.13(dd,J＝5.6,2.4Hz,1H),5.97(d,J＝6.4Hz,1H),5.23-5.18(m,1H),4.69-4.62(m,1H),3.66(s,3H),3.40(d,J＝10.6Hz,1H),3.19(s,3H),2.95-2.86(m,1H),2.82-2.72(m,1H),2.70-2.60(m,1H),2.39(t,J＝6.0Hz,2H),2.01(dt,J＝14.4,3.2Hz,2H),1.93-1.82(m,2H)。
Example 19: preparation of the Compound IXAb
To compound XIb (6g, 17.2mmol, 1eq.) and Pd2(dba)3(530mg) was dissolved in acetonitrile (60 mL). Epoxide XII (5.65g) was added at 50 ℃ and the reaction was stirred for a further 4h at this temperature, TLC showed complete conversion of the starting material. The reaction was quenched with water, extracted with ethyl acetate, and the concentrate was purified by column chromatography to give IXAb (5.83 g).
MS(ESI)m/z:432(M+H+)。
1HNMR(400MHz,CDCl3):δ7.67(dd,J＝8.0,1.6Hz,1H),7.16(dd,J＝7.5,1.5Hz,1H),6.78(t,J＝7.8Hz,1H),6.13-6.09(m,1H),6.04-6.00(m,1H),5.15-5.09(m,1H),4.73-4.65(m,1H),3.65(s,3H),3.40(d,J＝11.2Hz,1H),3.19(s,3H),2.95-2.86(m,1H),2.82-2.72(m,1H),2.68-2.60(m,1H),2.39(t,J＝6.0Hz,2H),2.00(dt,J＝14.2,3.2Hz,2H),1.93-1.81(m,2H)。
Example 20: preparation of Compound IXAc
To compound XIc (6g, 18.3mmol, 1eq.) and Pd2(dba)3Toluene (60mL) was added to the mixture (550mg) to dissolve it. Epoxide XII (5.88g) was added at-10 ℃ and after stirring the reaction at this temperature for 8h, TLC showed complete conversion of the starting material. Adding water to quenchThe reaction was quenched, extracted with ethyl acetate, and the concentrate was purified by column chromatography to give IXAc (5.98 g).
MS(ESI)m/z:412,414(M+H+)。
Example 21: preparation of Compound IXAd
To compound XId (6g, 16.8mmol, 1eq.) and Pd (PPh)3)4(755mg) was added to the mixture and dissolved in methylene chloride (60 mL). Epoxide XII (6.8g) was added at 0 ℃ and the reaction was stirred for 2h at this temperature, after which TLC showed complete conversion of the starting material. The reaction was quenched with water, extracted with ethyl acetate, and the concentrate was purified by column chromatography to give IXAd (6.15 g).
MS(ESI)m/z:440,442(M+H+)。
Example 22: preparation of the Compound IXAe
To compound XIe (6g, 16.8mmol, 1eq.) and Pd (PPh)3)4(755mg) was added to the mixture and dissolved in tetrahydrofuran (60 mL). Epoxide XII (6.8g) was added at-20 ℃ and after stirring the reaction at this temperature for a further 3h, TLC showed complete conversion of the starting material. The reaction was quenched with water, extracted with ethyl acetate, and the concentrate was purified by column chromatography to give IXAe (6.02 g).
MS(ESI)m/z:440,442(M+H+)。
Example 23: preparation of the Compound IXAf
To compound XIf (6g, 22.1mmol, 1eq.) and Pd (PPh)3)4(1.9g) to the mixture was added tetrahydrofuran (60mL) to dissolve. Epoxide XII (9.2g) was added at 0 ℃ and the reaction was stirred for a further 1h at this temperature, TLC showed complete conversion of the starting material. The reaction was quenched with water, extracted with ethyl acetate, and the concentrate was purified by column chromatography to give the compound IXAf (6.05 g).
MS(ESI)m/z:354,356(M+H+)。
Example 24: preparation of Compound IXAg
To compound XIg (6g, 13.2mmol, 1eq.) and Pd (PPh)3)4Tetrahydrofuran (60mL) was added to the mixture (920mg) to dissolve. Epoxide XII (5.2g) was added at 0 ℃ and the reaction was stirred for a further 1h at this temperature, TLC showed complete conversion of the starting material. Adding water to quench the reaction, bAfter extraction with ethyl acetate, the concentrate was purified by column chromatography to give IXAg (6.01 g).
MS(ESI)m/z:536,538(M+H+)。
Example 25: preparation of Compound IXAh
To compound XIh (6g, 16.5mmol, 1eq.) and Pd (PPh)3)4(530mg) the mixture was dissolved in tetrahydrofuran (60 mL). Epoxide XII (7.3g) was added at 0 ℃ and the reaction was stirred for a further 1h at this temperature, TLC showed complete conversion of the starting material. The reaction was quenched with water, extracted with ethyl acetate, and the concentrate was purified by column chromatography to give the compound IXAh (6.1 g).
MS(ESI)m/z:494,496(M+H+)。
Example 26: preparation of Compound IXBA
To a mixture of compound IXBa (5g, 10.7mmol, 1eq.) and DMAP (3.45g) was added dichloromethane (50mL) to dissolve, acetic anhydride (2.2g) was added thereto at room temperature, the reaction was continued stirring at that temperature for 30min, TLC showed complete conversion of the starting material, water was added to quench the reaction, ethyl acetate was extracted, and the concentrate was purified by column chromatography to give compound IXBa (4.98 g).
MS(ESI)m/z:426,428(M+H+)。
1HNMR(400MHz,CDCl3):δ7.42(dd,J＝8.0,1.5Hz,1H),7.18(dd,J＝7.5,1.5Hz,1H),6.92(t,J＝7.5Hz,1H),6.22(d,J＝5.6Hz,1H),6.06(d,J＝6.4Hz,1H),5.55-5.49(m,1H),5.11-5.05(m,1H),3.66(s,3H),3.19(s,3H),2.97-2.87(m,1H),2.84-2.66(m,2H),2.39(t,J＝6.0Hz,2H),2.01(dt,J＝14.4,3.2Hz,1H),2.10(s,3H),1.93-1.82(m,2H)。
Example 27: preparation of Compound IXBb
Tetrahydrofuran (50mL) was added to a mixture of the compound IXAb (5g, 11.6mmol, 1eq.) and triethylamine (4.65g) to dissolve it, acetyl chloride (2.5g) was added to it at-10 deg.C, the reaction was continued stirring at this temperature for 30min, TLC showed complete conversion of the starting material, water was added to quench the reaction, and after extraction with ethyl acetate, the concentrate was purified by column chromatography to give compound IXBA (4.82 g).
MS(ESI)m/z:474(M+H+)。
1HNMR(400MHz,CDCl3):δ7.66(dd,J＝8.0,1.6Hz,1H),7.21(dd,J＝7.5,1.5Hz,1H),6.80(t,J＝7.8Hz,1H),6.23-6.19(m,1H),6.06-6.03(m,1H),5.56-5.49(m,1H),5.09-5.05(m,1H),3.64(s,3H),3.17(s,3H),3.00-2.90(m,1H),2.84-2.66(m,2H),2.41(t,J＝6.0Hz,2H),2.01(dt,J＝14.4,3.2Hz,1H),2.10(s,3H),1.93-1.82(m,2H).
Example 28: preparation of Compound IXBc
Acetonitrile (50mL) was added to a mixture of the compound IXAa (5g, 13mmol, 1eq.) and diisopropylethylamine (5.12g), DMAP (160mg) to dissolve it, benzoyl chloride (3.65g) was added thereto at 50 ℃ and the reaction was stirred for 3h at that temperature, TLC showed complete conversion of the starting material, water was added to quench the reaction, the concentrate was extracted with ethyl acetate and purified by column chromatography to give the compound IXBc (5.05 g).
MS(ESI)m/z:488,450(M+H+)。
Example 29: preparation of Compound IXBd
To a mixture of compound ixxb (5g, 11.6mmol, 1eq.) and 2, 6-lutidine (3.44g) was added toluene (50mL) to dissolve it, TBSOTf (5.3g) was added to it at-30 ℃, the reaction was stirred for a further 6h at this temperature, TLC showed complete conversion of starting material, water was added to quench the reaction, and after extraction with ethyl acetate the concentrate was purified by column chromatography to give compound IXBd (5.1 g).
MS(ESI)m/z:546(M+H+)。
1HNMR(400MHz，CDCl3):δ7.65(dd,J＝7.8,1.6Hz,1H),7.16(dd,J＝7.5,1.5Hz,1H),6.77(t,J＝7.8Hz,1H),5.99(dt,J＝5.6,1.6Hz,1H),5.94(dt,J＝5.6,1.6Hz,1H),5.04-4.99(m,1H),4.70-4.65(m,1H),3.64(s,3H),3.17(s,3H),2.88-2.77(m,2H),2.70-2.62(m,1H),2.38(t,J＝6.0Hz,2H),2.01(dt,J＝14.4,3.2Hz,1H),2.05-1.86(m,3H),0.92(s,9H),0.11(s,3H),0.10(s,3H).
Example 30: preparation of Compound IXBe
Tetrahydrofuran (50mL) was added to a mixture of compound IXAc (5g, 12.2mmol, 1eq.) and DMAP (4.9g) to dissolve it, acetic anhydride (2.6g) was added to it at room temperature, the reaction was stirred for 2h at this temperature, TLC showed complete conversion of the starting material, water was added to quench the reaction, and after extraction with ethyl acetate, the concentrate was purified by column chromatography to give compound IXBe (4.8 g).
MS(ESI)m/z:454,456(M+H+)。
Example 31: preparation of Compound IXBf
Tetrahydrofuran (50mL) was added to a mixture of compound IXAg (5g, 9.3mmol, 1eq.) and pyridine (4.3g) to dissolve it, acetic anhydride (2.2g) was added to it at-20 ℃ and the reaction was allowed to continue stirring at this temperature for 2h, TLC showed complete conversion of the starting material, water was added to quench the reaction, and after extraction with ethyl acetate, the concentrate was purified by column chromatography to give compound IXBf (4.6 g).
MS(ESI)m/z:578,580(M+H+)。
Examples 32 to 42 Synthesis of Compounds represented by the formula VIII
Example 32: preparation of Compound VIIIAa
To a mixture of compound IXAa (4g, 10.4mmol, 1eq.), compound X (10.2g) and AIBN (360mg) was added toluene to dissolve (40mL), and after the reaction was stirred at 110 ℃ for 4h, TLC showed complete conversion of the starting material. Cooling to room temperature, adding water to quench the reaction, extracting with ethyl acetate, and purifying the concentrated solution through a column to obtain a compound VIIIAa (2.76 g).
MS(ESI)m/z:346(M+H+)。
1HNMR(400MHz,CDCl3):δ7.03(d,J＝7.5Hz,1H),6.95(d,J＝7.5Hz,1H),6.78(t,J＝7.5Hz,1H),5.98-5.84(m,1H),5.21-5.11(m,3H),4.00(dd,J＝10.2,5.2Hz,1H),3.63(s,3H),3.46(dd,J＝8.6,4.6Hz,1H),3.15(s,3H),2.70-2.54(m,2H),2.48-2.37(m,3H),2.42(t,J＝6.0Hz,2H),2.01(dt,J＝14.4,3.2Hz,1H),1.93-1.80(m,2H).
Example 33: preparation of Compound VIIIAb
Xylene was added to a mixture of compound IXAd (4g, 9.1mmol, 1eq.) compound X (8.8g) and AIBN (299mg) to dissolve (40mL), and after stirring the reaction at 80 ℃ for 5h, TLC showed complete conversion of the starting material. Cooling to room temperature, adding water to quench the reaction, extracting with ethyl acetate, and purifying the concentrated solution through a column to obtain compound VIIIAb (2.86 g).
MS(ESI)m/z:402(M+H+)。
Example 34: preparation of Compound VIIIAc
To a mixture of compound IXAe (4g, 9.1mmol, 1eq.), compound X (8.8g) and AIBN (299mg) was added toluene to dissolve (40mL), and after the reaction was stirred at 100 ℃ for 3h, TLC showed complete conversion of the starting material. Cooling to room temperature, adding water to quench the reaction, extracting with ethyl acetate, and purifying the concentrated solution through a column to obtain a compound VIIIAc (3.2 g).
MS(ESI)m/z:402(M+H+)。
Example 35: preparation of Compound VIIIAd
To a mixture of compound IXAf (4g, 11.3mmol, 1eq.) compound X (12.6g) and AIBN (2.1g) was added toluene to dissolve (40mL), and after the reaction was stirred at 110 ℃ for 12h, TLC showed complete conversion of the starting material. Cooling to room temperature, adding water to quench the reaction, extracting with ethyl acetate, and purifying the concentrated solution through a column to obtain a compound VIIIAd (2.7 g).
MS(ESI)m/z:360(M+H+)。
Example 36: preparation of Compound VIIIAe
To a mixture of compound IXAh (4g, 8.1mmol, 1eq.), compound X (8.9g) and AIBN (720mg) was added toluene to dissolve (40mL), and after the reaction was stirred at 110 ℃ for 2h, TLC showed complete conversion of the starting material. Cooling to room temperature, adding water to quench the reaction, extracting with ethyl acetate, and purifying the concentrated solution through a column to obtain a compound VIIIAe (3.5 g).
MS(ESI)m/z:408(M+H+)。
Example 37: preparation of Compound VIIIBa
To a mixture of compound IXBa (4g, 9.08mmol, 1eq.), compound X (18g) and AIBN (750mg) was added toluene to dissolve (50mL), and after the reaction was stirred at 110 ℃ for 1h, TLC showed complete conversion of the starting material. Cooling to room temperature, adding water to quench the reaction, extracting with ethyl acetate, and purifying the concentrated solution through a column to obtain compound VIIIBa (2.81 g).
MS(ESI)m/z:388(M+H+)。
1HNMR(400MHz,CDCl3):δ6.98(d,J＝7.5Hz,1H),6.94(d,J＝7.5Hz,1H),6.75(t,J＝7.5Hz,1H),5.92-5.80(m,1H),5.27-5.21(m,1H),5.16-5.14(m,1H),5.13-5.10(m,1H),4.93-4.88(m,1H),3.65(s,3H),3.57(dd,J＝8.6,4.2Hz,1H),3.17(s,3H),2.65-2.54(m,2H),2.47(t,J＝6.0Hz,2H),2.45-2.30(m,2H),2.28-2.08(m,3H),1.93-1.80(m,2H),1.66(s,3H).
Example 38: preparation of Compound VIIIBa
Xylene was added to a mixture of compound IXBb (5g, 10.5mmol, 1eq.) compound X (7.98g) and AIBN (286mg) to dissolve (40mL), and after the reaction was stirred at 80 ℃ for 4h, TLC showed complete conversion of the starting material. Cooling to room temperature, adding water to quench the reaction, extracting with ethyl acetate, and purifying the concentrated solution through a column to obtain a compound VIIIBa (2.66 g).
MS(ESI)m/z:388(M+H+)。
1HNMR(400MHz,CDCl3):δ6.98(d,J＝7.5Hz,1H),6.94(d,J＝7.5Hz,1H),6.75(t,J＝7.5Hz,1H),5.92-5.80(m,1H),5.27-5.21(m,1H),5.16-5.14(m,1H),5.13-5.10(m,1H),4.93-4.88(m,1H),3.65(s,3H),3.57(dd,J＝8.6,4.2Hz,1H),3.17(s,3H),2.65-2.54(m,2H),2.47(t,J＝6.0Hz,2H),2.45-2.30(m,2H),2.28-2.08(m,3H),1.93-1.80(m,2H),1.66(s,3H).
Example 39: preparation of Compound VIIIBb
To a mixture of compound IXBc (3.6g, 7.4mmol, 1eq.) compound X (4.88g) and AIBN (605mg) was added tetrahydrofuran to dissolve (36mL) and after the reaction was stirred at 60 ℃ for 6h, TLC showed complete conversion of the starting material. Cooling to room temperature, adding water to quench the reaction, extracting with ethyl acetate, and purifying the concentrated solution through a column to obtain compound VIIIBb (2.59 g).
MS(ESI)m/z:450(M+H+)。
1HNMR(400MHz，CDCl3):δ。
Example 40: preparation of Compound VIIIBc
To a mixture of compound IXBd (3.9g, 7.8mmol, 1eq.) compound X (15.5g) and AIBN (1.28g) was added toluene to dissolve (39mL) and after the reaction was stirred at 110 ℃ for 3h, TLC showed complete conversion of the starting material. Cooling to room temperature, adding water to quench the reaction, extracting with ethyl acetate, and purifying the concentrated solution through a column to obtain compound VIIIBc (2.89 g).
MS(ESI)m/z:460(M+H+)。
1HNMR(400MHz，CDCl3):δ。
Example 41: preparation of Compound VIIIBd
To a mixture of compound IXBe (3.7g, 8.2mmol, 1eq.) compound X (16.3g) and AIBN (790mg) was added toluene to dissolve (37mL) and after the reaction was stirred at 110 ℃ for 2h TLC showed complete conversion of the starting material. Cooling to room temperature, adding water to quench the reaction, extracting with ethyl acetate, and purifying the concentrated solution through a column to obtain compound VIIIBd (2.9 g).
MS(ESI)m/z:416(M+H+)。
Example 42: preparation of Compound VIIIBe
To a mixture of compound IXBf (4g, 6.9mmol, 1eq.), compound X (12.7g) and AIBN (856mg) was added toluene to dissolve (40mL) and after the reaction was stirred at 110 ℃ for 2h, TLC showed complete conversion of the starting material. Cooling to room temperature, adding water to quench the reaction, extracting with ethyl acetate, and purifying the concentrated solution through a column to obtain compound VIIIBe (2.7 g).
MS(ESI)m/z:540(M+H+)。
Examples 43 to 52 are syntheses of Compounds of formula VII
Example 43: preparation of Compound VIIAa
To compound VIIIAa (2.5g, 7.24mmol, 1eq.) and ruthenium catalyst RuHCl (CO) (PPh)3)3(390mg) was added to the mixture and dissolved in toluene (60mL), and after the reaction was stirred at 80 ℃ for 10h, TLC showed complete conversion of the starting material. Cooling to room temperature, adding water to quench the reaction, extracting with ethyl acetate, and purifying the concentrated solution through a column to obtain a compound VIIAa (2.35 g).
MS(ESI)m/z:346(M+H+).
1HNMR(400MHz,CDCl3):δ6.99(d,J＝7.5Hz,1H),6.97(d,J＝7.5Hz,1H),6.76(t,J＝7.5Hz,1H),5.66-5.55(m,1H),5.48-5.39(m,1H),5.14-5.08(m,1H),3.96-3.86(m,1H),3.64(s,3H),3.45(dd,J＝8.2,8.2Hz,1H),3.16(s,3H),2.68-2.55(m,3H),2.44(t,J＝6.0Hz,2H),2.01-1.99(m,3H),1.74(dd,J＝6.4,1.0Hz,2H).
Example 44: preparation of Compound VIIAb
To compound VIIIAb (2.5g, 6.2mmol, 1eq.) and ruthenium catalyst RuHCl (CO) (PPh)3)3(360mg) was added to the mixtureXylene (60mL) was dissolved and after stirring the reaction at 110 ℃ for 2h, TLC showed complete conversion of starting material. After cooling to room temperature, water was added to quench the reaction, and ethyl acetate was used for extraction, the concentrate was purified by column chromatography to obtain compound VIIAb (2.44 g).
MS(ESI)m/z:402(M+H+).
Example 45: preparation of Compound VIIAc
To compound VIIIAc (2.5g, 6.2mmol, 1eq.) and ruthenium catalyst RuHCl (CO) (PPh)3)3(360mg) was dissolved by addition of xylene (60mL), and after stirring the reaction at 110 ℃ for 2h, TLC showed complete conversion of the starting material. Cooling to room temperature, adding water to quench the reaction, extracting with ethyl acetate, and purifying the concentrated solution through a column to obtain a compound VIIAc (2.41 g).
MS(ESI)m/z:402(M+H+).
Example 46: preparation of Compound VIIAd
To compound VIIIAd (2.5g, 7.0mmol, 1eq.) and ruthenium catalyst RuHCl (CO) (PPh)3)3(460mg) was dissolved by addition of toluene (60mL), and after stirring the reaction at 110 ℃ for 1h, TLC showed complete conversion of the starting material. Cooling to room temperature, adding water to quench the reaction, extracting with ethyl acetate, and purifying the concentrated solution through a column to obtain compound VIIAd (2.48 g).
MS(ESI)m/z:360(M+H+).
Example 47: preparation of Compound VIIAe
To compound VIIIAe (2.5g, 6.1mmol, 1eq.) and ruthenium catalyst RuHCl (CO) (PPh)3)3(390mg) was added to the mixture and dissolved in toluene (60mL), and after stirring the reaction at 110 ℃ for 1h, TLC showed complete conversion of the starting material. Cooling to room temperature, adding water to quench the reaction, extracting with ethyl acetate, and purifying the concentrated solution through a column to obtain compound VIIAe (2.48 g).
MS(ESI)m/z:408(M+H+).
Example 48: preparation of Compound VIIBa
To compound VIIIBa (2.5g, 6.4mmol, 1eq.) and ruthenium catalyst RuHCl (CO) (PPh)3)3(315mg) was dissolved by addition of toluene (50mL), and after stirring the reaction at 110 ℃ for 1h, TLC showed complete conversion of the starting material. Cooling to room temperatureThen water is added to quench the reaction, and after ethyl acetate extraction, the concentrated solution is purified by column to obtain compound VIIBa (2.45 g).
MS(ESI)m/z:388(M+H+)。
1HNMR(400MHz,CDCl3):δ6.98(d,J＝7.5Hz,1H),6.96(d,J＝7.5Hz,1H),6.76(t,J＝7.5Hz,1H),5.64-5.53(m,1H),5.45-5.37(m,1H),5.27-5.18(m,1H),4.92-4.84(m,1H),3.65(s,3H),3.58(dd,J＝8.4,5.6Hz,1H),3.17(s,3H),2.79-2.72(m,1H),2.66-2.41(m,5H),1.99-1.88(m,2H),1.76and 1.73(s,3H),1.69-1.66(m,1H).
Example 49: preparation of Compound VIIBb
To compound VIIIBb (2.5g, 5.55mmol, 1eq.) and RhCl3(150mg) was dissolved by adding acetonitrile (60mL), and after stirring the reaction at 90 ℃ for 6h, TLC showed complete conversion of the starting material. Cooling to room temperature, adding water to quench the reaction, extracting with ethyl acetate, and purifying the concentrated solution through a column to obtain compound VIIBb (2.22 g).
MS(ESI)m/z:450(M+H+)。
Example 50: preparation of Compound VIIBc
To compound VIIIBc (2.5g, 5.4mmol, 1eq.) and PdCl2(MeCN)2(180mg) was dissolved by addition of toluene (60mL), and after stirring the reaction at 100 ℃ for 4h, TLC showed complete conversion of the starting material. Cooling to room temperature, adding water to quench the reaction, extracting with ethyl acetate, and purifying the concentrated solution through a column to obtain a compound VIIBc (2.16 g).
MS(ESI)m/z:460(M+H+)。
Example 51: preparation of Compound VIIBd
To compound VIIIBd (2.5g, 6.0mmol, 1eq.) and ruthenium catalyst RuHCl (CO) (PPh)3)3(430mg) was dissolved by addition of toluene (60mL), and after stirring the reaction at 80 ℃ for 16h, TLC showed complete conversion of the starting material. Cooling to room temperature, adding water to quench the reaction, extracting with ethyl acetate, and purifying the concentrated solution through a column to obtain compound VIIBd (2.39 g).
MS(ESI)m/z:416(M+H+)。
Example 52: preparation of Compound VIIBe
To the compound VIIIBe (2.5g, 4.6mmol, 1eq.) and the ruthenium catalyst RuHCl (CO) (PPh)3)3(270mg) was dissolved by adding toluene (60mL), and after the reaction was stirred at 100 ℃ for 2h, TLC showed complete conversion of the starting material. Cooling to room temperature, adding water to quench the reaction, extracting with ethyl acetate, and purifying the concentrated solution through a column to obtain compound VIIBe (2.43 g).
MS(ESI)m/z:540(M+H+)。
Examples 53 to 58 are syntheses of Compounds represented by formula VI
Example 53: preparation of the Compound VIAa
To a solution of compound VIIAa (1.8g, 5.21mmol, 1eq.) in acetone (10mL) and water (2mL) was added potassium osmate (19mg) and NMO (1.06g), the reaction was stirred at 0 ℃ for 16h, TLC showed complete conversion of the starting material. The reaction was quenched with saturated aqueous sodium thiosulfate, extracted with ethyl acetate, and concentrated to give crude compound via (1.82g), which was used in the next reaction without purification.
MS(ESI)m/z:380(M+H+)。
Example 54: preparation of the Compound VIBa
To a solution of compound VIIBa (1.3g, 1eq.) in acetone (30mL) and water (4mL) was added potassium osmate (20mg) and NMO (1.00g), the reaction was stirred at room temperature for 3h, and TLC indicated complete conversion of the starting material. The reaction was quenched with saturated aqueous sodium thiosulfate, extracted with ethyl acetate, and concentrated to give crude compound VIBa (1.3g), which was used in the next reaction without purification.
MS(ESI)m/z:422(M+H+)。
Example 55: preparation of the Compound VIBb
To a solution of compound VIIBb (1.8g, 4.00mmol, 1eq.) in acetonitrile (10mL) and water (10mL) was added ruthenium trichloride (27mg) and NMO (1.7g), the reaction was stirred at 20 ℃ for 16h and TLC showed complete conversion of the starting material. The reaction was quenched with saturated aqueous sodium thiosulfate, extracted with ethyl acetate, and concentrated to give crude compound VIBb (1.7g), which was used in the next reaction without purification.
MS(ESI)m/z:494(M+H+)。
Example 56: preparation of Compound VIBc
To a solution of compound VIIBc (1.9g, 4.13mmol, 1eq.) in tert-butanol (10mL) and water (10mL) was added potassium osmate (18mg) and potassium ferricyanide (2g) and the reaction was stirred at 50 ℃ for 8h, TLC showed complete conversion of the starting material. The reaction was quenched with saturated aqueous sodium thiosulfate, extracted with ethyl acetate, and concentrated to give crude compound VIBc (1.6g), which was used in the next reaction without purification.
MS(ESI)m/z:484(M+H+)。
Example 57: preparation of Compound VIBd
To a solution of compound VIIBd (2.0g, 4.8mmol, 1eq.) in acetone (20mL) and water (5mL) was added potassium osmate (40mg) and NMO (2.5g) and the reaction was stirred at 0 deg.C for 6h, TLC showed complete conversion of the starting material. The reaction was quenched with saturated aqueous sodium thiosulfate, extracted with ethyl acetate and concentrated to give crude compound VIBd (2.06g), which was then reacted without further purification.
MS(ESI)m/z:450(M+H+)。
Example 58: preparation of Compound VIBe
To a solution of compound VIIBe (2.0g, 3.7mmol, 1eq.) in acetone (20mL) and water (5mL) was added potassium osmate (35mg) and NMO (2.0g), the reaction was stirred at 50 ℃ for 1h, TLC showed complete conversion of the starting material. The reaction was quenched with saturated aqueous sodium thiosulfate, extracted with ethyl acetate, and concentrated to give crude compound VIBe (2.1g), which was used in the next reaction without purification.
MS(ESI)m/z:574(M+H+)。
Examples 59 to 72 Synthesis of Compounds represented by formula IV
Example 59: preparation of compound IVAa
To a solution of compound VIBa (1.5g, 3.95mmol, 1eq.) in THF (15mL) and water (15mL) was added sodium periodate (1.69g), the reaction was stirred at 25 ℃ for 2h, TLC showed complete conversion of the starting material, water was added to quench the reaction, and after extraction with ethyl acetate, the crude compound iva a (1.33g) was concentrated and the crude product was directly subjected to the next reaction without purification.
MS(ESI)m/z:334(M+H+)。
1HNMR(400MHz,CDCl3):δ7.02(d,J＝7.5Hz,1H),6.96(d,J＝7.5Hz,1H),6.81(t,J＝7.5Hz,1H),5.30-5.23(m,1H),4.62-4.57(m,1H),4.19(dd,J＝8.4,4.2Hz,1H),3.64(s,3H),3.21-3.08(m,4H),2.76-2.25(m,6H),1.99-1.83(m,2H).
Example 60: preparation of compound IVAa
Ozone was bubbled into a solution of compound VIIAa (1.5g, 4.34mmol, 1eq.) in dichloromethane (15mL) at-70 ℃ and the reaction was stirred for an additional 2h at that temperature and the solution turned blue in color. Triphenylphosphine (2.28g) was added and the reaction stirred at room temperature for 2h, TLC showed complete conversion of the intermediate, water was added to quench the reaction, ethyl acetate was extracted and the concentrate was purified on column to give compound IVAa (1.33 g).
MS(ESI)m/z:334(M+H+)。
1HNMR(400MHz,CDCl3):δ7.02(d,J＝7.5Hz,1H),6.96(d,J＝7.5Hz,1H),6.81(t,J＝7.5Hz,1H),5.30-5.23(m,1H),4.62-4.57(m,1H),4.19(dd,J＝8.4,4.2Hz,1H),3.64(s,3H),3.21-3.08(m,4H),2.76-2.25(m,6H),1.99-1.83(m,2H).
Example 61: preparation of Compound IVAb
Ozone was bubbled into a solution of compound VIIAb (2g, 5.0mmol, 1eq.) in n-heptane (20mL) at-40 ℃ and the reaction was stirred for an additional 1h at that temperature and the solution turned blue in color. Dimethyl sulfide (2.02g) was added and the reaction stirred at room temperature for 4h, TLC showed complete conversion of the intermediate, water was added to quench the reaction, ethyl acetate was extracted and the concentrate was purified by column chromatography to give compound IVAb (1.29 g).
MS(ESI)m/z:390(M+H+)。
Example 62: preparation of the Compound IVAc
Ozone was bubbled into a solution of compound VIIAc (2g, 5.0mmol, 1eq.) in isopropanol (20mL) at-60 ℃ and the reaction was stirred for an additional 1h at that temperature and the solution turned blue in color. Dithiodipropionic acid (2.49g) was added and the reaction stirred at room temperature for 4h, TLC showed complete conversion of the intermediate, water was added to quench the reaction, and after extraction with ethyl acetate, the concentrate was purified by column chromatography to give compound IVAc (1.16 g).
MS(ESI)m/z:390(M+H+)。
Example 63: preparation of Compound IVAd
Ozone was bubbled through a solution of compound viiid (2g, 5.6mmol, 1eq.) in ethyl acetate (20mL) at-50 ℃ and the reaction was stirred for an additional 30min at that temperature and the solution turned blue in color. Triphenylphosphine (2.88g) was added and the reaction stirred at room temperature for 4h, TLC showed complete conversion of the intermediate, water was added to quench the reaction, and after extraction with ethyl acetate, the concentrate was purified on a column to give compound IVAd (1.38 g).
MS(ESI)m/z:348(M+H+)。
Example 64: preparation of the Compound IVAe
A solution of compound VIIAe (2g, 4.9mmol, 1eq.) in dichloromethane (20mL) was sparged with ozone at-50 deg.C and the reaction stirred for an additional 1h at that temperature, the solution turning blue in color. Triphenylphosphine (2.51g) was added and the reaction stirred at 50 ℃ for 1h, TLC showed complete conversion of the intermediate, water was added to quench the reaction, and after extraction with ethyl acetate, the concentrate was purified by column chromatography to give compound IVAe (1.32 g).
MS(ESI)m/z:396(M+H+)。
Example 65: preparation of the Compound IVBa
To a solution of compound VIBa (1.3g, 3.1mmol, 1eq.) in THF (20mL) and water (20mL) was added sodium periodate (1.98g), the reaction was stirred at 25 ℃ for 1h, TLC showed complete conversion of the starting material, water was added to quench the reaction, and after extraction with ethyl acetate, the crude compound IVBa (1.16g) was concentrated and the crude product was directly subjected to the next reaction without purification.
MS(ESI)m/z:376(M+H+)。
1HNMR(400MHz,CDCl3):δ6.98(d,J＝7.5Hz,1H),6.96(d,J＝7.5Hz,1H),6.78(t,J＝7.5Hz,1H),5.40-5.34(m,1H),5.31-5.25(m,1H),4.24(dd,J＝8.2,3.2Hz,1H),3.66(s,3H),3.17(s,3H),2.68-2.55(m,2H),2.53-2.42(m,2H),2.37-2.16(m,2H),2.00-1.86(m,2H),1.68(s,3H).
Example 66: preparation of the Compound IVBa
Ozone was bubbled into a solution of compound VIIBa (1.5g, 3.87mmol, 1eq.) in dichloromethane (15mL) at-78 ℃, and the reaction was stirred for an additional 3h at that temperature, with the solution turning blue in color. Triphenylphosphine (2.03g) was added and the reaction stirred at room temperature for 2h, TLC showed complete conversion of the intermediate, water was added to quench the reaction, ethyl acetate was extracted and the concentrate was purified on a column to give compound IVBa (1.38 g).
MS(ESI)m/z:376(M+H+)。
1HNMR(400MHz,CDCl3):δ6.98(d,J＝7.5Hz,1H),6.96(d,J＝7.5Hz,1H),6.78(t,J＝7.5Hz,1H),5.40-5.34(m,1H),5.31-5.25(m,1H),4.24(dd,J＝8.2,3.2Hz,1H),3.66(s,3H),3.17(s,3H),2.68-2.55(m,2H),2.53-2.42(m,2H),2.37-2.16(m,2H),2.00-1.86(m,2H),1.68(s,3H).
Example 67: preparation of the Compound IVBb
Sodium periodate (2.98g) was added to a solution of compound VIBb (1.2g, 2,48mmol, 1eq.) in tert-butanol (20mL) and water (20mL), the reaction was stirred at 25 ℃ for 6h, TLC showed complete conversion of the starting material, water was added to quench the reaction, ethyl acetate was extracted and concentrated to give crude compound IVBb (1.18g) which was directly subjected to the next reaction without purification.
MS(ESI)m/z:438(M+H+)。
1HNMR(400MHz，CDCl3):δ。
Example 68: preparation of the Compound IVBb
Ozone was bubbled into a solution of compound VIIBb (1.5g, 3.34mmol, 1eq.) in ethyl acetate (15mL) at-40 ℃ and the reaction was stirred for an additional 30min at that temperature and the solution turned blue in color. Zinc powder (1.75g) was added and the reaction stirred at room temperature for 5h, TLC showed complete conversion of the intermediate, quenched with water, extracted with ethyl acetate and the concentrate was purified on column to give compound IVBb (1.33 g).
MS(ESI)m/z:438(M+H+)。
Example 69: preparation of Compound IVBc
To a solution of compound VIBc (1.2g, 2.43mmol, 1eq.) in methanol (16mL) and water (4mL) was added sodium periodate (1.04g), the reaction was stirred at 25 ℃ for 3h, TLC showed complete conversion of the starting material, water was added to quench the reaction, the reaction was extracted with ethyl acetate, and the concentrate was purified by column chromatography to give compound IVBc (1.02 g).
MS(ESI)m/z:448(M+H+)。
Example 70: preparation of Compound IVBc
Ozone was bubbled into a solution of compound VIIBc (1.5g, 3.26mmol, 1eq.) in n-heptane (15mL) at-60 ℃ and the reaction was stirred for an additional 1h at that temperature and the solution turned blue in color. Triphenylphosphine (1.71g) was added and the reaction stirred at room temperature for 1h, TLC showed complete conversion of the intermediate, water was added to quench the reaction, ethyl acetate was extracted and the concentrate was purified on a column to give compound IVBc (1.29 g).
MS(ESI)m/z:448(M+H+)。
Example 71: preparation of Compound IVBd
To a solution of compound VIBd (2g, 4.4mmol, 1eq.) in THF (20mL) and water (20mL) was added sodium periodate (1.9g), the reaction was stirred at 0 ℃ for 4h, TLC showed complete conversion of the starting material, water was added to quench the reaction, and after extraction with ethyl acetate, the crude compound IVBd was concentrated and the crude product was directly subjected to the next reaction without purification.
MS(ESI)m/z:404(M+H+)。
Example 72: preparation of compound IVBe
To a solution of compound VIBe (2g, 3.5mmol, 1eq.) in THF (20mL) and water (20mL) was added sodium periodate (1.7g), the reaction was stirred at 30 ℃ for 2h, TLC showed complete conversion of the starting material, water was added to quench the reaction, after extraction with ethyl acetate, concentrated to give crude compound IVBe, which was directly subjected to the next reaction without purification.
MS(ESI)m/z:528(M+H+)。
Examples 73 to 82 Synthesis of Compounds represented by the formula III
Example 73: preparation of Compound IIIAa
To a mixture of compound IVAa (1g, 3mmol, 1eq.) and compound Va (1.39g) was added acetonitrile (20mL) to dissolve, lithium chloride (254mg) and triethylamine (776mg) were added at-20 deg.C, and the reaction was stirred at 0 deg.C for 8 h. TLC showed complete conversion of the starting material, saturated ammonium chloride was added to quench the reaction, and after extraction with ethyl acetate, the concentrate was purified by column chromatography to give Compound IIIAa (1.04 g).
MS(ESI)m/z:440(M+H+)。
1HNMR(400MHz,CDCl3):δ6.99(d,J＝7.5Hz,1H),6.96(d,J＝7.5Hz,1H),6.89(dd,J＝16.0,8.8Hz,1H),6.78(t,J＝7.5Hz,1H),6.34(d,J＝16.0Hz,1H),5.22-5.13(m,1H),4.16-4.07(m,1H),3.65(s,3H),3.63-3.56(m,1H),3.16(s,3H),2.75-2.11(m,8H),2.00-1.74(m,4H),1.20(d,J＝7.2Hz,3H),1.19(s,3H).
Example 74: preparation of Compound IIIAb
To a mixture of compound IVAB (1g, 2.6mmol, 1eq.) and compound Va (1.75g) was added acetonitrile (20mL) to dissolve, lithium chloride (380mg) and pyridine (750mg) were added at-20 ℃ and the reaction stirred at 0 ℃ for 16 h. TLC showed complete conversion of the starting material, and after quenching the reaction with saturated ammonium chloride and extraction with ethyl acetate, the concentrate was purified by column chromatography to give compound IIIAb (1.17 g).
MS(ESI)m/z:496(M+H+)。
Example 75: preparation of Compound IIIAc
To a mixture of compound IVAc (1g, 2.6mmol, 1eq.) and compound Va (1.75g) was added tetrahydrofuran (20mL) to dissolve, lithium chloride (380mg) and diisopropylethylamine (770mg) were added at-20 deg.C, and the reaction was stirred at 50 deg.C for 5 h. TLC showed complete conversion of the starting material, and saturated ammonium chloride was added to quench the reaction, which was then extracted with ethyl acetate and the concentrate was purified by column chromatography to give compound IIIAc (1.11 g).
MS(ESI)m/z:496(M+H+)。
Example 76: preparation of Compound IIIAd
To a mixture of compound IVAd (1g, 2.9mmol, 1eq.) and compound Va (1.82g) was added tetrahydrofuran (20mL) to dissolve, and at 0 deg.C, lithium chloride (460mg) and diisopropylethylamine (910mg) were added and the reaction stirred at 40 deg.C for 3 h. TLC showed complete conversion of the starting material, and after quenching with saturated ammonium chloride, extraction with ethyl acetate, the concentrate was purified on a column to give Compound IIIAd (1.29 g).
MS(ESI)m/z:454(M+H+)。
Example 77: preparation of Compound IIIAe
To a mixture of compound IVAe (1g, 2.5mmol, 1eq.) and compound Va (1.63g) was added tetrahydrofuran (20mL) to dissolve, and at 30 deg.C, lithium chloride (388mg) and diisopropylethylamine (815mg) were added and the reaction stirred at 30 deg.C for 6 h. TLC showed complete conversion of the starting material, and saturated ammonium chloride was added to quench the reaction, which was then extracted with ethyl acetate and the concentrate was purified by column chromatography to give compound IIIAe (1.18 g).
MS(ESI)m/z:502(M+H+)。
Example 78: preparation of the Compound IIIBa
To a mixture of compound IVBa (1.16g, 3.1mmol, 1eq.) and compound Va (1.08g) was added acetonitrile (50mL) to dissolve, under ice-water bath, lithium chloride (1.31g) and diisopropylethylamine (1.20g) were added, and the reaction was stirred at room temperature for 4 h. TLC showed complete conversion of the starting material, saturated ammonium chloride was added to quench the reaction, and after extraction with ethyl acetate, the concentrate was purified by column chromatography to give compound IIIBa (970 mg).
MS(ESI)m/z:482(M+H+)。
1HNMR(400MHz,CDCl3):δ6.99(d,J＝7.5Hz,1H),6.95(d,J＝7.5Hz,1H),6.83(dd,J＝15.6,8.0Hz,1H),6.77(t,J＝7.5Hz,1H),6.29(dd,J＝15.6,5.0Hz,1H),5.27-5.20(m,1H),5.05-4.97(m,1H),3.72-3.61(m,4H),3.17(s,3H),3.00-2.86(m,2H),2.70-2.56(m,3H),2.52-2.41(m,3H),2.31-2.22(m,1H),2.18-2.10(m,1H),2.00-1.88(m,2H),1.86-1.74(m,5H),1.21(d,J＝7.2Hz,3H),1.19(s,3H).
Example 79: preparation of Compound IIIBb
To a mixture of compound IVBb (1g, 2.29mmol, 1eq.) and compound Vb (1.06g) was added dimethyl sulfoxide (20mL) to dissolve, pyridine (885mg) was added at 25 ℃, and the reaction was stirred at 50 ℃ for 1 h. TLC showed complete conversion of the starting material, saturated ammonium chloride was added to quench the reaction, and after extraction with ethyl acetate, the concentrate was purified by column chromatography to give compound IIIBb (0.93 g).
MS(ESI)m/z:544(M+H+)。
Example 80: preparation of Compound IIIBc
To a mixture of compound IVBc (1g, 2.23mmol, 1eq.) and compound Va (1.04g) was added tetrahydrofuran (20mL) to dissolve, and at 0 deg.C, lithium chloride (968mg) and potassium carbonate (620mg) were added and the reaction stirred at 30 deg.C for 16 h. TLC showed complete conversion of the starting material, saturated ammonium chloride was added to quench the reaction, and after extraction with ethyl acetate, the concentrate was purified by column chromatography to give Compound IIIBc (1.11 g).
MS(ESI)m/z:554(M+H+)。
Example 81: preparation of Compound IIIBd
To a mixture of compound IVBd (1g, 2.5mmol, 1eq.) and compound Va (1.88g) was added tetrahydrofuran (20mL) to dissolve, and at 0 deg.C, lithium chloride (389mg) and 2, 6-lutidine (720mg) were added and the reaction stirred at 30 deg.C for 6 h. TLC showed complete conversion of the starting material, saturated ammonium chloride was added to quench the reaction, and after extraction with ethyl acetate, the concentrate was purified by column chromatography to give compound IIIBd (1.18 g).
MS(ESI)m/z:510(M+H+)。
Example 82: preparation of Compound IIIBe
To a mixture of compound IVBe (1g, 1.9mmol, 1eq.) and compound Va (1.45g) was added tetrahydrofuran (20mL) to dissolve, and at 0 deg.C, lithium chloride (270mg) and triethylamine (680mg) were added and the reaction stirred at 20 deg.C for 8 h. TLC showed complete conversion of the starting material, and after quenching with saturated ammonium chloride, extraction with ethyl acetate, the concentrate was purified by column chromatography to give Compound IIIBe (1.33 g).
MS(ESI)m/z:634(M+H+)。
Examples 83 to 97 Synthesis of Compounds represented by the formula II
Example 83: preparation of the Compound IIBa
Under an ice-water bath, adding cerium trichloride (460mg) and sodium borohydride (110mg) into a methanol (50mL) solution of a compound IIIBa (900mg, 1.87mmol), stirring the reaction for 2 hours under the ice-water bath, performing TLC to show that the raw material is completely converted, adding saturated sodium bicarbonate to quench the reaction, extracting the reaction by ethyl acetate, and performing column purification on the concentrated solution to obtain a compound IIBa (900 mg).
MS(ESI)m/z:484(M+H+)。
1HNMR(400MHz,CDCl3):δ7.00-6.93(m,2H),6.76(t,J＝7.5Hz,1H),5.75-5.56(m,2H),5.25-5.17(m,1H),4.96-4.88(m,1H),4.26-4.18(m,0.5H),4.09-4.02(m,0.5H),3.65(s,3H),3.63-3.58(m,1H),3.17(s,3H),2.84-2.77(m,1H),2.65-2.56(m,3H),2.52-2.42(m,2H),2.30-2.18(m,1H),2.15-2.06(m,1H),2.00-1.89(m,2H),1.86-1.73(m,8H),1.02-0.94(m,3H).
Example 84: preparation of the Compound IIBb
Under an ice-water bath, adding cerous chloride (544mg) and sodium borohydride (83mg) into an isopropanol (10mL) solution of a compound IIIBb (800mg, 1.47mmol), reacting at 30 ℃, stirring for 30min, TLC shows that the raw material is completely converted, adding saturated sodium bicarbonate to quench the reaction, extracting with ethyl acetate, and purifying the concentrated solution through a column to obtain a compound IIBb (781 mg).
MS(ESI)m/z:546(M+H+)。
Example 85: preparation of Compound IIBc
After adding a solution of compound IIIBc (800mg, 1.44mmol) in dichloromethane (10mL) at-78 ℃ to a solution of compound IIIBc (800mg, 1.44mmol) in n-hexane (1.0M, 1.44mL) and stirring the reaction at-78 ℃ for 16H, TLC indicated complete conversion of the starting material, saturated sodium bicarbonate was added to quench the reaction, ethyl acetate extraction was performed and the concentrate was purified by column chromatography to give compound IIBc (632 mg).
MS(ESI)m/z:556(M+H+)。
Example 86: preparation of the Compound IIBd
Adding cerous chloride (450mg) and sodium borohydride (100mg) into an ethanol (40mL) solution of a compound IIIBd (900mg, 1.77mmol) at the temperature of minus 30 ℃, stirring for 4 hours at the temperature of minus 30 ℃, then TLC shows that the raw material is completely converted, adding saturated sodium bicarbonate to quench the reaction, extracting with ethyl acetate, and then passing the concentrated solution through a column to purify to obtain a compound IIBd (890 mg).
MS(ESI)m/z:512(M+H+)。
Example 87: preparation of the Compound IIBe
Cerium trichloride (416mg) and sodium borohydride (92mg) were added to a solution of compound IIIBe (900mg, 1.42mmol) in methanol (40mL) at-10 ℃, the reaction was stirred at-10 ℃ for 2h, TLC showed complete conversion of the starting material, saturated sodium bicarbonate was added to quench the reaction, ethyl acetate was extracted, and the concentrate was purified by column chromatography to give compound IIBe (885 mg).
MS(ESI)m/z:636(M+H+)。
Example 88: preparation of compound IIAa
Under an ice-water bath, cerous chloride (756mg) and sodium borohydride (116mg) are added into an isopropanol (10mL) solution of a compound IIIAa (900mg, 2.05mmol), the reaction is stirred at 50 ℃ for 2 hours, TLC shows that the raw material is completely converted, saturated sodium bicarbonate is added to quench the reaction, and after ethyl acetate extraction, the concentrated solution passes through a column to be purified to obtain a compound IIAa (440 mg).
MS(ESI)m/z:442(M+H+)。
1HNMR(400MHz,CDCl3):δ7.00-6.90(m,2H),6.75(td,J＝7.5,3.0Hz,1H),5.77-5.52(m,2H),5.17-5.02(m,1H),4.18-4.12(m,0.5H),4.06-3.99(m,0.5H),3.97-3.85(m,1H),3.65(s,3H),3.48-3.39(m,1H),3.16(s,3H),2.70-2.56(m,3H),2.49-2.36(m,3H),2.31-2.21(m,1H),2.14-1.86(m,5H),1.82-1.71(m,4H),1.02and 0.98(d,J＝6.8Hz,3H).
Example 89: preparation of compound IIAa
To a solution of compound IIBa (700mg, 1.44mmol) in methanol (50mL) was added 30% sodium hydroxide (10mL), and after the reaction was stirred at room temperature for 10min, TLC showed complete conversion of the starting material. 1N hydrochloric acid was added to quench the reaction, and after extraction with ethyl acetate, the concentrate was purified by column chromatography to give compound IIAa (270 mg).
MS(ESI)m/z:442(M+H+)。
1HNMR(400MHz,CDCl3):δ7.00-6.90(m,2H),6.75(td,J＝7.5,3.0Hz,1H),5.77-5.52(m,2H),5.17-5.02(m,1H),4.18-4.12(m,0.5H),4.06-3.99(m,0.5H),3.97-3.85(m,1H),3.65(s,3H),3.48-3.39(m,1H),3.16(s,3H),2.70-2.56(m,3H),2.49-2.36(m,3H),2.31-2.21(m,1H),2.14-1.86(m,5H),1.82-1.71(m,4H),1.02and 0.98(d,J＝6.8Hz,3H).
Example 90: preparation of compound IIAa
To a solution of compound IIBb (500mg, 0.92mmol, 1eq.) in dimethylsulfoxide (20mL) was added potassium carbonate (253mg) and after stirring the reaction at 50 ℃ for 6h, TLC showed complete conversion of the starting material. 1N hydrochloric acid was added to quench the reaction, and after extraction with ethyl acetate, the concentrate was purified by column chromatography to give compound IIAa (230 mg).
MS(ESI)m/z:442(M+H+)。
1HNMR(400MHz,CDCl3):δ7.00-6.90(m,2H),6.75(td,J＝7.5,3.0Hz,1H),5.77-5.52(m,2H),5.17-5.02(m,1H),4.18-4.12(m,0.5H),4.06-3.99(m,0.5H),3.97-3.85(m,1H),3.65(s,3H),3.48-3.39(m,1H),3.16(s,3H),2.70-2.56(m,3H),2.49-2.36(m,3H),2.31-2.21(m,1H),2.14-1.86(m,5H),1.82-1.71(m,4H),1.02and 0.98(d,J＝6.8Hz,3H).
Example 91: preparation of compound IIAa
To a solution of compound IIBc (500mg, 0.90mmol, 1eq.) in methanol (20mL) was added a solution of hydrochloric acid (3.0M, 1.8mL) and the reaction was stirred at 30 ℃ for 4h, after which TLC showed complete conversion of the starting material. The reaction was quenched by addition of saturated aqueous sodium bicarbonate, extracted with ethyl acetate, and the concentrate was purified by column chromatography to give compound IIAa (210 mg).
MS(ESI)m/z:442(M+H+)。
1HNMR(400MHz,CDCl3):δ7.00-6.90(m,2H),6.75(td,J＝7.5,3.0Hz,1H),5.77-5.52(m,2H),5.17-5.02(m,1H),4.18-4.12(m,0.5H),4.06-3.99(m,0.5H),3.97-3.85(m,1H),3.65(s,3H),3.48-3.39(m,1H),3.16(s,3H),2.70-2.56(m,3H),2.49-2.36(m,3H),2.31-2.21(m,1H),2.14-1.86(m,5H),1.82-1.71(m,4H),1.02and 0.98(d,J＝6.8Hz,3H).
Example 92: preparation of Compound IIAb
To a solution of compound IIBd (800mg, 1.56mmol, 1eq.) in ethanol (20mL) was added potassium carbonate (278mg) and after stirring the reaction at 30 ℃ for 2h, TLC showed complete conversion of the starting material. The reaction was quenched by addition of 1N hydrochloric acid, extracted with ethyl acetate, and the concentrate was purified by column chromatography to give compound IIAb (380 mg).
MS(ESI)m/z:498(M+H+)。
Example 93: preparation of the Compound IIAc
Cerium trichloride (722mg) and sodium borohydride (108mg) were added to a solution of compound IIIAb (800mg, 1.62mmol, 1eq.) in tert-butanol (30mL) in an ice-water bath, the reaction was stirred at 10 ℃ for 3 hours, TLC showed complete conversion of the starting material, saturated sodium bicarbonate was added to quench the reaction, ethyl acetate was extracted, and the concentrate was purified by column chromatography to give compound IIAc (393 mg).
MS(ESI)m/z:498(M+H+)。
Example 94: preparation of Compound IIAd
Cerium trichloride (722mg) and sodium borohydride (108mg) were added to a solution of compound IIIAc (800mg, 1.62mmol, 1eq.) in methanol (30mL) in an ice-water bath, the reaction was stirred at 0 ℃ for 2 hours, TLC showed complete conversion of the starting material, saturated sodium bicarbonate was added to quench the reaction, ethyl acetate was extracted, and the concentrate was purified by column chromatography to give compound IIAd (366 mg).
MS(ESI)m/z:498(M+H+)。
Example 95: preparation of the Compound IIAe
Cerium trichloride (760mg) and sodium borohydride (110mg) were added to a solution of compound IIIAd (800mg, 1.77mmol, 1eq.) in methanol (30mL) in an ice-water bath, the reaction was stirred at 10 ℃ for 1 hour, TLC showed complete conversion of the starting material, saturated sodium bicarbonate was added to quench the reaction, ethyl acetate was extracted, and the concentrate was purified by column chromatography to give compound IIAe (385 mg).
MS(ESI)m/z:456(M+H+)。
Example 96: preparation of the Compound IIAf
To a solution of compound IIBe (800mg, 1.26mmol) in methanol (40mL) was added 10% sodium hydroxide (10mL) and after stirring the reaction at-20 ℃ for 2h, TLC showed complete conversion of the starting material. The reaction was quenched by addition of 1N hydrochloric acid, extracted with ethyl acetate, and the concentrate was purified by column chromatography to give compound IIAf (370 mg).
MS(ESI)m/z:594(M+H+)。
Example 97: preparation of the Compound IIAg
Cerium trichloride (710mg) and sodium borohydride (110mg) were added to a methanol (30mL) solution of compound IIIAe (800mg, 1.59mmol, 1eq.) in an ice-water bath, the reaction was stirred at 20 ℃ for 30min, TLC showed complete conversion of the starting material, saturated sodium bicarbonate was added to quench the reaction, ethyl acetate was extracted, and the concentrate was purified by column chromatography to give compound IIAg (390 mg).
MS(ESI)m/z:504(M+H+)。
Examples 98 to 106 are syntheses of Compounds of formula I
Example 98: preparation of Compound I
To a solution of compound IIAa (300mg, 0.62mmol) in methanol (40mL) was added 30% aqueous sodium hydroxide (10mL), and after the reaction was stirred at room temperature for 16h, TLC showed complete conversion of the starting material. The reaction was quenched by addition of 1N hydrochloric acid, extracted with ethyl acetate, and the concentrate was purified by column chromatography to give Compound I (240 mg).
MS(ESI)m/z:399(M+H+)。
1HNMR(400MHz,CDCl3):δ6.99-6.90(m,2H),6.75(td,J＝7.5,3.0Hz,1H),5.73-5.50(m,2H),5.13-5.02(m,1H),4.13(dd,J＝7.5,7.5Hz,0.5H),4.02(dd,J＝7.5,7.5Hz,0.5H),3.93-3.83(m,1H),3.44-3.36(m,1H),2.70-2.53(m,3H),2.44-2.20(m,5H),2.13-1.86(m,4H),1.82-1.72(m,4H),1.02and 0.98(d,J＝6.8Hz,3H).
Example 99: preparation of Compound I
To a solution of compound IIAb (300mg, 0.64mmol) in ethanol (20mL) was added 10% aqueous sodium hydroxide (5mL), and after the reaction was stirred at 60 ℃ for 5h, TLC showed complete conversion of the starting material. The reaction was quenched by addition of 1N hydrochloric acid, extracted with ethyl acetate, and the concentrate was purified by column chromatography to give Compound I (240 mg).
MS(ESI)m/z:399(M+H+)。
1HNMR(400MHz,CDCl3):δ6.99-6.90(m,2H),6.75(td,J＝7.5,3.0Hz,1H),5.73-5.50(m,2H),5.13-5.02(m,1H),4.13(dd,J＝7.5,7.5Hz,0.5H),4.02(dd,J＝7.5,7.5Hz,0.5H),3.93-3.83(m,1H),3.44-3.36(m,1H),2.70-2.53(m,3H),2.44-2.20(m,5H),2.13-1.86(m,4H),1.82-1.72(m,4H),1.02and 0.98(d,J＝6.8Hz,3H).
Example 100: preparation of Compound I
To a solution of compound IIAc (300mg, 0.60mmol) in ethanol (20mL) was added 20% aqueous sodium hydroxide (5mL) and the reaction was stirred at 60 ℃ for 4h, after which TLC indicated complete conversion of the starting material. 1N hydrochloric acid was added to quench the reaction, and after extraction with ethyl acetate, the concentrate was purified by column chromatography to give Compound I (233 mg).
MS(ESI)m/z:399(M+H+)。
1HNMR(400MHz,CDCl3):δ6.99-6.90(m,2H),6.75(td,J＝7.5,3.0Hz,1H),5.73-5.50(m,2H),5.13-5.02(m,1H),4.13(dd,J＝7.5,7.5Hz,0.5H),4.02(dd,J＝7.5,7.5Hz,0.5H),3.93-3.83(m,1H),3.44-3.36(m,1H),2.70-2.53(m,3H),2.44-2.20(m,5H),2.13-1.86(m,4H),1.82-1.72(m,4H),1.02and 0.98(d,J＝6.8Hz,3H).
Example 101: preparation of Compound I
To a solution of compound IIAd (300mg, 0.60mmol) in ethanol (20mL) was added 30% aqueous sodium hydroxide (5mL), and after stirring the reaction at 80 ℃ for 2h, TLC showed complete conversion of the starting material. 1N hydrochloric acid was added to quench the reaction, and after extraction with ethyl acetate, the concentrate was purified by column chromatography to give Compound I (228 mg).
MS(ESI)m/z:399(M+H+)。
1HNMR(400MHz,CDCl3):δ6.99-6.90(m,2H),6.75(td,J＝7.5,3.0Hz,1H),5.73-5.50(m,2H),5.13-5.02(m,1H),4.13(dd,J＝7.5,7.5Hz,0.5H),4.02(dd,J＝7.5,7.5Hz,0.5H),3.93-3.83(m,1H),3.44-3.36(m,1H),2.70-2.53(m,3H),2.44-2.20(m,5H),2.13-1.86(m,4H),1.82-1.72(m,4H),1.02and 0.98(d,J＝6.8Hz,3H).
Example 102: preparation of Compound I
To a solution of compound IIAe (300mg, 0.66mmol) in t-butanol (20mL) was added 40% aqueous lithium hydroxide (5mL) and the reaction was stirred at 70 ℃ for 8h, after which TLC indicated complete conversion of the starting material. The reaction was quenched by addition of 1N hydrochloric acid, extracted with ethyl acetate, and the concentrate was purified by column chromatography to give Compound I (260 mg).
MS(ESI)m/z:399(M+H+)。
1HNMR(400MHz,CDCl3):δ6.99-6.90(m,2H),6.75(td,J＝7.5,3.0Hz,1H),5.73-5.50(m,2H),5.13-5.02(m,1H),4.13(dd,J＝7.5,7.5Hz,0.5H),4.02(dd,J＝7.5,7.5Hz,0.5H),3.93-3.83(m,1H),3.44-3.36(m,1H),2.70-2.53(m,3H),2.44-2.20(m,5H),2.13-1.86(m,4H),1.82-1.72(m,4H),1.02and 0.98(d,J＝6.8Hz,3H).
Example 103: preparation of Compound I
To a solution of compound IIAf (300mg, 0.51mmol) in N, N-dimethylformamide (20mL) was added 50% aqueous potassium hydroxide (5mL) and the reaction was stirred at 60 ℃ for 4h, after which TLC indicated complete conversion of the starting material. 1N hydrochloric acid was added to quench the reaction, and after extraction with ethyl acetate, the concentrate was purified by column chromatography to give Compound I (188 mg).
MS(ESI)m/z:399(M+H+)。
1HNMR(400MHz,CDCl3):δ6.99-6.90(m,2H),6.75(td,J＝7.5,3.0Hz,1H),5.73-5.50(m,2H),5.13-5.02(m,1H),4.13(dd,J＝7.5,7.5Hz,0.5H),4.02(dd,J＝7.5,7.5Hz,0.5H),3.93-3.83(m,1H),3.44-3.36(m,1H),2.70-2.53(m,3H),2.44-2.20(m,5H),2.13-1.86(m,4H),1.82-1.72(m,4H),1.02and 0.98(d,J＝6.8Hz,3H).
Example 104: preparation of Compound I
To a solution of compound IIAg (300mg, 0.59mmol, 1eq.) in isopropanol (20mL) was added 20% aqueous sodium carbonate (5mL) and after stirring the reaction at 50 ℃ for 9h, TLC showed complete conversion of the starting material. The reaction was quenched by addition of 1N hydrochloric acid, extracted with ethyl acetate, and the concentrate was purified by column chromatography to give Compound I (219 mg).
MS(ESI)m/z:399(M+H+)。
1HNMR(400MHz,CDCl3):δ6.99-6.90(m,2H),6.75(td,J＝7.5,3.0Hz,1H),5.73-5.50(m,2H),5.13-5.02(m,1H),4.13(dd,J＝7.5,7.5Hz,0.5H),4.02(dd,J＝7.5,7.5Hz,0.5H),3.93-3.83(m,1H),3.44-3.36(m,1H),2.70-2.53(m,3H),2.44-2.20(m,5H),2.13-1.86(m,4H),1.82-1.72(m,4H),1.02and 0.98(d,J＝6.8Hz,3H).
Example 105: preparation of Compound I
To a solution of compound IIBa (400mg, 0.82mmol) in isopropanol (4mL) was added 60% potassium hydroxide (2mL) and after stirring the reaction at 0 ℃ for 12h, TLC showed complete conversion of the starting material. The reaction was quenched by addition of 1N hydrochloric acid, extracted with ethyl acetate, and the concentrate was purified by column chromatography to give Compound I (166 mg).
MS(ESI)m/z:399(M+H+)。
1HNMR(400MHz,CDCl3):δ6.99-6.90(m,2H),6.75(td,J＝7.5,3.0Hz,1H),5.73-5.50(m,2H),5.13-5.02(m,1H),4.13(dd,J＝7.5,7.5Hz,0.5H),4.02(dd,J＝7.5,7.5Hz,0.5H),3.93-3.83(m,1H),3.44-3.36(m,1H),2.70-2.53(m,3H),2.44-2.20(m,5H),2.13-1.86(m,4H),1.82-1.72(m,4H),1.02and 0.98(d,J＝6.8Hz,3H).
Example 106: preparation of Compound I
To a solution of compound IIBb (400mg, 0.74mmol) in dimethylsulfoxide (4mL) was added potassium carbonate (100mg), and after the reaction was stirred at 100 ℃ for 24h, TLC showed complete conversion of the starting material. The reaction was quenched by addition of 1N hydrochloric acid, extracted with ethyl acetate, and the concentrate was purified by column chromatography to give Compound I (152 mg).
MS(ESI)m/z:399(M+H+)。
1HNMR(400MHz,CDCl3):δ6.99-6.90(m,2H),6.75(td,J＝7.5,3.0Hz,1H),5.73-5.50(m,2H),5.13-5.02(m,1H),4.13(dd,J＝7.5,7.5Hz,0.5H),4.02(dd,J＝7.5,7.5Hz,0.5H),3.93-3.83(m,1H),3.44-3.36(m,1H),2.70-2.53(m,3H),2.44-2.20(m,5H),2.13-1.86(m,4H),1.82-1.72(m,4H),1.02and 0.98(d,J＝6.8Hz,3H).
Since the present invention has been described in terms of specific embodiments thereof, certain modifications and equivalent variations will be apparent to those of ordinary skill in the art and are intended to be included within the scope of the present invention.

Claims (19)

1. A compound shown as a formula II in the specification,
Figure FDA0002417047490000011
wherein R is1Is hydrogen or a hydroxy protecting group;
R2and R3Independently selected from C1-C6Alkyl or aryl.
2. The compound of formula II according to claim 1, wherein R is1Is hydrogen or a hydroxy protecting group; r2And R3Independently a methyl group.
3. A method for preparing beraprost shown as a formula I and salts thereof is characterized in that: comprises the following steps of carrying out hydrolysis reaction on a compound shown as a formula II to obtain a compound shown as a formula I,
Figure FDA0002417047490000012
wherein R is1Is hydrogen or a hydroxy protecting group;
R2and R3Independently selected from C1-C6Alkyl or aryl.
4. A process for the preparation of a compound of formula IIA as claimed in claim 1, wherein: comprises the following steps of carrying out deprotection reaction on a compound shown as a formula IIB to obtain a compound shown as a formula IIA,
Figure FDA0002417047490000013
wherein R is4Is a hydroxy protecting group;
R2and R3Independently selected from C1-C6Alkyl or aryl.
5. A process for the preparation of a compound of formula II according to claim 1, wherein: comprises the following steps of carrying out reduction reaction on a compound shown as a formula III to obtain a compound shown as a formula II,
Figure FDA0002417047490000021
wherein R is1Is hydrogen or a hydroxy protecting group;
R2and R3Independently selected from C1-C6Alkyl or aryl.
6. A compound of formula III, IV, VI, VII, VIII, IX or XI:
Figure FDA0002417047490000022
wherein R is1Is hydrogen orA hydroxy protecting group;
R2and R3Independently selected from C1-C6An alkyl or aryl group;
x is halogen or a leaving group.
7. A compound of formula III, IV, VI, VII, VIII, IX or XI according to claim 6 wherein R is1Is hydrogen or a hydroxy protecting group; r2And R3Independently is methyl; x is bromine or iodine.
8. A process for the preparation of a compound of formula III according to claim 6, wherein: the method comprises the following steps of reacting a compound shown as a formula IV with a compound shown as a formula V through Horner-Wadsworth-Emmons reaction (HWE) to obtain a compound shown as a formula III;
Figure FDA0002417047490000031
wherein R is1Is hydrogen or a hydroxy protecting group;
R2and R3Independently selected from C1-C6An alkyl or aryl group;
R5is C1-C6An alkyl group.
9. A process for the preparation of a compound of formula IV according to claim 6, which is process a or process B;
the method A comprises the following steps: the method comprises the following steps of carrying out ozonization reaction on a compound shown as a formula VII to obtain a compound shown as a formula IV;
Figure FDA0002417047490000032
the method B comprises the following steps: comprises the following steps of (a) carrying out,
1) carrying out dihydroxylation reaction on the compound shown as the formula VII to obtain a compound shown as the formula VI;
2) carrying out oxidation reaction on the compound shown as the formula VI to obtain the compound shown as the formula IV;
Figure FDA0002417047490000033
wherein R is1Is hydrogen or a hydroxy protecting group;
R2and R3Independently selected from C1-C6Alkyl or aryl.
10. A process for the preparation of a compound of formula VI according to claim 6, wherein: the method comprises the following steps of carrying out dihydroxylation reaction on a compound shown as a formula VII to obtain the compound shown as a formula VI;
Figure FDA0002417047490000041
wherein R is1Is hydrogen or a hydroxy protecting group;
R2and R3Independently selected from C1-C6Alkyl or aryl.
11. A process for the preparation of a compound of formula VII as claimed in claim 6, wherein: the method comprises the following steps of carrying out double bond shift reaction on a compound shown as a formula VIII to obtain the compound shown as a formula VII;
Figure FDA0002417047490000042
wherein R is1Is hydrogen or a hydroxy protecting group;
R2and R3Independently selected from C1-C6Alkyl or aryl.
12. A process for the preparation of a compound of formula VIII according to claim 6, wherein: the method comprises the following steps of carrying out cyclization reaction on a compound shown as a formula IX to obtain the compound shown as a formula VIII;
Figure FDA0002417047490000043
wherein R is1Is hydrogen or a hydroxy protecting group;
R2and R3Independently selected from C1-C6An alkyl or aryl group;
x is halogen or a leaving group.
13. A process for the preparation of a compound of formula IXA according to claim 6 wherein: the method comprises the following steps of carrying out coupling reaction on a compound shown as a formula XI and a compound shown as a formula XII to obtain the compound shown as a formula IXA;
Figure FDA0002417047490000051
wherein R is2And R3Independently selected from C1-C6An alkyl or aryl group;
x is halogen or a leaving group.
14. A process for the preparation of a compound of formula IXB, as claimed in claim 6, wherein: the method comprises the following steps of carrying out hydroxyl protection reaction on a compound shown as a formula IXA to obtain the compound shown as the formula IXB;
Figure FDA0002417047490000052
wherein R is2And R3Independently selected from C1-C6An alkyl or aryl group;
R4is a hydroxyl protecting group.
15. A process for the preparation of a compound of formula XI according to claim 6, wherein: which is method C or method D;
the method C comprises the following steps: comprises the following steps of (a) carrying out,
1) carrying out Bayer-Villiger oxidation reaction on the compound shown in the formula XVI to obtain a compound shown in a formula XV;
2) carrying out ring-opening reaction on a compound shown as a formula XV and N, O-disubstituted hydroxylamine or salt thereof to obtain a compound shown as a formula XIII;
3) performing halogenation reaction on a compound shown in a formula XIII to obtain a compound shown in a formula XI;
Figure FDA0002417047490000053
the method D comprises the following steps: comprises the following steps of (a) carrying out,
1) carrying out Bayer-Villiger oxidation reaction on the compound shown in the formula XVII to obtain a compound shown in a formula XIV;
2) carrying out a ring-opening reaction on a compound shown as a formula XIV to obtain a compound shown as a formula XI;
Figure FDA0002417047490000061
wherein R is2And R3Independently selected from C1-C6An alkyl or aryl group;
x is halogen or a leaving group.
16. A method E for preparing beraprost and its salt shown in formula I is characterized in that: comprises the following steps of (a) carrying out,
1) carrying out coupling reaction on a compound shown as a formula XI and a compound shown as a formula XII to obtain a compound shown as a formula IXA;
2) carrying out hydroxyl protection reaction on the compound shown in the formula IXA to obtain a compound shown in the formula IXB;
3) carrying out cyclization reaction on the compound shown in the formula IXB to obtain a compound shown in a formula VIIIB;
4) carrying out double bond shift reaction on the compound shown in the formula VIIIB to obtain a compound shown in a formula VIIB;
5) carrying out dihydroxylation reaction on the compound shown in the formula VIIB to obtain a compound shown in a formula VIB;
6) carrying out oxidation reaction on the compound shown as the formula VIB to obtain a compound shown as a formula IVB;
or carrying out ozonization reaction on the compound shown in the formula VIIB to obtain a compound shown in the formula IVB;
7) reacting a compound shown in a formula IVB with a compound shown in a formula V through HWE to obtain a compound shown in IIIB;
8) carrying out reduction reaction on the compound shown in the formula IIIB to obtain a compound shown in the formula IIB;
9) carrying out deprotection reaction on the compound shown in the formula IIB to obtain a compound shown in the formula IIA;
10) carrying out hydrolysis reaction on a compound shown in a formula IIA or a compound shown in a formula IIB to obtain a compound shown in a formula I; the reaction equation is as follows:
Figure FDA0002417047490000071
wherein R is2And R3Independently selected from C1-C6An alkyl or aryl group;
R4is a hydroxy protecting group;
R5is C1-C6An alkyl group;
x is halogen or a leaving group.
17. A method F for preparing beraprost and its salt shown in formula I is characterized in that: comprises the following steps of (a) carrying out,
1) carrying out coupling reaction on a compound shown as a formula XI and a compound shown as a formula XII to obtain a compound shown as a formula IXA;
2) carrying out cyclization reaction on a compound shown in a formula IXA to obtain a compound shown in a formula VIIIA;
3) carrying out double bond shift reaction on the compound shown in the formula VIIIA to obtain a compound shown in the formula VIIA;
4) carrying out dihydroxylation reaction on the compound shown in the formula VIIA to obtain a compound shown in the formula VIA;
5) carrying out oxidation reaction on a compound shown in a formula VIA to obtain a compound shown in a formula IVA;
or carrying out ozonization reaction on the compound shown in the formula VIIA to obtain a compound shown in the formula IVA;
6) reacting a compound shown in formula IVA with a compound shown in formula V through HWE to obtain a compound shown in IIIA;
7) carrying out reduction reaction on the compound shown in the formula IIIA to obtain a compound shown in the formula IIA;
8) carrying out hydrolysis reaction on the compound shown in the formula IIA to obtain a compound shown in a formula I;
the reaction equation is as follows:
Figure FDA0002417047490000091
wherein R is2And R3Independently selected from C1-C6An alkyl or aryl group;
R5is C1-C6An alkyl group;
x is halogen or a leaving group.
18. A method for preparing beraprost and its salt is characterized in that: a process for the preparation of beraprost and its salts from a compound of formula II as defined in claim 1, or from a compound of formula III, IV, VI, VII, VIII, IX, XI as defined in claim 6.
19. The use of a compound of formula II according to claim 1, or a compound of formula III, IV, VI, VII, VIII, IX or XI according to claim 6 for the preparation of beraprost and its salts or analogues.
CN202010194363.9A 2020-03-19 2020-03-19 Intermediate of beraprost and salt thereof and preparation method thereof Pending CN113493430A (en)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5202447A (en) * 1989-02-27 1993-04-13 Toray Industries, Inc. Process of producing 5,6,7-trinor-4,8-inter-m-phenylene pgi2 derivatives
CN103509044A (en) * 2012-06-21 2014-01-15 上海天伟生物制药有限公司 Beraprost sodium intermediates and preparation method thereof
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
CN107325122A (en) * 2017-01-06 2017-11-07 常州博海威医药科技有限公司 Prepare new intermediate of beraprost and preparation method thereof
CN108463457A (en) * 2015-08-12 2018-08-28 联合治疗学有限公司 The method for preparing beraprost
CN109219601A (en) * 2016-04-05 2019-01-15 奇诺因药物和化学工厂私人有限公司 The method for preparing optical activity beraprost

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5202447A (en) * 1989-02-27 1993-04-13 Toray Industries, Inc. Process of producing 5,6,7-trinor-4,8-inter-m-phenylene pgi2 derivatives
CN103509044A (en) * 2012-06-21 2014-01-15 上海天伟生物制药有限公司 Beraprost sodium intermediates and preparation method 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
CN108463457A (en) * 2015-08-12 2018-08-28 联合治疗学有限公司 The method for preparing beraprost
CN109219601A (en) * 2016-04-05 2019-01-15 奇诺因药物和化学工厂私人有限公司 The method for preparing optical activity 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
CN107325122A (en) * 2017-01-06 2017-11-07 常州博海威医药科技有限公司 Prepare new intermediate of beraprost and preparation method thereof

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