WO2013097456A1 - 西洛多辛中间体及其制备方法 - Google Patents

西洛多辛中间体及其制备方法 Download PDF

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WO2013097456A1
WO2013097456A1 PCT/CN2012/079253 CN2012079253W WO2013097456A1 WO 2013097456 A1 WO2013097456 A1 WO 2013097456A1 CN 2012079253 W CN2012079253 W CN 2012079253W WO 2013097456 A1 WO2013097456 A1 WO 2013097456A1
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compound
formula
group
compound according
base
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French (fr)
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张斌
胡小威
严普查
张现毅
高红军
李原强
车达庆
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浙江九洲药业股份有限公司
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Priority to EP12862614.0A priority Critical patent/EP2801567A4/en
Priority to US14/365,638 priority patent/US9394251B2/en
Publication of WO2013097456A1 publication Critical patent/WO2013097456A1/zh

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D209/00Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04Indoles; Hydrogenated indoles
    • C07D209/08Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07FACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07FACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02Silicon compounds
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07FACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02Silicon compounds
    • C07F7/08Compounds having one or more C—Si linkages
    • C07F7/18Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07FACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02Phosphorus compounds
    • C07F9/547Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6536Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms
    • C07F9/6539Five-membered rings
    • C07F9/65392Five-membered rings containing two nitrogen atoms
    • C07F9/65397Five-membered rings containing two nitrogen atoms having the two nitrogen atoms in positions 1 and 3
    • YGENERAL 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
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02PCLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00Technologies relating to chemical industry
    • Y02P20/50Improvements relating to the production of bulk chemicals
    • Y02P20/55Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to the technical field of heterocyclic chemistry, in particular to the technical field of five-membered heterocyclic chemistry containing nitrogen atoms. Background technique
  • Silodosin is said present Kissei Pharmaceuticals developed a r receptor antagonist clinically useful for the treatment of dysuria due to benign prostatic hyperplasia, chemical name: 2,3-dihydro small ( 3-hydroxypropyl)-5-[(2R)-2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethylamino]propyl] -1H-indole ⁇ -7-indoleamide, its structural formula is as follows:
  • the Chinese Patent Application Publication No. CN101759627 also uses a 1-step porphyrin as a raw material to obtain a racemic intermediate having the structure of the above formula a by a multi-step reaction, and is also subjected to chiral separation by mandelic acid, followed by a subsequent reaction step. .
  • the reaction reagent 2-bromopropionyl chloride, N-bromosuccinimide (NBS) is used in the reaction, and trifluoroacetic acid is used twice.
  • 2-Bromopropionyl chloride is difficult to obtain.
  • the radical reaction with N-bromosuccinimide does not result in a single monobromo product.
  • the reaction by-products are numerous.
  • the trifluoroacetic acid is highly corrosive to the equipment. The above disadvantages lead to the reaction operation. It is difficult and not conducive to industrial production.
  • JP2002265444 discloses that a racemic intermediate having the following structure is prepared by a multi-step reaction of hydrazine as a raw material, followed by a resolving agent cis-(lR,2S)-(-)-benzylamine.
  • the cyclohexane sterol is resolved to give an optically pure compound of formula b:
  • the present invention provides a novel intermediate compound for the preparation of optically pure silodosin, the specific scheme is as follows: A compound having the structural formula of formula A below:
  • X is hydrogen or bromine
  • R 1 is hydrogen, decanoyl or a group having the formula:
  • R 7 is a protecting group for an acid
  • the R 7 is preferably an alkyl group, a substituted alkyl group; the substituted alkyl group is preferably an aralkyl group, a substituted aralkyl group; the alkyl group is preferably a mercapto group, an ethyl group, a propyl group; Is trichloroindolyl, trifluoromethyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, m-nitrobenzyl, p-chlorobenzyl, m-chlorobenzyl, p-bromobenzyl, m-bromo Benzyl, benzyl.
  • R 2 is a 3-hydroxypropyl group or a group having the formula:
  • the W is preferably acetyl, trifluoroacetyl, allyloxycarbonyl, tert-butoxycarbonyl (Boc), trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), benzoyl , triphenylsulfonyl, p-methoxybenzyl, p-methoxybenzyloxycarbonyl (Moz), p-nitrobenzyl, m-nitrobenzyl, p-chlorobenzyl, m-chlorobenzyl, p-bromobenzyl , m-bromobenzyl, benzyl.
  • the compound of the formula A is preferably a compound represented by the following chemical structural formula:
  • the compound of the formula A-2 described above is prepared by reacting the compound of the formula A-1 with the compound of the formula C (referred to as phosphorus ylide).
  • Ph 3 P C(CH 3 )COOR 7
  • the molar ratio of the compound of the formula A-1 to the compound C is preferably 1: (1 to 4).
  • the solvent used for the preparation of the compound of the formula A-2 is preferably an amide solvent or an aromatic hydrocarbon solvent, and the amide solvent is preferably hydrazine, fluorenyl-dimercaptocarboxamide (DMF), hydrazine, hydrazine-diethylacetamide (DEA). , hydrazine, hydrazine-dimercaptopropionamide (DMP) or hydrazine, hydrazine-diethylpropionamide (DEP); the aromatic hydrocarbon solvent is preferably benzene, toluene or diphenylbenzene.
  • the solvent used is 20 to 100 times, preferably 30 to 60 times, the compound of the formula A-1.
  • the compound of the formula A-3 described herein is obtained by hydrolyzing the compound of the formula A-2 under basic conditions.
  • the base used in the preparation of the compound of the formula A-3 is preferably an alkali metal base, which is preferably lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate or potassium hydrogencarbonate. .
  • the molar ratio of the compound of the formula A-2 to the base is 1: (1 to 10); preferably 1: (2 to 6).
  • the solvent used for preparing the compound of the formula A-3 is preferably a polar protic solvent; the polar protic solvent is preferably an alcohol solvent or water; and the alcohol solvent may specifically be decyl alcohol, ethanol, propanol or isopropanol. Or n-butanol and so on.
  • the solvent is used in an amount of 10 to 50 times, preferably 20 to 30 times, that of the compound of the formula A-2.
  • the optimum reaction temperature for the preparation of A-3 is as follows: the optimum reaction temperature is 0 to 90 ° C, and the optimum reaction time is 2 to 24 hours.
  • the compound of the formula A-4 is prepared by subjecting the compound of the formula A-3 to asymmetric catalytic hydrogenation in the presence of a base.
  • the base used for preparing the compound of the formula A-4 is preferably an alkali metal base or an organic base;
  • the alkali metal base is preferably lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium hydrogencarbonate or potassium hydrogencarbonate.
  • the organic base is preferably an amine compound.
  • the amine compound is preferably an arylamine or an alkylamine, and specifically may be aniline, anthracene, fluorenyl-diphenylaniline, fluorenyl-mercaptomorpholine, diisopropylamine, hydrazine, hydrazine-isopropylethylamine, Ethylamine or pyridine.
  • the catalyst used to prepare the compound of formula ⁇ -4 is Ir LiXL nY, wherein:
  • R 3 is an aryl group; preferably a C 6 -C 16 aryl group.
  • R 4 is hydrogen, alkyl, aryl or arylalkyl; the alkyl group is preferably CH ⁇ alkyl; the aryl group is preferably a C 6 -C 16 aryl group; the arylalkyl group is preferably arylalkyl group of C 7 ⁇ C 16.
  • L 2 is preferably cyclooctene, 1,5-cyclooctadiene, ethylene, 1,5-hexadiene or norbornadiene;
  • n 1 or 2;
  • Y is chlorine, bromine, iodine, fluorine, trifluoroacetyl, tetrafluoroborate, tetrakis[(3,5-di(trifluorodecyl)phenyl]borate, tetraphenylborate, hexafluoroantimonate , hexafluorophosphate, trifluorosulfonate, sulfonate, perchlorate, perbromate, periodate, nitrate, hydrogen sulfate or acetylacetonate.
  • the molar ratio of the compound of the formula A-3 to the base is preferably 1: (1 to 3).
  • the molar ratio of the compound of the formula A-3 to the catalyst Ir LiXL nY is 1: ( 0.00001 ⁇ 0.04); 4 is especially selected as 1: (0.0001 ⁇ 0.005).
  • the hydrogen pressure for the preparation of the compound of the formula A-4 is 0.1 to 10 MPa; preferably 0.5 to 1.0 MPa.
  • the solvent used to prepare the compound of the formula A-4 is preferably an alcohol or ether solvent, or any mixture thereof.
  • the alcohol solvent is preferably decyl alcohol, ethanol, isopropanol, n-propanol, n-butanol or a mixture of any two or more thereof.
  • the ether solvent is preferably tetrahydrofuran, decyltetrahydrofuran.
  • the solvent used is 20 to 80 times, preferably 30 to 50 times, the compound of the formula A-3.
  • reaction temperature Good reaction temperature, optimum reaction temperature is 30 ⁇ 70 °C; reaction time is 0.5 ⁇ 10 hours, compound with structure of formula A-4, further, in the presence of diphenyl phosphate and diisopropylethylamine Conversion with a compound having the structure of the following formula E to a compound having the structure of the following formula D, - ' ⁇
  • the solvent used for the preparation of the compound of the formula A is preferably a chlorinated alkane or an amide solvent; the chlorinated alkane is preferably dichlorosilane, chloroform; the pro-amine solvent is preferably ruthenium, osmium-dimercaptoamide or ⁇ , ⁇ -diethylacetamide.
  • the solvent used in the preparation of the hydrazine compound is used in an amount of from 15 to 60 times; preferably from 20 to 40 times, the compound of the formula B.
  • the reaction temperature of the compound of the formula A is preferably -10 to 10 °C.
  • the compound of the formula A is preferably a compound represented by the following chemical formula:
  • the compound of the formula 1 is prepared by electrophilic reaction of a porphyrin with 3-chloropropyl acetate in the presence of a base.
  • the base used in the preparation of the compound of the formula 1 is preferably an amine compound.
  • the amine compound is preferably an arylamine or an alkylamine, and specifically may be aniline, anthracene, fluorenyl-dimercaptoaniline, fluorenyl-mercaptomorpholine, diisopropylamine, hydrazine, hydrazine-diisopropylethylamine, Triethylamine or pyridine.
  • the molar ratio of the porphyrin to the 3-chloropropyl acetate is 1 : (1 ⁇ 3 ).
  • the molar ratio of the porphyrin to the base is 1: (1 ⁇ 3).
  • the solvent used for preparing the compound of Formula 1 is preferably a polar protic solvent; the polar protic solvent is preferably an alcohol solvent, specifically sterol, ethanol, propanol, isopropanol, n-butanol or iso Pentanol.
  • the solvent is used in an amount of from 20 to 100 times, preferably from 40 to 60 times, of the porphyrin.
  • the reaction temperature for the preparation of the formula 1 is from 60 ° C to reflux, and the reaction time of the reaction is from 6 to 24 hours.
  • the molar ratio of the compound of the formula 1 to phosphorus oxychloride is 1: (1-3).
  • the solvent used for preparing the compound of the formula 2 is preferably an amide solvent, and the amide solvent is preferably
  • the reaction temperature for preparing the compound of the formula 2 is -10 ° C to 40 ° C, and the reaction time is 2 to 20 hours.
  • Lid is prepared.
  • Ph 3 P C(CH 3 )C0 2 Et
  • the preparation method of the compound of the formula b can be referred to the method of Tetrahedron, 66 (26), 4745-4759;
  • the molar ratio of the compound of the formula 2 to the compound of the formula b is 1: (1 to 4).
  • the solvent used for preparing the compound of the formula 3 is preferably an amide solvent, and the amide solvent is preferably
  • the reaction temperature of the compound of the formula 3 is from 50 ° C to reflux, and the reaction time is from 1 to 20 hours.
  • the base is preferably an alkali metal base, and the alkali metal base is preferably lithium hydroxide, sodium hydroxide, potassium hydroxide or barium hydroxide.
  • the molar ratio of the compound of the formula 3 to the base is 1: (1 to 10); preferably 1: (2 to 6). 1 - - > ⁇ -9- human ⁇ , ;
  • the human agent is preferably an alcohol solvent or water; the alcohol solvent may specifically be decyl alcohol, ethanol, propanol, isopropanol or n-butanol.
  • the solvent is used in an amount of 10 to 50 times, preferably 20 to 30 times, that of the compound of the formula 3.
  • the reaction temperature for preparing the compound of the formula 4 is 0 to 40 ° C, and the reaction time is 2 to 24 hours. get.
  • the base is preferably an alkali metal base or an organic base; the alkali metal base is preferably lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, potassium carbonate or carbonic acid.
  • the organic base is preferably an amine compound or pyridine.
  • the amine compound is preferably an arylamine or an alkylamine, and specifically may be aniline, anthracene, fluorenyl-diphenylaniline, fluorenyl-mercaptomorpholine, diisopropylamine, hydrazine, hydrazine-isopropylethylamine, triethylamine or pyridine 1 set.
  • the catalyst used to prepare the compound of formula 5 is Ir LiXL nY, wherein:
  • R 3 is an aryl group; preferably a C 6 -C 16 aryl group;
  • R 4 is a hydrogen, an alkyl group, an aryl group or an arylalkyl group; and the alkyl group is preferably a d-C 8 alkyl group;
  • the aryl group is preferably a C 6 -C 16 aryl group;
  • the arylalkyl group is preferably a C 7 -C 16 arylalkyl group.
  • L 2 is preferably cyclooctene, 1,5-cyclooctadiene, ethylene, 1,5-hexadiene or norbornadiene;
  • n 1 or 2;
  • Y is chlorine, bromine, iodine, fluorine, trifluoroacetyl, tetrafluoroborate, tetrakis[(3,5-di(trifluorodecyl)phenyl]borate, tetraphenylborate, hexafluoroantimonate , hexafluorophosphate, trifluorosulfonate, sulfonate, perchlorate, perbromate, periodate, nitrate, hydrogen sulfate or acetylacetonate.
  • the molar ratio of the compound of the formula 4 to the base is 1: (1 to 3).
  • the molar ratio of the compound of the formula 4 to the catalyst Ir LiXL nY is 1: (0.0001 ⁇ 0.04); 4 is particularly selected as 1: (0.001 ⁇ 0.005).
  • the hydrogen pressure for preparing the compound of the formula 5 is 0.1 to 10 MPa; preferably 0.5 to 1.0 MPa.
  • the solvent used to prepare the compound of the formula 5 is preferably an alcohol or ether solvent, or any mixture thereof.
  • the alcohol solvent is preferably decyl alcohol, ethanol, isopropanol, n-propanol, n-butanol or a mixture of two or more thereof.
  • the ether solvent is preferably tetrahydrofuran, decyltetrahydrofuran.
  • the solvent used is 20 to 80 times, preferably 30 to 50 times, the compound of the formula 4.
  • the reaction temperature for preparing the compound of the formula 5 is 30 to 70 ° C; and the reaction time is 0.5 to 10 hours.
  • the compound of the formula 6 is prepared by electrophilic substitution of the compound of the formula 5 with an electrophile. It is also possible to add a base to the reaction.
  • the electrophile is preferably acetic anhydride, acetyl chloride, benzyl chloride, benzyl bromide, p-methoxybenzyl bromide, p-oxobenzyl bromide.
  • the base is preferably an amine compound; the amine compound is preferably an arylamine or an alkylamine, specifically aniline, anthracene, fluorenyl-dimercaptoaniline, fluorenyl-mercaptomorpholine, diisopropylamine, hydrazine, ⁇ - diisopropylethylamine, triethylamine or pyridine 1 set.
  • the amine compound is preferably an arylamine or an alkylamine, specifically aniline, anthracene, fluorenyl-dimercaptoaniline, fluorenyl-mercaptomorpholine, diisopropylamine, hydrazine, ⁇ - diisopropylethylamine, triethylamine or pyridine 1 set.
  • the molar ratio of the compound of the formula 5 to the electrophile is 1: (1 ⁇ 2).
  • the molar ratio of the compound of the formula 5 to the base is 1 : (1 to 3).
  • the solvent used for the preparation of the compound of the formula 6 is preferably an ether, an alcohol or a chlorinated alkane solvent;
  • the ether solvent may specifically be tetrahydrofuran or decyl tert-butyl ether;
  • the alcohol solvent may specifically be decyl alcohol, ethanol, Isopropanol, n-propanol, n-butanol, isoamyl alcohol or a mixture of any two or more thereof;
  • the chlorinated alkane solvent may specifically be dichlorosilane, chloroform, 1,1-dichloro Ethane or a mixture of any two or more thereof.
  • the reaction temperature for preparing the compound of the formula 6 is from 30 ° C to reflux; the reaction time is from 5 to 30 hours.
  • the silodosin intermediate provided by the invention and the preparation method thereof have the beneficial effects of: enriching the pharmaceutical intermediate in the field of medicine and chemical industry; and simultaneously undergoing electrophilic substitution reaction, catalytic hydrogenation reaction, etc. Types of reactions, each intermediate can be easily converted; in the synthesis of chiral compounds, it is not necessary to use expensive resolving agents, but Ir LiXL nY is used as a catalyst, which has good selectivity and can be obtained high.
  • a single-form pharmaceutical intermediate compound of purity was analyzed by chiral HPLC to have an ee value greater than 99%.
  • the molar amount of the catalyst is only 1/10000 of the reaction substrate to achieve the optical purity, the cost is greatly saved, the reaction yield is also high, and the raw material is saved. Also avoiding the use of prior art 2-bromopropionyl chloride, N-bromosuccinimide, trifluoroacetic acid, sodium cyanide, sodium azide and other undesirable reagents, high atomic economy, environmentally friendly, therefore
  • the silodosin intermediate given by the invention and the preparation method thereof have the medical application value of 4 ⁇ . detailed description
  • the invention discloses a silodosin intermediate and a preparation method thereof, and those skilled in the art can learn from the contents of the paper and appropriately improve the process parameters. It is to be understood that all such alternatives and modifications are obvious to those skilled in the art and are considered to be included in the present invention.
  • the products and methods of the present invention have been described in terms of the preferred embodiments, and it is obvious that those skilled in the art can change or modify and combine the methods and applications described herein to achieve the The technique of the present invention is applied.
  • Example 1 Preparation of a compound of formula A-1-1 (W is acetyl and X is bromine)
  • Example 13 Preparation of a compound of the formula A-2-1 (W is acetyl, X is bromine, R 7 is fluorenyl)
  • a 100-ml single-necked round bottom flask was sequentially charged with A-1-1 compound (2.0 g, 6.14 mmol).
  • De reagent (3.21g, 9.21mmol) and 40ml of toluene, heated to 90 ⁇ 100 °C under nitrogen protection, the temperature was kept at this temperature.
  • the reaction was followed by TLC until the conversion of the starting material was complete.
  • the residue was concentrated under reduced pressure, and the residue was subjected to column chromatography to give 1.96 g of the compound of formula A-2-1 to a molar yield of 80.7%.
  • W is a different alcohol protecting group
  • X is bromine
  • R 7 is a different acid protecting group
  • Example 25 Preparation of a compound of formula A-3-1 (W is benzyl and X is bromine)
  • a 100 ml single neck round bottom flask was charged with a compound of the formula A-2-12 (2 g, 4.37 mmol), 50% aqueous potassium hydroxide (0.73 g, 6.48 mmol), and 30 ml of decyl alcohol. TLC tracking The reaction is completed until the conversion of the starting material is complete. After the reaction was completed, the solution was concentrated to dryness under reduced pressure. The residue was subjected to column chromatography to give 1.84 g of the compound of formula A-3-1 to a yield of 97.9%.
  • Anhydrous decyl alcohol was pressurized to 12 MPa under a hydrogen atmosphere, and stirred at 70 ° C until the hydrogen pressure was no longer lowered. Then stop the reaction and release hydrogen. After concentrating the reaction system, it was diluted with 100 mL of diethyl ether, and the system was acidified with 3 N hydrochloric acid. The mixture was separated, and the aqueous phase was extracted twice with diethyl ether (100 mL). The organic phase was combined and washed with brine. The sodium salt was dried and concentrated to give 1.91 g of the compound of formula A-4-1. The ee value was analyzed by chiral HPLC to be 97%. The product yield by column chromatography was 95.0%.
  • Examples 31 to 48 are in accordance with Example 30
  • the method in the same manner as the operation, when W is benzyl, or p-methoxybenzyl, X is bromine, the experimental results obtained when the catalyst IrO ⁇ XL ⁇ Y is selected with different substituent groups are as follows:
  • a 500 ml single neck round bottom flask was charged with a compound of formula A-4-1 (25.0 g, 57.8 mmol), diphenyl azide (15.9 g, 57.8 mmol), diisopropylethylamine (8.2 g, 63.6 mmol). )), heat up to 60 ⁇ 65 °C, and keep the reaction at this temperature for 1-3 hours. Phenylhydrin (9.4 g, 87.0 mmol) was added, and the temperature was raised to 90 to 95 ° C, and the reaction was kept for 10 to 24 hours. After completion of the reaction, the residue was concentrated under reduced pressure, and the residue was subjected to column chromatography to give the compound of formula D-1, 24.1 g, with a molar yield of 77.7%.
  • reaction mixture was poured into cold water, extracted with ethyl acetate was added 200mL off the impurities, the aqueous phase with 50% NaOH solution to adjust pH> 13 Stir, extracted with 800mL of ethyl acetate, the organic phase was dried over anhydrous MgS0 4, Save The solvent was removed by pressure to obtain 150.2 g of a white solid compound 2 in a yield of 85.3%.
  • R 3 is a phenyl group in the catalyst
  • R 4 is a benzyl group
  • L 2 is a cyclooctyl group
  • n is 1
  • Y is tetrafluoroboric acid
  • the catalyst is from Zhejiang Jiuzhou Pharmaceutical Co., Ltd.
  • Triethylamine 50 mg, 0.5 mmol
  • 2 mL of anhydrous methanol were added, and the mixture was pressurized to 0.6 Mpa under a hydrogen atmosphere, and stirred at 60 ° C for 1 hour.
  • the compound of formula 5 (2.6 g, O. Olmol) was dissolved in 40 mL of THF, triethylamine (1.52 g, 0.015 mol) was added and stirred; acetyl chloride (1.2 g, 0.015 mol) was added dropwise at 0 to 5 °C. After the completion of the dropwise addition, the reaction was carried out at room temperature for 12 hours; after the completion of the reaction, the solvent was evaporated under reduced pressure, ethyl acetate was evaporated, washed with EtOAc EtOAc EtOAc EtOAc. -1 compound in a yield of 92.3%.
  • Example 72 The same procedure as in Example 72 was carried out, and benzyl bromide (2.57 g, 0.015 mol) was added dropwise to give 2.74 g of the compound of formula 6-2 with a yield of 77.6%.

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Abstract

本发明公开了西洛多辛中间体及其制备方法。所述的西洛多辛中间体具有如式(A)结构。其中:X为氢或溴,R1为氢,甲酰基或为具有式I结构的基团。其中R7为酸的保护基;R2为3-羟丙基或为具有式II结构的基团。其中W为醇的保护基;本发明所述的式(A)化合物进一步的可用于制备具有式(D)结构的化合物。利用本发明所提供的中间体及其制备方法可以高纯度的制备得到光学纯西洛多辛,光学纯度达到99%以上。

Description

西洛多辛中间体及其制备方法
本申请要求于 2011年 12月 26日提交中国专利局、 申请号为
201110440481.4、发明名称为"西洛多辛中间体及其制备方法"的中国专利申请的 优先权, 其全部内容通过引用结合在本申请中。 技术领域
本发明涉及杂环化学技术领域, 尤其涉及含氮原子五元杂环化学技术领域。 背景技术
西洛多辛 ( Silodosin )是曰本 Kissei制药公司开发的 ar受体拮抗剂, 临床 上用于治疗由于前列腺良性增生所致的排尿困难,其化学名称为: 2,3-二氢小(3- 羟基丙基) -5-[(2R)-2-[2-[2-(2,2,2-三氟乙氧基)苯氧基]乙胺基]丙基] -1H-吲哚 -7-曱 酰胺, 其结构式如下:
Figure imgf000003_0001
从目前已有的西洛多辛的合成文献可以看出, 光学纯西洛多辛主要通过不 同的合成路线得到消旋中间体后采用手性拆分方法获得, 并且在一些反应中, 其所使用的试剂并不是 4艮理想, 例如欧洲专利 EP0600675以 1-乙酰吲哚啉为原 料经过多步反应得到具有下列式 a结构的消旋中间体, 然后用拆分剂扁桃酸进 行拆分得到光学纯的式 a化合物:
Figure imgf000003_0002
欧洲专利 EP0600675提供的制备西洛多辛的反应路线比较长共 12步,反应 过程中要用到价格昂贵的氧化铂, 剧毒的氰化钠和易燃易爆的叠氮化钠, 不利 于劳动和环境保护, 以上存在的现实问题, 导致其工业化的不可行性。
专利公开号为 CN101759627的中国专利申请文件也是以 1-乙酰吲哚啉为原 料经过多步反应得到具有上述式 a结构的消旋中间体, 也是经扁桃酸手性拆分 后, 进行后继反应步骤。 并且反应过程中需要用到反应试剂 2-溴丙酰氯, N-溴 代丁二酰亚胺(NBS ), 两次用到三氟乙酸。 2-溴丙酰氯难以获得, 用 N-溴代丁 二酰亚胺进行自由基反应并不能得到单一的单溴代产物, 反应副产物多, 三氟 乙酸对设备腐蚀严重, 以上缺点导致反应操作难度大, 不利于工业化生产。
公开号为 JP2002265444的日本专利申请文件是以吲哚为原料经过多步反应 后制备得到具有下列结构的消旋中间体, 然后用拆分剂顺 -(lR,2S)-(-)-苄胺环己 烷曱醇进行拆分得到光学纯的式 b化合物:
BnO(H2C)3 CN
b
拆分剂价格昂贵且回收困难, 这些拆分方法为了得到较高的 ee值, 通常需 要多次重结晶, 这样会浪费大量的原料, 既不经济, 又造成环境污染。 并且由 光学纯的式 b化合物制备合成具有下列式 c化合物过程中要先将式 b化合物制 备成酰胺, 然后进行 Hofmann降解(霍夫曼降解), 增加了反应的步骤, 降低了 反应收率,
Figure imgf000004_0001
发明内容
为了解决上述现有技术中, 反应过程中需要用到拆分剂, 并且需要多次重 结晶, 浪费原料, 产物损失严重, 生产成本高, 反应收率低, 化学试剂污染严 重, 毒性大等技术问题, 本发明提供了一种新的用于制备光学纯西洛多辛的中 间体化合物, 具体方案如下: 一种具有下列式 A结构式的化合物:
Figure imgf000005_0001
其中:
X为氢或溴, R1为氢, 曱酰基或为具有下式结构的基团:
Figure imgf000005_0002
其中 R7为酸的保护基;
所述 R7优选为烷基, 取代烷基; 所述取代烷基优选为芳烷基, 取代芳烷基; 所述烷基优选为曱基, 乙基, 丙基; 所述取代烷基优选为三氯曱基, 三氟 曱基, 苄基, 对曱氧基苄基, 对硝基苄基, 间硝基苄基, 对氯苄基, 间氯苄基, 对溴苄基, 间溴苄基, 苄基。
R2为 3-羟丙基或为具有下式结构的基团:
.w 其中 W为醇的保护基;
所述 W优选为乙酰基, 三氟乙酰基, 烯丙氧羰基, 叔丁氧羰基(Boc ), 三 曱基硅烷基(TMS ), 叔丁基二曱基硅烷基(TBDMS ), 苯曱酰基, 三苯曱基, 对曱氧基苄基, 对曱氧基苄氧羰基(Moz ), 对硝基苄基, 间硝基苄基, 对氯苄 基, 间氯苄基, 对溴苄基, 间溴苄基, 苄基。
其中所述式 A化合物优选为具有下列化学结构式所表示的化合物:
Figure imgf000005_0003
Figure imgf000006_0001
A-3 , A-4 , 其中 X, W, R7的定义与上述定义相同。
其中所述的式 A-2化合物由所述的式 A- 1化合物与下列的式 C化合物 (称 为: 磷叶立德)作用制备得到,
Ph3P=C(CH3)COOR7
C
其中 R7的定义与上述式 A-2化合物中 R7的定义相同。
所述式 C化合物的制备可参考 Tetrahedron, 66(26), 4745-4759; 2010或 J. Org. Chem.1984, 49, 4293-4295中的方法。
所述式 A-1化合物与所述 C化合物的摩尔用量比优选为 1: (1~4)。
制备式 A-2化合物所用溶剂优选为酰胺类溶剂或芳烃类溶剂, 所述酰胺类 溶剂优选为 Ν,Ν-二曱基曱酰胺(DMF), Ν,Ν-二乙基乙酰胺 (DEA), Ν,Ν-二曱基 丙酰胺 (DMP)或 Ν,Ν-二乙基丙酰胺 (DEP); 所述芳烃类溶剂优选为苯, 曱苯, 二 曱苯。 所用溶剂用量为所述式 A-1化合物的 20~100倍, 优选 30~60倍。
佳的反应温度, 最佳反应温度为 50°C~回流, 最佳反应时间为 1 ~20小时。 其中所述的式 A-3化合物由所述的式 A-2化合物在碱性条件下水解制备得 到。
制备式 A-3化合物所用碱优选为碱金属碱, 所述碱金属碱优选为氢氧化锂, 氢氧化钠, 氢氧化钾, 氢氧化铯, 碳酸钠, 碳酸钾, 碳酸氢钠或碳酸氢钾。
所述式 A-2化合物与所述碱的摩尔用量比为 1: ( 1 ~ 10);优选为 1: (2~6)。 制备式 A-3化合物所用溶剂优选为极性质子性溶剂; 所述极性质子性溶剂 优选为醇类溶剂或水; 所述醇类溶剂具体可以为曱醇, 乙醇, 丙醇, 异丙醇或 正丁醇等。 所述溶剂用量为所述式 A-2化合物的 10 ~ 50倍, 优选为 20~30倍。 制备 A-3化 最佳 的反应温度, 最佳反应温度为 0 ~ 90°C, 最佳反应时间为 2 ~ 24小时。 所述的式 A-4化合物由所述式 A-3化合物在碱存在下进行不对称催化加氢 反应制备得到。
制备所述式 A-4化合物所用碱优选为碱金属碱或有机碱; 所述碱金属碱优 选为氢氧化锂, 氢氧化钠, 氢氧化钾, 氢氧化铯, 碳酸氢钠, 碳酸氢钾, 碳酸 钠, 碳酸钾或碳酸铯; 所述有机碱优选为胺类化合物。 所述胺类化合物优选为 芳胺或烷基胺, 具体可以为苯胺, Ν,Ν-二曱基苯胺, Ν-曱基吗啉, 二异丙胺, Ν,Ν-异丙基乙胺, 三乙胺或吡啶。
制备所述式 Α-4化合物所用催化剂为 Ir LiXL nY, 其中:
为定义的化合物 (Sa,S)-SIPHOX;
Figure imgf000007_0001
(Sa,S)-SIPHOX
其中, R3为芳基; 优选为 C6~C16的芳基。 R4为氢, 烷基, 芳基或芳基烷基; 所述烷基优选为 CH^ 烷基; 所述芳基优选为 C6~C16的芳基; 所述芳基烷基 优选为 C7~C16的芳基烷基。
L2优选为环辛烯, 1,5-环辛二烯, 乙烯, 1,5-己二烯或降冰片二烯;
n为 1或 2;
Y为氯, 溴, 碘, 氟, 三氟乙酰基, 四氟硼酸根, 四 [(3,5-二 (三氟曱基)苯基] 硼酸根, 四苯基硼酸根, 六氟锑酸根, 六氟磷酸根, 三氟曱磺酸根, 曱磺酸根, 高氯酸根, 高溴酸根, 高碘酸根, 硝酸根, 硫酸氢根或乙酰丙酮根。
所述式 A-3化合物与所述碱的摩尔用量比优选为 1 : ( 1 ~ 3 )。
所述式 A-3化合物与所述催化剂 Ir LiXL nY的摩尔用量比为 1 : ( 0.00001 ~ 0.04 ); 4尤选为 1 : ( 0.0001 ~ 0.005 )。
制备式 A-4化合物所用氢气压力为 0.1~10Mpa; 优选 0.5~1.0Mpa。
制备式 A-4化合物所用溶剂优选为醇类或醚类溶剂, 或其任意混合物。 所 述醇类溶剂优选为曱醇, 乙醇, 异丙醇, 正丙醇, 正丁醇或其任意两种或两种 以上的混合物。 所述醚类溶剂优选为四氢呋喃, 曱基四氢呋喃。 所用溶剂用量 为式 A-3化合物的 20~80倍, 优选 30~50倍。
/ 反 Π
佳的反应温度, 最佳反应温度为 30 ~ 70 °C; 反应时间为 0.5 ~ 10小时 具有式 A-4结构的化合物进一步地, 在叠氮磷酸二苯酯和二异丙基乙胺存 在下与具有下列式 E结构的化合物作用转化为具有下列式 D结构的化合物, - ' 〇
R6OH WO(H2C)3 χ
E , D 其中 X, W的定义与上述定义相同, R6为酯的保护基; 具体可以为叔丁基, 乙婦基, 烯丙基, 苄基, 对曱氧苄基, 对硝基苄基, 二苯基曱基。 所述的式 D化合物进一步地被转化为西洛多辛。 具体合成方法可参考公开 号为 JP2006188470的日本专利申请文件。 当 X为溴时, 所述式 A结构的化合物, 由具有下列式 B结构的化合物在溴 素作用下制备得到,
WO(H2
Figure imgf000008_0001
B , 其中 R1 , W的定义与上述定义相同。
其中所述式 B化合物与所述溴素的摩尔用量比优选为 1 : ( 1 制备式 A化合物所用溶剂优选为氯代烷类或酰胺类溶剂; 所述氯代烷类优 选为二氯曱烷, 氯仿; 所述先胺类溶剂优选为 Ν,Ν-二曱基曱酰胺或 Ν,Ν-二乙基 乙酰胺。
制备式 Α化合物所用溶剂用量为所述式 B化合物的 15 ~ 60倍;优选为 20 ~ 40倍。
制备式 A化合物反应温度优选为 -10 ~ 10°C。 一种所述式 A化合物的用途, 用于制备西洛多辛。 本发明的一种优选的技术方案, 所述的式 A化合物优选为具有下列化学结 构式所表示的化合物:
HO(H
Figure imgf000009_0001
其中 W的定义与上述定义相同。
其中所述式 1化合物由吲哚啉与 3-氯丙基乙酸酯在碱存在下进行亲电反应 制备得到。
制备所述式 1化合物所用碱优选为胺类化合物。 所述胺类化合物优选为芳 胺或烷基胺, 具体可以为苯胺, Ν,Ν-二曱基苯胺, Ν-曱基吗啉, 二异丙胺, Ν,Ν- 二异丙基乙胺, 三乙胺或吡啶。
所述吲哚啉与所述 3-氯丙基乙酸酯摩尔用量比为 1 : ( 1 ~ 3 )。
所述吲哚啉与所述碱的摩尔用量比为 1 : ( 1 ~ 3 )。
制备所述式 1化合所用溶剂优选为为极性质子性溶剂; 所述极性质子性溶 剂优选为醇类溶剂, 具体可以为曱醇, 乙醇, 丙醇, 异丙醇, 正丁醇或异戊醇。 所用溶剂用量为所述吲哚啉的 20~100倍, 优选 40~60倍。
制备所述式 1化合的反应温度为 60°C至回流, 所述反应的反应时间为 6 ~ 24小时。
其中所述式 2化合物由所述式 1化合物在三氯氧磷 ( P0C13 )作用下制备得 到。
所述式 1化合物与三氯氧磷的摩尔用量比为 1: ( 1-3 )。
制备所述式 2化合物所用溶剂优选为酰胺类溶剂, 所述酰胺类溶剂优选为
Ν,Ν-二曱基曱酰胺或 Ν,Ν-二乙基乙酰胺。 所用溶剂用量为所述式 1化合物的
20~100倍, 优选 40~60倍。
制备所述式 2化合物的反应温度为 -10°C ~ 40°C, 反应时间为 2 ~ 20小时。
立德)作用制备得到。
Ph3P=C(CH3)C02Et
b
所述式 b化合物的制备方法可参考 Tetrahedron, 66(26), 4745-4759; 2010中的 方法。
所述式 2化合物与所述式 b化合物的摩尔用量比为 1: ( 1 ~4)。
制备所述式 3化合物所用溶剂优选为酰胺类溶剂, 所述酰胺类溶剂优选为
Ν,Ν-二曱基曱酰胺或 Ν,Ν-二乙基乙酰胺。 所用溶剂用量为所述式 1化合物的
20~100倍, 优选 30~60倍。
制备所述式 3化合物的反应温度为 50°C至回流, 反应时间为 1 ~ 20小时。
所述碱优选为碱金属碱, 所述碱金属碱优选为氢氧化锂, 氢氧化钠, 氢氧 化钾或氢氧化铯。
所述式 3化合物与所述碱的摩尔用量比为 1: ( 1 ~ 10); 优选为 1: (2~6)。 1 - - > ^ -9- 人 ^ 、 ; 人 剂优选为醇类溶剂或水; 所述醇类溶剂具体可以为曱醇, 乙醇, 丙醇, 异丙醇 或正丁醇等。 所述溶剂用量为所述式 3化合物的 10 ~ 50倍, 优选为 20 ~ 30倍。
制备所述式 4化合物的反应温度为 0 ~ 40 °C, 反应时间为 2 ~ 24小时。 得到。
所述碱优选为碱金属碱或有机碱; 所述碱金属碱优选为氢氧化锂, 氢氧化 钠, 氢氧化钾, 氢氧化铯, 碳酸氢钠, 碳酸氢钾, 碳酸钠, 碳酸钾或碳酸铯; 所述有机碱优选为胺类化合物或吡啶。 所述胺类化合物优选为芳胺或烷基胺, 具体可以为苯胺, Ν,Ν-二曱基苯胺, Ν-曱基吗啉, 二异丙胺, Ν,Ν-异丙基乙胺, 三乙胺或吡 1定。
制备所述式 5化合物所用催化剂为 Ir LiXL nY, 其中:
为定义的化合物 (Sa,S)-SIPHOX;
Figure imgf000011_0001
(Sa,S)-SIPHOX
其中, R3为芳基; 优选为 C6~C16的芳基; R4为氢, 烷基, 芳基或芳基烷基; 所述烷基优选为 d~C8的烷基; 所述芳基优选为 C6~C16的芳基; 所述芳基烷基 优选为 C7~C16的芳基烷基。
L2优选为环辛烯, 1,5-环辛二烯, 乙烯, 1,5-己二烯或降冰片二烯;
n为 1或 2;
Y为氯, 溴, 碘, 氟, 三氟乙酰基, 四氟硼酸根, 四 [ (3,5-二(三氟曱基) 苯基]硼酸根, 四苯基硼酸根, 六氟锑酸根, 六氟磷酸根, 三氟曱磺酸根, 曱磺 酸根, 高氯酸根, 高溴酸根, 高碘酸根, 硝酸根, 硫酸氢根或乙酰丙酮根。
所述式 4化合物与所述碱的摩尔用量比为 1 : ( 1 ~ 3 )。 所述式 4化合物与所述催化剂 Ir LiXL nY的摩尔用量比为 1 : ( 0.0001 ~ 0.04 ); 4尤选为 1 : ( 0.001 ~ 0.005 )。
制备所述式 5化合物所用氢气压力为 0.1~10Mpa; 优选 0.5~1.0Mpa。
制备所述式 5化合物所用溶剂优选为醇类或醚类溶剂, 或其任意混合物。 所述醇类溶剂优选为曱醇, 乙醇, 异丙醇, 正丙醇, 正丁醇或其任意两种或两 种以上的混合物。 所述醚类溶剂优选为四氢呋喃, 曱基四氢呋喃。 所用溶剂用 量为式 4化合物的 20~80倍, 优选 30~50倍。
制备所述式 5化合物的反应温度为 30 ~ 70 °C; 反应时间为 0.5 ~ 10小时。 其中所述式 6化合物由所述式 5化合物与亲电试剂进行亲电取代反应制备 得到。 也可以在所述反应中加入碱。
所述亲电试剂优选为醋酐, 乙酰氯, 苄氯, 苄溴, 对曱氧基苄溴, 对曱氧 基苄溴。
所述碱优选为胺类化合物; 所述胺类化合物优选为芳胺或烷基胺, 具体可 以为苯胺, Ν,Ν-二曱基苯胺, Ν-曱基吗啉, 二异丙胺, Ν,Ν-异丙基乙胺, 三乙 胺或吡 1定。
所述式 5化合物与所述亲电试剂的摩尔用量比为 1 : ( 1 ~ 2 )。
所述式 5化合物与所述碱的摩尔用量比为 1 : ( 1 ~ 3 )。
制备所述式 6化合物所用溶剂优选为醚类, 醇类或氯代烷类溶剂; 所述醚 类溶剂具体可以为四氢呋喃或者曱基叔丁基醚; 醇类溶剂具体可以为曱醇, 乙 醇, 异丙醇, 正丙醇, 正丁醇, 异戊醇或其任意两种或两种以上的混合物; 所 述氯代烷类溶剂具体可以为二氯曱烷, 氯仿, 1 , 1-二氯乙烷或其任意两种或两 种以上的混合物。
制备所述式 6化合物的反应温度为 30 °C至回流; 反应时间为 5 ~ 30小时。 本发明给出的西洛多辛中间体及其制备方法, 具有的有益效果为: 丰富了 医药化工领域中的药物中间体; 同时经过亲电取代反应, 催化加氢反应等筒单 类型的反应, 各中间体就可以轻松转换; 在手性化合物的合成过程中, 不需要 用到价格昂贵的拆分剂,而是应用 Ir LiXL nY作为催化剂,具有良好的选择性, 可得到高纯度的单一构型的药物中间体化合物, 用手性 HPLC分析其 ee值大于 99%。并且此催化剂的摩尔用量仅为反应底物的 1/10000即可达到所述的光学纯 度, 大大节省了成本, 反应收率也较高, 节约了原料。 也避免了使用现有技术 中的 2-溴丙酰氯, N-溴代丁二酰亚胺, 三氟乙酸, 氰化钠, 叠氮化钠等不良试 剂, 原子经济性高, 利于环保, 因此本发明给出的西洛多辛中间体及其制备方 法具有 4艮高的医药应用价值。 具体实施方式
本发明公开了西洛多辛中间体及其制备方法, 本领域技术人员可以借鉴本 文内容, 适当改进工艺参数实现。 特别需要指出的是, 所有类似的替换和改动 对本领域技术人员来说是显而易见的, 它们都被视为包括在本发明。 本发明的 产品及方法已经通过较佳实施例进行了描述, 相关人员明显能在不脱离本发明 内容、 精神和范围内对本文所述的方法和应用进行改动或适当变更与组合, 来 实现和应用本发明技术。
为了更好的理解本发明的内容, 下面结合具体实施例来做进一步的说明, 但具体的实施方式并不是对本发明的内容所做的限制。 实施例 1: 式 A-1-1化合物(W为乙酰基, X为溴) 的制备
Figure imgf000013_0001
A-1-1
100ml两颈圓底烧瓶中依次加入 1-(3- (乙酰基)丙基)吲哚啉 -5-曱醛(2.0g, 8.10mmol )和二氯曱烷 40ml, 降温至 -10 ~ 10°C , 在此温度下滴加溴素( 1.36g, 8.51mmol )。 滴毕, 于 -10 ~ 10°C继续搅拌反应。 TLC跟踪反应, 直至原料转化 完全。 反应毕, 加入 5ml饱和亚疏酸钠水溶液和 10ml饱和碳酸氢钠水溶液, 搅 拌 10分钟。 分层, 取下层有机相。 有机相用 15ml饱和氯化钠水溶液洗涤后浓 缩, 最终的得到式 A-1-1化合物 2.57g, 摩尔收率为 97.3%。 实施例 2 ~ 12是 W为不同的醇保护基时, X为溴, 按照实施例 1的方法同 法 , 所得到的实验结果列表如下:
Figure imgf000014_0001
A-1
实施例 产物 W 收率 (% ) m/z
2 A-1-2 三氟乙酰基 87.0 379/380/381
3 A-1-3 烯丙氧羰基 92.9 367/368/369
4 A-1-4 叔丁氧羰基 97.7 383/384/385
5 A-1-5 三曱基硅烷基 97.1 355/357/358
6 A-1-6 叔丁基二曱基硅烷 96.1 397/398/399
7 A-1-7 苯曱醜基 86.8 387/388/389
8 A-1-8 对曱氧基苄基 97.2 403/404/405
9 A-1-9 对曱氧基苄氧羰基 91.5 433/434/435
10 A-1-10 对硝基苄基 90.1 418/419/420
11 A-1-11 对氯苄基 92.4 407/409/411
12 A-1-12 苄基 96.8 373/374/375
实施例 13: 式 A-2-1化合物(W为乙酰基, X为溴, R7为曱基) 的制备
Figure imgf000014_0002
A-2-1
100ml单颈圓底烧瓶中依次加入 A-1-1化合物 (2.0g, 6.14mmol ), 磷叶立 德试剂 (3.21g, 9.21mmol )和曱苯 40ml, 氮气保护下升温至 90 ~ 100°C , 在此 温度下保温反应。 TLC跟踪反应, 直至原料转化完全。 反应毕, 减压浓缩料液, 残留物进行柱层析, 最终的得到式 A-2-1化合物 1.96g, 摩尔收率 80.7%。 实施例 14 ~ 24是 W为不同的醇保护基, X为溴, R7为不同的酸保护基时, 按照 施例 13的方法同法操作, 所得到的实验结果列表如下:
Figure imgf000015_0001
A-:
实施例 产物 W R7 收率 (% ) m/z
14 A-2-2 三氟乙酰基 曱基 76.1% 449/450/451
15 A-2-3 烯丙氧羰基 曱基 72.0% 437/438/439
16 A-2-4 叔丁氧羰基 三氟曱基 65.1% 507/508/509
17 A-2-5 三曱基硅烷基 苄基 78.7% 501/503/504
18 A-2-6 叔丁基二曱基硅烷基 对曱氧基苄基 83.5% 573/575/576
19 A-2-7 苯曱醜基 对硝基苄基 68.2% 578/579/580
20 A-2-8 对曱氧基苄基 对氯苄基 70.9% 583/585/586
21 A-2-9 对曱氧基苄氧羰基 苄基 83.3% 593/594/595
22 A-2-10 对硝基苄基 丙基 85.3% 516/517/518
23 A-2-11 对氯苄基 乙基 80.0% 491/493/494
24 A-2-12 苄基 乙基 78.9% 457/458/459
实施例 25: 式 A-3-1化合物(W为苄基, X为溴) 的制备
Figure imgf000015_0002
A-3-1
100ml单颈圓底烧瓶中依次加入式 A-2-12化合物(2g, 4.37mmol ), 50%氢氧 化钾(0.73g, 6.48mmol )水溶液, 曱醇 30ml, 升温至回流继续反应。 TLC跟踪 反应, 直至原料转化完全。 反应毕, 减压浓缩料液至干。 残留物进行柱层析, 最终的得到式 A-3-1化合物 1.84g, 摩尔收率为 97.9%。
¾ NMR (400 MHz, DMSO): δ = 1.80-1.87 (m, 2H), δ = 2.02 (s, 3Η), δ = 2.96 (t, / = 8.8 Hz, 2H), δ = 3.49-3.54 (m, 4H), δ = 3.61 (t, /= 7.6 Hz, 2H), δ = 4.47 (s, 2H), δ = 7.19 (s, 1H), δ = 7.27-7.37 (m, 6H), δ = 7.41 (s, 1H), δ = 12.26 (s, 1H). 实施例 26 ~ 29是选取实施例 20 ~ 24所制备得到的化合物为原料, 按照实 施例 25的方法同法操作进行酯解反应所得到的不同结果, 所得到的实验结果列 表如下:
Figure imgf000016_0001
A-3
实施例 产物 原料 试剂 收率( % ) m/z
26 A-3-9 A-2-8 K2C03 85.7 459/460/461
27 A-3- 10 A-2-9 LiOH 96.3 503/504/505
28 A-3-11 A-2-10 KOH 97.8 474/475/476
29 A-3-12 A-2-11 KOH 98.3 463/465/466 实施例 30: 式 A-4-1化合物(W为苄基, X为溴) 的制备
Figure imgf000016_0002
A-4-1
称取式 A-3-1化合物 (2g, 4.65mmol )和催化剂 Ir LiXL nY ( 0.74g, 0.00078mmol ) (此时催化剂中 R3为苯基, R4为苄基, L2为环辛基, n为 1 , Y 为四氟硼酸根)(此催化剂来自浙江九洲药业股份有限公司 ), 于装有搅拌子的 反应内管中, 加入三乙胺 (0.47g, 4.7mmol )和 150mL无水曱醇, 在氢气氛围 下加压至 12MPa, 70°C搅拌至氢气压力不再降低。 而后停止反应, 放出氢气, 将反应体系浓缩后,加入 100 mL乙醚稀释, 以 3 N盐酸调节体系至酸性,分液, 水相以乙醚 ( 100 mL )萃取两次, 合并有机相, 用饱和食盐水洗涤一次, 无水 石克酸钠干燥后浓缩得式 A-4-1化合物 1.91g, ifiNMR分析其转化率大于 99%。 用手性 HPLC分析其 ee值为 97%。 经柱层析得到产物收率 95.0%。
^ NMR (400 MHz, CDC13): δ = 1.15 (d, J = 6.8 Hz, 3H), δ = 1.87-1.94 (m, 2H), δ = 2.46-2.52 (m, 1H), δ = 2.61-2.70 (m, 1H), δ = 2.89-2.95 (m, 3H), δ = 3.45 (t, J = 8.4 Hz, 2H), δ = 3.57-3.60 (m, 4H), δ = 4.52 (s, 2H), 5 = 6.80 (s, 1H), δ = 7.00 (s, 1H), δ = 7.25-7.34 (m, 5H), δ = 9.52 (s, 1H). 实施例 31 ~ 48是按照实施例 30中的方法同法操作, 当 W为苄基, 或对曱氧基 苄基, X为溴,所用催化剂 IrO^XL^Y选用不同取代基团时所得到的实验结果, 如下:
Figure imgf000017_0001
A-4 (Sa,S)-SIPHOX
( )
31 苄基 苯基 氢 环辛基 1 氯 > 99 90
32 苄基 苯基 乙基 环辛基 1 三氟乙酰基 91
33 苄基 2, 5-二 苄基 1 , 5-环辛二 1 四 [ (3,5-二(三 > 99 95
异丙基 烯 氟曱基)苯基]
苯基 硼酸才艮
34 苄基 2, 5-二 苯基 1 , 5-环辛二 1 四苯基硼酸根 > 99 97
异丙基 烯
苯基
35 苄基 对曱基 乙基 乙烯 1 六氣碑酸才艮 > 99 97
苯基
36 苄基 2-异丁 苄基 1 , 5-己二烯 2 三氟曱磺酸根 > 99 93 基苯基
苄基 对曱基 对曱基 1, 5-己二烯 2 高氯酸根 > 99 98 苯基 苯基
苄基 降;;水片二 2 硝酸根 > 99 95 异戊基 异戊基
Figure imgf000018_0001
笨基 苯基
苄基 3-异丙 4-曱基 降冰片二 2 硫酸氢根 > 99 94 基苯基 苄基 烯
对曱 苯基 环辛基 > 99 91 氧基
苄基
对曱 苯基 环辛基 1 三氟乙酰基
氧基
苄基
对曱 苄基 1, 5-环辛 1 四 [ (3,5-二( . > 99 96 氧基 异丙基 婦 氟甲基)苯基:
苄基 苯基 硼酸才艮
对曱 苯基 1, 5-环辛 1 四苯基硼酸根 > 99 97 氧基 异丙基 烯
苄基 苯基
对曱 对曱基 乙基 乙烯 1 六氟磷酸根 > 99 96 氧基 苯基
苄基
对曱 2-异丁 苄基 1, 5-己二烯 2 三氟曱磺酸根 > 99 95 氧基 基苯基
苄基
对曱 对曱基 对曱基 1, 5-己二烯 2 高氯酸才艮 > 99 99 氧基 苯基 苯基
苄基
对甲 降冰片二 2 硝酸根 > 99 98 氧基 异戊基 异戊基 烯 苄基 苯基 苯基
48 对曱 3-异丙 4-曱基 降;;水片二 2 硫酸氢根 >99 93
氧基 基苯基 苄基 烯
苄基 实施例 49: 式 D-1 (W为苄基, X为溴, R6为苄基)化合物的制备
Figure imgf000019_0001
D-1
500ml单颈圓底烧瓶中依次加入式 A-4-1化合物(25.0g, 57.8mmol)、 叠氮磷 酸二苯酯(15.9g, 57.8mmol)、 二异丙基乙胺(8.2g, 63.6mmol) ), 升温至 60 ~ 65 °C, 在此温度下保温反应 1 ~3小时。 加入苯曱醇(9.4g, 87.0mmol), 升温至 90~95°C, 保温反应 10~24小时。 反应毕, 减压浓缩料液, 残留物进行柱层析, 最终的得到式 D-1化合物 24.1g, 摩尔收率为 77.7%。
¾ NMR (400 MHz, CDC13): δ= 1.09 (d,J= 6.8 Hz, 3H), δ = 1.87-1.94 (m, 2H), δ = 2.47-2.52 (m, 1H), δ = 2.66-2.71 (m, 1H), δ = 2.92 (t,J= 8.8 Hz, 2H), δ = 3.45 (t,J= 8.8 Hz, 2H), δ = 3.57-3.60 (m, 4H), δ = 3.83-3.91 (m, 1H), δ = 4.52 (s, 2H), δ = 4.594.63 (m, 1H), δ = 5.09 (s, 2H), δ = 6.79 (s, 1H), δ = 6.97 (s, 1H), δ = 7.25-7.37 (m, 10H). 实施例 50 ~ 57是选取实施例 31 ~48所制备得到的化合物为原料, 按照实 施 49的方法同法操作所得到的不同结果, 所得到的实验结果, 列表如下:
Figure imgf000019_0002
50 苄基 叔丁基 叔丁醇 Ί2Λ 502/503/504
51 苄基 对曱氧苄基 对曱氧苄醇 65.0 566/567/568 52 苄基 对硝基苄基 对硝基苄醇 55.4 581/582/583 53 苄基 二苯基曱基 二苯基曱醇 57.2 612/613/614 54 对曱氧基苄 叔丁基 叔丁醇 71.5 532/533/534 基
55 对曱氧基苄 对曱氧苄基 对曱氧苄醇 62.3 596/597/598 基
56 对曱氧基苄 对硝基苄基 对硝基苄醇 50.2 611/612/613 基
57 对曱氧基苄 二苯基曱基 二苯基曱醇 52.9 642/643/645 基 实施例 58: 式 1化合物的制备
Figure imgf000020_0001
将吲哚啉(92.05g, 0.774mol ), 3-氯丙基乙酸酯 ( 122.0g, 0.893mol), N, N-二异丙基乙胺( 336.2mL, 1.935mol ), 依次投入 lOOOmL三口瓶中, 加入异戊 醇机械搅拌, 装备冷凝回流装置, 回流反应 12小时。 反应液减压蒸馏去除大部 分异戊醇, 加入乙酸乙酯萃取, 有机层用无水 MgS04干燥, 减压蒸馏除去溶剂, 得到 189g深红色固体式 1化合物的粗品, 可无需纯化, 直接投入下步反应。
^MR ( 400MHz, CDC13 ): 5=1.953-1.987 ( m, 2H ), δ=2.102 ( s, 3H ), 5=2.971-3.012 ( t, 2H, J=8.4Hz ), 5=3.159-3.195 ( t, 2H, J=7.2Hz ), 5=3.346-3.388 ( t, 2H, J=8.4Hz ), 5=4.203-4.235 ( t, 2H, J=6.4Hz ), 5=6.484-6.504 ( d, 1H, J=8Hz ), 5=6.660-6.697 ( t, 1H, J=7.2Hz ), 5=7.072-7.110 ( m, 2H )。 实施例 59: 式 2化合物的制备
AcO(H2
Figure imgf000020_0002
取一三口瓶, 配温度计、 机械搅拌, 先将 400ml Ν,Ν-二曱基曱酰胺加入反 应瓶中, 冰水浴条件下滴加 POCl3 ( 163g, 1.07mol )大约 20~30分钟滴加完毕, 然后保持冰水浴反应搅拌 30分钟; 然后开始滴加式 1化合物( 156g, 0.713mol ) 的 Ν,Ν-二曱基曱酰胺溶液, 20~30分钟滴加完毕, 然后升温到 30°C反应 2~5小 时。 TLC检测跟踪至反应结束。 将反应液倒入冷水中, 加入 200mL乙酸乙酯萃 取掉其中的杂质, 水相用 50%NaOH溶液调 pH>13搅拌均匀, 加入 800mL乙酸 乙酯萃取, 有机相用无水 MgS04干燥, 减压去除溶剂得 150.2g白色固体式 2化 合物, 收率为 85.3%。
ifiNMR ( 400MHz, CDC13 ): 5=1.927-1.993 ( m, 2H ), δ=2.074 ( s, 3H ), 5=3.041-3.083 ( t, 2H, J=8.4Hz ), 5=3.301-3.337 ( t, 2H, J=7.2Hz ), 5=3.580-3.623 ( t, 2H, J=8.4Hz ), 5=4.140-4.171 ( t, 2H, J=6.4Hz ), 5=6.373-6.395 ( d, 1H, J=8.4Hz ), 5=7.546-7.563 ( m, 2H ), 5=9.664 ( s, 1H )。 实施例 60: 式 3化合物的制备
AcO(H2
Figure imgf000021_0001
取一两口瓶,将式 2化合物 ( 23.0g, 0.084mol )和磷叶立德 (50.8g, 0.133mol) 依次投入 400mLN,N-二曱基曱酰胺中, 回流搅拌 5 ~ 10小时, TLC跟踪至反应 结束, 柱层析分离得 28g黄色粘稠液体式 3化合物, 收率为 90%。
ifiNMlU 400MHz, CDC13 ): 5=1.315-1.351 ( t, 3H, J=7.2Hz ), 5=1.909-1.976 ( m, 2H ), 5=2.074 ( s, 3H ), 5=2.144-2.147 ( d, 3H, J=1.2Hz ), 5=2.984-3.026 ( t, 2H, J=8.4Hz ), 5=3.192-3.227 ( t, 2H, J=7.2Hz ), 5=3.424-3.466 ( t, 2H, J=8.4Hz ), 5=4.157-4.189 ( t, 2H, J=6.4Hz ), 5=4.215-4.269 ( m, 2H ), 5=6.414-6.434 ( d, 1H, J=8.4Hz ), 5=7.190-7.211 ( m, 2H ), 5=7.600 ( s, 1H )。 实施例 61 ~ 71是 W为不同的醇保护基, X为氢, R7为不同的酸保护基时, 按照 施例 60的方法同法操作, 所得到的实验结果列表如下:
Figure imgf000022_0001
A- 实施例 产物 W R7 收率 (% ) m/z
61 A-2-a 三氟乙酰基 曱基 93.2% 371/372
62 A-2-b 烯丙氧羰基 曱基 89.1% 359/360
63 A-2-c 叔丁氧羰基 三氟曱基 91.0% 429/430
64 A-2-d 三曱基硅烷基 苄基 85.2% 423/424
65 A-2-e 叔丁基二曱基硅烷基 对曱氧基苄基 86.4% 495/496
66 A-2-f 苯曱醜基 对硝基苄基 88.7% 500/501
67 A-2-g 对曱氧基苄基 对氯苄基 74.5% 505/506
68 A-2-h 对曱氧基苄氧羰基 苄基 84.1% 515/516
69 A-2-i 对硝基苄基 丙基 81.7% 438/439
70 A-2-j 对氯苄基 乙基 83.5% 413/415
71 A-2-k 苄基 乙基 81.3% 379/380 实施例 72: 式 4化合物的制备
Figure imgf000022_0002
取一单口瓶, 投入式 3化合物 ( 20.0g, 0.06mol ), 加入 300mL曱醇溶解, 另外溶解 NaOH ( 3.6g, 0.09mol )在 50mL水中加入其中, 搅拌, 内温控制在 10~25°C, TLC检测至反应完毕,减压蒸馏除去大部分曱醇,在用乙酸乙酯萃取, 水相用稀盐酸调节 pH=3~4, 过滤得到 13.7g黄色固体产物式 4化合物, 收率 87.7%。
ifiNMR ( 400MHz, DMSO ): 5=1.668-1.704 ( m, 2H ), 5=2.030-2.032 ( d, 3H, J=0.92Hz ), δ=2.915-2.957( t, 2H, J=8.4Hz ), δ=3.153-3.189( t, 2H, J=7.2Hz ), 5=3.393-3.435 (t, 2H, J=8.4Hz ), 5=3.464-3.495 (t, 2H, J=6.4Hz ), 5=4.453 (s, 1H), 5=6.474-6.495 ( d, 1H, J=8.4Hz ), 5=7.156-7.201 (m, 2H), 5=7.470 (s, 1H), 5=12.133 (s, 1H)。 实施例 73 ~ 78是选取实施例 61 ~ 66所制备得到的化合物为原料, 按照实 施例 72的方法同法操作进行酯解反应所得到的不同结果, 所得到的实验结果列 其中 X为氢:
Figure imgf000023_0001
A-3
实施例 产物 原料 试剂 收率(% )
73 A-3-2 A-2-a NaOH 88.3
74 A-3-3 A-2-b NaOH 86.8
75 A-3-4 A-2-c KOH 86.7
76 A-3-5 A-2-d NaHC03 76.3
77 A-3-6 A-2-e Na2C03 82.1
78 A-3-7 A-2-f NaOH 89.1 实施例 79: 式 5化合物的制备
HO(H2C')3
5
称取式 4化合物( 130mg, 0.5mmol )和催化剂 Ir(L (L2)nY( 1.9mg, 0.002mmol )
(此时催化剂中 R3为苯基, R4为苄基, L2为环辛基, n为 1, Y为四氟硼酸)(此 催化剂来自浙江九洲药业股份有限公司), 于装有搅拌子的反应内管中。 加入三 乙胺(50mg, 0.5mmol)和 2mL无水曱醇, 在氢气氛围下加压至 0.6 Mpa, 于 60°C下搅拌 1小时。 而后停止反应,放出氢气, 将反应体系浓缩后, 加入 10mL 乙醚稀释, 以 3N盐酸调节体系至酸性, 分液, 水相以 10mL乙醚萃取两次, 合 并有机相,用饱和食盐水洗涤,无水硫酸钠干燥。得 120mg式 5化合物, ^NMR 分析其转化率大于 99%, 用手性 HPLC分析其 ee值大于 99%。 经柱层析得到产 物收率 92%。
ifiNMlU 400MHz, DMSO ): δ=1.002-1.018( d, 3Η, J=6.4Hz ), 5=1.655-1.691 (m, 2H), 5=2.413-2.534 (m, 2H), 5=2.736-2.839 (m, 3H), 5=3.017-3.056 ( t, 2H, J=7.2Hz ), 5=3.217-3.258 (t, 2H, J=8.4Hz ), 5=3.473-3.504 ( t, 2H, J=6.4Hz ), 5=4.453 ( s, 1H), 5=6.365-6.384 ( d, 1H, J=8.4Hz), 5=6.775-6.795 ( d, 1H, J=8Hz ), 5=6.843 ( s, 1H), 5=12.034 ( s, 1H)。
MS: SIL50: 263.1521。 实施例 80 ~ 88是按照实施例 79的方法同法操作, 所用催化剂
Figure imgf000024_0001
选用不同取代基团时所得到的实验结果, 列表如下:
实施例 R3 R4 n Y ee ( % ) 收率 ( % )
80 苯基 氢 环辛基 1 氯 >99 88
81 苯基 乙基 环辛基 1 三氟乙酰 90
82 2, 5-二异 苄基 1, 5-环辛 1 四 [(3,5- >99 93
丙基苯基 二烯 二(三氟
曱基)苯
基]硼酸
根,
83 2, 5-二异 苯基 1, 5-环辛 1 四苯基硼 >99 93
丙基苯基 二烯 酸才艮
84 对曱基苯 乙基 乙烯 1 六氟磷酸 >99 94
基 根
85 2-异丁基 苄基 1, 5-己二 2 三氟曱磺 >99 92
苯基 烯 酸才艮
86 对曱基苯 对曱基苯 1, 5-己二 2 高氯酸才艮 >99 94
基 基 烯 3, 5-二异 3, 5-二异 降水片二 2 硝酸才艮 > 99 93 戊基苯基 戊基苯基 烯
3-异丙基 4-曱基苄 降水片二 2 硫酸氢根 > 99 91 苯基 基 烯 实施例 89: 式 6-1化合物 (式 6化合物中取 W为乙酰基 )的制备
Figure imgf000025_0001
将式 5化合物 ( 2.6g, O.Olmol )溶于 40mLTHF中, 加入三乙胺( 1.52g, 0.015mol), 搅拌; 在 0~5°C的条件下滴加乙酰氯( 1.2g, 0.015mol); 滴加完毕, 常温反应 12小时; 反应完毕, 减压蒸馏除去溶剂, 乙酸乙酯萃取, 水洗 2~3遍, 无水硫酸镁干燥,减压浓缩得 2.82g淡黄色粘稠液体式 6-1化合物,收率为 92.3%。
ifiNMl 400MHz, CDC13 ): δ=1.143-1.160( d, 3H, J=10.8Hz ), 5=1.911-1.946 (m, 2H), 5=2.070 (s, 3H), 5=2.512-2.566 (m, H), 5=2.668-2.686 (m, H), 5=2.906-2.946 (t, 2H, J=8.4Hz ), 5=2.964-2.995 (m, H), 5=3.095-3.131 (t, 2H, J=7.2Hz ), 5=3.293-3.334 (t, 2H, J=8.4Hz), 5=4.166-4.182 ( t, 2H, J=3.2Hz), 5=6.378-6.398 (d, 1H, J=8Hz ), 5=6.861-6.881 ( d, 1H, J=8Hz ), 5=6.903 ( s, 1H)。 实施例 90: 式 6-2化合物(式 6化合物中取 为苄基)的制备
Figure imgf000025_0002
按照实施例 72的方法同法操作, 滴加苄溴(2.57g, 0.015mol)得 2.74g式 6-2化合物, 收率为 77.6%。
需要说明的是在本发明中提及的所有文献在本申请中引用作为参考, 就如 同每一篇文献被单独引用作为参考那样。 此外应理解, 以上所述的是本发明的 具体实施例及所运用的技术原理, 在阅读了本发明的上述内容之后, 本领域技 术人员可以对本发明作各种改动或修改而不背离本发明的精神与范围, 这些等 价形式同样落在本发明的范围内。

Claims

权 利 要 求 、 一种具有下列式(A )结构式的化合物:
Figure imgf000027_0001
其中: X为氢或溴, R1为氢, 曱酰基或为具有下式结构的基团
Figure imgf000027_0002
R7为酸的保护基;
R2为 3-羟丙基或为具有下式结构的基团 其中 W为醇的保护基。
、 根据权利要求 1所述的化合物, 其特征在于, 其中所述 W选自乙酰基, 三氟 乙酰基, 烯丙氧羰基, 叔丁氧羰基, 三曱基硅烷基, 叔丁基二曱基硅烷基, 苯 曱酰基, 三苯曱基, 对曱氧基苄基, 对曱氧基苄氧羰基, 对硝基苄基, 间硝基 苄基, 对氯苄基, 间氯苄基, 对溴苄基, 间溴苄基, 苄基。
、 根据权利要求 1所述的化合物, 其特征在于, 其中所述 R7选自烷基或取代烷 基。
、 根据权利要求 3所述的化合物, 其特征在于, 其中所述烷基选自曱基, 乙基, 丙基; 所述取代烷基选自三氯曱基, 三氟曱基, 苄基, 对曱氧基苄基, 对硝基 苄基, 间硝基苄基, 对氯苄基, 间氯苄基, 对溴苄基, 间溴苄基或苄基。
、 根据权利要求 1所述的化合物, 其特征在于, 所述化合物选自具有以下结构 的化合物:
Figure imgf000027_0003
Figure imgf000028_0001
其中 W, X, R7的定义与权利要求 1的定义相同。
、 根据权利要求 5所述的化合物, 其特征在于, 其中所述式(A-2 )化合物由所 述的式(A-1 )化合物与下列的式(C )化合物作用制备得到,
Ph3P=C(CH3)COOR7
C , 其中所述 R7的定义与式(A-2 )化合物中 R7的定义相同。
、 根据权利要求 5所述的化合物, 其特征在于, 其中所述的式( A-3 )化合物由 所述的式(A-2 )化合物在碱性条件下水解制备得到。
、 根据权利要 7所述的化合物, 其特征在于, 其中所述碱为碱金属碱。
、 根据权利要求 5所述的化合物, 其特征在于, 其中所述式( A-4 )化合物由所 述式(A-3 )化合物在碱存在下进行不对称催化加氢反应制备得到。
、 根据权利要求 9所述的化合物, 其特征在于, 其中所述反应所用催化剂为 Ir(L (L2)nY, 其中:
为定义的化合物 (Sa,S)-SIPHOX;
Figure imgf000028_0002
(Sa,S)-SIPHOX 其中, R3为芳基; R4为氢, 烷基, 芳基或芳基烷基;
L2为环辛烯, 1,5-环辛二烯, 乙烯, 1,5-己二烯或降冰片二烯;
n为 1或 2;
Y为氯, 溴, 碘, 氟, 三氟乙酰基, 四氟硼酸根, 四 [(3,5-二 (三氟曱基)苯基]硼 酸根, 四苯基硼酸根, 六氟锑酸根, 六氟磷酸根, 三氟曱磺酸根, 曱磺酸根, 高氯酸根, 高溴酸根, 高碘酸根, 硝酸根, 硫酸氢根或乙酰丙酮根。 、 根据权利要求 9所述的化合物, 其特征在于, 其中所述碱为碱金属碱或有机 碱。
、 根据权利要求 5所述的化合物, 其中所述的式( A-4 )化合物进一步地, 在叠 氮磷酸二苯酯和二异丙基乙胺存在下与具有下列式(E )结构的化合物作用转化 为具有下列式(D )结构的化合物,
R。〇H
Figure imgf000029_0001
E , D
其中 X, W的定义与权利要求 1的定义相同, R6为酯的保护基。
、 根据权利要求 12所述的化合物, 其特征在于, 其中所述 R6选自叔丁基, 乙 婦基, 烯丙基, 苄基, 对曱氧苄基, 对硝基苄基或二苯基曱基。
、 一种具有所述式(A )结构的化合物的制备方法, 其特征在于, 由具有下列 式(B ) 结构的化合物在溴素作用下制备得到,
Figure imgf000029_0002
其中 X为溴, W, R1的定义与权利要求 1的定义相同。
、 一种具有式(A )结构化合物的用途, 用于制备西洛多辛。
、 根据权利要求 1所述的化合物, 其特征在于, 所述化合物选自具有以下结构 的化合物:
HO(H
Figure imgf000029_0003
其中 W的定义与权利要求 1的定义相同。
、 根据权利要求 16所述的化合物, 其特征在于, 其中所述式( 1 )化合物由吲 哚啉与 3-氯丙基乙酸酯在碱存在下进行亲电反应制备得到。
、 根据权利要求 16所述的化合物, 其特征在于, 其中所述式(2 )化合物由所 述的式( 1 )化合物在三氯氧磷作用下制备得到。
、 根据权利要求 16所述的化合物, 其特征在于, 其中所述式(4 )化合物由所 述的式(3 )化合物在碱作用下制备得到。
、 根据权利要求 16所述的化合物, 其特征在于, 其中所述式(6 )化合物由所 述的式(5 )化合物与亲电试剂进行反应制备得到。
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