CN1330071A - Synthetic method for benzo [b] thiophene derivative - Google Patents

Synthetic method for benzo [b] thiophene derivative Download PDF

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CN1330071A
CN1330071A CN00130796A CN00130796A CN1330071A CN 1330071 A CN1330071 A CN 1330071A CN 00130796 A CN00130796 A CN 00130796A CN 00130796 A CN00130796 A CN 00130796A CN 1330071 A CN1330071 A CN 1330071A
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D·W·霍尔德
W·D·卢克
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Eli Lilly and Co
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/10—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C323/11—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/16—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C313/00—Sulfinic acids; Sulfenic acids; Halides, esters or anhydrides thereof; Amides of sulfinic or sulfenic acids, i.e. compounds having singly-bound oxygen atoms of sulfinic or sulfenic groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C313/00—Sulfinic acids; Sulfenic acids; Halides, esters or anhydrides thereof; Amides of sulfinic or sulfenic acids, i.e. compounds having singly-bound oxygen atoms of sulfinic or sulfenic groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C313/08—Sulfenic acids; Derivatives thereof
    • C07C313/18—Sulfenamides
    • C07C313/20—Sulfenamides having sulfur atoms of sulfenamide groups bound to acyclic carbon atoms
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D223/08—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/56—Radicals substituted by oxygen atoms
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    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0834—Compounds having one or more O-Si linkage
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages

Abstract

The present invention is directed to novel vinyl sulfenic acid derivatives are useful for the synthesis of benzo[b]thiophenes, in particular 2-aryl-benzo[b]thiophenes.R9,R10,R11 and R12 defined in the description.

Description

The synthetic method of benzo [b] thiophene derivant
The application is that Chinese patent application number is 96195947.9, the applying date is on June 4th, 1996, denomination of invention is divided an application for the Chinese patent application of " synthetic method of ethene sulfenic acid derivative ".
The present invention is directed to new ethene sulfenic acid derivative and new synthetic method thereof.And ethene sulfenic acid derivative is used for the novel method of synthetic benzo [b] thiophene, especially for the novel method of Synthetic 2-aryl-benzo [b] thiophene.
Benzo [b] thiophene is by a lot of different route of synthesis preparations, and the method for an extensive employing is the oxidative cyclization reaction of adjacent mercapto-cinnamic acid.This approach is limited to prepare benzo [b] thiophene-2-carboxylate.2-phenyl benzo [b] thiophene is prepared through the acid catalysis cyclisation by 2-phenyl sulfoacetoaldehyde dioxane acetal.Unsubstituted benzo [b] thiophene is by vinylbenzene and sulfur catalysis condensation prepared.3-replaces benzo [b] thiophene by the preparation of aryl sulphomethyl ketone acid catalytic cyclization, but this approach is confined to prepare 3-alkyl benzo [b] thiophene.Referring to Campaigne, " Thiophenes and their BenzoDerivatives:(iii) Synthesis and Applications; " in ComprehensiveHeterocyclic Chemistry (Katritzky and Rees, eds.), Volume IV, Part III, 863-934 (1984).3-chloro-2-phenyl benzo [b] thiophene makes (Barton and Zika, J.Org.Chem., 35,1729-1733 (1970)) by dibenzenyl and sulfur dichloride reaction.Benzo [b] thiophene still because output is very low, and needs excessive temperature also by vinylbenzene sulfoxide pyrolysis preparation, makes this method be unsuitable for extensive synthetic production.Referring to Ando, J.Chem.Soc., Chem.Comm., 704-705 (1975).
Sulfenic acid is counted as the key intermediate of various chemical reactions, but the separation of these compounds but seldom has example to comply with, referring to Shelton and Davis, J.Am.Chem.Soc., 89 (3), people such as 718-719 (1968) and Davis, J.Am.Chem.Soc., 100,2844 (1978).Hypoiodous acid produces in original position, and with alkene and acetylene molecule in or intermolecular cyclization.Referring to people such as Mazzanti, J.Chem.Soc., Perkin Trans.I, people such as 3299-3004 (1944) and Davis, J.Org.Chem., 45,1650-1653 (1980).From corresponding N-Ben Yajiaji fragrance sulfinyl amine has been prepared a series of fragrant sulfenic acid trimethyl silyl esters, but the output of this trimethyl silyl ester is generally very low.People such as Davis, J.Org.Chem., 45,1650-1653 (1980).
United States Patent (USP) 4,133,814 and 4,380,635 have introduced the preparation method of 6-hydroxyl-2-(4-hydroxyphenyl) benzo [b] thiophene.The described method of this patent is (3-methoxyphenyl sulfo-)-4-methoxyacetophenone acid catalysis intramolecular cyclization/rearrangement.This starting compound is in pure Tripyrophosphoric acid, react about 3: 1 mixtures that obtain two kinds of regional isomer products, i.e. 6-methoxyl group-2-(4-methoxyphenyl)-benzo [b] thiophene and 4-methoxyl group-2-(4-methoxyphenyl) benzo [b]-thiophene down in about 85 ℃-Yue 90 ℃.These isomer benzo [b] thiophene co-precipitation from reaction mixture go out, and obtain containing the mixture of these two kinds of compounds.For obtaining the single area isomer, essential with this regional isomer separation, for example adopt chromatogram or fractionation crystallization.Therefore, need a kind ofly at present, the method for regiospecificity ground Synthetic 2-aryl benzo [b] thiophene is effectively arranged from the raw material that is easy to get.
The present invention is directed to new ethene sulfenic acid derivative: new sulfenic acid silicomethane ester, sulphenamide, and disulphide; And at the synthetic method of ethene sulfenic acid derivative.Specifically, the present invention relates to following formula: compound:
Figure A0013079600051
Wherein
R 1Be hydrogen, C 1-C 4Alkoxyl group, aralkoxy, halogeno-group, or amino;
R 2Be hydrogen, C 1-C 4Alkoxyl group, aralkoxy, halogeno-group, or amino;
R 4Be OSi (R) 3, NR 5R 6, or SR 8
Each R is respectively C separately 1-C 6Alkyl, aryl, or aralkyl;
R 5And R 6Be respectively hydrogen, C separately 1-C 6Alkyl, aralkyl or aryl, perhaps R 5And R 6Form ring with nitrogen-atoms, described ring is selected from piperidines, tetramethyleneimine, morpholine or hexamethylene imine;
R 8Be C 1-C 6Alkyl, aryl or aralkyl.
The present invention includes the independently E and the Z isomer of formula III compound, or its mixture.These E and Z regional isomer are represented by following structural formula:
Figure A0013079600061
Another aspect of the present invention is the method for preparing sulfenic acid silicomethane ester sulphenamide and disulphide.The present invention is directed to the method for preparing following formula: compound,
Figure A0013079600062
Wherein
R 1Be hydrogen, C 1-C 4Alkoxyl group, aralkoxy, halogeno-group, or amino;
R 2Be hydrogen, C 1-C 4Alkoxyl group, aralkoxy, halogeno-group, or amino;
R 4Be OSi (R) 3, NR 5R 6, or SR 8
Each R distinguishes each C naturally 1-C 6Alkyl, aryl, or aralkyl;
R 5And R 6Be respectively hydrogen, C separately 1-C 6Alkyl, aralkyl or aryl; Perhaps R 5And R 6Form ring with nitrogen-atoms, described ring is selected from piperidines, tetramethyleneimine, morpholine or hexamethylene imine;
R 8Be C 1-C 6Alkyl, aryl or aralkyl;
This method comprises:
(1) with following formula: compound:
Figure A0013079600063
(R wherein 1And R 2Define the same, and R 3Be thermolability, or the C of acid labile 2-C 10Alkyl, C 4-C 10Alkenyl or aryl (C 1-C 10Alkyl)) with the silylation reagent react, generate the sulfenic acid silyl ester of following formula,
Figure A0013079600071
(R wherein 1And R 2Define the same; R 7Be OSi (R) 3Each R is respectively C separately 1-C 6Alkyl, aryl, or aralkyl);
(2) arbitrarily with above-mentioned sulfenic acid silyl ester and formula HNR 5R 6(R wherein 5And R 6Define the same) amine reaction; Perhaps
(3) arbitrarily with above-mentioned sulfenic acid silyl ester and formula HSR 8(R wherein 8Define the same) mercaptan, in the presence of amine alkali the reaction.
One aspect of the present invention is synthetic sulfenic acid silicomethane ester, and promptly the method for formula IV compound specifically, the present invention relates to prepare the method for following formula: compound, Wherein
R 1Be hydrogen, C 1-C 4Alkoxyl group, aralkoxy, halogeno-group, or amino;
R 2Be hydrogen, C 1-C 4Alkoxyl group, aralkoxy, halogeno-group, or amino;
R 7Be OSi (R) 3
Each R is respectively C separately 1-C 6Alkyl, aryl, or aralkyl;
This method comprises reacts following formula: compound and sillylation reagent,
Figure A0013079600081
Wherein
R 1And R 2Define the same;
R 3Be thermolability or acid labile C 2-C 10Alkyl, C 4-C 10Alkenyl, or aryl (C 1-C 10Alkyl).
Another aspect of the present invention is synthetic sulphenamide, and promptly the method for formula V compound specifically, the present invention relates to prepare the method for following formula: compound, Wherein
R 1Be hydrogen, C 1-C 4Alkoxyl group, aralkoxy, halogeno-group or amino;
R 2Be hydrogen, C 1-C 4Alkoxyl group, aralkoxy, halogeno-group or amino;
R 5And R 6Be respectively hydrogen, C separately 1-C 6Alkyl, aralkyl or aryl, perhaps R 5And R 6Form ring with nitrogen-atoms, described ring is selected from piperidines, tetramethyleneimine, morpholine or hexamethylene imine;
This method comprises the following steps:
(1) makes following formula: compound
Figure A0013079600083
(R wherein 1And R 2Define the same, and R 3Be thermolability or acid labile C 2-C 10Alkyl, C 4-C 10Alkenyl, or aryl (C 1-C 10Alkyl)), produce following formula sulfenic acid silicomethane ester with the sillylation reagent reaction:
Figure A0013079600091
Wherein
R 1And R 2Define the same;
R 7Be OSi (R) 3
Each R is respectively C 1-C 6Alkyl, aryl or aralkyl;
(2) with described sulfenic acid silicomethane ester and formula HNR 5R 6(R wherein 5And R 6Define the same) the amine reaction.
Another aspect of the present invention is a synthesizing disulfides, i.e. the method for formula XIV compound.Specifically, the present invention relates to prepare the method for following formula: compound,
Figure A0013079600092
Wherein
R 1Be hydrogen, C 1-C 4Alkoxyl group, aralkoxy, halogeno-group, amino;
R 2Be hydrogen, C 1-C 4Alkoxyl group, aralkoxy, halogeno-group, amino;
R 8Be C 1-C 6Alkyl, aryl or aralkyl;
This method comprises the steps:
(1) with following formula: compound,
Figure A0013079600101
(R wherein 1And R 2Define the same, and 3Be thermolability or acid labile C 2-C 10Alkyl, C 4-C 10Alkenyl or aryl (C 1-C 10Alkyl)) with the sillylation reagent reaction, produce following formula sulfenic acid silicomethane ester,
Figure A0013079600102
It is
R 1And R 2Define the same;
R 7Be OSi (R) 3
Each R is respectively C separately 1-C 6Alkyl, aryl or aralkyl;
(2) make described sulfenic acid silicomethane ester and formula HSR 8(R wherein 8Define the same) mercaptan, in the presence of amine alkali the reaction.
Another aspect of the present invention is the method for synthetic following formula: compound,
Figure A0013079600103
Wherein
R 9Be hydrogen, halogeno-group, amino or hydroxyl;
R 10Be hydrogen, halogeno-group, amino or hydroxyl;
R 11And R 12Be respectively C separately 1-C 4Alkyl, or R 11And R 12The nitrogen-atoms that is adjacent forms heterocycle together, and described heterocycle is selected from pyrrolidino (i.e. 1 base), piperidino-(1-position only), hexamethylene imine and morpholino (4 bases);
HX is HCl or HBr;
This method comprises the steps:
(a) in the presence of acid catalyst, make the following formula: compound cyclisation, Wherein
R 1Be hydrogen, C 1-C 4Alkoxyl group, aralkoxy, halogeno-group, or amino;
R 2Be hydrogen, C 1-C 4Alkoxyl group, aralkoxy, halogeno-group, or amino;
R 4Be OSi (R) 3, NR 5R 6Or SR 8
Each R distinguishes each C naturally 1-C 6Alkyl, aryl, or aralkyl;
R 5And R 6Be respectively hydrogen, C separately 1-C 6Alkyl or aryl, or R 5And R 6Form ring with nitrogen-atoms, described ring is selected from piperidines, tetramethyleneimine, morpholine and hexamethylene imine;
R 8Be C 1-C 6Alkyl, aryl or aralkyl; Prepare the following formula benzothienyl compounds thus, R wherein 1And R 2Define the same;
(b) use the following formula acylting agent, with described benzothienyl compounds acylations,
Figure A0013079600121
Wherein
R 11, R 12, and HX definition the same;
R 13Be chloro base, bromo base or hydroxyl; The described BX ' that is reflected at 3(wherein X ' is chloro base or bromo base) carries out under existing;
(c) if R 1And/or R 2Be C 1-C 4Alkoxyl group or aralkoxy are then by adding extra BX ' 3(wherein X ' definition is the same) makes one or more phenolic group dealkylations of the acylations product of step (b);
(d) isolate formula XIII compound.
So-called " acid catalyst " expression Lewis acid or Bronsted acid.Representational Lewis acid comprises zinc chloride, zinc iodide, aluminum chloride and aluminum bromide.Representational Bronsted acid comprises mineral acid, for example sulfuric acid and phosphoric acid; Comprise carboxylic acid, for example acid and trifluoroacetic acid; Comprise sulfonic acid, for example methylsulfonic acid, Phenylsulfonic acid, 1-naphthalene sulfonic aicd, 1-fourth sulfonic acid, ethyl sulfonic acid, 4-ethyl phenenyl azochlorosulfonate acid, the own sulfonic acid of 1-, 1,5-naphthene sulfonic acid, the hot sulfonic acid of 1-, camphorsulfonic acid, trifluoromethanesulfonic acid and tosic acid; And comprise polymerization aryl sulfonic acid, for example Nafion , Amberlyst , or Amberlite It is sulfonic acid or polymkeric substance sulfonic acid that the inventive method is used for catalytic preferred acid catalyzer.Preferred acid catalyst is a sulfonic acid, for example methylsulfonic acid, Phenylsulfonic acid, camphorsulfonic acid and tosic acid.Most preferred acid catalyst is a tosic acid.
In the top molecular formula, so-called " C 1-C 4Alkoxyl group " representation methoxy, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, tert.-butoxy and similar group.So-called " halogeno-group " refers to fluorine, chlorine, bromine or iodine group.
So-called " C 1-C 6Alkyl " represent the 1-6 carbon alkyl of straight or branched.General C 1-C 6Alkyl comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, n-hexyl, 2-methyl amyl or the like.So-called " C 1-C 4Alkyl " represent the 1-4 carbon alkyl of straight or branched, it comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-and the tertiary butyl.
So-called " aryl " represents the group of phenyl and substituted-phenyl and so on.So-called " substituted-phenyl " representative is by the phenyl that is selected from the following one or more replacements of group, i.e. halogeno-group, hydroxyl, nitro, C 1-C 4Alkyl, C 1-C 4The phenyl that alkoxyl group, trichloromethyl and trifluoromethyl replace.The example of substituted-phenyl comprises the 4-chloro-phenyl-, 2, the 6-dichlorophenyl, 2, the 5-dichlorophenyl, 3, the 4-dichlorophenyl, the 3-chloro-phenyl-, the 3-bromophenyl, the 4-bromophenyl, 3, the 4-dibromo phenyl, 3-chloro-4-fluorophenyl, the 2-fluorophenyl, the 4-hydroxyphenyl, the 3-hydroxyphenyl, 2, the 4-dihydroxyphenyl, 3-nitre phenyl, 4-nitre phenyl, 2,4-dinitro phenyl, the 4-tolyl, 4-ethylbenzene base, the 4-methoxyphenyl, the 4-propyl phenyl, 4-n-butyl benzene base, 4-trimethylphenylmethane base, 3-fluoro-2-tolyl, 2, the 3-difluorophenyl, 2, the 6-difluorophenyl, 2, the 6-xylyl, 2-fluoro-5-tolyl, 2,4, the 6-trifluorophenyl, 2-fluoroform phenyl, 2-chloro-5-fluoroform phenyl, 3,5-two (trifluoromethyl) phenyl, the 2-methoxyphenyl, the 3-methoxyphenyl, 3, the 5-dimethoxy phenyl, 4-hydroxyl-3-tolyl, 3, the 5-xylyl, the 4-hydroxyphenyl, 2-methyl-4-nitre phenyl, 4-methoxyl group-2-nitre phenyl or the like.
So-called " aralkyl " expression has the C of one or more aryl 1-C 4Alkyl.Representational this gene comprises benzyl, ortho-nitrophenyl methyl, p-nitrophenyl methyl, to halogeno-benzene methyl (for example to the chlorinated benzene methyl, to bromobenzene methyl, right-the phenyl-iodide methyl), 1-styroyl, 2-styroyl, 3-hydrocinnamyl, 4-benzene butyl, 2-methyl-2-hydrocinnamyl, (2, the 6-dichlorophenyl) methyl, two (2, the 6-dichlorophenyl) methyl, (4-hydroxyphenyl) methyl, (2,4-dinitro phenyl) methyl, diphenyl-methyl, trityl, (right-methoxyphenyl) diphenyl-methyl, two (p-methoxyphenyl) methyl, two (2-nitre phenyl) methyl or the like.
So-called " aralkoxy " expression has the C of one or more aryl 1-C 4Alkoxyl group.Representational this group comprises benzyloxy, adjacent nitro benzyloxy, to the nitro benzyloxy, to the halo benzyloxy (for example to chloro benzyloxy, to the bromo benzyloxy, to the iodo benzyloxy), the 1-phenyl ethoxy, the 2-phenyl ethoxy, 3-phenyl propoxy-, 4-phenyl butoxy, 2-methyl-2-phenyl propoxy-, (2, the 6-dichlorophenyl) methoxyl group, two (2, the 6-dichlorophenyl) methoxyl group, (4-hydroxyphenyl) methoxyl group, (2, the 4-dinitrophenyl) methoxyl group, two benzyloxies, three benzyloxies, (right-methoxyphenyl)-two benzyloxies, two (right-methoxyphenyl) methoxyl group, two (2-nitre phenyl) methoxyl group or the like.
So-called " thermolability or acid labile C 2-C 10Alkyl, C 4-C 10Alkenyl or aryl (C 1-C 10Alkyl) " be illustrated in and be heated or, easily the group of from sulfoxide (SO) base, removing with under the acid catalyst treatment condition.Described thermolability or acid labile C 2-C 10Alkyl is a tool 2-10 carbon atom, and the straight or branched alkyl chain of at least one β-hydrogen atom is arranged.Representational thermolability or acid labile C 2-C 10Alkyl comprises ethyl, n-propyl, sec.-propyl, 1,1-dimethylpropyl, normal-butyl, sec-butyl, the tertiary butyl, 1,1-diformazan butyl, 2-first butyl, 3-first butyl, 1-first butyl, 1,2-diformazan butyl, 1,3-diformazan butyl, 2,4-diformazan butyl, 3,3-diformazan butyl, n-pentyl, 1-first amyl group, 2-first amyl group, 3-first amyl group, 4-first amyl group, n-hexyl or the like.Thermolability or acid labile C 4-C 10Alkenyl is to have a 4-10 carbon atom, at least one unsaturated position, the straight or branched alkenylene chain of β-hydrogen atom or δ-hydrogen atom.Representational thermolability or acid labile C 4-C 10Alkenyl comprises crotyl, the 3-butenyl, 2-methyl-2-butene base, 3-methyl-2-butene base, 2-methyl-3-butenyl, pentenyl, the 3-pentenyl, the 4-pentenyl, 2-methyl-pentenyl, 3-methyl-pentenyl, 4-methyl-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, the 2-hexenyl, the 3-hexenyl, the 4-hexenyl, 5-hexenyl or the like.So-called thermolability or acid labile aryl (C 1-C 10Alkyl) expression also contains the thermolability or the acid labile C of one or more aryl and aryl substituent methyl in addition 2-C 10Alkyl.Representational aryl (C 1-C 10Alkyl) comprise benzyl, diphenyl-methyl, trityl, to methoxybenzyl, 2-styroyl, 2-hydrocinnamyl, 3-hydrocinnamyl or the like.
One group of product of the present invention is a sulfenic acid silicomethane ester.Specifically, formula III compound (R wherein 4Be OSi (R) 3, and each R distinguishes each C naturally 1-C 6Alkyl, aryl or aralkyl) and formula IV compound all are silicomethane esters of sulfenic acid.The nomenclature that preferred sulfenic acid silicomethane ester uses chemical field to generally acknowledge is given and abbreviation, and is as shown in the table.Table 1
Be called for short Silyl
????TMS ????TES ????TIPS Trimethyl silyl triethylsilyl triisopropyl silyl
????DMIPS ????DEIPS ????TDS ????TBDMS ????TBDPS ????TBS ????TPS ????DPMS ????TBMPS The dimethyl isopropyl silicyl diethyl isopropyl silicyl dimethyl hexyl silicyl t-butyldimethylsilyl t-butyldiphenylsilyl tribenzyl silicyl triphenyl silicyl diphenyl methyl silicyl tert-butyl group two (anisyl) silicyl
So-called " sillylation reagent ", expression is used for the sulfenic acid intermediate is converted into the compound of sulfenic acid silyl ester, or combination of compounds.Representational sillylation reagent comprises two (trialkylsilkl) urea, for example 1,3-two (trimethyl silyl) urea, 1,3-two (triethylsilyl) urea, 1,3-two (dimethyl sec.-propyl silyl) urea, 1,3-two (triisopropyl silyl) urea, 1,3-two (diethyl sec.-propyl silyl) urea, 1,3-two (dimethyl hexyl silyl) urea and 1,3-two (t-butyldimethylsilyl) urea; Comprise two (diarye silyl) urea, for example 1,3-two (triphenyl silyl) urea; Comprise two (alkyl diaryl silyl) urea, for example 1,3-two (diphenyl methyl silyl) urea and 1,3-two (t-butyldiphenylsilyl) urea; And comprise six alkyl disilazanes (hexaalkyldisilylzane), for example hexamethyl-disilazane (hexamethyldisilylzane); The perhaps binding substances of the chloro trialkyl silane of six alkyl disilazanes and catalytic amount (for example chloro trimethyl silane).
The formula III compound is with two kinds of regional isomer forms, and promptly E type and Z type exist.These E types and Z type regional isomer are represented by following structural formula:
Figure A0013079600151
Can prepare the raw materials used compound of the inventive method by a lot of approach.A kind of method of preparation formula II compound is shown in scheme 1.Scheme 1
Figure A0013079600161
Generally be with formula VII compound and formula HSR 3Mercaptan in the presence of Lewis acid, react, make it to change into the vinylbenzene thioether.And then formula VIII compound oxidation become the vinylbenzene sulfoxide, i.e. formula II compound.
More particularly, handle formula VII (wherein, R with the Lewis acid of titanium chloride (IV) and so on 1And R 2Define the same) compound.This is reflected in the anhydrous organic solvent (for example anhydrous tetrahydro furan), carries out under about 0 ℃-Yue 35 ℃ of temperature.After about 15 minutes to about 1 hour, with amine alkali and formula HSR 3The thiol treatment reaction mixture, formula HSR 3Middle R 3Be thermolability or acid labile C 1-C 10Alkyl, C 4-C 10Alkenyl or aryl (C 1-C 10Alkyl).The solution that preferably this sulphur alkohol and amine alkali is made into reaction solvent adds.Representational amine alkali is triethylamine.Add after the sulphur alkohol and amine alkali, generally reactant is heated to about 35 ℃-Yue 65 ℃, preferred about 50 ℃.Use the chemical field known technology this reaction product can be purified, for example by crystallization, or chromatogram etc.
Then with formula VIII compound (R wherein 1, R 2And R 3Define the same) oxidation production II compound.The suitable oxygenant of this reaction is a peracid, for example peracetic acid and metachloroperbenzoic acid, and hydrogen peroxide.This oxidizing reaction is for example carried out in toluene, methylene dichloride, chloroform or the tetracol phenixin generally at organic solvent.If make oxygenant with peracid, then this reaction is generally being carried out under-30 ℃-Yue 15 ℃ of temperature approximately, preferred-20 ℃ approximately.Adopt recrystallization method to be easy to reaction product is purified.If R 3Be the tertiary butyl, then the crystallized product of this reaction result is a formula II E type regional isomer.
If R 3Tertiary carbon atom and sulphur atom adjacency are arranged, then can be by second kind of approach shown in the following scheme 2, the Z type regional isomer of preparation formula II compound selectively.Scheme 2
Figure A0013079600171
In general, with benzylalcohol, i.e. formula IX compound is with formula R 3The thiol reactant of SH produces benzyl thioether, i.e. formula X compound.Make the reaction of this benzyl thioether and highly basic, form the benzyl anionic compound, make it and the phenyl aldehyde condensation.This condensation product and chloride of acid reaction are handled the gained intermediate with second highly basic, generate the vinylbenzene thioether, i.e. formula VIIIZ compound.Then with oxygenant with this vinylbenzene sulfide oxidation, production IIZ compound.
Should synthesize the first step of Z type vinylbenzene sulfoxide compound, be that benzylalcohol is converted into benzyl thioether, i.e. formula X compound.In the presence of Lewis acid, make formula IX compound (R wherein 2Define the same) and formula R 3SH (R wherein 3Be thermolability or acid labile C 2-C 10Alkyl, C 4-C 10Alkenyl or aryl (C 1-C 10Alkyl), these groups have tertiary carbon atom and sulphur atom in abutting connection with) thiol reactant, generate benzyl thioether, i.e. formula X compound.The suitable Lewis acid of this conversion is zinc bromide, zinc chloride, zinc iodide, iron(ic) chloride, titanium chloride (IV), aluminum chloride and alchlor, preferred zinc iodide.This reaction is generally at organic solvent, and for example 1, carry out in 2-ethylene dichloride or the methylene dichloride.If reaction is at room temperature carried out, then this is finished after reacting on about 18 hours.
Benzyl thioether and highly basic reaction form the benzyl anionic compound.The suitable highly basic of this reaction comprises metal alkoxide, for example sodium methylate, sodium ethylate, lithium ethoxide, trimethyl carbinol lithium and potassium tert.-butoxide; Comprise sodium hydride; And comprise lithium alkylide, for example n-Butyl Lithium, tert-butyl lithium, s-butyl lithium and lithium methide.This reacts preferred highly basic is n-Butyl Lithium.This reacts preferred solvent is anhydrous tetrahydro furan.If make highly basic with n-Butyl Lithium, then this reacts on approximately and carries out under-35 ℃-Yue-15 ℃ temperature.
Benzyl anionic compound and phenyl aldehyde condensation, condensation product in the middle of preparing.Described phenyl aldehyde general formula is p-R 1(C 6H 4) CHO, wherein R 1Be hydrogen, C 1-C 4Alkoxyl group, aralkoxy, halogeno-group or amino.Preferred preparation benzyl anionic compound, and by adding phenyl aldehyde in the cold soln of benzyl anionic compound and original position forms condensation product.
Handle this condensation product with chloride of acid and produce midbody compound.Representational chloride of acid comprises acyl chlorides, for example Acetyl Chloride 98Min. and benzyl acyl chlorides; Comprise SULPHURYL CHLORIDE, for example methylsulfonyl chloride, benzene sulfonyl chloride, 1-fourth SULPHURYL CHLORIDE, ethyl sulfonyl chloride, different third SULPHURYL CHLORIDE and Tosyl chloride; Comprise carbalkoxy chlorine, for example methoxycarbonyl chlorine, and Carbobenzoxy Chloride; And comprise dialkylamino carbonyl chlorine, N for example, N-dimethylamino carbonyl chlorine; Preferred SULPHURYL CHLORIDE.After forming, preferred condensation product in very short time methylsulfonyl chloride is added in the reaction mixture.
The reaction of described midbody compound and second highly basic generates the vinylbenzene thioether, i.e. formula VIIIZ compound (R wherein 1, R 2And R 3Define the same).The suitable highly basic of this reaction comprises metal alkoxide, for example sodium methylate, sodium ethylate, lithium ethoxide, trimethyl carbinol lithium and potassium tert.-butoxide; Comprise sodium hydride; Comprise lithium alkylide, for example n-Butyl Lithium, tert-butyl lithium, s-butyl lithium and lithium methide; And comprise metal amide, for example sodium amide, diisopropylaminoethyl magnesium and diisopropylaminoethyl lithium.This reacts preferred highly basic is potassium tert.-butoxide.In general, this reacts under about 15 ℃-Yue room temperature and carries out, preferred room temperature.
With the vinylbenzene sulfide oxidation, prepare corresponding vinylbenzene sulfoxide.The oxygenant that is suitable for this reaction is a peracid, for example a peracetic acid and a chloro peroxybenzoic acid; Be organo-peroxide, tert-butyl peroxide for example; And be hydrogen peroxide.Preferred oxidant is a peracetic acid.This oxidizing reaction is generally at organic solvent, for example toluene, benzene, dimethylbenzene, methyl alcohol, ethanol, methyl acetate, ethyl acetate, methylene dichloride, 1, and the 2-ethylene dichloride, or carry out in the chloroform; Preferred methylene dichloride.This oxidizing reaction can be in carrying out under-40 ℃-Yue 0 ℃ of temperature approximately.
In addition, if R 3Tertiary carbon atom and sulphur atom adjacency are arranged, and this benzyl thioether intermediate (formula X compound) can be used for producing the vinylbenzene sulfoxide, i.e. the E type of formula II compound and Z type mixture of isomers.Should be synthetic shown in scheme 3.Scheme 3
Figure A0013079600191
With the benzyl thioether oxidation of preparation as mentioned above, generate corresponding benzyl sulfoxide.This benzyl sulfoxide again with highly basic reaction, the gained anionic compound again with the phenyl aldehyde condensation.The gained condensation product reacts with chloride of acid again, and the gained midbody compound reacts with second highly basic again, produces the vinylbenzene sulfoxide.
Benzyl thioether, i.e. formula X compound (R wherein 2Define the same, and R 3Be thermolability or acid labile C 2-C 10Alkyl, C 4-C 10Alkenyl or aryl (C 1-C 10Alkyl), these groups have tertiary carbon atom and sulphur atom adjacency) oxidized, produce corresponding benzyl sulfoxide, i.e. formula XI compound.The suitable oxygenant of this reaction is a peracid, for example a peracetic acid and a chloro peroxybenzoic acid; Be organo-peroxide, tert-butyl peroxide for example; And be hydrogen peroxide.Preferred oxidant is a peracetic acid.This oxidizing reaction is generally at organic solvent, and for example toluene, benzene, dimethylbenzene, methyl alcohol, ethanol, methyl acetate, ethyl acetate, methylene dichloride, 1 carry out in 2-ethylene dichloride or the chloroform; Be preferable over approximately and carry out under-30 ℃-Yue 5 ℃ of temperature.
Make benzyl sulfoxide, i.e. formula XI compound (R wherein 2And R 3Define the same) react with highly basic, generate the benzyl anionic compound.The suitable highly basic of this reaction comprises metal alkoxide, for example sodium methylate, sodium ethylate, lithium ethoxide, trimethyl carbinol lithium and potassium tert.-butoxide; Comprise sodium hydride; Comprise lithium alkylide, for example n-Butyl Lithium, tert-butyl lithium, s-butyl lithium and lithium methide; Comprise the metal amide, for example sodium amide, diisopropylaminoethyl magnesium and diisopropylaminoethyl lithium.The preferred alkali of this conversion reaction is n-Butyl Lithium.This deprotonation is reflected at anhydrous organic solvent, tetrahydrofuran (THF) for example, or 1, in the 2-glycol dimethyl ether, carry out under-25 ℃ of left and right sides temperature.
Need not separate and make this benzyl anionic compound and formula p-R 1(C 6H 4) CHO (R wherein 1Define the same) the benzaldehyde compound condensation.Preferably about 1 equivalent phenyl aldehyde is joined in the cold soln of preparation as in the previous paragraph.The non-enantiomer mixture of gained condensation product can be separated, perhaps preferably not separate and be used for the next step.
This condensation product and chloride of acid reaction produce midbody compound.Use alkali (for example n-Butyl Lithium) to handle arbitrarily this condensation product, and react with chloride of acid.Representational chloride of acid comprises acyl chlorides, for example Acetyl Chloride 98Min. and benzyl acyl chlorides; Comprise SULPHURYL CHLORIDE, for example methylsulfonyl chloride, benzene sulfonyl chloride, 1-fourth SULPHURYL CHLORIDE, ethyl sulfonyl chloride, different third SULPHURYL CHLORIDE and p-toluenesulfonyl chloride; Comprise carbalkoxy chlorine, for example methoxycarbonyl chlorine and Carbobenzoxy Chloride; And comprise dialkylamino carbonyl chlorine, N for example, N-dimethylamino carbonyl chlorine; Preferred SULPHURYL CHLORIDE.Chloride of acid is joined in the cold reaction mixture, make the gained mixture rise to room temperature then.Preferred condensation product forms the back and in very short time methylsulfonyl chloride is joined in the reaction mixture, in order to avoid need to add extra alkali.
The reaction of gained midbody compound and second highly basic produces E type and Z type vinylbenzene sulfoxide, i.e. formula II compound (R wherein 1, R 2And R 3Define the same).Second highly basic that representativeness is used for this elimination reaction comprises metal alkoxide, for example sodium methylate, sodium ethylate, lithium ethoxide, trimethyl carbinol lithium, and potassium tert.-butoxide; Comprise sodium hydride; Comprise lithium alkylide, for example n-Butyl Lithium, tert-butyl lithium, s-butyl lithium and lithium methide; Comprise the metal amide, for example sodium amide, diisopropylaminoethyl magnesium and diisopropylaminoethyl lithium.The preferred alkali of this conversion reaction is potassium tert.-butoxide.It is excessive 20% that preferred this second highly basic adds, for example 1.2 equivalents.Generally speaking, this is reflected under about 15 ℃-room temperature and carries out, preferred room temperature.
Can be from formula II compound The compounds of this invention.Prepare new sulfenic acid silicomethane ester shown in scheme 4 from the vinylbenzene sulfoxide.Scheme 4
Generally be with formula II compound and sillylation reagent reaction, prepare sulfenic acid silicomethane ester, wherein R 1, R 2And R 7Define the same, and R 3Be thermolability or acid labile C 1-C 10Alkyl, C 4-C 10Alkenyl or aryl (C 1-C 10Alkyl), this reaction The suitable solvent comprises that benzene,toluene,xylene and boiling point are greater than or equal to 80 ℃ high boiling point halogenated hydrocarbon solvent, for example, and vinyl trichloride.Suitable sillylation reagent comprises two (trialkylsilkl) urea, for example 1,3-two (trimethyl silyl) urea, 1,3-two (triethylsilyl) urea, 1,3-two (dimethyl sec.-propyl silyl) urea, 1,3-two (t-butyldimethylsilyl) urea; Comprise two (diarye silyl) urea, for example 1,3-two (triphenyl silyl) urea; Comprise two (di alkylaryl silyl) urea, for example 1,3-two (diphenyl methyl silyl) urea; And comprise six alkyl disilazane, for example hexamethyl-disilazanes; The perhaps binding substances of six alkyl disilazanes and catalytic amount chloro trialkyl silane (for example chloro trimethyl silane).For optimum, after addition reaction was finished, the ultimate density of formula II compound was the about 0.5M of about 0.001M-.Preferred excessive slightly (for example 10%) sillylation reagent that uses.This is reflected at about 80 ℃-Yue 140 ℃ and carried out about 10 minutes-Yue 2 hours.Therefore because Z type isomerization reaction is more faster than corresponding E-isomer,, finish then that to transform required time shorter if when having only Z type isomer to make starting compound to use.
By scheme 5, prepare new sulphenamide from sulfenic acid silicomethane ester.Scheme 5
Figure A0013079600212
Usually be to prepare sulfenic acid silicomethane ester (R wherein from the vinylbenzene sulfoxide 1, R 2And R 7Define the same), preferably need not separate or purify, make itself and formula HNR 5R 6(R wherein 5And R 6Define the same) amine reaction, normally, during preparation sulfenic acid silicomethane ester, reaction soln is chilled to about 0 ℃-Yue 50 ℃, and with described amine processing.The preferred 1 equivalent-2 equivalent amine that uses.Changing into sulphenamide from the silicomethane ester generally is to finish after about 2 hours to about 8 hours.Gained sulphenamide available standards has machine technology that it is purified, and for example uses silica gel chromatography.
By shown in the scheme 6, prepare new disulphide from sulfenic acid silicomethane ester.Scheme 6
Figure A0013079600221
In general, prepare sulfenic acid silicomethane ester (R wherein with the vinylbenzene sulfoxide 1, R 2And R 7Define the same), and preferably do not add and separate or purify, in the presence of amine alkali, make itself and formula HSR 8(R wherein 8Define the same) thiol reactant prepare.During preferred preparation sulfenic acid silicomethane ester this reaction soln is cooled to room temperature, and with the solution-treated of this reaction mixture with sulfur-bearing alkohol and amine alkali.The solvent of this mercaptan and amine aqueous solution, same with the solvent phase in the mixture that contains sulfenic acid silicomethane ester.Representational amine alkali comprises triethylamine, diisopropylethylamine, pyridine, morpholine, N-methyl-morpholine, and collidine.The conversion of sulfenic acid silicomethane ester was generally finished after about 1 hour to about 8 hours.The use standard has machine technology gained disulphide can be purified, and for example uses silica gel chromatography.
Intermediate sulfenic acid silicomethane ester, sulphenamide and disulphide can be used for Synthetic 2-aryl benzo [b] thiophene, shown in scheme 7.Scheme 7
Generally speaking, sulfenic acid silicomethane ester, sulphenamide or disulphide are handled production I compound with acid catalyst.The acid catalyst that is suitable for this reaction comprises Lewis acid or Bronsted acid.Representational Lewis acid comprises zinc chloride, zinc iodide, aluminum chloride and aluminum bromide.Representational Bronsted acid comprises mineral acid, for example sulfuric acid and phosphoric acid; Comprise carboxylic acid, for example caproic acid and trifluoroacetic acid; Comprise sulfonic acid, for example methylsulfonic acid, Phenylsulfonic acid, 1-naphthalene sulfonic aicd, 1-fourth sulfonic acid, ethyl sulfonic acid, 4-ethyl phenenyl azochlorosulfonate acid, the own sulfonic acid of 1-, 1,5-naphthene sulfonic acid, the hot sulfonic acid of 1-, camphorsulfonic acid, trifluoromethanesulfonic acid and tosic acid; And comprise polymerization aryl sulfonic acid, for example Nafion , Amberlyst Or Amberlite Preferred acid catalyst is a sulfonic acid, for example methylsulfonic acid, Phenylsulfonic acid, camphorsulfonic acid and tosic acid.Most preferred acid catalyst is a tosic acid.Generally be with acid catalyst in organic solvent with solution (for example at toluene, benzene, dimethylbenzene or 1,1, in the high boiling point halogenated hydrocarbon solvent of 2-three chloro ethane and so on) be heated to about 80 °-Yue 140 ℃, and with the sulfenic acid silicomethane ester in the same solvent, sulphenamide or disulfide solution are handled.Use the excess acid catalyzer, preferred 3 angelic acids.For getting optimum, the ultimate density of starting compound is about 0.01M～about 0.2M, preferred 0.05M.And, if the output that obtains when sulfenic acid silicomethane ester slowly being joined in the acid solution of heating during about 15 minutes-Yue 3 hours is the highest.For obtaining optimum, use Dean-Stark trap or Soxhlet extraction agent from reaction soln, to remove residual water.
The vinylbenzene sulfoxide also is used to prepare benzo thiophene phenol vinylbenzene thioether, shown in scheme 8.Scheme 8
Figure A0013079600231
These benzo thiophene phenol vinylbenzene thioethers (R wherein 1And R 2Define the same) make from the vinylbenzene sulfoxide.Generally speaking be with vinylbenzene sulfoxide (R wherein 1And R 2Define the same, and R 3Be thermolability or acid labile C 1-C 10Alkyl, C 4-C 10Alkenyl or aryl (C 1-C 10Alkyl)) solution under about 100 ℃-Yue 140 ℃ of temperature, joins in the acid catalyst solutions, and wherein said acid catalyst definition is the same.Acid catalyst concentration depends on the ultimate density of formula II compound, and the speed that adds of formula II compound, if vinylbenzene sulfoxide ultimate density be about 0.2M, and with the adding of 6 hours time, then Suan concentration is about 0.002M.If the ultimate density of vinylbenzene sulfoxide is about 0.05M, and add with 30 fens clock times, so Suan concentration is about 0.025M.After about 1-2 hour, tangible formula VI compound amount appears in the reaction.The longer reaction times causes production I compound.
With the acid (about 3 equivalents of for example about 0.5-) of extra adding, and be heated to about 100 ℃-Yue 140 ℃ of processing, these formulas VI compound can be converted into formula I compound subsequently.The about 0.5M of the about 0.01M-of formula VI compound concentrations scope.For forming formula VI compound and finishing it to formula I conversion of compounds, The suitable solvent comprises toluene, dimethylbenzene and 1,2-ethylene dichloride.
Formula I compound is used as the intermediate of synthetic a series of 3-aroyls-2-aryl benzo [b] thiophene.United States Patent (USP) 4,133,814 and 4,418,068 (being incorporated herein by reference) have been introduced these 3-aroyls-2-aryl benzo [b] thiophene, and from their method of formula I compound.From formula I compound (R wherein 1And R 2Be hydrogen, C 1-C 4Alkoxyl group or aralkoxy) improving one's methods of synthetic this class 3-aroyl-2-aryl benzo [b] thiophene concluded in the scheme 9.Scheme 9
Figure A0013079600241
Formula I compound (R wherein 1And R 2Be hydrogen, C 1-C 4Alkoxyl group or aralkoxy) with formula XII compound (R wherein 13Be chlorine or hydroxyl), in the presence of boron trichloride or boron tribromide (preferred boron trichloride), carry out acylation reaction.This reaction can be in various organic solvents, for example chloroform, methylene dichloride, 1, and 2-ethylene dichloride, 1,2,3-propylene dichloride, sym.-tetrachloroethane, 1 carry out in 2-dichlorobenzene, chlorobenzene and the fluorobenzene.Should synthetic preferred solvent be 1, the 2-ethylene dichloride.This is reflected at approximately and carries out preferred 0 ℃ under-10 ℃-Yue 25 ℃ of temperature.This reaction is preferably in thionaphthene formula I compound concentration and carries out to about 1.0M condition for about 0.2M.Generally after about 2 hours to about 8 hours, this acylation reaction is finished.
If R 1And/or R 2Be C 1-C 4Alkoxyl group or aralkoxy, then this acylations thionaphthene preferably is converted into formula XIII compound (R wherein 5And/or R 6Be hydroxyl), need not from this acylation reaction, isolate product.This transforms by adding extra boron trichloride or boron tribromide, and reacting by heating mixture and carrying out.The preferred 2-5 molar equivalent boron trichloride that adds most preferably adds 3 molar equivalents in reaction mixture.This is reflected at about 25 ℃ and carries out preferred 35 ℃ to about 40 ℃ of temperature.This reaction was generally finished after about 4 hours to about 48 hours.
Make acylation reaction or acylations/dealkylation reaction all standing with alcohol or pure mixture.Suitable alcohol comprises methyl alcohol, ethanol and Virahol to be used for this reaction of all standing.Preferably this acylations/dealkylation reaction mixture is joined in 95: 5 ethanol and the methanol mixture (3A ethanol).This 3A ethanol can be room temperature, or be heated to backflow, the preferred backflow.If all standing by this way, then formula XIII compound can crystallize out from the gained alcohol mixture easily.In general, every mmole thionaphthene raw material uses 1.25ml to 3.75ml ethanol.
The following examples further specify the present invention.These embodiment do not attempt to cause limitation of the scope of the invention in all senses, and should not do explanation like this yet.All experiments are all carried out at the direct draught of drying nitrogen.All solvents and reagent use acquired.Percentage (w/w) generally by weight calculates; But high-pressure liquid chromatography (HPLC) solvent is to be basic calculation with volume (v/v).Proton magnetic resonance (PMR) ( 1HNMR) spectrum and 13The C nucleus magnetic resonance ( 13CNMR) spectrum on Bruker AC-300 FTNMR nuclear magnetic resonance spectrometer, is located to obtain respectively in 300.135MHz (proton spectra) or 75.469MHz (carbon spectrum), perhaps on GE QE-300 nuclear magnetic resonance spectrometer, obtains in the 300.15MHz place.It is described that flash chromatography on silica gel is pressed people such as Still, and (the 230-400 order E.Merok) carries out people such as (, J.Org.Chem., 43,2923 (1978)) Still with silica gel 60.To the ultimate analysis of carbon, hydrogen and nitrogen, on Control EquipmentCorporation 440 elemental analysers, measure.Ultimate analysis to sulphur is measured on the BrinkmanColorimetric elemental analyser.Fusing point on Mel-Temp II fusing point device, or is measured on the Mettler FP 62 automatic instrument in the opening glass capillary, and is not calibrated.Field desorption(FD) mass spectrum (FDMS) uses Varian Instruments VG 70-SE or VGZAB-3F mass spectrograph to obtain.High resolution free atom bombardment mass spectrum (FABMS) uses VarianInstruments VG ZAB-2SE mass spectrograph to obtain.
The original position productive rate of 6-methoxyl group-2-(4-methoxyphenyl)-benzo [b] thiophene by high-pressure liquid chromatography (HPLC), compares with authentic sample by this compound of disclosed route of synthesis preparation and to measure.See U.S patent 4,133,814.Generally be with the diluted sample of acetonitrile, use Zorbax reaction mixture RX-C8 post (4.6mm * 25cm) cooperate UV-detector (280nm) to detect dilute sample through HPLC.Following linear gradient solvent systems is used for this analysis: the gradient solvent system
Time (branch) ????A(％) ????B(％)
????0 ????2 ????20 ????35 ????37 ????45 ????50 ????50 ????20 ????20 ????50 ????50 ????50 ????50 ????80 ????80 ????50 ????50
A:0.01M sodium phosphate aqueous solution (pH2.0)
B: acetonitrile
Measure hydrochloric acid 6-hydroxyl-2-(4-hydroxyphenyl)-3-[4-(2-piperidino-(1-position only) oxyethyl group) benzyl acyl group in the crystalline material as follows] amount (percentage ratio, content) of benzo [b] thiophene.Crystalline solid sample (5mg) weighed to add in the 100ml volume flask, and is dissolved in the mixture of 70/30 (v/v) 75mM potassium phosphate buffer (pH2.0) and acetonitrile.Use Zorbax RX-C8 post (25cm * 4.6mm ID, 5m particle) cooperates UV detector (280nm), detects the five equilibrium sample (10ml) of this solution through high-pressure liquid chromatography.Use following gradient solvent system:
Gradient solvent system (content)
Time (branch) ????A(％) ????B(％)
????0 ????12 ????14 ????16 ????25 ????70 ????70 ????25 ????70 ????70 ????30 ????30 ????75 ????30 ????30
A:75mM KH 2PO 4Damping fluid (pH2.0)
B: acetonitrile
Formula below adopting is with hydrochloric acid 6-hydroxyl-2-(4-hydroxyphenyl)-3-[4-(2-piperidino-(1-position only) oxyethyl group) benzyl acyl group in peak area, slope (m) and intercept (b) calculation sample of calibration curve] percentage composition of benzo [b] thiophene:
Amount (percentage ratio) by the solvent in the gas Chromatographic Determination crystalline material (for example 1,2-ethylene dichloride).The sample (50mg) of crystalline solid weighed to add in the 10ml volume flask, and is dissolved in the dimethyl sulphoxide solution of 2-butanols (0.025mg/ml).Use DB Wax post (30m * 0.53mm ID, 1m particle), column flow rate 10ml/ divides and cooperates flame ionic detector, through this solution example of gas chromatographic analysis.This column temperature was heated to 230 ℃ from 35 ℃ during 12 minutes.By going out the amount of solvent with interior mark (2-butanols) comparative measurement.
The embodiment 1E-tertiary butyl 4,4 '-dimethoxy stilbene sulfoxide A. prepare the E-tertiary butyl 4,4 '-dimethoxy stilbene base thioether
The tetrahydrofuran (THF) (THF) of deoxidation anisoin (12.82g) solution in (100ml) (10.43g) is handled with titanium chloride (IV).During dripping titanium chloride, the reaction mixture cooling is maintained the temperature at below 35 ℃.After adding, the gained mixture stirs down at 30 ℃.After 30 minutes, with this mixture of THF (15ml) solution-treated of 2-methyl-2-propylmercaptan (6.76ml) and triethylamine (16.70ml).The gained mixture is in 50 ℃ of stirrings.After 2 hours, this mixture joins in 10% yellow soda ash (500ml).With dichloromethane extraction gained mixture.With the dichloromethane extract that dried over mgso merges, filtration, vacuum concentration obtain 17.2g oily matter, crystallization when being chilled to room temperature.From hot ethanol,, obtain the 12.3g title compound with the crystallisate recrystallization.Fusing point 71-73 ℃.
Analytical calculation value C 20H 24O 2S:C, 73.13; H, 7.36; S, 9.76.Experimental value: C, 73.37; H, 7.51; S, 9.87.B. prepare the E-tertiary butyl 4,4 '-dimethoxy stilbene base sulfoxide
The crystalline compounds of embodiment 1A preparation is dissolved in the toluene (150ml), gained solution is chilled to-20 ℃ approximately, during 10 minutes, (32%w/w 1.24g) handles this cold soln in acetic acid,diluted with peracetic acid.With saturated sodium sulfite and saline water extraction gained mixture.The vacuum concentration organic phase, residue is recrystallization from ethyl acetate/heptane, obtains the 14.11g title compound.104 ℃ of fusing points (decomposition).
Analytical calculation value C 20H 24O 2S:C, 69.74; H, 7.02; S, 9.31.Experimental value: C, 69.47; H, 7.04; S, 9.54.
The embodiment 2Z-tertiary butyl 4,4 '-dimethoxy stilbene sulfoxide A. prepares tertiary butyl 4-methoxybenzyl thioether
1, the mixture in the 2-monochloroethane (120ml) is handled with 1 part of 2-methyl-2-propylmercaptan (9.92ml) and is stirred the gained mixture under the room temperature with 4-methoxy benzylalcohol (10.13g) and zinc iodide (11.7g).After about 18 hours, water (100ml) and methylene dichloride (100ml) dilute this reactant.Tell organic phase with dried over mgso, filtration, vacuum concentration, obtain 14.4g oily matter.
Analytical calculation value C 12H 18OS:C, 68.52; H, 8.63.Experimental value: C, 68.80; H, 8.67.B. prepare the Z-tertiary butyl 4,4 '-dimethoxy stilbene base thioether
THF (50ml) solution of the compound (2.51g) of embodiment 2A preparation is cooled to-20 ℃ approximately.(1.6M 7.47ml) handles this cold soln to the hexane solution of usefulness n-Butyl Lithium during 10 minutes.Gained solution is warmed up to about 0 ℃.(1.46ml) handles this cold soln with aubepine.After 15 minutes, (0.95ml) handles this reaction soln with methylsulfonyl chloride.Make the gained reactant rise to room temperature.After 45 minutes, with THF solution (1.0M, 12.0ml) reaction mixture of potassium tert.-butoxide.After 45 minutes, add 1N hydrochloric acid (12.0ml) and make the reaction all standing.Tell organic phase, with dried over mgso, filtration and be condensed into oily matter (4.4g).
1H?NMR(CDCl 3)：d7.95(d，H)，7.05(s，H)，6.9(d，H)，6.8(dd，2H)，3.75(s，3H)，0.95(s，9H).
13CNMR (CDCl 3): d153,139,137,114,56,32.C. prepare the Z-tertiary butyl 4,4 '-dimethoxy stilbene sulfoxide
Use and the described essentially identical method of embodiment 1B, embodiment 2B gained compound is transformed the cost title compound.
1H?NMR(CDCl 3)：d7.61(d，H)，7.56(d，H)，7.1(s，H)，6.9(dd，2H)，3.83(s，3H)，1.05(s，9H).
13C?NMR(CDCl 3)：d142，132.5，131，118，117，56，24.
Analytical calculation value C 20H 24O 2S:C, 69.74; H, 7.02.Experimental value: C, 69.98; H, 6.94.
The embodiment 3E and the Z-tertiary butyl 4,4 '-dimethoxy stilbene sulfoxide A. prepares tertiary butyl 4-methoxyl group stilbene base thioether
Handle 4-methoxyl group benzylalcohol (10.13g) and zinc iodide (11.7g) 1 with a 2-methyl-2-propylmercaptan (9.92ml), the mixture in the 2-ethylene dichloride (120ml).The gained mixture at room temperature stirs, and after about 18 hours, water (100ml) and methylene dichloride (100ml) dilute this reactant.Tell organic phase,, obtain 14.4g oily matter with dried over mgso, filtration, vacuum concentration.
1H?NMF(CDCl 3)：d7.28(d，2H)，6.85(d，2H)，3.77(s，3H)，3.73(s，2H)，1.36(s，9H).
13C?NMR(CDCl 3)：d130，114，56，35，32.
Analytical calculation value C 12H 18OS:C, 68.52; H, 8.63.Experimental value: C, 68.80; H, 8.67.B. prepare tertiary butyl 4-methoxybenzyl sulfoxide
With 1 of the compound (14.4g) of embodiment 3A preparation, 2-ethylene dichloride (50ml) solution is chilled to about 5 ℃, with peracetic acid (32%w/w in acetic acid,diluted, 14.2ml), during 30 minutes in this cold soln of processing.When adding peracetic acid, handle this reactant with salt solution and sodium bicarbonate.Tell organic phase, with dried over mgso, filtration and be concentrated into yellow mercury oxide.(100ml) handles this residue with hexane, stirs the gained mixture under room temperature.After about 18 hours, filter this mixture, (100ml) washs this solid with hexane.This solids of vacuum-drying obtains the 14.07g title compound.Fusing point 124-126 ℃.
1H?NMR(CDCl 3)：d7.26(d，2H)，6.89(d，2H)，3.79(d，H)，3.78(s，3H)，3.58(d，H)，1.3(s，9H).
13C?NMR(CDCl 3)：d132，114，56，53，23.
Analytical calculation value C 12H 18O 2S:C, 63.68; H, 8.02.Experimental value: C, 63.72; H, 7.93.C. prepare the E and the Z-tertiary butyl 4,4 '-dimethoxy stilbene sulfoxide
THF (140ml) solution of the made compound of embodiment 3B (10.0g) is chilled to-30 °-Yue-25 ℃ (dry ice/acetone batch) approximately.During 25 minutes, (1.6M 27.65ml) handles this cold soln with the n-Butyl Lithium in the hexanaphthene.After stirring 35 minutes, (5.4ml) handles this reaction mixture with aubepine.Remove dry ice/acetone batch, reactant is risen to about 20 ℃.(3.5ml) handles this mixture with methylsulfonyl chloride, after adding methylsulfonyl chloride, temperature of reaction risen to about 35 ℃ from about 20 ℃.Mixture is chilled to about 25 ℃, uses THF liquid (1M, 50.9ml) processing of potassium tert.-butoxide then.Behind the restir 35 minutes, (51.0ml) handles this reactant with 1N hydrochloric acid.Be separated, use MgSO 4Dry organic layer filters, and is condensed into oily matter (16.67g).Do not need further purification, this material is used for the next step.Its carbon is similar to the corresponding NMR spectrum of the compound of embodiment 1 and 2 preparations with proton N MR spectrum.Embodiment 4E and Z type 4,4 '-dimethoxy stilbene sulfenic acid trimethyl silyl ester
With the compound (350mg) and 1 of embodiment 1 preparation, the mixture heating up of 3-two (trimethyl silyl) urea (116mg) in toluene (11ml) refluxes.1.5 after hour, make reaction mixture be chilled to room temperature, filter, and vacuum concentrated filtrate, obtain 7: 1 mixture of title compound E/Z type regional isomer.FDMS：m/z＝361(M＋1)。E-isomer: 1H NMR (d 6-benzene): d7.39 (d, 2H), 7.10 (d, 2H), 6.68 (d, 2H), 6.68 (s, 1H), 6.57 (d, 2H), 3.18 (s, 3H), 3.17 (s, 3H), 0.23 (s, 9H) .Z type isomer: 1H NMR (d 6-benzene): d7.71 (d, 2H), 7.31 (d, 2H), 6.85 (d, 2H), 6.79 (d, 2H), 6.60 (s, 1H), 3.28 (s, 3H), 3.26 (s, 3H) ,-0.05 (s, 9H).
Embodiment 5E and Z type 4,4 '-dimethoxy stilbene sulfenic acid trimethyl silyl ester
With the compound and 1 of embodiment 2 preparations, the mixture heating up of 3-two (trimethyl silyl) urea in toluene refluxes.After 10 minutes, make mixture cooling, filter, and vacuum concentration, obtain 7: 1 mixtures of title compound E/Z type regional isomer.E-isomer: C 13NMR (d 6-benzene, 8 ℃): d160.49,158.53,141.54,131.97,129.91,129.65,125.59,116.41,114.68,113.98,54.56 ,-0.09.
Embodiment 6E and Z-N, N-dimethyl-4,4 '-dimethoxy stilbene base sulphenamide
With embodiment 1 prepared compound (1.74g) and 1, the mixture heating up of 3-two (trimethyl silyl) urea (578mg) in toluene (54ml) refluxes.1.5 after hour, reactant is chilled to room temperature, and handles with dimethylamine (2.80ml, 2.0M is in THF).After 2 hours, reaction soln is evaporated to dried, obtain 7: 1 mixtures of title compound E/Z type regional isomer.Use flash chromatography on silica gel that this residue is purified,, obtain 8: 1 mixtures of 1.06g title compound E/Z type regional isomer with ethyl acetate/hexane (9: 1) mixture wash-out.FDMS:m/z=315 (M +) analytical calculation value C 18H 21NO 2S:C, 68.54; H, 6.71; N, 4.44.Experimental value: C, 68.40; H, 6.69; N, 4.22.E isomer: 1H NMR (d 6-benzene): d7.44 (d, 2H), 7.11 (d, 2H), 6.99 (s, 1H), 6.71 (d, 2H), 6.56 (d, 2H), 3.22 (s, 3H), 3.18 (s, 3H), 2.66 (s, 6H). 13C NMR (d 6-benzene): d160.00,158.83,139,70,131.48,130.78,130.51,129.94,123.77,114.55,113.97,54.63,54.61, the 48.17.Z isomer: 1H NMR (d 6-benzene): d7.61 (d, 4H), 6.82 (d, 2H), 6.80 (d, 2H), 6.80 (s, 1H), 3.32 (s, 3H), 3.27 (s, 3H), 2.41 (s, 6H). 13C NMR (d 6-benzene): d159.89,159.30,139.76,136.46,131.94,131.82,130.22,130.2 0,113.83,113.76,54.81,54.73,48.61.
Embodiment 7E and Z-N-benzyl-4,4 ,-dimethoxy stilbene base sulphenamide
With the compound (1.74g) and 1 of embodiment 1 preparation, the mixture heating up of 3-two (trimethyl silyl) urea (578mg) in toluene (54ml) refluxes.1.5 after hour, reactant is chilled to room temperature, and handles with benzylamine (0.575ml).After two hours, reaction soln is evaporated to dried, obtain 7: 1 mixtures of the E/Z regional isomer of title compound.With the flash chromatography on silica gel residual mixture of purifying,, obtain 6: 1 elder brother's compounds of the E/Z type regional isomer of title compound with ethyl acetate/hexane (7: 1) mixture wash-out.Analytical calculation value C 23H 23NO 2S:C, 73.18; H, 6.14; N, 3.71.Experimental value: C, 73.16; H, 6.18; N, the 3.50E isomer: 1H NMR (d 6-benzene): d7.41 (d, 2H), 7.13 (d, 2H), 7.12-7.03 (m, 5H), 6.87 (s, 1H), 6.71 (d, 2H), 6.59 (d, 2H), 3.89 (d, 2H), 3.23 (s, 3H), 3.20 (s, 3H), 2.71 (t, 1H). 13C NMR (d 6-benzene): d159.98,158.91,140.53,139.77,131.45,130.50,129.87,128.77,128.66,128.59,127.53,123.10,114.74,114.02,56.14,54.69, the 54.64.Z isomer: 1H NMR (d 6-benzene): d7.59 (d, 2H), 7.53 (d, 2H), 7.01-6.91 (m, 5H), 6.83 (s, 1H), 6.79 (d, 2H), 6.77 (d, 2H), 3.62 (d, 2H), 3.31 (s, 3H), 3.27 (s, 3H), 2.82 (t, 1H). 13CNMR (d 6-benzene): d160.05,159.14,140.48,139.27,132.50,131.32,130.04,129.86,128.87,128.58,128.46,127.49,114.48,114.00,56.23,54.90,54.78.
Embodiment 86-methoxyl group-2-(4-methoxyphenyl) benzo [b] thiophene
The solution of tosic acid monohydrate (552mg) is added in the toluene (15ml), and reflux, removes from reactant and anhydrates by water being collected in the Dean-Stark trap.With the solution of regional isomer (523mg) in toluene (15ml) of embodiment 4 preparation, during 15 minutes in this reflux solution of processing.In case after adding, shift out the five equilibrium sample and carry out the HPLC analysis.This title compound original position productive rate 46.6% of this analysis revealed.
Embodiment 96-methoxyl group-2-(4-methoxyphenyl) benzo [b] thiophene
With toluene (20ml) vlil of tosic acid monohydrate (1.26g), make water be collected into the Dean-Stark trap and the water in the reactant is removed.Toluene (9ml) solution with the regional isomer compound (650mg) of embodiment 6 preparation joined during 1.8 hours in the acid solution of backflow.With ethanol (10ml) processing reaction solution, and the gained mixture is chilled to room temperature.Stir the gained slurries under the room temperature.After about 18 hours, this mixture is chilled to about 5 ℃, filter the 290mg title compound.Fusing point 199-200 ℃. 1H NMR (d 6-DMSO): d7.67 (d, 1H), 7.64 (d, 2H), 7.61 (s, 1H), 7.52 (d, 1H), 7.01 (d, 2H), 6.98 (dd, 1H), 3.81 (s, 3H), 3.79 (s, 3H). analytical calculation value C 16H 14O 2S:C, 71.09; H, 5.22.Experimental value: C, 71.09; H, 5.27.
Embodiment 10E and Z-3-(4,4 '-dimethoxy stilbene base thioether)-6-methoxyl group-2-(4-methoxyphenyl) benzo [b] thiophene
With toluene (111ml) vlil of tosic acid monohydrate (552mg), remove water in the reactant by water being collected into the Dean-Stark trap.Toluene (34ml) solution of the compound (10g) of embodiment 1 preparation was joined in the acid solution of this backflow during 6 hours.After 2 hours, this mixture is chilled to 0 ℃.After 18 hours, this cold mixt is filtered, tell sedimentary 6-methoxyl group-2-(4-methoxyphenyl) benzo [b] thiophene.Extract filtrate with the equal-volume saturated sodium bicarbonate solution.Tell organic phase,, obtain the 4.8g orange with dried over sodium sulfate, filtration and vacuum concentration.This oily matter is divided into 2 parts, and each personal flash chromatography on silica gel is purified, with hexane/ethyl acetate (3.5: 1) wash-out.The included level part of desired zone isomer is condensed into oily matter.Handle this oily matter with ether, optionally crystallization goes out the regional isomer (155mg) that morning, wash-out went out.These crystalline mother solutions then enrichment obtain the regional isomer that the back wash-out goes out.Wash-out isomer early 1H NMR (CDCl 3): d7.71 (d, 2H), 7.64 (d, 1H), 7.46 (d, 2H), 7.06 (d, 1H), 6.94 (d, 2H), 6.92 (d, 2H), 6.90 (m, 1H), 6.85 (d, 2H), 6.59 (s, 1H), 6.45 (d, 2H), 3.86 (s, 3H), 3.85 (s, 3H), 3.80 (s, 3H), 3.66 (s, 3H). high resolution FABMS calculated value C 32H 29O 4S 2(MH +) 541.1507.Experimental value: 541.1491.Late wash-out isomer 1H NMR (CDCl 3): d7.90 (d, 1H), 7.62 (d, 2H), 7.24 (1H), 7.08 (d, 2H), 7.02 (dd, 1H), 6.96 (d, 2H), 6.74-6.71 (d, 2H), 6.70 (d, 2H), 6.55 (d, 2H), 6.21 (s, 1H), 3.86 (s, 3H), 3.85 (s, 3H), 3.76 (s, 3H), 3.67 (s, 3H) .FDMS:m/z=540 (m +) embodiment 116-methoxyl group-2-(4-methoxyphenyl) benzo [b] thiophene
(early the wash-out isomer 125mg) joins in toluene (1.5ml) reflux solution of tosic acid monohydrate (4.2mg) compound that embodiment 10 is prepared.After 6 hours, (7.5ml) joins in the reaction mixture with methylsulfonic acid.After 1 hour, reaction mixture is chilled to room temperature.Obtain mixture with dilution in acetonitrile, and detect with HPLC, the original position productive rate that shows title compound is 71.1%.
Embodiment 12 hydrochloric acid 6-hydroxyl-2-(4-hydroxyphenyl)-3-[4-(2-piperidino-(1-position only) oxyethyl group) benzyl acyl groups] benzo [b] thiophene 1,2-ethylene dichloride solvate A. prepares 4-(2-piperidino-(1-position only) oxyethyl group) ethyl benzoate
With the mixture heating up to 80 of 4-nipagin A (8.31g), 1-(2-chloroethyl) piperidines mono-hydrochloric salts (10.13g), salt of wormwood (16.59g) and methylethylketone (60ml) ℃.After 1 hour, this mixture is chilled to about 55 ℃, and handles with extra 1-(2-chloroethyl) piperidines mono-hydrochloric salts (0.92g), with gained mixture heating up to 80 ℃.(TLC) monitors this reaction with thin-layer chromatography, and this chromatogram use silica-gel plate and ethylacetate/acetonitrile/triethylamine (10: 6: 1, v/v) carry out.Adding several parts of 1-(2-chloroethyl) piperidine hydrochlorate again consumes until raw material 4-hydroxybenzoate.In case reaction is finished, water (60ml) reaction mixture, and make it be chilled to room temperature.Discard water layer, concentrate organic layer under 40 ℃ in vacuum and the 40mmHg condition.The gained oily matter that do not need further to purify is used for the next step.B. prepare hydrochloric acid 4-(2-piperidino-(1-position only) oxyethyl group) phenylformic acid
Methyl alcohol (30ml) solution of the compound (about 13.87g) of embodiment 12A preparation with 5N sodium hydroxide (15ml) processing, and is heated to 40 ℃.After 4  hours, add entry (40ml).The gained mixture is chilled to 5-10 ℃, slowly adds concentrated hydrochloric acid (18ml).Title compound crystallizes out during the acidifying.Filter and collect this crystallized product,, obtain the title compound of 83% productive rate in 40-50 ℃ of vacuum-drying.Fusing point: 270-271 ℃.C. prepare hydrochloric acid 4-(2-piperidino-(1-position only) oxyethyl group) benzyl acyl chlorides
The compound (30.01g) of embodiment 12B preparation and methylene dichloride (500ml) solution of dimethyl formamide (2ml) were handled it with oxalyl chloride (10.5ml) during 30-35 minute.After the stir about 18 hours, should react whether fully with the HPLC analyzing and testing.If also have this carboxylic acid raw material, then add extra oxalyl chloride.When reaction is finished, reaction soln vacuum-evaporation is extremely done.Residue is dissolved in the methylene dichloride (200ml), and the gained solution evaporation is extremely done.Repeat this dissolving/evaporation step, obtain the solid title compound.D. prepare hydrochloric acid 6-hydroxyl-2-(4-hydroxyphenyl)-3-[4-(2-piperidines
Base oxethyl) benzyl acyl group] benzo [b] thiophene 1,2-ethylene dichloride solvate
With the compound (2.92g) of embodiment 8 or 9 preparations, the compound (3.45g) and 1 of embodiment 12C preparation, the mixture of 2-ethylene dichloride (52ml) is cooled to about 0 ℃.With in the condensing refrigerative graduated cylinder of packing into of boron trichloride gas (2.8ml), and it is joined in the above-mentioned cooling mixture.After 0 ℃ is kept 8 hours, use boron trichloride (2.8ml) to handle this reaction mixture again.Gained solution is heated to 35 ℃, and this reaction is finished after 16 hours.
During 20 minutes, handle methyl alcohol (30ml), make methanol eddy with above-mentioned reaction mixture.In 25 ℃ of stirring gained slurries, 1 hour after-filtration crystallized product, with cold methanol (8ml) washing, 40 ℃ of vacuum-dryings obtain the 5.14g title compound.225 ℃ of fusing points.
Content (HPLC): 86.8%
1,2-ethylene dichloride (gas-chromatography): 6.5%
Embodiment 136-methoxyl group-2-(4-methoxyphenyl) benzo [b] thiophene
With toluene (20ml) vlil of tosic acid monohydrate (1.05g), water is collected in the Dean-Stark trap and water is removed.Toluene (9ml) solution of the regional isomer compound (780mg) of embodiment 7 preparation is joined in the acid solution of above-mentioned backflow with 10 fens clock times.After 1 hour, use ethanol (10ml) processing reaction solution, and the gained mixture is chilled to room temperature.Stir the gained slurries under the room temperature.After 18 hours, filter this mixture, obtain the 149mg title compound.Fusing point 199-200 ℃.Analytical calculation value C 16H 14O 2S:C, 71.09; H, 5.22.Experimental value: C, 71.05; H, 5.22.
Embodiment 14E and Z-4,4 '-dimethoxy stilbene ethyl disulphide
With the solution of the toluene (54ml) of the regional isomer compound (1.83g) of embodiment 4 preparation with sulfur alcohol (0.433ml) and triethylamine (0.715ml) processing.After following 2.5 hours of the room temperature, this reaction soln vacuum-evaporation to doing, is obtained regional isomer intermixture.With silica gel chromatography residue is purified,, obtain 5.7: 1 mixtures of 1.14g title compound E/Z regional isomer with ethyl acetate/hexane (9: 1) wash-out.Analytical calculation value C 18H 20O 2S 2: C, 65.03; H, 6.06.Experimental value: C, 65.32; H, 6.28.E isomer: 1H NMR (d 6-benzene): d7.35 (d, 2H), 7.19 (s, 1H), 7.05 (d, 2H), 6.72 (d, 2H), 6.54 (d, 2H), 3.21 (s, 3H), 3.14 (s, 3H), 2.39 (q, 2H), 1.09 (t, 3H). 13C NMR (d 6-benzene): d160.09,159.16,135.95,131.71,130.61,130.16,129.48,126.88,114.54,113.99,54.64,54.61,32.29, the 14.33.Z isomer: 1H NMR (d 6-benzene): d7.67 (d, 2H), 7.58 (d, 2H), 6.90 (s, 1H), 6.83 (d, 2H), 6.80 (d, 2H), 3.30 (s, 3H), 3.28 (s, 3H), 2.26 (q, 2H), 0.94 (t, 3H). 13C NMR (d 6-benzene): d159.98,159.53,137.58,134.03,132.79,131.69,130.45,113.91,113.87,54.79,54.73,32.61,14.25.
Embodiment 156-methoxyl group-2-(4-methoxyphenyl) benzo [b] thiophene
With toluene (20ml) vlil of tosic acid monohydrate (1.21g), by water being collected into the Dean-Stark trap, and remove water in the dereaction.Toluene (9ml) solution of embodiment 14 made regional isomer compounds (685mg, 5.7: 1 regional isomer intermixtures) was joined in the acid solution of above-mentioned backflow with 1.8 hour time.With the five equilibrium sample of HPLC analysis of mixtures, show the original position productive rate 23.2% of title compound.

Claims (1)

1. the method for preparing formula XIII compound shown below,
Figure A0013079600021
Wherein
R 9Be hydrogen, halogeno-group, amino or hydroxyl;
R 10Be hydrogen, halogeno-group, amino or hydroxyl;
R 11And R 12Be respectively C separately 1-C 4Alkyl, or R 11And R 12The nitrogen-atoms that is adjacent forms heterocycle together, and described heterocycle is selected from pyrrolidino (1 base), piperidino-(1-position only), hexamethylene imine and morpholino (4 bases);
HX is HCl or HBr;
This method comprises the steps:
(a) in the presence of acid catalyst, make the following formula: compound cyclisation,
Figure A0013079600022
Wherein
R 1Be hydrogen, C 1-C 4Alkoxyl group, aralkoxy, halogeno-group, or amino;
R 2Be hydrogen, C 1-C 4Alkoxyl group, aralkoxy, halogeno-group, or amino;
R 4Be OSi (R) 3, NR 5R 6Or SR 8
Each R is respectively C separately 1-C 6Alkyl, aryl, or aralkyl;
R 5And R 6Be respectively hydrogen, C separately 1-C 6Alkyl or aryl, or R 5And R 6Form ring with nitrogen-atoms, described ring is selected from piperidines, tetramethyleneimine, morpholine and hexamethylene imine;
R 8Be C 1-C 6Alkyl, aryl or aralkyl; With the benzothienyl compounds of preparation following formula,
Figure A0013079600031
R in the formula 1And R 2Define the same;
(b) use the following formula acylting agent, with described benzothienyl compounds acylations,
Figure A0013079600032
In the formula
R 11, R 12And the HX definition as mentioned above;
R 13Be chloro base, bromo base or hydroxyl;
Described reaction is that X ' is the BX ' of chloro base or bromo base therein 3Carry out under existing;
(c) if R 1And/or R 2Be C 1-C 4Alkoxyl group or aralkoxy then define aforesaid BX ' by adding extra wherein X ' 3, make one or more phenolic group dealkylations of the acylations product of step (b);
(d) isolate formula XIII compound.
CN00130796A 1995-06-07 2000-12-12 Synthetic method for benzo [b] thiophene derivative Pending CN1330071A (en)

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