CN1030388C - Process of manufacture of 1,5-benzothiazepine derivates - Google Patents

Process of manufacture of 1,5-benzothiazepine derivates Download PDF

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CN1030388C
CN1030388C CN87100139A CN87100139A CN1030388C CN 1030388 C CN1030388 C CN 1030388C CN 87100139 A CN87100139 A CN 87100139A CN 87100139 A CN87100139 A CN 87100139A CN 1030388 C CN1030388 C CN 1030388C
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benzothiazepine
ethyl
alkali
methyl alcohol
chloro
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CN87100139A (en
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井上博纯
大塚久男
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Tanabe Seiyaku Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02—Seven-membered rings
    • C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D281/10—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention provides a novel process for preparing 1,5-benzothiazepine derivatives of the formula: wherein R1 is a lower alkyl group, R2 is a hydrogen atom or a lower alkanoyl group, and X1 is a hydrogen atom or a lower alkyl group. The derivative (I) and its salts have potent hypotensive, coronary or cerebral vasodilating or platelet aggregation-inhibiting activities.

Description

Process of manufacture of 1,5-benzothiazepine derivates
The present invention relates to a kind of 1, the 5-Benzothiazepine (1,5-benzothiazepine suberene, 1, the 5-benzothiazepine) manufacture method of derivative, this derivative has following general formula:
Figure 87100139X_IMG4
R wherein 1Be a kind of low alkyl group, R 2Be H or a kind of low-grade alkane acidyl, X is H or a kind of low alkyl group or the salt that makes from it.
United States Patent (USP) 3,562,257 disclose the derivative of various Benzothiazepines, comprising 7-chloro-1, the 5-Benzothiazepine derivatives is as the 2-(4-p-methoxy-phenyl)-3-hydroxyl (or acetoxyl group)-5-(2-(dimethylamino) ethyl)-7-chloro-2,3-dihydro-1,5-Benzothiazepine-4(5H)-ketone, this patent also put down in writing these Benzothiazepine derivatives have resistance to compression strongly fragrant, calm and (or) effect of coronary artery diastole.
As with the comparison of these known compounds, for compound of the present invention (I), work as X 1When being a kind of low alkyl group, show stronger hypotensive effect and brain or coronary vasodilator diastole effect, for treatment, improve and (or) preventing hypertension; Cerebral disorders is as cerebri cerebral vasospasm or cerebral infarction; Heart disease as stenocardia, irregular pulse or myocardial infarction, is more useful medicine.In addition, for compound of the present invention (I), work as X 1When being H, has the thrombocyte anticoagulation, for treatment, improve and (or) prevent thrombosed disease, as big cerebral thrombosis (cerebrum block), moment cerebrum ischemia, coronary artery thrombosis (myocardial infarction), pulmonary infarction, not tip blood vessel embolism, thromboangiitis and (or) other thromboembolism (for example, the thromboembolism behind the heart valve xenograft).According to the present invention, compound (I) can prepare with a following step or multistep:
ⅰ) have the alkylation of the compound of following general formula:
R wherein 3Be H or a kind of low-grade alkane acidyl, X 2Be H, a kind of low alkyl group or a kind of blocking group,
ⅱ) work as X 2When being a kind of blocking group, remove said blocking group therefrom,
ⅲ) work as R 3When being a kind of low-grade alkane acidyl, selectively remove said alkanol groups therefrom,
ⅳ) if desired, further transmutation product to a kind of its salt.
In Xu Shu the reaction,, there is the blocking group of numerous species to can be used as blocking group X usually in the above in order to protect a kind of amino group 2, the example of this class blocking group comprises carbobenzoxy-(Cbz) unsubstituted or that replace, as carbobenzoxy-(Cbz) or right-methoxyl group benzyloxy carbonyl; Unsubstituted or replace lower alkoxycarbonyl, as tertbutyloxycarbonyl, β, β, β-trichloro-ethoxycarbonyl or iodine ethoxycarbonyl; Unsubstituted or replace phenyl-low alkyl group is as benzyl, right-methoxy-benzyl or 3,4-dimethoxy-benzyl.
Alkylating of the present invention can be realized with a kind of low alkyl group agent treated compound (II), for example, this alkylating reagent comprises a kind of low-level chain triacontanol, a kind of sulfuric acid lower alkyl esters, as methyl-sulfate, a kind of lower alkyl ester of alkyl or aryl sulfonic acid, as the toluenesulphonic acids methyl esters, methyl mesylate and 2-oxygen-1,3-propane disulfonic acid dimethyl ester, a kind of elementary alkyl halide, as methyl iodide and monobromethane, a kind of low alkyl group quaternary ammonium compound, oxyhydroxide as the trimethylphenyl ammonium, a kind of low alkyl sulfonium or sulfur oxide compound, oxyhydroxide as trimethylsulfonium, iodate trimethylammonium sulfoxonium, a kind of selenium compound of low alkyl group, as oxyhydroxide and a kind of diazonium lower paraffin hydrocarbons of trimethylammonium selenium, as diazomethane.
When using low-level chain triacontanol as alkylating reagent, be preferably under the dewatering agent existence and react, the dewatering agent commonly used that can be used for this purpose have dicyclohexyl carbon imide or three season phosphine and diazene diethyl dicarboxylate's mixture, reaction is preferably under the 0-40 ℃ of temperature to be carried out.
When adopting above-mentioned sulfuric acid lower alkyl esters, alkyl or aryl sulfonic acid lower alkyl ester or elementary alkyl halide are during as alkylating reagent, reaction is preferably under a kind of alkali existence to be carried out, the example of this class alkali comprises mineral alkali, as alkalimetal oxide, alkali-metal carbonate, alkali-metal acid carbonate, alkali-metal hydride or alkali-metal alkoxide, and organic bases, as ethyl diisopropyl amine, reaction is preferably between 0 ℃ and the reflux temperature to be carried out, particularly under 10-40 ℃ of temperature He in a kind of inert solvent, (for example carry out, acetone, acetonitrile, methyl alcohol, benzene diox, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO) and dimethyl formamide), reaction also is preferably under the phase-transfer catalyst existence to be carried out, as tetrabutylammonium fluoride.
In addition, when above-mentioned low alkyl group quaternary ammonium compound, low alkyl group sulfonium and sulfur oxide compound or low alkyl group selenium compound during as alkylating reagent, reaction is preferably under the temperature between 10 ℃ and the reflux temperature to be carried out, and particularly carries out in a kind of inert solvent or under solvent-free condition under 50-100 ℃ of temperature.Suitable have toluene, dioxan, methyl alcohol, dimethyl formamide and a dimethyl sulfoxide (DMSO) as solvent.
When diazonium lower paraffin hydrocarbons during as alkylating reagent, reaction is preferably under the 0-40 ℃ of temperature to be carried out, and particularly carries out in a kind of inert solvent 20-30 ℃ of temperature.The suitable solvent You diox, tetrahydrofuran (THF), methyl alcohol and their mixture.R when initial compounds (II) 3When being a kind of low-grade alkane acidyl group, reaction is preferably in fluoroboric acid or silica gel and carries out under existing.
When stating alkylated reaction in realization, as the X of initial compounds (II) 2Be H and R 3When being low-grade alkane acidyl, good especially is as alkylating reagent with sulfuric acid lower alkyl esters, sulfonic acid lower alkyl esters or elementary alkyl halide; The X that perhaps works as initial compounds (II) 2And R 3When all being H, alternately low alkyl group quaternary ammonium compound, low alkyl group sulfonium or sulfur oxide compound, low alkyl group selenium compound or diazonium lower paraffin hydrocarbons as alkylating reagent.
X in the product that obtains like this 2When being a kind of blocking group; can remove said protecting group with method commonly used; for example; when protecting group is a kind of unsubstituted or carbobenzoxy-(Cbz) or unsubstituted lower alkoxycarbonyl of replacing; said group can easily be removed used acid such as hydrogen bromide, hydrogenchloride or trifluoroacetic acid with a kind of acid-treated method in a kind of solvent.When blocking group was a kind of lower alkoxycarbonyl of replacement, the method that said group can be handled with zinc in solvent was removed.In addition; when blocking group was the phenyl lower alkyl of a kind of not replacement or replacement, said group at first replaced (for example, carbobenzoxy-(Cbz)) with a kind of blocking group; this substituting group is easily to be removed by a kind of acid, this blocking group is removed by above-mentioned identical method later on again.Phenyl lower alkyl unsubstituted or that the replace replacement of carbobenzoxy-(Cbz); preferably under the temperature between 50 ℃ and 130 ℃; use the benzyloxy carbonyl halides,, handle product (promptly protecting the imino-of compound) with phenyl lower alkyl unsubstituted or that replace as benzyloxy carbon amide nitrogen.
Work as R 3When being low-grade alkane acidyl, blocking group and said low-grade alkane acidyl can be removed simultaneously, perhaps do not remove said alkyloyl and only blocking group are removed.These reactions can be controlled with the method that changes reaction conditions, as the amount of reaction reagent, reaction times and (or) used reaction solvent.
If desired, its acid salt class (acid addition salts) can be handled and obtain to the The compounds of this invention that obtains thus (I) with a kind of acid to it, the example of acid salt class comprises inorganic acid addition salt, example hydrochloric acid salt, hydrogen bromide salt, iodine hydrohalogenic acid salt, perchlorate, vitriol, phosphoric acid salt, organic acid addition salt, as oxalate, maleate, fumarate, methane sulfonates or the like.
Because the effect that does not have racemization of above-mentioned reaction of the present invention, a kind of optically active isomer of using compound (II) can obtain being in a kind of compound (I) of optical activity form at an easy rate as initial compounds.
For example, initial compounds (II) can be with 3-(4-benzyloxy phenyl) step or the polystep reaction of glycidic acid methyl esters and the amino thioic acid sulfoacid of 5-chloro-2-provide 2-(4-benzyloxy phenyl)-3-hydroxyl-8-chloro-2,3-dihydro-1,5-Benzothiazepine-4(5H)-ketone or its a kind of salt, with product and compound condensation with following general formula:
Figure 87100139X_IMG6
Wherein Y is a halogen atom, X 2With above define identical or its a kind of salt, obtain the compound of following general formula:
Figure 87100139X_IMG7
X wherein 2With above define identically, remove benzyl group from compound (IV), if desired, before removing said benzyl or after, change the hydroxyl of resulting product on the 3-position of Benzothiazepine ring into a kind of low-grade alkane acidyl group.
Because can be (for example with two kinds of diastereoisomers comprising two unsymmetrical carbon compounds (I) and initial compounds (II), genial anti-) or four kinds of optical isomers are (for example, (+)-suitable, (-)-suitable, (+)-anti-and (-)-instead) form exists, and these whole isomer or their mixture all are included among the scope of the present invention, still, among these isomer, as medicinal application with the cis-isomeride of compound (I) for well.
Embodiment 1:
(+)-suitable-2-(4-hydroxy phenyl with 690mg)-3-hydroxyl-5-(2-(N, the N-dimethylamino) ethyl)-8-chloro-2,3-dihydro-1,5-Benzothiazepine-4(5H)-ketone is dissolved in the tetrahydrofuran (THF) of 20ml, the sodium hydride (60% oily) that at room temperature adds 78mg, under same temperature, stirred 30 minutes, the solution that will contain the 245mg methyl-sulfate in the 10ml dimethyl formamide adds, after at room temperature mixture being stirred 1 hour, reaction mixture is poured in the water and is used into ethyl acetate extraction, extract washes with water, dry and evaporation is desolvated to remove, residue is with the mixture recrystallization of ethyl acetate and just-hexane, obtain (+)-suitable-2-(4-p-methoxy-phenyl of 509mg)-3-hydroxyl-5-(2-(N, the N-dimethylamino) ethyl)-and 8-chloro-2,3-dihydro-1, the 5-Benzothiazepine-4(5H)-ketone.
Fusing point: 122-124 ℃ (decomposition)
(α)+144.6 ° (C=0.85, methyl alcohol)
Embodiment 2 to 4:
Handle corresponding initial compounds with embodiment 1 identical method, the compound that obtains sees Table 1.
Table 1
(R 1, X 1And X 2=-CH 3, R 3=R 2)
(R 1, X 1And X 2=-CH 3, R 3=R 2)
Example compound (I) optical activity character
Numbering R 2
2-H is suitable-(-) fusing point: 121-123 ℃ (decomposition)
〔α〕 20 D-142.7°
(C=1.04, methyl alcohol)
3-COCH 3Suitable-(+) maleate (using the alcohol-ether recrystallization)
Fusing point: 158-160 ℃
(α) 20 D+ 75.4 ° of (C=1.0, methyl alcohol
4-COCH 3Suitable-(-) hydrochloride
Fusing point: 128-132 ℃ (decomposition)
(α) 20 D-93.3 ° (C0.872, methyl alcohol)
Embodiment 5:
With 210mg(+)-suitable-2-(4-hydroxy phenyl)-3-acetoxyl group-5-[2-(N-methylamino) ethyl]-8-chloro-2,3-dihydro-1,5-Benzothiazepine-4(5H)-ketone, 250mgK 2CO 3Be dissolved in the methyl alcohol of 5ml with the 140mg methyl-sulfate, solution at room temperature stirs and spends the night, with the insolubles elimination, the filtrate evaporation is desolvated to remove, resistates is with (the solvent: benzene: ethyl acetate=4: 1) of chromatography column purification on the silicagel column, and make and change maleate into, with ethanol and ether mixed solution recrystallization, obtain 212mg(+)-suitable-2-(4-p-methoxy-phenyl)-3-acetoxyl group-5-[2-(N, the N-dimethylamino) ethyl]-8-chloro-2,3-dihydro-1, the 5-Benzothiazepine-4(5H)-the ketone maleate.
The physico-chemical property of this compound is identical with the product of embodiment 3 preparations.
Embodiment 6:
(1) use the method identical to handle (-)-suitable-2-(4-hydroxy phenyl with embodiment 1)-3-hydroxyl-5-(2-(N-benzyl-N-methylamino) ethyl)-8-chloro-2,3-dihydro-1, the 5-Benzothiazepine-4-(5H)-ketone, obtain (-)-suitable-the 2-(4-p-methoxy-phenyl)-3-hydroxyl-5-(2-(N-benzyl-N-methylamino) ethyl)-8-chloro-2,3-dihydro-1, the 5-Benzothiazepine-4(5H)-ketone.
Perchlorate (using ethyl alcohol recrystallization)
Fusing point: 161-163 ℃ (decomposition)
(α) 20 D-76.4 ° (C=0.589, methyl alcohol)
(2) product that 4.3 grams are obtained in (1) is dissolved in the benzene of 50ml and refluxes, dropwise be added in the solution that contains the 4.55g benzyloxycarbonylchloride in the 10ml benzene at 15 minutes in the clock time, solution was refluxed 1 hour, cool to room temperature, evaporation is desolvated to remove, the NaOH aqueous solution that in resistates, adds 30ml ethanol and 50ml 5%, at room temperature mixture was stirred 2 hours, the reaction mixture dilute with water is used chloroform extraction, wash extract with water, dry and evaporation is desolvated to remove.Obtain 4.79 gram (-)-suitable-2-(4-p-methoxy-phenyls)-3-hydroxyl-5-(2-(N-carbobenzoxy-(Cbz)-N-methylamino) ethyl)-8-chloro-2,3-dihydro-1, the 5-Benzothiazepine-4(5H)-ketone.
CHCl 3
Infrared spectra wave number (Cm -1): 3510,1695,1660
max
(α) 20 D-133.3 ° (C=0.582, methyl alcohol)
(3) product that 1.07 grams are obtained in (2) is dissolved in the 2ml benzene, adds hydrogen bromide-acetum of 1.7ml 25% again, at room temperature with solution stirring 2 hours, add ether, with filtration method collecting precipitation thing,, water and benzene are added in the throw out mixture K with the ether washing 2CO 3Be adjusted to alkalescence, the benzene layer washes with water, dry evaporation is desolvated to remove, ether is added in the residue, with filtration method collecting precipitation thing,, obtain 0.47g(-with ethyl acetate and just-hexane recrystallization)-suitable-2-(4-p-methoxy-phenyl)-3-hydroxyl-5-(2-(N-methylamino) ethyl)-8-chloro-2,3-dihydro-1, the 5-Benzothiazepine-4(5H)-ketone.
Fusing point: 142-145 ℃
(α) 20 D-147.7 ° (C=0.814, chloroform)
Fumarate (using ethyl alcohol recrystallization)
Fusing point: 164-167 ℃ (decomposition)
Embodiment 7 to 9:
(1) corresponding initial compounds is pressed and embodiment 6-(1) identical method processing, the compound tool table 2 that obtains.
Table 2
Figure 87100139X_IMG9
（R 1＝-CH 3，X 2＝-CH 2C 6H 5）
Embodiment compound (V) optical property
Numbering R 3Active
7-H is suitable-(+) perchlorate (using ethyl alcohol recrystallization)
Fusing point: 161-163 ℃ (decomposition)
[α] 20 D+76.5°
(C=0.446, methyl alcohol)
8-COCH 3Suitable-(-) oxalate (using ethyl alcohol recrystallization)
Fusing point: 192-194 ℃ (decomposition)
[α] 20 D-96.5°
(C=1.0, dimethyl formamide)
9-COCH is suitable-(+) oxalate (using ethyl alcohol recrystallization)
Fusing point: 191-194 ℃ (decomposition)
[α] 20 D+96.8°
(C=0.73, dimethyl formamide)
(2) product that obtains above (V) is pressed and embodiment 6-(2) identical method processing, the compound that obtains sees Table 3.
Table 3
Figure 87100139X_IMG10
（R 1＝-CH 3）
Embodiment compound (the optical property of V-b)
Numbering R 3Active
7-H is suitable-(+) [α] 20 D+ 132.6 °
(C=0.550, methyl alcohol)
CHCl 3
8-COCH 3* suitable-(-) infrared spectra wave number
max
（cm -1）：1740，1685
[α] 20 D-115.4°
(C=1.0, methyl alcohol)
9-COCH 3* suitable-(+) [α] 20 D+ 115.5 °
(C=1.0, methyl alcohol)
Annotate: after the * reaction, residue is handled without ethanol-NaOH aqueous solution.
(3) method that the product that obtains above (V-b) press embodiment 6-(3) is identical is handled, and the compound that obtains sees Table 4.
Table 4
Figure 87100139X_IMG11
(R 1=CH 3, R 2=-H, R 3=-H or-COCH 3)
The embodiment compound (I-a)
Numbering optical activity character
7 suitable-(+) hydrochloride 1/2 hydrates
(with ethanol and ether mixture recrystallization)
Fusing point: 137-140 ℃
[α] 20 D+ 83.4 ° (C=0.415, methyl alcohol)
8 suitable-(-) and embodiment 6-(3) product that makes is identical
9 suitable-(+) and embodiment 7-(3) product that makes is identical
Embodiment 10:
(-)-suitable-2-(4-hydroxy phenyl with 450mg)-and 3-hydroxyl-5-[2-(N-benzyl-N-methylamino) ethyl]-8-chloro-2,3-dihydro-1,5-benzo thiophene is assorted flat-4(5H)-and ketone is dissolved in the toluene of 20ml, under 80 ℃ temperature, be added in the solution that contains the 490mg benzyloxycarbonylchloride in the 10ml toluene, under 80 ℃ of temperature, stirred 5 hours, after the reaction, distillation removes and desolvates, the NaOH aqueous solution and the 10ml methyl alcohol of 10ml 5% are joined in the residue, at room temperature, mixture was stirred 2 hours, the mixture ethyl acetate extraction, extract washes with water, drying, evaporation is desolvated to remove, then, resistates is with chromatography column purification on the silicagel column (solvent: chloroform: methyl alcohol=9: 1), obtain 410mg(-)-suitable-2-(4-hydroxy phenyl)-3-hydroxyl-5-
[2-(N-benzyloxycarbonyl-N-methylamino) ethyl]-8-chloro-2,3-dihydro-1,5-benzo thiophene is assorted puts down-4(5H)-ketone.
(2) with 410mg(1) in the product, the 340mg K that obtain 2CO 3, 170mg methyl iodide and 10ml methanol mixture at room temperature stirred 40 hours, after the reaction, solvent in the evaporative removal mixture, residue is dissolved in the ethyl acetate, solution is with 10% the NaOH aqueous solution and water washing, and dry and evaporative removal solvent obtains 315mg(-)-suitable-2-(4-p-methoxy-phenyl)-3-hydroxyl-5-[2-(N-carbobenzoxy-(Cbz)-N-methylamino) ethyl]-8-chloro-2,3-dihydro-1,5-benzo thiophene is assorted puts down-4(5H)-ketone.
The physico-chemical property of product and embodiment 6-(2) product that makes is identical.
(3) with the product that obtains in (2) by with embodiment 6-(3) identical method handles, thereby obtain (-)-suitable-the 2-(4-p-methoxy-phenyl)-3-alkyl-5-[2-N-methylamino) ethyl]-8-chloro-2,3-dihydro-1,5-benzo thiophene is assorted puts down-4(5H)-ketone.
Embodiment 11:
(1) (-)-suitable-2-(4-hydroxy phenyl)-and 3-acetoxyl group-5-[2-N-benzyl-N-methylamino) ethyl]-8-chloro-2,3-dihydro-1,5-benzo thiophene is assorted flat-4(5H)-ketone by and embodiment 8-(2) identical method handles, obtain (-)-suitable-the 2-(4-hydroxy phenyl)-3-acetyl oxygen-5-[2-(N-benzyloxycarbonyl-N-methylamino) ethyl]-8-chloro-2,3-dihydro-1,5-benzo thiophene is assorted puts down-4(5H)-ketone.
[α] 20 D-106.0 ° (C=0.50, chloroform)
(2), with the product that obtains in (1) by with just 10-(2 of embodiment) identical method handles, obtain (-)-suitable-the 2-(4-p-methoxy-phenyl)-3-acetoxyl group-5-[2-(N-benzyloxycarbonyl-N-methylamino) ethyl]-8-chloro-2,3-dihydro-1,5-benzo thiophene is assorted puts down-4(5H)-ketone.
(3) with 37.5g(2) in hydrogen bromide one acetic acid and the 95ml methylene dichloride of the product, the 75ml 25% that obtain mix down ice-cooled, mixture was at room temperature stirred 3 hours, after reaction finishes, remove methylene dichloride with distillation method, ether is joined in the residue, after throw out is washed with ether, throw out is dissolved in the water solution K 2CO 3Neutralization is also used extracted with diethyl ether, extract washes with water, drying and evaporative removal solvent, residue is transformed into oxalate, use recrystallizing methanol, obtain 18.7g(-)-cis-2-(4-p-methoxy-phenyl)-3-acetoxyl group-5-[2-N-methylamino) ethyl]-8-chloro-2,3-dihydro-1,5-benzo thiophene is assorted flat-45H)-oxalate of ketone.
Fusing point: 174-176 ℃
[α] 20 D-74.2 ° (C=0.814, methyl alcohol)
Embodiment 12:
645mg toluenesulphonic acids front three ammonium salt is added in the sodium methylate (with 46mg sodium Metal 99.5 and the preparation of 4.5ml methyl alcohol), mixture was at room temperature stirred 3 hours, the elimination insolubles, filtrate being added to contained 570mg(-)-suitable-2-(4-hydroxy phenyl)-3-hydroxyl-5-[2-(N-methylamino) ethyl]-8-chloro-2,3-dihydro-1,5-benzo thiophene is assorted flat-4(5H)-the 20ml toluene solution of ketone in, after with distillation for removing methanol, solution refluxed 2 hours, after reaction finishes, from mixture, boil off solvent, resistates is with (the solvent: chloroform: ethanol=95: 5) and with ethyl acetate and positive second hexanes mixtures recrystallization of chromatography column purification on the silicagel column, obtain 275mg(-)-suitable-2-(4-p-methoxy-phenyl)-3-hydroxyl-5-[2-(N-methylamino) ethyl]-8-chloro-2,3-dihydro-1,5-benzo thiophene is assorted puts down-4(5H)-ketone.
The physico-chemical property of product and embodiment 6-(3) product that makes is identical.
[preparation initial compounds]
Preparation 1:
(1) with (±)-anti--3-(4-benzyloxy phenyl) mixture of glycidic acid methyl esters and the amino thiophenols of 5-chloro-2-constant temperature 16 hours under 160 ℃ of temperature; (S)-N-(2-naphthalene sulfonyl base) tetramethyleneimine-2-carbonyl chloride and pyridine be added in the reaction soln; with solution stirring; after reaction finishes; product separates (solvent: benzene: ethyl acetate=4: 1) obtain its (+)-isomer and (-)-isomer with chromatography column on the silicagel column; after the separation, K 2CO 3, water and methyl alcohol is added in each isomer, mixture at room temperature stirs and spends the night, with ethyl acetate to each product recrystallization, obtain cis-2-(4-benzyloxy phenyl respectively)-3-hydroxyl-8-chloro-2,3-dihydro-1,5-benzo thiophene is assorted flat-4(5H)-(+) of ketone 1/5 ethyl acetate-and (-)-isomer.
(+)-isomer 1/5 ethyl acetate:
[α] 20 D-74.2 ° (C=1.00, dimethyl formamide)
(-)-isomer 1/5 ethyl acetate:
[α] 20 D-75.0 ° (C=1.00, dimethyl formamide)
(2) with (+)-suitable-2-(4-benzyloxy phenyl)-3-hydroxyl-8-chloro-2,3-dihydro-1,5-benzo thiophene is assorted flat-4(5H)-ketone, 2-(N-benzyl-N-methylamino) diethylaluminum monochloride hydrochloride, K 2CO 3, acetone, ethyl acetate and water mixture reflux, after reaction finishes, the elimination insolubles, evaporative removal solvent from filtrate, residue is transformed into the mixture recrystallization that oxalate is also used methyl alcohol and ether, obtain (+)-suitable-2-(4-benzyloxy phenyl)-3-hydroxyl-5-[2-(N-benzyl-N-methylamino) ethyl]-8-chloro-2,3-dihydro-1,5-benzo thiophene is assorted puts down-4(5H)-the ketone oxalate.
Fusing point: 108-115 ℃
[α] 20 D+ 85.8 ° (C=1.00, methyl alcohol)
(3) product (free alkali) that obtains in (2) is dissolved in the pyridine, add the solution of Acetyl Chloride 98Min. in methylene dichloride, mixture is stirred, after reaction finishes, evaporative removal solvent from mixture, residue is dissolved in ethyl acetate, solution is water in succession, 5% NaHCO, water washing, then, drying solution and evaporative removal solvent, change residue into oxalate,, obtain (+)-suitable-2-(4-benzyloxy phenyl with methyl alcohol and ether recrystallization)-3-acetoxyl group-5-[2-(N-benzyl-N-methylamino) ethyl]-8-chloro-2,3-dihydro-1,5-benzo thiophene is assorted flat-4(5H)-oxalate of ketone.
Fusing point: 173-175 ℃
[α] 20 D+ 78.4 ° (C=1.00, methyl alcohol)
(-)-along the isomer oxalate
Fusing point: 172-175 ℃
(4) product that obtains in (3) (free alkali) is dissolved in toluene, dropwise add the solution of benzyloxycarbonylchloride in toluene, under heating, stir the mixture, after reaction finishes, distillation removes and desolvates, residue is with (the solvent: chloroform: ethyl acetate=95: 5) of chromatography column purification on the silicagel column, with ethyl acetate and just-the mixture recrystallization of hexane, obtain (+)-suitable-2-(4-benzyl p-methoxy-phenyl)-3-acetoxyl group-5-[2-(N-benzyloxycarbonyl-N-methylamino) ethyl]-8-chloro-2,3-dihydro-1,5-benzo thiophene is assorted puts down-4(5H)-ketone.
[α] 20 D+ 79.0 ° (C=1.00, chloroform)
(-)-isomer:
[α] 20 D-79.2 ° (C=1.00, chloroform)
(5) product that obtains in (4) is dissolved in ethyl acetate, hydrogen bromide-the acetate of adding 25% under cooling, after reaction finishes, distillation removes and desolvates, and residue washs with ether, neutralizes to obtain corresponding free alkali with strong aqua, gather with chloroform, extract washes with water, dry and evaporative removal solvent, and residue is with chromatography column purification on the silicagel column and change oxalate into.Obtain (+)-suitable-the 2-(4-hydroxy phenyl)-3-acetoxyl group-5-[2-(N-methylamino) ethyl]-8-chloro-2,3-dihydro-1,5-benzo thiophene is assorted flat-4-5H)-oxalate of ketone.
Fusing point: 186-187 ℃
[α] 20 D+ 81.2 ° (C=0.50, methyl alcohol)
(-)-suitable-isomer
Fusing point: 187-189 ℃
[α] 20 D-81.6 ° (C=0.50, methyl alcohol)
Preparation 2:
(1) by and prepare 1-(4) identical method processing (+)-suitable-2-(4-benzyloxy phenyl)-3-hydroxyl-5-[2-(N-benzyl-N-methylamino) ethyl]-8-chloro-2,3-dihydro-1,5-benzo thiophene is assorted puts down-4(5H)-and ketone, obtain (+)-suitable-2-(4-benzyloxy phenyl)-3-hydroxyl-5-[2-(N-benzyloxycarbonyl-N-methylamino) ethyl]-8-chloro-2,3-dihydro-1,5-benzo thiophene is assorted puts down-4(5H)-ketone.
Fusing point: 94-96 ℃
[α] 20 D+ 126.0 ° (C=1.00, chloroform)
(-)-suitable-isomer:
Fusing point: 93-95 ℃
[α] 20 D-125.6 ° (C=1.00, chloroform)
(2) the product that obtains in (1) by with prepare 1-(5) identical method handles; the free alkali that obtains is transformed into corresponding 2-(4-hydroxyl-benzoyl) benzoate; use the aqueous ethanolic solution recrystallization; obtain (+)-suitable-the 2-(4-hydroxy phenyl)-3-hydroxyl-5-[2-(N-methylamino) ethyl]-8-chloro-2; 3-dihydro-1,5-benzo thiophene is assorted puts down-4(5H)-and ketone 2-(4-hydroxy benzoyl) benzoate 3/2 hydrate.
Fusing point: 124-127 ℃
[α] 20 D+ 198.1 ° (C=0.120, methyl alcohol)
(-)-suitable-isomer 2-(4-hydroxyl-benzoyl) benzoate 3/2 hydrate:
Fusing point: 124-127 ℃
[α] 20 D-197.5 ° (C=0.120, methyl alcohol)
Preparation 3:
(1) by and prepare 1-(2) identical method processing (+)-suitable-2-(4-benzyloxy phenyl)-3-hydroxyl-8-chloro-2,3-dihydro-1,5-benzo thiophene is assorted puts down-4(5H)-and ketone and 2-(N, the N-dimethylamino) diethylaluminum monochloride hydrochloride, obtain (+)-suitable-2-(4-benzyloxy phenyl) 3-hydroxyl-5-[2-(N, the N-dimethylamino) ethyl]-8-chloro-2,3-dihydro-1,5-benzo thiophene is assorted flat-4(5H)-oxalate of ketone.
Fusing point: 148-151 ℃ (decomposition)
[α] 20 D+ 94.0 ° (C=1.00, methyl alcohol)
(-)-suitable-isomer oxalate
Fusing point: 149-152 ℃ (decomposition)
[α] 20 D-94.2 ° (C=1.00, methyl alcohol)
(2) under heating, the mixture of product (free alkali), acetic anhydride and pyridine that stirring (1) obtains, after reaction finishes, distillation removes and desolvates, and residue is transformed into oxalate, with the mixture recrystallization of ethanol and ether, obtain (+)-suitable-2-(4-benzyloxy phenyl)-3-acetoxyl group-5-[2-(N, the N-dimethylamino) ethyl]-8-chloro-2,3-dihydro-1,5-benzo thiophene is assorted puts down-4(5H)-ketone 1/2 oxalate.
Fusing point: 168-172 ℃ (decomposition)
[α] 20 D+ 78.4 ° (C=1.00, methyl alcohol)
(-)-suitable-isomer 1/2 oxalate
Fusing point: 168-172 ℃ (decomposition)
[α] 20 D-78.8 ° (C=1.00, methyl alcohol)
(3) product that obtains in (2) (free alkali) is dissolved in acetic acid, under cooling and stirring condition, hydrogen bromide-the acetic acid of adding 25%, after reaction finishes, distillation removes and desolvates, and residue washs with ether, neutralizes with strong aqua, obtain free alkali, use chloroform extraction, extract washes with water, and dry and evaporation removes desolvates, residue is transformed into oxalate, use ethyl alcohol recrystallization, obtain (+)-suitable-the 2-(4-hydroxy phenyl)-3-acetoxyl group-5-[2-(N, the N-dimethylamino) ethyl]-8-chloro-2,3-dihydro-1,5-benzo thiophene is assorted puts down-4(5H)-ketone oxalate 1 hydrate.
Fusing point: 142-149 ℃
[α] 20 D+ 79.2 ° (C=0.50, methyl alcohol)
(-)-suitable-isomer oxalate 1 hydrate:
Fusing point: 143-149 ℃
[α] 20 D-78.3 ° (C=0.50, methyl alcohol)
Preparation 4 to 6:
By and prepare 3-(3) identical method handles corresponding initial compounds, the compound that obtains sees Table 5:
Table 5
Figure 87100139X_IMG12
Preparation compound (II) optical property
Numbering R 3X 2Active
4-H CH 3Suitable-(+) 2-(4-hydroxy benzoyl) benzoate
(with the mixture recrystallization of acetone and isopropyl ether)
Fusing point: 165-170 ℃ (decomposition)
[α] 20 D+ 79.8 ° (C=01.00, methyl alcohol)
Suitable-(-) 2-(4-hydroxy benzoyl) benzoate
(with the mixture recrystallization of acetone and isopropyl ether)
Fusing point: 166-170 ℃ (decomposition)
[α] 20 D-80.1 ° (C=1.00, methyl alcohol)
5-H-CH 2C 6H 5Suitable-(+) oxalate (heavily tie by the mixture with ethanol and ether
Brilliant)
Fusing point: 130-135 ℃ (decomposition)
[α] 20 D+ 97.6 ° (C=0.50, methyl alcohol)
Suitable-(-) oxalate (heavily tie by the mixture with ethanol and ether
Brilliant)
Fusing point: 130-135 ℃ (decomposition)
[α] 20 D-97.5 ° (C=0.50, methyl alcohol)
6 CoCH 3-CH 2C 6H 5Suitable-(+) 1/2 oxalate 1 hydrate (with acetone and ether
The mixture recrystallization)
Fusing point 103-113 ℃ (decomposition)
[α] 20 D+ 78.4 ° (C=1.00, methyl alcohol)
Suitable-(-) 1/2 oxalate 1 hydrate (with acetone and ether
The mixture recrystallization)
(continued on next page)
(brought forward)
Fusing point: 103-114 ℃ (decomposition)
[α] 20 D-78.8 ° (C=1.00, methyl alcohol)

Claims (2)

1, a kind of manufacturing 1, the 5-Benzothiazepine (1,5-benzothiazepine suberene, 1, the 5-benzothiazepine) method of derivative cis-isomeride, this derivative has following general formula:
Figure 87100139X_IMG2
R wherein 1Be methyl, R 2Be H or a kind of low-grade alkane acidyl, X 1Be a kind of low alkyl group, or the salt that makes from it, this method comprises a following step or a multistep:
I) have the alkylation of following general formula compound:
Figure 87100139X_IMG3
R wherein 3Be H or low-grade alkane acidyl, X 2Be H atom or a kind of low alkyl group, alkylating agent comprises: in the presence of a kind of alkali, methyl-sulfate or methyl iodide, this alkali can be selected from a kind of alkaline carbonate, a kind of alkali metal hydrocarbonate, a kind of alkalimetal hydride, a kind of alkali metal alkoxide and ethyl Isopropylamine.
Ii) work as R 3When being a kind of low-grade alkane acidyl, selectively remove said alkyloyl therefrom,
Iii) if desired, can further be transformed into product its salt.
2, the method for claim 1, alkylation wherein be 0 ℃ under the temperature between the reflux temperature, a kind of alkali in the presence of and in a kind of inert solvent, carry out with the method for methyl-sulfate or methyl iodide processing, said alkali is selected from a kind of alkaline carbonate, a kind of alkali metal hydrocarbonate, a kind of alkaline earth metal hydride, a kind of alkaline-earth metal alkyl oxide and ethyl Isopropylamine.
CN87100139A 1986-01-07 1987-01-07 Process of manufacture of 1,5-benzothiazepine derivates Expired - Fee Related CN1030388C (en)

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JP61001845A JPS62161776A (en) 1986-01-07 1986-01-07 Production of 1,5-benzothiazepine derivative

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US4567175A (en) * 1983-06-03 1986-01-28 Tanabe Seiyaku Co., Ltd. 8-Chloro-1,5-benzothiazepine derivatives
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