CN1894256A - Method for preparing spironolactone compounds - Google Patents

Abstract

This invention relates to a process for making spirolactone compounds of general formula I, having an improved Ia/Ib ratio, according to the following shceme.

Description

The method for preparing spironolactone compounds

Technical background

The present invention relates to the preparation method of formula I spironolactone compounds:

Formula I compound is the intermediate that preparation formula II spironolactone compounds is used.

Formula II compound and as the NPY5 antagonist in the purposes of treatment in Bulimia nerovsa, obesity or the diabetes at United States Patent (USP) 6,335,345 (its content all is incorporated herein by reference at this) and WO01/14376 (open day: disclose on February 3rd, 01).Formula II compound also can be as the therapeutical agent of the treatment various diseases relevant with NPY, these diseases include but not limited to cardiovascular disorder such as hypertension, ephrosis, heart trouble, vasospasm, arteriosclerosis etc., central nervous system disease such as Bulimia nerovsa, dysthymia disorders, anxiety disorder, outbreak, epilepsy, dementia, pain, alcoholism, drug withdrawal symptom etc., metabolic disease such as obesity, diabetes, hormone abnormality, hypercholesterolemia, hyperlipoidemia etc., property and reproductive dysfunction, gastrointestinal upset, respiratory tract disease, inflammation or glaucoma or the like.

United States Patent (USP) 6,335,345 and WO01/14376 method by formula I spironolactone preparation formula II compound has been described.

United States Patent (USP) 6,388,077 and USSN 60/352,451 method of preparation I compound has been described.But these methods need many synthetic step of converting (the longest LINEAR CONTINUOUS step was about for 7 steps), and total recovery is about 15-20%.

The cis of carrying out in aforementioned synthetic method is separated with trans spironolactone acid IA and IB's, and what cause preparing does not need isomer material complete loss.The present invention relates to formula I spironolactone acid trans that a kind of enrichment comprises spironolactone acid mixture IC (shown in page 3): the method for cis ratio.With respect to the content of cis spironolactone acid IB among the spironolactone acid mixture IC, this method has improved the content of trans spironolactone acid IA among the spironolactone acid mixture IC.This enriching method produces the trans spironolactone acid IA of higher yields.

Synthetic Communications 20 (17), and pp.26230-2629 (1990) has set forth the method for preparing organolithium reagent, 3-benzyl-pyridine formic acid and 3-benzyl Yi Yansuan and the method for lactone Cheng Huan.J.Org.Chem., vol.57 has described the method for ortho lithiation N-propenylbenzene methane amide and N-propenyl-toluamide among the pp.2700-2705 (1992).Tidwell, T.T. is at " ketenes " (John Wiley ﹠amp; Sons:New York, NY, 1995, introduced the reaction that alcohol and ketenes generate ester in p.592-597).Following document description go application racemization aspect of hindered alcohols at the prochirality carboxylic acid: Larsen R.D. etc., J.Am.Chem.Soc.1989,111,7650; Calmes, M. etc., Tetrahedron:Asymmetry 2002,13, and 293; And Calmes, M. etc., Tetrahedron, 1997,40,13719.

Summary of the invention

The invention provides the method for preparing structural formula I compound:

The inventive method comprises the negatively charged ion that forms aromatic substance, for example carries out ortho position-lithiation, and then the pimelinketone with the ester replacement reacts, and hydrolysis also forms lactonic ring.The spironolactone acid that obtains is converted into acyl chlorides, changes into hindered ester via the ketenes intermediate subsequently.With this hindered ester hydrolysis, obtain the formula IC spironolactone of needs, be mainly trans (IA) form.With spironolactone IC or its salt crystallization, separate the isomer IA and the IB that obtain high-purity forms, or its salt.

Shown in generalized flowsheet 1, isolating formula IA or IB spironolactone separately with formula H ₂NAr ¹Reaction produces corresponding spironolactone acid amides IIA or IIB.

In flow process 1, pimelinketone B that the 4-ester replaces and the aromatic substance A of ortho position-lithiumation reaction are followed ester hydrolysis and are formed lactonic ring, produce spironolactone IC, are the mixture of about 1: 1 IA: IB.With spironolactone IC activation, change into carboxylic acid halides E then, subsequently again by using hindered alcohols R ³OH handles, and is converted into hindered ester F via the ketenes intermediate.The hindered ester F that hydrolysis obtains generates spironolactone IC, is the mixture of formula IA and the acid of IB spironolactone, and wherein trans (IA) is about 80: 20 with the ratio of cis (IB).The mixture of IA and IB can be by generating the salt of IB, separating the mode of IA and IB through Crystallization Separation subsequently with acid treatment.Trans spironolactone acid IA and IB subsequently separately with H ₂NAr ¹Reaction, the compound of production IIA and IIB.

Flow process 1

Summary of the invention

The invention provides the method for preparing structural formula IC compound or its salt,

Wherein

T, U, V and W independently are selected from separately:

(1) nitrogen and

(2) methyne,

Wherein the methyne group is that unsubstituted or optional quilt is selected from following substituting group replacement:

(a) halogen,

(b) low alkyl group,

(c) hydroxyl and

(d) lower alkoxy, and

At least two is methyne among T wherein, U, V and the W;

This method may further comprise the steps:

(a) in solvent, handle formula IC compound, the spironolactone carboxylic acid halides of production E with halogenating agent:

Wherein X is a chlorine or bromine, and the definition of T, U, V and W is the same;

(b) the spironolactone carboxylic acid halides of usefulness alkali and pure processing formula E in solvent, the spironolactone ester of production F:

R wherein ³Be selected from the tertiary butyl, methyl, cyclohexyl, methylcyclopentyl and neo-pentyl, and the definition of T, U, V and W is the same;

(c) the spironolactone ester of usefulness aqueous acids hydrolyzing type F, the spironolactone acid of production IC:

Wherein the definition of T, U, V and W is the same; With

(d) separate the product that obtains.

In one embodiment of the present invention, the inventive method comprises the content with respect to isomer IB in the structural formula IC compound,

Increased the content of trans-isomer(ide) IA in the formula IC compound:

T wherein, U, V and W independently are selected from separately:

(1) nitrogen and

(2) methyne,

Wherein the methyne group is that unsubstituted or optional quilt is selected from following substituting group replacement:

(a) halogen,

(b) low alkyl group,

(c) hydroxyl and

(d) lower alkoxy, and

At least two is methyne among T wherein, U, V and the W.

In another embodiment of the invention, T, V and W are methyne, and methyne wherein is that unsubstituted or optional quilt is selected from following substituting group replacement:

(a) halogen,

(b) low alkyl group,

(c) hydroxyl and

(d) lower alkoxy; And

U is a nitrogen.

In this embodiment of a class, T, V and W are unsubstituted methyne; And U is a nitrogen.

In another embodiment of the invention, T, U, V and W are methyne, and methyne wherein is that unsubstituted or optional quilt is selected from following substituting group replacement:

(a) halogen,

(b) low alkyl group,

(c) hydroxyl and

(d) lower alkoxy.

In this embodiment of a class, the methyne group is unsubstitutedly or optional to be replaced by halogen.

In another embodiment of the invention, the solvent in the step (a) is selected from chloroform, ethyl acetate, tetrahydrofuran (THF), glycol dimethyl ether, diglyme, 2-methyltetrahydrofuran, 1,4-two  alkane and methylene diethyl ethers.In this embodiment of a class, the solvent in the step (a) is a tetrahydrofuran (THF).

In another embodiment of the invention, the halogenating agent in the step (a) is selected from phosphoryl chloride, oxalyl chloride, phosphorus trichloride, phosphorus tribromide, thionyl chloride, thionyl bromide and oxalyl bromine.In this embodiment of a class, the halogenating agent in the step (a) is a phosphoryl chloride.In the group scheme of such scheme, with respect to spironolactone acid IC, the consumption of phosphoryl chloride is about 0.7 equivalent to 2.0 equivalent.In another group scheme of such scheme, with respect to spironolactone acid IC, the consumption of phosphoryl chloride is about 1.15 equivalents.In another group scheme of such scheme, the consumption of phosphoryl chloride is about 1.05 equivalents with respect to the sour IC of spironolactone.

In another embodiment of the invention, the formula E spironolactone carboxylic acid halides in the step (a) is the spironolactone acyl chlorides.

In another embodiment of the invention, the reaction of step (a) further comprises catalyzer.In this embodiment of a class, catalyzer is a dimethyl formamide.In the group scheme of such scheme, the consumption of dimethyl formamide is about 0.2 equivalent to about 5 equivalents, is benchmark with the amount of formula IC spironolactone acid.In the another kind of group scheme of such scheme, with respect to the amount of formula IC spironolactone acid, the consumption of dimethyl formamide is about 1 equivalent.

In another embodiment of the invention, the reaction of step (a) is to carry out to about 80 ℃ temperature at about 20 ℃.In this embodiment of a class, the reaction of step (a) is to carry out under about 40 ℃ temperature.In the group scheme of such scheme, being reflected at of step (a) carried out about 2 hours under about 40 ℃ temperature.

In another embodiment of the invention, alkali in the step (b) is selected from N, N, N ', N '-Tetramethyl Ethylene Diamine, triethylamine, N, N-diisopropylethylamine, N, N-dimethyl amine, pyridine, collidine, 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene, N-methylmorpholine and N, N, N ', N '-tetramethyl--1,6-hexanediamine.In this embodiment of a class, the alkali in the step (b) is N, N, N ', N '-Tetramethyl Ethylene Diamine.In the group scheme of such scheme, N, N, N ', the consumption of N '-Tetramethyl Ethylene Diamine is counted about 1 equivalent to about 10 equivalents with formula F spironolactone ester.In another group scheme of such scheme, N, N, N ', the consumption of N '-Tetramethyl Ethylene Diamine is about 3.5 equivalents with respect to formula F spironolactone ester.

In another embodiment of the invention, the alcohol that uses in the step (b) is selected from the trimethyl carbinol, methyl-cyclohexanol, methylcyclopentanol and neopentyl alcohol.In this embodiment of a class, the alcohol that uses in the step (b) is the trimethyl carbinol.In the group scheme of such scheme, the consumption of the trimethyl carbinol is about 1 equivalent to 10 equivalent with respect to the spironolactone ester of formula F.In another group scheme of such scheme, the consumption of the trimethyl carbinol is counted about 1.5 equivalents with formula F spironolactone ester.

In one embodiment of the present invention, the solvent of step (b) usefulness is selected from tetrahydrofuran (THF), glycol dimethyl ether, diglyme, 2-methyltetrahydrofuran, 1,4-two  alkane and methylene diethyl ethers.In this embodiment of a class, the solvent of step (b) usefulness is a tetrahydrofuran (THF).

In another embodiment, the reaction of step (b) further comprises salt.In this embodiment of a class, described salt is selected from lithiumbromide, lithium chloride, lithium iodide, lithium perchlorate and LiBF4.In the group scheme of such scheme, described salt is lithium chloride.In the subclass scheme of this group scheme, the consumption of lithium chloride is counted about 0.5 equivalent to about 5 equivalents with the consumption of formula F spironolactone ester.In another subclass scheme of this group scheme, the consumption of lithium chloride is counted about 1 equivalent by formula F spironolactone ester consumption.

In another embodiment of the invention, step (b) is reflected at about 20 ℃ and carries out to about 80 ℃ temperature.In this embodiment of a class, being reflected under about 40 ℃ temperature of step (b) carried out.In the group scheme of such scheme, being reflected at of step (b) carried out about 2 hours-about 24 hours under about 40 ℃ temperature.In another group scheme of such embodiment, being reflected at of step (b) carried out about 19 hours under about 40 ℃ temperature.

In another embodiment of the invention, the aqueous acids of using in the step (c) is selected from sulfuric acid, hydrochloric acid, Hydrogen bromide, phosphoric acid and formic acid.In this embodiment of a class, the aqueous acids of step (c) usefulness is a sulfuric acid.

In another embodiment of the invention, the hydrolysis reaction of step (c) is to carry out to about 100 ℃ temperature at about 20 ℃.In this embodiment of a class, the hydrolysis reaction of step (c) carries out under about 50 ℃ temperature.In the group scheme of such scheme, the hydrolysis of step (c) is to carry out under about 50 ℃ temperature about 2 hours.

In another embodiment of the invention, the separation of step (d) product comprises that the pH with alkali regulating step (c) solution arrives between about 0-4, and the extractive reaction mixture obtains Compound I C.In the group scheme of such embodiment, described alkali is sodium hydroxide.In another group scheme, the pH of regulating step (c) solution is between about 2-about 3.In the subclass scheme of this group scheme, the pH of regulating step (c) solution is to about 2.4.

According to the present invention, further provide the method for preparation and separate type IA spironolactone or its salt and formula IB spironolactone or its salt:

Wherein:

T, U, V and W independently are selected from separately:

(1) nitrogen and

(2) methyne,

Wherein the methyne group is that unsubstituted or optional quilt is selected from following substituting group replacement:

(a) halogen,

(b) low alkyl group,

(c) hydroxyl and

(d) lower alkoxy, and

Wherein among T, U, V and the W at least two be methyne;

This method may further comprise the steps:

(a) in formula IC compound, add solvent, form mixture,

Wherein the definition of T, U, V and W is the same;

(b) in the mixture of step (e), add acid, form mixture; With

(c) the mixture certain hour of aging step (f) under the condition of effective production I compound or its salt:

Wherein the definition of T, U, V and W is the same.

In one embodiment of the present invention, T, V and W are methyne, and methyne group wherein is that unsubstituted or optional quilt is selected from following substituting group replacement:

(a) halogen,

(b) low alkyl group,

(c) hydroxyl and

(d) lower alkoxy; And

U is a nitrogen.

In this embodiment of a class, T, V and W are unsubstituted methyne; And U is a nitrogen.

In another embodiment of the invention, T, U, V and W are methyne, and wherein the methyne group is that unsubstituted or optional quilt is selected from following substituting group replacement:

(a) halogen,

(b) low alkyl group,

(c) hydroxyl and

(d) lower alkoxy.

In this embodiment of a class, the methyne group is unsubstitutedly or optional to be replaced by halogen.

In another embodiment of the invention, the solvent in the step (e) is selected from glycol dimethyl ether, acetonitrile, tetrahydrofuran (THF) or its mixture.In this embodiment of a class, the solvent in the step (e) is a tetrahydrofuran (THF).In another kind of this embodiment, the solvent in the step (e) is an acetonitrile.

In another embodiment of the invention, the acid of step (f) usefulness is selected from hydrochloric acid, Hydrogen bromide, tartrate, methylsulfonic acid, toluenesulphonic acids, succsinic acid and sulfuric acid.In this embodiment of a class, the acid of step (f) usefulness is hydrochloric acid.In another embodiment of the invention, step (g) is aging under about 10 ℃ to 60 ℃ temperature.In this embodiment of a class, the digestion time of step (g) is about 1 hour to about 48 hours.In the group scheme of such scheme, wearing out of step (g) carried out about 3 hours under about 25 ℃ temperature.In another embodiment of the invention, this method further comprises the step (h) of separate type IA compound or its salt.In this embodiment of a class, formula IA compound separates by the mode that filtration and concentrated filtrate obtain slurries.In the group scheme of such scheme, with the slurries solvent cut, and aging under certain condition certain hour, obtain formula IA compound.In another group scheme of such scheme, slurries were worn out about 20 hours down with the hexane dilution and at about 0 ℃.In the subclass scheme of this group scheme, formula IA compound separates by filtering slurries, obtains the product of wanting.In another group scheme of such scheme, by concentrated slurry, use dilution in acetonitrile, and aging under certain condition certain hour, thereby obtain formula IA compound.

The present invention also provides the method for preparing structural formula IC compound or its salt,

Wherein

T, U, V and W independently are selected from separately:

(1) nitrogen and

(2) methyne,

Wherein the methyne group is that unsubstituted or optional quilt is selected from following substituting group replacement:

(a) halogen,

(b) low alkyl group,

(c) hydroxyl and

(d) lower alkoxy, and

Wherein among T, U, V and the W at least two be methyne;

This method may further comprise the steps:

(a) in aprotonic solvent, make highly basic and formula A compound carry out chemical combination, generate solution,

Wherein the definition of T, U, V and W is the same;

(b) make the solution reaction of formula B compound and step (a),

Wherein

R ²Be selected from:

(a) low alkyl group and

(b)-CH ₂-phenyl, wherein phenyl is unsubstituted or is selected from following substituting group replacement:

(1) low alkyl group,

(2) lower alkoxy and

(3)-NO ₂，

Be created on the formula C ester in the solution

T wherein, U, the definition of V and W is the same;

(c) in the solution of step (b) Chinese style IC ester, add entry, the acid of production D:

T wherein, U, the definition of V and W is the same;

(d) handle the acid of formula D with aqueous acids, the spironolactone acid of production IC:

T wherein, U, the definition of V and W is the same;

(e) in solvent, handle formula IC compound, the spironolactone carboxylic acid halides of production E with halogenating agent:

Wherein X is a chlorine or bromine, and T, U, and the definition of V and W is the same;

(f) in solvent, with the spironolactone carboxylic acid halides of alkali and pure processing formula E, the spironolactone ester of production F:

R wherein ³Be selected from the tertiary butyl, methyl, cyclohexyl, methylcyclopentyl and neo-pentyl, and the definition of T, U, V and W is the same;

(g) the spironolactone ester of usefulness aqueous acids hydrolyzing type F, the spironolactone acid of production IC:

T wherein, U, the definition of V and W is the same; With

(h) separate the product that obtains.

In one embodiment of the present invention, this method comprises the content with respect to isomer IB in the structural formula IC compound,

The content of trans-isomer(ide) IA in the raising formula IC compound:

T wherein, U, V and W independently are selected from separately:

(1) nitrogen and

(2) methyne,

Wherein the methyne group is that unsubstituted or optional quilt is selected from following substituting group replacement:

(a) halogen,

(b) low alkyl group,

(c) hydroxyl and

(d) lower alkoxy, and

Wherein among T, U, V and the W at least two be methyne.

In another embodiment of the invention, T, V and W are methyne, and methyne group wherein is that unsubstituted or optional quilt is selected from following substituting group replacement:

(a) halogen,

(b) low alkyl group,

(c) hydroxyl and

(d) lower alkoxy; And

U is a nitrogen.

In this embodiment of a class, T, V and W are unsubstituted methyne; And U is a nitrogen.

In another embodiment of the invention, T, U, V and W are methyne, and wherein the methyne group is that unsubstituted or optional quilt is selected from following substituting group replacement:

(a) halogen,

(b) low alkyl group,

(c) hydroxyl and

(d) lower alkoxy.

In this embodiment of a class, the methyne group is unsubstitutedly or optional to be replaced by halogen.

In another embodiment of the invention, step (a) and (b) approximately-50 ℃ to-80 ℃ temperature, carrying out.In this embodiment of a class, step (a) wears out being lower than approximately under-55 ℃ the temperature.In the group scheme of such scheme, the digestion time of step (a) is about 5 minutes to 18 hours.

In another embodiment of the invention, the aprotonic solvent of step (a) usefulness is selected from tetrahydrofuran (THF), toluene, heptane, glycol dimethyl ether, benzene and hexane, ether, dimethylbenzene or its mixture.In this embodiment of a class, the aprotonic solvent in the step (a) is a tetrahydrofuran (THF).

In another embodiment of the invention, the highly basic in the step (a) is selected from n-BuLi, the second month in a season-BuLi, t-BuLi, LiHMDS, NaHMDS, KHMDS and LiTMP.In this embodiment of a class, the highly basic in the step (a) is n-BuLi.

In another embodiment of the invention, step (a) comprises that further adding is selected from following salt: LiBr, LiCl, LiI, LiBF ₄, LiClO ₄And CeCl ₃In this embodiment of a class, the salt in the step (a) is LiBr.

In another embodiment of the invention, R ²Be selected from :-CH ₃,-CH ₂CH ₃,-(CH ₂) ₂CH ₃,-CH (CH ₃) ₂,-(CH ₂) ₃CH ₃, and-CH (CH ₃) ₃In this embodiment of a class, R ²Be-CH ₂CH ₃

In another embodiment of the invention, in step (c), be approximately-60 ℃ to about-50 ℃ temperature, in formula C ester solution, add entry.In this embodiment of a class, water is to add under temperature approximately-55 ℃.

In another embodiment of the invention, step (c) is carried out under about 0 ℃ to 50 ℃ temperature after adding entry.In this embodiment of a class, step (c) is carried out under about 40 ℃ temperature after adding entry.In the group scheme of such scheme, step (c) was carried out about 1 hour to 4 hours.

In another embodiment of the invention, the aqueous acids of using in the step (d) is selected from hydrochloric acid, sulfuric acid, methylsulfonic acid, trifluoromethanesulfonic acid or its mixture.In this embodiment of a class, the aqueous acids of step (d) usefulness is a sulfuric acid.In the group scheme of such scheme, described acid is to add being lower than under about 30 ℃ temperature.In another group scheme of such scheme, described acid is to add being lower than under about 30 ℃ temperature, and about 50 ℃ to about 70 ℃ temperature range aging about 1 hour to about 4 hours.

In another embodiment of the invention, the formula E spironolactone carboxylic acid halides that generates in the step (e) is the spironolactone acyl chlorides.

In another embodiment of the invention, the solvent of using in the step (e) is selected from chloroform, ethyl acetate, tetrahydrofuran (THF), glycol dimethyl ether, diglyme, 2-methyltetrahydrofuran, 1,4-two  alkane and methylene diethyl ethers.In this embodiment of a class, the solvent in the step (e) is a tetrahydrofuran (THF).

In another embodiment of the invention, the halogenating agent of using in the step (e) is selected from phosphoryl chloride, oxalyl chloride, phosphorus trichloride, phosphorus tribromide, thionyl chloride, thionyl bromide and oxalyl bromine.In this embodiment of a class, the halogenating agent in the step (e) is a phosphoryl chloride.In the group scheme of such scheme, the consumption of phosphoryl chloride is counted about 0.7 equivalent to about 2.0 equivalents with spironolactone acid IC.In another group scheme of such scheme, the consumption of phosphoryl chloride is counted about 1.15 equivalents with spironolactone acid IC.In another group scheme of such scheme, the consumption of phosphoryl chloride is counted about 1.05 equivalents with spironolactone acid IC.

In another embodiment of the invention, the reaction of step (e) further comprises catalyzer.In this embodiment of a class, described catalyzer is a dimethyl formamide.In the group scheme of such scheme, the consumption of dimethyl formamide is counted about 0.2 equivalent to about 5 equivalents with the acid of formula IC spironolactone.In another group scheme of such scheme, the consumption of dimethyl formamide is counted about 1 equivalent with the acid of formula IC spironolactone.

In another embodiment of the invention, the reaction of step (e) is to carry out to about 80 ℃ temperature at about 20 ℃.In this embodiment of a class, the reaction of step (e) is to carry out under about 40 ℃ temperature.In the group scheme of such scheme, the reaction of step (e) is to carry out about 2 hours in about 40 ℃ temperature.

In another embodiment of the invention, the alkali of step (f) usefulness is selected from N, N, N ', N '-Tetramethyl Ethylene Diamine, triethylamine, N, N-diisopropylethylamine, N, N-dimethyl amine, pyridine, collidine, 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene, N-methylmorpholine and N, N, N ', N '-tetramethyl--1,6-hexanediamine.In this embodiment of a class, the alkali of step (f) usefulness is N, N, N ', N '-Tetramethyl Ethylene Diamine.In the group scheme of such scheme, N, N, N ', the consumption of N '-Tetramethyl Ethylene Diamine is counted about 1 equivalent to about 10 equivalents with formula F spironolactone ester.In another group scheme of such scheme, N, N, N ', the consumption of N '-Tetramethyl Ethylene Diamine is counted about 3.5 equivalents with formula F spironolactone ester.

In another embodiment of the invention, the alcohol that uses in the step (f) is selected from the trimethyl carbinol, methyl-cyclohexanol, methylcyclopentanol and neopentyl alcohol.In this embodiment of a class, the alcohol that uses in the step (f) is the trimethyl carbinol.In the group scheme of such scheme, the consumption of the trimethyl carbinol is counted about 1 equivalent to 10 equivalent with formula F spironolactone ester.In another group scheme of such scheme, the consumption of the trimethyl carbinol is counted about 1.5 equivalents with formula F spironolactone ester.

In one embodiment of the present invention, the solvent of step (f) usefulness is selected from tetrahydrofuran (THF), glycol dimethyl ether, diglyme, 2-methyltetrahydrofuran, 1,4-two  alkane and methylene diethyl ethers.In this embodiment of a class, the solvent of step (f) usefulness is a tetrahydrofuran (THF).

In another embodiment, the reaction of step (f) further comprises salt.In this embodiment of a class, described salt is selected from lithiumbromide, lithium chloride, lithium iodide, lithium perchlorate and LiBF4.In the group scheme of such scheme, described salt is lithium chloride.In the subclass scheme of this group scheme, the consumption of lithium chloride is counted about 0.5 equivalent to about 5 equivalents with the consumption of formula F spironolactone ester.In another subclass scheme of this group scheme, the consumption of lithium chloride is counted about 1 equivalent by formula F spironolactone ester consumption.

In another embodiment of the invention, the reaction of step (f) is to carry out to about 80 ℃ temperature at about 20 ℃.In this embodiment of a class, being reflected under about 40 ℃ temperature of step (f) carried out.In the group scheme of such scheme, being reflected at of step (b) carried out about 2 hours to about 24 hours under about 40 ℃ temperature.In another group scheme of such embodiment, being reflected at of step (f) carried out about 19 hours under about 40 ℃ temperature.

In another embodiment of the invention, the aqueous acids of using in the step (g) is selected from sulfuric acid, hydrochloric acid, Hydrogen bromide, phosphoric acid and formic acid.In this embodiment of a class, the aqueous acids of step (g) usefulness is a sulfuric acid.

In another embodiment of the invention, the hydrolysis reaction of step (g) is to carry out to about 100 ℃ temperature at about 20 ℃.In this embodiment of a class, the hydrolysis reaction of step (g) is to carry out under about 50 ℃ temperature.In the group scheme of such scheme, the hydrolysis of step (g) is to carry out under about 50 ℃ temperature about 2 hours.

In another embodiment of the invention, the separation of step (h) product comprises that the pH with alkali regulating step (g) solution arrives between about 0-4, and the extractive reaction mixture, thereby obtains Compound I C.In the group scheme of such embodiment, described alkali is sodium hydroxide.In another group scheme, the pH of regulating step (g) solution arrives between about 2 to about 3.In the subclass scheme of this group scheme, pH regulator is to about 2.4.

According to the present invention, further provide the method for preparation and separate type IA spironolactone or its salt and formula IB spironolactone or its salt:

Wherein:

T, U, V and W independently are selected from separately:

(1) nitrogen and

(2) methyne,

Wherein the methyne group is that unsubstituted or optional quilt is selected from following substituting group replacement:

(a) halogen,

(b) low alkyl group,

(c) hydroxyl and

(d) lower alkoxy, and

Wherein among T, U, V and the W at least two be methyne;

This method may further comprise the steps:

(a) in formula IC compound, add solvent, form mixture,

Wherein the definition of T, U, V and W is the same;

(b) in the mixture of step (i), add acid, form mixture; With

(c) the mixture certain hour of aging step (j) under the condition of effective production IA compound or its salt:

The definition of T wherein, U, V and W is the same.

In one embodiment of the present invention, T, V and W are methyne, and methyne group wherein is that unsubstituted or optional quilt is selected from following substituting group replacement:

(a) halogen,

(b) low alkyl group,

(c) hydroxyl and

(d) lower alkoxy; And

U is a nitrogen.

In this embodiment of a class, T, V and W are unsubstituted methynes; And U is a nitrogen.

In another embodiment of the invention, T, U, V and W are methynes, and wherein this methyne group is that unsubstituted or optional quilt is selected from following substituting group replacement:

(a) halogen,

(b) low alkyl group,

(c) hydroxyl and

(d) lower alkoxy.

In this embodiment of a class, described methyne group is unsubstitutedly or optional to be replaced by halogen.

In another embodiment of the invention, the solvent in the step (i) is selected from glycol dimethyl ether, acetonitrile, tetrahydrofuran (THF) or its mixture.In this embodiment of a class, the solvent in the step (i) is a tetrahydrofuran (THF).In another kind of this embodiment, the solvent in the step (i) is an acetonitrile.

In another embodiment of the invention, the acid of step (j) usefulness is selected from hydrochloric acid, Hydrogen bromide, tartrate, methylsulfonic acid, toluenesulphonic acids, succsinic acid and sulfuric acid.In this embodiment of a class, the acid of step (j) usefulness is hydrochloric acid.

In another embodiment of the invention, aging in the step (k) is to carry out under about 10 ℃ to 60 ℃ temperature.In this embodiment of a class, the digestion time of step (k) is about 1 hour to about 48 hours.In the group scheme of such scheme, the aging of step (k) is to carry out under about 25 ℃ temperature about 3 hours.

In another embodiment of the invention, this method further comprises the step (l) of separate type IA compound or its salt.In this embodiment of a class, formula IA compound separates by the mode that filtration and concentrated filtrate obtain slurries.In the group scheme of such scheme, with the slurries solvent cut, and aging under certain condition certain hour, obtain formula IA compound.In another group scheme of such scheme, slurries were worn out about 20 hours down with the hexane dilution and at about 0 ℃.In the subclass scheme of this group scheme, formula IA compound separates by filtering slurries, thereby obtains the product of wanting.In another group scheme of such scheme, by concentrated slurry, use dilution in acetonitrile, and aging under certain condition certain hour, thereby obtain formula LA compound.

Another embodiment of the present invention provides the compound or its salt with following structural formula:

Wherein X is selected from chlorine and bromine, and

T, U, V and W independently are selected from separately:

(1) nitrogen and

(2) methyne,

Wherein the methyne group is that unsubstituted or optional quilt is selected from following substituting group replacement:

(a) halogen,

(b) low alkyl group,

(c) hydroxyl and

(d) lower alkoxy, and

At least two is methyne among T wherein, U, V and the W;

In this embodiment of a class, T, V and W are methyne, and methyne group wherein is that unsubstituted or optional quilt is selected from following substituting group replacement:

(a) halogen,

(b) low alkyl group,

(c) hydroxyl and

(d) lower alkoxy; And

U is a nitrogen.

In the group scheme of such scheme, T, V and W are unsubstituted methynes; And U is a nitrogen.

In another kind of this embodiment, T, U, V and W are methynes, and wherein these methyne groups are that unsubstituted or optional quilt is selected from following substituting group replacement:

(a) halogen,

(b) low alkyl group,

(c) hydroxyl and

(d) lower alkoxy.

In the group scheme of such scheme, described methyne group is unsubstitutedly or optional to be replaced by halogen.

In another embodiment of the invention, provide compound or its salt with following structural formula:

In another embodiment of the invention, provide and comprised about 83%-52% Compound I A:

With the composition of about 17%-48% compd B,

T wherein, U, V and W independently are selected from separately:

(1) nitrogen and

(2) methyne,

Wherein the methyne group is that unsubstituted or optional quilt is selected from following substituting group replacement:

(a) halogen,

(b) low alkyl group,

(c) hydroxyl and

(d) lower alkoxy, and

At least two is methyne among T wherein, U, V and the W;

In this embodiment of a class, T, V and W are methyne, and methyne group wherein is that unsubstituted or optional quilt is selected from following substituting group replacement:

(a) halogen,

(b) low alkyl group,

(c) hydroxyl and

(d) lower alkoxy; And

U is a nitrogen.

In the group scheme of such scheme, T, V and W are unsubstituted methynes; And U is a nitrogen.

In another kind of this embodiment, T, U, V and W are methynes, and wherein these methyne groups are that unsubstituted or optional quilt is selected from following substituting group replacement:

(a) halogen,

(b) low alkyl group,

(c) hydroxyl and

(d) lower alkoxy.

In the group scheme of such scheme, described methyne group is unsubstitutedly or optional to be replaced by halogen.

The composition of the compound 1-9 that comprises about 79% compound 1-8 and about 21% is provided in another embodiment of the invention:

In another embodiment of the present invention, provide the composition of the compound 1-9 that comprises about 83% compound 1-8 and about 17%:

" T, U, V and W " used herein is meant nitrogen or methyne, and wherein the methyne group is the substituting group replacement that unsubstituted or optional quilt is selected from halogen, low alkyl group, hydroxyl and lower alkoxy, and T, U, and at least two is methyne among V and the W.

" the methyne group is the substituting group replacement that unsubstituted or optional quilt is selected from halogen, low alkyl group, hydroxyl and lower alkoxy " is meant unsubstituted methyne or has substituent methyne that described substituting group can be selected from halogen, low alkyl group, hydroxyl and lower alkoxy.Aforementioned substituting group preferably includes halogen etc.

" halogen " or " halogenide " is meant fluorine atom, chlorine atom, bromine atoms and iodine atom.Preferably include fluorine atom, chlorine atom etc. as above-mentioned substituent halogen atom.

" low alkyl group " is meant the C of straight or branched ₁-C ₆Alkyl, for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, hexyl, isohexyl etc.Preferably include methyl, ethyl etc. as above-mentioned substituent low alkyl group.

" lower alkoxy " is meant the C of straight or branched ₁-C ₆Alkoxy base, for example methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, sec-butoxy, isobutoxy, tert.-butoxy, pentyloxy, isopentyloxy, hexyloxy, different hexyloxy etc.As above-mentioned substituting group, lower alkoxy preferably includes methoxyl group, oxyethyl group etc.

" cycloalkyl " is meant saturated C ₃-C ₆Monocycle carbocyclic ring, one of them carboatomic ring atom are link position.The example of cycloalkyl includes, but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.

" Heterocyclylalkyl " is meant and contains the heteroatomic C that at least one is selected from N, S and O ₃-C ₆Saturated monocycle, wherein link position can be carbon or nitrogen.The example of " Heterocyclylalkyl " includes, but not limited to pyrrolidyl, piperidyl, piperazinyl, imidazolidyl, tetrahydrofuran base, morpholinyl etc.

" aryl " is meant aromaticity monocycle or two rings that only comprise carbon atom.This term also comprises and monocyclic cycloalkyl or monocyclic heterocycles alkyl condensed aryl that link position wherein is positioned at aromatic portion.The example of aryl comprises phenyl, naphthyl, 2,3-dihydro indenyl, indenyl, tetralyl, 2,3-dihydro benzo furyl, dihydrobenzopyrans base, 1,4-benzo two  alkyl etc.Aryl rings can be unsubstituted or be substituted on one or more carbon atoms.

" heteroaryl " is meant and comprises at least one heteroatomic monocycle that is selected from N, O and S or two cyclophane rings, and wherein each ring comprises 5-6 atom.The example of heteroaryl comprise pyrryl, different  azoles base, isothiazolyl, pyrazolyl, pyridyl,  azoles base,  di azoly, thiadiazolyl group, thiazolyl, imidazolyl, triazolyl, tetrazyl, furyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazol base, benzothiazolyl, benzimidazolyl-, benzofuryl, benzothienyl, furo (2,3-b) pyridyl, quinolyl, indyl, isoquinolyl etc.Heteroaryl ring can be unsubstituted or be substituted on one or more carbon atoms.

Term used herein " negatively charged ion " is meant single anion or two negatively charged ion.

Compound in the inventive method comprises steric isomer, diastereomer and geometrical isomer, or tautomer, and these all depend on the replacement mode.Therefore these compounds can contain one or more asymmetric centers, can racemic modification, the form of racemic mixture and exist with the form of independent diastereomer, non-enantiomer mixture, mixture of enantiomers or single enantiomorph or tautomer.This invention is intended to comprise all these isomeric forms of the compound in the present composition and their mixture.Therefore, when compound had chirality, the independent enantiomorph and the diastereomer that are substantially free of other compositions were included within the scope of the invention; And further comprise whole mixtures of various enantiomorphs and whole mixtures of various diastereomers.The salt, polymorphic form, hydrate and the solvate that within the scope of the invention, equally also comprise The compounds of this invention and intermediate.

The compound of structural formula I and structural formula II comprises steric isomer, for example the general formula I A of trans forms and IIA compound:

And the general formula I B of cis form and IIB compound:

Preferred trans forms.

The salt of the compound of formula I, IA, IB and IC is meant pharmaceutically acceptable common salt, for example, when compound has carboxyl at the base addition salt of carboxyl, or when compound has amino or alkaline heterocyclic radical at the acid salt of amino or alkaline Heterocyclylalkyl, or the like.

Base addition salt comprises an alkali metal salt (including but not limited to sodium salt, sylvite); Alkaline earth salt (including but not limited to calcium salt, magnesium salts); Ammonium salt or the salt (these organic amines include but not limited to Trimethylamine 99, triethylamine, dicyclohexylamine, thanomin, diethanolamine, trolamine, PROCAINE HCL, PHARMA GRADE, N, N '-dibenzyl-ethylenediamin) that forms with organic amine, or the like.

Acid salt comprises inorganic acid salt (described acid includes but not limited to hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid), (this organic acid comprises organic acid salt, but be not limited to, toxilic acid, fumaric acid, tartrate, citric acid, xitix, trifluoroacetic acid, acetate), (described sulfonic acid comprises sulfonate, but be not limited to methylsulfonic acid, isethionic acid, Phenylsulfonic acid, tosic acid, tosic acid monohydrate, tosic acid hydrate, camphorsulfonic acid), or the like.

In below the flow process and embodiment, all ingredients symbol and abbreviation have following implication:

N-BuLi or BuLi: n-Butyl Lithium

Sec-BuLi: s-butyl lithium

T-BuLi: tert-butyl lithium

T-BuOH: the trimethyl carbinol

DBU:1,8-diazabicylo [5.4.0] 11 carbon-7-alkene

DMF: dimethyl formamide

DMSO: methyl-sulphoxide

-Et： -CH ₂CH ₃

G: gram

H: hour

HCl: hydrochloric acid

H ₂SO ₄: sulfuric acid

KHMDS: hexamethyldisilane base ammonification potassium

LiBr: lithiumbromide

LiCl: lithium chloride

LiHMDS: hexamethyldisilane base lithamide

LiTMP: tetramethyl piperidine lithium (lithium tetramethyl piperadide)

NaHMDS: hexamethyldisilane base ammonification sodium

-Me: methyl

ML: milliliter

Mmol: milliliter

Mmol: mmole

Mol: mol

POCl ₃: phosphoryl chloride

THF: tetrahydrofuran (THF)

TMEDA: Tetramethyl Ethylene Diamine or N, N, N ', N '-Tetramethyl Ethylene Diamine

The compounds of this invention can adopt the universal method preparation in the flow process 1.Novel method of the present invention sees that flow process 2 illustrates, and this flow process has been described the spironolactone of structural formula I, IA, IB and IC and the preparation of salt thereof.Separate IA and IB salt, and respectively with amine H ₂NAr ¹Reaction.For example, by neutralizing, activate and make subsequently IA salt and H ₂NAr ¹Reaction obtains formula II compound.

In flow process 2, the pimelinketone that the 4-ethyl ester replaces changed into carboxylic acid via intermediate C earlier before by cyclic lactone formation spironolactone IC.In the presence of salt such as LiBr, in solvent such as THF in approximately-55 ℃ to-65 ℃ the temperature with alkali such as n-Butyl Lithium with Isonicotinamide 1-1 deprotonation, generate metallized N-anilide.Being lower than approximately under-55 ℃ the temperature, above-mentioned metallized N-anilide is joined in the solution of 4-oxo hexahydrobenzoic acid ethyl ester 1-2 in solvent such as THF, then add water and generate diacid 1-3.Diacid 1-3 is handled being lower than under about 30 ℃ temperature with aqueous acids such as sulfuric acid then, generates the lactonic ring of spironolactone acid 1-4, is the mixture of about 1: 1 cis and trans spironolactone acid.In the presence of DMF, handle with halogenating agent in solvent such as THF subsequently, 1-4 activates into carboxylic acid halides 1-5 with spironolactone acid.This carboxylic acid halides is acyl chlorides preferably, is about to described acid and handles and get with phosphoryl chloride.Alcohol as the trimethyl carbinol and salt such as LiCl in the presence of, in solvent such as THF with alkali such as N, N, N ', N '-Tetramethyl Ethylene Diamine processing acyl chlorides 1-5 is via ketenes intermediate generation ester 1-6.Ester 1-6 uses the hydrolysis in addition under about 50 ℃ temperature of aqueous acids such as sulfuric acid subsequently, generates sour 1-7 (IC), is 80: 20 trans/cis mixture.Acid 1-7 can be further purified and be separated into 1-8 (IA in the following manner, trans) and 1-9 (IB, cis): handle the salt that forms 1-9 with sour example hydrochloric acid, and by from separating these compounds such as the mode of recrystallization the kind solvent of acetonitrile, tetrahydrofuran (THF), heptane or its mixture.This method produces the IB that is substantially free of the IA of IB and is substantially free of IA.

Flow process 2

The present invention is illustrated with the following example, but they must not be taken as and limit the scope of the present invention.

Embodiment 1

Anti-form-1 '-oxo spiral shell [hexanaphthene-1,3 ' (1 ' H)-furo [3,4-C] pyridine]-4-carboxylic acid, the preparation of 1-5 (method A)

Steps A: the preparation of compound 1-3

In flask, mix Isonicotinamide 1-1(100g, 0.50mol, Kingchem), the LiBr solution (dissolving 1.50molLiBr makes in 1.5L THF) of THF (0.5L) and 1M.Gained solution outgases with nitrogen, and is cooled to-65 ℃.Add n-BuLi (1.56M hexane solution then; 666mL 1.04mol), keeps feed temperature simultaneously and is lower than-55 ℃.Be lower than subsequently under-55 ℃ the temperature aging 1-7 hour of gained solution, obtaining metallized N-anilide mixture.

Cooling 4-oxo hexahydrobenzoic acid ethyl ester in another flask 1-2THF (1L) solution of (100ml, 0.63mol, EMS Dottikon AG) is to the temperature that is lower than-60 ℃.In this solution, add above-mentioned metallized N-anilide mixture, keep feed temperature simultaneously and be lower than-55 ℃.Gained solution is lower than under-55 ℃ the temperature aging 1 hour, pouring H then carefully into ₂Termination reaction among the O (1L).Warm gained mixture to 40 ℃, and at 40 ℃ of aging 1-4 hours.Behind the cool to room temperature, remove organic layer, with water layer (1.3L; PH～11) with THF (1L) washing, obtain diacid 1-3The aqueous solution.

Step B: the preparation of compound 1-4

Keeping below under 30 ℃ the temperature, to the diacid of steps A 1-3The aqueous solution in add H ₂O (500mL, 5mL/g N-anilide) and 47% moisture H ₂SO ₄, regulate pH2～3.The white suspension that obtains was worn out 1-4 hour under 30 ℃-70 ℃ temperature.Cool off feed liquid, add the NaCl aqueous solution (600ml) of THF (2500mL) and 20% afterwards, be used for extraction product acid 1-4Separates two extracts water layer with THF (1000mL) then once more.Merge THF extraction liquid (3500mL), be concentrated to 1250mL.Mixture is transformed into spironolactone acid during the distillation 1-4Suspension.

Selected signal: ¹H NMR (300.13MHz, DMSO-d ₆): Λ 12.31 (br, 1H), 9.10 (d, 1H), 8.85 (m, 1H), 7.82 (m, 1H), 2.70 (m, 0.45H), 2.43 (m, 0.55H), 1.65-2.25 (m, 8H).

Step C: the preparation of compound 1-7

Spironolactone acid 1-4 (800g, the trans mixture of 55A% cis: 45%A%) is joined in the 50L container that THF (17.6L) is housed.With DMF (260mL 3.2mol) handles the gained slurries,, then at 22 ℃, in 10 minutes, use POCl ₃(350mL) handle, generate acyl chlorides 1-5.In 45 minutes this solution is warming to 40 ℃, aging 2 hours, is cooled to 24 ℃ then.Order adds in another 12L flask: THF (3.3L), TMEDA (1.7L), the trimethyl carbinol (465ml) and LiCl (143g).At 25 ℃ after aging 1 hour, the solution that obtains in 24-30 ℃, was joined in the solution of above-mentioned acyl chlorides 1-5 in 25 minutes, and in 35-39 ℃ aging 19 hours.Reaction mixture to 0 ℃, in 20 minutes by slowly adding the H of 4.2L 33% ₂SO ₄Termination reaction, internal temperature rises to 22 ℃ between charge period.Heating gained solution to 50 ℃ maintenance 3 hours.Cooling solution to 22 ℃ is regulated pH to 2.4 with 6N NaOH (7.0kg) then.Tell organic layer, wash with 2 * 8L HCl/NaCl aqueous solution (pH2.5).In organic layer, add THF (3.3L), liquor capacity is increased to about 26L, be encased in then in the 50L flask.By normal pressure constant volume distillatory mode azeotropic drying organic layer, reach 0.3%. (using about 51kg THF) until KF, obtain the solution of spironolactone acid 1-7.

Step D: compound 1-7 is separated into compound 1-8 and 1-9

The solution of spironolactone 1-7 is cooled to 22 ℃, and in this solution, slowly adds concentrated hydrochloric acid (60mL).25 ℃ of aging gained slurries 3 hours remove by filter throw out, and with THF (1 * 1L) washing.(internal temperature=38-42 ℃) concentrates the filtrate that comprises spironolactone acid 1-8 and arrives 6.5L under vacuum, and in 1 hour the gained slurries is cooled to 22 ℃, aging 1 hour then.Add the 6L heptane in 2 hours, the gained slurries are cooled to 0 ℃, aging 20 hours, vacuum distilling subsequently, product cake piece THF-heptane (2/3; 2 * 600mL) flushings, and, obtain spironolactone acid 1-8 in 45 ℃ of vacuum-dryings.

¹H NMR (400.13MHz; DMSO-d ₆): Λ 12.34 (br, 1H), 9.04 (d, J=1.0Hz, 1H), 8.85 (d, J=5.0Hz, 1H), 7.82 (dd, J=5.0Hz, 1.0Hz, 1H), 2.70 (br m, 1H), 2.08-1.89 (the eclipsed multiplet, 6H), 1.82-1.76 (the eclipsed multiplet, 2H).

¹³C?NMR(100.62MHz；DMSO-d ₆)：175.9，167.9，150.6，147.5，144.9，133.1，119.1，87.2，38.1，33.1，23.9.

On the other hand, spironolactone 1-8 can be according to the acetonitrile crystallization of following step.Filtrate (the 250ml of spironolactone acid 1-8 will be comprised among the step D; The 15g/L trans acids) is concentrated to 44ml by distillation, is cooled to 40 ℃ then.Add acetonitrile (7.5mL) and 50mg crystal seed simultaneously.The slurries that obtain were worn out 2.5 hours at 40 ℃, be cooled to 22 ℃, aging 2 hours again.Remove remaining THF by adding acetonitrile constant volume distillatory mode, until THF concentration＜2A%.Cooling feed liquid to 0 ℃, aging 2 hours, filter then, (1 * 10mL) washing obtains the sour 1-8 of spironolactone through vacuum-drying with ice-cold acetonitrile.

Although invention has been described and given to illustrate with reference to some specific embodiments, it will be appreciated by those skilled in the art that under the prerequisite that does not deviate from the spirit and scope of the present invention, can carry out various changes, modification and replacement to it.Therefore, the present invention is that the scope by claims is limited, and these claims should reasonably explained in the wide region.

Claims (34)

1. the method for preparation formula IC compound or its salt

Wherein

T, U, V and W independently are selected from separately:

(1) nitrogen and

(2) methyne,

Wherein the methyne group is that unsubstituted or optional quilt is selected from following substituting group replacement:

(a) halogen,

(b) low alkyl group,

(c) hydroxyl and

(d) lower alkoxy, and

At least two is methyne among T wherein, U, V and the W;

This method may further comprise the steps:

(a) in solvent, handle formula IC compound, the spironolactone carboxylic acid halides of production E with halogenating agent:

Wherein X is a chlorine or bromine, and the definition of T, U, V and W is the same;

(b) the spironolactone carboxylic acid halides of usefulness alkali and pure processing formula E in solvent, the spironolactone ester of production F:

R wherein ³Be selected from the tertiary butyl, methyl, cyclohexyl, methylcyclopentyl and neo-pentyl, and the definition of T, U, V and W is the same;

(c) the spironolactone ester of usefulness aqueous acids hydrolyzing type F, the spironolactone acid of production IC:

Wherein the definition of T, U, V and W is the same; With

(d) separate the product that obtains.

2. the process of claim 1 wherein that the solvent of step (a) usefulness is selected from chloroform, ethyl acetate, tetrahydrofuran (THF), glycol dimethyl ether, diglyme, 2-methyltetrahydrofuran, 1,4-two  alkane and methylene diethyl ethers.

3. the method for claim 2, wherein the solvent of step (a) usefulness is a tetrahydrofuran (THF).

4. the process of claim 1 wherein that the halogenating agent of using in the step (a) is selected from phosphoryl chloride, oxalyl chloride, phosphorus trichloride, phosphorus tribromide, thionyl chloride, thionyl bromide and oxalyl bromine.

5. the method for claim 4, wherein the halogenating agent of using in the step (a) is a phosphoryl chloride.

6. the process of claim 1 wherein that the formula E spironolactone carboxylic acid halides in the step (a) is the spironolactone acyl chlorides.

7. the process of claim 1 wherein that step (a) further comprises catalyzer.

8. the method for claim 7, wherein the catalyzer of step (a) is a dimethyl formamide.

9. the method for claim 1, wherein the alkali in the step (b) is selected from N, N, N ', N '-Tetramethyl Ethylene Diamine, triethylamine, N, N-diisopropylethylamine, N, N-dimethyl amine, pyridine, collidine, 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene, N-methylmorpholine and N, N, N ', N '-tetramethyl--1,6-hexanediamine.

10. the method for claim 9, wherein the alkali in the step (b) is N, N, N ', N '-Tetramethyl Ethylene Diamine.

11. the alcohol in the step of the process of claim 1 wherein (b) is selected from the trimethyl carbinol, methyl-cyclohexanol, methylcyclopentanol and neopentyl alcohol.

12. the method for claim 11, wherein the alcohol in the step (b) is the trimethyl carbinol.

13. the solvent in the step of the process of claim 1 wherein (b) is selected from tetrahydrofuran (THF), glycol dimethyl ether, diglyme, 2-methyltetrahydrofuran, 1,4-two  alkane and methylene diethyl ethers.

14. the method for claim 13, wherein the solvent in the step (b) is a tetrahydrofuran (THF).

15. the step of the process of claim 1 wherein (b) further comprises salt.

16. the method for claim 15, wherein the salt of step (b) is selected from lithiumbromide, lithium chloride, lithium iodide, lithium perchlorate and LiBF4.

17. the method for claim 16, wherein the salt of step (b) is lithium chloride.

18. the aqueous acids of the step of the process of claim 1 wherein (c) usefulness is selected from sulfuric acid, hydrochloric acid, Hydrogen bromide, phosphoric acid and formic acid.

19. the method for claim 18, wherein the aqueous acids of step (c) usefulness is a sulfuric acid.

20. the method for claim 1 further comprises step:

(e) in formula IC compound, add solvent, form mixture,

Wherein the definition of T, U, V and W is the same;

(f) in the mixture of step (e), add acid, form mixture; With

(g) the mixture certain hour of aging step (f) under the condition of effective production I compound or its salt:

Wherein the definition of T, U, V and W is the same.

21. the method for claim 20, wherein the solvent of step (e) usefulness is selected from glycol dimethyl ether, acetonitrile, tetrahydrofuran (THF) or its mixture.

22. the method for claim 21, wherein the solvent of step (e) usefulness is a tetrahydrofuran (THF).

23. the method for claim 20, wherein the acid of step (f) usefulness is selected from hydrochloric acid, Hydrogen bromide, tartrate, methylsulfonic acid, toluenesulphonic acids, succsinic acid and sulfuric acid.

24. the method for claim 23, wherein the acid of step (f) usefulness is hydrochloric acid.

25. the method for claim 20, wherein step (g) is aging under about 10 ℃ to 60 ℃ temperature.

26. the method for claim 25, wherein step (g) is to wear out 3 hours under about 25 ℃ temperature.

27. the method for claim 20 further comprises the step (h) of separate type IA compound or its salt.

28. the process of claim 1 wherein that T, V and W are methyne, methyne group wherein is that unsubstituted or optional quilt is selected from following substituting group replacement:

(a) halogen,

(b) low alkyl group,

(c) hydroxyl and

(d) lower alkoxy; And

U is a nitrogen.

29. the method for claim 29, T wherein, V and W are unsubstituted methyne; And U is a nitrogen.

30. the process of claim 1 wherein that T, U, V and W are methyne, wherein the methyne group is that unsubstituted or optional quilt is selected from following substituting group replacement:

(a) halogen,

(b) low alkyl group,

(c) hydroxyl and

(d) lower alkoxy.

31. the process of claim 1 wherein with respect to cis-isomeride IB

Content in structural formula IC compound has improved trans-isomer(ide) IA:

Content in structural formula IC compound:

T wherein, U, V and W independently are selected from separately:

(1) nitrogen and

(2) methyne,

Wherein the methyne group is that unsubstituted or optional quilt is selected from following substituting group replacement:

(a) halogen,

(b) low alkyl group,

(c) hydroxyl and

(d) lower alkoxy, and

At least two is methyne among T wherein, U, V and the W.

32. a composition, it comprises the Compound I A of about 83%-52%

Compound I B with about 17%-48%:

T wherein, U, V and W independently are selected from separately:

(1) nitrogen and

(2) methyne,

Wherein the methyne group is that unsubstituted or optional quilt is selected from following substituting group replacement:

(a) halogen,

(b) low alkyl group,

(c) hydroxyl and

(d) lower alkoxy, and

At least two is methyne among T wherein, U, V and the W.

33. the composition of claim 32, it comprises about 79% compound 1-8:

With about 21% compound 1-9:

34. the composition of claim 32, it comprises about 83% compound 1-8:

With about 17% compound 1-9: