CN1078475A - A kind of improved with the steroid 3-halogen-3 that replaces, the 5-diene derivatives is converted into the steroid 3 of replacement, the method for 5-diene-3-carboxylic acid derivative and used intermediate - Google Patents

A kind of improved with the steroid 3-halogen-3 that replaces, the 5-diene derivatives is converted into the steroid 3 of replacement, the method for 5-diene-3-carboxylic acid derivative and used intermediate Download PDF

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CN1078475A
CN1078475A CN 93102531 CN93102531A CN1078475A CN 1078475 A CN1078475 A CN 1078475A CN 93102531 CN93102531 CN 93102531 CN 93102531 A CN93102531 A CN 93102531A CN 1078475 A CN1078475 A CN 1078475A
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compound
diene
formula
carboxylic acid
steroid
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N·H·贝恩
F·F·奥因斯
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SmithKline Beecham Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J75/00—Processes for the preparation of steroids in general
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J3/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom
    • C07J3/005—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom the carbon atom being part of a carboxylic function
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J3/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0066—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by a carbon atom forming part of an amide group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0094—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 containing nitrile radicals, including thiocyanide radicals

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Toxicology (AREA)
  • Steroid Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Invent a kind of improved method that is used to prepare the steroid diene of replacement, invent the new intermediate that in said method, uses simultaneously.

Description

A kind of improved with the steroid 3-halogen-3 that replaces, the 5-diene derivatives is converted into the steroid 3 of replacement, the method for 5-diene-3-carboxylic acid derivative and used intermediate
The present invention relates to a kind of steroid 3-halogen-3 that will replace of being used for, the 5-diene derivatives is converted into the steroid 3 of replacement, the improving one's methods of 5-diene-3-carboxylic acid derivative.This compounds is used to suppress steroid 5-alpha-reductase and is described in people's such as disclosed Holt. on the 21st May in 1991 United States Patent (USP) 5,017,568.
From the steroid 3-halogen-3 that replaces, the steroid 3 that the preparation of 5-diene intermediate replaces, the method for 5-diene-3-carboxylic acid derivative is former to be described.Particularly use catalysis or lithium alkylide to mediate to make steroid 3-bromo-3,5-diene intermediate carboxylation produces steroid-3, and 5-diene-3-carboxylic acid derivative (productive rate is 15% when using n-Butyl Lithium) is in U.S. Patent No. 5,017, explanation in 568.In the time of suitable, superincumbent reaction is used alkaline medium before adding dehalogenation reagent, the acid-hydrolysis atom of the intermediate that has bromizated is selectively sloughed proton to improve resulting steroid 3, the U.S. Patent application No.07/817 that the method for 5-diene-3-carboxylic acid derivative productive rate has proposed on January 6th, 1992, explanation is (from the N-tertiary butyl-androstane-3 in 179, the N-tertiary butyl-the androstane-3 of 5-diene-3-bromo-17 β-carboxylic acid amides preparation, 5-diene-17 β-carboxylic acid amides-3-carboxylic acid productive rate is 63%).Wherein the alkaline medium of being mentioned preferably uses ethyl-magnesium-bromide and ethyl-magnesium-chloride in preparation.
Except total production rate was low, the major defect of these methods was that n-Butyl Lithium and ethyl-magnesium-bromide and ethyl-magnesium-chloride all are expensive reagent, will increase a large amount of expenses concerning industrial production.In addition, n-Butyl Lithium is inflammable, and its carboxylation reaction will carry out under dilute concentration.Therefore need a kind of safe, economic, reliable method to make the steroid 3-halogen-3 of replacement in this technology, the 5-diene derivatives changes into the steroid 3 of replacement, 5-diene-3-carboxylic acid derivative.
The present invention relates to a kind of halogen-3 with steroid 3-that is used for, the 5-diene derivatives is converted into steroid 3, the improving one's methods of 5-diene-3-carboxylic acid derivative.
The present invention be more particularly directed to a kind of improved N-tertiary butyl-androstane-3 that is used to prepare, the method for 5-diene-17 β-carboxylic acid amides-3-carboxylic acid.
Another object of the present invention provides a kind of new intermediate that uses in the method for the invention.
Above and the alphabetical label of the numbering of the carbon of the employed steroide nuclear of specification sheets and claims part and ring as follows
Figure 931025311_IMG6
The pharmaceutical salts hydrate of the compound of formula (1) and solvate are to make with the method for knowing in this technical field.
Unless other special explanation is arranged, the term that uses in specification sheets and claims " halogen " is meant chlorine, bromine or iodine.
Term used herein " halogen " preferably is meant bromine or iodine.
The invention provides a kind of method that is used to produce the compound of formula I,
Figure 931025311_IMG7
Wherein, R 1Be
(ⅰ) CONR 2R 3, R 2And R 3Independently of one another from hydrogen, C 1-8Alkyl, C 3-6Choose in cycloalkyl and the phenyl; Or R 2And R 3With connected nitrogen together, represent 5-6 joint saturated rings, it contains another heteroatoms of choosing from oxygen and nitrogen; Or
(ⅱ) can be chemically converted into the group of group in (ⅰ), for example-C ≡ N ,-COOH or-COOC 1-6Alkyl; Or its a kind of pharmaceutical salts, hydrate or solvate, it comprises the cyanogenation of formula II compound.
Figure 931025311_IMG8
R wherein 1The definition as above and X be halogen; In a kind of cyanating reagent and a kind of appropriate solvent, preferably there is generation formula III compound down in dimethyl formamide:
Figure 931025311_IMG9
R wherein 1Definition as above generates the compound of formula I with the compound of after saponification formula III, after this, generates its a kind of pharmaceutical salts, hydrate or solvate selectively.
The preferred R that uses in the top method 1Be
(ⅰ) CONR 2R 3, R 2And R 3Independently of one another from hydrogen, C 1-8Alkyl, C 3-6Choose in cycloalkyl and the phenyl; Or
(ⅱ)-C ≡ N ,-COOH ,-COOC 1-6Alkyl or-CON(H) tertiary butyl.
In most cases, the preferred R that uses in the top method 1Be β-CONR 2R 3, R 2And R 3Independently of one another from hydrogen.C 1-8Alkyl, C 3-6Choose in cycloalkyl and the phenyl.
The compound of formula I is by R 1Or can be chemically converted into R by known chemical reactions 1Composition constitute, this known chemical reactions was for example described in " comprehensive organic chemistry: the synthetic and reaction of organic compound " (Pergamon Press published in 1979) of Derek Barton and U.D.Ollis, it proposes R 1Do not comprise any to the inoperative group of method of the present invention.Said groups converted is become R 1Reaction be that product according to explanation here or the route of synthesis that requires carries out, or with suitable or preferably carry out with the definite intermediate of these route of synthesis.For example, can then itself and amine reaction be changed into carboxylic acid amides by earlier carboxylic acid substituent being changed into acid halide.Ester can change into acid and handle by top method.Nitrile can by with alkylating agent, as, the tert.-butylacetic acid ethyl ester or the trimethyl carbinol react under the condition of acid catalyst and change into carboxylic acid amides.
Utilize method of the present invention to prepare in the process of formula I compound, synthesized the new intermediate of following formula IV
Figure 931025311_IMG10
R wherein 1Be:
(ⅰ) CONR 2R 3, R 2And R 3Independently of one another from hydrogen, C 1-8Alkyl, C 3-6Choose in cycloalkyl and the phenyl; Or R 2, R 3Represent a 5-6 joint saturated rings together with connected nitrogen, comprising another heteroatoms of from oxygen and nitrogen, choosing; Or
(ⅱ) can be chemically converted into the group of group in (ⅰ), for example ,-C ≡ N ,-COOH ,-COOC 1-6Alkyl or CON(H) tertiary butyl;
The preferred R that uses in the compound of top formula IV 1Be
(ⅰ) CONR 2R 3, R 2And R 3Independently of one another from hydrogen, C 1-8Alkyl, C 3-6Choose in cycloalkyl and the phenyl; Or
(ⅱ)-and C ≡ N ,-COOH ,-COOC 1-6Alkyl or CON(H) tertiary butyl.
The R that most preferably uses in the compound of top formula IV 1Be β-CONR 2R 3, R wherein 2And R 3Independently of one another from hydrogen, C 1-8Alkyl, C 3-6Choose in cycloalkyl or the phenyl.
Method of the present invention is compared with the reference of quoting has a plurality of advantages.Particularly with 3-halogen steroid-3, the 5-diene changes into steroid-3, employed reagent of 5-diene 3-carboxylic acid and reaction conditions safety, economy, can react under high density and required compound productive rate height, so this method is suitable in industrial application.
Unless stated otherwise, the C that uses in specification sheets and claims 1-nAlkyl is meant that has a C 1-nThe alkyl of the straight or branched of carbon.
The term that uses in specification sheets and claims " cyanating reagent " is meant at the reagent of determining can form with the reaction of halo composition under the condition cyaniding composition.Said cyaniding composition preferably passes through corresponding halo composition and cyanating reagent in appropriate solvent, as N, N-dimethyl-N, N-propylene urea (DMPU), N, dinethylformamide (DMF) or N-N-methyl-2-2-pyrrolidone N-(NMP), preferably in DMF, prepared in reaction in higher temperature.
The term that uses in specification sheets and claims " saponification " is meant a kind of compound or reagent or a series of reagent that can generate a kind of carboxylic acid-substituted composition under proper condition with the nitrile reaction.Said carboxylic acid-substituted composition is preferably by corresponding cyaniding composition and hydroxide bases, and aqueous sodium hydroxide solution preferably is in appropriate solvent, as 1,2 ethylene glycol, Virahol or ethanol, preferably ethanol, react under higher temperature, acidifying is prepared then.
The term that uses in specification sheets and claims " higher temperature " is meant more than 25 ℃, preferably reflux temperature.
The preferred cyanating reagent that uses is a cyanide complex in the method for the present invention, and for example Richard C.Larock is described in the P861 of " comprehensive organic transformation: functional group prepares guide " (VCH Publishers company published in 1989).The example of a kind of cyanide complex used herein is KCN, NiBr 2(pph 3) 2, pph 3, the mixture on the spot of Zn.Other example comprises Co(CN) 3- 4; K 4Ni 2(CH) 6, KCH; KCN, (pph 3) 4Catalyst P d; Co(CN) 3- 5; CuCN and NaCu(CN) 2Term used herein " NaCu(CN) 2" be meant that CuCN and NaCN mix formed reagent at the scene.
That preferred use is CuCN and NaCu(CN in the top cyaniding title complex) 2
That preferred especially use is NaCu(CN in the top cyaniding title complex) 2
Said NaCu(CN) 2Title complex preferably adopts the sodium cyanide preparation that adds 1 molar equivalent at the scene in cuprous cyanide.
The term that uses in specification sheets and claims " solvent " or " appropriate solvent " are meant a kind of solvent, for example methylene dichloride, ethylene chloride, chloroform, 1, the 2-ethylidene glycol, tetracol phenixin, tetrahydrofuran (THF) (THF), ether, toluene, ethyl acetate, methyl-sulphoxide, N, N '-dimethyl-N, N '-propylene urea, positive N-methyl-2-2-pyrrolidone N-, methyl alcohol, Virahol, dimethyl formamide, water, pyridine, quinoline or ethanol.
Therefore, method of the present invention is particularly useful for making the compound of a kind of structural formula for (III A)
Figure 931025311_IMG11
And convert it into the compound of following structural formula (I A)
Figure 931025311_IMG12
Need not to further describe, can believe the description that utilizes the front, those skilled in the art can farthest use the present invention.Therefore the following examples only are as indicative explanation, rather than to the qualification of scope of the present invention where face in office.
Embodiment
Dimethyl formamide and cupric cyanide can use Aldrich chemical company (Milwaukee, product WI).Androstane-4-alkene-3-ketone-17 β-carboxylic acid can use Berlichem company (Wayne, product NJ).
Embodiment 1
The N-tertiary butyl-androstane-3,5-diene-17 β-carboxylic acid amides-3-carboxylic acid
(ⅰ) the N-tertiary butyl-androstane-3,5-diene-3-bromo-17 β-carboxylic acid amides
Under condition of nitrogen gas with 100ml methylene dichloride and 6.12ml(2.5 molar equivalent) dimethyl formamide pack in the flask.This solution is cooled to 0-5 ℃, when temperature maintenance is between 0-10 ℃, uses the 6.9ml(2.5 molar equivalent) oxalyl chloride handle this solution.Generate white precipitate.Stir after 1 hour, the bromize hydrogen gas with 50.1 grams (19.6 molar equivalent) when solution temperature remains between 0-10 ℃ feeds in the solution.Suspension becomes thorough clearly colourless solution.Making the solution degassing make an appointment with half also to add methylene dichloride the volume minimizing of this solution by underpressure distillation makes it return to original volume.Repeat this step of concentrate/reinjecting.In the white suspension that generates, add 10.0 gram (1 molar equivalent) androstane-4-alkene-3-ketone-17 β-carboxylic acid.Mixture heating up is to room temperature and stirred 2 hours.Reaction mixture injected 100ml methylene dichloride and 23.1 gram (10 molar equivalent) tert-butylamine temperature are housed remain on container quenching between 0-10 ℃.Mixture was stirred 30 minutes.Add about 100ml water and filter two-phase mixture by diatomite bed course (pad of Celite).Isolate organic phase and make its volume approximately reduce half by underpressure distillation.Make solution return to its original volume with acetone.This concentrates/and implantation step repeats more than twice.Resulting acetone soln (about 300ml) is heated to about 50 ℃ and also uses about 100ml water treatment with the precipitation product.With the suspension cooling, make the N-tertiary butyl-androstane-3 with drying after filtration, 5-diene-3-bromo-17 β-carboxylic acid amides product separation comes out.Productive rate 89%, 181～183 ℃ of fusing points.
(ⅱ) the N-tertiary butyl-androstane-3,5-diene-3-cyano group-17 β-carboxylic acid amides
The N-tertiary butyl-androstane-3 through stirring, 5-diene-3-bromo-17 β-carboxylic acid amides (50 grams, 1 molar equivalent), cyanogen was for the mixture reflux of inferior ketone (11.0 grams, 1.1 molar equivalents) and dimethyl formamide (200ml) 3.5 hours.Reactant is cooled to 90-100 ℃, quenching and stirring in the solution of 100ml strong aqua and 200ml water.The dimethyl formamide that is added to equally in the quench solution with 25ml washes reaction flask.The suspension that generates is with the dichloromethane extraction twice of every part of 200ml, and by diatomite bed course filtration organic extraction.With 3 parts every part is 200ml(50/50V/V) strong aqua/water washing organic phase, and then be the water washing of 200ml with 2 parts every part.Organic phase is concentrated to 150ml and adds 250ml ethanol under vacuum.This solution is concentrated to 150ml once more and adds 250ml ethanol under vacuum, under vacuum, solution concentration is arrived 300ml, add 30ml water and bring out its crystallization.The suspension that generates was 0-5 ℃ of cooling 2 hours.Collect solid product after filtration, under 65 ℃ vacuum, be dried and obtain the 37.0 gram N-tertiary butyl-androstanes-3,5-diene-3-cyano group-17 β-carboxylic acid amides yellow crystals.Productive rate 85%, molten some 195-197 ℃.
(ⅲ) the N-tertiary butyl-androstane-3,5-diene-17 β-carboxylic acid amides-3-carboxylic acid
With the N-tertiary butyl-androstane-3, the mixture reflux of 5-diene-3-cyano group-17 β-carboxylic acid amides (20.0 gram, 1 molar equivalent), 50% aqueous sodium hydroxide solution (80ml, 30 molar equivalents) and ethanol (200ml) 18 hours.With reaction suspension be cooled to 50 ℃ and join the 6N hydrochloric acid (300ml) that stirring and the mixture of methylene dichloride (200ml) in.It contains the final PH of water is 1.5-2.0.Isolate organic phase and extract once more and contain water with the methylene dichloride of 250ml.Stirred 2 hours and filtered with the organic phase of 2 gram decoloration active carbons by the diatomite bed course with merging.Under vacuum with the organic phase reconcentration to 120ml and add the 200ml ethyl acetate.Under vacuum, once more suspension is concentrated to 120ml and adds the 200ml ethyl acetate again, gained suspension was concentrated to the final volume of 120ml and reflux 2 hours once more under vacuum.Suspension was also filtered 0-5 ℃ of cooling in 2 hours.Dried solid product obtains 14.8 grams, the N-tertiary butyl-androstane-3 of productive rate 71%, 5-diene-17 β-carboxylic acid amides-3-carboxylic acid under 65 ℃ vacuum.The mother liquor recrystallization is obtained the product of 3.14 other grams (productive rate 15%).Reaction overall yield 86%.Fusing point 250-251 ℃.
Embodiment 2
The N-tertiary butyl-androstane-3,5-diene-3-cyano group-17 β-carboxylic acid amine
The 250 gram N-tertiary butyl-androstanes-3 of packing in being equipped with the 5 liters 3 mouthfuls flasks (Morton) of mechanical stirrer, thermometer and reflux exchanger, 5-diene-3-bromo-17 β-carboxylic acid amides (press the method preparation of (ⅰ) among the embodiment 1), 55 gram cuprous cyanides, 29 restrain sodium cyanide and 1 liter of dimethyl formamide.Reaction mixture refluxed heating (152-153 ℃) at least 12 hours.With cooling bath reaction mixture is cooled to 25-30 ℃ at leisure, uses 1 liter 50% ammonium hydroxide aqueous solution (50/50V/V strong aqua/water) quenching and stirring fast then.Stir and add 1 liter of methylene dichloride after 15-20 minute and allow two to be separated.The each methylene dichloride with 500ml in back that respectively is separated repeats water to extract twice.Remove insoluble mantoquita in the dichloromethane extract of merging by the diatomite filtration pad.With 150ml dichloromethane rinse diatomite bed course.Each methylene dichloride that is combined with 500ml ammonium hydroxide washes mutually, removes last micro-mantoquita totally for three times.Concentrate organic phase by air distillation and remove about 1.5 liters of methylene dichloride.Concentrated/displacement methylene dichloride will be continued in the ethanol adding reactor of a 600ml and by the solvent that distills second part of 500ml.In reactor, add the ethanol of second part of 600ml and proceed air distillation and reach 82-84 ℃ up to vapor temperature.In reactor, add the water of a 60ml and with the suspension that obtains 0-5 ℃ of cooling at least 2 hours.Collect solid,, generate 191.3 gram title compounds altogether with the aqueous ethanolic solution flushing of 75ml50% and dry under 60-65 ℃ vacuum.Productive rate 88%; Fusing point 190-192 ℃.
More than be explanation preferred embodiment of the present invention, be appreciated that the present invention is not confined in disclosed herein the offering some clarification on, and be retained in the interior modification of the scope right of the present invention of following claim.

Claims (16)

1, a kind of method for preparing the formula I compound
Figure 931025311_IMG1
R wherein 1Be
(i) CONR 2R 3, R 2And R 3Independently of one another from hydrogen, C 1-8Alkyl, C 3-6Choose in cycloalkyl and the phenyl; Or R 2And R 3With the nitrogen that is connected with it, represent a 5-6 joint saturated rings, this ring contains another heteroatoms of choosing from oxygen or nitrogen; Or
(ii) can be chemically converted into the group of group in (i); Or a kind of pharmaceutical salts, its hydrate or solvate, it comprises the cyanogenation of formula II compound,
Figure 931025311_IMG2
R wherein 1The definition as above and X be halogen, in the presence of a kind of cyanating reagent and a kind of appropriate solvent the generation formula III compound
Figure 931025311_IMG3
R wherein 1Definition as above generates the compound of formula I with the compound of after saponification formula III, after this forms a kind of pharmaceutical salts selectively, its hydrate or solvate.
2, method according to claim 1 is characterized in that: cyanating reagent is CuCN and NaCu(CN by molecular formula) 2The oxide compound title complex form.
3, method according to claim 2 is characterized in that: cyanating reagent is NaCu(CN by molecular formula) 2Cyanide complex form.
4, method according to claim 3 is characterized in that: molecular formula is NaCu(CN) 2Cyanide complex be sodium cyanide preparation by in cuprous cyanide, adding 1 molar equivalent at the scene.
5, method according to claim 2 is characterized in that: cyanide complex wherein is a cuprous cyanide.
6, method according to claim 1 is characterized in that: X wherein is a bromine.
7, method according to claim 1 is characterized in that: wherein said solvent is a dimethyl formamide.
8, method according to claim 1 is characterized in that: saponification wherein comprises the N-tertiary butyl-androstane-3, and 5-diene-3-cyano group-17 β-carboxylic acid amides and hydroxide bases are reacted in a kind of appropriate solvent, acidifying then.
9, method according to claim 8 is characterized in that: wherein appropriate solvent is an ethanol.
10, method according to claim 9 is characterized in that; Alkali wherein is aqueous sodium hydroxide solution.
11, method according to claim 1 is characterized in that: wherein prepared compound is
Figure 931025311_IMG4
Or a kind of pharmaceutical salts, its hydrate or solvate.
12, the following compound of a kind of structural formula
Figure 931025311_IMG5
R wherein 1Be:
(ⅰ) CONR 2R 3, R 2And R 3Independently of one another from hydrogen, C 1-8Alkyl, C 3-6Choose in cycloalkyl and the phenyl; Or R 2And R 3With the nitrogen that is connected with it, represent a 5-6 joint saturated rings, this ring contains another heteroatoms of choosing from oxygen and nitrogen; Or
(ⅱ) can be chemically converted into the group of group in (ⅰ).
13, compound according to claim 12, wherein R 1Be-C ≡ N ,-COOH ,-COOC 1-6Alkyl or-CON(H) tertiary butyl.
14, compound according to claim 13, wherein R 1Be-CON(H) tertiary butyl.
15, compound according to claim 13, wherein R 1Be-COOH.
16, compound according to claim 13, wherein R 1Be-C ≡ N.
CN 93102531 1992-02-07 1993-02-06 A kind of improved with the steroid 3-halogen-3 that replaces, the 5-diene derivatives is converted into the steroid 3 of replacement, the method for 5-diene-3-carboxylic acid derivative and used intermediate Pending CN1078475A (en)

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US5683995A (en) * 1992-11-18 1997-11-04 Smithkline Beecham Corporation 17 substituted acyl-3-carboxy 3,5-diene steroidals as α-reductase inhibitors
US5641765A (en) * 1992-11-18 1997-06-24 Smithkline Beecham Corporation 17-αand 17-βsubstituted acyl-3-carboxy-3,5-dienes and use in inhibiting 5-α-reductase

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