CN101775064B - Synthesis method of 3-carbonyl-4-azepine-5alpha-androstane compound - Google Patents
Synthesis method of 3-carbonyl-4-azepine-5alpha-androstane compound Download PDFInfo
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Abstract
The invention discloses a synthesis method of a 3-carbonyl-4-azepine-5alpha-androstane compound, which comprises the following steps of: (1), carrying out cyclization hydrogenation reaction on 3-carboxylic acid-A-decarbonization-3,5 cracked-5-carbonyl androstane compound, methanoic acid and nitrogen-containing hydrogen donator reagent under stirring at the temperature of 105-130 DEG C, continuously stirring and keeping the temperature to react for 8-24h, and then carrying out post-treatment: removing methanoic acid by means of pressure reduction distillation, gradually adding remained materials to ice water to separate out a crystal under stirring, and continuously stirring the remained materials for 2-3h, filtering and drying to obtain a 3-carbonyl-4-azepine-5alpha-androstane compound crude product; and (2) adding the 3-carbonyl-4-azepine-5alpha-androstane compound crude product obtained in the step (1) to a recrystallization solvent for refining to obtain a refined product. The method has the advantages of easy acquisition of raw materials, lower cost, shortened reaction steps and mild reaction condition, and is suitable for industrialized mass production.
Description
Technical field
The present invention relates to a kind of compound method of steroid drug midbody, particularly the compound method of one type of 3-carbonyl-4-aza-5 alpha-androstane compound.
Background technology
(Benign Prostatic Hyperplasia BPH) is the common disease of middle-aging male to benign prostate hyperplasia, receives people's common concern always.As the pathogeny of benign prostate hyperplasia, according to this theory, in the process of seeking the BPH medicine, 5 alpha-reductases become the action target spot of screening of medicaments to the Standone theory always, and its suppressor factor also becomes the focus of medicament research and development.5 alpha-reductases (5e-reductase) are the membrane proteolytic enzymes that relies on DPNH I (NADPH); Its function is that catalysis testosterone (T) is converted into Standone (DHT);, DHT can cause many pathological changes when running up to higher level in prostate gland and skin after, like BPH, acne, male baldness, female hirsutism etc.The 5a reductase enzyme of known person has I type and two kinds of isozyme of II type.I type enzyme mainly is distributed in skin, and II type enzyme mainly is distributed in body of prostate, and through suppressing this enzymic activity, reduce DHT and produce, be the main path of BHP non-operative treatment, also be effective treatment means of androgen-dependent disorders.Finasteride and GI 198745 are the representative medicines of 5 alpha reductase inhibitors, and 3-carbonyl-4-aza-5 alpha-androstane compound then is the important intermediate of synthetic 5 alpha reductase inhibitors.
Chinese patent document CN101456897A discloses the preparation method of a kind of 3-carbonyl-4-aza-5 alpha-androstane compound, and the structural formula of the 3-carbonyl in the document-4-aza-5 alpha-androstane compound is following:
Wherein R is hydroxyl, methoxyl group, TERTIARY BUTYL AMINE base, diethylin or 2,5-two 5-trifluoromethylanilines.
The document is that 3-carbonyl-4-aza-5 alpha-androstane ene compound and formic acid and hydrogen donor reagent are carried out hydrogenation under 61～101 ℃ temperature, and this hydrogen donor reagent is formate, comprises ammonium formiate, potassium formiate, sodium formiate or formic acid triethylamine salt.The shortcoming of this method is that raw material 3-carbonyl-4-aza-5 alpha-androstane ene compound is more difficult to get, and price is higher.
Summary of the invention
The objective of the invention is the above-mentioned deficiency to prior art, provide a kind of raw material to be easy to get, cost is lower, reactions step is few, reaction conditions is gentle, be fit to the compound method of the 3-carbonyl-4-aza-5 alpha-androstane compound of industrialized mass.
The technical scheme that realizes the object of the invention is: the compound method of a kind of 3-carbonyl-4-aza-5 alpha-androstane compound; Have following steps: make 3-carboxylic acid-A-lose carbon-3 under 1. stirring; The cyclization hydrogenation reaction of 3-carbonyl-4-aza-5 alpha-androstane compound takes place to generate in the system of 5 cracking-5-carbonyl androstanes, organic solvent formic acid and nitrogenous hydrogen donor reagent under 105 ℃～130 ℃ temperature, continue to stir insulation reaction 8h～24h; Carry out aftertreatment then: underpressure distillation and steaming except that formic acid, stir down leftover materials are joined gradually in the frozen water and separate out crystallization, continue to stir 2h～3h after-filtration, drying obtains 3-carbonyl-4-aza-5 alpha-androstane compound bullion; The mol ratio that said 3-carboxylic acid-A-loses carbon-3,5 cracking-5-carbonyl androstane and nitrogenous hydrogen donor reagent is 1: 30～1: 129; 2. the 3-carbonyl that 1. step is obtained-4-aza-5 alpha-androstane compound bullion join make with extra care in the recrystallization solvent elaboration.
Reaction formula is following:
In the formula: I representes 3-carbonyl-4-aza-5 alpha-androstane compound; II representes that 3-carboxylic acid-A-loses carbon-3,5 cracking-5-carbonyl androstane; I is identical with R among the II, and R is hydroxyl, methoxyl group or TERTIARY BUTYL AMINE base.
The nitrogenous hydrogen donor reagent of above-mentioned steps described in 1. is ammonium formiate, methylamine, aniline, thanomin or methyl hydrazine.
The nitrogenous hydrogen donor reagent of above-mentioned steps described in 1. is ammonium formiate or methylamine.
The recrystallization solvent of above-mentioned steps described in 2. is ETHYLE ACETATE, acetone or N, N '-N.
The weightmeasurement ratio (g/mL) that the 3-carboxylic acid of above-mentioned steps described in 1.-A-loses carbon-3,5 cracking-5-carbonyl androstane and formic acid is 1: 10～1: 40; Preferred 1: 25.
3-carboxylic acid-the A-of step in 1. loses carbon-3; 5 cracking-5-carbonyl androstanes are that the N-tertiary butyl-3 carboxylic acids-A-loses carbon-3; 5-cracking-5-carbonyl-androstane-17 β-methane amide, 3 carboxylic acids-A-lose carbon-3; 5-cracking-5-carbonyl-androstane-17 β-carboxylic acid, 3 carboxylic acids-A-lose carbon-3; 5-cracking-5-carbonyl-androstane-17 β-carboxylate methyl ester, the N-tertiary butyl-3 carboxylic acids-A-lose carbon-3; 5-cracking-5-carbonyl-androstane-17 β-methane amide, 3 carboxylic acids-A-lose carbon-3; 5-cracking-5-carbonyl-androstane-17 β-carboxylic acid or the N-tertiary butyl-3 carboxylic acids-A-loses carbon-3; 5-cracking-5-carbonyl androstane-17 β-methane amide, corresponding, the 3-carbonyl-4-aza-5 alpha-androstane compound of step in 1. then should be the N-tertiary butyl-3-carbonyl-4-aza-5 alpha-androstane-17 β-methane amide, 3-carbonyl-4-aza-5 alpha-androstane-17 β-carboxylic acid, 3-carbonyl-4-aza-5 alpha-androstane-17 β-carboxylate methyl ester, the N-tertiary butyl-3-carbonyl-4-aza-5 alpha-androstane-17 β-methane amide, 3-carbonyl-4-aza-5 alpha-androstane-17 β-carboxylic acid or the N-tertiary butyl-3-carbonyl-4-aza-5 alpha-androstane-17 β-methane amide mutually.
The present invention has positive effect: raw material 3-carboxylic acid-A-that the present invention adopts loses carbon-3; 5 cracking-5-carbonyl androstanes are than the 3-carbonyl-4-aza-5 alpha-androstane ene compound obtains more easily, and price is lower, and the hydrogen donor reagent of employing is nitrogenous compound; Protium and N element are provided so simultaneously; Make 3-carboxylic acid-A-lose carbon-3,5 cracking-5-carbonyl androstane and can make 3-carbonyl-4-aza-5 alpha-androstane compound through single step reaction, reactions step shortens; Reaction conditions is gentle, is fit to industrialized mass.
Embodiment
(embodiment 1)
Present embodiment is the preparation method of the N-tertiary butyl-3-carbonyl-4-aza-5 alpha-androstane-17 β-methane amide, and step is following:
1. the N-tertiary butyl-3 carboxylic acids-A-is lost carbon-3; 5-cracking-5-carbonyl-androstane-17 β-methane amide 10g (0.0256mol), nitrogenous hydrogen donor reagent ammonium formiate 100g (1.587mol) and organic solvent formic acid 250mL add in the exsiccant reaction flask; Thereby stirring is warming up to 116 ℃ of cyclization hydrogenation reactions that the N-tertiary butyl-3-carbonyl-4-aza-5 alpha-androstane-17 β-methane amide takes place to generate, and continues to stir insulation reaction 24h.Carry out aftertreatment then: underpressure distillation and steaming except that formic acid; Stir down leftover materials are joined gradually in the frozen water of 1000mL and separate out crystallization; Continue to stir the 2.5h after-filtration, get the N-tertiary butyl-3-carbonyl-4-aza-5 alpha-androstane-17 β-methane amide bullion 8.9g after the oven dry.
2. after bullion being joined the dissolving that refluxes in the recrystallization solvent ETHYLE ACETATE; Get the N-tertiary butyl-3-carbonyl-4-aza-5 alpha-androstane-17 β-methane amide white crystals of 5.5g at 0～5 ℃ of recrystallization, measure with HPLC (performance liquid chromatography) method that the α body is 98.5% in the finished product.
(embodiment 2～embodiment 6)
All the other are identical with embodiment 1, and difference is seen table 1.
Table 1
| Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 | Embodiment 6 | |
| 3-carbonyl-4-aza-5 alpha-androstane compound (product) | 3-carbonyl-4-azepine-5 α-androstane-17 β-carboxylic acid | 3-carbonyl-4-aza-5 alpha-androstane-17 β-carboxylate methyl ester | The N-tertiary butyl-3-carbonyl-4-azepine-5 α-androstane-17 β-methane amide | 3-carbonyl-4-aza-5 alpha-androstane-17 β-carboxylic acid | The N-tertiary butyl-3-carbonyl-4-aza-5 alpha-androstane-17 β-methane amide |
| 3-carboxylic acid-A-loses carbon-3,5 cracking-5-carbonyl androstane (reactant) | 3 carboxylic acids-A-loses carbon-3,5-cracking-5-carbonyl-androstane-17 β-carboxylic acid 10g | 3 carboxylic acids-A-loses carbon-3,5-cracking-5-carbonyl-androstane-17 β-carboxylate methyl ester 10g | The N-tertiary butyl-3 carboxylic acids-A loses carbon-3,5-cracking-5-carbonyl-androstane-17 β-methane amide 10g | 3 carboxylic acids-A-loses carbon-3,5-cracking-5-carbonyl-androstane-17 β-carboxylic acid 10g | The N-tertiary butyl-3 carboxylic acids-A-loses carbon-3,5-cracking-5-carbonyl-androstane-17 β-methane amide 10g |
| Nitrogenous hydrogen donor reagent | Methylamine 90g | Ammonium formiate 100g | Ammonium formiate 95g | Ammonium formiate 100g | Ammonium formiate 100g |
| Organic solvent formic acid mL | ?200 | 200 | 250 | 250 | 200 |
| Temperature ℃ | ?130 | 120 | 115 | 127 | 115 |
| Time h | ?16 | 15 | 24 | 18 | 20 |
| Bullion weight g | ?9.1 | 8.8 | 9.2 | 8.7 | 8.9 |
| Recrystallization solvent | N, N '-NMF | ETHYLE ACETATE | N, N '-NMF | ETHYLE ACETATE | Acetone |
| Finished weight g | ?4.5 | 5.4 | 5.6 | 5.1 | 4.5 |
| HPLC surveys the α body | ?98.3％ | 98.5％ | 99％ | 98.8％ | 98.6％ |
Claims (7)
1. the compound method of 3-carbonyl-4-aza-5 alpha-androstane compound is characterized in that having following steps:
1. make 3-carboxylic acid-A-lose carbon-3 under stirring; The cyclization hydrogenation reaction of 3-carbonyl-4-aza-5 alpha-androstane compound takes place to generate in the system of 5 cracking-5-carbonyl androstanes, organic solvent formic acid and nitrogenous hydrogen donor reagent under 105 ℃～130 ℃ temperature, continue to stir insulation reaction 8h～24h; Carry out aftertreatment then: underpressure distillation and steaming except that formic acid, stir down leftover materials are joined gradually in the frozen water and separate out crystallization, continue to stir 2h～3h after-filtration, drying obtains 3-carbonyl-4-azepine-5 α androstane bullion; The mol ratio that said 3-carboxylic acid-A-loses carbon-3,5 cracking-5-carbonyl androstane and nitrogenous hydrogen donor reagent is 1: 30～1: 129;
2. the 3-carbonyl that 1. step is obtained-4-aza-5 alpha-androstane compound bullion join make with extra care in the recrystallization solvent elaboration;
Reaction formula is following:
In the formula: I representes 3-carbonyl-4-aza-5 alpha-androstane compound; II representes that 3-carboxylic acid-A-loses carbon-3,5 cracking-5-carbonyl androstane; I is identical with R among the II, and R is hydroxyl, methoxyl group or TERTIARY BUTYL AMINE base.
2. the compound method of 3-carbonyl according to claim 1-4-aza-5 alpha-androstane compound is characterized in that: the nitrogenous hydrogen donor reagent of step described in 1. is ammonium formiate, methylamine, aniline, thanomin or methyl hydrazine.
3. the compound method of 3-carbonyl according to claim 2-4-aza-5 alpha-androstane compound is characterized in that: the nitrogenous hydrogen donor reagent of step described in 1. is ammonium formiate or methylamine.
4. the compound method of 3-carbonyl according to claim 1-4-aza-5 alpha-androstane compound is characterized in that: the recrystallization solvent of step described in 2. is ETHYLE ACETATE, acetone or N, N '-N.
5. the compound method of 3-carbonyl according to claim 1-4-aza-5 alpha-androstane compound; It is characterized in that: the weightmeasurement ratio (g/mL) that the 3-carboxylic acid of step described in 1.-A-loses carbon-3,5 cracking-5-carbonyl androstane and formic acid is 1: 10～1: 40.
6. the compound method of 3-carbonyl according to claim 5-4-aza-5 alpha-androstane compound is characterized in that: the weightmeasurement ratio (g/mL) that described 3-carboxylic acid-A-loses carbon-3,5 cracking-5-carbonyl androstane and formic acid is 1: 25.
7. according to the compound method of the described 3-carbonyl of one of claim 1 to 6-4-aza-5 alpha-androstane compound; It is characterized in that: the 3-carboxylic acid-A-of step in 1. loses carbon-3; 5 cracking-5-carbonyl androstanes are that the N-tertiary butyl-3 carboxylic acids-A-loses carbon-3; 5-cracking-5-carbonyl-androstane-17 β-methane amide, 3 carboxylic acids-A-lose carbon-3; 5-cracking-5-carbonyl-androstane-17 β-carboxylic acid, 3 carboxylic acids-A-lose carbon-3; 5-cracking-5-carbonyl-androstane-17 β-carboxylate methyl ester, the N-tertiary butyl-3 carboxylic acids-A-lose carbon-3; 5-cracking-5-carbonyl-androstane-17 β-methane amide, 3 carboxylic acids-A-lose carbon-3; 5-cracking-5-carbonyl-androstane-17 β-carboxylic acid or the N-tertiary butyl-3 carboxylic acids-A-loses carbon-3; 5-cracking-5-carbonyl-androstane-17 β-methane amide, corresponding, the 3-carbonyl-4 aza-5 alpha-androstane compound of step in 1. then should be the N-tertiary butyl-3-carbonyl-4-aza-5 alpha-androstane-17 β-methane amide, 3-carbonyl-4-aza-5 alpha-androstane-17 β-carboxylic acid, 3-carbonyl-4-aza-5 alpha-androstane-17 β-carboxylate methyl ester, the N-tertiary butyl-3-carbonyl-4-aza-5 alpha-androstane-17 β-methane amide, 3-carbonyl-4-aza-5 alpha-androstane-17 β-carboxylic acid or the N-tertiary butyl-3-carbonyl-4-aza-5 alpha-androstane-17 β-methane amide mutually.
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| WO2004016595A1 (en) * | 2002-08-19 | 2004-02-26 | Hanmi Pharm. Co., Ltd. | Method for the selective preparation of 3-oxo-4-aza-5a-androstane compound |
| WO2005075497A1 (en) * | 2004-01-07 | 2005-08-18 | Ranbaxy Laboratories Limited | PROCESS FOR THE PREPARATION OF 17ß-SUBSTITUTED-3-OXO-4-AZA-5ALPHA-ANDROSTANE DERIVATIVES |
| CN101456897A (en) * | 2008-08-14 | 2009-06-17 | 常州佳尔科药业集团有限公司 | Method for preparing 3-carbonyl-4-aza-5alpha-androstanes |
| CN101531698A (en) * | 2009-04-08 | 2009-09-16 | 重庆浩康医药化工有限公司 | Synthesis technology of finasteride |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004016595A1 (en) * | 2002-08-19 | 2004-02-26 | Hanmi Pharm. Co., Ltd. | Method for the selective preparation of 3-oxo-4-aza-5a-androstane compound |
| WO2005075497A1 (en) * | 2004-01-07 | 2005-08-18 | Ranbaxy Laboratories Limited | PROCESS FOR THE PREPARATION OF 17ß-SUBSTITUTED-3-OXO-4-AZA-5ALPHA-ANDROSTANE DERIVATIVES |
| CN101456897A (en) * | 2008-08-14 | 2009-06-17 | 常州佳尔科药业集团有限公司 | Method for preparing 3-carbonyl-4-aza-5alpha-androstanes |
| CN101531698A (en) * | 2009-04-08 | 2009-09-16 | 重庆浩康医药化工有限公司 | Synthesis technology of finasteride |
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