CN105017377A - Preparation method for intermediate of adrenal cortex hormone drug - Google Patents
Preparation method for intermediate of adrenal cortex hormone drug Download PDFInfo
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Abstract
The invention discloses a preparation method for an intermediate of an adrenal cortex hormone drug. The preparation method comprises the following steps: adding a cyaniding reagent in a compound I, which serves as a raw material, for cyano substitution reaction, so as to obtain a compound II; enabling the compound II and a silico-alkoxy reagent to be subjected to siloxane group protection reaction in an alkaline environment, so as to obtain a compound III; enabling the compound III and an alkali amide reagent to be subjected to intramolecular nucleophilic substitution reaction in an alkaline environment, so as to obtain a compound IV; enabling the compound IV and organic carboxylate to be subjected to substitution reaction in an alkaline environment, so as to obtain a compound V; enabling the compound V and a bromination reagent to be subjected to bromination reaction in an acidic environment, so as to obtain a compound VI; and enabling the compound VI to be subjected to epoxy reaction in an alkaline environment, so as to obtain the intermediate of the adrenal cortex hormone drug, wherein the adrenal cortex hormone drug is betamethasone or dexamethasone. The preparation method disclosed by the invention is simple, the raw materials are easily obtained, and the intermediate of the adrenal cortex hormone drug is high in yield and is stable.
Description
Technical field
The present invention relates to chemosynthesis technical field, particularly relate to a kind of preparation method of adrenocortical hormone pharmaceutical intermediate.
Background technology
Betamethasone Valerate and dexamethasone all belong to adrenocortical hormone medicine, and both chemical structural formulas are similar:
Betamethasone Valerate is a kind of Adrenal Glucocorticoid medicine, is the isomers of dexamethasone, acts on identical with dexamethasone, but anti-inflammatory action comparatively dexamethasone, triamcinolone etc. are all strong.Be mainly used in supersensitivity and diseases associated with inflammation.Clinical be mainly used in organ transplantation in case rejection; Also as the first aid using medicine of critical illness, as cerebral edema, shock, serious anaphylaxis, collagen disease, rheumatosis, leukemia, polyneuritis, endocrine disturbance and Atomizing inhalation etc.
Dexamethasone is a kind of Adrenal Glucocorticoid medicine, and because its anti-inflammatory action is powerful, consumption is less, and sodium storage gives over to slight, can alleviate body tissue and damaging be stimulated to the pathologic reaction produced, be widely used in clinical.Become now a line medication of the aspects such as treatment cerebral edema, shock, anaphylactic disease, minimizing inflammation.Dexamethasone medicine series conventional in addition also has dexamethasone acetate, dexamethasone sodium phosphate etc., and their bulk drug can make clinical injection injection, oral tablet and external preparation etc.
CN101397319, CN101397320 report Betamethasone Valerate, dexamethasone generally with
for key intermediate prepares, the long yield of syntheti c route is low, and preparation method's cost of this intermediate is also high.
Summary of the invention
The technical problem to be solved in the present invention overcomes the deficiencies in the prior art, provides the preparation method of the adrenocortical hormone pharmaceutical intermediate that a kind of preparation method is simple, raw material is easy to get, yield is high and stable.
For solving the problems of the technologies described above, the technical solution used in the present invention there is provided a kind of preparation method of adrenocortical hormone pharmaceutical intermediate, and described preparation method comprises the following steps:
(1) cyano group substitution reaction: be raw material with chemical compounds I, adds cyanating reagent and carries out cyano group substitution reaction and obtain compound ii;
(2) silicon alkoxyl group protective reaction: described compound ii and silicon alkoxyl group reagent are carried out siloxanes protective reaction under alkaline environment and obtains compound III;
(3) intramolecular nucleophilic substitution reaction: described compound III and alkali amide reagent are carried out intramolecular nucleophilic substitution reaction under alkaline environment and obtains compounds Ⅳ;
(4) substitution reaction: described compounds Ⅳ and organic carboxylate are carried out substitution reaction under alkaline environment and obtains compound V;
(5) upper bromine reaction: on described compound V and brominated reagent being carried out under sour environment, bromine reaction obtains compound VI;
(6) epoxy reaction: compound VI is carried out under alkaline environment epoxy reaction and obtain adrenocortical hormone pharmaceutical intermediate; Described adrenocortical hormone pharmaceutical intermediate is described Betamethasone Valerate intermediate or Dexamethasone Intermediate;
The structural formula of described chemical compounds I is:
The structural formula of described compound ii is:
The structural formula of described compound III is:
The structural formula of described compounds Ⅳ is:
The structural formula of described compound V is:
The structural formula of described compound VI is:
The structural formula of described Betamethasone Valerate intermediate is:
the structural formula of described Dexamethasone Intermediate is:
Above-mentioned preparation method, preferably, described cyano group substitution reaction is specially: be 1: 0.3 ~ 1 be dissolved in organic solvent by described chemical compounds I and described cyanating reagent according to mass ratio; Compound ii is obtained by reacting in-10 DEG C ~ 100 DEG C; Described cyanating reagent is acetone cyanohydrin, sodium cyanide or potassium cyanide.Preferred further, temperature of reaction is 30 ~ 35 DEG C.Organic solvent be preferably in lower aliphatic alcohols, lower aliphatic acids and ethers one or more, be further preferably methyl alcohol.
Above-mentioned preparation method, preferably, add the catalyzer accounting for chemical compounds I weight 0.04 ~ 2.0 times in described cyano group substitution reaction, described catalyzer is lower aliphatic acids, salt of wormwood or sodium carbonate.
Above-mentioned preparation method; preferably; the protective reaction of described silicon alkoxyl group is specially: add alkali in organic solvent; then be 1: 0.5 ~ 2.0 be dissolved in described organic solvent by described compound ii and described silicon alkoxyl group reagent according to mass ratio, be obtained by reacting described compound III in-10 DEG C ~ 20 DEG C.Further preferred, temperature of reaction is 0 ~ 5 DEG C.
Above-mentioned preparation method, preferably, silicon alkoxyl group reagent described in the protective reaction of described silicon alkoxyl group is CMDMCS chloromethyl dimethyl chlorosilane or brooethyl dimethylchlorosilane; Described organic solvent is one or more in halogenated hydrocarbon organic solvent, ether organic solvent, amides organic solvent or pyridine.Further preferred, organic solvent is tetrahydrofuran (THF).Alkali is preferably imidazoles, triethylamine or DMAP.
Above-mentioned preparation method, preferably, described intramolecular nucleophilic substitution reaction is specially: be dissolved in organic solvent by compound III and alkali, in-80 DEG C ~-10 DEG C reactions, then add the alkali amide reagent accounting for compound III molar equivalent 3.0 ~ 5.0 times, after being separated drying, obtain compounds Ⅳ.Further preferred, temperature of reaction is-40 ~-30 DEG C.
Above-mentioned preparation method, preferably, described intramolecular nucleophilic substitution reaction carries out under nitrogen protection, and described alkali amide reagent is lithium diisopropyl amido or hexamethyldisilazane lithium; Described organic solvent is organic solvent is ether organic solvent.
Above-mentioned preparation method, preferably, described substitution reaction is specially: be dissolved in organic solvent by compounds Ⅳ and organic carboxylate according to mass ratio 1: 1.0 ~ 3.0, in 0 DEG C ~ 100 DEG C reactions, obtains compound V after being then separated drying; Described organic carboxylate is Potassium ethanoate or sodium-acetate.
Above-mentioned preparation method, preferably, described upper bromine reaction is specially: be 1: 0.5 ~ 1: 1.0 ~ 3.0 join in organic solvent by compound V, bromide reagent and acid according to mass ratio, and at-10 DEG C ~ 50 DEG C, be obtained by reacting compound VI, described acid is perchloric acid, fluoroboric acid or the vitriol oil; Described brominated reagent is C5H6Br2N2O2 or N-bromo-succinimide.Organic solvent is one or more in organic solvent of ketone, amides organic solvent.
Above-mentioned preparation method, preferably, described epoxy reaction is specially: be 1: 0.1 ~ 2 be dissolved in organic solvent by compound VI and alkali according to mass ratio, at-10 DEG C ~ 50 DEG C, be obtained by reacting adrenocortical hormone pharmaceutical intermediate, described alkali is sodium hydroxide, potassium hydroxide, sodium carbonate or salt of wormwood.Organic solvent is one or more in alcohol organic solvent, organic solvent of ketone, amides organic solvent.
In the present invention, when adrenocortical hormone pharmaceutical intermediate is Betamethasone Valerate intermediate, its reaction scheme is:
When adrenocortical hormone pharmaceutical intermediate is Dexamethasone Intermediate, its reaction scheme is:
Compared with prior art, the invention has the advantages that:
The present invention adopts with plant sterol intermediate cheap and easy to get
for starting raw material, through cyaniding, silicon alkoxyl group reagent protection 17-position hydroxyl, react at low temperatures with lithium diisopropyl amido LDA and move through intramolecular migration; build chloromethyl ketone; with soap through nucleophilic substitution reaction, then after upper brominated eopxy, obtain the important intermediate of Betamethasone Valerate, dexamethasone
from then on key intermediate only needs three steps just can obtain Betamethasone Valerate, dexamethasone, and yield is high, and cost is low, environmental friendliness.
Embodiment
Below in conjunction with concrete preferred embodiment, the invention will be further described, but protection domain not thereby limiting the invention.
The material adopted in following examples and instrument are commercially available.
Embodiment 1:
The preparation method of Betamethasone Valerate intermediate, specifically comprises the following steps:
(1) with 16 β methyl-pregnant steroid-4,9 (11)-diene-3,17-diketone (chemical compounds I) is raw material, add acetone cyanohydrin to carry out cyano group substitution reaction and prepare 16 β methyl-17 β cyano group, 17a-monohydric pregnant-4,9 (11)-diene-3-ketone (compound ii), concrete preparation method is:
1.1 reactions: room temperature; under nitrogen protection; add 30ml methyl alcohol successively toward being equipped with in 250ml tetra-mouthfuls of round-bottomed flasks of thermometer, reflux condensing tube, mechanical stirring bar of a clean dried, 8ml concentration is 99% acetone cyanohydrin, 20.0g chemical compounds I; after stirring, add the wet chemical that 10ml mass concentration is 10%.After four mouthfuls of round-bottomed flasks are reacted 20 hours at 40 ~ 45 DEG C, detect raw material with TLC and no longer reduce, stopped reaction.
1.2 suction filtrations: drop in 400ml water by the reaction system in four mouthfuls of round-bottomed flasks, stir 2 hours.Suction filtration gets filter cake, and filter cake is washed to neutrality, in 50 DEG C of oven dry after draining, obtains the compound ii crude product of 19.0g.The yield calculating crude compound II is 95%, and (moving phase of HPLC is: methyl alcohol: water=55: 45) detecting purity is 93.8% to adopt HPLC.
1.3 purify: compound ii crude product is dissolved in 20ml methyl alcohol pulls an oar, and suction filtration gets filter cake.17.6g compound ii sterling is obtained after being dried by filter cake.The yield of compound ii sterling is 92.6%, and (moving phase of HPLC is: methyl alcohol: water=55: 45) detecting purity is 97.1% to adopt HPLC.
In step (1), the structural formula of chemical compounds I is:
The structural formula of compound ii is:
(2) by 16 β methyl-17 β cyano group; 17a-monohydric pregnant-4; 9 (11)-diene-3-ketone (compound ii) and CMDMCS chloromethyl dimethyl chlorosilane carry out the protective reaction of silicon alkoxyl group and prepare 16 β methyl-17 β cyano group-17a-monohydric pregnants-4; 9 (11)-diene-3-ketone-17-(chloromethyl) dimethyl-silicon ether (compound III), its concrete preparation method is:
2.1 reactions: room temperature; under nitrogen protection; 50ml tetrahydrofuran (THF), 15.0g compound ii, 5.2g imidazoles is added successively in 250ml tetra-mouthfuls of round-bottomed flasks of the fitting temperature meter of a clean dried, agitator arm; after stirring; ice bath is cooled to-5 DEG C ~ 0 DEG C; temperature control-5 DEG C ~ 5 DEG C, then slowly drip the CMDMCS chloromethyl dimethyl chlorosilane (CH of 10g
3cl (CH
3)
2siCl), about 20min dropwises, then insulation reaction 1 hour at-5 DEG C ~ 5 DEG C, and TLC detects without starting material left.
2.2 suction filtrations: drop in 200ml water by the reaction system in four mouthfuls of round-bottomed flasks, stir and obtain mixing solutions in 2 hours.Mixing solutions suction filtration is got filter cake, and washing filter cake, to neutral, in 50 DEG C of oven dry after being drained by filter cake, obtains the compound III of 18.3g.As calculated, the yield of compound III is 122%, and (moving phase of HPLC is: methyl alcohol: water=55: 45) detecting purity is 96.1% to adopt HPLC.
The structural formula of compound III is:
(3) by 16 β methyl-17 β cyano group-17a-monohydric pregnants-4,9 (11)-diene-3-ketone-17-(chloromethyl) dimethyl-silicon ether (compound III) and lithium diisopropyl amido carry out intramolecular nucleophilic substitution reaction and prepare the chloro-17a-monohydric pregnant-4 of 16 β methyl-21-, 9 (11)-diene-3,20-diketone (compounds Ⅳ), concrete reactions steps is:
3.1: room temperature; under nitrogen protection; 100ml tetrahydrofuran (THF), 10.0g compound III is added successively in 250ml tetra-mouthfuls of round-bottomed flasks of the fitting temperature meter of a clean dried, reflux condensing tube, agitator arm; after stirring; reaction system is cooled to-40 DEG C ~-35 DEG C; then control and be-30 DEG C to system temperature, in reaction system, slowly drip the lithium diisopropyl amido (LiN (C that 45.8ml concentration is 2mol/L
3h
7)
2), about 30min dropwises, then insulation reaction 0.5 hour, and TLC detects without starting material left.
3.2: the temperature controlling reaction system is less than 20 DEG C, and then reaction system being dropped to 20ml massfraction is in 36.5% hydrochloric acid, stirs 5 hours.Then the pH value of reaction system is adjusted to be 7 (pH value be 6 ~ 7 all can implement) with 20% aqueous sodium hydroxide solution, temperature control T≤40 DEG C, and be concentrated into without obvious cut, then in the residue system after concentrated, 100ml water is dripped, stir 1 hour, suction filtration gets filter cake, and washing filter cake is to neutral, then by filter cake in 50 DEG C of oven dry, obtain the compounds Ⅳ of 7.6g.The yield calculating compounds Ⅳ is 72.0%, and (moving phase of HPLC is: methyl alcohol: water=55: 45) detecting purity is 90.9% to adopt HPLC.
Compounds Ⅳ IV structural formula be:
(4) by the chloro-17a-monohydric pregnant-4 of 16 β methyl-21-, 9 (11)-diene-3,20-diketone (compounds Ⅳ) and Potassium ethanoate carry out substitution reaction and prepare 16 β methyl-17 a, 21-dimonohydric pregnant-4,9 (11)-diene-3,20-diketone-21-acetic ester (compound V), concrete reactions steps is:
4.1: room temperature; under nitrogen protection, in 250ml tetra-mouthfuls of round-bottomed flasks of the fitting temperature meter of a clean dried, reflux condensing tube, agitator arm, add 35ml dimethyl formamide (DMF), 7.0g compounds Ⅳ, 1.4ml Glacial acetic acid, 10.8g Potassium ethanoate, 1.4ml water successively.After reaction system being stirred, reaction system is warming up to 55 DEG C ~ 60 DEG C insulation reaction 8 hours, TLC detects without starting material left.
4.2: the reaction system after 4.1 steps is down to room temperature, in reaction system, drip 70ml water, dropwise rear continuation stirring 1 hour, suction filtration, washing filter cake, to neutral, in 50 DEG C of oven dry after then being drained by filter cake, obtains 7.0g compound V crude product.The yield of computerized compound V crude product is 100.0%, and (moving phase of HPLC is: methyl alcohol: water=55: 45) detect purity and be greater than 95.0% to adopt HPLC.
4.3: by compound V crude product chloroform and acetone recrystallization, obtain 6.2g off-white color solid, i.e. compound V sterling.The yield of computerized compound V sterling is 88.6%; (moving phase of HPLC is: methyl alcohol: water=55: 45) detecting purity is 98.8% to adopt HPLC.
The structural formula of compound V is:
Compound V is prepared two Duplicate Samples, the fusing point of detection compound V is respectively 210 ~ 212 DEG C, 209 ~ 213 DEG C, detects specific rotation and be respectively 138.6 °, 140.2 ° at 20 DEG C.
Compound V is carried out magnetic resonance detection, and detected result is as follows:
1H NMR(400MHz,CDCl3):5.73(1H,4-H),5.54(1H,11-H),4.94(2H,dd,21-CH
2-),2.17(3H,s,-OCCH
3),1.32(3H,19-CH
3),1.16(3H,d,J＝6.8,16β-CH
3)and 0.77(3H,s,18-CH
3)。
Disclosed in magnetic resonance detection result and J.Chem.Soc., Perkin Trans.1,1992,1995-1196 document, the nuclear magnetic resonance result of 16 β methyl-17 a, 21-dimonohydric pregnant-4,9 (11)-diene-3,20-diketone-21-acetic ester is similar.
(5) by 16 β methyl-17 a, 21-dimonohydric pregnant-4,9 (11)-diene-3,20-diketone-21-acetic ester (compound V) and C5H6Br2N2O2 carry out upper bromine reaction and prepare 16 β methyl-17 a, 11 β, 21-trihydroxy--9-bromine DELTA4-pregn-3,20-dione-21-acetic ester (compound VI), concrete reactions steps is:
5.1: room temperature, under nitrogen protection, in 500ml tetra-mouthfuls of round-bottomed flasks of the fitting temperature meter of a cleaning, agitator arm, add 250ml dimethyl formamide (DMF), 50.0g compound V, 1.4ml perchloric acid successively.After reaction system being stirred, temperature control 10 DEG C ~ 20 DEG C, then adds 25.6g C5H6Br2N2O2, adds rear system and stirs 1 hour, and TLC detects without starting material left.
5.2: will pour in 2L water through the reacted reaction system of step 5.1, continue stirring 1 hour, suction filtration obtains filter cake, and filter cake is washed to neutrality, in 50 DEG C of oven dry after draining, obtains the compound VI of 49.5g.The yield of computerized compound VI is 99.0%, and (moving phase of HPLC is: methyl alcohol: water=55: 45) detect purity and be greater than 95.0% to adopt HPLC.
The structural formula of compound VI is:
(6) by 16 β methyl-17 a, 21-dimonohydric pregnant-4,9 (11)-diene-3,20-diketone-21-acetic ester (compound V) carries out epoxy reaction and prepares 16 β methyl under alkaline environment, 17a, 21-dimonohydric pregnant-(9,11) epoxy-4-alkene-3,20-diketone-21-acetic ester (Betamethasone Valerate intermediate), concrete reactions steps is;
6.1: under N2 protective atmosphere; 100ml methylene dichloride is added successively in 500ml tetra-mouthfuls of round-bottomed flask A of the fitting temperature meter of a cleaning, agitator arm; 100ml methyl alcohol, 20.0g compound VI, 2ml massfraction are 20% aqueous sodium hydroxide solution, stir 1 hour, and TLC detects without starting material left.
6.2: in reaction system, adjust pH to neutral with appropriate Glacial acetic acid, temperature control 40 ~ 50 DEG C, concentrating under reduced pressure goes out solvent, divides and adds water displacement for 2 times, add 50ml at every turn.Be cooled to 5 ~ 10 DEG C subsequently to stir 2 hours, suction filtration, washing filter cake is to neutral, in 50 DEG C of oven dry after draining, obtain 16.3g Betamethasone Valerate intermediate, yield: 81.5%, (moving phase of HPLC is: methyl alcohol: water=55: 45) detecting purity is 98.5% to adopt HPLC.
Betamethasone Valerate intermediate is carried out magnetic resonance detection, and detected result is as follows:
1H NMR(400MHz,CDCl3):5.73(s,1H,4-H),4.94(dd,2H,21-CH
2-),3.19(br s,1H),2.17(s,3H,-OCH
3),1.32(s,3H,19-CH
3),1.16(d,J＝6.8Hz,3H,16β-CH
3)and 0.77(s,3H,19-CH
3)。
From nuclear magnetic resonance result: the intermediate prepared according to the method for embodiment 1 is Betamethasone Valerate intermediate.
Meanwhile, the structural formula of Betamethasone Valerate intermediate is:
Embodiment 2:
The preparation method of Dexamethasone Intermediate, specifically comprises the following steps:
(1) with 16 α methyl-pregnant steroid-4,9 (11)-diene-3,17-diketone (chemical compounds I) is raw material, add acetone cyanohydrin to carry out cyano group substitution reaction and prepare 16 α methyl-17 β cyano group, 17a-monohydric pregnant-4,9 (11)-diene-3-ketone (compound ii), concrete preparation method is:
1.1 reactions: room temperature; under nitrogen protection; 40ml methyl alcohol, 10ml 99% acetone cyanohydrin, 20.0g chemical compounds I is added successively toward being equipped with in 250ml tetra-mouthfuls of round-bottomed flasks of thermometer, reflux condensing tube, agitator arm of a clean dried; after stirring, add the wet chemical that 15ml mass concentration is 10%.After four mouthfuls of round-bottomed flasks are reacted 20 hours at 40 ~ 45 DEG C, detect raw material with TLC and no longer reduce, stopped reaction.
1.2 suction filtrations: drop in 400ml water by the reaction system in four mouthfuls of round-bottomed flasks, stir 2 hours.Suction filtration gets filter cake, and filter cake is washed to neutrality, in 50 DEG C of oven dry after draining, obtains the compound ii crude product of 19.7g.The yield calculating crude compound II is 98.5%, and (moving phase of HPLC is: methyl alcohol: water=55: 45) detecting purity is 95.8% to adopt HPLC.
1.3 purify: compound ii crude product is dissolved in 20ml methyl alcohol pulls an oar, and suction filtration gets filter cake.18.8g compound ii sterling is obtained after being dried by filter cake.The yield of compound ii sterling is 94.0%, and (moving phase of HPLC is: methyl alcohol: water=55: 45) detecting purity is 99.1% to adopt HPLC.
In step (1), the structural formula of chemical compounds I is:
The structural formula of compound ii is:
(2) by 16 α methyl-17 β cyano group; 17a-monohydric pregnant-4; 9 (11)-diene-3-ketone (compound ii) and CMDMCS chloromethyl dimethyl chlorosilane carry out the protective reaction of silicon alkoxyl group and prepare 16 α methyl-17 β cyano group-17a-monohydric pregnants-4; 9 (11)-diene-3-ketone-17-(chloromethyl) dimethyl-silicon ether (compound III), its concrete preparation method is:
2.1 reactions: room temperature; under nitrogen protection; 50ml tetrahydrofuran (THF), 10.0g compound ii, 5.2g imidazoles is added successively in 250ml tetra-mouthfuls of round-bottomed flasks of the fitting temperature meter of a clean dried, agitator arm; after stirring; ice bath is cooled to-5 DEG C ~ 0 DEG C; temperature control-5 DEG C ~ 5 DEG C, then slowly drip the CMDMCS chloromethyl dimethyl chlorosilane (CH of 18g
3cl (CH
3)
2siCl), about 40min dropwises, then insulation reaction 2 hours at-5 DEG C ~ 5 DEG C, and TLC detects without starting material left.
2.2 suction filtrations: drop in 200ml water by the reaction system in four mouthfuls of original place flasks, stir and obtain mixing solutions in 2 hours.Mixing solutions suction filtration is got filter cake, and washing filter cake, to neutral, in 50 DEG C of oven dry after being drained by filter cake, obtains the compound III of 12.6g.As calculated, the weight yield of compound III is 126%, and (moving phase of HPLC is: methyl alcohol: water=55: 45) detecting purity is 97.1% to adopt HPLC.
The structural formula of compound III is:
(3) by 16 α methyl-17 β cyano group-17a-monohydric pregnants-4,9 (11)-diene-3-ketone-17-(chloromethyl) dimethyl-silicon ether (compound III) and lithium diisopropyl amido carry out intramolecular nucleophilic substitution reaction and prepare the chloro-17a-monohydric pregnant-4 of 16 α methyl-21-, 9 (11)-diene-3,20-diketone (compounds Ⅳ), concrete reactions steps is:
3.1: room temperature; under nitrogen protection; 60ml tetrahydrofuran (THF), 10.0g compound III is added successively in 250ml tetra-mouthfuls of round-bottomed flasks of the fitting temperature meter of a clean dried, reflux condensing tube, agitator arm; after stirring; reaction system is cooled to-40 DEG C ~-35 DEG C; then control and be-30 DEG C to system temperature, in reaction system, slowly drip the lithium diisopropyl amido (LiN (C that 45.8ml concentration is 2mol/L
3h
7)
2), about 30min dropwises, then insulation reaction 0.5 hour, and TLC detects without starting material left.
3.2: the temperature controlling reaction system is less than 20 DEG C, then dripping 20ml massfraction to reaction system is 30% hydrochloric acid, stirs 5 hours.Then the pH value of reaction system is adjusted to be 7 (pH value be 6 ~ 7 all can implement) with 20% aqueous sodium hydroxide solution, temperature control T≤40 DEG C, and be concentrated into without obvious cut, then in the residue system after concentrated, 100ml water is dripped, stir 1 hour, suction filtration gets filter cake, and washing filter cake is to neutral, then by filter cake in 50 DEG C of oven dry, obtain the compounds Ⅳ of 7.2g.The yield calculating compounds Ⅳ is 72.0%, and (moving phase of HPLC is: methyl alcohol: water=55: 45) detecting purity is 90.9% to adopt HPLC.
Compounds Ⅳ IV structural formula be:
(4) by the chloro-17a-monohydric pregnant-4 of 16 α methyl-21-, 9 (11)-diene-3,20-diketone (compounds Ⅳ) and Potassium ethanoate carry out substitution reaction and prepare 16 α methyl-17 a, 21-dimonohydric pregnant-4,9 (11)-diene-3,20-diketone-21-acetic ester (compound V), concrete reactions steps is:
4.1: room temperature; under nitrogen protection, in 250ml tetra-mouthfuls of round-bottomed flasks of the fitting temperature meter of a clean dried, reflux condensing tube, agitator, add 35ml dimethyl formamide (DMF), 7.0g compounds Ⅳ, 1.4ml Glacial acetic acid, 10.8g Potassium ethanoate, 1.4ml water successively.After reaction system being stirred, reaction system is warming up to 55 DEG C ~ 60 DEG C insulation reaction 8 hours, TLC detects without starting material left.
4.2: the reaction system after 4.1 steps is down to room temperature, in reaction system, drip 70ml water, dropwise rear continuation stirring 1 hour, suction filtration, washing filter cake, to neutral, in 50 DEG C of oven dry after then being drained by filter cake, obtains 7.0g compound V crude product.The yield of computerized compound V crude product is 100.0%, and (moving phase of HPLC is: methyl alcohol: water=55: 45) detect purity and be greater than 95.0% to adopt HPLC.
4.3: by compound V crude product chloroform and acetone recrystallization, obtain 6.2g off-white color solid, i.e. compound V sterling.The yield of computerized compound V sterling is 88.6%; (moving phase of HPLC is: methyl alcohol: water=55: 45) detecting purity is 98.8% to adopt HPLC.
The structural formula of compound V is:
Compound V is prepared two Duplicate Samples, the fusing point of detection compound V is respectively 203 ~ 205 DEG C, 202 ~ 204 DEG C, detects specific rotation and be respectively 99.7 °, 99.3 ° at 20 DEG C.
Compound V is carried out magnetic resonance detection, and detected result is as follows:
1H NMR(400MHz,CDCl3):5.72(1H,4-H),5.51(1H,11-H),4.91(2H,dd,21-CH
2-),2.15(3H,s,-OCCH
3),1.31(3H,19-CH
3),0.92(3H,d,J＝6.8,16α-CH
3)and 0.70(3H,s,18-CH
3)。
Disclosed in magnetic resonance detection result and US4990612 (Upjohn) document, the nuclear magnetic resonance result of 16 α methyl-17 a, 21-dimonohydric pregnant-4,9 (11)-diene-3,20-diketone-21-acetic ester is similar.
(5) by 16 α methyl-17 a, 21-dimonohydric pregnant-4,9 (11)-diene-3,20-diketone-21-acetic ester (compound V) and C5H6Br2N2O2 carry out upper bromine reaction and prepare 16 α methyl-17 a, 11 β, 21-trihydroxy--9-bromine DELTA4-pregn-3,20-dione-21-acetic ester (compound VI), concrete reactions steps is:
5.1: room temperature, under nitrogen protection, in 500ml tetra-mouthfuls of round-bottomed flasks of the fitting temperature meter of a cleaning, agitator arm, add 250ml dimethyl formamide (DMF), 50.0g compound V, 1.4ml perchloric acid successively.After reaction system being stirred, temperature control 10 DEG C ~ 20 DEG C, then adds 25.6g C5H6Br2N2O2, adds rear system and stirs 1 hour, and TLC detects without starting material left.
5.2: will pour in 2L water through the reacted reaction system of step 5.1, continue stirring 1 hour, suction filtration obtains filter cake, and filter cake is washed to neutrality, in 50 DEG C of oven dry after draining, obtains the compound VI of 49.5g.The yield of computerized compound VI is 99.0%, and (moving phase of HPLC is: methyl alcohol: water=55: 45) detect HPLC purity and be greater than 95.0% to adopt HPLC.
The structural formula of compound VI is:
(6) by 16 α methyl-17 a, 11 β, the pregnant Gona-4-ene-3 of 21-trihydroxy--9-bromine, 20-diketone-21-acetic ester (compound V) carries out epoxy reaction and prepares 16 α methyl under alkaline environment, 17a, 21-dimonohydric pregnant-(9,11) epoxy-4-alkene-3,20-diketone-21-acetic ester (Dexamethasone Intermediate), concrete reactions steps is;
6.1: under N2 protective atmosphere; 100ml methylene dichloride is added successively in 500ml tetra-mouthfuls of round-bottomed flask A of the fitting temperature meter of a cleaning, agitator arm; 100ml methyl alcohol, 20.0g compound VI, 2ml massfraction are 20% aqueous sodium hydroxide solution, stir 1 hour, and TLC detects without starting material left.
6.2: in reaction system, adjust PH to neutral with appropriate Glacial acetic acid, temperature control 40 ~ 50 DEG C, concentrating under reduced pressure goes out solvent, divides and adds water displacement for 2 times, add 50ml at every turn.Be cooled to 5 ~ 10 DEG C subsequently to stir 2 hours, suction filtration, washing filter cake is to neutral, in 50 DEG C of oven dry after draining, obtain 16.5g Dexamethasone Intermediate, yield: 82.5%, (moving phase of HPLC is: methyl alcohol: water=55: 45) detect purity and be greater than 98.0% to adopt HPLC.
Dexamethasone Intermediate is carried out magnetic resonance detection, and detected result is as follows:
1H NMR(400MHz,CDCl3):5.72(s,1H,4-H),4.91(dd,2H,21-CH
2-),3.19(br s,1H),2.15(s,3H,-OCH
3),1.31(s,3H,19-CH
3),0.92(d,J＝6.8Hz,3H,16β-CH
3)and 0.70(s,3H,19-CH
3)。
From nuclear magnetic resonance result: the intermediate prepared according to the method for embodiment 2 is Dexamethasone Intermediate.
Meanwhile, the structural formula of Dexamethasone Intermediate is:
The above is only preferred embodiment of the present invention, not does any pro forma restriction to the present invention.Although the present invention discloses as above with preferred embodiment, but and be not used to limit the present invention.Any those of ordinary skill in the art, when not departing from spirit of the present invention and technical scheme, the Method and Technology content of above-mentioned announcement all can be utilized to make many possible variations and modification to technical solution of the present invention, or be revised as the Equivalent embodiments of equivalent variations.Therefore, every content not departing from technical solution of the present invention, according to technical spirit of the present invention to any simple modification made for any of the above embodiments, equivalent replacement, equivalence change and modification, all still belongs in the scope of technical solution of the present invention protection.
Claims (10)
1. adrenocortical hormone pharmaceutical intermediate a preparation method, it is characterized in that, described preparation method comprises the following steps:
(1) cyano group substitution reaction: be raw material with chemical compounds I, adds cyanating reagent and carries out cyano group substitution reaction and obtain compound ii;
(2) silicon alkoxyl group protective reaction: described compound ii and silicon alkoxyl group reagent are carried out siloxanes protective reaction under alkaline environment and obtains compound III;
(3) intramolecular nucleophilic substitution reaction: described compound III and alkali amide reagent are carried out intramolecular nucleophilic substitution reaction under alkaline environment and obtains compounds Ⅳ;
(4) substitution reaction: described compounds Ⅳ and organic carboxylate are carried out substitution reaction under alkaline environment and obtains compound V;
(5) upper bromine reaction: on described compound V and brominated reagent being carried out under sour environment, bromine reaction obtains compound VI;
(6) epoxy reaction: compound VI is carried out under alkaline environment epoxy reaction and obtain adrenocortical hormone pharmaceutical intermediate;
Described adrenocortical hormone pharmaceutical intermediate is Betamethasone Valerate intermediate or Dexamethasone Intermediate;
The structural formula of described chemical compounds I is:
The structural formula of described compound ii is:
The structural formula of described compound III is:
The structural formula of described compounds Ⅳ is:
The structural formula of described compound V is:
The structural formula of described compound VI is:
The structural formula of described Betamethasone Valerate intermediate is:
the structural formula of described Dexamethasone Intermediate is:
2. preparation method according to claim 1, it is characterized in that, described cyano group substitution reaction is specially: be 1: 0.3 ~ 1 be dissolved in organic solvent by described chemical compounds I and described cyanating reagent according to mass ratio, is obtained by reacting compound ii in-10 DEG C ~ 100 DEG C; Described cyanating reagent is acetone cyanohydrin, sodium cyanide or potassium cyanide.
3. preparation method according to claim 2, is characterized in that, adds the catalyzer accounting for chemical compounds I weight 0.04 ~ 2.0 times in described cyano group substitution reaction, and described catalyzer is lower aliphatic acids, salt of wormwood or sodium carbonate.
4. preparation method according to claim 1; it is characterized in that; the protective reaction of described silicon alkoxyl group is specially: add alkali in organic solvent; then be 1: 0.5 ~ 2.0 be dissolved in described organic solvent by described compound ii and described silicon alkoxyl group reagent according to mass ratio, be obtained by reacting described compound III in-10 DEG C ~ 20 DEG C.
5. preparation method according to claim 4, is characterized in that, described silicon alkoxyl group reagent is CMDMCS chloromethyl dimethyl chlorosilane or brooethyl dimethylchlorosilane; Described organic solvent is one or more in halogenated hydrocarbon organic solvent, ether organic solvent, amides organic solvent or pyridine.
6. preparation method according to any one of claim 1 to 5, it is characterized in that, described intramolecular nucleophilic substitution reaction is specially: be dissolved in organic solvent by compound III and alkali, in-80 DEG C ~-10 DEG C reactions, then add the alkali amide reagent accounting for compound III molar equivalent 3.0 ~ 5.0 times, after being separated drying, obtain compounds Ⅳ.
7. preparation method according to claim 6, is characterized in that, described intramolecular nucleophilic substitution reaction carries out under nitrogen protection, and described alkali amide reagent is lithium diisopropyl amido or hexamethyldisilazane lithium; Described organic solvent is ether organic solvent.
8. preparation method according to any one of claim 1 to 5, it is characterized in that, described substitution reaction is specially: be dissolved in organic solvent by compounds Ⅳ and organic carboxylate according to mass ratio 1: 1.0 ~ 3.0, in 0 DEG C ~ 100 DEG C reactions, obtains compound V after being then separated drying; Described organic carboxylate is Potassium ethanoate or sodium-acetate.
9. preparation method according to any one of claim 1 to 5, it is characterized in that, described upper bromine reaction is specially: be 1: 0.5 ~ 1: 1.0 ~ 3.0 join in organic solvent by compound V, bromide reagent and acid according to mass ratio, at-10 DEG C ~ 50 DEG C, be obtained by reacting compound VI, described acid is perchloric acid, fluoroboric acid or the vitriol oil; Described brominated reagent is C5H6Br2N2O2 or N-bromo-succinimide.
10. preparation method according to any one of claim 1 to 5, it is characterized in that, described epoxy reaction is specially: be 1: 0.1 ~ 2 be dissolved in organic solvent by compound VI and alkali according to mass ratio, at-10 DEG C ~ 50 DEG C, be obtained by reacting adrenocortical hormone pharmaceutical intermediate, described alkali is sodium hydroxide, potassium hydroxide, sodium carbonate or salt of wormwood.
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