CN103421070A - Improved pregnane alkene compound C21-acetoxylation method - Google Patents
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Abstract
The invention discloses a synthetic method of steroid medicine and intermediates, particularly relates to improvement of a pregnane alkene compound C21-acetoxylation synthesis technology, and belongs to the field of medicine synthesis. According to an improved pregnane alkene compound C21-acetoxylation method, a 3-pyrrolidine hydrochloride method is used for protecting an unsaturated ketone carbonyl group, specificity bromination of C21-position happens after a reaction between the unsaturated ketone carbonyl group and bromine is carried out, the defects that a traditional iodination technology is high in cost, low in yield, unstable in intermediate and the like are overcome, the reactions of the first three steps can be continuously carried out in the same reactor, the reactions of the later two steps, namely deprotection and replacement of C21-position bromide, can be accomplished through a one-pot reaction, and the yield and efficiency are improved. Due to the facts that bromine is adopted by the improved pregnane alkene compound C21-acetoxylation method to replace iodine, and the cost of the bromine is lower than that of the iodine, reaction selectivity is good, the yield is high, energy consumption is low, and the improved pregnane alkene compound C21-acetoxylation method is applicable to industrial production.
Description
Technical field
The present invention relates to the synthetic method of steroidal drug and intermediate, relate in particular to a kind of improvement of pregnene compounds C21-acetoxylation synthesis technique, belong to the synthetic field of medicine.
Background technology
In the building-up process of the steroid hormone medicines such as cortisone acetate, Prednisone acetate, at C
21The upper needs realized the conversion to acetoxyl group by methyl, and what apply at most is halogenation, esterification route.At C
21Upper generation halogenating reaction, obtain C
21-halides, then introduce acetoxyl group with nucleophilic reagent generation nucleophilic substitution reaction.
At present, in most of steroid drugss synthetic, what 21 acetoxylations adopted is all the iodo method, elemental iodine is as halogenating agent (Bowers A, Ringold H J. A new route to 6 α-methylcortisone[J]. Journal of the American Chemical Society. 1958,80 (12): 3091-3093; CN101397320).In many synthetic routes of cortisone, most iodine that adopts is as halogenating agent (Halpern O, Djerassi C. Synthesis of cortisone from botogenin[J]. Journal of the American Chemical Society. 1959,81 (2): 439-441).
Ringold(Ringold H J, Stork G. Introduction of the cortical hormone side-chain[J]. Journal of the American Chemical Society. 1958,80 (1): the method for 250) having invented the earliest iodo, be that iodide reaction carries out under the calcium oxide existence condition, take THF as solvent, obtain C
21-mono-iodo thing, yield only has at most the 72-73%(crude product).The people such as Joly have improved this reaction, with alcohol, make solvent, not only use iodine and calcium oxide, have also added calcium chloride, and the crude product yield can reach 88%.The people such as Chen Wei (Chen Wei, Qiu Zhilin, pregnene compounds C
21The improvement of-process or acetoxylation [J]. Acta Pharmaceutica Sinica, 1979 (09): 563-565) when the method by Joly is applied to 17-hydroxyl progesterone and 17-hydroxyl-11 ketone group Progesterone, find that productive rate can not reach so high.Therefore, carried out again some explorations, found to adopt this mixed solvent of chloroform-methanol, for yield, improved very big help is arranged.
The mechanism of this reaction is not illustrated, someone thinks free radical reaction, someone thinks ionic reaction (Claudel E, Arbez-Gindre C, Berl V, et al. An efficient hemisynthesis of 20-and 21-[13c]-labeled cortexolone:a model for the study of skin sensitization to corticosteroids[J]. Synthesis. 2009,2009 (20): 3391-3398).
The people such as Sun Liang to the complete synthesis route application of hydrocortisone patent protection (CN101397323).Its synthetic route is as follows.What wherein, the iodo process adopted is calcium chloride, calcium oxide system.In literary composition, point out, the iodo thing of generation is two iodine substituents mostly, and a small amount of single iodine substituent is also arranged.No matter two iodo things, or single iodo thing are all to participate in replacement(metathesis)reaction.
The hydrocortisone synthetic route
The human hairs such as Wang Jiazhen understand the chemical synthesis process (CN101230084) of methylprednisolone.Upper Iod R is used the solid catalysts such as calcium chloride, calcium oxide, contains methyl alcohol in solvent, adds aqueous acetic acid after having reacted, and the iodo thing is separated out.
The human hairs such as Li Jinlu understand the preparation method (CN101397324) of prednisolone and derivative thereof.Upper Iod R carries out under nitrogen protection, the main pair iodo things that generate, and single iodo thing can not have influence on next step reaction.Processing mode after iodide reaction is, reaction solution is joined in aqueous ammonium chloride solution, standing, separates out solid, filters.Wet iodo thing can not be dry, because be easy to, decomposes.
The human hairs such as Deng Lei understand the synthetic route (CN101397319) of Betamethasone Valerate and series product thereof, after upper Iod R completes, not except desolventizing, but reaction solution is diluted in 2% aqueous ammonium chloride solution, separate out solid, filter, the iodo thing solid obtained does not carry out drying, is directly used in the next step.
To sum up, the synthesis technique of iodo displacement is widely used industrial.At present, the synthetic route that realizes scale operation is all iodo, esterification route.The enol ester route of its analogue, lead tetraacetate route are reported seldom, and all are only limited to the laboratory study stage, unrealized suitability for industrialized production.
C
21Halogenating reaction, except the method for iodo, can also use the method for bromo.The activity of bromine is very high, and speed of response is very fast.Especially for 4-alkene-3-ketone substrate, when bromination, addition reaction can occur, cause the destruction to pregnant steroid parent nucleus, and 3 is that the 20-ketone compound of acetoxyl group also has report (Koechlin B A with reacting of bromine, Garmaise D L, Kritchevsky T H, et al. Preparation of adrenal cortical hormones[J]. Journal of the American Chemical Society. 1949,71 (9): 3262-3263).
Therefore, although iodide reaction is maximum method of applying at present.But the shortcoming of the method is unstable (the Cutler F A of iodo thing generated, Conbere J P, Lukes R M, et al. Synthesis of cortisone-21 phosphate[J]. Journal of the American Chemical Society. 1958,80 (23): 6300-6303; Li Ping, Lu Junrui, Li Xia, etc. the mensuration [J] of HPLC to pregnant steroid 21-iodide rate of decomposition. Institutes Of Technology Of Tianjin's journal, 2007 (03): 24-25).In some reaction, the iodine content fluctuation of the iodo thing of generation is larger, and repeating of test is poor.While especially in substrate, containing 4-alkene-3-ketone, iodo unstable result (Rothman E S, Perlstein T, Wall M E. C-21 acetoxylation of 12-keto steroids[J]. The Journal of Organic Chemistry. 1960,25 (11): 1966-1968).And iodide reaction is had relatively high expectations to reaction conditions, need lucifuge, low temperature etc.Energy consumption of reaction is larger.
And China's iodine natural resources shortage, in recent years, the price of iodine continues to raise up, and has brought larger challenge to the cost control of enterprise.From composition principle, iodine just plays transitional function in the whole piece route, and in target product, not containing iodine, the synthesis technique of therefore designing an alternative iodine will have good market outlook.
Summary of the invention
Technical problem to be solved by this invention is to overcome the defect that above-mentioned prior art exists, and provides a kind of employing bromine to substitute the improved pregnene compounds of iodine C21-acetoxylation synthesis technique.
For realizing purpose of the present invention, the present invention adopts following technical scheme: the pregnene compounds that contains C21 position methyl of take is raw material, add tetramethyleneimine and alcoholic solvent, C3 is carried out to selective protection, obtain the 3-enamine compound: then with hydrochloric acid reaction, obtain 3-pyrrolidine hydrochloride compound: then with bromine, react, obtain 3-pyrrolidine hydrochloride-21-bromo compound: then add the alkali deprotection, obtain the 21-bromo-derivative; After finally adding KOAc, AcOH, obtain C21-acetoxyl group pregnene compounds.
Synthetic route of the present invention is as follows:
X=H-wherein, HO-, O=;
Wherein
Mean: in structure, have or unparalleled key all can;
Concrete steps are as follows:
Step 1, the pregnene compounds that contains C21 position methyl that the structure of take is following is raw material, adds tetramethyleneimine and alcoholic solvent, and C3 is carried out to selective protection, obtains formula 1 compound:
Pregnene compounds formula 1
The choosing of the alcoholic solvent that uses: methyl alcohol, ethanol one of them;
Optimum condition: pregnene class raw material and tetramethyleneimine mol ratio 1:1.6,30 ℃ of temperature of reaction, reaction times 0.5h;
Step 2, formula 1 compound and hydrochloric acid reaction obtain formula 2 compounds:
Formula 2
Optimum condition: formula 1 compound and HCl mol ratio 1:1.2,25 ℃ of temperature of reaction, reaction times 0.5h;
Step 3, formula 2 compounds and bromine or containing bromine solutions or bromine chloride solution reaction obtain formula 3 compounds:
Comprise containing bromine solutions: the ethanolic soln of bromine, chloroformic solution, dichloromethane solution, methanol solution one of them; Bromine chloride solution is its ethanolic soln or methanol solution or chloroformic solution;
Optimum condition: formula 2 compounds and HCl, bromine mol ratio 1:1:1.6,35 ℃ of temperature of reaction, reaction times 3h;
Step 4, after adding alkali in formula 3 compounds, obtains formula 4 compounds:
Formula 4
The alkali choosing of using: KOAc, NaOAc, KHCO
3, NaHCO
3, K
2CO
3, Na
2CO
3, KOH, NaOH one of them;
Optimum condition: formula 3 compounds and Potassium ethanoate mol ratio 1:1,25 ℃ of temperature of reaction, reaction times 2h;
Step 5, formula 4 compounds are dissolved in solvent, add KOAc or/and, after AcOH, obtain following structural formula target compound:
The solvent that step 5 is used is preferred: DMF, acetone, acetonitrile, chloroform one of them; Optimum condition: formula 4 compounds and Potassium ethanoate, acetic anhydride mol ratio 1:1:0.5,30 ℃ of temperature of reaction, reaction times 3h.
Step 1, step 2 and step 3 be " original position " reaction continuously, i.e. step 1 reaction is complete after decompression or air distillation are except desolventizing and tetramethyleneimine, directly carries out the step 2 reaction; Step 2 after completion of the reaction, is directly carried out the step 3 reaction.
Step 4 and step 5 can " one pot " be reacted, i.e. step 4 reaction is reacted in reactor and carried out simultaneously with step 5, obtains target compound;
Beneficial effect of the present invention is:
(1) this synthetic method adopts the bromo replacing process to substitute conventional iodine for replacing process, has and reduces production costs, and reduces energy consumption, improves the advantage of product quality.
(2) step 1, step 2, step 3 can " original position " reactions continuously in same equipment, realize that three-step reaction is coupling in a workshop section and completes, i.e. step 1 reaction is complete after decompression or air distillation are except desolventizing and tetramethyleneimine, directly carries out the step 2 reaction; Step 2 after completion of the reaction, is directly carried out the step 3 reaction; Plant factor and productivity have been improved.
(3) deprotection of step 4 and step 5 and replacement(metathesis)reaction realize that " one pot " react, i.e. step 4 reaction is reacted in reactor and carried out simultaneously with step 5, in reaction medium, realizes replacement(metathesis)reaction in the time of deprotection, or realize deprotection when replacing; Improved production efficiency;
(4) three wastes are less, good reaction selectivity, and product purity is high, and yield is higher; The raw material bromine is easy to get, and cost is lower, and synthesis technique is simple; Be applicable to suitability for industrialized production.
Detail of the present invention is described in detail in embodiment below, but embodiment should not be construed as restriction protection scope of the present invention.
Embodiment
For the present invention will be described better, enumerate embodiment as follows:
Embodiment 1
(1) step 1: get 1 part of 21-desoxycortisone, methyl alcohol 10-100 part, put in reactor, stir temperature control-20-50 ℃; Add tetramethyleneimine 1-10 part, isothermal reaction 0.1-6 h.Reaction solution is cooled to room temperature, places but 0.2-2h of refrigerator and cooled, suction filtration, with the cold methanol washing, obtain pale yellow crystals, yield 83.56% after vacuum-drying.
The FTIR of enamine (KBr): 3395.76 (OH), 2966.86 (CH
3), 1709.72 (C=O), 1682.92 (C=O), 1632.49 (C=C), 1603.20 (C=C) cm
-1.
Enamine
1The HNMR data analysis:
1HNMR (CDC1
3): δ=0.624 (3H, H-19), 1.391 (3H, H-18), 2.227 (3H, H-21), 3.956-4.237 (4H, H-1 ', 4 '), 4.838 (1H, H-4), 6.456 (1H, H-6).
(2) step 2: get ethanolic soln 1-10 part of 1 part of previous step product, 0.001-0.1 g/mL hydrogenchloride, put in reactor stirring at room 1-60 min, ethanol is removed in underpressure distillation, adds proper amount of acetone, has solid to separate out, suction filtration, obtain white crystal after vacuum-drying, yield 95.04%.
The FTIR of pyrroles's salt (KBr): 3387.97 (OH), 3160.94 (
), 2957.47 (CH
3), 1702.07 (C=O), 1621.82 (C=C) cm
-1
Pyrroles's salt
1The HNMR data analysis:
1HNMR (D
2O): δ=0.546 (3H, H-19), 1.290 (3H, H-18), 2.176 (3H, H-21), 3.773-3.868 (4H, H-1 ', 4 '), 6.329 (1H, H-4).
Pyrroles's salt
13the CNMR data analysis:
13CNMR (D
2O): δ=15.270 (C-19), 16.667 (C-18), 22.418 (C-15), 23.966 (C-2 ' or C-3 '), 24.096 (C-3 ' or C-2 '), 26.093 (C-21), 27.182 (C-7), 31.709 (C-2), 31.959 (C-8), 33.028 (C-16), 33.143 (C-6), 36.066 (C-1), 38.426 (C-10), 49.067 (C-12), 50.243 (C-13), 50.615 (C-14), 52.089 (C-1 ' or C-4 '), 52.415 (C-4 ' or C-1 '), 61.277 (C-9), 89.536 (C-17), 115.653 (C-4), 172.214 (C-5), 179.314 (C-3), 214.444 (C-11), 214.482 (C-20).
(3) step 3: get ethanolic soln 1-10 part of 1 part of pyrroles's salt that step 2 makes, dehydrated alcohol 10-50 part, 0.001-1 g/mL hydrogenchloride, put in reactor, stir, temperature control is to-20-80 ℃; Drip ethanolic soln 1-5 part of bromine, drip off isothermal reaction 1-12 h in 0.2-3h.Reaction solution is cooled to room temperature, places but 30 min of refrigerator and cooled, suction filtration, use cold washing with alcohol, obtains white solid after vacuum-drying, yield 97.53%.
The FTIR of bromo salt (KBr): 3431.22 (OH), 3198.45 (
), 2939.12 (CH
3), 1708.86 (C=O), 1626.84 (C=C), 637.37 (C-Br) cm
-1
Bromo salt
1The HNMR data analysis:
1HNMR (CD
3OD): δ=0.618 (3H, H-19), 1.423 (3H, H-18), 4.239-4.276 (1H, H-21), 4.428-4.465 (1H, H-21), 6.466 (1H, H-4).
Bromo salt
13the CNMR data analysis:
13CNMR (CDCl
3+ CD
3OD): δ=15.799 (C-19), 17.291 (C-18), 23.012 (C-15), 24.227 (C-2 ' or C-3 '), 24.354 (C-2 ' or C-3 '), 26.875 (C-7), 31.959 (C-21), 32.000 (C-2), 33.803 (C-16), 34.405 (C-8), 35.453 (C-6), 36.268 (C-1), 38.847 (C-10), 49.492 (C-12), 50.258 (C-13), 50.981 (C-14), 52.611 (C-1 ' or C-4 '), 53.010 (C-1 ' or C-4 '), 60.878 (C-9), 88.931 (C-17), 116.153 (C-4), 172.539 (C-5), 180.075 (C-3), 203.431 (C-20), 209.800 (C-11).
(4) step 4: get 1 part of the bromo salt that step 3 makes, mixing solutions 10-100 part, salt of wormwood 1-20 part of alcohol-water (volume ratio is 2:1), put in reactor, stir, temperature control is to-20-80 ℃, isothermal reaction 0.5-12h.Reaction solution is cooled to room temperature, and underpressure distillation, remove most of solvent, adds distilled water 50-100 part, has solid to separate out, and suction filtration, wash with water, obtains faint yellow solid, yield 74.97%.
The FTIR of bromo-derivative (KBr): 3539.38 (OH), 2951.35 (CH
3), 1699.12 (C=O), 1651.42 (C=C), 636.71 (C-Br) cm
-1.
Bromo-derivative
1The HNMR data analysis:
1HNMR (CDCl
3): δ=0.689 (3H, H-19), 1.412 (3H, H-18), 4.023-4.057 (1H, H-21), 4.290-4.324 (1H, H-21), 5.738 (1H, H-4)
Bromo-derivative
13The CNMR data analysis:
13CNMR (CDCl
3): δ=15.947 (C-19), 17.271 (C-18), 23.150 (C-15), 32.022 (C-7), 32.320 (C-6), 33.772 (1), 33.961 (16), 34.295 (C-2), 36.349 (C-21), 36.383 (C-8), 38.187 (C-10), 49.254 (C-12), 50.655 (C-13), 50.793 (C-14), 61.404 (C-9), 88.861 (C-17), 124.147 (C-4), 169.551 (C-5), 198.717 (C-3), 203.541 (C-20), 210.566 (C-11).
(5) step 5: get DMF 10-100 part, put in reactor, stir temperature control-20-80 ℃, 1 part of the bromo-derivative that adds Potassium ethanoate 1-20 part, acetic anhydride 0.5-20 part, step 4 to make, isothermal reaction 1-12 h.Reaction solution is cooled to room temperature, places but 15 min of refrigerator and cooled, suction filtration, use cold DMF, distilled water wash successively, obtains the white powder solid after vacuum-drying, yield 75.73%.
The FTIR of cortisone acetate (KBr): 3454.72 (OH), 2946.60 (CH
3), 1704.12 (C=O), 1603.79 (C=C) cm
-1.Consistent with the standard diagram of cortisone acetate.
Cortisone acetate
1The HNMR data analysis:
1HNMR (CDCl
3): δ=0.669 (3H, H-19), 1.404 (3H, H-18), 2.162 (3H, H-23), 4.647-4.691 (1H, H-21), 5.077-5.120 (1H, H-21), 5.726 (1H, H-4).
Cortisone acetate
13The CNMR data analysis:
13CNMR (CDCl
3): δ=15.436 (C-19), 17.124 (C-23), 20.496 (C-18), 23.225 (C-15), 32.269 (C-7), 32.340 (C-6), 33.709 (C-8), 34.726 (C-2), 34.940 (C-16), 36.467 (C-1), 38.235 (C-10), 49.796 (C-12), 49.909 (C-13), 51.251 (C-14), 62.528 (C-9), 67.638 (C-21), 88.859 (C-17), 124.521 (C-4), 168.991 (C-22), 170.618 (C-5), 200.028 (C-3), 204.709 (C-11), 209.039 (C-20).
Embodiment 2:
(1) step 1, step 2, step 3 " original position " successive reaction:
Get 1 part of 21-desoxycortisone, 10 parts of methyl alcohol, put in reactor, stir, temperature control is at-20-50 ℃; Add 1-5 part tetramethyleneimine, isothermal reaction 0.5-6h.10-30 ℃ of decompression steams solvent, adds the ethanolic soln of 1-5 part hydrogenchloride, stirs 1-60min, drips the ethanolic soln of 1-5 part bromine, drips off isothermal reaction 1-12 h in 0.5-2.5 h.Reaction solution is cooling, crystallize out, suction filtration, use cold washing with alcohol, obtains 3-pyrrolidine hydrochloride-21-bromo-derivative.Yield 95%.
(2) step 4, step 5 " one kettle way " reaction:
Get 3-pyrrolidine hydrochloride-1 part of 21-bromo-derivative, DMF solution 10-100 part, salt of wormwood 1-20 part, acetic anhydride 1-10 part, put in reactor, stirs ℃-50 ℃, temperature control-5, isothermal reaction 1-6 h.Reaction solution is cooled to room temperature, places but 15 min of refrigerator and cooled, suction filtration, use cold DMF, distilled water wash successively, obtains cortisone acetate after vacuum-drying.Yield 90%.
Embodiment 3:
(1) coupling reaction that step 1, step 2, step 3 " original position " successive reaction are reacted with step 4, step 5 " one kettle way "
Get 1 part of 21-desoxycortisone, 10 parts of methyl alcohol, put in reactor, stir, temperature control is at-20-50 ℃; Add 1-5 part tetramethyleneimine, isothermal reaction 0.5-6h.10-30 ℃ of decompression steams solvent, adds the ethanolic soln of 1-5 part hydrogenchloride, stirs 1-60min, drip the ethanolic soln of 1-5 part bromine, drip off isothermal reaction 1-12 h in 0.5-2.5 h, 10-30 ℃ of decompression steams solvent, adds DMF solution 10-100 part, salt of wormwood 1-20 part, stir 0.5-2h, acetic anhydride 1-10 part, put in reactor, stirs, ℃-50 ℃, temperature control-5, isothermal reaction 1-6 h.Reaction solution is cooled to room temperature, places but 15 min of refrigerator and cooled, suction filtration, use cold DMF, distilled water wash successively, obtains cortisone acetate after vacuum-drying.Yield 90%.
Embodiment 4:
(1) step 4: adopt bromine chloride technique.
With embodiment 1,2,3,4, by the ethanolic soln of bromine or bromine, replace to ethanolic soln or methanol solution or the chloroformic solution of bromine chloride, effect is suitable.
Embodiment 5
The compound that the structure of take is following is raw material, according to the described method of embodiment 1, prepares the cortisone acetate derivative,
Yield 90%, its nuclear magnetic data is as follows:
1H NMR data analysis:
1HNMR (CDCl
3): δ=1.00 (3H, H-19), 1.18 (3H, H-18), 2.15 (3H, 21-OCOCH
3), 5.24 (2H, H-21), 6.12 (1H, H-4), 6.35 (1H, H-1), 6.69 (1H, H-2).
13C NMR data analysis:
13CNMR (CDCl
3): δ=211.5,206.8,185.7,170.2,165.3,154.3,128.3,124.2,90.3,67.7,61.5,51.2,49.4,47.8,42.2,35.3,32.6,32.6,31.2,23.5,20.4,19.0,15.8.
Embodiment 6
The compound that the structure of take is following is raw material, according to the described method of embodiment 1, prepares the cortisone acetate derivative,
Yield 90%, its nuclear magnetic data is as follows:
FTIR(KBr):?3500(OH),?2946.60(CH
3),?1735(C=O),?1704?(C=O),?1700?(C=O),?1600(C=C)?cm
-1。
1H NMR data analysis:
1HNMR (CDCl
3): δ=0.85 (3H, H-19), 1.14 (3H, H-18), 1.95 (1H, 17-OH), 2.14 (3H, 21-OCOCH
3), 5.25 (2H, H-21), 5.75 (1H, H-4).
13C NMR data analysis:
13CNMR (CDCl
3): δ=206.8,198.9,170.2,170.2,124.0,90.8,67.7,53.7,49.5,48.0,38.6,35.7,35.2,34.1,33.2,32.5,31.6,30.2,23.8,21.1,20.4,19.0,16.4.
Claims (5)
1. an improved pregnene compounds C21-process or acetoxylation, is characterized in that, concrete steps are as follows:
Step 1, the pregnene compounds that contains C21 position methyl that the structure of take is following is raw material, adds tetramethyleneimine and alcoholic solvent, and C3 is carried out to selective protection, obtains formula 1 compound:
Pregnene compounds formula 1
The choosing of the alcoholic solvent that uses: methyl alcohol, ethanol one of them;
Step 2, formula 1 compound and hydrochloric acid reaction obtain formula 2 compounds:
Step 3, formula 2 compounds and bromine, containing bromine solutions or bromine chloride solution reaction obtain formula 3 compounds:
Formula 3
Comprise containing bromine solutions: the ethanolic soln of bromine, chloroformic solution, dichloromethane solution, methanol solution one of them; Bromine chloride solution is its ethanolic soln or methanol solution or chloroformic solution;
Step 4, after adding alkali in formula 3 compounds, obtains formula 4 compounds:
Formula 4
The alkali choosing of using: KOAc, NaOAc, KHCO
3, NaHCO
3, K
2CO
3, Na
2CO
3, KOH, NaOH one of them;
Step 5, formula 4 compounds are dissolved in solvent, after adding KOAc and/or AcOH, obtain following structural formula target compound:
。
2. a kind of improved pregnene compounds C21-process or acetoxylation as claimed in claim 1, is characterized in that the step 1 optimum condition: pregnene class raw material and tetramethyleneimine mol ratio 1:1.6,30 ℃ of temperature of reaction, reaction times 0.5h; Step 2 optimum condition: formula 1 compound and HCl mol ratio 1:1.2,25 ℃ of temperature of reaction, reaction times 0.5h; Step 3 optimum condition: formula 2 compounds and HCl, bromine mol ratio 1:1:1.6,35 ℃ of temperature of reaction, reaction times 3h; Step 4 optimum condition: formula 3 compounds and Potassium ethanoate mol ratio 1:1,25 ℃ of temperature of reaction, reaction times 2h; Step 5 optimum condition: formula 4 compounds and Potassium ethanoate, acetic anhydride mol ratio 1:1:0.5,30 ℃ of temperature of reaction, reaction times 3h.
3. a kind of improved pregnene compounds C21-process or acetoxylation as claimed in claim 1 or 2, it is characterized in that, step 1, step 2 and step 3 be " original position " reaction continuously, be that step 1 reaction is complete after decompression or air distillation are except desolventizing and tetramethyleneimine, directly carry out the step 2 reaction; Step 2 after completion of the reaction, is directly carried out the step 3 reaction.
4. a kind of improved pregnene compounds C21-process or acetoxylation as claimed in claim 1 or 2, it is characterized in that, step 4 and step 5 can " one pot " be reacted, i.e. step 4 reaction is reacted in reactor and carried out simultaneously with step 5, obtains target compound.
5. a kind of improved pregnene compounds C21-process or acetoxylation as claimed in claim 1 or 2, is characterized in that, the solvent that step 5 reaction is used is preferred: DMF, acetone, acetonitrile, chloroform one of them.
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|---|---|---|---|---|
| CN104761607A (en) * | 2015-03-17 | 2015-07-08 | 河南利华制药有限公司 | Preparation of prednisolone acetate |
| CN113416226A (en) * | 2021-06-28 | 2021-09-21 | 佳尔科生物科技南通有限公司 | New preparation method of cortisone acetate |
| ES2943573R1 (en) * | 2020-10-19 | 2024-04-09 | Ind Chimica Srl | Process for the preparation of 21-(acetyloxy)-17-(1-oxopropoxy)-pregn-4-ene-3,20-dione |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5622797A (en) * | 1979-07-24 | 1981-03-03 | Edinen Zentar Chim | Manufacture of steroid hormone having pregnane skeleton |
| CN103232514A (en) * | 2013-04-28 | 2013-08-07 | 赵云现 | Preparation method of cortisone acetate |
-
2013
- 2013-08-30 CN CN2013103865884A patent/CN103421070A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5622797A (en) * | 1979-07-24 | 1981-03-03 | Edinen Zentar Chim | Manufacture of steroid hormone having pregnane skeleton |
| CN103232514A (en) * | 2013-04-28 | 2013-08-07 | 赵云现 | Preparation method of cortisone acetate |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104761607A (en) * | 2015-03-17 | 2015-07-08 | 河南利华制药有限公司 | Preparation of prednisolone acetate |
| ES2943573R1 (en) * | 2020-10-19 | 2024-04-09 | Ind Chimica Srl | Process for the preparation of 21-(acetyloxy)-17-(1-oxopropoxy)-pregn-4-ene-3,20-dione |
| CN113416226A (en) * | 2021-06-28 | 2021-09-21 | 佳尔科生物科技南通有限公司 | New preparation method of cortisone acetate |
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