CN102367262A - Preparation method of hydrocortisone - Google Patents
Preparation method of hydrocortisone Download PDFInfo
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- CN102367262A CN102367262A CN2011102017291A CN201110201729A CN102367262A CN 102367262 A CN102367262 A CN 102367262A CN 2011102017291 A CN2011102017291 A CN 2011102017291A CN 201110201729 A CN201110201729 A CN 201110201729A CN 102367262 A CN102367262 A CN 102367262A
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Abstract
The invention, relating to the field of pharmaceutical synthesis, particularly relates to a preparation method of hydrocortisone, comprising the following steps: using an intermediate 17 alfa-hydroxy-4-pregnene-3,11,20- triketone (II) in a Rhizopus nigricans method as raw material, successively carrying out ketal reaction, reduction reaction, hydrolysis reaction, iodine adding reaction, and displacement reaction to obtain hydrocortisone acetate (VII), and finally carrying out sodium hydroxide hydrolysis reaction to obtain the hydrocortisone (I). The invention has the advantages of easy obtainment of raw material, common auxiliary materials, and no need of using toxic, highly toxic, and carcinogenic reagents. The method is more efficient than the process in the prior art, and the products has good quality and yield.
Description
Technical field
The present invention relates to the synthetic field of medicine, be specifically related to a kind of preparation method of HYDROCORTISONE INJECTIONS of environmental protection.
Background technology
(Hydrocortisone HC) claims hydrocortisone (Cortisol) again to HYDROCORTISONE INJECTIONS, and chemical name is 11 β; 17 α; The pregnant steroid of 21-trihydroxy--4-alkene-3, the 20-diketone is one of maximum kind of output in the steroid hormone class medicine, also is the bulk drug of other several kinds of important steroid drugss of preparation.At present, state such as American and Britain, method, day and European Pharmacopoeia all record.HYDROCORTISONE INJECTIONS is middle effect adrenal cortex hormones drug; Can influence carbohydrate metabolism; Have effects such as anti-inflammatory, antiviral, shock and antianaphylaxis; Be mainly used in the replacement therapy of adrenocortical insufficiency and the treatment of congenital adrenal function hyperplasia disease clinically, also be used for rheumatoid arthritis, rheumatic fever, gout, bronchial asthma, anaphylactic disease, and can be used for some severe infections and shock treatment etc.
The preparation of HYDROCORTISONE INJECTIONS, full chemical synthesis is long because of operational path, and it is special to react, and technological process is numerous and diverse, and total recovery is low, so no industrial production is worth.Full biological synthesis process is concerned by people, but also is in the starting stage, and industrial production remains time.
At present, the HYDROCORTISONE INJECTIONS suitability for industrialized production is semi-synthesis method basically.Domestic abroad mostly is to carry out suitability for industrialized production with curvularia lunata mainly with bread mould method and two kinds of operational path productions of the mould method of pears head, and domestic also have correlative study to carry out bio-transformation production HYDROCORTISONE INJECTIONS with curvularia lunata, but suitability for industrialized production is less.
The bread mould method is produced: by 16 α; 17 α-epoxy Progesterone is earlier behind α-OH in the bread mould oxidation of C11 position; α-OH is ketone group on the chromic anhydride oxidation C11 position through using, goes up the bromine debrominate again, last iodization gets cortisone acetate, then protects the ketone group on C3, the C20 position with semicarbazone; Use that ketone group is β-OH on the potassium borohydride reduction C11 position, slough behind protection base and the ethanoyl on the hydrolysis C21 position on C3, the C20 position HYDROCORTISONE INJECTIONS.Reaction formula is following:
Reaction formula 1:
Wherein semicarbazone is protected the ketone group on C3, the C20 position; Use that ketone group is β-OH on the potassium borohydride reduction C11 position; Slough the protection base on C3, the C20 position again; All there are deficiency in this method quality and yield, and the semicarbazone protection base of sloughing on C3, the C20 position needs use Sodium Nitrite, are a kind of known malicious and carcinogenic materials.
The mould method production of pears head: by 16 α; 17 α-epoxy Progesterone is gone up the bromine debrominate earlier, upward iodization gets 17 α; 21-dihydroxyl-4-pregnene-3,20-diketone-21-acetic ester (acetic acid compound S) introduces directly through the mould oxidation of pears head that β-OH gets HYDROCORTISONE INJECTIONS on the C11 position again.Reaction formula is following:
Reaction formula 2:
β-OH on the C11 position is directly introduced in the mould oxidation of pears head, has shortened the operational path of synthesizing hydrogenated KE, and the bacterial classification of domestic production HYDROCORTISONE INJECTIONS is an Absidia coerulea at present, but Absidia coerulea oxidation specificity is low, and the yield of HYDROCORTISONE INJECTIONS is restricted.
The curvularia lunata method is produced: by 17 α; 21-dihydroxyl-4-pregnene-3; Ethanoyl on the first hydrolysis C21 of 20-diketone-21-acetic ester (acetic acid compound S) position gets 17 α; 21-dihydroxyl-4-pregnene-3,20-diketone (compound S) introduces directly through the curvularia lunata oxidation that β-OH gets HYDROCORTISONE INJECTIONS on the C11 position again.Reaction formula is following:
Reaction formula 3:
Generally speaking, curvularia lunata is to 17 α, 21-dihydroxyl-4-pregnene-3, and 20-diketone-21-acetic ester (acetic acid compound S) has lower deacetylase activity; Substrate transforms through curvularia lunata, though can on the C11 position, obtain HYDROCORTISONE INJECTIONS by β-OH, also can produce 14 α-OH by product simultaneously; Ethanoyl on the common first hydrolysis C21 position is directly introduced β-OH on the C11 position through the curvularia lunata oxidation again, and operational path is more succinct, but the curvularia lunata conversion rate of oxidation is not high, and the yield of HYDROCORTISONE INJECTIONS is restricted.
In addition, in the recent period the disclosed semi-synthesis method of the Chinese patent document novel process for preparing HYDROCORTISONE INJECTIONS has:
Preparing method in China's invention application 200710061256.3, with 17 Alpha-hydroxies-4,9-diene-pregnant steroid-3,20-diketone are raw material, get HYDROCORTISONE INJECTIONS through last iodization, bromination debrominate, hydrolysis.Reaction formula is following:
Reaction formula 4:
Alkyl below the R=-OCOR1 wherein, 11 carbon of R1=.
Preparing method among the China invention application 200710061260.X, with 17 Alpha-hydroxies-4,9-diene-pregnant steroid-3,20-diketone are raw material, get HYDROCORTISONE INJECTIONS through bromination debrominate, last iodization, hydrolysis.Reaction formula is following:
Reaction formula 5:
Alkyl below the R=-OCOR1 wherein, 11 carbon of R1=.
Two kinds of preparing methods of China's invention application 200710061256.3 and China invention application 200710061260.X all belong to the bread mould method.All with 17 Alpha-hydroxies-4,9-diene-pregnant steroid-3,20-diketone are raw material; And 17 Alpha-hydroxies-4,9-diene-pregnant steroid-3, the preparation of 20-diketone; Producing at present and going up classical way is to utilize methane sulfonyl chloride earlier with 11 α-OH compound sulphur esterification, again with acetic acid, sodium-acetate elimination react 9 (11)-ene compounds, wherein the content of impurity 11 (12)-ene compounds is 8-15%; Need repeatedly refining could be qualified, and methane sulfonyl chloride is highly toxic product, corrodibility is also very big.The preparation method of 9 (11)-ene compounds also describes in Chinese patent 200510014479.5: need use acidic dehydration agent phosphorus pentachloride (PCl
5), phosphorus trichloride (PCl
3), POCl3 (POCl
3) etc., being than poison or highly toxic product, acid attack property is also very big.And need deep freeze refrigeration plant when producing, input is big, energy consumption is more.The debromination of β-OH need be used debrominate reductive agent such as tributyltin hydride for than drugs on the C11 position, and chromic salts is a heavy metallic salt.
Therefore, the novel process of developing a kind of environmental protection and economy is significant.
Summary of the invention
Shortcoming and defect to above-mentioned prior art existence; The object of the invention aims to provide the preparation method of a kind of HYDROCORTISONE INJECTIONS (I); This preparation method can avoid some uses of poison, severe toxicity, carcinogenic reagent, and environmental protection is and effective, and the quality of product and yield are all better.
For realizing goal of the invention of the present invention, the contriver provides following technical scheme:
A kind of preparation method of HYDROCORTISONE INJECTIONS comprises the steps:
(1) ketal reaction:
With 17 Alpha-hydroxies-4-pregnene-3,11,20-triketone (II) adds in terepthaloyl moietie and the triethyl orthoformate; Add tosic acid again, more than 8 hours, reaction finishes in 30～35 ℃ of stirring reactions; Add the water elutriation, filter, be washed with water to neutrality; Drying gets 17 Alpha-hydroxies-4-pregnene-11-ketone-3,20-Diethylene Glycol ketal (III); Wherein: 17 Alpha-hydroxies-4-pregnene-3,11,20-triketone: terepthaloyl moietie: triethyl orthoformate: the amount ratio of tosic acid is 1:3～5:3～5:0.05～0.1 (w/v/v/w);
(2) reduction reaction:
With 17 Alpha-hydroxies-4-pregnene-11-ketone-3,20-Diethylene Glycol ketal (III) adds in THF and the methyl alcohol, stirs; Add hydroborate, reflux more than 48 hours, concentrating under reduced pressure reclaims solvent; Add the water elutriation, filter, be washed with water to neutrality; Drying gets 11 β, 17 alpha-dihydroxy-s-4-pregnene-3; 20-Diethylene Glycol ketal (IV), wherein: 17 Alpha-hydroxies-4-pregnene-11-ketone-3,20-Diethylene Glycol ketal: THF: methyl alcohol: the amount ratio of hydroborate is 1:10～15:1～2:0.3～0.5 (w/v/v/w);
(3) hydrolysis reaction:
With 11 β, 17 alpha-dihydroxy-s-4-pregnene-3,20-Diethylene Glycol ketal (IV) adds in haloalkane and the methyl alcohol, adds mineral acid again; More than 3 hours, reaction finishes in 10～20 ℃ of stirring reactions, adds the ammoniacal liquor neutralization, and concentrating under reduced pressure reclaims solvent; Be concentrated into no haloalkane, add the water elutriation, filter, use water washing; Drying gets 11 β, 17 alpha-dihydroxy-s-4-pregnene-3,20-diketone (V); Wherein: 11 β, 17 alpha-dihydroxy-s-4-pregnene-3,20-Diethylene Glycol ketal: haloalkane: methyl alcohol: the amount ratio of mineral acid is 1:4～7:4～7:0.2～0.5 (w/v/v/v);
(4) go up Iod R:
With 1/3 amount calcium chloride-methanol solution, compound 11 β, 17 alpha-dihydroxy-s-4-pregnene-3,20-diketone (V) add in the trichloromethane; Stirring and dissolving; Add quicklime again, temperature adjustment to 0～5 ℃ drip iodo-calcium chloride-methanol solution that iodine is dissolved in 2/3 amount calcium chloride-methanol solution preparation; Add, react more than 2 hours in 0～5 ℃; Reaction finishes, and adds the chlorination aqueous ammonium, filters, and water layer extracts with trichlorine four alkane; Merge, concentrating under reduced pressure reclaims solvent, is concentrated into dried; Get 21-iodo-11 β, 17 alpha-dihydroxy-s-4-pregnene-3,20-diketone (VI); Wherein: 11 β, 17 alpha-dihydroxy-s-4-pregnene-3,20-diketone: trichloromethane: calcium chloride: methyl alcohol: quicklime: iodine: the amount ratio of ammonium chloride is 1:5～10:0.3～0.5:3～5:0.6～0.8:0.9～1.0:1～1.2 (w/v/w/v/ w/w/w);
(5) replacement(metathesis)reaction:
With 21-iodo-11 β, 17 alpha-dihydroxy-s-4-pregnene-3,20-diketone (VI) add in the acetone, add Potassium ethanoate, acetic acid; Temperature adjustment to back flow reaction is more than 3 hours, and reaction finishes, and concentrating under reduced pressure reclaims solvent, adds the water elutriation; Filter, use water washing, drying gets HYDROCORTONE ACETATE (VII); Wherein: 21-iodo-11 β, 17 alpha-dihydroxy-s-4-pregnene-3,20-diketone: acetone: Potassium ethanoate: the amount ratio of acetic acid is 1.4:8～12:0.8～1.2:0.1～0.2 (w/v/w/v);
(6) hydrolysis reaction:
HYDROCORTONE ACETATE (VII) is added in the methyl alcohol, add the methanol solution of 2% sodium hydroxide, in 0～8 ℃ of stirring reaction more than 4 hours; Reaction finishes, and adds the acetic acid neutralization, and concentrating under reduced pressure reclaims solvent; Methanol crystallization is filtered, and uses methanol wash; Drying gets HYDROCORTISONE INJECTIONS (I), and wherein: HYDROCORTONE ACETATE: methyl alcohol: sodium hydroxide: the amount ratio of acetic acid is 1:18～25:0.04～0.06:0.06～0.09 (w/v/w/v).
Preparing method of the present invention is with the midbody 17 Alpha-hydroxies-4-pregnene-3 of bread mould method; 11,20-triketone (II) is a raw material, spent glycol, triethyl orthoformate, tosic acid ketal reaction; Obtain 17 Alpha-hydroxies-4-pregnene-11-ketone-3,20-Diethylene Glycol ketal (III); With the borohydride reduction reaction, obtain 11 β, 17 alpha-dihydroxy-s-4-pregnene-3,20-Diethylene Glycol ketal (IV); With the mineral acid hydrolysis reaction, obtain 11 β, 17 alpha-dihydroxy-s-4-pregnene-3,20-diketone (V); With Iod R on iodine, the quicklime, obtain 21-iodo-11 β, 17 alpha-dihydroxy-s-4-pregnene-3,20-diketone (VI); With Potassium ethanoate, acetic acid replacement(metathesis)reaction, obtain HYDROCORTONE ACETATE (VII); At last with sodium hydroxide hydrolysis react HYDROCORTISONE INJECTIONS (I).Reaction formula is following:
Reaction formula 6:
Last Iod R among the present invention mainly is that iodine replaces the reaction for Wasserstoffatoms on the C21 position, and the primary product of this reaction is single iodine substituent, and it is two iodine things that small portion is also arranged, but two iodine thing can not have influence on next step replacement(metathesis)reaction.
As preferred version, according to the preparation method of a kind of HYDROCORTISONE INJECTIONS of the present invention, wherein, the hydroborate in the described step (2) is Peng Qinghuana or POTASSIUM BOROHYDRIDE 97MIN.
As preferred version, according to the preparation method of a kind of HYDROCORTISONE INJECTIONS of the present invention, wherein, the haloalkane in the described step (3) is methylene dichloride or trichloromethane.
As preferred version, according to the preparation method of a kind of HYDROCORTISONE INJECTIONS of the present invention, wherein, the mineral acid in the described step (3) is hydrochloric acid or sulfuric acid.
As preferred version, according to the preparation method of a kind of HYDROCORTISONE INJECTIONS of the present invention, wherein, calcium chloride-methanol solution is pressed calcium chloride in the described step (4): methyl alcohol=1:10 (w/v) preparation.
Compared with prior art, the present invention has following advantage:
The preparation method of HYDROCORTISONE INJECTIONS of the present invention (I) is a new synthesis route; Raw material is easy to get, and auxiliary material is common, does not need some uses of poison, severe toxicity, carcinogenic reagent of original technology; And this method is more effective than original technology, and the quality of product and yield are all better.Also avoided receiving the restriction of environmental protection and in preparation, produced gathering the refuse that contains heavy metal in a large number, need not only to spend but also require great effort for removing these refuses again.
Environmental protection of the present invention is and effective, and the quality of product and yield are all better, and HPLC content reaches more than 98.5%, and yield reaches more than 77%.
Embodiment
Below in conjunction with embodiment, content of the present invention is described more specifically.Should be appreciated that enforcement of the present invention is not limited to following embodiment, all will fall into protection domain of the present invention any pro forma accommodation and/or the change that the present invention made.
In the present invention, if not refer in particular to, all part, per-cents are weight unit, and all equipment and raw material etc. all can be buied from market or the industry is commonly used.Do not specialize if having, the method that embodiment adopts is this area current techique.
Embodiment 1
A kind of preparation method of HYDROCORTISONE INJECTIONS comprises the steps:
(1) ketal reaction: prepare 17 Alpha-hydroxies-4-pregnene-11-ketone-3,20-Diethylene Glycol ketal (III)
In reaction flask, drop into 17 Alpha-hydroxies-4-pregnene-3,11,20-triketone (II) 50g, terepthaloyl moietie 150ml and triethyl orthoformate 150ml stirred, and add tosic acid 2.5g, in 30～35 ℃ of stirring reactions 8 hours; Reaction finishes, and adds water 1500ml elutriation, filters, and is washed with water to neutrality, drains, and drying obtains 17 Alpha-hydroxies-4-pregnene-11-ketone-3,20-Diethylene Glycol ketal (III) 60.8g.MP:228～233 ℃, [α]
D 20=-12.2 ° (10mg/ml trichloromethane).
(2) reduction reaction: prepare 11 β, 17 alpha-dihydroxy-s-4-pregnene-3,20-Diethylene Glycol ketal (IV)
In reaction flask, drop into 17 Alpha-hydroxies-4-pregnene-11-ketone-3,20-Diethylene Glycol ketal (III) 50g, THF 500ml, methyl alcohol 50ml stir, and slowly add Peng Qinghuana 15g, back flow reaction 48 hours; Concentrating under reduced pressure reclaims solvent, adds water 1500ml elutriation, filters, and is washed with water to neutrality, drains, and drying obtains 11 β, 17 alpha-dihydroxy-s-4-pregnene-3,20-Diethylene Glycol ketal (IV) 49.6g.MP:220～226 ℃, [α]
D 20=-39.9 ° (10mg/ml trichloromethane).
(3) hydrolysis reaction: prepare 11 β, 17 alpha-dihydroxy-s-4-pregnene-3,20-diketone (V)
In reaction flask, drop into 11 β, 17 alpha-dihydroxy-s-4-pregnene-3,20-Diethylene Glycol ketal (IV) 50g, methylene dichloride 200ml and methyl alcohol 200ml added hydrochloric acid 10ml, in 10～20 ℃ of stirring reactions 3 hours.Reaction finishes, and adds the ammoniacal liquor neutralization, and concentrating under reduced pressure reclaims solvent, is concentrated into no methylene dichloride, adds water 1500ml elutriation, filters, and washing is drained, and drying gets 11 β, 17 alpha-dihydroxy-s-4-pregnene-3,20-diketone (V) 38.4g.MP:215～218 ℃, [α]
D 20=+153.8 ° (10mg/ml absolute ethyl alcohol).
(4) go up Iod R: preparation 21-iodo-11 β, 17 alpha-dihydroxy-s-4-pregnene-3,20-diketone (VI)
Calcium chloride 6g is dissolved in the 60ml methyl alcohol, gets its 2/3 amount, in all the other 1/3 input reaction flasks in order to dissolving iodine 18g; Drop into 11 β, 17 alpha-dihydroxy-s-4-pregnene-3,20-diketone (V) 20g, trichloromethane 100ml; Stirring and dissolving adds quicklime 12g again, temperature adjustment to 0～5 ℃; Drip iodo-calcium chloride-methanol solution, add, in 0～5 ℃ of reaction 2 hours; Reaction finishes, and adds 20% aqueous ammonium chloride solution 100ml, filters, and water layer extracts with trichlorine four alkane, merges, and concentrating under reduced pressure reclaims solvent, is concentrated into driedly, gets 21-iodo-11 β, 17 alpha-dihydroxy-s-4-pregnene-3,20-diketone (VI) 28g.
(5) replacement(metathesis)reaction: preparation HYDROCORTONE ACETATE (VII)
In reaction flask, drop into 21-iodo-11 β, 17 alpha-dihydroxy-s-4-pregnene-3,20-diketone (VI) 28g, acetone 160ml add Potassium ethanoate 16g, acetic acid 2ml, temperature adjustment to back flow reaction 3 hours; Reaction finishes, and concentrating under reduced pressure reclaims solvent, adds water 600ml elutriation, filters, and washing is drained, and drying gets HYDROCORTONE ACETATE (VII) 21.9g.MP:211～214 ℃, [α]
D 20=+160.8 ° (10mg/ml dioxane).
(6) hydrolysis reaction: preparation HYDROCORTISONE INJECTIONS (I)
In reaction flask, drop among HYDROCORTONE ACETATE (VII) 20g, the methyl alcohol 360ml, drip the methanol solution 40ml of 2% sodium hydroxide, in 0～8 ℃ of stirring reaction 4 hours.Reaction finishes, and adds acetic acid 1.2ml neutralization, and concentrating under reduced pressure reclaims solvent, and methanol crystallization is chilled to 0～5 ℃, filters, and washing is drained, and drying gets HYDROCORTISONE INJECTIONS (I) 15.3g.
Through detecting, MP:215～219 of the HYDROCORTISONE INJECTIONS of present embodiment preparation ℃, [α]
D 20(specific rotatory power)=+ 164.5 ° (10mg/ml absolute ethyl alcohol), HPLC content: 98.6%, yield is 77.6%.
Embodiment 2
Other operations are with embodiment 1, and difference is:
(2) reduction reaction: prepare 11 β, 17 alpha-dihydroxy-s-4-pregnene-3,20-Diethylene Glycol ketal (IV)
In reaction flask, drop into 17 Alpha-hydroxies-4-pregnene-11-ketone-3,20-Diethylene Glycol ketal (III) 50g, THF 500ml, methyl alcohol 50ml stir, and slowly add POTASSIUM BOROHYDRIDE 97MIN 25g, back flow reaction 48 hours; Concentrating under reduced pressure reclaims solvent, adds water 1500ml elutriation, filters, and is washed with water to neutrality, drains, and drying obtains 11 β, 17 alpha-dihydroxy-s-4-pregnene-3,20-Diethylene Glycol ketal (IV) 49.5g.MP:219～225 ℃, [α]
D 20=-39.0 ° (10mg/ml trichloromethane).
Through detecting, MP:215.5～219 of the HYDROCORTISONE INJECTIONS of present embodiment preparation ℃, [α]
D 20(specific rotatory power)=+ 165.8 ° (10mg/ml absolute ethyl alcohol), HPLC content: 98.7%, yield is 77.1%.
Embodiment 3
Other operations are with embodiment 1, and difference is:
(3) hydrolysis reaction: prepare 11 β, 17 alpha-dihydroxy-s-4-pregnene-3,20-diketone (V)
In reaction flask, drop into 11 β, 17 alpha-dihydroxy-s-4-pregnene-3,20-Diethylene Glycol ketal (IV) 50g, trichloromethane 200ml and methyl alcohol 200ml added 50% sulfuric acid 10ml, in 10～20 ℃ of stirring reactions 3 hours.Reaction finishes, and adds ammoniacal liquor neutralization, and concentrating under reduced pressure reclaims solvent, concentrates as for band methylene dichloride to the greatest extent, adds water 1500ml elutriation, filters, and washing is drained, drying, 11 β, 17 alpha-dihydroxy-s-4-pregnene-3,20-diketone (V) 38.2g.MP:214～217.5 ℃, [α]
D 20=+152.6 ° (10mg/ml absolute ethyl alcohol).
Through detecting, MP:215～219 of the HYDROCORTISONE INJECTIONS of present embodiment preparation ℃, [α]
D 20(specific rotatory power)=+ 164.1 ° (10mg/ml absolute ethyl alcohol), HPLC content: 98.5%, yield is 77.8%.
Experimental study shows; Main technologic parameters of the present invention is controlled in the scope of summary of the invention announcement: in step (1): 17 Alpha-hydroxies-4-pregnene-3; 11,20-triketone: terepthaloyl moietie: triethyl orthoformate: the amount ratio of tosic acid is 1:3～5:3～5:0.05～0.1 (w/v/v/w); 17 Alpha-hydroxies in the step (2)-4-pregnene-11-ketone-3,20-Diethylene Glycol ketal: THF: methyl alcohol: the amount ratio of hydroborate is 1:10～15:1～2:0.3～0.5 (w/v/v/w); In the step (3): 11 β, 17 alpha-dihydroxy-s-4-pregnene-3,20-Diethylene Glycol ketal: haloalkane: methyl alcohol: the amount ratio of mineral acid is 1:4～7:4～7:0.2～0.5 (w/v/v/v); In the step (4): 11 β; 17 alpha-dihydroxy-s-4-pregnene-3,20-diketone: trichloromethane: calcium chloride: methyl alcohol: quicklime: iodine: the amount ratio of ammonium chloride is 1:5～10:0.3～0.5:3～5:0.6～0.8:0.9～1.0:1～1.2 (w/v/w/v/w/w/w); In the step (5): 21-iodo-11 β, 17 alpha-dihydroxy-s-4-pregnene-3,20-diketone: acetone: Potassium ethanoate: the amount ratio of acetic acid is 1.4:8～12:0.8～1.2:0.1～0.2 (w/v/w/v); In the step (6): HYDROCORTONE ACETATE: methyl alcohol: sodium hydroxide: the amount ratio of acetic acid is 1:18～25:0.04～0.06:0.06～0.09 (w/v/w/v).The HYDROCORTISONE INJECTIONS product that can both obtain conforming to quality requirements, the contriver gives unnecessary details at this no longer one by one.
Although the contriver has done comparatively detailed elaboration to technical scheme of the present invention and has enumerated; Be to be understood that; For the those skilled in the art in this area, be obvious to the replacement scheme that the foregoing description modifies, flexible perhaps employing is equal to, all can not break away from the essence of spirit of the present invention; The term that occurs among the present invention is used for can not being construed as limiting the invention the elaboration of technical scheme of the present invention and understanding.
Claims (5)
1. the preparation method of a HYDROCORTISONE INJECTIONS is characterized in that, described preparation method comprises the steps:
(1) ketal reaction:
With 17 Alpha-hydroxies-4-pregnene-3,11,20-triketone (II) adds in terepthaloyl moietie and the triethyl orthoformate; Add tosic acid again, more than 8 hours, reaction finishes in 30～35 ℃ of stirring reactions; Add the water elutriation, filter, be washed with water to neutrality; Drying gets 17 Alpha-hydroxies-4-pregnene-11-ketone-3,20-Diethylene Glycol ketal (III); Wherein: 17 Alpha-hydroxies-4-pregnene-3,11,20-triketone: terepthaloyl moietie: triethyl orthoformate: the amount ratio of tosic acid is 1:3～5:3～5:0.05～0.1 (w/v/v/w);
(2) reduction reaction:
With 17 Alpha-hydroxies-4-pregnene-11-ketone-3,20-Diethylene Glycol ketal (III) adds in THF and the methyl alcohol, stirs; Add hydroborate, reflux more than 48 hours, concentrating under reduced pressure reclaims solvent; Add the water elutriation, filter, be washed with water to neutrality; Drying gets 11 β, 17 alpha-dihydroxy-s-4-pregnene-3; 20-Diethylene Glycol ketal (IV), wherein: 17 Alpha-hydroxies-4-pregnene-11-ketone-3,20-Diethylene Glycol ketal: THF: methyl alcohol: the amount ratio of hydroborate is 1:10～15:1～2:0.3～0.5 (w/v/v/w);
(3) hydrolysis reaction:
With 11 β, 17 alpha-dihydroxy-s-4-pregnene-3,20-Diethylene Glycol ketal (IV) adds in haloalkane and the methyl alcohol, adds mineral acid again; More than 3 hours, reaction finishes in 10～20 ℃ of stirring reactions, adds the ammoniacal liquor neutralization, and concentrating under reduced pressure reclaims solvent; Be concentrated into no haloalkane, add the water elutriation, filter, use water washing; Drying gets 11 β, 17 alpha-dihydroxy-s-4-pregnene-3,20-diketone (V); Wherein: 11 β, 17 alpha-dihydroxy-s-4-pregnene-3,20-Diethylene Glycol ketal: haloalkane: methyl alcohol: the amount ratio of mineral acid is 1:4～7:4～7:0.2～0.5 (w/v/v/v);
(4) go up Iod R:
With 1/3 amount calcium chloride-methanol solution, compound 11 β, 17 alpha-dihydroxy-s-4-pregnene-3,20-diketone (V) add in the trichloromethane; Stirring and dissolving; Add quicklime again, temperature adjustment to 0～5 ℃ drip iodo-calcium chloride-methanol solution that iodine is dissolved in 2/3 amount calcium chloride-methanol solution preparation; Add, react more than 2 hours in 0～5 ℃; Reaction finishes, and adds the chlorination aqueous ammonium, filters, and water layer extracts with trichlorine four alkane; Merge, concentrating under reduced pressure reclaims solvent, is concentrated into dried; Get 21-iodo-11 β, 17 alpha-dihydroxy-s-4-pregnene-3,20-diketone (VI); Wherein: 11 β, 17 alpha-dihydroxy-s-4-pregnene-3,20-diketone: trichloromethane: calcium chloride: methyl alcohol: quicklime: iodine: the amount ratio of ammonium chloride is 1:5～10:0.3～0.5:3～5:0.6～0.8:0.9～1.0:1～1.2 (w/v/w/v/ w/w/w);
(5) replacement(metathesis)reaction:
With 21-iodo-11 β, 17 alpha-dihydroxy-s-4-pregnene-3,20-diketone (VI) add in the acetone, add Potassium ethanoate, acetic acid; Temperature adjustment to back flow reaction is more than 3 hours, and reaction finishes, and concentrating under reduced pressure reclaims solvent, adds the water elutriation; Filter, use water washing, drying gets HYDROCORTONE ACETATE (VII); Wherein: 21-iodo-11 β, 17 alpha-dihydroxy-s-4-pregnene-3,20-diketone: acetone: Potassium ethanoate: the amount ratio of acetic acid is 1.4:8～12:0.8～1.2:0.1～0.2 (w/v/w/v);
(6) hydrolysis reaction:
HYDROCORTONE ACETATE (VII) is added in the methyl alcohol, add the methanol solution of 2% sodium hydroxide, in 0～8 ℃ of stirring reaction more than 4 hours; Reaction finishes, and adds the acetic acid neutralization, and concentrating under reduced pressure reclaims solvent; Methanol crystallization is filtered, and uses methanol wash; Drying gets HYDROCORTISONE INJECTIONS (I), and wherein: HYDROCORTONE ACETATE: methyl alcohol: sodium hydroxide: the amount ratio of acetic acid is 1:18～25:0.04～0.06:0.06～0.09 (w/v/w/v).
2. the preparation method of a kind of HYDROCORTISONE INJECTIONS as claimed in claim 1 is characterized in that, the hydroborate in the described step (2) is Peng Qinghuana or POTASSIUM BOROHYDRIDE 97MIN.
3. the preparation method of a kind of HYDROCORTISONE INJECTIONS as claimed in claim 1 is characterized in that, the haloalkane in the described step (3) is methylene dichloride or trichloromethane.
4. the preparation method of a kind of HYDROCORTISONE INJECTIONS as claimed in claim 1 is characterized in that, the mineral acid in the described step (3) is hydrochloric acid or sulfuric acid.
5. the preparation method of a kind of HYDROCORTISONE INJECTIONS as claimed in claim 1 is characterized in that, calcium chloride-methanol solution is pressed calcium chloride in the described step (4): methyl alcohol=1:10 (w/v) preparation.
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| CN102827230A (en) * | 2012-09-25 | 2012-12-19 | 河南利华制药有限公司 | Preparation method of hydrocortisone acetate |
| CN102942613A (en) * | 2012-09-21 | 2013-02-27 | 天津狄克特科技有限公司 | Method for preparing anti-inflammatory and anti-allergic drug deflazacort |
| CN103304615A (en) * | 2013-07-10 | 2013-09-18 | 赵云现 | Preparation method of cortisone |
| CN103641877A (en) * | 2013-11-22 | 2014-03-19 | 湖南新合新生物医药有限公司 | Preparation method for hydrocortisone intermediate |
| CN104356187A (en) * | 2014-10-23 | 2015-02-18 | 华中药业股份有限公司 | Method for recycling hydrocortisone in hydrocortisone butyrate mother liquor |
| CN104892712A (en) * | 2015-05-27 | 2015-09-09 | 浙江仙琚制药股份有限公司 | Preparation method of 3beta,21-dihydroxy-16alpha-methylpregna-5-ene-20-one-21-acetate |
| CN110642911A (en) * | 2019-10-18 | 2020-01-03 | 海南顿斯医药科技有限公司 | 1/10 water hydrocortisone compound |
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| CN102942613A (en) * | 2012-09-21 | 2013-02-27 | 天津狄克特科技有限公司 | Method for preparing anti-inflammatory and anti-allergic drug deflazacort |
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| CN103641877B (en) * | 2013-11-22 | 2016-02-10 | 湖南新合新生物医药有限公司 | The preparation method of hydrocortisone intermediate |
| CN104356187A (en) * | 2014-10-23 | 2015-02-18 | 华中药业股份有限公司 | Method for recycling hydrocortisone in hydrocortisone butyrate mother liquor |
| CN104892712A (en) * | 2015-05-27 | 2015-09-09 | 浙江仙琚制药股份有限公司 | Preparation method of 3beta,21-dihydroxy-16alpha-methylpregna-5-ene-20-one-21-acetate |
| CN110642911A (en) * | 2019-10-18 | 2020-01-03 | 海南顿斯医药科技有限公司 | 1/10 water hydrocortisone compound |
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