CN1061984C - Introduction method of 9-11 double bond into steroid hormone compound - Google Patents
Introduction method of 9-11 double bond into steroid hormone compound Download PDFInfo
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- CN1061984C CN1061984C CN96116326A CN96116326A CN1061984C CN 1061984 C CN1061984 C CN 1061984C CN 96116326 A CN96116326 A CN 96116326A CN 96116326 A CN96116326 A CN 96116326A CN 1061984 C CN1061984 C CN 1061984C
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Abstract
The present invention provides a method for introducing 9-11 double bonds to steroid hormone compounds, which uses delta <1, 4>-3 of which the general formula is II and a 20-diketone-11, 17, 21-trihydroxy pregnane compound 2 as raw materials; the raw materials, the mixture of phosphorous halides, phosphorus oxychloride, sulfuryl chloride and imidazole or the mixture of triphenylphosphine and carbon tetrachloride, etc. carry out elimination reaction to prepare corresponding delta <1, 4, 9 (11)> compound 3, or the compound 2 is made into 11 beta-chlorine pregna compound 3A of which the general formula is III, and the compound 3A carries out elimination reaction in a polar solvent to prepare the compound 3. The method has the advantages of position specificity and high yield of 9-11 double bond sterides and has significant significance for the preparation technology of steroid hormones.
Description
The invention relates to a kind of method of introducing the two keys of 9-11 in the steroid hormone compound, belong to the technical field of chemical substance preparation.
The steroid hormone compound is the medicine that a class is widely used clinically, and wherein halo steroid hormone curative effect is powerful, has critical role as glucocorticosteroid.Dexamethasone, Betamethasone Valerate etc. are exactly the halogenated steroid hormone of a class 11-hydroxyl 9-, and the introducing of their 9,11 functional groups mainly is to finish by the intermediate with the two keys of 9-11.Among the steroid hormone preparation technology, the introducing of the two keys of 9-11 is a kind of basic, important techniques.For example: more common method is that the 11-hydroxy steroid is made the 11-methanesulfonates, obtains the two keys of 9-11 again through eliminating reaction.But the shortcoming of this method is the position specific that 11 Alpha-hydroxy steroidals is lacked reaction, when generating the two key steroidals of 9-11, and the two key steroidal products of the 11-12 of the 10-15% that also has an appointment; And the separation of these two kinds of isomer is also relatively more difficult, generally can only separate on a small scale, and expense is also higher.So, study a kind of have position specific, be the method that raw material is produced the two key steroidals of 9-11 with the 11-hydroxy steroid, steroid hormone preparation technology is had important meaning.
The invention provides a kind of is the method that raw material is produced the two key steroidals of 9-11 with the 11-hydroxy steroid.By method provided by the invention, reaction has position specific, can reduce the generation of the two key by products of 11-12, has overcome that existing method yield is low, the shortcoming of the two key separation of by-products difficulties of 11-12.
It below is detailed description to the inventive method.
(1): the present invention is the Δ of (I) with general formula
1,4-3,20-diketone-11,17,21-trihydroxy-pregnane compound 1 is a starting raw material, and the 21-hydroxy esterification is protected, and makes the compound 2 of general formula for (II):
The R here
1Expression hydrogen, R
2Expression methyl or R
1Expression methyl, R
2Expression hydrogen; R
3Expression-COOR
4Perhaps-SO
2R
5R wherein
4The expression carbonatoms is the alkyl of 1-6, for example, and R
4Can be in methyl, ethyl, propyl group, butyl or the isobutyl-any one; R
5The expression carbonatoms is the phenyl that the alkyl of 1-4 or methyl, ethyl replace.
Esterification is carried out under the alkali existence condition, and used alkali can be that triethylamine, pyridine, N-ethyl are sent pyridine, N, any one in the tertiary amines such as N-dimethyl aminopyridine;
Reaction medium is lower alcohols such as methyl alcohol, ethanol, low-grade carboxylic acids such as acetate, ester classes such as ethyl acetate, any one in the organic solvents such as benzene, low alkyl group benzene, methylene dichloride, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO);
Be reflected under the anhydrous condition and carry out, used esterifying agent can be the chloro-formic ester shown in right formula, that is: ClCOOR
4, R wherein
4The group of expression is (R as mentioned above
3Expression-COOR
4); Used esterifying agent also can be the chlorsulfonic acid ester shown in right formula, that is: ClSO
2R
5, R wherein
5The group of expression is (R as mentioned above
3Expression-SO
2R
5);
Temperature of reaction can be subzero 20-60 ℃, and 0-40 ℃ better, preferably 10-30 ℃.
In the reagent such as mixture of (two A): compound 2A (11 Alpha-hydroxy) and phosphorus pentachloride, phosphorus trichloride or triphenyl phosphorus and tetracol phenixin any one carries out chlorination reaction, makes the Δ of general formula for (III)
1,4-3,20-diketone-17,21-dihydroxyl-11 β-chloro pregnane compound 3A:
When being chlorizating agent with the phosphorus pentachloride, reaction should be carried out under the alkali existence condition, and used alkali can be that triethylamine, pyridine, N-ethyl are sent pyridine, N, any one in the tertiary amines such as N-dimethyl aminopyridine;
Reaction medium is suitable organic solvents such as methylene dichloride, ethylene dichloride, tetrahydrofuran (THF);
The temperature of reaction be 20-100 ℃ better.
For example: used chlorizating agent is a phosphorus pentachloride when producing compound 3A as stated above, and used alkali is pyridine, and reaction medium is methylene dichloride or ethylene dichloride, and the temperature of reaction is a room temperature, and the reaction times is 30-60 minute.
Perhaps, used chlorizating agent is a phosphorus trichloride when producing compound 3A as stated above, and reaction medium is a tetrahydrofuran (THF), and the reaction times is 4-5 hour.
Perhaps, when producing compound 3A as stated above compound 2, tetrahydrofuran (THF) and tetracol phenixin are mixed, add triphenyl phosphorus, stir about 1 hour; 70 ℃ of temperature of reaction are better.
Compound 3A eliminates reaction in any one in the mixture isopolarity solvent of mixture, water and the dioxane of dimethyl sulfoxide (DMSO), dimethyl formamide, water and first cyanogen again, makes the Δ of general formula for (IV)
1,4,9 (11)-3,20-diketone-17,21-dimonohydric pregnant compound 3:
The temperature of eliminating reaction is 20-150 ℃, and 50-120 ℃ better, preferably 80-110 ℃.The R here
1, R
2, R
3, R
4, R
5The group of expression as mentioned above.
For example: compound 3A in 90-100 ℃, stirs insulation 15-20 hour in the dimethyl sulfoxide (DMSO) polar solvent, make compound 3.
Perhaps: compound 3A in 100 ℃, stirs insulation 4-6 hour in the dimethyl formamide polar solvent, make compound 3.
Perhaps: compound 3A is heated to backflow in the mixture polar solvent of Shui Hejia cyanogen, stirs 8-10 hour, makes compound 3.
Perhaps: compound 3A is heated to about 100 ℃ in the mixture polar solvent of water and dioxane, stirs insulation 4-6 hour, makes compound 3.
(two B): compound 2 and phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride, SULPHURYL CHLORIDE (SO
2Cl
2) with the reagent such as mixture of the mixture of imidazoles or triphenyl phosphorus and tetracol phenixin in any one eliminate reaction, directly make the Δ that general formula is (IV)
1,4,9 (11)-3,20-diketone-17,21-dimonohydric pregnant compound 3:
The R here
1, R
2, R
3, R
4, R
5The group of expression as mentioned above.
The medium of eliminating reaction is any one in the suitable organic solvent such as methylene dichloride, ethylene dichloride, tetrahydrofuran (THF), first cyanogen;
For example: when the reagent of elimination reaction was phosphorus pentachloride, reaction medium was suitable organic solvents such as tetrahydrofuran (THF) or methylene dichloride; Reaction should be carried out at low temperatures, for example carry out at subzero 100-0 ℃, subzero 90-subzero 40 ℃ better, subzero 60 ℃ of preferably subzero 90-;
When the reagent of elimination reaction was phosphorus trichloride, temperature of reaction is subzero 80-50 ℃ carried out, and subzero 40-30 ℃ better, preferably subzero 20-25 ℃; Reaction medium is suitable organic solvents such as tetrahydrofuran (THF) or methylene dichloride;
When the reagent of elimination reaction was the mixture of triphenyl phosphorus and tetracol phenixin, temperature of reaction was 0-100 ℃, preferably 20-80 ℃; Reaction medium is suitable organic solvents such as first cyanogen;
The reagent of eliminating reaction is SULPHURYL CHLORIDE (SO
2Cl
2) during with the mixture of imidazoles, temperature of reaction is subzero 100-0 ℃, subzero 80-subzero 10 ℃ better, subzero 20 ℃ of preferably subzero 78-; Reaction medium is suitable organic solvents such as tetrahydrofuran (THF), methylene dichloride or ethylene dichloride;
When the reagent of elimination reaction is phosphorus oxychloride, is reflected under the pyridine existence and carries out, temperature of reaction is subzero 40-100 ℃, and subzero 20-80 ℃ better, preferably subzero 5-60 ℃; Reaction medium is suitable organic solvents such as tetrahydrofuran (THF), methylene dichloride, ethylene dichloride or first cyanogen.
For example: compound 2 is eliminated reaction with phosphorus pentachloride, and reaction medium is a tetrahydrofuran (THF), subzero 80 ℃ in subzero 90-, slowly adds phosphorus pentachloride, and keeps subzero 90-and continue to stir 60-90 minute for subzero 80 ℃; Slowly be warmed up to 10-20 ℃, add entry, continued insulated and stirred 30 minutes; Acidity with alkali aqueous solution conditioned reaction liquid is about 7.5 to pH value; Make compound 3.Here used tetrahydrofuran (THF) can be used any one replacement in the suitable organic solvent such as methylene dichloride, ethylene dichloride, first cyanogen.11 of the compound 2 here also can be 11 beta-hydroxies.
Perhaps: compound 2 is eliminated reaction with phosphorus pentachloride, and reaction medium is a tetrahydrofuran (THF), subzero 70 ℃ in subzero 80-, slowly adds the phosphorus pentachloride of half amount, about 1 hour of insulated and stirred; Slowly add second half phosphorus pentachloride again, about 1 hour of insulated and stirred; Stirred 1 hour in subzero 60 ℃; Stirred 3 hours in subzero 50 ℃; Slowly be warmed up to 10-20 ℃, add entry, continued insulated and stirred 30 minutes; Acidity with alkali aqueous solution conditioned reaction liquid is about 7.5 to pH value; Make compound 3.Here used tetrahydrofuran (THF) can be used any one replacement in the suitable organic solvent such as methylene dichloride, ethylene dichloride, first cyanogen.11 of the compound 2 here also can be 11 beta-hydroxies.
Perhaps: compound 2 mixes with methylene dichloride, pyridine, stirs; In subzero 10-subzero 5 ℃, drip phosphorus oxychloride, in stirring at room 24 hours; Add pyridine, in 60 ℃ of left and right sides insulated and stirred 20 hours; Processing can obtain compound 3.Here used methylene dichloride can be used any one replacement in the suitable organic solvent such as tetrahydrofuran (THF), ethylene dichloride, first cyanogen.
Perhaps: compound 2 mixes with tetrahydrofuran (THF), stirs; In subzero 80-subzero 70 ℃, add SULPHURYL CHLORIDE, stirring; Add imidazoles, stir; Processing can obtain compound 3.Here used tetrahydrofuran (THF) can be used any one replacement in the suitable organic solvent such as methylene dichloride, ethylene dichloride, first cyanogen.
Perhaps: compound 2 mixes with triphenyl phosphorus, tetracol phenixin and first cyanogen; In stirring at room 3 hours; Reacting by heating liquid, backflow is spent the night; Reaction solution is handled can obtain compound 3.The terminal point of reaction can be monitored with HPLC; As starting raw material not fully or come major part to convert three ene products to, but the proper extension reaction times.
(3) directly eliminate reaction by (two B) described method, when making general formula, can produce a spot of Δ for the compound 3 of (IV)
1,4,11 (12)The isomer by product, but its content generally can not surpass 2%; In addition, also can produce a spot of Δ 1,4-3,20-diketone-17,21-dihydroxyl 11 β-chloro pregnane compound 3A.That is: any one in the mixture of compound 2 and phosphorus pentachloride, phosphorus trichloride or triphenyl phosphorus and tetracol phenixin carries out chlorination reaction, makes the Δ of general formula for (III)
1,4-3,20-diketone-17,21-dihydroxyl-11 β-chloro pregnane compound 3A:
When being chlorizating agent with the phosphorus pentachloride, reaction should be carried out under the alkali existence condition, and used alkali can be that triethylamine, pyridine, N-ethyl are sent pyridine, N, any one in the N-dimethyl aminopyridine;
Reaction medium is methylene dichloride, ethylene dichloride or tetrahydrofuran (THF);
The temperature of reaction is 20-100 ℃.
As required, compound 3A can be separated, in polar solvent, eliminate reaction, make the Δ of general formula for (IV) by (two A) described method
1,4,9 (11)-3,20-diketone-17,21-dimonohydric pregnant compound 3.That is: compound 3A eliminates reaction in any one in the mixture of mixture, water and the dioxane of dimethyl sulfoxide (DMSO), dimethyl formamide, water and first cyanogen again, makes compound 3:
The temperature of eliminating reaction is 20-150 ℃, and 50-120 ℃ better, preferably 80-110 ℃.11 of the compound 2 here is 11 Alpha-hydroxies; The R here
1, R
2, R
3, R
4, R
5The group of expression as mentioned above.
For example: will be dissolved in methylene dichloride by the product that (two B) described method makes, and use 6N aqueous hydrochloric acid, 1N aqueous hydrochloric acid, water, salt water washing organic layer successively; Behind the concentrating under reduced pressure, products therefrom is carried out chromatographic separation, just can obtain compound 3A; In polar solvent, eliminate reaction, make compound 3.
React by the elimination that method of the present invention, introduce the two keys of 9-11 in the steroid hormone compound is carried out, compare with the prior art of the 11-hydroxy steroid being made the 11-methanesulfonates, obtain the two keys of 9-11 through eliminating reaction again, has higher position specific, prepared Δ
1,4,9 (11)The product purity height, Δ
1,4,9 (12)It is about 2% that the isomer by-products content generally is no more than, thereby improved Δ greatly
1,4,9 (11)The quality of product and yield.Used 11-hydroxy steroid raw material can be 11 Alpha-hydroxy steroidals, also can be 11 beta-hydroxy steroidals.
Following embodiment can further specify method of the present invention, but and the purposes of unrestricted the inventive method.
Embodiment 1,
30 gram 16 Beta-methyls-Δs
1,4-3,20 diketone-11 α, 17 α, the pregnant steroid of 21-trihydroxy-(about 0.08 mole) under anhydrous condition, is put into 120 milliliters of methylene dichloride and 45 milliliters of triethylamines in the reactor, stirs, and is cooled to subzero 10 ℃ of subzero 20-; The mixture that slowly adds 10 milliliters of Vinyl chloroformates and 15 milliliters of methylene dichloride added in about 1 hour, and kept subzero 20-and continue to stir half an hour for subzero 10 ℃; Slowly be warmed up to room temperature, restir 2-4 hour; Add 60 milliliters of tetrahydrofuran (THF)s in the reactor, 120 ml waters stir, and the acidity with concentrated hydrochloric acid conditioned reaction liquid equals 2 to pH value; Static, layering, with the washed with dichloromethane water layer for several times; Merge organic layer and washed with dichloromethane liquid, concentrating under reduced pressure is about 60 milliliters to remaining volume; Cooling can obtain 16 Beta-methyls-Δ
1,4-3,20-diketone-11 α, 17 α, 21 ethyl (alkoxymethyl)-2 acid esters of the pregnant steroid of 21-trihydroxy-:
The R here
1Expression methyl, R
2Expression hydrogen, R
3Expression-COOR
4, R
4The expression ethyl.
Embodiment 2,
Press embodiment 1 described method, but R wherein
1Expression hydrogen, R
2Expression methyl or R
1Expression methyl, R
2Expression hydrogen;
Used esterifying agent is the chloro-formic ester shown in right formula, that is: ClCOOR
4, R wherein
4In expression methyl, ethyl, propyl group, butyl or the isobutyl-any one;
Used alkali can be that triethylamine, pyridine, N-ethyl are sent pyridine, N, any one in the tertiary amines such as N-dimethyl aminopyridine;
Reaction medium is any one in the organic solvents such as pyridine, benzene, low alkyl group benzene, methylene dichloride, ethylene dichloride, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO);
Temperature of reaction is subzero 20-60 ℃, and 0-40 ℃ better, preferably 10-30 ℃.
Embodiment 3,
Press embodiment 1,2 described methods, but used esterifying agent is the chlorsulfonic acid ester shown in right formula, that is: ClSO
2R
5, R wherein
5The expression carbonatoms is the phenyl that the alkyl of 1-4 or methyl, ethyl replace.
Embodiment 4,
Press embodiment 1,2,3 described methods, but its 11 is 11 Alpha-hydroxies or 11 beta-hydroxies.
Embodiment 5,
10 gram 16 Beta-methyls-Δs
1,4-3,20-diketone-11 α, 17 α, the 21-isobutyl-(alkoxymethyl)-2 acid esters (about 0.02 mole) of the pregnant steroid of 21-trihydroxy-, 150 milliliters of methylene dichloride and 30 milliliters of pyridines are put in the reactor, stir; Add about 0.04 mole phosphorus pentachloride, at room temperature continue to stir 30-60 minute.
Add the less water termination reaction then, add 500 milliliters of methylene dichloride, with 250 milliliters of 6N aqueous hydrochloric acid washing reaction liquid; Layering also separates, and uses the dichloromethane extraction water layer, merges organic layer; Use 1N aqueous hydrochloric acid, water, salt water washing organic layer successively; Behind the concentrating under reduced pressure, products therefrom is carried out chromatographic separation, can obtain 11 β chloro-16 Beta-methyls-Δs
1,4-3,20 diketone-17 α, the 21-isobutyl-of 21-dimonohydric pregnant
The (alkoxymethyl)-2 acid esters:
The R here
1Expression methyl, R
2Expression hydrogen, R
3Expression-COOR
4, R
4The expression isobutyl-.
Embodiment 6,
Pressing the method for embodiment 5, carry out but be reflected in the tetrahydrofuran (THF), is chlorizating agent with the phosphorus trichloride, and the consumption of phosphorus trichloride is about 0.04 mole, reaction times 4-5 hour.Separation can obtain 11 β chloro-products.
Embodiment 7,
10 gram 16 Beta-methyls-Δs
1,4-3,20 diketone-11 α, 17 α, the 21-ethyl (alkoxymethyl)-2 acid esters (about 0.022 mole) of the pregnant steroid of 21-trihydroxy-, 100 milliliters of tetrahydrofuran (THF)s and 50 milliliters of tetracol phenixin are put in the reactor, stir; Add 0.035 mole of triphenyl phosphorus, in 70 ℃ of stir abouts 1 hour; Obtain corresponding 11 β-chloro-product by the method separation of embodiment 5.
Embodiment 8,
10 grams, 11 β chloro-16 Beta-methyls-Δs
1,4-3,20-diketone-17 α, the 21-isobutyl-(alkoxymethyl)-2 acid esters of 21-dimonohydric pregnant is heated to 90-100 ℃ with 20 milliliters of dimethyl sulfoxide (DMSO), stirs insulation 15-20 hour, can obtain corresponding Δ
1,4,9 (11)Product.The terminal point of reaction can be monitored with HPLC; As starting raw material not fully or not major part convert three ene products to, but the proper extension reaction times and/or is improved temperature of reaction.
Embodiment 9,
10 grams, 11 β chloro-16 Beta-methyls-Δs
1,4-3,20-diketone-17 α, the 21-ethyl (alkoxymethyl)-2 acid esters of 21-dimonohydric pregnant, the method for pressing embodiment 8 is a dimethyl formamide but eliminate the polar solvent that reacts, and is heated to 100 ℃ better, stirs insulation 4-6 hour; Or the mixture of water and first cyanogen, be heated to backflow, stirred 8-10 hour; Or the mixture of water and dioxane, be heated to about 100 ℃, stir insulation 4-6 hour; Can obtain corresponding Δ
1,4,9 (11)Product.
Embodiment 10,
60 milliliters of 16 Beta-methyls-Δs of embodiment 1 gained
1,4-3,20-diketone-11 α, 17 α, the 21-ethyl (alkoxymethyl)-2 acid esters (about 0.08 mole) of the pregnant steroid of 21-trihydroxy-, 150 milliliters of tetrahydrofuran (THF)s join in the reactor, be cooled to subzero 80 ℃ of subzero 90-, slowly add about 0.15 mole phosphorus pentachloride, added in about 1 hour, and keep subzero 90-and continue to stir 60-90 minute for subzero 80 ℃; Slowly be warmed up to 10-20 ℃, add about 120 ml distilled waters, continued insulated and stirred 30 minutes; The acidity of the aqueous sodium hydroxide solution conditioned reaction liquid with 50% is about 7.5 to pH value; Static, leaching precipitation, washing, vacuum-drying below 60 ℃ promptly obtain 16 Beta-methyls-Δ
1,4,9 (11)-3,20-diketone-17 α, the 21-ethyl (alkoxymethyl)-2 acid esters of 21-dimonohydric pregnant.
The R here
1Expression methyl, R
2Expression hydrogen, R
3Expression-COOR
4, R
4The expression ethyl; Here used tetrahydrofuran (THF) can be used any one replacement in the suitable organic solvent such as methylene dichloride, ethylene dichloride, first cyanogen.
Embodiment 11,
0.022 mole 16 Beta-methyls-Δ 1,4-3,20-diketone-11 α, 17 α, the 21-(alkoxymethyl)-2 acid esters or the sulphonate of the pregnant steroid of 21-trihydroxy-, 70 milliliters of tetrahydrofuran (THF)s join in the reactor, stir to make dissolving; Be cooled to subzero 70 ℃ of subzero 80-, slowly add about 0.04 mole phosphorus pentachloride, added in about 1 hour, and keep subzero 80-and continue to stir 30-60 minute for subzero 70 ℃; Slowly be warmed up to 10-20 ℃, add 400 ml distilled waters, continued insulated and stirred 30 minutes; Static, leaching precipitation, washing, in vacuum-drying below 60 ℃ promptly obtain 16 Beta-methyls-Δ
1,4,9 (11)-3,20-diketone-17 α, the 21-(alkoxymethyl)-2 acid esters or the sulphonate of 21-dimonohydric pregnant.Resulting product records Δ with HPLC
1,4,9 (11)With Δ
1,4,11 (12)Ratio be 98: 2.
The R here
1Expression methyl, R
2Expression hydrogen, R
3Expression-COOR
4Perhaps-SO
2R
5R wherein
4In expression methyl, ethyl, propyl group, butyl or the isobutyl-any one; R
5The expression carbonatoms is the phenyl that the alkyl of 1-4 or methyl, ethyl replace.Here used tetrahydrofuran (THF) can be used any one replacement in the suitable organic solvent such as methylene dichloride, ethylene dichloride, first cyanogen.
Embodiment 12,
0.022 mole 16 Beta-methyls-Δ
1,4-3,20-diketone-11 β, 17 α, the 21-isobutyl-(alkoxymethyl)-2 acid esters or the sulphonate of the pregnant steroid of 21-trihydroxy-, 70 milliliters of tetrahydrofuran (THF)s join in the reactor, stir to make dissolving; Be cooled to subzero 70 ℃ of subzero 80-, slowly add 0.02 mole phosphorus pentachloride, about 1 hour of insulated and stirred; The phosphorus pentachloride that slowly adds 0.02 mole again, about 1 hour of insulated and stirred; Stirred 1 hour in subzero 60 ℃; Stirred 3 hours in subzero 50 ℃; Pressing the method for embodiment 11 handles.The product that obtains records Δ with HPLC
1,4,9 (11)With Δ
1,4,44 (12)Ratio be 93: 7.
Embodiment 13,
0.022 mole 16 Alpha-Methyls-Δ
1,4-3,20-diketone-11 β, 17 α, the 21-isobutyl-(alkoxymethyl)-2 acid esters or the sulphonate of the pregnant steroid of 21-trihydroxy-, the method for pressing embodiment 10,11,12 can make corresponding Δ
1,4,9 (11)Product.
Embodiment 14,
0.022 mole 16 Alpha-Methyls-Δ
1,4-3,20-diketone-11 α, 17 α, the 21-isobutyl-(alkoxymethyl)-2 acid esters or the sulphonate of the pregnant steroid of 21-trihydroxy-, perhaps 0.022 mole of 16 Beta-methyls-Δ
1,4-3,20-diketone-11 α, 17 α, the 21-isobutyl-(alkoxymethyl)-2 acid esters or the sulphonate of the pregnant steroid of 21-trihydroxy-, 100 milliliters of methylene dichloride, 25 milliliters of pyridines join in the reactor, stir; Be cooled to subzero 5 ℃ of subzero 10-, slowly drip 4.2 milliliters of phosphorus oxychloride (about 0.045 mole), in stirring at room 24 hours; Add 50 milliliters of pyridines, in 60 ℃ of left and right sides insulated and stirred 20 hours; Processing can obtain 16 Alpha-Methyls or-16 Beta-methyls-Δ
1,4,9 (11)-3,20-diketone-17 α, the 21-isobutyl-(alkoxymethyl)-2 acid esters or the sulphonate of 21-dimonohydric pregnant.Resulting product records Δ with HPLC
1,4,9 (11)With Δ
1,4,11 (12)Ratio be 98: 2.
The R here
1Expression methyl, R
2Expression hydrogen or R
2Expression methyl, R
1Expression hydrogen; R
3Expression-COOR
4Perhaps-SO
2R
5R wherein
4The expression isobutyl-; R
5The expression carbonatoms is the phenyl that the alkyl of 1-4 or methyl, ethyl replace.Here used methylene dichloride can be used any one replacement in the suitable organic solvent such as tetrahydrofuran (THF), ethylene dichloride, first cyanogen.
Embodiment 15,
0.022 mole 16 Alpha-Methyls-Δ
1,4-3,20-diketone-11 α, 17 α, the 21-ethyl (alkoxymethyl)-2 acid esters or the sulphonate of the pregnant steroid of 21-trihydroxy-, perhaps 0.022 mole of 16 Beta-methyls-Δ
1,4-3,20 diketone-11 α, 17 α, the 21-ethyl (alkoxymethyl)-2 acid esters or the sulphonate of the pregnant steroid of 21-trihydroxy-, 100 milliliters of tetrahydrofuran (THF)s join in the reactor, stir; Be cooled to subzero 70 ℃ of subzero 80-, slowly drip 2.5 milliliters of SULPHURYL CHLORIDE (about 0.03 mole), stirred 20 minutes; Add about 0.1 mole of imidazoles, stirred 1 hour; Processing can obtain 16 Alpha-Methyls or-16 Beta-methyls-Δ
1,4,9 (11)-3,20-diketone-17 α, the 21-ethyl (alkoxymethyl)-2 acid esters or the sulphonate of 21-dimonohydric pregnant.Resulting product records Δ with HPLC
1,4,9 (11)With Δ
1,4,11 (12)Ratio be 92: 8.
The R here
1Expression methyl, R
2Expression hydrogen or R
2Expression methyl, R
1Expression hydrogen; R
3Expression-COOR
4Perhaps-SO
2R
5R wherein
4The expression ethyl; R
5The expression carbonatoms is the phenyl that the alkyl of 1-4 or methyl, ethyl replace.Here used tetrahydrofuran (THF) can be used any one replacement in the suitable organic solvent such as methylene dichloride, ethylene dichloride, first cyanogen.
Embodiment 16,
0.022 mole 16 α methyl Δs
1,4-3,20-diketone-11 α, 17 α, the 21-ethyl (alkoxymethyl)-2 acid esters or the sulphonate of the pregnant steroid of 21-trihydroxy-, perhaps 0.022 mole of 16 Beta-methyls-Δ
1,4-3,20-diketone-11 α, 17 α, the 21-ethyl (alkoxymethyl)-2 acid esters or the sulphonate of the pregnant steroid of 21-trihydroxy-, 10 gram triphenyl phosphorus (about 0.038 mole) and 20 milliliters of tetracol phenixin (about 0.206 mole) and 50 milliliters of first cyanogen, join in the reactor, stirred 3 hours in room temperature; Reacting by heating liquid, backflow is spent the night; The terminal point of reaction can be monitored with HPLC; As starting raw material not fully or not major part convert three ene products to, but the proper extension reaction times; Reaction solution handle can obtain 16 Alpha-Methyls or-16 Beta-methyls-Δ
1,4,9 (11)-3,20 diketone-17 α, the 21-ethyl (alkoxymethyl)-2 acid esters or the sulphonate of 21-dimonohydric pregnant.
The R here
1Expression methyl, R
2Expression hydrogen or R
2Expression methyl, R
1Expression hydrogen; R
3Expression-COOR
4Perhaps-SO
2R
5R wherein
4The expression ethyl; R
5The expression carbonatoms is the phenyl that the alkyl of 1-4 or methyl, ethyl replace.
Embodiment 17,
0.022 mole 16 Alpha-Methyls or 16 Beta-methyl Δs
1,4-3,20-diketone-11 α, 17 α, the 21-(alkoxymethyl)-2 acid esters or the sulphonate of the pregnant steroid of 21-trihydroxy-, the method for pressing embodiment 12,14,15,16 can make corresponding Δ
1,4,9, (11)Product.
Embodiment 18,
0.022 mole 16-methyl-Δ
1,4-3,20-diketone-11,17 α, the 21-(alkoxymethyl)-2 acid esters or the sulphonate of the pregnant steroid of 21-trihydroxy-in suitable organic solvent such as tetrahydrofuran (THF) or methylene dichloride, join in the reactor, stir to make dissolving; Be cooled to subzero 20-25 ℃, slowly add about 0.04 mole phosphorus trichloride, added in about 1-hour, insulated and stirred adds 400 ml distilled waters, continues insulated and stirred 30 minutes: static, leaching precipitation, washing, in vacuum-drying below 60 ℃, promptly obtain corresponding Δ
1,4,9 (11)Product.Resulting product records Δ with HPLC
1,4,9 (11)With Δ
1,4,11 (12)Ratio be 97: 3.
Claims (15)
1, a kind of is the Δ of (II) with general formula
1,4-3,20-diketone-11,17,21-trihydroxy-pregnane compound 2 is a raw material, makes the Δ of general formula for (IV) through eliminating reaction
1,4,9 (11)-3,20-diketone-17, the method for 21-dimonohydric pregnant compound 3 is characterized in that:
(1): compound 2 and phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride, SULPHURYL CHLORIDE (SO
2Cl
2) with the mixture of the mixture of imidazoles or triphenyl phosphorus and tetracol phenixin in any-kind eliminate reaction, make compound 3:
The medium of reaction is any one in methylene dichloride, ethylene dichloride, tetrahydrofuran (THF), the first cyanogen; The R here
1Expression hydrogen, R
2Expression methyl or R
1Expression methyl, R
2Expression hydrogen; R
3Expression-COOR
4Perhaps-SO
2R
5R wherein
4In expression methyl, ethyl, propyl group, butyl or the isobutyl-any one; R
5The expression carbonatoms is the phenyl that the alkyl of 1-4 or methyl, ethyl replace;
Perhaps:
(2): any one in the mixture of compound 2 and phosphorus pentachloride, phosphorus trichloride or triphenyl phosphorus and tetracol phenixin carries out chlorination reaction, makes the Δ of general formula for (III)
1,4-3,20-diketone-17,21-dihydroxyl-11 β-chloro pregnane compound 3A:
When being chlorizating agent with the phosphorus pentachloride, reaction should be carried out under the alkali existence condition, and used alkali can be that triethylamine, pyridine, N-ethyl are sent pyridine, N, any one in the N-dimethyl aminopyridine;
Reaction medium is methylene dichloride, ethylene dichloride or tetrahydrofuran (THF);
The temperature of reaction is 20-100 ℃;
Compound 3A eliminates reaction in any one in the mixture of mixture, water and the dioxane of dimethyl sulfoxide (DMSO), dimethyl formamide, water and first cyanogen again, makes compound 3:
The temperature of eliminating reaction is 20-150 ℃; 11 of the compound 2 here is 11 Alpha-hydroxies; The R here
1, R
2, R
3, R
4, R
5The group of expression as mentioned above.
2, by the described method of claim 1, used chlorizating agent is a phosphorus pentachloride when it is characterized in that producing compound 3A in the method (two), and used alkali is pyridine, and reaction medium is methylene dichloride or ethylene dichloride, the temperature of reaction is a room temperature, and the reaction times is 30-60 minute.
3, by the described method of claim 1, used chlorizating agent is a phosphorus trichloride when it is characterized in that producing compound 3A in the method (two), and reaction medium is a tetrahydrofuran (THF), and the reaction times is 4-5 hour.
4, by the described method of claim 1, when it is characterized in that producing compound 3A in the method (two), compound 2, tetrahydrofuran (THF) and tetracol phenixin are mixed, add triphenyl phosphorus, stir about 1 hour; 70 ℃ of temperature of reaction.
5, by the described method of claim 1, it is characterized in that the polar solvent in the method (two) is a dimethyl sulfoxide (DMSO), the temperature of eliminating reaction is 90-100 ℃, stirs insulation 15-20 hour, makes compound 3.
6, by the described method of claim 1, it is characterized in that the polar solvent in the method (two) is a dimethyl formamide, the temperature of eliminating reaction is 100 ℃, stirs insulation 4-6 hour;
Perhaps polar solvent is the mixture of water and first cyanogen, is heated to backflow, stirs 8-10 hour;
Perhaps polar solvent is the mixture of water and dioxane, is heated to about 100 ℃, stirs insulation 4-6 hour; Make compound 3.
7, by the described method of claim 1, it is characterized in that compound 2 is eliminated reaction with phosphorus pentachloride in the method (), reaction medium is a tetrahydrofuran (THF), subzero 80 ℃ in subzero 90-, slowly add phosphorus pentachloride, and keep subzero 90-and continue to stir 60-90 minute for subzero 80 ℃; Slowly be warmed up to 10-20 ℃, add entry, continued insulated and stirred 30 minutes; Acidity with alkali aqueous solution conditioned reaction liquid is about 7.5 to pH value; Make compound 3;
Here used tetrahydrofuran (THF) can be used any one replacement in methylene dichloride, ethylene dichloride, the first cyanogen.
8, by the described method of claim 1, it is characterized in that compound 2 is eliminated reaction with phosphorus pentachloride in the method (), reaction medium is a tetrahydrofuran (THF), subzero 70 ℃ in subzero 80-, slowly adds the phosphorus pentachloride of half amount, about 1 hour of insulated and stirred; Slowly add second half phosphorus pentachloride again, about 1 hour of insulated and stirred; Stirred 1 hour in subzero 60 ℃; Stirred 3 hours in subzero 50 ℃; Bury at the place by the described method of claim 7; Make compound 3;
Here used tetrahydrofuran (THF) can be used any one replacement in methylene dichloride, ethylene dichloride, the first cyanogen.
9,, it is characterized in that 11 of the middle compound 2 of method () are 11 beta-hydroxies by claim 7,8 described methods.
10, by the described method of claim 1, it is characterized in that compound 2 mixes with methylene dichloride, pyridine in the method (), stir; In subzero 10-subzero 5 ℃, drip phosphorus oxychloride, in stirring at room 24 hours; Add pyridine, in 60 ℃ of left and right sides insulated and stirred 20 hours; Processing can obtain compound 3;
Here used methylene dichloride can be used any-kind of the replacement in tetrahydrofuran (THF), ethylene dichloride, the first cyanogen.
11, by the described method of claim 1, it is characterized in that compound 2 mixes with tetrahydrofuran (THF) in the method (), stir; In subzero 80-subzero 70 ℃, add SULPHURYL CHLORIDE, stirring; Add imidazoles, stir; Processing can obtain compound 3;
Here used tetrahydrofuran (THF) can be used any one replacement in methylene dichloride, ethylene dichloride, the first cyanogen.
12,, it is characterized in that compound 2 mixes with triphenyl phosphorus, tetracol phenixin and first cyanogen in the method () by the described method of claim 1; In stirring at room 3 hours; Reacting by heating liquid, backflow is spent the night; Reaction solution is handled can obtain compound 3;
The terminal point of reaction can be monitored with HPLC; As starting raw material not fully or not major part convert three ene products to, but the proper extension reaction times.
13, by claim 7,8,10,11,12 described methods, it is characterized in that compound 2 is 16 Alpha-Methyls or-16 β methyl Δs
1,4-3,20 diketone-11 α, 17 α, the 21-(alkoxymethyl)-2 acid esters or the sulphonate of the pregnant steroid of 21 trihydroxyies.
14, by the described method of claim 13, it is characterized in that compound 2 is 16 Alpha-Methyls or-16 Beta-methyl Δs
1,4-3,20-diketone-11 β, 17 α, the 21-(alkoxymethyl)-2 acid esters or the sulphonate of the pregnant steroid of 21-trihydroxy-.
15, by claim 7,8 described methods, it is characterized in that compound 2 at subzero 20-25 ℃, adds phosphorus trichloride in the method () in tetrahydrofuran (THF) or methylene dichloride, insulated and stirred makes compound 3.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN96116326A CN1061984C (en) | 1996-04-18 | 1996-04-18 | Introduction method of 9-11 double bond into steroid hormone compound |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN96116326A CN1061984C (en) | 1996-04-18 | 1996-04-18 | Introduction method of 9-11 double bond into steroid hormone compound |
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| CN1160719A CN1160719A (en) | 1997-10-01 |
| CN1061984C true CN1061984C (en) | 2001-02-14 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN96116326A Expired - Fee Related CN1061984C (en) | 1996-04-18 | 1996-04-18 | Introduction method of 9-11 double bond into steroid hormone compound |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100429222C (en) * | 2006-01-20 | 2008-10-29 | 浙江仙琚制药股份有限公司 | Synthesis process of a pregnane compound |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102061320B (en) * | 2010-12-02 | 2013-04-03 | 浙江仙琚制药股份有限公司 | Preparation method of 11 alpha,17 alpha-dyhydroxyl-androst-4-ene-3,20-dione |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1068120A (en) * | 1991-06-25 | 1993-01-20 | 鲁索-艾克勒夫公司 | Pregnant steroid-1,4-diene-3, the preparation method of the 16-methyl sterol analog derivative of the new replacement of 20-diketone |
| CN1141301A (en) * | 1988-04-08 | 1997-01-29 | 吉斯特·布罗卡德斯股份有限公司 | 9-alpha-hydroxyl-17-methylene steroids, process for their prepn. and their use in prepn. of corticosteroids |
-
1996
- 1996-04-18 CN CN96116326A patent/CN1061984C/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1141301A (en) * | 1988-04-08 | 1997-01-29 | 吉斯特·布罗卡德斯股份有限公司 | 9-alpha-hydroxyl-17-methylene steroids, process for their prepn. and their use in prepn. of corticosteroids |
| CN1068120A (en) * | 1991-06-25 | 1993-01-20 | 鲁索-艾克勒夫公司 | Pregnant steroid-1,4-diene-3, the preparation method of the 16-methyl sterol analog derivative of the new replacement of 20-diketone |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100429222C (en) * | 2006-01-20 | 2008-10-29 | 浙江仙琚制药股份有限公司 | Synthesis process of a pregnane compound |
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