CN1274708C - Process for connecting side chain to androstane compound at 17th position - Google Patents
Process for connecting side chain to androstane compound at 17th position Download PDFInfo
- Publication number
- CN1274708C CN1274708C CN 200410019724 CN200410019724A CN1274708C CN 1274708 C CN1274708 C CN 1274708C CN 200410019724 CN200410019724 CN 200410019724 CN 200410019724 A CN200410019724 A CN 200410019724A CN 1274708 C CN1274708 C CN 1274708C
- Authority
- CN
- China
- Prior art keywords
- interior
- parts
- carbon atoms
- acid
- contain
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Images
Landscapes
- Steroid Compounds (AREA)
Abstract
The present invention relates to a preparation method for connecting side chains to and rest compounds at the 17th position. A raw material steroid (1) containing and rest 4-ene-3, 17-diketone or and rest 1, 4-diene-3, 17-diketone as a main body, a double bond at 9(11), oxygen atoms at position 11 and halogen or methyl at position 6 is serially prepared into a substance (2) containing 3, 5(6)-diene3-ethyoxyl, a substance (3) containing 17-(2-diethyl malonate)ene, a substance (4) containing 17(20) ene-21-carboxylic ethyl ester, a substance (5) containing 4, 17(20) diene-21-hydroxide, to a substance (6) containing 21-acetate, to a substance (7) containing 17, 20-dihydroxyl, and finally to a product of a substance (8) containing pregna-4-ene-3, 20-diketone-21-acetate-17-hydroxy. 17 hydroxy and 20 ketone of the substance (8)are produced by a method of selective oxidation; the process of technological production provided by the present invention has easy operation, and reagents are safe and cheap.
Description
Technical field
The invention belongs to the steroidal chemical synthesising technology, particularly a kind ofly androstane compound is carried out 17 meet the preparation method that side chain generates pregnant steroid.
Background technology
Pregnant steroid-4-alkene-3,20-diketone-2,1-acetic ester and derivative thereof are the key intermediates of synthetic pregnane compound, are used for making as dexamethasone, times its Mi Song, methylprednisolone or the like steroid drugs, have higher economic value.Method commonly used now is Schwarz in 1973, the technology that people such as V deliver at Cesk Farm magazine (Czech) 22 volumes the 5th phase 231-233 page or leaf.Utilize pregnant steroid-5 exactly, 16-diene-20-ketone-3-hydroxyl-3-acetic ester (be called for short diene thing) is a feedstock production.Later on this method was carried out some improvement, but raw material does not change basically.But as pregnant steroid-5,16-diene-20-ketone-3-hydroxyl-3-acetic ester is to be generated through cracking, oxidation, three steps of hydrolysis by diosgenin, need a large amount of sulfuric acid, easily environment is produced a large amount of the pollution, be used to extract diosgenin as the most of Chinese yam of plant in addition, raw material as the synthesizing steroid hormone, in recent years because the turnout of steroid hormone is bigger, the a large amount of imports of some developed countries cause this resource to lack gradually in addition, so find a kind of raw material of alternative diene thing, the method for comparatively economic synthetic this product is imperative.External Nitta, people such as I delivered on Bull.Chem.Soc.Jpn (1985,58,978) and have utilized androstane-14-alkene-3 in 1985, and 17-diketone (being called for short 4AD) generates pregnant steroid-4-alkene-3, the method for 20-diketone-21-acetic ester, yield is 67%.4AD, ADD (androstane 1,4-diene-3, the 17-diketone) can generate through biological process from the tankage behind the soybean extract oil-plant sterol, and its derivative can obtain by simple chemical reaction comparatively, so 4AD, ADD and derivative thereof are with low cost, polluting very for a short time in the production process is a kind of advantageous raw material.17 ketone of 4AD, ADD are become the key that the Protosol side chain becomes this product of production.But they have adopted this violent in toxicity of potassium cyanide and the higher reagent of other costs, are that production cost or the processing of producing the back waste liquid all can cause certain problem.
Summary of the invention
Technology of the present invention is to utilize 4AD, ADD and this production of derivative raw material of reduced contamination, with low cost thereof, and a kind of process easy handling of production is provided, and adopts safe agent to finish 17 of androstanes are met the preparation method that side chain generates pregnant steroid.
Technological step of the present invention is as follows: as shown in Figure 1.Need to prove, following proportioning is 1 part in steroidal raw material weight content in the reaction of this step all, what relate in the reaction of hereinafter per step 1 all is 1 parts of steroidal raw material in reacting in this step, and the umber of the ratio of other material all is in relatively reacting with this step 1 part of the steroidal raw material and definite umber can be used weight unit in the actually operating.Also have, the numeral in the middle square brackets is and the digital position that forms two keys, front in the reaction hereinafter.
1. will contain androstane-14-alkene-3,17-diketone or androstane 1,4-diene-3,17-diketone are main body and 9[11 thereof] steroidal compounds (1) that contain the halogen-containing or methyl of Sauerstoffatom, 6 for two keys, 11 and ethanol is by 1: 8～20 parts triethyl orthoformates and 1 that mix 1: 0.897～8.897 parts of back addings: be connected with three carbon atoms on 0.01-0.2 part phenyl ring with the Phenylsulfonic acid of interior alkyl or the halogen acid salt of pyridine.This reaction medium keeps down stirring 3～10 hours in 40～100 ℃ in oil bath, pours 1 into after being cooled to 10-20 ℃: in 20-50 part water, separate subsequently, wash crystallization with water, dryly must contain 3,5[6]-material (2) of diene 3-oxyethyl group.
2. will contain 3,5[6]-material (2) of diene 3-oxyethyl group by 1: 4.39～26.36 parts with dry-out benzene or phenyl ring on and contain three carbon atoms and add propanedioic acid and three carbon atoms with 1: 1.06～10.55 parts of the dibasic acid esters of interior alcohol formation with the interior alkyl derivative back that is mixed, and potassium tert.-butoxide 1: after 0.05-1 part, this reaction medium in 80～95 ℃ of backflows, and takes division box to its moisture removal of being produced of reaction under the oil bath condition.Refluxing, this mixture stops heating after 1～4 hour, and reduce to 0～30 ℃, this organic phase is mixed the back layering by 1: 5～20 parts water, water layer discarded, organic layer is evaporated to dried, get brown solid,, obtain the material (3) that yellow solid contains 17-(2-diester malonate) alkene with 60～90 ° of 1: 0.63～6.3 parts after-filtration that stir of sherwood oil.
3. after the material (3) that will contain 17-(2-diester malonate) alkene mixes with dimethyl formamide by 1: 2.53～13.22 parts, this reaction medium is heated to 110～140 ℃ of reactions after 10～30 hours with oil bath, be cooled to 0～30 ℃, this mixture poured in 1: 15～100 parts the water, wash solid after the separation with water, dry back with 1: 0.63～1.88 parts after-filtration that stir of interior alcohol, obtains the material (4) that faint yellow solid contains 17 (20) alkene-21-carboxylic acid, ethyl ester with oil ethers or two carbon atoms.
With the hydroboration monovalent salt by 1: 1-0.1 part and 1: 0.8～4.79 parts three carbon atoms mix the back with interior alcohol and add the material (4) that contains 17 (20) alkene-21-carboxylic acid, ethyl ester, two carbon atoms that stir after 1～10 minute the aluminum chloride that slowly adds 2～4M concentration or haloid acid are with 1: 0.5～1.2 parts of interior alcoholic solutions, the control mixture temperature is no more than 40～60 ℃, after finishing, this mixture was stirred 1 hour down in 12.5～19 ℃, reheat to 25～60 ℃ were reduced to 10～20 ℃ after 1 hour.In mixture, add 1: 0.46～1.39 part 36% hydrochloric acid and 1 again: 0.4-1.2 part water, stir down and after 30～40 ℃ are evaporated to nearly no organic solvent, pour mixture into 1 after 0.5～1 hour: in 20-50 part water, separation, crystallization wash with water to pH value neutrality, must contain 4 after the drying, 17[20]-diene-21-hydroxyl material (5).
5. will contain 4,17[20]-after diene-21-hydroxyl material (5) and 1: 5.25～21 parts acetic acid and 1: 1.08～6.48 parts aceticanhydrides mix, be warming up to 90～100 ℃ of reactions 1～4 hour, be cooled to 10～20 ℃ again, pour 1 into: in 100-150 part water, separate, solid washes with water to the neutral after drying of PH must contain 21-acetic ester material (6) by solid.
6. will contain 21-acetic ester material (6) and 1: 0.4～1.5 parts N-methylmorpholine-N oxide compounds (NMMNO) and 1: 0.1～1 part perosmic anhydride or chromium trioxide and at room temperature stir three days, and add again and stirred evenly 1～2 hour for 1: 7～12 parts with one of carbonic acid monovalent salt, hydrogen-carbonate monovalent salt, sulfuric acid monovalent salt, hydrogen sulfate monovalent salt or sulfurous acid monovalent salt saturated solution in 1: 8～15 parts pyridines.This liquid merges the ester layer after using six carbon atom to extract three times with 1: 9.02～27.06 parts of interior esters altogether, uses CuSO again
41: 6～24 parts of saturated solutions, 1: 7.5～30 parts of NaCl saturated solutions, after 1: 6～24 parts of one of unsaturated carbonate monovalent salt, hydrogen-carbonate monovalent salt, sulfuric acid monovalent salt, hydrogen sulfate monovalent salt or sulfurous acid monovalent salt solution are washed the ester layer respectively, after underpressure distillation closely does after with anhydrous sodium sulfate drying with interior ester layer with six carbon atom, pouring three carbon atoms again has mass crystallization to separate out with behind 1: 0.79～3.96 parts of the interior alcohol, separate, crystallization with three carbon atoms with interior pure drip washing, must contain 17 after the drying, the two hydroxylated materials (7) of 20-.
7. will contain 17, the two hydroxylated materials (7) of 20-and three carbon atoms are with 1: 15.83～39.58 parts of interior alcohol, 1: 3～9.6 parts aluminum isopropylates 1 of pimelinketone: after 0.5-4 part mixes, after heated and stirred refluxed 1～2 hour, remove organic solvent with steam distillation, residuum extracts three to four times with interior alkane with containing three intraatomic two carbon atoms of chlorine, at every turn with contain three intraatomic two carbon atoms of chlorine with 1: 7.42～14.84 parts of interior alkane after, merge contain three chlorine atoms with two interior carbon atoms with interior alkane, in 30～50 ℃ of underpressure distillation, pour three carbon atoms with 1: 1～3 parts of interior alcohol after near the doing, have mass crystallization to separate out, separate, crystallization with three carbon atoms with 1: 0.5～2 parts drip washing of interior alcohol, dryly must contain the steroid of being pregnant-4-alkene-3, the material (8) of 20-diketone-21-acetic ester-17-hydroxyl.
The present invention utilizes special catalyst that diethyl malonate is reacted 17 ketone, generates many carbon side chain, makes it to generate 17 hydroxyls and 20 ketone by process for selective oxidation.Like this our process recovery ratio of providing with abroad compare similar, but the process easy handling of producing, the security of reagent and price are also better.
Figure of description
Fig. 1: main intermediate product flow process synoptic diagram;
Among the figure dotted line show two keys whether exist all can, on behalf of α, β key, curve all can.
R2=CH
3Or halogen (α, β all can) or H
R when 9 (11) exist two key
1=H,
R when 9 (11) do not exist two key
1=OH (α, β all can) or O (ketone) or H.
Embodiment
Embodiment 1:
1. prepare androstane-3,5[6]-diene-17-ketone-3-oxyethyl group (2)
With androstane-14-alkene-3,17-diketone 40g and 640g ethanol mix the back and add 71.76g triethyl orthoformate and 4g PTS (tosic acid).This reaction medium keeps down stirring 4 hours in 45 ℃ in oil bath, pours in the 1000g water after being cooled to 20 ℃, separates subsequently, washes crystallization with water, dry 43.2g material (2), yield 98.4%.
2. prepare androstane-3,5[6]-diene-3-oxyethyl group-17-(2-diethyl malonate) alkene (3)
Material (2) 30g and the 263.61g dry-out benzene back that is mixed is added 1, and 3-diethyl malonate 48.65g, and behind the potassium tert.-butoxide 3g, this reaction medium in 90 ℃ of backflows, and take division box that the moisture that its reaction is produced is gone under the oil bath condition.Refluxing, this mixture stops heating after 4 hours, and reduce to 20 ℃, this organic phase is mixed the back layering with 300g water, water layer discarded, organic layer is evaporated to dried, brown solid, with sherwood oil (60～90 °) the 31.25g after-filtration that stirs, obtain yellow solid matter (3) 41.2g, yield 94.6%.
3. prepare pregnant steroid-3,5[6], 17 (20) triolefins-3-oxyethyl group-21-carboxylic acid, ethyl ester (4)
After material (3) 21g and 141.68g dimethyl formamide mixed, this reaction medium is heated to 125～130 ℃ of reactions after 24 hours with oil bath, be cooled to 20 ℃, this mixture is poured in the 1500g water, wash solid after the separation with water, dry back obtains faint yellow solid material (4) 16.1g, yield 91.0% with sherwood oil (60～90 °) the 31.25g after-filtration that stirs.
4. prepare pregnant steroid-4,17[20]-diene-3-ketone-21-hydroxyl (5)
POTASSIUM BOROHYDRIDE 2g and 39.9g ethanol are mixed back adding 12g material (4), stir the aluminum chloride/ethanolic soln 8g that slowly adds 2M concentration after 10 minutes, the control mixture temperature is no more than 50 ℃, after finishing, this mixture was stirred 1 hour down in 15 ℃, reheat to 40 ℃ was reduced to 20 ℃ after 1 hour.In mixture, add 11.6g 36% hydrochloric acid and 10g water again, stir after following 1 hour mixture is poured in the 400g water after 40 ℃ are evaporated to the nearly no organic solvent, separation, crystallization wash with water to pH value neutrality, get material (5) 9.1g, yield 92.8% after the drying.
5. prepare pregnant steroid-4,17[20]-diene-3-ketone-21-acetic ester (6)
After material (5) 7g and 52.45g acetic acid and 21.6g aceticanhydride mixed, be warming up to 90 ℃ of reactions 2 hours, be cooled to 10 ℃ again, pour in the 700g water, separate, solid wash with water to the PH=7 after drying solid 7.6g, yield 95.7%.
6. prepare pregnant steroid-4-alkene-3-ketone-17, the two hydroxyls of 20--21-acetic ester (7)
Material (6) 6g and 4.5g NMMNO (N-methylmorpholine-N oxide compound) and 1.2g perosmic anhydride were at room temperature stirred three days in the 49.9g pyridine, add again and use NaHSO
4Saturated solution 55g stirred evenly 1 hour.Combined ethyl acetate layer after this liquid extracts three times with ethyl acetate 135.3g is altogether used CuSO again
4Saturated solution 51.1g, NaCl saturated solution 55g, saturated NaHCO
3After solution 53.4g washes ethyl acetate layer respectively, after underpressure distillation closely does after with anhydrous sodium sulfate drying with ethyl acetate layer, have mass crystallization to separate out after pouring methyl alcohol 15.8g again, separate, crystallization methyl alcohol drip washing must material (7) 6.1g after the drying, yield 92.8%.
7. prepare pregnant steroid-4-alkene-3,20-diketone-21-acetic ester (8)
With material (7) 5g and methyl alcohol 158g, after cyclohexanone 18.96g aluminum isopropylate 4g mixes, after heated and stirred refluxed 2 hours, remove organic solvent with steam distillation, residuum chloroform extraction three times are at every turn with adding isolated solid behind the chloroform 43.8g, the combined chloroform layer, in 40 ℃ of underpressure distillation, pour methyl alcohol 10g after near the doing, there is mass crystallization to separate out, separate, crystallization 3g methyl alcohol drip washing, dry 4.6g, the yield 92.6% of getting.
Embodiment 2:
1. prepare androstane-3,5[6]-diene-17-ketone-3-oxyethyl group-6 Alpha-Methyl (2)
With androstane-14-alkene-3,17-diketone-6 Alpha-Methyl 40g and 400g ethanol mix back adding 107.64g triethyl orthoformate and the 5g pyrrole is stung hydrogen bromide salt.This reaction medium keeps down stirring 5 hours in 80 ℃ in oil bath, pours in the 850g water after being cooled to 15 ℃, separates subsequently, washes crystallization with water, dry 40.9g material (2), yield 93.5%.
2. prepare androstane-3,5[6]-diene-3-oxyethyl group-17-(2-diethyl malonate) alkene-6 Alpha-Methyl (3)
Material (2) 30g and the 263.6g dry toluene back that is mixed is added 1, and 3-diethyl malonate 38g, and behind the potassium tert.-butoxide 3g, this reaction medium in 85 ℃ of backflows, and take division box that the moisture that its reaction is produced is gone under the oil bath condition.Refluxing, this mixture stops heating after 3 hours, and reduce to 20 ℃, this organic phase is mixed the back layering with 400g water, water layer discarded, organic layer is evaporated to dried, brown solid, with sherwood oil (60～90 °) the 31.39g after-filtration that stirs, obtain yellow solid matter (3) 37.9g after the drying, yield 88.18%.
3. prepare pregnant steroid-3,5[6], 17[20] triolefin-3-oxyethyl group-21-carboxylic acid, ethyl ester-6 Alpha-Methyl (4)
After material (3) 21g and 198.3g dimethyl formamide mixed, this reaction medium is heated to 125～130 ℃ of reactions after 30 hours with oil bath, be cooled to 20 ℃, this mixture is poured in the 2100g water, wash solid after the separation with water, dry back obtains faint yellow solid material 13.1g, yield 73.7% with sherwood oil (60～90 °) the 32.5g after-filtration that stirs after the drying.
4. prepare pregnant steroid-4,17[20]-diene-3-ketone-21-hydroxyl-6 Alpha-Methyl (5)
POTASSIUM BOROHYDRIDE 3.6g and 47.9g ethanol are mixed back adding 12g material (4), stir the methanol hydrochloride solution 6.8g that slowly adds 2M concentration after 10 minutes, the control mixture temperature is no more than 55 ℃, after finishing, this mixture was stirred 1 hour down in 18 ℃, reheat to 60 ℃ was reduced to 20 ℃ after 1 hour.In mixture, add 13.9g 36% hydrochloric acid and 12g water again, stir after following 1 hour and after mixture is after 40 ℃ are evaporated to nearly no organic solvent, pour in the 300g water, separation, crystallization wash with water to neutrality, get material (5) 8.3g, yield 83.9% after the drying.
5. prepare pregnant steroid-4,17[20]-diene-3-ketone-21-acetic ester-6 Alpha-Methyl (6)
After material (5) 7g and 88.1g acetic acid and 30.2g aceticanhydride mixed, be warming up to 100 ℃ of reactions 2 hours, be cooled to 10 ℃ again, pour in the 840g water, separate, solid wash with water to the PH=7 after drying solid 7.2g, yield 91.1%.
6. prepare pregnant steroid-4-alkene-3-ketone-17, the two hydroxyls of 20--21-acetic ester-6 Alpha-Methyl (7)
Material (6) 6g and 6g NMMNO (N-methylmorpholine-N oxide compound) and 1.2g perosmic anhydride were at room temperature stirred three days in the 70.4g pyridine, add again and use NaHSO
4Saturated solution 70g stirred evenly 2 hours.Combined ethyl acetate layer after this liquid extracts three times with ethyl acetate 116.5g is altogether used CuSO again
4Saturated solution 61.7g, NaCl saturated solution 67.3g, saturated NaHCO
3After solution 68.2g washes ethyl acetate layer respectively, after underpressure distillation closely does after with anhydrous sodium sulfate drying with ethyl acetate layer, have mass crystallization to separate out after pouring ethanol 7.98g again, separate, crystallization ethanol drip washing must material (7) 6g after the drying, yield 91.6%.
7. prepare pregnant steroid-4-alkene-3,20-diketone-21-acetic ester-6 Alpha-Methyl
With material (7) 5g and propyl alcohol 200ml, after cyclohexanone 25.7g aluminum isopropylate 10g mixes, after heated and stirred refluxed 2 hours, remove organic solvent with steam distillation, residuum chloroform extraction three times use 1 at every turn, add isolated solid behind the 2-ethylene dichloride 47.5g, the combined chloroform layer is in 40 ℃ of underpressure distillation, pour methyl alcohol 9g after near the doing, there are a large amount of white crystals to separate out, separate, crystallization 4g methyl alcohol drip washing, dry 3.9g, the yield 78.5% of getting.
Embodiment 3:
1. prepare androstane-3,5[6], 9[11]-triolefin-17-ketone-3-oxyethyl group (2)
With androstane-14,9 (11)-dienes-3,17-diketone (1) 40g and 552.7g ethanol mix the back and add 67.28g triethyl orthoformate and 3.4g PTS (tosic acid).This reaction medium keeps down stirring 8 hours in 48 ℃ in oil bath, pours in the 800g water after being cooled to 10 ℃, separates subsequently, washes crystallization with water, dry 42.6g material (2), yield 96.9%.
2. prepare androstane-3,5[6], 9[11]-triolefin-3-oxyethyl group-17-(2-diethyl malonate) alkene (3)
Material (2) 30g and the 237.25g dry-out benzene back that is mixed is added 1, and 3-dimethyl malonate 44.38g, and behind the potassium tert.-butoxide 1.8g, this reaction medium in 90 ℃ of backflows, and take division box that the moisture that its reaction is produced is gone under the oil bath condition.Refluxing, this mixture stops heating after 4 hours, and reduce to 10 ℃, this organic phase is mixed the back layering with 270g water, water layer discarded, organic layer is evaporated to dried, brown solid, with sherwood oil (60～90 °) the 39.5g after-filtration that stirs, obtain faint yellow solid material (3) 41.7g after the drying, yield 95.6%.
3. prepare pregnant steroid-3,5[6], 9[11], 17[20]-tetraene-3-oxyethyl group-21-carboxylic acid, ethyl ester (4)
After material (3) 21g and 234.46g dimethyl formamide mixed, this reaction medium is heated to 125～130 ℃ of reactions after 18 hours with oil bath, be cooled to 10 ℃, this mixture is poured in the 1800g water, wash solid after the separation with water, dry back obtains faint yellow solid material 14.1g, yield 79.8% with the methyl alcohol 34.5g after-filtration that stirs after the drying.
4. prepare pregnant steroid-4,, 9[11], 17[20]-triolefin-3-ketone-21-hydroxyl (5)
POTASSIUM BOROHYDRIDE 2.5g and 53.46g ethanol are mixed back adding 12g material (4), stir the aluminum chloride methanol solution 7.5g that slowly adds 3M concentration after 10 minutes, the control mixture temperature is no more than 60 ℃, after finishing, this mixture was stirred 1 hour down in 13 ℃, reheat to 40 ℃ was reduced to 10 ℃ after 1 hour.Add 13g36% hydrochloric acid and 13g water again in mixture, stir after following 1 hour mixture is poured in the 360g water after 40 ℃ are evaporated to nearly no organic solvent, separation, crystallization wash with water to neutrality, get material (5) 8.7g, yield 88.8% after the drying.
5. prepare pregnant steroid-4,9[11], 17[20]-triolefin-3-ketone-21-acetic ester (6)
After material (5) 7g and 73.4g acetic acid and 22.7g aceticanhydride mixed, be warming up to 85 ℃ of reactions 6 hours, be cooled to 10 ℃ again, slowly pour in the 900g water, separate, solid wash with water to the PH=7 after drying solid 7.4g, yield 93.2%.
6. prepare pregnant steroid-4,9[11]-diene-3-ketone-17, the two hydroxyls of 20--21-acetic ester (7)
Material (6) 6g and 5.4g NMMNO (N-methylmorpholine-N oxide compound) and 1.2g perosmic anhydride were at room temperature stirred two days in the 58.7g pyridine, add again and use Na
2SO
4Saturated solution 70.8g stirred evenly 1 hour.This liquid merges the butylacetate layer after extracting three times with butylacetate 128.9g altogether, uses CuSO again
4Saturated solution 76.3g, NaCl saturated solution 72.8g, saturated NaHCO
3After solution 69.4g washs the butylacetate layer respectively, after underpressure distillation closely does after with anhydrous sodium sulfate drying with the butylacetate layer, there is mass crystallization to separate out after pouring methyl alcohol 18.1g again, separate, crystallization methyl alcohol drip washing gets off-white color material (7) 6.1g, yield 92.7% after the drying.
7. prepare pregnant steroid-4,9[11]-diene-3,20-diketone-21-acetic ester
With material (7) 5g and n-propyl alcohol 88.53g, cyclohexanone 15g is after aluminum isopropylate 4.5g mixes, heated and stirred was removed organic solvent with steam distillation after refluxing 2 hours, residuum dichloromethane extraction three times, each with adding isolated solid behind the methylene dichloride 41.2g, the combined dichloromethane layer is in 40 ℃ of underpressure distillation, pour methyl alcohol 12g after near the doing, there is mass crystallization to separate out, separates, crystallization methyl alcohol 3g drip washing, dry 4.4g, the yield 88.5% of getting.
Embodiment 4:
1. prepare androstane-1,3,5[6]-triolefin-17-ketone-3-oxyethyl group (2)
With androstane 1,4-diene-3,17-diketone (1) 40g and 717.6g ethanol mix the back and add 89.7g triethyl orthoformate and 4.6g PTS (tosic acid).This reaction medium keeps down stirring 10 hours in 70 ℃ in oil bath, pours 2000g water, separates subsequently, washes crystallization with water, dry 43.1g material (2), the yield 98.1% of getting.
2. prepare androstane-1,3,5[6]-triolefin-3-oxyethyl group-17-(2-diethyl malonate) alkene (3)
Material (2) 30g and the 316.3g dry-out benzene back that is mixed is added 1, and 3-dimethyl malonate 47.8g, and behind the potassium tert.-butoxide 2.3g, this reaction medium in 90 ℃ of backflows, and take division box that the moisture that its reaction is produced is gone under the oil bath condition.Refluxing, this mixture stops heating after 3.5 hours, and reduce to 20 ℃, this organic phase is mixed the back layering with 360g water, water layer discarded, organic layer is evaporated to dried, brown solid, with sherwood oil (60～90 °) the 31.3g after-filtration that stirs, obtain yellow solid matter (3) 42.5g after the drying, yield 97.4%.
3. prepare pregnant steroid-1,3,5[6], 17[20]-tetraene-3-oxyethyl group-21-carboxylic acid, ethyl ester (4)
After material (3) 21g and 198.4g dimethyl formamide mixed, this reaction medium is heated to 125～130 ℃ of reactions after 24 hours with oil bath, be cooled to 20 ℃, this mixture is poured in the 2100g water, wash solid after the separation with water, dry back obtains faint yellow solid material (4) 12.9g, yield 73.0% with the 95% ethanol 30g after-filtration that stirs after the drying.
4. prepare pregnant steroid-1,4,17[20]-triolefin-3-ketone-21-hydroxyl (5)
Sodium borohydride 2.3g and 64g ethanol are mixed back adding 12g material (4), stir the aluminum chloride ethanolic soln 7.8g that slowly adds 2M concentration after 10 minutes, the control mixture temperature is no more than 50 ℃, after finishing, this mixture was stirred 1 hour down in 15 ℃, reheat to 50 ℃ was reduced to 20 ℃ after 1 hour.In mixture, add 10.3g 36% hydrochloric acid and 10.3g water again, stir after following 1 hour mixture is poured in the 400g water after 40 ℃ are evaporated to nearly no organic solvent, separation, crystallization wash with water to neutrality, get material (5) 9.3g, yield 94.9% after the drying.
5. prepare pregnant steroid-1,4,17[20]-triolefin-3-ketone-21-acetic ester (6)
After material (5) 7g and 73.4g acetic acid and 27g aceticanhydride mixed, be warming up to 90 ℃ of reactions 2 hours, be cooled to 10 ℃ again, slowly pour in the 950g water, separate, solid wash with water to the PH=7 after drying solid 7.1g, yield 89.4%.
6. prepare pregnant steroid-1,4-diene-3-ketone-17, the two hydroxyls of 20--21-acetic ester (7)
Material (6) 6g and 5.8g NMMNO (N-methylmorpholine-N oxide compound) and 0.95g perosmic anhydride were at room temperature stirred three days in the 58.7g pyridine, add again and use NaHSO
4Saturated solution 63.8g stirred evenly 1 hour.This liquid merges the butylacetate layer after extracting three times with butylacetate 133.7g, uses CuSO again
4Saturated solution 42.7g, NaCl saturated solution 48.36g, saturated NaHCO
3After solution 37.7g washes the butylacetate layer respectively, after underpressure distillation closely does after with anhydrous sodium sulfate drying with the butylacetate layer, there is mass crystallization to separate out after pouring 95% ethanol 16.5g again, separate, crystallization gets off-white color material (7) 5.6g, yield 85.1% with 95% ethanol 6g drip washing after the drying.
7. prepare pregnant steroid-1,4-diene-3,20-diketone-21-acetic ester (8)
With material (7) 5g and ethanol 119.7g, after cyclohexanone 16.2g aluminum isopropylate 3.8g mixes, after heated and stirred refluxed 1.5 hours, remove organic solvent with steam distillation, residuum chloroform extraction three times are at every turn with adding isolated solid behind the chloroform 59.7g, the combined chloroform layer, in 40 ℃ of underpressure distillation, pour 8g methyl alcohol after near the doing, there is mass crystallization to separate out, separate, crystallization methyl alcohol 5g drip washing, dry white mass (8) 4.6g, the yield 92.6% of getting.
Open and the preparation method that proposes of the present invention, those skilled in the art can be by using for reference this paper content, and links such as appropriate change raw material, processing parameter, structure design realize.Method of the present invention is described by preferred embodiment, person skilled obviously can be in not breaking away from content of the present invention, spirit and scope to method as herein described with product is changed or suitably change and combination, realize the technology of the present invention.Special needs to be pointed out is, the replacement that all are similar and change apparent to those skilled in the artly, they are regarded as being included in spirit of the present invention, scope and the content.
Claims (8)
1. one kind is carried out 17 preparation methods that connect side chain to androstane compound, what relate in the reaction of hereinafter per step 1 all is to be 1 part in steroidal raw material weight content in this step reaction, and the umber of the ratio of other material all is 1 part of the steroidal raw material and definite umbers in reacting with this step relatively; Numeral in hereinafter in the reaction in the square brackets is the position that forms two keys with the front numeral, and step is as follows:
1). will contain androstane-14-alkene-3,17-diketone or androstane 1,4-diene-3,17-diketone are main body and 9[11 thereof] steroidal compounds (1) that contain the halogen-containing or methyl of Sauerstoffatom, 6 for two keys, 11 and ethanol is by 1: 8～20 parts triethyl orthoformates and 1 that mix 1: 0.897～8.897 parts of back addings: be connected with three carbon atoms on 0.01-0.2 part phenyl ring with the Phenylsulfonic acid of interior alkyl or the halogen acid salt of pyridine; This reaction medium oil bath in 40～100 ℃ keep down stirring 3～10 hours after, pour 1 into after being cooled to 10-20 ℃: in 20-50 part water, separate subsequently, wash crystallization with water, dryly must contain 3,5[6]-material (2) of diene 3-oxyethyl group;
2). will contain 3,5[6]-material (2) of diene 3-oxyethyl group by 1: 4.39～26.36 parts with dry-out benzene or phenyl ring on be connected with three carbon atoms and add propanedioic acid and three carbon atoms with 1: 1.06～10.55 parts of interior alcohol formation dibasic acid esters with the derivative of the interior alkyl back that is mixed, and behind 1: 0.05～1 part of the potassium tert.-butoxide, this reaction medium in 80～95 ℃ of backflows, and takes division box to its moisture removal of being produced of reaction under the oil bath condition; Refluxing, this mixture stops heating after 1～4 hour, and reduce to 0～30 ℃, this organic phase is mixed the back layering by 1: 5～20 parts water, water layer discarded, organic layer is evaporated to dried, get brown solid,, obtain the material (3) that yellow solid contains 17-(2-diester malonate) alkene with 60～90 ℃ of 1: 0.63～6.3 parts after-filtration that stir of sherwood oil;
3). after the material (3) that will contain 17-(2-diester malonate) alkene mixes with dimethyl formamide by 1: 2.53～13.22 parts, this reaction medium is heated to 110～140 ℃ of reactions after 10～30 hours with oil bath, be cooled to 0～30 ℃, this mixture poured in 1: 15～100 parts the water, wash solid after the separation with water, dry back, obtains faint yellow solid and contains 17[20 with 1: 0.63～1.88 parts after-filtration that stir of interior alcohol with oil ethers or two carbon atoms] material (4) of alkene-21-carboxylic acid, ethyl ester;
4). with the hydroboration monovalent salt by 1: 1-0.1 part and 1: 0.8～4.79 parts three carbon atoms with interior alcohol mix the back add contain 17[20] material (4) of alkene-21-carboxylic acid, ethyl ester, two carbon atoms that stir after 1～10 minute the aluminum chloride that slowly adds 2～4M concentration with two carbon atoms of interior alcoholic solution or haloid acid with 1: 0.5～1.2 parts of interior alcoholic solutions, the control mixture temperature is no more than 40～60 ℃, after finishing, this mixture was stirred 1 hour down in 12.5～19 ℃, reheat to 25～60 ℃ were reduced to 10～20 ℃ after 1 hour; In mixture, add 1: 0.46～1.39 part 36% hydrochloric acid and 1 again: 0.4-1.2 part water, stir down and after 30～40 ℃ are evaporated to no organic solvent, pour mixture into 1 after 0.5～1 hour: in 20-50 part water, separation, crystallization wash with water to pH value neutrality, must contain 4,17 (20)-dienes-21-hydroxyl material (5) after the drying;
5). will contain 4, after 17 (20)-dienes-21-hydroxyl material (5) and 1: 5.25～21 parts acetic acid and 1: 1.08～6.48 parts aceticanhydrides mix, be warming up to 90～100 ℃ of reactions 1～4 hour, be cooled to 10～20 ℃ again, pour 1 into: in 100-150 part water, separate, solid washes with water to the neutral after drying of PH must contain 21-acetic ester material (6) by solid;
6). will contain 21-acetic ester material (6) and 1: 0.4～1.5 parts N-methylmorpholine-N oxide compounds and 1: 0.1～1 part perosmic anhydride or chromium trioxide and at room temperature stir three days, and add again and stirred evenly 1～2 hour for 1: 7～12 parts with one of carbonic acid monovalent salt, hydrogen-carbonate monovalent salt, sulfuric acid monovalent salt, hydrogen sulfate monovalent salt or sulfurous acid monovalent salt saturated solution in 1: 8～15 parts pyridines; This liquid merges the ester layer after using six carbon atom to extract three times with 1: 9.02～27.06 parts of interior esters altogether, uses CuSO again
41: 6～4 parts of saturated solutions, 1: 7.5～30 parts of NaCl saturated solutions, after 1: 6～24 parts of one of unsaturated carbonate monovalent salt, hydrogen-carbonate monovalent salt, sulfuric acid monovalent salt, hydrogen sulfate monovalent salt or sulfurous acid monovalent salt solution are washed the ester layer respectively, after underpressure distillation does after with anhydrous sodium sulfate drying with interior ester layer with six carbon atom, pouring three carbon atoms again has mass crystallization to separate out with behind 1: 0.79～3.96 parts of the interior alcohol, separate, crystallization with three carbon atoms with 1: 0.5～2 parts drip washing of interior alcohol, must contain 17 after the drying, the two hydroxylated materials (7) of 20-;
7). will contain 17, the two hydroxylated materials (7) of 20-and three carbon atoms are with 1: 15.83～39.58 parts of interior alcohol, 1: 3～9.6 parts of pimelinketone and aluminum isopropylate 1: after 0.5-4 part mixes, after heated and stirred refluxed 1～2 hour, remove organic solvent with steam distillation, residuum extracts three to four times with interior alkane with two interior carbon atoms with containing three chlorine atoms, each with contain three chlorine atoms with two interior carbon atoms with 1: 7.42～14.84 parts of interior alkane after, merge contain three chlorine atoms with two interior carbon atoms with interior alkane in 30～50 ℃ of underpressure distillation, pour three carbon atoms with 1: 1～3 parts of interior alcohol, there is mass crystallization to separate out, separate, crystallization with interior pure drip washing, dry must contain the steroid of being pregnant-4-alkene-3, the material (8) of 20-diketone-21-acetic ester-17-hydroxyl with three carbon atoms.
2. as claimed in claim 1ly a kind of androstane compound is carried out 17 preparation methods that connect side chain, it is characterized in that the androstane-14-alkene-3 in the described step 1), 17-diketone or androstane 1,4-diene-3,17-diketone are main body and 9[11 thereof] for two keys, 11 contain Sauerstoffatom, 6 steroidal compounds halogen-containing or methyl are androstane-14-alkene-3,17-diketone, androstane 1,4-diene-3,17-diketone, androstane-14-alkene-3,17-diketone-6 Alpha-Methyl or androstane-14,9[11]-diene-3, the 17-diketone; Described three carbon atoms are tosic acid or pyridinium tribromide hydrohalogenic acid salt with the Phenylsulfonic acid of interior groups or the halogen acid salt of pyridine.
3. as claimed in claim 1ly a kind of androstane compound is carried out 17 preparation methods that connect side chain, it is characterized in that described step 2) in propanedioic acid and three carbon atoms be 1 with the ester of interior alcohol formation, the esters that 3-propanedioic acid and three carbon atoms form with interior alcohol, benzene or to contain three carbon atoms be dry-out benzene or dry toluene with interior alkyl derivative.
4. as claimed in claim 3ly a kind of androstane compound is carried out 17 preparation methods that connect side chain, it is characterized in that described step 2) in 1,3-propanedioic acid and three carbon atoms are 1 with the ester that interior alcohol forms, 3-diethyl malonate or 1,3-dimethyl malonate.
5. as claimed in claim 1ly a kind of androstane compound is carried out 17 preparation methods that connect side chain, it is characterized in that two carbon atoms in the described step 3) are methyl alcohol or 95% ethanol with interior alcohol.
6. as claimed in claim 1ly a kind of androstane compound is carried out 17 preparation methods that connect side chain, it is characterized in that the hydroboration monovalent salt in the described step 4) is POTASSIUM BOROHYDRIDE or sodium borohydride; Described three carbon atoms are methyl alcohol or ethanol with interior alcohol; Two carbon atoms of described aluminum chloride or haloid acid are aluminum chloride ethanolic soln, aluminum chloride methyl alcohol or methanol hydrochloride solution with interior alcoholic solution.
7. as claimed in claim 1ly a kind of androstane compound is carried out 17 preparation methods that connect side chain, it is characterized in that carbonic acid monovalent salt, hydrogen-carbonate monovalent salt, sulfuric acid monovalent salt, hydrogen sulfate monovalent salt or the sulfurous acid monovalent salt saturated solution in the described step 6) is NaHSO
4, Na
2SO
4, NaHCO
3; Described six carbon atom is ethyl acetate, butylacetate with interior ester; Described three carbon atoms are methyl alcohol or ethanol or 95% ethanol with interior alcohol.
8. as claimed in claim 1ly a kind of androstane compound is carried out 17 preparation methods that connect side chain, it is characterized in that three chlorine atoms in the described step 7) are chloroform, methylene dichloride with two interior carbon atoms with interior alkyl derivative.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410019724 CN1274708C (en) | 2004-06-21 | 2004-06-21 | Process for connecting side chain to androstane compound at 17th position |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410019724 CN1274708C (en) | 2004-06-21 | 2004-06-21 | Process for connecting side chain to androstane compound at 17th position |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1594349A CN1594349A (en) | 2005-03-16 |
| CN1274708C true CN1274708C (en) | 2006-09-13 |
Family
ID=34663065
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200410019724 Expired - Fee Related CN1274708C (en) | 2004-06-21 | 2004-06-21 | Process for connecting side chain to androstane compound at 17th position |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1274708C (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100469786C (en) * | 2005-06-20 | 2009-03-18 | 中国科学院理化技术研究所 | Method for synthesizing 16-dehydropregndiketonic alcohol acetic ester and its analogs |
| CN102617697A (en) * | 2011-01-26 | 2012-08-01 | 上海博悦生物科技有限公司 | New method for preparing eplerenone |
| CN103030677A (en) * | 2012-09-26 | 2013-04-10 | 宜城市共同药业有限公司 | High-yield Boldenone synthesis method |
| CN103450305B (en) * | 2013-08-30 | 2016-02-17 | 郑州大学 | A kind of synthetic method being prepared steroidal compounds by 3,17-diones steroidal |
-
2004
- 2004-06-21 CN CN 200410019724 patent/CN1274708C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN1594349A (en) | 2005-03-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103890001B (en) | For the preparation of the method for E4 | |
| CN103347525A (en) | Methods and compounds for preparing 3alpha-oxygen substituted steroids | |
| KR102527821B1 (en) | 6.alpha.-alkyl-6,7-dione steroids as intermediates for the production of steroidal fxr modulators | |
| CN103641878B (en) | The preparation method of Betamethasone Valerate intermediate or its analogue | |
| KR102526632B1 (en) | 5.beta.-6-alkyl-7-hydroxy-3-one steroids as intermediates for the production of steroidal fxr modulators | |
| KR102546748B1 (en) | 6.alpha.-alkyl-3,7-dione steroids as intermediates for the production of steroidal fxr modulators | |
| CN109776644B (en) | Synthesis method of progesterone | |
| CN103965277A (en) | Method for synthesizing difluprednate from sterol fermentation product | |
| Weihe et al. | Stereoselective synthesis of 23-deoxyantheridiol | |
| CN101061132A (en) | Method for preparing 17- hydroxy- 6beta, 7beta, 15beta, 16beta- bisacrylamide- 17alpha- pregnane- 4- ene- 3- ketone- 21- carboxylate gamma- lactone and key intermediate used for the said method | |
| CN114874277A (en) | Synthesis method of cholesterol | |
| CN1274708C (en) | Process for connecting side chain to androstane compound at 17th position | |
| CN103601782A (en) | Preparation method of prednisone acetate or analogues thereof | |
| CN105980396A (en) | Synthesis of ent-progesterone and intermediates thereof | |
| CN114315942B (en) | Synthesis method of estrone | |
| CN101323636A (en) | Preparation of rocuronium | |
| CN101851264B (en) | Preparation method of intermediate of steroidal drug with 16-beta-methyl | |
| CN114276406B (en) | Preparation method of intermediate of deoxomilpine | |
| DE3231827A1 (en) | 11SS-ARYL-17 (ALPHA) -ALKINYL-17SS-HYDROXY-4.9 (10) - ESTRADIEN-3-ON DERIVATIVES, THEIR PRODUCTION AND THEIR PHARMACEUTICAL PREPARATIONS CONTAINING THEM | |
| CN104725460A (en) | Preparation method of androst-4-ene-6beta,19-epoxy-3,17-dione | |
| CN113045616B (en) | Preparation method of 6-dehydronandrolone acetate | |
| CN111018936B (en) | Synthesis method of fulvestrant related substance E | |
| Moon | Synthesis of dehydro-oogoniol and oogoniol: the adrenosterone route | |
| CN103421070A (en) | Improved pregnane alkene compound C21-acetoxylation method | |
| CN1793159A (en) | Process for synthesizing cholester-3 bata, 5 alpha, 6 bata, 19-tetrahydroxy-24-one and derivative |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20060913 Termination date: 20110621 |