CN116751242A - Preparation method of estradiol-17 beta-alkyl acid ester - Google Patents
Preparation method of estradiol-17 beta-alkyl acid ester Download PDFInfo
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- CN116751242A CN116751242A CN202310581641.XA CN202310581641A CN116751242A CN 116751242 A CN116751242 A CN 116751242A CN 202310581641 A CN202310581641 A CN 202310581641A CN 116751242 A CN116751242 A CN 116751242A
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- estradiol
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- alkyl acid
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- 239000002253 acid Substances 0.000 title claims abstract description 33
- 150000002148 esters Chemical class 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 18
- 239000000203 mixture Substances 0.000 claims abstract description 16
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 14
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 13
- 239000003960 organic solvent Substances 0.000 claims abstract description 13
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 claims abstract description 11
- 229960005309 estradiol Drugs 0.000 claims abstract description 11
- 229930182833 estradiol Natural products 0.000 claims abstract description 11
- 239000012024 dehydrating agents Substances 0.000 claims abstract description 10
- 239000003054 catalyst Substances 0.000 claims abstract description 9
- 238000005886 esterification reaction Methods 0.000 claims abstract description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 5
- 230000007062 hydrolysis Effects 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 17
- 239000007864 aqueous solution Substances 0.000 claims description 14
- 239000000758 substrate Substances 0.000 claims description 13
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical group CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 11
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 claims description 8
- 239000012044 organic layer Substances 0.000 claims description 8
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 230000007935 neutral effect Effects 0.000 claims description 6
- 238000010791 quenching Methods 0.000 claims description 6
- 238000007670 refining Methods 0.000 claims description 6
- 230000001105 regulatory effect Effects 0.000 claims description 6
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 5
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 5
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 5
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 230000003301 hydrolyzing effect Effects 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 230000000171 quenching effect Effects 0.000 claims description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- 230000032050 esterification Effects 0.000 abstract description 2
- 231100000171 higher toxicity Toxicity 0.000 abstract description 2
- 239000003270 steroid hormone Substances 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract 1
- RSEPBGGWRJCQGY-RBRWEJTLSA-N Estradiol valerate Chemical compound C1CC2=CC(O)=CC=C2[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)CCCC)[C@@]1(C)CC2 RSEPBGGWRJCQGY-RBRWEJTLSA-N 0.000 description 8
- RFWTZQAOOLFXAY-BZDYCCQFSA-N estradiol enanthate Chemical compound C1CC2=CC(O)=CC=C2[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)CCCCCC)[C@@]1(C)CC2 RFWTZQAOOLFXAY-BZDYCCQFSA-N 0.000 description 8
- 229960004766 estradiol valerate Drugs 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000006297 dehydration reaction Methods 0.000 description 3
- UCVODTZQZHMTPN-UHFFFAOYSA-N heptanoyl chloride Chemical compound CCCCCCC(Cl)=O UCVODTZQZHMTPN-UHFFFAOYSA-N 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 229940011871 estrogen Drugs 0.000 description 2
- 239000000262 estrogen Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 description 2
- 239000011736 potassium bicarbonate Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 235000011181 potassium carbonates Nutrition 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 201000000736 Amenorrhea Diseases 0.000 description 1
- 206010001928 Amenorrhoea Diseases 0.000 description 1
- 206010027304 Menopausal symptoms Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 206010046788 Uterine haemorrhage Diseases 0.000 description 1
- 239000012445 acidic reagent Substances 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 231100000540 amenorrhea Toxicity 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- JYYOBHFYCIDXHH-UHFFFAOYSA-N carbonic acid;hydrate Chemical compound O.OC(O)=O JYYOBHFYCIDXHH-UHFFFAOYSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- -1 estradiol valerate Chemical compound 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 201000004535 ovarian dysfunction Diseases 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000001850 reproductive effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0051—Estrane derivatives
- C07J1/0066—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa
- C07J1/007—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
- C07J1/0074—Esters
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Abstract
The invention discloses a preparation method of estradiol-17 beta-alkyl acid ester, belonging to the technical field of preparation and processing of steroid hormone medicines. The method takes estradiol as a raw material, the raw material is dissolved in an organic solvent, alkyl acid is added, then a catalyst and a dehydrating agent are added to react to generate a mixture of 3, 17 beta-dialkyl acid ester and 17 beta-alkyl acid ester, and then a hydrolysis reagent is added to hydrolyze to generate 17 beta-alkyl acid ester. The method can solve the problems of higher temperature, lower yield, more expensive reagent, higher toxicity and the like in the esterification process of the estradiol 17 beta-hydroxyl in the traditional process by using the novel dehydrating agent and the specific catalyst, ensures that the process condition is milder, the purity and the yield of the prepared product are higher, and the reagent is more environment-friendly and accords with the industrial development trend of green chemistry.
Description
Technical Field
The invention relates to the technical field of preparation and processing of steroid hormone medicaments, in particular to a preparation method of estradiol-17 beta-alkyl acid ester.
Background
The estradiol-17 beta-alkyl acid ester is an estrogen medicine, has the pharmacological action of estrogen, can promote and regulate the normal development of female reproductive organs and side sex characteristics, and participates in the regulation of the function of an ovary axis. Clinically, the traditional Chinese medicine composition is used for various symptoms caused by ovarian insufficiency or ovarian hormone deficiency, mainly comprising functional uterine bleeding, primary amenorrhea, menopausal syndrome, prostate cancer and the like. Estradiol valerate and estradiol heptanoate are the most representative esters of estradiol-17 beta-alkyl acids.
The traditional preparation process of the estradiol valerate mainly takes the estradiol as a raw material, and is subjected to azeotropic dehydration with n-valeric acid to prepare 3, 17 beta-dipentaerythritol ester, and then alkaline hydrolysis is carried out to obtain the estradiol valerate, and the synthetic route is as follows:
the method has the defects that the azeotropic dehydration reaction temperature is up to 170-200 ℃, so that more impurities are caused, and the yield is low.
Chinese patent CN 109503690A reports a preparation method of estradiol heptanoate, which takes estradiol as a raw material and performs esterification reaction with heptanoyl chloride under the action of pyridine to prepare a mixture of 3, 17 beta-diheptanoate and 17 beta-heptanoate, and then alkaline hydrolysis is performed to obtain the estradiol heptanoate, wherein the synthesis route is as follows:
pyridine and heptanoyl chloride used in the method are chemical reagents with high toxicity, the heptanoyl chloride is high in price and high in cost, and the yield of the whole route is low.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides a preparation method of estradiol-17 beta-alkyl acid ester, which has the advantages of mild reaction, environmental protection and high yield.
The aim of the invention is achieved by the following modes:
a preparation method of estradiol-17 beta-alkyl acid ester comprises the following synthetic route:
wherein R is C2-C18 alkyl;
the method specifically comprises the following steps:
1) Esterification reaction: dissolving a compound I, namely estradiol, in an organic solvent A, adding an alkyl acid, a catalyst and a dehydrating agent, stirring at 5-35 ℃ for complete reaction, adding water for quenching, adding alkali for regulating pH to be neutral, layering, and concentrating an organic layer until the organic layer is dry to obtain a mixture of the compounds II and III;
further, the organic solvent A is at least one of dichloromethane, chloroform or toluene, and the volume dosage of the organic solvent A is 2-20 times of the weight of the substrate compound I;
further, the alkyl acid is one of C2-C18 alkyl acid, and the volume or weight dosage of the alkyl acid is 0.2-2 times of the weight of the substrate compound I;
preferably, the alkyl acid is n-valeric acid or n-heptanoic acid;
further, the catalyst is 4-dimethylaminopyridine, and the weight dosage of the catalyst is 0.02-0.5 times of the weight of the substrate compound I;
further, the dehydrating agent is one or more of N, N-diisopropyl carbodiimide (DIC), 1' -Carbonyl Diimidazole (CDI) or 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCl), and the weight dosage of the dehydrating agent is 0.4-2 times of the weight of the substrate compound I;
further, the alkali is one or more of hydroxide, carbonate or bicarbonate water solution with the mass concentration of 2-20%;
2) Hydrolysis reaction: dissolving the mixture of the compounds II and III obtained in the step 1 in an organic solvent B, adding a hydrolysis reagent, stirring at the temperature of-10-20 ℃ for complete reaction, adding acid to adjust the pH value to 6-7, concentrating, carrying out water separation, filtering, drying and refining to obtain the compound III, namely the estradiol-17 beta-alkyl acid ester.
Further, the organic solvent B is one or more of methanol, ethanol, acetone or dichloromethane, and the volume dosage of the organic solvent B is 2-20 times of the weight of the substrate compound I;
further, the hydrolytic reagent is one or more of sulfite, carbonate or bicarbonate aqueous solution with the mass concentration of 2-20%, and the volume dosage of the hydrolytic reagent is 1-10 times of the weight of the substrate compound I;
further, the acid is one or more of acetic acid, formic acid, hydrochloric acid or sulfuric acid aqueous solution with the mass concentration of 5-100%;
preferably, the alcohol is methanol or ethanol.
The invention has the technical characteristics and beneficial effects that:
1) The method uses the novel dehydrating agent and the specific catalyst to form active ester by combining the dehydrating agent with the acid reagent and then reacts with the substrate to generate the ester, avoids the azeotropic dehydration mode and uses reagents such as acyl chloride, pyridine and the like, thereby solving the problems of higher temperature, lower yield, more expensive reagent, higher toxicity and the like in the esterification process of the 17 beta-hydroxy of the estradiol in the traditional preparation process;
2) The synthesis process of the estradiol-17 beta-alkyl acid ester can be smoothly carried out at the temperature of 5-35 ℃, the condition is milder, the process flow is simple, the controllability is good, and the method is more suitable for industrial production;
3) The purity of the product prepared by the preparation method is higher than 99%, the yield of estradiol valerate is higher than 110%, the yield of estradiol heptanoate is higher than 115%, and the quality is stable;
4) The preparation method provided by the invention has the advantages of low cost of the used reagent, environmental protection, good economic and social benefits, and is more in line with the industrial development trend of green chemistry.
Detailed Description
The invention is further illustrated below in connection with examples, which are not intended to limit the invention.
The specific experimental procedures or conditions are not illustrated in the examples and can be carried out according to the operation of conventional experimental methods described in the publications in the field, the reagents or equipment used not to mention the manufacturer are conventional products available commercially.
EXAMPLE 1 preparation of estradiol valerate
1) The reaction flask is added with 20g of estradiol as compound I, 200mL of dichloromethane and 12mL of n-valeric acid, 2g of 4-dimethylaminopyridine, 15g of N, N-diisopropylcarbodiimide and the mixture is stirred at 25 ℃ for complete reaction, 50mL of water is added for quenching reaction, 10wt% of sodium carbonate aqueous solution is used for regulating pH to be neutral, layering is carried out, and the organic layer is concentrated to remove the solvent, thus obtaining the mixture of the compounds II and III.
2) Adding the mixture of the compounds II and III obtained in the previous step into a reaction bottle, adding 200mL of methanol, adding 100mL of 10wt% sodium carbonate aqueous solution, stirring at 20 ℃ for complete reaction, adding acetic acid to adjust the pH to 6-7, concentrating, water separating, filtering, drying, refining with ethanol to obtain 22g of compound III, namely estradiol valerate, and obtaining the total mass yield: 110%, HPLC purity: 99.3%.
EXAMPLE 2 preparation of estradiol valerate
1) The reaction flask was charged with 20g of estradiol as compound I, 200mL of toluene and 12mL of n-valeric acid, 2g of 4-dimethylaminopyridine, 15g of 1,1' -carbonyldiimidazole were added, the reaction was completed under stirring at 10℃and 50mL of water was added to quench the reaction, the pH was adjusted to neutral with 10wt% aqueous potassium bicarbonate, the layers were separated, and the organic layer was concentrated to remove the solvent to give a mixture of compounds II and III.
2) Adding the mixture of the compounds II and III obtained in the previous step into a reaction bottle, adding 200mL of ethanol, adding 100mL of 2wt% sodium sulfite aqueous solution, stirring at 0 ℃ for complete reaction, adding 10wt% hydrochloric acid aqueous solution for regulating the pH to 6-7, concentrating, water separating, filtering, drying, and refining the ethanol to obtain the compound III, namely 22.2g of estradiol valerate, wherein the total mass yield is: 111%, HPLC purity: 99.2%.
EXAMPLE 3 preparation of estradiol heptanoate
1) The reaction flask was charged with 20g of estradiol as compound I, 200mL of chloroform and 13mL of n-heptanoic acid, 20g of 4-dimethylaminopyridine and 20g of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride were added, the reaction was completed under stirring at 25℃and 50mL of water was added to quench the reaction, the pH was adjusted to be neutral with 2wt% aqueous sodium hydroxide solution, the layers were separated, and the organic layer was concentrated to remove the solvent to obtain a mixture of compounds II and III.
2) Adding the mixture of the compounds II and III obtained in the previous step into a reaction bottle, adding 200mL of methanol, adding 100mL of 10wt% potassium carbonate aqueous solution, stirring at 20 ℃ for complete reaction, adding 5wt% sulfuric acid aqueous solution for regulating the pH to 6-7, concentrating, water separating, filtering, drying, and refining the methanol to obtain the compound III, namely 23.1g of estradiol heptanoate, wherein the total mass yield is: 115.5%, HPLC purity: 99.4%.
EXAMPLE 4 preparation of estradiol heptanoate
1) The reaction flask is added with 20g of estradiol as compound I, 200mL of dichloromethane and 13mL of n-heptanoic acid, 2g of 4-dimethylaminopyridine, 15g of N, N-diisopropylcarbodiimide and 50mL of water for quenching reaction under stirring at 10 ℃, the pH is adjusted to be neutral by using 10wt% of potassium carbonate aqueous solution, the mixture of the compounds II and III is obtained by layering, and the organic layer is concentrated to remove the solvent.
2) Adding the mixture of the compounds II and III obtained in the previous step into a reaction bottle, adding 200mL of acetone, adding 100mL of 20wt% potassium bicarbonate aqueous solution, stirring at 20 ℃ for complete reaction, adding 10wt% hydrochloric acid aqueous solution for regulating the pH to 6-7, concentrating, water separating, filtering, drying, and refining methanol to obtain the compound III, namely 23.3g of estradiol heptanoate, wherein the total mass yield is: 116.5%, HPLC purity: 99.2%.
The present invention is not limited to the above-mentioned embodiments, and any changes or substitutions that can be easily understood by those skilled in the art within the technical scope of the present invention are intended to be included in the scope of the present invention.
Claims (5)
1. A preparation method of estradiol-17 beta-alkyl acid ester is characterized by comprising the following synthetic route:
wherein R is C2-C18 alkyl;
the method specifically comprises the following steps:
1) Esterification reaction: dissolving a compound I, namely estradiol, in an organic solvent A, adding an alkyl acid, a catalyst and a dehydrating agent, stirring at 5-35 ℃ for complete reaction, adding water for quenching, adding alkali for regulating pH to be neutral, layering, and concentrating an organic layer until the organic layer is dry to obtain a mixture of the compounds II and III;
2) Hydrolysis reaction: dissolving the mixture of the compounds II and III obtained in the step 1 in an organic solvent B, adding a hydrolysis reagent, stirring at the temperature of-10-20 ℃ for complete reaction, adding acid to adjust the pH value to 6-7, concentrating, water separating, filtering, drying, and refining with alcohols to obtain the compound III, namely the estradiol-17 beta-alkyl acid ester.
2. The method for preparing estradiol-17 beta-alkyl acid ester according to claim 1, wherein in the step 1), the organic solvent a is at least one of dichloromethane, chloroform or toluene, and the volume amount of the organic solvent a is 2-20 times of the weight of the substrate compound I; the alkyl acid is one of C2-C18 alkyl acid, and the volume or weight dosage of the alkyl acid is 0.2-2 times of the weight of the substrate compound I; the catalyst is 4-dimethylaminopyridine, and the weight dosage of the catalyst is 0.02-0.5 times of the weight of the substrate compound I; the dehydrating agent is one or more of N, N-diisopropyl carbodiimide (DIC), 1' -Carbonyl Diimidazole (CDI) or 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI), and the weight dosage of the dehydrating agent is 0.4-2 times of the weight of the substrate compound I; the alkali is one or more of hydroxide, carbonate or bicarbonate aqueous solution with mass concentration of 2-20%.
3. The process for the preparation of estradiol-17 beta-alkyl acid esters according to claim 1, characterized in that in step 1) the alkyl acid is n-valeric acid or n-heptanoic acid.
4. The method for preparing estradiol-17 beta-alkyl acid ester according to claim 1, wherein in the step 2), the organic solvent B is one or more of methanol, ethanol, acetone or methylene dichloride, and the volume dosage of the organic solvent B is 2-20 times of the weight of the substrate compound I; the hydrolytic reagent is one or more of sulfite, carbonate or bicarbonate aqueous solution with the mass concentration of 2-20%, and the volume dosage of the hydrolytic reagent is 1-10 times of the weight of the substrate compound I; the acid is one or more of acetic acid, formic acid, hydrochloric acid or sulfuric acid aqueous solution with the mass concentration of 5-100%.
5. The process for the preparation of estradiol-17 beta-alkyl acid esters according to claim 1, characterized in that in step 2) the alcohol is methanol or ethanol.
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2023
- 2023-05-23 CN CN202310581641.XA patent/CN116751242A/en active Pending
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