CN111647035A - Preparation method of levonorgestrel - Google Patents
Preparation method of levonorgestrel Download PDFInfo
- Publication number
- CN111647035A CN111647035A CN202010540656.8A CN202010540656A CN111647035A CN 111647035 A CN111647035 A CN 111647035A CN 202010540656 A CN202010540656 A CN 202010540656A CN 111647035 A CN111647035 A CN 111647035A
- Authority
- CN
- China
- Prior art keywords
- organic solvent
- levonorgestrel
- reaction
- potassium
- acid
- 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.)
- Pending
Links
- WWYNJERNGUHSAO-XUDSTZEESA-N (+)-Norgestrel Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](CC)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 WWYNJERNGUHSAO-XUDSTZEESA-N 0.000 title claims abstract description 26
- 229960004400 levonorgestrel Drugs 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- 238000000034 method Methods 0.000 claims abstract description 16
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 20
- 239000003960 organic solvent Substances 0.000 claims description 16
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- 239000000243 solution Substances 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 14
- 239000007864 aqueous solution Substances 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 10
- 239000012043 crude product Substances 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 239000000758 substrate Substances 0.000 claims description 8
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 7
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- 238000005905 alkynylation reaction Methods 0.000 claims description 6
- 238000006386 neutralization reaction Methods 0.000 claims description 6
- 150000007530 organic bases Chemical class 0.000 claims description 6
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 5
- 238000007670 refining Methods 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- WQKGAJDYBZOFSR-UHFFFAOYSA-N potassium;propan-2-olate Chemical compound [K+].CC(C)[O-] WQKGAJDYBZOFSR-UHFFFAOYSA-N 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 3
- 235000010265 sodium sulphite Nutrition 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
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 2
- CBMSDILKECEMOT-UHFFFAOYSA-N potassium;2-methylpropan-1-olate Chemical compound [K+].CC(C)C[O-] CBMSDILKECEMOT-UHFFFAOYSA-N 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 2
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 239000007858 starting material Substances 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 230000007062 hydrolysis Effects 0.000 abstract description 2
- 230000007547 defect Effects 0.000 abstract 1
- 230000007935 neutral effect Effects 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- CIHXIRAAMAUYLZ-UHFFFAOYSA-N [K+].[K+].[C-]#[C-] Chemical compound [K+].[K+].[C-]#[C-] CIHXIRAAMAUYLZ-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 206010013908 Dysfunctional uterine bleeding Diseases 0.000 description 1
- 102000002322 Egg Proteins Human genes 0.000 description 1
- 108010000912 Egg Proteins Proteins 0.000 description 1
- 201000009273 Endometriosis Diseases 0.000 description 1
- 208000019255 Menstrual disease Diseases 0.000 description 1
- 206010027514 Metrorrhagia Diseases 0.000 description 1
- 210000003756 cervix mucus Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940095053 emergency contraceptive drug Drugs 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 229940127234 oral contraceptive Drugs 0.000 description 1
- 239000003539 oral contraceptive agent Substances 0.000 description 1
- 230000016087 ovulation Effects 0.000 description 1
- 210000004681 ovum Anatomy 0.000 description 1
- FWFGVMYFCODZRD-UHFFFAOYSA-N oxidanium;hydrogen sulfate Chemical compound O.OS(O)(=O)=O FWFGVMYFCODZRD-UHFFFAOYSA-N 0.000 description 1
- 239000003408 postcoitus contraceptive agent Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 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
- C07J1/0081—Substituted in position 17 alfa and 17 beta
- C07J1/0088—Substituted in position 17 alfa and 17 beta the substituent in position 17 alfa being an unsaturated hydrocarbon group
- C07J1/0096—Alkynyl derivatives
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 levonorgestrel, belonging to the technical field of preparation and processing of medicines. The levonorgestrel is prepared by taking 18-methylestra-2, 5(10) -diene-3-methoxy-17-ketone as a starting material through the steps of ethynylation and hydrolysis. The preparation method of the levonorgestrel has the advantages of improving the defects of the traditional process, along with mild reaction conditions, high overall conversion rate, simple and convenient operation, suitability for industrial production and wide market prospect.
Description
Technical Field
The invention relates to the technical field of preparation of medicines, and particularly relates to a preparation method of levonorgestrel.
Background
The chemical name of the levonorgestrel is D (-) -17 alpha-ethynyl-17 beta-hydroxy-18-methylestra-4-en-3-one, and the levonorgestrel is an oral contraceptive with wider application. Levonorgestrel can inhibit ovulation and prevent pregnant ovum implantation, and simultaneously increases cervical mucus concentration and prevents sperm progression, thus being one of the most widely applied emergency contraceptives at home and abroad at present. Levonorgestrel can also be used for treating menoxenia, dysfunctional uterine bleeding and endometriosis.
The existing synthesis methods of levonorgestrel mainly comprise two methods:
the method is characterized in that DL-18-methyl-4-estrene-3, 17-diketone is used as a starting material, acetylene is introduced to react in the presence of potassium hydroxide, and the synthetic route of the 18-methylnorethindrone is as follows:
the method is characterized in that 18-methylestra-2, 5(10) -diene-3-methoxy-17-ketone is used as a starting material, potassium hydroxide is reacted with acetylene to prepare potassium acetylide, the potassium acetylide is subjected to ethynylation reaction with the starting material, and hydrolysis is carried out to obtain 18-methylnorethindrone, wherein the synthetic route is as follows:
in the two synthetic routes, water is generated in the reaction process, which is not beneficial to the proceeding of the ethynylation reaction, and the total conversion rate is not high, so that the method is not suitable for industrial production.
Disclosure of Invention
In order to solve the problems, the invention provides a preparation method of levonorgestrel, which has the advantages of simple reaction process, mild conditions and high conversion rate.
The purpose of the invention is realized by the following modes: a preparation method of levonorgestrel comprises the following steps:
the method specifically comprises the following steps:
1) alkynylation reaction: dissolving 18-methylestra-2, 5(10) -diene-3-methoxy-17-ketone (1) in an organic solvent A, adding an organic base A, controlling the temperature to be minus 20-30 ℃, introducing acetylene, stirring for reaction, adding an acid solution A for neutralization after the reaction is finished, concentrating, adding water for elutriation, and filtering to obtain an intermediate 2;
2) and (3) hydrolysis reaction: dissolving the intermediate (2) obtained in the step 1) in an organic solvent B, adding an acid solution B, reacting at-10-50 ℃, adding an alkali B for neutralization after the reaction is finished, concentrating, adding water for elutriation, filtering to obtain a crude product, refining the crude product with an organic solvent C, and drying to obtain the levonorgestrel.
Further, in the step 1), the organic solvent A is at least one of acetone, butanone, tetrahydrofuran, methyltetrahydrofuran, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, toluene, xylene or sulfolane, and the volume amount of the organic solvent A is 5-30 times that of the substrate 18-methylestra-2, 5(10) -diene-3-methoxy-17-one (1); wherein the organic base A is one of potassium tert-butoxide, potassium isobutoxide, potassium isopropoxide, potassium ethoxide, sodium ethoxide or sodium methoxide, and the weight consumption of the organic base A is 1-5 times of that of 18-methylestra-2, 5(10) -diene-3-methoxy-17-ketone (1) serving as a substrate; wherein the acid solution A is one of aqueous solutions of hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid or formic acid, and the mass concentration of the acid solution A is 5-30%.
Further, the organic solvent B in the step 2) is one of acetone, butanone, tetrahydrofuran or methyl tetrahydrofuran, and the volume consumption of the organic solvent B is 5-30 times that of the substrate intermediate (2); wherein the acid solution B is a hydrochloric acid or sulfuric acid aqueous solution, the mass concentration of the acid solution B is 5-30%, and the dosage of the acid solution B is 0.5-5 times of that of the substrate intermediate (2); the alkali B is one of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium sulfite, sodium hydroxide and potassium hydroxide aqueous solutions, and the mass concentration of the alkali B is 5-30%.
Further, the organic solvent C is one of methanol, ethanol and acetone.
Compared with the prior art, the invention has the beneficial effects that:
1. the reaction raw materials of the invention are cheap and easy to obtain.
2. The method has the advantages of short reaction route, low operation cost and simple and convenient operation, and is suitable for industrial production.
3. The method is carried out at low temperature or slightly higher than room temperature, the overall reaction is mild, the total mass yield is higher than 85%, and the product purity is higher than 99.0%.
4. In the traditional process, water is generated when potassium hydroxide is used for carrying out the alkynylation reaction, and the reaction is not carried out.
Detailed Description
The invention is further illustrated with reference to the following examples, which are not intended to limit the invention.
The specific experimental procedures or conditions are not shown in the examples, and the procedures can be performed according to the conventional experimental methods described in the publications in the field, and the reagents or equipment used are not indicated by manufacturers, and are all conventional products which can be obtained commercially.
Example 1 a method for the preparation of levonorgestrel, comprising the steps of:
1) alkynylation reaction: dissolving 18 g of methyl estra-2, 5(10) -diene-3-methoxy-17-ketone (1) in 750ml of tetrahydrofuran, adding 50g of potassium tert-butoxide, introducing acetylene at the controlled temperature of 5 ℃, stirring for reaction, adding a 5% hydrochloric acid aqueous solution for neutralization to neutrality after the reaction is finished, concentrating, adding water for elutriation, and filtering to obtain 52g of an intermediate 2;
2) and (3) hydrolysis reaction: dissolving 52g of the intermediate (2) obtained in the step 1) in 1500ml of acetone, adding 250ml of 5% hydrochloric acid aqueous solution, reacting at 0 ℃, adding 10% sodium carbonate aqueous solution to neutralize to be neutral after the reaction is finished, concentrating, adding water for elutriation, filtering to obtain a crude product, refining the crude product with methanol, and drying to obtain 43g of levonorgestrel, wherein the total mass yield of the product is 86% and the HPLC content is 99.3%.
Example 2 a method for preparing levonorgestrel, comprising the steps of:
1) alkynylation reaction: dissolving 18 g of methyl estra-2, 5(10) -diene-3-methoxy-17-ketone (1) in 250ml of dimethyl sulfoxide, adding 100g of potassium isopropoxide, controlling the temperature and introducing acetylene at 30 ℃, stirring for reaction, adding 10% sulfuric acid water solution A to neutralize to be neutral after the reaction is finished, concentrating, adding water for elutriation, and filtering to obtain 53g of intermediate 2;
2) and (3) hydrolysis reaction: dissolving 53g of the intermediate (2) obtained in the step 1) in 250ml of tetrahydrofuran, adding 27ml of 30% hydrochloric acid aqueous solution, reacting at-10 ℃, adding 5% sodium hydroxide aqueous solution to neutralize to be neutral after the reaction is finished, concentrating, adding water for elutriation, filtering to obtain a crude product, refining the crude product with ethanol, and drying to obtain 43.5g of levonorgestrel, wherein the total mass yield of the product is 87%, and the HPLC content is 99.2%.
Example 3 a method of preparing levonorgestrel, comprising the steps of:
1) alkynylation reaction: dissolving 18 g of methyl estra-2, 5(10) -diene-3-methoxy-17-ketone (1) in 1500ml of toluene, adding 250g of sodium ethoxide, controlling the temperature to be minus 20 ℃, introducing acetylene, stirring for reaction, adding 30% acetic acid aqueous solution for neutralization to be neutral after the reaction is finished, concentrating, adding water for water precipitation, and filtering to obtain 51g of an intermediate 2;
2) and (3) hydrolysis reaction: dissolving 51g of the intermediate (2) obtained in the step 1) in 750ml of butanone, adding 70ml of 10% sulfuric acid aqueous solution, reacting at 50 ℃, adding 30% sodium sulfite aqueous solution to neutralize to be neutral after the reaction is finished, concentrating, adding water for elutriation, filtering to obtain a crude product, refining the crude product with acetone, and drying to obtain 43g of levonorgestrel, wherein the total mass yield of the product is 86% and the HPLC content is 99.4%.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope of the present invention are included in the scope of the present invention.
Claims (3)
1. A preparation method of levonorgestrel is characterized by comprising the following preparation route:
the method specifically comprises the following steps:
1) alkynylation reaction: dissolving 18-methylestra-2, 5(10) -diene-3-methoxy-17-ketone (1) in an organic solvent A, adding an organic base A, controlling the temperature to be minus 20-30 ℃, introducing acetylene, stirring for reaction, adding an acid solution A for neutralization after the reaction is finished, concentrating, adding water for elutriation, and filtering to obtain an intermediate 2;
2) and (3) hydrolysis reaction: dissolving the intermediate (2) obtained in the step 1) in an organic solvent B, adding an acid solution B, reacting at-10-50 ℃, adding an alkali B for neutralization after the reaction is finished, concentrating, adding water for elutriation, filtering to obtain a crude product, refining the crude product with an organic solvent C, and drying to obtain the levonorgestrel.
2. The method for preparing levonorgestrel according to claim 1, wherein the organic solvent A in step 1) is at least one selected from acetone, butanone, tetrahydrofuran, methyltetrahydrofuran, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, toluene, xylene and sulfolane, and the volume of the organic solvent A is 5-30 times that of the 18-methylestra-2, 5(10) -diene-3-methoxy-17-one (1) serving as a substrate; wherein the organic base A is one of potassium tert-butoxide, potassium isobutoxide, potassium isopropoxide, potassium ethoxide, sodium ethoxide or sodium methoxide, and the weight consumption of the organic base A is 1-5 times of that of 18-methylestra-2, 5(10) -diene-3-methoxy-17-ketone (1) serving as a substrate; wherein the acid solution A is one of aqueous solutions of hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid or formic acid, and the mass concentration of the acid solution A is 5-30%.
3. The method for preparing levonorgestrel according to claim 1, wherein the organic solvent B in the step 2) is one of acetone, butanone, tetrahydrofuran or methyltetrahydrofuran, and the volume of the organic solvent B is 5-30 times that of the substrate intermediate (2); wherein the acid solution B is a hydrochloric acid or sulfuric acid aqueous solution, the mass concentration of the acid solution B is 5-30%, and the dosage of the acid solution B is 0.5-5 times of that of the substrate intermediate (2); wherein the alkali B is one of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium sulfite, sodium hydroxide and potassium hydroxide aqueous solutions, and the mass concentration of the alkali B is 5-30%; the organic solvent C is one of methanol, ethanol and acetone.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010540656.8A CN111647035A (en) | 2020-06-15 | 2020-06-15 | Preparation method of levonorgestrel |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010540656.8A CN111647035A (en) | 2020-06-15 | 2020-06-15 | Preparation method of levonorgestrel |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN111647035A true CN111647035A (en) | 2020-09-11 |
Family
ID=72345710
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010540656.8A Pending CN111647035A (en) | 2020-06-15 | 2020-06-15 | Preparation method of levonorgestrel |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111647035A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114031659A (en) * | 2021-11-22 | 2022-02-11 | 湖南科益新生物医药有限公司 | Preparation method of levonorgestrel impurity O |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3418326A (en) * | 1966-03-22 | 1968-12-24 | American Home Prod | 5-alkyl-13-polycarbon-gonanes |
| WO2012110947A1 (en) * | 2011-02-17 | 2012-08-23 | Lupin Limited | An improved process for preparation of levonorgestrel |
-
2020
- 2020-06-15 CN CN202010540656.8A patent/CN111647035A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3418326A (en) * | 1966-03-22 | 1968-12-24 | American Home Prod | 5-alkyl-13-polycarbon-gonanes |
| WO2012110947A1 (en) * | 2011-02-17 | 2012-08-23 | Lupin Limited | An improved process for preparation of levonorgestrel |
Non-Patent Citations (1)
| Title |
|---|
| VON CLEMENS RUFER ET AL.: "Totalsynthese optisch aktiver Steroide, III Totalsynthese von optisch aktiven 13-Athyl-gonan-Derivaten", 《LIEBIGS ANN. CHEM.》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114031659A (en) * | 2021-11-22 | 2022-02-11 | 湖南科益新生物医药有限公司 | Preparation method of levonorgestrel impurity O |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN111606962B (en) | Synthesis method of levonorgestrel | |
| CN114181272B (en) | Synthesis method of levonorgestrel | |
| CN104262442A (en) | Preparation method for progestin | |
| CN103664923B (en) | The preparation method of Nifuratel | |
| CN112062801B (en) | Progesterone refining method | |
| CN110003298A (en) | A kind of synthetic method of Promestriene | |
| CN111647035A (en) | Preparation method of levonorgestrel | |
| CN110204585B (en) | Synthesis method of progesterone | |
| CN110218234A (en) | The synthesis technology of Promestriene | |
| CN104098640A (en) | Progesterone preparation method | |
| BRPI0814887B1 (en) | process for toluidine compound production | |
| CN110483594B (en) | Method for synthesizing azithromycin | |
| CN113416227A (en) | Novel method for preparing medroxyprogesterone acetate | |
| CN108623579B (en) | Synthesis method of piroxicam | |
| CN101844989B (en) | Preparation method for clofedanol and hydrochloride thereof | |
| CN111470946A (en) | Preparation method of 2-ethyl-1-butanol serving as midbody of Reidesciclovir | |
| CN104311456A (en) | Preparation method of guaiacol potassium sulfoacid | |
| CN101955466A (en) | Synthesis method of 5-trifluoromethyluracil | |
| CN110627611A (en) | A method for synthesizing 1,4-dibromo-2,5-diiodobenzene | |
| CN118420442B (en) | Method for preparing vanillin by reducing vanillin with silicon powder | |
| CN110054558A (en) | A kind of preparation method of 1- trifluoromethyl cyclopropane -1- formic acid | |
| CN111995651A (en) | Progesterone preparation method | |
| CN114409724A (en) | Novel preparation method of danazol | |
| CN113956317A (en) | Impurity removal method for progesterone | |
| WO2023115524A1 (en) | Method for preparing 1,4-butanedisulfonic acid sodium salt |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20200911 |
|
| RJ01 | Rejection of invention patent application after publication |