CN113817011A - The preparation method of androstane 16ɑ-methyl protected by 3-enol ether or ester - Google Patents
The preparation method of androstane 16ɑ-methyl protected by 3-enol ether or ester Download PDFInfo
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- CN113817011A CN113817011A CN202010557700.6A CN202010557700A CN113817011A CN 113817011 A CN113817011 A CN 113817011A CN 202010557700 A CN202010557700 A CN 202010557700A CN 113817011 A CN113817011 A CN 113817011A
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- C07—ORGANIC CHEMISTRY
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- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0003—Androstane derivatives
- C07J1/0011—Androstane derivatives substituted in position 17 by a keto group
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Abstract
本发明涉及一种高选择性、高收率制备16ɑ‑甲基雄甾药物中间体的制备方法。通过不断地实验研究，3位烯醇醚或酯保护的雄甾为底物采用N，N‑二甲基丙烯基脲，与一种或多种金属锂试剂的拔氢试剂反应后，再与氯甲烷、溴甲烷、碘甲烷中的一种或多种的取代试剂反应，可以高收率、高选择性的制备16ɑ‑甲基雄甾药物中间体。The invention relates to a preparation method for preparing a 16ɑ-methylandrostane drug intermediate with high selectivity and high yield. Through continuous experimental research, the 3-enol ether or ester-protected androstane as the substrate adopts N,N-dimethylpropenyl urea, reacts with one or more hydrogen-extracting reagents of metal lithium reagents, and then reacts with One or more substitution reagents among methyl chloride, methyl bromide and methyl iodide can prepare 16ɑ-methyl androstane drug intermediate with high yield and high selectivity.
Description
The technical field is as follows:
the invention relates to a chemical synthesis method of a steroid drug intermediate, in particular to a preparation method of a 16 alpha-methyl androstane drug intermediate.
Background art:
glucocorticoids are steroid compounds secreted by the adrenal cortex, the physiological effects of which are manifested in the effects on sugars, proteins, fats, water and electrolytes. It can inhibit synthesis and release of inflammatory mediators such as bradykinin, prostaglandin E2, 5-hydroxytryptamine, histamine, etc., reduce vascular permeability, stabilize lysosome membrane, and inhibit phagocytosis. Has strong anti-inflammatory effect on inflammation caused by various reasons, can relieve exudation, edema, telangiectasia, leukocyte infiltration and phagocytosis reaction in early stage of inflammation, inhibit proliferation of capillary and fibroblast in later stage of inflammation, inhibit pathological change caused by immunoreaction, and relieve symptoms of the disease.
Pregnane compounds with 16 alpha-methyl, such as dexamethasone, have better anti-inflammatory effect, and in recent years, dexamethasone prepared by taking androstane compounds as substrates and side chains is gradually realized, so that the preparation of dexamethasone by taking 16 alpha-methyl androstane compounds as substrates is possible.
A Bowers et al ("Steroids. CLXIX. The preparation of 16. alpha. -methyl-and 16. beta. -methyl oxysterone", Journal of The Chemical Society, 1961, p. 4057-4060, 1.1.1961) reported a preparation method for androstanes by removing The 17-position side chain of pregna 16. alpha. -methyl compounds (p. 4057):
a method for methylating the 16-position of an androstane compound is reported by Nichols I.Cartithers et al ("Synthesis of Corticoids from 9. alpha. -Hydroxyyandrost-4-ene-3, 17-dione", J. org. chem., Vol.57, 3, p.961-965, p.1992, 12.31), in the following scheme:
compound 1 with (CH) dissolved in THF3O)3CH and p-TSA. H2O reaction to obtain a compound 2; dissolving the compound 2 in dichloromethane, and reacting with diethyl oxalate, NaOMe and MeI in sequence to obtain a compound 7 with 16 beta-methyl position.
Rene Maltais et al ("Solid-phase synthesis of model ligands of 3 α,17 β -dihydroxy-16 α - (N-substistuted-aminoethane) -5 α -anstaties for the resolution of steroidal therapeutic agents", Molecular Diversity, Vol.9, pp.1-3, pp.67-79, 31.2005) reported a process for the preparation of 16 α -substituted steroids at a reaction temperature of-78 ℃ using tetrahydrofuran, the substitution reagent methyl bromoacetate, the catalyst hexamethylphosphoric triamide, and the hydrogen abstraction reagent lithium diisopropylamide.
Disclosure of Invention
The invention relates to a preparation method for preparing a 16 alpha-methyl androstane drug intermediate with high selectivity and high yield.
Through continuous experimental research, surprisingly, the 16 alpha-methyl androstane drug intermediate can be prepared with high yield and high selectivity by reacting N, N-dimethyl propylene urea with a hydrogen extraction reagent of one or more metal lithium reagents and then reacting with a substitution reagent of one or more of methyl chloride, methyl bromide and methyl iodide.
N, N-Dimethylpropenylurea (1, 3-Dimethyl-3,4, 5,6-tetrahydro-2(1H) -pyrimidinone
DMPU) is a non-toxic, high-stability material which is solid at normal temperature, and has wider application range when other similar compounds are added.
A process for the preparation of a compound of formula 2, characterized in that:
adding the compound 1 into a solvent, firstly using a hydrogen removing reagent to remove hydrogen of 16-site alpha hydrogen under the action of a catalyst N, N-dimethyl propylene urea, and then using a substitution reagent to perform substitution reaction to obtain a compound shown in a formula 2, wherein the solvent is one or more of 2-6 carbon ethers, 2-4 carbon nitriles and 5-10 carbon alkanes which are liquid at normal temperature; the hydrogen drawing reagent is one or more of hexamethyldisilazane-based amino lithium, alkyl amino lithium and alkyl lithium, and the alkyl is alkyl with 3-8 carbons; the substitution reagent is one or more of chloromethane, bromomethane and iodomethane;
R1= -OCH3、-OCH2CH3or-OCH (CH)3)2、-O-COR4；
R2= -H or-OH;
R3= -H, OH, Cl, F, or Br;
R4h or alkyl of 1 to 3 carbons;
9（11）bit "
"represents a single bond or a double bond;
16 bit "
"represents 16. alpha. -methyl.
The preparation method is characterized in that the reaction temperature is-80-20 ℃.
The preparation method is characterized in that the reaction temperature is-80-0 ℃.
The preparation method is characterized in that the reaction temperature is-80 to-30 ℃.
The preparation method is characterized in that the molar ratio of the compound 1 to the catalyst N, N-dimethyl propylene urea is 1:0.1-2, the molar ratio of the compound 1 to the hydrogen-removing reagent is 1:1-3, and the molar ratio of the compound 1 to the substitution reagent is 1: 1-3.
The preparation method is characterized in that the molar ratio of the compound 1 to the catalyst N, N-dimethyl propylene urea is 1:0.5-2, the molar ratio of the compound 1 to the hydrogen-removing reagent is 1:1-2, and the molar ratio of the compound 1 to the substitution reagent is 1: 1-2.
The preparation method is characterized in that the molar ratio of the compound 1 to the catalyst N, N-dimethyl propylene urea is 1:1-2, the molar ratio of the compound 1 to the hydrogen extraction reagent is 1:1.2-2, and the molar ratio of the compound 1 to the substitution reagent is 1: 1.2-2.
The above production method is characterized in that the ether having 2 to 6 carbon atoms is a cyclic ether.
The preparation method is characterized in that the ether with 2-6 carbon atoms is diethyl ether and tetrahydrofuran.
The preparation method is characterized in that the alkane with 5-10 carbon atoms is one or more of n-hexane, isohexane, cyclohexane, n-heptane, isoheptane, cycloheptane, n-octane and isooctane.
The preparation method is characterized in that the alkane with 5-10 carbon atoms is one or more of normal hexane, isohexane and cyclohexane.
The preparation method is characterized in that the nitrile with 2-4 carbon atoms is acetonitrile.
The preparation method is characterized in that the lithium alkyl amide hydrogen-withdrawing reagent is lithium diisopropylamide, and the lithium alkyl hydrogen-withdrawing reagent is one or more of n-butyl lithium and tert-butyl lithium.
The above production method is characterized in that the hydrogen abstraction reagent is lithium diisopropylamide.
The method according to claim 1, wherein the substitution reagent is one or more of methyl chloride and methyl bromide.
The above production process, characterized in that R is in the substituent of the compound1= -O-COR4And R is4= -CH3。
The above production process, characterized in that the substituent R of the compound1=-OCH3、-OCH2CH3or-OCH (CH)3)。
The above production process, characterized in that the substituent R of the compound1= -OCH3or-OCH2CH3，R2R when = -H3= H or OH, R2R when = -OH3= H, Cl, F or Br.
The above production process, characterized in that the substituent R of the compound1= -OCH3，R2R when = -H3= H or OH, R2R when = -OH3= H, Cl, F or Br.
The above production process, characterized in that the substituent R of the compound1= -OCH3，R2R when = -H3And 9 (11) bit = -H "
"means a double bond.
Detailed Description
HPLC: high performance liquid chromatography
A process for the preparation of compounds of different structural formula 1:
R1= -OCH3、-OCH2CH3or-OCH (CH)3)2；
R2= -H or-OH;
R3= -H, OH, Cl, F, or Br;
9 (11) bit "
"represents a single bond or a double bond;
steroid 0 added R1H, further trimethyl orthoformate (triethyl orthoformate), and p-toluenesulfonic acid monohydrate. The above solution was reacted with stirring to steroid-free 0 and then treated with triethylamine (NEt 3) and water in that order. After evaporation of the solvent a wet cake was obtained, which was added to water and stirred together and filtered. The resulting solid was washed with water and dried under vacuum at 50 ℃ to give compound 1.
R1= -O-COR4；
R2= -H or-OH;
R3= -H, OH, Cl, F, or Br;
R4h or alkyl of 1 to 3 carbons;
9 (11) bit "
"represents a single bond or a double bond;
steroid 0 addition R1--COR4Then p-toluenesulfonic acid is added. The above solution was reacted with stirring until free of steroids and then treated with triethylamine (NEt 3) and water. After evaporation of the solvent a wet cake was obtained, which was added to water and stirred together and filtered. The resulting solid was washed with water and dried under vacuum at 50 ℃ to give compound 1.
In the examples M is defined as molar.
The compound of formula 2, substituted in position 16 by a beta-methyl group, is the 16 beta species in the examples table, substituent R1，R2，R3And bit 9 (11) "
Corresponding compound 1.
Example 1
R1 = -OCH3
Under the protection of nitrogen, 0.1M compound 1, solvent catalyst N, N-dimethyl propylene urea and hydrogen drawing reagent are mixed uniformly, then substitution reagent is added for substitution reaction, and the reaction is carried out at the lowest temperature under the reaction temperature until the reaction is finished to obtain the compound shown in the formula 2.
The compound of formula 2 can be obtained as a solid compound by a conventional method such as water dilution, concentration under reduced pressure and recrystallization, and in this example, water dilution is used.
Example 2
R1= -OCH2CH3
Under the protection of nitrogen, 0.1M compound 1, solvent catalyst N, N-dimethyl propylene urea and hydrogen drawing reagent are mixed uniformly, then substitution reagent is added for substitution reaction, and the reaction is carried out at the lowest temperature under the reaction temperature until the reaction is finished to obtain the compound shown in the formula 2.
The compound of formula 2 can be obtained as a solid compound by a conventional method such as water dilution, concentration under reduced pressure and recrystallization, and in this example, water dilution is used.
Example 3
R1= -OCH(CH3)2
Under the protection of nitrogen, 0.1M compound 1, solvent catalyst N, N-dimethyl propylene urea and hydrogen drawing reagent are mixed uniformly, then substitution reagent is added for substitution reaction, and the reaction is carried out at the lowest temperature under the reaction temperature until the reaction is finished to obtain the compound shown in the formula 2.
The compound of formula 2 can be obtained as a solid compound by a conventional method such as water dilution, concentration under reduced pressure and recrystallization, and in this example, water dilution is used.
Example 4
R1 = -O-COCH3
Under the protection of nitrogen, 0.1M compound 1, solvent catalyst N, N-dimethyl propylene urea and hydrogen drawing reagent are mixed uniformly, then substitution reagent is added for substitution reaction, and the reaction is carried out at the lowest temperature under the reaction temperature until the reaction is finished to obtain the compound shown in the formula 2.
The compound of formula 2 can be obtained as a solid compound by a conventional method such as water dilution, concentration under reduced pressure and recrystallization, and in this example, water dilution is used.
Example 5
R1= -OCH2CH3
Under the protection of nitrogen, 0.1M compound 1, solvent catalyst N, N-dimethyl propylene urea and hydrogen drawing reagent are mixed uniformly, then substitution reagent is added for substitution reaction, and the reaction is carried out at the lowest temperature under the reaction temperature until the reaction is finished to obtain the compound shown in the formula 2.
The compound of formula 2 can be obtained as a solid compound by a conventional method such as water dilution, concentration under reduced pressure and recrystallization, and in this example, water dilution is used.
Example 6
R1= -OCH(CH3)2
Under the protection of nitrogen, 0.1M compound 1, solvent catalyst N, N-dimethyl propylene urea and hydrogen drawing reagent are mixed uniformly, then substitution reagent is added for substitution reaction, and the reaction is carried out at the lowest temperature under the reaction temperature until the reaction is finished to obtain the compound shown in the formula 2.
The compound of formula 2 can be obtained as a solid compound by a conventional method such as water dilution, concentration under reduced pressure and recrystallization, and in this example, water dilution is used.
Claims (10)
1. A process for the preparation of a compound of formula 2, characterized in that:
adding the compound 1 into a solvent, firstly using a hydrogen removing reagent to remove hydrogen of 16-site alpha hydrogen under the action of a catalyst N, N-dimethyl propylene urea, and then using a substitution reagent to perform substitution reaction to obtain a compound shown in a formula 2, wherein the solvent is one or more of 2-6 carbon ethers, 2-4 carbon nitriles and 5-10 carbon alkanes which are liquid at normal temperature; the hydrogen drawing reagent is one or more of hexamethyldisilazane-based amino lithium, alkyl amino lithium and alkyl lithium, and the alkyl is alkyl with 3-8 carbons; the substitution reagent is one or more of chloromethane, bromomethane and iodomethane;
R1= -OCH3、-OCH2CH3or-OCH (CH)3)2、-O-COR4；
R2= -H or-OH;
R3= -H, OH, Cl, F, or Br;
R4h or alkyl of 1 to 3 carbons;
9 (11) bit "
"represents a single bond or a double bond;
16 bit "
"represents 16. alpha. -methyl.
2. The process according to claim 1, wherein the reaction temperature is-80 to 20 ℃.
3. The process according to claim 1, wherein the molar ratio of the compound 1 to the catalyst N, N-dimethylpropyleneurea is 1:0.1-2, the molar ratio of the compound 1 to the hydrogen-withdrawing agent is 1:1-3, and the molar ratio of the compound 1 to the substituting agent is 1: 1-3.
4. The process according to claim 1, wherein the C2-C6 ether is a cyclic ether.
5. The process according to claim 1, wherein the C2-C6 ether is diethyl ether or tetrahydrofuran.
6. The method according to claim 1, wherein the C5-C10 alkane is one or more selected from the group consisting of n-hexane, isohexane, cyclohexane, n-heptane, isoheptane, cycloheptane, n-octane, and isooctane.
7. The process according to claim 1, wherein the C2-C4 nitrile is acetonitrile.
8. The process according to claim 1, wherein the lithium alkylamide hydrogen abstraction reagent is lithium diisopropylamide, and the lithium alkylamide hydrogen abstraction reagent is one or more of n-butyllithium and t-butyllithium.
9. The method according to claim 1, wherein the substitution reagent is one or more of methyl chloride and methyl bromide.
10. The process according to claim 1, wherein R is a substituent of said compound1= -O-COR4And R is4= -CH3。
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114560760A (en) * | 2022-01-28 | 2022-05-31 | 浙江大学杭州国际科创中心 | Method for synthesizing diterpene Pepluanol A in Euphorbiaceae |
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| CN87106868A (en) * | 1986-10-10 | 1988-04-27 | 吉斯特·布罗卡德斯公司 | 9-alpha-hydroxy steroids, process for their preparation, corresponding 9(11) -dehydro derivatives and pharmaceutical compositions containing them |
| CN107746420A (en) * | 2017-09-28 | 2018-03-02 | 湖南新合新生物医药有限公司 | The preparation method of 16 β alkyl steroid compounds |
| CN109734762A (en) * | 2018-12-05 | 2019-05-10 | 郑良彬 | The method of one pot process 16- β methyl steroidal compound |
-
2020
- 2020-06-18 CN CN202010557700.6A patent/CN113817011A/en active Pending
Patent Citations (3)
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| CN87106868A (en) * | 1986-10-10 | 1988-04-27 | 吉斯特·布罗卡德斯公司 | 9-alpha-hydroxy steroids, process for their preparation, corresponding 9(11) -dehydro derivatives and pharmaceutical compositions containing them |
| CN107746420A (en) * | 2017-09-28 | 2018-03-02 | 湖南新合新生物医药有限公司 | The preparation method of 16 β alkyl steroid compounds |
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Non-Patent Citations (4)
| Title |
|---|
| NICHOLAS I. CARRUTHERS等: "Synthesis of Corticoids from 9a-Hydroxyandrost-4-ene-3, 17-dio", 《J. ORG. CHEM., vol. 57, no. 3, 31 December 1992 (1992-12-31), pages 961 - 965 * |
| RENE MALTAIS等: "Solid-phase synthesis of model libraries of 3α, 17β-dihydroxy-16α-(aminoethyl-N-substituted)-5α-androstanes for the development of steroidal therapeutic agents", 《MOLECULAR DIVERSITY》, vol. 9, 31 December 2005 (2005-12-31), pages 67 - 79, XP019258591 * |
| 微信公众号文章: "常用溶 剂----DMPU", pages 1, Retrieved from the Internet <URL:https://mp.weixin.qq.com/s?__biz=MzA3MTkyNzcxMg==&mid=2650327118&idx=1&sn=56e814a374286699b95e6b4438693274&chksm=872a7a81b05df39792acc035ad506bd2e47645f67a69f5296fe3ceecba45c6eece909e2e2f81&scene=27> * |
| 胡跃飞等: "《现代有机合成试剂——性质、制备和反应》", 31 July 2006, 化学工业出版社, pages: 107 - 108 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114560760A (en) * | 2022-01-28 | 2022-05-31 | 浙江大学杭州国际科创中心 | Method for synthesizing diterpene Pepluanol A in Euphorbiaceae |
| CN114560760B (en) * | 2022-01-28 | 2024-05-17 | 浙江大学杭州国际科创中心 | Synthesis method of euphorbiaceae diterpene Pepluanol A |
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Application publication date: 20211221 |