CN109206471B

CN109206471B - Preparation method of halcinonide

Info

Publication number: CN109206471B
Application number: CN201710523645.7A
Authority: CN
Inventors: 韩昆颖; 李亚玲; 齐海迪; 耿磊
Original assignee: Tianjin Pharmaceutical Research Institute Co ltd
Current assignee: Tianjin Pharmaceutical Research Institute Co ltd
Priority date: 2017-06-30
Filing date: 2017-06-30
Publication date: 2022-07-12
Anticipated expiration: 2037-06-30
Also published as: CN109206471A

Abstract

The invention provides a preparation method of halcinonide, which comprises the following steps: 1) chlorination reaction: in SO₂Reacting compound 1 with a chlorinating agent in the presence ofForming a compound 2, wherein the chlorinated reagent is selected from one or more of acetyl chloride, propionyl chloride, benzoyl chloride, lithium chloride, carbon tetrachloride, chlorosuccinimide and dichlorohydantoin; 2) ring opening reaction: and reacting the compound 2 with hydrogen fluoride to obtain halcinonide. The method has the advantages of mild reaction conditions, environmental friendliness, easy operation, low cost, industrial value, effective control of side reactions, and improvement of reaction yield and quality; the process design does not involve high-risk reaction, and industrialization is easy to realize; no high pollution reaction exists, and the environmental protection treatment pressure is reduced.

Description

Preparation method of halcinonide

Technical Field

The invention belongs to the field of medicines, and particularly relates to a preparation method of halcinonide.

Background

Halcinonide (Halcinonide), also known as clorsulon, halett, chemical name 16 alpha, 17- [ (1-methylethylidene) bis (oxy)]-11 β -hydroxy-21-chloro-9-fluoropregn-4-ene-3, 20-dione. The molecular formula is as follows: c₂₄H₃₂ClFO₅Molecular weight: 454.9. halcinonide is a synthetic powerful glucocorticoid containing fluorine and chlorine for local application, and has relatively light antiinflammatory, antiallergic, antipruritic, and immunity inhibiting effects. The local application can reduce the permeability of capillary walls and cell membranes, reduce the moisture permeability, and inhibit the formation and release of histamine and other inflammatory mediators, the local application is not easy to cause systemic side effects, the effect of treating psoriasis and eczematous dermatitis is outstanding, the pharmacokinetic behavior after percutaneous absorption is the same as that of the system application, namely the combination with plasma protein in different degrees is mainly excreted from the kidney after the liver metabolism, and part of the excretion is also excreted from the bile.

The document Ein neuartiges Verfahren zur Uberfuhrung von 11 beta, 17a,21-Trihydroxy-20-oxo-Steroidein die 21-chror-20-oxo-_△ ^9(11)16A synthesis process of halcinonide is disclosed in Derivate (Liebigs Annalen der Chemie; nb.5; (1982); p.966-972), wherein the starting material is 21-methanesulfonate, which belongs to common chlorination or bromination reaction after sulfonation of 21-hydroxy, and the method has the disadvantages of need of sulfonation first, low reaction yield, easy introduction of genotoxic impurities and increased risk of introducing genotoxic impurities into the product.

Disclosure of Invention

The invention aims to provide a preparation method of halcinonide, which has simple process, mild reaction condition and environmental protection.

The technical scheme of the invention is as follows: the preparation method of halcinonide comprises the following processes and steps

1) Chlorination reaction: in SO₂In the presence of the catalyst, reacting the compound 1 with a chlorinated reagent to generate a compound 2, wherein the chlorinated reagent is selected from one or more of acetyl chloride, propionyl chloride, benzoyl chloride, lithium chloride, carbon tetrachloride, chlorosuccinimide and dichlorohydantoin;

2) ring-opening reaction: and reacting the compound 2 with hydrogen fluoride to obtain halcinonide.

In order to obtain better technical effect, organic amine is added into the reaction system in the step 1), and the organic amine is selected from one or more of pyridine, lutidine, diethylamine, triethylamine, piperidine, formamide and tetrahydropyrrole. The organic amine is preferably pyridine.

SO used₂The weight volume ratio of the amount of the organic amine to the organic amine is 15-30%.

In order to obtain better technical effect, the chlorinating reagent in the step 1) is selected from chlorosuccinimide or dichlorohydantoin.

In order to obtain better technical effect, the mol ratio of the chlorinated reagent to the compound 1 in the step 1) is 1.05-3: 1. preferably 1.1: 1.

In order to obtain better technical effect, the reaction temperature in the step 1) is selected from-20 ℃ to 40 ℃, and preferably 0 ℃ to 10 ℃.

In order to obtain better technical effect, the reaction solvent of the reaction system in the step 1) is selected from one or more of pyridine, DMF, dichloromethane, chloroform, acetone and acetonitrile.

In order to obtain better technical effect, the concentration of the compound 1 in the step 1) in the reaction solvent is selected from 0.3-5 mol/L. Preferably 0.5 mol/L.

In order to obtain better technical effect, the reaction time of the reaction in the step 1) is selected from 1-3 h.

For better technical effect, the reaction solvent in step 2) is selected from dimethylformamide or tetrahydrofuran;

in order to obtain better technical effect, the reaction temperature in the step 2) is selected from-5 to 10 ℃.

In the preparation method of halcinonide, chlorination is a key step, chlorination of steroid compounds is generally carried out after 21-site sulfonation and then chlorination of sulfonyl leaving chlorinated reagent, and the chlorination reaction is not easy to control and has low yield through a method experiment used in literature in the research and development process, SO that the further intensive research on the chlorination reaction is found to be carried out in SO ₂In the presence of the catalyst, the chlorination reaction has higher yield, fast reaction and simple reaction process, and is caused by SO₂Is a gas, and is generally adsorbed in an organic amine solvent, so that the reaction efficiency can be improved. Adding SO into the reaction system₂Organic amine solution can obviously promote reaction and improve product quality, and experiments prove that no SO is added₂In the case of a solution, the reaction does not substantially proceed.

The invention has the advantages and positive effects that: by adopting the technical scheme, the method for chlorinating the steroid 21-hydroxy has the advantages of mild reaction conditions, environmental friendliness, easiness in operation, low cost and high yield, and the novel process has higher industrial value, can effectively control side reactions and improves the reaction yield and quality; the process design does not involve high-risk reaction, and industrialization is easy to realize; no high pollution reaction exists, and the environmental protection treatment pressure is reduced.

Detailed Description

The invention will now be further described by way of the following examples, which are not intended to limit the scope of the invention in any way. It will be understood by those skilled in the art that equivalent substitutions for the technical features of the present invention, or corresponding modifications, can be made within the scope of the present invention.

EXAMPLE 1 Chlorination

Examples 1 to 1

7.0g of Compound 1(0.017mol) are dissolved in 34ml of pyridine, nitrogen is passed through and the temperature is reduced to 5 ℃. 2.5g of chlorobutane were addedImide (0.018mol), SO is added dropwise₂Pyridine (15ml, 20%). After 1.5h of reaction, the reaction mixture was diluted to 500ml of water at 0 ℃, stirred for 1h, filtered and dried to obtain Compound 2(7.2g, molar yield 97.6%, purity of HPCL 98.6%).

Comparative example 1-1

7.0g of Compound 1(0.017mol) are dissolved in 34ml of pyridine, nitrogen is passed through and the temperature is reduced to 5 ℃. 2.5g of chlorosuccinimide (0.018mol) was added and pyridine (15ml) was added dropwise. After 1.5h of reaction, compound 1 was not reacted by TLC.

Examples 1 to 2

14.0g (0.034mol) of Compound 1 are dissolved in 80ml of dichloromethane, nitrogen is passed through and the temperature is reduced to-8 ℃. Adding 15ml of triethylamine and introducing SO₂(the weight ratio of triethylamine absorbed was 20%), 2.8g of acetyl chloride (0.036mol) was added. After 2 hours of reaction, the reaction mixture was diluted to 600ml of 0 ℃ water, stirred for 10min, and then separated, and the organic phase was distilled under reduced pressure to remove the solvent, to obtain compound 2(13.6g, molar yield 92.2%, purity of HPCL 96.4%).

Comparative examples 1 to 2

14.0g (0.034mol) of Compound 1 are dissolved in 80ml of dichloromethane, nitrogen is passed through and the temperature is reduced to-8 ℃. Introducing SO ₂2.8g of acetyl chloride (0.036mol) was added as a gas. After 2h of reaction, compound 1 was not reacted by TLC.

Examples 1 to 3

Dissolving 21.0g (0.05mol) of Compound 1 in 80ml of acetone, introducing nitrogen, cooling to 10 ℃, adding 25ml of imidazole, and introducing SO₂(SO absorbed into imidazole)₂20% by weight) 30g of benzoyl chloride (0.21mol) were added. After 3 hours of reaction, the reaction mixture was diluted to 900ml of 0 ℃ water, stirred for 3 hours, filtered and dried to obtain compound 2(19.8g, molar yield 91.2%, purity of HPCL 97.9%).

Comparative examples 1 to 3

21.0g (0.05mol) of Compound 1 are dissolved in 80ml of acetone, nitrogen is passed through, the temperature is reduced to 10 ℃ and 30g of benzoyl chloride (0.21mol) are added. After 3h reaction, compound 1 was not reacted by TLC.

Examples 1 to 4

21.0g of the total weight(0.05mol) Compound 1 is dissolved in 80ml acetone, nitrogen is introduced and the temperature is reduced to 10 ℃. 30g of dichlorohydantoin (0.21mol) are added, 25ml of imidazole are added, and SO is introduced₂(the imidazole was absorbed in a weight ratio of 20%). After reaction for 3 hours, the reaction mixture was diluted to 900ml of 0 ℃ water, stirred for 3 hours, filtered and dried to obtain compound 2(20.8g, molar yield 95.9%, purity of HPCL 98.9%).

Comparative examples 1-4-1

21.0g (0.05mol) of Compound 1 are dissolved in 80ml of acetone, nitrogen is passed through and the temperature is reduced to 10 ℃. 30g dichlorohydantoin (0.21mol) was added, 25ml imidazole was added, and after 3 hours of reaction, compound 1 was not reacted by TLC.

Comparative examples 1 to 4 to 2

21.0g (0.05mol) of Compound 1 are dissolved in 80ml of acetone, nitrogen is passed through and the temperature is reduced to 10 ℃. 30g of dichlorohydantoin (0.21mol) are added and SO is introduced₂After 3 hours of reaction, compound 1 was not reacted by TLC.

Comparative examples 1 to 4 to 3

21.0g (0.05mol) of Compound 1 are dissolved in 80ml of acetone, nitrogen is passed through and the temperature is reduced to 10 ℃. 30g of dichlorohydantoin (0.21mol) was added and reacted for 3 hours, followed by TLC to detect that Compound 1 did not react.

EXAMPLE 2 Ring opening reaction

Example 2-1

In a reverse flask, 7g of compound 2(0.016mol) and 60ml of dimethylformamide were added, the mixture was stirred, the temperature was reduced to-5 ℃, hydrogen fluoride gas was introduced, the reaction was maintained at-5 to 0 ℃, the progress of the reaction was monitored by thin layer chromatography until the end of the reaction, the mixture was diluted in ice water, the pH was adjusted to 7 with ammonia water, and 6.9g of halcinonide was obtained after filtration and drying (molar yield 95.0%, HPLC purity 98.5%).

Examples 2 to 2

A reverse flask was charged with 10.5g of compound 2(0.024mol) and 60ml of tetrahydrofuran, stirred, cooled to-5 ℃, added with 30ml of 47% aqueous hydrogen fluoride, reacted at 5 to 10 ℃, followed by monitoring the progress of the reaction by thin layer chromatography until the reaction was completed, diluted in ice water, adjusted to pH 7 with ammonia water, filtered, and dried to obtain 10.4g of halcinonide (molar yield 95.4%, HPLC purity 99.1%).

Examples 2 to 3

In a reaction flask, 15g of compound 2(0.035mol) and 80ml of dimethylformamide were added, stirred, cooled to-5 ℃, 50ml of 47% aqueous hydrogen fluoride was added, the reaction was maintained at 0 to 5 ℃, the progress of the reaction was monitored by thin layer chromatography until the end of the reaction, the reaction mixture was diluted in ice water, the pH was adjusted to 7 using aqueous ammonia, and the mixture was filtered and dried to obtain 14.7g of halcinonide (yield 92.5%, HPLC purity 98.8%).

Claims

1. A preparation method of halcinonide is characterized by comprising the following steps: comprises the following processes and steps

1) Chlorination reaction: in SO₂In the presence of the organic amine, reacting the compound 1 with a chlorinating reagent and an organic amine to generate a compound 2, wherein the chlorinating reagent is one or more selected from acetyl chloride, propionyl chloride, benzoyl chloride, chlorosuccinimide and dichlorohydantoin; the organic amine is selected from one or more of pyridine, lutidine, diethylamine, triethylamine, piperidine or tetrahydropyrrole;

2) ring opening reaction: and reacting the compound 2 with hydrogen fluoride to obtain halcinonide.

2. The method for preparing halcinonide according to claim 1, characterized in that: the chlorinated reagent in the step 1) is selected from chlorosuccinimide or dichlorohydantoin.

3. The method for preparing halcinonide according to claim 1 or 2, characterized in that: in the step 1), the organic amine is selected from pyridine.

4. The method for preparing halcinonide according to claim 3, characterized in that: SO used in step 1)₂The weight volume ratio of the amount of the organic amine to the organic amine is 15-30%.

5. The method of any one of claims 1, 2 or 4 for the preparation of halcinonide, wherein: the mol ratio of the chlorinated reagent to the compound 1 is 1.05-3: 1.

6. the method for preparing halcinonide according to claim 5, characterized in that: the molar ratio of the chlorinating reagent to compound 1 is 1.1: 1.

7. the method of any one of claims 1, 2, 4 or 6, wherein: the reaction solvent of the reaction system in the step 1) is one or more selected from pyridine, DMF, dichloromethane, chloroform, acetone and acetonitrile.

8. The method for preparing halcinonide according to claim 7, wherein: the concentration of the compound 1 in the reaction solvent in the step 1) is selected from 0.3-5 mol/L.

9. The method of any one of claims 1, 2, 4, 6 or 8 for preparing halcinonide, wherein: the concentration of the compound 1 in the reaction solvent in the step 1) is selected from 0.5 mol/L.

10. The method for preparing halcinonide according to claim 9, characterized in that: the reaction temperature in the step 1) is selected from-20 ℃ to 40 ℃.

11. The method for preparing halcinonide according to claim 10, characterized in that: the reaction temperature in the step 1) is selected from 0-10 ℃.

12. The method of any one of claims 1, 2, 4, 6, 8, 10 or 11 for the preparation of halcinonide, wherein: the reaction time of the reaction in the step 1) is selected from 1-3 h.

13. The method for preparing halcinonide according to claim 12, characterized in that: the reaction solvent in the step 2) is selected from dimethylformamide or tetrahydrofuran.

14. The method of any one of claims 1, 2, 4, 6, 8, 10, 11 or 13 for preparing halcinonide, wherein: the reaction temperature in the step 2) is selected from-5 to 10 ℃.

15. The method for preparing halcinonide according to claim 14, wherein: the hydrogen fluoride of step 2) is selected from aqueous hydrogen fluoride.