CN111018932B - 9-position dehalogenation method for steroid compound - Google Patents
9-position dehalogenation method for steroid compound Download PDFInfo
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- CN111018932B CN111018932B CN201911195212.9A CN201911195212A CN111018932B CN 111018932 B CN111018932 B CN 111018932B CN 201911195212 A CN201911195212 A CN 201911195212A CN 111018932 B CN111018932 B CN 111018932B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
- C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
- C07J5/0053—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa not substituted in position 16
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
- C07J5/0007—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond not substituted in position 17 alfa
- C07J5/0015—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond not substituted in position 17 alfa not substituted in position 16
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
- C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
- C07J5/0061—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16
- C07J5/0069—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group
- C07J5/0076—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group by an alkyl group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
- C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
- C07J5/0061—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16
- C07J5/0092—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16 by an OH group free esterified or etherified
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses a method for dehalogenating steroid compound 9-site, which comprises the following steps: dissolving 9-halogenated-11-hydroxy ester steroid compound and a certain amount of auxiliary agent in an organic solvent, heating to a certain temperature, dropwise adding tributyl tin hydride, reacting for a period of time, detecting, concentrating under reduced pressure to remove part of solvent after the reaction is complete, performing water precipitation or adding solvent for crystallization, filtering to obtain the target product 11-hydroxy ester steroid compound, and obtaining tributyl tin oxide for reuse after mother liquor is layered. Compared with the traditional steroid chromium salt dehalogenation process, the method has the advantages of simple operation, high safety, recycling of tributyl tin oxide, reduction of three-waste pollution and cost reduction.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a method for dehalogenation of a chromium-free steroid hormone compound at the 9-position.
Background
Steroid hormone drugs (steroid hormon drugs) refer to hormone drugs containing a steroid structure in a molecular structure, and have wide clinical application, mainly including adrenocortical hormone and sex hormone. The adrenocortical hormone has a plurality of pharmacological actions such as anti-inflammation, anti-allergy, immunity suppression, stress reaction enhancement, endotoxin resistance, shock resistance and the like, can be clinically used for treating a plurality of diseases, and is an indispensable important medicament in clinic. In the synthesis process of many cortical hormone drugs, in order to obtain 11 beta-hydroxy steroid, the 9, 11-alkene steroid needs to be oxidized, brominated and hydroxylated, and then the 9-halogen is subjected to reduction dehalogenation reaction. The divalent chromium metal reduction method is commonly used in industry, but the method is not green and environment-friendly, and has the defects of difficult treatment, high cost and the like of wastewater containing chromium salt.
Patent EP 0994119A1 reports that 9-bromine (iodine) -substituted budesonide is dissolved in tetrahydrofuran, tri-n-butyl tin hydrogen is used as a hydrogen donor, a small amount of Azobisisobutyronitrile (AIBN) is added as a catalyst, reflux reaction is carried out for l6h, and then the efficient anti-asthma medicine budesonide can be obtained by refining, wherein the reaction conditions are mild, and the yield is 88 percent (formula I). We tried to synthesize 16-alpha hydroxyprednisolone by this method, but found almost all the impurities and no target product (formula II), and adding excess tributyltin hydride directly without adding azobisisobutyronitrile initiator also produced similar by-products, and did not obtain the desired target product.
Disclosure of Invention
The invention aims to provide a preparation method of protecting group-free steroid compound 9-site dehalogenation, which can improve the reaction yield and the product purity while solving the technical problems.
The invention provides a preparation method of a steroid compound by 9-position dehalogenation, which comprises the following steps:
the method comprises the following steps: unprotected 9-halogenated-11-hydroxy ester steroid compound and a certain amount of auxiliary agent are dissolved in organic solvent, tributyl tin hydride is added dropwise after the temperature is raised to a certain temperature, the detection is carried out after the reaction is carried out for a period of time, partial solvent is removed by decompression concentration, water separation or solvent addition crystallization is carried out, the target product 11-hydroxy ester steroid compound is obtained by filtration, and the tributyl tin oxide can be obtained by recycling after mother liquor is layered.
The auxiliary agent is organic acid.
The inventor analyzes that the reason why almost all impurities are generated in the synthesis of 16-alpha hydroxy prednisolone by adopting the method provided by EP 0994119A1 is that the existence of 16, 17-dihydroxyl is easy to generate the impurities under the reaction condition, so that the patent EP 0994119A1 needs to firstly carry out the debromination of the 16, 17-dihydroxyl by a protecting group and then by tri-n-butyl tin hydrogen, and the 9-position dehalogenation reaction of the unprotected steroid compound cannot be directly realized.
In the technical scheme of the invention, the inventor improves the process, tributyltin hydrogen is used as a reduction dehalogenation reagent, the use of a free radical initiator azobisisobutyronitrile is cancelled, a small amount of organic acid is added as an auxiliary agent to stabilize the product, and the unprotected 9-site chromium-free dehalogenation reaction of the steroid compound is realized.
Preferably, the organic acid is one or more of thioglycolic acid, mercaptopropionic acid, mercaptobutyric acid, glycolic acid, benzoic acid, oxalic acid, formic acid and acetic acid.
More preferably, the organic acid is thioglycolic acid.
Preferably, the solvent is tetrahydrofuran, 2-methyltetrahydrofuran, ethanol, isopropanol, acetone, butanone, dichloromethane, N-Dimethylformamide (DMF), acetonitrile, ethyl acetate, or the like.
Further preferred is tetrahydrofuran.
The 9-halo-11-hydroxy ester steroid compound (X in the following general formula represents a halogen atom (chlorine/bromine/iodine), R1Represents a hydrogen atom or a hydroxy-protecting group such as formyl, acetyl, benzoyl, etc., R2Representing a hydrogen atom or a hydroxyl protecting group such as formyl, acetyl, benzoyl) including but not limited to the following molecules:
preferably, the molar ratio of the 9-halo-11-hydroxy ester steroid to tributyltin hydride and the auxiliary agent is 1: (1.0-3.0): (0.2-3.0).
More preferably 1: (1.0-2.0): (0.2-1.0).
Still more preferably 1: 1.2: 0.5.
the reaction temperature is 40-105 ℃, preferably 50-60 ℃.
Compared with the traditional steroid chromium salt dehalogenation process, the method has the advantages of simple operation, high safety, recycling of tributyl tin oxide, reduction of three-waste pollution and cost reduction.
Detailed Description
The examples given are merely intended to be illustrative of the products or methods of the invention in general terms, and are intended to facilitate a better understanding of the invention, and not to limit the scope of the invention. The experimental methods described in the following examples are all conventional methods unless otherwise specified; the materials are commercially available, unless otherwise specified.
Example 1
Adding 50.8g (0.10 mol, 1.0 equiv) of 9-bromo-11-methyl prednisolone acetate in formula (I), 4.6g (0.05 mol, 0.5 equiv) of thioglycolic acid and 1500ml of tetrahydrofuran into a reaction kettle under the protection of nitrogen, heating and refluxing, slowly dropwise adding 29.0g (0.10 mol, 1.0 equiv) of tributyltin hydride, detecting and controlling the reaction end point by TLC, reducing the temperature of the reaction kettle after the reaction is finished, carrying out reduced pressure distillation (the distillation temperature is not more than 50 ℃, and the vacuum degree is about-0.08 MPa), removing about 1400ml of tetrahydrofuran, adding 400ml of drinking water under stirring, cooling to 0 ℃, filtering, pulping by using 200ml of n-heptane and hot water in sequence, and drying to obtain 40.5g of white solid prednisolone acetate 11-methyl acetate, wherein the molar yield is 94.3%, and the HPLC purity is 98.8%.
Example 2
Adding 45.4g (0.10 mol, 1.0 equiv) of 9-bromo-11-hydroxy-16-hydroxyprednisolone in formula (I), 9.2g (0.10 mol, 1.0 equiv) of mercaptopropionic acid and 1200ml of acetone into a reaction kettle under the protection of nitrogen, heating and refluxing, slowly dropwise adding 58.0g (0.20 mol, 2.0 equiv) of tributyltin hydride, detecting and controlling the reaction end point by TLC, reducing the temperature of the reaction kettle after the reaction is finished, carrying out reduced pressure distillation (the distillation temperature is not more than 40 ℃ and the vacuum degree is about-0.08 MPa), removing about 1100ml of acetone, adding 400ml of drinking water while stirring, cooling to 0 ℃, filtering, pulping by using 200ml of n-heptane and hot water in sequence, and drying to obtain 33.7g of white solid 11-hydroxy-16-hydroxyprednisolone, wherein the molar yield is 89.6% and the purity of HPLC is 98.6%.
Example 3
Under the protection of nitrogen, 66.0g (0.10 mol, 1.0 equiv) of 9-bromo-11-benzoate-16-methyl-21-benzoate prednisolone in formula (I), 15.2g (0.20 mol, 2.0 equiv) of glycolic acid and 1500ml of butanone are added into a reaction kettle for heating and refluxing, 40.6g (0.14 mol, 1.4 equiv) of tributyltin hydride are slowly added dropwise, the TLC detection controls the reaction end point, after the reaction is finished, the temperature of the reaction kettle is reduced, about 1350ml of butanone is removed through reduced pressure distillation (the distillation temperature is not more than 50 ℃ and the vacuum degree is about-0.08 MPa), 500ml of drinking water is added under stirring, the temperature is reduced to 0 ℃, the filtration is carried out, 200ml of n-heptane and hot water are sequentially used for pulping and drying, 51.5g of white solid 11-benzoate-16-methyl-21-benzoate prednisolone is obtained, the molar yield was 88.6% and the HPLC purity was 97.5%.
Example 4
Adding 55.8g (0.10 mol, 1.0 equiv) of 9-iodine-11-formate-21-hydrocortisone acetate in the formula (I), 12.0g (0.20 mol, 2.0 equiv) of acetic acid and 2000ml of dichloromethane into a reaction kettle under the protection of nitrogen, heating and refluxing, slowly dropwise adding 58.0g (0.20 mol, 2.0 equiv) of tributyltin hydride, detecting and controlling the reaction end point by TLC, reducing the temperature of the reaction kettle after the reaction is finished, carrying out reduced pressure distillation (the distillation temperature is not more than 50 ℃, the vacuum degree is about-0.08 MPa), removing 1900ml of dichloromethane, adding 500ml of n-heptane under stirring, cooling to 0 ℃, filtering, pulping by using 200ml of n-heptane and hot water in sequence, and drying to obtain 35.0g of white solid 11-formate-21-hydrocortisone acetate, the molar yield is 81.0%, and the HPLC purity is 99.4%.
Example 5
Under the protection of nitrogen, 47.8g (0.10 mol, 1.0 equiv) of 6-methyl-9-chloro-11-formic ester-21-prednisolone acetate in formula (V), 36.0g (0.3 mol, 3.0 equiv) of mercaptobutyric acid and 300ml of N, N-Dimethylformamide (DMF) are added into a reaction kettle, 87.0g (0.30 mol, 3.0 equiv) of tributyltin hydride is slowly and dropwise added, the temperature is increased to 105 ℃ for reaction for a period of time, the TLC detection controls the reaction end point, the temperature of the reaction kettle is reduced after the reaction is finished, about 1800ml of drinking water is added into the reaction kettle, the temperature is reduced to 0 ℃, and 34.0g of the white solid 6-methyl-11-formic ester-21-prednisolone acetate is obtained through filtering and drying, the molar yield is 76.5%, and the HPLC purity is 98.1%.
Example 6
Adding 46.2g (0.10 mol, 1.0 equiv) of 9-bromo-11-hydroxy-16, 17-ene-21-acetate prednisolone in the formula (V) into a reaction kettle under the protection of nitrogen, 24.4g (0.2 mol, 2.0 equiv) of benzoic acid and 1000ml of acetonitrile, 58.0g (0.20 mol, 2.0 equiv) of tributyltin hydride is slowly added dropwise, the temperature is raised to 70 ℃ for reaction for a period of time, the TLC detection controls the reaction endpoint, after the reaction is finished, the temperature of the reaction kettle is reduced, about 900ml of acetonitrile is removed by reduced pressure distillation (the distillation temperature is not more than 50 ℃, and the vacuum degree is about-0.08 MPa), 500ml of drinking water is added under stirring, the temperature is reduced to 0 ℃, and the mixture is filtered and dried to obtain 34.3g of white solid, namely 11-hydroxy-16, 17-ene-21-prednisolone acetate, the molar yield is 89.3 percent, and the HPLC purity is 98.6 percent.
In the above embodiments, the water layer after the reaction is finished and the water separation can be layered to obtain tributyltin oxide for reuse, in order to avoid the toxicity of organic tin to aquatic organisms, the water layer can be discharged after being extracted with n-heptane, and the ICP-MS detects that the tin content in the water layer is less than 10 ppm.
The 9-halogenated-11-hydroxy ester steroid compound can be prepared by adding a halogenating agent into a 9, 11-alkene steroid compound to react with perchloric acid.
Comparative example 1
Adding 50.8g (0.10 mol, 1.0 equiv) of 9-bromo-11-methyl acetate prednisolone in formula (I) into a reaction kettle under the protection of nitrogen, heating and refluxing 1500ml of tetrahydrofuran, slowly adding 29.0g (0.10 mol, 1.0 equiv) of tributyltin hydride dropwise, detecting by TLC to control the reaction endpoint, reducing the temperature of the reaction kettle after the reaction is finished, carrying out reduced pressure distillation (the distillation temperature is not more than 50 ℃ and the vacuum degree is about-0.08 MPa), removing about 1400ml of tetrahydrofuran, adding 400ml of drinking water while stirring, cooling to 0 ℃, filtering, pulping by using 200ml of n-heptane and hot water in sequence, and drying to obtain white solid 9-bromo-D-homostane and D-homostane, wherein the HPLC ratio is 15: 85.
Claims (5)
1. a method for dehalogenating steroid compound 9-position is characterized in that: dissolving a 9-halo-11-hydroxy ester steroid compound and a certain amount of an auxiliary agent in an organic solvent, heating to a certain temperature, dropwise adding tributyl tin hydride, reacting for a period of time, detecting, removing part of the solvent after the reaction is complete, carrying out water precipitation or adding the solvent for crystallization, and filtering to obtain a target product; wherein the structural formula of the 9-halogenated-11-hydroxy ester steroid compound is shown as follows,
wherein: x represents a halogen atom, R1Represents hydrogen or a hydroxy-protecting group, R2Represents hydrogen or a hydroxy protecting group which is formyl, acetyl or benzoyl; the auxiliary agent is glycolic acid, benzoic acid, oxalic acid, formic acid and acetic acid.
2. The process for the 9-position dehalogenation of steroid hormone compounds as claimed in claim 1 wherein: the mol ratio of the 9-halogenated-11-hydroxy ester steroid compound to the tributyl tin hydride and the auxiliary agent is 1: (1.0-3.0): (0.2-3.0).
3. The process for the 9-position dehalogenation of steroid hormone compounds as claimed in claim 2 wherein: the mol ratio of the 9-halogenated-11-hydroxy ester steroid compound to the tributyl tin hydride and the auxiliary agent is 1: 1.2: 0.5.
4. the process for the 9-position dehalogenation of steroid hormone compounds as claimed in claim 1 wherein: the reaction temperature is 40-105 ℃.
5. A process for the preparation of a steroid compound according to claim 1 by dehalogenation at the 9-position, wherein: the solvent is tetrahydrofuran, 2-methyltetrahydrofuran, ethanol, isopropanol, acetone, butanone, dichloromethane, N-dimethylformamide, acetonitrile and ethyl acetate.
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| CN111560047B (en) * | 2020-05-09 | 2021-07-20 | 浙江神洲药业有限公司 | Preparation method of budesonide |
| CN116102605B (en) * | 2023-01-18 | 2024-01-30 | 奥锐特药业股份有限公司 | Dehalogenation method of 9-halogenated steroid compound |
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| EP0994119A1 (en) * | 1998-10-13 | 2000-04-19 | Farmabios S.r.l. | Stereoselective process for the preparation of the 22R epimer of budesonide |
| CN101397324A (en) * | 2007-09-29 | 2009-04-01 | 天津药业研究院有限公司 | Preparation of metacortandralone and derivatives thereof |
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| ATE85620T1 (en) * | 1987-08-14 | 1993-02-15 | Upjohn Co | PROCEDURE FOR 9-ALPHA DEHALOGENATION OF 9-ALPHA STEROIDS. |
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| EP0994119A1 (en) * | 1998-10-13 | 2000-04-19 | Farmabios S.r.l. | Stereoselective process for the preparation of the 22R epimer of budesonide |
| CN101397324A (en) * | 2007-09-29 | 2009-04-01 | 天津药业研究院有限公司 | Preparation of metacortandralone and derivatives thereof |
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| CN101928318A (en) * | 2009-06-24 | 2010-12-29 | 天津金耀集团有限公司 | Preparation of fluorine-containing steroid hormone |
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| CN107619423A (en) * | 2016-07-15 | 2018-01-23 | 天津金耀集团有限公司 | A kind of preparation method of hydrocortisone |
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