CN116410254A - Synthesis method of 17 alpha-hydroxy steroid compound - Google Patents

Synthesis method of 17 alpha-hydroxy steroid compound Download PDF

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CN116410254A
CN116410254A CN202111674797.XA CN202111674797A CN116410254A CN 116410254 A CN116410254 A CN 116410254A CN 202111674797 A CN202111674797 A CN 202111674797A CN 116410254 A CN116410254 A CN 116410254A
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张超
陈伟
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Tianjin Pharmaceutical Research Institute Co ltd
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Tianjin Pharmaceutical Research Institute Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
    • C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
    • C07J7/004—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group substituted in position 17 alfa
    • C07J7/0045—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group substituted in position 17 alfa not substituted in position 16
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
    • C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
    • C07J7/004—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group substituted in position 17 alfa
    • C07J7/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group substituted in position 17 alfa substituted in position 16
    • C07J7/0055—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C07J7/008—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms substituted in position 21
    • 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

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention provides a synthesis method of 17 alpha-hydroxy steroid compounds, and relates to the technical field of chemical synthesis. The synthesis method of the 17 alpha-hydroxy steroid compound comprises the following steps: adding an alkali reagent and a reducing reagent into an organic solvent 2 to prepare a reaction raw material liquid 2, and respectively introducing a solution containing a compound II, the reaction raw material liquid 2 and an oxygen-containing gas into a continuous flow reactor at a certain flow rate to react to obtain a compound III containing 17 alpha-hydroxyl. The invention provides a method for synthesizing 17 alpha-hydroxy steroid compounds by adopting a micro-channel continuous flow technology, which has the characteristics of good product quality, high safety guarantee and the like.

Description

Synthesis method of 17 alpha-hydroxy steroid compound
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a method for synthesizing 17 alpha-hydroxy steroid compounds.
Background
17 alpha-hydroxy steroid compounds such as 17 alpha-hydroxy progesterone are important intermediates for synthesizing other steroid drugs, can be used for synthesizing various progestogens (such as angustogestrone, megestrol acetate, chlordydrogesterone and the like) and corticosteroids (such as hydrocortisone, prednisone, prednisolone and the like), and have wide market prospect.
The currently reported synthetic routes for 17 alpha-hydroxysteroids mainly include the following methods:
(1) 17 alpha-hydroxy progesterone is prepared from diosgenin: the saponin is extracted from plants, and then subjected to multi-step reactions such as ring opening, oxidation, hydrolysis, epoxidation, oxidation of Orthoxy, bromine adding, bromine removing and the like to prepare the 17 alpha-hydroxy progesterone. The process has long steps, low yield and high cost, and the yam plant resources are gradually exhausted, and the yam saponin extraction process is complex and has high cost, so the process is gradually replaced, and the reaction process is as follows:
Figure BDA0003450731440000021
(2) Preparation of 17 alpha-hydroxy progesterone from androstenedione (4-AD):
patent CN10340305A reports that the 4-AD is taken as a raw material, 17,20 double bonds are selectively oxidized through C3 carbonyl selective protection and C17 wittg reaction, and 17-hydroxy progesterone is prepared through oxidation reaction. The route uses a large amount of phosphorus ylide reagent, is high in price, is troublesome in aftertreatment due to the oxidant oxone, is difficult to treat a large amount of waste solids, has the defects of low reaction yield and poor oxidation selectivity, and is not suitable for industrial production.
Figure BDA0003450731440000022
Patent CN106317154a reports that 17 alpha-hydroxy progesterone is prepared from 4-AD by 4 steps of reaction of alkynylation, nitration, translocation and carbonylation, introducing side chain by the alkynylation reaction, and converting 17 beta into 17 alpha by translocation. The method uses dangerous reagents such as acetylene gas, acetic anhydride, nitric acid and the like, has low reaction yield and high preparation difficulty, and is not suitable for industrial production.
Figure BDA0003450731440000031
Patent CN103910775a reports that 17 alpha-hydroxy progesterone is prepared from 4-AD by cyano addition, C3 carbonyl protection, C17 hydroxyl protection, and hydrolysis. The route uses the acutely toxic substances of acetone cyanohydrin and Grignard reagent, has complex operation danger and is not suitable for industrial production.
Figure BDA0003450731440000032
(3) Preparing 17 alpha-hydroxy steroid compound by taking 11 alpha-hydroxy progesterone as raw material: the document Synthesis of New Steroidal Inhibitors of P-glycin-mediated Multidrug Resistance and Biological Evaluation on K/R7 Erythroleukemia Cells reports that 11 alpha-hydroxy progesterone is used as a raw material to prepare 11 alpha, 17 alpha-hydroxy progesterone through the protection of C3 carbonyl, C11 hydroxyl and C20 carbonyl, hydrolysis, oxidation and re-hydrolysis reactions. The route uses sodium hydride in the oxidation reaction, and oxygen is required to be continuously introduced, so that the reaction yield is low, the danger coefficient is high, and the method is not suitable for industrial production.
Figure BDA0003450731440000041
The synthetic routes of the 17 alpha-hydroxy steroid compounds have certain defects, such as high risk coefficient, harsh reaction conditions and low yield in the preparation process by using extremely toxic, expensive and unstable special reagents, do not conform to the green chemistry concept, and are limited in large-scale industrial production.
In view of this, the present invention has been made.
Disclosure of Invention
The main object of the present invention is to provide a method for synthesizing 17 alpha-hydroxysteroids, in order to at least partially solve at least one of the above technical problems.
The invention provides a synthesis method of 17 alpha-hydroxy steroid compounds, which comprises the following steps:
b) Adding an alkali reagent and a reducing reagent into an organic solvent 2 to prepare a reaction raw material liquid 2, and respectively introducing a solution containing a compound II, the reaction raw material liquid 2 and an oxygen-containing gas into a continuous flow reactor at a certain flow rate to react to obtain a compound III; the reaction formula is as follows:
Figure BDA0003450731440000051
wherein R is represented by the structural formula of compound II and compound III 1 、R 2 、R 3 、R 4 、R 5 Selected independently of each other, and:
R 1 =oh or H;
R 2 =halogen or H, halogen is F, cl or Br;
R 3 ＝CH 2 R 6 ，R 6 ＝H、OH、halogen or OCOR 7 ，R 7 Alkyl groups of six carbons or less;
R 4 =h or CH 3 ；
R 5 Alkyl within six carbons;
the dotted line is a single bond or a double bond.
The invention uses a corning microchannel reactor, model: corning micro-channel G1 reactor, material: silicon carbide material. The microchannel reactor comprises a plurality of reaction modules, each reaction module having a volume of about 8.2mL. The specific number of reaction modules may be selected according to the progress of the reaction.
Further, in the step (b), the alkali reagent is selected from one or a combination of several of potassium tert-butoxide, sodium tert-butoxide or sodium ethoxide; the reducing agent is one or a combination of a plurality of sodium sulfite, triethyl phosphite or trimethyl phosphite; the organic solvent 2 is selected from tetrahydrofuran or DMF.
Further, in the step (b), the molar ratio of the compound ii to the alkali agent is 1: (0.2-1.2); the molar ratio of the compound II to the reducing agent is 1: (0.5-1.5).
Further, in the step (b), the flow rate of the solution containing the compound II is 38.6-76.0g/min; the flow rate of the reaction raw material liquid 2 is 3.8-41.5g/min; the flow rate of the oxygen is 80-150mL/min.
Further, the preparation method of the compound II comprises the following steps: and adding the compound I and the catalyst into the organic solvent 1 to prepare a reaction raw material liquid 1, and reacting an etherification reagent with the reaction raw material liquid 1 to obtain the compound II.
Further, the preparation method of the compound II comprises the following steps:
(a) Adding a compound I and a catalyst into an organic solvent 1 to prepare a reaction raw material liquid 1, and respectively introducing an etherification reagent and the reaction raw material liquid 1 into a continuous flow reactor at a certain flow rate to react to obtain a solution containing a compound II; the reaction formula is as follows:
Figure BDA0003450731440000061
wherein R is represented by the structural formula of compound I and compound II 1 、R 2 、R 3 、R 4 、R 5 Selected independently of each other, and:
R 1 =oh or H;
R 2 =halogen or H, halogen is F, cl or Br;
R 3 ＝CH 2 R 6 ，R 6 = H, OH, halogen or OCOR 7 ，R 7 Alkyl groups of six carbons or less;
R 4 =h or CH 3 ；
R 5 Alkyl within six carbons;
the dotted line is a single bond or a double bond.
Further, in the step (a), the catalyst is selected from p-toluenesulfonic acid and/or pyridine hydrobromide; the etherification reagent is selected from one or a combination of a plurality of triethyl orthoformate, trimethyl orthoacetate or trimethyl orthoformate; the organic solvent 1 is selected from tetrahydrofuran or DMF.
Further, in the step (a), the molar ratio of the compound i to the catalyst is 1: (0.05-0.1); the molar ratio of the compound I to the etherification reagent is 1: (0.5-1.3).
Further, in the step (a), the flow rate of the reaction raw material liquid 1 is 35.0-75.0g/min; the flow rate of the etherification reagent is 1.0-3.6g/min.
Further, the synthesis method of the 17 alpha-hydroxy steroid compound comprises the following steps:
(a) Adding a compound I and a catalyst into an organic solvent 1 to prepare a reaction raw material liquid 1, and respectively introducing an etherification reagent and the reaction raw material liquid 1 into a continuous flow reactor at a certain flow rate to react to obtain a solution containing a compound II;
(b) Adding an alkali reagent and a reducing reagent into an organic solvent 2 to prepare a reaction raw material liquid 2, and respectively introducing the solution containing the compound II, the reaction raw material liquid 2 and an oxygen-containing gas in the step (a) into a continuous flow reactor at a certain flow rate to react to obtain a compound III; the reaction formula is as follows:
Figure BDA0003450731440000071
wherein R is represented by the structural formula of compound I, compound II and compound III 1 、R 2 、R 3 、R 4 、R 5 Selected independently of each other, and:
R 1 =oh or H;
R 2 =cl or H;
R 3 ＝CH 2 R 6 ，R 6 =h or OCOR 7 ，R 7 Alkyl groups of three carbons or less;
R 4 =h or CH 3 ；
R 5 Alkyl within three carbons;
the dotted line is a single bond or a double bond.
Further, the synthesis method of the 17 alpha-hydroxy steroid compound comprises the following steps:
(a) Adding a compound I and a catalyst into an organic solvent 1 to prepare a reaction raw material liquid 1, respectively introducing an etherification reagent and the reaction raw material liquid 1 into a plurality of reaction modules connected in series of a continuous flow reactor 1 at a certain flow rate to react to obtain a solution containing a compound II;
(b) Adding an alkali reagent and a reducing reagent into an organic solvent 2 to prepare a reaction raw material liquid 2, respectively introducing the solution containing the compound II, the reaction raw material liquid 2 and oxygen-containing gas in the step (a) into a plurality of reaction modules connected in series in a continuous flow reactor 2 at a certain flow rate to react, and deprotecting the effluent reaction liquid under an acidic condition to obtain a compound III; the reaction formula is as follows:
Figure BDA0003450731440000081
wherein the compound I, the compoundR shown in structural formula II and compound III 1 、R 2 、R 3 、R 4 、R 5 Selected independently of each other, and:
R 1 =oh or H;
R 2 =cl or H;
R 3 ＝CH 2 R 6 ，R 6 =h or OCOR 7 ，R 7 Alkyl groups of three carbons or less;
R 4 =h or CH 3 ；
R 5 Alkyl within three carbons;
the dotted line is a single bond or a double bond.
Further, the deprotection is selected from hydrochloric acid, hydrobromic acid or sulfuric acid.
Further, the compound III is 17 alpha-hydroxy progesterone.
Further, each reaction module of the continuous flow reactor 1 is provided with an external heat exchanger, and the temperature of the external heat exchanger is set to be 5-15 ℃; each reaction module of the continuous flow reactor 2 is provided with an external heat exchanger, and the temperature of the external heat exchanger is set to be 0-20 ℃.
Further, each reaction module of the continuous flow reactor 1 is provided with an external heat exchanger, and the temperature of the external heat exchanger is set to be 8-12 ℃; each reaction module of the continuous flow reactor 2 is provided with an external heat exchanger, and the temperature of the external heat exchanger is set to be 5-10 ℃.
Further, the number of the reaction modules of the continuous flow reactor 1 and the continuous flow reactor 2 which are sequentially connected in series is 5-25.
In the present invention, the typical but non-limiting number of reaction modules in the sequential series of the continuous flow reactor 1 and the continuous flow reactor 2 may be, for example, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25.
Further, the molar ratio of the compound I to the catalyst is 1: (0.06-0.08);
the molar ratio of the compound I to the etherification reagent is 1: (0.6-1.0);
the molar ratio of the compound II to the alkali reagent is 1: (0.5 to 1.0);
the molar ratio of the compound II to the reducing agent is 1: (0.8-1.2).
Further, the oxygen flow rate is 100-130mL/min.
Further, the oxygen-containing gas is oxygen or air.
Further, the oxygen-containing gas is oxygen.
In the step (b), an alkali reagent and a reducing reagent are added into the organic solvent 2 to prepare a solution with the mass concentration of the reducing reagent of 12-30%.
Further, when DMF is selected as the organic solvent 1, the amount of solvent added per 1g of compound I is 5-10mL; when tetrahydrofuran is selected as the organic solvent 1, the amount of the solvent added per 1g of the compound I is 6 to 10mL.
Compared with the prior art, the invention has the following beneficial effects:
compared with the existing kettle type process, the micro-scale characteristic of the micro-channel reactor used by the invention ensures that the reactor has intrinsic safety and greatly reduces the danger coefficient of oxygen; compared with the prior art, the synthesis method provided by the invention has the characteristics of less impurities and high purity, and reduces the generation of 20-site etherate and other impurities; the microchannel reactor has high-efficiency mass and heat transfer effect, can greatly reduce the consumption of organic solvents in the reaction process, improves the product yield, reduces the raw material cost, and simultaneously reduces the discharge amount of three wastes; meanwhile, the specific surface area and the mass heat transfer coefficient of the reactor are far higher than those of the traditional reactor, so that the reaction can obtain higher product purity under the controllable continuous condition; has the characteristics of good product quality, high safety and security, etc.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to examples, but it will be understood by those skilled in the art that the following examples are only for illustrating the present invention and should not be construed as limiting the scope of the present invention. The examples were conducted under conventional conditions, except that the specific conditions were not specified.
The raw materials and the auxiliary materials related to each embodiment and the comparative embodiment of the invention are all from the same batch number.
Example 1
Examples 1 to 1a
Figure BDA0003450731440000111
Adding 500mL of LDMF (500 mL of crystallization-assisted crystallization) into 3.1g of paratoluenesulfonic acid monohydrate, cooling to 5 ℃, dropwise adding 61.3g of triethyl orthoformate, reacting for 2h under heat preservation and stirring, adding 2500mL of water into the reaction solution for precipitation, filtering, washing with 200mL of water for 2 times, and drying to obtain 98.1g of compound II-1, wherein the yield is 90.9%.
Examples 1 to 1b
Figure BDA0003450731440000112
Adding 1LDMF into 5.1g of pyridine hydrobromide and 5.1g of compound I-1100 g, cooling to 5 ℃, dropwise adding 19.2g of trimethyl orthoacetate, adding 5000mL of water into the reaction solution to precipitate, filtering, washing with 200mL of water for 2 times, and drying to obtain 94.8g of compound II-1', wherein the yield is 90.7%.
Examples 1 to 1c
Figure BDA0003450731440000113
Adding 600mL of tetrahydrofuran to 4.9g of p-toluenesulfonic acid monohydrate and the compound I-1100 g, cooling to 5 ℃, dropwise adding 20.4g of trimethyl orthoformate, adding 5000mL of water into the reaction solution to precipitate, filtering, washing 200mL of water for 2 times, and drying to obtain 92.2g of compound II-1', wherein the yield is 88.3%.
Examples 1 to 2
Figure BDA0003450731440000121
(1) 100g of compound II-1 was put into 500mL of DMF to prepare a compound II-1 solution; 23.0g of sodium tert-butoxide and 100.0g of triethyl phosphite are put into 500mL of DMF to prepare a reaction raw material liquid 2; setting the temperature of the continuous flow reactor to be 0 ℃, conveying a compound II-1 solution into the continuous flow reactor at 76.0g/min through a material pump 4, and conveying a reaction raw material liquid 2 into the continuous flow reactor at 18.5g/min through a material pump 3; simultaneously, oxygen is introduced into the continuous flow reactor at 80 mL/min; the three are reacted in 5 reaction modules which are sequentially connected in series in a continuous flow reactor;
(2) Continuously collecting the reaction solution obtained in the step (1) for 5min, flowing into hydrochloric acid aqueous solution with the pH of 1 at the temperature of 5 ℃, controlling the pH to be less than 2, stirring to precipitate solid, filtering, leaching a filter cake with water until the filter cake is neutral, and drying to obtain the compound III-1 with the HPLC purity of 95.2% and the yield of 88.1%.
Example 2
Example 2-1
Figure BDA0003450731440000131
100g of compound I-2 and 3.5g of paratoluenesulfonic acid monohydrate are put into 700mL of tetrahydrofuran to prepare a reaction raw material liquid 1;
setting the temperature of a continuous flow reactor 1 to be 5 ℃, conveying a reaction raw material liquid 1 into the continuous flow reactor by using a material pump 1 at 42.3g/min, simultaneously conveying 22.0g of triethyl orthoformate into the continuous flow reactor by using a material pump 2 at 1.3g/min, and reacting the two in 15 reaction modules which are sequentially connected in series in the continuous flow reactor to obtain a solution containing a compound II-2.
Example 2-2
Figure BDA0003450731440000132
(1) 72.3g of potassium tert-butoxide and 100.0g of triethyl phosphite are put into 300mL of tetrahydrofuran to prepare a reaction raw material liquid 2;
setting the temperature of the continuous flow reactor to 20 ℃, and introducing the compound II-2 solution obtained in the example 2-1 into the continuous flow reactor at 43.6 g/min; feeding the reaction raw material liquid 2 into a continuous flow reactor at a speed of 12.5g/min through a material pump 3; simultaneously, oxygen is introduced into the continuous flow reactor at 150 mL/min; the three are reacted in 15 reaction modules which are sequentially connected in series in a continuous flow reactor;
(2) Continuously collecting the reaction liquid obtained in the step (1) for 5min, flowing into hydrobromic acid aqueous solution with the temperature of 5 ℃ and the pH value of 1, controlling the pH value to be less than 2, stirring to precipitate solid, filtering, leaching a filter cake with water until the filter cake is neutral, and drying to obtain the compound III-2, wherein the purity of HPLC is 94.6%, and the yield of the two-step reaction is 83.7%.
Example 3
Figure BDA0003450731440000141
(1) 100g of compound I-1 and 3.1g of paratoluenesulfonic acid monohydrate are put into 500mL of DMF to prepare a reaction raw material liquid 1;
setting the temperature of a continuous flow reactor 1 to be 5 ℃, conveying a reaction raw material liquid 1 into the continuous flow reactor 1 by using a material pump 1 at a speed of 35g/min, conveying 65g of triethyl orthoformate into the continuous flow reactor 1 by using a material pump 2 at a speed of 3.6g/min, and reacting the two in 25 reaction modules which are sequentially connected in series in the continuous flow reactor 1 to obtain a reaction liquid containing a compound II-1;
(2) 9.0g of potassium tert-butoxide and 100.0g of triethyl phosphite are put into 770mL of DMF to prepare a reaction raw material liquid 2;
setting the temperature of the continuous flow reactor 2 to be 0 ℃, and directly introducing the reaction liquid containing the compound II-1 obtained in the step (1) into the continuous flow reactor 2; feeding the reaction raw material liquid 2 into the continuous flow reactor 2 at the speed of 41.5g/min through a material pump 3; simultaneously, oxygen is introduced into the continuous flow reactor 2 at the speed of 150 mL/min; the three are reacted in 5 reaction modules which are sequentially connected in series in a continuous flow reactor 2;
(3) Continuously collecting the reaction solution obtained in the step (2) for 5min, flowing into hydrochloric acid aqueous solution with the pH of 1 at the temperature of 5 ℃, controlling the pH to be less than 2, stirring to precipitate solid, filtering, leaching a filter cake with water until the filter cake is neutral, and drying to obtain the compound III-1 with the HPLC purity of 94.5% and the yield of 82.5%.
Example 4
Figure BDA0003450731440000151
(1) 100g of compound I-3 and 4.8g of pyridine hydrobromide are put into 700mL of DMF to prepare reaction raw material liquid 1;
setting the temperature of a continuous flow reactor to 15 ℃, conveying a reaction raw material liquid 1 into the continuous flow reactor 1 by using a material pump 1 at 60g/min, conveying 19.2g of trimethyl orthoacetate into the continuous flow reactor 1 by using a material pump 2 at 1.5g/min, and reacting the two in 5 reaction modules which are sequentially connected in series in the continuous flow reactor 1 to obtain a reaction liquid containing a compound II-3;
(2) 92.5g of sodium tert-butoxide and 50.0g of trimethyl phosphite are put into 300mL of DMF to prepare a reaction raw material liquid 2;
setting the temperature of a continuous flow reactor to 20 ℃, and directly introducing the reaction liquid containing the compound II-3 obtained in the step (1) into a continuous flow reactor 2; the reaction raw material liquid 2 is delivered into a continuous flow reactor at a speed of 12g/min through a material pump 3; simultaneously, oxygen is introduced into the continuous flow reactor 2 at 80 mL/min; the three are reacted in 25 reaction modules which are sequentially connected in series in a continuous flow reactor 2;
(3) Continuously collecting the reaction liquid obtained in the step (2) for 5min, flowing into hydrobromic acid aqueous solution with the temperature of 5 ℃ and the pH value of 1.5, controlling the pH value to be less than 2, stirring to precipitate solid, filtering, leaching a filter cake with water until the filter cake is neutral, and drying to obtain the compound III-3, wherein the HPLC purity is 94.7%, and the yield is 81.9%.
Example 5
Figure BDA0003450731440000161
(1) 100g of compound I-4 and 2.4g of pyridine hydrobromide are put into 1L of DMF to prepare reaction raw material liquid 1;
setting the temperature of a continuous flow reactor 1 to 8 ℃, conveying a reaction raw material liquid 1 into the continuous flow reactor 1 by using a material pump 1 at a speed of 75.0g/min, conveying 14.0g of trimethyl orthoformate into the continuous flow reactor 1 by using a material pump 2 at a speed of 1.0g/min, and reacting the two in 15 reaction modules which are sequentially connected in series in the continuous flow reactor 1 to obtain a reaction liquid containing a compound II-4;
(2) 21.9g of sodium ethoxide and 100.0g of trimethyl phosphite are put into 220mL of DMF to prepare a reaction raw material liquid 2;
setting the temperature of the continuous flow reactor 2 to be 5 ℃, and directly introducing the reaction liquid containing the compound II-4 obtained in the step (1) into the continuous flow reactor 2; feeding the reaction raw material liquid 2 into the continuous flow reactor 2 at a speed of 3.8g/min through a material pump 3; simultaneously, oxygen is introduced into the continuous flow reactor 2 at a rate of 100 mL/min; the three are reacted in 10 reaction modules which are sequentially connected in series in a continuous flow reactor 2;
(3) Continuously collecting the reaction liquid obtained in the step (2) for 5min, flowing into hydrobromic acid aqueous solution with the temperature of 4 ℃ and the pH value of 1.5, controlling the pH value to be less than 2, stirring to precipitate solid, filtering, leaching a filter cake with water until the filter cake is neutral, and drying to obtain the compound III-4, wherein the purity of HPLC is 95.2%, and the yield is 85.3%.
Example 6
Figure BDA0003450731440000171
(1) 100g of Compound I-4 and 3.6g of paratoluenesulfonic acid monohydrate were added to 600mL of tetrahydrofuran to prepare a reaction raw material liquid 1;
setting the temperature of a continuous flow reactor 1 to 7 ℃, conveying a reaction raw material liquid 1 into the continuous flow reactor 1 by using a material pump 1 at 63.0g/min, conveying 20.4g of trimethyl orthoformate into the continuous flow reactor 1 by using a material pump 2 at 1.7g/min, and reacting the two in 10 reaction modules which are sequentially connected in series in the continuous flow reactor 1 to obtain a reaction liquid containing a compound II-4;
(2) 22.5g of sodium ethoxide and 100.0g of sodium sulfite are put into 500mL of tetrahydrofuran to prepare a reaction raw material liquid 2;
setting the temperature of the continuous flow reactor 2 to 15 ℃, and directly introducing the reaction liquid containing the compound II-4 obtained in the step (1) into the continuous flow reactor 2; delivering the reaction raw material liquid 2 into the continuous flow reactor 2 at 20.8g/min through a material pump 3; simultaneously, oxygen is introduced into the continuous flow reactor 2 at a rate of 140 mL/min; the three are reacted in 10 reaction modules which are sequentially connected in series in a continuous flow reactor 2;
(3) Continuously collecting the reaction liquid obtained in the step (2) for 5min, flowing into hydrobromic acid aqueous solution with the temperature of 4 ℃ and the pH value of 1.3, controlling the pH value to be less than 2, stirring to precipitate solid, filtering, leaching a filter cake with water until the filter cake is neutral, and drying to obtain the compound III-4, wherein the purity of HPLC is 94.5%, and the yield is 82.8%.
Example 7
Figure BDA0003450731440000181
(1) 100g of Compound I-5 and 2.7g of pyridine hydrobromide were put into 1.2L of tetrahydrofuran to prepare a reaction raw material liquid 1;
setting the temperature of a continuous flow reactor to be 12 ℃, conveying a reaction raw material liquid 1 into the continuous flow reactor 1 by using a material pump 1 at 60g/min, conveying 47.4g of triethyl orthoformate into the continuous flow reactor 1 by using a material pump 2 at 2.2g/min, and reacting the two in 20 reaction modules which are sequentially connected in series in the continuous flow reactor 1 to obtain a reaction liquid containing a compound II-5';
(2) 84.3g of potassium tert-butoxide and 100.0g of triethyl phosphite are put into 500mL of tetrahydrofuran to prepare a reaction raw material liquid 2;
setting the temperature of the continuous flow reactor 2 to be 10 ℃, and directly introducing the reaction liquid containing the compound II-5' obtained after the reaction in the step (1) into the continuous flow reactor 2; feeding the reaction raw material liquid 2 into the continuous flow reactor 2 at a speed of 13.6g/min through a material pump 3; simultaneously, oxygen is introduced into the continuous flow reactor at 130 mL/min; the three are reacted in 20 reaction modules which are sequentially connected in series in a continuous flow reactor;
(3) Continuously collecting the reaction solution obtained in the step (2) for 5min, flowing into hydrobromic acid aqueous solution with the temperature of 0 ℃ and the pH value of 1.2, controlling the pH value to be less than 2, stirring to precipitate solid, filtering, leaching a filter cake with water until the filter cake is neutral, and drying to obtain the compound III-5, wherein the purity of HPLC is 95.3%, and the yield is 85.9%.
Example 8
Figure BDA0003450731440000191
(1) 100g of compound I-1 and 4.2g of paratoluenesulfonic acid monohydrate are put into 1L of DMF to prepare reaction raw material liquid 1;
setting the temperature of a continuous flow reactor 1 to be 10 ℃, conveying a reaction raw material liquid 1 into the continuous flow reactor 1 by using a material pump 1 at 49.5g/min, conveying 30.7g of trimethyl orthoacetate into the continuous flow reactor 1 by using a material pump 2 at 1.5g/min, and reacting the two in 10 reaction modules which are sequentially connected in series in the continuous flow reactor 1 to obtain a reaction liquid containing a compound II-1';
(2) 54.2g of sodium tert-butoxide and 100g of trimethyl phosphite are put into 200mL of DMF to prepare a reaction raw material liquid 2;
setting the temperature of the continuous flow reactor 2 to 8 ℃, and directly introducing the reaction liquid containing the compound II-1' obtained in the step (1) into the continuous flow reactor 2; feeding the reaction raw material liquid 2 into the continuous flow reactor 2 at a rate of 8.0g/min through a material pump 3; simultaneously, oxygen is introduced into the continuous flow reactor 2 at a rate of 120 mL/min; the three are reacted in 15 reaction modules which are sequentially connected in series in the continuous flow reactor 2;
(3) Continuously collecting the reaction solution obtained in the step (2) for 5min, flowing into hydrochloric acid aqueous solution with the pH of 1.5 at the temperature of 5 ℃, controlling the pH to be less than 2, stirring to precipitate solid, filtering, leaching a filter cake with water until the filter cake is neutral, and drying to obtain the compound III-1, wherein the purity of HPLC is 95.6%, and the yield is 86.7%.
Comparative examples
The preparation of Compound II-1 is described with reference to the preparation in example 1-1 a.
5.8g of sodium tert-butoxide is stirred and dissolved in 120mLDMF, cooled to 5 ℃, 24.9g of triethyl phosphite is added, air is blown in, 100g of compound II-1 is added until TLC shows that the reaction is complete; 40mL of 6N hydrochloric acid was added to the reaction solution, stirred at room temperature for 30 minutes, and TLC showed complete reaction; adding 500mL of water into the reaction solution, cooling and stirring in an ice water bath, filtering and pumping out; 100mL of water is washed 3 times, and the 17 alpha-hydroxy progesterone is obtained by 69.4g after drying, and the yield is about 72.0%.
Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention, and not for limiting the same; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some or all of the technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit of the invention.

Claims (10)

1. The synthesis method of the 17 alpha-hydroxy steroid compound is characterized by comprising the following steps:
(b) Adding an alkali reagent and a reducing reagent into an organic solvent 2 to prepare a reaction raw material liquid 2, and respectively introducing a solution containing a compound II, the reaction raw material liquid 2 and an oxygen-containing gas into a continuous flow reactor at a certain flow rate to react to obtain a compound III; the reaction formula is as follows:
Figure FDA0003450731430000011
wherein R is represented by the structural formula of compound II and compound III 1 、R 2 、R 3 、R 4 、R 5 Selected independently of each other, and:
R 1 =oh or H;
R 2 =halogen or H, halogen is F, cl or Br;
R 3 ＝CH 2 R 6 ，R 6 = H, OH, halogen or OCOR 7 ，R 7 Alkyl groups of six carbons or less;
R 4 =h or CH 3 ；
R 5 Alkyl within six carbons;
the dotted line is a single bond or a double bond.
2. The method for synthesizing a 17 a-hydroxysteroid compound according to claim 1, wherein in the step (b), the alkali agent is selected from one or a combination of several of potassium tert-butoxide, sodium tert-butoxide or sodium ethoxide; the reducing agent is one or a combination of a plurality of sodium sulfite, triethyl phosphite or trimethyl phosphite; the organic solvent 2 is selected from tetrahydrofuran or DMF.
3. The method of synthesizing a 17 α -hydroxysteroid compound according to claim 2, wherein in the step (b), the molar ratio of the compound ii to the alkali agent is 1: (0.2-1.2); the molar ratio of the compound II to the reducing agent is 1: (0.5-1.5).
4. A method of synthesizing a 17 α -hydroxysteroid compound according to claim 3, wherein in the step (b), the flow rate of the solution containing the compound ii is 38.6-76.0g/min; the flow rate of the reaction raw material liquid 2 is 3.8-41.5g/min; the flow rate of the oxygen is 80-150mL/min.
5. A method of synthesizing a 17 α -hydroxysteroid compound according to any one of claims 1 to 3, wherein the method of preparing the compound II comprises the steps of:
(a) Adding a compound I and a catalyst into an organic solvent 1 to prepare a reaction raw material liquid 1, and respectively introducing an etherification reagent and the reaction raw material liquid 1 into a continuous flow reactor at a certain flow rate to react to obtain a solution containing a compound II; the reaction formula is as follows:
Figure FDA0003450731430000021
wherein R is represented by the structural formula of compound I and compound II 1 、R 2 、R 3 、R 4 、R 5 Selected independently of each other, and:
R 1 =oh or H;
R 2 =halogen or H, halogen is F, cl or Br;
R 3 ＝CH 2 R 6 ，R 6 = H, OH, halogen or OCOR 7 ，R 7 Alkyl groups of six carbons or less;
R 4 =h or CH 3 ；
R 5 Alkyl within six carbons;
the dotted line is a single bond or a double bond.
6. The method of synthesizing a 17 a-hydroxysteroid compound according to claim 5, wherein in the step (a), the catalyst is selected from p-toluenesulfonic acid and/or pyridine hydrobromide; the etherification reagent is selected from one or a combination of a plurality of triethyl orthoformate, trimethyl orthoacetate or trimethyl orthoformate; the organic solvent 1 is selected from tetrahydrofuran or DMF.
7. The method of synthesizing a 17 α -hydroxysteroid compound according to claim 6, wherein in the step (a), the molar ratio of the compound i to the catalyst is 1: (0.05-0.1); the molar ratio of the compound I to the etherification reagent is 1: (0.5-1.3).
8. The method for synthesizing a 17 a-hydroxysteroid compound according to claim 6, wherein in the step (a), the flow rate of the reaction raw material liquid 1 is 35.0 to 75.0g/min; the flow rate of the etherification reagent is 1.0-3.6g/min.
9. The method for synthesizing 17 a-hydroxysteroids according to claim 2, comprising the steps of:
(a) Adding a compound I and a catalyst into an organic solvent 1 to prepare a reaction raw material liquid 1, respectively introducing an etherification reagent and the reaction raw material liquid 1 into a plurality of reaction modules connected in series of a continuous flow reactor 1 at a certain flow rate to react to obtain a solution containing a compound II;
(b) Adding an alkali reagent and a reducing reagent into an organic solvent 2 to prepare a reaction raw material liquid 2, respectively introducing the solution containing the compound II, the reaction raw material liquid 2 and oxygen-containing gas in the step (a) into a plurality of reaction modules connected in series in a continuous flow reactor 2 at a certain flow rate to react, and deprotecting the effluent reaction liquid under an acidic condition to obtain a compound III; the reaction formula is as follows:
Figure FDA0003450731430000031
wherein R is represented by the structural formula of compound I, compound II and compound III 1 、R 2 、R 3 、R 4 、R 5 Selected independently of each other, and:
R 1 =oh or H;
R 2 =cl or H;
R 3 ＝CH 2 R 6 ，R 6 =h or OCOR 7 ，R 7 Alkyl groups of three carbons or less;
R 4 =h or CH 3 ；
R 5 Alkyl within three carbons;
the dotted line is a single bond or a double bond.
10. The method for synthesizing a 17α -hydroxysteroid compound according to any one of claims 1 to 4,6 to 9, wherein the compound iii is 17α -hydroxyprogesterone.
CN202111674797.XA 2021-12-31 2021-12-31 Synthesis method of 17 alpha-hydroxy steroid compound Pending CN116410254A (en)

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