CN112175034A - Method for preparing 17 alpha-hydroxyprogesterone - Google Patents
Method for preparing 17 alpha-hydroxyprogesterone Download PDFInfo
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- 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
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Abstract
The invention provides a method for preparing 17 alpha-hydroxyprogesterone, which comprises the following steps: step 1, preparing a first reaction solution containing a compound II based on a hydroxyl etherification reaction by using the compound I; step 2, preparing a second reaction solution containing the following compound III by using the first reaction solution based on a cyanomethylation reaction; and 3, based on hydrolysis reaction, preparing the 17 alpha-hydroxyprogesterone IV by using the second reaction solution. The invention adopts a one-pot method to prepare the 17 alpha-hydroxyprogesterone IV from the compound I, has the advantages of high yield, good selectivity, simple and safe operation, low cost, small pollution and the like, and is stable in reaction in each step and easy to realize industrial production.
Description
Technical Field
The invention belongs to the field of medical environment chemical industry, and particularly relates to a method for preparing 17 alpha-hydroxyprogesterone.
Background
The 17 alpha-hydroxyprogesterone is an important steroid drug intermediate, and can be used for synthesizing steroid drugs such as cortisone acetate, hydrocortisone, dexamethasone, fluocinolone, uterus series and the like. The 17 alpha-hydroxyprogesterone is white or off-white crystalline powder, the melting point is 212-220 ℃, and the structural formula is as follows:
the traditional synthesis method of 17 alpha-hydroxyprogesterone takes saponin (diene) as a raw material and prepares the saponin through oxygen bridge, Wolff oxidation, bromination and debromination, and has the defects of long synthesis route, dangerous reaction, serious pollution, low yield, high cost and the like, so the synthesis route is basically eliminated.
At present, 17 alpha-hydroxyprogesterone is mainly synthesized by taking 4-androstenedione as a raw material. The 4-androstenedione can be prepared by degrading cholesterol and phytosterol by microorganisms, and compared with the method for preparing 17 alpha-hydroxyprogesterone by taking saponin (diene) as a raw material, the method has the characteristics of wide raw material source, low cost and small pollution. However, the existing process route for synthesizing 17 α -hydroxyprogesterone by using 4-androstenedione as a raw material still has the defects of low product yield (the molar yield for preparing 17 α -hydroxyprogesterone is about 82%), high production cost and complex operation.
Therefore, a new preparation process is needed, which can achieve the purpose of efficiently synthesizing 17 α -hydroxyprogesterone while achieving simple operation.
Disclosure of Invention
To solve the above problems in the prior art in whole or in part, the present invention provides a method for preparing 17 α -hydroxyprogesterone, comprising:
step 2, based on the cyanomethylation reaction, preparing a second reaction solution containing a compound III by using the first reaction solution;
step 3, based on hydrolysis reaction, preparing 17 alpha-hydroxyprogesterone IV by using the second reaction solution;
preferably, the operation of the hydroxyl etherification reaction comprises:
under the protection of inert gas, uniformly mixing the compound I, diethoxymethane, butyl vinyl ether and a catalyst, and stirring to obtain a first reaction solution containing a compound II;
in the reaction conditions of the hydroxyl etherification, the reaction temperature is 40-60 ℃, and the reaction time is 1-4 h.
Preferably, the catalyst is at least one of pyridine hydrochloride and trifluoroacetic acid.
Preferably, in the hydroxyl etherification reaction,
the mass ratio of the compound I to the diethoxymethane is 1: 4-10;
the molar ratio of the compound I to the butyl vinyl ether is 1: 1-4;
the mass ratio of the compound I to the catalyst is 1: 0.03-0.1.
Preferably, the operation of the cyanomethylation reaction comprises:
under the protection of inert gas, adding a methyllithium reagent into the first reaction liquid, and stirring to obtain a first reaction system;
dropwise adding the first reaction system into 30% ammonium chloride aqueous solution by mass, and performing a liquid-liquid layering process to obtain a second reaction system consisting of a water phase and an organic phase;
extracting the organic phase from the second reaction system, and concentrating the organic phase to obtain a concentrated solution;
and adding a hydrolysis reaction solvent into the concentrated solution to obtain a second reaction solution containing the compound III.
Preferably, in the cyanomethylation reaction, the reaction temperature is 10 ℃ to 20 ℃ and the reaction time is 2h to 4h under the reaction conditions for preparing the first reaction system.
Preferably, in the cyanomethylation reaction, the hydrolysis reaction solvent is at least one of acetone, tetrahydrofuran or isopropanol.
Preferably, in the cyanomethylation reaction,
the molar ratio of the compound I to the methyllithium reagent is 1: 2-6 based on the molar weight of the compound I;
the mass ratio of the compound I to the ammonium chloride aqueous solution is 1: 2-8 based on the mass of the compound I;
the mass ratio of the compound I to the hydrolysis reaction solvent is 1: 2-6 based on the weight of the compound I.
Preferably, the operation of the hydrolysis reaction comprises:
adding 20 mass percent hydrochloric acid aqueous solution into the second reaction solution, controlling the temperature to be 20-30 ℃, reacting for 1-6 h, adding triethylamine to adjust the pH value to be 6-8, cooling to be-10-0 ℃, controlling the temperature for 1-6 h, carrying out solid-liquid separation, and drying to obtain the compound 17 alpha-hydroxyprogesterone IV.
Preferably, in the hydrolysis reaction,
the mass ratio of the compound I to the hydrochloric acid aqueous solution is 1: 0.5-1.0 by taking the weight of the compound I as a reference.
The embodiment of the invention provides a method for preparing 17 alpha-hydroxyprogesterone, which comprises the following steps: preparing a first reaction liquid containing a compound II by using a compound I based on a hydroxyl etherification reaction; preparing a second reaction liquid containing a compound III by using the first reaction liquid based on a cyanomethylation reaction; the second reaction solution was used to prepare 17 α -hydroxyprogesterone IV based on hydrolysis. Compared with the prior art, the method of the invention has the following advantages:
(1) in the embodiment of the invention, pyridine hydrochloride or trifluoroacetic acid with mild chemical activity is selected as a catalyst for 17-position hydroxyl etherification, so that on one hand, side reaction can be inhibited, the reaction selectivity is improved, and the process yield is further improved; on the other hand, under the condition, the butyl vinyl ether can not generate polymerization reaction, and further the color problem caused by the polymer is solved, so that in the invention, a qualified product can be directly obtained without a refining process.
(2) In the embodiment of the invention, diethoxymethane is a solvent of methyllithium reagent, and diethoxymethane is selected as a reaction solvent in the steps 1 and 2, so that on one hand, the activity of the methyllithium reagent can be ensured, the selectivity of the 17-position cyanomethylation reaction is improved, side reactions are inhibited, and the process yield is further improved; on the other hand, a single solvent is helpful for solvent recovery.
(3) In the embodiment of the invention, the hydrolysis reaction solvent is selected as the reaction solvent in the step 3, so that the selectivity of the reaction in the step can be improved, and the hydrolysis reaction solvent is used as a crystallization solvent, so that impurities in the 17 alpha-hydroxyprogesterone can be effectively removed, and a qualified product can be obtained without refining.
(4) In the embodiment of the invention, by adopting the method, the molar yield of the prepared 17 alpha-hydroxyprogesterone IV is more than 94 percent and is far higher than that (about 82 percent) of the existing process, and the product purity is more than 99.5 percent and the content is more than 99 percent.
(5) The method of the invention also has the characteristics of good selectivity, simple and safe operation, low cost, small pollution and the like, and each step of the method has stable reaction and is easy to realize industrial production.
Drawings
FIG. 1 shows a synthetic scheme for the preparation of 17 α -hydroxyprogesterone in an example of the present invention;
FIG. 2 shows a process flow diagram for the preparation of 17 α -hydroxyprogesterone in an example of the present invention;
FIG. 3 shows the HPLC assay results of 17 α -hydroxyprogesterone synthesized in example 1 of the present invention;
FIG. 4 shows an IR spectrum of 17 α -hydroxyprogesterone synthesized in example 1 of the present invention;
fig. 5 shows a liquid chromatography-mass spectrum of 17 α -hydroxyprogesterone synthesized in example 1 of the present invention.
Detailed Description
In order to make the aforementioned objects, features and advantages of the present invention comprehensible, embodiments accompanied with figures are described in further detail below. The following examples are given for the detailed implementation and specific operation of the present invention, but the scope of the present invention is not limited to the following examples.
Generally, the molar yield of 17 α -hydroxyprogesterone IV prepared from compound I is about 82%, which is relatively low. The result of the low yield is mainly caused by the following problems:
(1) when the 17-position hydroxyl group is subjected to etherification reaction, p-toluenesulfonic acid is selected as a catalyst, and the activity of the p-toluenesulfonic acid is too high, so that the reaction is difficult to control, side reactions are more, and the yield is reduced; (2) during the 17-position hydroxyl etherification reaction, the p-toluenesulfonic acid can cause butyl vinyl ether to generate violent polymerization reaction, the polymer can cause the color of a 17 alpha-hydroxyprogesterone product to be heavier and not easy to remove, and the increase of a refining process is one of the reasons for low yield of the prior art; (3) in the 17-position cyanomethylation reaction, more side reactions exist in the prior art, and further the process yield is reduced.
Therefore, in order to solve the above problems, embodiments of the present invention provide a method for preparing 17 α -hydroxyprogesterone.
Fig. 1 shows a synthesis scheme for preparing 17 α -hydroxyprogesterone in the example of the present invention, as shown in fig. 1, compound I is used as a raw material for preparing 17 α -hydroxyprogesterone by a "one-pot method", and 17 α -hydroxyprogesterone IV is obtained through hydroxyl etherification, cyanomethylation and hydrolysis. According to the method, the intermediate products (the compound II and the compound III) do not need to be taken out separately, and the next step operation can be directly carried out in a reaction system, so that the method has the advantage of simple operation, and is easy for industrial production.
Fig. 2 shows a process flow diagram for the preparation of 17 α -hydroxyprogesterone in an example of the present invention. Referring to fig. 2, the method for preparing 17 α -hydroxyprogesterone provided by the embodiment of the present invention includes the following steps:
step 1(S21) of preparing a first reaction solution containing a compound II using a compound I based on a hydroxyl etherification reaction;
step 2(S22) of preparing a second reaction solution containing compound III based on the cyanomethylation reaction using the first reaction solution;
step 3(S23), preparing 17 α -hydroxyprogesterone IV using the first reaction solution based on the hydrolysis reaction.
In the embodiment of the present invention, preferably, the operation of the hydroxyl etherification reaction includes:
under the protection of inert gas, uniformly mixing the compound I, diethoxymethane, butyl vinyl ether and a catalyst, and stirring to obtain a first reaction solution containing a compound II; in the reaction condition of the hydroxyl etherification, the reaction temperature is 40-60 ℃, and the reaction time is 1-4 h.
The diethoxymethane is a solvent of the methyllithium reagent, and the diethoxymethane is selected as a reaction solvent in the first step and the second step, so that the activity of the methyllithium reagent can be ensured, the selectivity of the 17-position cyanomethylation reaction is improved, side reactions are inhibited, and the process yield is improved; on the other hand, the single solvent is beneficial to the recovery and utilization of the solvent.
In the embodiment of the present invention, preferably, the catalyst is at least one of pyridine hydrochloride and trifluoroacetic acid.
According to the invention, pyridine hydrochloride or trifluoroacetic acid with mild chemical activity is used as a catalyst for 17-position hydroxyl etherification, so that side reactions can be inhibited, the reaction selectivity is improved, and the process yield is improved; on the other hand, under the condition, butyl vinyl ether can not generate polymerization reaction, thereby solving the color problem caused by the polymer.
In the embodiment of the present invention, preferably, in the hydroxyl group etherification reaction,
the mass ratio of the compound I to the diethoxymethane is 1: 4-10;
the molar ratio of the compound I to the butyl vinyl ether is 1: 1-4;
the mass ratio of the compound I to the catalyst is 1: 0.03-0.1.
In embodiments of the present invention, it is preferred that the operation of the cyanomethylation reaction comprises:
under the protection of inert gas, adding a methyllithium reagent into the first reaction liquid, and stirring to obtain a first reaction system;
dropwise adding the first reaction system into 30% ammonium chloride aqueous solution by mass, and performing a liquid-liquid layering process to obtain a second reaction system consisting of a water phase and an organic phase;
extracting an organic phase from the second reaction system, and concentrating the organic phase to obtain a concentrated solution;
adding a hydrolysis reaction solvent to the concentrated solution to obtain a second reaction solution containing the compound III. Wherein, the selected hydrolysis reaction solvent is used as the reaction solvent and the precipitation solvent (namely crystallization solvent) in the third step, so that the selectivity of the reaction in the step can be improved, the impurities in the 17 alpha-hydroxyprogesterone can be effectively removed, and the qualified product can be obtained without refining.
In the embodiment of the present invention, preferably, in the cyanomethylation reaction, the reaction conditions for preparing the first reaction system are that the reaction temperature is 10 ℃ to 20 ℃ and the reaction time is 2h to 4 h.
In the present embodiment, preferably, in the cyanomethylation reaction, the hydrolysis reaction solvent is at least one of acetone, tetrahydrofuran or isopropanol.
In the present embodiment, preferably, in the cyanomethylation reaction,
the molar ratio of the compound I to the methyllithium reagent is 1: 2-6 based on the molar weight of the compound I;
taking the mass of the compound I as a reference, wherein the mass ratio of the compound I to the ammonium chloride aqueous solution is 1: 2-8;
the mass ratio of the compound I to the hydrolysis reaction solvent is 1: 2-6 based on the weight of the compound I.
In the embodiment of the present invention, preferably, the operation of the hydrolysis reaction includes:
adding 20 mass percent hydrochloric acid aqueous solution into the second reaction solution, controlling the temperature to be 20-30 ℃, reacting for 1-6 h, adding triethylamine to adjust the pH value to be 6-8, cooling to be-10-0 ℃, controlling the temperature to be 1-6 h, carrying out solid-liquid separation, and drying to obtain the compound 17 alpha-hydroxyprogesterone IV.
In the embodiment of the present invention, preferably, in the hydrolysis reaction,
the mass ratio of the compound I to the hydrochloric acid aqueous solution is 1: 0.5-1.0 by taking the weight of the compound I as a reference.
The synthesis method of 17 alpha-hydroxyprogesterone provided by the embodiment of the invention is characterized in that a compound I is used as a raw material, 17-position hydroxyl is subjected to etherification reaction to obtain a compound II reaction solution, 17-position cyano of the compound II is subjected to methylation reaction to obtain a compound III reaction solution, and finally the compound III is subjected to hydrolysis reaction to obtain a compound 17 alpha-hydroxyprogesterone IV. According to the invention, reasonable catalyst and reaction solvent are selected according to the reaction characteristics, so that the reaction selectivity and the product quality are improved; in addition, the total molar yield of the 17 alpha-hydroxyprogesterone IV is more than 94 percent and is far higher than that of the traditional process (about 82 percent), the product purity is more than 99.5 percent, and the content is more than 99 percent.
In order that those skilled in the art may better understand the present invention, the method for preparing 17 α -hydroxyprogesterone provided by the present invention is illustrated below by means of a number of specific examples.
Example 1
step 2, 17-site cyanomethylation: under the protection of inert gas, adding 2.0mol/L methyllithium reagent into the first reaction solution obtained in the step 1, controlling the temperature at 20 ℃, reacting for 2 hours, dropwise adding the reaction solution into 30% ammonium chloride aqueous solution by mass fraction, carrying out liquid-liquid layering, carrying out sewage treatment on an aqueous phase, concentrating an organic phase to obtain diethoxymethane, and adding a hydrolysis reaction solvent to obtain a compound III solution;
step 3, hydrolysis reaction: adding 20 mass percent hydrochloric acid aqueous solution into the second reaction solution obtained in the step 2, controlling the temperature to be 20 ℃, reacting for 4 hours, adding triethylamine to adjust the pH value to 6-7, stopping the reaction, cooling to-10 ℃, controlling the temperature to be 6 hours, crystallizing, performing solid-liquid separation to obtain solid, and drying to obtain 95.64g of the compound 17 alpha-hydroxyprogesterone (IV), wherein the molar yield is 94.17%, and the content is 99.46%.
The purity of the prepared 17 α -hydroxyprogesterone was measured, and as shown in fig. 3, the HPLC (high performance liquid chromatography) measurement results were: the purity is equal to 99.85% and the maximum single impurity is 0.11%.
This example also carried out infrared spectroscopic examination of the obtained 17 α -hydroxyprogesterone, as shown in FIG. 4, in an infrared spectrum FT-IR (ATR, cm-1) 3424.95(s),2980.89(m),2961.53(w),2883.30(s),1702.10(s),1664.29(s),1433.42(s),1331.13(s),1231.05(m), 887.70(s). The structural analysis of these data was carried out as follows:
A.3424.95cm-1: O-H stretching vibration; 1231.05: and C-O stretching vibration of the tertiary alcohol. From these peaks, it was found that a tertiary alcohol-OH structure was present in the structure of the obtained target product.
B.2980.89cm-1：-CH3Symmetric telescopic vibration; 2961.53cm-1：-CH2-asymmetric stretching vibrations; 2883.30cm-1：-CH3Symmetric telescopic vibration; 1433.42cm-1：-CH2-bending vibrations; 1331.13cm-1：-CH3Bending vibration of (2); 887.70cm-1: C-H out-of-plane bending vibration. From these peaks, it was found that-CH was present in the structure of the target product3Substituent and unsaturated-CH2-。
C.1702.10cm-1: stretching vibration of ketone C ═ O；1664.29cm-1: stretching vibration of conjugated ketone carbonyl. From these peaks, it was found that the structure of the obtained target product contained ketone and conjugated ketone structures.
D.1457.12cm-1：-CH2The shear mode vibration of (2). From this peak, it was found that the structure of the target product had a carbon-carbon double bond structure.
According to an infrared spectrogram, the target product prepared by the method has structures such as tertiary alcoholic hydroxyl, carbon-carbon double bonds, conjugated ketocarbonyl, methyl and the like, and is consistent with a functional group in a 17 alpha-hydroxyprogesterone structure, so that the 17 alpha-hydroxyprogesterone can be successfully prepared by the method.
Fig. 5 shows a liquid chromatography-mass spectrum (LC-MS) of 17 α -hydroxyprogesterone synthesized in example 1 of the present invention; as shown in FIG. 5, [ M + H ] of 17 α -hydroxyprogesterone prepared by the method of the present invention]+And [ M + Na]+The peak mass to charge ratios were 331.3 and 353.3, respectively, i.e. the molecular weight of the 17 α -hydroxyprogesterone produced by the process of the present invention was 330.3, consistent with the molecular weight of 17 α -hydroxyprogesterone.
Example 2
And (3) etherification reaction of 17-position hydroxyl: under the protection of inert gas, 100g (0.306mol) of compound I, 400g of diethoxymethane, 30.6g (0.306mol) of butyl vinyl ether and 10g of trifluoroacetic acid are uniformly mixed, the temperature is controlled at 40 ℃, and reaction is carried out for 1h, so as to obtain compound II reaction liquid.
17-position cyanomethylation: under the protection of inert gas, adding 306mL of 2mol/L methyllithium reagent (0.612mol) into the reaction solution of the compound II, controlling the temperature at 20 ℃, reacting for 2h, dropwise adding the reaction solution into 200g of 30% ammonium chloride aqueous solution by mass, carrying out liquid-liquid layering, carrying out sewage treatment on an aqueous phase, concentrating an organic phase to obtain diethoxymethane, and adding 200g of isopropanol to obtain an isopropanol solution of the compound III;
and (3) hydrolysis reaction: adding 50g of 20 mass percent hydrochloric acid aqueous solution into isopropanol solution, controlling the temperature to be 30 ℃, reacting for 6h, adding triethylamine to adjust the pH value to be 6-8, cooling to-10 ℃, controlling the temperature to be 1h, filtering, and drying to obtain 94.91g of compound 17 alpha-hydroxyprogesterone (IV), wherein the molar yield is 94.00%, the purity is 99.59%, and the content is 99.43%.
Example 3
And (3) etherification reaction of 17-position hydroxyl: under the protection of inert gas, 100g (0.306mol) of compound I, 1000g of diethoxymethane, 122.4g (1.224mol) of butyl vinyl ether and 3g of pyridine hydrochloride are uniformly mixed, the temperature is controlled at 60 ℃, and reaction is carried out for 4 hours to obtain a compound II reaction solution.
17-position cyanomethylation: adding 918mL of 2mol/L methyllithium reagent (1.836mol) into a compound II reaction solution under the protection of inert gas, controlling the temperature at 15 ℃, reacting for 3h, dropwise adding the reaction solution into 200g of 30% ammonium chloride aqueous solution by mass fraction, carrying out liquid-liquid layering, treating water phase in sewage, concentrating organic phase to obtain diethoxymethane, and adding 200g of tetrahydrofuran to obtain a tetrahydrofuran solution of a compound III;
and (3) hydrolysis reaction: adding 100g of 20 mass percent hydrochloric acid aqueous solution into tetrahydrofuran solution, controlling the temperature to be 20 ℃, reacting for 1h, adding triethylamine to adjust the pH value to be 6-8, cooling to 10 ℃, controlling the temperature to be 6h, filtering and drying to obtain 95.37g of compound 17 alpha-hydroxyprogesterone (IV), wherein the molar yield is 94.41%, the purity is 99.77% and the content is 99.53%.
Example 4
And (3) etherification reaction of 17-position hydroxyl: under the protection of inert gas, 100g (0.306mol) of compound I, 700g of diethoxymethane, 61.2g (0.612mol) of butyl vinyl ether and 6g of trifluoroacetic acid are uniformly mixed, the temperature is controlled at 50 ℃, and reaction is carried out for 3 hours to obtain a compound II reaction solution.
17-position cyanomethylation: under the protection of inert gas, adding 612mL of 2mol/L methyllithium reagent (1.224mol) into the reaction solution of the compound II, controlling the temperature at 10 ℃, reacting for 4 hours, dropwise adding the reaction solution into 200g of 30% ammonium chloride aqueous solution by mass fraction, carrying out liquid-liquid layering, treating water phase in sewage, concentrating organic phase to obtain diethoxymethane, and adding 200g of acetone to obtain an acetone solution of the compound III;
and (3) hydrolysis reaction: adding 70g of 20 mass percent hydrochloric acid aqueous solution into the acetone solution, controlling the temperature to be 25 ℃, reacting for 6h, adding triethylamine to adjust the pH value to be 6-8, cooling to 0 ℃, controlling the temperature to be 3h, filtering and drying to obtain 95.10g of the compound 17 alpha-hydroxyprogesterone (IV), wherein the molar yield is 94.24%, the purity is 99.61% and the content is 99.37%.
In examples 2 to 4 of the present invention, the reaction conditions were changed, and 17 α -hydroxyprogesterone was prepared in the same manner as in example 1 in the HPLC (high performance liquid chromatography) detection chart and the infrared detection results were the same, so that the HPLC detection chart and the infrared detection chart were not repeated in examples 2 to 4.
In the above examples 1 to 4, the "content" means: the 17 alpha-hydroxyprogesterone prepared by the invention is subjected to external standard content results by taking the purchased 17 alpha-hydroxyprogesterone as a standard sample and serving as a control group.
For simplicity of explanation, the method embodiments are described as a series of acts or combinations, but those skilled in the art will appreciate that the present invention is not limited by the order of acts, as some steps may occur in other orders or concurrently in accordance with the invention. Further, those skilled in the art will appreciate that the embodiments described in the specification are preferred embodiments and that the acts and elements referred to are not necessarily required to practice the invention.
The method for preparing 17 α -hydroxyprogesterone provided by the present invention is described in detail above, and the principle and embodiments of the present invention are illustrated herein by using specific examples, which are only used to help understanding the method and the core concept of the present invention; meanwhile, for a person skilled in the art, according to the idea of the present invention, there may be variations in the specific embodiments and the application scope, and in summary, the content of the present specification should not be construed as a limitation to the present invention.
Claims (10)
1. A process for the preparation of 17 α -hydroxyprogesterone, comprising:
step 1, preparing a first reaction solution containing a compound II by using a compound I based on a hydroxyl etherification reaction;
step 2, based on the cyanomethylation reaction, preparing a second reaction solution containing a compound III by using the first reaction solution;
step 3, based on hydrolysis reaction, preparing 17 alpha-hydroxyprogesterone IV by using the second reaction solution;
2. the process according to claim 1, characterized in that the operation of the hydroxyl etherification reaction comprises:
under the protection of inert gas, uniformly mixing the compound I, diethoxymethane, butyl vinyl ether and a catalyst, and stirring to obtain a first reaction solution containing a compound II;
in the reaction conditions of the hydroxyl etherification, the reaction temperature is 40-60 ℃, and the reaction time is 1-4 h.
3. The process of claim 2, wherein the catalyst is at least one of pyridine hydrochloride and trifluoroacetic acid.
4. The method according to claim 2, wherein, in the hydroxyl etherification reaction,
the mass ratio of the compound I to the diethoxymethane is 1: 3-8;
the molar ratio of the compound I to the butyl vinyl ether is 1: 1-4;
the mass ratio of the compound I to the catalyst is 1: 0.03-0.1.
5. The method of claim 1, wherein the operation of the cyanomethylation reaction comprises:
under the protection of inert gas, adding a methyllithium reagent into the first reaction liquid, and stirring to obtain a first reaction system;
dropwise adding the first reaction system into 30% ammonium chloride aqueous solution by mass, and performing a liquid-liquid layering process to obtain a second reaction system consisting of a water phase and an organic phase;
extracting the organic phase from the second reaction system, and concentrating the organic phase to obtain a concentrated solution;
and adding a hydrolysis reaction solvent into the concentrated solution to obtain a second reaction solution containing the compound III.
6. The method according to claim 5, wherein the reaction conditions for preparing the first reaction system in the cyanomethylation reaction are 10 to 20 ℃ and 2 to 4 hours.
7. The method of claim 5, wherein in the cyanomethylation reaction, the hydrolysis reaction solvent is at least one of acetone, tetrahydrofuran, or isopropanol.
8. The process according to claim 5, characterized in that, in the cyanomethylation reaction,
the molar ratio of the compound I to the methyllithium reagent is 1: 2-6 based on the molar weight of the compound I;
the mass ratio of the compound I to the ammonium chloride aqueous solution is 1: 2-8 based on the mass of the compound I;
the mass ratio of the compound I to the hydrolysis reaction solvent is 1: 2-6 based on the weight of the compound I.
9. The method of claim 1, wherein the operation of the hydrolysis reaction comprises:
adding 20 mass percent hydrochloric acid aqueous solution into the second reaction solution, controlling the temperature to be 20-30 ℃, reacting for 1-6 h, adding triethylamine to adjust the pH value to be 6-8, cooling to be-10-0 ℃, controlling the temperature for 1-6 h, carrying out solid-liquid separation, and drying to obtain the compound 17 alpha-hydroxyprogesterone IV.
10. The method according to claim 9, wherein, in the hydrolysis reaction,
the mass ratio of the compound I to the hydrochloric acid aqueous solution is 1: 0.5-1.0 by taking the weight of the compound I as a reference.
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| CN104926906A (en) * | 2015-06-04 | 2015-09-23 | 保定北瑞甾体生物有限公司 | Method for preparing 17alpha-hydroxyl progesterone |
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| CN104327146A (en) * | 2014-10-24 | 2015-02-04 | 湖南科瑞生物科技有限公司 | Novel method of synthesizing 17 alpha-hydroxyl progesterone |
| CN104926906A (en) * | 2015-06-04 | 2015-09-23 | 保定北瑞甾体生物有限公司 | Method for preparing 17alpha-hydroxyl progesterone |
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