Preparation method of tetrahydroprogesterone

Abstract

The invention belongs to the technical field of preparation of steroid hormone drugs, and particularly relates to a preparation method of tetrahydroprogesterone, which comprises the following steps: dispersing a new 3-carboxylate intermediate compound in a mixed solvent, firstly adding alkali, reacting at a first suitable reaction temperature for a certain time, then adding inorganic acid at a second suitable temperature, and continuing reacting to obtain the tetrahydroprogesterone. And after the hydrolysis reaction is finished, carrying out post-treatment to obtain the target compound tetrahydroprogesterone. The invention effectively solves the problem of overhigh content of compound impurity 17 alpha-epimer in the prior art, and provides the preparation method of tetrahydroprogesterone with high productivity, low cost and wide commercial application prospect.

Description

Technical Field

[0001] The invention belongs to the technical field of preparation of steroid hormone drugs, and specifically relates to a preparation method of allopregnanolone. Background Art

[0002] Allopregnanolone, also known as allopregnanolone, is an endogenous pregnane neurosteroid and a GABA receptor positive allosteric modulator. It was originally developed by the University of California, USA, and then licensed to Sage Biopharmaceuticals, USA. It was approved for marketing by the U.S. FDA on March 19, 2019. It is an intravenous injection containing allopregnanolone and sulfobutyl ether β-cyclodextrin solubilizing drug. It is also the first drug approved by the FDA for the treatment of postpartum depression (PPD).

[0003]

[0004] The prior art reports that there are two main starting materials in the method for synthesizing allopregnanolone, which is directly using allopregnanolone as the starting material, or using pregnenolone as the starting material to first convert it into allopregnanolone, and then prepare allopregnanolone through a multi-step reaction. Both technical routes require the use of the Mitsunobu reaction to convert the 3β-hydroxyl group into a 3α-ester and subsequent derivatives, and the 3α-ester and its derivatives are then hydrolyzed to remove the ester group to obtain the target product. According to prior art reports, the key technology for its synthesis lies in the control of 17α-diamer impurities in the two processes of the Mitsunobu reaction and the hydrolysis reaction. The hydrolysis step seems simple, but there are often problems such as the difficulty in completely hydrolyzing the 3α-ester, the low conversion rate, the generation of 2 to 14% of 17α-diamers that are difficult to remove in the hydrolysis step, the difficulty in purification, the low yield of the finished product, and the lack of environmental protection.

[0005] For example, the international application WO2020187965 and its Chinese equivalent patent document CN113825764 disclose that allopregnanolone is first reacted with a strong acid with a pKa ≤ 3 through a Mitsunobu reaction to form a 3α-ester, and then hydrolyzed under alkaline conditions to prepare allopregnanolone (as shown below). The specification points out that the 3α-benzoate intermediate and the 3α-4-nitrobenzoate intermediate are either not easy to hydrolyze or are easy to form 17α-isomers that are difficult to purify. Example 12 of the patent shows that the 3α-benzoate intermediate uses alkaline hydrolysis conditions, the substrate remains 17-87%, and 2% to 14% of the isomer is significantly produced; under sulfuric acid / methanol acidic conditions, the substrate can be completely hydrolyzed, but 8% of the 17α-isomer is produced at the same time. The 3α-4-nitrobenzoate intermediate is hydrolyzed under alkaline conditions for 15h, and the substrate conversion is more thorough, and 14% of the isomer is produced.

[0006]

[0007] Another example is the Chinese patent document CN112888701A, which reports the classic route for preparing allopregnanolone, using pregnenolone as the starting material, and preparing allopregnanolone through a five-step reaction (synthetic route is shown in the following formula), and the hydrolysis step produces about 0.29% of 17α-diamer content, and the route total yield is about 46.8%. The CN112888701A specification states that EP2688902B uses benzoate intermediate hydrolysis to produce 16% of diastereomers, so the inventor of EP2688902B attempts to use ethylene glycol to protect the 20-carbonyl group as ketal, and attempts a variety of test conditions for ketal deprotection, but the hydrolysis step still produces a large 17α-diamer impurity. Therefore, a water-free iodine / acetone system is used for deprotection, which solves the problem of isomers. However, the process uses expensive and toxic iodine, and the hydrolysis is carried out in two steps, which increases the production cost and still has a large room for improvement.

[0008]

[0009] In order to meet market demand and obtain high-purity allopregnanolone API with high yield, it is necessary to develop a more efficient, simpler and cheaper preparation process. Summary of the invention

[0010] In view of the problems and shortcomings of the above-mentioned prior art, in order to seek a more efficient, simple and cost-effective synthesis route of allopregnanolone, and effectively reduce or control the generation of the impurity 17α-dimer in the preparation process, the purpose of the present invention is to provide a preparation method of allopregnanolone with high production capacity, low cost and broad commercial application prospects.

[0011] In order to achieve the purpose of the present invention, the inventor provides the following technical solution:

[0012] A method for preparing allopregnanolone of formula II comprises the following steps:

[0013] The ketal of formula I is dispersed in a mixed solvent, a base is first added to react at a first suitable reaction temperature for a certain time, and then an inorganic acid is added at a second suitable temperature to continue the reaction. After the hydrolysis reaction is completed, the target compound of formula II, allopregnanolone, is obtained by post-treatment. The reaction is as follows:

[0014]

[0015] Wherein, in the ketal of formula I, R on the aromatic formyl structure refers to one substituent or two substituents, and the R substituent is selected from one of 4-nitro, 2-nitro, 2,4-dinitro, 3-methyl-2-nitro, 2-chloro, 3-chloro, 4-chloro, 2-bromo, 3-bromo, 4-bromo, 2-iodo, 3-iodo, 4-iodo, 2,4-dichloro, and 2,4-dibromo.

[0016] In the present invention, based on the new 3-carboxylate intermediate (Formula I) compound, the optimized hydrolysis process is the core inventive step of the present invention, thereby obtaining the target product of Formula II, allopregnanolone, which contains less 17α-epimer impurities. The crude allopregnanolone of Formula II has an HPLC purity of more than 99%, wherein the 17α-epimer is less than or equal to 0.15%, and the total impurities are less than or equal to 0.5%.

[0017] Research has found that in some specific embodiments, if the ketal of formula I in the hydrolysis reaction step is hydrolyzed using a single solvent and reflux conditions similar to those of the present invention, hydrolysis may not occur, and the technical effect of the present invention cannot be achieved.

[0018] Research has found that, with respect to the hydrolysis reaction step, it is indicated in paragraph

[0046] of patent document CN112888701 that the ketal must be hydrolyzed in a neutral environment, and the presence of acid or base must be avoided, otherwise a larger 17α-diamer will be produced. In the present invention, however, inorganic acid hydrolysis conditions are adopted, and since the hydrolysis reaction of the ketal of the reaction substrate formula I of the present invention is fast and effective, the translocation phenomenon is avoided.

[0019] The improved method for preparing allopregnanolone described in the present invention comprises the following steps: using pregnenolone as a starting material, performing a hydrogenation reaction, a Mitsunobu reaction and a ketal protection step to obtain a new 3-carboxylate ketal intermediate (Formula I) compound, and finally performing an improved hydrolysis step to obtain allopregnanolone of Formula II, wherein the purity of the obtained crude product is greater than 99%, and the minimum 17α-diamer impurity is less than 0.15%.

[0020] Preferably, in the present invention, the mixed solvent refers to a mixture of a lower aliphatic alcohol having 1 to 5 carbon atoms and an aprotic solvent in a certain proportion, and the mixing ratio of the lower aliphatic alcohol solvent to the aprotic solvent ranges from a volume ratio of 1V:1 to 20V, wherein the lower aliphatic alcohol solvent is selected from one or more of methanol, ethanol, n-propanol, n-butanol, isopropanol, and isobutanol; and the aprotic solvent is selected from one or more of tetrahydrofuran, dioxane, dichloromethane, and chloroform.

[0021] More preferably, the mixing ratio of the lower aliphatic alcohol solvent to the aprotic solvent is in a volume ratio range of 1V:1 to 18V.

[0022] Preferably, in the present invention, the base is selected from one or more of potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium tert-butoxide and / or sodium tert-butoxide; the inorganic acid refers to hydrochloric acid and / or dilute sulfuric acid.

[0023] Preferably, in the present invention, based on the weight of the ketal of formula I, the weight-to-volume ratio of the ketal of formula I: mixed solvent: base: inorganic acid=1W:9-13V:0.1-0.5W:0.2-0.35W.

[0024] Preferably, in the present invention, the first suitable reaction temperature in the hydrolysis reaction is 10 to 70°C, more preferably 15 to 55°C, and most preferably 15 to 35°C.

[0025] Preferably, in the present invention, the second suitable reaction temperature in the hydrolysis reaction is 5 to 40°C, more preferably 5 to 35°C, and most preferably 15 to 30°C.

[0026] In particular, W in the present invention represents weight and V represents volume. When W is in g, V is in mL; when W is in kg, V is in L. All R substituents in the present invention are of the same type as the substituents in the ketal of formula I.

[0027] In some embodiments, the ketal of formula I containing the above-mentioned substituents is used to prepare allopregnanolone according to the hydrolysis scheme described in the present invention. The ketal substrate of formula I can achieve the beneficial effect of thorough hydrolysis described in the present invention and the 17α-diamer is usually produced in an amount not exceeding 0.15%, as shown in the following table:

[0028]

[0029]

[0030] In the preferred embodiments of the present invention, the reaction effect of using 4-nitro, 2-nitro, 2,4-dinitro, 3-methyl-2-nitro in the aromatic formyl structure is mainly demonstrated to embody the effect of the present invention.

[0031] In some embodiments, the crude product of the compound of formula II (allopregnanolone) can be further dissolved by stirring with 10-30V dichloromethane / methyl tert-butyl ether, or ethyl acetate, or methanol, or 2-propanol, or 2-propanol / water system, and then concentrated to 3-10V under reduced pressure, cooled for crystallization, filtered, washed with a small amount of solvent, and dried to obtain a fine product of formula II.

[0032] Regarding the hydrolysis reaction of the ketal of formula I, compared with the prior art, the innovation of the present invention is that the new process for preparing allopregnanolone by hydrolysis of the compound of formula I adopts a mixed solvent, and the hydrolysis reaction is carried out in a mixed solvent to produce unexpected outstanding effects, which are mainly reflected in:

[0033] 1) The ketal of formula I protected by the present invention undergoes a thorough hydrolysis reaction in a mixed solvent. Compared with methanol alone as a solvent, the use of an aprotic solvent in the hydrolysis step improves the conversion capacity of the ketal of formula I; without adding an aprotic solvent, only using alcohols as solvents, some ketal substrates of formula I are hardly converted, such as the R group of formula I is 4-nitro, which undergoes almost no reaction when hydrolyzed in a single alcohol or aprotic solvent; while adding a certain amount of an aprotic solvent achieves a thorough conversion of the substrate. However, the use of an aprotic solvent alone cannot achieve the reaction effect of a mixed solvent under reflux conditions, indicating that the use of a mixed solvent is very important for the conversion of the hydrolysis reaction.

[0034] 2) The hydrolysis step uses a mixed solvent, alkali first and then acid, mild reaction conditions, and accelerated reaction conversion rate, which are important factors for reducing the 17α-diamer in the hydrolysis reaction. According to the prior art CN112888701A, allopregnanolone is unstable when refluxed for 16 hours in an acidic or alkaline environment, and 18-19% of diastereomer impurities will be produced. The ketal of formula I in the present invention is hydrolyzed at the suitable temperature, the total conversion time in the mixed solvent is shortened to 4-5 hours, and the reaction time after alkaline hydrolysis is shortened to 1-2 hours. The 17α-diamerization in the product is significantly curbed, and the industrial energy consumption is significantly reduced. The hydrolysis method of the ketal of formula I is first alkali and then acid, and the purity of the allopregnanolone obtained is greater than 99%, and the minimum 17α-diamere impurity is less than 0.15%.

[0035] 3) In the hydrolysis step of the present invention, the ketal hydrolysis step of formula I adopts a mixed solvent to first use a base and then use an inorganic acid to obtain the allopregnanolone of formula II. The two-step hydrolysis disclosed in the prior art is completed by a one-step continuous reaction, which can be operated continuously, does not require discharging, and is simple in post-processing.

[0036] Compared with the prior art, the present invention has the following beneficial effects:

[0037] 1) Hydrolysis step: The ketal of formula I is dispersed in a mixed solvent, a base is first added to control the temperature, and the reaction is carried out at a suitable reaction temperature for a certain time, and then an inorganic acid is added at a suitable temperature for continued reaction. After the reaction is completed, the target compound of formula II is obtained through post-treatment, and the 17α-diamer in the obtained crude product of formula II can be stably controlled within 0.15%. The use of a mixed solvent greatly improves the reaction selectivity, the reaction rate and the yield, and the reaction conditions are mild and the operation is simple.

[0038] 2) Through the exploration of the hydrolysis step, the inventors provided a new ketal intermediate, which provided more options for the industrial production of allopregnanolone.

[0039] 3) Compared with the classical route of patent document CN112888701A, the process of the present invention uses pregnenolone as the starting material to prepare allopregnanolone, combining the two-step hydrolysis reaction in the classical method into one, avoiding the use of iodine, which is highly toxic, expensive and needs to be recovered. Compared with the classical process route, the total yield of the allopregnanolone route prepared by the process of the present invention is greatly improved. Allopregnanolone is optimized through the purification step, and the traditional use of chromatographic column purification is changed to solvent recrystallization, which avoids excessive purification and greatly improves production capacity. The invention of this case is low in cost and has broad commercial application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 This is the HPLC spectrum of the product allopregnanolone obtained in Example 1 of the present invention;

[0041] Figure 2 This is the HPLC spectrum of the product allopregnanolone obtained in Example 2 of the present invention;

[0042] Figure 3 This is the HPLC spectrum of the product allopregnanolone obtained in Example 3 of the present invention;

[0043] Figure 4 The HPLC spectrum of the product allopregnanolone obtained in Example 4 of the present invention is shown in FIG. DETAILED DESCRIPTION

[0044] The following is a more detailed description of the present invention in conjunction with the following embodiments. It should be understood that the implementation of the present invention is not limited to the following embodiments, and any modifications and / or changes made to the present invention will fall within the scope of protection of the present invention.

[0045] In the present invention, unless otherwise specified, all parts and percentages are by weight, and all equipment and raw materials can be purchased from the market or are commonly used in the industry. The methods in the following embodiments are conventional methods in the art unless otherwise specified.

[0046] The HPLC purity of the starting material formula I ketal used in the present invention is greater than 99.5%, and the single impurity is less than 0.1%. The solvents used in the examples are all commercially available industrial grades. In this description, W represents weight and V represents volume. When W is in g, V is in mL; when W is in kg, V is in L.

[0047] Comparative Example 1

[0048] According to the route for preparing allopregnanolone in CN112888701A, allopregnanolone is prepared by five steps of reaction with pregnenolone as the starting material, and the total yield of the route is about 47.6%. The content of 17α-diamer produced in the hydrolysis step is about 0.32%, the HPLC purity is 98.2%, and the isomer impurities are relatively large.

[0049] Comparative Example 2

[0050] According to the route for preparing allopregnanolone in CN112888701A, allopregnanolone is prepared by five steps of reaction with pregnenolone as the starting material, and the total yield of the route is about 48.1%, the content of 17α-diamer produced in the hydrolysis step is about 0.3%, the HPLC purity is 98.5%, and the isomer impurities are relatively large.

[0051] Example 1

[0052]

[0053] Take 10.0g of acetal of formula I, add 80mL of dioxane, 2.2g of potassium hydroxide and 50mL of methanol, control the temperature at about 35°C, and stir to react for 4-5h. Add 3.0g of concentrated hydrochloric acid, control the temperature at 30°C to react for 1-2h. After TLC monitoring, add 20V water precipitation, vacuum dry, and obtain 5.4g of crude product of target compound formula II allopregnanolone, with a yield of about 54%. After testing, HPLC purity is 99.77%, and diastereomer is 0.10%.

[0054] Example 2

[0055]

[0056] Add 10.0g of the ketal of the above compound I (b) to a reaction bottle, add 50mL of tetrahydrofuran, add 5.0g of potassium hydroxide and 40mL of ethanol, control the temperature at about 35°C, and stir to react for 4-5h. Add 3.5g of concentrated hydrochloric acid, control the temperature at about 30°C to react for 1-2h. Add 20V water to precipitate, and vacuum dry to obtain 5.3g of crude product of the target compound formula II allopregnanolone, with a yield of about 53%. After testing, HPLC purity is 99.81%, and diastereomers are 0.11%.

[0057] Example 3

[0058]

[0059] Add 12.0g of the ketal of the above compound I (c) to a reaction bottle, add 78mL of dioxane, 2.64g of potassium hydroxide, and 24mL of methanol, control the temperature at 35°C, and stir to react for 4-5h. Add 3.2g of 63% sulfuric acid, control the temperature at 30°C to react for 1-2h, add 20V water for precipitation, and vacuum dry to obtain 6.48g of crude allopregnanolone of the target compound formula II, with a yield of about 54%. After testing, HPLC purity was 99.84%, and diastereomers were 0.07%.

[0060] Example 4

[0061]

[0062] Add 12.0g of the ketal of the above compound I (d) to a reaction bottle, add 80mL of tetrahydrofuran, 1.0g of potassium hydroxide and 10mL of ethanol, control the temperature at 35°C, and stir to react for 5-6h. Add 2.4g of 63% sulfuric acid, control the temperature at 30°C to react for 1-2h, add 20V water for precipitation, and vacuum dry to obtain 7.2g of crude allopregnanolone of the target compound formula II, with a yield of about 60%. After testing, HPLC purity was 99.83%, and the diastereomer was 0.09%.

Claims

1. A method for preparing allopregnanolone, characterized in that The steps include: The ketal of formula I is dispersed in a mixed solvent, a base is first added to react at a first suitable reaction temperature for a certain time, and then an inorganic acid is added at a second suitable temperature to continue the reaction. After the hydrolysis reaction is completed, the target compound of formula II, allopregnanolone, is obtained by post-treatment. The reaction is as follows: Wherein, in the ketal of formula I, R on the aromatic formyl structure refers to one substituent or two substituents, and the R substituent is selected from one of 4-nitro, 2-nitro, 2,4-dinitro, 3-methyl-2-nitro, 2-chloro, 3-chloro, 4-chloro, 2-bromo, 3-bromo, 4-bromo, 2-iodo, 3-iodo, 4-iodo, 2,4-dichloro, and 2,4-dibromo.

2. The method for preparing allopregnanolone according to claim 1, characterized in that: The mixed solvent refers to a mixture of a lower aliphatic alcohol having 1 to 5 carbon atoms and an aprotic solvent in a certain proportion, and the mixing ratio of the lower aliphatic alcohol solvent to the aprotic solvent ranges from a volume ratio of 1V:1 to 20V, wherein the lower aliphatic alcohol solvent is selected from one or more of methanol, ethanol, n-propanol, n-butanol, isopropanol, and isobutanol; and the aprotic solvent is selected from one or more of tetrahydrofuran, dioxane, dichloromethane, and chloroform.

3. The method for preparing allopregnanolone according to claim 1, characterized in that: The base is selected from one or more of potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium tert-butoxide and / or sodium tert-butoxide.

4. The method for preparing allopregnanolone according to claim 1, characterized in that: The inorganic acid refers to hydrochloric acid and / or dilute sulfuric acid.

5. The method for preparing allopregnanolone according to claim 1, characterized in that: Based on the weight of the ketal of formula I, the weight-to-volume ratio of the ketal of formula I: mixed solvent: base: inorganic acid=1W:9-13V:0.1-0.5W:0.2-0.35W.

6. The method for preparing allopregnanolone according to claim 1, characterized in that: The first suitable reaction temperature in the hydrolysis reaction is 10-70°C.

7. The method for preparing allopregnanolone according to claim 1, characterized in that: The second suitable reaction temperature in the hydrolysis reaction is 5 to 40°C.

8. The method for preparing allopregnanolone according to claim 1, characterized in that: The post-treatment means that the crude allopregnanolone of formula II obtained by the hydrolysis reaction can be further dissolved by stirring with 10-30V dichloromethane / methyl tert-butyl ether, or ethyl acetate, or methanol, or 2-propanol, or 2-propanol / water system, and then concentrated to 3-10V under reduced pressure, cooled for crystallization, filtered, washed with a small amount of solvent, and dried to obtain the fine allopregnanolone of formula II.

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