A kind of synthetic method of dinavirine hydrochloride

Abstract

The present invention relates to the field of medicine preparation, and in particular to a method for synthesizing denavirine hydrochloride. The method comprises the following steps: S100, 2,2-diphenyl-2-hydroxyacetic acid, N,N-dimethylethanolamine, triphosphine I and azodicarboxylate I are subjected to a first Mitsunobu reaction to obtain an intermediate I; wherein the reaction temperature of the first Mitsunobu reaction is 40°C to 20°C; S200, intermediate I is subjected to a second Mitsunobu reaction with triphosphine II and azodicarboxylate II to generate an intermediate II, and a mixture containing the intermediate II is obtained; wherein the reaction temperature of the second Mitsunobu reaction is 30°C to 60°C; S300, extraction treatment; S400, salt formation treatment. The synthesis method has the following advantages: a short synthesis route and mild reaction conditions; low equipment requirements, convenient operation, and easy industrial production; the synthesis process does not require complex purification means, and the reaction yield of the target product denavirine hydrochloride is high.

Description

Technical Field

[0001] The invention relates to the field of medicine preparation, and in particular to a method for synthesizing denavirine hydrochloride. Background Art

[0002] Denavirine hydrochloride is a derivative of benzilic acid (i.e. 2,2-diphenyl-2-hydroxyacetic acid), with the chemical formula C 24 H 34 ClNO3. Its structure contains an ester group, diphenyl methyl ether and tertiary amine, which is unstable in aqueous solutions of strong acids or strong bases. Therefore, it is generally stored in the form of solid hydrochloride. The structural formula of denavirine hydrochloride is as follows:

[0003]

[0004] Denavirine hydrochloride is mainly used for the reproductive health of mammalian females. It acts on the uterus and promotes childbirth, which can effectively improve the normal delivery rate of females and the survival rate of fetuses. This drug has been widely used in European countries, and the effect is very ideal. Although its synthesis route seems simple, denavirine hydrochloride is not included in domestic and foreign pharmacopoeias, and its quality requirements are still undecided. There is no domestic company with the production qualification or drug production license number of denavirine hydrochloride.

[0005] The German patent with application number DE4133785 and publication date of September 23, 1993, discloses a method for synthesizing denavirine hydrochloride: using carboxylate and active halide to carry out esterification reaction to generate the first intermediate; then using thionyl chloride to carry out chlorination reaction to convert hydroxyl group into chlorine; in the third step, using 2-ethylbutanol to carry out high-temperature nucleophilic substitution reaction to generate the target product. However, the synthesis method has the following defects: thionyl chloride is used in the raw material, thionyl chloride is highly corrosive to the equipment, and the requirements for the equipment are high. In addition, 2-ethylbutanol is used as the solvent, which is expensive and used in large quantities, and is not suitable for process amplification. The process route is as follows:

[0006]

[0007] The Chinese patent application with publication number CN113061095A and publication date January 28, 2022 discloses a new synthetic route, including the following steps: first, halogenate diphenyl glycolic acid (i.e., 2,2-diphenyl-2-hydroxyacetic acid) under the action of acyl chloride to generate a hydroxyl halogenated intermediate; under the action of an acidifying agent, 2-ethylbutanol attacks the benzyl halogen to generate an intermediate by a nucleophilic substitution reaction; then, esterify with N,N-dimethylaminoethyl chloride hydrochloride, and then pass to hydrogen chloride gas to obtain the target product. This process route is similar to DE4133785, except that the order of the reaction is changed and the position of the functional group in the intermediate is adjusted. The essential mechanism of the chemical reaction is the same. Among them, thionyl chloride and 2-ethylbutanol are also used in this method, and the chlorination reaction is first performed in this method. The selectivity of the reaction is poor, and there are two molecules of esterification by-products in the synthesis path, which have an adverse effect on the reaction yield and purification yield. The process route is as follows:

[0008]

[0009] The Chinese patent application with publication number CN113979873A and publication date January 28, 2022, also uses the same starting material, thionyl chloride as the chlorination reagent, and simultaneously replaces the benzyl hydroxyl group and the carboxyl hydroxyl group, and then utilizes the difference in the reactivity of the functional groups to first carry out the substitution reaction of the acyl chloride, and finally the substitution reaction of the benzyl chlorine. This process combines the above two processes and carries out a one-pot multi-step reaction to prepare the target product, but the reaction mechanism of the change of functional groups at each position is the same. The disadvantage is that the intermediate has two chlorinated reaction sites, and there is a competitive relationship when performing SN1 nucleophilic substitution, which makes the reaction impurities difficult to control. Its process route is as follows:

[0010] . Summary of the invention

[0011] In order to solve the deficiencies of the prior art mentioned in the above background technology, the present invention provides a method for synthesizing dinavirine hydrochloride, which comprises the following steps:

[0012] S100, subjecting 2,2-diphenyl-2-hydroxyacetic acid, N,N-dimethylethanolamine, triphosphine I and azodicarboxylate I to a first Mitsunobu reaction to obtain an intermediate I; wherein the reaction temperature of the first Mitsunobu reaction is -40°C to -20°C;

[0013] S200, subjecting intermediate I to a second Mitsunobu reaction with triphosphine II, azodicarboxylate II, and 2-ethylbutanol to generate intermediate II, thereby obtaining a mixture containing intermediate II; wherein the reaction temperature of the second Mitsunobu reaction is 30° C. to 60° C.;

[0014] S300, extraction: after the reaction in S200 is completed, an extraction solvent is added to the mixture containing the intermediate II for extraction treatment to obtain an extract containing the intermediate II;

[0015] S400, salt formation: adding a salt-forming agent to the extract containing the intermediate II to precipitate the denavirine hydrochloride, thereby obtaining the denavirine hydrochloride;

[0016] Wherein, the structural formula of the 2,2-diphenyl-2-hydroxyacetic acid is ; The structural formula of the intermediate I is , the structural formula of the intermediate II is , the structural formula of the dinavirine hydrochloride is .

[0017] Among them, it is preferred that the reaction temperature of the first Mitsunobu reaction is -30°C, and the reaction temperature of the second Mitsunobu reaction is 40°C.

[0018] The invention provides a novel method for synthesizing denavirine hydrochloride, which uses 2,2-diphenyl-2-hydroxyacetic acid as a raw material, and prepares an intermediate I through a first Mitsunobu reaction. The reaction system of the intermediate I is not separated and purified, and a second Mitsunobu reaction is directly carried out under heating conditions to obtain an intermediate II (i.e., synthesizing free denavirine). The method can realize the splicing of functional groups through a one-pot method and two-step Mitsunobu reaction, synthesize free denavirine, and convert it into denavirine hydrochloride (i.e., denavirine hydrochloride) after simple extraction and salt treatment. The synthesis method is novel and unique, and has the following advantages: a short synthesis route and mild reaction conditions; low equipment requirements, convenient operation, and easy industrial production; the synthesis process does not require complex purification means, and the reaction yield of the target product denavirine hydrochloride is high.

[0019] In some embodiments, in the first Mitsunobu reaction, the triphosphine I is one or more combinations of triphenylphosphine, tri-tert-butylphosphine, and tributylphosphine; the azodicarboxylate I is one or more combinations of diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate, and N,N,N',N'-tetramethylazodicarboxamide.

[0020] Among them, the combination of triphosphine I and azodicarboxylate I used can be a combination of triphenylphosphine (PPh3) and diethyl azodicarboxylate (DEAD), triphenylphosphine (PPh3) and diisopropyl azodicarboxylate (DIAD), triphenylphosphine (PPh3) and di-tert-butyl azodicarboxylate (DTAD), tri-tert-butylphosphine and diethyl azodicarboxylate (DEAD), tributylphosphine and diisopropyl azodicarboxylate (DIAD), tributylphosphine and N,N,N',N'-tetramethylazodicarboxamide (TMAD), etc., preferably a combination of triphenylphosphine (PPh3) and diethyl azodicarboxylate (DEAD).

[0021] In some embodiments, in the first Mitsunobu reaction, the molar ratio of the 2,2-diphenyl-2-hydroxyacetic acid to the triphosphine I is 1:(1-2); the molar ratio of the 2,2-diphenyl-2-hydroxyacetic acid to the azodicarboxylate I is 1:(1-2); the molar ratio of the N,N-dimethylethanolamine to the 2,2-diphenyl-2-hydroxyacetic acid is 1:(1-1.1).

[0022] Among them, preferably, the molar ratio of the 2,2-diphenyl-2-hydroxyacetic acid to the triphosphine I is 1:1.5; the molar ratio of the 2,2-diphenyl-2-hydroxyacetic acid to the azodicarboxylate I is 1:1.5; and the molar ratio of the N,N-dimethylethanolamine to the 2,2-diphenyl-2-hydroxyacetic acid is 1:1.05.

[0023] In some embodiments, in the second Mitsunobu reaction, the triphosphine II is one or more combinations of tri-tert-butylphosphine and tributylphosphine; the azodicarboxylate II is one or more combinations of diethyl azodicarboxylate, diisopropyl azodicarboxylate, and N,N,N',N'-tetramethylazodicarboxamide.

[0024] The combination of the triphosphine II and the azodicarboxylate II used can be a combination of tri-tert-butylphosphine and diethyl azodicarboxylate (DEAD), tributylphosphine and diisopropyl azodicarboxylate (DIAD), tributylphosphine and N,N,N',N'-tetramethylazodicarboxamide (TMAD), etc.; among which the combination of tributylphosphine and N,N,N',N'-tetramethylazodicarboxamide (TMAD) is preferred.

[0025] In some embodiments, the molar ratio of the 2,2-diphenyl-2-hydroxyacetic acid to the triphosphine II is 1:(2-4); the molar ratio of the 2,2-diphenyl-2-hydroxyacetic acid to the azodicarboxylate II is 1:(2-4); the molar ratio of the 2-ethylbutanol to the 2,2-diphenyl-2-hydroxyacetic acid is 1:(2-4).

[0026] Among them, preferably, the molar ratio of the 2,2-diphenyl-2-hydroxyacetic acid to the triphosphine II is 1:3; the molar ratio of the 2,2-diphenyl-2-hydroxyacetic acid to the azodicarboxylate II is 1:3; and the molar ratio of the 2-ethylbutanol to the 2,2-diphenyl-2-hydroxyacetic acid is 1:3.

[0027] In some embodiments, the first Mitsunobu reaction and the second Mitsunobu reaction are performed in a solvent, and the solvent includes one or more combinations of dichloromethane, tetrahydrofuran, diethyl ether, toluene, ethyl acetate, acetonitrile, and N,N-dimethylformamide.

[0028] In some embodiments, in S300, the mixture containing intermediate II is added to water, and an acidic reagent is added to adjust the pH of the system to 4-5, and then a first extraction solvent is used to perform a first extraction treatment; the aqueous phase obtained by the first extraction treatment is taken, and an alkaline reagent is added to adjust the pH of the system to 8-9, and then a second extraction solvent is used to perform a second extraction treatment; the organic phase obtained by the second extraction treatment is washed and dried to obtain an extract containing intermediate II.

[0029] In some embodiments, the acidic reagent includes one or more combinations of hydrochloric acid, sulfuric acid, and phosphoric acid; the first extraction solvent is dichloromethane; the alkaline reagent includes one or more combinations of lithium hydroxide, sodium hydroxide, and potassium hydroxide; the second extraction solvent includes one or more combinations of ethyl acetate, tert-butyl methyl ether, and isopropyl acetate.

[0030] In some embodiments, in S400, the temperature of the extract system containing the intermediate II is cooled to -10°C to 10°C, and a salt-forming agent is added to precipitate the denavirine hydrochloride, thereby obtaining the denavirine hydrochloride. Preferably, the temperature of the extract system containing the intermediate II is cooled to 0°C.

[0031] In some embodiments, the salt-forming agent includes one or more combinations of hydrogen chloride gas, hydrogen chloride ethyl acetate solution, and hydrogen chloride methanol solution.

[0032] Compared with the existing technology, the synthesis method of dinavirine hydrochloride provided by the present invention has the following beneficial effects:

[0033] The synthesis method of denavirine hydrochloride is novel and unique, and the synthesis route is short and the reaction conditions are mild; the equipment requirements are low, the operation is convenient, and industrial production can be easily realized; the synthesis process does not require complicated purification means, and the reaction yield of the target product denavirine hydrochloride is high. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative labor.

[0035] Figure 1 The synthetic process route of the target product dinavirine hydrochloride in Example 1 provided by the present invention;

[0036] Figure 2 The intermediate I in Example 1 provided by the present invention 1 H-NMR spectrum;

[0037] Figure 3 The intermediate I in Example 1 provided by the present invention 13 C-NMR graph;

[0038] Figure 4 The target product dinavirine hydrochloride in Example 1 provided by the present invention 1 H-NMR spectrum;

[0039] Figure 5 The target product dinavirine hydrochloride in Example 1 provided by the present invention 13 C-NMR spectrum. DETAILED DESCRIPTION

[0040] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution in the embodiments of the present invention will be clearly and completely described below in conjunction with the accompanying drawings. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0041] The present invention provides the following embodiments and comparative examples: Embodiment 1:

[0042] Example 1: Figure 1 The synthetic process route of dinavirine hydrochloride shown in the figure specifically comprises the following steps:

[0043] Step (I) Preparation of Intermediate I

[0044] 2,2-diphenyl-2-hydroxyacetic acid (50 g, 0.219 mol, 1 eq), N,N-dimethylethanolamine (20.5 g, 0.230 mol, 1.05 eq), triphenylphosphine (86.1 g, 0.329 mol, 1.5 eq) and 1 L of dichloromethane were added to a 3L three-necked flask equipped with a constant pressure dropping funnel, a thermometer and a mechanical stirrer, and the above system was cooled to an internal temperature of ≤-30 °C and stirred at a constant temperature for 10 min. Diethyl azodicarboxylate (57.2 g, 0.329 mol, 1.5 eq) was slowly added dropwise, and the reaction temperature was controlled not higher than -30 °C and not lower than -40 °C; TLC monitored the completion of the reaction to obtain intermediate I, and the obtained intermediate I was characterized by nuclear magnetic resonance, and the structure of the intermediate product was determined by nuclear magnetic resonance characterization to qualitatively identify it.

[0045] Step (ii) Preparation of Intermediate II

[0046] After the reaction was completed by TLC monitoring, the temperature was slowly returned to 0°C, and 2-ethylbutanol (67.0 g, 0.657 mol, 3 eq) and tributylphosphine (132 g, 0.657 mol, 3 eq) were added dropwise, and finally TMAD (113 g, 0.657 mol, 3 eq) was added dropwise. After the addition was completed, the reaction was slowly heated to 40°C for reaction, and the reaction was completed by TLC monitoring.

[0047] Step 3: Extraction

[0048] After the reaction is completed by TLC monitoring, the reaction solution obtained in step (ii) is poured into 2L of water. The aqueous phase is acidified to pH=5 with 4 mol / L phosphoric acid, and then extracted with dichloromethane (500 mL*3), and the organic phase is discarded; the aqueous phase is neutralized to pH=9 with 1M sodium hydroxide solution, and extracted with ethyl acetate (500 mL*3), and the organic phases are combined and washed with saturated sodium chloride solution (1L) and dried with anhydrous sodium sulfate. The washed and dried extract (i.e., the ethyl acetate solution of intermediate II) can be directly used in the next step reaction.

[0049] Step (III) Preparation of Dinavirine Hydrochloride

[0050] In a 3L reactor equipped with a thermometer, a mechanical stirrer and a dropping funnel, an ethyl acetate solution of the intermediate II was added, stirring was started, and the above system was cooled to an internal temperature greater than or equal to -10°C and less than or equal to 0°C, and then hydrochloric acid / ethyl acetate solution (54 mL, 4 mol / L) was added dropwise to the reaction system, and stirred at a constant temperature for 1 hour to precipitate the denavirine hydrochloride; filtered, the filter cake was washed with ethyl acetate (200 mL*3), and dried to obtain denavirine hydrochloride (65.3 g, purity 99.8%, total yield 71%).

[0051] The prepared denavirine hydrochloride product was characterized by nuclear magnetic resonance and high-resolution mass spectrometry. 1 H-NMR spectrum, 13 C-NMR data Figure 4-5 The characterization results of the analysis example are as follows:

[0052] The finished product of denavirine hydrochloride obtained in the embodiment was characterized by nuclear magnetic resonance. 1 H-NMR spectra and 13 The C-NMR data showed that it was denavirine hydrochloride. The finished denavirine hydrochloride product prepared in the example was characterized by high-resolution mass spectrometry, and the HRMS-ESI data also showed that it was denavirine hydrochloride.

[0053] In summary, through the above-mentioned embodiment preparation process and its test results, it can be known that:

[0054] The novel method for synthesizing denavirine hydrochloride provided in the embodiment of the present invention uses 2,2-diphenyl-2-hydroxyacetic acid as a raw material, and prepares intermediate I through the first Mitsunobu reaction. The reaction system of intermediate I is not separated and purified, and the second Mitsunobu reaction is directly carried out under heating conditions to obtain intermediate II (i.e., synthesizing free denavirine). The method can realize the splicing of functional groups through a one-pot method and two-step Mitsunobu reaction, synthesize free denavirine, and convert it into denavirine hydrochloride (i.e., denavirine hydrochloride) after simple extraction and salt treatment. The synthesis method is novel and unique, and has the following advantages:

[0055] (1) The synthetic route is short and the reaction conditions are mild;

[0056] (2) Low equipment requirements, easy operation, and easy to achieve industrial production;

[0057] (3) The synthesis process does not require complicated purification methods. Only simple extraction and salt-forming treatment are required to obtain a high-purity target product, and the reaction yield of the target product, denavirine hydrochloride, is high.

[0058] It should be noted that:

[0059] In this article, “~” is used to indicate a numerical range, and the range indicated by this expression includes two endpoint values.

[0060] According to common knowledge in the art, triphenylphosphine is abbreviated as PPh3; diethyl azodicarboxylate is abbreviated as DEAD; diisopropyl azodicarboxylate is abbreviated as DIAD; di-tert-butyl azodicarboxylate is abbreviated as DTAD; N,N,N',N'-tetramethylazodicarbonamide is abbreviated as TMAD; N,N-dimethylformamide is abbreviated as DMF; dichloromethane is abbreviated as DCM; the above abbreviations are used in this article to refer to the above compounds.

[0061] The specific parameters or some commonly used reagents or raw materials in the above embodiments are specific embodiments or preferred embodiments of the present application, but are not intended to limit the present application. Those skilled in the art may make adaptive adjustments within the scope of the present application.

[0062] In addition, unless otherwise specified, the raw materials used may also be conventional commercial products in the art, or prepared by conventional methods in the art; that is, the reagents and instruments used in this embodiment are not indicated with information such as the manufacturer, and are all conventional products that can be purchased on the market.

[0063] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for synthesizing denavirine hydrochloride, characterized in that: The following steps are involved: S100, subjecting 2,2-diphenyl-2-hydroxyacetic acid, N,N-dimethylethanolamine, triphosphine I and azodicarboxylate I to a first Mitsunobu reaction to obtain an intermediate I; wherein the reaction temperature of the first Mitsunobu reaction is -40°C to -20°C; S200, subjecting intermediate I to a second Mitsunobu reaction with triphosphine II, azodicarboxylate II, and 2-ethylbutanol to generate intermediate II, thereby obtaining a mixture containing intermediate II; wherein the reaction temperature of the second Mitsunobu reaction is 30° C. to 60° C.; S300, extraction: after the reaction in S200 is completed, an extraction solvent is added to the mixture containing the intermediate II for extraction treatment to obtain an extract containing the intermediate II; S400, salt formation: adding a salt-forming agent to the extract containing the intermediate II to precipitate the denavirine hydrochloride, thereby obtaining the denavirine hydrochloride; Wherein, the structural formula of the intermediate I is , the structural formula of the intermediate II is ; In the first Mitsunobu reaction, the triphosphine compound I is one or more combinations of triphenylphosphine, tri-tert-butylphosphine, and tributylphosphine; In the second Mitsunobu reaction, the triphosphine II is a combination of one or more of tri-tert-butylphosphine and tributylphosphine.

2. The method for synthesizing dinavirine hydrochloride according to claim 1, wherein: In the first Mitsunobu reaction, the azodicarboxylic acid ester I is one or more combinations of diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate, and N,N,N',N'-tetramethylazodicarboxamide.

3. The method for synthesizing dinavirine hydrochloride according to claim 1, characterized in that: In the first Mitsunobu reaction, the molar ratio of the 2,2-diphenyl-2-hydroxyacetic acid to the triphosphine I is 1:(1-2); the molar ratio of the 2,2-diphenyl-2-hydroxyacetic acid to the azodicarboxylate I is 1:(1-2); The molar ratio of the N,N-dimethylethanolamine to the 2,2-diphenyl-2-hydroxyacetic acid is 1:(1-1.1).

4. The method for synthesizing dinavirine hydrochloride according to claim 1, characterized in that: The azodicarboxylic acid ester II in the second Mitsunobu reaction is one or more combinations of diethyl azodicarboxylate, diisopropyl azodicarboxylate, and N,N,N',N'-tetramethylazodicarboxamide.

5. The method for synthesizing dinavirine hydrochloride according to claim 1, characterized in that: The molar ratio of the 2,2-diphenyl-2-hydroxyacetic acid to the triphosphine II is 1:(2-4); the molar ratio of the 2,2-diphenyl-2-hydroxyacetic acid to the azodicarboxylate II is 1:(2-4); The molar ratio of the 2-ethylbutanol to the 2,2-diphenyl-2-hydroxyacetic acid is 1:(2-4).

6. The method for synthesizing dinavirine hydrochloride according to claim 1, characterized in that: The first Mitsunobu reaction and the second Mitsunobu reaction are carried out in a solvent, and the solvent includes one or more combinations of dichloromethane, tetrahydrofuran, ether, toluene, ethyl acetate, acetonitrile, and N,N-dimethylformamide.

7. The method for synthesizing dinavirine hydrochloride according to claim 1, characterized in that: In S300, the mixture containing the intermediate II is added to water, and an acidic reagent is added to adjust the pH of the system to 4-5, and then a first extraction solvent is used to perform a first extraction treatment; The aqueous phase obtained from the first extraction treatment is taken, an alkaline reagent is added to adjust the pH of the system to 8-9, and then a second extraction treatment is performed using a second extraction solvent; the organic phase obtained from the second extraction treatment is washed and dried to obtain an extract containing intermediate II.

8. The method for synthesizing dinavirine hydrochloride according to claim 7, characterized in that: The acidic reagent includes one or more combinations of hydrochloric acid, sulfuric acid, and phosphoric acid; the first extraction solvent is dichloromethane; The alkaline reagent includes one or more combinations of lithium hydroxide, sodium hydroxide, and potassium hydroxide; the second extraction solvent includes one or more combinations of ethyl acetate, tert-butyl methyl ether, and isopropyl acetate.

9. The method for synthesizing dinavirine hydrochloride according to claim 1, characterized in that: In the S400, the temperature of the extract system containing the intermediate II is cooled to -10°C to 10°C, and a salt-forming agent is added to precipitate the denavirine hydrochloride, thereby obtaining the denavirine hydrochloride.

10. The method for synthesizing dinavirine hydrochloride according to claim 1, characterized in that: The salt-forming agent includes one or more combinations of hydrogen chloride gas, hydrogen chloride ethyl acetate solution, and hydrogen chloride methanol solution.

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