A process for the synthesis of prothipendyl hydrochloride

Abstract

The application discloses a synthesis method of prothipendyl hydrochloride, which comprises the following steps: mixing diphenyl propanol, cyclohexyl imine, a catalyst and diphenyl phosphate, and stirring under an inert atmosphere at 100-120 DEG C for 15-25 hours; after the reaction is completed, cooling to room temperature to obtain a crude product of prothipendyl; adding ethyl acetate and saturated sodium bicarbonate aqueous solution to the crude product, stirring for 1-2 hours, extracting to obtain an organic phase, adding n-hexane to the organic phase and uniformly mixing to obtain a mixed solution; adding hydrochloric acid to the mixed solution, standing to precipitate a solid, filtering, washing, drying to obtain prothipendyl hydrochloride; the one-step method can obtain prothipendyl hydrochloride, the synthesis method does not need to use a large amount of toxic reagents and organic solvents, the reaction can be carried out under normal pressure, and the purification process of post-treatment is simple, and the atomic economy is high.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, and specifically relates to a method for synthesizing prozapine hydrochloride. Background Technology

[0002] Prozapine, a central nervous system drug, possesses multiple effects and functions, including sedation, anti-anxiety, antidepressant, muscle relaxant, and hypnosis, demonstrating significant medicinal value. Prozapine hydrochloride is the hydrochloride salt form of prozapine, but it is more stable and has better solubility, and is frequently used in clinical research. Therefore, developing efficient and rapid synthetic methods for prozapine hydrochloride has always been a key research focus in the fields of medicinal chemistry and pharmaceutical technology.

[0003] Prozapine hydrochloride can be directly synthesized from prozapine via the reaction of prozapine with hydrochloric acid. However, current synthetic routes for prozapine, both reported in the literature and widely used in industry, generally suffer from significant technical bottlenecks. Existing processes typically involve lengthy reaction steps, long total reaction times, and require high-temperature and high-pressure conditions. These drawbacks not only impose stringent requirements on the pressure resistance and corrosion resistance of production equipment, significantly increasing equipment investment and energy costs, but also introduce potential safety risks. Furthermore, the harsh reaction conditions easily trigger side reactions, affecting the purity and yield of the final product, which is detrimental to achieving green, economical, and controllable large-scale industrial production.

[0004] Currently, the publicly disclosed synthetic processes for prozapine mainly include the following three process routes: Route 1, described in "Chemoselective Three-Component Geminal Cross Couplings of Dihaloalkanes with Cr Catalysis: Rapid Access to Tertiary and Quaternary Alkanes via a Metal–Carbene Intermediate. Angew. Chem., Int. Ed. 2023, 62, e202312856."; Route 2, described in "Migratory Arylboration of Unactivated Alkenes Enabled by Nickel Catalysis. Angew. Chem., Int. Ed. 2019, 58, 4612-4616."; and Route 2, described in "Hydroaminomethylation with Novel Rhodium–Carbene complexes: An Efficient Catalytic Approach to Pharmaceuticals. Chemistry – A European Journal. 2007, 13(5): Process route three in "1594-1601".

[0005] Among them, process route one:

[0006] In process route one, 1-chloro-3,3-diphenylpropane (4) was first obtained by coupling reaction, and then 1-chloro-3,3-diphenylpropane was alkylated with cycloheximine to obtain prozapine. The yield of prozapine was only 51%. Both steps of the reaction in this process route involved long reflux (generally 15-24 h), which may cause side reactions and result in low yield and low efficiency. In addition, chromium (especially hexavalent chromium) is environmentally unfriendly and sensitive to air. Strict control of anhydrous and oxygen-free conditions is required during operation, which increases the experimental difficulty and fails to reflect atom economy.

[0007]

[0008] Process Route Two:

[0009]

[0010] In process route two, the hydroxyl group is first subjected to methanesulfonation, followed by a nucleophilic substitution reaction under alkaline catalysis to form a CN bond, yielding prozapine in 86% yield. In this process, acetonitrile needs to be refluxed for 24 hours, which is a relatively harsh condition for a heat-sensitive substrate, posing a risk of degradation. Furthermore, Li₂CO₃ has low solubility in acetonitrile, and the reaction system is heterogeneous, requiring vigorous stirring to ensure sufficient contact, significantly increasing the process difficulty. This process route still has significant room for optimization in industrial scale-up or the design of more efficient routes.

[0011] Process Route 3:

[0012]

[0013] In process route three, olefins react with CO / H2 under the catalysis of a rhodium-carbene complex to generate aldehydes. The aldehydes are then condensed with cyclohexylimine to form imines, which are finally reduced by H2 in the presence of a catalyst to yield compound 5 (prozapine). Although the yield of prozapine can reach 85%, this reaction uses a precious rhodium catalyst and requires a strictly anhydrous and oxygen-free environment, making it unsuitable for scale-up or industrial-scale preparation. Furthermore, CO is highly toxic, and H2 is flammable and explosive; the reaction must be carried out under high temperature and pressure, placing extremely stringent requirements on the reaction operation.

[0014] Therefore, developing a new synthetic process with mild reaction conditions, simple operation, high yield, and suitability for industrial scale-up is of great theoretical research significance and practical application value. Summary of the Invention

[0015] To address the shortcomings of existing technologies, the present invention aims to provide a method for synthesizing prozapine hydrochloride, which has the advantages of being simple to operate, environmentally friendly, and suitable for industrial production.

[0016] The objective of this invention is achieved through the following technical solutions.

[0017] A method for synthesizing prozapine hydrochloride includes the following steps:

[0018] Diphenylpropanol, cyclohexylimine, catalyst, and diphenyl phosphate were mixed and stirred under an inert atmosphere at 100-120 °C. The reaction was carried out at ℃ for 15-25 hours. After the reaction was completed, the mixture was cooled to room temperature to obtain crude prozapine. Ethyl acetate and saturated sodium bicarbonate aqueous solution were added to the crude product and stirred for 1-2 hours. The mixture was extracted to obtain an organic phase. Hexane was added to the organic phase and mixed evenly to obtain a mixed solution. Hydrochloric acid was added to the mixed solution and allowed to stand to precipitate a solid. The solid was filtered, washed, and dried to obtain prozapine hydrochloride. The catalyst was [2-[(amino-κN)diphenylmethyl]phenyl-κC]chloro[(1,2,3,4,5-η)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl]iridium. The ratio of diphenylpropanol, cycloheximine, catalyst and diphenyl phosphate was 1:(1-1.05):(0.001-0.01):(0.1-0.2) by molar amount.

[0019] In the above technical solution, the ratio of diphenylpropanol, cycloheximine, catalyst and diphenyl phosphate, by molar amount, is 1:(1~1.05):(0.001~0.005):(0.1~0.2).

[0020] In the above technical solution, the concentration of HCl in hydrochloric acid is 2~4 mol / L, the molar ratio of diphenylpropanol to the volume ratio of hydrochloric acid is 1.64:(3~4), the molar ratio is in mmol, and the volume ratio is in mL.

[0021] In the above technical solution, the ratio of ethyl acetate, saturated sodium bicarbonate aqueous solution, n-hexane and hydrochloric acid by volume is 1:(2~3):(1~1.5):(3~4).

[0022] In the above technical solution, the inert atmosphere includes nitrogen.

[0023] In the above technical solution, the settling time is 1 to 3 hours.

[0024] In the above technical solution, the drying temperature is 20~25 ℃ and the drying time is 1~2 hours.

[0025] In the above technical solution, the saturated sodium bicarbonate aqueous solution is a saturated solution at room temperature.

[0026] Compared with the prior art, the present invention has the following beneficial effects:

[0027] The synthesis method provided by this invention is simple, allowing for the one-step production of prozapine hydrochloride. This method eliminates the need for large quantities of toxic reagents and organic solvents, can be carried out under normal pressure, and features a simple post-treatment purification process, high atom economy, and a significantly improved yield compared to existing processes. The overall process conditions of this invention are mild, green, and efficient, possessing the potential for large-scale production. Attached Figure Description

[0028] Figure 1 The 1H NMR spectrum of the crude product of prozapine obtained in Example 1;

[0029] Figure 2 The carbon NMR spectrum of the crude prozapine product obtained in Example 1;

[0030] Figure 3 The 1H NMR spectrum of prozapine hydrochloride obtained in Example 1. Detailed Implementation

[0031] The reaction route for prozapine (crude product) in the synthesis method of prozapine hydrochloride in this invention is as follows:

[0032] The iridium catalyst is [2-[(amino-κN)diphenylmethyl]phenyl-κC]chloro[(1,2,3,4,5-η)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl]iridium.

[0033] The technical solution of the present invention will be further described in detail below with reference to the accompanying drawings and embodiments.

[0034] In the following examples, the sources of the raw materials are as follows:

[0035] [2-[(amino-κN)diphenylmethyl]phenyl-κC]chloro[(1,2,3,4,5-η)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl]iridium was prepared according to the literature "Synthesis and Reactivities of Cp*Ir Amide and Hydride Complexes Bearing C–N Chelate Ligands. Organometallics, 2008, 27, 2795–2802." The chemical structure of [2-[(amino-κN)diphenylmethyl]phenyl-κC]chloro[(1,2,3,4,5-η)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl]iridium is as follows: ;

[0036] Diiodo(pentamethylcyclopentadiene)iridium(III) dimer was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd., CAS No.: 33040-12-9, Item No.: D501268;

[0037] Ruthenium trichloride was purchased from Shanghai Maclean Biochemical Technology Co., Ltd., CAS No.: 10049-08-8, item number: R817350;

[0038] Dichloro(p-methylisopropylbenzene)ruthenium(II) dimer was purchased from Shanghai Haohong Biomedical Technology Co., Ltd., CAS No.: 52462-29-0, Item No.: 1034568;

[0039] 1,5-Cyclooctadiene iridium chloride dimer was purchased from Shanghai Maclean Biochemical Technology Co., Ltd., CAS No.: 12112-67-3, Item No.: B822948;

[0040] Methoxy(cyclooctadiene)iridium(I) dimer was purchased from Shanghai Maclean Biochemical Technology Co., Ltd., CAS No.: 12148-71-9, item number: C805784;

[0041] 1,5-Cyclooctadiene (acetoacetic acid) iridium was purchased from Shanghai Maclean Biochemical Technology Co., Ltd., CAS No.: 12154-84-6, item number: A871364;

[0042] Chloro(1,5-cyclooctadiene)[4,5-dimethyl-1,3-bis(2,4,6-trimethylphenyl)imidazol-2-alkylene]iridium (I) was purchased from Shanghai Maclean Biochemical Technology Co., Ltd., CAS No.: 1118917-09-1, Item No.: C939136;

[0043] Rhodium bis(1,5-cyclooctadiene)tetrafluoroborate (I) was purchased from Shanghai Haohong Biomedical Technology Co., Ltd., CAS No.: 35138-22-8, Item No.: 1030514;

[0044] Diphenylpropanol was purchased from Anhui Zesheng Technology Co., Ltd., CAS No.: 20017-67-8; Item No.: A041329-5g;

[0045] Cycloheximine was purchased from Anhui Zesheng Technology Co., Ltd., CAS No.: 111-49-9, item number: W6107670250;

[0046] Diphenyl phosphate was purchased from Shanghai Bid Pharmaceutical Technology Co., Ltd., CAS No.: 838-85-7, Product No.: BD125832.

[0047] Example 1

[0048] A method for synthesizing prozapine hydrochloride includes the following steps:

[0049] Diphenylpropanol (348.1 mg, 1.64 mmol), cycloheximine (1.64 mmol), catalyst (0.00164 mmol), and diphenyl phosphate (0.328 mmol) were mixed and reacted at 110 °C for 24 hours under an inert atmosphere (nitrogen) with stirring. After the reaction was completed, the mixture was cooled to room temperature (20-25 °C) to obtain crude prozapine (NMR yield of prozapine in the crude product was 98%). 1 mL of ethyl acetate was added to the crude product to dissolve it, followed by 2 mL of saturated sodium bicarbonate aqueous solution and stirring for 2 hours (the saturated sodium bicarbonate aqueous solution was a saturated solution at room temperature). The mixture was extracted and separated to obtain the organic phase. 1 mL of n-hexane was then added to the organic phase and mixed thoroughly to obtain a mixture. 3 mL of hydrochloric acid (HCl concentration of 2 mol / L) was slowly added to the mixture, and the mixture was allowed to stand for 1 hour to precipitate a white solid. The solid was filtered and washed three times with 15 mL of n-hexane (5 ml each time). (mL of n-hexane), dried at room temperature for 2 hours, yielded prozapine hydrochloride (yield: 461.77 mg, yield of prozapine hydrochloride: 87%), wherein the catalyst was [2-[(amino-κN)diphenylmethyl]phenyl-κC]chloro[(1,2,3,4,5-η)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl]iridium.

[0050] The 1H NMR spectrum of the crude prozapine product prepared in Example 1 is shown below. Figure 1 As shown, the carbon NMR spectrum of the crude product of prozapine is as follows: Figure 2 As shown, the 1H NMR spectrum of prozapine hydrochloride is as follows: Figure 3 As shown.

[0051] The 1H NMR data of the crude product of prozapine are as follows: 1 H NMR (500 MHz, Chloroform-d) δ 7.24(d, J = 4.7 Hz, 8H), 7.14 (q, J = 4.5 Hz, 2H), 4.00 (t, J = 7.8 Hz, 1H), 2.58(t, J = 5.3 Hz, 4H), 2.41 (t, J = 7.3 Hz, 2H), 2.23 (q, J = 7.6 Hz, 2H), 1.66- 1.53 (m, 8H);

[0052] The C1NMR data of the crude prozapine product are as follows: 13C NMR (126 MHz, Chloroform-d) δ144.99, 128.44, 127.90, 126.12, 56.45, 55.52, 49.05, 33.38, 27.95, 27.02;

[0053] The 1H NMR data for prozapine hydrochloride are as follows: 1 H NMR (500 MHz, Chloroform-d) δ 12.20(s, 1H), 7.31 – 7.25 (m, 8H), 7.21 (t, J = 7.2 Hz, 2H), 3.96 (t, J = 7.9 Hz,1H), 3.50 (t, J = 10.8 Hz, 2H), 2.96 – 2.82 (m, 4H), 2.69 (dq, J = 12.4, 7.5,5.6 Hz, 2H), 2.15 (dt, J = 18.4, 9.4 Hz, 2H), 1.79 (ddt, J = 31.9, 15.9, 8.2Hz, 4H), 1.59 (d, J = 6.6 Hz, 2H).

[0054] Depend on Figures 1-3 It can be seen that prozapine and prozapine hydrochloride were successfully synthesized.

[0055] Example 2

[0056] A method for synthesizing prozapine hydrochloride is basically the same as the method for synthesizing prozapine hydrochloride in Example 1, except that the amount of catalyst added is 0.0082 mmol in this example.

[0057] The NMR yield of prozapine in the crude product was 97%, and the yield of prozapine hydrochloride was 87%.

[0058] Example 3

[0059] A method for synthesizing prozapine hydrochloride includes the following steps:

[0060] Diphenylpropanol (1 g, 4.71 mmol), cycloheximine (4.71 mmol), catalyst (0.00471 mmol), and diphenyl phosphate (0.942 mmol) were mixed and reacted at 110 °C for 24 hours under an inert atmosphere (nitrogen) with stirring. After the reaction, the mixture was cooled to room temperature to obtain crude prozapine (NMR yield of prozapine in the crude product was 95%). 3 mL of ethyl acetate was added to the crude product to dissolve it, followed by 6 mL of saturated sodium bicarbonate aqueous solution and stirring for 2 hours. The mixture was extracted and separated to obtain an organic phase. 3 mL of n-hexane was then added to the organic phase and mixed thoroughly to obtain a mixture. 9 mL of hydrochloric acid (HCl concentration of 2 mol / L) was slowly added to the mixture, and the mixture was allowed to stand for 1 hour to precipitate a white solid. The solid was filtered, washed three times with 30 mL of n-hexane (10 mL each time), and dried at room temperature for 2 hours to obtain prozapine hydrochloride (yield: 1.30). g, yield of prozapine hydrochloride: 88%), wherein the catalyst is [2-[(amino-κN)diphenylmethyl]phenyl-κC]chloro[(1,2,3,4,5-η)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl]iridium.

[0061] The reaction process of this invention does not require the use of organic solvents, only simple post-treatment, and uses [2-[(amino-κN)diphenylmethyl]phenyl-κC]chloro[(1,2,3,4,5-η)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl]iridium as a catalyst. It has high catalytic efficiency, good atom economy, and high yield, making it suitable for large-scale industrial production.

[0062] Comparative Examples 1-8

[0063] A method for synthesizing prozapine hydrochloride is essentially the same as that in Example 1, except for the catalyst. The catalysts used in the synthesis methods of Comparative Examples 1-8 and the NMR yields of prozapine in the crude products are shown in Table 1.

[0064] Table 1

[0065]

[0066] The present invention has been described above by way of example. It should be noted that any simple modifications, alterations or other equivalent substitutions that can be made by those skilled in the art without creative effort without departing from the core of the present invention fall within the protection scope of the present invention.

Claims

1. A method for synthesizing prozapine hydrochloride, characterized in that, Includes the following steps: Diphenylpropanol, cyclohexylimine, catalyst, and diphenyl phosphate were mixed and stirred under an inert atmosphere at 100-120 °C. The reaction was carried out at ℃ for 15-25 hours. After the reaction was completed, the mixture was cooled to room temperature to obtain crude prozapine. Ethyl acetate and saturated sodium bicarbonate aqueous solution were added to the crude product and stirred for 1-2 hours. The mixture was extracted to obtain an organic phase. Hexane was added to the organic phase and mixed evenly to obtain a mixed solution. Hydrochloric acid was added to the mixed solution and allowed to stand to precipitate a solid. The solid was filtered, washed, and dried to obtain prozapine hydrochloride. The catalyst was [2-[(amino-κN)diphenylmethyl]phenyl-κC]chloro[(1,2,3,4,5-η)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl]iridium. The ratio of diphenylpropanol, cycloheximine, catalyst and diphenyl phosphate was 1:(1-1.05):(0.001-0.01):(0.1-0.2) by molar amount.

2. The synthesis method according to claim 1, characterized in that, The concentration of HCl in hydrochloric acid is 2~4 mol / L.

3. The synthesis method according to claim 1, characterized in that, The molar ratio of diphenylpropanol to the volume ratio of hydrochloric acid is 1.64:(3~4), with the molar ratio expressed in mmol and the volume ratio in mL.

4. The synthesis method according to claim 1, characterized in that, The ratio of ethyl acetate, saturated sodium bicarbonate aqueous solution, n-hexane and hydrochloric acid by volume is 1:(2~3):(1~1.5):(3~4).

5. The synthesis method according to claim 1, characterized in that, Inert atmospheres include nitrogen.

6. The synthesis method according to claim 1, characterized in that, The settling time is 1 to 3 hours.

7. The synthesis method according to claim 1, characterized in that, The drying temperature is 20~25℃, and the drying time is 1~2 hours.

8. The synthesis method according to claim 1 or 4, characterized in that, A saturated sodium bicarbonate aqueous solution is a saturated solution at room temperature.

9. The use of a catalyst in the synthesis of prozapine, characterized in that, The catalyst is [2-[(amino-κN)diphenylmethyl]phenyl-κC]chloro[(1,2,3,4,5-η)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl]iridium.

10. The use of a catalyst in the synthesis of prozapine hydrochloride, characterized in that, The catalyst is [2-[(amino-κN)diphenylmethyl]phenyl-κC]chloro[(1,2,3,4,5-η)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl]iridium.

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