Preparation method of Mavaktai

Abstract

The invention relates to the technical field of medicine synthesis, and particularly provides a preparation method of Mavaktai. The method comprises the following steps: carrying out nucleophilic substitution reaction on barbituric acid and 2-chloropropane or 2-hydroxypropane to obtain 1-isopropyl barbituric acid; the preparation method comprises the following steps: reacting 1-isopropyl barbituric acid with a chlorination reagent to prepare 6-chloro-3-isopropyl pyrimidine-2, 4 (1H, 3H)-diketone; the preparation method comprises the following steps: carrying out nucleophilic substitution reaction on 6-chloro-3-isopropylpyrimidine-2, 4 (1H, 3H)-diketone and S-1-phenylethylamine under the condition of base catalysis, so as to prepare a crude product of the macavaktai. According to the method, the process operation is simplified, and the cost is reduced.

Description

Technical Field

[0001] This application relates to the technical field of drug synthesis, and specifically provides a preparation method of Mavacamten. Background Art

[0002] Mavacamten (Camzyos, Mavacamten, Structural formula I) is an orally administered small molecule myosin inhibitor for the treatment of adult patients with symptomatic obstructive hypertrophic cardiomyopathy (oHCM) with a cardiac function classification of II-III to improve the function and symptoms of the patients. Mavacamten belongs to a selective allosteric myosin inhibitor. It reversibly inhibits the excessive formation of myosin-actin cross-bridges by selectively reducing the ATPase activity of myosin heavy chain, and at the same time promotes the entire myosin population to turn to an energy-saving super-relaxed state, thereby inhibiting myocardial overcontraction, improving diastolic compliance and energy metabolism.

[0003]

[0004] Patent WO2014205223A describes the synthesis and characterization of pyrimidine dione compounds and their medicinal salts and methods for treating HCM and other forms of heart diseases, which can be used to treat hypertrophic cardiomyopathy (HCM), left ventricular hypertrophy or diastolic dysfunction diseases. The synthetic route is as follows:

[0005] The route uses isopropylamine (1-1) as the starting material, reacts with trimethylsilyl isocyanate (1-2) in an inert solvent under an inert environment and low temperature conditions to form isopropylurea (1-3); then it is purified and reacts with diethyl malonate (1-4) in a polar solvent under high temperature and base-catalyzed conditions to form 1-isopropylbarbituric acid (1-5); after purification, it continues to react with phosphorus oxychloride in an inert environment, in the presence of a phase transfer catalyst and high temperature conditions to form 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione (1-6); after column purification, it reacts with S-1-phenylethylamine in dioxane under high temperature conditions to form Mavacamten (1-8), and after further refining, Mavacamten is obtained, with an overall yield of about 20%.

[0006] The synthetic method has the following defects: 1. In the process of preparing isopropylurea (1-3) from isopropylamine (1-1) and trimethylsilyl isocyanate (1-2), 1-isopropylurea is a solid particle and is very fine, making suction filtration difficult. In the refining process, highly toxic and explosive diethyl ether is required because 1-isopropylurea has low polarity and is partially soluble in diethyl ether, resulting in a low yield. Trimethylsilyl isocyanate (1-2) is expensive and has many by-products. 2. In the process of preparing 1-isopropylbarbituric acid (1-5), the reaction time is long, the post-treatment is difficult, and subsequent refining requires column purification, which is not suitable for industrial production. 3. In the process of preparing 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione (1-6), phosphorus oxychloride is used, which is toxic and the amount used is too large. There is no solvent, the reaction is carried out at high temperature, and the post-treatment of a large amount of phosphorus oxychloride is difficult. When the temperature is high during post-treatment, spraying will occur, and the post-treatment product is hydrochloric acid. The product needs to be purified by column chromatography, which is not conducive to industrial production. 4. When preparing marvacetam, the yield is low and the reaction is incomplete.

[0007] In view of this, the present invention is specifically proposed. Summary of the Invention

[0008] One of the purposes of the present invention is to provide a preparation method of marvacetam to provide an efficient and low-cost preparation process.

[0009] In order to achieve the above purpose, the present invention provides the following technical solutions.

[0010] The present invention provides a preparation method of marvacetam, comprising the following steps:

[0011] S1: Barbituric acid undergoes a nucleophilic substitution reaction with 2-chloropropane or 2-hydroxypropane to obtain 1-isopropylbarbituric acid;

[0012] S2: 1-Isopropylbarbituric acid reacts with a chlorinating reagent to prepare 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione;

[0013] S3: Under the condition of alkali catalysis, 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione undergoes a nucleophilic substitution reaction with S-1-phenylethylamine to prepare the crude product of marvacetam.

[0014] Further, S1 is: Under the condition of alkali catalysis, barbituric acid in an organic solvent reacts with 2-chloropropane, the reaction temperature is 80-100 °C, and the reaction time is 12-24 h.

[0015] Further, the organic solvent is a protic solvent, and the protic solvent is at least one of N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, and acetonitrile, preferably N,N-dimethylformamide;

[0016] Preferably, the base is an inorganic base, and the inorganic base is at least one of K2CO3, Cs2CO3, and Na2CO3, preferably K2CO3;

[0017] Preferably, the base is an organic base, and the organic base is at least one of triethylamine, 4-dimethylaminopyridine, N,N-diisopropylethylamine, and triethylenediamine, preferably triethylamine.

[0018] Furthermore, S1 is: barbituric acid and 2-hydroxypropane undergo a Mitsunobu nitrogen substitution reaction, and the reaction conditions include first reacting at -15 to -5 °C for 0.5 to 1.5 h, and then reacting at 20 to 30 °C for 18 to 22 h.

[0019] Furthermore, S2 is: the chlorinating reagent is thionyl chloride, 1-isopropylbarbituric acid and thionyl chloride are cooled to -4 to 0 °C under solvent-free conditions, a phase transfer catalyst is added, and the temperature is raised to 60 to 100 °C, and the reaction is carried out for 4 to 12 h.

[0020] Furthermore, the phase transfer catalyst is at least one of benzyltriethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hydrogensulfate, and water, preferably benzyltriethylammonium chloride or water.

[0021] Furthermore, S2 is: the chlorinating reagent is thionyl chloride, 1-isopropylbarbituric acid and thionyl chloride react in an organic solvent, the reaction temperature is 70 to 90 °C, and the reaction time is 10 to 14 h; after the reaction is completed, post-treatment is carried out, and finally recrystallization is carried out with an alcohol solvent, and an antisolvent is added to improve the yield and prepare a high-purity intermediate;

[0022] Preferably, the organic solvent is at least one of acetonitrile, acetone, tetrahydrofuran, and dioxane, preferably acetonitrile;

[0023] Preferably, the antisolvent is an alkane solvent, and the alkane solvent is one of petroleum ether, n-hexane, and n-heptane, preferably n-heptane;

[0024] Preferably, the alcohol solvent is one of ethanol and isopropanol, preferably isopropanol.

[0025] Furthermore, S3 is: under the catalysis of a base, 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione in an organic solvent reacts with S-1-phenylethylamine, the reaction temperature is 80 to 90 °C, the reaction time is 12 to 24 h, and water is added to precipitate to prepare the crude product of marvacetam.

[0026] Furthermore, the organic solvent is at least one of acetonitrile, acetone, isopropanol, methanol, tetrahydrofuran, dioxane, and ethanol, preferably isopropanol or dioxane;

[0027] Preferably, the base is an inorganic base, and the inorganic base is at least one of K2CO3, Cs2CO3, and Na2CO3, preferably K2CO3;

[0028] Preferably, the base is an organic base, and the organic base is at least one of triethylamine, 4-dimethylaminopyridine, N,N-diisopropylethylamine, and triethylenediamine, preferably triethylamine.

[0029] Furthermore, the preparation method further comprises S4: recrystallizing with an alcohol solvent to prepare high-purity Mavaketel;

[0030] Preferably, the alcohol solvent is at least one of methanol, ethanol, and isopropanol, preferably isopropanol or ethanol.

[0031] Compared with the prior art, the technical effects of the present invention are:

[0032] 1. Reduce costs by using cheap barbituric acid as raw material and avoiding the use of trimethylsilyl isocyanate. During the synthesis process, the price of all materials used is less than 100 yuan / kg;

[0033] 2. Effectively improve the reaction yield, reduce side reactions and impurities, simple reaction, short steps;

[0034] 3. Optimized the reaction conditions and shortened the reaction time;

[0035] 4. Provides purification / refining methods for each intermediate, improves the purity of the intermediate, facilitates reaction control, avoids column chromatography operation, and is suitable for industrial production.

[0036] In addition, the present invention provides a purification method of mavaket, which can obtain the target product with a higher yield and reduce the preparation cost. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 is the mass spectrum of (S)-3-isopropyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione;

[0038] Figure 2 is the hydrogen spectrum of (S)-3-isopropyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione;

[0039] Figure 3 This is the carbon spectrum of (S)-3-isopropyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione. DETAILED DESCRIPTION

[0040] Below, the specific implementation methods of this application are described in detail.

[0041] The present invention provides a preparation method of marvacetam, which mainly includes the following steps.

[0042] Step 1: Prepare 1-isopropylbarbituric acid (also known as 1-isopropylpyrimidine-2,4,6(1H,3H,5H)-trione) (intermediate a)

[0043] In some embodiments, barbituric acid undergoes a nucleophilic substitution reaction with 2-chloropropane.

[0044] In a more preferred embodiment, barbituric acid and 2-chloropropane react in an organic solvent under base-catalyzed conditions. The reaction temperature is 80-100 °C (for example, but not limited to, 80 °C, 82 °C, 84 °C, 86 °C, 88 °C, 90 °C, 92 °C, 94 °C, 96 °C, 98 °C or 100 °C), and the reaction time is 12-24 h (for example, but not limited to, 12 h, 14 h, 16 h, 18 h, 20 h, 22 h or 24 h). In a specific embodiment, the organic solvent is a protic solvent, which can be at least one of N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, and acetonitrile, preferably N,N-dimethylformamide. In a specific embodiment, the base is an inorganic base, which can be at least one of K2CO3, Cs2CO3, and Na2CO3, preferably K2CO3. In a specific embodiment, the base is an organic base, which can be at least one of triethylamine, 4-dimethylaminopyridine, N,N-diisopropylethylamine, and triethylenediamine, preferably triethylamine.

[0045] In some embodiments, the purification method after the reaction is: pulping with an alkane solvent. Preferably, the alkane solvent is one of petroleum ether, n-hexane, and n-heptane, preferably n-heptane.

[0046] In a more preferred embodiment, barbituric acid undergoes a nucleophilic substitution reaction with 2-hydroxypropane.

[0047] In some embodiments, barbituric acid and 2-hydroxypropane undergo a Mitsunobu nitrogen substitution reaction. Preferably, the reaction conditions include reacting first at -15 to -5 °C (for example, but not limited to, -15 °C, -13 °C, -11 °C, -9 °C, -7 °C or -5 °C) for 0.5 to 1.5 h (for example, but not limited to, 0.5 h, 0.7 h, 0.9 h, 1.1 h, 1.3 h or 1.5 h), and then reacting at 20 to 30 °C (for example, but not limited to, 20 °C, 22 °C, 24 °C, 26 °C, 28 °C or 30 °C) for 18 to 22 h (for example, but not limited to, 18 h, 19 h, 20 h, 21 h or 22 h).

[0048] In some embodiments, the purification method after the reaction is: slurrying with an alkane solvent. Preferably, the alkane solvent is one of petroleum ether, n-hexane, and n-heptane, and more preferably n-heptane.

[0049] Step 2: Prepare 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione (Intermediate b)

[0050] In some embodiments, 1-isopropylbarbituric acid prepared in Step 1 reacts with a chlorinating reagent to prepare 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione.

[0051] In a more preferred embodiment, the chlorinating reagent is thionyl chloride. 1-Isopropylbarbituric acid and thionyl chloride are cooled to -4 to 0 °C (such as, but not limited to, -4 °C, -3 °C, -2 °C, -1 °C, or 0 °C) under solvent-free conditions, a phase transfer catalyst is added, and the temperature is raised to 60 to 100 °C (such as, but not limited to, 60 °C, 65 °C, 70 °C, 75 °C, 80 °C, 85 °C, 90 °C, 95 °C, or 100 °C), and the reaction is carried out for 4 to 12 h (such as, but not limited to, 4 h, 6 h, 8 h, 10 h, or 12 h). Preferably, the phase transfer catalyst is at least one of benzyltriethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hydrogensulfate, and water, and more preferably benzyltriethylammonium chloride or water.

[0052] In some embodiments, 1-isopropylbarbituric acid and thionyl chloride are cooled to 0 °C under solvent-free conditions, a phase transfer catalyst is added, and the temperature is raised to 80 to 90 °C (such as, but not limited to, 80 °C, 82 °C, 84 °C, 86 °C, 88 °C, or 90 °C), and the reaction is carried out for 4 to 12 h (such as, but not limited to, 4 h, 6 h, 8 h, 10 h, or 12 h).

[0053] In some embodiments, recrystallization is carried out with an alcohol solvent. Preferably, the alcohol solvent is one of isopropanol and ethanol, and more preferably isopropanol. After the solid is precipitated, an anti-solvent is added. Preferably, the anti-solvent is an alkane solvent such as petroleum ether, n-hexane, or n-heptane, and more preferably n-heptane, to increase the yield and the purity of the Marvacetam intermediate.

[0054] In a more preferred embodiment, the chlorinating reagent is thionyl chloride. 1-Isopropylbarbituric acid and thionyl chloride react in an organic solvent at a reaction temperature of 70 to 90 °C (such as, but not limited to, 70 °C, 75 °C, 80 °C, 85 °C, or 90 °C), and the reaction time is 10 to 14 h (such as, but not limited to, 10 h, 11 h, 12 h, 13 h, or 14 h). Preferably, the organic solvent is at least one of acetonitrile, acetone, tetrahydrofuran, and dioxane, and more preferably acetonitrile.

[0055] In some embodiments, recrystallization is carried out using an alcohol solvent. Preferably, the alcohol solvent is one of isopropyl alcohol and ethanol, more preferably isopropyl alcohol. After the solid is precipitated, an anti-solvent is added. Preferably, the anti-solvent is one of alkane solvents such as petroleum ether, n-hexane, and n-heptane, more preferably n-heptane, to improve the yield and the purity of the marvacetam intermediate.

[0056] Step 3: Preparation of crude marvacetam (intermediate c)

[0057] In some embodiments, 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione undergoes a nucleophilic substitution reaction with S-1-phenylethylamine.

[0058] In a more preferred embodiment, under the condition of base catalysis, 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione undergoes a nucleophilic substitution reaction with S-1-phenylethylamine to prepare crude marvacetam.

[0059] In some embodiments, under the condition of base catalysis, 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione in an organic solvent reacts with S-1-phenylethylamine. The reaction temperature is 80 - 90 °C (for example, but not limited to 80 °C, 82 °C, 84 °C, 86 °C, 88 °C or 90 °C), and the reaction time is 12 - 24 h (for example, but not limited to 12 h, 14 h, 16 h, 18 h, 20 h, 22 h or 24 h). Water is added for precipitation to prepare crude marvacetam. In some embodiments, the organic solvent is at least one of acetonitrile, acetone, isopropyl alcohol, methanol, tetrahydrofuran, dioxane, and ethanol, preferably isopropyl alcohol or dioxane. In some embodiments, the base is an inorganic base, and the inorganic base can be at least one of K2CO3, Cs2CO3, and Na2CO3, preferably K2CO3. In some embodiments, the base is an organic base, and the organic base can be at least one of triethylamine, 4-dimethylaminopyridine, N,N-diisopropylethylamine, and triethylenediamine, preferably triethylamine.

[0060] In some embodiments, the purification method after the reaction is: filtering the precipitated solid by suction filtration and slurrying with an alkane solvent. Preferably, the alkane solvent is one of petroleum ether, n-hexane, and n-heptane, more preferably n-heptane.

[0061] Step 4: Preparation of high-purity marvacetam

[0062] In some embodiments, recrystallization is carried out using an alcohol solvent to prepare high-purity marvacetam.

[0063] In some embodiments, the alcohol solvent is at least one of methanol, ethanol, and isopropyl alcohol, preferably isopropyl alcohol or ethanol.

[0064] In one embodiment, marvacetam can be prepared by the following process route:

[0065]

[0066] In one embodiment, marvacetam can be prepared by the following process route:

[0067]

[0068] Example 1:

[0069] I. 1-Isopropylbarbituric acid:

[0070] Take a 500 ml three-necked flask, dissolve barbituric acid (10 g, 77.5 mmol, 1 equivalent) in N,N-dimethylformamide (100 mL), add 2-chloropropane (4.9 g, 62 mmol, 0.8 equivalent), and triethylamine (31.4 g, 310 mmol, 4 equivalents). Stir the resulting mixture overnight at 100 °C. After the reaction is complete, cool the reaction to 20 °C, wash the reaction mixture with brine (250 mL), extract the aqueous phase twice with ethyl acetate (500 mL), combine the organic phases, dry the organic layer with anhydrous Na2SO4, filter, and then concentrate the organic solution in vacuo to obtain 8.5 g of crude intermediate compound a. Take 8.5 g of the obtained crude compound a, slurry it with 85 mL of n-heptane, filter by suction, and dry to obtain 6.5 g of the compound, with a yield of 76.7%.

[0071] II. 6-Chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione

[0072] In a three-neck reaction flask equipped with a stirrer, add 200 ml of thionyl chloride and 20 g of 1-isopropylbarbituric acid, and cool to 0 °C. Take 5 mL of water (phase transfer catalyst) and slowly add it to the mixture; after the addition is complete, raise the temperature to 78 °C and stir for 4 h until the reaction is complete; after cooling the reaction solution to room temperature, add it to 500 mL of ice water, filter, wash the filter cake twice with 200 ml of water, dry to obtain 20 g of crude product, add 100 mL of isopropanol, stir and dissolve at 80 °C, cool to -10 °C, precipitate a solid, add 300 mL of n-heptane, stir for 1 h, filter by suction, and then dry in vacuo at about 50 °C for 12 hours to obtain 18.8 g of 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione, with a yield of 85%.

[0073] III. (S)-3-Isopropyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione

[0074] Take a 1000 mL round-bottom flask, dissolve 6-chloro-3-isopropyl-pyrimidine-2,4-dione (11.3 g, 60 mmol, 1 equivalent) in isopropanol (120 mL), add potassium carbonate (33 g, 240 mmol, 4 equivalents), and slowly add S-1-phenylethylamine (18.1 g, 150 mmol, 2.5 equivalents). Heat the mixture to 80 °C and stir for 12 hours. TLC shows that the raw materials are completely consumed. Add purified water (500 mL), then cool to 25 °C, continue to stir to precipitate a solid, filter by suction, and dry to obtain (S)-3-isopropyl-6-((phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione, 15 g of yellow solid. The obtained 15 g of yellow solid is slurried with 150 mL of n-heptane, filtered by suction, and dried to obtain 14.5 g of pale yellow solid, with a yield of 88.5%.

[0075] IV. Refining:

[0076] Take a 250 mL round-bottom flask, add 14.5 g of the crude product of (S)-3-isopropyl-6-((phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione, add 50 mL of ethanol, heat under reflux until completely dissolved, cool to room temperature to precipitate a white solid, filter by suction, and dry to obtain 12 g of the refined product of (S)-3-isopropyl-6-((phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione, with a yield of 82.7% and an HPLC purity of 99%. The test results are as Figures 1-3 shown.

[0077] ES: Calcd For C 15 H 19 N3O2[M+H]+: 274.15; 1 H NMR (400 MHz, Chloroform-d) δ 10.36(1H), 7.36 - 7.20(5H), 5.86(1H), 5.08(1H), 4.72(s, 1H), 4.41(1H), 1.46(3H), 1.40(6H).

[0078] Example 2:

[0079] I. 1-Isopropylbarbituric acid (also known as 1-isopropylpyrimidine-2,4,6(1H,3H,5H)-trione):

[0080] Take a 100 mL three-necked flask, dissolve Ph3P (triphenylphosphine, 26.2 g, 0.1 mol) in THF (tetrahydrofuran, 120 mL), stir at -10 °C, dissolve diethyl azodicarboxylate (DEAD, 17.4 g, 0.1 mmol) in anhydrous THF (60 mL), add it to the reaction, and stir the mixture at -10 °C for 0.5 h. Dissolve barbituric acid (6.5 g, 50 mmol) and 2-hydroxypropane (2.4 g, 40 mmol) in THF (120 mL), add the solution dropwise within 30 min, and stir the mixture at -10 °C for 1 h and at 25 °C for 20 h. Concentrate the resulting mixture under reduced pressure. After adding ethyl acetate - petroleum ether, triphenylphosphine oxide crystallizes out. Concentrate the combined filtrate in vacuo, quench the concentrated solution with saturated sodium bicarbonate (200 mL), extract with ethyl acetate (200×3), combine the organic phases, concentrate under reduced pressure to obtain 5 g of crude intermediate compound a. Pulp 5 g of the obtained crude compound a with 50 mL of n-heptane, filter by suction, and dry to obtain 3.2 g of the compound, with a yield of 77.1%.

[0081] II. 6-Chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione

[0082] Take a 1000 mL single-necked flask, dissolve 1-isopropylpyrimidine-2,4,6(1H,3H,5H)-trione (26.5 g, 160 mmol, 1 equivalent) in anhydrous acetonitrile (260 mL), add thionyl chloride (55.9 g, 470 mmol, 3 equivalents), heat the mixture to 80 °C and stir for 12 h. Check by thin-layer chromatography (TLC) that the reaction is complete, then cool the mixture to 24 °C, add purified water (260 mL) within 31 min, extract with ethyl acetate (300 mL) three times, combine the organic phases, dry, concentrate under reduced pressure until no more distillate, add 100 mL of isopropanol, stir and dissolve at 80 °C, cool to -10 °C, precipitate a solid, add 300 mL of n-heptane, stir for 1 h, filter by suction, and then dry in vacuo at about 50 °C for 12 h to obtain 25 g of 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione (Compound 1.3), which is a pale yellow solid with a yield of 85%.

[0083] III. (S)-3-Isopropyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione

[0084] Take a 1000 mL round-bottom flask, dissolve 6-chloro-3-isopropyl-pyrimidine-2,4-dione (12.5 g, 67 mmol, 1 equivalent) in isopropanol (120 mL), add triethylamine (26.8 g, 265 mmol, 4 equivalents), and slowly add S-1-phenylethylamine (17.7 g, 150 mmol, 2.2 equivalents). Heat the mixture to 80 °C and stir for 12 hours. TLC shows that the raw materials are completely consumed. Add purified water (500 mL), then cool to 25 °C, continue stirring to precipitate solids, filter by suction, and dry to obtain (S)-3-isopropyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione, 16 g of yellow solid. Take the obtained 16 g of yellow solid, slurry with 160 mL of n-heptane, filter by suction, and dry to obtain 15.5 g of light yellow solid, with a yield of 85.6%.

[0085] IV. Purification:

[0086] Take a 250 mL round-bottom flask, add 15.5 g of the crude product of (S)-3-isopropyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione, add 50 mL of isopropanol, heat to reflux until completely dissolved, cool to room temperature to precipitate white solids, filter by suction, and dry to obtain 13 g of the refined product of (S)-3-isopropyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione, with a yield of 83.9% and an HPLC purity of 99%.

[0087] Example 3:

[0088] I. 1-Isopropylbarbituric acid (also known as 1-isopropylpyrimidine-2,4,6(1H,3H,5H)-trione):

[0089] Isopropylurea: Dissolve isopropylamine (10 g, 0.17 mol) in anhydrous dichloromethane (100 mL), cool the temperature to 0 °C, and under argon protection, add trimethylsilyl isocyanate (19.5 g, 0.17 mol) dropwise to the reaction solution. After the addition is complete, stir the reactant at room temperature overnight. After detecting the reaction by LC / MS, cool the reaction solution to 0 °C, add 20 mL of anhydrous methanol dropwise, and continue stirring at room temperature for 3 hours. Concentrate under reduced pressure, slurry with methyl tert-butyl ether for 4 h and filter. Dry the filter cake at 50 °C to obtain 14.4 g of white solid, with a yield of 84.7%.

[0090] 1-Isopropylbarbituric acid: Isopropylurea (14.4 g, 0.14 mol, 1.00 equivalent) was dissolved in methanol (144 mL), and diethyl malonate (23.7 g, 0.148 mol, 1.05 equivalents) and sodium methoxide (18.9 g, 0.35 mol, 2.50 equivalents) were added. The resulting mixture was stirred overnight at 65 °C. After cooling to ambient temperature and then to 0 °C, the pH was carefully adjusted to 3 using concentrated HCl. The resulting mixture was concentrated under reduced pressure. The resulting residue was dissolved in EtOH (200 mL) and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH = 100 / 1 (v / v). The organic phases were combined and concentrated in vacuo to give 16.8 g of compound a in 71% yield.

[0091] II. 6-Chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione

[0092] A 1000 mL single-necked flask was charged with 1-isopropylpyrimidine-2,4,6(1H,3H,5H)-trione (32.5 g, 190 mmol, 1 equivalent), benzyltriethylammonium chloride (BTEAC, phase transfer catalyst) (65 g, 286 mmol, 1.50 equivalents), and phosphorus oxychloride (100 mL). The mixture was purged with nitrogen three times, heated to 50 °C, and stirred for 12 h. TLC indicated the reaction was complete, then the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in dichloromethane (500 mL), and then purified water (300 mL) was slowly added. The layers were separated and the organic layer was washed with purified water (300 mL), dried, concentrated under reduced pressure until no more distillate was obtained, and the residue was purified by silica gel column chromatography using ethyl acetate: n-heptane = 1:1 as the eluent to give 29 g of 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione as a pale yellow solid in 80.5% yield.

[0093] III. (S)-3-Isopropyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione

[0094] Take a 1000 mL round-bottom flask, dissolve 6-chloro-3-isopropyl-pyrimidine-2,4-dione (12.5 g, 67 mmol, 1 equivalent) in isopropanol (120 mL), and slowly add S-1-phenylethylamine (17.7 g, 150 mmol, 2.2 equivalents). Heat the mixture to 80 °C and stir for 72 hours. TLC shows that the raw materials are completely consumed. Add purified water (500 mL), then cool to 25 °C, continue stirring to precipitate solids, filter by suction, and dry to obtain (S)-3-isopropyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione, 12 g of yellow solid, with a yield of 66.2%.

[0095] IV. Refining:

[0096] Take a 250 mL round-bottom flask, add 12 g of the crude product of (S)-3-isopropyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione, add 36 mL of ethanol, heat to reflux until completely dissolved, cool to room temperature to precipitate white solids, filter by suction, and dry to obtain 10 g of the refined product of (S)-3-isopropyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione, with an HPLC purity of 99% and a yield of 83.3%.

[0097] Note that the above is only the preferred embodiment of this application and the technical principles applied. Those skilled in the art will understand that this application is not limited to the specific embodiments described here. Various obvious changes, re-adjustments, and substitutions can be made by those skilled in the art without departing from the protection scope of this application. Therefore, although this application has been described in more detail through the above embodiments, this application is not limited to the above embodiments. Without departing from the technical concept of this application, more other equivalent embodiments can be included, all of which fall within the protection scope of this application.

Claims

1. A preparation method of marvacetide, characterized in that, It includes the following steps: S1: Barbituric acid undergoes a nucleophilic substitution reaction with 2-chloropropane or 2-hydroxypropane to obtain 1-isopropylbarbituric acid; S2: 1-Isopropylbarbituric acid reacts with a chlorinating reagent to prepare 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione; S3: Under the condition of alkali catalysis, 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione reacts with S-1-phenylethylamine through a nucleophilic substitution reaction to prepare the crude product of maraviroc.

2. The preparation method according to claim 1, wherein S1 is as follows: Under the condition of alkali catalysis, barbituric acid in an organic solvent reacts with 2-chloropropane, the reaction temperature is 80 - 100 °C, and the reaction time is 12 - 24 h.

3. The preparation method according to claim 2, characterized in that, The organic solvent is a protic solvent, and the protic solvent is at least one of N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, and acetonitrile, preferably N,N-dimethylformamide; Preferably, the alkali is an inorganic base, and the inorganic base is at least one of K2CO3, Cs2CO3, and Na2CO3, preferably K2CO3; Preferably, the alkali is an organic base, and the organic base is at least one of triethylamine, 4-dimethylaminopyridine, N,N-diisopropylethylamine, and triethylenediamine, preferably triethylamine.

4. The preparation method according to claim 1, characterized in that, S1 is as follows: Barbituric acid and 2-hydroxypropane undergo a Mitsunobu nitrogen substitution reaction, and the reaction conditions include reacting at -15 to -5 °C for 0.5 to 1.5 h first, and then reacting at 20 to 30 °C for 18 to 22 h.

5. The preparation method according to claim 1, characterized in that, S2 is as follows: The chlorinating reagent is thionyl chloride. 1-Isopropylbarbituric acid and thionyl chloride are cooled to -4 to 0 °C under solvent-free conditions, a phase transfer catalyst is added, and the temperature is raised to 60 to 100 °C, and the reaction is carried out for 4 to 12 h.

6. The preparation method according to claim 5, characterized in that, The phase transfer catalyst is at least one of benzyltriethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hydrogensulfate, and water, preferably benzyltriethylammonium chloride or water.

7. The preparation method according to claim 1, wherein S2 is as follows: The chlorinating reagent is thionyl chloride. 1-Isopropylbarbituric acid and thionyl chloride react in an organic solvent, the reaction temperature is 70 to 90 °C, and the reaction time is 10 to 14 h; after the reaction is completed, post-treatment is carried out, and finally recrystallization is carried out with an alcohol solvent, and an antisolvent is added to increase the yield and prepare an intermediate with high purity; Preferably, the organic solvent is at least one of acetonitrile, acetone, tetrahydrofuran, and dioxane, preferably acetonitrile; Preferably, the antisolvent is an alkane solvent, and the alkane solvent is one of petroleum ether, n-hexane, and n-heptane, preferably n-heptane; Preferably, the alcohol solvent is one of ethanol and isopropyl alcohol, preferably isopropyl alcohol.

8. The preparation method according to claim 1, characterized in that, S3 is as follows: Under the condition of alkali catalysis, 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione in an organic solvent reacts with S-1-phenylethylamine, the reaction temperature is 80 to 90 °C, the reaction time is 12 to 24 h, and water is added to precipitate to prepare the crude product of maraviroc.

9. The preparation method according to claim 8, characterized in that, The organic solvent is at least one of acetonitrile, acetone, isopropyl alcohol, methanol, tetrahydrofuran, dioxane, and ethanol, preferably isopropyl alcohol or dioxane; Preferably, the base is an inorganic base, and the inorganic base is at least one of K2CO3, Cs2CO3, and Na2CO3, preferably K2CO3; Preferably, the base is an organic base, and the organic base is at least one of triethylamine, 4-dimethylaminopyridine, N,N-diisopropylethylamine, and triethylenediamine, preferably triethylamine.

10. The preparation method according to any one of claims 1 to 9, characterized in that, The preparation method further includes S4: recrystallizing with an alcohol solvent to prepare high-purity marvacetide; Preferably, the alcohol solvent is at least one of methanol, ethanol, and isopropanol, preferably isopropanol or ethanol.

Images