Preparation method of tadalafil

Abstract

The invention discloses a preparation method of tadalafil, which comprises the following steps: S1, taking sarcosine as a raw material, and carrying out carboxyl hydroxyl chlorination reaction under the action of thionyl chloride or oxalyl chloride to generate sarcosine chloride hydrochloride; s2, taking tryptophan methyl ester hydrochloride and piperonitrile as raw materials, and carrying out nitrile-amine condensation to generate an intermediate A; s3, taking the intermediate A as a raw material, and carrying out ring closing under the action of phosphorus oxychloride to generate an intermediate B; s4, reducing the intermediate B under the action of sodium borohydride to generate an intermediate C crude product, and purifying; and S5, carrying out an amide condensation reaction on the intermediate C and sarcosine chloride, carrying out amine ester exchange to generate a tadalafil crude product, and refining to obtain the tadalafil product. The tadalafil is synthesized with high yield, high specificity and selectivity, and the process route has the advantages of cheap and easily available raw materials, specific reaction, high product yield, safety and simplicity in operation, environmental friendliness, low equipment requirement, easiness in industrialization and the like.

Description

Technical Field

[0001] The invention relates to the field of organic synthesis, and in particular to a method for preparing tadalafil. Background Art

[0002] Tadalafil is a phosphodiesterase 5 (PDE5) inhibitor that can be used for a variety of diseases, including male erectile dysfunction (ED), pulmonary arterial hypertension (PAH) and benign prostatic hyperplasia (BPH). As a drug for the treatment of ED, tadalafil has the characteristics of rapid onset, long duration of efficacy, good tolerability, and is not affected by high-fat diet and alcohol intake.

[0003] The piperonal required in the traditional synthesis process of tadalafil is a controlled chemical, and the methylamine used in it is also a flammable and explosive gas with a strong irritating ammonia-like odor. This has brought a series of problems to the production of tadalafil, such as difficulty in purchasing raw materials, severe pollution to the operating environment, and high requirements for equipment safety. Summary of the invention

[0004] The technical problem to be solved by the present invention is to provide a method for preparing tadalafil in view of the deficiencies in the above-mentioned prior art.

[0005] In order to solve the above technical problems, the technical solution adopted by the present invention is: a method for preparing tadalafil, comprising the following steps:

[0006] Step S1, using sarcosine as a raw material, undergoing a carboxyl hydroxyl chlorination reaction under the action of thionyl chloride or oxalyl chloride to generate sarcosyl chloride hydrochloride;

[0007] Step S2, using tryptophan methyl ester hydrochloride and piperonitrile as raw materials, generating intermediate A through nitrile amide condensation;

[0008] Step S3, using intermediate A as a raw material, under the action of phosphorus oxychloride, ring-closes to generate intermediate B;

[0009] Step S4, reducing intermediate B under the action of sodium borohydride to generate a crude intermediate C, which is then purified;

[0010] Step S5, the purified intermediate C is subjected to an amide condensation reaction with sarkosyl chloride, followed by an ester exchange reaction to generate a crude tadalafil product, which is then refined to obtain a tadalafil product;

[0011] The synthetic route is as follows:

[0012]

[0013] Preferably, step S1 is specifically one of the following methods:

[0014] S1a, mixing sarcosine with dichloromethane and N,N-dimethylformamide, adding oxalyl chloride dropwise at 0-5°C, and then reacting at room temperature to obtain sarcosyl chloride hydrochloride;

[0015] S1b, adding sarcosine to thionyl chloride in batches at 0-5°C, and reflux reaction to obtain sarcosyl chloride hydrochloride.

[0016] Preferably, in step S1a:

[0017] The molar ratio of oxalyl chloride to sarcosine is 1.2:1 to 2.0:1, and the molar ratio of N,N-dimethylformamide to sarcosine is 0.05:1 to 0.2:1;

[0018] The ratio of the volume of dichloromethane to the mass of sarcosine is 4:1 to 8:1, where the volume unit is mL and the mass unit is g;

[0019] The reaction time at room temperature is 2 to 6 hours.

[0020] Preferably, in step S1b, the molar ratio of thionyl chloride to sarcosine is 1.5:1 to 3.0:1, the reflux reaction time is 5 h to 9 h, and the reaction temperature is room temperature.

[0021] Preferably, step S2 specifically comprises:

[0022] S2-1. Synthesize intermediate A by one of the following methods:

[0023] S2-1a, using tryptophan methyl ester hydrochloride and piperonitrile as raw materials, zinc trifluoromethanesulfonate and hydroxylamine hydrochloride as catalysts, heating reaction in the presence of water to generate intermediate A;

[0024] S2-1b, using tryptophan methyl ester hydrochloride and piperonitrile as raw materials and ferric nitrate nonahydrate as a catalyst, heating the reaction to generate intermediate A;

[0025] S2-2, purification of intermediate A:

[0026] After the reaction is completed, sodium bicarbonate solution is added to the product to quench it, and the product is extracted with an organic solvent. The organic phase is washed with water, dried, and concentrated. The obtained crude intermediate A is slurried with a mixed solvent of ethyl acetate and petroleum ether, filtered, and dried to obtain a pure intermediate A.

[0027] Preferably, in step S2-1a, the molar ratio of piperonitrile to tryptophan methyl ester hydrochloride is 1.5:1-3:1, the molar ratio of zinc trifluoromethanesulfonate:hydroxylamine hydrochloride:tryptophan methyl ester hydrochloride is 0.05-0.25:0.05-0.25:0.5-2, and the molar ratio of water to tryptophan methyl ester hydrochloride is 2:1-4:1;

[0028] The reaction temperature is 115°C to 140°C, and the reaction time is 10 to 18 hours.

[0029] Preferably, in step S2-1b, the molar ratio of piperonitrile to tryptophan methyl ester hydrochloride is 1.5:1-3:1, the molar ratio of ferric nitrate nonahydrate to tryptophan methyl ester hydrochloride is 0.05:1-0.25:1, the reaction temperature is 115°C-140°C, and the reaction time is 10-18h.

[0030] Preferably, in step S2-2, slurrying is performed using a mixed solvent with a volume ratio of ethyl acetate:petroleum ether = 1:2.

[0031] Preferably, step S3 specifically comprises:

[0032] Add intermediate A to organic solvent 1, add phosphorus oxychloride dropwise at room temperature, and then react at room temperature. After the reaction is completed, add the reaction solution into ice water to quench, adjust the pH to 7-8, separate the liquids, extract the aqueous phase with organic solvent 2, combine the obtained organic phases, and concentrate to obtain a solution of intermediate B in organic solvent 2.

[0033] Preferably, in step S3:

[0034] The molar ratio of phosphorus oxychloride to intermediate A is 1.5:1 to 3.0:1;

[0035] The ratio of the volume of the organic solvent 1 to the mass of the intermediate A is 4 to 12, wherein the volume unit is mL and the mass unit is g;

[0036] The reaction time after adding phosphorus oxychloride is 4 to 10 hours.

[0037] Preferably, the organic solvent 1 and the organic solvent 2 are one or more of ethyl acetate, dichloromethane, isopropyl acetate, 1,2-dichloroethane, 1,4-dioxane, and methyltetrahydrofuran.

[0038] Preferably, step S4 is specifically:

[0039] S4-1, add an alcohol solvent to the organic solvent 2 solution of intermediate B, add sodium borohydride in batches under stirring at room temperature, and then react at room temperature. After the reaction is completed, add the reaction solution into water to quench, separate the liquids, extract the aqueous phase with organic solvent 3, combine the obtained organic phases, wash with water, and concentrate to dryness to obtain a crude intermediate C;

[0040] S4-2. Purify the obtained crude intermediate C to obtain intermediate C.

[0041] Preferably, step S4-2 is specifically as follows: adding the obtained crude intermediate C to 6N hydrochloric acid, reacting at 50-55°C for 20-24h, then cooling to 0-5°C, filtering, washing the filter cake with water, and drying to obtain intermediate C.

[0042] Preferably, the alcohol solvent in step S4-1 is one or more of methanol, ethanol, n-propanol, and isopropanol, the volume of the alcohol solvent is 0.25 to 1 times the volume of the organic solvent 2 solution of the intermediate B, and the molar ratio of sodium borohydride to the intermediate B is 0.5 to 2:1;

[0043] The reaction time after adding sodium borohydride is 15 to 60 minutes;

[0044] The organic solvent 3 is one or more of ethyl acetate, dichloromethane, isopropyl acetate, 1,2-dichloroethane, 1,4-dioxane, and methyltetrahydrofuran.

[0045] Preferably, step S5 is specifically:

[0046] The intermediate C, sarkosyl chloride hydrochloride and organic solvent 4 are mixed, cooled to -15°C to 5°C, and then the first part of the organic base is added, and the current temperature is maintained for reaction; the second part of the organic base is added, the temperature is increased, and the reaction is continued. After the reaction is completed, the temperature is lowered to room temperature, filtered, and the filter cake is slurried with water and methanol, filtered, and the filter cake is dried to obtain the tadalafil product.

[0047] Preferably, in step S5:

[0048] The molar ratio of sarkosyl chloride hydrochloride to intermediate C is 1.1:1 to 1.5:1;

[0049] The organic solvent 4 is one or more of dichloromethane, tetrahydrofuran, and methyltetrahydrofuran. The ratio of the volume of the organic solvent 4 to the mass of the intermediate C is 4 to 10, wherein the volume unit is mL and the mass unit is g.

[0050] Preferably, the organic base is triethylamine or diisopropylethylamine, and the two parts of organic base added before and after have the same composition, the molar ratio of the first part of organic base to intermediate C is 2:1 to 3:1, and the molar ratio of the second part of organic base to intermediate C is 1:1 to 1.8:1.

[0051] Preferably, in step S5, the reaction time after adding the first portion of organic base is 0.5 to 2.5 hours; the temperature after adding the second portion of organic base is raised to 40 to 70° C., and the reaction time after the temperature is raised is 4 to 12 hours.

[0052] The beneficial effects of the present invention are:

[0053] The present invention uses piperonitrile and sarcosine as raw materials, replacing piperonal, chloroacetyl chloride and methylamine used in the traditional process, and synthesizes tadalafil with high yield, high specificity and selectivity through five steps of synthesis of acyl chloride, nitrile amine condensation, ring closure, reduction splitting and amide condensation amine ester exchange. The process route has the advantages of cheap and easy to obtain raw materials, specific reaction, high product yield, safe and simple operation, environmental friendliness, low equipment requirements and easy industrialization, and has broad market application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0054] Figure 1 This is the H NMR spectrum (nuclear magnetic resonance hydrogen spectrum) of tadalafil prepared in Example 1. DETAILED DESCRIPTION

[0055] The present invention is further described in detail below in conjunction with embodiments so that those skilled in the art can implement the invention with reference to the description.

[0056] It should be understood that the terms such as “having”, “including” and “comprising” used herein do not exclude the existence or addition of one or more other elements or combinations thereof.

[0057] The test methods used in the following examples are conventional methods unless otherwise specified. The materials and reagents used in the following examples are all commercially available unless otherwise specified. In the following examples, if no specific conditions are specified, the experiments were carried out under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used, if the manufacturer is not specified, are all conventional products that can be purchased commercially.

[0058] The present invention provides a method for preparing tadalafil. The method uses tryptophan methyl ester hydrochloride, piperonitrile, sarcosine and the like as raw materials, and synthesizes tadalafil in high yield, high specificity and selectivity through five steps of synthesis of acyl chloride, nitrile amide condensation, ring closure, reduction splitting and amide condensation amine ester exchange. The method specifically comprises the following steps:

[0059] Step S1, using sarcosine as a raw material, undergoing a carboxyl hydroxyl chlorination reaction under the action of thionyl chloride or oxalyl chloride to generate sarcosyl chloride hydrochloride;

[0060] Step S2, using tryptophan methyl ester hydrochloride and piperonitrile as raw materials, generating intermediate A through nitrile-amide condensation under the action of Lewis acid such as iron nitrate or zinc trifluoromethanesulfonate;

[0061] Step S3, using intermediate A as a raw material, under the action of phosphorus oxychloride, ring-closes to generate intermediate B;

[0062] Step S4, reducing intermediate B under the action of sodium borohydride to generate a crude intermediate C, which is then purified (and then subjected to kinetic resolution under the action of hydrochloric acid to obtain a pure intermediate C with a de value greater than 99.5%);

[0063] Step S5, the purified intermediate C is subjected to an amide condensation reaction with sarkosyl chloride, followed by an ester exchange reaction to generate a crude tadalafil product, which is then refined to obtain a tadalafil product;

[0064] The synthetic route is as follows:

[0065]

[0066] In a preferred embodiment, step S1 is specifically one of the following methods:

[0067] S1a, mixing sarcosine with dichloromethane and N,N-dimethylformamide, adding oxalyl chloride dropwise at 0-5°C, and then reacting at room temperature to obtain sarcosyl chloride hydrochloride;

[0068] S1b, adding sarcosine to thionyl chloride in batches at 0-5°C, and reflux reaction to obtain sarcosyl chloride hydrochloride.

[0069] 1-1. For the method of step S1a, in a preferred embodiment, wherein:

[0070] The molar ratio of oxalyl chloride to sarcosine is 1.2:1 to 2.0:1, for example, 1.2:1, 1.4:1, 1.6:1, 1.8:1, 2.0:1 or any value between them. To ensure that the sarcosine reacts completely and the oxalyl chloride is not excessive, more preferably, the ratio is 1.3:1.

[0071] The molar ratio of N,N-dimethylformamide to sarcosine is 0.05:1 to 0.2:1; for example, 0.05:1, 0.1:1, 0.15:1, 0.2:1 or any value between them. To ensure that the reaction proceeds quickly but not too violently, more preferably, the ratio is 0.1:1.

[0072] The ratio of the volume of dichloromethane to the mass of sarcosine is 4:1 to 8:1, wherein the volume unit is mL and the mass unit is g; for example, 4:1, 5:1, 6:1, 7:1, 8:1 or any value between them; in order to ensure sufficient stirring of the reaction and avoid slowing down the reaction due to too low concentration of the reaction solution, more preferably, the ratio is 5:1.

[0073] After adding oxalyl chloride dropwise, the temperature is raised to room temperature and the reaction time is continued for 2 to 6 hours, for example, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours or any number between them; the end point of the reaction is confirmed by TLC sarcosine reaction completion.

[0074] 1-2. For the method of step S1b, in a preferred embodiment, wherein:

[0075] The molar ratio of thionyl chloride to sarcosine is 1.5:1 to 3.0:1, for example, 1.5:1, 2.0:1, 2.5:1, 3.0:1 or any values ​​between them; to ensure that the sarcosine reacts completely and the thionyl chloride is not excessive, more preferably, the ratio is 2.0:1.

[0076] The reflux reaction time after the dropwise addition of sarcosine is 5 h to 9 h, for example, 5 h, 6 h, 7 h, 8 h, 9 h or any value between any two of them; the end point of the reaction is confirmed by the completion of the sarcosine reaction by TLC.

[0077] The reaction temperature is room temperature.

[0078] In a preferred embodiment, after the reaction is completed, step S1 further comprises:

[0079] The reaction solution was concentrated to constant weight, and the residue was directly used in step S5.

[0080] In a preferred embodiment, step S2 is specifically as follows:

[0081] S2-1. Synthesize intermediate A by one of the following methods:

[0082] S2-1a, using tryptophan methyl ester hydrochloride and piperonitrile as raw materials, zinc trifluoromethanesulfonate and hydroxylamine hydrochloride as catalysts, heating reaction in the presence of water to generate intermediate A;

[0083] S2-1b, using tryptophan methyl ester hydrochloride and piperonitrile as raw materials and ferric nitrate nonahydrate as a catalyst, heating the reaction to generate intermediate A;

[0084] S2-2, purification of intermediate A:

[0085] After the reaction is completed, sodium bicarbonate solution is added to the product to quench it, and the product is extracted with an organic solvent. The organic phase is washed with water, dried, and concentrated. The obtained crude intermediate A is slurried with a mixed solvent of ethyl acetate and petroleum ether, filtered, and dried to obtain a pure intermediate A.

[0086] 2-1, for the method of step S2-1a, in a preferred embodiment, wherein:

[0087] The molar ratio of piperonitrile to tryptophan methyl ester hydrochloride is 1.5:1 to 3:1, for example, 1.5:1, 2:1, 2.5:1, 3:1 or any value between them. To ensure that the tryptophan methyl ester hydrochloride reacts completely and the amount of piperonitrile is minimized, more preferably, the ratio is 2:1.

[0088] The molar ratio of zinc trifluoromethanesulfonate:hydroxylamine hydrochloride:tryptophan methyl ester hydrochloride is 0.05-0.25:0.05-0.25:0.5-2, 0.05:0.05:1, 0.1:0.1:1, 0.15:0.15:1, 0.2:0.2:1, 0.25:0.25:1 or any value between them. Under the premise of ensuring the reaction speed, preferably, the molar ratio of zinc trifluoromethanesulfonate, hydroxylamine hydrochloride and tryptophan methyl ester hydrochloride is 0.1:0.1:1.

[0089] The molar ratio of water to tryptophan methyl ester hydrochloride is 2:1 to 4:1; 2:1, 2.5:1, 3:1, 3.5:1, 4:1 or any value between them. To ensure complete reaction conversion, preferably, the ratio is 3:1.

[0090] The reaction temperature is 115°C to 140°C, which can be 115°C, 120°C, 125°C, 130°C, 135°C, 140°C or any value therebetween. To ensure the reaction speed and generate as few impurities as possible, preferably, the temperature is 115°C.

[0091] The reaction time is 10 to 18 hours, which can be 10 hours, 12 hours, 14 hours, 16 hours, 18 hours or any value between any two of them. The reaction endpoint is determined based on the complete reaction of tryptophan methyl ester hydrochloride.

[0092] 2-1, for the method of step S2-1b, in a preferred embodiment, wherein:

[0093] In step S2-1b, the molar ratio of piperonitrile to tryptophan methyl ester hydrochloride is 1.5:1 to 3:1, for example, 1.5:1, 2:1, 2.5:1, 3:1 or any value between them. To ensure that the reaction of tryptophan methyl ester hydrochloride is complete and the amount of piperonitrile is minimized, more preferably, the ratio is 2:1.

[0094] The molar ratio of ferric nitrate nonahydrate to tryptophan methyl ester hydrochloride is 0.05:1 to 0.25:1, for example, 0.05:1, 0.1:1, 0.15:1, 0.2:1, 0.25:1 or any values ​​between any two of them. By comparing the reaction yields of different molar ratios, more preferably, the ratio is 0.2:1.

[0095] The reaction temperature is 115°C to 140°C, for example, 115°C, 120°C, 125°C, 130°C, 135°C, 140°C or any value therebetween. To ensure the reaction speed and generate as few impurities as possible, more preferably, the temperature is 125°C.

[0096] The reaction time is 10 to 18 hours, for example, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours or any value between any two of them. The reaction endpoint is determined based on the complete reaction of tryptophan methyl ester hydrochloride.

[0097] In a preferred embodiment, in step S2-2, slurrying is performed using a mixed solvent with a volume ratio of ethyl acetate:petroleum ether = 1:2.

[0098] In a preferred embodiment, step S3 is specifically as follows:

[0099] Add intermediate A to organic solvent 1, add phosphorus oxychloride dropwise at room temperature, and then react at room temperature. After the reaction is completed, add the reaction solution into ice water to quench, adjust the pH to 7-8, separate the liquids, extract the aqueous phase with organic solvent 2, combine the obtained organic phases, and concentrate to obtain a solution of intermediate B in organic solvent 2.

[0100] In a preferred embodiment, in step S3:

[0101] The molar ratio of phosphorus oxychloride to intermediate A is 1.5:1 to 3.0:1; for example, 1.5:1, 1.8:1, 2.1:1, 2.4:1, 2.7:1, 3.0:1 or any value between them. To ensure complete reaction of the raw materials, more preferably, the ratio is 1.8:1.

[0102] The ratio of the volume of the organic solvent 1 to the mass of the intermediate A is 4 to 12, wherein the volume unit is mL and the mass unit is g; for example, 4, 6, 8, 10, 12 or any value between any two of them. To ensure sufficient stirring, more preferably, the ratio is 8.

[0103] The reaction time after adding phosphorus oxychloride is 4 to 10 hours, for example, 4, 6, 8, 10 hours or any value between them. To ensure the complete reaction of the raw materials, the confirmation of the reaction endpoint is based on the complete reaction of the intermediate A.

[0104] In a preferred embodiment, organic solvent 1 and organic solvent 2 are one or more of ethyl acetate, dichloromethane, isopropyl acetate, 1,2-dichloroethane, 1,4-dioxane, and methyltetrahydrofuran.

[0105] In a preferred embodiment, step S4 is specifically as follows:

[0106] S4-1, add an alcohol solvent to the organic solvent 2 solution of intermediate B, add sodium borohydride in batches under stirring at room temperature, and then react at room temperature. After the reaction is completed, add the reaction solution into water to quench, separate the liquids, extract the aqueous phase with organic solvent 3, combine the obtained organic phases, wash with water, and concentrate to dryness to obtain a crude intermediate C;

[0107] S4-2. Purify the obtained crude intermediate C to obtain intermediate C.

[0108] In a preferred embodiment, step S4-2 is specifically as follows: adding the obtained crude intermediate C to 6N hydrochloric acid, reacting at 50-55°C for 20-24h, then cooling to 0-5°C, filtering, washing the filter cake with water, and drying to obtain intermediate C.

[0109] In a preferred embodiment, the alcohol solvent in step S4-1 is one or more of methanol, ethanol, n-propanol, and isopropanol.

[0110] In a preferred embodiment, the volume of the alcohol solvent is 0.25 to 1 times of the organic solvent 2 solution of intermediate B, for example, 0.25, 0.5, 0.75, 1 times or any value in between. To ensure that the reaction can proceed quickly, more preferably, the ratio is 0.5.

[0111] In a preferred embodiment, the molar ratio of sodium borohydride to intermediate B is 0.5 to 2:1; for example, 0.5, 1, 1.5, 2 or any value between them. To ensure that the raw materials react completely without causing waste of sodium borohydride, more preferably, the ratio is 1.

[0112] The reaction time after adding sodium borohydride is 15 to 60 minutes; for example, 15, 30, 45, 60 minutes or any value between them. To ensure the complete reaction of the raw materials, the confirmation of the reaction endpoint is based on the complete reaction of the intermediate B.

[0113] The organic solvent 3 is one or more of ethyl acetate, dichloromethane, isopropyl acetate, 1,2-dichloroethane, 1,4-dioxane, and methyltetrahydrofuran.

[0114] In a preferred embodiment, step S5 is specifically as follows:

[0115] The intermediate C, sarkosyl chloride hydrochloride and organic solvent 4 are mixed, cooled to -15°C to 5°C, and then the first part of the organic base is added, and the current temperature is maintained for reaction; the second part of the organic base is added, the temperature is increased, and the reaction is continued. After the reaction is completed, the temperature is lowered to room temperature, filtered, and the filter cake is slurried with water and methanol, filtered, and the filter cake is dried to obtain the tadalafil product.

[0116] In a preferred embodiment, in step S5:

[0117] The molar ratio of sarkosyl chloride hydrochloride to intermediate C is 1.1:1 to 1.5:1; for example, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1 or any value between them. In order to maximize the content of tadalafil in the reaction solution product, more preferably, the ratio is 1.2:1;

[0118] The organic solvent 4 is one or more of dichloromethane, tetrahydrofuran, and methyltetrahydrofuran;

[0119] The ratio of the volume of the organic solvent 4 to the mass of the intermediate C is 4 to 10, wherein the volume unit is mL and the mass unit is g. For example, it is 4, 6, 8, 10 or any value between them. To ensure sufficient stirring, the ratio is more preferably 6.

[0120] In a preferred embodiment, the organic base is triethylamine or diisopropylethylamine, and the two parts of organic base added before and after have the same composition, and the molar ratio of the first part of the organic base to the intermediate C is 2:1 to 3:1, for example, 2:1, 2.2:1, 2.4:1, 2.6:1, 2.8:1, 3:1 or any value between them, more preferably, the ratio is 2.2:1;

[0121] The molar ratio of the second part of the organic base to the intermediate C is 1:1 to 1.8:1, for example, 1:1, 1.2:1, 1.4:1, 1.6:1, 1.8:1 or any value between them, more preferably, the ratio is 1.2:1.

[0122] In a preferred embodiment, in step S5, the reaction time after adding the first portion of organic base is 0.5 to 2.5 h; for example, 0.5, 1, 1.5, 2, 2.5 h or any value between any two of them. The reaction endpoint is determined based on the complete reaction of the raw material intermediate C.

[0123] In step S5, the cooling temperature of the mixture of intermediate C, sarkosyl chloride hydrochloride and organic solvent 4 is -15, -10, -5, 0, 5 or any value between them, more preferably, -5°C to ensure the reaction speed and minimize the side reactions.

[0124] The temperature after adding the second portion of organic base is raised to 40-70°C, for example, 40, 50, 60, 70°C or any value between them, more preferably, the ratio is 50°C.

[0125] The reaction time after heating is 4 to 12 hours, for example, 4, 6, 8, 10, 12 or any value between them. The reaction endpoint is determined based on the complete reaction of the raw materials.

[0126] The above is the overall concept of the present invention, and detailed embodiments and comparative examples are provided below on the basis of the overall concept of the present invention to further illustrate the present invention.

[0127] Example 1

[0128] S1. Add 30.8 g (1.0 eq, 0.346 mol) of sarcosine, 2.5 g (0.1 eq, 0.035 mol) of DMF (N,N-dimethylformamide) and 150 mL of DCM (dichloromethane) into a 500 mL three-necked flask, cool to 0°C, drop 52.7 g (1.2 eq, 0.415 mol) of oxalyl chloride, and then heat to room temperature for 3 h. After the raw material sarcosine reacts completely, the reaction solution is directly concentrated and used in the next step according to the theoretical amount.

[0129] S2, add 100.0g (1.0eq, 0.393mol) of tryptophan methyl ester hydrochloride, 194.0g (2.0eq, 0.785mol) of piperonitrile, 14.2g (0.1eq, 0.039mol) of zinc trifluoromethanesulfonate, 2.7g (0.1eq, 0.039mol) of hydroxylamine hydrochloride and 21.2g (3.0eq, 1.178mol) of water to a 500mL three-necked flask, replace with nitrogen, heat to 115°C and reflux for 12h. After the reaction is completed, add 500mL of saturated sodium bicarbonate solution to quench, add 2*500mL of dichloromethane to extract, combine the organic phases, wash with water, dry, and concentrate. The obtained crude product is slurried with 500mL of a mixed solvent of EA (ethyl acetate): PE (petroleum ether) = 1:2, filtered, and dried to obtain 131.6g of intermediate A1, with a yield of 91.5%.

[0130] S3, add intermediate A131.6g (1.0eq, 0.359mol) and ethyl acetate 1050mL into a 2L three-necked flask, add phosphorus oxychloride g (1.8eq, 0.647mol) dropwise at room temperature, and then continue to react at room temperature for 6h. After the reaction of intermediate A is complete, the reaction solution is added dropwise to ice water to quench, the pH is adjusted to 7, the liquid is separated, the aqueous phase is extracted with 660mL ethyl acetate, the organic phase is combined and washed with water, and the obtained ethyl acetate solution of intermediate B is concentrated to about 600mL and directly used in the next step according to the theoretical amount.

[0131] S4, add 300mL of ethanol to the ethyl acetate solution of the above intermediate B, add 13.6g (1.0eq, 0.359mol) of sodium borohydride in batches under stirring at room temperature, and then continue to stir at room temperature for 30min. After the reaction of intermediate B is complete, the reaction solution is quenched with 600mL of water, separated, the aqueous phase is extracted with 600mL of ethyl acetate, the organic phase is combined, washed with water, concentrated to dryness, the resulting crude product is added with 6N hydrochloric acid (i.e., hydrochloric acid with a concentration of 6mol / L), then reacted at 50°C for 24h, then cooled to 0°C, filtered with suction, the filter cake is washed with water, and dried to obtain 111.4g of khaki solid intermediate C, and the yield from intermediate A to C is 80.2%.

[0132] S5, 111.4g intermediate C (1.0eq, 0.288mol), sarcosyl chloride hydrochloride (theoretical amount 49.8g) (1.2eq, 0.346mol) and 670mL THF (tetrahydrofuran) were added to a 1L three-necked flask, cooled to -5°C in an ice-salt bath, 64.0g triethylamine (2.2eq, 0.634mol) was added dropwise, and then the reaction was continued at this temperature for 1h. The reaction was warmed to room temperature, 35.0g triethylamine (1.2eq, 0.346mol) was added, and then heated to 50°C and the reaction was continued for 8h. After the reaction was completed, the temperature was lowered to room temperature, filtered, the filter cake was slurried with water and methanol, filtered, and the filter cake was dried to obtain 96.6g of tadalafil white crystalline powder with a yield of 86.1%.

[0133] The H NMR data of tadalafil in the middle of this example are as follows, and the spectrum is as follows Figure 1 shown.

[0134] 1 H NMR (400MHz, DMSO): δ11.02(s,1H), 7.54(d,J=7.7Hz,1H), 7.30(d,J=8.1Hz,1H), 7.06(t d,J=8.1,7.6,1.3Hz,1H), 6.99(td,J=7.5,1.1Hz,1H), 6.86(s,1H), 6.78(s,2H), 6.13(s ,2H), 5.92(s,3H), 4.40(dd,J=11.7,4.5Hz,2H), 4.18(dd,J=17.1,1.6Hz,2H), 3.95(d,J =17.2Hz, 2H), 3.52 (dd, J = 15.8, 4.6Hz, 2H), 2.97 (dd, J = 15.6, 11.6Hz, 1H), 2.93 (s, 3H).

[0135] Example 2

[0136] S1. Add 86.6 g (2.0 eq, 0.728 mol) of thionyl chloride to a 500 mL three-necked flask, cool to 0°C, add 32.4 g (1.0 eq, 0.364 mol) of sarcosine in batches, and then heat to room temperature to react for 7 hours. After the raw material sarcosine reacts completely, the reaction solution is directly concentrated and used in the next step according to the theoretical amount.

[0137] S2, add 100.0g (1.0eq, 0.393mol) of tryptophan methyl ester hydrochloride, 213.4g (2.2eq, 0.865mol) of piperonitrile, and 31.6g (0.2eq, 0.079mol) of ferric nitrate nonahydrate to a 500mL three-necked flask, replace with nitrogen, and heat to 125°C for reflux reaction for 14h. After the reaction is completed, add 500mL of saturated sodium bicarbonate solution to quench, add 2*500mL of dichloromethane to extract, combine the organic phases, wash with water, dry, and concentrate. The obtained crude product is slurried with 500mL of a mixed solvent of EA:PE=1:2, filtered, and dried to obtain 129.7g of intermediate A, with a yield of 90.2%.

[0138] S3, add intermediate A129.7g (1.0eq, 0.354mol) and dichloromethane 1300mL into a 2L three-necked flask, add phosphorus oxychloride g (2.0eq, 0.708mol) dropwise at room temperature, and then continue to react at room temperature for 5h. After the reaction of intermediate A is complete, the reaction solution is added dropwise to ice water to quench, the pH is adjusted to 7, the liquid is separated, the aqueous phase is extracted with 650mL dichloromethane, the organic phase is combined and washed with water, and the dichloromethane solution of intermediate B is concentrated to about 600mL and directly used in the next step according to the theoretical amount.

[0139] S4, add 250mL of methanol to the dichloromethane solution of the above intermediate B, add 16.1g (1.2eq, 0.425mol) of sodium borohydride in batches under stirring at room temperature, and then continue to stir at room temperature for 20min. After the reaction of intermediate B is complete, the reaction solution is quenched with 600mL of water, separated, the aqueous phase is extracted with 600mL of dichloromethane, the organic phase is combined, washed with water, concentrated to dryness, 6N hydrochloric acid is added to the obtained crude product, and then reacted at 50°C for 24h, then cooled to 0°C, filtered, the filter cake is washed with water, and dried to obtain 108.5g of khaki solid intermediate C, and the yield from intermediate A to C is 79.2%.

[0140] S5, 108.5g intermediate C (1.0eq, 0.280mol), sarcosyl chloride hydrochloride (theoretical amount 52.4g) (1.3eq, 0.364mol) and 540mL dichloromethane were added to a 1L three-necked flask, cooled to 0°C in an ice-salt bath, 83.3g N, N-diisopropylethylamine (2.3eq, 0.644mol) was added dropwise, and then the reaction was continued at this temperature for 1.5h. The reaction was warmed to room temperature, 47.0g N, N-diisopropylethylamine (1.3eq, 0.364mol) was added, and then heated to 40°C and the reaction was continued for 10h. After the reaction was completed, the temperature was lowered to room temperature, filtered, the filter cake was slurried with water and methanol, filtered, and the filter cake was dried to obtain 92.2g of tadalafil white crystalline powder with a yield of 84.4%.

[0141] Although the embodiments of the present invention have been disclosed as above, they are not limited to the applications listed in the specification and the implementation modes. They can be fully applied to various fields suitable for the present invention. For those familiar with the art, additional modifications can be easily implemented. Therefore, without departing from the general concept defined by the claims and the scope of equivalents, the present invention is not limited to specific details.

Claims

1. A method for preparing tadalafil, characterized in that: The following steps are involved: Step S1, using sarcosine as a raw material, undergoing a carboxyl hydroxyl chlorination reaction under the action of thionyl chloride or oxalyl chloride to generate sarcosyl chloride hydrochloride; Step S2, using tryptophan methyl ester hydrochloride and piperonitrile as raw materials, generating intermediate A through nitrile amide condensation; Step S3, using intermediate A as a raw material, under the action of phosphorus oxychloride, ring-closes to generate intermediate B; Step S4, reducing intermediate B under the action of sodium borohydride to generate a crude intermediate C, which is then purified; Step S5, the purified intermediate C is subjected to an amide condensation reaction with sarkosyl chloride, followed by an ester exchange reaction to generate a crude tadalafil product, which is then refined to obtain a tadalafil product; The synthetic route is as follows:

2. The method for preparing tadalafil according to claim 1, characterized in that: Step S1 is specifically one of the following methods: S1a, mixing sarcosine with dichloromethane and N,N-dimethylformamide, adding oxalyl chloride dropwise at 0-5°C, and then reacting at room temperature to obtain sarcosyl chloride hydrochloride; S1b, adding sarcosine to thionyl chloride in batches at 0-5°C, and reflux reaction to obtain sarcosyl chloride hydrochloride.

3. The method for preparing tadalafil according to claim 2, characterized in that: In step S1a: The molar ratio of oxalyl chloride to sarcosine is 1.2:1 to 2.0:1, and the molar ratio of N,N-dimethylformamide to sarcosine is 0.05:1 to 0.2:1; The ratio of the volume of dichloromethane to the mass of sarcosine is 4:1 to 8:1, where the volume unit is mL and the mass unit is g; The reaction time at room temperature is 2 to 6 hours.

4. The method for preparing tadalafil according to claim 2, characterized in that: In step S1b, the molar ratio of thionyl chloride to sarcosine is 1.5:1 to 3.0:1, the reflux reaction time is 5 h to 9 h, and the reaction temperature is room temperature.

5. The method for preparing tadalafil according to claim 1, characterized in that: Step S2 is specifically as follows: S2-1. Synthesize intermediate A by one of the following methods: S2-1a, using tryptophan methyl ester hydrochloride and piperonitrile as raw materials, zinc trifluoromethanesulfonate and hydroxylamine hydrochloride as catalysts, heating reaction in the presence of water to generate intermediate A; S2-1b, using tryptophan methyl ester hydrochloride and piperonitrile as raw materials and ferric nitrate nonahydrate as a catalyst, heating the reaction to generate intermediate A; S2-2, purification of intermediate A: After the reaction is completed, sodium bicarbonate solution is added to the product to quench it, and the product is extracted with an organic solvent. The organic phase is washed with water, dried, and concentrated. The obtained crude intermediate A is slurried with a mixed solvent of ethyl acetate and petroleum ether, filtered, and dried to obtain a pure intermediate A.

6. The method for preparing tadalafil according to claim 5, characterized in that: In step S2-1a, the molar ratio of piperonitrile to tryptophan methyl ester hydrochloride is 1.5:1-3:1, the molar ratio of zinc trifluoromethanesulfonate:hydroxylamine hydrochloride:tryptophan methyl ester hydrochloride is 0.05-0.25:0.05-0.25:0.5-2, and the molar ratio of water to tryptophan methyl ester hydrochloride is 2:1-4:1; The reaction temperature is 115°C to 140°C, and the reaction time is 10 to 18 hours.

7. The method for preparing tadalafil according to claim 5, characterized in that: In step S2-1b, the molar ratio of piperonitrile to tryptophan methyl ester hydrochloride is 1.5:1-3:1, the molar ratio of ferric nitrate nonahydrate to tryptophan methyl ester hydrochloride is 0.05:1-0.25:1, the reaction temperature is 115°C-140°C, and the reaction time is 10-18h.

8. The method for preparing tadalafil according to claim 5, characterized in that: In step S2-2, slurry is performed using a mixed solvent of ethyl acetate:petroleum ether in a volume ratio of 1:

2.

9. The method for preparing tadalafil according to claim 1, characterized in that: Step S3 is specifically as follows: Add intermediate A to organic solvent 1, add phosphorus oxychloride dropwise at room temperature, and then react at room temperature. After the reaction is completed, add the reaction solution into ice water to quench, adjust the pH to 7-8, separate the liquids, extract the aqueous phase with organic solvent 2, combine the obtained organic phases, and concentrate to obtain a solution of intermediate B in organic solvent 2.

10. The method for preparing tadalafil according to claim 9, characterized in that: In step S3: The molar ratio of phosphorus oxychloride to intermediate A is 1.5:1 to 3.0:1; The ratio of the volume of the organic solvent 1 to the mass of the intermediate A is 4 to 12, wherein the volume unit is mL and the mass unit is g; The reaction time after adding phosphorus oxychloride is 4 to 10 hours.

11. The method for preparing tadalafil according to claim 9, characterized in that: The organic solvent 1 and the organic solvent 2 are one or more of ethyl acetate, dichloromethane, isopropyl acetate, 1,2-dichloroethane, 1,4-dioxane, and methyltetrahydrofuran.

12. The method for preparing tadalafil according to claim 1, characterized in that: Step S4 is specifically as follows: S4-1, add an alcohol solvent to the organic solvent 2 solution of intermediate B, add sodium borohydride in batches under stirring at room temperature, and then react at room temperature. After the reaction is completed, add the reaction solution into water to quench, separate the liquids, extract the aqueous phase with organic solvent 3, combine the obtained organic phases, wash with water, and concentrate to dryness to obtain a crude intermediate C; S4-2. Purify the obtained crude intermediate C to obtain intermediate C.

13. The method for preparing tadalafil according to claim 12, characterized in that: Step S4-2 is specifically as follows: adding the obtained crude intermediate C to 6N hydrochloric acid, reacting at 50-55°C for 20-24h, then cooling to 0-5°C, filtering, washing the filter cake with water, and drying to obtain intermediate C.

14. The method for preparing tadalafil according to claim 12, characterized in that: The alcohol solvent in step S4-1 is one or more of methanol, ethanol, n-propanol, and isopropanol, the volume of the alcohol solvent is 0.25 to 1 times the volume of the organic solvent 2 solution of the intermediate B, and the molar ratio of sodium borohydride to the intermediate B is 0.5 to 2:1; The reaction time after adding sodium borohydride is 15 to 60 minutes; The organic solvent 3 is one or more of ethyl acetate, dichloromethane, isopropyl acetate, 1,2-dichloroethane, 1,4-dioxane, and methyltetrahydrofuran.

15. The method for preparing tadalafil according to claim 1, characterized in that: Step S5 is specifically as follows: The intermediate C, sarkosyl chloride hydrochloride and organic solvent 4 are mixed, cooled to -15°C to 5°C, and then the first part of the organic base is added, and the current temperature is maintained for reaction; the second part of the organic base is added, the temperature is increased, and the reaction is continued. After the reaction is completed, the temperature is lowered to room temperature, filtered, and the filter cake is slurried with water and methanol, filtered, and the filter cake is dried to obtain the tadalafil product.

16. The method for preparing tadalafil according to claim 15, characterized in that: In step S5: The molar ratio of sarkosyl chloride hydrochloride to intermediate C is 1.1:1 to 1.5:1; The organic solvent 4 is one or more of dichloromethane, tetrahydrofuran, and methyltetrahydrofuran. The ratio of the volume of the organic solvent 4 to the mass of the intermediate C is 4 to 10, wherein the volume unit is mL and the mass unit is g.

17. The method for preparing tadalafil according to claim 15, characterized in that: The organic base is triethylamine or diisopropylethylamine, and the two parts of organic base added before and after have the same components. The molar ratio of the first part of organic base to the intermediate C is 2:1-3:1, and the molar ratio of the second part of organic base to the intermediate C is 1:1-1.8:

1.

18. The method for preparing tadalafil according to claim 15, characterized in that: In step S5, the reaction time after adding the first portion of the organic base is 0.5 to 2.5 hours; After adding the second portion of organic base, the temperature is raised to 40-70° C., and the reaction time after the temperature is raised is 4-12 hours.

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