A process for the preparation of tadalafil and epi-tadalafil

Abstract

The application relates to the technical field of organic synthesis, and discloses a method for preparing tadalafil or epi-tadalafil, which comprises the following steps: reacting N-(1,3-benzodioxol-5-methyl)-D-tryptophan methyl ester with Fomc-Ala-Cl to prepare compound IIa or compound IIb; and performing a deprotection / aminolysis reaction and a cyclization reaction on the compound IIa or the compound IIb in the presence of methylamine to prepare tadalafil or epi-tadalafil. Through the selection of a specific (Fomc-Ala-Cl) acylation reagent, the purity and / or yield of the compound IIa or the compound IIb are improved, so that the yield and / or purity of the tadalafil and / or epi-tadalafil are improved.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis, and more specifically to a method for preparing tadalafil and epi-tadalafil. Background Technology

[0002] Tadalafil, a commonly used phosphodiesterase 5 (PDE5) inhibitor, is primarily used to treat erectile dysfunction and other conditions in men. Its chemical structure comprises a tetrahydro-β-carboline skeleton and a pyrazinidine ring system; the configurational integrity of the chiral center directly determines its pharmacological activity and safety. Currently, the mainstream industrial synthesis route for tadalafil uses D-tryptophan derivatives (such as D-tryptophan methyl ester hydrochloride) and piperonal / heliotropin as starting materials. The core skeleton is constructed via a Pictet–Spengler condensation reaction, followed by three key reactions: acylation, aminolysis / cyclization, and finally, the target product (see US7223863B2 and US8871932B2).

[0003] In the existing technology, this synthetic route has two major technical pain points, and these pain points directly restrict the quality control and industrial production efficiency of tadalafil: 1. Poor controllability of chiral impurities: The Pictet–Spengler reaction is a stereoselective reaction, which is easily affected by reaction conditions (such as solvent polarity, temperature, and catalyst), and readily generates isomeric epimers such as 12a-epi-tadalafil (Tetrahedron: Asymmetry 19 (4):435-442, 2008). The yield and purity of products prepared by existing processes need to be improved.

[0004] 2. Insufficient process safety and environmental friendliness: The acylation steps of existing routes mostly use active acyl chloride reagents such as chloroacetyl chloride and bromoacetyl bromide (such as the process disclosed in US7223863B2). These reagents are highly irritating (corrosive to the respiratory tract and skin mucous membranes) and highly corrosive (react violently with water to generate toxic gases). The operation must be carried out in special protective equipment. At the same time, the acidic waste liquid generated by the reaction contains halide ions, which is difficult and costly to treat, and does not conform to the development trend of green chemical industry. Summary of the Invention

[0005] This invention provides a method for preparing tadalafil and epi-tadalafil to solve the problems of low product yield and / or purity.

[0006] In a first aspect, the present invention provides a method for preparing tadalafil or epi-tadalafil, comprising: The N-(1,3-benzodioxanol-5-methyl)-D-tryptophan methyl ester was reacted with Fomc-Ala-Cl to prepare (3R,12aS)-2-(9H-fluorene-9-ylmethoxycarbonyl)-3,4,6,7,12,12a-hexahydro-2H-pyrazino[1',2':1,6]pyridino[3,4-b]indol-1-one or (3R,12aR)-2-(9H-fluorene-9-ylmethoxycarbonyl)-3,4,6,7,12,12a-hexahydro-2H-pyrazino[1',2':1,6]pyridino[3,4-b]indol-1-one; Tadalafil or epi-tadalafil is prepared by deprotection / amineclation of (3R,12aS)-2-(9H-fluorene-9-ylmethoxycarbonyl)-3,4,6,7,12,12a-hexahydro-2H-pyrazino[1',2':1,6]pyridino[3,4-b]indole-1-one or (3R,12aR)-2-(9H-fluorene-9-ylmethoxycarbonyl)-3,4,6,7,12,12a-hexahydro-2H-pyrazino[1',2':1,6]pyridino[3,4-b]indole-1-one in the presence of methylamine, followed by cyclization.

[0007] In one alternative implementation, at least one of the following is satisfied: The reaction of N-(1,3-benzodioxol-5-methyl)-D-tryptophan methyl ester with Fomc-Ala-Cl is carried out in dichloromethane, ethyl acetate or tetrahydrofuran, optionally in dichloromethane; The reaction of N-(1,3-benzodioxanol-5-methyl)-D-tryptophan methyl ester with Fomc-Ala-Cl is carried out in the presence of a first organic base and a second organic base, wherein the second organic base is 4-dimethylaminopyridine. The molar ratio of N-(1,3-benzodioxol-5-methyl)-D-tryptophan methyl ester to Fmoc-Ala-Cl is 1:1.0–1.5; The reaction temperature of N-(1,3-benzodioxanol-5-methyl)-D-tryptophan methyl ester with Fomc-Ala-Cl is -10–30℃. The reaction time of N-(1,3-benzodioxol-5-methyl)-D-tryptophan methyl ester with Fomc-Ala-Cl is 0.5–24 h; The reaction of N-(1,3-benzodioxanol-5-methyl)-D-tryptophan methyl ester with Fomc-Ala-Cl is carried out in the presence of a solid additive selected from neutral alumina and 4Å molecular sieves. After the reaction of N-(1,3-benzodioxol-5-methyl)-D-tryptophan methyl ester with Fomc-Ala-Cl is completed, a separation and purification step is also included, in which silica gel column chromatography is used for separation.

[0008] In one alternative implementation, at least one of the following is satisfied: In the reaction of N-(1,3-benzodioxol-5-methyl)-D-tryptophan methyl ester with Fmoc-Ala-Cl, the pre-cooling stage lasts for 15-40 minutes, optionally 15 minutes; the dropping and holding stage lasts for 1-4 hours, optionally 1 hour; and the subsequent reaction stage lasts for 4-6 hours, optionally 6 hours. The solid additive is selected from neutral alumina; The molar ratio of N-(1,3-benzodioxol-5-methyl)-D-tryptophan methyl ester to Fmoc-Ala-Cl is 1:1.2; The organic base is selected from triethylamine, N,N-diisopropylethylamine and 1,8-diazacyclo[5.4.0]undec-7-ene, and optionally the organic base is triethylamine; The molar ratio of N-(1,3-benzodioxanol-5-methyl)-D-tryptophan methyl ester to 4-dimethylaminopyridine is 1:0.01–0.2, optionally 1:0.1; The mass ratio of the solid additive to N-(1,3-benzodioxanol-5-methyl)-D-tryptophan methyl ester is (2–10):1, optionally 5:1; Silica gel column chromatography was performed using ethyl acetate and petroleum ether in a volume ratio of 1:1 to 3:2 as the eluent. Silica gel column chromatography employs isocratic elution or fractional elution.

[0009] In one alternative implementation, at least one of the following is satisfied: The methylamine is a methylamine methanol solution or an methylamine aqueous solution; The molar ratio of (3R,12aS)-2-(9H-fluorene-9-ylmethoxycarbonyl)-3,4,6,7,12,12a-hexahydro-2H-pyrazino[1',2':1,6]pyridino[3,4-b]indol-1-one or (3R,12aR)-2-(9H-fluorene-9-ylmethoxycarbonyl)-3,4,6,7,12,12a-hexahydro-2H-pyrazino[1',2':1,6]pyridino[3,4-b]indol-1-one to methylamine is 1:(2–20). The reaction temperatures for deprotection / amine hydrolysis and cyclization are 30–80 °C. The total reaction time for deprotection / amine degradation and cyclization is 2–48 h; The silica gel column chromatography employed isocratic elution, and the eluent used was ethyl acetate and petroleum ether in a volume ratio of 1:1 or 2:1. Silica gel column chromatography employs fractional elution, which consists of two stages. In the first stage, 4-9 column volumes are eluted with an ethyl acetate / petroleum ether volume ratio of 1:2-3:2. In the second stage, 6-12 column volumes are eluted with an ethyl acetate / petroleum ether volume ratio of 1:1-2:1. Optionally, in the first stage, the ethyl acetate / petroleum ether volume ratio is 1:2, 2:3, 1:1, or 3:2, and the column volumes are 9.0, 8.0, 7.0, 6.0, or 4.0. In the second stage, the ethyl acetate / petroleum ether volume ratio is 1:1, 2:1, or 3:1, and the column volumes are 9.0, 8.0, 7.0, 12.0, or 6.0.

[0010] In one alternative implementation, at least one of the following is satisfied: The molar ratio of (3R,12aS)-2-(9H-fluorene-9-ylmethoxycarbonyl)-3,4,6,7,12,12a-hexahydro-2H-pyrazino[1',2':1,6]pyridino[3,4-b]indol-1-one or (3R,12aR)-2-(9H-fluorene-9-ylmethoxycarbonyl)-3,4,6,7,12,12a-hexahydro-2H-pyrazino[1',2':1,6]pyridino[3,4-b]indol-1-one to methylamine is 1:10; The methylamine methanol solution has a mass concentration of 33%, or the methylamine aqueous solution has a mass concentration of 40%. The deprotection / amine reaction and cyclization reaction are performed at a temperature of 50–55°C, optionally 53°C. The deprotection / amine reaction and cyclization reaction take 6–24 h, optionally at 14–24 °C.

[0011] In an optional embodiment, the preparation method of N-(1,3-benzodioxanol-5-methyl)-D-tryptophan methyl ester includes: D-tryptophan methyl ester hydrochloride undergoes a Pictet–Spengler condensation reaction with piperine.

[0012] In one alternative implementation, at least one of the following is satisfied: In a solvent, D-tryptophan methyl ester hydrochloride undergoes a Pictet–Spengler condensation reaction with piperaldehyde, wherein the solvent is selected from dichloromethane, toluene, ethyl acetate, tetrahydrofuran, or mixtures thereof; The Pictet–Spengler condensation reaction is carried out in the presence of an organic base and a dehydrating agent; The reaction temperature for the Pictet–Spengler condensation reaction is 0–40℃; The reaction time for the Pictet–Spengler condensation reaction is 1–24 h; The molar ratio of D-tryptophan methyl ester hydrochloride to piperine is 1:1.0-1.2; The molar ratio of D-tryptophan methyl ester hydrochloride to organic base is 1:1.5-2.0; The molar ratio of D-tryptophan methyl ester hydrochloride to the dehydrating agent is 1:2.0-3.0; The solvent volume to D-tryptophan methyl ester hydrochloride mass ratio is 5-10 mL / g.

[0013] In one alternative implementation, at least one of the following is satisfied: The organic base used in the Pictet–Spengler condensation reaction is selected from triethylamine, N,N-diisopropylethylamine and 1,8-diazacyclic [5.4.0]undec-7-ene; The dehydrating agents used in the Pictet–Spengler condensation reaction are selected from anhydrous magnesium sulfate, anhydrous sodium sulfate, and 4Å molecular sieve.

[0014] In one alternative implementation, at least one of the following is satisfied: The organic base used in the Pictet–Spengler condensation reaction is triethylamine; The dehydrating agent used in the Pictet–Spengler condensation reaction is anhydrous magnesium sulfate.

[0015] Compound IIa: Chemical name: (3R,12aS)-2-(9H-fluorene-9-ylmethoxycarbonyl)-3,4,6,7,12,12a-hexahydro-2H-pyrazino[1',2':1,6]pyridino[3,4-b]indol-1-one CAS No.: 749864-19-5, Molecular Formula: C 29 H 25 N3O3, molecular weight: 463.53 Compound IIb: Chemical name: (3R,12aR)-2-(9H-fluorene-9-ylmethoxycarbonyl)-3,4,6,7,12,12a-hexahydro-2H-pyrazino[1',2':1,6]pyridino[3,4-b]indol-1-one CAS No.: 749864-18-4, Molecular Formula: C 29 H 25 N3O3, molecular weight: 463.53 Tadalafil: Chemical name: (6R,12aR)-6-(1,3-benzodioxacyclopenten-5-yl)-2-methyl-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyridino[3,4-b]indole-1,4-dione CAS No.: 171596-29-5, Molecular Formula: C 22 H 19 N3O4, molecular weight: 389.41 epi-tadalafil (tadalafil chiral isomer): Chemical name: (6R,12aS)-6-(1,3-benzodioxacyclopenten-5-yl)-2-methyl-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyridino[3,4-b]indole-1,4-dione CAS No.: 171596-30-8, Molecular Formula: C 22 H 19 N3O4, molecular weight: 389.41 N-(1,3-benzodioxol-5-methyl)-D-tryptophan methyl ester is also known as compound I.

[0016] The technical solution of this invention has the following advantages: 1. The preparation method provided by the present invention improves the purity and / or yield of (3R,12aS)-2-(9H-fluorene-9-ylmethoxycarbonyl)-3,4,6,7,12,12a-hexahydro-2H-pyrazino[1',2':1,6]pyridino[3,4-b]indole-1-one or (3R,12aR)-2-(9H-fluorene-9-ylmethoxycarbonyl)-3,4,6,7,12,12a-hexahydro-2H-pyrazino[1',2':1,6]pyridino[3,4-b]indole-1-one by selecting a specific (Fomc-Ala-Cl) acylation reagent, thereby improving the yield and / or purity of tadalafil and / or epi-tadalafil.

[0017] 2. The preparation method provided by the present invention improves the yield and / or purity of N-(1,3-benzodioxanol-5-methyl)-D-tryptophan methyl ester by selecting specific solvents, bases and / or dehydrating agents, thereby improving the yield and / or purity of tadalafil and / or epi-tadalafil.

[0018] 3. The preparation method provided by the present invention further improves the purity and / or yield of (3R,12aS)-2-(9H-fluorene-9-ylmethoxycarbonyl)-3,4,6,7,12,12a-hexahydro-2H-pyrazino[1',2':1,6]pyridino[3,4-b]indole-1-one or (3R,12aR)-2-(9H-fluorene-9-ylmethoxycarbonyl)-3,4,6,7,12,12a-hexahydro-2H-pyrazino[1',2':1,6]pyridino[3,4-b]indole-1-one by selecting specific amounts of acylation agent, alkali, temperature and / or solid auxiliaries, thereby further improving the yield and / or purity of tadalafil and / or epi-tadalafil.

[0019] 4. The preparation method provided by the present invention further improves the yield and / or purity of tadalafil and / or epi-tadalafil by selecting specific methylamine forms, amounts of methylamine, temperatures and / or times. Detailed Implementation

[0020] The following embodiments are provided to better understand the present invention, but the following embodiments do not constitute a limitation on the content and scope of protection of the present invention. Any product that is the same as or similar to the present invention, derived by any person under the guidance of the present invention or by combining the features of the present invention with other prior art, falls within the scope of protection of the present invention.

[0021] Unless otherwise specified, all experimental steps or conditions in the examples were performed according to conventional experimental procedures and conditions in the art. Reagents or instruments whose manufacturers are not specified are all commercially available products.

[0022] N,N-diisopropylethylamine is DIPEA, and 1,8-diazacyclic [5.4.0]undec-7-ene is DBU.

[0023] Fmoc-Ala-Cl used in the examples: CAS 103321-50-2, FMOC-alanyl chloride; Fmoc-Gly-Cl used in the examples: CAS 103321-49-9; Fmoc-Sar-Cl used in the examples: CAS 160617-43-6 The DMAP used in this example is CAS 1122-58-3. DIPEA used in the examples: CAS 7087-68-5; The DBU used in this embodiment is CAS 6674-22-2.

[0024] Example 1: Method for preparing tadalafil and epi-tadalafil Step S1: Pictet–Spengler condensation / ring-closing precursor formation (preparation of compound I) 1. Raw material and reagent ratio: The molar ratio of D-tryptophan methyl ester hydrochloride to piperine is 1.0:1.0. The molar ratio of D-tryptophan methyl ester hydrochloride to the organic base (triethylamine) is 1.0:2.0. The molar ratio of D-tryptophan methyl ester hydrochloride to dehydrating agent (anhydrous magnesium sulfate) is 1.0:2.27. Solvent (dichloromethane): 8 mL / g (relative to D-tryptophan methyl ester hydrochloride) 2. Specific operating steps: (1) Under nitrogen protection, add D-tryptophan methyl ester hydrochloride (10.0 g, 36.5 mmol) and anhydrous magnesium sulfate (10.0 g, 83.0 mmol) to a 250 mL three-necked flask, and add dichloromethane (80 mL) to form a suspension; (2) Add triethylamine (7.4 g, 73.0 mmol) to the suspension, add piperonal (5.5 g, 36.5 mmol) to the suspension, and react at 25-30℃ for 8-12 h; (3) After the reaction was completed, anhydrous magnesium sulfate was removed by filtration, and a yellow oily substance was obtained, which was compound I (CAS: 749864-17-3), with a yield of 94.1% and a purity (HPLC) of 92.8%.

[0025] 3. Product characterization data: ¹H NMR (400 MHz, CDCl3): δ 8.12 (s, 1H, NH), 7.56 (d, J=7.8 Hz, 1H, Ar-H), 7.32 (t, J=7.6 Hz, 1H, Ar-H), 7.18 (t, J=7.5 Hz, 1H, Ar-H), 7.05 (d, J=7.7 Hz, 1H, Ar-H), 6.85 (s, 1H, Ar-H), 6.78 (d, J=8.0 Hz, 1H, Ar-H), 6.65 (d, J=8.0 Hz, 1H, Ar-H), 5.98 (s, 2H, O-CH2-O), 4.92 (dd, J=10.2, 5.1 Hz, 1H,CH), 4.25 (q, J=7.1 Hz, 2H, O-CH2-CH3), 3.78 (s, 3H, COOCH3), 3.25-3.18 (m,2H, CH2), 2.95-2.88 (m, 1H, CH), 2.72-2.65 (m, 1H, CH), 1.32 (t, J=7.1 Hz,3H,CH3); MS (ESI): m / z 381.2 [M+H] + (Theoretical molecular weight 380.44).

[0026] Step S2: Acylation to generate paired intermediates (preparation of compounds IIa / IIb) 1. Raw material and reagent ratio: The molar ratio of compound I to Fmoc-Ala-Cl was 1.0:1.2. The molar ratio of compound I to the organic base (triethylamine) is 1.0:1.5. The molar ratio of compound I to catalyst (4-dimethylaminopyridine, DMAP) was 1.0:0.1. The solid additive (neutral alumina) to compound I has a mass ratio of 5.0:1. Solvent (dichloromethane, DCM): 10 mL / g (relative to compound I) 2. Specific operating steps: (1) Under nitrogen protection, add compound I (10.0 g, 26.3 mmol), neutral alumina (50.0 g), and dichloromethane (100 mL) to a 500 mL three-necked flask and stir; (2) Triethylamine (4.0 g, 39.5 mmol) and DMAP (0.32 g, 2.63 mmol) were added, and the resulting reaction system was pre-cooled to -10℃ for 15 min. After pre-cooling, a dichloromethane solution of Fmoc-Ala-Cl (10.2 g, 31.6 mmol) was added dropwise. During the dropwise addition, the temperature was controlled not to exceed -5–0℃. After the dropwise addition was completed, the temperature was kept warm for 1 h. Then the temperature was raised to 25℃ for the subsequent reaction stage, which lasted for 6 h.

[0027] (3) After the reaction was completed, the alumina was removed by filtration, the filtrates were combined, and the solution was concentrated under reduced pressure to obtain a pale yellow solid, which was then separated by silica gel column chromatography. The column chromatography was performed by fractional elution, first eluting with ethyl acetate / petroleum ether at a volume ratio of 1:1 for 7.0 column volumes, and then eluting with ethyl acetate / petroleum ether at a volume ratio of 2:1 for 8.0 column volumes. Compound IIb was collected first (Rf=0.45), and then compound IIa (Rf=0.50) was collected. White solid IIa was obtained with a yield of 44.0% and a purity of 92.4%. White solid IIb was obtained with a yield of 43.1% and a purity of 92.7%. The total yield was 87.1%.

[0028] 3. Product characterization data: Compound IIa (CAS: 749864-19-5): ¹H NMR (400 MHz, CDCl₃): δ 7.78 (d, J=7.5 Hz, 2H, Fmoc-Ar-H), 7.60 (d, J=7.5 Hz, 2H, Fmoc-Ar-H), 7.40 (t, J=7.5 Hz, 2H, Fmoc-Ar-H), 7.32 (t, J=7.5 Hz, 2H, Fmoc-Ar-H), 7.20–7.12 (m, 4H, carboline ring Ar-H), 6.85 (s, 1H, piperonaldehyde ring Ar-H), 6.78 (d, J=8.0 Hz, 1H, piperonaldehyde ring Ar-H), 6.65 (d, J=8.0 Hz, 1H, piperonaldehyde ring Ar-H), 5.98 (s, 2H, O-CH2-O), 5.25 (d, J=8.5 Hz, 1H, NH), 4.92 (dd, J=10.2,5.1 Hz, 1H, carboline ring CH), 4.45-4.38 (m, 2H, Fmoc-CH2), 4.25 (t, J=7.5 Hz, 1H,Fmoc-CH), 4.12-4.05 (m, 1H, Ala-CH), 3.78 (s, 3H, COOCH3), 3.25-3.18 (m, 2H,CH2), 2.95-2.88 (m, 1H, CH), 2.72-2.65 (m, 1H, CH), 1.45 (d, J=7.0 Hz, 3H,Ala-CH3); MS (ESI): m / z 644.3 [M+H] + (Theoretical molecular weight 643.73); Compound IIb (CAS: 749864-18-4): ¹H NMR (400 MHz, CDCl₃): δ 7.76 (d, J=7.5 Hz, 2H, Fmoc-Ar-H), 7.58 (d, J=7.5 Hz, 2H, Fmoc-Ar-H), 7.38 (t, J=7.5 Hz, 2H, Fmoc-Ar-H), 7.30 (t, J=7.5 Hz, 2H, Fmoc-Ar-H), 7.18–7.10 (m, 4H, carboline ring Ar-H), 6.83 (s, 1H, piperonaldehyde ring Ar-H), 6.76 (d, J=8.0 Hz, 1H, piperonaldehyde ring Ar-H), 6.63 (d, J=8.0 Hz, 1H, piperonaldehyde ring Ar-H), 5.96 (s, 2H, O-CH2-O), 5.22 (d, J=8.5 Hz, 1H, NH), 4.88 (dd, J=10.2,5.1 Hz, 1H, carboline ring CH), 4.42-4.35 (m, 2H, Fmoc-CH2), 4.23 (t, J=7.5 Hz, 1H,Fmoc-CH), 4.10-4.03 (m, 1H, Ala-CH), 3.76 (s, 3H, COOCH3), 3.22-3.15 (m, 2H,CH2), 2.92-2.85 (m, 1H, CH), 2.70-2.63 (m, 1H, CH), 1.43 (d, J=7.0 Hz, 3H,Ala-CH3); MS (ESI): m / z 644.3 [M+H] + (Theoretical molecular weight 643.73).

[0029] Step S3: Deprotection and cyclization of methylamine (preparation of tadalafil / epi-tadalafil) 1. Raw material and reagent ratio: The molar ratio of the intermediate compound (IIa or IIb) to methylamine (33% methanol solution) was 1.0:10.0. Solvent (methanol): 16 mL / g (relative to the intermediate) 2. Specific operating steps (taking the preparation of tadalafil in IIa as an example; the preparation of epi-tadalafil in IIb is the same): (1) Add compound IIa (5.0 g, 7.77 mmol) to a three-necked flask and add methanol (80 mL); (2) Add 33% methylamine methanol solution (23.5 g, 77.7 mmol), heat to 50-55°C, reflux for 12-16 h, and carry out deprotection / amine hydrolysis and cyclization reactions in the same reaction system; (3) After the reaction was completed, the mixture was cooled to room temperature and filtered to obtain pure tadalafil with a yield of 78.2% and a purity (HPLC) of 99.5%. Similarly, using compound IIb as a starting material, epi-tadalafil was obtained through the above steps with a yield of 76.8% and a purity (HPLC) of 99.0%. 3. Product characterization data: Tadalafil (CAS: 171596-29-5): ¹H NMR (400 MHz, DMSO-d6): δ 10.72 (s, 1H, NH), 7.56 (d, J=7.8 Hz, 1H, Ar-H), 7.32 (t, J=7.6 Hz, 1H, Ar-H), 7.18 (t, J=7.5 Hz, 1H, Ar-H), 7.05 (d, J=7.7 Hz, 1H, Ar-H), 6.85 (s, 1H, Ar-H), 6.78 (d, J=8.0 Hz, 1H, Ar-H), 6.65 (d, J=8.0 Hz, 1H, Ar-H), 5.98 (s, 2H, O-CH2-O), 4.92 (dd, J=10.2, 5.1 Hz, 1H,CH), 3.78 (s, 3H, N-CH3), 3.25-3.18 (m, 2H, CH2), 2.95-2.88 (m, 1H, CH), 2.72-2.65 (m, 1H, CH), 2.52-2.45 (m, 2H, CH2); MS (ESI): m / z 389.2 [M+H] + (Theoretical molecular weight 389.41); epi-tadalafil (CAS: 171596-30-8): ¹H NMR (400 MHz, DMSO-d6): δ 10.68 (s, 1H, NH), 7.54 (d, J=7.8 Hz, 1H, Ar-H), 7.30 (t, J=7.6 Hz, 1H, Ar-H), 7.16 (t, J=7.5 Hz, 1H, Ar-H), 7.03 (d, J=7.7 Hz, 1H, Ar-H), 6.83 (s, 1H, Ar-H), 6.76 (d, J=8.0 Hz, 1H, Ar-H), 6.63 (d, J=8.0 Hz, 1H, Ar-H), 5.96 (s, 2H, O-CH2-O), 4.88 (dd, J=10.2, 5.1 Hz, 1H,CH), 3.76 (s, 3H, N-CH3), 3.22-3.15 (m, 2H, CH2), 2.92-2.85 (m, 1H, CH), 2.70-2.63 (m, 1H, CH), 2.50-2.43 (m, 2H, CH2); MS (ESI): m / z 389.2 [M+H] + (Theoretical molecular weight 389.41).

[0030] The differences between Examples 2-3 and Example 1, as well as the yield and purity of Compound I, are shown in the table below: Table 1. Differences between Examples 2-3 and Example 1, and the yield and purity of Compound I.

[0031] The differences between Examples 4-5 and Example 1, as well as the yield and purity of Compound I, are shown in the table below: Table 2. Differences between Examples 4-5 and Example 1, and the yield and purity of Compound I.

[0032] The differences between Examples 6-7 and Example 1, as well as the yield and purity of Compound I, are shown in the table below: Table 3. Differences between Examples 6-7 and Example 1, and the yield and purity of Compound I.

[0033] The differences between Examples 8-9 and Example 1, as well as the yields and purities of IIa and IIb, are shown in the table below: Table 4. Differences between Examples 8-9 and Example 1, and yields and purity of IIa and IIb.

[0034] The differences between Examples 10-11 and Example 1, as well as the yields and purities of IIa and IIb, are shown in the table below: Table 5. Differences between Examples 10-11 and Example 1, and yields and purity of IIa and IIb.

[0035] The differences between Examples 12-13 and Example 1, as well as the yields and purities of IIa and IIb, are shown in the table below: Table 6. Differences between Examples 12-13 and Example 1, and yields and purity of IIa and IIb.

[0036] The differences between Examples 14-15 and Example 1, as well as the yields and purities of IIa and IIb, are shown in the table below: Table 7. Differences between Examples 14-15 and Example 1, and yields and purity of IIa and IIb.

[0037] The differences between Example 16 and Example 1, as well as the yields and purity of tadalafil, epi-tadalafil, are shown in the table below: Table 8. Differences between Example 16 and Example 1, and yields and purity of tadalafil, epi-tadalafil, and products.

[0038] The differences between Examples 17-18 and Example 1, as well as the yields and purity of tadalafil, epi-tadalafil, are shown in the table below: Table 9. Differences between Examples 17-18 and Example 1, and the yield and purity of tadalafil, epi-tadalafil.

[0039] The differences between Examples 19-20 and Example 1, as well as the yields and purity of tadalafil, epi-tadalafil, are shown in the table below: Table 10. Differences between Examples 19-20 and Example 1, and the yield and purity of tadalafil, epi-tadalafil.

[0040] The differences between Examples 21-22 and Example 1, as well as the yields and purity of tadalafil, epi-tadalafil, are shown in the table below: Table 11. Differences between Examples 21-22 and Example 1, and the yield and purity of tadalafil, epi-tadalafil.

[0041] The differences between Examples 23-30 and Example 1, the yields of IIa and IIb, and the purity are shown in the table below. The fractional elution includes two stages: Table 12 Differences between Examples 23-30 and Example 1, Yields and Purities of IIa and IIb

[0042] The differences between Comparative Examples 1-2 and Example 1, as well as the product yield and purity, are shown in the table below: Table 13. Differences between Comparative Examples 1-2 and Example 1, product yield, and product purity.

[0043] Table 14: Yields and purity of tadalafil and epi-tadalafil in Comparative Examples 1-2 and Example 1

[0044] Obviously, the above embodiments are merely illustrative examples for clear explanation and are not intended to limit the implementation. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.

Claims

1. A method for preparing tadalafil or epi-tadalafil, characterized in that, include: The N-(1,3-benzodioxanol-5-methyl)-D-tryptophan methyl ester was reacted with Fomc-Ala-Cl to prepare (3R,12aS)-2-(9H-fluorene-9-ylmethoxycarbonyl)-3,4,6,7,12,12a-hexahydro-2H-pyrazino[1',2':1,6]pyridino[3,4-b]indol-1-one or (3R,12aR)-2-(9H-fluorene-9-ylmethoxycarbonyl)-3,4,6,7,12,12a-hexahydro-2H-pyrazino[1',2':1,6]pyridino[3,4-b]indol-1-one; Tadalafil or epi-tadalafil is prepared by deprotection / amineclation of (3R,12aS)-2-(9H-fluorene-9-ylmethoxycarbonyl)-3,4,6,7,12,12a-hexahydro-2H-pyrazino[1',2':1,6]pyridino[3,4-b]indole-1-one or (3R,12aR)-2-(9H-fluorene-9-ylmethoxycarbonyl)-3,4,6,7,12,12a-hexahydro-2H-pyrazino[1',2':1,6]pyridino[3,4-b]indole-1-one in the presence of methylamine, followed by cyclization.

2. The method according to claim 1, characterized in that, Meet at least one of the following: The reaction of N-(1,3-benzodioxol-5-methyl)-D-tryptophan methyl ester with Fomc-Ala-Cl is carried out in dichloromethane, ethyl acetate or tetrahydrofuran, optionally in dichloromethane; The reaction of N-(1,3-benzodioxanol-5-methyl)-D-tryptophan methyl ester with Fomc-Ala-Cl is carried out in the presence of a first organic base and a second organic base, wherein the second organic base is 4-dimethylaminopyridine. The molar ratio of N-(1,3-benzodioxol-5-methyl)-D-tryptophan methyl ester to Fmoc-Ala-Cl is 1:1.0–1.5; The reaction of N-(1,3-benzodioxol-5-methyl)-D-tryptophan methyl ester with Fmoc-Ala-Cl includes a pre-cooling stage, a dropping and holding stage, and a subsequent reaction stage; the temperature of the pre-cooling stage is -10°C; the temperature of the dropping and holding stage is -5–25°C, optionally -5–10°C, and even optionally -5–0°C; the temperature of the subsequent reaction stage is 25°C; The reaction of N-(1,3-benzodioxanol-5-methyl)-D-tryptophan methyl ester with Fomc-Ala-Cl is carried out in the presence of a solid additive selected from neutral alumina and 4Å molecular sieves. After the reaction of N-(1,3-benzodioxol-5-methyl)-D-tryptophan methyl ester with Fomc-Ala-Cl is completed, a separation and purification step is also included, in which silica gel column chromatography is used for separation.

3. The method according to claim 2, characterized in that, Meet at least one of the following: In the reaction of N-(1,3-benzodioxol-5-methyl)-D-tryptophan methyl ester with Fmoc-Ala-Cl, the pre-cooling stage lasts for 15-40 minutes, optionally 15 minutes; the dropping and holding stage lasts for 1-4 hours, optionally 1 hour; and the subsequent reaction stage lasts for 4-6 hours, optionally 6 hours. The solid additive is selected from neutral alumina; The molar ratio of N-(1,3-benzodioxanol-5-methyl)-D-tryptophan methyl ester to Fmoc-Ala-Cl is 1:1.2; The organic base is selected from triethylamine, N,N-diisopropylethylamine and 1,8-diazacyclo[5.4.0]undec-7-ene, and optionally the organic base is triethylamine; The molar ratio of N-(1,3-benzodioxol-5-methyl)-D-tryptophan methyl ester to 4-dimethylaminopyridine is 1:0.01–0.2, optionally 1:0.1; The mass ratio of the solid additive to N-(1,3-benzodioxanol-5-methyl)-D-tryptophan methyl ester is (2–10):1, optionally 5:1; Silica gel column chromatography was performed using ethyl acetate and petroleum ether in a volume ratio of 1:1 to 3:2 as the eluent. Silica gel column chromatography employs isocratic elution or fractional elution.

4. The method according to any one of claims 1-3, characterized in that, Meet at least one of the following: The methylamine is a methanol solution of methylamine or an aqueous solution of methylamine; The molar ratio of (3R,12aS)-2-(9H-fluorene-9-ylmethoxycarbonyl)-3,4,6,7,12,12a-hexahydro-2H-pyrazino[1',2':1,6]pyridino[3,4-b]indol-1-one or (3R,12aR)-2-(9H-fluorene-9-ylmethoxycarbonyl)-3,4,6,7,12,12a-hexahydro-2H-pyrazino[1',2':1,6]pyridino[3,4-b]indol-1-one to methylamine is 1:(2–20). The reaction temperatures for deprotection / amine hydrolysis and cyclization are 30–80 °C. The total reaction time for deprotection / amine degradation and cyclization is 2–48 h; The silica gel column chromatography employed isocratic elution, and the eluent used was ethyl acetate and petroleum ether in a volume ratio of 1:1 or 2:

1. Silica gel column chromatography employs fractional elution, which consists of two stages. In the first stage, 4-9 column volumes are eluted with an ethyl acetate / petroleum ether volume ratio of 1:2-3:

2. In the second stage, 6-12 column volumes are eluted with an ethyl acetate / petroleum ether volume ratio of 1:1-2:

1. Optionally, in the first stage, the ethyl acetate / petroleum ether volume ratio is 1:2, 2:3, 1:1, or 3:2, and the column volumes are 9.0, 8.0, 7.0, 6.0, or 4.

0. In the second stage, the ethyl acetate / petroleum ether volume ratio is 1:1, 2:1, or 3:1, and the column volumes are 9.0, 8.0, 7.0, 12.0, or 6.

0.

5. The method according to claim 4, characterized in that, Meet at least one of the following: The molar ratio of (3R,12aS)-2-(9H-fluorene-9-ylmethoxycarbonyl)-3,4,6,7,12,12a-hexahydro-2H-pyrazino[1',2':1,6]pyridino[3,4-b]indol-1-one or (3R,12aR)-2-(9H-fluorene-9-ylmethoxycarbonyl)-3,4,6,7,12,12a-hexahydro-2H-pyrazino[1',2':1,6]pyridino[3,4-b]indol-1-one to methylamine is 1:10; The methylamine methanol solution has a mass concentration of 33%, or the methylamine aqueous solution has a mass concentration of 40%. The deprotection / amine reaction and cyclization reaction are performed at a temperature of 50–55°C, optionally 53°C. The deprotection / amine reaction and cyclization reaction take 6–24 h, optionally at 14–24 °C.

6. The method according to any one of claims 1-5, characterized in that, The preparation methods of N-(1,3-benzodioxanol-5-methyl)-D-tryptophan methyl ester include: D-tryptophan methyl ester hydrochloride undergoes a Pictet–Spengler condensation reaction with piperine.

7. The method according to claim 6, characterized in that, Meet at least one of the following: In a solvent, D-tryptophan methyl ester hydrochloride undergoes a Pictet–Spengler condensation reaction with piperaldehyde, wherein the solvent is selected from dichloromethane, toluene, ethyl acetate, tetrahydrofuran, or mixtures thereof; The Pictet–Spengler condensation reaction is carried out in the presence of an organic base and a dehydrating agent; The reaction temperature for the Pictet–Spengler condensation reaction is 0–40℃; The reaction time for the Pictet–Spengler condensation reaction is 1–24 h; The molar ratio of D-tryptophan methyl ester hydrochloride to piperine is 1:1.0-1.2; The molar ratio of D-tryptophan methyl ester hydrochloride to organic base is 1:1.5-2.0; The molar ratio of D-tryptophan methyl ester hydrochloride to the dehydrating agent is 1:2.0-3.0; The solvent volume to D-tryptophan methyl ester hydrochloride mass ratio is 5-10 mL / g.

8. The method according to claim 7, characterized in that, Meet at least one of the following: The organic base used in the Pictet–Spengler condensation reaction is selected from triethylamine, N,N-diisopropylethylamine and 1,8-diazacyclic [5.4.0]undec-7-ene; The dehydrating agents used in the Pictet–Spengler condensation reaction are selected from anhydrous magnesium sulfate, anhydrous sodium sulfate, and 4Å molecular sieve.

9. The method according to claim 8, characterized in that, Meet at least one of the following: The organic base used in the Pictet–Spengler condensation reaction is triethylamine; The dehydrating agent used in the Pictet–Spengler condensation reaction is anhydrous magnesium sulfate.

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