A synthetic method of tadalafil

Abstract

The invention relates to a synthetic method of tadalafil, which comprises the following steps: 1) using p-hydroxybenzaldehyde as a raw material to carry out a condensation reaction to obtain intermediate V; 2) chlorinating intermediate V to obtain intermediate IV; 3) reacting intermediate IV with formaldehyde solution to obtain intermediate III; 4) condensing intermediate III with chloroacetyl chloride to obtain intermediate II; 5) reacting intermediate II with methylamine solution to obtain tadalafil (I). This synthetic method avoids the use of easily controlled raw materials for drug production such as piperonal and its derivative compounds or other expensive raw materials. This invention is reported for the first time. The preparation method proposed by this invention has the characteristics of easily available raw materials, low cost, simple method, convenient operation, high product purity, and suitability for industrial production, and can be applied to the production of tadalafil.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and particularly relates to a method for synthesizing tadalafil raw material drug. Background Art

[0002] Tadalafil is a phosphodiesterase type V (PDE5) inhibitor developed by Eli Lilly and Company in the United States, which has the advantages of high selectivity, rapid onset, long half-life, etc. It was approved for marketing by the FDA in 2003 under the trade name CIALIS for the treatment of erectile dysfunction (ED) and benign prostatic hyperplasia (BPH); in 2009, the FDA approved tadalafil tablets for the treatment of pulmonary arterial hypertension (PAH) under the trade name ADCIRCA. In 2004, the State Food and Drug Administration of China approved the import of tadalafil tablets (CIALIS) of Eli Lilly and Company in the United States, and the approved indication was erectile dysfunction (ED).

[0003] Tadalafil is a white crystal or crystalline powder, slightly sour in taste and pungent. Its molecular formula is C 22 H 19 N3O4, and the CAS number is 171596-29-5. Its structural formula is as follows:

[0004] 。

[0005] At present, there are many reported methods for synthesizing tadalafil in the literature and materials, but most of them use piperonal or simple derivatives of piperonal such as piperonal acyl chloride, acetal, etc. as starting materials.

[0006] According to the report of "Schematic Diagram of Tadalafil Synthesis Route" in the 127th issue of "Chinese Journal of Medicinal Chemistry", the synthesis routes of tadalafil are summarized into 11 kinds of synthesis routes, among which 10 routes need to use piperonal and 1 route uses an acyl chloride derivative of piperonal.

[0007] Chinese Patent 201511014807.1 proposed a substitute for piperonal, 3,4-dimethylbenzaldehyde. Using the starting materials D-tryptophan methyl ester hydrochloride, chloroacetyl chloride, and 3,4-dihydroxy-benzoyl chloride for two-step acylation reaction, then cyclization reaction with phosphoryl halide, then asymmetric hydrogenation reaction, and finally reaction with methylamine and cyclization reaction with dibromomethane to obtain the final product tadalafil.

[0008] Piperonal is a class I precursor chemical under the control of the public security system, which brings difficulties in procurement and inconvenience in use. Although its derivatives such as acyl chloride or acetal are not themselves controlled, they still need to be prepared from piperonal, with the same difficulties, and there are also problems such as instability, unstable supply, and high price. 3,4-Dimethylbenzaldehyde, also known as protocatechualdehyde, is mainly obtained by extracting from Salvia miltiorrhiza, with characteristics such as lack of raw materials and high price, and the same is true for its series of derivatives.

[0009] Therefore, exploring a new synthesis method of tadalafil to replace the currently mainstream used piperonal or other derivatives is of great significance for reducing the production cost of tadalafil and thus reducing the price of tadalafil tablets or other related drugs. Summary of the Invention

[0010] Based on the above technical background, the present invention proposes a new synthesis method of tadalafil, which solves the procurement and use problems of piperonal, a class of precursor chemicals, and also avoids the problems such as unavailability and high price of other existing reported substitutes. At the same time, the synthesis method proposed by the present invention has the characteristics of easily available raw materials, low cost, simple method, convenient operation, high product purity, and suitability for industrial production, and can be applied to the production of tadalafil.

[0011] The synthesis method of tadalafil proposed by the present invention is realized through the following steps:

[0012] Step 1: Using p-hydroxybenzaldehyde as a raw material and reacting with D-tryptophan methyl ester hydrochloride to obtain intermediate V;

[0013] Step 2: Subjecting intermediate V to chlorination reaction to obtain intermediate IV;

[0014] Step 3: Reacting intermediate IV with formaldehyde solution to obtain intermediate III;

[0015] Step 4: Condensing intermediate III with chloroacetyl chloride to obtain intermediate II;

[0016] Step 5: Reacting intermediate II with methylamine solution to obtain tadalafil (I), and the synthesis route is as follows:

[0017] .

[0018] The reaction temperature of Step 1 is 60~100 °C, preferably 70~80 °C, and the reaction solvent is a protic solvent.

[0019] The chlorinating reagent in Step 2 is NCS, thionyl chloride or chlorine gas, preferably thionyl chloride.

[0020] In Step 3, an acidic reagent is used to catalyze the hemiacetal transition state, and a certain amount of water is used to control the conversion of the hemiacetal transition state to acetal. After the hemiacetal reaction for a period of time, a basic reagent is added to the reaction system to control the pH value of the reaction solution to convert the hemiacetal transition state to Intermediate III. The acidic catalyst used in Step 3 is preferably p-toluenesulfonic acid or hydrogen chloride, the water content in the reaction system is preferably 10% - 30%, and the pH value control is preferably 4 - 6.

[0021] The reaction temperature in Step 4 is -10 to 30 °C, preferably 0 to 10 °C.

[0022] The reaction temperature in Step 5 is 20 to 50 °C, and the crystallization temperature is -10 to 20 °C. Preferably, the reaction temperature is 20 to 30 °C, and the crystallization temperature is 10 to 15 °C.

[0023] The present invention has the following beneficial effects:

[0024] Using p-hydroxybenzaldehyde and D-tryptophan methyl ester hydrochloride as starting materials, it avoids the use of piperonal and its derivatives, which are a type of precursor chemicals for drug production, solves the problems of difficult availability and high price of other alternatives, and significantly reduces the production cost and management cost. The reaction conditions are mild, the operation is simple, there are no high-risk processes and highly polluting processes, and it is suitable for industrial production. The yield of each step is high, the obtained intermediates and products have high purity, few by-product impurities, and obvious quality advantages. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 It is the synthetic route diagram of tadalafil proposed by the present invention;

[0026] Figure 2 It is the HPLC purity diagram of tadalafil obtained by the present invention;

[0027] Figure 3 It is the 1H NMR spectrum diagram of tadalafil obtained by the present invention;

[0028] Figure 4 It is the NMR mass spectrum diagram of tadalafil obtained by the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0029] The following further describes the present invention in detail with specific embodiments. The embodiments provided below are only used to further illustrate the present invention, but do not limit the present invention in any way.

[0030] Example 1: Preparation of Intermediate V

[0031] Dissolve p-hydroxybenzaldehyde (0.6 kg) in isopropanol (10 L). After stirring evenly, add D-tryptophan methyl ester hydrochloride (1 kg) and stir while heating to 70 - 75 °C. Keep the temperature for reaction for 3 - 4 h, then cool down to 20 - 25 °C. Stir for 1 h and then centrifuge. The filter cake is slurried with isopropanol (3 L) and then filtered. After drying at 60 °C, a grayish-yellow solid is obtained, with a yield of 92.7% and a purity of 98.75%.

[0032] Example 2: Preparation of Intermediate IV

[0033] Mix Intermediate V (1.4 kg) and sulfonyl chloride (1.1 kg), start stirring, heat to 50 - 60 °C, and react for 2 - 3 h. Then, concentrate under reduced pressure until no liquid distillate comes out. Add dichloromethane (20 L) to dissolve, and then wash with water (20 L) and saturated brine (20 L) respectively. The obtained solution is directly used for the next reaction step.

[0034] Example 3: Preparation of Intermediate III

[0035] Mix the dichloromethane solution of Intermediate IV obtained in Example 2 and aqueous formaldehyde solution (40%, 3 L), start stirring, add p-toluenesulfonic acid (0.1 kg), and react for 2 - 3 h. Then, dropwise add aqueous sodium hydroxide solution (20%) to the reaction system, control the pH value of the reaction system to about 5 - 6, continue to react for 6 - 8 h, add water (20 L), continue to stir for 0.5 h, separate the layers, and take the organic layer to wash with water (20 L) and saturated brine (20 L) respectively. After drying with anhydrous sodium sulfate, the mother liquor is directly used for the next reaction step.

[0036] Example 4: Preparation of Intermediate II

[0037] While stirring the dichloromethane solution of Intermediate III obtained in Example 3, add triethylamine (0.85 kg) and cool down to 0 - 5 °C. Slowly dropwise add dichloromethane solution of chloroacetyl chloride (50%), controlling the temperature below 10 °C. After the addition is complete, keep the temperature for reaction for 0.5 - 1 h. After the reaction is completed, add 4 L of water, stir for 0.5 h, then add 26 L of dichloromethane to dissolve the solid in the kettle, separate the layers, take the lower organic phase, wash the organic phase with water (10 L * 3), then wash with 15 L of saturated brine. Concentrate the obtained mother liquor to 1 / 3 of its volume, add 11 L of methyl tert-butyl ether, and yellow solid will precipitate. Stir at 20 - 25 °C for 4 h, then filter and dry to obtain a yellow solid. The total yield of the three steps is 85.7% and the purity is 99.34%.

[0038] Example 5: Preparation of tadalafil

[0039] The intermediate II obtained in Example 4 was added to 11 L of ethanol at room temperature with 40% aqueous methylamine solution. The mixture was stirred and heated to reflux, and reacted for 1 - 1.5 h. Then it was cooled to 10 - 15 °C and stirred for 2 h, followed by filtration. The filter cake was slurried with ethanol (13 L) and water (4 L), and after filtration, it was dried to obtain off-white tadalafil crude product.

[0040] Acetic acid (9 L) and tadalafil crude product were added to a 50 L reaction kettle. The mixture was stirred and heated until dissolved and clarified, stirred for 0.5 h, then cooled to room temperature and stirred for 2 h. After filtration, the filter cake was washed with water and then with ethanol, and dried to obtain a white solid with a yield of 92.5% and a purity of 99.98%.

[0041] Example 6: Preparation of Intermediate V

[0042] p-Hydroxybenzaldehyde (10 g) was dissolved in anhydrous ethanol (100 mL). After stirring evenly, D-tryptophan methyl ester hydrochloride (25 g) was added, and the mixture was stirred and heated to reflux, and kept reacting for 23 h. Then it was cooled to 10 - 15 °C, stirred for 1 h, and filtered. The filter cake was dried to obtain a grayish-yellow solid.

[0043] Example 7: Preparation of Intermediate IV

[0044] The intermediate V obtained in Example 6 and sulfonyl chloride (60 g) were mixed. Stirring was started and heated to 80 - 90 °C. After reacting for 2 - 3 h, it was concentrated under reduced pressure until no liquid distillate was obtained to get a pale yellow solid.

[0045] Example 8: Preparation of Intermediate III

[0046] The intermediate IV obtained in Example 7 was dissolved in a mixture of dichloromethane solution (200 mL) and 40% aqueous formaldehyde solution (60 mL). Stirring was started, p-toluenesulfonic acid (2 g) was added, and after reacting for 5 h, an aqueous sodium hydroxide solution (10%) was added dropwise to the reaction system, controlling the pH value of the reaction system to about 4. After continuing to react for 10 h, water (200 mL) was added, and stirring was continued for 0.5 h. Then liquid separation was carried out, and the organic layer was washed with water (200 mL) and saturated brine (200 mL) respectively, and dried with anhydrous sodium sulfate and concentrated to dryness to obtain a pale yellow solid.

[0047] Example 9: Preparation of Intermediate II

[0048] The intermediate III obtained in Example 8 was dissolved in dichloromethane (200 mL). Triethylamine (50 g) was added under stirring, and chloroacetyl chloride was slowly added dropwise at room temperature while controlling the temperature below 30 °C. After the addition was completed, the reaction was carried out under insulation for 1 h. Water (200 mL) was added, and after stirring for 0.5 h, liquid separation was carried out. The lower organic phase was taken, and the organic phase was washed with water and saturated brine respectively. The obtained mother liquor was concentrated to dryness to obtain a yellow solid, and the yellow solid was refined with dichloromethane (50 mL) and n-hexane (200 mL) to obtain a pale yellow solid.

[0049] Example 10: Preparation of tadalafil

[0050] The intermediate II obtained in Example 9 was added to methanol at room temperature, and the mixture was stirred and heated to reflux. The reaction was carried out for 3 h, cooled to room temperature, stirred for 2 h, then water was added and stirring was continued for 2 h. Filtration was carried out, and the filter cake was slurried with methanol and water, and then dried after filtration to obtain a crude off-white tadalafil.

[0051] The crude tadalafil was added to acetic acid, and the mixture was stirred and heated until dissolved and clarified. After stirring for 0.5 h, it was cooled to room temperature and stirred for 2 h. Filtration was carried out, the filter cake was washed with water and then with methanol, and after drying, a white solid, namely tadalafil, was obtained.

Claims

1. A synthetic method of tadalafil, characterized in that It has the following steps: 1) Using p-hydroxybenzaldehyde as a raw material to carry out a condensation reaction to obtain intermediate V, 2) chlorinating intermediate V to obtain intermediate IV, 3) reacting intermediate IV with formaldehyde solution to obtain intermediate III, 4) condensing intermediate III with chloroacetyl chloride to obtain intermediate II, 5) reacting intermediate II with methylamine solution to obtain tadalafil (I), and the synthetic route is as follows:

2. The synthesis method of tadalafil according to claim 1, characterized in that The reaction temperature of step 1 is 60 - 100 °C, and the reaction solvent is a protic solvent.

3. The synthesis method of tadalafil according to claim 1, characterized in that The chlorinating reagent for step 2 is NCS, sulfuryl chloride or chlorine.

4. The synthesis method of tadalafil according to claim 1, characterized in that, In step 3, an acidic reagent is used to catalyze the hemiacetal transition state, and a certain amount of water is used to control the conversion of the hemiacetal transition state to acetal. After the hemiacetal reaction for a period of time, a basic reagent is added to the reaction system to control the pH value of the reaction solution to enable the conversion of the hemiacetal transition state to intermediate III.

5. The synthesis method of tadalafil according to claim 4, wherein The acidic reagent used in step 3 is p-toluenesulfonic acid or hydrogen chloride, the water content in the reaction system is 10% - 30%, and the pH value is controlled to be 4 - 6.

6. The synthesis method of tadalafil according to claim 1, characterized in that The reaction temperature of step 4 is -10 - 30 °C.

7. The synthesis method of tadalafil according to claim 1, characterized in that The reaction temperature of step 5 is 20 - 50 °C, and the crystallization temperature is -10 - 20 °C.

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