Disclosure of Invention
The technical problem to be solved by the invention is to provide a preparation method of tadalafil aiming at the defects in the prior art.
In order to solve the technical problems, the technical scheme adopted by the invention is that the preparation method of tadalafil comprises the following steps:
step S1, taking sarcosine as a raw material, and generating a carboxyl hydroxyl chlorination reaction under the action of thionyl chloride or oxalyl chloride to generate creatine chloride hydrochloride;
s2, taking tryptophan methyl ester hydrochloride and piperonyl as raw materials, and generating an intermediate A through nitrile-amine condensation;
s3, using the intermediate A as a raw material, and closing a ring to generate an intermediate B under the action of phosphorus oxychloride;
s4, reducing the intermediate B under the action of sodium borohydride to generate a crude intermediate C, and purifying;
s5, performing amide condensation reaction on the purified intermediate C and creatinyl chloride, performing amine transesterification to generate a tadalafil crude product, and refining to obtain a tadalafil product;
the synthetic route is as follows:
preferably, step S1 is specifically one of the following methods:
s1a, mixing sarcosine with dichloromethane and N, N-dimethylformamide, dropwise adding oxalyl chloride at 0-5 ℃, and then reacting at room temperature to obtain creatine chloride hydrochloride;
and S1b, adding sarcosine into thionyl chloride in batches at the temperature of 0-5 ℃ for reflux reaction to obtain creatine chloride hydrochloride.
Preferably, in step S1 a:
the molar ratio of oxalyl chloride to sarcosine is 1.2:1-2.0:1, and the molar ratio of N, N-dimethylformamide to sarcosine is 0.05:1-0.2:1;
The ratio of the volume of dichloromethane to the mass of sarcosine is 4:1-8:1, wherein the volume unit is mL, and the mass unit is g;
The reaction time at room temperature is 2-6 h.
Preferably, in the step S1b, the molar ratio of the thionyl chloride to the sarcosine is 1.5:1-3.0:1, the reflux reaction time is 5-9 h, and the reaction temperature is room temperature.
Preferably, step S2 specifically includes:
S2-1, synthesizing an intermediate A by adopting one of the following methods:
s2-1a, taking tryptophan methyl ester hydrochloride and piperonyl as raw materials, taking zinc triflate and hydroxylamine hydrochloride as catalysts, and heating to react in the presence of water to generate an intermediate A;
S2-1b, heating and reacting tryptophan methyl ester hydrochloride and piperonyl alcohol serving as raw materials and ferric nitrate nonahydrate serving as a catalyst to generate an intermediate A;
s2-2, purifying an intermediate A:
And adding sodium bicarbonate solution into the product after the reaction is finished for quenching, extracting by using an organic solvent, washing an organic phase by using water, drying, concentrating, pulping the obtained intermediate A crude product by using a mixed solvent of ethyl acetate and petroleum ether, filtering and drying to obtain a pure intermediate A product.
Preferably, in the step S2-1a, the molar ratio of the piperonyl cyanide to the tryptophan methyl ester hydrochloride is 1.5:1-3:1, the molar ratio of the zinc triflate to the hydroxylamine hydrochloride to the tryptophan methyl ester hydrochloride is 0.05-0.25:0.05-0.25:0.5-2, and the molar ratio of the water to the tryptophan methyl ester hydrochloride is 2:1-4:1;
the reaction temperature is 115-140 ℃ and the reaction time is 10-18 h.
Preferably, in the step S2-1b, the molar ratio of the piperonyl-nitrile to the tryptophan methyl ester hydrochloride is 1.5:1-3:1, the molar ratio of the ferric nitrate nonahydrate to the tryptophan methyl ester hydrochloride is 0.05:1-0.25:1, the reaction temperature is 115-140 ℃, and the reaction time is 10-18 h.
Preferably, in step S2-2, the slurry is prepared with a mixed solvent of ethyl acetate and petroleum ether in a volume ratio=1:2.
Preferably, the step S3 specifically includes:
And adding the intermediate A into the organic solvent 1, dropwise adding phosphorus oxychloride at room temperature, reacting at room temperature, adding the reaction solution into ice water for quenching after the reaction is finished, adjusting pH=7-8, separating the solution, extracting the water phase by using the organic solvent 2, merging the obtained organic phases, and concentrating to obtain an organic solvent 2 solution of the intermediate B.
Preferably, in step S3:
The mol ratio of phosphorus oxychloride to the intermediate A is 1.5:1-3.0:1;
the ratio of the volume of the organic solvent 1 to the mass of the intermediate A is 4-12, wherein the volume unit is mL, and the mass unit is g;
the reaction time after the phosphorus oxychloride is added dropwise is 4-10 hours.
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.
Preferably, step S4 specifically includes:
s4-1, adding an alcohol solvent into the organic solvent 2 solution of the intermediate B, stirring at room temperature, adding sodium borohydride in batches, reacting at room temperature, adding the reaction solution into water for quenching after the reaction is finished, separating the solution, extracting the water phase by using the organic solvent 3, merging the obtained organic phases, washing with water, and concentrating to dryness to obtain a crude intermediate C;
s4-2, purifying the obtained crude intermediate C to obtain the intermediate C.
Preferably, the step S4-2 is specifically that the obtained crude intermediate C is added into 6N hydrochloric acid to react for 20-24 hours at 50-55 ℃, then cooled to 0-5 ℃, filtered, and the filter cake is washed with water and dried to obtain the intermediate C.
Preferably, the alcohol solvent in the step S4-1 is one or more of methanol, ethanol, n-propanol and isopropanol, the volume of the alcohol solvent is 0.25-1 time of that of the organic solvent 2 solution of the intermediate B, and the molar ratio of sodium borohydride to the intermediate B is 0.5-2:1;
the reaction time after the sodium borohydride is added is 15-60 min;
The organic solvent 3is one or more of ethyl acetate, dichloromethane, isopropyl acetate, 1, 2-dichloroethane, 1, 4-dioxane and methyl tetrahydrofuran.
Preferably, step S5 specifically includes:
Mixing the intermediate C, creatine chloride hydrochloride and an organic solvent 4, cooling to-15 ℃ to 5 ℃, adding a first part of organic alkali, keeping the current temperature for reaction, adding a second part of organic alkali, heating, continuing the reaction, cooling to room temperature after the reaction is finished, carrying out suction filtration, pulping a filter cake by using water and methanol in sequence, carrying out suction filtration, and drying the filter cake to obtain a tadalafil product.
Preferably, in step S5:
the molar ratio of the creatine chloride hydrochloride to the intermediate C is 1.1:1-1.5:1;
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 4-10, wherein the volume unit is mL, and the mass unit is g.
Preferably, the organic base is triethylamine or diisopropylethylamine, the components of the two parts of organic bases added before and after are the same, 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.
Preferably, in the step S5, the reaction time after adding the first part of organic base is 0.5-2.5 h, the temperature after adding the second part of organic base is 40-70 ℃, and the reaction time after heating is 4-12 h.
The beneficial effects of the invention are as follows:
The invention takes piperonyl and sarcosine as raw materials to replace piperonyl aldehyde, chloracetyl chloride and methylamine used in the traditional process, and synthesizes tadalafil with high yield, high specificity and selectivity through five steps of reactions of acyl chloride synthesis, nitrile-amine condensation, ring closure, reduction resolution and amide condensation amine transesterification. The process route has the advantages of low cost and availability of raw materials, specific reaction, high product yield, safe and simple operation, environmental protection, low requirement on equipment, easy industrialization and the like, and has wide market application prospect.
Detailed Description
The present invention is described in further detail below with reference to examples to enable those skilled in the art to practice the same by referring to the description.
It will be understood that terms, such as "having," "including," and "comprising," as used herein, do not preclude the presence or addition of one or more other elements or groups thereof.
The test methods used in the following examples are conventional methods unless otherwise specified. The material reagents and the like used in the following examples are commercially available unless otherwise specified. The following examples were conducted under conventional conditions or conditions recommended by the manufacturer, without specifying the specific conditions. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
The invention provides a preparation method of tadalafil, which takes tryptophan methyl ester hydrochloride, piperonyl, sarcosine and the like as raw materials, and synthesizes tadalafil with high yield, high specificity and selectivity through five steps of reactions of synthesis of acyl chloride, nitrile-amine condensation, ring closure, reduction resolution and amide condensation amine transesterification. The method specifically comprises the following steps:
step S1, taking sarcosine as a raw material, and generating a carboxyl hydroxyl chlorination reaction under the action of thionyl chloride or oxalyl chloride to generate creatine chloride hydrochloride;
s2, taking tryptophan methyl ester hydrochloride and piperonyl as raw materials, and generating an intermediate A through nitrile-amine condensation under the action of Lewis acids such as ferric nitrate or zinc triflate;
s3, using the intermediate A as a raw material, and closing a ring to generate an intermediate B under the action of phosphorus oxychloride;
S4, reducing the intermediate B under the action of sodium borohydride to generate a crude intermediate C, and purifying (then carrying out kinetic resolution under the action of hydrochloric acid to obtain a pure intermediate C with a de value of more than 99.5 percent);
s5, performing amide condensation reaction on the purified intermediate C and creatinyl chloride, performing amine transesterification to generate a tadalafil crude product, and refining to obtain a tadalafil product;
the synthetic route is as follows:
In a preferred embodiment, step S1 is specifically one of the following methods:
s1a, mixing sarcosine with dichloromethane and N, N-dimethylformamide, dropwise adding oxalyl chloride at 0-5 ℃, and then reacting at room temperature to obtain creatine chloride hydrochloride;
and S1b, adding sarcosine into thionyl chloride in batches at the temperature of 0-5 ℃ for reflux reaction to obtain creatine chloride hydrochloride.
1-1 For the method of step S1a, in a preferred embodiment, wherein:
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 number between them, and more preferably, the ratio is 1.3:1 in order to ensure that the sarcosine reaction is complete and not too much oxalyl chloride is excessive.
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 number between them, and more preferably, the ratio is 0.1:1 in order to ensure that the reaction proceeds faster and not too severe.
The ratio of the volume of the dichloromethane to the mass of the sarcosine is 4:1-8:1, wherein the volume unit is mL, the mass unit is g, and the ratio is, for example, any value formed by 4:1, 5:1, 6:1, 7:1, 8:1 or two by two, and more preferably, the ratio is 5:1 in order to ensure that the reaction is sufficiently stirred and avoid slow reaction caused by too low concentration of the reaction solution.
And dropwise adding oxalyl chloride, and then, heating to room temperature for continuous reaction for 2-6 hours. For example, the reaction time is 2h, 3h, 4h, 5h, 6h or any number of two or more of them, and the confirmation of the end point of the reaction is based on the completion of the TLC sarcosine reaction.
1-2 For the method of step S1b, in a preferred embodiment, wherein:
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 number between two of them, and more preferably, the ratio is 2.0:1 in order to ensure that the sarcosine reaction is complete and not too much of the thionyl chloride is excessive.
The reflux reaction time after the dropping of sarcosine is 5h to 9h, for example, 5h, 6h, 7h, 8h, 9h or any numerical value formed between two of them, and the confirmation of the end point of the reaction is based on the completion of TLC sarcosine reaction.
The reaction temperature was room temperature.
In a preferred embodiment, step S1 further comprises, after the reaction is completed:
the reaction solution was concentrated to constant weight, and the residue was directly used in step S5.
In a preferred embodiment, step S2 is specifically:
S2-1, synthesizing an intermediate A by adopting one of the following methods:
s2-1a, taking tryptophan methyl ester hydrochloride and piperonyl as raw materials, taking zinc triflate and hydroxylamine hydrochloride as catalysts, and heating to react in the presence of water to generate an intermediate A;
S2-1b, heating and reacting tryptophan methyl ester hydrochloride and piperonyl alcohol serving as raw materials and ferric nitrate nonahydrate serving as a catalyst to generate an intermediate A;
s2-2, purifying an intermediate A:
And adding sodium bicarbonate solution into the product after the reaction is finished for quenching, extracting by using an organic solvent, washing an organic phase by using water, drying, concentrating, pulping the obtained intermediate A crude product by using a mixed solvent of ethyl acetate and petroleum ether, filtering and drying to obtain a pure intermediate A product.
2-1, For the method of step S2-1a, in a preferred embodiment, wherein:
The molar ratio of piperonyl cyanide to tryptophan methyl ester hydrochloride is 1.5:1-3:1, for example, 1.5:1, 2:1, 2.5:1, 3:1 or any number between them, and more preferably, the ratio is 2:1 in order to ensure that the reaction of tryptophan methyl ester hydrochloride is complete and the amount of piperonyl cyanide is minimal.
The molar ratio of zinc triflate to tryptophan methyl ester hydrochloride is 0.05-0.25:0.05-0.25:0.5-2, and is any value formed by 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 two of the two, and on the premise of ensuring the reaction speed, the molar ratio of zinc triflate, hydroxylamine hydrochloride and tryptophan methyl ester hydrochloride is preferably 0.1:0.1:1.
The molar ratio of water to tryptophan methyl ester hydrochloride is 2:1-4:1, and is any numerical value formed by 2:1, 2.5:1, 3:1, 3.5:1 and 4:1 or two by two, and the ratio is preferably 3:1 in order to ensure complete reaction conversion.
The reaction temperature is 115 ℃ to 140 ℃, is 115 ℃, 120 ℃, 125 ℃, 130 ℃, 135 ℃ and 140 ℃ or any numerical value formed between the two, and is preferably 115 ℃ in order to ensure the reaction speed and generate as few impurities as possible.
The reaction time is 10-18 h, and is 10h, 12h, 14h, 16h and 18h or any numerical value formed by two of the two, and the confirmation of the reaction end point is based on the complete reaction of tryptophan methyl ester hydrochloride.
2-1, For the method of step S2-1b, in a preferred embodiment, wherein:
In step S2-1b, the molar ratio of piperonyl cyanide to tryptophan methyl ester hydrochloride is 1.5:1-3:1, for example, 1.5:1, 2:1, 2.5:1, 3:1 or any numerical value formed between two of them, and more preferably, the ratio is 2:1 in order to ensure that the tryptophan methyl ester hydrochloride is completely reacted and the amount of piperonyl cyanide is minimum.
The molar ratio of ferric nitrate nonahydrate to tryptophan methyl ester hydrochloride is 0.05:1-0.25:1, for example, is any value of 0.05:1, 0.1:1, 0.15:1, 0.2:1, 0.25:1 or two by two, and the ratio is more preferably 0.2:1 when compared with the reaction yields of different molar ratios.
The reaction temperature is 115 ℃ to 140 ℃, for example, 115 ℃, 120 ℃, 125 ℃, 130 ℃, 135 ℃, 140 ℃ or any numerical value formed between two of them, and more preferably, the temperature is 125 ℃ in order to ensure the reaction speed and the reaction generates as few impurities as possible.
The reaction time is 10-18 h, for example, 10h, 12h, 14h, 16h, 18h or any numerical value formed between two of them, and the confirmation of the reaction end point is based on the complete reaction of tryptophan methyl ester hydrochloride.
In a preferred embodiment, in step S2-2, the slurry is prepared with a mixed solvent of ethyl acetate to petroleum ether in a volume ratio=1:2.
In a preferred embodiment, step S3 is specifically:
And adding the intermediate A into the organic solvent 1, dropwise adding phosphorus oxychloride at room temperature, reacting at room temperature, adding the reaction solution into ice water for quenching after the reaction is finished, adjusting pH=7-8, separating the solution, extracting the water phase by using the organic solvent 2, merging the obtained organic phases, and concentrating to obtain an organic solvent 2 solution of the intermediate B.
In a preferred embodiment, in step S3:
the molar ratio of phosphorus oxychloride to the intermediate A is 1.5:1-3.0:1, for example, 1.5:1, 1.8:1, 2.1:1, 2.4:1, 2.7:1, 3.0:1 or any numerical value formed between every two of the two, and more preferably, the ratio is 1.8:1 to ensure complete reaction of the raw materials.
The ratio of the volume of the organic solvent 1 to the mass of the intermediate A is 4-12, wherein the volume unit is mL, the mass unit is g, and the ratio is, for example, any value of 4, 6, 8, 10, 12 or any value formed between every two of the two, and more preferably, the ratio is 8 in order to ensure sufficient stirring.
The reaction time after the phosphorus oxychloride is added dropwise is 4-10 hours, for example, 4, 6, 8 and 10 hours or any numerical value formed between every two of the phosphorus oxychloride, and the confirmation of the reaction end point is based on the complete reaction of the intermediate A in order to ensure the complete reaction of the raw materials.
In a preferred embodiment, the organic solvent 1 and the organic solvent 2 are each one or more of ethyl acetate, dichloromethane, isopropyl acetate, 1, 2-dichloroethane, 1, 4-dioxane, methyl tetrahydrofuran.
In a preferred embodiment, step S4 is specifically:
s4-1, adding an alcohol solvent into the organic solvent 2 solution of the intermediate B, stirring at room temperature, adding sodium borohydride in batches, reacting at room temperature, adding the reaction solution into water for quenching after the reaction is finished, separating the solution, extracting the water phase by using the organic solvent 3, merging the obtained organic phases, washing with water, and concentrating to dryness to obtain a crude intermediate C;
s4-2, purifying the obtained crude intermediate C to obtain the intermediate C.
In a preferred embodiment, step S4-2 is specifically implemented by adding the obtained crude intermediate C into 6N hydrochloric acid, reacting for 20-24 hours at 50-55 ℃, then cooling to 0-5 ℃, carrying out suction filtration, washing a filter cake with water, and drying to obtain the intermediate C.
In a preferred embodiment, the alcoholic solvent in step S4-1 is one or more of methanol, ethanol, n-propanol, isopropanol.
In a preferred embodiment, the volume of the alcohol solvent is 0.25 to 1 times, for example, 0.25, 0.5, 0.75, 1 times or any number between two of the organic solvent 2 solutions of the intermediate B, and more preferably, the ratio is 0.5 in order to ensure rapid progress of the reaction.
In a preferred embodiment, the molar ratio of sodium borohydride to intermediate B is 0.5-2:1, for example, 0.5, 1, 1.5, 2 or any numerical value formed between two of them, and more preferably, the ratio is 1 in order to ensure that the raw materials react completely without wasting sodium borohydride.
The reaction time after the sodium borohydride is added is 15-60 min, for example, 15, 30, 45 and 60min or any numerical value formed between every two of the two, and the confirmation of the reaction end point is based on the complete reaction of the intermediate B in order to ensure the complete reaction of the raw materials.
The organic solvent 3is one or more of ethyl acetate, dichloromethane, isopropyl acetate, 1, 2-dichloroethane, 1, 4-dioxane and methyl tetrahydrofuran.
In a preferred embodiment, step S5 is specifically:
Mixing the intermediate C, creatine chloride hydrochloride and an organic solvent 4, cooling to-15 ℃ to 5 ℃, adding a first part of organic alkali, keeping the current temperature for reaction, adding a second part of organic alkali, heating, continuing the reaction, cooling to room temperature after the reaction is finished, carrying out suction filtration, pulping a filter cake by using water and methanol in sequence, carrying out suction filtration, and drying the filter cake to obtain a tadalafil product.
In a preferred embodiment, in step S5:
The molar ratio of the creatine chloride hydrochloride to the intermediate C is 1.1:1-1.5:1, for example, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1 or any numerical value formed between the two, and the ratio is 1.2:1 more preferably in order to make the tadalafil content of the reaction liquid product be the highest;
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 4-10, wherein the volume unit is mL, and the mass unit is g. For example, 4, 6, 8, 10 or any number therebetween, and more preferably, the ratio is 6 in order to ensure sufficient stirring.
In a preferred embodiment, the organic base is triethylamine or diisopropylethylamine, and the two organic base components added before and after are the same, the molar ratio of the first 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 number between them, more preferably, the ratio is 2.2:1;
The molar ratio of the second part of organic base to 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 number between them, more preferably the ratio is 1.2:1.
In a preferred embodiment, in step S5, the reaction time after adding the first portion of the organic base is 0.5 to 2.5 hours, for example, 0.5, 1, 1.5, 2, 2.5 hours or any number between them, and the confirmation of the reaction end point is based on the complete reaction of the raw material intermediate C.
In step S5, the cooling temperature at which intermediate C, creatine chloride hydrochloride and organic solvent 4 are mixed is-15, -10, -5, 0, 5 or any value therebetween, and more preferably-5 ℃ to ensure the reaction rate with minimal side reactions.
The temperature of the second organic base is raised to 40-70 ℃, for example 40, 50, 60, 70 ℃ or any value between them, more preferably the ratio is 50 ℃.
The reaction time is 4-12 hours after the temperature is raised. For example, the reaction end point is confirmed by any value of 4, 6, 8, 10, 12 or a combination of two or more of them, and the reaction of the raw materials is completely confirmed.
The foregoing is a general inventive concept and the following detailed examples and comparative examples are provided on the basis thereof to further illustrate the invention.
Example 1
To a three-necked flask of S1 and 500mL, 30.8g (1.0 eq, 0.348 mol) of sarcosine, 2.5g (0.1 eq,0.035 mol) of DMF (N, N-dimethylformamide) and 150mL of DCM (dichloromethane) were added, the temperature was lowered to 0-. Degree.C, 52.7g (1.2 eq, 0.418 mol) of oxalyl chloride was added dropwise, and then the reaction was carried out at room temperature for 3 hours. After the raw material sarcosine is completely reacted, the reaction liquid is directly concentrated and is used for the next reaction according to the theoretical amount.
Into a 500mL three-necked flask, 100.0g (1.0 eq,0.393 mol) of tryptophan methyl ester hydrochloride, 194.0g (2.0 eq,0.785 mol) of piperonyl cyanide, 14.2g (0.1 eq,0.039 mol) of zinc triflate, 2.7g (0.1 eq,0.039 mol) of hydroxylamine hydrochloride and 21.2g (3.0 eq,1.178 mol) of water were charged, and after nitrogen substitution, the mixture was heated to 115℃and refluxed for 12 hours. After the reaction, 500mL of saturated sodium bicarbonate solution is added for quenching, 2 x 500mL of dichloromethane is added for extraction, the organic phases are combined, washed with water, dried and concentrated, and the obtained crude product is pulped by 500mL of mixed solvent of EA (ethyl acetate): PE (petroleum ether) =1:2, filtered by suction and dried, thereby obtaining 131.6g of intermediate A with the yield of 91.5%.
Into a 2L three-necked flask, 131.6g (1.0 eq, 0.399 mol) of intermediate A and 1050mL of ethyl acetate were charged, and phosphorus oxychloride g (1.8 eq,0.647 mol) was added dropwise at room temperature, followed by further reaction at room temperature for 6 hours. After the intermediate A is completely reacted, the reaction solution is dripped into ice water for quenching, the pH=7 is regulated, the liquid is separated, the aqueous phase is extracted by 660mL of ethyl acetate, the organic phase is combined and washed, and the obtained ethyl acetate solution of the intermediate B is concentrated to about 600mL and is directly used for the next reaction according to theoretical amount.
S4, adding 300mL of ethanol into the ethyl acetate solution of the intermediate B, adding 13.6g (1.0 eq, 0.399 mol) of sodium borohydride in batches at room temperature under stirring, and then continuing stirring for 30min at room temperature. After the intermediate B is completely reacted, adding 600mL of water into the reaction solution to quench, separating the solution, extracting the water phase by using 600mL of ethyl acetate, merging the organic phases, washing the organic phases with water, concentrating the organic phases to dryness, adding 6N hydrochloric acid (namely hydrochloric acid with the concentration of 6 mol/L) into the obtained crude product, then reacting for 24 hours at 50 ℃, cooling to 0 ℃, carrying out suction filtration, washing a filter cake with water, and drying to obtain 111.4g of a earthy yellow solid intermediate C, wherein the yield of 80.2% from the intermediate A to the C.
Into a 1L three-necked flask, 111.4g of intermediate C (1.0 eq, 0.284 mol), sarcosyl chloride hydrochloride (theoretical amount 49.8 g) (1.2 eq, 0.348 mol) and 670mL of THF (tetrahydrofuran) were charged, the ice-salt bath was cooled to-5℃and 64.0g of triethylamine (2.2 eq,0.634 mol) was added dropwise, followed by further heat-retaining reaction at this temperature for 1 hour. The reaction was warmed to room temperature, 35.0g (1.2 eq,0.346 mol) of triethylamine was added and then heated to 50 ℃ for further reaction for 8h. After the reaction is finished, the temperature is reduced to room temperature, the mixture is filtered, filter cakes are pulped by water and methanol in sequence, the filter cakes are filtered, and the obtained filter cakes are dried to obtain 96.6g of tadalafil white crystalline powder with the yield of 86.1%.
H NMR data of tadalafil in the middle of this example are shown below, and the spectrum is shown in fig. 1.
1H NMR(400MHz,DMSO):δ11.02(s,1H),7.54(d,J＝7.7Hz,1H),7.30(d,J＝8.1Hz,1H),7.06(td,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).
Example 2
To a 500mL three-necked flask, 86.6g (2.0 eq, 0.428 mol) of thionyl chloride was added, the temperature was lowered to 0℃and 32.4g (1.0 eq, 0.264 mol) of sarcosine was added in portions, followed by reaction at room temperature for 7 hours. After the raw material sarcosine is completely reacted, the reaction liquid is directly concentrated and is used for the next reaction according to the theoretical amount.
Into a three-necked 500mL flask of S2, 100.0g (1.0 eq,0.393 mol) of tryptophan methyl ester hydrochloride, 213.4g (2.2 eq,0.865 mol) of piperonyl cyanide, 31.6g (0.2 eq,0.079 mol) of ferric nitrate nonahydrate, and after nitrogen substitution, the flask was heated to 125℃and refluxed for 14 hours. After the reaction, 500mL of saturated sodium bicarbonate solution is added for quenching, 2 x 500mL of dichloromethane is added for extraction, the organic phases are combined, washed with water, dried and concentrated, and the obtained crude product is pulped by 500mL of mixed solvent of EA:PE=1:2, filtered by suction and dried, thereby obtaining 129.7g of intermediate A with the yield of 90.2 percent.
To a 2L three-necked flask, 129.7g (1.0 eq,0.354 mol) of intermediate A and 1300mL of methylene chloride were added dropwise at room temperature, followed by reaction at room temperature for 5 hours. After the intermediate A is completely reacted, the reaction solution is dripped into ice water for quenching, the pH=7 is regulated, the liquid is separated, the aqueous phase is extracted by 650mL of dichloromethane, the organic phase is combined and washed, and the obtained dichloromethane solution of the intermediate B is concentrated to about 600mL and is directly used for the next reaction according to theoretical amount.
S4, adding 250mL of methanol into the dichloromethane solution of the intermediate B, adding 16.1g (1.2 eq,0.425 mol) of sodium borohydride in batches at room temperature under stirring, and then continuing stirring at room temperature for 20min. After the intermediate B is completely reacted, adding 600mL of water into the reaction solution, quenching, separating the solution, extracting the water phase by using 600mL of dichloromethane, merging the organic phases, washing with water, concentrating to dryness, adding 6N hydrochloric acid into the obtained crude product, reacting for 24 hours at 50 ℃, cooling to 0 ℃, carrying out suction filtration, washing a filter cake with water, and drying to obtain 108.5g of a earthy yellow solid intermediate C, wherein the yield of the intermediate A to C is 79.2%.
To a 1L three-necked flask, 108.5g of intermediate C (1.0 eq,0.280 mol), sarcosyl chloride hydrochloride (theoretical amount 52.4 g) (1.3 eq, 0.264 mol) and 540mL of methylene chloride were added, the ice salt bath was cooled to 0℃and 83.3g of N, N-diisopropylethylamine (2.3 eq,0.644 mol) were added dropwise, followed by further heat-retaining reaction at this temperature for 1.5h. The reaction was warmed to room temperature, 47.0g (1.3 eq, 0.284 mol) of N, N-diisopropylethylamine was added and then heated to 40℃for a further reaction of 10h. After the reaction is finished, the temperature is reduced to room temperature, the mixture is filtered, filter cakes are pulped by water and methanol in sequence, the filter cakes are filtered, and the obtained filter cakes are dried to obtain 92.2g of tadalafil white crystalline powder with the yield of 84.4%.
Although embodiments of the present invention have been disclosed above, it is not limited to the use of the description and embodiments, it is well suited to various fields of use for the invention, and further modifications may be readily apparent to those skilled in the art, and accordingly, the invention is not limited to the particular details without departing from the general concepts defined in the claims and the equivalents thereof.