CN113754612B - Preparation method of sildenafil intermediate - Google Patents
Preparation method of sildenafil intermediate Download PDFInfo
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- CN113754612B CN113754612B CN202111248346.XA CN202111248346A CN113754612B CN 113754612 B CN113754612 B CN 113754612B CN 202111248346 A CN202111248346 A CN 202111248346A CN 113754612 B CN113754612 B CN 113754612B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
- C07D295/26—Sulfur atoms
Abstract
The invention discloses a preparation method of a sildenafil intermediate. Firstly, performing BOC protection on amino, then performing thionyl chloride, reacting with N-methylpiperazine, and removing BOC in an acidic environment to obtain 2-amino-5- (4-methylpiperazine-1-ylsulfonyl) -benzoic acid; then diazotizing and brominating, and etherifying with ethanol to obtain the target product. According to the invention, 2-amino-5- (4-methylpiperazine-1-ylsulfonyl) -benzoic acid is subjected to diazotization reaction to convert amino into bromine, and then ethanol is used for etherification, so that the use of bromoethane and dimethyl sulfate with higher toxicity is avoided, and the preparation method is environment-friendly and beneficial to large-scale production.
Description
Technical Field
The invention relates to a preparation method of sildenafil intermediate 2-ethoxy-5- (4-methylpiperazine-1-ylsulfonyl) benzoic acid, belonging to the technical field of medical intermediate synthesis.
Background
Sildenafil (Sildenafil), chemical name: 1- [ 4-ethoxy-3- [5- (6, 7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [4,3 d)]Pyrimidine]Benzenesulfonyl group]-4-methylpiperazine of the formula C 22 H 30 N 6 O 4 S, S. Sildenafil is a phosphodiesterase type 5 (PDE 5) inhibitor developed by the american type of sciences pharmaceutical company and is well known under its commercial name Viagra (victoria).
2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) benzoic acid is an important intermediate for the synthesis of sildenafil, of the formula: c (C) 14 H 20 N 2 O 5 S, molecular weight: 328.38, the structural formula is shown below.
The synthesis methods reported in the patent literature for 2-ethoxy-5- (4-methylpiperazine-1-sulfonyl) benzoic acid mainly comprise the following two methods:
the method comprises the following steps: EP0812845A1 and CN1168376A disclose a synthesis method for obtaining 2-ethoxy-5- (4-methylpiperazine-1-ylsulfonyl) benzoic acid from o-ethoxybenzoic acid by chlorosulfonation and sulfonylation, wherein the synthesis route is as follows:
the starting material of the above route is o-ethoxybenzoic acid, and the preparation route of o-ethoxybenzoic acid (see, for details, tensegrity, etc. the synthesis of o-ethoxybenzoic acid [ J ]. Fine chemical, 2011 (2), 186-187) synthetic route is shown below:
the two routes are comprehensively considered, so that the problems of longer route and higher cost exist, the total yield is 47.8%, and the yield is lower, so that the method is difficult to be suitable for industrial production.
The second method is as follows: chinese patent CN105777669a discloses a method for preparing 2-ethoxy-5- (4-methylpiperazine-1-ylsulfonyl) benzoic acid from methyl salicylate, wherein methyl salicylate is used as a starting material, chlorosulfonic acid and thionyl chloride are used, chlorosulfonated, bromoethane etherified and hydrolyzed to obtain 2-ethoxy-5- (4-methylpiperazine-1-sulfonyl) benzoic acid, and the synthetic route is shown as follows:
the common etherification reagent bromoethane in the route is 3 kinds of carcinogens, has relatively high toxicity and increases great pressure for producing sildenafil by a pharmaceutical enterprise. Other common etherification reagents are diethyl sulfate, the diethyl sulfate is a good etherification agent, the product yield is high, the etherification process is simple and easy to control, but dimethyl sulfate belongs to 2 types of carcinogens, skin contact or inhalation is seriously harmful, so that the purchase is extremely inconvenient, and meanwhile, sulfuric acid in byproducts has serious corrosion to equipment and difficult post-treatment. Therefore, the two etherification reagents have great harm to human bodies and are not friendly to the environment, the optimal total yield of the reaction in the route is 71%, and the yield is low, so that the method is difficult to be suitable for industrial production.
Disclosure of Invention
In view of the above, the present invention provides a method for preparing sildenafil intermediates. Firstly, performing BOC protection on amino, then performing thionyl chloride, reacting with N-methylpiperazine, and removing BOC in an acidic environment to obtain 2-amino-5- (4-methylpiperazine-1-ylsulfonyl) -benzoic acid; then diazotizing and brominating, and etherifying with ethanol to obtain the target product. According to the invention, 2-amino-5- (4-methylpiperazine-1-ylsulfonyl) -benzoic acid is subjected to diazotization reaction to convert amino into bromine, and then ethanol is used for etherification, so that the use of bromoethane and dimethyl sulfate with higher toxicity is avoided, and the preparation method is environment-friendly and beneficial to large-scale production.
The technical scheme of the invention is as follows: a preparation method of sildenafil intermediate is characterized in that,
1) Taking 2-amino-5-sulfonic acid benzoic acid as a starting material, firstly performing BOC protection on amino to obtain 2-N (BOC) -5-sulfonic acid benzoic acid (a compound shown in formula 2);
2) The compound of formula 2 is chlorinated by thionyl chloride, reacts with N-methylpiperazine, and removes BOC in an acidic environment to obtain 2-amino-5- (4-methylpiperazine-1-ylsulfonyl) benzoic acid (compound of formula 3);
3) Diazotizing and brominating the compound of the formula 3 to obtain 2-bromo-5- (4-methylpiperazine-1-ylsulfonyl) benzoic acid (compound of the formula 4);
4) And etherifying the compound of formula 4 with ethanol under alkaline conditions to obtain 2-ethoxy-5- (4-methylpiperazine-1-ylsulfonyl) benzoic acid (the compound of formula 5).
The synthetic route is as follows:
the method comprises the following specific steps:
1) Synthesis of 2-N (BOC) -5-sulfobenzoic acid (Compound of formula 2)
2-amino-5-sulfonic benzoic acid is dissolved in an organic solvent, and di-tert-butyl dicarbonate is added dropwise for reaction; washing after the reaction is finished, and carrying out reduced pressure distillation on an organic phase until the organic phase is dried, wherein dichloromethane is dissolved again to obtain a dichloromethane solution of the compound shown in the formula 2;
2) Synthesis of 2-amino-5- (4-methylpiperazin-1-ylsulfonyl) benzoic acid (Compound of formula 3)
(a) Dropwise adding thionyl chloride into a dichloromethane solution of a compound shown in formula 2 for thermal insulation reaction at the temperature of 0-10 ℃, adding water for quenching after the reaction is finished, adding alkali for regulating the pH value to 7-8, and washing with water to obtain a dichloromethane solution of 2-N (BOC) -5-sulfonyl benzoic acid;
(b) The temperature is controlled to be 0-10 ℃, and the obtained dichloromethane solution is dropwise added into the dichloromethane solution of N-methylpiperazine for thermal insulation reaction for 15-45 min; then adding water into the system, adjusting pH to 1-2 with acid, controlling temperature to 25-35 ℃ and stirring for reaction, and after the reaction is finished, obtaining the compound of formula 3 through post-treatment;
3) Synthesis of 2-bromo-5- (4-methylpiperazin-1-ylsulfonyl) benzoic acid (Compound of formula 4)
Adding ethanol, hydrobromic acid and a compound of formula 3 into a reaction vessel, controlling the temperature to-10-0 ℃, dropwise adding an aqueous solution of sodium nitrite, controlling the temperature to-10-0 ℃ after the dropwise adding is finished, reacting, and performing post-treatment after the reaction is finished to obtain a compound of formula 4;
4) Synthesis of 2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) benzoic acid
Adding ethanol, a compound of formula 4 and alkali into a reaction vessel, reacting at a reaction temperature of 80 ℃ to a reflux temperature, and performing aftertreatment after the reaction is finished to obtain 2-ethoxy-5- (4-methylpiperazine-1-ylsulfonyl) benzoic acid.
The molar ratio of the 2-amino-5-sulfonic acid benzoic acid to the di-tert-butyl dicarbonate in the step 1) is 1 (1.05-1.5), preferably 1:1.1, and the organic solvent is one or more of dichloromethane and chloroform, preferably dichloromethane.
The temperature of the dropwise adding of the di-tert-butyl dicarbonate in the step 1) is 20-30 ℃, the reaction temperature is 20-30 ℃ and the reaction time is 1-3 h.
In the step 2), the molar ratio of the 2-amino-5-sulfonic acid benzoic acid to the N-methylpiperazine is 1 (1.02-1.1), preferably 1:1.05. The molar ratio of the 2-amino-5-sulfonic acid benzoic acid to the thionyl chloride is 1:2-4, preferably 1:3.
The reaction time in the step (a) of the step 2) is 5-8 h; the reaction time in step (b) is 3 to 8 hours. The post-treatment is as follows: adjusting pH to 6-7 with alkali (preferably 30% liquid alkali), layering, back-extracting aqueous phase with dichloromethane once, mixing organic phases, controlling temperature T to be less than or equal to 35 ℃, concentrating under reduced pressure, adding n-heptane into the system after concentrating, controlling temperature to be 0-10 ℃, crystallizing for 1h, and suction filtering.
The molar ratio of the 2-amino-5- (4-methylpiperazine-1-ylsulfonyl) benzoic acid to hydrobromic acid to sodium nitrite in the step 3) is 1:2.5-3.5:1.2-1.8, preferably 1:3:1.5, and the reaction time is 1-3 h. The post-treatment of the step 3) is as follows: after the reaction is finished, the system is heated to 0-20 ℃, dichloromethane is used for extraction, the organic phases are combined and then washed for 1 time, the temperature T is less than or equal to 35 ℃, the pressure is reduced and concentrated to 1/5-1/4 of the original volume, n-heptane is added, the temperature is controlled to 0-20 ℃, and crystallization is carried out, so that the compound of the formula 4 is obtained.
The alkali in the step 4) is one or more of sodium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate and lithium hydroxide, preferably sodium bicarbonate, and the molar ratio of the compound in the formula 4 to the sodium carbonate is 1:2.5-3.5; the ethanol is preferably 95% ethanol, the dosage is 5 g/g-8 g/g (compound of formula 4), and the reaction time is 15-30 h.
The post-treatment of the step 4) is as follows: vacuum distilling until the volume is 1/4-1/3 of the volume, adding water 3-5 times the mass of the compound of formula 4, controlling the temperature to 0-10 ℃, adjusting the pH to 6.5-7.5 by acid, crystallizing, and suction filtering to obtain the target product.
The principle of the invention is as follows: 2-amino-5-sulfonic acid is taken as an initial raw material, and BOC protection is carried out on amino in a proper solvent at a certain temperature to obtain 2-N (BOC) -5-sulfonic acid shown in a formula 2; then, at a certain temperature, performing chlorination by thionyl chloride to obtain 2-N (BOC) -5-sulfoacid chlorobenzoic acid, reacting with N-methylpiperazine to obtain 2-N (BOC) -5-sulfonyl benzoic acid, and removing BOC in an acidic environment to obtain 2-amino-5- (4-methylpiperazine-1-ylsulfonyl) -benzoic acid shown in formula 3; then diazotizing and brominating to obtain 2-bromo-5- (4-methylpiperazine-1-ylsulfonyl) -benzoic acid shown in formula 4; and then, using ethanol as a solvent, and carrying out etherification at a certain temperature to obtain the 2-ethoxy-5- (4-methylpiperazine-1-ylsulfonyl) -benzoic acid shown in the formula 5.
Compared with the prior art, the invention has the following outstanding advantages and positive effects:
1. ethanol is used as an etherification reagent to replace high-toxicity dimethyl sulfate and bromoethane, so that the safety and the health of first-line staff can be effectively protected.
2. In the first step and the second step, BOC anhydride protection, chlorosulfonation and sulfonamide can be carried out without taking out solids, and the materials are continuously fed, so that the production efficiency is improved, and the generation of dangerous waste is reduced.
3. Through practice, the invention discovers that the dichloromethane and the n-heptane in the crystallization mother liquor of the second step, the third step and the fourth step can be recycled and sleeved in the step, thereby effectively reducing the production cost and not affecting the product quality and the yield.
4. The total yield of the invention can reach 75.3%, which is improved by about 5% compared with the optimal total yield of 70.4% in the prior art, and the invention has the advantages of mature and stable process, small yield fluctuation, high practicability and suitability for industrial production.
Detailed Description
Example 1:
1) Synthesis of 2-N (BOC) -5-sulfobenzoic acid (Compound of formula 2)
50g of 2-amino-5-sulfonic acid benzoic acid is added into 250ml of dichloromethane, 55.27g of di-tert-butyl dicarbonate is dropwise added at the temperature of 20-30 ℃, then the mixture is reacted for 2 hours at the temperature of 20-30 ℃, the dichloromethane solution of 2- (N-BOC) -5-sulfonic acid benzoic acid is obtained after twice washing with 250g of water, the temperature T is less than or equal to 35 ℃, 250ml of dichloromethane is added after reduced pressure distillation until the mixture is dried, and KF is detected to be less than or equal to 0.1%.
2) Synthesis of 2-amino-5- (4-methylpiperazin-1-ylsulfonyl) benzoic acid (Compound of formula 3)
(a) Dropwise adding 82.2g of thionyl chloride into a dichloromethane solution of a compound shown in formula 2 at the temperature of 0-10 ℃ for reaction for 6 hours, slowly adding the mixture of 500g of water and 50g of sodium bicarbonate at the temperature of 0-10 ℃ after the reaction is finished, quenching the mixture until the pH value is 7-8, and washing the mixture to obtain the dichloromethane solution of 2-N (BOC) -5-sulfonyl benzoic acid.
(b) Dropwise adding the obtained dichloromethane solution into the dichloromethane solution of 24.2-g N-methylpiperazine at the temperature of 0-10 ℃ for reaction for 0.5h, adding water into the system, regulating the pH value to 1-2 by using 3mol/L hydrochloric acid, stirring for reaction for 5h, regulating the pH value to 6-7 by using liquid alkali after the reaction is finished, layering, carrying out back extraction on the water phase by using dichloromethane once, merging organic phases, regulating the temperature T to be less than or equal to 35 ℃, concentrating under reduced pressure to 1/4 of the original volume, concentrating, adding n-heptane into the system, regulating the temperature to 0-10 ℃ for crystallization for 1h, carrying out suction filtration and drying to obtain 63.40g of 2-amino-5- (4-methylpiperazine-1-ylsulfonyl) benzoic acid, wherein the yield is 92.0%, and the purity is 98.6%.
3) Synthesis of 2-bromo-5- (4-methylpiperazin-1-ylsulfonyl) benzoic acid (Compound of formula 4)
Sequentially adding 150g of 95% ethanol, 40.5g of hydrobromic acid, 50g of 2-amino-5- (4-methylpiperazine-1-ylsulfonyl) benzoic acid, dropwise adding an aqueous solution consisting of 17.3g of sodium nitrite and 50g of water at a temperature of-10-0 ℃, reacting for 2 hours at a temperature of-10-0 ℃ after the dropwise adding, returning the system to 0-20 ℃ after the reaction, extracting for 3 times by using dichloromethane, merging organic phases, washing with water once, concentrating under reduced pressure to 1/4 of the original volume at a temperature of less than or equal to 35 ℃, adding 100g of n-heptane, crystallizing at a temperature of 0-20 ℃ to obtain 51.57g of solid 2-bromo-5- (4-methylpiperazine-1-ylsulfonyl) benzoic acid, and obtaining the solid with a yield of 85.0% and a purity of 98.9%.
4) Synthesis of 2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) benzoic acid
350g of 95% ethanol, 50g of 2-bromo-5- (4-methylpiperazine-1-ylsulfonyl) benzoic acid, 42.77g of sodium carbonate, controlling the reflux temperature at 80-85 ℃, reacting for 20h, reducing the pressure and distilling until the volume is 1/3 after the reaction is finished, adding 200g of water, controlling the temperature to 0-10 ℃, adjusting the pH value to 6.5-7.5 by acid, controlling the temperature to 0-10 ℃, crystallizing for 1h, and carrying out suction filtration to obtain 42.94g of 2-ethoxy-5- (4-methylpiperazine-1-ylsulfonyl) benzoic acid, wherein the yield is 95.0%, and the purity is 99.5%.
Example 2:
1) Synthesis of 2-N (BOC) -5-sulfobenzoic acid (Compound of formula 2)
50g of 2-amino-5-sulfonic acid benzoic acid is added into 250ml of dichloromethane, 55.2g of di-tert-butyl dicarbonate is dropwise added at the temperature of 20-30 ℃, then the mixture is reacted for 2 hours at the temperature of 20-30 ℃, the dichloromethane solution of 2- (N-BOC) -5-sulfonic acid benzoic acid is obtained after twice washing with 250g of water, the temperature T is less than or equal to 35 ℃, 250ml of dichloromethane is added after reduced pressure distillation until the mixture is dried, and KF is detected to be less than or equal to 0.1%.
2) Synthesis of 2-amino-5- (4-methylpiperazin-1-ylsulfonyl) benzoic acid (Compound of formula 3)
(a) Dropwise adding 82.1g of thionyl chloride into a dichloromethane solution of a compound shown in formula 2 at the temperature of 0-10 ℃ for reaction for 6 hours, slowly adding the mixture of 500g of water and 50.1g of sodium bicarbonate at the temperature of 0-10 ℃ after the reaction is finished, quenching the mixture until the pH value is 7-8, and washing the mixture to obtain the dichloromethane solution of 2-N (BOC) -5-sulfonyl benzoic acid.
(b) Dropwise adding the obtained dichloromethane solution into the dichloromethane solution of 24.1-g N-methylpiperazine at the temperature of 0-10 ℃ for reaction for 0.5h, adding water into the system, adjusting the pH value to 1-2 by using 3mol/L hydrochloric acid, stirring for reaction for 5h, adjusting the pH value to 6-7 by using liquid alkali after the reaction is finished, layering, carrying out back extraction on the water phase by using dichloromethane once, merging organic phases, controlling the temperature T to be less than or equal to 35 ℃, concentrating under reduced pressure to 1/3 of the original volume, concentrating, adding n-heptane into the system, controlling the temperature to be 0-10 ℃ for crystallization for 1h, carrying out suction filtration and drying to obtain 63.21g of 2-amino-5- (4-methylpiperazine-1-ylsulfonyl) benzoic acid, wherein the yield is 91.7%, and the purity is 98.2%.
3) Synthesis of 2-bromo-5- (4-methylpiperazin-1-ylsulfonyl) benzoic acid (Compound of formula 4)
Sequentially adding 150g of 95% ethanol, 40.4g of hydrobromic acid, 50g of 2-amino-5- (4-methylpiperazine-1-ylsulfonyl) benzoic acid, dropwise adding an aqueous solution consisting of 17.2g of sodium nitrite and 50g of water at a temperature of-10-0 ℃, reacting for 2 hours at a temperature of-10-0 ℃ after the dropwise adding, returning the system to 0-20 ℃ after the reacting, extracting for 3 times by using dichloromethane, merging organic phases, washing with water once, concentrating under reduced pressure to 1/4 of the original volume at a temperature of less than or equal to 35 ℃, adding 100g of n-heptane, crystallizing at a temperature of 0-20 ℃ to obtain 51.75g of solid 2-bromo-5- (4-methylpiperazine-1-ylsulfonyl) benzoic acid, and obtaining the product with a yield of 85.3% and a purity of 99.0%.
4) Synthesis of 2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) benzoic acid
250g of 95% ethanol, 50g of 2-bromo-5- (4-methylpiperazine-1-ylsulfonyl) benzoic acid, 43.80g of sodium carbonate, controlling the reflux temperature at 80-85 ℃, reacting for 25h, reducing the pressure and distilling until the volume is 1/4 after the reaction is finished, adding 200g of water, controlling the temperature to 0-10 ℃, adjusting the pH value to 6.5-7.5 by acid, controlling the temperature to 0-10 ℃ for crystallization for 1h, and carrying out suction filtration to obtain 42.38g of 2-ethoxy-5- (4-methylpiperazine-1-ylsulfonyl) benzoic acid, wherein the yield is 93.8% and the purity is 99.1%.
Example 3:
1) Synthesis of 2-N (BOC) -5-sulfobenzoic acid (Compound of formula 2)
50g of 2-amino-5-sulfonic acid benzoic acid is added into 250ml of dichloromethane, 55.10g of di-tert-butyl dicarbonate is dripped at the temperature of 20-30 ℃, then the mixture is reacted for 2 hours at the temperature of 20-30 ℃, the dichloromethane solution of 2- (N-BOC) -5-sulfonic acid benzoic acid is obtained after twice washing with 250g of water, the temperature T is less than or equal to 35 ℃, 250ml of dichloromethane is added after reduced pressure distillation is carried out until the mixture is dried, and KF is detected to be less than or equal to 0.1%.
2) Synthesis of 2-amino-5- (4-methylpiperazin-1-ylsulfonyl) benzoic acid (Compound of formula 3)
(a) Dropwise adding 82.3g of thionyl chloride into a dichloromethane solution of a compound shown in formula 2 at the temperature of 0-10 ℃ for reaction for 6 hours, slowly adding the mixture of 500g of water and 50g of sodium bicarbonate at the temperature of 0-10 ℃ after the reaction is finished, quenching the mixture until the pH value is 7-8, and washing the mixture to obtain the dichloromethane solution of 2-N (BOC) -5-sulfonyl benzoic acid.
(b) Dropwise adding the obtained dichloromethane solution into the dichloromethane solution of 24.3-g N-methylpiperazine at the temperature of 0-10 ℃ for reaction for 0.5h, adding water into the system, adjusting the pH value to 1-2 by using 3mol/L hydrochloric acid, stirring for reaction for 5h, adjusting the pH value to 6-7 by using liquid alkali after the reaction is finished, layering, carrying out back extraction on the water phase by using dichloromethane once, merging organic phases, controlling the temperature T to be less than or equal to 35 ℃, concentrating under reduced pressure to 1/4 of the original volume, concentrating, adding n-heptane into the system, controlling the temperature to be 0-10 ℃ for crystallization for 1h, carrying out suction filtration and drying to obtain 63.54g of 2-amino-5- (4-methylpiperazine-1-ylsulfonyl) benzoic acid, wherein the yield is 92.2%, and the purity is 98.9%.
3) Synthesis of 2-bromo-5- (4-methylpiperazin-1-ylsulfonyl) benzoic acid (Compound of formula 4)
Sequentially adding 150g of 95% ethanol, 40.6g of hydrobromic acid, 50g of 2-amino-5- (4-methylpiperazine-1-ylsulfonyl) benzoic acid, dropwise adding an aqueous solution consisting of 17.3g of sodium nitrite and 50g of water at a temperature of-10-0 ℃, reacting for 2 hours at a temperature of-10-0 ℃ after the dropwise adding, returning the system to 0-20 ℃ after the reacting, extracting for 3 times by using dichloromethane, merging organic phases, washing with water once, concentrating under reduced pressure to 1/5 of the original volume at a temperature of less than or equal to 35 ℃, adding 100g of n-heptane, crystallizing at a temperature of 0-20 ℃ to obtain 51.66g of solid 2-bromo-5- (4-methylpiperazine-1-ylsulfonyl) benzoic acid, and obtaining the product with a yield of 85.1% and a purity of 99.1%.
4) Synthesis of 2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) benzoic acid
400g of 95% ethanol, 50g of 2-bromo-5- (4-methylpiperazine-1-ylsulfonyl) benzoic acid, 43.8g of sodium carbonate, reflux temperature of 80-85 ℃ and reaction time of 22h are added into the system, after the reaction is finished, the reaction is completed, the reaction is reduced in pressure and distilled until the volume is 1/3, 200g of water is added, the temperature is controlled to 0-10 ℃, the pH is regulated to 6.5-7.5 by acid, the temperature is controlled to 0-10 ℃, crystallization is carried out for 1h, suction filtration is carried out, 43.21g of 2-ethoxy-5- (4-methylpiperazine-1-ylsulfonyl) benzoic acid is obtained, the yield is 95.6%, and the purity is 99.4%.
Example 4:
1) Synthesis of 2-N (BOC) -5-sulfobenzoic acid (Compound of formula 2)
50g of 2-amino-5-sulfonic acid benzoic acid is added into 250ml of dichloromethane (dichloromethane is recovered in the first two steps), 55.11g of di-tert-butyl dicarbonate is dropwise added at the temperature of 20-30 ℃, then the mixture is reacted for 2 hours at the temperature of 20-30 ℃, 250g of water is washed twice to obtain a dichloromethane solution of 2- (N-BOC) -5-sulfonic acid benzoic acid, the temperature T is less than or equal to 35 ℃, 250ml of dichloromethane is added after reduced pressure distillation is carried out until the mixture is dried, and KF is detected to be less than or equal to 0.1%.
2) Synthesis of 2-amino-5- (4-methylpiperazin-1-ylsulfonyl) benzoic acid (Compound of formula 3)
(a) Dropwise adding 82.3g of thionyl chloride into a dichloromethane solution of a compound shown in formula 2 at the temperature of 0-10 ℃ for reaction for 6 hours, slowly adding the mixture of 500g of water and 50.1g of sodium bicarbonate at the temperature of 0-10 ℃ after the reaction is finished, quenching the mixture until the pH value is 7-8, and washing the mixture to obtain the dichloromethane solution of 2-N (BOC) -5-sulfonyl benzoic acid.
(b) Dropwise adding the obtained dichloromethane solution into the dichloromethane solution of 24.2-g N-methylpiperazine at the temperature of 0-10 ℃ for reaction for 0.5h, adding water into the system, adjusting the pH value to 1-2 by using 3mol/L hydrochloric acid, stirring for reaction for 5h, adjusting the pH value to 6-7 by using liquid alkali after the reaction is finished, layering, carrying out back extraction on the water phase by using dichloromethane once, merging organic phases, controlling the temperature T to be less than or equal to 35 ℃, concentrating under reduced pressure to 1/3 of the original volume, concentrating, adding n-heptane (recovering the n-heptane in the previous two steps), controlling the temperature to 0-10 ℃, crystallizing for 1h, carrying out suction filtration and drying to obtain 63.60g of 2-amino-5- (4-methylpiperazine-1-ylsulfonyl) benzoic acid, wherein the yield is 92.3%, and the purity is 98.7%.
3) Synthesis of 2-bromo-5- (4-methylpiperazin-1-ylsulfonyl) benzoic acid (Compound of formula 4)
Sequentially adding 150g of 95% ethanol (ethanol is recovered in the third step) into a system, 40.6g of hydrobromic acid, 50g of 2-amino-5- (4-methylpiperazine-1-ylsulfonyl) benzoic acid, dropwise adding an aqueous solution consisting of 17.4g of sodium nitrite and 50g of water at a temperature of-10-0 ℃, reacting for 2 hours at a temperature of-10-0 ℃ after the dropwise adding, heating the system to 0-20 ℃, extracting for 3 times by using dichloromethane, combining organic phases, washing once by using water, concentrating at a temperature of less than or equal to 35 ℃ under reduced pressure to 1/4 of the original volume, adding 100g of n-heptane (n-heptane is recovered in the third step), crystallizing at a temperature of 0-20 ℃, and obtaining 51.35g of solid 2-bromo-5- (4-methylpiperazine-1-ylsulfonyl) benzoic acid, wherein the yield is 84.6%, and the purity is 98.9%.
4) Synthesis of 2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) benzoic acid
350g of 95% ethanol (ethanol is recovered in the fourth step) is added into the system, 50g of 2-bromo-5- (4-methylpiperazine-1-ylsulfonyl) benzoic acid, 43.9g of sodium carbonate, the reflux temperature of the temperature is controlled at 80-85 ℃, the reaction time is 25h, after the reaction is finished, the temperature is reduced, the reaction is distilled under reduced pressure until the volume is 1/4 of the rest, 200g of water is added, the temperature is controlled at 0-10 ℃, the pH value is regulated to 6.5-7.5 by acid, the temperature is controlled at 0-10 ℃, the crystallization is carried out for 1h, the suction filtration is carried out, 42.76g of 2-ethoxy-5- (4-methylpiperazine-1-ylsulfonyl) benzoic acid is obtained, the yield is 94.6%, and the purity is 99.1%.
Claims (9)
1. The preparation method of the sildenafil intermediate is characterized by comprising the following steps of:
1) Taking 2-amino-5-sulfonic benzoic acid as a starting material, and firstly performing BOC protection on amino to obtain a compound of formula 2;
2) The compound of the formula 2 is subjected to thionyl chloride to react with N-methylpiperazine, and BOC is removed in an acidic environment to obtain a compound of the formula 3;
3) Diazotizing and brominating the compound of the formula 3 to obtain a compound of the formula 4;
4) The compound of formula 4 is etherified by ethanol under alkaline condition to obtain 2-ethoxy-5- (4-methylpiperazine-1-ylsulfonyl) benzoic acid;
the compound of formula 2 is 2-N (BOC) -5-sulfobenzoic acid;
the compound of formula 3 is 2-amino-5- (4-methylpiperazin-1-ylsulfonyl) benzoic acid;
the compound of formula 4 is 2-bromo-5- (4-methylpiperazin-1-ylsulfonyl) benzoic acid;
the compound of formula 5 is 2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) benzoic acid.
2. A process for the preparation of a sildenafil intermediate as claimed in claim 1 comprising the steps of:
1) Synthesis of Compounds of formula 2
2-amino-5-sulfonic benzoic acid is dissolved in an organic solvent, and di-tert-butyl dicarbonate is added dropwise for reaction; washing after the reaction is finished, and carrying out reduced pressure distillation on an organic phase until the organic phase is dried, wherein dichloromethane is dissolved again to obtain a dichloromethane solution of the compound shown in the formula 2;
2) Synthesis of Compound 3
(a) Dropwise adding thionyl chloride into a dichloromethane solution of a compound shown in formula 2 for thermal insulation reaction at the temperature of 0-10 ℃, adding water for quenching after the reaction is finished, adding alkali for regulating the pH value to 7-8, and washing with water to obtain a dichloromethane solution of 2-N (BOC) -5-sulfonyl benzoic acid;
(b) Controlling the temperature to be 0-10 ℃, dropwise adding the dichloromethane solution obtained in the step (a) into the dichloromethane solution of N-methylpiperazine, and carrying out an insulation reaction for 15-45 min; then adding water into the system, adjusting pH to 1-2 with acid, controlling temperature to 25-35 ℃ and stirring for reaction, and after the reaction is finished, obtaining the compound of formula 3 through post-treatment;
3) Synthesis of Compounds of formula 4
Adding ethanol, hydrobromic acid and a compound of formula 3 into a reaction vessel, controlling the temperature to-10-0 ℃, dropwise adding an aqueous solution of sodium nitrite, controlling the temperature to-10-0 ℃ after the dropwise adding is finished, reacting, and performing post-treatment after the reaction is finished to obtain a compound of formula 4;
4) Synthesis of 2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) benzoic acid
Adding ethanol, a compound of formula 4 and alkali into a reaction vessel, reacting at a reaction temperature of 80 ℃ to a reflux temperature, and performing aftertreatment after the reaction is finished to obtain 2-ethoxy-5- (4-methylpiperazine-1-ylsulfonyl) benzoic acid.
3. The process for preparing a sildenafil intermediate according to claim 2, wherein the organic solvent of step 1) is dichloromethane or chloroform.
4. The process for preparing sildenafil intermediate as claimed in claim 2, wherein the temperature of dropwise adding di-tert-butyl dicarbonate in step 1) is 20-30 ℃, the reaction temperature is 20-30 ℃ and the reaction time is 1-3 h.
5. The process for the preparation of a sildenafil intermediate according to claim 2, characterized in that the reaction time in step (a) is 5-8 h; the reaction time in step (b) is 3 to 8 hours.
6. A process for the preparation of a sildenafil intermediate according to claim 2, characterized in that the post-treatment in step (b) is: regulating pH to 6-7 with alkali, layering, back extracting water phase with dichloromethane once, merging organic phases, controlling temperature T not higher than 35 deg.c, concentrating under reduced pressure, adding n-heptane into the system, controlling temperature to 0-10 deg.c, crystallizing and suction filtering.
7. A process for the preparation of a sildenafil intermediate according to claim 2, characterized in that the post-treatment of step 3) is: after the reaction is finished, the system is heated to 0-20 ℃, dichloromethane is used for extraction, the organic phases are combined and then washed for 1 time, the temperature T is less than or equal to 35 ℃, the pressure is reduced and concentrated to 1/5-1/4 of the original volume, n-heptane is added, the temperature is controlled to 0-20 ℃, and crystallization is carried out, so that the compound of the formula 4 is obtained.
8. The process for preparing a sildenafil intermediate according to any one of claims 2 to 7, wherein the base of step 4) is one or more of sodium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, lithium hydroxide; the reaction time is 15-30 h.
9. A process for the preparation of a sildenafil intermediate according to any one of claims 2 to 7, characterized in that the post-treatment of step 4) is: distilling under reduced pressure until the volume is 1/4-1/3 of the volume, adding water 3-5 times the mass of the compound of formula 4, controlling the temperature to 0-10 ℃, adjusting the pH to 6.5-7.5 by acid, crystallizing, and filtering by suction to obtain 2-ethoxy-5- (4-methylpiperazine-1-ylsulfonyl) benzoic acid.
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