CN112608317A - Sildenafil citrate preparation method - Google Patents
Sildenafil citrate preparation method Download PDFInfo
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- CN112608317A CN112608317A CN202011477773.0A CN202011477773A CN112608317A CN 112608317 A CN112608317 A CN 112608317A CN 202011477773 A CN202011477773 A CN 202011477773A CN 112608317 A CN112608317 A CN 112608317A
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- intermediate compound
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/38—Nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/38—Nitrogen atoms
- C07D231/40—Acylated on said nitrogen atom
Abstract
The invention discloses a preparation method of sildenafil, which comprises the steps of activating an intermediate compound B in an aprotic solvent by using thionyl chloride, and then condensing the intermediate compound B with 1-methyl-4-nitro-3-propyl-1H-pyrazole-5 formamide in a zinc powder-ammonium chloride system in the presence of an acid-binding agent to prepare an intermediate compound E through reduction to obtain an intermediate compound C; and (3) in an alcohol solvent, carrying out ring closure on the intermediate compound C under an alkaline condition to prepare the sildenafil. The preparation method disclosed by the invention has the advantages of short reaction time, greatly reduced production period, reduced production cost, simple operation and capability of large-scale production.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of sildenafil.
Background
Sildenafil is an oral drug for treating male erectile dysfunction. The action target is phosphodiesterase type 5 (PDE5), can effectively inhibit the activity of phosphodiesterase V in vitro, prevent cGMP and cAMP from being hydrolyzed to generate corresponding 5-monophosphate nucleotide, improve the concentration of cGMP between tissues and inhibit the relaxation of smooth muscle, thereby achieving the effect of treating sexual dysfunction. The former research corporation is the american pfeiri corporation, approved by the U.S. FDA in 1998, and is an oral drug for the treatment of male sexual dysfunction.
Peverine patent CN1149206C discloses an industrial synthesis method of a compound B07-D, in particular a method for preparing B07-D by ring closure of B07-C under alkaline, neutral or acidic conditions; document org.Process Res.Dev.2000,4,17-22 further discloses that o-ethoxybenzoic acid (B07-SM1) is used as a starting material, B07-A is prepared in chlorosulfonic acid and thionyl chloride, B07-A is condensed with N-methylpiperazine to obtain B07-B, B07-B is added into ethyl acetate, carbonyldiimidazole is added for half an hour and heated to 55 ℃, the mixture is refluxed for 2 hours for activation, cooled to 27 ℃, then reacted with another amino side chain B07-E free base in triethylamine as an acid-binding agent for 70 hours at room temperature, a part of product B07-C is obtained by filtering, and mother liquor is continuously concentrated to obtain a second part of product B07-C; the intermediate B07-C is subjected to ring closure in a solvent of tert-butyl alcohol under the alkaline condition of potassium tert-butoxide to prepare sildenafil; the prior art US5250534A discloses that a side chain (B07-E) adopts stannous chloride ethanol to reduce nitro, 2N sodium hydroxide is adopted for adjusting the pH value to 9.0 in the post-treatment, and dichloromethane of up to 130ml/g is adopted for extraction, and the method has the problems that the consumption of a treatment solvent dichloromethane after the reaction is large, the extraction is easy to emulsify, and tin heavy metal is inevitably introduced; the document org.process res.dev.2000,4,17-22 adopts ethyl acetate as solvent for palladium hydrogenation reduction, the method has the main problems that special hydrogenation equipment is needed in production, serious potential safety hazards exist, a large amount of impurities and unreduced intermediate state are introduced after palladium hydrogenation, most of the impurities are genetic toxic impurities with warning structures, and effective removal means is not available, so that the safety risk of the medicine is increased; in the condensation reaction of B07-C, B07-C is precipitated twice, so that the problem of inconsistent product quality cannot be avoided; carbonyl diimidazole is used as a condensing agent, B07-C contains a large amount of imidazole impurities, and meanwhile, imidazole related quality standards are required to be established in raw material medicines; meanwhile, the reaction time is as long as 70 hours, so that the production period is longer and the production cost is greatly increased.
Disclosure of Invention
The invention provides a preparation method of sildenafil, which avoids the use of special hydrogenation equipment, has simple post-treatment and short production period and is more suitable for industrial production.
The invention provides a preparation method of sildenafil, which comprises the following steps:
step 110: reducing 1-methyl-4-nitro-3-propyl-1H-pyrazole-5 formamide by adopting zinc powder and ammonium chloride in aqueous ethanol, and salifying with acid to obtain an intermediate compound E acid salt;
step 120: activating the intermediate compound B in an aprotic solvent by using thionyl chloride, adding the intermediate compound E acid salt prepared in the step 110, dropwise adding an acid-binding agent, and obtaining an intermediate compound C after dropwise adding;
step 130: 120, performing a ring closing reaction on the intermediate compound C in a lower alkyl alcohol solvent under an alkaline condition to prepare sildenafil;
in the above embodiment of the present invention, the molar ratio of 1-methyl-4-nitro-3-propyl-1H-pyrazole-5-carboxamide to zinc powder and ammonium chloride in step 110 is:
1-methyl-4-nitro 3-propyl-1H-pyrazole-5-carboxamide: zinc powder: the molar ratio of ammonium chloride is 1 (12+ X) to (10+ Y), wherein X and Y are each independently 0 or a number greater than 0.
In the above embodiment, the acid in step 110 is hydrochloric acid, sulfuric acid, oxalic acid, or citric acid, preferably hydrochloric acid.
In the above embodiment, the aqueous ethanol in step 110 is 75% to 98% by weight of aqueous ethanol, preferably 94.2% aqueous ethanol.
In the above embodiment, the acid scavenger for the reaction in step 120 is one or a mixture of two of triethylamine and pyridine.
The beneficial results of the invention are:
the preparation method of sildenafil provided by the invention avoids the use of special hydrogenation equipment, is simple in post-treatment, and simultaneously has short condensation reaction time of an intermediate compound C, wherein the reaction time is 70 hours, and the reaction time is 2.5 hours when carbonyl diimidazole is activated as reported in org. Process Res. Dev.2000,4, 17-22; the activation time of the invention is 2 hours, the time of dripping the acid-binding agent in the condensation reaction is generally 1-3 hours, and the reaction is finished after the dripping is finished, thereby greatly shortening the production period and being applicable to commercial production.
Detailed Description
The following examples further illustrate the invention, but the scope of the invention is not limited thereto.
Comparative example 1 preparation of intermediate Compound C
Process res.dev.2000,4,17-22 intermediate compound C preparation process according to document org.process res.dev.2000: adding 12.2g of intermediate compound B12 and 86mL of ethyl acetate into a 250mL reaction bottle, adding 6.8g of CDI, heating to 55 ℃, preserving the temperature for 0.5 hour, refluxing for 2 hours, cooling to 27 ℃, adding 6.8g of intermediate compound E, dissolving in 71mL of ethyl acetate solution, reacting for 70 hours at room temperature, and detecting by TLC (thin layer chromatography), wherein the detection conditions are as follows: ultraviolet color development; the developing agent is 2ml dichloromethane and methanol with the volume ratio of 10:1, 2 drops of glacial acetic acid mixed system are dripped, a large amount of raw material intermediate compound E and intermediate compound B are remained, a filter cake TLC is detected to be intermediate compound B, the intermediate compound B is dried under reduced pressure to obtain 4.9656g, and the intermediate compound B is recovered by 40.7%.
Comparative example 2 preparation of intermediate Compound E
Intermediate compound E was prepared according to the procedure reported in US 5250534A: adding 10.0g of 1-methyl-4-nitro-3-propyl-1H-pyrazole-5 formamide into a reaction bottle, adding 50ml of absolute ethyl alcohol, adding SnCl2.2H2And (3) 53.0g of O, heating up, carrying out reflux reaction for 2 hours, sampling 10% sodium hydroxide, neutralizing, detecting, completely reacting the raw materials, wherein the detection purity of the intermediate compound E is 90.7%, cooling to 25 ℃, dropwise adding 10% sodium hydroxide, neutralizing pH to 8-9, adding 150ml of dichloromethane, stirring, extracting, wherein the system is a solid-liquid phase, filtering is very slow, no liquid separation is observed in the filtrate, directly concentrating the filtrate under reduced pressure, and treating the whole system as a waste liquid, wherein the whole system is dark reddish brown and has a darker color.
The detection conditions for HPLC were as follows:
a chromatographic column: agilent ZORBAX Eclipse XDB-C18, 250X 4.6mm, 5.0 μm, flow rate: 1.0ml/min, detection wavelength: 230nm, column temperature: 35 ℃, sample introduction: 10 μ l.
Mobile phase B: acetonitrile; mobile phase A: 0.1% aqueous phosphoric acid (triethylamine adjusted to pH 3.5) was subjected to gradient elution according to the following table:
| time (minutes) | A(％) | B(％) |
| 0 | 85 | 15 |
| 20 | 65 | 35 |
| 35 | 30 | 70 |
| 45 | 30 | 70 |
| 46 | 85 | 15 |
| 55 | 85 | 15 |
。
Comparative example 3 preparation of intermediate Compound E
Intermediate compound E was prepared according to the method of document org.process res.dev.2000,4, 17-22: adding 23.77g of 1-methyl-4-nitro-3-propyl-1H-pyrazole-5 formamide into a reaction bottle, adding 200mL of ethyl acetate, adding 4.75 g of 5% palladium carbon, heating to 50 ℃, reacting for 4 hours under the pressure of 50psi, stopping hydrogen absorption of the system, sampling, detecting by HPLC, reducing the temperature, filtering, and washing a filter cake by ethyl acetate to obtain an E free base ethyl acetate solution.
Preparative example 1 preparation of intermediate Compound A
Adding 683.68g of chlorosulfonic acid and 231.96g of thionyl chloride into a 2L four-mouth reaction bottle, dropwise adding 300.00g of o-ethoxybenzoic acid at the temperature of 15-25 ℃ after adding, reacting for 8 hours at the temperature of 15-25 ℃ after dropwise adding, adding 1500ml of tap water into another 3L three-mouth reaction bottle, cooling to 10-15 ℃, dropwise adding the reaction solution into the system, and controlling the dropwise adding temperature to be not more than 20 ℃; after dripping, stirring for 1-3h, filtering, soaking and washing the filter cake for 2 times with tap water, each time 450ml, and pumping to dry to obtain a wet product of the intermediate compound A of the filter cake, which is directly used for the next reaction.
Preparative example 2 Synthesis of intermediate B
Adding a wet intermediate compound A prepared in example 1 into a 2L four-mouth reaction bottle, adding 1175ml of purified water, cooling to 0-10 ℃, dropwise adding 163.20g of N-methylpiperazine, continuously maintaining the temperature range, dropwise adding a 20% sodium hydroxide solution prepared in advance, adjusting the pH of the system to be neutral, continuously maintaining the temperature range at 0-10 ℃ after dropwise adding, keeping the temperature for 1-3h, filtering, and washing a filter cake with 390ml of purified water; adding the wet product in the previous step into a 1L reaction bottle, adding 780ml of purified water, heating to 75-85 ℃ for dissolving, cooling to 0-20 ℃, controlling the temperature range, keeping the temperature for 1-4h, filtering, washing a filter cake with 390ml of pure water, drying the filter cake at 60-70 ℃ to constant weight, and obtaining the yield of 80% (based on 2-ethoxybenzoic acid).
EXAMPLE 1 preparation of intermediate Compound E
Adding 1-methyl-4-nitro-3-propyl-1H-pyrazole-5 formamide, 95% ethanol (10.34g/g) and ammonium chloride (10.0eq) into a reaction bottle under the protection of nitrogen, controlling the temperature to be-20-10 ℃, adding zinc powder (12.0eq) in batches, controlling the temperature to be 0-10 ℃ after adding, reacting for 4.5 hours, filtering, washing a filter cake with 3.94g/g absolute ethanol, controlling the temperature of a filtrate to be 20-30 ℃, dropwise adding 30.2% hydrogen chloride ethanol solution (1.0eq) into the filtrate to form salt for 1.0 hour, filtering, washing the filter cake with absolute ethanol for 2 times, each time for 2.6g/g, drying the filter cake at 40-50 ℃ under the vacuum degree of not less than-0.09 MPa to obtain a white crystalline solid intermediate compound E, wherein the yield is 90.0% and the purity is 99.9%;
EXAMPLE 2 preparation of intermediate Compound E
Under the protection of nitrogen, 50.00g of 1-methyl-4-nitro 3-propyl-1H-pyrazole-5 formamide, 75% ethanol (10.34g/g) and ammonium chloride (10.0eq) are added into a reaction bottle, zinc powder (13.0eq) is added in batches at the temperature of minus 20 to 10 ℃, the temperature is controlled to be 0 to 10 ℃ after the addition is finished, the reaction is carried out for 4.5H, the filter cake is filtered, the filter cake is washed by 3.94g/g of absolute ethanol, the temperature of the filtrate is controlled to be 20 to 30 ℃, oxalic acid ethanol solution (1.0eq) is dripped to form salt for 1.0H, the filter cake is filtered, the filter cake is washed by absolute ethanol for 2 times, 2.0g/g each time, the filter cake is dried at the temperature of 40 to 50 ℃, the vacuum degree is not lower than minus 0.09Mpa, and a white crystalline solid intermediate compound E.
EXAMPLE 3 preparation of intermediate Compound E
Under the protection of nitrogen, 50.00g of 1-methyl-4-nitro 3-propyl-1H-pyrazole-5 formamide, 98% ethanol (10.00g/g) and ammonium chloride (13.0eq) are added into a reaction bottle, zinc powder (13.0eq) is added in batches at the temperature of minus 20 to 10 ℃, the temperature is controlled to be 0 to 10 ℃ after the addition is finished, the reaction is carried out for 4.5H, the filter cake is filtered, the filter cake is washed by 4.00g/g of absolute ethanol, the temperature of the filtrate is controlled to be 20 to 30 ℃, oxalic acid ethanol solution (1.0eq) is dripped to form salt for 1.0H, the filter cake is filtered, the filter cake is washed by absolute ethanol for 2 times, 2.0g/g each time, the filter cake is dried at the temperature of 40 to 50 ℃, the vacuum degree is not lower than minus 0.09Mpa, and a white crystalline solid intermediate compound E.
EXAMPLE 4 preparation of intermediate Compound C
Under the protection of nitrogen, 195.57g of intermediate compound B and 480ml of dichloromethane are added into a 2L four-mouth reaction bottle, the temperature is controlled to be 15-30 ℃, 80.53g of thionyl chloride is dropwise added, after dropwise addition, activation is carried out for 2h, after reduced pressure distillation of a solvent, 1466ml of dichloromethane is added, stirring and dissolving are carried out, the temperature is reduced to be 0-20 ℃, 65.08g of intermediate compound E prepared in example 3 is added, the temperature is controlled to be 0-20 ℃, 90.37g of triethylamine is dropwise added, after dropwise TLC detection, raw materials are completely reacted, saturated sodium bicarbonate solution is added for washing for 2 times, 480ml of purified water is added for washing for 1 time, after organic phase separation, the mixture is transferred into a 3L reaction bottle, the temperature is reduced to be 10-20 ℃, 1466ml of n-heptane is dropwise added, after dropwise addition, the temperature is kept for 2h at: washing with a mixed solvent with the volume ratio of dichloromethane of 1:1, drying by pumping, and drying a filter cake at 60-70 ℃ and under a vacuum degree of not less than-0.09 MPa under reduced pressure to obtain an intermediate compound C with a yield of 95%.
EXAMPLE 5 preparation of intermediate Compound C
Under the protection of nitrogen, 195.00g of intermediate compound B and 480ml of dichloromethane are added into a 2L four-mouth reaction bottle, the temperature is controlled to be 15-30 ℃, 80.41g of thionyl chloride is dropwise added, after dropwise addition, activation is carried out for 2h, after vacuum distillation of a solvent, 1000ml of dichloromethane is added, stirring and dissolving are carried out, the temperature is reduced to be 0-20 ℃, 65.02g of intermediate compound E prepared in example 4 is added, the temperature is controlled to be 0-20 ℃, 70.37g of pyridine is dropwise added, after dropwise addition, TLC detection is completed, raw materials are completely reacted, saturated sodium bicarbonate solution is added for washing for 2 times, 480ml of purified water is added for washing for 1 time, after organic phase separation, the mixture is transferred into a 3L reaction bottle, the temperature is reduced to be 13 ℃, 1000ml of n-heptane is dropwise added, after dropwise addition, the temperature is kept for 2: washing with mixed solvent with dichloromethane volume ratio of 1:1, pumping to dry, and drying filter cake at 60-70 deg.C under vacuum degree of not less than-0.09 MPa to obtain intermediate B07-C with yield of 93%.
Example 6 preparation of sildenafil
Adding 110.02 g of the intermediate compound C prepared in the example 6 and 27.57g of potassium tert-butoxide into a 2L four-mouth reaction flask, adding 550ml of tert-butyl alcohol, heating and refluxing, reacting for 5h, cooling to 20-30 ℃, adding 550ml of purified water, controlling the temperature to 20-30 ℃, dropwise adding 3.0% hydrochloric acid to adjust the pH value to be neutral to alkalescence, filtering, and drying a filter cake at 60-70 ℃ under vacuum and reduced pressure to obtain sildenafil with the yield of 90%.
Finally, it is noted that the above-mentioned embodiments illustrate rather than limit the invention, and that, while the invention has been described with reference to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.
Claims (7)
1. A method for preparing sildenafil, comprising the steps of:
step 110: reducing 1-methyl-4-nitro-3-propyl-1H-pyrazole-5 formamide by adopting zinc powder and ammonium chloride in aqueous ethanol, and salifying with acid to obtain an intermediate compound E acid salt;
step 120: activating the intermediate compound B in an aprotic solvent by using thionyl chloride, adding the intermediate compound E acid salt prepared in the step 110, dropwise adding an acid-binding agent, and obtaining an intermediate compound C after dropwise adding;
step 130: 120, performing a ring closing reaction on the intermediate compound C in a lower alkyl alcohol solvent under an alkaline condition to prepare sildenafil;
2. the method according to claim 1, wherein the ratio of 1-methyl-4-nitro-3-propyl-1H-pyrazole-5-carboxamide in step 110: zinc powder: the molar ratio of ammonium chloride is 1 (12+ X): 10+ Y, wherein X and Y are each independently 0 or a value greater than 0, step 3) the proportion of zinc powder ammonium chloride is B07-SM 2: zinc powder: the molar ratio of ammonium chloride is 1 (12+ X) to (10+ Y), wherein X, Y is a value of 0 or more.
3. The method of claim 1, wherein the acid in step 110 is hydrochloric acid, sulfuric acid, oxalic acid, citric acid.
4. The method of claim 3, wherein the acid in step 110 is hydrochloric acid.
5. The method of any one of claims 1-4, wherein the aqueous ethanol in step 110 is 75% to 98% ethanol by weight.
6. The method of claim 5, wherein the aqueous ethanol in step 110 is 94.2% by weight.
7. The method of any one of claims 1 to 4, wherein the acid scavenger in step 120 is one or a mixture of triethylamine and pyridine.
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Cited By (1)
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| CN113754612A (en) * | 2021-10-26 | 2021-12-07 | 山东安舜制药有限公司 | Preparation method of sildenafil intermediate |
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