CN112209879A - Sildenafil impurity and preparation method and application thereof - Google Patents

Sildenafil impurity and preparation method and application thereof Download PDF

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Publication number
CN112209879A
CN112209879A CN202011120239.4A CN202011120239A CN112209879A CN 112209879 A CN112209879 A CN 112209879A CN 202011120239 A CN202011120239 A CN 202011120239A CN 112209879 A CN112209879 A CN 112209879A
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sildenafil
impurity
preparation
organic phase
reaction
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马春艳
封淑华
段琼
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Hebei Institute Of Drug And Medical Device Inspection
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Hebei Institute Of Drug And Medical Device Inspection
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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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N24/00—Investigating or analyzing materials by the use of nuclear magnetic resonance, electron paramagnetic resonance or other spin effects
    • G01N24/08—Investigating or analyzing materials by the use of nuclear magnetic resonance, electron paramagnetic resonance or other spin effects by using nuclear magnetic resonance
    • G01N24/087—Structure determination of a chemical compound, e.g. of a biomolecule such as a protein
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/62—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating the ionisation of gases, e.g. aerosols; by investigating electric discharges, e.g. emission of cathode

Abstract

The invention relates to the technical field of chemical synthesis, and particularly discloses a sildenafil impurity and a preparation method and application thereof. The sildenafil impurity is shown as a formula 1, and the preparation method comprises the following steps: adding 4- (2-ethoxy phenyl formamido) -1-methyl-3-propyl pyrazole-5-formamide and a dehydrating agent into a solvent, heating and refluxing, carrying out quenching reaction after the reaction is completed, collecting an organic phase, and concentrating and crystallizing the organic phase to obtain the sildenafil impurity which can be used as a standard product for detecting the content of related substances of the sildenafil. The invention provides a new reference substance for detecting impurities in sildenafil intermediates and sildenafil products, and is more beneficial to fully detecting the sildenafil impurities, thereby controlling the quality of the sildenafil products.

Description

Sildenafil impurity and preparation method and application thereof
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a sildenafil impurity and a preparation method and application thereof.
Background
Sildenafil citrate was developed by Pfizer and approved by the U.S. Food and Drug Administration (FDA) for marketing at 27/3 of 1998 for use in the treatment of male Erectile Dysfunction (ED). Sildenafil citrate is marketed in China in 2000 and 7 months, brings gospel to thousands of ED patients worldwide, and becomes an absolute monopoly of the ED drug market.
The existing sildenafil synthesis routes are of two kinds, wherein the first route is as follows: after the intermediate (I) is prepared by condensing the intermediate 4-amino-1-methyl-3-n-propylpyrazole-5-formamide and o-ethoxybenzoic acid, the ring is closed to generate a pyrimidine ring, and then sulfonamide is introduced to generate a target product sildenafil, wherein the specific synthetic route is as follows:
Figure BDA0002731780020000011
the second route is as follows: after the intermediate 4-amino-1-methyl-3-n-propyl pyrazole-5-formamide is condensed with o-ethoxybenzoic acid to prepare an intermediate (I), sulfonamide is firstly introduced, and then ring closure is carried out to generate a pyrimidine ring, so that a target product sildenafil is finally obtained, wherein the specific synthetic route is as follows:
Figure BDA0002731780020000021
in the two sildenafil synthesis routes, 4-amino-1-methyl-3-n-propylpyrazole-5-formamide and o-ethoxybenzoyl chloride are condensed to prepare the key intermediate (I), and the intermediate (I) generates impurities in the subsequent reaction process, and the impurities are introduced into the next reaction and finally affect the quality of sildenafil products. Therefore, how to better monitor the purity of sildenafil intermediate (i) during the synthesis and the content of this impurity produced by it is critical to control sildenafil. However, no corresponding standards for the new impurities produced by this intermediate (I) are currently available for monitoring and judging them.
Disclosure of Invention
Aiming at the problem that no corresponding standard substance is used for monitoring and judging new impurities generated by a sildenafil intermediate (I) in the existing sildenafil synthesis process, the invention provides sildenafil impurities and a preparation method and application thereof.
In order to achieve the purpose of the invention, the embodiment of the invention adopts the following technical scheme:
a sildenafil impurity of the formula:
Figure BDA0002731780020000022
the sildenafil impurity provided by the invention provides a new reference substance for detecting impurities in sildenafil intermediates (I) and sildenafil products, and is beneficial to fully detecting the sildenafil impurity so as to control the quality of the sildenafil products.
The invention also provides a preparation method of the sildenafil impurity. The preparation method comprises the following steps: adding 4- (2-ethoxy phenyl formamido) -1-methyl-3-propyl pyrazole-5-formamide and a dehydrating agent into a solvent, heating and refluxing, carrying out quenching reaction after complete reaction, collecting an organic phase, and concentrating and crystallizing the organic phase to obtain sildenafil impurities;
the mass ratio of the 4- (2-ethoxy phenyl formamido) -1-methyl-3-propyl pyrazole-5-formamide to the dehydrating agent is 1: 2-2.5; 10-20ml of the solvent is added per gram of the 4- (2-ethoxyphenylcarboxamido) -1-methyl-3-propylpyrazole-5-carboxamide.
According to the preparation method of the sildenafil impurity, 4- (2-ethoxy phenyl formamido) -1-methyl-3-propyl pyrazole-5-formamide is adopted as a raw material in the preparation process, and is subjected to dehydration reaction with a dehydrating agent and a specific solvent under the condition of heating and refluxing, so that the reaction selectivity can be remarkably improved, the conversion of the reaction to the positive direction is facilitated, the yield of the sildenafil impurity is increased, the high-purity and high-quality sildenafil impurity is favorably obtained through subsequent concentration and crystallization steps, and a high-quality standard product is provided for the sildenafil quality judgment. However, in the research process, the reaction raw materials are difficult to convert into the sildenafil impurities in the preparation process of the sildenafil impurities, so that the reaction is easy to generate the phenomenon of large amount of residual raw materials, and the dosage of the dehydrating agent and the solvent is very critical to the full conversion of the raw materials.
Preferably, the dehydrating agent is P2O5、POCl3、PCl5At least one of concentrated sulfuric acid, thionyl chloride, EDC, DCC, DIC, trifluoroacetic anhydride, methanesulfonyl chloride and titanium tetrachloride.
Preferably, the dehydrating agent is P2O5、POCl3、PCl5And thionyl chloride.
The preferable type of the dehydrating agent can further improve the yield of sildenafil impurities.
Preferably, the solvent is at least one of dichloromethane, chloroform, tetrahydrofuran, toluene, dimethyl sulfoxide, 1, 4-dioxane, ethyl acetate, n-hexane and DMF.
Preferably, the solvent is at least one of dichloromethane, chloroform and toluene.
The preferred type of dehydrating agent can further improve the purity and yield of sildenafil impurities.
Preferably, the temperature of the quenching reaction is-10-40 ℃.
Preferably, the temperature of the quenching reaction is 0-20 ℃.
Preferably, the crystallization method is as follows: and adding a poor solvent into the concentrated organic phase for crystallization, wherein the addition amount of the poor solvent is 4-6 times of the volume of the organic phase, and the poor solvent is at least one of methanol, ethanol, isopropanol and propanol.
Preferably, the poor solvent is one or a combination of two of ethanol and methanol.
The preferred poor solvent can further improve the purity and yield of sildenafil impurities.
The invention also provides application of the sildenafil impurity as a reference substance in sildenafil related substance detection.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1
10g of 4- (2-ethoxyphenylcarboxamido) -1-methyl-3-propylpyrazole-5-carboxamide and 20g of P2O5Adding into a three-necked flask containing 130ml of dichloromethane, heating to reflux for reaction, after the reaction is completed (the reaction reaches equilibrium), pouring the reaction solution obtained by the reaction into 500ml of ice water under the condition of stirring for quenching reaction, stirring in the ice water for 20min, and separating and collecting an organic phase. The collected organic phase was dried by adding anhydrous magnesium sulfate, and then decolorized by adding activated carbon. And (3) carrying out suction filtration on the decolored organic phase, concentrating to 30ml, adding 150ml of methanol into the concentrated organic phase for crystallization, carrying out suction filtration and vacuum drying after crystallization is finished, and obtaining 3.6g of sildenafil impurity, wherein the purity is 98.6% and the yield is 36%.
[M+H]+313.17；1HNMR(δ-DMSO):δ0.91(t,3H),1.43(t,3H),1.63(h,3H),2.57(t,3H),3.96(s,3H),4.21(q,2H),7.08(m,1H),7.19(m,1H),7.52(m,1H),7.75(m,1H),9.83(s,1H)。
Example 2
10g of 4- (2-ethoxyphenylcarboxamido) -1-methyl-3-propylpyrazole-5-carboxamide and 20g of POCl3Adding into a three-necked flask containing 100ml of chloroform, heating to reflux for reaction, after the reaction is completed (the reaction reaches equilibrium), pouring the reaction solution obtained by the reaction into 500ml of ice water under the condition of stirring for quenching reaction, stirring in the ice water for 20min, and separating and collecting an organic phase. The collected organic phase was dried by adding anhydrous magnesium sulfate, and then decolorized by adding activated carbon. And (3) carrying out suction filtration on the decolored organic phase, concentrating to 28ml, adding 120ml of ethanol into the concentrated organic phase for crystallization, carrying out suction filtration and vacuum drying after crystallization is finished to obtain 3.4g of sildenafil impurity, wherein the purity is 98.8% and the yield is 34%.
Example 3
10g of 4- (2-ethoxyphenylcarboxamido) -1-methyl-3-propylpyrazole-5-carboxamide and 25g of PCl5Adding into a three-neck flask containing 200ml of toluene, and heating to refluxAnd (3) carrying out reaction under the condition of complete reaction (the reaction reaches equilibrium), pouring the reaction liquid obtained by the reaction into 500ml of ice water under the condition of stirring for quenching reaction, stirring in the ice water for 20min, and separating and collecting an organic phase. The collected organic phase was dried by adding anhydrous magnesium sulfate, and then decolorized by adding activated carbon. And (3) carrying out suction filtration on the decolored organic phase, concentrating to 35ml, adding 210ml of methanol into the concentrated organic phase for crystallization, carrying out suction filtration and vacuum drying after crystallization is finished to obtain 3.9g of sildenafil impurity, wherein the purity is 98.2% and the yield is 39%.
Example 4
10g of 4- (2-ethoxyphenylcarboxamido) -1-methyl-3-propylpyrazole-5-carboxamide and 25g of PCl5Adding the mixture into a three-necked bottle filled with 200ml of toluene, heating to reflux for reaction, pouring the reaction liquid obtained by the reaction into 500ml of ice water under the condition of stirring for quenching reaction after the reaction is completed (the reaction reaches the equilibrium), stirring in the ice water for 20min, and separating and collecting an organic phase. The collected organic phase was dried by adding anhydrous magnesium sulfate, and then decolorized by adding activated carbon. And (3) carrying out suction filtration on the decolored organic phase, concentrating to 35ml, adding 210ml of methanol into the concentrated organic phase for crystallization, carrying out suction filtration and vacuum drying after crystallization is finished to obtain 3.9g of sildenafil impurity, wherein the purity is 98.2% and the yield is 39%.
Example 5
Adding 10g of 4- (2-ethoxyphenylformamido) -1-methyl-3-propylpyrazole-5-formamide and 25g of thionyl chloride into a three-necked flask containing 200ml of tetrahydrofuran, heating to reflux for reaction, after the reaction is completed (the reaction reaches equilibrium), pouring reaction liquid obtained by the reaction into 500ml of ice water under the stirring condition for quenching reaction, stirring in the ice water for 20min, and separating and collecting an organic phase. The collected organic phase was dried by adding anhydrous magnesium sulfate, and then decolorized by adding activated carbon. And (3) carrying out suction filtration on the decolored organic phase, concentrating to 32ml, adding 160ml of methanol into the concentrated organic phase for crystallization, carrying out suction filtration and vacuum drying after crystallization is finished, and obtaining 3.4g of sildenafil impurity, wherein the purity is 98.6% and the yield is 34%.
Example 6
Adding 10g of 4- (2-ethoxyphenylcarboxamido) -1-methyl-3-propylpyrazole-5-formamide and 25g of EDC into a three-necked flask filled with 200ml of ethyl acetate, heating to reflux for reaction, after the reaction is completed (the reaction reaches equilibrium), pouring the reaction solution obtained by the reaction into 500ml of ice water under the stirring condition for quenching reaction, stirring in the ice water for 20min, and separating and collecting an organic phase. The collected organic phase was dried by adding anhydrous magnesium sulfate, and then decolorized by adding activated carbon. And (3) carrying out suction filtration on the decolored organic phase, concentrating to 30ml, adding 150ml of propanol into the concentrated organic phase for crystallization, carrying out suction filtration and vacuum drying after crystallization is finished to obtain 3.0g of sildenafil impurity, wherein the purity is 98.5% and the yield is 30%.
Example 7
Adding 10g of 4- (2-ethoxyphenylformamido) -1-methyl-3-propylpyrazole-5-formamide and 25g of methanesulfonyl chloride into a three-necked flask containing 200ml of dimethyl sulfoxide, heating to reflux for reaction, after the reaction is completed (the reaction reaches equilibrium), pouring reaction liquid obtained by the reaction into 500ml of ice water under the stirring condition for quenching reaction, stirring in the ice water for 20min, and separating and collecting an organic phase. The collected organic phase was dried by adding anhydrous magnesium sulfate, and then decolorized by adding activated carbon. And (3) carrying out suction filtration on the decolored organic phase, concentrating to 25ml, adding 140ml of isopropanol into the concentrated organic phase for crystallization, carrying out suction filtration and vacuum drying after crystallization is finished to obtain 2.8g of sildenafil impurity, wherein the purity is 98.7% and the yield is 28%.
The sildenafil impurities obtained in examples 2-7 were subjected to the same mass spectrometry and nuclear magnetic characterization as in example 1, and the successful preparation of the target product was confirmed.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents or improvements made within the spirit and principle of the present invention should be included in the scope of the present invention.

Claims (10)

1. A sildenafil impurity characterized by: the sildenafil impurity has the following structural formula:
Figure FDA0002731780010000011
2. a process for the preparation of sildenafil impurities according to claim 1, characterized in that: adding 4- (2-ethoxy phenyl formamido) -1-methyl-3-propyl pyrazole-5-formamide and a dehydrating agent into a solvent, heating and refluxing, carrying out quenching reaction after complete reaction, collecting an organic phase, and concentrating and crystallizing the organic phase to obtain the sildenafil impurity;
the mass ratio of the 4- (2-ethoxy phenyl formamido) -1-methyl-3-propyl pyrazole-5-formamide to the dehydrating agent is 1: 2-2.5; adding 10-20ml of the solvent into each gram of the 4- (2-ethoxy phenyl formamido) -1-methyl-3-propyl pyrazole-5-formamide.
3. A process for the preparation of sildenafil impurity according to claim 2, characterized in that: the dehydrating agent is P2O5、POCl3、PCl5At least one of concentrated sulfuric acid, thionyl chloride, EDC, DCC, DIC, trifluoroacetic anhydride, methanesulfonyl chloride and titanium tetrachloride; and/or
The solvent is at least one of dichloromethane, chloroform, tetrahydrofuran, toluene, dimethyl sulfoxide, 1, 4-dioxane, ethyl acetate, n-hexane and DMF.
4. A process for the preparation of sildenafil impurity according to claim 3, characterized in that: the dehydrating agent is P2O5、POCl3、PCl5And thionyl chloride.
5. A process for the preparation of sildenafil impurity according to claim 3, characterized in that: the solvent is at least one of dichloromethane, chloroform and toluene.
6. A process for the preparation of sildenafil impurity according to claim 2, characterized in that: the temperature of the quenching reaction is-10-40 ℃.
7. The process for preparing sildenafil impurities according to claim 6, wherein: the temperature of the quenching reaction is 0-20 ℃.
8. A process for the preparation of sildenafil impurity according to claim 2, characterized in that: the crystallization method comprises the following steps: and adding a poor solvent into the concentrated organic phase for crystallization, wherein the addition amount of the poor solvent is 4-6 times of the volume of the organic phase, and the poor solvent is at least one of methanol, ethanol, isopropanol and propanol.
9. A process for the preparation of sildenafil impurity according to claim 8, characterized in that: the poor solvent is at least one of ethanol and methanol.
10. Use of the sildenafil impurity of claim 1 as a control in the detection of sildenafil-related substances.
CN202011120239.4A 2020-10-19 2020-10-19 Sildenafil impurity and preparation method and application thereof Pending CN112209879A (en)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102690273A (en) * 2012-06-07 2012-09-26 杭州奥默医药技术有限公司 Preparation method of sildenafil
CN105753870A (en) * 2016-04-01 2016-07-13 重庆康刻尔制药有限公司 Sildenafil impurity F and preparing method and application thereof
CN105837578A (en) * 2016-04-05 2016-08-10 重庆康刻尔制药有限公司 Synthesis method of sildenafil impurity D
CN109081810A (en) * 2018-09-20 2018-12-25 沈阳药科大学 The synthetic method of 1- methyl-3-((methylamino) methyl)-1H- pyrazoles-5- nitrile
CN111362967A (en) * 2020-04-28 2020-07-03 南京雷正医药科技有限公司 Benzoxadiazatetetradecene derivatives and use thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102690273A (en) * 2012-06-07 2012-09-26 杭州奥默医药技术有限公司 Preparation method of sildenafil
CN105753870A (en) * 2016-04-01 2016-07-13 重庆康刻尔制药有限公司 Sildenafil impurity F and preparing method and application thereof
CN105837578A (en) * 2016-04-05 2016-08-10 重庆康刻尔制药有限公司 Synthesis method of sildenafil impurity D
CN109081810A (en) * 2018-09-20 2018-12-25 沈阳药科大学 The synthetic method of 1- methyl-3-((methylamino) methyl)-1H- pyrazoles-5- nitrile
CN111362967A (en) * 2020-04-28 2020-07-03 南京雷正医药科技有限公司 Benzoxadiazatetetradecene derivatives and use thereof

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Application publication date: 20210112