CN104530017A - Avanafil preparation method - Google Patents
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Abstract
The invention relates to an avanafil preparation method. The method comprises the steps that a hydrolysis reaction is carried out on 4-(3-chlorin-4-methoxy benzyl amino)-2-methylehio pyrimidine-5-carboxylic acid ethyl ester, namely a compound (2) to obtain 4-(3-chlorin-4-methylehio pyrimidine)-2-methylehio pyrimidine-5-carboxylic acid, namely a compound (6); an acylation reaction is carried out on the compound (6) and thionyl chloride, and then the product and 2-sulfadoxine-pyrimethamine or a salt of 2-sulfadoxine-pyrimethamine are condensed to obtain 4-(3-chlorin-4-methylehio pyrimidine)-2-methylehio pyrimidine-N-(2- pyrimidine methyl)-5-pyrimidine formamide, namely a compound (7); the compound (7) is oxidized by metachloroperbenzoic acid to obtain 4-(3-chlorin-4-methylehio pyrimidine)-2-methylsulfonyl pyrimidine-N-(2-pyrimidine methyl)-5-pyrimidine formamide, namely a compound (8), a nucleophilic substitution reaction is carried out on the compound (8) and L-prolinol to obtain avanafil. The method is low in cost, easy and convenient to operate, high in product purity, high in reaction yield and suitable for industrialization scale production.
Description
Technical field
The invention belongs to pharmaceutical synthesis field, particularly relate to the synthetic method of avanaphil.
Background technology
Avanaphil (Avanafil, commodity are called Stendra) be the medicine being used for the treatment of male erectile dysfunction of authorizing Vivus company of the U.S. to develop by Japanese Tanabe Mitsubishi Pharmaceutical Co, April 27 in 2012, the approval of Nikkei U.S. FDA was gone on the market in the U.S..Avanaphil is a kind of oral quick-acting highly selective phosphodiesterase-5 (PDE-5) inhibitor, is the fastest and product that side effect is minimum of taking effect in the similar drugs for the treatment of erectile disfunction (ED).Avanaphil (compound 1) Chinese chemical name: (S)-4-(3-chloro-4-methoxy benzyl is amino)-2-(2-methylol-1-pyrrolidyl)-N-(2-pyrimidine methyl)-5-pyrimidine carboxamide; English language Chemical title: (S)-4-[(3-chloro-4-methoxybenzyl) amino]-2-(2-hydroxymethyl-1-pyrrolidinyl)-N-(2-pyrimidinylmethyl)-5-pyrimidinecarboxamide; Molecular formula:
C
23h
26clN
7o
3; Molecular weight: 483.95; CAS registration number: 330784-47-9; Structural formula is as follows:
Tanabe Mitsubishi Pharmaceutical Co of Japan records the preparation method of avanaphil in patent CN201210006859.4, and reaction scheme is as follows:
The concrete steps of aforesaid method are:
(1) under ice-cooling, in compound 2, add chloroform, after stirring, add metachloroperbenzoic acid, washing, dry, revolve steaming after obtain compound 3 crude product;
(2) with after tetrahydrofuran (THF) dissolved compound 3 sample, L-dried meat ammonia alcohol and triethylamine is added, reaction overnight, reaction solution through washing, dry, revolve steaming and obtain residue, residue, by silica gel chromatography, with ether and normal hexane recrystallization, obtains compound 4;
(3) at room temperature agitate compounds 4 adds the aqueous sodium hydroxide solution of 10%, with the mixture recrystallization of tetrahydrofuran (THF) and ether, obtains compound 5;
(4) agitate compounds 5,2-amino methylpyrimidine, 1-(3-dimethylaminopropyl)-3-ethyl phosphinylidyne diimmonium salt hydrochlorate, I-hydroxybenzotriazole hydrate, N under normal temperature, dinethylformamide mixture eight hours, be extracted with ethyl acetate, salt water washing, anhydrous sodium sulfate drying, obtains compound 1 after purifying.
According to reaction and the yield calculating unit consumption of this patent application embodiment 1, with 4-(3-chloro-4-methoxy benzyl is amino)-5-ethoxy carbonyl-2-methylthiopyrimidine (compound 2) for raw material reaction, be divided into four steps, one or two step yield is 82.5%, 3rd step yield 82.5%, 4th step yield 79%, four step total recovery 53.8%.Analytic process sees table 1.
Table 1
As can be seen from Table 1, unit consumption is comparatively large by key intermediate 4-(3-chloro-4-methoxy benzyl is amino)-5-ethoxy carbonyl-2-methylthiopyrimidine price, so just accurate after finally should being set price by purchasing department.Do not consider that the price of solvent recuperation is 10211.5 yuan/kilogram, consider that the price of solvent recuperation (calculating by 70%) is 9758 yuan/kilogram.Therefore, there is shortcoming with high costs in this preparation method.
Except above-mentioned cost factor, the preparation method of patent CN201210006859.4 also also exists the shortcomings such as complicated operation, product purity are not high, reaction yield is low.Therefore, need to improve above-mentioned reaction scheme, to solve foregoing problems better.
Summary of the invention
The object of this invention is to provide a kind of preparation method of avanaphil, this preparation method comprises the following steps:
The first step, there is hydrolysis reaction and obtain 4-(3-chloro-4-methoxy benzyl is amino)-2-methylthiopyrimidine-5-carboxylic acid and compound (6) in 4-(3-chloro-4-methoxy benzyl is amino)-2-methylthiopyrimidine-5-carboxylic acid, ethyl ester and compound (2);
Second step, compound (6) and sulfur oxychloride carry out acylation reaction and obtain chloride product, then obtain 4-(3-chloro-4-methoxy benzyl is amino)-2-methylthiopyrimidine-N-(2-pyrimidine methyl)-5-pyrimidine carboxamide and compound (7) with 2-pyrimidine ethamine or its salt condensation;
3rd step; compound (7) metachloroperbenzoic acid oxidation obtains 4-(3-chloro-4-methoxy benzyl is amino)-2-methanesulfonyl pyrimidine-N-(2-pyrimidine methyl)-5-pyrimidine carboxamide and compound (8), and compound (8) and L-dried meat ammonia alcohol generation nucleophilic substitution reaction obtain avanaphil.
The first step is carried out in the basic conditions, and the hydrolysate generated under alkaline condition uses acid to be adjusted to pH<7.0.Wherein, alkaline reagents can organic bases or inorganic alkali solution.Preferably inorganic caustic solutions.Inorganic basis is as being common sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, sodium bicarbonate, Quilonum Retard, salt of wormwood etc.Hydrolysis reaction can carry out in the temperature range of 10-100 DEG C, is preferably 20-90 DEG C, more preferably 30-80 DEG C.The acid regulating pH to use is hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, nitric acid etc.
After hydrolysis reaction, also comprise following purification step: hydrolysate is filtered, use water and washing with alcohol, be dried to anhydrous.
Acylation reaction reflux under anhydrous inert solvent exists of second step.Heating temperature is 50-100 DEG C, is preferably 60-90 DEG C, is preferably 70-85 DEG C further.Anhydrous inert solvent is preferably toluene.
The condensation reaction of second step is carried out in the basic conditions.Wherein, alkaline reagents is preferably organic bases, such as triethylamine, pyridine, sodium methylate, potassium tert.-butoxide etc.The temperature of condensation reaction can be 0-50 DEG C, more preferably 10-40 DEG C, is more preferably and at room temperature carries out.
After condensation reaction, also comprise following purification step: except desolventizing, add the ethanol/water of 1:2, pull an oar under heating condition, suction filtration of then lowering the temperature, use the cold ethanol/water washing of 1:2, dry.
In the third step, the oxygenant that oxidizing reaction uses is metachloroperbenzoic acid (MCPBA).Those skilled in the art will recognize that other suitable oxygenant such as carboxylic acid peroxide or hydrogen peroxide equally can as the oxygenants of this reaction.The temperature of oxidizing reaction can be-10-40 DEG C, preferably 0-30 DEG C, is preferably 10-20 DEG C further.
The nucleophilic substitution reaction of the 3rd step carries out equally in the basic conditions.Wherein, alkaline reagents is preferably organic bases, such as triethylamine, pyridine, sodium methylate, potassium tert.-butoxide etc., preferably triethylamine.Nucleophilic substitution reaction temperature can be 0-60 DEG C, preferably 10-50 DEG C, is preferably 20-40 DEG C further.
After nucleophilic substitution reaction, also comprise following purification step: be separated organic phase, except desolventizing, add dehydrated alcohol backflow, after cooling, use ice washing with alcohol, dry.
For the reaction times of each step, usually there is not strict restriction.Those skilled in the art can pass through end point determination, judges whether raw material reacts completely; Such as high performance liquid chromatography (HPLC) can be passed through or thin-layer chromatography (TLC) carries out end point determination.Fully react as long as the reaction times meets raw material.
For the add-on of the raw material of each step, those skilled in the art know the theory reaction mol ratio between them.On this basis, as required, a certain reaction raw materials can suitably be adjusted excessive or less slightly.
Compared with prior art, the preparation method of avanaphil of the present invention has following beneficial effect:
(1) by each step reaction order of the preparation method of the existing avanaphil of adjustment, efficiently solve the problem of purification of intermediate and chiral centre racemization, and decrease the generation of by product and spent solvent, significantly reduce production cost.In addition, relative to prior art, also add a step acylation reaction, further increase reaction yield and product purity.
(2) in the preparation process in accordance with the present invention, when purify intermediates and product, do not use comparatively complicated pillar layer separation, only use the means such as recrystallization and washing, therefore, operate more easy, thus be more applicable to commercial scale production.
Embodiment
Further illustrate preparation method of the present invention as embodiment below, will contribute to further understanding of the invention, protection scope of the present invention is not limited to the examples, and its protection domain is decided by claims.
Embodiment 1
The first step is hydrolyzed
Its reaction formula is as follows:
Add in there-necked flask by 5g compound 2 (thioether), add 50g water, normal temperature (20 DEG C) drips 27% sodium hydroxide solution, is warming up to 90 DEG C, is heated to clearly molten.Clearly molten after 3.5h, system is faint yellow, be cooled to room temperature (20 DEG C), adjust pH to 4.0 with 10% hydrochloric acid, share 6g 10% hydrochloric acid (initial pH value is about 12.5), suction filtration after pH is stable, 25ml washes 3 times, 20ml ethanol washes 1 time, and 45 DEG C of vacuum-dryings, are dried to moisture <0.1%.The raw material of this step and charging capacity are see table 2.
Table 2
| Title | Charging capacity | Molecular weight | Mole number | Mol ratio |
| Thioether (compound 2) | 5g | 367.85 | 0.014 | 1 |
| Sodium hydroxide | 1.31g | 40.00 | 0.033 | 1.2 |
| Water (reaction is used) | 50ml | |||
| 10% hydrochloric acid | 6g |
Second step condensation
Its reaction formula is as follows:
Added in single port flask by 15g compound 6 (hydrolysis acid), add 150ml toluene, 12g sulfur oxychloride, system is molten unclear, system thickness.Oil bath 85 DEG C backflow 5h, subtract and steam to dry, add 125ml methylene dichloride, system is molten unclear, and system is faint yellow.Add 8.5g 2-amino methylpyrimidine hydrochloric acid hydrochlorate, molten unclear, drip 14g triethylamine, about 15min drips off (using frozen water control temperature), heat release has white cigarette, and color burn spends the night, system becomes off-white color, revolve and steam to dry, add ethanol water (1:2) 200ml, pull an oar 15 minutes for 50 DEG C, be cooled to 0 DEG C, suction filtration, cold ethanol water (1:2) washes twice 100ml*2, obtains white solid 34g, 45 DEG C of vacuum-dryings, 48h, obtains off-white color solid 18.1g, and HPLC product purity is 99.34%, moisture is 0.22%, and yield is 84%.The raw material of this step and charging capacity are see table 3.
Table 3
| Title | Charging capacity | Molecular weight | Mole number | Mol ratio |
| Hydrolysis acid (compound 6) | 15 | 339.80 | 0.044 | 1 |
| Sulfur oxychloride | 12g | 118.96 | 0.10 | 2 |
| 2-amino methylpyrimidine hydrochloric acid hydrochlorate | 8.5g | 145.59 | 0.058 | 1.15 |
| Triethylamine | 14g | 101.19 | 0.138 | |
| Toluene | 150ml |
3rd step oxidation, nucleophilic substitution
Its reaction formula is as follows:
Get the condensation product 5.0g that previous step is obtained, add 30ml methylene dichloride, be cooled to-10 DEG C, divide and drip MCBPA/DCM (2.5/15ml) solution six times, per half an hour drips once, after dripping for 5th time, system is clearly molten, add rear half an hour 6th time, HPLC raw material <0.1%, slow dropping 3.03g triethylamine, disposablely add 1.76gL-dried meat ammonia alcohol, be warming up to 20 DEG C, reaction 3h, sulfoxide purity is 15.68%, be warming up to 30 DEG C, reaction 1h, sulfoxide purity is 8.18%, add 0.3 equivalent L-dried meat ammonia alcohol, reaction is spent the night, HPLC does not detect raw material, 40ml water is added in system, separatory washing organic layer, 40ml*2, the 15g10%NaOH aqueous solution is added in organic layer, stirring at room temperature 15min, separatory, washing organic layer 40ml*2, anhydrous sodium sulfate dehydration, filter, 50ml dehydrated alcohol is added after being spin-dried for filtrate, 80 DEG C of backflows molten clear after, be cooled to 0 DEG C, suction filtration, 20ml*2 washed by ice ethanol, obtain white solid 6.75g, 45 DEG C of vacuum-drying 48h, obtain white solid 2.94g, HPLC purity is 98.67%.The raw material of this step and charging capacity are see table 4.
Table 4
| Title | Charging capacity | Molecular weight | Mole number | Mol ratio |
| Acid amides (compound 7) | 5.0g | 430.91 | 0.0116 | 1 |
| 87％mcpba | 2.5g | 172.57 | 0.0143 | 1.07 |
| L-dried meat ammonia alcohol | 1.76g | 101.15 | 0.021 | 1.8 |
| Triethylamine | 3.03g | 101.19 | 0.03 | |
| Dehydrated alcohol | 50ml | |||
| 10％NaOH | 15g | |||
| Methylene dichloride | 40ml |
Calculated by project, the product price of embodiment 1 is 6786 yuan, and therefore, the production cost of preparation method of the present invention is more cheap.And the product purity that preparation method of the present invention obtains is higher, yield is also higher.
The foregoing is only the preferred embodiments of the present invention, be not limited to the present invention, for a person skilled in the art, the present invention can have various modifications and variations.Within the spirit and principles in the present invention all, any amendment done, equivalent replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (7)
1. prepare a method for avanaphil, it is characterized in that, comprise the following steps:
The first step, there is hydrolysis reaction and obtain 4-(3-chloro-4-methoxy benzyl is amino)-2-methylthiopyrimidine-5-carboxylic acid and compound (6) in 4-(3-chloro-4-methoxy benzyl is amino)-2-methylthiopyrimidine-5-carboxylic acid, ethyl ester and compound (2);
Second step, compound (6) and sulfur oxychloride carry out acylation reaction and obtain chloride product, then obtain 4-(3-chloro-4-methoxy benzyl is amino)-2-methylthiopyrimidine-N-(2-pyrimidine methyl)-5-pyrimidine carboxamide and compound (7) with 2-pyrimidine ethamine or its salt condensation;
3rd step; compound (7) metachloroperbenzoic acid oxidation obtains 4-(3-chloro-4-methoxy benzyl is amino)-2-methanesulfonyl pyrimidine-N-(2-pyrimidine methyl)-5-pyrimidine carboxamide and compound (8), and compound (8) and L-dried meat ammonia alcohol generation nucleophilic substitution reaction obtain avanaphil.
2. preparation method according to claim 1, is characterized in that, the wherein said the first step is carried out in the basic conditions, and hydrolysate uses acid to be adjusted to pH<7.0.
3. preparation method according to claim 1, is characterized in that, wherein after the hydrolysis reaction of the described the first step, also comprises following purification step: filter hydrolysate, uses water and washing with alcohol, is dried to anhydrous.
4. preparation method according to claim 1, is characterized in that, acylation reaction reflux under anhydrous inert solvent exists of wherein said second step; Condensation reaction is carried out in the basic conditions.
5. preparation method according to claim 1, is characterized in that, wherein after the condensation reaction of described second step, also comprise following purification step: except desolventizing, add the ethanol/water of 1:2, pull an oar under heating condition, then to lower the temperature suction filtration, use the cold ethanol/water washing of 1:2, dry.
6. preparation method according to claim 1, is characterized in that, the nucleophilic substitution reaction of wherein said 3rd step carries out in the basic conditions.
7. preparation method according to claim 1, is characterized in that, wherein after the nucleophilic substitution reaction of described 3rd step, also comprise following purification step: be separated organic phase, except desolventizing, add dehydrated alcohol backflow, ice washing with alcohol is used after cooling, dry.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109232542A (en) * | 2018-09-25 | 2019-01-18 | 重庆奥舍生物化工有限公司 | A method of preparing pharmaceutical compound avanaphil |
| CN109280050A (en) * | 2018-09-25 | 2019-01-29 | 重庆奥舍生物化工有限公司 | A kind of preparation method of pharmaceutical compound avanaphil |
| CN109280049A (en) * | 2018-09-25 | 2019-01-29 | 重庆奥舍生物化工有限公司 | A kind of synthetic method of pharmaceutical compound avanaphil |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103833736A (en) * | 2014-03-04 | 2014-06-04 | 北京澳合药物研究院有限公司 | Method for preparing avanafil |
| CN104059025A (en) * | 2013-03-20 | 2014-09-24 | 广州朗圣药业有限公司 | Novel intermediate used for preparation of avanafil and preparation method thereof |
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2015
- 2015-01-05 CN CN201510002941.3A patent/CN104530017A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104059025A (en) * | 2013-03-20 | 2014-09-24 | 广州朗圣药业有限公司 | Novel intermediate used for preparation of avanafil and preparation method thereof |
| CN103833736A (en) * | 2014-03-04 | 2014-06-04 | 北京澳合药物研究院有限公司 | Method for preparing avanafil |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109232542A (en) * | 2018-09-25 | 2019-01-18 | 重庆奥舍生物化工有限公司 | A method of preparing pharmaceutical compound avanaphil |
| CN109280050A (en) * | 2018-09-25 | 2019-01-29 | 重庆奥舍生物化工有限公司 | A kind of preparation method of pharmaceutical compound avanaphil |
| CN109280049A (en) * | 2018-09-25 | 2019-01-29 | 重庆奥舍生物化工有限公司 | A kind of synthetic method of pharmaceutical compound avanaphil |
| CN109280050B (en) * | 2018-09-25 | 2021-01-29 | 重庆奥舍生物化工有限公司 | Preparation method of medical compound avanafil |
| CN109280049B (en) * | 2018-09-25 | 2021-02-02 | 重庆奥舍生物化工有限公司 | Synthetic method of medical compound avanafil |
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