CN104059025A - Novel intermediate used for preparation of avanafil and preparation method thereof - Google Patents
Novel intermediate used for preparation of avanafil and preparation method thereof Download PDFInfo
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
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Abstract
The invention provides a novel intermediate IV which is used for preparation of avanafil. The intermediate has a general formula IV as described in the specification; and in the general formula IV, R represents a C1-20 alkylsulfinyl group or a C1-20 alkylsulfonyl group. The intermediate has high purity, is suitable for industrial production and can be subjected to a one-step chemical reaction to prepare avanafil. The invention also provides a preparation method for the intermediate and a method for preparing avanafil from the intermediate.
Description
Technical field
The present invention relates to the key intermediate of avanaphil, i.e. 4-(3-chloro-4-methoxy benzyl amino)-2-R base-N-(2-Pyrimidylmethyl) preparation method of pyrimidine-5-methane amide and the application in avanaphil preparation thereof, belong to pharmaceutical chemistry field.
Background technology
Avanaphil, chemical name be (
s)-4-[(3-chloro-4-methoxy benzyl) amino]-2-[2-(methylol)-1-pyrrolidyl]-N-(2-Pyrimidylmethyl)-5-pyrimidine carboxamide, structural formula is suc as formula V:
Avanaphil is a kind of new medicine that is used for the treatment of erective dysfunction of being produced by Vivus company, on April 27th, 2012 is by FDA approval listing, with Virga (Sildenafil, Pfizer), Tadalafil (Cialis) (Tadalafil, gift comes) the same with the mechanism of action of Vardenafil (Vardenafil, Baeyer), be 5-phosphodiesterase (PED-5) inhibitor.Research shows, this drug effect time is only 15 minutes, is significantly shorter than 30 ~ 60 minutes of other similar drugs reports, greatly improved clinical ease of use, improved patient's conformability.
At present, Patent document data prepared by relevant avanaphil is few, and patent US6797709 has announced the method for preparing avanaphil shown in route 1:
In the method, intermediate product purity is lower, and each step aftertreatment is loaded down with trivial details, and the aftertreatment of reaction C and reaction E all needs column chromatography purification, and industrialization is difficulty relatively.
Summary of the invention
The present invention is directed to prior art and need column chromatography purification, the deficiency of the aspects such as aftertreatment is loaded down with trivial details, to avanaphil, preparation method further studies, invent one and utilized 4-(3-chloro-4-methoxy benzyl amino)-2-R base-N-(2-Pyrimidylmethyl) pyrimidine-5-methane amide is the variation route that key intermediate is prepared avanaphil, this post-reaction treatment process is simpler and more direct, and intermediate is more easily purified, and product purity is higher, be applicable to industrialized production, there is higher economic worth.
One aspect of the present invention discloses the key intermediate prepared for avanaphil and the preparation method of this key intermediate, discloses on the other hand the method for preparing avanaphil by this key intermediate.
The invention discloses intermediate IV, it is a kind of key intermediate of preparing avanaphil, and its chemical name is: 4-(3-chloro-4-methoxy benzyl amino)-2-R base-N-(2-Pyrimidylmethyl) pyrimidine-5-methane amide, structural formula is suc as formula shown in IV:
Wherein, R represents C
1-C
20alkyl sulphinyl, C
1-C
20alkyl sulphonyl.
The invention also discloses a kind of intermediate III, it is the raw material midbody for the preparation of intermediate IV, and its chemical name is: 4-(3-chloro-4-methoxy benzyl amino)-2-R ' base-N-(2-Pyrimidylmethyl) pyrimidine-5-methane amide, structural formula is suc as formula shown in III:
Wherein, R ' represents C
1-C
20alkyl sulfenyl.
The present invention discloses intermediate II, III, the application of IV in avanaphil preparation in addition.
Utilize key intermediate IV to prepare avanaphil as shown in Scheme 2:
In formula I, formula II, formula III, R ' represents C
1-C
20alkyl thioether, in formula IV, R represents C
1-C
20alkyl sulphinyl, C
1-C
20alkyl sulphonyl.
In the general formula that reaction scheme of the present invention relates to, the conventional technical term of chemistry have common implication, and for example " alkyl " refers to saturated or undersaturated straight or branched, has the monovalent alkyl part of indication number carbon atom.
Reaction scheme Chinese style III of the present invention, formula IV compound are not reported.
In reaction scheme 2, intermediate I, the i.e. chloro-4-methoxy of 4-(3-benzyl amino) preparation of-5-ethoxy carbonyl-2-R ' yl pyrimidines can be with reference to patent US6797709.Preferably R ' base is methylthio group, and the chloro-5-ethoxy carbonyl-2-of 4-methylthiopyrimidine reacts and makes the chloro-4-methoxy of 4-(3-benzyl amino with 3-chloro-4-methoxy benzyl amine under triethylamine effect)-5-ethoxy carbonyl-2-methylthiopyrimidine.
According to the present invention, the method for preparing avanaphil comprises following steps:
(a) intermediate I issues raw hydrolysis reaction in the effect of alkaline solution, 10 ~ 80 DEG C of temperature of reaction, and in 0.5 ~ 20 hour reaction times, the rear pH value by acid solution adjusting reaction system is 4 ~ 5, makes intermediate II;
(b) intermediate II, under the effect of condensing agent, makes intermediate III with 2-aminomethyl pyrimidine hydrochloride by condensation reaction, 0 ~ 50 DEG C of temperature of reaction, 2 ~ 48 hours reaction times;
(c) intermediate III, under the effect of oxygenant, makes intermediate IV by oxidizing reaction, temperature of reaction-20 ~ 80 DEG C, and the reaction times is 0.5 ~ 48 hour;
(d) intermediate IV is reacted and is obtained avanaphil V with L-dried meat ammonia alcohol under alkali effect.
According to the present invention, intermediate I makes in the hydrolysis reaction of intermediate II, and the alkaline solution of use is selected from the one in sodium hydroxide solution, potassium hydroxide solution, solution of potassium carbonate, wherein preferred sodium hydroxide solution; Reaction solvent is selected from the one in ethanol, methyl alcohol, methyl-sulphoxide, tetrahydrofuran (THF), dimethyl formamide or water, wherein preferred alcohol; Preferred temperature of reaction is 15 ~ 35 DEG C, and the preferred reaction times is 1 ~ 3 hour; After hydrolysis reaction, need to regulate reaction solution acid-basicity with acid solution, the acid solution of use is selected from the one in citric acid, acetic acid, hydrochloric acid or dilute sulphuric acid, wherein optimization citric acid.
According to the present invention, made by intermediate II in the condensation reaction of intermediate III, condensing agent is selected from the one in EDCI+HOBt, CDI, DCC+DMAP, HATU, TBTU, PyBOP or TBTU, wherein preferred EDCI+HOBt; Reaction solvent is selected from the one in acetonitrile, methylene dichloride, tetrahydrofuran (THF) or DMF, wherein preferred DMF; Preferred temperature of reaction is 10 ~ 30 DEG C, and the preferred reaction times is 10 ~ 20 hours.
According to the present invention, made by intermediate III in the oxidizing reaction of intermediate IV, oxygenant is metachloroperbenzoic acid (MCPBA), reaction solvent is selected from the one in ethyl acetate, methylene dichloride or trichloromethane, wherein preferential ethyl acetate, preferred temperature of reaction is 5 ~ 30 DEG C, and the preferred reaction times is 1 ~ 3 hour.
According to the present invention, under alkali effect, react and obtain in avanaphil with L-dried meat ammonia alcohol by intermediate IV, the alkali using is selected from the one in triethylamine, sodium carbonate, sodium bicarbonate or diisopropylethylamine, wherein preferred triethylamine; Reaction solvent be selected from ethyl acetate, methylene dichloride, acetic acid, formic acid, trifluoroacetic acid or or trichloromethane in one, wherein ethyl acetate.
Beneficial effect: prior art adopts an in the end step introducing 2-aminomethyl pyrimidine to prepare two kinds of oily matter of meeting generation in avanaphil preparation process, is unfavorable for subsequent purification; Introduce this group and method of the present invention is creationary in the 3rd step, it is oily matter that this introducing in advance can be avoided intermediate, is conducive to purify, and also can avoid the possibility of product racemization simultaneously.In addition, method of the present invention, has reduced the use of column chromatography, and reaction treatment process is simpler and more direct, respectively walks intermediate and more easily purifies, and more can meet industrial requirement, for the preparation of avanaphil provides new more major path.
Embodiment
According to following embodiment, the present invention may be better understood.But, those skilled in the art will readily understand, the described content of embodiment is only for the present invention is described, and should also can not limit the present invention described in detail in claims.
embodiment 1
(1) the chloro-4-methoxy of 4-(3-benzyl amino) preparation of-5-ethoxy carbonyl-2-methylthiopyrimidine (VI):
Chloro-15g 4-5-ethoxy carbonyl-2-methylthiopyrimidine and 18ml triethylamine are added respectively in 130ml tetrahydrofuran (THF) and dissolved, be cooled to 0 DEG C, add 13.5g 3-chloro-4-methoxy benzyl amine in batches, 0 ~ 5 DEG C of reaction 30min, 20 ~ 30 DEG C of reactions again, with HPLC detection reaction terminal.By reactant concentrating under reduced pressure, then add ethyl acetate and the each 120ml washing of aqueous citric acid solution, organic phase is water and salt water washing again, dry, filtration, and concentrating under reduced pressure obtains crude product 22g.Finally use dehydrated alcohol to dissolve crude product at 55 ~ 60 DEG C, stirred crystallization is spent the night, and filters, and dries and obtains product 15g.
1H NMR：8.78（t,
J=6.0Hz, 1H），8.55（s, 1H），7.43（s, 1H），7.29（d,
J=8.4Hz, 1H），7.10（d,
J=8.4Hz, 1H），4.62（d,
J=6.0Hz, 2H），4.29（dd, 2H），3.82（s, 3H），2.44（s, 3H），1.30（t,
J=6.8Hz, 3H）。MS（m/z）：368.0。Ultimate analysis: calculated value: C 52.24, H 4.93, Cl 9.64, N 11.42, O 13.05, S 8.72;
Measured value: C 52.23, H 4.93, Cl 9.63, N 11.43, O 13.06, S 8.72.
(2) the chloro-4-methoxybenzyl amino-2-(of 4-(3-methylthio group) pyrimidine-5-carboxylic acid's's (VII) preparation:
The product VI that step (1) is obtained adds in 450ml ethanol, 50 ~ 55 DEG C of heated and stirred are dissolved, and treat that material temperature is chilled to 20 ~ 30 DEG C, and 105ml 10% sodium hydroxide solution adds wherein, 20 ~ 30 DEG C are stirred 1.5 ~ 2h, drip 10% citric acid solution regulator solution pH ≈ 4 ~ 5, solid is separated out in a large number, and 20 ~ 30 DEG C are stirred 1 ~ 1.5h, filter, solid washing, 50 DEG C of vacuum-drying 3h obtain white solid 14.0g, yield 93.3%.
1H NMR：13.24（s, 1H）， 8.86（t,
J=5.6Hz, 1H），8.52（s, 1H），7.42（s, 1H），7.28（d,
J=8.4Hz, 1H），7.09（d,
J=8.8Hz, 1H），4.61（d,
J=6.0Hz, 2H），3.81（s, 3H），2.42（s, 3H）。MS(m/z): 340.0。Ultimate analysis: calculated value: C 49.49, H 4.15, Cl 10.43, N 12.37, O 14.13, S 9.44; Measured value: C 49.51, H 4.14, Cl 10.42, N 12.37, O 14.12, S 9.45.
(3) 4-(3-chloro-4-methoxybenzyl amino)-2-(methylthio groups)-N-(2-Pyrimidylmethyl) preparation of pyrimidine-5-methane amide (VIII):
The product VII (1.0g) that step (2) is obtained adds 8ml N, in dinethylformamide, logical nitrogen, 20 ~ 30 DEG C of stirrings, EDCI(732mg), HOBt(556mg) add in reaction solution simultaneously, stir 2min, triethylamine (0.7ml) adds in reaction solution, and solution colour becomes deep yellow, stir 1h, 2-aminomethyl pyrimidine hydrochloride (471mg) and triethylamine (0.6ml) join in 8ml DMF, mix, to mix rear solution and add in reaction solution, reaction solution 20-30 DEG C is stirred 5 ~ 18h.In reaction solution, add 48ml water, it is muddy that solution becomes, there is solid to separate out, in solution, add ethyl acetate extracting twice (20ml × 2), merge organic phase, organic phase is stirred and is washed 2 times with 30ml 5% sodium carbonate solution, 40ml water stirs washes 1 time, anhydrous sodium sulfate drying organic phase, filters, and organic phase is directly used in next step reaction.
1H NMR：9.24（s, 1H），8.80（d,
J=5.2Hz, 3H），8.53（s, 1H），7.38（t,
J=4.8Hz, 2H），7.24（d,
J=7.8Hz, 1H），7.09（d,
J=8.4Hz, 1H），4.58（d,
J=5.8Hz, 2H），4.51（d,
J=5.8Hz, 2H），3.82（s, 3H），2.52（s, 3H）。MS(m/z): 431.0。Ultimate analysis: calculated value: C 52.96, H 4.44, Cl 8.23, N 19.50, O 7.43, S 7.44
; Measured value: C 52.96, H 4.45, Cl 8.23, N 19.51, O 7.42, S 7.43.
(4) 4-(3-chloro-4-methoxy benzyl amino)-2-(methylsulfinyl)-N-(2-Pyrimidylmethyl) preparation of pyrimidine-5-methane amide (IX):
Be down to approximately-10 DEG C to compound VIII organic phase direct ice salt bath to the temperature obtaining in step (3), metachloroperbenzoic acid (471mg) is dissolved in 10ml ethyl acetate, slowly drop in reaction solution, 0.5h dropwises, and metachloroperbenzoic acid (377mg) is dissolved in 2ml ethyl acetate, adds and splashes in reaction solution, rising temperature is to-5-0 DEG C stirring reaction 0.5h, filter, filtrate is used 30ml 5% sodium carbonate solution washed twice, and 20ml water washing once.Anhydrous sodium sulfate drying, filters, and organic phase is directly used in next step reaction.
1H NMR：9.26（s, 1H），8.82（d,
J=6.0Hz, 3H），8.50（s, 1H），7.42（t,
J=5.2Hz, 2H），7.28（d,
J=8.0Hz, 1H），7.08（d,
J=8.4Hz, 1H），4.60（d,
J=6.0Hz, 2H），4.52（d,
J=5.8Hz, 2H），3.78（s, 3H），2.46（s, 3H）。MS(m/z): 447.0。Ultimate analysis: calculated value: C 51.06, H 4.29, Cl 7.93, N 18.80, O 10.74, S 7.17; Measured value: C 51.06, H 4.28, Cl 7.92, N 18.82, O 10.73, S 7.18.
(5) preparation of avanaphil (V):
In the compound VIII organic phase obtaining in step (4), directly add 215mg L-dried meat ammonia alcohol and 1ml triethylamine, 20 ~ 30 DEG C are stirred 1h, in reaction solution, add 50ml water, separate organic phase, organic phase is stirred and is washed (30ml × 3) 3 times with 5% sodium carbonate solution, saturated aqueous common salt stirs washes (30ml × 3) 3 times, anhydrous sodium sulfate drying organic phase, filters concentrating under reduced pressure, crystallization obtains white solid 1.1g, three step yields 77.5%.
1H NMR：9.15（s, 1H），8.75（d,
J=4.8Hz, 3H），8.51（s, 1H），7.37（t,
J=4.8Hz, 2H），7.26（dd,
J=1.8Hz, 1H），7.07（d,
J=8.4Hz, 1H），4.57（d,
J=5.7Hz, 2H），4.49（d,
J=5.7Hz, 2H），4.09（s, 1H），3.80（s, 3H），3.61（s, 1H），3.48（d,
J=6.0Hz, 2H），2.08（s, 2H），1.92（t,
J=9.6Hz, 4H）。MS(m/z): 484.1。Ultimate analysis: calculated value: C 57.08, H 5.42, Cl 7.33, N 20.26, O 9.92; Measured value: C 57.09, H 5.42, Cl 7.32, N 20.27, O 9.91.
embodiment 2
(1) the chloro-4-methoxy of 4-(3-benzyl amino) preparation of-5-ethoxy carbonyl-2-methylthiopyrimidine (VI):
Chloro-15g 4-5-ethoxy carbonyl-2-methylthiopyrimidine and 18ml triethylamine are added respectively in 130ml tetrahydrofuran (THF) and dissolved, be cooled to 0 DEG C, add 13.5g 3-chloro-4-methoxy benzyl amine in batches, 0 ~ 5 DEG C of reaction 30min, 20 ~ 30 DEG C of reactions again, with HPLC detection reaction terminal.By reactant concentrating under reduced pressure, then add ethyl acetate and the each 120ml washing of aqueous citric acid solution, organic phase is water and salt water washing again, dry, filtration, and concentrating under reduced pressure obtains crude product 22g.Finally use dehydrated alcohol to dissolve crude product at 55 ~ 60 DEG C, stirred crystallization is spent the night, and filters, and dries and obtains product 15g.
(2) the chloro-4-methoxybenzyl amino-2-(of 4-(3-methylthio group) pyrimidine-5-carboxylic acid's's (VII) preparation:
The product VI that step (1) is obtained adds in 450ml methyl alcohol, 50 ~ 55 DEG C of heated and stirred are dissolved, and treat that material temperature is chilled to 20 ~ 30 DEG C, and 105ml 10% potassium hydroxide solution adds wherein, 15 ~ 35 DEG C are stirred 1.5 ~ 2h, drip 10% citric acid solution regulator solution PH ≈ 4 ~ 5, solid is separated out in a large number, and 20 ~ 30 DEG C are stirred 1 ~ 1.5h, filter, solid washing, 50 DEG C of vacuum-drying 3h obtain white solid 13.0g, yield 86.7%.
(3) 4-(3-chloro-4-methoxybenzyl amino)-2-(methylthio groups)-N-(2-Pyrimidylmethyl) preparation of pyrimidine-5-methane amide (VIII):
The product VII (1.0g) that step (2) is obtained adds 15ml N, in dinethylformamide, logical nitrogen, ice-water bath cooling, HATU(1.67g) add reaction solution, triethylamine (1.3ml) is added dropwise in reaction solution, stirs 10min, 2-aminomethyl pyrimidine hydrochloride (471mg), is slowly warming up to 20 ~ 30 DEG C and stirs 3 ~ 18h.In reaction solution, add 48ml water, it is muddy that solution becomes, there is solid to separate out, in solution, add ethyl acetate extracting twice (25ml × 2), merge organic phase, organic phase is stirred and is washed 2 times with 30ml 5% sodium carbonate solution, 30ml water stirs washes 1 time, anhydrous sodium sulfate drying organic phase, filters, and concentrating under reduced pressure obtains 1.1g white solid.
(4) 4-(3-chloro-4-methoxy benzyl amino)-2-(methylsulfinyl)-N-(2-Pyrimidylmethyl) preparation of pyrimidine-5-methane amide (IX):
Be dissolved in 10ml tetrahydrofuran (THF) to the compound VIII 1.1g obtaining in step (3), direct ice salt bath to temperature is down to approximately-10 DEG C, metachloroperbenzoic acid (623mg) is dissolved in 5ml tetrahydrofuran (THF), slowly drop in reaction solution, 0.5h dropwises, metachloroperbenzoic acid (250mg) is dissolved in 2ml tetrahydrofuran (THF), add and splash in reaction solution, rising temperature is to-5 ~ 0 DEG C of stirring reaction 0.5h, filter, filtrate is used 30ml 5% sodium carbonate solution washed twice, add again ethyl acetate extracting twice (30ml × 2), 30ml 5% sodium carbonate solution washed twice for organic phase, use again 30ml water washing once.Anhydrous sodium sulfate drying, filters, and concentrating under reduced pressure obtains 0.9g white solid.
(5) preparation of avanaphil (V):
Be dissolved in 15ml ethyl acetate to the compound VIII 0.9g obtaining in step (4), 204 mg L-dried meat ammonia alcohol and 0.56ml triethylamine add wherein, and 20 ~ 30 DEG C are stirred 0.5h, add 40ml water in reaction solution, add the extraction of 45ml ethyl acetate, separate organic phase, organic phase is stirred and is washed (30ml × 3) 3 times with 5% sodium carbonate solution, and saturated aqueous common salt stirs washes (30ml × 3) 3 times, anhydrous sodium sulfate drying organic phase, filter, concentrating under reduced pressure, crystallization obtains white solid 0.7g.
embodiment 3
(1) the chloro-4-methoxy of 4-(3-benzyl amino) preparation of-5-ethoxy carbonyl-2-methylthiopyrimidine (VI):
Chloro-2.32g 4-5-ethoxy carbonyl-2-methylthiopyrimidine and 3.06ml triethylamine are added respectively in 30ml ethyl acetate and dissolved, be cooled to 0 ~ 5 DEG C, add 2.28g 3-chloro-4-methoxy benzyl amine, 0 ~ 5 DEG C of reaction 30min, 20 ~ 30 DEG C of reactions again, with HPLC detection reaction terminal.By reactant concentrating under reduced pressure, add the each 120ml washing of ethyl acetate and aqueous citric acid solution, organic phase is water and salt water washing again, dry, filtration, concentrating under reduced pressure obtains crude product 3.1g.Finally use dehydrated alcohol to dissolve crude product at 55 ~ 60 DEG C, stirred crystallization is spent the night, and filters, and dries and obtains product 2.0g.
(2) the chloro-4-methoxybenzyl amino-2-(of 4-(3-methylthio group) pyrimidine-5-carboxylic acid's's (VII) preparation:
The product VI that step (1) is obtained adds in 20ml methyl-sulphoxide, 50 ~ 55 DEG C of heated and stirred are dissolved, and treat that material temperature is chilled to 20 ~ 30 DEG C, and 14ml 10% sodium hydroxide solution adds wherein, 20 ~ 30 DEG C are stirred 1.5 ~ 2h, add water 50ml, then add 10% acetum regulator solution PH ≈ 4 ~ 5, solid is separated out in a large number, 20 ~ 30 DEG C are stirred 1 ~ 1.5h, filter, solid washing, 50 DEG C of vacuum-drying 3h obtain white solid 1.7g.
(3) 4-(3-chloro-4-methoxybenzyl amino)-2-(methylthio groups)-N-(2-Pyrimidylmethyl) preparation of pyrimidine-5-methane amide (VIII):
The product VII (1.0g) that step (2) is obtained adds in 10ml tetrahydrofuran (THF), logical nitrogen, EDCI(732mg), HOBt(556mg) add reaction solution simultaneously, stir 2min, triethylamine (0.7ml) adds in reaction solution, stir 1h, 2-aminomethyl pyrimidine hydrochloride (471mg) and triethylamine (0.6ml) join in 1ml tetrahydrofuran (THF), mix, to mix rear solution and add in reaction solution, 20 ~ 30 DEG C are stirred 5 ~ 18h.In reaction solution, add 48ml 5% sodium carbonate solution, have solid to separate out, stirring at room temperature 1h, filters, and solid is washed once with 50ml, and 50 DEG C of dry 3h of valve tube obtain 1.0g white solid.
(4) 4-(3-chloro-4-methoxy benzyl amino)-2-(methylsulfinyl)-N-(2-Pyrimidylmethyl) preparation of pyrimidine-5-methane amide (IX):
Be dissolved in 10ml methylene dichloride to the compound VIII 1.0g obtaining in step (3), direct ice salt bath to temperature is down to approximately-10 DEG C, metachloroperbenzoic acid (471mg) is dissolved in 5ml methylene dichloride, slowly drop in reaction solution, 0.5h dropwises, metachloroperbenzoic acid (188mg) is dissolved in 2ml methylene dichloride, add and splash in reaction solution, rising temperature is to-5 ~ 0 DEG C of stirring reaction 0.5h, filter, filtrate is used 30ml 5% sodium carbonate solution washed twice, add again dichloromethane extraction twice (30ml × 2), 30ml 5% sodium carbonate solution washed twice for organic phase, use again 30ml water washing once.Anhydrous sodium sulfate drying, filters, and concentrating under reduced pressure obtains 0.6g white solid.
(5) preparation of avanaphil (V):
Be dissolved in 15ml ethyl acetate to the compound VIII 0.6g obtaining in step (4), 204 mg L-dried meat ammonia alcohol and 0.56ml triethylamine add wherein, and 20 ~ 30 DEG C are stirred 5h, add 40ml water in reaction solution, add the extraction of 45ml ethyl acetate, separate organic phase, organic phase is stirred and is washed (30ml × 3) 3 times with 5% sodium carbonate solution, and saturated aqueous common salt stirs washes (30ml × 3) 3 times, anhydrous sodium sulfate drying organic phase, filter, concentrating under reduced pressure, crystallization obtains white solid 0.4g.
embodiment 4:
(1) the chloro-4-methoxy of 4-(3-benzyl amino) preparation of-5-ethoxy carbonyl-2-methylthiopyrimidine (VI):
Chloro-50.0g 4-5-ethoxy carbonyl-2-methylthiopyrimidine and 59.9ml triethylamine are added respectively in 430ml ethyl acetate and dissolved, be cooled to 0 DEG C, add 44.7g 3-chloro-4-methoxy benzyl amine, 0 ~ 5 DEG C of reaction 30min, then 20 ~ 30 DEG C of reaction 0.5-1h in batches.By reactant concentrating under reduced pressure, then add ethyl acetate and the each 400ml of aqueous citric acid solution washing 2 times, organic phase water and the each washing of saturated brine 1 time again, dry, filter, concentrating under reduced pressure obtains crude product 73.0g.Finally use dehydrated alcohol to dissolve crude product at 55 ~ 60 DEG C, stirred crystallization 12-18h, filters, and dries and obtains product 42.3g.
(2) the chloro-4-methoxybenzyl amino-2-(of 4-(3-methylthio group) pyrimidine-5-carboxylic acid's's (VII) preparation:
The product VI 15g that step (1) is obtained adds in 450ml methyl alcohol, 50 ~ 55 DEG C of heated and stirred are dissolved, treat that material temperature is chilled to 20 ~ 30 DEG C, 105ml 10% potassium hydroxide solution adds wherein, and 20 ~ 30 DEG C are stirred 1.5 ~ 2h, drip 10% citric acid solution regulator solution pH ≈ 4 ~ 5, solid is separated out in a large number, and 20 ~ 30 DEG C are stirred 1 ~ 1.5h, filter, solid washing, 50 DEG C of vacuum-drying 3h obtain white solid 13.0g.
(3) 4-(3-chloro-4-methoxybenzyl amino)-2-(methylthio groups)-N-(2-Pyrimidylmethyl) preparation of pyrimidine-5-methane amide (VIII):
The product VII (1.0g) that step (2) is obtained adds 15ml N, in dinethylformamide, logical nitrogen, ice-water bath, HATU(1.67g) add in reaction solution, triethylamine (1.3ml) adds in reaction solution, stirs 10min, 2-aminomethyl pyrimidine hydrochloride (471mg) joins in reaction solution, is slowly warming up to 20-30 DEG C and stirs 3 ~ 18h.In reaction solution, add 48ml water, it is muddy that solution becomes, there is solid to separate out, in solution, add ethyl acetate extracting twice (25ml × 2), merge organic phase, organic phase is stirred and is washed 2 times with 30ml 5% sodium carbonate solution, 30ml water stirs washes 1 time, anhydrous sodium sulfate drying organic phase, filters, and concentrating under reduced pressure obtains 1.1g white solid.
(4) 4-(3-chloro-4-methoxy benzyl amino)-2-(methyl sulphonyl)-N-(2-Pyrimidylmethyl) preparation of pyrimidine-5-methane amide (IX):
Be dissolved in 10ml tetrahydrofuran (THF) to the compound VIII 1.1g obtaining in step (3), direct ice salt bath to temperature is down to approximately-15 to-10 DEG C, MCPBA(1036mg) be dissolved in 5mlTHF, slowly drop in reaction solution, 0.5h dropwises, and-15 to-10 DEG C are stirred 0.5h, in solution, add 30ml water, add again EA extracting twice (30ml × 2), 30ml5%Na2CO3 solution washing twice for organic phase, then use 30ml water washing once.Anhydrous sodium sulfate drying, filters, and concentrating under reduced pressure obtains 0.9g white solid.
(5) preparation of avanaphil (V):
Be dissolved in 15ml ethyl acetate to the compound X 0.9g obtaining in step (4), in organic phase, directly add 196mg L-dried meat ammonia alcohol and 0.54ml triethylamine, 20 ~ 30 DEG C are stirred 1-16h, add 40ml water in reaction solution, add the extraction of 45ml ethyl acetate, separate organic phase, organic phase is stirred and is washed (30ml × 3) 3 times with 5% sodium carbonate solution, and saturated aqueous common salt water stirs washes (30ml × 3), anhydrous sodium sulfate drying organic phase 3 times, filter, concentrating under reduced pressure obtains white solid 0.7g.
Claims (10)
1. for the preparation of an intermediate for avanaphil, its chemical name is: 4-(3-chloro-4-methoxy benzyl amino)-2-R base-N-(2-Pyrimidylmethyl) pyrimidine-5-methane amide, structural formula is suc as formula shown in IV:
Ⅳ
Wherein, R representative following group: C
1-C
20alkyl sulphinyl or C
1-C
20alkyl sulphonyl.
2. intermediate IV as claimed in claim 1, preferably methylsulfinyl of R substituting group.
3. the preparation method of intermediate IV as claimed in claim 1, is characterized in that comprising following steps:
(1) intermediate I issues raw hydrolysis reaction in the effect of alkaline solution, 10 ~ 80 DEG C of temperature of reaction, and in 0.5 ~ 20 hour reaction times, the rear pH value by acid solution adjusting reaction system is 4 ~ 5, makes intermediate II;
(2) intermediate II, under the effect of condensing agent, makes intermediate III with 2-aminomethyl pyrimidine hydrochloride by condensation reaction, 0 ~ 50 DEG C of temperature of reaction, 2 ~ 48 hours reaction times;
(3) intermediate III, under the effect of oxygenant, makes intermediate IV by oxidizing reaction, temperature of reaction-20 ~ 80 DEG C, and the reaction times is 0.5 ~ 48 hour;
Wherein, the structural formula of intermediate I, intermediate II, intermediate III is respectively suc as formula shown in I, formula II, formula III:
Wherein, R ' represents C
1-C
20alkyl thioether.
4. hydrolysis reaction as claimed in claim 3, it is characterized in that the alkaline solution using is selected from the one in sodium hydroxide solution, potassium hydroxide solution or solution of potassium carbonate, acid solution is selected from the one in citric acid, acetic acid, formic acid, dilute sulphuric acid or hydrochloric acid, and reaction solvent is selected from the one in ethanol, methyl alcohol, methyl-sulphoxide, tetrahydrofuran (THF), dimethyl formamide or water.
5. condensation reaction as described in claim 3, it is characterized in that condensing agent is selected from the one in EDCI+HOBt, CDI, DCC+DMAP, HATU, TBTU, PyBOP or TBTU, reaction solvent is selected from the one in acetonitrile, methylene dichloride, tetrahydrofuran (THF) or DMF.
6. oxidizing reaction as described in claim 3, is characterized in that oxygenant is metachloroperbenzoic acid (MCPBA), and reaction solvent is selected from the one in ethyl acetate, methylene dichloride or trichloromethane.
7. the preparation method of intermediate IV as claimed in claim 3, is characterized in that preferred step is:
(1) intermediate I is under the effect of sodium hydroxide solution, and taking ethanol as reaction solvent generation hydrolysis reaction, temperature of reaction is 15 ~ 35 DEG C, and the reaction times is 1 ~ 3 hour, and the rear pH value by citric acid adjusting reaction system is 4 ~ 5, makes intermediate II;
(2) intermediate II and 2-aminomethyl pyrimidine hydrochloride, under the effect of condensing agent EDCI+HOBt, taking DMF as reaction solvent, make intermediate III by condensation reaction, and temperature of reaction is 10 ~ 30 DEG C, and the reaction times is 10 ~ 20 hours;
(3) intermediate III and oxygenant metachloroperbenzoic acid, taking ethyl acetate as reaction solvent, makes intermediate IV by oxidizing reaction, and temperature of reaction is 5 ~ 30 DEG C, and the reaction times is 1 ~ 3 hour.
8. intermediate IV as claimed in claim 1, in the application of preparing in avanaphil, is characterized in that being reacted and preparing avanaphil with L-dried meat ammonia alcohol under alkali effect by intermediate IV.
9. prepare as claimed in claim 8 avanaphil, it is characterized in that alkali used be selected from triethylamine, sodium carbonate, sodium bicarbonate or diisopropylethylamine one or more, reaction solvent is selected from the one in ethyl acetate, methylene dichloride, acetic acid, formic acid, trifluoroacetic acid or trichloromethane.
10. prepare as claimed in claim 9 avanaphil, preferred alkali is triethylamine, and preferred reaction solvent is ethyl acetate.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
| CN104530017A (en) * | 2015-01-05 | 2015-04-22 | 南京晓庄学院 | Avanafil preparation method |
| CN104628708A (en) * | 2013-11-13 | 2015-05-20 | 北大方正集团有限公司 | Avanaphil crystal form as well as preparation method, application and pharmaceutical composition thereof |
| CN104628707A (en) * | 2013-11-13 | 2015-05-20 | 北大方正集团有限公司 | Amorphous form of avanafil, preparation method of, application and medicine composition of amorphous form of avanafil |
| CN104710411A (en) * | 2015-03-13 | 2015-06-17 | 安润医药科技（苏州）有限公司 | Synthesis method of avanafil |
| CN104650045B (en) * | 2013-11-19 | 2017-04-19 | 苏州旺山旺水生物医药有限公司 | Preparation method of avanafil |
| CN113917027A (en) * | 2021-10-11 | 2022-01-11 | 山东省药学科学院 | Optical isomer separation detection method for avanafil and intermediate thereof |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104628708A (en) * | 2013-11-13 | 2015-05-20 | 北大方正集团有限公司 | Avanaphil crystal form as well as preparation method, application and pharmaceutical composition thereof |
| CN104628707A (en) * | 2013-11-13 | 2015-05-20 | 北大方正集团有限公司 | Amorphous form of avanafil, preparation method of, application and medicine composition of amorphous form of avanafil |
| CN104650045B (en) * | 2013-11-19 | 2017-04-19 | 苏州旺山旺水生物医药有限公司 | Preparation method of avanafil |
| 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 |
| CN104530017A (en) * | 2015-01-05 | 2015-04-22 | 南京晓庄学院 | Avanafil preparation method |
| CN104710411A (en) * | 2015-03-13 | 2015-06-17 | 安润医药科技（苏州）有限公司 | Synthesis method of avanafil |
| CN104710411B (en) * | 2015-03-13 | 2017-04-26 | 安润医药科技（苏州）有限公司 | Synthesis method of avanafil |
| CN113917027A (en) * | 2021-10-11 | 2022-01-11 | 山东省药学科学院 | Optical isomer separation detection method for avanafil and intermediate thereof |
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