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330784-47-9

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  • 4-((3-Chloro-4-methoxybenzyl)amino)-2-(2-(hydroxymethyl)-1-pyrrolidinyl)-n-(2-pyrimidinylmethyl)-5-pyrimidinecarboxamide

    Cas No: 330784-47-9

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330784-47-9 Usage

Description

Avanafil, also known as Zepped, is a highly selective type 5 phosphodiesterase (PDE5) inhibitor that was approved by the Korean Health Ministry for the treatment of erectile dysfunction (ED) in August 2011. It is reported to be the most selective PDE5 inhibitor on the market, with a fast onset of action reaching Tmax in 0.6 hours and a half-life of 1.2 hours. The main elimination route of avanafil is through the bile and feces, and it is also found to be reabsorbed through enterohepatic recirculation.

Uses

Used in Pharmaceutical Industry:
Avanafil is used as a highly selective PDE5 inhibitor for the treatment of erectile dysfunction. It has an IC50 of 1 nM and is considered the most selective PDE5 inhibitor on the market. Its fast onset of action and relatively short half-life make it a popular choice for patients seeking treatment for ED.

Originator

Mitsubishi Tanabe Pharma Corporation (Japan)

Clinical Use

Avanafil was originally discovered at Tanabe Seiyaku (now Mitsubishi Tanabe). JW Pharmaceutical (previously Choongwae Pharma) and VIVUS have since developed and launched avanafil, which is an oral PDE5 inhibitor for the treatment of erectile dysfunction (ED). Although many marketed PDE5 inhibitors (e.g. sildenafil, vardenafil and tadalafil) are available for the treatment of ED, many patients are still unable to achieve the desired results and experience undesired side-effects with these existing medications. As such, second-generation PDE5 inhibitors with enhanced PDE5 selectivity, shorter systemic half-lives, and improved tolerability are desired. Developed to meet these criteria, Avanafil exhibited good oral bioavailability and PDE5 selectivity in both preclinical studies and clinical trials. Avanafil had a short onset of action (35 min) and short half-life (1.5 h).

Synthesis

The synthesis presented is based on the published patent procedure and is outlined in the scheme. Commercially available 4-chloro-2-(methylsulfanyl)pyrimidine- 5-carboxylic acid ethyl ester (25) was treated with 3- chloro-4-methoxybenzylamine (26) and triethylamine at room temperature to give 4-benzylaminopyrimidine derivative 27 in 96% yield. Sulfide 27 was then oxidized with m-chloroperbenzoic acid (m-CPBA), followed bytreatment with L-prolinol and triethylamine to afford ethyl pyrimidinate 28 in 83% yield. This ester was then saponified with 10% sodium hydroxide to give pyrimidine- 5-carboxylic acid 29 in 80% yield, which then underwent conventional amide bond formation using 2-(aminomethyl) pyrimidine (29a), N-(3-dimethylaminopropal)-N0-ethylcarbodiimide hydrochloride (EDCI) and 1-hydroxybenzotriazole hydrate (HOBt) to give avanafil (IV) in 83% yield.

Drug interactions

Potentially hazardous interactions with other drugs Alpha-blockers: enhanced hypotensive effect - maximum dose 50 mg. Antibacterials: concentration possibly increased by clarithromycin and telithromycin - avoid; concentration increased by erythromycin - reduce avanafil dose; concentration reduced by rifampicin - avoid. Antifungals: concentration increased by ketoconazole - avoid and fluconazole - reduce avanafil dose; concentration possibly increased by itraconazole and voriconazole - avoid. Antivirals: concentration possibly increased by atazanavir, indinavir and saquinavir - avoid; concentration possibly reduced by efavirenz - avoid; concentration possibly increased by fosamprenavir - reduce avanafil dose; concentration significantly increased by ritonavir - avoid. Aprepitant: concentration possibly increased by aprepitant - reduce avanafil dose. Calcium channel blockers: concentration possibly increased by diltiazem and verapamil - reduce avanafil dose. Cobicistat: concentration of avanafil possibly increased - avoid. Nicorandil: possibly enhanced hypotensive effect - avoid. Nitrates: enhanced hypotensive effect - avoid. Riociguat: possibly enhanced hypotensive effect - avoid.

Metabolism

Avanafil is metabolised in the liver mainly by the cytochrome P450 isoenzyme CYP3A4 and to a minor extent by the CYP2C isoform. Two major metabolites are produced, one of which is active. Avanafil is excreted as metabolites mainly in the faeces (approximately 63%) in the urine (approximately 21%).

references

[1] kotera j, mochida h, inoue h, noto t, fujishige k, sasaki t, kobayashi t, kojima k, yee s, yamada y, kikkawa k, omori k. avanafil, a potent and highly selective phosphodiesterase-5 inhibitor for erectile dysfunction. j urol. 2012 aug;188(2):668-74. [2] cui ys, li n, zong ht, yan hl, zhang y. avanafil for male erectile dysfunction: a systematic review and meta-analysis. asian j androl. 2014 may-jun;16(3):472-7.

Check Digit Verification of cas no

The CAS Registry Mumber 330784-47-9 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 3,3,0,7,8 and 4 respectively; the second part has 2 digits, 4 and 7 respectively.
Calculate Digit Verification of CAS Registry Number 330784-47:
(8*3)+(7*3)+(6*0)+(5*7)+(4*8)+(3*4)+(2*4)+(1*7)=139
139 % 10 = 9
So 330784-47-9 is a valid CAS Registry Number.
InChI:InChI=1/C23H26ClN7O3/c1-34-19-6-5-15(10-18(19)24)11-27-21-17(22(33)28-13-20-25-7-3-8-26-20)12-29-23(30-21)31-9-2-4-16(31)14-32/h3,5-8,10,12,16,32H,2,4,9,11,13-14H2,1H3,(H,28,33)(H,27,29,30)/t16-/m0/s1

330784-47-9SDS

SAFETY DATA SHEETS

According to Globally Harmonized System of Classification and Labelling of Chemicals (GHS) - Sixth revised edition

Version: 1.0

Creation Date: Aug 19, 2017

Revision Date: Aug 19, 2017

1.Identification

1.1 GHS Product identifier

Product name avanafil

1.2 Other means of identification

Product number -
Other names Avanafil

1.3 Recommended use of the chemical and restrictions on use

Identified uses For industry use only.
Uses advised against no data available

1.4 Supplier's details

1.5 Emergency phone number

Emergency phone number -
Service hours Monday to Friday, 9am-5pm (Standard time zone: UTC/GMT +8 hours).

More Details:330784-47-9 SDS

330784-47-9Synthetic route

4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]pyrimidine-5-carboxylic acid
330785-84-7

4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]pyrimidine-5-carboxylic acid

2-aminomethylpyrimidine
75985-45-4

2-aminomethylpyrimidine

avanafil
330784-47-9

avanafil

Conditions
ConditionsYield
With dicyclohexyl-carbodiimide; 1-hydroxy-1,2,3-benzotriazine-4(3H)-one In N,N-dimethyl-formamide at 0℃; Temperature;99%
With 5, 10, 15, 20-tetrakis[4-(dihydroxyboryl)phenyl]-21H,23H-porphine In toluene for 16h; Time; Reflux; Green chemistry;91.2%
With benzotriazol-1-ol; dicyclohexyl-carbodiimide In dimethyl sulfoxide at 20℃; for 4h;90%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In DMF (N,N-dimethyl-formamide) at 20℃; for 8h;
2-chloro-4-((3-chloro-4-methoxybenzyl)amino)-N-[pyrimidin-2ylmethyl]pyrimidine-5-carboxamide

2-chloro-4-((3-chloro-4-methoxybenzyl)amino)-N-[pyrimidin-2ylmethyl]pyrimidine-5-carboxamide

(S)-1-Pyrrolidin-2-yl-methanol
23356-96-9

(S)-1-Pyrrolidin-2-yl-methanol

avanafil
330784-47-9

avanafil

Conditions
ConditionsYield
With triethylamine In tetrahydrofuran at 20℃; for 20h;97.2%
4-((3-chloro-4-methoxybenzyl)amino)-2-(methylthio)-N-(pyrimidin-2-ylmethyl)pyrimidine-5-formamide

4-((3-chloro-4-methoxybenzyl)amino)-2-(methylthio)-N-(pyrimidin-2-ylmethyl)pyrimidine-5-formamide

(S)-1-Pyrrolidin-2-yl-methanol
23356-96-9

(S)-1-Pyrrolidin-2-yl-methanol

avanafil
330784-47-9

avanafil

Conditions
ConditionsYield
With 1H-imidazole In toluene at 20℃; for 18h; Solvent; Reagent/catalyst;97%
With triethylamine at 20 - 30℃; for 1h; Solvent;1.1 g
4-[(3-chloro-4-methoxybenzyl)amino]-2-methanesulfonyl-N-(2-pyrimidinylmethyl)-5-pyrimidinecarboxamide

4-[(3-chloro-4-methoxybenzyl)amino]-2-methanesulfonyl-N-(2-pyrimidinylmethyl)-5-pyrimidinecarboxamide

(S)-1-Pyrrolidin-2-yl-methanol
23356-96-9

(S)-1-Pyrrolidin-2-yl-methanol

avanafil
330784-47-9

avanafil

Conditions
ConditionsYield
With N-ethyl-N,N-diisopropylamine In chloroform at 50℃; Temperature;90.5%
With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 20℃; for 5h;87.5%
With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; Temperature; Green chemistry;87%
ethyl (S)-4-((3-chloro-4-methoxybenzyl)amino)-2-(2-(hydroxymethyl)tetrahydropyrrole-1-yl)-5-pyrimidinecarboxylate

ethyl (S)-4-((3-chloro-4-methoxybenzyl)amino)-2-(2-(hydroxymethyl)tetrahydropyrrole-1-yl)-5-pyrimidinecarboxylate

2-aminomethylpyrimidine
75985-45-4

2-aminomethylpyrimidine

avanafil
330784-47-9

avanafil

Conditions
ConditionsYield
Stage #1: ethyl (S)-4-((3-chloro-4-methoxybenzyl)amino)-2-(2-(hydroxymethyl)tetrahydropyrrole-1-yl)-5-pyrimidinecarboxylate With dimethyl sulfoxide; citric acid; sodium hydroxide In water for 15h;
Stage #2: 2-aminomethylpyrimidine With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide for 8h;
87%
In dichloromethane at 20℃;44%
6-(3-chloro-4-methoxy-benzylamino)-1,2-dihydropyrimidin-2-one-5-(N-2-methylpyrimidinyl)formamide

6-(3-chloro-4-methoxy-benzylamino)-1,2-dihydropyrimidin-2-one-5-(N-2-methylpyrimidinyl)formamide

(S)-1-Pyrrolidin-2-yl-methanol
23356-96-9

(S)-1-Pyrrolidin-2-yl-methanol

avanafil
330784-47-9

avanafil

Conditions
ConditionsYield
Stage #1: 6-(3-chloro-4-methoxy-benzylamino)-1,2-dihydropyrimidin-2-one-5-(N-2-methylpyrimidinyl)formamide With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 20 - 60℃; for 24h; Inert atmosphere;
Stage #2: (S)-1-Pyrrolidin-2-yl-methanol With sodium hydride In tetrahydrofuran at 65℃; for 5h;
81.3%
4-[(3-chloro-4-methoxybenzyl)amino]-2-[2-(hydroxymethyl)-1-pyrrolidinyl]pyrimidine

4-[(3-chloro-4-methoxybenzyl)amino]-2-[2-(hydroxymethyl)-1-pyrrolidinyl]pyrimidine

N-(2-methylpyrimidine)methanamide

N-(2-methylpyrimidine)methanamide

avanafil
330784-47-9

avanafil

Conditions
ConditionsYield
Stage #1: 4-[(3-chloro-4-methoxybenzyl)amino]-2-[2-(hydroxymethyl)-1-pyrrolidinyl]pyrimidine With bromine; sodium hydroxide for 0.0833333h; Microwave irradiation;
Stage #2: N-(2-methylpyrimidine)methanamide With tris(2,4-di-t-butyl)phenoxy phosphazene; sodium methylate; nickel diacetate In 1,2-dimethoxyethane at 120℃; for 10h; Inert atmosphere;
81.1%
4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]pyrimidine-5-carboxylic acid
330785-84-7

4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]pyrimidine-5-carboxylic acid

2-aminomethylpyrimidine methanesulfonate

2-aminomethylpyrimidine methanesulfonate

avanafil
330784-47-9

avanafil

Conditions
ConditionsYield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 15 - 25℃;67%
2-aminomethylpyrimidine acetate
1246834-64-9

2-aminomethylpyrimidine acetate

(S)-1-Pyrrolidin-2-yl-methanol
23356-96-9

(S)-1-Pyrrolidin-2-yl-methanol

(3-chloro-4-methoxyphenyl)methylamine hydrogen chloride
41965-95-1

(3-chloro-4-methoxyphenyl)methylamine hydrogen chloride

2,4-dichloropyrimidine-5-carbonyl chloride
2972-52-3

2,4-dichloropyrimidine-5-carbonyl chloride

avanafil
330784-47-9

avanafil

Conditions
ConditionsYield
Stage #1: 2-aminomethylpyrimidine acetate; 2,4-dichloropyrimidine-5-carbonyl chloride With triethylamine In dichloromethane for 1h; Cooling with ice;
Stage #2: (3-chloro-4-methoxyphenyl)methylamine hydrogen chloride With triethylamine In dichloromethane for 2h;
Stage #3: (S)-1-Pyrrolidin-2-yl-methanol In dichloromethane at 20℃;
64%
4-(3-chloro-4-methoxybenzylamino)-2-[(S)-2-hydroxymethylpyrrolidinyl-1-yl]-5-pyrimidinecarboxylic acid chloride

4-(3-chloro-4-methoxybenzylamino)-2-[(S)-2-hydroxymethylpyrrolidinyl-1-yl]-5-pyrimidinecarboxylic acid chloride

2-aminomethylpyrimidine
75985-45-4

2-aminomethylpyrimidine

avanafil
330784-47-9

avanafil

Conditions
ConditionsYield
With triethylamine In dichloromethane at 20℃;64%
2-chloro-4-((3-chloro-4-methoxybenzyl)amino)-N-[pyrimidin-2ylmethyl]pyrimidine-5-carboxamide

2-chloro-4-((3-chloro-4-methoxybenzyl)amino)-N-[pyrimidin-2ylmethyl]pyrimidine-5-carboxamide

avanafil
330784-47-9

avanafil

Conditions
ConditionsYield
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 100℃; Reagent/catalyst; Solvent; Temperature;61%
4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]pyrimidine-5-carboxylic acid
330785-84-7

4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]pyrimidine-5-carboxylic acid

2-aminomethylpyrimidine acetate
1246834-64-9

2-aminomethylpyrimidine acetate

avanafil
330784-47-9

avanafil

Conditions
ConditionsYield
Stage #1: 2-aminomethylpyrimidine acetate With triethylamine In N,N-dimethyl-formamide for 0.5h;
Stage #2: 4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]pyrimidine-5-carboxylic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 8h;
60%
2,4-dichloro-N-(pyrimidin-2-ylmethyl)-5-pyrimidinecarboxamide

2,4-dichloro-N-(pyrimidin-2-ylmethyl)-5-pyrimidinecarboxamide

(S)-1-Pyrrolidin-2-yl-methanol
23356-96-9

(S)-1-Pyrrolidin-2-yl-methanol

(3-chloro-4-methoxyphenyl)methylamine hydrogen chloride
41965-95-1

(3-chloro-4-methoxyphenyl)methylamine hydrogen chloride

avanafil
330784-47-9

avanafil

Conditions
ConditionsYield
Stage #1: 2,4-dichloro-N-(pyrimidin-2-ylmethyl)-5-pyrimidinecarboxamide; (3-chloro-4-methoxyphenyl)methylamine hydrogen chloride With triethylamine for 2h;
Stage #2: (S)-1-Pyrrolidin-2-yl-methanol at 20℃; for 4h;
32%
4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]pyrimidine-5-carboxylic acid
330785-84-7

4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]pyrimidine-5-carboxylic acid

2-aminomethylpyrimidine acetic acid

2-aminomethylpyrimidine acetic acid

avanafil
330784-47-9

avanafil

Conditions
ConditionsYield
Stage #1: 4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]pyrimidine-5-carboxylic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 25 - 35℃; for 0.333333h;
Stage #2: 2-aminomethylpyrimidine acetic acid With triethylamine In N,N-dimethyl-formamide at 25 - 35℃; for 9h;
Stage #3: In methanol at 25 - 35℃; for 0.75h;
68 g
4-[(3-chloro-4-methoxybenzyl)amino]-2-(methylsulfanyl)pyrimidine-5-carboxylic acid
330786-34-0

4-[(3-chloro-4-methoxybenzyl)amino]-2-(methylsulfanyl)pyrimidine-5-carboxylic acid

avanafil
330784-47-9

avanafil

Conditions
ConditionsYield
Multi-step reaction with 3 steps
1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 20 °C
2: 3-chloro-benzenecarboperoxoic acid / 0 °C
3: 20 - 120 °C
View Scheme
Multi-step reaction with 3 steps
1.1: thionyl chloride / toluene; N,N-dimethyl-formamide / 2.5 h / Reflux
1.2: 15 - 30 °C
2.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 1 h / 25 - 30 °C
3.1: triethylamine / dichloromethane
View Scheme
Multi-step reaction with 4 steps
1.1: thionyl chloride / toluene; N,N-dimethyl-formamide / 2.5 h / Reflux
1.2: 15 - 30 °C
2.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 1 h / 25 - 30 °C
3.1: triethylamine / dichloromethane
4.1: sulfuric acid / ethanol / Reflux
4.2: 5 h
View Scheme
4-((3-chloro-4-methoxybenzyl)amino)-2-(methylthio)-N-(pyrimidin-2-ylmethyl)pyrimidine-5-formamide

4-((3-chloro-4-methoxybenzyl)amino)-2-(methylthio)-N-(pyrimidin-2-ylmethyl)pyrimidine-5-formamide

avanafil
330784-47-9

avanafil

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1: 3-chloro-benzenecarboperoxoic acid / 0 °C
2: 20 - 120 °C
View Scheme
Multi-step reaction with 2 steps
1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 1 h / 25 - 30 °C
2: triethylamine / dichloromethane
View Scheme
Multi-step reaction with 3 steps
1.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 1 h / 25 - 30 °C
2.1: triethylamine / dichloromethane
3.1: sulfuric acid / ethanol / Reflux
3.2: 5 h
View Scheme
Multi-step reaction with 4 steps
1.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 1 h / 25 - 30 °C
2.1: triethylamine / dichloromethane
3.1: thionyl chloride / toluene; N,N-dimethyl-formamide / 2.5 h / Reflux
4.1: sodium tetrahydroborate / tetrahydrofuran / 0 - 5 °C
4.2: 60 - 70 °C
View Scheme
4-chloro-2-methanesulfanylpyrimidine-5-carboxylic acid ethyl ester
5909-24-0

4-chloro-2-methanesulfanylpyrimidine-5-carboxylic acid ethyl ester

avanafil
330784-47-9

avanafil

Conditions
ConditionsYield
Multi-step reaction with 5 steps
1: triethylamine / tetrahydrofuran / 20 °C
2: sodium hydroxide / water; ethanol / 20 °C
3: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 20 °C
4: 3-chloro-benzenecarboperoxoic acid / 0 °C
5: 20 - 120 °C
View Scheme
Multi-step reaction with 5 steps
1: sodium carbonate / water / 4 h / 25 - 30 °C
2: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 1 h / 0 - 5 °C
3: triethylamine / dichloromethane / 5 - 10 °C
4: sodium hydroxide / water / 8.17 h / 25 - 100 °C
5: triethylamine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 14 h / 0 - 5 °C
View Scheme
Multi-step reaction with 5 steps
1: sodium carbonate; tetrabutylammomium bromide / water / 8 h / 25 - 30 °C
2: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 1 h / 0 - 5 °C
3: triethylamine / dichloromethane / 5 - 10 °C
4: sodium hydroxide / water / 8.17 h / 25 - 100 °C
5: triethylamine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 14 h / 0 - 5 °C
View Scheme
ethyl 4-[(3-chloro-4-methoxybenzyl)amino]-2-(methylsulfanyl)pyrimidine-5-carboxylate
330785-81-4

ethyl 4-[(3-chloro-4-methoxybenzyl)amino]-2-(methylsulfanyl)pyrimidine-5-carboxylate

avanafil
330784-47-9

avanafil

Conditions
ConditionsYield
Multi-step reaction with 4 steps
1: sodium hydroxide / water; ethanol / 20 °C
2: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 20 °C
3: 3-chloro-benzenecarboperoxoic acid / 0 °C
4: 20 - 120 °C
View Scheme
Multi-step reaction with 4 steps
1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 1 h / 0 - 5 °C
2: triethylamine / dichloromethane / 5 - 10 °C
3: sodium hydroxide / water / 8.17 h / 25 - 100 °C
4: triethylamine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 14 h / 0 - 5 °C
View Scheme
Multi-step reaction with 4 steps
1.1: water; sodium hydroxide / methanol / Reflux
2.1: thionyl chloride / toluene; N,N-dimethyl-formamide / 2.5 h / Reflux
2.2: 15 - 30 °C
3.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 1 h / 25 - 30 °C
4.1: triethylamine / dichloromethane
View Scheme
(3-chloro-4-methoxyphenyl)methanamine
115514-77-7

(3-chloro-4-methoxyphenyl)methanamine

avanafil
330784-47-9

avanafil

Conditions
ConditionsYield
Multi-step reaction with 5 steps
1: triethylamine / tetrahydrofuran / 20 °C
2: sodium hydroxide / water; ethanol / 20 °C
3: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 20 °C
4: 3-chloro-benzenecarboperoxoic acid / 0 °C
5: 20 - 120 °C
View Scheme
Multi-step reaction with 6 steps
1: methanol / 0.25 h / 60 - 65 °C
2: sodium carbonate; tetrabutylammomium bromide / water / 8 h / 25 - 30 °C
3: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 1 h / 0 - 5 °C
4: triethylamine / dichloromethane / 5 - 10 °C
5: sodium hydroxide / water / 8.17 h / 25 - 100 °C
6: triethylamine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 14 h / 0 - 5 °C
View Scheme
Multi-step reaction with 5 steps
1.1: tetrabutylammomium bromide; sodium carbonate / dichloromethane; water / 25 - 30 °C
2.1: water; sodium hydroxide / methanol / Reflux
3.1: thionyl chloride / toluene; N,N-dimethyl-formamide / 2.5 h / Reflux
3.2: 15 - 30 °C
4.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 1 h / 25 - 30 °C
5.1: triethylamine / dichloromethane
View Scheme
ethyl 4-hydroxy-2-(methylthio)pyrimidine-5-carboxylate
53554-29-3

ethyl 4-hydroxy-2-(methylthio)pyrimidine-5-carboxylate

avanafil
330784-47-9

avanafil

Conditions
ConditionsYield
Multi-step reaction with 6 steps
1: trichlorophosphate / toluene / 4 h / 55 - 105 °C
2: sodium carbonate; tetrabutylammomium bromide / water / 8 h / 25 - 30 °C
3: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 1 h / 0 - 5 °C
4: triethylamine / dichloromethane / 5 - 10 °C
5: sodium hydroxide / water / 8.17 h / 25 - 100 °C
6: triethylamine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 14 h / 0 - 5 °C
View Scheme
Multi-step reaction with 6 steps
1: trichlorophosphate / toluene / 4 h / 55 - 105 °C
2: sodium carbonate / water / 4 h / 25 - 30 °C
3: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 1 h / 0 - 5 °C
4: triethylamine / dichloromethane / 5 - 10 °C
5: sodium hydroxide / water / 8.17 h / 25 - 100 °C
6: triethylamine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 14 h / 0 - 5 °C
View Scheme
Multi-step reaction with 6 steps
1: trichlorophosphate / acetonitrile / 6 h / Reflux
2: triethylamine / acetone / 3 h / 20 °C
3: methanol; sodium hydroxide / 4.5 h / 20 - 30 °C
4: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; triethylamine / N,N-dimethyl-formamide; N,N-dimethyl-aniline / 7 h / 60 °C
5: acetic acid; dihydrogen peroxide / 4 h / 65 - 80 °C
6: N-ethyl-N,N-diisopropylamine / isopropyl alcohol / 5 h / 20 °C
View Scheme
4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonyl-2-methylsulfinylpyrimidine
330785-82-5

4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonyl-2-methylsulfinylpyrimidine

avanafil
330784-47-9

avanafil

Conditions
ConditionsYield
Multi-step reaction with 3 steps
1: triethylamine / dichloromethane / 5 - 10 °C
2: sodium hydroxide / water / 8.17 h / 25 - 100 °C
3: triethylamine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 14 h / 0 - 5 °C
View Scheme
Multi-step reaction with 3 steps
1: triethylamine / dichloromethane / -5 - 30 °C / Large scale
2: sodium hydroxide / dimethyl sulfoxide; water / 25 - 35 °C / Large scale
3: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 15 - 25 °C
View Scheme
ethyl (S)-4-((3-chloro-4-methoxybenzyl)amino)-2-(2-(hydroxymethyl)tetrahydropyrrole-1-yl)-5-pyrimidinecarboxylate

ethyl (S)-4-((3-chloro-4-methoxybenzyl)amino)-2-(2-(hydroxymethyl)tetrahydropyrrole-1-yl)-5-pyrimidinecarboxylate

avanafil
330784-47-9

avanafil

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1: sodium hydroxide / water / 8.17 h / 25 - 100 °C
2: triethylamine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 14 h / 0 - 5 °C
View Scheme
Multi-step reaction with 2 steps
1.1: sodium hydroxide / water; dimethyl sulfoxide / 20 °C / Cooling with ice
2.1: triethylamine / N,N-dimethyl-formamide / 0.5 h
2.2: 8 h / 20 °C
View Scheme
Multi-step reaction with 3 steps
1: sodium hydroxide / water; dimethyl sulfoxide / 20 °C / Cooling with ice
2: thionyl chloride / 4 h / 80 °C
3: triethylamine / dichloromethane / 20 °C
View Scheme
1-(pyrimidin-2-yl)methanamine hydrochloride
372118-67-7

1-(pyrimidin-2-yl)methanamine hydrochloride

4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]pyrimidine-5-carboxylic acid
330785-84-7

4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]pyrimidine-5-carboxylic acid

avanafil
330784-47-9

avanafil

Conditions
ConditionsYield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 0 - 5℃; for 14h; Time;145 g
(3-chloro-4-methoxyphenyl)methanamine malate

(3-chloro-4-methoxyphenyl)methanamine malate

avanafil
330784-47-9

avanafil

Conditions
ConditionsYield
Multi-step reaction with 5 steps
1: sodium carbonate; tetrabutylammomium bromide / water / 8 h / 25 - 30 °C
2: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 1 h / 0 - 5 °C
3: triethylamine / dichloromethane / 5 - 10 °C
4: sodium hydroxide / water / 8.17 h / 25 - 100 °C
5: triethylamine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 14 h / 0 - 5 °C
View Scheme
4-[(3-chloro-4-methoxybenzyl)amino]-2-(methyl sulfinyl)-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide

4-[(3-chloro-4-methoxybenzyl)amino]-2-(methyl sulfinyl)-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide

avanafil
330784-47-9

avanafil

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1.1: triethylamine / dichloromethane
2.1: sulfuric acid / ethanol / Reflux
2.2: 5 h
View Scheme
Multi-step reaction with 3 steps
1.1: triethylamine / dichloromethane
2.1: thionyl chloride / toluene; N,N-dimethyl-formamide / 2.5 h / Reflux
3.1: sodium tetrahydroborate / tetrahydrofuran / 0 - 5 °C
3.2: 60 - 70 °C
View Scheme
4-[(3-chloro-4-methoxybenzyl)amino]-2-(methyl sulfinyl)-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide

4-[(3-chloro-4-methoxybenzyl)amino]-2-(methyl sulfinyl)-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide

(S)-1-Pyrrolidin-2-yl-methanol
23356-96-9

(S)-1-Pyrrolidin-2-yl-methanol

avanafil
330784-47-9

avanafil

Conditions
ConditionsYield
With triethylamine In dichloromethane8 g
C23H24ClN7O4

C23H24ClN7O4

avanafil
330784-47-9

avanafil

Conditions
ConditionsYield
Stage #1: C23H24ClN7O4 With sulfuric acid In ethanol Reflux;
Stage #2: With sodium tetrahydroborate; lithium bromide In ethanol for 5h;
7.5 g
C23H23Cl2N7O3

C23H23Cl2N7O3

avanafil
330784-47-9

avanafil

Conditions
ConditionsYield
Stage #1: C23H23Cl2N7O3 With sodium tetrahydroborate In tetrahydrofuran at 0 - 5℃;
Stage #2: With potassium hydroxide In water at 60 - 70℃;
40 g
4-(bromomethyl)-2-chloro-1-methoxybenzene
320407-92-9

4-(bromomethyl)-2-chloro-1-methoxybenzene

avanafil
330784-47-9

avanafil

Conditions
ConditionsYield
Multi-step reaction with 3 steps
1.1: potassium iodide; triethylamine / ethanol / 3 h / 50 - 80 °C
2.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate / acetonitrile / 24 h / 20 - 60 °C / Inert atmosphere
2.2: 5 h / 55 °C
3.1: bromine; sodium hydroxide / 0.08 h / Microwave irradiation
3.2: 10 h / 120 °C / Inert atmosphere
View Scheme
Multi-step reaction with 3 steps
1.1: potassium iodide; triethylamine / ethanol / 3 h / 50 - 80 °C
2.1: sodium hydroxide; iodine / 0.08 h / Microwave irradiation
2.2: 10 h / 110 °C / Inert atmosphere
3.1: 1,8-diazabicyclo[5.4.0]undec-7-ene; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate / acetonitrile / 24 h / 20 - 60 °C / Inert atmosphere
3.2: 5 h / 65 °C
View Scheme
avanafil
330784-47-9

avanafil

citric acid
77-92-9

citric acid

avanafil-citric acid

avanafil-citric acid

Conditions
ConditionsYield
In acetone at 25℃; for 8h; Solvent; Sealed tube;96.5%
avanafil
330784-47-9

avanafil

4-nitrophenyl 3-[(25)-2,3-bis(nitrooxy)propoxy] propanoate

4-nitrophenyl 3-[(25)-2,3-bis(nitrooxy)propoxy] propanoate

[(2S)-1-(4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-5-{[(pyrimidin-2-yl)methyl]carbamoyl}pyrimidin-2-yl)pyrrolidin-2-yl]methyl 3-[(2S)-2,3-bis(nitrooxy)propoxy]propanoate

[(2S)-1-(4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-5-{[(pyrimidin-2-yl)methyl]carbamoyl}pyrimidin-2-yl)pyrrolidin-2-yl]methyl 3-[(2S)-2,3-bis(nitrooxy)propoxy]propanoate

Conditions
ConditionsYield
With dmap In dichloromethane at 20℃;95%
avanafil
330784-47-9

avanafil

(5S)-5,6-bis(nitrooxy)hexanoic acid
1178531-55-9

(5S)-5,6-bis(nitrooxy)hexanoic acid

[(2S)-1-(4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-5-{[(pyrimidin-2-yl)methyl]carbamoyl}pyrimidin-2-yl)pyrrolidin-2-yl]methyl (5S)-5,6-bis(nitrooxy)hexanoate

[(2S)-1-(4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-5-{[(pyrimidin-2-yl)methyl]carbamoyl}pyrimidin-2-yl)pyrrolidin-2-yl]methyl (5S)-5,6-bis(nitrooxy)hexanoate

Conditions
ConditionsYield
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃;94.5%
avanafil
330784-47-9

avanafil

6-(nitrooxy)hexanoic acid
74754-55-5

6-(nitrooxy)hexanoic acid

(S)-(1-(4-(3-chloro-4-methoxybenzylamino)-5-(pyrimidin-2-ylmethylcarbamoyl)pyrimidin-2-yl)pyrrolidin-2-yl)methyl 6-(nitrooxy)hexanoate

(S)-(1-(4-(3-chloro-4-methoxybenzylamino)-5-(pyrimidin-2-ylmethylcarbamoyl)pyrimidin-2-yl)pyrrolidin-2-yl)methyl 6-(nitrooxy)hexanoate

Conditions
ConditionsYield
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃;93%
avanafil
330784-47-9

avanafil

2-(2-(nitrooxy)ethoxy)acetic acid
1321458-84-7

2-(2-(nitrooxy)ethoxy)acetic acid

(S)-(1-(4-(3-chloro-4-methoxybenzylamino)-5-(pyrimidin-2-ylmethylcarbamoyl)pyrimidin-2-yl)pyrrolidin-2-yl)methyl 2-(2-(nitrooxy)ethoxy)acetate

(S)-(1-(4-(3-chloro-4-methoxybenzylamino)-5-(pyrimidin-2-ylmethylcarbamoyl)pyrimidin-2-yl)pyrrolidin-2-yl)methyl 2-(2-(nitrooxy)ethoxy)acetate

Conditions
ConditionsYield
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃;52%
avanafil
330784-47-9

avanafil

boron monobromide
19961-29-6

boron monobromide

sodium hydrogencarbonate
144-55-8

sodium hydrogencarbonate

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-hydroxybenzylamino)-5-[N-(2-pyrimidylmethyl)carbamoyl]pyrimidine
330785-05-2

(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-hydroxybenzylamino)-5-[N-(2-pyrimidylmethyl)carbamoyl]pyrimidine

Conditions
ConditionsYield
In tetrahydrofuran; methanol; dichloromethane; chloroform; ethyl acetate

330784-47-9Relevant articles and documents

Method of preparing medical compound stendra

-

, (2019/02/04)

The invention discloses a method of preparing a medical compound stendra and belongs to the technical field of medical compounds. The key point of the technical scheme is as follows: the synthetic route of the method of preparing the medical compound stendra is as follows: a formula as shown in the description. The method has the advantages of being high in yield, low in cost, economical and environment-friendly, suitable for industrialization, high in product impurity and the like, and is a synthetic method which has industrial production value.

A pharmaceutical compound atorvastatin that non-synthetic method (by machine translation)

-

, (2019/02/10)

The present invention discloses a pharmaceutical compound atorvastatin that non-synthetic method, which belongs to the technical field of pharmaceutical synthesis of the compounds. Technical proposal of the invention points are: a pharmaceutical compound atorvastatin that non-synthetic method, its synthetic route is: The invention has the step is short, high yield, low cost, environmentally friendly and it is suitable for industrial, purity of the product and the like, is a with the value of industrial production of synthetic method. (by machine translation)

Preparation method of avanafil

-

, (2018/11/22)

The invention provides a preparation method of avanafil, and specifically relates to the technical field of pharmaceutical chemistry. The preparation method of avanafil comprises the following steps:sequentially carrying out cyclization and chlorination reactions on methyl thiourea sulfuric acid and diethyl ethoxymethylene malonate which serve as initial raw materials to obtain 4-chloro-2-methylthiopyrimidine-5-carboxylic acid ethyl ester; then substituting and hydrolyzing with 3-chloro-4-methoxybenzylamine; condensing with 2-pyrimidinemethanamine to obtain a key intermediate, namely, 4-[(3-chloro-methoxybenzyl)amino]-2-methylthio-N-(2-pyrimidine methyl)-5-pyrimidine formamide; oxidizing the intermediate and reacting with L-prolinol to generate the avanafil. The preparation method has theadvantages of easy availability of raw materials, easiness and convenience in operation, mild reaction conditions and higher product yield.

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