330784-47-9

Basic information

• Product Name: Avanafil
• Synonyms: 4-[[(3-Chloro-4-Methoxyphenyl)Methyl] aMino]-2-[(2S)-2-(hydroxyMethyl)-1-pyrrolidinyl]-N-(2-pyriMidinylMethyl)-5-pyriMidinecarboxaMide;4-((3-chloro-4-Methoxybenzyl)aMino)-2-(2-(hydroxyMethyl)pyrrolidin-1-yl)-N-(pyriMidin-2-ylMethyl)pyriMidine-5-carboxaMide;(S)-4-((3-Chloro-4-Methoxybenzyl)aMino)-2-(2-(hydroxyMethyl)pyrrolidin-1-yl)-N-(pyriMidin-2-ylMethyl)pyriMidine-5-carboxaMide;Avanafil 4-[(3-Chloro-4-methoxybenzyl)amino]-2-[2-(hydroxymethyl)-1-pyrrolidinyl]-N-(2-pyrimidinylmethyl)-5-pyrimidinecarboxamide;avanfil;avanafil:4-((3-chloro-4-methoxybenzyl)amino)-2-(2-(hydroxymethyl)-1-pyrrolidinyl)-n-(2-pyrimidinylmethyl)-5-pyrimidinecarboxamide: (s)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylami;(S)-4-[(3-Chloro-4-methoxybenzyl)amino]-2-[2-(hydroxymethyl)-1-pyrrolidinyl]-N-(2pyrimidinylmethyl)-5-pyrimidinecarboxamide;(S)-4-((3-Chloro-4-methoxybenzyl)amino)-2-(2-(hydroxymethyl)pyrrolidin-1-yl)-N-(pyrimidin-2-yl
• CAS NO: 330784-47-9
• Molecular Formula: C₂₃H₂₆ClN₇O₃
• Molecular Weight: 483.95
• Product Categories: Intermediates & Fine Chemicals;Pharmaceuticals;Inhibitor;Avanafil;Inhibitors;Aromatics;Chiral Reagents;Heterocycles
• Mol File: 330784-47-9.mol

Chemical Properties

• Melting Point: 150-152°C
• Appearance: White solid
• Density: 1.372
• Refractive Index: 1.651
• Storage Temp.: Refrigerator
• Solubility: DMSO (Slightly), Methanol (Slightly, Heated)
• PKA: 11.84±0.46(Predicted)
• CAS DataBase Reference: Avanafil(CAS DataBase Reference)
• NIST Chemistry Reference: Avanafil(330784-47-9)
• EPA Substance Registry System: Avanafil(330784-47-9)

Safety Data

• Hazardous Substances Data: 330784-47-9(Hazardous Substances Data)

Usage

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.

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

Synthetic route

4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]pyrimidine-5-carboxylic acid (330785-84-7) + 2-aminomethylpyrimidine (75985-45-4) → avanafil (330784-47-9)

Conditions	Yield
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 + (S)-1-Pyrrolidin-2-yl-methanol (23356-96-9) → avanafil (330784-47-9)

Conditions	Yield
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 + (S)-1-Pyrrolidin-2-yl-methanol (23356-96-9) → avanafil (330784-47-9)

Conditions	Yield
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 + (S)-1-Pyrrolidin-2-yl-methanol (23356-96-9) → avanafil (330784-47-9)

Conditions	Yield
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 + 2-aminomethylpyrimidine (75985-45-4) → avanafil (330784-47-9)

Conditions	Yield
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 + (S)-1-Pyrrolidin-2-yl-methanol (23356-96-9) → avanafil (330784-47-9)

Conditions	Yield
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 + N-(2-methylpyrimidine)methanamide → avanafil (330784-47-9)

Conditions	Yield
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) + 2-aminomethylpyrimidine methanesulfonate → avanafil (330784-47-9)

Conditions	Yield
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) + (S)-1-Pyrrolidin-2-yl-methanol (23356-96-9) + (3-chloro-4-methoxyphenyl)methylamine hydrogen chloride (41965-95-1) + 2,4-dichloropyrimidine-5-carbonyl chloride (2972-52-3) → avanafil (330784-47-9)

Conditions	Yield
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 + 2-aminomethylpyrimidine (75985-45-4) → avanafil (330784-47-9)

Conditions	Yield
With triethylamine In dichloromethane at 20℃;	64%

2-chloro-4-((3-chloro-4-methoxybenzyl)amino)-N-[pyrimidin-2ylmethyl]pyrimidine-5-carboxamide → avanafil (330784-47-9)

Conditions	Yield
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) + 2-aminomethylpyrimidine acetate (1246834-64-9) → avanafil (330784-47-9)

Conditions	Yield
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 + (S)-1-Pyrrolidin-2-yl-methanol (23356-96-9) + (3-chloro-4-methoxyphenyl)methylamine hydrogen chloride (41965-95-1) → avanafil (330784-47-9)

Conditions	Yield
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) + 2-aminomethylpyrimidine acetic acid → avanafil (330784-47-9)

Conditions

Yield

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) → avanafil (330784-47-9)

Conditions	Yield
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 → avanafil (330784-47-9)

Conditions	Yield
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) → avanafil (330784-47-9)

Conditions	Yield
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) → avanafil (330784-47-9)

Conditions	Yield
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) → avanafil (330784-47-9)

Conditions	Yield
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) → avanafil (330784-47-9)

Conditions	Yield
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) → avanafil (330784-47-9)

Conditions	Yield
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 → avanafil (330784-47-9)

Conditions	Yield
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) + 4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]pyrimidine-5-carboxylic acid (330785-84-7) → avanafil (330784-47-9)

Conditions	Yield
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 → avanafil (330784-47-9)

Conditions

Yield

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 → avanafil (330784-47-9)

Conditions	Yield
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 + (S)-1-Pyrrolidin-2-yl-methanol (23356-96-9) → avanafil (330784-47-9)

Conditions	Yield
With triethylamine In dichloromethane	8 g

C23H24ClN7O4 → avanafil (330784-47-9)

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

C23H23Cl2N7O3 → avanafil (330784-47-9)

Conditions	Yield
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) → avanafil (330784-47-9)

Conditions	Yield
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) + citric acid (77-92-9) → avanafil-citric acid

Conditions	Yield
In acetone at 25℃; for 8h; Solvent; Sealed tube;	96.5%

avanafil (330784-47-9) + 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

Conditions	Yield
With dmap In dichloromethane at 20℃;	95%

avanafil (330784-47-9) + (5S)-5,6-bis(nitrooxy)hexanoic acid (1178531-55-9) → [(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	Yield
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃;	94.5%

avanafil (330784-47-9) + 6-(nitrooxy)hexanoic acid (74754-55-5) → (S)-(1-(4-(3-chloro-4-methoxybenzylamino)-5-(pyrimidin-2-ylmethylcarbamoyl)pyrimidin-2-yl)pyrrolidin-2-yl)methyl 6-(nitrooxy)hexanoate

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃;	93%

avanafil (330784-47-9) + 2-(2-(nitrooxy)ethoxy)acetic acid (1321458-84-7) → (S)-(1-(4-(3-chloro-4-methoxybenzylamino)-5-(pyrimidin-2-ylmethylcarbamoyl)pyrimidin-2-yl)pyrrolidin-2-yl)methyl 2-(2-(nitrooxy)ethoxy)acetate

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃;	52%

avanafil (330784-47-9) + boron monobromide (19961-29-6) + sodium hydrogencarbonate (144-55-8) → (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-hydroxybenzylamino)-5-[N-(2-pyrimidylmethyl)carbamoyl]pyrimidine (330785-05-2)

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

Upstream product

• 1638497-22-9 ethyl (S)-4-((3-chloro-4-methoxybenzyl)amino)-2-(2-(hydroxymethyl)tetrahydropyrrole-1-yl)-5-pyrimidinecarboxylate 
• 75985-45-4 2-aminomethylpyrimidine 
• 372117-76-5 2-methylsulfonyl-5-ethoxycarbonyl-4-(3-chloro-4-methoxybenzylamino)pyrimidine 
• 330786-00-0 2-chloro-4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonylpyrimidine 
• 41965-95-1 (3-chloro-4-methoxyphenyl)methylamine hydrogen chloride 
• 330785-84-7 4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]pyrimidine-5-carboxylic acid 
• 28485-17-8 5-carbethoxyuracil 
• 51940-64-8 ethyl 2,4-dichloropyrimidine-5-carboxylate 
• 3346-68-7 uracil-5-formyl chloride 
• 23945-44-0 2,4-dihydroxypyrimidine-5-carboxylic acid 
• 1246834-64-9 2-aminomethylpyrimidine acetate 
• 23356-96-9 (S)-1-Pyrrolidin-2-yl-methanol 
• 2972-52-3 2,4-dichloropyrimidine-5-carbonyl chloride 

Downstream Products

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

Relevant articles and documents

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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.

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The invention discloses a preparation method of a pharmaceutical compound avanafil, and belongs to the technical field of synthesis of pharmaceutical compounds. The key point of the technical scheme of the invention is as follows: a synthesis route of the synthetic method of the pharmaceutical compound avanafil is shown in the specification. The synthetic method has the advantages that the yield is high, the cost is low, the method is economical and environmentally friendly and is suitable for industrialization, the product purity is high and the like, and the method is a synthetic method withindustrial production values.

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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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The invention provides a synthesis method of avanafil. The synthesis method of avanafil comprises the following steps: carrying out nucleophilic substitution reaction with a compound (13) or a compound (3) by a compound (18), hydrolyzing to prepare a compound (21) or a compound (22), reacting the compound (21) or the compound (22) with sulfonic acid chloride or pivaloyl chloride to obtain mixed anhydride, reacting the mixed anhydride with a compound (23) to prepare a compound (24) or a compound (25), then oxidizing the compound (24), subsequently reacting the compound (24) with a compound (9) to prepare avanafil, or directly reacting the compound (25) with the compound (9) to prepare avanafil. The synthesis method is high in controllability, simple in step, high in yield and low in cost, and is suitable for industrial production. The reaction route is shown in the description.

Method for preparing avanafil raw material medicine

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