123654-26-2

Basic information

• Product Name: 4-Amino-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid
• Synonyms: 4-Amino-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid;4-Amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid;4-aMino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid;4-AMino-5-chloro-2,3-dihydro-7-benzofurane karboxylic acid;4-amino-5-chloro-2,3-dihydro-1-benzofuran-7-carboxylic acid;Prucalopride Impurity A
• CAS NO: 123654-26-2
• Molecular Formula: C₉H₈ClNO₃
• Molecular Weight: 213.61772
• EINECS: 1592732-453-0
• Mol File: 123654-26-2.mol
• Article Data: 6

Chemical Properties

• Melting Point: 242 °C(dec.)
• Boiling Point: 406.498 °C at 760 mmHg
• Flash Point: 199.643 °C
• Appearance: /
• Density: 1.566
• Storage Temp.: 2-8°C(protect from light)
• Solubility: DMSO (Slightly), Methanol (Slightly, Heated)
• PKA: 4.45±0.20(Predicted)
• CAS DataBase Reference: 4-Amino-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid(CAS DataBase Reference)
• NIST Chemistry Reference: 4-Amino-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid(123654-26-2)
• EPA Substance Registry System: 4-Amino-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid(123654-26-2)

Safety Data

• Hazardous Substances Data: 123654-26-2(Hazardous Substances Data)

Usage

Uses

4-Amino-5-chloro-2,3-dihydro-7-benzofurancarboxylic Acid, can be used as an intermediate for the synthesis of Prucalopride (P838950), a selective 5-HT4 receptor agonist used effective for chronic constipation.

Synthetic route

4-acetylamino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid sodium salt → 4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid (123654-26-2)

Conditions	Yield
With sodium hydroxide In water at 100℃; for 3h;	97%
Multi-step reaction with 2 steps 1: sulfuric acid / 8 h / 10 °C / Reflux 2: water; sodium hydroxide / methanol / 2 h / Reflux View Scheme

4-acetamido-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid methyl ester (143878-29-9) → 4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid (123654-26-2)

Conditions	Yield
With sodium hydroxide In methanol for 2h; Heating;	90.3%
With 1-methoxy-2-propanol; water; sodium hydroxide at 90℃; for 8h;	89.8%
With water; sodium hydroxide for 5h; Reagent/catalyst;	89%
Multi-step reaction with 3 steps 1: water; sodium hydroxide / methanol / 2.17 h / 25 - 55 °C 2: sulfuric acid / 8 h / 10 °C / Reflux 3: water; sodium hydroxide / methanol / 2 h / Reflux View Scheme

methyl 4-acetamido-2-hydroxybenzoate (4093-28-1) → 4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid (123654-26-2)

Conditions	Yield
Multi-step reaction with 8 steps 1: 95.5 percent / K2CO3, tetra-n-butylammonium chloride / acetonitrile / 22 h / Heating 2: 94.9 percent / N-methylpyrrolidone / 1.5 h / Heating 3: OsO4 / diethyl ether; H2O / 0.17 h / 20 - 25 °C 4: NaIO4 / diethyl ether; H2O / 12 h / 20 - 25 °C 5: NaBH4 / methanol / 2 h / 20 - 25 °C 6: 86.7 percent / diethyl azodicarboxylate, Ph3P / tetrahydrofuran / 1 h / 20 - 25 °C 7: NCS / dimethylformamide / 3 h / 70 °C 8: 90.3 percent / 4N NaOH / methanol / 2 h / Heating View Scheme
Multi-step reaction with 5 steps 1.1: sulfuryl dichloride / ethyl acetate / 2 h / -5 - 0 °C 2.1: N-Bromosuccinimide / N,N-dimethyl-formamide / 20 °C 3.1: potassium carbonate / N,N-dimethyl acetamide / 0.5 h / 20 °C 3.2: 5 h / 50 °C 4.1: zinc / N,N-dimethyl acetamide / 22 h / 20 - 50 °C / Inert atmosphere 4.2: 0.5 h / 70 °C / Inert atmosphere 5.1: sodium hydroxide; 1-methoxy-2-propanol; water / 8 h / 90 °C View Scheme

methyl 2-allyloxy-4-acetylaminobenzoate (91958-13-3) → 4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid (123654-26-2)

Conditions

Yield

Multi-step reaction with 7 steps 1: 94.9 percent / N-methylpyrrolidone / 1.5 h / Heating 2: OsO4 / diethyl ether; H2O / 0.17 h / 20 - 25 °C 3: NaIO4 / diethyl ether; H2O / 12 h / 20 - 25 °C 4: NaBH4 / methanol / 2 h / 20 - 25 °C 5: 86.7 percent / diethyl azodicarboxylate, Ph3P / tetrahydrofuran / 1 h / 20 - 25 °C 6: NCS / dimethylformamide / 3 h / 70 °C 7: 90.3 percent / 4N NaOH / methanol / 2 h / Heating View Scheme

methyl 2-hydroxy-3-allyl-4-acetaminobenzoate (110751-41-2) → 4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid (123654-26-2)

Conditions	Yield
Multi-step reaction with 6 steps 1: OsO4 / diethyl ether; H2O / 0.17 h / 20 - 25 °C 2: NaIO4 / diethyl ether; H2O / 12 h / 20 - 25 °C 3: NaBH4 / methanol / 2 h / 20 - 25 °C 4: 86.7 percent / diethyl azodicarboxylate, Ph3P / tetrahydrofuran / 1 h / 20 - 25 °C 5: NCS / dimethylformamide / 3 h / 70 °C 6: 90.3 percent / 4N NaOH / methanol / 2 h / Heating View Scheme

4-(acetylamino)-2-hydroxy-3-(2-oxoethyl)benzoic acid methyl ester (202664-83-3) → 4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid (123654-26-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: NaBH4 / methanol / 2 h / 20 - 25 °C 2: 86.7 percent / diethyl azodicarboxylate, Ph3P / tetrahydrofuran / 1 h / 20 - 25 °C 3: NCS / dimethylformamide / 3 h / 70 °C 4: 90.3 percent / 4N NaOH / methanol / 2 h / Heating View Scheme

methyl 4-acetylamino-2-hydroxy-3-(2-hydroxyethyl)benzoate (202664-85-5) → 4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid (123654-26-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: 86.7 percent / diethyl azodicarboxylate, Ph3P / tetrahydrofuran / 1 h / 20 - 25 °C 2: NCS / dimethylformamide / 3 h / 70 °C 3: 90.3 percent / 4N NaOH / methanol / 2 h / Heating View Scheme
Multi-step reaction with 5 steps 1.1: triphenylphosphine / tetrahydrofuran / 0.25 h / 25 - 30 °C 1.2: 1 h / 10 - 30 °C 2.1: N-chloro-succinimide / N,N-dimethyl-formamide / 2.17 h / 25 - 75 °C 3.1: water; sodium hydroxide / methanol / 2.17 h / 25 - 55 °C 4.1: sulfuric acid / 8 h / 10 °C / Reflux 5.1: water; sodium hydroxide / methanol / 2 h / Reflux View Scheme

methyl 4-acetylamino-2,3-dihydrobenzo[b]furan-7-carboxylate (149466-67-1) → 4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid (123654-26-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: NCS / dimethylformamide / 3 h / 70 °C 2: 90.3 percent / 4N NaOH / methanol / 2 h / Heating View Scheme
Multi-step reaction with 4 steps 1: N-chloro-succinimide / N,N-dimethyl-formamide / 2.17 h / 25 - 75 °C 2: water; sodium hydroxide / methanol / 2.17 h / 25 - 55 °C 3: sulfuric acid / 8 h / 10 °C / Reflux 4: water; sodium hydroxide / methanol / 2 h / Reflux View Scheme
Multi-step reaction with 2 steps 1: N-chloro-succinimide / N,N-dimethyl-formamide / 2 h / 65 °C 2: water; sodium hydroxide / 5 h View Scheme

4-Acetylamino-3-(2,3-dihydroxy-propyl)-2-hydroxy-benzoic acid methyl ester → 4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid (123654-26-2)

Conditions	Yield
Multi-step reaction with 5 steps 1: NaIO4 / diethyl ether; H2O / 12 h / 20 - 25 °C 2: NaBH4 / methanol / 2 h / 20 - 25 °C 3: 86.7 percent / diethyl azodicarboxylate, Ph3P / tetrahydrofuran / 1 h / 20 - 25 °C 4: NCS / dimethylformamide / 3 h / 70 °C 5: 90.3 percent / 4N NaOH / methanol / 2 h / Heating View Scheme

7-bromo-5-chloro-2,3-dihydro-4-benzofuranamine + carbon dioxide (124-38-9) → 4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid (123654-26-2)

Conditions	Yield
With n-butyllithium In tetrahydrofuran; hexane; water	1.1 parts (32.2%)

methyl 4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylate → 4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid (123654-26-2)

Conditions	Yield
With water; sodium hydroxide In methanol for 2h; Reflux;

4-acetamido-3-bromo-5-chloro-2-hydroxybenzoic acid methyl ester → 4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid (123654-26-2)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: potassium carbonate / N,N-dimethyl acetamide / 0.5 h / 20 °C 1.2: 5 h / 50 °C 2.1: zinc / N,N-dimethyl acetamide / 22 h / 20 - 50 °C / Inert atmosphere 2.2: 0.5 h / 70 °C / Inert atmosphere 3.1: sodium hydroxide; 1-methoxy-2-propanol; water / 8 h / 90 °C View Scheme

methyl 4-aminosalicylate (4136-97-4) → 4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid (123654-26-2)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: acetic acid / 1 h / 40 °C 2.1: sulfuryl dichloride / ethyl acetate / 2 h / -5 - 0 °C 3.1: N-Bromosuccinimide / N,N-dimethyl-formamide / 20 °C 4.1: potassium carbonate / N,N-dimethyl acetamide / 0.5 h / 20 °C 4.2: 5 h / 50 °C 5.1: zinc / N,N-dimethyl acetamide / 22 h / 20 - 50 °C / Inert atmosphere 5.2: 0.5 h / 70 °C / Inert atmosphere 6.1: sodium hydroxide; 1-methoxy-2-propanol; water / 8 h / 90 °C View Scheme

4-Aminosalicylic acid (65-49-6) → 4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid (123654-26-2)

Conditions

Yield

Multi-step reaction with 7 steps 1.1: sulfuric acid / 6 h / 0 - 80 °C 2.1: acetic acid / 1 h / 40 °C 3.1: sulfuryl dichloride / ethyl acetate / 2 h / -5 - 0 °C 4.1: N-Bromosuccinimide / N,N-dimethyl-formamide / 20 °C 5.1: potassium carbonate / N,N-dimethyl acetamide / 0.5 h / 20 °C 5.2: 5 h / 50 °C 6.1: zinc / N,N-dimethyl acetamide / 22 h / 20 - 50 °C / Inert atmosphere 6.2: 0.5 h / 70 °C / Inert atmosphere 7.1: sodium hydroxide; 1-methoxy-2-propanol; water / 8 h / 90 °C View Scheme

methyl 4-acetylamino-5-chloro-2-hydroxybenzoate (24190-77-0) → 4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid (123654-26-2)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: N-Bromosuccinimide / N,N-dimethyl-formamide / 20 °C 2.1: potassium carbonate / N,N-dimethyl acetamide / 0.5 h / 20 °C 2.2: 5 h / 50 °C 3.1: zinc / N,N-dimethyl acetamide / 22 h / 20 - 50 °C / Inert atmosphere 3.2: 0.5 h / 70 °C / Inert atmosphere 4.1: sodium hydroxide; 1-methoxy-2-propanol; water / 8 h / 90 °C View Scheme

4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid (123654-26-2) → 4-amino-5-chloro-2,3-dihydro-7-benzofurancarbonyl chloride

Conditions	Yield
In thionyl chloride; chloroform; toluene	100%

4-amino-1-(3-methoxypropyl)piperidine (179474-79-4) + succinic acid (110-15-6) + 4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid (123654-26-2) → prucalopride succinic acid

Conditions	Yield
Stage #1: 4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid With 1,1'-carbonyldiimidazole In tetrahydrofuran for 1.5h; Stage #2: 4-amino-1-(3-methoxypropyl)piperidine In tetrahydrofuran at 45℃; for 4h; Stage #3: succinic acid In ethanol at 20℃; for 2h; Solvent; Reagent/catalyst; Temperature;	94%

methanol (67-56-1) + 4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid (123654-26-2) → methyl 4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylate

Conditions	Yield
With thionyl chloride at 0 - 20℃; for 2h; Reflux;	92.9%
With thionyl chloride at 0℃; Reflux;	92.9%

4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid (123654-26-2) → 4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxamide

Conditions	Yield
Stage #1: 4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 70℃; for 2.5h; Stage #2: With ammonium hydroxide In N,N-dimethyl-formamide at 20 - 70℃; for 20h;	86%

4-amino-1-(3-methoxypropyl)piperidine (179474-79-4) + 4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid (123654-26-2) → prucalopride (179474-81-8)

Conditions	Yield
Stage #1: 4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid With 1,1'-carbonyldiimidazole In tetrahydrofuran for 0.416667h; Stage #2: 4-amino-1-(3-methoxypropyl)piperidine In tetrahydrofuran at 45 - 50℃; for 4h;	85%

(4-((tetrahydro-2H-pyran-4-yl)methyl)morpholin-2-yl)methylamine hydrochloride + 4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid (123654-26-2) → 4-amino-5-chloro-N-((4-((tetrahydro-2H-pyran-4-yl)methyl)morpholin-2-yl)methyl)-2,3-dihydrobenzofuran-7-carboxamide

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In tetrahydrofuran at 20℃; for 20h;	61%

4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid (123654-26-2) + 4-amine-1-(3-fluoro)benzylpiperidine (160358-07-6) → 4-amino-5-chloro-N-(1-(3-fluorobenzyl)piperidin-4-yl)-2,3-dihydrobenzofuran-7-carboxamide

Conditions	Yield
Stage #1: 4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid With triethylamine; isobutyl chloroformate In dichloromethane at 0℃; for 2h; Stage #2: 4-amine-1-(3-fluoro)benzylpiperidine In dichloromethane for 15h;	58.1%

1-(3-(cyclopentyloxy)propyl)piperidine-4-amine hydrochloride + 4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid (123654-26-2) → 4-amino-5-chloro-N-(1-(3-(cyclopentyloxy)propyl)piperidin-4-yl)-2,3-dihydrobenzofuran-7-carboxamide

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 4h;	57%

4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid (123654-26-2) + 4-amino-1-[(4-fluorophenyl)methyl]piperidine (92539-14-5) → 4-amino-5-chloro-N-(1-(4-fluorobenzyl)piperidin-4-yl)-2,3-dihydrobenzofuran-7-carboxamide

Conditions	Yield
Stage #1: 4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid With triethylamine; isobutyl chloroformate In dichloromethane at 0℃; for 2h; Stage #2: 4-amino-1-[(4-fluorophenyl)methyl]piperidine In dichloromethane for 15h;	54%

1-((tetrahydro-2H-pyran-4-yl)methyl)piperidine-4-amine hydrochloride + 4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid (123654-26-2) → 4-amino-5-chloro-N-(1-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)-2,3-dihydrobenzofuran-7-carboxamide

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 20h;	52%

ClH*C12H20N4O2S + 4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid (123654-26-2) → C21H26ClN5O4S

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 16h;	52%

2-(aminomethyl)morpholine-4-carboxylic acid tert-butyl ester (140645-53-0) + 4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid (123654-26-2) → 2-((4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxamido)methyl)morpholine-4-carboxylic acid tert-butyl ester

Conditions	Yield
Stage #1: 4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid With triethylamine; isobutyl chloroformate In dichloromethane at 0℃; for 1h; Stage #2: 2-(aminomethyl)morpholine-4-carboxylic acid tert-butyl ester In dichloromethane for 29.5h;	51.9%

1-(tetrahydro-2H-pyran-4-yl)piperidine-4-amine hydrochloride (876716-13-1) + 4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid (123654-26-2) → 4-amino-5-chloro-N-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-2,3-dihydrobenzofuran-7-carboxamide

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In tetrahydrofuran at 20℃; for 20h;	46%

methyl 2-(3-(4-aminopiperidin-1-yl)propoxy)pyrimidine-4-carboxylate hydrochloride + 4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid (123654-26-2) → methyl 2-(3-(4-(4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxamido)piperidin-1-yl)propoxy)pyrimidine-4-carboxylate

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 22h;	39%

2-(3-(4-aminopiperidin-1-yl)propoxy)-4-methylthiazole-5-carboxamide hydrochloride + 4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid (123654-26-2) → 2-(3-(4-(4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxamido)piperidin-1-yl)propoxy)-4-methylthiazole-5-carboxamide

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 16h;	39%

1-(3-((5-fluoropyrimidin-2-yl)oxy)propyl)piperidine-4-amine hydrochloride + 4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid (123654-26-2) → 4-amino-5-chloro-N-(1-(3-((5-fluoropyrimidin-2-yl)oxy)propyl)piperidin-4-yl)-2,3-dihydrobenzofuran-7-carboxamide

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 22h;	37%

(4-(tetrahydro-2H-pyran-4-yl)morpholin-2-yl)methylamine hydrochloride + 4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid (123654-26-2) → 4-amino-5-chloro-N-((4-(tetrahydro-2H-pyran-4-yl)morpholin-2-yl)methyl)-2,3-dihydrobenzofuran-7-carboxamide

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 12h;	36%

1-(2-((5-fluoropyrimidin-2-yl)oxy)ethyl)piperidine-4-amine hydrochloride + 4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid (123654-26-2) → 4-amino-5-chloro-N-(1-(2-((5-fluoropyrimidin-2-yl)oxy)ethyl)piperidin-4-yl)-2,3-dihydrobenzofuran-7-carboxamide

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 12h;	30%

(4-(3-methoxypropyl)morpholin-2-yl)methylamine hydrochloride + 4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid (123654-26-2) → 4-amino-5-chloro-N-((4-(3-methoxypropyl)morpholin-2-yl)methyl)-2,3-dihydrobenzofuran-7-carboxamide

Conditions	Yield
Stage #1: 4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid With triethylamine; isobutyl chloroformate In dichloromethane at 0℃; for 4h; Stage #2: (4-(3-methoxypropyl)morpholin-2-yl)methylamine hydrochloride In dichloromethane at 20℃; for 19h;	25%

1-piperidinoethanol (3040-44-6) + 4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid (123654-26-2) → 4-Amino-5-chloro-2,3-dihydro-benzofuran-7-carboxylic acid 2-piperidin-1-yl-ethyl ester

Conditions	Yield
With 1,8-diazabicyclo[5.4.0]undec-7-ene; 1,1'-carbonyldiimidazole 1.) THF, 40 deg C, 1 h, 2.) DMF, 40 deg C, 2 h; Multistep reaction;

1-(2-aminoethyl)piperidine (27578-60-5) + 4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid (123654-26-2) → 4-Amino-5-chloro-2,3-dihydro-benzofuran-7-carboxylic acid (2-piperidin-1-yl-ethyl)-amide

Conditions	Yield
With 1,1'-carbonyldiimidazole 1.) THF, 40 deg C, 1 h, 2.) THF, 40 deg C, 2 h; Multistep reaction;

1-(3-aminopropyl)piperidine (3529-08-6) + 4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid (123654-26-2) → 4-Amino-5-chloro-2,3-dihydro-benzofuran-7-carboxylic acid (3-piperidin-1-yl-propyl)-amide; hydrochloride

Conditions	Yield
With 1,1'-carbonyldiimidazole 1.) THF, 40 deg C, 1 h, 2.) THF, 40 deg C, 2 h; Multistep reaction;

3-piperidinopropan-1-ol (104-58-5) + 4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid (123654-26-2) → 4-Amino-5-chloro-2,3-dihydro-benzofuran-7-carboxylic acid 3-piperidin-1-yl-propyl ester

Conditions	Yield
With 1,8-diazabicyclo[5.4.0]undec-7-ene; 1,1'-carbonyldiimidazole 1.) THF, 40 deg C, 1 h, 2.) DMF, 40 deg C, 2 h; Multistep reaction;

1-(1-butyl-4-piperidinyl)methanamine (65017-57-4) + 4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid (123654-26-2) → 4-Amino-5-chloro-2,3-dihydro-benzofuran-7-carboxylic acid (1-butyl-piperidin-4-ylmethyl)-amide

Conditions	Yield
With 1,1'-carbonyldiimidazole 1.) THF, 40 deg C, 1 h, 2.) THF, 40 deg C, 2 h; Multistep reaction;

(S)-3-aminoquinuclidine (120570-05-0) + 4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid (123654-26-2) → ADR-932

Conditions	Yield
With 1,1'-carbonyldiimidazole 1.) THF, 40 deg C, 1 h, 2.) THF, 40 deg C, 2 h; Multistep reaction;

(R)-3-aminoquinuclinine (123536-15-2) + 4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid (123654-26-2) → C16H20ClN3O2

Conditions	Yield
With 1,1'-carbonyldiimidazole 1.) THF, 40 deg C, 1 h, 2.) THF, 40 deg C, 2 h; Multistep reaction;

N-butyl-4-hydroxymethyl-piperidine (148703-15-5) + 4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid (123654-26-2) → 4-Amino-5-chloro-2,3-dihydro-benzofuran-7-carboxylic acid 1-butyl-piperidin-4-ylmethyl ester; hydrochloride

Conditions	Yield
With 1,8-diazabicyclo[5.4.0]undec-7-ene; 1,1'-carbonyldiimidazole 1.) THF, 40 deg C, 1 h, 2.) DMF, 40 deg C, 2 h; Multistep reaction;

4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylic acid (123654-26-2) + (S)-quinuclidin-3-ol (3684-26-2, 25333-42-0, 34583-34-1, 1619-34-7) → 4-Amino-5-chloro-2,3-dihydro-benzofuran-7-carboxylic acid (S)-(1-aza-bicyclo[2.2.2]oct-3-yl) ester

Conditions	Yield
With 1,8-diazabicyclo[5.4.0]undec-7-ene; 1,1'-carbonyldiimidazole 1.) THF, 40 deg C, 1 h, 2.) DMF, 40 deg C, 2 h; Multistep reaction;

Upstream product

• 24190-77-0 methyl 4-acetylamino-5-chloro-2-hydroxybenzoate 
• 65-49-6 4-Aminosalicylic acid 
• 4136-97-4 methyl 4-aminosalicylate 
• 232941-14-9 4-acetamido-3-bromo-5-chloro-2-hydroxybenzoic acid methyl ester 
• 182808-04-4 methyl 4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylate 
• 124-38-9 carbon dioxide 
• 149466-67-1 methyl 4-acetylamino-2,3-dihydrobenzo[b]furan-7-carboxylate 
• 202664-85-5 methyl 4-acetylamino-2-hydroxy-3-(2-hydroxyethyl)benzoate 
• 202664-83-3 4-(acetylamino)-2-hydroxy-3-(2-oxoethyl)benzoic acid methyl ester 
• 110751-41-2 methyl 2-hydroxy-3-allyl-4-acetaminobenzoate 
• 91958-13-3 methyl 2-allyloxy-4-acetylaminobenzoate 
• 4093-28-1 methyl 4-acetamido-2-hydroxybenzoate 
• 143878-29-9 4-acetamido-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid methyl ester 

Downstream Products

• 182808-04-4 methyl 4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylate 
• 138559-57-6 N-(1-azabicyclo [2.2.2]oct-3-yl)-4-amino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxamide 
• 137211-64-4 4-amino-5-chloro-2,3-dihydro-N-(4-piperidinyl)benzofuran-7-carboxamide 
• 179474-81-8 prucalopride 
• 179474-85-2 prucalopride succinate 
• 138559-57-6 ADR-932 

Relevant articles and documents

Continuous synthesis method of succinate (by machine translation)

The invention discloses a method for continuously synthesizing succinic acid, which is designed according to 3D printing technology, and sequentially combines the chlorination, hydrolysis, condensation, salt forming and refining steps of 4 -acetylamino -2, 3 -dihydrobenzofuran -7 - methyl formate into each reaction chamber to realize the continuous synthesis of drugs. To the method, tedious manual operation is not needed, chemical synthesis is carried out rapidly, the yield of a synthetic route is improved in a flowing chemical manner, and the safety problem caused by manual operation is avoided. The method provided by the invention can greatly reduce the cost generated in the aspects of drug storage, transportation and the like, thereby improving the medicine supply efficiency and stability, and bringing great economic and social benefits for the development of the pharmaceutical industry. (by machine translation)

PROCESSES FOR THE PREPARATION OF HIGHLY PURE PRUCALOPRIDE SUCCINATE AND ITS INTERMEDIATES

Provided herein are purification processes for the preparation of highly pure prucalopride succinate salt. Provided also herein are improved, commercially viable and industrially advantageous processes for the preparation of Prucalopride and its intermediate compounds, for example, methyl 4-acetylamino-5-chloro-2,3-dihydrobenzo[b]furan-7-carboxylate and alkyl 4-[[(4-amino-5-chloro-2,3-dihydro-7-benzofuranyl)carbonyl]-amino]-1-piperidinecarboxylate.

Synthesis and structure-activity relationship of 3-substituted benzamide, benzo[b]furan-7-carboxamide, 2,3-dihydrobenzo[b]furan-7- carboxamide, and indole-5-carboxamide derivatives as selective serotonin 5- HT4 receptor agonists

The title compounds (6-9) were prepared and evaluated for serotonin 5- HT4 agonistic activity in in vitro tests. Introducing a propyl or allyl group at the 3-position of benzamide caused only a slight enhancement of agonistic activity. Construction of the benzo[b']furan skeleton and 2,3- dihydrobenzo[b]furan skeleton caused a significant enhancement of the activity. 4-Amino-N-[2-(1-azabicyclo[3.3.0]octan-5-yl)ethyl]-5-chloro-2- methylbenzo[b]furan-7-carboxamide (7b) hemifumarate was as potent as cisapride. 4-Amino-N-[2-(1-azabicyclo[3.3.0]octan-5-yl)ethyl]-5-chloro-2,3- dihydro-2-methylbenzo[b]furan-7-carboxamide (8a) hemifumarate, 4-amino-N-[2- (1-azabicyclo [3.3.0]octan-5-yl)ethyl]5-chloro-2,3-dihydro-2- ethylbenzo[b]furan-7-carboxamide (8c) hemifumarate, and 4-amino-N-]2-(1- azabicyclo[3.3.0]octan-5-yl]-5-chloro-2,3-dihydro-2,3-dimethylhenzo[b]furan- 7-carboxamide (8d) hemifumarate were more potent than cisapride. Furthermore, 8a hemifumarate was free from dopamine D1, D2, serotonin 5-HT1, 5-HT2 and muscarine M1, M2 receptor binding activity in the in vitro tests. On the other hand, construction of the indole skeleton caused a remarkable decrease in activity.