137281-39-1

Basic information

• Product Name: 4-[2-(2-Amino-4,7-dihydro-4-oxo-1H-pymol[2,3-d]pyrimodin-5-yl)ethyl]benzoic acid
• Synonyms: 4-[2-(2-Amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic Acid;4-(2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo(2,3-d)pyrimidin-5-yl)ethyl)benzoic acid (intermediate of pemetrexed);4-[2-(2-AMINO-4,7-DIHYDRO-4-OXO-1H-PYMOL[2,3-D]PYRIMODIN-5-YL)ETHYL]BENZOIC ACID;4-[2-(2-Amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]-Benzoic Acid;4-[2-（2-Amino-4-oxo-4,7- Dihydro-3H-pyrrolo[2,3-d]pyrimidine -5-yl）ethyl]benzoic acid;4-[2-(2-Amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)-ethyl]benzoic acid ,98%;4-[2-(2-Amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)-ethyl]-benzoic acid ,99%;4-[2-(2-Amino-4,7-di
• CAS NO: 137281-39-1
• Molecular Formula: C₁₅H₁₄N₄O₃
• Molecular Weight: 298.29666
• EINECS: 429-790-9
• Product Categories: Organic acids;PEMETREXED DISODIUM;(intermediate of pemetrexed);Various Intermediates;Intermediates;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 137281-39-1.mol
• Article Data: 18

Chemical Properties

• Melting Point: >270°C (dec.)
• Boiling Point: 609.183 °C at 760 mmHg
• Flash Point: 322.223 °C
• Appearance: pale pink solid
• Density: 1.559 g/cm³
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.746
• Storage Temp.: -20?C Freezer
• Solubility: DMSO (Slightly), Methanol (Slightly, Heated)
• PKA: 4.30±0.10(Predicted)
• CAS DataBase Reference: 4-[2-(2-Amino-4,7-dihydro-4-oxo-1H-pymol[2,3-d]pyrimodin-5-yl)ethyl]benzoic acid(CAS DataBase Reference)
• NIST Chemistry Reference: 4-[2-(2-Amino-4,7-dihydro-4-oxo-1H-pymol[2,3-d]pyrimodin-5-yl)ethyl]benzoic acid(137281-39-1)
• EPA Substance Registry System: 4-[2-(2-Amino-4,7-dihydro-4-oxo-1H-pymol[2,3-d]pyrimodin-5-yl)ethyl]benzoic acid(137281-39-1)

Safety Data

• Statements: 36/37/38
• Safety Statements: 26-36/37/39
• Hazardous Substances Data: 137281-39-1(Hazardous Substances Data)

Usage

Chemical Properties

Pale Pink Solid

Uses

Pemetrexed intermediate

InChI:InChI=1/C15H14N4O3/c16-15-18-12-11(13(20)19-15)10(7-17-12)6-3-8-1-4-9(5-2-8)14(21)22/h1-2,4-5,7H,3,6H2,(H,21,22)(H4,16,17,18,19,20)

Synthetic route

4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid methyl ester → 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid (137281-39-1)

Conditions	Yield
With water; sodium hydroxide at 40℃; for 1h;	100%
With sodium hydroxide In water at 40℃; for 1.5h; Large scale;	91%
With ethanol at 40℃; for 3h; Molecular sieve; Industrial scale;	85.1%

4-[3-(2,4-diamino-6-oxo-1,6-dihydropyrimidin-5-yl)-4-nitrobutyl]benzoic acid ethyl ester (229470-22-8) → 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid (137281-39-1)

Conditions	Yield
With sodium hydroxide; sulfuric acid; acetic acid In water; ethyl acetate	98%
Multistep reaction;	57%
Stage #1: 4-[3-(2,4-diamino-6-oxo-1,6-dihydropyrimidin-5-yl)-4-nitrobutyl]benzoic acid ethyl ester With sodium hydroxide at 20℃; for 2h; Stage #2: With sulfuric acid at 0℃; for 3h; Nef reaction; Stage #3: With sodium hydroxide at 20℃; for 1h; pH=7;	57%

4-(3-bromo-4-oxobutyl)benzoic acid methyl ester + 2,6-diaminopyrimidin-4-ol (56-06-4) → 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid (137281-39-1)

Conditions	Yield
With sodium acetate In methanol; water at 50 - 55℃; for 5h; Inert atmosphere;	75%

N-[4-[2-(2-amino-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]-benzoyl]-L-glutamic acid disodium salt → 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid (137281-39-1)

Conditions	Yield
With hydrogenchloride; water at 100℃; for 120h;	37%
With hydrogenchloride; water at 100℃; for 120h;	37%

4-[3-(2,4-Diamino-6-oxo-1,6-dihydro-pyrimidin-5-yl)-4,4-dimethoxy-butyl]-benzoic acid tert-butyl ester (146943-41-1) → 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid (137281-39-1)

Conditions	Yield
With water; trifluoroacetic acid

ethyl 4-(3-oxopropyl)benzoate (151864-81-2) → 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid (137281-39-1)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: 68 percent / aq. NaOH / ethanol / 48 h / 38 °C 2.1: 90 percent / CH3SO2Cl; Et3N / CH2Cl2 / 0 - 20 °C 3.1: 91 percent / H2O; ethyl acetate / 24 h / 50 °C 4.1: aq. NaOH / 2 h / 20 °C 4.2: aq. H2SO4 / 3 h / 0 °C 4.3: 57 percent / aq. NaOH / 1 h / 20 °C / pH 7 View Scheme
Multi-step reaction with 4 steps 1: 72 percent / NaOH / ethanol 2: 90 percent / CH3SO2Cl; Et3N 3: 91 percent / ethyl acetate; H2O / 24 h / 50 °C 4: 57 percent View Scheme

4-(3-hydroxy-4-nitrobutyl)benzoic acid ethyl ester (259145-25-0) → 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid (137281-39-1)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: 90 percent / CH3SO2Cl; Et3N / CH2Cl2 / 0 - 20 °C 2.1: 91 percent / H2O; ethyl acetate / 24 h / 50 °C 3.1: aq. NaOH / 2 h / 20 °C 3.2: aq. H2SO4 / 3 h / 0 °C 3.3: 57 percent / aq. NaOH / 1 h / 20 °C / pH 7 View Scheme
Multi-step reaction with 3 steps 1: 90 percent / CH3SO2Cl; Et3N 2: 91 percent / ethyl acetate; H2O / 24 h / 50 °C 3: 57 percent View Scheme

4-(4-nitrobut-3-enyl)benzoic acid ethyl ester → 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid (137281-39-1)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: 91 percent / H2O; ethyl acetate / 24 h / 50 °C 2.1: aq. NaOH / 2 h / 20 °C 2.2: aq. H2SO4 / 3 h / 0 °C 2.3: 57 percent / aq. NaOH / 1 h / 20 °C / pH 7 View Scheme

4-iodobenzoic acid ethyl ester (51934-41-9) → 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid (137281-39-1)

Conditions	Yield
Multi-step reaction with 5 steps 1: 98 percent / Pd(OAc)2 2: 72 percent / NaOH / ethanol 3: 90 percent / CH3SO2Cl; Et3N 4: 91 percent / ethyl acetate; H2O / 24 h / 50 °C 5: 57 percent View Scheme
Multi-step reaction with 4 steps 1: lithium chloride; lithium acetate; tetrabutyl-ammonium chloride; palladium diacetate / N,N-dimethyl-formamide / 3 h / 70 °C 2: 2,2-dimethyl-5,5-dibromo-1,3-dioxane-4,6-dione; hydrogenchloride / diethyl ether / 24 h / 20 °C 3: sodium acetate / water; methanol / 3 h / 45 °C 4: sodium hydroxide / methanol / 24 h / 40 - 50 °C / Inert atmosphere View Scheme

4-((E)-4-Nitro-but-3-enyl)-benzoic acid ethyl ester (229470-21-7) → 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid (137281-39-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: 91 percent / ethyl acetate; H2O / 24 h / 50 °C 2: 57 percent View Scheme

4-(tert-butoxycarbonyl)benzaldehyde (65874-27-3) → 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid (137281-39-1)

Conditions

Yield

Multi-step reaction with 8 steps 1: 94 percent / toluene / 1 h / Heating 2: 100 percent / H2 / 10percent Pd/C / ethyl acetate; methanol / 4 h 3: 99 percent / LiBH4 / diethyl ether / 15 h / Ambient temperature 4: 87 percent / oxalyl chloride, DMSO / CH2Cl2 / 0.25 h / -60 °C 5: 1) t-BuOK / 1) THF, toluene, 10 min, 2) toluene, 0 deg C, 20 min 6: 1) CH2Cl2, molecular sieves 3A, UV, 0 - 5 deg C 7: 74 percent / 1 M BuOK / tetrahydrofuran; 2-methyl-propan-2-ol / Heating 8: CF3COOH, H2O View Scheme

tert-Butyl 4-(3-hydroxy-1-propyl)benzoate (126931-32-6) → 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid (137281-39-1)

Conditions	Yield
Multi-step reaction with 5 steps 1: 87 percent / oxalyl chloride, DMSO / CH2Cl2 / 0.25 h / -60 °C 2: 1) t-BuOK / 1) THF, toluene, 10 min, 2) toluene, 0 deg C, 20 min 3: 1) CH2Cl2, molecular sieves 3A, UV, 0 - 5 deg C 4: 74 percent / 1 M BuOK / tetrahydrofuran; 2-methyl-propan-2-ol / Heating 5: CF3COOH, H2O View Scheme

3-(4-<2,2-dimethylethyl>carboxyphenyl)-1-propanal (134372-99-9) → 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid (137281-39-1)

Conditions	Yield
Multi-step reaction with 4 steps 1: 1) t-BuOK / 1) THF, toluene, 10 min, 2) toluene, 0 deg C, 20 min 2: 1) CH2Cl2, molecular sieves 3A, UV, 0 - 5 deg C 3: 74 percent / 1 M BuOK / tetrahydrofuran; 2-methyl-propan-2-ol / Heating 4: CF3COOH, H2O View Scheme

tert-butyl 4-(4-methoxy-3-butenyl)benzoate (134373-00-5) → 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid (137281-39-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: 1) CH2Cl2, molecular sieves 3A, UV, 0 - 5 deg C 2: 74 percent / 1 M BuOK / tetrahydrofuran; 2-methyl-propan-2-ol / Heating 3: CF3COOH, H2O View Scheme

methyl 3-<4-(tert-butoxycarbonyl)phenyl>propenoate (146943-27-3) → 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid (137281-39-1)

Conditions

Yield

Multi-step reaction with 7 steps 1: 100 percent / H2 / 10percent Pd/C / ethyl acetate; methanol / 4 h 2: 99 percent / LiBH4 / diethyl ether / 15 h / Ambient temperature 3: 87 percent / oxalyl chloride, DMSO / CH2Cl2 / 0.25 h / -60 °C 4: 1) t-BuOK / 1) THF, toluene, 10 min, 2) toluene, 0 deg C, 20 min 5: 1) CH2Cl2, molecular sieves 3A, UV, 0 - 5 deg C 6: 74 percent / 1 M BuOK / tetrahydrofuran; 2-methyl-propan-2-ol / Heating 7: CF3COOH, H2O View Scheme

methyl 3-<4-(tert-butoxycarbonyl)phenyl>propanoate (126931-31-5) → 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid (137281-39-1)

Conditions	Yield
Multi-step reaction with 6 steps 1: 99 percent / LiBH4 / diethyl ether / 15 h / Ambient temperature 2: 87 percent / oxalyl chloride, DMSO / CH2Cl2 / 0.25 h / -60 °C 3: 1) t-BuOK / 1) THF, toluene, 10 min, 2) toluene, 0 deg C, 20 min 4: 1) CH2Cl2, molecular sieves 3A, UV, 0 - 5 deg C 5: 74 percent / 1 M BuOK / tetrahydrofuran; 2-methyl-propan-2-ol / Heating 6: CF3COOH, H2O View Scheme

4-(4-Cyano-3-dimethoxymethyl-4-ethoxycarbonyl-butyl)-benzoic acid tert-butyl ester → 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid (137281-39-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: 74 percent / 1 M BuOK / tetrahydrofuran; 2-methyl-propan-2-ol / Heating 2: CF3COOH, H2O View Scheme

4-(4-carbomethoxyphenyl)butanal (106200-41-3) → 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid (137281-39-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: 5,5-dibromobarbituric acid; hydrogen bromide; acetic acid / dichloromethane / 25 °C / Large scale 2: sodium acetate / water; acetonitrile / 3 h / 40 °C / Large scale 3: sodium hydroxide / water / 1.5 h / 40 °C / Large scale View Scheme
Multi-step reaction with 3 steps 1: hydrogen bromide; acetic acid; bromine / ethyl acetate / 1 h / 0 °C 2: sodium acetate / water; acetonitrile / 3.5 h / 40 °C 3: sodium hydroxide; water / 1 h / 40 °C View Scheme
Multi-step reaction with 3 steps 1: bromine / acetonitrile / 2 h / 0 - 20 °C 2: sodium acetate 3: sodium hydroxide; water View Scheme
Multi-step reaction with 3 steps 1: pyridinium hydrobromide perbromide / acetonitrile / 0.17 h / -5 - 5 °C 2: sodium acetate; sodium hydrogensulfite / water / 2 h / 40 °C 3: sodium hydroxide; water / 2 h / 40 °C View Scheme
Multi-step reaction with 3 steps 1: acetic acid; 5,5-dibromobarbituric acid; hydrogen bromide / dichloromethane / 16 h / 20 °C 2: sodium acetate / acetonitrile; water / 3 h / 40 °C 3: sodium hydroxide / 1.5 h / 40 °C View Scheme

4-(3-bromo-4-oxobutyl)benzoic acid methyl ester → 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid (137281-39-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium acetate / water; acetonitrile / 3 h / 40 °C / Large scale 2: sodium hydroxide / water / 1.5 h / 40 °C / Large scale View Scheme
Multi-step reaction with 2 steps 1.1: sodium acetate 2.1: sodium hydroxide 2.2: 0 °C View Scheme
Multi-step reaction with 2 steps 1: sodium acetate / water; acetonitrile / 3.5 h / 40 °C 2: sodium hydroxide; water / 1 h / 40 °C View Scheme
Multi-step reaction with 2 steps 1: sodium acetate 2: sodium hydroxide; water View Scheme
Multi-step reaction with 2 steps 1: sodium acetate / acetonitrile; water / 3 h / 40 °C 2: sodium hydroxide / 1.5 h / 40 °C View Scheme

4-(4-hydroxy-1-butynyl)benzoic acid methyl ester (123910-86-1) → 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid (137281-39-1)

Conditions	Yield
Multi-step reaction with 5 steps 1: hydrogen; 5%-palladium/activated carbon / dichloromethane / 3.5 h / 3345.86 Torr / Inert atmosphere; Autoclave; Large scale 2: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; potassium bromide; sodium hypochlorite; sodium hydrogencarbonate / dichloromethane; water / -10 - 20 °C / pH 9.5 / Large scale 3: 5,5-dibromobarbituric acid; hydrogen bromide; acetic acid / dichloromethane / 25 °C / Large scale 4: sodium acetate / water; acetonitrile / 3 h / 40 °C / Large scale 5: sodium hydroxide / water / 1.5 h / 40 °C / Large scale View Scheme
Multi-step reaction with 4 steps 1: palladium 10% on activated carbon; hydrogen / ethyl acetate / 5 h / 25 - 30 °C / 6464.52 Torr / Inert atmosphere 2: potassium bromide; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hypochlorite / water; dichloromethane / 0.5 h / 25 - 30 °C / Inert atmosphere 3: pyridinium hydrobromide perbromide / tert-butyl methyl ether / 8 h / 25 - 30 °C / Inert atmosphere 4: sodium acetate / water; methanol / 5 h / 50 - 55 °C / Inert atmosphere View Scheme
Multi-step reaction with 5 steps 1: palladium 10% on activated carbon; hydrogen / dichloromethane / 30 °C / 37503.8 Torr / Flow reactor 2: sodium acetate; pyridinium chlorochromate / dichloromethane / 5 h / 20 °C 3: acetic acid; 5,5-dibromobarbituric acid; hydrogen bromide / dichloromethane / 16 h / 20 °C 4: sodium acetate / acetonitrile; water / 3 h / 40 °C 5: sodium hydroxide / 1.5 h / 40 °C View Scheme

4-methoxycarbonylphenyl bromide (619-42-1) → 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid (137281-39-1)

Conditions	Yield
Multi-step reaction with 6 steps 1: palladium dichloride; triphenylphosphine; copper(l) iodide; diethylamine / ethyl acetate / 4 h / 50 °C / Large scale 2: hydrogen; 5%-palladium/activated carbon / dichloromethane / 3.5 h / 3345.86 Torr / Inert atmosphere; Autoclave; Large scale 3: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; potassium bromide; sodium hypochlorite; sodium hydrogencarbonate / dichloromethane; water / -10 - 20 °C / pH 9.5 / Large scale 4: 5,5-dibromobarbituric acid; hydrogen bromide; acetic acid / dichloromethane / 25 °C / Large scale 5: sodium acetate / water; acetonitrile / 3 h / 40 °C / Large scale 6: sodium hydroxide / water / 1.5 h / 40 °C / Large scale View Scheme
Multi-step reaction with 4 steps 1: lithium acetate; lithium chloride; tetrabutyl-ammonium chloride; palladium diacetate / N,N-dimethyl-formamide / 75 °C / Inert atmosphere 2: hydrogen bromide; acetic acid; bromine / ethyl acetate / 1 h / 0 °C 3: sodium acetate / water; acetonitrile / 3.5 h / 40 °C 4: sodium hydroxide; water / 1 h / 40 °C View Scheme
Multi-step reaction with 5 steps 1: triethylamine; copper(l) iodide; triphenylphosphine; palladium dichloride / 3 h / 75 °C / Inert atmosphere 2: palladium 10% on activated carbon; hydrogen / ethyl acetate / 5 h / 25 - 30 °C / 6464.52 Torr / Inert atmosphere 3: potassium bromide; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hypochlorite / water; dichloromethane / 0.5 h / 25 - 30 °C / Inert atmosphere 4: pyridinium hydrobromide perbromide / tert-butyl methyl ether / 8 h / 25 - 30 °C / Inert atmosphere 5: sodium acetate / water; methanol / 5 h / 50 - 55 °C / Inert atmosphere View Scheme
Multi-step reaction with 4 steps 1: lithium acetate; lithium chloride; tetrabutylammomium bromide; palladium diacetate / N,N-dimethyl-formamide / 2 h / 60 °C / Inert atmosphere 2: pyridinium hydrobromide perbromide / acetonitrile / 0.17 h / -5 - 5 °C 3: sodium acetate; sodium hydrogensulfite / water / 2 h / 40 °C 4: sodium hydroxide; water / 2 h / 40 °C View Scheme
Multi-step reaction with 6 steps 1: triphenylphosphine; palladium dichloride; copper(l) iodide; diethylamine / ethyl acetate / 4 h / 50 °C 2: palladium 10% on activated carbon; hydrogen / dichloromethane / 30 °C / 37503.8 Torr / Flow reactor 3: sodium acetate; pyridinium chlorochromate / dichloromethane / 5 h / 20 °C 4: acetic acid; 5,5-dibromobarbituric acid; hydrogen bromide / dichloromethane / 16 h / 20 °C 5: sodium acetate / acetonitrile; water / 3 h / 40 °C 6: sodium hydroxide / 1.5 h / 40 °C View Scheme

methyl 4-(4-hydroxybut-1-yl)benzoate (123910-88-3) → 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid (137281-39-1)

Conditions	Yield
Multi-step reaction with 4 steps 1: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; potassium bromide; sodium hypochlorite; sodium hydrogencarbonate / dichloromethane; water / -10 - 20 °C / pH 9.5 / Large scale 2: 5,5-dibromobarbituric acid; hydrogen bromide; acetic acid / dichloromethane / 25 °C / Large scale 3: sodium acetate / water; acetonitrile / 3 h / 40 °C / Large scale 4: sodium hydroxide / water / 1.5 h / 40 °C / Large scale View Scheme
Multi-step reaction with 3 steps 1: potassium bromide; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hypochlorite / water; dichloromethane / 0.5 h / 25 - 30 °C / Inert atmosphere 2: pyridinium hydrobromide perbromide / tert-butyl methyl ether / 8 h / 25 - 30 °C / Inert atmosphere 3: sodium acetate / water; methanol / 5 h / 50 - 55 °C / Inert atmosphere View Scheme
Multi-step reaction with 4 steps 1: sodium acetate; pyridinium chlorochromate / dichloromethane / 5 h / 20 °C 2: acetic acid; 5,5-dibromobarbituric acid; hydrogen bromide / dichloromethane / 16 h / 20 °C 3: sodium acetate / acetonitrile; water / 3 h / 40 °C 4: sodium hydroxide / 1.5 h / 40 °C View Scheme

4-(4-carboxymethoxyphenyl)butanal sodium bisulfite adduct → 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid (137281-39-1)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: chloro-trimethyl-silane; bromine 2.1: sodium acetate 3.1: sodium hydroxide 3.2: 0 °C View Scheme

ethyl 4-(3-formylpropyl)benzoate (72313-37-2) → 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid (137281-39-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: 2,2-dimethyl-5,5-dibromo-1,3-dioxane-4,6-dione; hydrogenchloride / diethyl ether / 24 h / 20 °C 2: sodium acetate / water; methanol / 3 h / 45 °C 3: sodium hydroxide / methanol / 24 h / 40 - 50 °C / Inert atmosphere View Scheme

ethyl 4-(3-bromo-4-oxobutyl)benzoate (927897-33-4) → 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid (137281-39-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium acetate / water; methanol / 3 h / 45 °C 2: sodium hydroxide / methanol / 24 h / 40 - 50 °C / Inert atmosphere View Scheme

ethyl 4-(2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]-pyrimidin-5-yl)ethyl)benzoate (151864-75-4) → 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid (137281-39-1)

Conditions	Yield
With sodium hydroxide In methanol at 40 - 50℃; for 24h; Inert atmosphere;

methyl 4-iodobenzoate (619-44-3) → 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid (137281-39-1)

Conditions	Yield
Multi-step reaction with 4 steps 1: palladium diacetate; lithium chloride; lithium acetate; tetrabutylammomium bromide / N,N-dimethyl-formamide / 10 h / 60 °C / Inert atmosphere 2: bromine / acetonitrile / 2 h / 0 - 20 °C 3: sodium acetate 4: sodium hydroxide; water View Scheme

acetic anhydride (108-24-7) + 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid (137281-39-1) → 4-[2-(2-acetylamino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid

Conditions	Yield
With acetic acid at 50℃; for 1h; Temperature;	97.1%
With acetic acid at 30 - 50℃; for 1h; Temperature;	97.1%

benzyl chloride (100-44-7) + 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid (137281-39-1) → 4-[2-(2-benzylamino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid

Conditions	Yield
With triethylamine In N,N-dimethyl-formamide at 30 - 60℃; for 1h; Temperature;	96.9%
With triethylamine In N,N-dimethyl-formamide at 30 - 50℃; for 1h; Temperature;

p-toluenesulfonyl chloride (98-59-9) + 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid (137281-39-1) → 4-[2-(2-(p-tolylsulfonyl)amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid

Conditions	Yield
With triethylamine In N,N-dimethyl-formamide at 0 - 5℃; for 1h;	96.7%
With triethylamine In N,N-dimethyl-formamide at 0 - 30℃; for 1h;

trityl chloride (76-83-5) + 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid (137281-39-1) → 4-[2-(2-triphenylmethylamino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid

Conditions	Yield
With triethylamine In N,N-dimethyl-formamide at 30 - 35℃; for 1h;	96.3%
With triethylamine In N,N-dimethyl-formamide at 30 - 35℃; for 1h;

diethyl-L-glutamate hydrochloride (1118-89-4) + 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid (137281-39-1) → N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]-pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid diethyl ester (146943-43-3)

Conditions	Yield
With 4-methyl-morpholine; 2-chloro-4,6-dimethoxy-1 ,3,5-triazine; sodium hydroxide In ethanol; water at 40℃; for 3h;	94.5%
With 4-methyl-morpholine; 2-chloro-4,6-dimethoxy-1 ,3,5-triazine at 20℃; Condensation;	62%
Stage #1: 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid With 4-methyl-morpholine; 2-chloro-4,6-dimethoxy-1 ,3,5-triazine In N,N-dimethyl-formamide at 20℃; for 2h; Stage #2: diethyl-L-glutamate hydrochloride With 4-methyl-morpholine In N,N-dimethyl-formamide at 20℃; for 3.5h;	62%
With 2-chloro-4,6-dimethoxy-1 ,3,5-triazine; 4-methylmorpholine N-oxide In N,N-dimethyl-formamide at 25℃; for 1.5h; Large scale;
With 4-methyl-morpholine; 2-chloro-4,6-dimethoxy-1 ,3,5-triazine In N,N-dimethyl-formamide at 20℃; for 6h;

3,5-dimethylisoxazol-4-amine (31329-64-3) + 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid (137281-39-1) → 4-(2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl)-N-(3,5-dimethylisoxazol-4-yl)benzamide

Conditions	Yield
With diethyl cyanophosphonate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0.1℃; for 3.25h; Inert atmosphere;	93%

4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid (137281-39-1) + N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]-pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid diethyl ester (146943-43-3) → C39H41N9O8

Conditions	Yield
With triethylamine; 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 25 - 30℃; for 2h; Temperature; Reagent/catalyst; Solvent;	92.6%

4-chlorophenylethylamine (156-41-2) + 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid (137281-39-1) → 4-(2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl)-N-(4-chlorophenethyl)benzamide

Conditions	Yield
With diethyl cyanophosphonate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0.1℃; for 3.25h; Inert atmosphere;	92%

2-thiazolylamine (96-50-4) + 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid (137281-39-1) → 4-(2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl)-N-(thiazol-2-yl)benzamide

Conditions	Yield
With diethyl cyanophosphonate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0.1℃; for 3.25h; Inert atmosphere;	91%

L-glutamic dimethyl ester hydrochloride (23150-65-4) + 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid (137281-39-1) → dipotassium (S)-2-(4-(2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl)benzamido) pentanedioate

Conditions	Yield
Stage #1: 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid With 4-methyl-morpholine; 2-chloro-4,6-dimethoxy-1 ,3,5-triazine In N,N-dimethyl-formamide at 0 - 30℃; Inert atmosphere; Stage #2: L-glutamic dimethyl ester hydrochloride In N,N-dimethyl-formamide at 0 - 5℃; Stage #3: With potassium hydroxide In dichloromethane; water for 1.5h;	90.38%

1-(o-fluorophenyl)piperazine (1011-15-0) + 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid (137281-39-1) → 2-amino-5-(4-(4-(2-fluorophenyl)piperazine-1-carbonyl)phenethyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one

Conditions	Yield
With diethyl cyanophosphonate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0.1℃; for 3.25h; Inert atmosphere;	90%

1-Methylhomopiperazine (4318-37-0) + 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid (137281-39-1) → 2-amino-5-(4-(4-methyl-1,4-diazepane-1-carbonyl)phenethyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one

Conditions	Yield
With diethyl cyanophosphonate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0.1℃; for 3.25h; Inert atmosphere;	89%

2-(aminoethyl)pyridine (2706-56-1) + 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid (137281-39-1) → 4-(2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl)-N-(2-(pyridin-2-yl)ethyl)benzamide

Conditions	Yield
With diethyl cyanophosphonate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0.1℃; for 3.25h; Inert atmosphere;	88%

4-methyl-morpholine (109-02-4) + 2-chloro-4,6-dimethoxy-1 ,3,5-triazine (3140-73-6) + diethyl-L-glutamate hydrochloride (1118-89-4) + 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid (137281-39-1) → N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]-pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid diethyl ester (146943-43-3) + 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-morpholine

Conditions	Yield
Stage #1: 4-methyl-morpholine; 2-chloro-4,6-dimethoxy-1 ,3,5-triazine; 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid In N,N-dimethyl-formamide at 20℃; for 1h; Cooling with ice; Inert atmosphere; Stage #2: diethyl-L-glutamate hydrochloride In N,N-dimethyl-formamide at 35℃; for 2h; Inert atmosphere;	A 85.5% B 4%

toluene-4-sulfonic acid (104-15-4) + 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid (137281-39-1) + (R)-2-aminoglutaric acid diethyl ester hydrochloride → C24H29N5O6*C7H8O3S

Conditions	Yield
Stage #1: (R)-2-aminoglutaric acid diethyl ester hydrochloride With sodium hydrogencarbonate In water at 20℃; for 0.5h; Stage #2: toluene-4-sulfonic acid; 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid With 4-methyl-morpholine; 2-chloro-4,6-dimethoxy-1 ,3,5-triazine In dichloromethane at 0 - 50℃; for 3h;	85%

1-(2-aminoethyl)piperidine (27578-60-5) + 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid (137281-39-1) → 4-(2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl)-N-(2-(piperidin-1-yl)ethyl)benzamide

Conditions	Yield
With diethyl cyanophosphonate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0.1℃; for 3.25h; Inert atmosphere;	84%

L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-L-glutamic acid heptakis-t-butyl ester (118252-57-6) + 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid (137281-39-1) → C73H112N10O21

Conditions

Yield

Stage #1: 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 10 - 20℃; for 0.5h; Large scale; Stage #2: L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-L-γ-glutamyl-L-glutamic acid heptakis-t-butyl ester In N,N-dimethyl-formamide at 20℃; for 20h; Large scale;

82.5%

L-glutamic dimethyl ester hydrochloride (23150-65-4) + 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid (137281-39-1) → N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic dimethyl ester (155405-81-5)

Conditions	Yield
Stage #1: 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere; Stage #2: L-glutamic dimethyl ester hydrochloride With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 20℃;	80.4%
Stage #1: 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid With 4-methyl-morpholine; 2-chloro-4,6-dimethoxy-1 ,3,5-triazine In N,N-dimethyl-formamide at 0 - 5℃; for 1.5h; Stage #2: L-glutamic dimethyl ester hydrochloride In N,N-dimethyl-formamide at 0 - 30℃;	65.5%

(S)-1-(pyrrolidin-3-yl)piperidine (917560-78-2) + 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid (137281-39-1) → (S)-2-amino-5-(4-(3-(piperidin-1-yl)pyrrolidine-1-carbonyl)phenethyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one

Conditions	Yield
With diethyl cyanophosphonate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0.1℃; for 3.25h; Inert atmosphere;	78%

(S)-benzyl 5-acetoxy-4-aminopentanoate (1376616-07-7) + 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid (137281-39-1) → (S)-benzyl 5-acetoxy-4-(4-(2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl)benzamido)pentanoate (1376616-08-8)

Conditions	Yield
Stage #1: 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid With 4-methyl-morpholine; 2-chloro-4,6-dimethoxy-1 ,3,5-triazine In N,N-dimethyl-formamide at 20℃; for 3h; Stage #2: (S)-benzyl 5-acetoxy-4-aminopentanoate With 4-methyl-morpholine In N,N-dimethyl-formamide at 20℃;	77%
Stage #1: 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid With 4-methyl-morpholine; 2-chloro-4,6-dimethoxy-1 ,3,5-triazine In N,N-dimethyl-formamide at 20℃; for 3h; Stage #2: (S)-benzyl 5-acetoxy-4-aminopentanoate With 4-methyl-morpholine In N,N-dimethyl-formamide at 20℃;	77%

[(1S)-1-cyclohexylethyl]amine (17430-98-7) + 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid (137281-39-1) → (S)-4-(2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl)-N-(1-cyclohexylethyl)benzamide

Conditions	Yield
With diethyl cyanophosphonate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0.1℃; for 3.25h; Inert atmosphere;	72%

4-fluoro-2-phenethylamine (1583-88-6) + 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid (137281-39-1) → 4-(2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl)-N-(4-fluorophenethyl)benzamide

Conditions	Yield
With diethyl cyanophosphonate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0.1℃; for 3.25h; Inert atmosphere;	71%

amine SDC-TRAP-0004 (1207601-67-9) + 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid (137281-39-1) → 4-(2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl)-N-(2-(5-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)-1H-indol-1-yl)ethyl)-N-methylbenzamide

Conditions	Yield
With 1,2-dichloro-ethane In N,N-dimethyl-formamide at 20℃; for 18h;	70%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 18h;	70%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 18h;	70%

amine SDC-TRAP-0004 (1207601-67-9) + 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid (137281-39-1) → 4-(2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl)-N-(2-(5-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)-1H-indol-1-yl)ethyl)-N-methylbenzamide

Conditions	Yield
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 18h;	70%

diethyl-L-glutamate hydrochloride (1118-89-4) + toluene-4-sulfonic acid (104-15-4) + 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid (137281-39-1) → N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]-pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid diethyl ester 4-methylbenzenesulfonic acid salt (165049-28-5)

Conditions	Yield
Stage #1: diethyl-L-glutamate hydrochloride; 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid With 4-methyl-morpholine; 2-chloro-4,6-dimethoxy-1 ,3,5-triazine In N,N-dimethyl-formamide at 20℃; for 3h; Inert atmosphere; Industrial scale; Stage #2: toluene-4-sulfonic acid In ethanol; N,N-dimethyl-formamide at 70℃; Temperature; Inert atmosphere; Industrial scale;	68.1%
Stage #1: 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 50 - 60℃; for 2h; Stage #2: diethyl-L-glutamate hydrochloride With potassium carbonate In water; N,N-dimethyl-formamide at 80℃; for 3.5h; Stage #3: toluene-4-sulfonic acid In ethanol for 1h; Reflux;	55.4 g

diethyl-L-glutamate hydrochloride (1118-89-4) + toluene-4-sulfonic acid (104-15-4) + 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid (137281-39-1) → (2R)-2-[[4-[2-(2-amino-4-oxo-4,7-dihydro-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]amino]pentanedioic acid diethyl ester p-toluenesulfonate

Conditions	Yield
Stage #1: 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid With 4-methyl-morpholine; 2-chloro-4,6-dimethoxy-1 ,3,5-triazine In dichloromethane; N,N-dimethyl-formamide at 38 - 40℃; for 2h; Stage #2: diethyl-L-glutamate hydrochloride In dichloromethane; N,N-dimethyl-formamide for 2h; Stage #3: toluene-4-sulfonic acid In ethanol for 2h; Reflux;	66%

C10H21NO4Si + 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid (137281-39-1) → C25H33N5O6Si

Conditions	Yield
Stage #1: 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl )ethyl]benzoic acid With 4-methyl-morpholine; 2-chloro-4,6-dimethoxy-1 ,3,5-triazine In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: C10H21NO4Si In N,N-dimethyl-formamide at 20℃; for 3h;	64%

Upstream product

• 113100-81-5 4-(3-oxo-propyl)-benzoic acid methyl ester 
• 15403-22-2 4-(3-hydroxy-propyl)-benzoic acid methyl ester 
• 151937-09-6 3-(4-methoxycarbonylphenyl)propanoic acid 
• 19473-96-2 4-(2-carboxyvinyl)benzoic acid methyl ester 
• 157848-17-4 4-(3-hydroxy-4,4-dimethoxybutyl)benzoic acid methyl ester 
• 1007376-45-5 C₁₅H₁₃N₄O₃^(1-)*Na⁽¹⁺⁾ 
• 155405-80-4 C₁₆H₁₆N₄O₃ 
• 157848-19-6 4-{3-[(methylsulfonyl)oxy]-4-oxobutyl}benzoic acid methyl ester 
• 157848-18-5 4-{3-[(methylsulfonyl)oxy]-4,4-dimethoxybutyl}benzoic acid methyl ester 
• 1571-08-0 methyl 4-formylbenzoate 
• 155405-79-1 4-(3-bromo-4-oxobutyl)benzoic acid methyl ester 
• 56-06-4 2,6-diaminopyrimidin-4-ol 
• 619-44-3 methyl 4-iodobenzoate 
• 151864-75-4 ethyl 4-(2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]-pyrimidin-5-yl)ethyl)benzoate 

Downstream Products

• 146943-43-3 N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]-pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid diethyl ester 
• 155405-81-5 C₂₂H₂₅N₅O₆ 
• 1006872-74-7 N-[4-[2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid monosodium salt 
• 1376616-08-8 (S)-benzyl 5-acetoxy-4-(4-(2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl)benzamido)pentanoate 
• 1376616-09-9 (S)-5-acetoxy-4-(4-(2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl)benzamido)pentanoic acid 
• 165049-28-5 N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]-pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid diethyl ester 4-methylbenzenesulfonic acid salt 
• 1209465-70-2 C₂₀H₁₉N₇O₅ 
• 869791-42-4 (2S)-2-[[4-[2-(2-amino-1-methyl-4-oxo-4,7-dihydro-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]amino]pentanedioic acid 
• 241483-00-1 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-morpholine 

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Belonging to the technical field of organic compound synthesis, the invention in particular relates to a preparation method of pemetrexed acid. The method is characterized by utilizing methyl p-formylbenzoate and malonic acid as the starting materials to synthesize the target product. Compared with the methods for synthesis of the compound reported in previous literatures, the method provided by the invention has the advantages of easily available raw materials, low price and no pollution, greatly reduces the production cost, and is suitable for large-scale industrial production. The method isa brand new synthetic route for the compound.

Synthesis and antiviral study of novel 4-(2-(6-amino-4-oxo-4,5-dihydro-1H-pyrrolo[2,3-d]pyrimidin-3-yl)ethyl)benzamide derivatives

A series of ten new compounds (7a–j) has been synthesized by absolutely replacing the glutamic acid part of Pemetrexed drug, chemically known as N-{4-[2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl}-l-glutamic acid, with primary, secondary, and aryl amines in high yields using diethylphosphorocyanidate (DEPC) as a peptide coupling agent. All the synthesized compounds are characterized by 1H and 13C NMR, LCMS, and FT-IR spectral techniques. All the synthesized novel non-glutamate 4-(2-(6-amino-4-oxo-4,5-dihydro-1H-pyrrolo[2,3-d]pyrimidin-3-yl)ethyl)benzamide derivatives showed 4- to 7-folds higher antiviral activity than its structurally similar commercial drug Pemetrexed against Newcastle disease virus, an avian paramyxovirus. Among the lot, compounds possessing carboxamide synthesized using five-membered heteroaryl amines (7i and 7j) exhibited the highest antiviral activity. [Figure not available: see fulltext.].