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

• 106200-41-3 4-(4-carbomethoxyphenyl)butanal 
• 155405-79-1 4-(3-bromo-4-oxobutyl)benzoic acid methyl ester 
• 123910-86-1 4-(4-hydroxybut-1-ynyl)benzoic acid methyl ester 
• 619-42-1 4-methoxycarbonylphenyl bromide 
• 123910-88-3 methyl 4-(4-hydroxybut-1-yl)benzoate 
• 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 
• 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 
• 927897-33-4 ethyl 4-(3-bromo-4-oxobutyl)benzoate 
• 72313-37-2 ethyl 4-(3-formylpropyl)benzoate 

Downstream Products

• 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 
• 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 
• 241483-00-1 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-morpholine 
• 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 
• 146943-43-3 diethyl pemetrexed 

Relevant articles and documents

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