6981-18-6

Basic information

• Product Name: 5-(4,5-dimethoxy-2-methylbenzyl)-2,4-diaminopyrimidine
• Synonyms: ORMETHOPRIM;ORMETOPRIM;ORMETOPRIN;OMP;5-(4,5-dimethoxy-2-methylbenzyl)-2,4-diaminopyrimidine;L-Ascorbic Phosphate Magnesium;2,4-Diamino-5-(6-methylveratryl)pyrimidine;5-(4,5-Dimethoxy-2-methylbenzyl)pyrimidine-2,4-diamine
• CAS NO: 6981-18-6
• Molecular Formula: C₁₄H₁₈N₄O₂
• Molecular Weight: 274.32
• EINECS: 230-246-6
• Product Categories: Active Pharmaceutical Ingredients;Heterocycles;Inhibitors;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 6981-18-6.mol
• Article Data: 12

Chemical Properties

• Melting Point: 231.0 to 235.0 °C
• Boiling Point: 521.5 °C at 760 mmHg
• Flash Point: 269.2 °C
• Appearance: /
• Density: 1.223 g/cm³
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.609
• Storage Temp.: 0-6°C
• Solubility: Chloroform (Slightly, Heated), DMSO (Slightly), Methanol (Slightly, Heated)
• PKA: 7.11±0.10(Predicted)
• Stability: Hygroscopic
• CAS DataBase Reference: 5-(4,5-dimethoxy-2-methylbenzyl)-2,4-diaminopyrimidine(CAS DataBase Reference)
• NIST Chemistry Reference: 5-(4,5-dimethoxy-2-methylbenzyl)-2,4-diaminopyrimidine(6981-18-6)
• EPA Substance Registry System: 5-(4,5-dimethoxy-2-methylbenzyl)-2,4-diaminopyrimidine(6981-18-6)

Safety Data

• Safety Statements: 24/25
• Hazardous Substances Data: 6981-18-6(Hazardous Substances Data)

Usage

Uses

Different sources of media describe the Uses of 6981-18-6 differently. You can refer to the following data:
1. It is a potent and selective inhibitor of bacterial dihydrofolate reductase, the enzyme responsible for the NADPH-dependent reduction of 7,8-dihydrofolate to 5,6,7,8-tetrahydrofolate. Antibacterial.
2. It is a potent and selective inhibitor of bacterial dihydrofolate reductase, the enzyme responsible for the NADPH-dependent reduction of 7,8-dihydrofolate to 5,6,7,8-tetrahydrofolate. Antibacterial.This compound is a contaminant of emerging concern (CECs).

Synthesis Reference(s)

Journal of Medicinal Chemistry, 14, p. 462, 1971 DOI: 10.1021/jm00287a029

InChI:InChI=1/C14H18N4O3/c1-19-10-6-12(21-3)11(20-2)5-8(10)4-9-7-17-14(16)18-13(9)15/h5-7H,4H2,1-3H3,(H4,15,16,17,18)

Synthetic route

guanidine carbonate (593-85-1) + C14H17NO3 (7520-75-4) → ormetoprim (6981-18-6)

Conditions	Yield
Stage #1: C14H17NO3 With sodium methylate In N,N-dimethyl-formamide at 110℃; Stage #2: guanidine carbonate In N,N-dimethyl-formamide at 130℃; Temperature;	90%

1,2-dimethoxy-4-methylbenzene (494-99-5) + 2,4-diamino-5-methoxymethylpyrimidine (54236-98-5) → ormetoprim (6981-18-6)

Conditions	Yield
With hydrogenchloride In methanol for 7.5h; Ambient temperature;	62%
With potassium hydroxide; phosphoric acid In water	104 %

2-(methoxymethylene)-3-methoxypropanenitrile (39800-76-5) + 1,2-dimethoxy-4-methylbenzene (494-99-5) + guanidine hydrochloride (50-01-1) → ormetoprim (6981-18-6)

Conditions	Yield
Yield given. Multistep reaction;

4,5-dimethoxy-2-methyl-2'-(methoxymethyl)cinnamonitrile (7520-75-4) + sodium methylate (124-41-4) + diguanidine carbonate (593-85-1) → ormetoprim (6981-18-6)

Conditions	Yield
1) DMSO, MeOH, 85 deg C, 3.5 h, 2) DMSO, a) 125 deg C, 1.25 h, b) 115 deg C, 1.5; Yield given. Multistep reaction;

1,2-dimethoxy-4-methylbenzene (494-99-5) → ormetoprim (6981-18-6)

Conditions	Yield
Multi-step reaction with 3 steps 2: 85.6 percent / methanol / 18 h / Ambient temperature 3: 1) DMSO, MeOH, 85 deg C, 3.5 h, 2) DMSO, a) 125 deg C, 1.25 h, b) 115 deg C, 1.5 View Scheme
Multi-step reaction with 3 steps 1.1: trichlorophosphate / 0.5 h / Cooling with ice 1.2: 90 °C 2.1: methanol / 50 °C 3.1: sodium methylate / N,N-dimethyl-formamide / 110 °C 3.2: 130 °C View Scheme
Multi-step reaction with 4 steps 1: acetic acid; hydrogenchloride / water / 8 h / 100 °C 2: trichlorophosphate / 4 h / 120 °C 3: N,N-dimethyl-formamide / 12 h / 190 - 200 °C 4: hydrazine hydrate / methanol / 3.5 h / Reflux View Scheme

4,5-dimethoxy-2-methylbenzaldehyde (7721-62-2) → ormetoprim (6981-18-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: 85.6 percent / methanol / 18 h / Ambient temperature 2: 1) DMSO, MeOH, 85 deg C, 3.5 h, 2) DMSO, a) 125 deg C, 1.25 h, b) 115 deg C, 1.5 View Scheme

2-bromo-4-methylanisole (22002-45-5) → ormetoprim (6981-18-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: CuCl / dimethylformamide; methanol / 4.5 h / Heating View Scheme
Multi-step reaction with 2 steps 1: CuCl / dimethylformamide; methanol / 4.5 h / Heating 2: 62 percent / conc. HCl / methanol / 7.5 h / Ambient temperature View Scheme
Multi-step reaction with 4 steps 1: CuCl / dimethylformamide; methanol / 4.5 h / Heating 3: 85.6 percent / methanol / 18 h / Ambient temperature 4: 1) DMSO, MeOH, 85 deg C, 3.5 h, 2) DMSO, a) 125 deg C, 1.25 h, b) 115 deg C, 1.5 View Scheme
Multi-step reaction with 4 steps 1.1: copper(l) chloride / methanol / Reflux 2.1: trichlorophosphate / 0.5 h / Cooling with ice 2.2: 90 °C 3.1: methanol / 50 °C 4.1: sodium methylate / N,N-dimethyl-formamide / 110 °C 4.2: 130 °C View Scheme

methanolic sodium methoxide + chloroform (67-66-3) + 2-(methoxymethylene)-3-methoxypropanenitrile (39800-76-5) + 1,2-dimethoxy-4-methylbenzene (494-99-5) + guanidine hydrochloride (50-01-1) → ormetoprim (6981-18-6)

Conditions	Yield
With trifluoroborane diethyl ether In N-methyl-acetamide; methanol; (2S)-N-methyl-1-phenylpropan-2-amine hydrate; ethyl acetate

guanidine carbonate (593-85-1) + 4,5-dimethoxy-2-methyl-2'-(methoxymethyl)cinnamonitrile (7520-75-4) → ormetoprim (6981-18-6)

Conditions	Yield
With sodium methylate In dimethyl sulfoxide at 85 - 125℃; for 6.5h;

C14H18N4O3 → ormetoprim (6981-18-6)

Conditions	Yield
With triethylsilane; trifluoroacetic acid In dichloromethane

4,5-dimethoxy-2-methyl-2'-(methoxymethyl)cinnamonitrile (7520-75-4) + guanidine hydrogen carbonate (124-46-9, 20734-13-8, 100224-74-6, 593-85-1) → ormetoprim (6981-18-6)

Conditions	Yield
Stage #1: 4,5-dimethoxy-2-methyl-2'-(methoxymethyl)cinnamonitrile With sodium methylate In dimethyl sulfoxide at 85℃; for 3.5h; Stage #2: guanidine hydrogen carbonate In dimethyl sulfoxide at 125℃; for 3h;

4-Methylanisole (104-93-8) → ormetoprim (6981-18-6)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: nitric acid; potassium bromide; acetic anhydride / 50 °C / Cooling with ice 2.1: copper(l) chloride / methanol / Reflux 3.1: trichlorophosphate / 0.5 h / Cooling with ice 3.2: 90 °C 4.1: methanol / 50 °C 5.1: sodium methylate / N,N-dimethyl-formamide / 110 °C 5.2: 130 °C View Scheme

p-cresol (106-44-5) → ormetoprim (6981-18-6)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: tetrabutylammomium bromide; potassium carbonate / Reflux 2.1: nitric acid; potassium bromide; acetic anhydride / 50 °C / Cooling with ice 3.1: copper(l) chloride / methanol / Reflux 4.1: trichlorophosphate / 0.5 h / Cooling with ice 4.2: 90 °C 5.1: methanol / 50 °C 6.1: sodium methylate / N,N-dimethyl-formamide / 110 °C 6.2: 130 °C View Scheme
Multi-step reaction with 8 steps 1.1: 4 h / 146 °C 2.1: aluminum (III) chloride / 1 h / 110 - 165 °C 2.2: 1 h / 80 - 90 °C 3.1: sodium hydroxide; dihydrogen peroxide / water; 1,4-dioxane / 3 h / 0 - 10 °C / Inert atmosphere 4.1: sodium hydroxide / water; toluene / 0.03 h / 30 °C 4.2: 1.5 h 5.1: acetic acid; hydrogenchloride / water / 8 h / 100 °C 6.1: trichlorophosphate / 4 h / 120 °C 7.1: N,N-dimethyl-formamide / 12 h / 190 - 200 °C 8.1: hydrazine hydrate / methanol / 3.5 h / Reflux View Scheme

4-methyl-1,2-dihydroxybenzene (452-86-8) → ormetoprim (6981-18-6)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: sodium hydroxide / water; toluene / 0.03 h / 30 °C 1.2: 1.5 h 2.1: acetic acid; hydrogenchloride / water / 8 h / 100 °C 3.1: trichlorophosphate / 4 h / 120 °C 4.1: N,N-dimethyl-formamide / 12 h / 190 - 200 °C 5.1: hydrazine hydrate / methanol / 3.5 h / Reflux View Scheme

5-hydroxymethyl uracil (4433-40-3) → ormetoprim (6981-18-6)

Conditions	Yield
Multi-step reaction with 4 steps 1: acetic acid; hydrogenchloride / water / 8 h / 100 °C 2: trichlorophosphate / 4 h / 120 °C 3: N,N-dimethyl-formamide / 12 h / 190 - 200 °C 4: hydrazine hydrate / methanol / 3.5 h / Reflux View Scheme

C14H16N2O4 → ormetoprim (6981-18-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: trichlorophosphate / 4 h / 120 °C 2: N,N-dimethyl-formamide / 12 h / 190 - 200 °C 3: hydrazine hydrate / methanol / 3.5 h / Reflux View Scheme

C30H22N4O6 → ormetoprim (6981-18-6)

Conditions	Yield
With hydrazine hydrate In methanol for 3.5h; Reflux;	1.06 g

1-acetoxy-4-methylbenzene (140-39-6) → ormetoprim (6981-18-6)

Conditions

Yield

Multi-step reaction with 7 steps 1.1: aluminum (III) chloride / 1 h / 110 - 165 °C 1.2: 1 h / 80 - 90 °C 2.1: sodium hydroxide; dihydrogen peroxide / water; 1,4-dioxane / 3 h / 0 - 10 °C / Inert atmosphere 3.1: sodium hydroxide / water; toluene / 0.03 h / 30 °C 3.2: 1.5 h 4.1: acetic acid; hydrogenchloride / water / 8 h / 100 °C 5.1: trichlorophosphate / 4 h / 120 °C 6.1: N,N-dimethyl-formamide / 12 h / 190 - 200 °C 7.1: hydrazine hydrate / methanol / 3.5 h / Reflux View Scheme

5-methyl-2-hydroxyacetophenone (1450-72-2) → ormetoprim (6981-18-6)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: sodium hydroxide; dihydrogen peroxide / water; 1,4-dioxane / 3 h / 0 - 10 °C / Inert atmosphere 2.1: sodium hydroxide / water; toluene / 0.03 h / 30 °C 2.2: 1.5 h 3.1: acetic acid; hydrogenchloride / water / 8 h / 100 °C 4.1: trichlorophosphate / 4 h / 120 °C 5.1: N,N-dimethyl-formamide / 12 h / 190 - 200 °C 6.1: hydrazine hydrate / methanol / 3.5 h / Reflux View Scheme

Upstream product

• 39800-76-5 2-(methoxymethylene)-3-methoxypropanenitrile 
• 494-99-5 1,2-dimethoxy-4-methylbenzene 
• 50-01-1 guanidine hydrochloride 
• 593-85-1 guanidine carbonate 
• 7520-75-4 4,5-dimethoxy-2-methyl-2'-(methoxymethyl)cinnamonitrile 
• 124-46-9 guanidine hydrogen carbonate 
• 1450-72-2 5-methyl-2-hydroxyacetophenone 
• 140-39-6 1-acetoxy-4-methylbenzene 
• 4433-40-3 5-hydroxymethyl uracil 
• 452-86-8 4-methyl-1,2-dihydroxybenzene 
• 106-44-5 p-cresol 
• 104-93-8 p-methylanizole 
• 7520-75-4 C₁₄H₁₇NO₃ 
• 67-66-3 chloroform 

Relevant articles and documents

A process for preparing 5 - substituted benzyl - 2, 4 - diamino pyrimidine and its derivatives (by machine translation)

The invention discloses a process for preparing 5 - substituted benzyl - 2, 4 - diamino pyrimidine and derivatives thereof, in particular can be used for preparing omay pullin, b a oxygen animal pen amine pyrimidine, such as palestinian kuikui purin. The invention relates to 5 - hydroxymethyl uracil as raw materials, through the electrophilic substitution reaction, chlorinated, amino and hydrolysis step preparation 5 - substituted benzyl - 2, 4 - diamino pyrimidine and its derivatives. The method can be used for preparing various 5 - substituted benzyl - 2, 4 - diaminopyrimidines of the molecule, thereby avoiding the high-pressure reaction step, the safety is high, and is suitable for industrial production. (by machine translation)

Identification and SAR of novel diaminopyrimidines. Part 1: The discovery of RO-4, a dual P2X3/P2X2/3 antagonist for the treatment of pain

P2X purinoceptors are ligand-gated ion channels whose endogenous ligand is ATP. Both the P2X3 and P2X2/3 receptor subtypes have been shown to play an important role in the regulation of sensory function and dual P2X3/P2X2/3 antagonists offer significant potential for the treatment of pain. A high-throughput screen of the Roche compound collection resulted in the identification of a novel series of diaminopyrimidines; subsequent optimization resulted in the discovery of RO-4, a potent, selective and drug-like dual P2X3/P2X2/3 antagonist.

Diaminopyrimidines as P2X3 and P2X2/3 antagonists

Compounds and methods for treating diseases mediated by a P2X3 and/or a P2X2/3 receptor antagonist, the methods comprising administering to a subject in need thereof an effective amount of a compound of formula (I): or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein D, X, Y, R1, R2, R3, R4, R5, R6, R7 and R8 are as defined herein.