74974-54-2

Basic information

• Product Name: 1,1,1-Trimethoxy-2-chloroethane
• Synonyms: 2-CHLORO-1,1,1-TRIMETHOXYETHANE;1,1,1-trimethoxy-2-chloroethane;TMOCA;TRIMETHYL CHLORO-ORTHOACETATE;2-Chloro-1,1,1-trimethoxyethane,Trimethyl chloro-orthoacetate;2-Chloro-1,1,1-trimethoxyethane 98%
• CAS NO: 74974-54-2
• Molecular Formula: C₅H₁₁ClO₃
• Molecular Weight: 154.59
• EINECS: 629-378-0
• Mol File: 74974-54-2.mol
• Article Data: 8

Chemical Properties

• Boiling Point: 138 °C(lit.)
• Flash Point: 109 °F
• Appearance: /
• Density: 1.147 g/mL at 25 °C(lit.)
• Vapor Pressure: 6.77mmHg at 25°C
• Refractive Index: n20/D 1.425(lit.)
• Storage Temp.: 2-8°C
• CAS DataBase Reference: 1,1,1-Trimethoxy-2-chloroethane(CAS DataBase Reference)
• NIST Chemistry Reference: 1,1,1-Trimethoxy-2-chloroethane(74974-54-2)
• EPA Substance Registry System: 1,1,1-Trimethoxy-2-chloroethane(74974-54-2)

Safety Data

• Hazard Codes: T
• Statements: 10
• Safety Statements: 16-45
• RIDADR: UN 1993 3/PG 3
• WGK Germany: 3
• Hazardous Substances Data: 74974-54-2(Hazardous Substances Data)

Usage

Uses

2-Chloro-1,1,1-trimethoxyethane may be used for the synthesis of chlorotriazolinone, an NK1 antagonist and 2-chloromethyl-7-[3-(trifluoromethyl)pyridin-2-yl]-3H-quinazolin-4-one.

General Description

2-Chloro-1,1,1-trimethoxyethane is a chloromethyl heterocyclic compound. It participates in the synthesis of 2-phenyl-1,3,4-oxadiazole derivatives.

InChI:InChI=1/C5H11ClO3/c1-7-5(4-6,8-2)9-3/h4H2,1-3H3

Synthetic route

methyl chloroacetate (96-34-4) + trimethyl orthoformate (149-73-5) → 2-chloro-1,1,1-trimethoxyethane (74974-54-2)

Conditions	Yield
With sulfuric acid In methanol at -10 - 45℃; for 2h; Concentration; Temperature;	95.1%
With sulfuric acid In methanol at 20℃;

Trimethyl orthoacetate (1445-45-0) → 2-chloro-1,1,1-trimethoxyethane (74974-54-2)

Conditions	Yield
With sodium methylate; chlorine at 15℃; for 4h;	76%
With methanol; chlorine at 15℃; for 4h;	69%
With chlorine at 15℃; for 4h;	67%
With tert-butylhypochlorite In tetrachloromethane at 50 - 60℃; for 0.25h;	57%
With hydrogenchloride; N-chloro-succinimide In methanol at 70 - 80℃; for 3.5h;	32%

methanol (67-56-1) + methyl 2-chloroacetimidate hydrochloride (70737-12-1) → 2-chloro-1,1,1-trimethoxyethane (74974-54-2) + Chloroacetamide (79-07-2)

Conditions	Yield
at 20℃; for 24h;	A 65% B n/a

methanol (67-56-1) + 1,2-dichloro-2-fluoroethene (430-58-0) → 1,2-dichloro-1-methoxy-ethene (42345-81-3) + 2-chloro-1,1,1-trimethoxyethane (74974-54-2) + (Z)-2-Chloro-1-fluoro-1-methoxy-ethene

Conditions	Yield
With sodium at 60 - 70℃; for 3h;
With sodium at 60 - 70℃; for 3h; Title compound not separated from byproducts;

(S)-3-(4-amino-3-(oxetan-2-ylmethylamino)phenyl)-1,2,4-oxadiazol-5 (4H)-one + 2-chloro-1,1,1-trimethoxyethane (74974-54-2) → (S)-3-(2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazol-6-yl)-1,2,4-oxadiazol-5(4H)-one

Conditions	Yield
With toluene-4-sulfonic acid at 60℃;	100%

ethyl 4-amino-2-fluoro-3-[[(2S)-oxetan-2-yl]methylamino]benzoate + 2-chloro-1,1,1-trimethoxyethane (74974-54-2) → ethyl (S)-2-(chloromethyl)-7-fluoro-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

Conditions	Yield
With toluene-4-sulfonic acid In acetonitrile at 60℃; for 1.5h;	98.5%

semicarbazide hydrochloride (563-41-7) + 2-chloro-1,1,1-trimethoxyethane (74974-54-2) → 3-(chloromethyl)-1H-1,2,4-triazol-5(4H)-one (252742-72-6)

Conditions	Yield
In methanol at 20℃; for 72h;	98%
In methanol at 20℃;	62%
In methanol at 20℃; for 72h;
In methanol at 20℃; for 144h;
In methanol at 20℃; for 3h;

1-(2-O-tert-butyldimethylsilyloxy-6-methoxyphenyl)-3-methylbut-3-en-1-ol (871732-09-1) + 2-chloro-1,1,1-trimethoxyethane (74974-54-2) → methyl (4E)-6-(2-O-tert-butyldimethylsilyloxy-6-methoxyphenyl)-2-chloro-4-methylhex-4-enoate (871732-15-9)

Conditions	Yield
With propionic acid In xylene at 145℃; Claisen-Johnson ortho ester rearrangement;	98%

2-hydrazino-5-nitropyridine (6343-98-2) + 2-chloro-1,1,1-trimethoxyethane (74974-54-2) → 3-(chloromethyl)-6-nitro[1,2,4]triazolo[4,3-a]pyridine

Conditions	Yield
In ethanol for 1h; Reflux;	95%

methyl 4-amino-3-[[(2S)-oxetan-2-yl]methylamino]benzoate + 3-fluoro-4-(((6-(piperidin-4-yl)pyridiny-2-yl)oxy)methyl)nemzonitrile bis(4-methylbenzenesulfonate) + 2-chloro-1,1,1-trimethoxyethane (74974-54-2) → methyl (S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

Conditions	Yield
Stage #1: methyl 4-amino-3-{[(2S)-oxetan-2-ylmethyl]amino}benzoate; 2-chloro-1,1,1-trimethoxyethane With toluene-4-sulfonic acid In acetonitrile at 50℃; for 2h; Stage #2: 3-fluoro-4-(((6-(piperidin-4-yl)pyridiny-2-yl)oxy)methyl)nemzonitrile bis(4-methylbenzenesulfonate) With potassium carbonate In acetonitrile for 2h;	95%
Stage #1: methyl 4-amino-3-{[(2S)-oxetan-2-ylmethyl]amino}benzoate; 2-chloro-1,1,1-trimethoxyethane With toluene-4-sulfonic acid In acetonitrile at 50℃; for 2h; Stage #2: 3-fluoro-4-(((6-(piperidin-4-yl)pyridiny-2-yl)oxy)methyl)nemzonitrile bis(4-methylbenzenesulfonate) With potassium carbonate In acetonitrile at 50℃; for 2h;	95%

1,1-dimethylethyl (3R)-3-{[(2-aminophenyl)amino]methyl}-1-piperidinecarboxylate (876590-07-7) + 2-chloro-1,1,1-trimethoxyethane (74974-54-2) → 1,1-dimethylethyl (3R)-3-{[2-(chloromethyl)-1H-benzimidazol-1-yl]-methyl}-1-piperidinecarboxylate (876590-08-8)

Conditions	Yield
toluene-4-sulfonic acid In dichloromethane at 20℃; for 18h;	94%
Stage #1: 1,1-dimethylethyl (3R)-3-{[(2-aminophenyl)amino]methyl}-1-piperidinecarboxylate; 2-chloro-1,1,1-trimethoxyethane With toluene-4-sulfonic acid In dichloromethane at 20℃; for 18h; Stage #2: With sodium hydrogencarbonate In dichloromethane; water	94%
With toluene-4-sulfonic acid In dichloromethane	85%

2-chloro-1,1,1-trimethoxyethane (74974-54-2) + 4-chloro-1-N-methylbenzene-1,2-diamine (59681-66-2) → 5-chloro-2-(chloromethyl)-1-methyl-1,3-benzodiazole (75487-56-8)

Conditions	Yield
Stage #1: 2-chloro-1,1,1-trimethoxyethane; 4-chloro-1-N-methylbenzene-1,2-diamine With hydrogenchloride In water at 20℃; Stage #2: With sodium hydrogencarbonate In water	93.9%

4-methoxybenzoic acid hydrazide (3290-99-1) + 2-chloro-1,1,1-trimethoxyethane (74974-54-2) → 2-(chloromethyl)-5-(4-methoxyphenyl)-1,3,4-oxadiazole (24023-71-0)

Conditions	Yield
at 160℃; for 0.0833333h; microwave irradiation;	93%

tert-butyl (3R)-3-[(2-amino-4-chlorophenyl)amino]pyrrolidine-1-carboxylate + 2-chloro-1,1,1-trimethoxyethane (74974-54-2) → tert-butyl (3R)-3-[5-chloro-2-(chloromethyl)-1H-benzimidazol-1-yl]pyrrolidine-1-carboxylate

Conditions	Yield
In ethanol for 2h; Reflux;	92.5%

2-chloro-1,1,1-trimethoxyethane (74974-54-2) + diethylene glycol (111-46-6) → C16H28Cl2O9*Na(1+)

Conditions	Yield
With sodium tetrakis[(3,5-di-trifluoromethyl)phenyl]borate; trifluoroacetic acid In chloroform Molecular sieve;	92%

methyl 4-amino-3-((2-methoxyethyl)amino)benzoate + 2-chloro-1,1,1-trimethoxyethane (74974-54-2) → methyl 2-(chloromethyl)-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylate

Conditions	Yield
With toluene-4-sulfonic acid In tetrahydrofuran at 45℃; for 5h;	91%
With toluene-4-sulfonic acid In tetrahydrofuran at 45℃; for 5h;	91%
With toluene-4-sulfonic acid In tetrahydrofuran at 45℃; for 5h;	91%

4-fluorobenzoyl hydrazide (456-06-4) + 2-chloro-1,1,1-trimethoxyethane (74974-54-2) → 3-(4-fluorophenyl)-5-(chloromethyl)-1,2,4-oxadiazole (721428-34-8)

Conditions	Yield
With acetic acid at 160℃; for 0.5h; Microwave;	89%
With acetic acid at 160℃; for 0.5h; Microwave irradiation;	89%

2-chloro-1,1,1-trimethoxyethane (74974-54-2) + 5-bromo-N2-phenylpyridine-2,3-diamine → 6-bromo-2-(chloromethyl)-3-phenyl-3H-imidazo[4,5-b]pyridine (1404085-40-0)

Conditions	Yield
With toluene-4-sulfonic acid In dichloromethane at 30℃; for 1h;	89%
With toluene-4-sulfonic acid In dichloromethane at 30℃; for 1h;	89%

3-N-phenylpyridine-2,3-diamine (68765-56-0) + 2-chloro-1,1,1-trimethoxyethane (74974-54-2) → 2-(chloromethyl)-1-phenyl-1H-imidazo[4,5-b]pyridine (1404085-62-6)

Conditions	Yield
With toluene-4-sulfonic acid In dichloromethane at 20℃;	89%
Stage #1: 3-N-phenylpyridine-2,3-diamine; 2-chloro-1,1,1-trimethoxyethane With toluene-4-sulfonic acid In dichloromethane at 20℃; Stage #2: With sodium hydroxide In dichloromethane; water	89%

3-Amino-4-ethylamino-6-(3-trifluoromethyl-phenyl)-pyridine-2-carbonitrile (944388-89-0) + 2-chloro-1,1,1-trimethoxyethane (74974-54-2) → 2-chloromethyl-1-ethyl-6-(3-trifluoromethyl-phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (944388-90-3)

Conditions	Yield
ytterbium(III) triflate In acetonitrile for 48h; Heating / reflux;	87%

4-(2-amino-4-bromoanilino)butanenitrile + 2-chloro-1,1,1-trimethoxyethane (74974-54-2) → 4-[5-bromo-2-(chloromethyl)benzimidazole-1-yl]butanenitrile

Conditions	Yield
With p-toluenesulfonyl chloride In dichloromethane at 20℃; for 4h; Inert atmosphere;	87%

2-chloro-1,1,1-trimethoxyethane (74974-54-2) + 2-hydroxy-5-nitroaniline (99-57-0) → 2-(chloromethyl)-6-nitrobenzo[d]oxazole (221638-74-0)

Conditions	Yield
In ethanol at 80℃; for 3h;	86%
In ethanol at 80℃; for 3h;	86%

N4-isopropyl-N2-(2-(4-methoxypiperidin-1-yl)pyrimidin-4-yl)pyridine-2,4,5-triamine (1612171-77-3) + 2-chloro-1,1,1-trimethoxyethane (74974-54-2) → (2-chloromethyl-1-isopropyl-1H-imidazo[4,5-c]pyridin-6-yl)-[2-(4-methoxypiperidin-1-yl)pyrimidin-4-yl]amine (1612171-81-9)

Conditions	Yield
With toluene-4-sulfonic acid at 100℃; for 1h;	86%
With toluene-4-sulfonic acid at 100℃; for 1h;	86%

3-amino-4-hydroxybenzonitrile (14543-43-2) + 2-chloro-1,1,1-trimethoxyethane (74974-54-2) → 2-(chloromethyl)benzo[d]oxazole-5-carbonitrile

Conditions	Yield
In ethanol for 5h; Inert atmosphere; Reflux;	86%

methyl 2-hydroxymethylacrylate (15484-46-5) + 2-chloro-1,1,1-trimethoxyethane (74974-54-2) → dimethyl 2-chloro-4-methylenepentanedioate

Conditions	Yield
With acetic acid In toluene at 130℃; for 24h;	85%

3-amino-4-(tetrahydropyran-4-ylamino)benzonitrile (320406-78-8) + 2-chloro-1,1,1-trimethoxyethane (74974-54-2) → 2-(chloromethyl)-1-tetrahydropyran-4-yl-benzimidazole-5-carbonitrile

Conditions	Yield
In ethanol at 130℃; for 0.5h; Inert atmosphere; Microwave irradiation;	85%

5-[(2-amino-4-chlorophenyl)amino]pyridine-2-carbonitrile + 2-chloro-1,1,1-trimethoxyethane (74974-54-2) → 5-[5-chloro-2-(chloromethyl)-1H-benzimidazol-1-yl]pyridine-2-carbonitrile

Conditions	Yield
In ethanol for 2h; Reflux;	84.6%

2-chloro-1,1,1-trimethoxyethane (74974-54-2) + (R)-2-methylpropane-2-sulfinamide (196929-78-9) → methyl (R(S))-tert-butanesulfinyl-2-chloroethanimidate + N-(tert-butanesulfinyl)-tert-butanesulfinimide

Conditions	Yield
With toluene-4-sulfonic acid at 100℃; for 4h;	A 84% B 10%

methyl 4-amino-3-[[(2S)-oxetan-2-yl]methylamino]benzoate + 2-((4-chloro-2-fluorobenzyl)oxy)-6-(piperidin-4-yl)pyridine bis(4-methylbenzenesulfonate) + 2-chloro-1,1,1-trimethoxyethane (74974-54-2) → methyl (S)-2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

Conditions	Yield
Stage #1: methyl 4-amino-3-{[(2S)-oxetan-2-ylmethyl]amino}benzoate; 2-chloro-1,1,1-trimethoxyethane With toluene-4-sulfonic acid In acetonitrile at 60℃; for 1h; Stage #2: 2-((4-chloro-2-fluorobenzyl)oxy)-6-(piperidin-4-yl)pyridine bis(4-methylbenzenesulfonate) With potassium carbonate In acetonitrile for 2h;	84%

4-tert-butylbenzoic acid hydrazide (43100-38-5) + 2-chloro-1,1,1-trimethoxyethane (74974-54-2) → 2-(chloromethyl)-5-(4-t-butylphenyl)-1,3,4-oxadiazole

Conditions	Yield
at 160℃; for 0.0833333h; microwave irradiation;	83%

6-chloro-2-(4-fluoro-1H-indol-2-yl)pyridin-3-amine (1621888-52-5) + 2-chloro-1,1,1-trimethoxyethane (74974-54-2) → 2-chloro-6-(chloromethyl)-11-fluoropyrido[3',2':4,5]pyrimido[1,6-a]indole (1621888-61-6)

Conditions	Yield
With hydrogenchloride In 1,4-dioxane at 60℃; for 4h; Sealed tube;	81%
With hydrogenchloride In 1,4-dioxane at 60℃; for 4h;	81%

4-{[(hexyloxy)carbonyl]carbamimidoyl}aniline (255706-13-9) + 2-chloro-1,1,1-trimethoxyethane (74974-54-2) → C19H31N3O5

Conditions	Yield
With sodium hydrogencarbonate; potassium iodide In N,N-dimethyl-formamide at 60℃;	80.1%

Upstream product

• 96-34-4 methyl chloroacetate 
• 149-73-5 trimethyl orthoformate 
• 67-56-1 methanol 
• 70737-12-1 methyl 2-chloroacetimidate hydrochloride 
• 430-58-0 1,2-dichloro-2-fluoroethene 
• 1445-45-0 Trimethyl orthoacetate 

Downstream Products

• 350672-16-1 2-chloromethyl-5-(3-fluoro-phenyl)-[1,3,4]oxadiazole 
• 350672-14-9 2-(chloromethyl)-5-(4-fluorophenyl)-1,3,4-oxadiazole 
• 350672-17-2 2-chloromethyl-5-(2-fluoro-phenyl)-[1,3,4]oxadiazole 
• 36770-18-0 2-Chlormethyl-5-(m-anisyl)-1,3,4-oxadiazol 
• 754214-34-1 2-chloromethyl-5-(2-methoxy-phenyl)-[1,3,4]oxadiazole 
• 657424-48-1 2-(5-chloro-2-fluoro-phenyl)-5-chloromethyl-[1,3,4]oxadiazole 
• 252742-72-6 3-(chloromethyl)-1H-1,2,4-triazol-5(4H)-one 
• 944388-90-3 2-chloromethyl-1-ethyl-6-(3-trifluoromethyl-phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile 
• 110704-48-8 5-bromo-2-(chloromethyl)benzo[d]oxazole 
• 110704-19-3 5-chloro-2-(chloromethyl)-1,3-benzothiazole 
• 37908-98-8 methyl 3-chloro-p-anisate 
• 79-11-8 chloroacetic acid 
• 412010-99-2 4-<(Methoxycarbonyl)chloromethyl>-4-(2,3-dimethoxyphenyl)-1-methyl-3-methylene-2-piperidinone 
• 1092352-10-7 C₇H₅ClN₂O 

Relevant articles and documents

Synthesis method of crude carboxylic ester (by machine translation)

The method is characterized in that the carboxylic ester and the ether are prepared by reacting a carboxylic ester with an ether at a certain temperature under the catalysis of a catalyst at a certain pressure for a certain time. (by machine translation)

Divergent Diels-Alder methodology from methyl coumalate toward functionalized aromatics

An inverse electron-demand Diels-Alder reaction between methyl coumalate and electron-rich dienophiles produces substituted benzoates. A high-yielding, single-pot procedure transforms readily accessible vinyl ether, ketal, or orthoester dienophiles into functionalized aromatic systems in a versatile route.

A new synthesis of 1,2,4-triazolin-5-ones: Application to the convergent synthesis of an NK1 antagonist

Chlorotriazolinone 4 has been synthesised in a single step via the novel condensation of semicarbazide hydrochloride with orthoester 8. Alkylation of secondary amine 3 with compound 4 proceeds in 99% yield to afford the target NK1 antagonist 1. (C) 2000 Published by Elsevier Science Ltd.