67004-64-2

Basic information

• Product Name: 1-Methyl-2-pyrrolidineethanol
• Synonyms: N-METHYL-2-PYRROLIDINEETHANOL;2-(2-HYDROXYETHYL)-N-METHYL-PYRROLIDINE;2-(2-HYDROXYETHYL)-1-METHYLPYRROLIDINE;1-METHYL-2-PYRROLIDINEETHANOL;2-PYRROLIDINEETHANOL, 1-METHYL-;N-Methyl-2-hydroxy-ethylpyrrolidine;N-Methyl-2-ethanol-pyrrolidine;2-(1-methyl-2-pyrrolidine)ethanol
• CAS NO: 67004-64-2
• Molecular Formula: C₇H₁₅NO
• Molecular Weight: 129.2
• EINECS: 266-538-5
• Product Categories: Building Blocks;Heterocyclic Building Blocks;Pyrrolidines
• Mol File: 67004-64-2.mol
• Article Data: 4

Chemical Properties

• Boiling Point: 110-112 °C14 mm Hg(lit.)
• Flash Point: 184 °F
• Appearance: clear yellow to brownish liquid
• Density: 0.951 g/mL at 25 °C(lit.)
• Vapor Pressure: 0.035mmHg at 25°C
• Refractive Index: n20/D 1.4713(lit.)
• Storage Temp.: 2-8°C(protect from light)
• PKA: 15.03±0.10(Predicted)
• CAS DataBase Reference: 1-Methyl-2-pyrrolidineethanol(CAS DataBase Reference)
• NIST Chemistry Reference: 1-Methyl-2-pyrrolidineethanol(67004-64-2)
• EPA Substance Registry System: 1-Methyl-2-pyrrolidineethanol(67004-64-2)

Safety Data

• Hazard Codes: Xn
• Statements: 22-38-41
• Safety Statements: 26-39
• WGK Germany: 3
• Hazardous Substances Data: 67004-64-2(Hazardous Substances Data)

Usage

Chemical Properties

clear yellow to brownish liquid

General Description

1-Methyl-2-pyrrolidine ethanol is an important pharmaceutical intermediate.

InChI:InChI=1/C7H15NO/c1-8-5-2-3-7(8)4-6-9/h7,9H,2-6H2,1H3/p+1/t7-/m0/s1

Synthetic route

methyl 2-(1-methylpyrrolidin-2-yl)acetate (51856-76-9, 118353-50-7) → 2-(1-methyl-2-pyrrolidine)ethanol (67004-64-2)

Conditions	Yield
With methanol; sodium tetrahydroborate for 12h; Reflux;	85%
With methanol; sodium tetrahydroborate for 12h; Reflux;	3.5 g

methanol (67-56-1) + Clemastine (7723-51-5, 15686-51-8, 61826-27-5, 61826-28-6, 61826-31-1, 63813-90-1, 63813-91-2) → 2-(1-methyl-2-pyrrolidine)ethanol (67004-64-2) + 1-(4-chloro-phenyl)-1-phenyl-ethanol (59767-24-7) + 1-Chloro-4-(1-methoxy-1-phenyl-ethyl)-benzene

Conditions	Yield
Ambient temperature; 6 weeks;

propan-1-ol (71-23-8) + Clemastine (7723-51-5, 15686-51-8, 61826-27-5, 61826-28-6, 61826-31-1, 63813-90-1, 63813-91-2) → 2-(1-methyl-2-pyrrolidine)ethanol (67004-64-2) + 1-(4-chloro-phenyl)-1-phenyl-ethanol (59767-24-7) + 1-Phenyl-1-(4-chlorphenyl)-ethylenglycol (28523-14-0) + 1-methyl-2-vinylpyrrolidine (85151-07-1) + 4-chlorobenzophenone (134-85-0) + 1-Phenyl-1-(4-chlorphenyl)-1-n-propoxyethan (117932-40-8)

Conditions	Yield
With sodium hydroxide for 53h; Heating; further time and temp.; also without n-propanol, with H2O or HCl addition;

ethanol (64-17-5) + Clemastine (7723-51-5, 15686-51-8, 61826-27-5, 61826-28-6, 61826-31-1, 63813-90-1, 63813-91-2) → 2-(1-methyl-2-pyrrolidine)ethanol (67004-64-2) + 1-(4-chloro-phenyl)-1-phenyl-ethanol (59767-24-7) + 1-Chloro-4-(1-ethoxy-1-phenyl-ethyl)-benzene (87273-95-8)

Conditions	Yield
Ambient temperature; 6 weeks;

(+)-2-<2-<1-(4-Chlorphenyl)-1-phenylethoxy>ethyl>-1-methylpyrroliden-hydrogenfumarat (14976-57-9, 20271-71-0, 61826-29-7, 61826-30-0, 61826-32-2, 61826-33-3, 61826-34-4, 61826-35-5, 61826-36-6, 63537-12-2, 66727-90-0) → 2-(1-methyl-2-pyrrolidine)ethanol (67004-64-2) + 1-(4-chloro-phenyl)-1-phenyl-ethanol (59767-24-7) + 1-Phenyl-1-(4-chlorphenyl)-ethylenglycol (28523-14-0) + 4-chlorobenzophenone (134-85-0)

Conditions	Yield
With water Heating;

Clemastin-hydrogenfumarat (63537-12-2) → 2-(1-methyl-2-pyrrolidine)ethanol (67004-64-2) + 1-(4-chlorophenyl)-1-phenylethene (18218-20-7) + 1-(4-chloro-phenyl)-1-phenyl-ethanol (59767-24-7) + 1-(4-Chlorphenyl)-1-(4'-hydroxyphenyl)ethen (110203-93-5) + 1-(4-Chlorphenyl)-1-(4'-hydroxyphenyl)ethanol + 4-{1-(4-Chloro-phenyl)-1-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-ethyl}-phenol

Conditions	Yield
With 1H-imidazole; water; dihydrogen peroxide; MnTPFPS4PCl In methanol; dichloromethane at 20℃; for 24h; Product distribution; also without water, var. catalyst;

Clemastin-hydrogenfumarat (63537-12-2) → 2-(1-methyl-2-pyrrolidine)ethanol (67004-64-2) + 1-(4-chloro-phenyl)-1-phenyl-ethanol (59767-24-7) + 2-{2-[1-(4-Chloro-phenyl)-1-phenyl-ethoxy]-ethyl}-pyrrolidine + Clemastin-N-oxid

Conditions	Yield
With 1H-imidazole; dihydrogen peroxide; manganese(III)-5,10,15,20-tetrakis(pentafluorophenyl)porphyrin chloride In methanol; dichloromethane at 20℃; for 24h; Further byproducts given;

(+-)-<1-methyl-pyrrolidin-2-yl>-acetic acid ethyl ester → 2-(1-methyl-2-pyrrolidine)ethanol (67004-64-2)

Conditions	Yield
With lithium aluminium tetrahydride; diethyl ether

formaldehyd (50-00-0) + 2-<β-oxy-ethyl>-pyrrolidine → 2-(1-methyl-2-pyrrolidine)ethanol (67004-64-2)

Conditions	Yield
With water at 110 - 124℃;

1-methyl-pyrrolidin-2-one (872-50-4) → 2-(1-methyl-2-pyrrolidine)ethanol (67004-64-2)

Conditions	Yield
Multi-step reaction with 5 steps 1: bis(trichloromethyl) carbonate / dichloromethane / 1 h / 30 °C 2: triethylamine / dichloromethane / 7 h / 10 - 30 °C 3: sodium methylate / methanol / 1 h / Reflux 4: 5%-palladium/activated carbon; hydrogen / methanol / 24 h 5: sodium tetrahydroborate; methanol / 12 h / Reflux View Scheme
Multi-step reaction with 5 steps 1: bis(trichloromethyl) carbonate / dichloromethane / 1 h / 10 - 30 °C 2: triethylamine / dichloromethane / 6 h / 10 - 30 °C 3: methanol / 1 h / Reflux 4: acetic acid; sodium tetrahydroborate / 6 h / 5 - 30 °C 5: methanol; sodium tetrahydroborate / 12 h / Reflux View Scheme

(2,2-dimethyl-5-(1-methylpyrrolidin-2-ylidene)-1,3-dioxane-4,6-dione) (86208-87-9) → 2-(1-methyl-2-pyrrolidine)ethanol (67004-64-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium methylate / methanol / 1 h / Reflux 2: 5%-palladium/activated carbon; hydrogen / methanol / 24 h 3: sodium tetrahydroborate; methanol / 12 h / Reflux View Scheme
Multi-step reaction with 3 steps 1: methanol / 1 h / Reflux 2: acetic acid; sodium tetrahydroborate / 6 h / 5 - 30 °C 3: methanol; sodium tetrahydroborate / 12 h / Reflux View Scheme

2-(1-methyl-2-pyrrolidine)ethanol (67004-64-2) → 2-(2-chloro-ethyl)-1-methyl-pyrrolidine (54777-54-7, 61771-17-3, 63527-58-2, 67529-19-5)

Conditions	Yield
With thionyl chloride In dichloromethane at 40 - 50℃; for 2h; Inert atmosphere;	95%

2-(1-methyl-2-pyrrolidine)ethanol (67004-64-2) + methyl (E)-5-[4-(2,2-dimethylpropanoyloxy)phenyl]-5-(4-hydroxyphenyl)-4-phenyl-pent-4-enoate → (E)-methyl 5-(4-(2-(1-methylpyrrolidin-2-yl)ethoxy)phenyl)-4-phenyl-5-(4-(pivaloyloxy)phenyl)pent-4-enoate

Conditions	Yield
With di-isopropyl azodicarboxylate; triphenylphosphine In dichloromethane at 0 - 20℃; Mitsunobu Displacement;	80%

2-(1-methyl-2-pyrrolidine)ethanol (67004-64-2) + isopropyl chloroformate (108-23-6) → C11H21NO3

Conditions	Yield
In dichloromethane; toluene at 20℃; for 10h;	79%

2-(1-methyl-2-pyrrolidine)ethanol (67004-64-2) + 2-Iodobenzoic acid (88-67-5) → 2-(1-methylpyrrolidin-2-yl)ethyl 2-iodophenylcarbamate

Conditions	Yield
Stage #1: 2-Iodobenzoic acid With diphenyl phosphoryl azide; triethylamine In toluene at 20℃; for 1.5h; Reflux; Stage #2: 2-(1-methyl-2-pyrrolidine)ethanol In toluene for 12h; Reflux;	77%

2-(1-methyl-2-pyrrolidine)ethanol (67004-64-2) + 4-Nitrophenyl chloroformate (7693-46-1) → 2-(1-methylpyrrolidin-2-yl)ethyl 4-nitrophenyl carbonate hydrochloride

Conditions	Yield
In diethyl ether at 20℃;	54%

2-(1-methyl-2-pyrrolidine)ethanol (67004-64-2) + 6-hydroxy-quinoline-2-carboxylic acid ethyl ester (883311-73-7) → 6-[2-(1-Methyl-pyrrolidin-2-yl)-ethoxy]-quinoline-2-carboxylic acid ethyl ester (883311-80-6)

Conditions	Yield
With di-tert-butyl-diazodicarboxylate; triphenylphosphine In tetrahydrofuran; toluene at 35℃;	53%

2-(1-methyl-2-pyrrolidine)ethanol (67004-64-2) + 2-(4-phenylbutyl)phenol (167145-50-8) → 1-methyl-2-{2-[2-(4-phenylbutyl)phenoxy]ethyl}pyrrolidine

Conditions	Yield
With triphenylphosphine; diethylazodicarboxylate In dichloromethane Ambient temperature;	52%

2-(1-methyl-2-pyrrolidine)ethanol (67004-64-2) → R(+)-1-methyl-2-(2-hydroxyethyl)pyrrolidine (60307-26-8)

Conditions	Yield
With malic acid In methanol at 45 - 50℃; for 1h; Reagent/catalyst; Solvent;	48.7%
With D-arginine In methanol; water at 60℃; Large scale;

2-(1-methyl-2-pyrrolidine)ethanol (67004-64-2) + 2-(4-phenylbutyl)phenol (167145-50-8) + diethylazodicarboxylate (1972-28-7) → 1-methyl-2-{2-[2-(4-phenylbutyl)phenoxy]ethyl}pyrrolidine

Conditions	Yield
With sodium chloride; triphenylphosphine In dichloromethane	38%

2-(1-methyl-2-pyrrolidine)ethanol (67004-64-2) + 2-[2-(3-methoxyphenyl)ethyl]phenol (167145-13-3) → 2-[2-[2-[2-(3-methoxyphenyl)ethyl]phenoxyl]ethyl]-1-methylpyrrolidine

Conditions	Yield
With triphenylphosphine; diethylazodicarboxylate In dichloromethane at 20℃; Condensation;	36%

2-(1-methyl-2-pyrrolidine)ethanol (67004-64-2) + bis(trichloromethyl) carbonate (32315-10-9) + (19Z,22Z)-octacosa-19,22-dien-11-ol → 2-(1-methylpyrrolidin-2-yl)ethyl (9Z,12Z)-octacosa-19,22-dien-11-yl carbonate

Conditions	Yield
Stage #1: bis(trichloromethyl) carbonate; (19Z,22Z)-octacosa-19,22-dien-11-ol With pyridine In toluene at 0 - 10℃; for 1.25h; Stage #2: 2-(1-methyl-2-pyrrolidine)ethanol In toluene at 0 - 20℃;	36%

2-(1-methyl-2-pyrrolidine)ethanol (67004-64-2) + 3-(2-((3r,5r,7r)-adamantan-1-yl)acetoxy)-2-(hydroxymethyl)propyl (9Z,12Z)-octadeca-9,12-dienoate → 3-(2-((3r,5r,7r)-adamantan-1-yl)acetoxy)-2-((((2-(1-methylpyrrolidin-2-yl)ethoxy)carbonyl)oxy)methyl)propyl (9Z,12Z)-octadeca-9,12-dienoate

Conditions	Yield
	34%

2-(1-methyl-2-pyrrolidine)ethanol (67004-64-2) + {4-[4-(4-bromo-phenylcarbamoyl)-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylsulfanyl]-phenyl}-carbamic acid 2,2,2-trichloro-ethyl ester (943772-98-3) + trifluoroacetic acid (76-05-1) → {4-[4-(4-bromo-phenylcarbamoyl)-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylsulfanyl]-phenyl}-carbamic acid 2-(1-methyl-pyrrolidin-2-yl)-ethyl ester trifluoroacetate

Conditions	Yield
Stage #1: 2-(1-methyl-2-pyrrolidine)ethanol; {4-[4-(4-bromo-phenylcarbamoyl)-2-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-phenylsulfanyl]-phenyl}-carbamic acid 2,2,2-trichloro-ethyl ester With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 60℃; for 1h; Stage #2: trifluoroacetic acid	27%

2-(1-methyl-2-pyrrolidine)ethanol (67004-64-2) + (E)-methyl 5-(4-bromophenyl)-5-(4-hydroxyphenyl)-4-phenylpent-4-enoate → (E)-methyl 5-(4-bromophenyl)-5-(4-(2-(1-methylpyrrolidin-2-yl)ethoxy)phenyl)-4-phenylpent-4-enoate

Conditions	Yield
With di-isopropyl azodicarboxylate; triphenylphosphine In dichloromethane at 0 - 20℃; Mitsunobu Displacement;	27%

2-(1-methyl-2-pyrrolidine)ethanol (67004-64-2) + 4’-fluoro-[1,1’-biphenyl]-2-carboxylic acid (1841-57-2) → 2-(1-methylpyrrolidin-2-yl)ethyl (4'-fluoro[1,1'-biphenyl]-2-yl)amino formic acid

Conditions	Yield
Stage #1: 4’-fluoro-[1,1’-biphenyl]-2-carboxylic acid With diphenyl phosphoryl azide; triethylamine In toluene at 20℃; for 1.5h; Reflux; Stage #2: 2-(1-methyl-2-pyrrolidine)ethanol In toluene for 12h; Reflux;	24%

2-(1-methyl-2-pyrrolidine)ethanol (67004-64-2) + 3'-chloro-5-fluoro-[1,1'-biphenyl]-2-carboxylic acid → 2-(1-methylpyrrolidin-2-yl)ethyl(3'-chloro-5-fluoro[1,1'-biphenyl]-2-yl)amino formic acid

Conditions	Yield
Stage #1: 3'-chloro-5-fluoro-[1,1'-biphenyl]-2-carboxylic acid With diphenyl phosphoryl azide; triethylamine In toluene at 20℃; for 1.5h; Reflux; Stage #2: 2-(1-methyl-2-pyrrolidine)ethanol In toluene for 12h; Reflux;	21%

2-(1-methyl-2-pyrrolidine)ethanol (67004-64-2) + 5-methylethyl-4-(3-methoxycarbomoyl-4-methylphenylamino)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid (658085-50-8) → [4-[[3-[(methoxyamino)carbonyl]-4-methylphenyl]amino]-5-(1-methylethyl)pyrrolo[2,1-f][1,2,4]triazine-6-yl]carbamic acid 2-(1-methyl-2-pyrrolidinyl)ethyl ester

Conditions	Yield
With diphenylphosphoryl azide; 4 A molecular sieve; triethylamine In 1,4-dioxane at 20 - 80℃; for 4h;	20%

2-(1-methyl-2-pyrrolidine)ethanol (67004-64-2) + 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (1093254-29-5) + ethyl 5-hydroxyindole-2-carboxylate (24985-85-1) → N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-5-{[2-(1-methyl-2-pyrrolidinyl)ethyl]oxy}-1H-indole-2-carboxamide (1093255-61-8)

Conditions	Yield
Stage #1: 2-(1-methyl-2-pyrrolidine)ethanol; ethyl 5-hydroxyindole-2-carboxylate With di-tert-butyl-diazodicarboxylate In tetrahydrofuran at 20℃; Stage #2: With water; lithium hydroxide In tetrahydrofuran at 20℃; for 6h; Stage #3: 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile	2%

2-(1-methyl-2-pyrrolidine)ethanol (67004-64-2) + 2.) 1,3-dimethyl-2-fluorobenzenetricarbonylchromium → (+/-)-2-<2-(2,6-dimethylphenoxy)ethyl>-1-methylpyrrolidine hydrochloride

Conditions	Yield
With iodine; sodium hydride 1.) THF, room temperature, 2.) room temperature; Yield given; Multistep reaction;

5-(6-(azidocarbonyl)-5-isopropylpyrrolo[2,1-f][1,2,4]triazin-4-ylamino)-2,4-difluoro-N-methoxybenzamide (658085-52-0) + 2-(1-methyl-2-pyrrolidine)ethanol (67004-64-2) → [4-(2,4-difluoro-5-methoxycarbamoyl-phenylamino)-5-isopropyl-pyrrolo[2,1-f][1,2,4]triazin-6-yl]-carbamic acid 2-(1-methyl-pyrrolidin-2-yl)-ethyl ester

Conditions	Yield
In N,N-dimethyl-formamide at 85℃; for 2h; Curtius rearrangement;

Upstream product

• 86208-87-9 (2,2-dimethyl-5-(1-methylpyrrolidin-2-ylidene)-1,3-dioxane-4,6-dione) 
• 872-50-4 1-methyl-pyrrolidin-2-one 
• 51856-76-9 methyl 2-(1-methylpyrrolidin-2-yl)acetate 
• 50-00-0 formaldehyd 
• 14976-57-9 (+)-2-<2-<1-(4-Chlorphenyl)-1-phenylethoxy>ethyl>-1-methylpyrroliden-hydrogenfumarat 
• 64-17-5 ethanol 
• 7723-51-5 Clemastine 
• 71-23-8 propan-1-ol 
• 67-56-1 methanol 
• 63537-12-2 Clemastin-hydrogenfumarat 

Downstream Products

• 1093255-61-8 N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-5-{[2-(1-methyl-2-pyrrolidinyl)ethyl]oxy}-1H-indole-2-carboxamide 
• 1469377-55-6 2-(3-methoxyphenylethynyl)-3-[2-(1-methylpyrrolidin-2-yl)-ethoxy]quinoxalin-6-ylamine 
• 1469377-56-7 3-[2-(1-methylpyrrolidin-2-yl)-ethoxy]-2-(p-tolylethynyl)quinoxalin-6-ylamine 
• 54777-54-7 2-(2-chloro-ethyl)-1-methyl-pyrrolidine 

Relevant articles and documents

Novel process for preparing 1-methyl-2-(2-hydroxyethyl)pyrrolidine

The present invention relates to a method for synthesizing 1-methyl-2-(2-hydroxyethyl)pyrrolidine, which is useful as an intermediate of a pharmaceutical. More specifically, the present invention relates to a novel synthesis method which uses metal borohydride as a reducing agent in a process of manufacturing 1-methyl-2-(2-hydroxyethyl)pyrrolidine, which is a target substance, from methyl (2E/Z)-2-(1-methylpyrrolidinyridin-2-ylidene)acetate, wherein the methyl (2E/Z)-2-(1-methylpyrrolidinyridin-2-ylidene)acetate is reduced in two stages sequentially, thereby being able to obtain the target substance with a safe process and cheap cost compared to an existing method.COPYRIGHT KIPO 2020

Biomimetic oxidation of clemastine fumarate

The reaction of clemastine fumarate (1) with the biomimetic system manganese(III)-5,10,15,20-tetrakis(pentafluorophenyl)porphyrin chloride (MnTPFPPCl)/imidazole/hydrogen peroxide in a mixture of dichlormethane/methanol affords several metabolites. These compounds are products of O-dealkylation, N-demethylation, N-oxidation and separation of water. The reaction of 1 in aqueous solution with manganese(III)-5,10,15,20-tetrakis(pentafluorophenyl)-β-tetrasulfonat oporphyrin chloride (MnTPFPS4PCl) as catalyst additional generates products of aromatic hydroxylation. Products were identified by TLC, UV, and MS. Thereby we found a close conformity with rat metabolism.