34381-71-0

Basic information

• Product Name: N-Methyl-L-prolinol
• Synonyms: (2S)-1-Methyl-2-pyrrolidinemethanol;(2S)-1-Methyl-2α-(hydroxymethyl)pyrrolidine;(2S)-1-Methyl-2α-pyrrolidinemethanol;(2S)-1-Methylpyrrolidine-2α-methanol;(S)-(+)-1-methyl-prolinol;[(2S)-1-Methylpyrrolidin-2-yl]Methanol;(S)-(-)-2-HYDROXYMETHYL-1-METHYLPYRROLID;(S)-(1-Methylpyrrolidin-2-yl)Methanol
• CAS NO: 34381-71-0
• Molecular Formula: C₆H₁₃NO
• Molecular Weight: 115.17
• EINECS: 251-981-9
• Product Categories: chiral;Chiral Reagent
• Mol File: 34381-71-0.mol
• Article Data: 27

Chemical Properties

• Boiling Point: 67-69 °C12 mm Hg(lit.)
• Flash Point: 146 °F
• Appearance: Colorless to yellow/Liquid
• Density: 0.968 g/mL at 25 °C(lit.)
• Vapor Pressure: 0.649mmHg at 25°C
• Refractive Index: n20/D 1.469(lit.)
• Storage Temp.: −20°C
• PKA: 14.77±0.10(Predicted)
• BRN: 79851
• CAS DataBase Reference: N-Methyl-L-prolinol(CAS DataBase Reference)
• NIST Chemistry Reference: N-Methyl-L-prolinol(34381-71-0)
• EPA Substance Registry System: N-Methyl-L-prolinol(34381-71-0)

Safety Data

• Hazard Codes: Xi
• Statements: 36/37/38
• Safety Statements: 23-24/25-36-26
• WGK Germany: 3
• F: 8-10-23
• HazardClass: IRRITANT
• Hazardous Substances Data: 34381-71-0(Hazardous Substances Data)

Usage

Uses

Different sources of media describe the Uses of 34381-71-0 differently. You can refer to the following data:
1. N-Methyl-L-prolinol is a reagent used in the synthesis of novel 4-hydroxytamoxifen analogs used as estrogen-related receptor γ (ERRγ) inverse agonists.
2. Precursor to phosphine ligands for catalytic asymmetric Grignard cross-coupling reactions.

Chemical Properties

white to light yellow crystal powde

InChI:InChI=1/C6H13NO/c1-7-4-2-3-6(7)5-8/h6,8H,2-5H2,1H3/t6-/m1/s1

Synthetic route

(S)-N-(tert-butoxycarbonyl)proline methyl ester (59936-29-7) → (S)-2-hydroxymethyl-1-methylpyrrolidine (34381-71-0)

Conditions	Yield
With lithium aluminium tetrahydride In diethyl ether	90%

formaldehyd (50-00-0) + (S)-1-Pyrrolidin-2-yl-methanol (23356-96-9) → (S)-2-hydroxymethyl-1-methylpyrrolidine (34381-71-0)

Conditions	Yield
With formic acid In water for 20h; Heating;	65%
With formic acid; water anschliessenden Erhitzen;
With hydrogen; platinum(IV) oxide In water for 24h;	2.4 g
With formic acid
With formic acid Yield given;

N-methyl-L-proline (475-11-6, 58123-62-9, 68078-09-1) → (S)-2-hydroxymethyl-1-methylpyrrolidine (34381-71-0)

Conditions	Yield
With lithium aluminium tetrahydride In tetrahydrofuran for 4h; Heating;	65%

L-proline (147-85-3) → (S)-2-hydroxymethyl-1-methylpyrrolidine (34381-71-0)

Conditions	Yield
With aq. sodium hydroxide; acetic anhydride In tetrahydrofuran; formic acid; water	57%
Multi-step reaction with 2 steps 1: NaBH4, H2SO4 2: HCOOH View Scheme
Multi-step reaction with 2 steps 1: NaBH4, conc. H2SO4 2: HCOOH View Scheme
Multi-step reaction with 2 steps 1: acetic anhydride / 2 h / Ambient temperature 2: LiAlH4 / tetrahydrofuran / 48 h / Heating View Scheme
Multi-step reaction with 3 steps 1: 94 percent / H2O 2: 95 percent / diethyl ether 3: 90 percent / 3 eq. LiAlH4 / diethyl ether View Scheme

N-Methyl-L-proline Methyl Ester (27957-91-1) → (S)-2-hydroxymethyl-1-methylpyrrolidine (34381-71-0)

Conditions	Yield
	53%
With lithium aluminium tetrahydride In tetrahydrofuran

N-Benzyloxycarbonyl-L-proline (1148-11-4) → (S)-2-hydroxymethyl-1-methylpyrrolidine (34381-71-0)

Conditions	Yield
With lithium aluminium tetrahydride In tetrahydrofuran 1.) room temp., 1 h, 2.) reflux, 3 h;	49%

formic acid (64-18-6) + L-proline (147-85-3) → (S)-2-hydroxymethyl-1-methylpyrrolidine (34381-71-0)

Conditions	Yield
Stage #1: formic acid; L-proline With acetic anhydride Stage #2: With lithium aluminium tetrahydride	48%

(2S)-1-formylpyrrolidine-2-carboxylic acid (13200-83-4) → (S)-2-hydroxymethyl-1-methylpyrrolidine (34381-71-0)

Conditions	Yield
With lithium aluminium tetrahydride In tetrahydrofuran for 48h; Heating; Yield given;

N-carbobenzyloxy-L-proline methyl ester (5211-23-4) → (S)-2-hydroxymethyl-1-methylpyrrolidine (34381-71-0)

Conditions	Yield
With lithium aluminium tetrahydride

N-methylproline (68078-09-1) → (R)-N-methylpyrrolidine-2-methanol (3554-65-2, 30727-24-3, 34381-71-0, 99494-01-6) + (S)-2-hydroxymethyl-1-methylpyrrolidine (34381-71-0)

Conditions	Yield
With lithium aluminium tetrahydride In tetrahydrofuran Heating; Title compound not separated from byproducts;

<(S)-1-formyl-pyrrolidin-2-yl>-methanol → (S)-2-hydroxymethyl-1-methylpyrrolidine (34381-71-0)

Conditions	Yield
With lithium aluminium tetrahydride; diethyl ether
With lithium aluminium tetrahydride; diethyl ether

(S)-(-)-1-Formyl-2-(hydroxymethyl)pyrrolidine (55456-46-7) → (S)-2-hydroxymethyl-1-methylpyrrolidine (34381-71-0)

Conditions	Yield
With lithium aluminium tetrahydride In tetrahydrofuran

methyl (2S)-pyrrolidine carboxylate (2577-48-2) → (S)-2-hydroxymethyl-1-methylpyrrolidine (34381-71-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium cyanoborohydride 2: LiAlH4 / tetrahydrofuran View Scheme

(S)-1-Pyrrolidin-2-yl-methanol (23356-96-9) → (S)-2-hydroxymethyl-1-methylpyrrolidine (34381-71-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: benzene 2: LiAlH4 / tetrahydrofuran View Scheme

N-Methyl-2-(tributylstannyl)pyrrolidine → (S)-2-hydroxymethyl-1-methylpyrrolidine (34381-71-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1.) TMEDA, BuLi / 1.) THF, hexane, -78 deg C, 15 min, 2.) -78 deg C, 1 h 2: LiAlH4 / tetrahydrofuran / Heating View Scheme

1-(tert-butoxycarbonyl)-L-proline (15761-39-4) → (S)-2-hydroxymethyl-1-methylpyrrolidine (34381-71-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: 95 percent / diethyl ether 2: 90 percent / 3 eq. LiAlH4 / diethyl ether View Scheme

(2S)-2-(methoxycarbonyl)-1-methylpyrrolidin-1-ium chloride (27871-48-3) → (S)-2-hydroxymethyl-1-methylpyrrolidine (34381-71-0)

Conditions	Yield
With lithium aluminium tetrahydride In diethyl ether at 0 - 20℃; for 3h; Inert atmosphere;	1.2 g

2-fluoro-5-trifluoromethyl-benzonitrile (4088-84-0) + (S)-2-hydroxymethyl-1-methylpyrrolidine (34381-71-0) → (S)-2-((1-methylpyrrolidin-2-yl)methoxy)-5-(trifluoromethyl)benzonitrile (1215230-56-0)

Conditions	Yield
With sodium hydride In tetrahydrofuran at 20℃; for 3h;	100%
With sodium hydride In tetrahydrofuran at 20℃; for 3h;	100%
Stage #1: (S)-2-hydroxymethyl-1-methylpyrrolidine With sodium hydride In tetrahydrofuran at 22℃; for 0.333333h; Stage #2: 2-fluoro-5-trifluoromethyl-benzonitrile In tetrahydrofuran at 22℃; for 3h;

(S)-2-hydroxymethyl-1-methylpyrrolidine (34381-71-0) + 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (214360-76-6) → (S)-1-methyl-2-[3-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenoxymethyl]pyrrolidine (1449321-17-8)

Conditions	Yield
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 36h;	100%

tert-butyl 7-(7-bromo-2-chloro-6-(trifluoromethoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate + (S)-2-hydroxymethyl-1-methylpyrrolidine (34381-71-0) → tert-butyl (S)-7-(7-bromo-2-((1-methylpyrrolidin-2-yl)methoxy)-6-(trifluoromethoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

Conditions	Yield
With sodium hydride In tetrahydrofuran at 0℃; for 1h;	100%

tert-butyl 4-(2-chloro-6-(naphthalen-1-ylmethyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate + (S)-2-hydroxymethyl-1-methylpyrrolidine (34381-71-0) → tert-butyl (S)-4-(2-((1-methylpyrrolidin-2-yl)methoxy)-6-(naphthalen-1-ylmethyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

Conditions	Yield
Stage #1: (S)-2-hydroxymethyl-1-methylpyrrolidine With sodium hydride In tetrahydrofuran at 20℃; for 0.5h; Stage #2: tert-butyl 4-(2-chloro-6-(naphthalen-1-ylmethyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate In tetrahydrofuran at 60℃; for 3h;	99%

benzyl (S)-4-(2-chloro-6-(2,3-dimethylbenzyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)-2-(cyanomethyl)piperazine-1-carboxylate + (S)-2-hydroxymethyl-1-methylpyrrolidine (34381-71-0) → benzyl (S)-2-(cyanomethyl)-4-(6-(2,3-dimethylbenzyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

Conditions	Yield
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; ruphos In toluene at 105℃; for 16h;	99%

2-hydroxynitrobenzene (88-75-5) + (S)-2-hydroxymethyl-1-methylpyrrolidine (34381-71-0) → 2-[(1-methyl-2(S)-pyrrolidinyl)methoxy]nitrobenzene

Conditions	Yield
Stage #1: 2-hydroxynitrobenzene With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran for 0.166667h; Stage #2: (S)-2-hydroxymethyl-1-methylpyrrolidine for 24h; Mitsunobu reaction;	98%

3-Bromophenyl isocyanate (23138-55-8) + (S)-2-hydroxymethyl-1-methylpyrrolidine (34381-71-0) → (3-bromophenyl)carbamic acid (S)-1-methylpyrrolidin-2-ylmethyl ester

Conditions	Yield
In toluene at 50 - 120℃; for 4h;	97%

2-chloropyrazin (14508-49-7) + (S)-2-hydroxymethyl-1-methylpyrrolidine (34381-71-0) → 2-((1-methyl-2-(S)-pyrrolidinyl)methoxy)pyrazine

Conditions	Yield
With NaH In tetrahydrofuran; mineral oil	97%
With hydrogenchloride; potassium tert-butylate In tetrahydrofuran; water
With hydrogenchloride; potassium tert-butylate In tetrahydrofuran; water
With hydrogenchloride; potassium tert-butylate In tetrahydrofuran; water

(S)-2-hydroxymethyl-1-methylpyrrolidine (34381-71-0) + 3-Phenylpropionic acid (501-52-0) → 3-Phenyl-propionic acid (S)-1-methyl-pyrrolidin-2-ylmethyl ester

Conditions	Yield
With N,N'-dimethylaminopyridine; di-tert-butyl dicarbonate In nitromethane at 50℃; for 16h;	95%

tert-butyl 4-[6-chloro-8-{[5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl]oxy}-2-(methylsulfonyl)pyrido[3,4-d]pyrimidin-4-yl]piperazine-1-carboxylate + (S)-2-hydroxymethyl-1-methylpyrrolidine (34381-71-0) → tert-butyl 4-(6-chloro-8-{[5-chloro-6-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl]oxy}-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}pyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

Conditions	Yield
With lithium hexamethyldisilazane In tetrahydrofuran at 0 - 20℃; for 1h;	95%

4-(4-bromo-7-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-f]quinazolin-9-yl)piperazine-1-carboxylic acid tert-butyl ester + (S)-2-hydroxymethyl-1-methylpyrrolidine (34381-71-0) → C29H40BrN7O4

Conditions	Yield
With caesium carbonate; N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 170℃; for 3h; Inert atmosphere; Sealed tube;	95%

toluene (108-88-3) + (S)-2-hydroxymethyl-1-methylpyrrolidine (34381-71-0) → C7H7Li*6C6H12NO(1-)*6Li(1+)

Conditions	Yield
Stage #1: (S)-2-hydroxymethyl-1-methylpyrrolidine With n-butyllithium In pentane at -90 - 20℃; Stage #2: toluene In pentane at -30℃; for 24h;	94%

4-methyl 1-(4-nitrophenyl) 4-{[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)sulfonyl]methyl}piperidine-1,4-dicarboxylate + (S)-2-hydroxymethyl-1-methylpyrrolidine (34381-71-0) → 4-methyl 1-{[(2S)-1-methylpyrrolidin-2-yl]methyl} 4-{[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)sulfonyl]methyl}piperidine-1,4-dicarboxylate (869189-88-8)

Conditions	Yield
With sodium hydride In tetrahydrofuran at 0 - 20℃; for 3h;	94%

tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-fluoroquinazolin-4-yl)piperazine-1-carboxylate + (S)-2-hydroxymethyl-1-methylpyrrolidine (34381-71-0) → tert-butyl (S)-4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-((1-methylpy rrolidin-2-yl)methoxy)quinazolin-4-yl)piperazine-1-carboxylate

Conditions	Yield
Stage #1: (S)-2-hydroxymethyl-1-methylpyrrolidine With sodium hydride In tetrahydrofuran; mineral oil at 25℃; for 0.0833333h; Stage #2: tert-butyl 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2-fluoroquinazolin-4-yl)piperazine-1-carboxylate In tetrahydrofuran; mineral oil at 25℃; for 1h;	93.4%

(S)-2-hydroxymethyl-1-methylpyrrolidine (34381-71-0) → (S)-(-)-1-methyl-2-chloromethylpyrrolidine hydrochloride (67824-38-8)

Conditions	Yield
With thionyl chloride In ethanol 1.) RT, 2 h, 2.) reflux, 30 min;	93%
With thionyl chloride In chloroform 1.) room temp., 30 min, 2.) reflux, 30 min;	88%
With hydrogenchloride; thionyl chloride In chloroform for 2h; Heating;	85%

trimethylamine alane (16842-00-5, 855944-65-9) + (S)-2-hydroxymethyl-1-methylpyrrolidine (34381-71-0) → [(-)-(S)-1-methylpyrrolidino-2-methoxy]alane dimer

Conditions	Yield
In toluene byproducts: H2, N(CH3)3; under Ar using Schlenk techniques; soln. N-methyl-L-prolinol added dropwise to soln. AlH3*NMe3 (1:1 mol) in toluene with stirring until gas evolution was ceased; stirring 1 h; repeated crystns. at -78°C; elem. anal.;	90.4%

(S)-2-hydroxymethyl-1-methylpyrrolidine (34381-71-0) + 2-(2,5-dimethylpyrrolyl)-6-(4-fluoronaphth-1-yl)pyridine (221087-79-2) → 2-(2,5-dimethylpyrrolyl)-6-(4-(1-methylpyrrolidin-2-ylmethoxy)naphth-1-yl)pyridine (675846-20-5)

Conditions	Yield
Stage #1: (S)-2-hydroxymethyl-1-methylpyrrolidine With sodium hydride In N,N-dimethyl-formamide at 70℃; Stage #2: 2-(2,5-dimethylpyrrolyl)-6-(4-fluoronaphth-1-yl)pyridine In N,N-dimethyl-formamide at 80℃; for 2h;	90%

hexadecanyl bromide (112-82-3) + (S)-2-hydroxymethyl-1-methylpyrrolidine (34381-71-0) → Br(1-)*C22H46NO(1+) (145707-12-6)

Conditions	Yield
In acetone for 72h; Reflux;	90%
In acetone at 50℃; for 48h;	73%
In 1,4-dioxane for 48h; Reflux;

4-(7-benzyl-2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester + (S)-2-hydroxymethyl-1-methylpyrrolidine (34381-71-0) → tert-butyl (S)-4-(7-benzyl-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate

Conditions	Yield
With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 110℃; for 6h; Inert atmosphere;	90%
Stage #1: (S)-2-hydroxymethyl-1-methylpyrrolidine With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 1h; Stage #2: 4-(7-benzyl-2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester In tetrahydrofuran; mineral oil at 70℃; for 11h;
Stage #1: (S)-2-hydroxymethyl-1-methylpyrrolidine With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 1h; Stage #2: 4-(7-benzyl-2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester In tetrahydrofuran; mineral oil at 0 - 70℃; for 11h;

4-nitro-phenol (100-02-7) + (S)-2-hydroxymethyl-1-methylpyrrolidine (34381-71-0) → 4-[(1-methyl-2(S)-pyrrolidinyl)methoxy]nitrobenzene

Conditions	Yield
Stage #1: 4-nitro-phenol With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran for 0.166667h; Stage #2: (S)-2-hydroxymethyl-1-methylpyrrolidine for 24h; Mitsunobu reaction;	89%

binaphthol chlorophosphite (137156-22-0, 171878-71-0, 155613-52-8) + (S)-2-hydroxymethyl-1-methylpyrrolidine (34381-71-0) → (2'S)-2-[(1'-methyl-pyrrolidinyl-2')-methoxy]dinaphtho[2,1-d:1',2'-f](1,3,2)dioxaphosphepine (479253-14-0)

Conditions	Yield
With triethylamine In toluene	89%

tert-butyl (2S)-2-(cyanomethyl)-4-((6R)-2-(methylsulfinyl)-3‘,4’,5,7-tetrahydro-1‘Hspiro[cyclopenta[d]pyrimidine-6,2’-naphthalen]-4-yl)piperazine-1-carboxylate + (S)-2-hydroxymethyl-1-methylpyrrolidine (34381-71-0) → tert-butyl (S)-2-(cyanomethyl)-4-((R)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-3',4’,5,7-tetrahydro-1‘H-spiro[cyclopenta[d]pyrimidine-6,2’-naphthalen]-4-yl)piperazine-1-carboxylate

Conditions	Yield
Stage #1: (S)-2-hydroxymethyl-1-methylpyrrolidine With potassium tert-butylate In tetrahydrofuran for 0.0833333h; Stage #2: tert-butyl (2S)-2-(cyanomethyl)-4-((6R)-2-(methylsulfinyl)-3‘,4’,5,7-tetrahydro-1‘Hspiro[cyclopenta[d]pyrimidine-6,2’-naphthalen]-4-yl)piperazine-1-carboxylate In tetrahydrofuran at 0℃; for 0.5h;	88%

4-((S)-4-((benzyloxy)carbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(methylsulfoxide)-5,6,7,9-tetrahydro-8H-pyrimidine[4,5-c]azepane-8-carboxylic acid tert-butyl ester + (S)-2-hydroxymethyl-1-methylpyrrolidine (34381-71-0) → 4-((S)-4-(benzyloxycarbonyl)-3-(cyanomethyl)piperazin-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6,7-dihydro-5H-pyrimido[4,5-c]azepane-8(9H)-carboxylic acid tert-butyl ester

Conditions	Yield
With sodium t-butanolate In toluene for 0.5h; Cooling with ice;	88%

tert-butyl (S)-4-(7-bromo-2,6-dichloroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate + (S)-2-hydroxymethyl-1-methylpyrrolidine (34381-71-0) → tert-butyl (S)-4-(7-bromo-6-chloro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazine-1-carboxylate

Conditions	Yield
Stage #1: (S)-2-hydroxymethyl-1-methylpyrrolidine With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.0833333h; Stage #2: tert-butyl (S)-4-(7-bromo-2,6-dichloroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate In N,N-dimethyl-formamide at 0℃; for 1h;	85.6%

5-nitroguaiacol (636-93-1) + (S)-2-hydroxymethyl-1-methylpyrrolidine (34381-71-0) → (S)-1-Methyl-2-(2-methoxy-5-nitrophenoxy)-pyrrolidine

Conditions	Yield
With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran	85%

benzyl (2S)-2-(cyanomethyl)-4-(2-methylsulfinyl-5,6-dihydrobenzo[h]quinazolin-4-yl)piperazine-1-carboxylate + (S)-2-hydroxymethyl-1-methylpyrrolidine (34381-71-0) → benzyl (2S)-2-(cyanomethyl)-4-[2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-5,6-dihydrobenzo[h]quinazolin-4-yl]piperazine-1-carboxylate

Conditions	Yield
With sodium t-butanolate In toluene for 1h; Cooling with ice;	85%

7-benzyl-2-chloro-4-methoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine + (S)-2-hydroxymethyl-1-methylpyrrolidine (34381-71-0) → (S)-7-benzyl-4-methoxy-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

Conditions	Yield
With palladium diacetate; caesium carbonate; ruphos In toluene at 110℃; for 8h; Inert atmosphere;	83%

tert-butyl (2S)-4-(2’-chloro-3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene-1,7’-quinazolin]-4’-yl)-2-(cyanomethyl)piperazine-1-carboxylate + (S)-2-hydroxymethyl-1-methylpyrrolidine (34381-71-0) → tert-butyl (2S)-2-(cyanomethyl)-4-(2’-(((S)-1-methylpyrrolidin-2-yl)methoxy)-3,4,5’,8’-tetrahydro-2H,6’H-spiro[naphthalene-1,7’-quinazolin]-4’-yl)piperazine-1-carboxylate

Conditions	Yield
With tris-(dibenzylideneacetone)dipalladium(0); [2'-(diphenylphosphanyl)-[1,1'-binaphthalen]-2-yl]diphenylphosphane; sodium t-butanolate In toluene at 110℃; for 2h; Inert atmosphere;	83%

(S)-2-hydroxymethyl-1-methylpyrrolidine (34381-71-0) → (S)-2-(chloromethyl)-1-methylpyrrolidine (137892-92-3)

Conditions	Yield
With thionyl chloride In dichloromethane	82%
With thionyl chloride
With tetrachloromethane; triphenylphosphine In acetonitrile Heating;

Upstream product

• 50-00-0 formaldehyd 
• 23356-96-9 (S)-1-Pyrrolidin-2-yl-methanol 
• 475-11-6 N-methyl-L-proline 
• 1148-11-4 N-Benzyloxycarbonyl-L-proline 
• 175725-27-6 (R)-1-ethoxycarbonylprolin 
• 68832-13-3 D-prolinol 
• 59378-81-3 1-(tert-butoxycarbonyl)prolin-2R-ol 
• 69610-40-8 N-(tert-butoxycarbonyl)-L-prolinol 
• 895160-34-6 (R)-pyrrolidine-1,2-dicarboxylic acid 2-tert-butyl ester 1-ethyl ester 
• 265660-44-4 (2S)-(+)-N-methyl-2-tributylstannylpyrrolidine 
• 344-25-2 D-Prolin 
• 74-88-4 methyl iodide 
• 68078-09-1 N-methylproline 
• 475-11-6 N-methyl-D-proline 

Downstream Products

• 67824-38-8 (S)-(-)-1-methyl-2-chloromethylpyrrolidine hydrochloride 
• 462102-49-4 bis(2,6-dimethylphenyl) [(2S)-1-methylpyrrolidin-2-yl]methyl phosphite 
• 852324-29-9 (S)-N-methylpyrrolidine-2-carboxaldehyde 
• 909783-58-0 (R)-2-(2-Methoxy-4-nitro-phenoxymethyl)-1-methyl-pyrrolidine 
• 630411-20-0 2-[((2S)-1-methylpyrrolidin-2-yl)methoxy]-6-nitrobenzenecarbonitrile 
• 630411-15-3 5-[((2S)-1-methylpyrrolidin-2-yl)methoxy]-2-nitrobenzenecarbonitrile 
• 60365-88-0 (S)-2-(bromomethyl)-1-methylpyrrolidine 
• 314061-38-6 (1-Methyl-2-pyrrolidyl)-methyl 3-nitrobenzoate 
• 174213-31-1 2(S)-(3-Fluorophenoxymethyl)-1-methyl-pyrrolidine hydrochloride 
• 220510-65-6 (S)-(+)-2-(3,4-dichlorophenoxymethyl)pyrrolidine 
• 1017590-65-6 1-methyl-2-(S)-(6-methyl-cyclohex-1-enyloxymethyl)-pyrrolidine 
• 1017590-64-5 1-methyl-2-(S)-(2-methyl-cyclohex-1-enyloxymethyl)-pyrrolidine 
• 1215230-56-0 (S)-2-((1-methylpyrrolidin-2-yl)methoxy)-5-(trifluoromethyl)benzonitrile 
• 1397922-61-0 (E)-N-[4-[[3-chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolyl]-3-[(2R)-1-methylpyrrolidin-2-yl]prop-2-enamide maleate 

Relevant articles and documents

CHIROPTICAL PROPERTIES OF 2-SUBSTITUTED PYRROLIDINES

The CD spectra of L-2-methylpyrrolidine, L-prolinol, and their N-methylated derivatives have been determined.As in the 2-substituted piperidines, N-methylation results in an inversion of the sign of the Cotton effects (CE).However, the sign of the long-wavelength CE does not follow the simple helicity rule found for 2-substituted piperidines, since the pyrrolidine ring is itself chiral and makes its own contributions to the observed CE's.The rotational contribution due to pyrrolidine ring chirality appears to be opposite in sign to and larger in magnitude than that due to the 2-substituent in both the secondary and the tertiary amines.

Pyrimidine derivative and application thereof in medicines

The invention discloses a pyrimidine derivative and application thereof in medicines, and particularly relates to a novel pyrimidine derivative and a pharmaceutical composition containing the compound. The invention also relates to a method for preparing the compound and the pharmaceutical composition, and application of the compound and the pharmaceutical composition in preparation of drugs for treating KRAS G12C-mediated diseases and/or symptoms, especially in preparation of drugs for treating cancers.

Chiral and Redox-Active Room-Temperature Ionic Liquids Based on Ferrocene and l-Proline

The syntheses of room-temperature ionic liquids (RTILs) combining the naturally occurring amino acid l-proline and ferrocene (Fc) building blocks are reported. After quaternization of ({[(2S)-N-methylpyrrolidine-2-yl]methyleneoxy}carbonyl)ferrocene (1) with alkyl iodides and anion exchange, the resulting diastereomeric (1S,2S)- and (1R,2S)-[(ferrocenylcarbonyl)oxy]methylene-N,N-dialkylpyrrolidine-1-ium RTILs are redox-active and air- and water-stable. They are also thermally stable up to 263 °C. The electrochemical FeII/FeIIIpotential is shifted to +0.28 V versus Fc/Fc+. Before anion exchange, several iodide derivatives were obtained as crystalline products, and their crystal structures are reported. According to the NMR spectroscopic data cation–anion aggregates are present in the non-coordinating solvent CDCl3. In contrast, in the polar solvent [D6]dimethyl sulfoxide ([D6]DMSO), the ion pairs are separated.

PHARMACEUTICALLY ACCEPTABLE SALT OF (E)-N-[4-[[3-CHLORO-4-(2-PYRIDYLMETHOXY)PHENYL]AMINO]-3-CYANO-7-ETHOXY-6-QUINOLYL]-3-[(2R)-1-METHYLPYRROLIDIN-2-YL]PROP-2-ENAMIDE, PREPARATION METHOD THEREFOR, AND MEDICAL USE THEREOF

Provided as represented by formula (I) is a pharmaceutically acceptable salt of (E)-N-[4-[[3-chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolyl] -3-[(2R)-1-methylpyrrolidin-2-yl]prop-2-enamide, a preparation method therefor, and a use thereof as a therapeutic agent and especially as a protein kinase inhibitor.