122536-94-1

Basic information

• Product Name: (S)-3-Hydroxypyrrolidine hydrochloride
• Synonyms: (S)-PYRROLIDIN-3-OL HCL;(S)-PYRROLIDINE-3-OL HYDROCHLORIDE;TIMTEC-BB SBB004272;(S)-3-HYDROXY PYRROLIDINE HCL;(S)-3-HYDROXYPYRROLIDINE HYDROCHLORIDE;(S)-(-)-3-PYRROLIDINOL HYDROCHLORIDE;(S)-3-PYRROLIDINOL HYDROCHLORIDE;3-PYRROLIDINOL, HYDROCHLORIDE, (3S)
• CAS NO: 122536-94-1
• Molecular Formula: C₄H₉NO*ClH
• Molecular Weight: 123.58
• EINECS: 1312995-182-4
• Product Categories: Alcohols and Derivatives;pharmacetical;Pyrrole&Pyrrolidine&Pyrroline;chiral;Heterocyclic Compounds;Benzenes;Chiral chemicals
• Mol File: 122536-94-1.mol
• Article Data: 6

Chemical Properties

• Melting Point: 104-107°C
• Boiling Point: 108-110℃/8mm
• Flash Point: 105.8 °C
• Appearance: white crystalline powder
• Vapor Pressure: 0.018mmHg at 25°C
• Storage Temp.: Room temperature.
• Solubility: DMSO (Sparingly), Methanol (Slightly)
• Stability: Hygroscopic
• CAS DataBase Reference: (S)-3-Hydroxypyrrolidine hydrochloride(CAS DataBase Reference)
• NIST Chemistry Reference: (S)-3-Hydroxypyrrolidine hydrochloride(122536-94-1)
• EPA Substance Registry System: (S)-3-Hydroxypyrrolidine hydrochloride(122536-94-1)

Safety Data

• Hazard Codes: Xi
• Statements: -36/37/38
• Safety Statements: 26-37
• Hazardous Substances Data: 122536-94-1(Hazardous Substances Data)

Usage

Chemical Properties

almost white crystalline powder

Uses

(S)-3-Hydroxypyrrolidine Hydrochloride is a useful intermediate for the synthesis of Asimadoline Hydrochlorine (A788250), used in the treatment of IBS, a disorder associated with pain and altered bowel function.

InChI:InChI=1/C4H9NO.ClH/c6-4-1-2-5-3-4;/h4-6H,1-3H2;1H/t4-;/m0./s1

Synthetic route

(3S)-1-benzyl-3-hydroxypyrrolidine-2,5-dione (101469-91-4) → (S)-3-hydroxypyrrolidine hydrochloride (122536-94-1)

Conditions	Yield
Stage #1: (3S)-1-benzyl-3-hydroxypyrrolidine-2,5-dione With palladium 10% on activated carbon; hydrogen In ethanol at 75℃; under 4125.41 Torr; for 5h; Autoclave; Stage #2: With hydrogenchloride In isopropyl alcohol at 20℃; Temperature; Pressure;	88%

(S)-4-chloro-3-hydroxy butyronitrile (127913-44-4) → (S)-3-hydroxypyrrolidine hydrochloride (122536-94-1)

Conditions	Yield
With hydrogenchloride; hydrogen In methanol; water at 80℃; under 7600.51 Torr;

(S)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (101469-92-5) → (S)-3-hydroxypyrrolidine hydrochloride (122536-94-1)

Conditions	Yield
With hydrogenchloride In 1,4-dioxane for 0.5h;
With hydrogenchloride In 1,4-dioxane for 0.5h; Inert atmosphere;
With hydrogenchloride In ethyl acetate at 20℃; for 12h;	21 g

3-pyrrolidinophenethyl mesylate (477779-05-8) + (S)-3-hydroxypyrrolidine hydrochloride (122536-94-1) → (S)-3-hydroxy-1-(3-pyrrolidinophenethyl)-pyrrolidine (477779-11-6)

Conditions	Yield
With potassium carbonate In acetonitrile at 100℃; for 12h;	100%

5-bromo-2-chloro-4-methyl-pyrimidine (633328-95-7) + (S)-3-hydroxypyrrolidine hydrochloride (122536-94-1) → (S)-1-(5-bromo-4-methylpyrimidin-2-yl)pyrrolidin-3-ol (1578253-13-0)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In ethanol at 75℃; for 18h;	100%

tetrahydro-2H-pyran-4-carbonylchloride (40191-32-0) + (S)-3-hydroxypyrrolidine hydrochloride (122536-94-1) → [(3S)-3-hydroxypyrrolidin-1-yl](tetrahydro-2H-pyran-4-yl)methanone (1354691-47-6)

Conditions	Yield
With triethylamine In dichloromethane at 3 - 10℃; for 1.5h;	98%
With triethylamine In dichloromethane at 3 - 10℃; for 1.5h;	98%
With triethylamine In dichloromethane at 3 - 10℃; for 1.5h;	98%
With triethylamine In dichloromethane at -3 - 20℃; for 1.5h;	98%

(5RS)-2-(3-chloro-4-fluorobenzyl)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylic acid + (S)-3-hydroxypyrrolidine hydrochloride (122536-94-1) → (5S)-2-(3-chloro-4-fluorobenzyl)-5-{[(3S)-3-hydroxypyrrolidin-1-yl]carbonyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one

Conditions	Yield
Stage #1: (5RS)-2-(3-chloro-4-fluorobenzyl)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylic acid With triethylamine; HATU In tetrahydrofuran at 20℃; for 0.25h; Stage #2: (S)-3-hydroxypyrrolidine hydrochloride In tetrahydrofuran at 20℃;	97%

di-tert-butyl dicarbonate (24424-99-5) + (S)-3-hydroxypyrrolidine hydrochloride (122536-94-1) → (S)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (101469-92-5)

Conditions	Yield
With triethylamine In methanol; dichloromethane at 0℃; for 1h;	96%
With triethylamine In methanol at 0 - 20℃; for 6h;	95%
With triethylamine In methanol at 20℃; for 6h;	95%

(S)-3-hydroxypyrrolidine hydrochloride (122536-94-1) + 4,6-diiodo-2-methoxypyrimidine → (S)-1-(6-iodo-2-methoxypyrimidin-4-yl)pyrrolidin-3-ol

Conditions	Yield
With triethylamine In isopropyl alcohol at 75℃; for 1h;	96%
With triethylamine In isopropyl alcohol at 20℃; for 18h;	73%

di-tert-butyl dicarbonate (24424-99-5) + (S)-3-hydroxypyrrolidine hydrochloride (122536-94-1) → N-tert-butoxycarbonyl-(S)-pyrrolidinol (133955-86-9)

Conditions	Yield
With triethylamine In methanol at 0 - 20℃; for 3h;	95%

formaldehyd (50-00-0) + (S)-3-hydroxypyrrolidine hydrochloride (122536-94-1) → (3S)-1-methylpyrrolidin-3-ol (104641-59-0)

Conditions	Yield
Stage #1: (S)-3-hydroxypyrrolidine hydrochloride With sodium hydroxide In tetrahydrofuran for 0.333333h; Stage #2: formaldehyd With formic acid In tetrahydrofuran; water at 60℃; for 2h; Reflux; Stage #3: With sodium hydroxide In tetrahydrofuran; water at 0℃; pH=Ca. 10;	95%

2,4-dichloro-pyrrolo[2,1-f][1,2,4]triazine (918538-05-3) + (S)-3-hydroxypyrrolidine hydrochloride (122536-94-1) → (S)-1-(2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)pyrrolidin-3-ol

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 90℃; for 1h;	94%

methyl 2-bromo-1,3-thiazole-5-carboxylate + (S)-3-hydroxypyrrolidine hydrochloride (122536-94-1) → methyl (S)-2-(3-hydroxypyrrolidin-1-yl)thiazole-5-carboxylate

Conditions	Yield
In 1,4-dioxane at 85℃; for 16h;	90%

2,6-dichloro-4-ethylpyridine-3,5-dicarbonitrile (18520-07-5) + (S)-3-hydroxypyrrolidine hydrochloride (122536-94-1) → (S)-2-chloro-4-ethyl-6-(3-hydroxypyrrolidin-1-yl)pyridine-3,5-dicarbonitrile

Conditions	Yield
With triethylamine In dichloromethane at 20℃; for 2h; Inert atmosphere;	89%

(5S)-3-oxo-2-{[2-(trifluoromethyl)quinolin-4-yl]methyl}-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylic acid + (S)-3-hydroxypyrrolidine hydrochloride (122536-94-1) → (5S)-5-{[(3S)-3-hydroxypyrrolidin-1-yl]carbonyl}-2-{[2-(trifluoromethyl)quinolin-4-yl]methyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one

Conditions	Yield
Stage #1: (5S)-3-oxo-2-{[2-(trifluoromethyl)quinolin-4-yl]methyl}-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylic acid With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 0.25h; Stage #2: (S)-3-hydroxypyrrolidine hydrochloride In tetrahydrofuran at 20℃; for 144h;	88%

7-chloro-4-oxo-N-[3,3,4,4,4-pentafluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide + (S)-3-hydroxypyrrolidine hydrochloride (122536-94-1) → 7-[(3S)-3-hydroxypyrrolidin-1-yl]-4-oxo-N-[3,3,4,4,4-pentafluorobutan-2-yl]-1-(2,4,6-trifluorophenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide	88%

1-(2-bromo-5-chlorophenoxy)-N-((6-fluoropyridin-2-yl)sulfonyl)cyclopropanecarboxamide + (S)-3-hydroxypyrrolidine hydrochloride (122536-94-1) → (S)-1-(2-bromo-5-chlorophenoxy)-N-((6-(3-hydroxypyrrolidin-1-yl)pyridin-2-yl)sulfonyl)cyclopropanecarboxamide

Conditions	Yield
With caesium carbonate In N,N-dimethyl acetamide at 120℃; for 18h;	88%

(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-amine (1223404-88-3) + (S)-3-hydroxypyrrolidine hydrochloride (122536-94-1) → (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate (1223405-08-0)

Conditions	Yield
Stage #1: 5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3-amine; (S)-3-hydroxypyrrolidine hydrochloride With triethylamine; 1,1'-carbonyldiimidazole for 3h; Stage #2: With sulfuric acid In ethanol	88%

1-methyl-5-nitro-1H-pyrazolo[3,4-b]pyridin-6-yl methanesulfonate + (S)-3-hydroxypyrrolidine hydrochloride (122536-94-1) → (S)-1-(1-methyl-5-nitro-1H-pyrazolo[3,4-b]pyridin-6-yl)pyrrolidin-3-ol

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 2h;	87.52%

(S)-3-hydroxypyrrolidine hydrochloride (122536-94-1) + 4-octylphenethyl methanesulfonate (162358-06-7) → (S)-1-[2-(4-octylphenyl)ethyl]pyrrolidin-3-ol

Conditions	Yield
Stage #1: 4-octylphenethyl methanesulfonate With potassium carbonate In acetonitrile at 20℃; for 0.166667h; Inert atmosphere; Stage #2: (S)-3-hydroxypyrrolidine hydrochloride In acetonitrile at 50℃; for 12h; Inert atmosphere;	86%
With potassium carbonate In acetonitrile at 20 - 50℃; for 12h;	86%

2-((3'-((2-chloro-5-((5-cyanopyridin-3-yl)methoxy)-4-formylphenoxy)methyl)-2'-methyl-[1,1'-biphenyl]-3-yl)oxy)acetic acid + (S)-3-hydroxypyrrolidine hydrochloride (122536-94-1) → (S)-5-((4-chloro-2-formyl-5-((3'-(2-(3-hydroxypyrrolidin-1-yl)-2-oxoethoxy)-2-methyl-[1,1'-biphenyl]-3-yl)methoxy)phenoxy)methyl)nicotinonitrile

Conditions	Yield
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 3h;	83%

6-(1H-benzo[d][1,2,3]triazol-1-yloxy)-9-((2R,4S,5R)-4-(tert-butyldimethylsilyloxy)-5-((tert-butyldimethylsilyloxy)methyl)tetrahydrofuran-2-yl)-9H-purine (927818-50-6) + (S)-3-hydroxypyrrolidine hydrochloride (122536-94-1) → C26H47N5O4Si2 (1614248-86-0)

Conditions	Yield
With caesium carbonate In tetrahydrofuran at 20℃; for 3.5h; Inert atmosphere;	82%

2,6-Dichloro-N-(cyclopropylmethyl)pyrimidine-4-carboxamide + (S)-3-hydroxypyrrolidine hydrochloride (122536-94-1) → (S)-2-Chloro-N-(cyclopropylmethyl)-6-(3-hydroxypyrrolidin-1-yl)pyrimidine-4-carboxamide

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In methanol at 0℃;	82%

3-[[4-(1-methyl-1H-pyrazol-4-yl)phenyl]methyl]-1H-indazole-5-carboxylic acid + (S)-3-hydroxypyrrolidine hydrochloride (122536-94-1) → ((S)-3-hydroxy-pyrrolidin-1-yl)-{3-[4-(1-methyl-1H-pyrazol-4-yl)benzyl]-1H-indazol-5-yl}methanone

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 25℃; for 3h;	79%
With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 1h;

methyl 6-chloro-3-pyridazinecarboxylate (65202-50-8) + (S)-3-hydroxypyrrolidine hydrochloride (122536-94-1) → methyl (S)-6-(3-hydroxypyrrolidin-1-yl)pyridazine-3-carboxylate

Conditions	Yield
With tetra-(n-butyl)ammonium iodide; potassium carbonate In tetrahydrofuran at 70℃; for 16h;	76%

6-fluoro-1-methyl-5-nitro-1H-indazole (1257303-08-4) + (S)-3-hydroxypyrrolidine hydrochloride (122536-94-1) → (S)-1-(1-methyl-5-nitro-1H-indazol-6-yl)pyrrolidin-3-ol

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 12h;	75%

(2R)-2-(2,5-difluorophenyl)-1-{3-isothiocyanatopyrazolo[1,5-a]pyrimidin-5-yl}pyrrolidine + (S)-3-hydroxypyrrolidine hydrochloride (122536-94-1) → (3S)-N-{5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3-yl}-3-hydroxypyrrolidine-1-carbothioamide

Conditions	Yield
Stage #1: (2R)-2-(2,5-difluorophenyl)-1-{3-isothiocyanatopyrazolo[1,5-a]pyrimidin-5-yl}pyrrolidine With sodium hydride In hexane; N,N-dimethyl-formamide at 0℃; for 0.25h; Inert atmosphere; Stage #2: (S)-3-hydroxypyrrolidine hydrochloride In N,N-dimethyl-formamide at 0 - 20℃; for 1h; Inert atmosphere;	75%
With triethylamine In dichloromethane for 1h;

1-(5-chloro-2-iodophenoxy)-N-((6-fluoropyridin-2-yl)sulfonyl)cyclopropanecarboxamide + (S)-3-hydroxypyrrolidine hydrochloride (122536-94-1) → (S)-1-(5-chloro-2-iodophenoxy)-N-((6-(3-hydroxypyrrolidin-1-yl)pyridin-2-yl)sulfonyl)cyclopropanecarboxamide

Conditions	Yield
With caesium carbonate In N,N-dimethyl acetamide at 120℃; for 18h;	74%

(S)-3-hydroxypyrrolidine hydrochloride (122536-94-1) + 2-nitro-benzaldehyde (552-89-6) → (3S)-1-[(2-aminophenyll)methyl]pyrrolidin-3-ol (1227263-77-5)

Conditions	Yield
Stage #1: (S)-3-hydroxypyrrolidine hydrochloride With potassium tert-butylate In N,N-dimethyl-formamide for 0.5h; Stage #2: 2-nitro-benzaldehyde With iron pentacarbonyl In N,N-dimethyl-formamide at 60℃; Inert atmosphere; Schlenk technique;	69%

5-chloro-2-methylthiazolo[4,5-d]pyrimidine-7-carboxylic acid + (S)-3-hydroxypyrrolidine hydrochloride (122536-94-1) → (S)-(5-chloro-2-methylthiazolo[4,5-d]pyrimidin-7-yl)(3-hydroxypyrrolidin-1-yl)methanone

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 2h;	64%

bis(trichloromethyl) carbonate (32315-10-9) + (4R)-4-[(3R,5S,6R,7R,8S,9S,10S,13R,14S,17R)-6-ethyl-10,13-dimethyl-3,7-di(tetrahydropyran-2-yloxy)-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentan-1-amine + (S)-3-hydroxypyrrolidine hydrochloride (122536-94-1) → (3S)-N-[(4R)-4-[(3R,6R,7R,8S,9S,10S,13R,14S,17R)-6-ethyl-10,13-dimethyl-3,7-di(tetrahydropyran-2-yloxy)-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentyl]-3-hydroxy-pyrrolidine-1-carboxamide

Conditions

Yield

Stage #1: bis(trichloromethyl) carbonate; (4R)-4-[(3R,5S,6R,7R,8S,9S,10S,13R,14S,17R)-6-ethyl-10,13-dimethyl-3,7-di(tetrahydropyran-2-yloxy)-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentan-1-amine With sodium hydrogencarbonate In dichloromethane; water at 0℃; for 1h; Cooling with ice; Stage #2: (S)-3-hydroxypyrrolidine hydrochloride With triethylamine In dichloromethane at 30℃; for 4h; Cooling with ice;

63%

6-fluoro-2-methyl-5-nitro-2H-indazole (1257303-13-1) + (S)-3-hydroxypyrrolidine hydrochloride (122536-94-1) → (S)-1-(2-methyl-5-nitro-2H-indazol-6-yl)pyrrolidin-3-ol

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 0℃; for 0.5h;	60.6%

Upstream product

• 127913-44-4 (S)-4-chloro-3-hydroxy butyronitrile 
• 101469-91-4 (3S)-1-benzyl-3-hydroxypyrrolidine-2,5-dione 
• 101469-92-5 (S)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester 

Downstream Products

• 1605327-39-6 3-((S)-1-((6-amino-5-((S)-3-hydroxypyrrolidine-1-carbonyl)pyrimidin-4-yl)amino)ethyl)-8-methyl-2-phenylpyrrolo[2,1-f][1,2,4]triazin-1(2H)-one 
• 1315054-87-5 C₇H₁₄N₂O₂ 

Relevant articles and documents

Synthesis method of (S)-3-pyrrolidinol hydrochloride

The invention discloses a synthesis method of (S)-3-pyrrolidinol hydrochloride, which belongs to the field of drug synthesis, and comprises the following steps: dehydrating and amidating L-malic acidand benzylamine as raw materials to obtain (3S)-N-benzyl-3-hydroxypyrrolidine-2,5-diketone, and carrying out one-pot reduction, debenzylation and salification to synthesize (S)-3-pyrrolidinol hydrochloride. The method is short in synthetic route, simple to operate, high in yield, good in product purity and beneficial to industrial production.

POLYCYCLIC DERIVATIVES, PREPARATION PROCESS AND PHARMACEUTICAL USE THEREOF

Disclosed in the present invention are polycyclic derivatives as represented by general formula (I), the preparation method thereof, pharmaceutical compositions containing the derivatives and uses thereof as therapeutic agents, especially the GPR40 agonist and in preparation of drugs for treating diseases such as diabetes and metabolic disorders, etc., wherein each substituent in the general formula (I) has the same definition as in the description.

Hydrogenation of chiral nitrile on highly ordered mesoporous carbon-supported Pd catalysts

A highly ordered mesoporous carbon (C-SBA-15 and C-SBA-16) was synthesized by nanocasting method using its corresponding mesoporous silica (SBA-15 and SBA-16) as a template. The obtained porous carbons have high surface areas, large pore volume and a narrow pore size distribution. The N2-adsorption data for C-SBA-15 have provided the BET area of 2029 m2 g-1 and the total pore volume of 1.7 cm3 g-1, and 1637 m2 g-1 and 1.1 cm3 g-1 for C-SBA-16, respectively. The palladium metal impregnated carbon catalysts were employed in the synthesis of (S)-3-pyrrolidinol from chiral (S)-4-chloro-3-hydroxybutyronitrile, and a high yield to (S)-3-pyrrolidinol-salt was obtained by using 1 wt% Pd/C-SBA-16. It was investigated that the well-dispersed Pd metals in the confined mesopores are efficient for the hydrogenation of cyano groups to amine.