104706-47-0

Basic information

• Product Name: (R)-(-)-3-Pyrrolidinol hydrochloride
• Synonyms: (R)-(-)-3-PYRROLIDINOL HCL;(R)-3-Hydroxypyrrolidine hydrochloride, (R)-3-Pyrrolidinol hydrochloride;(3R)-Pyrrolidin-3-ol hydrochloride;(R)-()-3-Pyrrolidinol hydrochloride ,97%;(R)-3-Hydroxypyrroli;(3R)-3-Hydroxypyrrolidine hydrochloride;(R)-3-Pyrrolindinol hydrochloride;Product naMe (R)-(-)-3-Pyrrolidinol hydrochloride
• CAS NO: 104706-47-0
• Molecular Formula: C₄H₉NO*ClH
• Molecular Weight: 123.58
• EINECS: 1592732-453-0
• Product Categories: chiral;Pyrrole&Pyrrolidine&Pyrroline;Benzenes;Chiral Building Blocks;Simple Alcohols (Chiral);Synthetic Organic Chemistry;Chiral chemicals;Alcohols and Derivatives;APIs Intermediate;pharmacetical
• Mol File: 104706-47-0.mol
• Article Data: 12

Chemical Properties

• Melting Point: 104-107 °C(lit.)
• Boiling Point: 224.7 °C at 760 mmHg
• Flash Point: 105.8 °C
• Appearance: /
• Refractive Index: -7.8 ° (C=3.5, MeOH)
• Storage Temp.: Room temperature.
• Solubility: Soluble in DMSO.
• BRN: 4450078
• CAS DataBase Reference: (R)-(-)-3-Pyrrolidinol hydrochloride(CAS DataBase Reference)
• NIST Chemistry Reference: (R)-(-)-3-Pyrrolidinol hydrochloride(104706-47-0)
• EPA Substance Registry System: (R)-(-)-3-Pyrrolidinol hydrochloride(104706-47-0)

Safety Data

• Hazard Codes: Xi
• Statements: 36/37/38-41-38-37
• Safety Statements: 26-36-38
• WGK Germany: 3
• F: 3-10
• Hazardous Substances Data: 104706-47-0(Hazardous Substances Data)

Usage

Chemical Properties

Llight brown crystalline

Uses

Different sources of media describe the Uses of 104706-47-0 differently. You can refer to the following data:
1. (R)-(-)-3-Pyrrolidinol hydrochloride is a chiral hydroxy derivative of pyrrlodine used in the preparation of chiral niologically active compounds such as muscarinic receptor antagonists and antimicrobial agents.
2. (R)-3-Hydroxypyrrolidine hydrochloride is used as a darifenacin Intermediate.
3. (R)-3-Pyrrolidinol hydrochloride can be used as a building block to synthesize:Biaryl carboxamide functional groups containing bis-aminopyrrolidine ureas as potential antagonists of the melanin-concentrating hormone receptor-1. Pyrrolidinol based ionic liquids. Optically active 2-tritylpyrrolidine based organocatalysts.

Purification Methods

The (±)-isomer is purified by repeated distillation ( b 102-104o/12mm, 108-110o/18mm), and the (±)-picrate crystallises from EtOH with m 140-141o. The R(+)-enantiomer has b 70o/0.6mm and [] D +5.6o (c 3.63, MeOH). Its hydrochloride has a negative rotation and its dimethiodide has m 230o and [] 24 -8.02o. [Suyama & Kanno Yakugaku Zasshi (J Pharm Soc Japan) 85 531 1965, Uno et al. J Heterocycl Chem 24 1025 1987, Flanagan & Joullie Heterocycles 26 2247 1987, Beilstein 21 III/IV 44.]

InChI:InChI=1/C4H9NO.ClH/c5-4-1-2-6-3-4;/h4H,1-3,5H2;1H/t4-;/m1./s1

Synthetic route

(R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (109431-87-0) → (R)-3-hydroxypyrrolidine hydrochloride (104706-47-0)

Conditions	Yield
With hydrogenchloride In 1,4-dioxane at 20℃; for 1h;	90%
With hydrogenchloride In methanol; water at 20℃;	63%
With hydrogenchloride In ethyl acetate at 0 - 20℃;

(3R)-N-acetyl-3-(tert-butyldimethylsilyloxy)propylamine (130680-56-7) → (R)-3-hydroxypyrrolidine hydrochloride (104706-47-0)

Conditions	Yield
With hydrogenchloride for 6h; Heating;	85%

2-chloro-5-trifluoromethylpyridine (52334-81-3) → 1-(5-trifluoromethyl-pyridin-2-yl)-pyrrolidin-3(R)-ol (475295-14-8) + (R)-3-hydroxypyrrolidine hydrochloride (104706-47-0)

Conditions	Yield
With potassium carbonate In ethanol; nitrogen; water	A n/a B 80.5%

4R-4-hydroxyproline (51-35-4) → (R)-3-hydroxypyrrolidine hydrochloride (104706-47-0)

Conditions	Yield
Stage #1: 4R-4-hydroxyproline In butanone; cyclohexanol at 45 - 154℃; for 5h; Stage #2: With hydrogenchloride In ethyl acetate; butanone; cyclohexanol at 0 - 25℃; for 2 - 3h; pH=1.0 - 2.0;	76%
In cyclohexene; cyclohexanol at 154℃; for 48h;	51%
Stage #1: 4R-4-hydroxyproline In cyclohexene-1-one, 2-; cyclohexanol at 155 - 160℃; for 11h; Stage #2: With hydrogenchloride In cyclohexene-1-one, 2-; ethanol; cyclohexanol at 0 - 5℃;	35%
With cyclohexenone In various solvent(s)

3-(R)-(-)-3-hydroxypyrrolidine hydrochloride + p-toluenesulfonyl chloride (98-59-9) → (R)-1-tosylpyrrolidin-3-ol (133034-00-1) + (R)-3-hydroxypyrrolidine hydrochloride (104706-47-0)

3-(R)-(-)-3-hydroxypyrrolidine hydrochloride + p-toluenesulfonyl chloride (98-59-9) → (R)-3-hydroxypyrrolidine hydrochloride (104706-47-0) + 1-tosyl-3-(R)-(-)-hydroxypyrrolidine (170456-83-4)

(R)-3-hydroxypyrrolidine hydrochloride (104706-47-0) + 5-({[1-(4-Chloro-phenyl)-methanoyl]-amino}-methyl)-thiophene-2-sulfonyl chloride (166964-34-7) → 4-chloro-N-[(5-{[(3R)-3-hydroxypyrrolidin-1-yl]sulfonyl}thien-2-yl)methyl]benzamide

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In DMF (N,N-dimethyl-formamide); dichloromethane	99.9%

di-tert-butyl dicarbonate (24424-99-5) + (R)-3-hydroxypyrrolidine hydrochloride (104706-47-0) → (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (109431-87-0)

Conditions	Yield
With triethylamine In dichloromethane at 0 - 20℃; for 0.12h;	99%
Stage #1: (R)-3-hydroxypyrrolidine hydrochloride With triethylamine In methanol; dichloromethane at 0℃; for 0.166667h; Stage #2: di-tert-butyl dicarbonate In methanol; dichloromethane at 0 - 25℃; for 16h;	99%
With potassium carbonate In tetrahydrofuran; water	96%

5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester (1224944-77-7) + (R)-3-hydroxypyrrolidine hydrochloride (104706-47-0) → ethyl 5-[(3R)-3-hydroxypyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxylate

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In acetonitrile at 60℃; for 1h; Inert atmosphere;	98%

(R)-3-hydroxypyrrolidine hydrochloride (104706-47-0) + 4,6-diiodo-2-methoxypyrimidine → (R)-1-(6-iodo-2-methoxypyrimidin-4-yl)pyrrolidin-3-ol

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

(R)-3-hydroxypyrrolidine hydrochloride (104706-47-0) + benzyl chloroformate (501-53-1) → (3R)-3-hydroxy-pyrrolidine-1-carboxylic acid benzyl ester (100858-33-1)

Conditions	Yield
With sodium hydroxide at 5℃; for 2h;	95%
With triethylamine In dichloromethane at 0℃; for 2h;
Stage #1: (R)-3-hydroxypyrrolidine hydrochloride; benzyl chloroformate With triethylamine In dichloromethane for 6h; Stage #2: With hydrogenchloride In dichloromethane; water
With triethylamine In dichloromethane for 6h;

methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (1268865-09-3) + (R)-3-hydroxypyrrolidine hydrochloride (104706-47-0) → (R)-methyl 3-(3-hydroxypyrrolidin-1-yl)-2-phenylquinoxaline-6-carboxylate (1268866-28-9)

Conditions	Yield
With potassium carbonate In dimethyl sulfoxide; toluene at 100℃; Sealed tube;	95%

(R)-3-hydroxypyrrolidine hydrochloride (104706-47-0) + tert-butylchlorodiphenylsilane (58479-61-1) → (R)-3-(tert-butyldiphenylsilanyloxy)pyrrolidine

Conditions	Yield
With pyridine; silver nitrate In tetrahydrofuran at 20℃; for 16h;	95%

(R)-3-hydroxypyrrolidine hydrochloride (104706-47-0) + Ethoxycarbonyl isothiocyanate (16182-04-0) → [(3R)-3-hydroxypyrrolidine-1-carbothioyl]carbamic acid ethyl ester

Conditions	Yield
In tetrahydrofuran at 0 - 20℃;	93%
In tetrahydrofuran	93%

formaldehyd (50-00-0) + (R)-3-hydroxypyrrolidine hydrochloride (104706-47-0) → (R)-1-methyl-3-pyrrolidinol (104641-60-3)

Conditions	Yield
With sodium hydroxide; formic acid In tetrahydrofuran; water at 60℃; for 2.33333h; Heating / reflux;	92%
Stage #1: (R)-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;	92%

5-chloro-2-morpholino-6-nitrooxazolo[4,5-b]pyridine + (R)-3-hydroxypyrrolidine hydrochloride (104706-47-0) → (R)-1-(2-morpholino-6-nitrooxazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-ol

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃; for 48h; Inert atmosphere;	91.7%

(R)-3-hydroxypyrrolidine hydrochloride (104706-47-0) + 4-nitrobenzyl chloroformate (4457-32-3) → (3R)-3-hydroxy-1-(4-nitrobenzyloxycarbonyl)-pyrrolidine (105601-88-5)

Conditions	Yield
Stage #1: (R)-3-hydroxypyrrolidine hydrochloride; 4-nitrobenzyl chloroformate With triethylamine In dichloromethane at 0 - 20℃; for 5h; Stage #2: With sodium hydrogencarbonate In dichloromethane; water; ethyl acetate	90%
With triethylamine In dichloromethane	90%
With triethylamine In dichloromethane at 0℃; for 0.5h;	89%

(R)-3-hydroxypyrrolidine hydrochloride (104706-47-0) + [6-oxo-3-(2-phenyl-pyrazolo[1,5-a]pyridin-3-yl)-1(6H)-pyridazin-1-yl]acetic acid (210880-36-7) → 2-[2-(3-hydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-6-(2-phenyl-pyrazolo[1,5-a]pyridin-3-yl)-2H-pyridazin-3-one

Conditions	Yield
With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide In N,N-dimethyl-formamide at 20℃;	90%

Benzyl 1-({[4-([2-[(phenoxycarbonyl)amino]pyridin-4-yl}oxy)-2,5-difluorophenyl]amino}carbonyl)cyclopropanecarboxylate (1009816-25-4) + (R)-3-hydroxypyrrolidine hydrochloride (104706-47-0) → Benzyl 1-[({2,5-difluoro-4-[(2-{[((R)-3-hydroxypyrrolidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}amino)carbonyl]cyclopropanecarboxylate (1009816-43-6)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 20℃; for 20.6667h;	90%

5-chloro-4-((3'-(3-chloropropoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-2-methoxybenzaldehyde + (R)-3-hydroxypyrrolidine hydrochloride (104706-47-0) → (R)-5-chloro-4-((3'-(3-(3-hydroxypyrrolidin-1-yl)propoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-2-methoxybenzaldehyde

Conditions	Yield
With potassium carbonate; sodium iodide In N,N-dimethyl-formamide at 80℃; for 16h;	90%

5-bromo-2-chloro-4-methyl-pyrimidine (633328-95-7) + (R)-3-hydroxypyrrolidine hydrochloride (104706-47-0) → (R)-1-(5-bromo-4-methylpyrimidin-2-yl)pyrrolidin-3-ol (1454301-74-6)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In ethanol at 70℃; for 18h;	89.5%

methyl (2S)-3-hydroxy-3-methyl-2-[[4-[4-(3-oxocyclobutyl)buta-1,3-diynyl]benzoyl]amino]butanoate + (R)-3-hydroxypyrrolidine hydrochloride (104706-47-0) → methyl (S)-3-hydroxy-2-(4-((3-((R)-3-hydroxypyrrolidin-1-yl)cyclobutyl)buta-1,3-diyn-1-yl)benzamido)-3-methylbutanoate

Conditions	Yield
With sodium tris(acetoxy)borohydride; N-ethyl-N,N-diisopropylamine In methanol at 20℃; for 0.75h;	88%

2,6-Dichloro-N-(cyclopropylmethyl)pyrimidine-4-carboxamide + (R)-3-hydroxypyrrolidine hydrochloride (104706-47-0) → (R)-2-Chloro-N-(cyclopropylmethyl)-6-(3-hydroxypyrrolidin-1-yl)pyrimidine-4-carboxamide

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In methanol at 0℃;	88%

(R)-3-hydroxypyrrolidine hydrochloride (104706-47-0) + p-toluenesulfonyl chloride (98-59-9) → (R)-1-tosylpyrrolidin-3-ol (133034-00-1)

Conditions	Yield
With sodium carbonate In dichloromethane at 25 - 38℃; for 3h;	87%

(R)-3-hydroxypyrrolidine hydrochloride (104706-47-0) → (R)-3-hydroxyl-N-nitrosopyrrolidine

Conditions	Yield
With Iron(III) nitrate nonahydrate; tetrabutylammonium perchlorate In acetonitrile at 70℃; Inert atmosphere; Electrolysis; Green chemistry;	87%

3-(2-fluoro-4-iodo-phenylamino)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (1030382-40-1) + (R)-3-hydroxypyrrolidine hydrochloride (104706-47-0) → [3-(2-fluoro-4-iodo-phenylamino)-1H-pyrrolo[3,2-c]pyridin-2-yl]-((R)-3-hydroxy-pyrrolidin-1-yl)-methanone (1030381-38-4)

Conditions	Yield
Stage #1: 3-(2-fluoro-4-iodo-phenylamino)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester With sodium hydroxide; water In tetrahydrofuran; methanol at 75℃; for 1h; Stage #2: (R)-3-hydroxypyrrolidine hydrochloride With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 16h;	85%

(±)-1-(sec-butyl)-6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine + (R)-3-hydroxypyrrolidine hydrochloride (104706-47-0) → (3R)-1-(1-sec-butyl-6-chloro-1H-pyrazolo[4,3-c]pyridin-3-yl)pyrrolidin-3-ol

Conditions	Yield
With copper(l) iodide; potassium carbonate; L-proline In dimethyl sulfoxide at 100℃; for 16h;	85%

(7R)-2,2-difluoro-N-(6-fluoropyridin-2-yl)-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carboxamide + (R)-3-hydroxypyrrolidine hydrochloride (104706-47-0) + trifluoroacetic acid (76-05-1) → (7R)-2,2-difluoro-N-{6-[(3R)-3-hydroxypyrrolidin-1-yl]pyridin-2-yl}-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carboxamide trifluoroacetate

Conditions	Yield
Stage #1: (7R)-2,2-difluoro-N-(6-fluoropyridin-2-yl)-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carboxamide; (R)-3-hydroxypyrrolidine hydrochloride With sodium carbonate In dimethyl sulfoxide at 80℃; for 15h; Stage #2: trifluoroacetic acid In water; acetonitrile	80%

3-[[4-(1-methyl-1H-pyrazol-4-yl)phenyl]methyl]-1H-indazole-5-carboxylic acid + (R)-3-hydroxypyrrolidine hydrochloride (104706-47-0) → ((R)-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;

chloroformic acid ethyl ester (541-41-3) + (R)-3-hydroxypyrrolidine hydrochloride (104706-47-0) → (R)-ethyl 3-hydroxypyrrolidine-1-carboxylate

Conditions	Yield
With potassium carbonate In methanol at 0 - 20℃;	78%

(R)-1-benzyl-3-[N-(4-nitrophenoxycarbonyl)-N-methylamino]pyrrolidine hydrochloride + (R)-3-hydroxypyrrolidine hydrochloride (104706-47-0) → (R)-3-Hydroxy-pyrrolidine-1-carboxylic acid ((R)-1-benzyl-pyrrolidin-3-yl)-methyl-amide (862847-07-2)

Conditions	Yield
With TEA In N,N-dimethyl-formamide at 70℃; for 18h;	77%

(R)-3-hydroxypyrrolidine hydrochloride (104706-47-0) + p-methoxybenzyl chloride (824-94-2) → (3R)-1-[(4-methoxyphenyl)methyl]pyrrolidin-3-ol

Conditions	Yield
With potassium carbonate In acetone at 60℃; for 16h;	76%

Upstream product

• 130680-56-7 (3R)-N-acetyl-3-(tert-butyldimethylsilyloxy)propylamine 
• 51-35-4 4R-4-hydroxyproline 
• 52334-81-3 2-chloro-5-trifluoromethylpyridine 
• 98-59-9 p-toluenesulfonyl chloride 
• 109431-87-0 (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate 

Downstream Products

• 474709-69-8 (3R)-1-[(4-iodophenyl)sulfonyl]-3-pyrrolidinol 
• 101385-90-4 (R)-N-benzyl-3-hydroxypyrrolidine 
• 1030381-38-4 [3-(2-fluoro-4-iodo-phenylamino)-1H-pyrrolo[3,2-c]pyridin-2-yl]-((R)-3-hydroxy-pyrrolidin-1-yl)-methanone 
• 850834-38-7 (R)-1-(3-fluorophenyl)pyrrolidin-3-ol 
• 1072227-55-4 (S)-3-chloro-pyrrolidine hydrochloride 
• 1009816-43-6 Benzyl 1-[({2,5-difluoro-4-[(2-{[((R)-3-hydroxypyrrolidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}amino)carbonyl]cyclopropanecarboxylate 
• 1054521-30-0 (R)-1-(2-fluoro-4-(methylsulfonyl)phenyl)pyrrolidin-3-ol 
• 1035922-79-2 2-(4-methoxybenzyl)-7-methyl-6-((R)-pyrrolidin-3-yloxy)-2H-isoquinolin-1-one hydrochloride 
• 929005-90-3 C₁₃H₁₉NO₄S 
• 109431-87-0 (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate 
• 95656-88-5 benzyl 3-hydroxypyrrolidine-1-carboxylate 

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COMPOUNDS

Disclosed are novel compounds that inhibit LRRK2 kinase activity, processes for their preparation, compositions containing them and their use in the treatment of or prevention of diseases characterized by LRRK2 kinase activity, for example Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis(ALS).

DIAMINOPYRIMIDINE DERIVATIVES AND PROCESSES FOR THE PREPARATION THEREOF

The present invention provides a diaminopyrimidine derivative or its pharmaceutically acceptable salt, a process for the preparation thereof, a pharmaceutical composition comprising the same, and a use thereof. The diaminopyrimidine derivative or its pharmaceutically acceptable salt functions as a 5-HT4 receptor agonist, and therefore can be usefully applied for preventing or treating dysfunction in gastrointestinal motility, one of the gastrointestinal diseases, such as gastroesophageal reflux disease (GERD), constipation, irritable bowel syndrome (IBS), dyspepsia, post-operative ileus, delayed gastric emptying, gastroparesis, intestinal pseudo-obstruction, drug-induced delayed transit, or diabetic gastric atony.

PREPARATION OF DARIFENACIN AND ITS SALTS

Provided are various processes and compounds related to darifenacin and/or its salts. For example, there is provided a process for preparing a free base of darifenacin: Formula, or the salt thereof, the process including reacting 3-(S)-(cyanodiphenylmethyl)-1-[2-(2,3-dihydrobenzofuran-5-yl) ethyl] pyrrolidine of the Formula (IV), or a salt thereof: Formula (IV) with a base effective to convert the nitrile group of the compound of the Formula (IV) to the amide group of the darifenacin in an organic solvent, the reaction being carried out in the organic solvent, with a proviso that the solvent is not 2-methyl-butan-2-ol, and with further proviso that the reaction produces less than about 0.5 % of the compound of the Formula (Ic): Formula (Ic) in the reaction mass, as measured by HPLC. Various embodiments and variants are provided.