62937-45-5

Basic information

• Product Name: D-Prolinamide
• Synonyms: (R)-PROLINAMIDE;(R)-PYRROLIDINE-2-CARBOXAMIDE;(R)-PYRROLIDINE-2-CARBOXYLIC ACID AMIDE;H-D-PRO-NH2;H-D-PYRD(2)-NH2;D-PROLINAMIDE;D-PROLINE AMIDE;D-PROLINE-NH2
• CAS NO: 62937-45-5
• Molecular Formula: C₅H₁₀N₂O
• Molecular Weight: 114.15
• EINECS: 1533716-785-6
• Product Categories: AMIDE;AMINOACIDS DERIVATIVES;Pyrrolidines;Proline [Pro, P];Amino Acids and Derivatives;amino acid
• Mol File: 62937-45-5.mol
• Article Data: 4

Chemical Properties

• Melting Point: 95-97°C
• Boiling Point: 303.6 °C at 760 mmHg
• Flash Point: 137.4 °C
• Appearance: Crystalline
• Density: 1.106 g/cm³
• Vapor Pressure: 0.000923mmHg at 25°C
• Refractive Index: 1.491
• Storage Temp.: -15°C
• Solubility: DMSO, Ethanol
• PKA: 16.21±0.20(Predicted)
• Water Solubility: Soluble in water.
• BRN: 471499
• CAS DataBase Reference: D-Prolinamide(CAS DataBase Reference)
• NIST Chemistry Reference: D-Prolinamide(62937-45-5)
• EPA Substance Registry System: D-Prolinamide(62937-45-5)

Safety Data

• Safety Statements: 24/25
• WGK Germany: 3
• Hazardous Substances Data: 62937-45-5(Hazardous Substances Data)

Usage

Chemical Properties

White to off-white crystalline powder. Slightly soluble in water, soluble in dimethyl sulfoxide, N,N-dimethylformamide, methanol, ethanol and other organic solvents.

Uses

D-Prolinamide, can be used in the synthesis of proline derivatives as efficient organocatalysts for aldol reaction on water.

InChI:InChI=1/C5H10N2O/c6-5(8)4-2-1-3-7-4/h4,7H,1-3H2,(H2,6,8)/t4-/m1/s1

Synthetic route

(2R)-2-carbamoyl-pyrrolidine-1-carboxylic acid benzyl ester (62937-47-7) → (R)-prolinamide (62937-45-5)

Conditions	Yield
With 10% palladium on carbon; hydrogen In methanol for 7h;	100%
With hydrogen; palladium on activated charcoal In methanol for 9h; Ambient temperature;	87.3%

D-proline ethyl ester hydrochloride → (R)-prolinamide (62937-45-5)

Conditions	Yield
With ammonia In ethanol at 0 - 20℃; Large scale;	80%

Z-D-proline (6404-31-5) → (R)-prolinamide (62937-45-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1.) triethylamine, isobutyl chloroformate, 2.) ammonia / 1.) chloroform, 0 deg C, 2 h, 2.) chloroform, RT, overnight 2: 87.3 percent / hydrogen / 10percent palladium on carbon / methanol / 9 h / Ambient temperature View Scheme

D-Prolin (344-25-2) → (R)-prolinamide (62937-45-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium hydroxide / H2O / Ambient temperature 2: 1.) triethylamine, isobutyl chloroformate, 2.) ammonia / 1.) chloroform, 0 deg C, 2 h, 2.) chloroform, RT, overnight 3: 87.3 percent / hydrogen / 10percent palladium on carbon / methanol / 9 h / Ambient temperature View Scheme

(R)-2-carbamoylpyrrolidine-1-carboxylic acid tert-butyl ester (70138-72-6) → (R)-prolinamide (62937-45-5)

Conditions	Yield
Stage #1: (R)-2-carbamoylpyrrolidine-1-carboxylic acid tert-butyl ester With trifluoroacetic acid at 25℃; Stage #2: With N-ethyl-N,N-diisopropylamine In dichloromethane at 25℃;

N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-N-phenylethenesulfonamide + (R)-prolinamide (62937-45-5) → (R)-1-(2-(N-(4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)benzyl)-N-phenylsulfamoyl)ethyl)pyrrolidine-2-carboxamide

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 18h;	92.9%

2-([1,1'-biphenyl]-4-yl)-4-methyl-5-(2-(methylsulfonyl)pyrimidin-4-yl)thiazole + (R)-prolinamide (62937-45-5) → (R)-1-{4-[2-((1,1'-biphenyl)-4-yl)-4-methylthiazol-5-yl]pyrimidin-2-yl}pyrrolidine-2-carboxamide

Conditions	Yield
In N,N-dimethyl-formamide at 80℃;	92%

9-bromo-10-(bromomethyl)-2,3,6,7-tetramethoxyphenanthrene (1215841-59-0) + (R)-prolinamide (62937-45-5) → (R)-1-[(9-bromo-2,3,6,7-tetramethoxyphenanthren-10-yl)methyl]pyrrolidine-2-carboxamide (1394286-36-2)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide for 8h; Reflux;	91%

2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)thieno[3,2-d]pyrimidin-4-amine + (R)-prolinamide (62937-45-5) → (R)-1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thieno[3,2-d]pyrimidin-2-yl)pyrrolidine-2-carboxamide hydrochloride

Conditions	Yield
Stage #1: 2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)thieno[3,2-d]pyrimidin-4-amine; (R)-prolinamide With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 130℃; for 18h; Microwave irradiation; Stage #2: With hydrogenchloride In water; acetonitrile	90%

2-((4-(4,6-bismorpholine-1,3,5-triazin-2-yl)phenyl)amino)-1H-benzo[d]imidazole-6-carboxylic acid + (R)-prolinamide (62937-45-5) → (R)-1-(2-((4-(4,6-bismorpholin-1,3,5-triazin-2-yl)phenyl)amino)-1H-benzo[d]imidazole-6-carbonyl)pyrrolidine-2-carboxamide

Conditions	Yield
Stage #1: 2-((4-(4,6-bismorpholine-1,3,5-triazin-2-yl)phenyl)amino)-1H-benzo[d]imidazole-6-carboxylic acid With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.666667h; Inert atmosphere; Stage #2: (R)-prolinamide In N,N-dimethyl-formamide at 80℃; for 8h; Inert atmosphere;	88%

Ph(3-Cl)(5-OCHF2)-(R,S)CH(OH)C(O)OH (433938-41-1) + (R)-prolinamide (62937-45-5) → (R)-3-chloro-5-difluoro-methoxy-mandelic acid D-prolinamide salt

Conditions	Yield
In water; 4-methyl-2-pentanone at 20 - 100℃; for 22.5h; Purification / work up; Resolution of racemate;	81.8%
In water; ethyl acetate at 0 - 75℃; for 3.16667 - 13.8333h; Product distribution / selectivity; Heating / reflux;	n/a
In water; ethyl acetate at 72 - 75℃; for 0.166667 - 0.5h; Purification / work up; Resolution of racemate; Heating / reflux;	n/a

2-chloro-7-isopropoxy-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)quinazolin-4-amine + (R)-prolinamide (62937-45-5) → (R)-1-(7-isopropoxy-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)quinazolin-2-yl)pyrrolidine-2-carboxamide

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 150℃; for 5h; Microwave irradiation;	81%

5-(4-chlorophenyl)-2-{[1-(4-chloropyridin-3-yl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one + (R)-prolinamide (62937-45-5) → 1-{3-[3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1H-1,2,4-triazol-1-yl]pyridin-4-yl}-D-prolinamide

Conditions	Yield
In ethanol Reflux;	79%

5'-(cis-3-cycloheptyl-4-oxo-3,4,4a,5,8,8a-hexahydrophthalazin-1-yl)-2'-methoxy-[1,1'-biphenyl]-4-carboxylic acid + (R)-prolinamide (62937-45-5) → (R)-1-(5'-(cis-3-cycloheptyl-4-oxo-3,4,4a,5,8,8a-hexahydrophthalazin-1-yl)-2'-methoxy-[1,1'-biphenyl]-4-carbonyl)pyrrolidine-2-carboxamide

Conditions	Yield
With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 3h; Inert atmosphere;	78%

2-chloro-7-tosyl-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine + (R)-prolinamide (62937-45-5) → (R)-1-(7-tosyl-4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)pyrrolidine-2-carboxamide

Conditions	Yield
In isopropyl alcohol at 150℃; for 3h; Microwave irradiation;	75%

(R)-prolinamide (62937-45-5) + 4-guanidinophenyl N-benzoylglycinate (288608-40-2) → Bz-Gly-D-Pro-NH2

Conditions	Yield
With clostripain; HEPES buffer; sodium chloride; calcium chloride at 25℃; pH=8.0;	72.6%

5-(4-chlorophenyl)-2-{[1-(2-chloropyridin-3-yl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one + (R)-prolinamide (62937-45-5) → 1-{3-[3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1H-1,2,4-triazol-1-yl]pyridin-2-yl}-D-prolinamide

Conditions	Yield
In ethanol Reflux;	70%

(R)-prolinamide (62937-45-5) + allyl (5R,6S)-2-<<(methylsulfonyl)oxy>methyl>-6-<(R)-1-<(tert-butyldimethylsilyl)oxy>ethyl>penem-3-carboxylate (88585-79-9) → allyl (5R,6S)-2-<((2R)-1-prolinamido)methyl>-6-<(R)-1-<(tert-butyldimethylsilyl)oxy>ethyl>penem-3-carboxylate (166374-72-7) + 2-[(S)-2-(tert-Butyl-dimethyl-silanyloxy)-1-((R)-2-carbamoyl-pyrrolidine-1-carbonyl)-propyl]-5-methyl-thiazole-4-carboxylic acid allyl ester

Conditions	Yield
With triethylamine In dimethyl sulfoxide for 20h; Ambient temperature;	A 66% B n/a

benzoylamino-acetic acid benzyl ester (19811-58-6) + (R)-prolinamide (62937-45-5) → Bz-Gly-D-Pro-NH2

Conditions	Yield
With syn-benzaldehyde oxime; triethylamine; diothiothreitol In toluene at 35℃; immobilized papain;	65%

(R)-prolinamide (62937-45-5) + Bz-D-Ala-OGp → Bz-D-Ala-D-Pro-NH2

Conditions	Yield
With clostripain; HEPES buffer; sodium chloride; calcium chloride at 25℃; pH=8.0;	60.7%

2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)-5,6,7,8-tetrahydroquinazolin-4-amine + (R)-prolinamide (62937-45-5) → (R)-1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-5,6,7,8-tetrahydroquinazolin-2-yl)pyrrolidine-2-carboxamide hydrochloride

Conditions	Yield
Stage #1: 2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)-5,6,7,8-tetrahydroquinazolin-4-amine; (R)-prolinamide In isopropyl alcohol at 150℃; for 3h; Microwave irradiation; Stage #2: With hydrogenchloride In water; acetonitrile	60%

2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)quinazolin-4-amine + (R)-prolinamide (62937-45-5) → (R)-1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)quinazolin-2-yl)pyrrolidine-2-carboxamide hydrochloride

Conditions	Yield
Stage #1: 2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)quinazolin-4-amine; (R)-prolinamide With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 130℃; for 18h; Microwave irradiation; Stage #2: With hydrogenchloride In water; acetonitrile	58%

2-[3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1H-1,2,4-triazol-1-yl]benzoyl chloride + (R)-prolinamide (62937-45-5) → 1-{2-[3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1H-1,2,4-triazol-1-yl]benzoyl}-D-prolinamide

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 1h;	57%

(R)-prolinamide (62937-45-5) → (S)-1-nitrosopyrrolidine-2-carboxamide

Conditions	Yield
With tert.-butylhydroperoxide; nitromethane; potassium iodide In water at 80℃; for 6h;	56%

5'-(cis-3-isopropyl-4-oxo-3,4,4a,5,8,8a-hexahydrophthalazin-1-yl)-2'-methoxy-[1,1'-biphenyl]-4-carboxylic acid + (R)-prolinamide (62937-45-5) → (R)-1-(5'-(cis-3-isopropyl-4-oxo-3,4,4a,5,8,8a-hexahydrophthalazin-1-yl)-2'-methoxy-[1,1'-biphenyl]-4-carbonyl)pyrrolidine-2-carboxamide

Conditions	Yield
With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 3h; Inert atmosphere;	56%

2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)thieno[2,3-d]pyrimidin-4-amine + (R)-prolinamide (62937-45-5) → (R)-1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)thieno[2,3-d]pyrimidin-2-yl)pyrrolidine-2-carboxamide hydrochloride

Conditions	Yield
Stage #1: 2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)thieno[2,3-d]pyrimidin-4-amine; (R)-prolinamide With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 130℃; for 18h; Microwave irradiation; Stage #2: With hydrogenchloride In water; acetonitrile	56%

2-(2-(4-(tert-butyl)phenyl)-4-methylthiazol-5-yl)-5-(methylsulfonyl)-1,3,4-oxadiazole + (R)-prolinamide (62937-45-5) → (R)-1-{5-[2-(4-(tert-butyl)phenyl)-4-methylthiazol-5-yl]-1,3,4-oxadiazol-2-yl}pyrrolidine-2-carboxamide

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 80℃;	56%

2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine + (R)-prolinamide (62937-45-5) → (R)-1-(4-((1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide hydrochloride

Conditions	Yield
Stage #1: 2-chloro-N-(1-(3,4,5-trimethoxyphenyl)-1H-imidazol-4-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine; (R)-prolinamide With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 125℃; for 15h; Microwave irradiation; Stage #2: With hydrogenchloride In water; acetonitrile	55%

(R)-prolinamide (62937-45-5) + Bz-D-Leu-OGp → Bz-D-Leu-D-Pro-NH2

Conditions	Yield
With clostripain; HEPES buffer; sodium chloride; calcium chloride In N,N-dimethyl-formamide at 25℃; pH=8.0;	46.2%

(R)-prolinamide (62937-45-5) → (-)-(R)-2-aminomethylpyrrolidine (57734-57-3, 69500-64-7, 123654-27-3, 72300-69-7)

Conditions	Yield
With lithium aluminium tetrahydride In tetrahydrofuran for 33h; Heating;	46.1%
Stage #1: (R)-prolinamide With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; Reflux; Stage #2: With water In tetrahydrofuran	30%
With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; Reflux;
With lithium aluminium tetrahydride
With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 75℃;

(R)-prolinamide (62937-45-5) + Bz-D-Phe-OGp → Bz-D-Phe-D-Pro-NH2

Conditions	Yield
With clostripain; HEPES buffer; sodium chloride; calcium chloride In N,N-dimethyl-formamide at 25℃; pH=8.0;	44%

3-{(S)-1-[4-(6-fluoro-pyridin-3-yl)-phenyl]-ethyl}-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one (1352754-29-0) + (R)-prolinamide (62937-45-5) → (R)-1-[5-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridin-2-yl]-pyrrolidine-2-carboxylic acid amide (1352753-90-2)

Conditions	Yield
With potassium carbonate In dimethyl sulfoxide at 100℃;	43%

Upstream product

• 344-25-2 D-Prolin 
• 70138-72-6 (R)-2-carbamoylpyrrolidine-1-carboxylic acid tert-butyl ester 
• 131477-20-8 D-proline ethyl ester hydrochloride 
• 6404-31-5 Z-D-proline 
• 62937-47-7 (2R)-2-carbamoyl-pyrrolidine-1-carboxylic acid benzyl ester 

Downstream Products

• 101617-18-9 Z-D-His(CH₂Ph)-L-Pro-NH₂ 
• 101617-18-9 Z-L-His(CH₂Ph)-L-Pro-NH₂ 
• 190654-11-6 1-[6-(3-chloro-phenylamino)-9-ethyl-9H-purin-2-yl]-pyrrolidine-2-carboxylic acid amide 
• 32159-20-9 L-His(CH₂Ph)-L-Pro-NH₂*2HBr 
• 697802-31-6 C₂₀H₃₄N₄O₆ 
• 195311-28-5 (S)-(+)-1-[(2-pyrrolidin-1-yl)methyl]-pyrrolidine 
• 1262381-39-4 C₂₀H₃₂N₂O₂ 
• 1262381-55-4 C₁₈H₂₀N₂O₂ 
• 1261530-78-2 methyl 3-{[(2R)-2-(aminocarbonyl)pyrrolidin-1-yl]methyl}-1-(4-fluorobenzyl)-1H-pyrrolo [2,3-c]pyridine-5-carboxylate 
• 1075736-85-4 1-{[3-(4-{[4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl]carbonyl}-D-prolinamide 
• 1075736-80-9 1-[(3-iodophenyl)carbonyl]-D-prolinamide 
• 78664-39-8 Z-pGlu-Leu-D-Pro-NH₂ 
• 146445-07-0 (R)-(-)-2,3-dimethoxy-5-iodo-N-(2-pyrrolidinylmethyl)benzamide 
• 146445-06-9 5-Iodo-2,3-dimethoxy-N-((R)-1-trityl-pyrrolidin-2-ylmethyl)-benzamide 

Relevant articles and documents

A method of refining prolinamides

The invention relates to a method for refining prolinamide, which includes the following steps: (a) dissolving prolinamide coarse product in an organic solvent, wherein the prolinamide coarse product contains ammonium chloride, prolinamide hydrochloride or mixture thereof; (b) adding inorganic alkali for treatment; and (c) separating to obtain the prolinamide. The method for refining prolinamide is simple, the content and optical purity of the obtained product are high, and the method is very suitable for industrial production.

Synthesis, characterisation and in vitro cytotoxicity studies of a series of chiral platinum(II) complexes based on the 2-aminomethylpyrrolidine ligand: X-ray crystal structure of [PtCl2(R-dimepyrr)] (R-dimepyrr = N-dimethyl-2(R)-aminomethylpyrrolidine)

A series of platinum(II) complexes were synthesised based on the enantiomerically pure amino acid proline. Novel synthetic pathways were developed, adapted from standard peptide chemistry, to produce the 2-aminomethylpyrrolidine (pyrr) ligand and its derivatives with differing arrangements of methyl substituents at the exocyclic amine sites. The crystal structure of [PtCl2(R-dimepyrr)] (R-dimepyrr = N,N-dimethyl-2(R)-aminomethylpyrrolidine) is reported and the five-membered ligand ring has been shown to be in an envelope conformation. Cytotoxicity studies were carried out on the ovarian cancer A2780 tumour cell line and its cisplatin-resistant variant, A2780cisR. Remarkably good activity was seen for several of the drugs when compared to cisplatin despite the addition of substantial steric bulk to the amine groups, and there was a lack of cross-resistance with cisplatin seen for some compounds.