3398-22-9

Basic information

• Product Name: trans-4-Hydroxy-D-proline
• Synonyms: TRANS-D-HYDROXYPROLINE;TRANS-D-4-HYDROXYPROLINE;TRANS-4-HYDROXY-D-PROLINE;(2R,4S)-(-)-4-HYDROXY-2-PYRROLINECARBOXYLIC ACID;(2R,4S)-4-HYDROXYPYRROLIDINE-2-CARBOXYLIC ACID;H-D-PRO(4-HYDROXY)-OH;H-D-PRO(TRANS-4-HYDROXY)-OH;H-D-HYP-OH
• CAS NO: 3398-22-9
• Molecular Formula: C₅H₉NO₃
• Molecular Weight: 131.13
• EINECS: 1806241-263-5
• Product Categories: Carboxylic Acids;Pyrrolidines;Chiral Compound;Carboxylic Acids
• Mol File: 3398-22-9.mol
• Article Data: 3

Chemical Properties

• Melting Point: 260°C
• Boiling Point: 355.2 °C at 760 mmHg
• Flash Point: 168.6 °C
• Appearance: /
• Density: 1.395 g/cm³
• Vapor Pressure: 1.8E-06mmHg at 25°C
• Refractive Index: 1.54
• Storage Temp.: Sealed in dry,Room Temperature
• PKA: 2.14±0.40(Predicted)
• CAS DataBase Reference: trans-4-Hydroxy-D-proline(CAS DataBase Reference)
• NIST Chemistry Reference: trans-4-Hydroxy-D-proline(3398-22-9)
• EPA Substance Registry System: trans-4-Hydroxy-D-proline(3398-22-9)

Safety Data

• Hazard Codes: Xn
• Statements: 22-36/37/38-43
• Safety Statements: 24/25-36/37-26
• WGK Germany: 3
• Hazardous Substances Data: 3398-22-9(Hazardous Substances Data)

Usage

Chemical Properties

White to pale pink solid

InChI:InChI=1/C5H9NO3/c7-3-1-4(5(8)9)6-2-3/h3-4,6-7H,1-2H2,(H,8,9)/t3?,4-/m1/s1

Synthetic route

(2R,4S)-4-(benzyloxy)-1-N-tosylpyrrolidine-2-carboxylic acid → trans-4-hydroxyproline (3398-22-9)

Conditions	Yield
With ammonia; sodium at -70℃; for 3.5h; Inert atmosphere;	79%

N-Acetyl-allo-4-(p-toluenesulfonyloxy)-D-proline (77449-96-8) → trans-4-hydroxyproline (3398-22-9)

Conditions	Yield
With sodium hydroxide Erhitzen des Reaktionsprodukts mit wss. HCl;

trans-1-(3,5-dinitro-benzoyl)-4-hydroxy-D-proline (114673-33-5) → trans-4-hydroxyproline (3398-22-9)

Conditions	Yield
With hydrogenchloride
With hydrogenchloride

1-anilinoformyl-d-a-<4-oxy-proline > → trans-4-hydroxyproline (3398-22-9)

Conditions	Yield
With ammonia at 95 - 100℃;

N-Acetyl-allo-4-(p-toluenesulfonyloxy)-D-proline (77449-96-8) + aqueous NaOH → trans-4-hydroxyproline (3398-22-9)

Conditions	Yield
anschliessend Erhitzen mit wss. HCl;

trans-4-hydroxy-D,L-proline (618-28-0) → trans-4-hydroxyproline (3398-22-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: aqueous NaOH 2: (1S,2S)-2-amino-1-<4-nitro-phenyl>-propane-1,3-diol 3: aqueous HCl View Scheme
Multi-step reaction with 3 steps 1: sodium hydroxide 2: (1S,2S)-2-amino-1-(4-nitrophenyl)propane-1,3-diol 3: hydrogenchloride View Scheme

N-Acetyl-allo-4-(p-toluenesulfonyloxy)-D-proline Methyl Ester (77449-95-7) → trans-4-hydroxyproline (3398-22-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: aqueous methanol. NaOH 2: aqueous NaOH / Erhitzen des Reaktionsprodukts mit wss. HCl View Scheme

trans-1-(3,5-dinitro-benzoyl)-4-hydroxy-DL-proline (103078-90-6, 114673-32-4, 114673-33-5) → trans-4-hydroxyproline (3398-22-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: brucine 2: aqueous HCl View Scheme
Multi-step reaction with 2 steps 1: (1S,2S)-2-amino-1-<4-nitro-phenyl>-propane-1,3-diol 2: aqueous HCl View Scheme
Multi-step reaction with 2 steps 1: (1S,2S)-2-amino-1-(4-nitrophenyl)propane-1,3-diol 2: hydrogenchloride View Scheme

trans-4-hydroxy-D,L-proline (618-28-0) → trans-4-hydroxyproline (3398-22-9) + 4R-4-hydroxyproline (51-35-4)

Conditions	Yield
With shaking calcined L-Pro chiral ordered mesoporous silica Resolution of racemate;

(3S,5R)-3-(benzyloxy)-2-hydroxy-5-(hydroxymethyl)-1-N-tosylpyrrolidine → trans-4-hydroxyproline (3398-22-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: triethylsilane; boron trifluoride diethyl etherate / dichloromethane / 3 h / 0 - 30 °C / Inert atmosphere 2: Jones reagent / acetone / 4 h / 0 °C / Inert atmosphere 3: ammonia; sodium / 3.5 h / -70 °C / Inert atmosphere View Scheme

4-O-benzyl-2,3-dideoxy-2-(p-toluenesulfonamido)-D-glucitol → trans-4-hydroxyproline (3398-22-9)

Conditions	Yield
Multi-step reaction with 4 steps 1: sodium periodate; sodium hydrogencarbonate / water; dichloromethane / 12 h / 0 - 30 °C / Inert atmosphere 2: triethylsilane; boron trifluoride diethyl etherate / dichloromethane / 3 h / 0 - 30 °C / Inert atmosphere 3: Jones reagent / acetone / 4 h / 0 °C / Inert atmosphere 4: ammonia; sodium / 3.5 h / -70 °C / Inert atmosphere View Scheme

1,6-di-O-acetyl-4-O-benzyl-2,3-dideoxy-2-(p-toluenesulfonamido)-D-glucopyranose → trans-4-hydroxyproline (3398-22-9)

Conditions

Yield

Multi-step reaction with 5 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 10 h / Reflux; Inert atmosphere 2: sodium periodate; sodium hydrogencarbonate / water; dichloromethane / 12 h / 0 - 30 °C / Inert atmosphere 3: triethylsilane; boron trifluoride diethyl etherate / dichloromethane / 3 h / 0 - 30 °C / Inert atmosphere 4: Jones reagent / acetone / 4 h / 0 °C / Inert atmosphere 5: ammonia; sodium / 3.5 h / -70 °C / Inert atmosphere View Scheme

benzyl chloroformate (501-53-1) + trans-4-hydroxyproline (3398-22-9) → (4S)-1-[(benzyloxy)carbonyl]-4-hydroxy-D-proline (155153-78-9)

Conditions	Yield
With sodium hydrogencarbonate In tetrahydrofuran; water at 0℃; for 1h;	100%
Stage #1: benzyl chloroformate; trans-4-hydroxyproline With sodium hydrogencarbonate In water; toluene at 20℃; for 16.25h; Stage #2: With hydrogenchloride In diethyl ether; water pH=2;	93%
Stage #1: benzyl chloroformate; trans-4-hydroxyproline With sodium hydrogencarbonate In water; toluene at 20℃; for 16h; Stage #2: With hydrogenchloride In water pH=2; Cooling with ice;	93%
With sodium hydrogencarbonate
With sodium hydrogencarbonate In water

di-tert-butyl dicarbonate (24424-99-5) + trans-4-hydroxyproline (3398-22-9) → (2R,4S )-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (147266-92-0)

Conditions	Yield
With sodium hydrogencarbonate In 1,4-dioxane; water at 0 - 20℃;	100%
With sodium hydroxide In 1,4-dioxane; water
With triethylamine In methanol for 2h; Reflux;	11 g

C8H3ClF5N + trans-4-hydroxyproline (3398-22-9) → (2R,4S)-N-(2,4-difluorophenyl)-4-hydroxy-1-(2,2,2-trifluoroacetyl)pyrrolidine-2-carboxamide

Conditions	Yield
With titanium(IV) oxide; sodium hydrogencarbonate In tetrahydrofuran; water at 20℃; for 8h; Inert atmosphere;	93%

N-(2,5-difluorophenyl)-2,2,2-trifluoroacetimidoyl chloride + trans-4-hydroxyproline (3398-22-9) → (2R,4S)-N-(2,5-difluorophenyl)-4-hydroxy-1-(2,2,2-trifluoroacetyl)pyrrolidine-2-carboxamide

Conditions	Yield
With titanium(IV) oxide; sodium hydrogencarbonate In tetrahydrofuran; water at 20℃; for 8h; Inert atmosphere;	92%
With sodium hydrogencarbonate; titanium(IV) oxide

trans-4-hydroxyproline (3398-22-9) + benzyl alcohol (100-51-6) → (2R,4S)-4-hydroxyproline benzyl ester

Conditions	Yield
With toluene-4-sulfonic acid In benzene at 125℃; for 20h; Dean-Stark;	91.1%

1,2-di(m-tolyl)disulfane (63930-17-6) + trans-4-hydroxyproline (3398-22-9) → (2S,4R)-2-carboxy-4-(3-fluorophenylthio)pyrrolidine

Conditions	Yield
With tributylphosphine In tetrahydrofuran at 60 - 65℃; for 25h; Concentration;	89.7%

trans-4-hydroxyproline (3398-22-9) → (2R,4S)-methyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride (481704-21-6)

Conditions	Yield
With acetyl chloride In methanol; diethyl ether at 20℃;	87.6%

C8H3BrCl2F3N (1453185-82-4) + trans-4-hydroxyproline (3398-22-9) → (2R,4S)-N-(2-bromo-4-chlorophenyl)-4-hydroxy-1-(2,2,2-trifluoroacetyl)pyrrolidine-2-carboxamide

Conditions	Yield
With titanium(IV) oxide; sodium hydrogencarbonate In tetrahydrofuran; water at 20℃; for 8h; Inert atmosphere;	87%

N-(4-chlorophenyl)-2,2,2-trifluoroethanimidoyl chloride (143681-32-7) + trans-4-hydroxyproline (3398-22-9) → (2R,4S)-N-(4-chlorophenyl)-4-hydroxy-1-(2,2,2-trifluoroacetyl)pyrrolidine-2-carboxamide

Conditions	Yield
With titanium(IV) oxide; sodium hydrogencarbonate In tetrahydrofuran; water at 20℃; for 8h; Inert atmosphere;	83%

maleic acid (110-16-7) + trans-4-hydroxyproline (3398-22-9) → (S)-pyrrolidin-3-ol hydrogen maleate (1092655-33-8)

Conditions	Yield
Stage #1: trans-4-hydroxyproline With cyclohexenone In cyclohexanol for 3h; Reflux; Stage #2: maleic acid at 35℃; for 0.5h;	80%
Stage #1: trans-4-hydroxyproline With cyclohexenone In cyclohexanol for 3h; Reflux; Stage #2: maleic acid In cyclohexanol at 35℃; for 0.5h;	80%

2,2,2-trifluoro-N-[2-(trifluoromethyl)phenyl]ethanimidoyl chloride (61984-67-6) + trans-4-hydroxyproline (3398-22-9) → (2R,4S)-4-hydroxy-1-(2,2,2-trifluoroacetyl)-N-(2-(trifluoromethyl)phenyl)pyrrolidine-2-carboxamide

Conditions	Yield
With titanium(IV) oxide; sodium hydrogencarbonate In tetrahydrofuran; water at 20℃; for 8h; Reagent/catalyst; Solvent; Time; Inert atmosphere;	78%

2,2,2-trifluoro-N-(3-(trifluoromethyl)phenyl)acetimidoyl chloride (69563-07-1) + trans-4-hydroxyproline (3398-22-9) → (2R,4S)-4-hydroxy-1-(2,2,2-trifluoroacetyl)-N-(3-(trifluoromethyl)phenyl)pyrrolidine-2-carboxamide

Conditions	Yield
With titanium(IV) oxide; sodium hydrogencarbonate In tetrahydrofuran; water at 20℃; for 8h; Inert atmosphere;	77%

C8H3ClF4N2O2 + trans-4-hydroxyproline (3398-22-9) → (2R,4S)-N-(4-fluoro-3-nitrophenyl)-4-hydroxy-1-(2,2,2-trifluoroacetyl)pyrrolidine-2-carboxamide

Conditions	Yield
With titanium(IV) oxide; sodium hydrogencarbonate In tetrahydrofuran; water at 20℃; for 8h; Inert atmosphere;	77%

N-(4-nitrophenyl)-2,2,2-trifluoroacetimidoyl chloride (145372-31-2) + trans-4-hydroxyproline (3398-22-9) → (2R,4S)-4-hydroxy-N-(4-nitrophenyl)-1-(2,2,2-trifluoroacetyl)pyrrolidine-2-carboxamide

Conditions	Yield
With titanium(IV) oxide; sodium hydrogencarbonate In tetrahydrofuran; water at 20℃; for 8h; Inert atmosphere;	73%

trans-4-hydroxyproline (3398-22-9) → 3-hydroxypyrrolidine (100243-39-8)

Conditions	Yield
With cyclohexenone; cyclohexanol for 2h; Heating;	70%

N-(3,5-bis(trifluoromethyl)phenyl)-2,2,2-trifluoroacetimidoyl chloride + trans-4-hydroxyproline (3398-22-9) → (2R,4S)-N-(3,5-bis(trifluoromethyl)phenyl)-4-hydroxy-1-(2,2,2-trifluoroacetyl)pyrrolidine-2-carboxamide

Conditions	Yield
With titanium(IV) oxide; sodium hydrogencarbonate In tetrahydrofuran; water at 20℃; for 8h; Inert atmosphere;	70%

C8H3Cl2F4N + trans-4-hydroxyproline (3398-22-9) → (2R,4S)-N-(3-chloro-4-fluorophenyl)-4-hydroxy-1-(2,2,2-trifluoroacetyl)pyrrolidine-2-carboxamide

Conditions	Yield
With titanium(IV) oxide; sodium hydrogencarbonate In tetrahydrofuran; water at 20℃; for 8h; Inert atmosphere;	70%

formaldehyd (50-00-0) + trans-4-hydroxyproline (3398-22-9) → C12H21N2O8P (1451370-71-0)

Conditions	Yield
Stage #1: trans-4-hydroxyproline With hydrogenchloride; hypophosphorous acid In water at 20℃; for 1h; Stage #2: formaldehyd In water at 20℃; for 24h;	28%

2-bromo-4-methylvaleryl bromide (74204-03-8) + trans-4-hydroxyproline (3398-22-9) → 1-(DL-α-bromo-isocaproyl)-4-oxy-L-proline

Conditions	Yield
With sodium hydroxide

potassium cyanate (590-28-3) + trans-4-hydroxyproline (3398-22-9) → 6-hydroxy-tetrahydro-pyrrolo[1,2-c]imidazole-1,3-dione (67943-20-8, 75281-55-9)

Conditions	Yield
With water Eindampfen der Reaktionsloesung mit Salzsaeure;

chloroacetyl chloride (79-04-9) + trans-4-hydroxyproline (3398-22-9) → 1-chloroacetyl-4-oxy-L-proline

Conditions	Yield
With sodium hydroxide

trans-4-hydroxyproline (3398-22-9) → 1-acetyl-4-acetoxy-L-prolin-ethyl ester (109492-71-9, 109525-34-0)

Conditions	Yield
With hydrogenchloride Erwaermen des entstandenen Aethylesters mit Acetanhydrid und Natriumacetat;

dihydrogen peroxide (7722-84-1) + copper(II) sulfate (7758-99-8) + trans-4-hydroxyproline (3398-22-9) + aqueous NaOH → pyrrole-2-carboxyl acid (634-97-9)

Conditions	Yield
Behandeln des Reaktionsgemisches mit Essigsaeure und wss. HCl;

trans-4-hydroxyproline (3398-22-9) → (2R,4S)-2-hydroxymethyl-4-hydroxy-N-(carbobenzyloxy)pyrrolidine

Conditions	Yield
Multi-step reaction with 3 steps 1: NaHCO3 / H2O 2: SOCl2 3: NaBH4; LiCl View Scheme
Multi-step reaction with 3 steps 1: NaHCO3 2: methanol 3: LiBH4 / tetrahydrofuran View Scheme

trans-4-hydroxyproline (3398-22-9) → (2R,4S)-1-benzyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (79433-95-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: NaHCO3 / H2O 2: SOCl2 View Scheme
Multi-step reaction with 2 steps 1: NaHCO3 2: methanol View Scheme
Multi-step reaction with 2 steps 1.1: sodium hydrogencarbonate / toluene; water / 16.25 h / 20 °C 1.2: pH 2 2.1: thionyl chloride / 0 - 20 °C View Scheme
Multi-step reaction with 2 steps 1.1: sodium hydrogencarbonate / toluene; water / 16 h / 20 °C 1.2: pH 2 / Cooling with ice 2.1: thionyl chloride / 12 h / 0 - 20 °C View Scheme

Upstream product

• 618-28-0 trans-4-hydroxy-D,L-proline 
• 103078-90-6 trans-1-(3,5-dinitro-benzoyl)-4-hydroxy-DL-proline 
• 77449-95-7 N-Acetyl-allo-4-(p-toluenesulfonyloxy)-D-proline Methyl Ester 
• 77449-96-8 N-Acetyl-allo-4-(p-toluenesulfonyloxy)-D-proline 
• 114673-33-5 trans-1-(3,5-dinitro-benzoyl)-4-hydroxy-D-proline 

Downstream Products

• 155153-78-9 (4S)-1-[(benzyloxy)carbonyl]-4-hydroxy-D-proline 
• 100243-39-8 3-hydroxypyrrolidine 
• 147266-92-0 (2R,4S )-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid 
• 72485-25-7 (1S,4S)-5-acetyl-2-oxa-5-azabicyclo<2.2.1>heptan-3-one 
• 1269622-71-0 (2S,4R)-4-fluoro-2-(1,3,5-trimethyl-1H-pyrazol-4-ylmethyl)-pyrrolidine-1-carboxylic acid benzyl ester 
• 1269622-64-1 (2R,4S)-4-(tert-butyl-dimethyl-silanyloxy)-2-[phenoxythiocarbonyloxy-(1,3,5-trimethyl-1H-pyrazol-4-yl)methyl]-pyrrolidine-1-carboxylic acid benzyl ester 
• 1269622-40-3 (2R,4S)-4-benzyloxy-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 
• 1269622-61-8 (2S,4S)-4-hydroxy-2-(1,3,5-trimethyl-1H-pyrazol-4-ylmethyl)-pyrrolidine-1-carboxylic acid benzyl ester 
• 1269622-60-7 (2S,4S)-4-(tert-butyl-dimethyl-silanyloxy)-2-(1,3,5-trimethyl-1H-pyrazol-4-ylmethyl)-pyrrolidine-1-carboxylic acid benzyl ester 
• 1269622-59-4 (2R,4S)-4-(tert-butyl-dimethyl-silanyloxy)-2-[hydroxy-(1,3,5-trimethyl-1H-pyrazol-4-yl)-methyl]-pyrrolidine-1-carboxylic acid benzyl ester 
• 1269622-58-3 (2R,4S)-4-(tert-butyl-dimethyl-silanyloxy)-2-formyl-pyrrolidine-1-carboxylic acid benzyl ester 
• 1269622-57-2 (2R,4S)-4-(tert-butyl-dimethyl-silanyloxy)-2-hydroxymethyl-pyrrolidine-1-carboxylic acid benzyl ester 
• 1269622-56-1 (2R,4S)-4-(tert-butyl-dimethyl-silanyloxy)-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester 
• 178962-09-9 methyl (2R,4S)-4-hydroxypyrrolidine-2-carboxylate 

Relevant articles and documents

A carbohydrate based straightforward approach to trans-4-hydroxy-D-proline and trans-4-hydroxy-D-prolinol

Synthesis of trans-4-hydroxy-D-proline and the corresponding prolinol has been accomplished starting from 4,6-di-O-benzyl-3-deoxy-D-glucal, an enol-ether derived from D-glucose, through oxidative cleavage of a vicinal diol intermediate as the key step. This work represents a practical approach to an unnatural, yet synthetically and biologically very significant, amino acid.

Compounds of N-benzoylpyroline

Compounds of the general formula (I): STR1 where A, R1, R2, R3, R4, R5 and R6 are defined in the description. Medicinal products.