364750-80-1

Basic information

• Product Name: (2S,4R)-N-Boc-4-methylpyrrolidine-2-carboxylic acid
• Synonyms: (2s,4r)-n-boc-4-methylpyrrolidine-2-carboxylic acid;(2S,4R)-1-(tert-Butoxycarbonyl)-4-methylpyrrolidine-2-carboxylic acid;(2S,4R)-4-Methyl-1,2-pyrrolidinedicarboxylic acid 1-(1,1-dimethylethyl) ester;RACEMIC MIXTURE (2S,4R)-N-Boc-4-Methylpyrrolidine-2-carboxylic acid;L-proline, trans-4-Methyl;(2S,4R)-4-Methylpyrrolidine-2-carboxylic acid, N-BOC protected;trans-4-Methyl-L-proline, N-BOC protected, (2S,4R)-1-(tert-Butoxycarbonyl)-4-methylpyrrolidine-2-carboxylic acid;(2S,4R)-1-Boc-4-Methylpyrrolidine-2-carboxylic acid
• CAS NO: 364750-80-1
• Molecular Formula: C₁₁H₁₉NO₄
• Molecular Weight: 229.27
• Mol File: 364750-80-1.mol
• Article Data: 8

Chemical Properties

• Boiling Point: 343 °C
• Flash Point: 161 °C
• Appearance: /
• Density: 1.150
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.491
• Storage Temp.: Sealed in dry,Room Temperature
• PKA: 4.02±0.40(Predicted)
• CAS DataBase Reference: (2S,4R)-N-Boc-4-methylpyrrolidine-2-carboxylic acid(CAS DataBase Reference)
• NIST Chemistry Reference: (2S,4R)-N-Boc-4-methylpyrrolidine-2-carboxylic acid(364750-80-1)
• EPA Substance Registry System: (2S,4R)-N-Boc-4-methylpyrrolidine-2-carboxylic acid(364750-80-1)

Safety Data

• Hazardous Substances Data: 364750-80-1(Hazardous Substances Data)

Usage

General Description

"(2S,4R)-N-Boc-4-methylpyrrolidine-2-carboxylic acid" is a chemical compound with a specific configuration. It contains a Boc (tert-butoxycarbonyl) protecting group, which is commonly used in organic synthesis to protect amine groups. The compound also features a pyrrolidine ring with a methyl group attached at the 4th position and a carboxylic acid group at the 2nd position. The stereochemistry of the compound is specified as (2S,4R), indicating the configuration of the chiral centers in the molecule. (2S,4R)-N-Boc-4-methylpyrrolidine-2-carboxylic acid could have potential applications in organic synthesis, medicinal chemistry, or material science due to its unique structure and properties.

InChI:InChI=1/C11H19NO4/c1-7-5-8(9(13)14)12(6-7)10(15)16-11(2,3)4/h7-8H,5-6H2,1-4H3,(H,13,14)/t7-,8+/m1/s1

Synthetic route

tert-butyl (2S,4R)-2-(hydroxymethyl)-4-methylpyrrolidine-1-carboxylate (220047-75-6) → (2S,4R)-1-[(tert-butoxy)carbonyl]-4-methylpyrrolidine-2-carboxylic acid (364750-80-1)

Conditions	Yield
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; [bis(acetoxy)iodo]benzene In water; acetonitrile at 20℃; for 15h;	100%
With 2,2,6,6-tetramethyl-piperidine-N-oxyl; sodium chlorite; NaH2PO4 buffer; sodium hypochlorite In water; acetonitrile at 45℃; for 24h; pH=6.6;	84%
With 2,2,6,6-tetramethyl-piperidine-N-oxyl; sodium hypochlorite; sodium hydrogencarbonate; potassium bromide In acetone at 0℃; for 2h;

C11H19NO4 → (2S,4R)-1-[(tert-butoxy)carbonyl]-4-methylpyrrolidine-2-carboxylic acid (364750-80-1)

Conditions	Yield
Stage #1: C11H19NO4 With trimethylaluminum; N,O-dimethylhydroxylamine*hydrochloride In tetrahydrofuran; toluene at -30 - 23℃; for 0.666667h; Inert atmosphere; Stage #2: With methanesulfonyl chloride; triethylamine In tetrahydrofuran at -78 - 23℃; for 1h; Inert atmosphere; Further stages;	44%

L-leucine (61-90-5) + di-tert-butyl dicarbonate (24424-99-5) → N-tert-Butyloxycarbonyl-(2S,4S)-4-methylproline (364750-81-2) + (2S)-2-(ter-butoxycarbonylamino)-4,4-dimethyl-4-butanolide + (2S,4R)-1-[(tert-butoxy)carbonyl]-4-methylpyrrolidine-2-carboxylic acid (364750-80-1)

Conditions	Yield
Multistep reaction;	A n/a B 12% C n/a

di-tert-butyl dicarbonate (24424-99-5) → (2S,4R)-1-[(tert-butoxy)carbonyl]-4-methylpyrrolidine-2-carboxylic acid (364750-80-1)

Conditions	Yield
Multi-step reaction with 9 steps 1.1: aqueous Na2CO3 / tetrahydrofuran; dioxane / 18 h 2.1: NMM / 1,2-dimethoxy-ethane / 0.5 h / -20 °C 3.1: 11.96 g / NaBH4 / 1,2-dimethoxy-ethane; H2O / 0.33 h / Cooling 4.1: 78 percent / TEA; DMAP / CH2Cl2 5.1: 88 percent / trichloroisocyanuric acid; TEMPO / CH2Cl2 / 1 h / 0 °C 6.1: n-BuLi / tetrahydrofuran; hexane / -78 °C 6.2: 73 percent / tetrahydrofuran; hexane / 5 h / -78 - 20 °C 7.1: Raney-Ni; hydrogen / methanol / Heating 8.1: TBAF / tetrahydrofuran 9.1: 84 percent / NaClO2; TEMPO; aqueous NaH2PO4 buffer / NaClO / H2O; acetonitrile / 24 h / 45 °C / pH 6.6 View Scheme
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 0 - 20 °C 2: lithium borohydride / tetrahydrofuran / 20 °C View Scheme

tert-butyl (2S,4R)-4-hydroxy-2-hydroxymethyl-pyrrolidine-1-carboxylate (61478-26-0) → (2S,4R)-1-[(tert-butoxy)carbonyl]-4-methylpyrrolidine-2-carboxylic acid (364750-80-1)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: 78 percent / TEA; DMAP / CH2Cl2 2.1: 88 percent / trichloroisocyanuric acid; TEMPO / CH2Cl2 / 1 h / 0 °C 3.1: n-BuLi / tetrahydrofuran; hexane / -78 °C 3.2: 73 percent / tetrahydrofuran; hexane / 5 h / -78 - 20 °C 4.1: Raney-Ni; hydrogen / methanol / Heating 5.1: TBAF / tetrahydrofuran 6.1: 84 percent / NaClO2; TEMPO; aqueous NaH2PO4 buffer / NaClO / H2O; acetonitrile / 24 h / 45 °C / pH 6.6 View Scheme

(2S,4R)-4-hydroxy-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid (13726-69-7) → (2S,4R)-1-[(tert-butoxy)carbonyl]-4-methylpyrrolidine-2-carboxylic acid (364750-80-1)

Conditions

Yield

Multi-step reaction with 8 steps 1.1: NMM / 1,2-dimethoxy-ethane / 0.5 h / -20 °C 2.1: 11.96 g / NaBH4 / 1,2-dimethoxy-ethane; H2O / 0.33 h / Cooling 3.1: 78 percent / TEA; DMAP / CH2Cl2 4.1: 88 percent / trichloroisocyanuric acid; TEMPO / CH2Cl2 / 1 h / 0 °C 5.1: n-BuLi / tetrahydrofuran; hexane / -78 °C 5.2: 73 percent / tetrahydrofuran; hexane / 5 h / -78 - 20 °C 6.1: Raney-Ni; hydrogen / methanol / Heating 7.1: TBAF / tetrahydrofuran 8.1: 84 percent / NaClO2; TEMPO; aqueous NaH2PO4 buffer / NaClO / H2O; acetonitrile / 24 h / 45 °C / pH 6.6 View Scheme

(2S,4R)-2-(tert-butyldimethylsilanyloxymethyl)-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (125653-58-9) → (2S,4R)-1-[(tert-butoxy)carbonyl]-4-methylpyrrolidine-2-carboxylic acid (364750-80-1)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: 88 percent / trichloroisocyanuric acid; TEMPO / CH2Cl2 / 1 h / 0 °C 2.1: n-BuLi / tetrahydrofuran; hexane / -78 °C 2.2: 73 percent / tetrahydrofuran; hexane / 5 h / -78 - 20 °C 3.1: Raney-Ni; hydrogen / methanol / Heating 4.1: TBAF / tetrahydrofuran 5.1: 84 percent / NaClO2; TEMPO; aqueous NaH2PO4 buffer / NaClO / H2O; acetonitrile / 24 h / 45 °C / pH 6.6 View Scheme

(2S,4R)-4-Hydroxy-2-isobutoxycarbonyloxycarbonyl-pyrrolidine-1-carboxylic acid tert-butyl ester → (2S,4R)-1-[(tert-butoxy)carbonyl]-4-methylpyrrolidine-2-carboxylic acid (364750-80-1)

Conditions

Yield

Multi-step reaction with 7 steps 1.1: 11.96 g / NaBH4 / 1,2-dimethoxy-ethane; H2O / 0.33 h / Cooling 2.1: 78 percent / TEA; DMAP / CH2Cl2 3.1: 88 percent / trichloroisocyanuric acid; TEMPO / CH2Cl2 / 1 h / 0 °C 4.1: n-BuLi / tetrahydrofuran; hexane / -78 °C 4.2: 73 percent / tetrahydrofuran; hexane / 5 h / -78 - 20 °C 5.1: Raney-Ni; hydrogen / methanol / Heating 6.1: TBAF / tetrahydrofuran 7.1: 84 percent / NaClO2; TEMPO; aqueous NaH2PO4 buffer / NaClO / H2O; acetonitrile / 24 h / 45 °C / pH 6.6 View Scheme

4R-4-hydroxyproline (51-35-4) → (2S,4R)-1-[(tert-butoxy)carbonyl]-4-methylpyrrolidine-2-carboxylic acid (364750-80-1)

Conditions

Yield

Multi-step reaction with 9 steps 1.1: aqueous Na2CO3 / tetrahydrofuran; dioxane / 18 h 2.1: NMM / 1,2-dimethoxy-ethane / 0.5 h / -20 °C 3.1: 11.96 g / NaBH4 / 1,2-dimethoxy-ethane; H2O / 0.33 h / Cooling 4.1: 78 percent / TEA; DMAP / CH2Cl2 5.1: 88 percent / trichloroisocyanuric acid; TEMPO / CH2Cl2 / 1 h / 0 °C 6.1: n-BuLi / tetrahydrofuran; hexane / -78 °C 6.2: 73 percent / tetrahydrofuran; hexane / 5 h / -78 - 20 °C 7.1: Raney-Ni; hydrogen / methanol / Heating 8.1: TBAF / tetrahydrofuran 9.1: 84 percent / NaClO2; TEMPO; aqueous NaH2PO4 buffer / NaClO / H2O; acetonitrile / 24 h / 45 °C / pH 6.6 View Scheme

(S)-tert-butyl 2-(hydroxymethyl)-4-methylenepyrrolidine-1-carboxylate (181295-78-3) → (2S,4R)-1-[(tert-butoxy)carbonyl]-4-methylpyrrolidine-2-carboxylic acid (364750-80-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: 90 percent / Ir(COD)PyPCy3PF6; hydrogen / CH2Cl2 / 18 h / 20 °C / 760 Torr 2: 84 percent / NaClO2; TEMPO; aqueous NaH2PO4 buffer / NaClO / H2O; acetonitrile / 24 h / 45 °C / pH 6.6 View Scheme

2-(tert-butyl-dimethyl-silanyloxymethyl)-4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester → (2S,4R)-1-[(tert-butoxy)carbonyl]-4-methylpyrrolidine-2-carboxylic acid (364750-80-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: TBAF / tetrahydrofuran 2: 84 percent / NaClO2; TEMPO; aqueous NaH2PO4 buffer / NaClO / H2O; acetonitrile / 24 h / 45 °C / pH 6.6 View Scheme

(S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-4-oxopyrrolidine-1-carboxylate (220993-22-6) → (2S,4R)-1-[(tert-butoxy)carbonyl]-4-methylpyrrolidine-2-carboxylic acid (364750-80-1)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: n-BuLi / tetrahydrofuran; hexane / -78 °C 1.2: 73 percent / tetrahydrofuran; hexane / 5 h / -78 - 20 °C 2.1: Raney-Ni; hydrogen / methanol / Heating 3.1: TBAF / tetrahydrofuran 4.1: 84 percent / NaClO2; TEMPO; aqueous NaH2PO4 buffer / NaClO / H2O; acetonitrile / 24 h / 45 °C / pH 6.6 View Scheme
Multi-step reaction with 5 steps 1: sodium hexamethyldisilazane / tetrahydrofuran / -78 °C 2: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate / 1,4-dioxane; water / 1 h / 100 °C 3: tetrabutyl ammonium fluoride / tetrahydrofuran / 6 h / 20 °C 4: hydrogen; Crabtree's catalyst / dichloromethane / 12 h / 20 °C 5: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; [bis(acetoxy)iodo]benzene / water; acetonitrile / 15 h / 20 °C View Scheme

(S)-2-tert-butyldimethylsilyloxymethyl-N-tert-butyloxycarbonyl-4-methylenepyrrolidine (540501-23-3) → (2S,4R)-1-[(tert-butoxy)carbonyl]-4-methylpyrrolidine-2-carboxylic acid (364750-80-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: 85 percent / TBAF / tetrahydrofuran / 6 h / 20 °C 2: 90 percent / Ir(COD)PyPCy3PF6; hydrogen / CH2Cl2 / 18 h / 20 °C / 760 Torr 3: 84 percent / NaClO2; TEMPO; aqueous NaH2PO4 buffer / NaClO / H2O; acetonitrile / 24 h / 45 °C / pH 6.6 View Scheme

(S)-2-tert-butyldimethylsilyloxymethyl-N-tert-butyloxycarbonyl-4-(phenylthio)methylenepyrrolidine (540501-65-3) → (2S,4R)-1-[(tert-butoxy)carbonyl]-4-methylpyrrolidine-2-carboxylic acid (364750-80-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: Raney-Ni; hydrogen / methanol / Heating 2: TBAF / tetrahydrofuran 3: 84 percent / NaClO2; TEMPO; aqueous NaH2PO4 buffer / NaClO / H2O; acetonitrile / 24 h / 45 °C / pH 6.6 View Scheme

(2S,4R)-1-tert-butoxycarbonyl-2-benzyloxymethyl-4-methylpyrrolidine (220047-73-4) → (2S,4R)-1-[(tert-butoxy)carbonyl]-4-methylpyrrolidine-2-carboxylic acid (364750-80-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: 92 percent / H2 / Pd/C / methanol / 18 h / 760 Torr / Ambient temperature 2: aq. NaHCO3, NaOCl, KBr, TEMPO / acetone / 2 h / 0 °C View Scheme

((R)-2-Benzenesulfonyl-1-benzyloxymethyl-ethyl)-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-amine (220047-57-4) → (2S,4R)-1-[(tert-butoxy)carbonyl]-4-methylpyrrolidine-2-carboxylic acid (364750-80-1)

Conditions	Yield
Multi-step reaction with 11 steps 1: 63 percent / K2CO3 / dimethylformamide / 48 h / 80 °C 2: 94 percent / aq. HCl / tetrahydrofuran / 3 h / Ambient temperature 3: 85 percent / pyridine / 24 h / 0 °C 4: 99 percent / K2CO3 / dimethylformamide; H2O / 24 h / Ambient temperature 5: 73 percent / Ti(O-i-Pr)4, KHMDS / tetrahydrofuran; toluene / 2 h / -70 °C 6: 95 percent / H2 / Pd/C / methanol / 3 h / 760 Torr / Ambient temperature 7: 100 percent / Na-Hg, Na2HPO4 / methanol / 2 h / 0 °C 8: 85 percent / DMAP / pyridine / 1.) 0 deg C, 30 min, 2.) room temp., 24 h 9: 87 percent / NaBH4 / dimethylsulfoxide / 16 h / 45 °C 10: 92 percent / H2 / Pd/C / methanol / 18 h / 760 Torr / Ambient temperature 11: aq. NaHCO3, NaOCl, KBr, TEMPO / acetone / 2 h / 0 °C View Scheme
Multi-step reaction with 11 steps 1: 90 percent / NaBH3CN / 1,2-dichloro-ethane / 6 h / Ambient temperature 2: 94 percent / aq. HCl / tetrahydrofuran / 3 h / Ambient temperature 3: 85 percent / pyridine / 24 h / 0 °C 4: 99 percent / K2CO3 / dimethylformamide; H2O / 24 h / Ambient temperature 5: 73 percent / Ti(O-i-Pr)4, KHMDS / tetrahydrofuran; toluene / 2 h / -70 °C 6: 95 percent / H2 / Pd/C / methanol / 3 h / 760 Torr / Ambient temperature 7: 100 percent / Na-Hg, Na2HPO4 / methanol / 2 h / 0 °C 8: 85 percent / DMAP / pyridine / 1.) 0 deg C, 30 min, 2.) room temp., 24 h 9: 87 percent / NaBH4 / dimethylsulfoxide / 16 h / 45 °C 10: 92 percent / H2 / Pd/C / methanol / 18 h / 760 Torr / Ambient temperature 11: aq. NaHCO3, NaOCl, KBr, TEMPO / acetone / 2 h / 0 °C View Scheme

(2S,4R)-2-Benzyloxymethyl-4-(toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (220047-71-2) → (2S,4R)-1-[(tert-butoxy)carbonyl]-4-methylpyrrolidine-2-carboxylic acid (364750-80-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: 87 percent / NaBH4 / dimethylsulfoxide / 16 h / 45 °C 2: 92 percent / H2 / Pd/C / methanol / 18 h / 760 Torr / Ambient temperature 3: aq. NaHCO3, NaOCl, KBr, TEMPO / acetone / 2 h / 0 °C View Scheme

(2S,4R)-1-tert-butoxycarbonyl-2-benzyloxymethyl-4-hydroxymethylpyrrolidine (212266-65-4) → (2S,4R)-1-[(tert-butoxy)carbonyl]-4-methylpyrrolidine-2-carboxylic acid (364750-80-1)

Conditions	Yield
Multi-step reaction with 4 steps 1: 85 percent / DMAP / pyridine / 1.) 0 deg C, 30 min, 2.) room temp., 24 h 2: 87 percent / NaBH4 / dimethylsulfoxide / 16 h / 45 °C 3: 92 percent / H2 / Pd/C / methanol / 18 h / 760 Torr / Ambient temperature 4: aq. NaHCO3, NaOCl, KBr, TEMPO / acetone / 2 h / 0 °C View Scheme

((3R,4S,5R)-4-Benzenesulfonyl-1-benzyl-5-benzyloxymethyl-pyrrolidin-3-yl)-methanol (220047-66-5) → (2S,4R)-1-[(tert-butoxy)carbonyl]-4-methylpyrrolidine-2-carboxylic acid (364750-80-1)

Conditions

Yield

Multi-step reaction with 6 steps 1: 95 percent / H2 / Pd/C / methanol / 3 h / 760 Torr / Ambient temperature 2: 100 percent / Na-Hg, Na2HPO4 / methanol / 2 h / 0 °C 3: 85 percent / DMAP / pyridine / 1.) 0 deg C, 30 min, 2.) room temp., 24 h 4: 87 percent / NaBH4 / dimethylsulfoxide / 16 h / 45 °C 5: 92 percent / H2 / Pd/C / methanol / 18 h / 760 Torr / Ambient temperature 6: aq. NaHCO3, NaOCl, KBr, TEMPO / acetone / 2 h / 0 °C View Scheme

((R)-2-Benzenesulfonyl-1-benzyloxymethyl-ethyl)-benzyl-oxiranylmethyl-amine → (2S,4R)-1-[(tert-butoxy)carbonyl]-4-methylpyrrolidine-2-carboxylic acid (364750-80-1)

Conditions

Yield

Multi-step reaction with 7 steps 1: 73 percent / Ti(O-i-Pr)4, KHMDS / tetrahydrofuran; toluene / 2 h / -70 °C 2: 95 percent / H2 / Pd/C / methanol / 3 h / 760 Torr / Ambient temperature 3: 100 percent / Na-Hg, Na2HPO4 / methanol / 2 h / 0 °C 4: 85 percent / DMAP / pyridine / 1.) 0 deg C, 30 min, 2.) room temp., 24 h 5: 87 percent / NaBH4 / dimethylsulfoxide / 16 h / 45 °C 6: 92 percent / H2 / Pd/C / methanol / 18 h / 760 Torr / Ambient temperature 7: aq. NaHCO3, NaOCl, KBr, TEMPO / acetone / 2 h / 0 °C View Scheme

(2R,3S,4R)-3-Benzenesulfonyl-2-benzyloxymethyl-4-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (220047-69-8) → (2S,4R)-1-[(tert-butoxy)carbonyl]-4-methylpyrrolidine-2-carboxylic acid (364750-80-1)

Conditions	Yield
Multi-step reaction with 5 steps 1: 100 percent / Na-Hg, Na2HPO4 / methanol / 2 h / 0 °C 2: 85 percent / DMAP / pyridine / 1.) 0 deg C, 30 min, 2.) room temp., 24 h 3: 87 percent / NaBH4 / dimethylsulfoxide / 16 h / 45 °C 4: 92 percent / H2 / Pd/C / methanol / 18 h / 760 Torr / Ambient temperature 5: aq. NaHCO3, NaOCl, KBr, TEMPO / acetone / 2 h / 0 °C View Scheme

(S)-3-[((R)-2-Benzenesulfonyl-1-benzyloxymethyl-ethyl)-benzyl-amino]-propane-1,2-diol (212266-69-8) → (2S,4R)-1-[(tert-butoxy)carbonyl]-4-methylpyrrolidine-2-carboxylic acid (364750-80-1)

Conditions

Yield

Multi-step reaction with 9 steps 1: 85 percent / pyridine / 24 h / 0 °C 2: 99 percent / K2CO3 / dimethylformamide; H2O / 24 h / Ambient temperature 3: 73 percent / Ti(O-i-Pr)4, KHMDS / tetrahydrofuran; toluene / 2 h / -70 °C 4: 95 percent / H2 / Pd/C / methanol / 3 h / 760 Torr / Ambient temperature 5: 100 percent / Na-Hg, Na2HPO4 / methanol / 2 h / 0 °C 6: 85 percent / DMAP / pyridine / 1.) 0 deg C, 30 min, 2.) room temp., 24 h 7: 87 percent / NaBH4 / dimethylsulfoxide / 16 h / 45 °C 8: 92 percent / H2 / Pd/C / methanol / 18 h / 760 Torr / Ambient temperature 9: aq. NaHCO3, NaOCl, KBr, TEMPO / acetone / 2 h / 0 °C View Scheme

((R)-2-Benzenesulfonyl-1-benzyloxymethyl-ethyl)-benzyl-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-amine (212266-68-7) → (2S,4R)-1-[(tert-butoxy)carbonyl]-4-methylpyrrolidine-2-carboxylic acid (364750-80-1)

Conditions

Yield

Multi-step reaction with 10 steps 1: 94 percent / aq. HCl / tetrahydrofuran / 3 h / Ambient temperature 2: 85 percent / pyridine / 24 h / 0 °C 3: 99 percent / K2CO3 / dimethylformamide; H2O / 24 h / Ambient temperature 4: 73 percent / Ti(O-i-Pr)4, KHMDS / tetrahydrofuran; toluene / 2 h / -70 °C 5: 95 percent / H2 / Pd/C / methanol / 3 h / 760 Torr / Ambient temperature 6: 100 percent / Na-Hg, Na2HPO4 / methanol / 2 h / 0 °C 7: 85 percent / DMAP / pyridine / 1.) 0 deg C, 30 min, 2.) room temp., 24 h 8: 87 percent / NaBH4 / dimethylsulfoxide / 16 h / 45 °C 9: 92 percent / H2 / Pd/C / methanol / 18 h / 760 Torr / Ambient temperature 10: aq. NaHCO3, NaOCl, KBr, TEMPO / acetone / 2 h / 0 °C View Scheme

Toluene-4-sulfonic acid (S)-3-[((R)-2-benzenesulfonyl-1-benzyloxymethyl-ethyl)-benzyl-amino]-2-hydroxy-propyl ester (212266-70-1) → (2S,4R)-1-[(tert-butoxy)carbonyl]-4-methylpyrrolidine-2-carboxylic acid (364750-80-1)

Conditions

Yield

Multi-step reaction with 8 steps 1: 99 percent / K2CO3 / dimethylformamide; H2O / 24 h / Ambient temperature 2: 73 percent / Ti(O-i-Pr)4, KHMDS / tetrahydrofuran; toluene / 2 h / -70 °C 3: 95 percent / H2 / Pd/C / methanol / 3 h / 760 Torr / Ambient temperature 4: 100 percent / Na-Hg, Na2HPO4 / methanol / 2 h / 0 °C 5: 85 percent / DMAP / pyridine / 1.) 0 deg C, 30 min, 2.) room temp., 24 h 6: 87 percent / NaBH4 / dimethylsulfoxide / 16 h / 45 °C 7: 92 percent / H2 / Pd/C / methanol / 18 h / 760 Torr / Ambient temperature 8: aq. NaHCO3, NaOCl, KBr, TEMPO / acetone / 2 h / 0 °C View Scheme

4-methyl-pyrrolidine-2-carboxylic acid methyl ester → (2S,4R)-1-[(tert-butoxy)carbonyl]-4-methylpyrrolidine-2-carboxylic acid (364750-80-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium hydrogencarbonate / 1,4-dioxane / 3 h / 20 °C 2: palladium on activated charcoal; hydrogen / ethyl acetate / 14 h / 20 °C / 760.05 Torr 3: lithium hydroxide monohydrate / tetrahydrofuran; methanol; water / 14 h / 20 °C View Scheme

C20H34N2O4Si (1353864-31-9) → (2S,4R)-1-[(tert-butoxy)carbonyl]-4-methylpyrrolidine-2-carboxylic acid (364750-80-1)

Conditions

Yield

Multi-step reaction with 5 steps 1: [bis(acetoxy)iodo]benzene; palladium diacetate; acetic acid / toluene / 24 h / 110 °C / Inert atmosphere 2: hydrogenchloride; water / 1,4-dioxane / 24 h / 20 °C 3: sodium hydrogencarbonate / 1,4-dioxane / 3 h / 20 °C 4: palladium on activated charcoal; hydrogen / ethyl acetate / 14 h / 20 °C / 760.05 Torr 5: lithium hydroxide monohydrate / tetrahydrofuran; methanol; water / 14 h / 20 °C View Scheme

C20H32N2O4Si (1353864-33-1) → (2S,4R)-1-[(tert-butoxy)carbonyl]-4-methylpyrrolidine-2-carboxylic acid (364750-80-1)

Conditions	Yield
Multi-step reaction with 4 steps 1: hydrogenchloride; water / 1,4-dioxane / 24 h / 20 °C 2: sodium hydrogencarbonate / 1,4-dioxane / 3 h / 20 °C 3: palladium on activated charcoal; hydrogen / ethyl acetate / 14 h / 20 °C / 760.05 Torr 4: lithium hydroxide monohydrate / tetrahydrofuran; methanol; water / 14 h / 20 °C View Scheme

C15H19NO4 (1353864-35-3) → (2S,4R)-1-[(tert-butoxy)carbonyl]-4-methylpyrrolidine-2-carboxylic acid (364750-80-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: palladium on activated charcoal; hydrogen / ethyl acetate / 14 h / 20 °C / 760.05 Torr 2: lithium hydroxide monohydrate / tetrahydrofuran; methanol; water / 14 h / 20 °C View Scheme

methyl (L)-leucinate hydrochloride (7517-19-3) → (2S,4R)-1-[(tert-butoxy)carbonyl]-4-methylpyrrolidine-2-carboxylic acid (364750-80-1)

Conditions

Yield

Multi-step reaction with 6 steps 1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / dichloromethane / 20 °C 2: [bis(acetoxy)iodo]benzene; palladium diacetate; acetic acid / toluene / 24 h / 110 °C / Inert atmosphere 3: hydrogenchloride; water / 1,4-dioxane / 24 h / 20 °C 4: sodium hydrogencarbonate / 1,4-dioxane / 3 h / 20 °C 5: palladium on activated charcoal; hydrogen / ethyl acetate / 14 h / 20 °C / 760.05 Torr 6: lithium hydroxide monohydrate / tetrahydrofuran; methanol; water / 14 h / 20 °C View Scheme

1-tert-butyl 2-methyl (2S,4R)-4-methylpyrrolidine-1,2-dicarboxylate (138512-74-0) → (2S,4R)-1-[(tert-butoxy)carbonyl]-4-methylpyrrolidine-2-carboxylic acid (364750-80-1)

Conditions	Yield
With lithium hydroxide monohydrate In tetrahydrofuran; methanol; water at 20℃; for 14h;
With water; lithium hydroxide In ethanol at 0 - 20℃; for 5h;
With lithium borohydride In tetrahydrofuran at 20℃;	92 g

2-oxo-2-phenylethyl ((benzyloxy)carbonyl)-L-allothreoninate (1542206-68-7) + (2S,4R)-1-[(tert-butoxy)carbonyl]-4-methylpyrrolidine-2-carboxylic acid (364750-80-1) → 2-((2S,3S)-3-(((benzyloxy)carbonyl)amino)-4-oxo-4-(2-oxo-2-phenylethoxy)butan-2-yl) 1-(tert-butyl) (2S,4S)-4-methylpyrrolidine-1,2-dicarboxylate

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃;	83%

(2S,4R)-1-[(tert-butoxy)carbonyl]-4-methylpyrrolidine-2-carboxylic acid (364750-80-1) → tert-butyl (2S,4R)-2-(hydroxymethyl)-4-methylpyrrolidine-1-carboxylate (220047-75-6)

Conditions	Yield
With borane-THF In tetrahydrofuran at 0 - 30℃; for 2h;	83%

methanol (67-56-1) + <2-(13)C>acetyl chloride (14770-40-2) + (2S,4R)-1-[(tert-butoxy)carbonyl]-4-methylpyrrolidine-2-carboxylic acid (364750-80-1) → N-(2-13CH3-acetyl)-(2S,4R)-4-methylproline methyl ester

Conditions	Yield
Stage #1: methanol; (2S,4R)-1-[(tert-butoxy)carbonyl]-4-methylpyrrolidine-2-carboxylic acid With acetyl chloride at 0 - 20℃; Stage #2: <2-(13)C>acetyl chloride With dmap In dichloromethane at 20℃; for 24h;	77%

4-Bromo-benzene-1,2-diamine (1575-37-7) + (2S,4R)-1-[(tert-butoxy)carbonyl]-4-methylpyrrolidine-2-carboxylic acid (364750-80-1) → C17H22BrN3O2

Conditions	Yield
Stage #1: (2S,4R)-1-[(tert-butoxy)carbonyl]-4-methylpyrrolidine-2-carboxylic acid With N-ethyl-N,N-diisopropylamine; HATU In tetrahydrofuran at 0 - 20℃; for 0.5h; Stage #2: 4-Bromo-benzene-1,2-diamine In tetrahydrofuran at 20℃; for 2h;	72%

diazomethane (186581-53-3, 908094-01-9) + (2S,4R)-1-[(tert-butoxy)carbonyl]-4-methylpyrrolidine-2-carboxylic acid (364750-80-1) → 1-tert-butyl 2-methyl (2S,4R)-4-methylpyrrolidine-1,2-dicarboxylate (138512-74-0)

Conditions	Yield
In diethyl ether Yield given;

(2S,4R)-1-[(tert-butoxy)carbonyl]-4-methylpyrrolidine-2-carboxylic acid (364750-80-1) → trans-4-methyl-L-proline (23009-50-9)

Conditions	Yield
With hydrogenchloride In 1,4-dioxane for 1.5h;
Multi-step reaction with 2 steps 1: diethyl ether 2: 1.) aq. HCl, 2.) propylene oxide / 1.) 100 deg C, 3 h, 2.) EtOH, heating View Scheme

methanol (67-56-1) + (2S,4R)-1-[(tert-butoxy)carbonyl]-4-methylpyrrolidine-2-carboxylic acid (364750-80-1) → (2S,4R)-4-Methyl-pyrrolidine-2-carboxylic acid methyl ester; hydrochloride

Conditions	Yield
With acetyl chloride at 0 - 20℃; for 6h;

(2S,4R)-1-[(tert-butoxy)carbonyl]-4-methylpyrrolidine-2-carboxylic acid (364750-80-1) → trans-4-methyl-L-proline hydrochloride

Conditions	Yield
With hydrogenchloride In 1,4-dioxane for 1.5h;

(2S,4R)-1-[(tert-butoxy)carbonyl]-4-methylpyrrolidine-2-carboxylic acid (364750-80-1) → N-9-fuorenylmethoxycarbonyl-(2S,4R)-4-methylprolyl-(2S)-prolyl-glycine (901139-04-6)

Conditions	Yield
Multi-step reaction with 4 steps 1: aq. HCl / dioxane / 1.5 h 2: 1.11 g / aq. NaHCO3 / dioxane / 27 h 3: 442 mg / PyBroP; DIEA / CH2Cl2 / 36 h / 20 °C 4: 84 percent / H2 / Pd/C / methanol / 5 h View Scheme

(2S,4R)-1-[(tert-butoxy)carbonyl]-4-methylpyrrolidine-2-carboxylic acid (364750-80-1) → N-9-fuorenylmethoxycarbonyl-(2S,4R)-4-methylprolyl-(2S,4S)-4-methylprolyl-glycine benzyl ester (901139-69-3)

Conditions	Yield
Multi-step reaction with 4 steps 1: aq. HCl / dioxane / 1.5 h 2: 1.11 g / aq. NaHCO3 / dioxane / 27 h 3: 520 mg / DIEA; PyBroP / CH2Cl2 / 40 h / 20 °C 4: 66 percent / hydrogen / Pd/C / methanol / 2.5 h View Scheme

(2S,4R)-1-[(tert-butoxy)carbonyl]-4-methylpyrrolidine-2-carboxylic acid (364750-80-1) → N-9-fuorenylmethoxycarbonyl-(2S,4R)-4-methylprolyl-(2S)-prolyl-glycine benzyl ester (901138-97-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: aq. HCl / dioxane / 1.5 h 2: 1.11 g / aq. NaHCO3 / dioxane / 27 h 3: 442 mg / PyBroP; DIEA / CH2Cl2 / 36 h / 20 °C View Scheme

(2S,4R)-1-[(tert-butoxy)carbonyl]-4-methylpyrrolidine-2-carboxylic acid (364750-80-1) → N-9-fuorenylmethoxycarbonyl-(2S,4R)-4-methylprolyl-(2S,4S)-4-methylprolyl-glycine benzyl ester (901139-63-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: aq. HCl / dioxane / 1.5 h 2: 1.11 g / aq. NaHCO3 / dioxane / 27 h 3: 520 mg / DIEA; PyBroP / CH2Cl2 / 40 h / 20 °C View Scheme

(2S,4R)-1-[(tert-butoxy)carbonyl]-4-methylpyrrolidine-2-carboxylic acid (364750-80-1) → (2S,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-methylpyrrolidine-2-carboxylic acid (333777-34-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: aq. HCl / dioxane / 1.5 h 2: 1.11 g / aq. NaHCO3 / dioxane / 27 h View Scheme

Upstream product

• 61-90-5 L-leucine 
• 24424-99-5 di-tert-butyl dicarbonate 
• 181295-78-3 tert-butyl (S)-2-(hydroxymethyl)-4-methylenepyrrolidine-1-carboxylate 
• 125653-58-9 (2S,4R)-2-(tert-butyldimethylsilanyloxymethyl)-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester 
• 13726-69-7 (2S,4R)-4-hydroxy-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid 
• 61478-26-0 tert-butyl (2S,4R)-4-hydroxy-2-hydroxymethyl-pyrrolidine-1-carboxylate 
• 220047-75-6 tert-butyl (2S,4R)-2-(hydroxymethyl)-4-methylpyrrolidine-1-carboxylate 
• 1560646-40-3 C₁₁H₁₉NO₃ 
• 118758-45-5 (2S, 4R)-2-amino-4-hydroxymethylpentanoic acid 
• 40216-83-9 L-4-hydroxyproline methyl ester hydrochloride 
• 196394-49-7 (2S,4R)-1-(tert-butyl) 2-methyl 4-methyl-5-oxopyrrolidine-1,2-dicarboxylate 
• 98-79-3 L-Pyroglutamic acid 
• 4931-66-2 methyl (S)-pyroglutamate 
• 108963-96-8 (S)-1-tert-butoxycarbonyl-5-methoxycarbonyl-pyrrolidin-2-one 

Downstream Products

• 32968-78-8 (2S,4R)-4-hydroxy-2-pyrrolidinecarboxylic acid hydrochloride 
• 333777-34-7 (2S,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-methylpyrrolidine-2-carboxylic acid 
• 901139-63-7 N-9-fuorenylmethoxycarbonyl-(2S,4R)-4-methylprolyl-(2S,4S)-4-methylprolyl-glycine benzyl ester 
• 901138-97-4 N-9-fuorenylmethoxycarbonyl-(2S,4R)-4-methylprolyl-(2S)-prolyl-glycine benzyl ester 
• 365280-18-8 trans-4-methyl-L-proline hydrochloride 
• 23009-50-9 trans-4-methyl-L-proline 
• 138512-74-0 1-tert-butyl 2-methyl (2S,4R)-4-methylpyrrolidine-1,2-dicarboxylate 

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