83056-79-5

Usage

InChI:InChI=1/C9H16N2O3/c1-9(2,3)14-7(12)6-5-11(4)8(13)10-6/h6H,5H2,1-4H3,(H,10,13)/t6-/m0/s1

Synthetic route

tert-butyl (4S)-3-(benzyloxycarbonyl)-1-methyl-2-oxoimidazolidine-4-carboxylate (83056-78-4) → (4S)-1-methyl-2-oxoimidazolidine-4-carboxylic acid t-butyl ester (83056-79-5)

Conditions	Yield
With hydrogen; palladium In methanol under 760 Torr; for 3h; Ambient temperature;	98.2%
In methanol; hydrogen	98.2%
palladium In methanol; hydrogen	98.2%

tert-Butyl (4S)-3-<(2R)-2-(N-benzylamino)propionyl>-1-methyl-2-oxoimidazolidine-4-carboxylate (157163-04-7) + benzyl alcohol (100-51-6) → (4S)-1-methyl-2-oxoimidazolidine-4-carboxylic acid t-butyl ester (83056-79-5) + Benzyl N-benzyl-D-alaninate

Conditions	Yield
With n-butyllithium In diethyl ether; benzene 1.) 0 deg C, 10 min, 2.) 0 deg C, 30 min;	A 76% B 87%
With n-butyllithium In diethyl ether; hexane 1.) 0 deg C, 10 min, 2.) 0 deg C, 30 min;	A 76% B 87%

(S)‐2‐oxoimidazolidine‐1,5‐dicarboxylate-5‐tert‐butyl ester-1‐benzyl ester (77999-24-7) → (4S)-1-methyl-2-oxoimidazolidine-4-carboxylic acid t-butyl ester (83056-79-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: 89.8 percent / K2CO3 / acetone / 72 h / Ambient temperature 2: 98.2 percent / H2 / Pd / methanol / 3 h / 760 Torr / Ambient temperature View Scheme

(4S)-1-methyl-2-oxoimidazolidine-4-carboxylic acid t-butyl ester (83056-79-5) + 2-Bromo-4-phenyl-butyryl bromide → (S)-3-(2-Bromo-4-phenyl-butyryl)-1-methyl-2-oxo-imidazolidine-4-carboxylic acid tert-butyl ester (195828-78-5)

Conditions	Yield
With potassium tert-butylate In tetrahydrofuran 1.) -50 deg C, 20 min, 2.) -30 deg C, 30 min;	84%

2-bromobutanoyl chloride (22118-12-3) + potassium tert-butylate (865-47-4) + (4S)-1-methyl-2-oxoimidazolidine-4-carboxylic acid t-butyl ester (83056-79-5) → tert.-butyl (4S)-1-methyl-3-(2-bromo-n-butyryl)-2-oxo-imidazolidine-4-carboxylate (195828-76-3)

Conditions	Yield
In tetrahydrofuran	80.3%

2-bromo-4-methylvaleryl bromide (74204-03-8) + (4S)-1-methyl-2-oxoimidazolidine-4-carboxylic acid t-butyl ester (83056-79-5) → (S)-3-(2-Bromo-4-methyl-pentanoyl)-1-methyl-2-oxo-imidazolidine-4-carboxylic acid tert-butyl ester (195828-77-4)

Conditions	Yield
With potassium tert-butylate In tetrahydrofuran 1.) -50 deg C, 20 min, 2.) -30 deg C, 30 min;	78%

(R)-2-(methanesulfonyloxy)propionic acid (136622-16-7) + (4S)-1-methyl-2-oxoimidazolidine-4-carboxylic acid t-butyl ester (83056-79-5) → tert-Butyl (4S)-1-Methyl-3-<(2R)-2-(4-methanesulfonyloxy)propionyl>-2-oxoimidazolidine-4-carboxylate (130368-72-8)

Conditions	Yield
	75.8%

(2R)-2-(4-toluenesulfonyloxy)propionyl chloride (88081-65-6) + (4S)-1-methyl-2-oxoimidazolidine-4-carboxylic acid t-butyl ester (83056-79-5) → tert-Butyl (4S)-1-Methyl-3-<(2R)-2-(4-toluenesulfonyloxy)propionyl>-2-oxoimidazolidine-4-carboxylate (130368-70-6)

Conditions	Yield
With potassium tert-butylate In tetrahydrofuran at -50℃; for 0.333333h;	74%
With potassium tert-butylate In tetrahydrofuran a) -50 deg C, 20 min, b) -30 deg C, 20 min; Yield given;

toluene-ethyl acetate + potassium tert-butylate (865-47-4) + (4S)-1-methyl-2-oxoimidazolidine-4-carboxylic acid t-butyl ester (83056-79-5) + (2S)-3-(benzoylthio)-2-methylpropionic acid (72679-02-8) + (2S)-3-benzoylthio-2-methylpropionyl chloride (72679-01-7) → tert.-butyl (4S)-1-methyl-3-[(2S)-3-benzoylthio-2-methylpropionyl]-2-oxo-imidazolidine-4-carboxylate

Conditions	Yield
With thionyl chloride In tetrahydrofuran; ethyl acetate	73.9%

potassium tert-butylate (865-47-4) + (4S)-1-methyl-2-oxoimidazolidine-4-carboxylic acid t-butyl ester (83056-79-5) + 2-Bromopropionyl chloride (7148-74-5) → tert.-butyl (4S)-1-methyl-3-(2-bromopropionyl)-2-oxo-imidazolidine-4-carboxylate (195828-75-2)

Conditions	Yield
In tetrahydrofuran	72.7%

(2S)-2-(4-toluenesulfonyloxy)propionyl chloride (83261-13-6) + (4S)-1-methyl-2-oxoimidazolidine-4-carboxylic acid t-butyl ester (83056-79-5) → tert-butyl (4S)-1-methyl-3-<(2S)-2-(4-toluenesulfonyloxy)propionyl>-2-oxoimidazolidine-4-carboxylate (143996-80-9)

Conditions	Yield
With potassium tert-butylate In tetrahydrofuran at -50℃; for 0.333333h;	70%

2-bromobutanoyl chloride (22118-12-3) + (4S)-1-methyl-2-oxoimidazolidine-4-carboxylic acid t-butyl ester (83056-79-5) → tert.-butyl (4S)-1-methyl-3-(2-bromo-n-butyryl)-2-oxo-imidazolidine-4-carboxylate (195828-76-3)

Conditions	Yield
With potassium tert-butylate 1) THF, -50 deg C, 20 min, 2) -30 deg C, 1 h; Yield given. Multistep reaction;

(2R)-2-(methanesulfonyloxy)propionyl chloride (85277-55-0) + (4S)-1-methyl-2-oxoimidazolidine-4-carboxylic acid t-butyl ester (83056-79-5) → tert-Butyl (4S)-1-Methyl-3-<(2R)-2-(4-methanesulfonyloxy)propionyl>-2-oxoimidazolidine-4-carboxylate (130368-72-8)

Conditions	Yield
With potassium tert-butylate In tetrahydrofuran a) -50 deg C, 20 min, b) -30 deg C, 20 min; Yield given;

(4S)-1-methyl-2-oxoimidazolidine-4-carboxylic acid t-butyl ester (83056-79-5) + (S)-2-[(S)-1-(2,5-Dioxo-pyrrolidin-1-yloxycarbonyl)-ethylamino]-4-phenyl-butyric acid benzyl ester → tert-butyl (4S)-1-methyl-3-{(2S)-2-[N-((1S)-1-benzyloxycarbonyl-3-phenylpropyl)amino]propionyl}-2-oxo-imidazolidine-4-carboxylate (89460-20-8)

Conditions	Yield
With potassium tert-butylate 1) THF, -50 deg C, 20 min, 2) THF, -30 deg C, 20 min; Multistep reaction;

(4S)-1-methyl-2-oxoimidazolidine-4-carboxylic acid t-butyl ester (83056-79-5) + N-succinimidyl (2S)-2-{N-[(1S)-1-(ethoxycarbonyl)-3-phenylpropyl]amino}propionate (89371-34-6) → tert-butyl (4S)-1-methyl-3-{(2S)-2-[N-((1S)-1-ethoxycarbonyl-3-phenylpropyl)amino]propionyl}-2-oxo-imidazolidine-4-carboxylate (89371-38-0)

Conditions	Yield
With potassium tert-butylate 1) THF, -50 deg C, 20 min, 2) THF, -30 deg C, 20 min; Yield given. Multistep reaction;

(4S)-1-methyl-2-oxoimidazolidine-4-carboxylic acid t-butyl ester (83056-79-5) + (S)-2-[(R)-1-(2,5-Dioxo-pyrrolidin-1-yloxycarbonyl)-ethylamino]-4-phenyl-butyric acid ethyl ester (89371-34-6) → (S)-3-[(R)-2-((S)-1-Ethoxycarbonyl-3-phenyl-propylamino)-propionyl]-1-methyl-2-oxo-imidazolidine-4-carboxylic acid tert-butyl ester (117605-22-8)

Conditions	Yield
With potassium tert-butylate 1) THF, -50 deg C, 20 min, 2) THF, -30 deg C, 20 min; Yield given. Multistep reaction;

(4S)-1-methyl-2-oxoimidazolidine-4-carboxylic acid t-butyl ester (83056-79-5) + (N-benzyloxycarbonyl)-L-alanine N-hydroxysuccinimide ester (3401-36-3) → tert-butyl (4S)-3-<(2S)-2-propionyl>-1-methyl-2-oxoimidazolidine-4-carboxylate (117560-20-0)

Conditions	Yield
With potassium tert-butylate 1) THF, -50 deg C, 10 min, 2) THF, -30 to -20 deg C, 30 min; Yield given. Multistep reaction;

(4S)-1-methyl-2-oxoimidazolidine-4-carboxylic acid t-butyl ester (83056-79-5) + 2-Bromopropionyl chloride (7148-74-5) → tert.-butyl (4S)-1-methyl-3-(2-bromopropionyl)-2-oxo-imidazolidine-4-carboxylate (195828-75-2)

Conditions	Yield
With potassium tert-butylate 1) THF, -50 deg C, 20 min, 2) -30 deg C, 1 h; Yield given. Multistep reaction;

(4S)-1-methyl-2-oxoimidazolidine-4-carboxylic acid t-butyl ester (83056-79-5) + 2,4-dibromobutanoyl chloride (82820-87-9) → (S)-3-(2,4-Dibromo-butyryl)-1-methyl-2-oxo-imidazolidine-4-carboxylic acid tert-butyl ester

Conditions	Yield
With potassium tert-butylate 1.) THF, -60 deg C, 20 min, 2.) THF, -30 deg C, 1 h; Yield given. Multistep reaction;

(4S)-1-methyl-2-oxoimidazolidine-4-carboxylic acid t-butyl ester (83056-79-5) → tert-Butyl (4S)-3-<(2R)-2-(N-benzylamino)-4-methylvaleryl>-1-methyl-2-oxoimidazolidine-4-carboxylate

Conditions	Yield
Multi-step reaction with 2 steps 1: 78 percent / t-BuOK / tetrahydrofuran / 1.) -50 deg C, 20 min, 2.) -30 deg C, 30 min 2: K2CO3 / hexamethylphosphoric acid triamide / 14 h / 25 °C View Scheme

(4S)-1-methyl-2-oxoimidazolidine-4-carboxylic acid t-butyl ester (83056-79-5) → tert-Butyl (4S)-3-<(2S)-2-(N-benzylamino)-4-methylvaleryl>-1-methyl-2-oxoimidazolidine-4-carboxylate

Conditions	Yield
Multi-step reaction with 2 steps 1: 78 percent / t-BuOK / tetrahydrofuran / 1.) -50 deg C, 20 min, 2.) -30 deg C, 30 min 2: K2CO3 / hexamethylphosphoric acid triamide / 14 h / 25 °C View Scheme

(4S)-1-methyl-2-oxoimidazolidine-4-carboxylic acid t-butyl ester (83056-79-5) → tert-Butyl (4S)-3-<(2S)-2-(N-benzylamino)-4-phenylbutyryl>-1-methyl-2-oxoimidazolidine-4-carboxylate

Conditions	Yield
Multi-step reaction with 2 steps 1: 84 percent / t-BuOK / tetrahydrofuran / 1.) -50 deg C, 20 min, 2.) -30 deg C, 30 min 2: K2CO3 / hexamethylphosphoric acid triamide / 14 h / 25 °C View Scheme

(4S)-1-methyl-2-oxoimidazolidine-4-carboxylic acid t-butyl ester (83056-79-5) → tert-Butyl (4S)-3-<(2R)-2-(N-benzylamino)-4-phenylbutyryl>-1-methyl-2-oxoimidazolidine-4-carboxylate

Conditions	Yield
Multi-step reaction with 2 steps 1: 84 percent / t-BuOK / tetrahydrofuran / 1.) -50 deg C, 20 min, 2.) -30 deg C, 30 min 2: K2CO3 / hexamethylphosphoric acid triamide / 14 h / 25 °C View Scheme

(4S)-1-methyl-2-oxoimidazolidine-4-carboxylic acid t-butyl ester (83056-79-5) → Imidapril hydrochloride (89396-94-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: 1) tBuOK / 1) THF, -50 deg C, 20 min, 2) THF, -30 deg C, 20 min 2: ethyl acetate; diisopropyl ether / 3 h / Ambient temperature 3: 1) K2CO3, 2) 15percent HCl/dioxane / 1) H2O, 2) rt, overnight View Scheme
Multi-step reaction with 4 steps 1: 1) KOtBu / 1) THF, -50 deg C, 20 min, 2) -30 deg C, 1 h 2: K2CO3 / hexamethylphosphoric acid triamide / 48 h / Ambient temperature 3: ethyl acetate; diisopropyl ether / 3 h / Ambient temperature 4: 1) K2CO3, 2) 15percent HCl/dioxane / 1) H2O, 2) rt, overnight View Scheme

(4S)-1-methyl-2-oxoimidazolidine-4-carboxylic acid t-butyl ester (83056-79-5) → tert-Butyl (4S)-3-<(2S)-2-amino>propionyl>-1-methyl-2-oxoimidazolidine-4-carboxylate Hydrogenmaleate (117605-23-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1) tBuOK / 1) THF, -50 deg C, 20 min, 2) THF, -30 deg C, 20 min 2: ethyl acetate; diisopropyl ether / 3 h / Ambient temperature View Scheme
Multi-step reaction with 3 steps 1: 1) KOtBu / 1) THF, -50 deg C, 20 min, 2) -30 deg C, 1 h 2: K2CO3 / hexamethylphosphoric acid triamide / 48 h / Ambient temperature 3: ethyl acetate; diisopropyl ether / 3 h / Ambient temperature View Scheme

(4S)-1-methyl-2-oxoimidazolidine-4-carboxylic acid t-butyl ester (83056-79-5) → tert-butyl (4S)-1-methyl-3-{(2S)-2-[N-((1S)-1-ethoxycarbonyl-3-phenylpropyl)amino]propionyl}-2-oxo-imidazolidine-4-carboxylate (89371-38-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1) KOtBu / 1) THF, -50 deg C, 20 min, 2) -30 deg C, 1 h 2: K2CO3 / hexamethylphosphoric acid triamide / 48 h / Ambient temperature View Scheme

(4S)-1-methyl-2-oxoimidazolidine-4-carboxylic acid t-butyl ester (83056-79-5) → tert-butyl (4S)-3-<(2S)-2-propionyl>-1-methyl-2-oxoimidazolidine-4-carboxylate hydrogen maleate (117605-21-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1) tBuOK / 1) THF, -50 deg C, 20 min, 2) THF, -30 deg C, 20 min 2: ethyl acetate; diisopropyl ether / 3 h / Ambient temperature View Scheme

(4S)-1-methyl-2-oxoimidazolidine-4-carboxylic acid t-butyl ester (83056-79-5) → (4S)-1-methyl-3-{(2S)-2-[N-((1S)-1-carboxy-3-phenylpropyl)amino]propionyl}-2-oxo-imidazolidine-4-carboxylic acid (89371-44-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: 1) tBuOK / 1) THF, -50 deg C, 20 min, 2) THF, -30 deg C, 20 min 2: ethyl acetate; diisopropyl ether / 3 h / Ambient temperature 3: H2 / Pd / methanol / 2 h / 760 Torr / Ambient temperature View Scheme

(4S)-1-methyl-2-oxoimidazolidine-4-carboxylic acid t-butyl ester (83056-79-5) → (4S)-3-<(2S)-aminopropionyl>-1-methyl-2-oxoimidazolidine-4-carboxylic acid (117581-62-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1) KOtBu / 1) THF, -50 deg C, 10 min, 2) THF, -30 to -20 deg C, 30 min 2: 72.2 percent / HCl / dioxane / Ambient temperature View Scheme

(4S)-1-methyl-2-oxoimidazolidine-4-carboxylic acid t-butyl ester (83056-79-5) → (4S)-1-methyl-3-{(2S)-2-[N-((1S)-1-carboxy-n-nonyl)amino]-n-butyryl}-2-oxo-imidazolidine-4-carboxylic acid (89371-74-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: 1) KOtBu / 1) THF, -50 deg C, 20 min, 2) -30 deg C, 1 h 2: 2.9 percent / K2CO3 / hexamethylphosphoric acid triamide / 48 h / Ambient temperature 3: H2 / Pd / methanol / 2 h / 760 Torr / Ambient temperature View Scheme

(4S)-1-methyl-2-oxoimidazolidine-4-carboxylic acid t-butyl ester (83056-79-5) → tert.-butyl (4S)-1-methyl-3-{(2S)-2-[N-((1S)-1-benzyloxycarbonyl-n-nonyl)amino]-n-butyryl}-2-oxo-imidazolidine-4-carboxylate (89371-73-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1) KOtBu / 1) THF, -50 deg C, 20 min, 2) -30 deg C, 1 h 2: 2.9 percent / K2CO3 / hexamethylphosphoric acid triamide / 48 h / Ambient temperature View Scheme

Upstream product

• 157163-04-7 tert-Butyl (4S)-3-<(2R)-2-(N-benzylamino)propionyl>-1-methyl-2-oxoimidazolidine-4-carboxylate 
• 100-51-6 benzyl alcohol 
• 77999-24-7 (S)‐2‐oxoimidazolidine‐1,5‐dicarboxylate-5‐tert‐butyl ester-1‐benzyl ester 
• 83056-78-4 tert-butyl (4S)-3-(benzyloxycarbonyl)-1-methyl-2-oxoimidazolidine-4-carboxylate 

Downstream Products

• 130368-70-6 tert-Butyl (4S)-1-Methyl-3-<(2R)-2-(4-toluenesulfonyloxy)propionyl>-2-oxoimidazolidine-4-carboxylate 
• 143996-80-9 tert-butyl (4S)-1-methyl-3-<(2S)-2-(4-toluenesulfonyloxy)propionyl>-2-oxoimidazolidine-4-carboxylate 
• 117560-20-0 tert-butyl (4S)-3-<(2S)-2-propionyl>-1-methyl-2-oxoimidazolidine-4-carboxylate 
• 195828-78-5 (S)-3-(2-Bromo-4-phenyl-butyryl)-1-methyl-2-oxo-imidazolidine-4-carboxylic acid tert-butyl ester 
• 89396-94-1 Imidapril hydrochloride 
• 89371-38-0 tert-butyl (4S)-1-methyl-3-{(2S)-2-[N-((1S)-1-ethoxycarbonyl-3-phenylpropyl)amino]propionyl}-2-oxo-imidazolidine-4-carboxylate 
• 117605-21-7 tert-butyl (4S)-3-<(2S)-2-propionyl>-1-methyl-2-oxoimidazolidine-4-carboxylate hydrogen maleate 
• 89371-44-8 (4S)-1-methyl-3-{(2S)-2-[N-((1S)-1-carboxy-3-phenylpropyl)amino]propionyl}-2-oxo-imidazolidine-4-carboxylic acid 
• 89371-73-3 tert.-butyl (4S)-1-methyl-3-{(2S)-2-[N-((1S)-1-benzyloxycarbonyl-n-nonyl)amino]-n-butyryl}-2-oxo-imidazolidine-4-carboxylate 
• 89371-81-3 tert.-butyl (4S)-1-methyl-3-{(2S)-2-[N-((1S)-1-benzyloxycarbonyl-n-nonyl)amino]propionyl}-2-oxo-imidazolidine-4-carboxylate 
• 89397-13-7 tert.-butyl (4S)-1-methyl-3-{(2R)-2-[N-((1S)-1-benzyloxycarbonyl-n-nonyl)amino]propionyl}-2-oxo-imidazolidine-4-carboxylate 
• 928142-34-1 t-butyl-(4S)-3-[(2S)-2-[[(1S)-1-(ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1-methyl-2-oxo-4-imidazolidinecarboxylate hydrochloride 

Relevant academic research and scientific papers

Stereospecific Amination by Dynamic Kinetic Resolution Utilizing 2-Oxoimidazolidine-4-carboxylate as a Novel Chiral Auxiliary

A novel type of stereospecific amination by dynamic kinetic resolution using (4S)-2-oxoimidazolidine-4-carboxylate (1) as a chiral auxiliary was developed. A reaction of a diastereomeric mixture of (4S)-3--2-oxoimidazolidine-4-carboxylates 4 with an amine in the presence of a base in HMPA predominantly afforded (4S)-3--2-oxoimidazolidine-4-carboxylates (S,R)-7 in good yields.The reaction proceeded by stereospecific SN2 type amination incorporated with rapid interconversion between the substrates (S,S)-4 and (S,R)-4.Mechanistic study suggested that the unique stereoselectivity was induced through the interaction between an amine and the ester group of (S,S)-4 in the transition state.The chiral auxiliary was easily removed with alkoxide anion to afford the α-amino acid synthon in good yields.

Studies on Angiotensin Converting Enzyme Inhibitors. 4. Synthesis and Angiotensin Converting Enzyme Inhibitory Activities of 3-Acyl-1-alkyl-2-oxoimidazolidine-4-carboxylic Acid Derivatives

(4S)-1-Alkyl-3-acyl>-2-oxoimidazolidine-4-carboxylic acid derivatives (3) were prepared by two methods.Their angiotensin converting enzyme (ACE) inhibitory activities and antihypertensive effects were evaluated, and the structure-activity relationships were discussed.The dicarboxylic acids 3a-n possessing S,S,S configuration showed potent in vitro ACE inhibitory activities with IC 50 values of 1.1x10-8-1.5x10-9 M.The most potent compound in this series, monoester 3p, had an ID 50 value of 0.24 mg/kg, po for inhibition of angiotensin I induced pressor response in normotensive rats and produced a dose-dependent decrease in systolic blood pressure of spontaneously hypertensive rats (SHRs) at doses of 1-10 mg/kg, po.

ANTIHYPERTENSIVE 2-OXO-IMIDAZOLIDINE DERIVATIVES

Novel 2-oxo-imidazolidine derivative of the formula: STR1 wherein R 1 is lower alkyl or phenyl-lower alkyl, R 2 is lower alkyl, R. sup.3 is alkyl of one to 12 carbon atoms or phenyl-lower alkyl and R 4 is hydrogen or lower alkyl, and a pharmaceutically acceptable salts thereof are disclsoed. Said compounds (I) and salts thereof are useful as hypotensive agents.

2-OXOIMIDAZOLIDINE DERIVATIVES

A 2-oxoimidazolidine derivative of the formula: STR1 wherein R 1 is lower alkyl or phenyl-lower alkyl and R 2 is lower alkyl or phenyl, and a process for preparation thereof are disclosed. Said 2-oxoimidazolidine derivative (I) or a pharmaceutically acceptable salt thereof is useful as a hypotensive agent.