62893-24-7

Basic information

• Product Name: (2R)-2-[(4-Ethyl-2,3-dioxopiperazinyl)carbonylamino]-2-(4-hydroxyphenyl)acetic acid
• Synonyms: (R)-(-)-ALPHA-[[(4-ETHYL-2,3-DIOXO-1-PIPERAZINYL)CARBONYL]AMINO]-4-HYDROXYBENZENEACETIC ACID;(R)-(-)-[[(4-ETHYL-2,3-DIOXO-1-PIPERAZINYL)CARBONYL]AMINO]-4-HYDROXYBENZENEACETIC ACID;D-(-)-A-(4-ETHYL-2,3-DIOXO PIPERZINYL) CARBOCAMIDE-4-HYDROXYPHENYL-ACETIC ACID;D-(-)-2-(2,3-DIOXO-4-ETHYL-1-PIPERAZIN-CARBOXAMIDE)-ALPHA-4-HYDROXY PHENYL ACETIC ACID;D-(-)-2-[(4-ETHYL-2,3-DIOXO-1-PIPERAZINEYL)-CARBONYLAMINO]-2-(4-HYDROXYPHENYL) ACETIC ACID;HO-EPCP;2R-2-((4-ETHYL-2,3-DIOXYPIPERAZYL)FORMAMIDE)-P-HYDROXY PHENYLACETIC ACID;(2R)-2-[(4-ETHYL-2,3-DIOXOPIPERAZINYL)CARBONYLAMINO]-2-(4-HYDROXYPHENYL)ACETIC ACID
• CAS NO: 62893-24-7
• Molecular Formula: C₁₅H₁₇N₃O₆
• Molecular Weight: 335.31
• EINECS: 279-328-3
• Product Categories: Chiral Building Blocks;Heterocyclic Building Blocks;Piperazines
• Mol File: 62893-24-7.mol
• Article Data: 1

Chemical Properties

• Melting Point: 205 °C (dec.)(lit.)
• Boiling Point: 471.96°C (rough estimate)
• Appearance: white crystalline powder
• Density: 1.2546 (rough estimate)
• Refractive Index: 1.5600 (estimate)
• Storage Temp.: Sealed in dry,Room Temperature
• Solubility: DMSO (Slightly), Methanol (Sparingly)
• PKA: 3.40±0.10(Predicted)
• CAS DataBase Reference: (2R)-2-[(4-Ethyl-2,3-dioxopiperazinyl)carbonylamino]-2-(4-hydroxyphenyl)acetic acid(CAS DataBase Reference)
• NIST Chemistry Reference: (2R)-2-[(4-Ethyl-2,3-dioxopiperazinyl)carbonylamino]-2-(4-hydroxyphenyl)acetic acid(62893-24-7)
• EPA Substance Registry System: (2R)-2-[(4-Ethyl-2,3-dioxopiperazinyl)carbonylamino]-2-(4-hydroxyphenyl)acetic acid(62893-24-7)

Safety Data

• Hazard Codes: Xi
• Statements: 36/37/38
• Safety Statements: 26-36-37/39
• WGK Germany: 3
• Hazardous Substances Data: 62893-24-7(Hazardous Substances Data)

Usage

Chemical Properties

white crystalline powder

Uses

(αR)-α-[[(4-Ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino]-4-hydroxy-benzeneacetic Acid is an intermediate used to prepare Cephalosporin derivatives with activities against both Gram-positive and Gram-negative bacteria.

InChI:InChI=1/C15H17N3O6/c1-2-17-7-8-18(13(21)12(17)20)15(24)16-11(14(22)23)9-3-5-10(19)6-4-9/h3-6,11,19H,2,7-8H2,1H3,(H,16,24)(H,22,23)/p-1/t11-/m1/s1

Synthetic route

D-4-hydroxyphenylglycine (22818-40-2) + 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride (59703-00-3) → (R)-<<(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl>amino>(4-hydroxyphenyl)acetic acid (62893-24-7)

Conditions	Yield
With sodium carbonate; zinc dibromide In water at 200℃; for 3h; Temperature; Reagent/catalyst; Autoclave;	83.5%

(R)-<<(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl>amino>(4-hydroxyphenyl)acetic acid (62893-24-7) → D-(-)-2-[(4-ethyl-2,3-dioxo-1-piperazinyl)amido]- 2-(4-hydroxyphenyl)acetic acid chloride (74769-12-3)

Conditions	Yield
With bis(trichloromethyl) carbonate; triethylamine In dichloromethane at 0℃; for 3h;	97.6%
With chloro-trimethyl-silane; trichlorophosphate In N,N-dimethyl acetamide; acetonitrile at -20℃;

C13H20N6O3S2Si*ClH + (R)-<<(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl>amino>(4-hydroxyphenyl)acetic acid (62893-24-7) → cefoperazone (62893-19-0, 68779-10-2)

Conditions	Yield
With benzotriazol-1-yl diethyl phosphate; triethylamine In N,N-dimethyl-formamide at 28℃; for 2h;	76.2%

bis(trimethylsilyl)aminomethaneboronate + (R)-<<(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl>amino>(4-hydroxyphenyl)acetic acid (62893-24-7) → C23H37BN4O7Si

Conditions	Yield
Stage #1: (R)-<<(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl>amino>(4-hydroxyphenyl)acetic acid With triethylamine; isobutyl chloroformate In tetrahydrofuran at 0℃; for 1h; Inert atmosphere; Stage #2: bis(trimethylsilyl)aminomethaneboronate In tetrahydrofuran at 0 - 20℃; Inert atmosphere;	54%

(R)-<<(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl>amino>(4-hydroxyphenyl)acetic acid (62893-24-7) + (6R)-trans-3-chloromethyl-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, diphenylmethyl ester → (6R,7R)-3-Chloromethyl-7-[(R)-2-[(4-ethyl-2,3-dioxo-piperazine-1-carbonyl)-amino]-2-(4-hydroxy-phenyl)-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester (153715-66-3)

Conditions	Yield
With benzotriazol-1-ol; dicyclohexyl-carbodiimide In dichloromethane

(R)-<<(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl>amino>(4-hydroxyphenyl)acetic acid (62893-24-7) → <6R-<6α,7β(R)>>-3-<<4-(carboxy-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-quinolinyl)-1-piperazinyl>methyl>-7-<<<<(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl>amino>(4-hydroxyphenyl)acetyl>amino>-8-oxo-5-thia-1-azabicyclo<4.2.0>oct-2-ene-2-carboxylic ...

Conditions	Yield
Multi-step reaction with 4 steps 1: 1-hydroxybenzotriazole, 1,3-dicyclohexylcarbodiimide / CH2Cl2 2: NaI / butan-2-one / 2 h / Ambient temperature 3: NaHCO3 / dimethylformamide / 3 h 4: anisole / CH2Cl2 / 0.25 h / 0 °C View Scheme

(R)-<<(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl>amino>(4-hydroxyphenyl)acetic acid (62893-24-7) → (6R,7R)-7-[(R)-2-[(4-Ethyl-2,3-dioxo-piperazine-1-carbonyl)-amino]-2-(4-hydroxy-phenyl)-acetylamino]-3-iodomethyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester (153715-68-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1-hydroxybenzotriazole, 1,3-dicyclohexylcarbodiimide / CH2Cl2 2: NaI / butan-2-one / 2 h / Ambient temperature View Scheme

(R)-<<(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl>amino>(4-hydroxyphenyl)acetic acid (62893-24-7) → C53H51FN8O11S (153715-70-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: 1-hydroxybenzotriazole, 1,3-dicyclohexylcarbodiimide / CH2Cl2 2: NaI / butan-2-one / 2 h / Ambient temperature 3: NaHCO3 / dimethylformamide / 3 h View Scheme

(6R-trans)-7-amino-3-chloromethyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid diphenylmethyl ester + (R)-<<(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl>amino>(4-hydroxyphenyl)acetic acid (62893-24-7) → [6R-[6α,7β(R)]]-3-[[4-(3-Carboxy-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-quinolinyl)-1-piperazinyl]methyl]-7-[[[[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino](4-hydroxyphenyl)-acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

C23H34BNO4 + (R)-<<(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl>amino>(4-hydroxyphenyl)acetic acid (62893-24-7) → (+)-pinanediol (1R)-2-[3-(tert-butoxycarbonyl)phenyl]-1-{(αR)-α-[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonylamino]-4-hydroxybenzenacetylamino}ethaneboronate (1421842-15-0)

Conditions	Yield
Stage #1: (R)-<<(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl>amino>(4-hydroxyphenyl)acetic acid With isobutyl chloroformate In tetrahydrofuran at -35 - -10℃; for 0.166667h; Inert atmosphere; Stage #2: With 4-methyl-morpholine In tetrahydrofuran at -10℃; for 1h; Inert atmosphere; Stage #3: C23H34BNO4 In tetrahydrofuran at -10 - 20℃; Inert atmosphere;

(6R,7R)-7-amino-3-[(1H-1-methyltetrazol-5-yl)thio]methylceph-3-em-4-carboxylic acid (24209-38-9) + (R)-<<(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl>amino>(4-hydroxyphenyl)acetic acid (62893-24-7) → cefoperazone (62893-19-0, 68779-10-2)

Conditions

Yield

Stage #1: (6R,7R)-7-amino-3-[(1H-1-methyltetrazol-5-yl)thio]methylceph-3-em-4-carboxylic acid With chloro-trimethyl-silane; 1,1,1,3,3,3-hexamethyl-disilazane In dichloromethane at 45℃; for 4h; Stage #2: (R)-<<(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl>amino>(4-hydroxyphenyl)acetic acid With pyridine; chloroformic acid ethyl ester; triethylamine In dichloromethane; N,N-dimethyl acetamide at -45 - -40℃; for 4h;

Upstream product

• 22818-40-2 D-4-hydroxyphenylglycine 
• 59703-00-3 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride 

Downstream Products

• 62893-19-0 cefoperazone 
• 1421842-15-0 (+)-pinanediol (1R)-2-[3-(tert-butoxycarbonyl)phenyl]-1-{(αR)-α-[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonylamino]-4-hydroxybenzenacetylamino}ethaneboronate 
• 74769-12-3 D-(-)-2-[(4-ethyl-2,3-dioxo-1-piperazinyl)amido]- 2-(4-hydroxyphenyl)acetic acid chloride 
• 153715-70-9 C₅₃H₅₁FN₈O₁₁S 
• 153715-68-5 (6R,7R)-7-[(R)-2-[(4-Ethyl-2,3-dioxo-piperazine-1-carbonyl)-amino]-2-(4-hydroxy-phenyl)-acetylamino]-3-iodomethyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester 
• 153715-66-3 (6R,7R)-3-Chloromethyl-7-[(R)-2-[(4-ethyl-2,3-dioxo-piperazine-1-carbonyl)-amino]-2-(4-hydroxy-phenyl)-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester 

Relevant articles and documents

A D (-)-α - (4-ethyl -2,3-dioxygen piperazin-1-carboxamido) method for the preparation of acetic acid the hydroxybenzotriazole

The invention discloses a method for preparing D(-)-alpha-(4-ethyl-2,3-dioxopiperazine-1-formamido) p-hydoxyphenylacetic acid. 4-ethyl-2,3-dioxopiperazine-1-formate and a salt of D(-)-alpha-p-hydoxyphenylglycine are subjected to a condensation reaction in an aqueous phase to obtain the D(-)-alpha-(4-ethyl-2,3-dioxopiperazine-1-formamido) p-hydoxyphenylacetic acid. The 4-ethyl-2,3-dioxopiperazine-1-formate is used as a raw material, zinc halide is used as a catalyst, and the aqueous phase reaction is adopted, so that the process is compact and environment-friendly, the intermediate EOCP is easy to separate, the use of organic solvents is completely avoided, the working environment is improved, the post treatment cost is saved, the treatment cost of 'three wastes' is greatly reduced, the purity of the obtained HO-EPCP is high, the purity of the one-step crystallized product is more than 96%, re-crystallization is not needed, and the economic and social benefits are significant.