99464-83-2

Usage

Uses

Used in Pharmaceutical Industry:
1-Chloroethyl cyclohexyl carbonate is used as a genotoxic impurity in the synthesis of Candesartan Cilexetil, which is an angiotensin II receptor antagonist. This application is crucial for the development of effective treatments for hypertension and heart failure.

InChI:InChI=1/C9H15ClO3/c1-7(10)12-9(11)13-8-5-3-2-4-6-8/h7-8H,2-6H2,1H3

Synthetic route

carbonochloridic acid 1-chloro-ethyl ester (50893-53-3) + cyclohexanol (108-93-0) → 1-chloroethyl cyclohexyl carbonate (99464-83-2)

Conditions	Yield
With pyridine In dichloromethane at 0 - 20℃;	94%
With pyridine In dichloromethane at 0 - 20℃; Inert atmosphere;	94%
With pyridine In dichloromethane at -78℃;	80%

paracetaldehyde (123-63-7) + cyclohexanol (108-93-0) + trichloromethyl chloroformate (503-38-8) → 1-chloroethyl cyclohexyl carbonate (99464-83-2)

Conditions	Yield
Stage #1: paracetaldehyde; trichloromethyl chloroformate With pyridine at -10 - 0℃; for 8h; Stage #2: cyclohexanol With pyridine at 20℃; for 3h; Reagent/catalyst; Temperature;	93%

acetaldehyde (75-07-0) + cyclohexyl chloroformate (13248-54-9) → 1-chloroethyl cyclohexyl carbonate (99464-83-2)

Conditions	Yield
With zinc(II) chloride

2-Ethoxy-1-[[2'-(N-triphenylmethyltetrazol-5-yl)-biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (139481-72-4) + 1-chloroethyl cyclohexyl carbonate (99464-83-2) → cilexetil trityl candesartan (170791-09-0)

Conditions	Yield
With N-benzyl-N,N,N-triethylammonium chloride; potassium carbonate In tetrahydrofuran at 20 - 65℃; for 6h; Product distribution / selectivity;	100%
With potassium carbonate In ISOPROPYLAMIDE at 60℃; for 4h;	98%
With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 4h; Temperature; Flow reactor; Alkaline conditions; Large scale;	96%

1-({4-[2-(1-benzyl-1H-1,2,3,4-tetrazol-5-yl)phenyl]phenyl}methyl)-2-ethoxy-1H-1,3-benzodiazole-7-carboxylic acid + 1-chloroethyl cyclohexyl carbonate (99464-83-2) → 1-{[(cyclohexyloxy)carbonyl]oxy}ethyl 1-({4-[2-(1-benzyl-1H-1,2,3,4-tetrazol-5-yl)phenyl]phenyl}methyl)-2-ethoxy-1H-1,3-benzodiazole-7-carboxylate (1307853-85-5)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 65℃; for 4h;	100%
With potassium carbonate In N,N-dimethyl-formamide at 65℃; for 4h; Time; Temperature;	100%
With potassium carbonate In N,N-dimethyl-formamide at 60 - 65℃; for 2 - 3h;

1-((2'-cyano-[1,1'-biphenyl]-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylic acid (632322-61-3) + 1-chloroethyl cyclohexyl carbonate (99464-83-2) → 2-ethoxy-1-[(2'-cyanobiphenyl-4-yl)methyl]-1H-benzimidazole-7-carboxylicacid-1-[[(cyclohexyloxy)carbonyl]oxy]ethyl ester (632322-62-4)

Conditions	Yield
Reflux;	97.43%
With potassium carbonate In N,N-dimethyl acetamide at 60℃; for 3h; Product distribution / selectivity;	64%

(R)-3-((tert-butoxycarbonyl)amino)-4-(5'-chloro-2'-fluoro-[1,1-biphenyl]-4-yl)butanoic acid (1621527-49-8) + 1-chloroethyl cyclohexyl carbonate (99464-83-2) → (1S,3R)-1-(((cyclohexyloxy)carbonyl)oxy)ethyl 3-((tert-butoxycarbonyl)amino)-4-(5'-chloro-2'-fluoro-[1,1'-biphenyl]-4-yl)butanoate

Conditions	Yield
With caesium carbonate In N,N-dimethyl-formamide at 0 - 23℃; for 22.5h; Cooling with ice;	97%

4-(1-hydroxy-1-methylethyl)-2-propyl-1-(4-(2-(1-(triphenylmethyl)tetrazol-5-yl)phenyl)phenyl)methylimidazole-5-carboxylic acid (761404-85-7) + 1-chloroethyl cyclohexyl carbonate (99464-83-2) → 1-{[(cyclohexyloxy)carbonyl]oxy}ethyl 4-(2-hydroxypropan-2-yl)-2-propyl-1-({2'-[1-(triphenylmethyl)-1H-1,2,3,4-tetrazol-5-yl]-[1,1'-biphenyl]-4-yl}methyl)-1H-imidazole-5-carboxylate (1337980-10-5)

Conditions	Yield
With potassium carbonate; potassium iodide In N,N-dimethyl acetamide at 70℃; for 2h;	95%

C31H26N6O3*C12H23N + 1-chloroethyl cyclohexyl carbonate (99464-83-2) → 1-{[(cyclohexyloxy)carbonyl]oxy}ethyl 1-({4-[2-(1-benzyl-1H-1,2,3,4-tetrazol-5-yl)phenyl]phenyl}methyl)-2-ethoxy-1H-1,3-benzodiazole-7-carboxylate (1307853-85-5)

Conditions	Yield
With potassium carbonate	94%

C32H28N6O4 (1307853-76-4) + 1-chloroethyl cyclohexyl carbonate (99464-83-2) → C41H42N6O7 (1307853-79-7)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 65℃; for 4h;	93%

1-chloroethyl cyclohexyl carbonate (99464-83-2) + levofloxacin (100986-85-4) → levofloxacin cilexetil ester

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 2h; Inert atmosphere;	89.3%

(4R,5S,6S)-3-{[1-(4,5-dihydro-1,3-thiazol-2-yl)azetidin-3-yl]sulfanyl}-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (161715-21-5) + 1-chloroethyl cyclohexyl carbonate (99464-83-2) → 3-[1-(4,5-dihydro-thiazol-2-yl)-azetidin-3-ylsulfanyl]-6-(1-hydroxy-ethyl)-4-methyl-7-oxo-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 1-cyclohexyloxycarbonyloxy-ethyl ester

Conditions	Yield
With N-benzyl-N,N,N-triethylammonium chloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 45℃; for 4h;	82%

1-(4-bromobenzyl)-2-ethoxy-benzoimidazole-7-carboxylic acid (854538-90-2) + 1-chloroethyl cyclohexyl carbonate (99464-83-2) → 1-[[(cyclohexyloxy)carbonyl]oxy]ethyl 1-(4-bromobenzyl)-2-ethoxy-1H-benzimidazole-7-carboxylate

Conditions	Yield
With potassium carbonate; potassium iodide In 1,2-dimethoxyethane at 60 - 70℃; for 10h;	79%

1-chloroethyl cyclohexyl carbonate (99464-83-2) + cefotaxime sodium salt (60846-23-3) → 1-(cyclohexyloxycarbonyloxy)ethyl 7β-<2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido>-3-acetoxymethyl-3-cephem-4-carboxylate

Conditions	Yield
With tetra(n-butyl)ammonium hydrogensulfate In N,N-dimethyl-formamide for 24h;	78%

1-chloroethyl cyclohexyl carbonate (99464-83-2) + ammonium thiocyanate → cyclohexyl 1-thiocyanoethylcarbonate (117972-03-9) + cyclohexyl 1-isothiocyanoethylcarbonate (117972-11-9)

Conditions	Yield
With tetrabutyl phosphonium bromide In acetone for 14h; Heating;	A 75% B 25%

2-bromo-3-(ethoxy(1-(2'-(1-trityl-1H-tetrazol-5-yl)bi-phenyl-4-yl)methylamino)methyleneamino)benzoic acid (1239349-14-4) + 1-chloroethyl cyclohexyl carbonate (99464-83-2) → 1-(cyclohexyloxycarbonyloxy)ethyl 2-bromo-3-(ethoxy(1-(2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl)methylamino)methyleneamino)benzoate (1239349-15-5)

Conditions	Yield
Stage #1: 2-bromo-3-(ethoxy(1-(2'-(1-trityl-1H-tetrazol-5-yl)bi-phenyl-4-yl)methylamino)methyleneamino)benzoic acid With sodium hydroxide In N,N-dimethyl-formamide at 20℃; Stage #2: 1-chloroethyl cyclohexyl carbonate In N,N-dimethyl-formamide at 70℃; for 8h;	75%

4-(1-hydroxy-1-methylethyl)-2-propyl imidazole-5-carboxylic acid (144690-04-0) + 1-chloroethyl cyclohexyl carbonate (99464-83-2) → 1-ethylcyclohexylcarbonyl-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate

Conditions	Yield
Stage #1: 4-(1-hydroxy-1-methylethyl)-2-propyl imidazole-5-carboxylic acid With N-ethyl-N,N-diisopropylamine In N,N-dimethyl acetamide at 20℃; for 0.25h; Stage #2: 1-chloroethyl cyclohexyl carbonate In N,N-dimethyl acetamide at 60℃;	71%

methyl 2-bromo-3-(ethoxy(1-(2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl)methylamino)methyleneamino)benzoate (1239349-13-3) + 1-chloroethyl cyclohexyl carbonate (99464-83-2) → 1-(cyclohexyloxycarbonyloxy)ethyl 2-bromo-3-(ethoxy(1-(2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl)methylamino)methyleneamino)benzoate (1239349-15-5)

Conditions	Yield
Stage #1: methyl 2-bromo-3-(ethoxy(1-(2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl)methylamino)methyleneamino)benzoate With sodium hydroxide In N,N-dimethyl-formamide at 20℃; for 5h; Stage #2: 1-chloroethyl cyclohexyl carbonate In N,N-dimethyl-formamide at 70℃; for 8h;	70%

(R)-7-[3-tertbutoxycarbonylamino-4-(2,4,5-tri-fluorophenyl)butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid (1174039-19-0) + 1-chloroethyl cyclohexyl carbonate (99464-83-2) → (R)-7-[3-amino-4-(2,4,5-trifluorophenyl)butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylic acid (1-cyclohexyloxycarbonyloxy) ethyl ester

Conditions	Yield
With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 65℃; for 2h; In a sealed tube;	69.4%

2-[2-methyl-1-[[4-methylsulfonyl-2-(trifluoromethyl)phenyl]methyl]pyrrolo[2,3-b]pyridine-3-yl]acetic acid + 1-chloroethyl cyclohexyl carbonate (99464-83-2) → C28H31F3N2O7S

Conditions	Yield
With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 50 - 60℃; for 6h;	69.1%

1-chloroethyl cyclohexyl carbonate (99464-83-2) → cyclohexyl (1-iodoethyl)carbonate (95789-69-8, 102672-57-1)

Conditions	Yield
With sodium iodide In acetonitrile at 50℃; for 5.5h;	69%
With sodium iodide In acetonitrile at 50℃; for 5.5h;	69%
With sodium iodide In acetonitrile at 60℃; for 1.5h;	40%

Cbz-D-Glu(D-Trp-OH)-O-Et (1382326-14-8) + 1-chloroethyl cyclohexyl carbonate (99464-83-2) → Cbz-D-Glu(D-Trp-O-CH(CH3)-O-CO-O-cyclohexyl)-O-Et (1401719-90-1)

Conditions	Yield
With potassium carbonate; sodium iodide In N,N-dimethyl-formamide at 20 - 40℃;	66%

1-chloroethyl cyclohexyl carbonate (99464-83-2) → 1-iodocyclohexane (626-62-0)

Conditions	Yield
With sodium iodide 1.) acetone, 56 deg C, 10 h, 2.) toluene, 100 deg C, 35 h; var.: LiI, KI or MgI2;	65%

2-ethoxy-1-((2'-(5-oxo-2-trityl-2,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylic acid + 1-chloroethyl cyclohexyl carbonate (99464-83-2) → 1-(((cyclohexyloxy)carbonyl)oxy)ethyl 2-ethoxy-1-((2'-(5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylate

Conditions	Yield
Stage #1: 2-ethoxy-1-((2'-(5-oxo-2-trityl-2,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylic acid; 1-chloroethyl cyclohexyl carbonate With sodium hydrogencarbonate In N,N-dimethyl-formamide at 70℃; Stage #2: With trifluoroacetic acid In dichloromethane at 20℃; for 3h; Cooling with ice;	60%

(S,S)-4-[2-benzyloxycarbonylamino-3-(4-methoxyphenyl)propionyl]-3-(3-benzyloxycarbonylaminopropyl)-2-oxopiperazine-1-acetic acid + (S,S)-[4-[2-benzyloxycarbonylamino-3-(4-methoxyphenyl)propionyl]-3-(3-benzyloxycarbonylaminopropyl)-2-oxopiperazin-1-yl]acetic acid + 1-chloroethyl cyclohexyl carbonate (99464-83-2) → (S,S)-[4-[2-benzyloxycarbonylamino-3-(4-methoxyphenyl)propionyl]-3-(3-benzyloxycarbonylaminopropyl)-2-oxopiperazin-1-yl]acetic acid 1-cyclohexyloxycarbonyloxy ethyl ester (189365-94-4)

Conditions	Yield
With potassium iodide; triethylamine In ethyl acetate; N,N-dimethyl-formamide	59%

(S,S)-4-[2-benzyloxycarbonylamino-3-(4-methoxyphenyl)propionyl]-3-(3-benzyloxycarbonylaminopropyl)-2-oxopiperazine-1-acetic acid + (S,S)-›4-[2-benzyloxycarbonylamino-3-(4-methoxyphenyl)propionyl)-3-(3-benzyloxycarbonylaminopropyl)-2-oxopiperazin-1-yl]acetic acid + 1-chloroethyl cyclohexyl carbonate (99464-83-2) → (S,S)-[4-[2-benzyloxycarbonylamino-3-(4-methoxyphenyl)propionyl]-3-(3-benzyloxycarbonylaminopropyl)-2-oxopiperazin-1-yl]acetic acid 1-cyclohexyloxycarbonyloxy ethyl ester (189365-94-4)

Conditions	Yield
With potassium iodide; triethylamine In N,N-dimethyl-formamide	59%

potassium 2-butyl-5-dimethylaminothiocarbonylmethyl-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidin-4-(3H)-one + 1-chloroethyl cyclohexyl carbonate (99464-83-2) → 1-(5-(4'-((2-butyl-5-(2-(dimethylamino)-2-thioxoethyl)-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl)-[1,1'-biphenyl]-2-yl)-2H-tetrazol-2-yl)ethyl cyclohexyl carbonate

Conditions	Yield
With potassium iodide In N,N-dimethyl-formamide at 20℃;	59%

(3-{2-[(4-Fluorophenyl)sulfonyl]benzyl}-2-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-1-yl)acetic acid (1415043-08-1) + 1-chloroethyl cyclohexyl carbonate (99464-83-2) → 1-{[(Cyclohexyloxy)carbonyl]oxy}ethyl (3-{2-[(4-fluorophenyl)sulfonyl]benzyl}-2-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-1-yl)acetate (1415043-84-3)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 20℃;	58%

1-chloroethyl cyclohexyl carbonate (99464-83-2) + Nα-(tert-butoxycarbony1)- Nτ-methyl-L-histidine (61070-20-0) → Nα-tert-butoxycarbonyl-Nϖ-methyl-L-histidine 1-(cyclohexyloxycarbonyloxy)ethyl ester

Conditions	Yield
Stage #1: Nα-(tert-butoxycarbony1)- Nτ-methyl-L-histidine With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃; Stage #2: 1-chloroethyl cyclohexyl carbonate In N,N-dimethyl-formamide at 0 - 20℃;	53%

L-N-Boc-Ala (15761-38-3) + 1-chloroethyl cyclohexyl carbonate (99464-83-2) → C17H29NO7

Conditions	Yield
Stage #1: L-N-Boc-Ala With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃; for 0.5h; Inert atmosphere; Stage #2: 1-chloroethyl cyclohexyl carbonate In N,N-dimethyl-formamide at 0 - 20℃;	53%

Upstream product

• 75-07-0 acetaldehyde 
• 13248-54-9 cyclohexyl chloroformate 
• 50893-53-3 carbonochloridic acid 1-chloro-ethyl ester 
• 108-93-0 cyclohexanol 
• 123-63-7 paracetaldehyde 
• 503-38-8 trichloromethyl chloroformate 

Downstream Products

• 95789-69-8 cyclohexyl (1-iodoethyl)carbonate 
• 117972-11-9 cyclohexyl 1-isothiocyanoethylcarbonate 
• 170791-09-0 cilexetil trityl candesartan 
• 1307853-85-5 1-{[(cyclohexyloxy)carbonyl]oxy}ethyl 1-({4-[2-(1-benzyl-1H-1,2,3,4-tetrazol-5-yl)phenyl]phenyl}methyl)-2-ethoxy-1H-1,3-benzodiazole-7-carboxylate 
• 189365-94-4 (S,S)-[4-[2-benzyloxycarbonylamino-3-(4-methoxyphenyl)propionyl]-3-(3-benzyloxycarbonylaminopropyl)-2-oxopiperazin-1-yl]acetic acid 1-cyclohexyloxycarbonyloxy ethyl ester 
• 1025828-93-6 1-(Cyclohexyloxycarbonyloxy)ethyl (5R,6S)-6-[(R)-1-hydroxyethyl]-2-(3-tetrahydrofuryl)methylpenem-3-carboxylate 
• 947331-20-6 C₅₀H₄₉ClN₆O₅ 
• 632322-62-4 2-ethoxy-1-[(2'-cyanobiphenyl-4-yl)methyl]-1H-benzimidazole-7-carboxylicacid-1-[[(cyclohexyloxy)carbonyl]oxy]ethyl ester 
• 1070891-23-4 3-(2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionic acid 1-cyclohexyloxycarbonyloxy-ethyl ester 
• 1239349-15-5 1-(cyclohexyloxycarbonyloxy)ethyl 2-bromo-3-(ethoxy(1-(2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl)methylamino)methyleneamino)benzoate 
• 145040-37-5 candesartan cilexetil 
• 1073117-28-8 (+/-)-1-[[(cyclohexyloxy)carbonyl]oxy]ethyl 2-[(N-tert-butoxycarbonyl)-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl]biphenyl-4-yl]methyl]amino]-3-nitrobenzoate 

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