78834-75-0

Basic information

• Product Name: Ethyl 7-chloro-2-oxoheptanoate
• Synonyms: ETHYL 7-CHLORO-2-OXOHEPTANOATE;Ethyl 7-Chloro-2-Otoheptanoate;7-Chloro-2-oxoheptanoic acid ethyl ester;Ethyl 7-chloro-2-oxohepanoate;ECO;ALPHA KETO ESTER (ETHYL 7-CHLORO-2-OXOHEPTANOATE);Heptanoic acid,7-chloro-2-oxo-, ethyl ester;ICK, active, GST tagged human
• CAS NO: 78834-75-0
• Molecular Formula: C₉H₁₅ClO₃
• Molecular Weight: 206.67
• EINECS: 278-992-1
• Product Categories: API
• Mol File: 78834-75-0.mol

Chemical Properties

• Boiling Point: 281.2 °C at 760 mmHg
• Flash Point: 111.3 °C
• Appearance: /
• Density: 1.093 g/cm³
• Vapor Pressure: 0.00361mmHg at 25°C
• Refractive Index: 1.4510 to 1.4560
• Storage Temp.: -70°C
• Solubility: Acetonitrile (Slightly), Chloroform (Slightly), Ethyl Acetate (Slightly)
• CAS DataBase Reference: Ethyl 7-chloro-2-oxoheptanoate(CAS DataBase Reference)
• NIST Chemistry Reference: Ethyl 7-chloro-2-oxoheptanoate(78834-75-0)
• EPA Substance Registry System: Ethyl 7-chloro-2-oxoheptanoate(78834-75-0)

Safety Data

• Hazardous Substances Data: 78834-75-0(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Synthesis:
Ethyl 7-chloro-2-oxoheptanoate is used as a reagent for the synthesis of selective BCL-XL inhibitor A1155463, which is utilized in the treatment of cancer. Its involvement in the synthesis process is crucial for developing this potential cancer therapy.
Used in the Production of Cilastatin:
In the pharmaceutical industry, Ethyl 7-chloro-2-oxoheptanoate is used as a precursor in the preparation of cilastatin. Cilastatin is a drug that inhibits cytochrome P450 enzymes, thereby prolonging the effectiveness of other drugs when administered in combination.
Used in Chemical Reactions:
Ethyl 7-chloro-2-oxoheptanoate also reacts with hydrochloric acid to form ethyl chloride and heptanoic acid. These products can be further utilized in chlorination reactions, contributing to the synthesis of a variety of chemical compounds.

Preparation

Ethyl 7-chloro-2-oxoheptanoate is an organochlorine compound that is obtained by reacting ethyl chloride with magnesium in the presence of benzene and cilastatin as a catalyst.

InChI:InChI=1/C9H15ClO3/c1-2-13-9(12)8(11)6-4-3-5-7-10/h2-7H2,1H3

Synthetic route

1-bromo-5-chloropentane (54512-75-3) + oxalic acid diethyl ester (95-92-1) → ethyl-7-Chloro-2-oxoheptanoate (78834-75-0)

Conditions	Yield
Stage #1: 1-bromo-5-chloropentane; oxalic acid diethyl ester In tetrahydrofuran at -25 - -10℃; for 1h; Inert atmosphere; Stage #2: With hydrogenchloride In tetrahydrofuran; water at 0℃; Reagent/catalyst; Inert atmosphere;	99.1%
Stage #1: 1-bromo-5-chloropentane With magnesium Stage #2: oxalic acid diethyl ester In tetrahydrofuran at -15℃; Stage #3: With hydrogenchloride In tetrahydrofuran Product distribution / selectivity;	90%
Grignard Reaction;

ethyl 7-chloro-α-hydroxyheptylate (1174680-07-9) → ethyl-7-Chloro-2-oxoheptanoate (78834-75-0)

Conditions	Yield
With sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hydrogencarbonate; potassium bromide In dichloromethane; water at -2 - 8℃; for 3h;	97%
With sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hydrogencarbonate; potassium bromide In dichloromethane; water at -1 - 5℃; for 2.5h; Product distribution / selectivity;

C9H16ClO6S(1-)*Na(1+) → ethyl-7-Chloro-2-oxoheptanoate (78834-75-0)

Conditions	Yield
With hydrogenchloride In water; toluene at 50 - 55℃; for 2h; Temperature; Solvent;	86.5%

ethanol (64-17-5) + C7H10ClNO → ethyl-7-Chloro-2-oxoheptanoate (78834-75-0)

Conditions	Yield
With sulfuric acid at 90℃; for 3.5h; Temperature;	78%

5-chloro-n-pentylmagnesium bromide (278605-08-6) + oxalic acid diethyl ester (95-92-1) → ethyl-7-Chloro-2-oxoheptanoate (78834-75-0)

Conditions	Yield
Stage #1: 5-chloro-n-pentylmagnesium bromide; oxalic acid diethyl ester In tetrahydrofuran at -30 - 5℃; Stage #2: With hydrogenchloride In tetrahydrofuran Product distribution / selectivity;	74%

ethyl (E)-7-chloro-2-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoate (1022895-93-7) → ethyl-7-Chloro-2-oxoheptanoate (78834-75-0) + (S)-2,2-dimethylcyclopropanecarboxamide (75885-58-4)

Conditions	Yield
Stage #1: ethyl (E)-7-chloro-2-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoate With toluene-4-sulfonic acid In dichloromethane at 20℃; Stage #2: With sodium hydroxide; water In dichloromethane pH=8 - 9; Product distribution / selectivity;
Stage #1: ethyl (E)-7-chloro-2-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoate With methanesulfonic acid In toluene at 30℃; Stage #2: With sodium hydroxide; water In toluene pH=8 - 9; Product distribution / selectivity;

6-chloro-1-hexanol (2009-83-8) → ethyl-7-Chloro-2-oxoheptanoate (78834-75-0)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: sodium hydrogencarbonate; sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / potassium bromide / dichloromethane; water / 0.83 h / -5 - 10 °C 2.1: sodium hydrogensulfite / water / 2.67 h / 5 °C 2.2: 12 h / 5 - 20 °C 3.1: hydrogenchloride; water / 140 h / 25 °C 4.1: sulfuric acid / Reflux 5.1: sodium hydrogencarbonate; sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / potassium bromide / dichloromethane; water / 2.5 h / -1 - 5 °C View Scheme

6-chlorohexanal (52387-36-7) → ethyl-7-Chloro-2-oxoheptanoate (78834-75-0)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: sodium hydrogensulfite / water / 2.67 h / 5 °C 1.2: 12 h / 5 - 20 °C 2.1: hydrogenchloride; water / 140 h / 25 °C 3.1: sulfuric acid / Reflux 4.1: sodium hydrogencarbonate; sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / potassium bromide / dichloromethane; water / 2.5 h / -1 - 5 °C View Scheme
Multi-step reaction with 4 steps 1.1: water; sodium hydrogensulfite / 1 h / 35 °C 1.2: 0.5 h / 35 - 40 °C 2.1: water; potassium carbonate; dihydrogen peroxide / dimethyl sulfoxide / 5 h / 35 - 40 °C 3.1: sulfuric acid / 9 h / Reflux 4.1: sodium hydrogencarbonate; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; potassium bromide; sodium hypochlorite / water; dichloromethane / 3 h / -2 - 8 °C View Scheme

7-chloro-2-hydroxyheptanoic acid (1174680-06-8) → ethyl-7-Chloro-2-oxoheptanoate (78834-75-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: sulfuric acid / Reflux 2: sodium hydrogencarbonate; sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / potassium bromide / dichloromethane; water / 2.5 h / -1 - 5 °C View Scheme

7-chloro-α-hydroxyheptonitrile (1174680-05-7) → ethyl-7-Chloro-2-oxoheptanoate (78834-75-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: hydrogenchloride; water / 140 h / 25 °C 2: sulfuric acid / Reflux 3: sodium hydrogencarbonate; sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / potassium bromide / dichloromethane; water / 2.5 h / -1 - 5 °C View Scheme
Multi-step reaction with 3 steps 1: water; potassium carbonate; dihydrogen peroxide / dimethyl sulfoxide / 5 h / 35 - 40 °C 2: sulfuric acid / 9 h / Reflux 3: sodium hydrogencarbonate; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; potassium bromide; sodium hypochlorite / water; dichloromethane / 3 h / -2 - 8 °C View Scheme

7-chloro(1-oxoethyl)heptanoic acid ethyl ester → ethyl-7-Chloro-2-oxoheptanoate (78834-75-0)

Conditions	Yield
Stage #1: 7-chloro(1-oxoethyl)heptanoic acid ethyl ester With nitrosylsulfuric acid at 0 - 5℃; for 1h; Stage #2: With formaldehyd In 1,2-dichloro-ethane at 0 - 25℃; for 2h;

ethyl-7-Chloro-2-oxoheptanoate (78834-75-0) + (S)-2,2-dimethylcyclopropanecarboxamide (75885-58-4) → (Z)-7-chloro-2-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid ethyl ester (877758-94-6)

Conditions	Yield
Stage #1: ethyl-7-Chloro-2-oxoheptanoate; (S)-2,2-dimethylcyclopropanecarboxamide With toluene-4-sulfonic acid In toluene for 10h; Reflux; Stage #2: at 30℃; for 1h; Solvent; Temperature; Irradiation;	99.5%

ethyl-7-Chloro-2-oxoheptanoate (78834-75-0) + triphenylborane (960-71-4) → C15H21ClO2

Conditions	Yield
With phosphorous acid trimethyl ester In tetrahydrofuran at 50℃;	60%

aqueous formalin + ethyl-7-Chloro-2-oxoheptanoate (78834-75-0) + 1-bromo-5-chloropentane (54512-75-3) + sodium carbonate (497-19-8) → 7-chloro(1-oxoethyl)heptanoic acid ethyl ester

Conditions	Yield
With nitrosylsulfuric acid; sulfuric acid In water; toluene

ethyl-7-Chloro-2-oxoheptanoate (78834-75-0) + (S)-2,2-dimethylcyclopropanecarboxamide (75885-58-4) → (Z)-7-chloro-2-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid ethyl ester (877758-94-6) + ethyl (E)-7-chloro-2-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoate (1022895-93-7)

ethyl-7-Chloro-2-oxoheptanoate (78834-75-0) + (S)-2,2-dimethylcyclopropanecarboxamide (75885-58-4) → ethyl 7-chloro-2-{[(1S)-2,2-dimethylcyclopropyl]formamido}hept-2-enoate (1022895-92-6)

Conditions	Yield
With toluene-4-sulfonic acid In toluene for 20h; Heating / reflux;

ethyl-7-Chloro-2-oxoheptanoate (78834-75-0) + (S)-2,2-dimethylcyclopropanecarboxamide (75885-58-4) → (Z)-7-chloro-2 ((2s)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid (877674-77-6) + (E)-7-chloro-2[[(1S)-2,2-dimethyl cyclopropane]carboxamide]-2-heptenoic acid

Conditions	Yield
Stage #1: ethyl-7-Chloro-2-oxoheptanoate; (S)-2,2-dimethylcyclopropanecarboxamide; toluene-4-sulfonic acid In toluene for 20h; Reflux; Stage #2: With water; sodium hydroxide In toluene at 5 - 30℃; for 8h;

ethyl-7-Chloro-2-oxoheptanoate (78834-75-0) → cilastatine (82009-34-5)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: toluene-4-sulfonic acid / toluene / 20 h / Reflux 1.2: 8 h / 5 - 30 °C 2.1: sodium hydroxide / methanol / 60 - 65 °C 2.2: pH 7 View Scheme
Multi-step reaction with 3 steps 1.1: toluene-4-sulfonic acid / toluene / 20 h / Reflux 1.2: 8 h / 5 - 30 °C 2.1: hydrogenchloride / toluene; water / 4 h / 25 - 30 °C 3.1: sodium hydroxide / methanol / 60 - 65 °C 3.2: pH 7 View Scheme
Multi-step reaction with 3 steps 1: toluene-4-sulfonic acid / toluene / 10 h / 130 °C 2: sodium hydroxide / cyclohexane; 1,4-dioxane / 12 h / 20 °C 3: 8.5 h / 55 - 60 °C / Inert atmosphere View Scheme

ethyl-7-Chloro-2-oxoheptanoate (78834-75-0) → (Z)-7-chloro-2 ((2s)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid (877674-77-6)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: toluene-4-sulfonic acid / toluene / 20 h / Reflux 1.2: 8 h / 5 - 30 °C 2.1: hydrogenchloride / toluene; water / 4 h / 25 - 30 °C View Scheme
Multi-step reaction with 2 steps 1: toluene-4-sulfonic acid / toluene / 10 h / 130 °C 2: sodium hydroxide / cyclohexane; 1,4-dioxane / 12 h / 20 °C View Scheme

ethyl-7-Chloro-2-oxoheptanoate (78834-75-0) → cilastatin sodium

Conditions	Yield
Multi-step reaction with 3 steps 1.1: toluene-4-sulfonic acid / toluene / 20 h / Reflux 1.2: 8 h / 5 - 30 °C 2.1: sodium hydroxide / methanol / 60 - 65 °C 2.2: pH 7 3.1: triethylamine / butan-1-ol / 25 - 30 °C 3.2: 3 h / 25 - 30 °C View Scheme
Multi-step reaction with 4 steps 1.1: toluene-4-sulfonic acid / toluene / 20 h / Reflux 1.2: 8 h / 5 - 30 °C 2.1: hydrogenchloride / toluene; water / 4 h / 25 - 30 °C 3.1: sodium hydroxide / methanol / 60 - 65 °C 3.2: pH 7 4.1: triethylamine / butan-1-ol / 25 - 30 °C 4.2: 3 h / 25 - 30 °C View Scheme

ethyl-7-Chloro-2-oxoheptanoate (78834-75-0) → α-Brom-δ-chlorvaleriansaeure-ethylester

Conditions	Yield
With bromine In tetrachloromethane at 20℃; for 1h;

ethyl-7-Chloro-2-oxoheptanoate (78834-75-0) → ethyl 2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-chloropropyl)thiazole-4-carboxylate (1235034-74-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: bromine / tetrachloromethane / 1 h / 20 °C 2: ethanol / 6 h / 50 °C / Inert atmosphere View Scheme

ethyl-7-Chloro-2-oxoheptanoate (78834-75-0) → ethyl 2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-iodopropyl)thiazole-4-carboxylate (1235034-75-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: bromine / tetrachloromethane / 1 h / 20 °C 2: ethanol / 6 h / 50 °C / Inert atmosphere 3: sodium iodide / acetonitrile / 5 h / 90 °C / Inert atmosphere View Scheme

ethyl-7-Chloro-2-oxoheptanoate (78834-75-0) → C32H30N4O4S2

Conditions	Yield
Multi-step reaction with 4 steps 1.1: bromine / tetrachloromethane / 1 h / 20 °C 2.1: ethanol / 6 h / 50 °C / Inert atmosphere 3.1: sodium iodide / acetonitrile / 5 h / 90 °C / Inert atmosphere 4.1: sodium hydride / N,N-dimethyl-formamide / 0.08 h / 20 °C 4.2: 1 h View Scheme

ethyl-7-Chloro-2-oxoheptanoate (78834-75-0) → 2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-phenoxypropyl)thiazole-4-carboxylic acid (1235032-77-5)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: bromine / tetrachloromethane / 1 h / 20 °C 2.1: ethanol / 6 h / 50 °C / Inert atmosphere 3.1: sodium iodide / acetonitrile / 5 h / 90 °C / Inert atmosphere 4.1: sodium hydride / N,N-dimethyl-formamide / 0.08 h / 20 °C 4.2: 1 h 5.1: hydrogenchloride / water View Scheme

ethyl-7-Chloro-2-oxoheptanoate (78834-75-0) → 3-bromo-7-chloro-2-oxoheptanoate (1235035-22-9)

Conditions	Yield
With bromine In tetrachloromethane at 20℃; for 1h;

ethyl-7-Chloro-2-oxoheptanoate (78834-75-0) → ethyl 2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(4-chlorobutyl)thiazole-4-carboxylate (1235035-23-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: bromine / tetrachloromethane / 1 h / 20 °C 2: N,N-dimethyl-formamide; ethanol / 6 h / 20 °C / Inert atmosphere View Scheme

ethyl-7-Chloro-2-oxoheptanoate (78834-75-0) → ethyl 2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(4-iodobutyl)thiazole-4-carboxylate (1235035-24-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: bromine / tetrachloromethane / 1 h / 20 °C 2: N,N-dimethyl-formamide; ethanol / 6 h / 20 °C / Inert atmosphere 3: sodium iodide / acetonitrile / 5 h / 90 °C / Inert atmosphere View Scheme

ethyl-7-Chloro-2-oxoheptanoate (78834-75-0) → C38H34N8O4S2

Conditions	Yield
Multi-step reaction with 4 steps 1.1: bromine / tetrachloromethane / 1 h / 20 °C 2.1: N,N-dimethyl-formamide; ethanol / 6 h / 20 °C / Inert atmosphere 3.1: sodium iodide / acetonitrile / 5 h / 90 °C / Inert atmosphere 4.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.5 h / 20 °C 4.2: 2 h / 20 °C View Scheme

ethyl-7-Chloro-2-oxoheptanoate (78834-75-0) → 5-(4-(4-(1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenoxy)butyl)-2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)thiazole-4-carboxylic acid (1235033-32-5)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: bromine / tetrachloromethane / 1 h / 20 °C 2.1: N,N-dimethyl-formamide; ethanol / 6 h / 20 °C / Inert atmosphere 3.1: sodium iodide / acetonitrile / 5 h / 90 °C / Inert atmosphere 4.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.5 h / 20 °C 4.2: 2 h / 20 °C 5.1: sodium hydroxide / methanol; tetrahydrofuran; water / 5 h / 70 °C View Scheme

ethyl-7-Chloro-2-oxoheptanoate (78834-75-0) → Reaxys ID: 30580581

Upstream product

• 54512-75-3 1-bromo-5-chloropentane 
• 95-92-1 oxalic acid diethyl ester 
• 278605-08-6 5-chloro-n-pentylmagnesium bromide 
• 136879-36-2 7-chloro(1-oxoethyl)heptanoic acid ethyl ester 
• 64-17-5 ethanol 
• 1174680-05-7 7-chloro-α-hydroxyheptonitrile 
• 1174680-06-8 7-chloro-2-hydroxyheptanoic acid 
• 52387-36-7 6-chlorohexanal 
• 2009-83-8 6-chloro-1-hexanol 
• 1022895-93-7 ethyl (E)-7-chloro-2-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoate 
• 1174680-07-9 ethyl 7-chloro-α-hydroxyheptylate 

Downstream Products

• 136879-36-2 7-chloro(1-oxoethyl)heptanoic acid ethyl ester 
• 877674-77-6 (Z)-7-chloro-2 ((2s)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid 
• 166037-21-4 7-chloro-2-[[(1S)-2,2-dimethylcyclopropane]carboxamide]-2-heptenoic acid 
• 82009-34-5 cilastatine 
• 166037-21-4 (E)-7-chloro-2[[(1S)-2,2-dimethyl cyclopropane]carboxamide]-2-heptenoic acid 

Relevant articles and documents

Intermediate for preparing n-7 -2 - halogenoisoheptanoic acid ethyl ester as well as synthesis method and application thereof

The invention relates to an intermediate for preparing 7-halogen-2-oxo ethyl oenanthate as well as a synthetic method and an application thereof. The application is preparation of 7-halogen-2-oxo ethyl oenanthate by the intermediate. 7-halogen-2-hydroyxl heptamide is prepared by means of a novel synthetic method. The 7-halogen-2-hydroyxl heptamide has good chemical stability and heat stability, and is easily purified, so that the process flow of preparing the 7-halogen-2-oxo ethyl oenanthate is simplified, the cost is lowered, the production environment is improved, and scaled production is facilitated.

Preparation method for ethyl 7-chloro-2-oxoheptanoate

The invention discloses a preparation method for ethyl 7-chloro-2-oxoheptanoate, belonging to the field of synthesis in pharmaceutical chemistry. The preparation method comprises the following steps:with 6-chloroacetyl chloride as shown in a formula (I) which is described in the specification as a starting material, subjecting 6-chloroacetyl chloride and a first nucleophilic reagent to a nucleophilic substitution reaction in the presence of a condensing agent and P2O5 so as to obtain 6-chloroacetyl cyanide as shown in a formula (II) which is described in the specification; and subjecting 6-chloroacetyl cyanide as shown in the formula (II) to hydrolysis under the action of acid and then to a nucleophilic substitution reaction with a second nucleophilic reagent so as to obtain the target product ethyl 7-chloro-2-oxoheptanoate as shown in a formula (III) which is described in the specification. The method synthesizes the target product only through two steps, is easily controllable in condition, low in cost, simple in aftertreatment, few in side reactions and high in yield, and meets the requirements of industrial production.

Synthesis method of ethyl 7-chloro-2-oxohepanoate

The invention discloses a synthesis method of ethyl 7-chloro-2-oxohepanoate. According to the synthesis method, Mg, 1-bromo-5-chloropentane, tetrahydrofuran, hydrochloric acid, NaHCO3, chlorinated polystyrene resin, imidazole, acetonitrile and diethyl oxalate are used as main raw materials. The synthesis method is characterized by carrying out addition and hydrolysis reaction of diethyl oxalate and 1-bromo-5-chloropentane in the presence of an immobilized ionic catalyst PSIM-MgBr to obtain ethyl 7-chloro-2-oxohepanoate. Compared with the conventional synthesis method, the raw materials are used for directly preparing ethyl 7-chloro-2-oxohepanoate through activation reaction of the catalyst; the yield is greatly improved; the process flows and the production cost are reduced.

Preparation method of 7-chlorin-(1-oxo ethyl) ethyl oenanthate

The invention provides a preparation method of 7-chlorin-(1-oxo ethyl) ethyl oenanthate. 1-bromine-5-chloropentane of a structural formula III and ethyl acetoacetate of a structural formula IV are adopted as starting materials, under the existence of a polar solvent, an acid binding agent and a phase transfer catalyst, normal pressure heating is performed till the polar solvent is boiling, a reaction is performed for 6-8 h, and 7-chlorin-(1-oxo ethyl) ethyl oenanthate of a structural formula V is obtained. The phase transfer catalyst is selected from one or more of tetrabutylammonium bromide, tetrabutyl ammonium chloride, benzyl trimethyl ammonium chloride, benzyl trimethyl ammonium bromide, 18-crown-6, dibenzo-18-crown-6, polyethylene glycol-400, benzyltrimethylammonium chloride-400 and polyethylene glycol-600, and preferentially polyethylene glycol-400. The molar ratio of the phase transfer catalyst to ethyl acetoacetate is 0.2-1.0:1.0, and preferentially 0.2-0.3:1.0. The preparation method is short in reaction time, high in product yield and good in purity.

Purification method of ethyl 7-chloro-2-oxoheptanoate

The invention provides a purification method of ethyl 7-chloro-2-oxoheptanoate, wherein the purification method comprises the steps: firstly, carrying out a reaction of ethyl 7-chloro-2-oxoheptanoate oil crude product and a hydrosulphite solution, and separating to obtain a sulfite solid of ethyl 7-chloro-2-oxoheptanoate; then, dissolving the sulfite solid of ethyl 7-chloro-2-oxoheptanoate in water, adding an acid or alkali at a certain temperature, and decomposing the sulfite of ethyl 7-chloro-2-oxoheptanoate into ethyl 7-chloro-2-oxoheptanoate; and finally, extracting with an organic solvent immiscible with water, to obtain ethyl 7-chloro-2-oxoheptanoate having the purity improved. The method is simple in operation and suitable for industrialized production, and ensures the purity of a subsequent product and final product cilastatin sodium.

INTERMEDIATE OF CILASTATIN AND PREPARATION METHOD THEREOF

Disclosed is a method for preparing 7-halo-2-oxoheptylate, an intermediate of cilastatin. The main steps are as follows: A. Addition reaction, in which 6-halo-hexanal is reacted with a cyanide to obtain 7-halo-α-hydroxyl-heptonitrile; B. Hydrolysis reaction, in which 7-halo-α-hydroxyl-heptonitrile is converted to 7-halo-α-hydroxyl-heptylic acid; C. Esterification reaction, in which 7-halo-α-hydroxyl-heptylic acid is converted to 7-halo-α-hydroxyl-heptylate; and D. Oxidation reaction, in which 7-halo-α-hydroxyl-heptylate is converted to 7-halo-2-oxoheptylate. 7-halo-α-hydroxyl-heptylic acid or ester thereof, which is a new intermediate for synthesizing 7-halo-2-oxoheptylate or cilastatin, and a method for synthesizing cilastatin are also disclosed. The methods of the invention are suitable for commercial production because of their simple process and mild reaction condition.

REACTION APPARATUS, AND REACTION METHOD

The present invention is directed at obtaining a high yield of a target substance and simultaneously securing high productivity. A reaction apparatus 10 has: a main flow channel 12 having an inner diameter of 3 mm, in which a raw material M1 flows; an introduction flow channel 14 in which a raw material M2 that causes a chemical reaction with the raw material M1 flows; and five branch introduction flow channels 16a to 16e which are branched from the introduction flow channel 14 and introduce the raw material M2 to the main flow channel 12, at predetermined introduction points 12o to 12s in the main flow channel 12. Here, in the main flow channel 12, the flow channel lengths of the flow channels 12b to 12d between adjacent introduction points 12p to 12s are not longer than those of the flow channels 12a to 12c between the next previous adjacent introduction points 12o to 12r in a flow direction of the raw material M1. At least one length of the flow channels 12b to 12d between the adjacent introduction points 12p to 12s is shorter than lengths of the flow channels 12a to 12c between previous adjacent introduction points 12o to 12r in the flow direction of the raw material M1.

Preparation method for (Z)-7-chloro-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid

Provided is a novel preparation method of (Z)-7-chloro-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid represented by the following formula (1), a key intermediate of cilastatin used as a supplement to imipenem. The novel preparation method of the invention produces a pure (Z)-7-chloro-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid, a key intermediate of cilastatin, by selective hydrolysis of E isomers.

NOVEL PROCESS FOR THE PREPARATION OF CILASTATIN SODIUM SALT

The present invention relates to a novel process for preparing cilastatin sodium salt used asa dehydropeptidase 1 inhibitor. The novel method of the present invention could prevent the formation of (E)-isomer from the preparation of intermediate for preparing cilastatin sodium, i.e., (Z)-7-chloro-2-((S)-2,2-dimethylcyclopropanecarboxarnido)-2-heptenoic acid metal salt and isolate the intermediate in situ providing simpler process with high yield and purity. Furthermore, it can provide with highly pure cilastatin sodium salt by isolating novel cilastatin amine salt and using by sodium hydroxide and cationic exchange resin. Accordingly, the method can be very useful in preparing cilastatin sodium salt with high yield and high purity.