78834-75-0|Ethyl 7-chloro-2-oxoheptanoate| Ambeed

Structure of 78834-75-0

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Quality Control of [ 78834-75-0 ] Purity: 97% SDS Specification

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Product Details of [ 78834-75-0 ]

CAS No. :	78834-75-0
Formula :	C₉H₁₅ClO₃
M.W :	206.67
SMILES Code :	O=C(OCC)C(CCCCCCl)=O
MDL No. :	MFCD07698675
InChI Key :	YJJLIIMRHGRCFM-UHFFFAOYSA-N
Pubchem ID :	3018793

Safety of [ 78834-75-0 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 78834-75-0 ] Show Less

Physicochemical Properties

Num. heavy atoms	13
Num. arom. heavy atoms	0
Fraction Csp3	0.78
Num. rotatable bonds	8
Num. H-bond acceptors	3.0
Num. H-bond donors	0.0
Molar Refractivity	51.66
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	43.37 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.95
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	1.96
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.92
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	1.59
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	2.56
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.99

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.83
Solubility	3.07 mg/ml ; 0.0149 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-2.5
Solubility	0.66 mg/ml ; 0.00319 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-2.96
Solubility	0.229 mg/ml ; 0.00111 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.17 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	2.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<2.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	2.1

Application In Synthesis of [ 78834-75-0 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Downstream synthetic route of [ 78834-75-0 ]

[ 78834-75-0 ] Synthesis Path-Downstream 1~32

1
[ 54512-75-3 ]
[ 95-92-1 ]
[ 78834-75-0 ]

Yield	Reaction Conditions	Operation in experiment
99.1%		Step 1. Under dry N2 protection, add 7.3 g of diethyl oxalate, 9.3 g of 1-bromo-5-chloropentane and a four-necked flask equipped with a condenser, a thermometer, a stirrer and a 50 ml constant pressure dropping funnel. a mixture of 30 ml of tetrahydrofuran;Step 2, at -25 ° C,Quickly add 1.0g PSIM-MgBr,During the dropwise addition reaction, the reaction temperature is kept at about -10 ° C, and after the completion of the dropwise addition, the reaction is continued for 1 h;Step 3. Hydrolyze with 15 ml of 4 M hydrochloric acid, and ensure the reaction temperature is below 0 °C during acid hydrolysis. The organic layer was separated, and the aqueous layer was extracted with dichloromethane, and washed with a saturated sodium chloride solution, and shaken with a NaHS03 saturated solution;Step 4: After the shaking is completed, the organic layer and the aqueous layer are neutralized with a saturated NaHC03 solution, and the organic layer is rotated to evaporate the tetrahydrofuran. The organic layer is combined, neutralized with saturated NaHC03, washed with NaHS03, then washed with NaCl until neutral, and evaporated.Evaporation under reduced pressure gave ethyl 7-chloro-2-oxoheptanoate.
90%		(Example 1) Example 1 was carried out in a reaction apparatus 10 shown in Figure 1. A main flow channel 12 is a circular pipe made from stainless steel, and introduction points 12o and 12p are 180-degree T-shaped mixture flow channels made from stainless steel. A Grignard reagent: 1-bromomagnesium-5-chloropentane (0.45 mol/L) was diluted by a tetrahydrofuran solvent and the diluted solution was used as a raw material M2. The reagent 1-bromomagnesium-5-chloropentane was prepared by adding a magnesium powder to 1-bromo-5-chloropentane. Diethyl oxalate (7.4 mol/L) which had not been diluted by the solvent was used as a raw material M1. The raw material M2 and the raw material M1 were supplied to a flowing-type fine reaction flow channel 32, at 110 mL/min and 5.1 mL/min, respectively. Used pumps 20 and 26 were a smooth flow pump made by TACMINA CORPORATION. From the above described conditions, a mixed solution of these materials stays in the flowing-type fine reaction flow channel 32 for approximately 14 seconds. The Grignard reagent and diethyl oxalate were accommodated in a supply container and controlled at 10°C and room temperature respectively, and a thermostatic liquid tank 28 accommodated methanol as a refrigerant 30 and was controlled at -15°C. The produced liquid was collected and quenched with a dilute hydrochloric acid. The target substance of ethyl-7-chloro-2-oxalic pentane was obtained in the yield of 90percent.
		l-bromo-5-chloropentane (29 lg, 1.57 mol) was reacted with diethyl oxalate (206.5g) through Grignard reaction to obtain ethyl 7-chloro-2-oxo-heptanoate (3) and the compound (3) was reacted with (S)-2,2-dimethylcyclopropanecarboxamide to obtain ethyl (Z)-7-chloro-2-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptanoate (237g, 0.79 mol). The above-described step was performed by the procedure according to the procedure disclosed in EP 48301 (Bl).

References: [1]Patent: CN108752206,2018,A .Location in patent: Paragraph 0008; 0010-0018; 0029.
[2]Patent: EP2065354,2009,A1 .Location in patent: Page/Page column 11-12.
[3]Patent: WO2006/22511,2006,A1 .Location in patent: Page/Page column 10-11.

2
[ 78834-75-0 ]
[ 75885-58-4 ]
[ 877758-94-6 ]

Yield	Reaction Conditions	Operation in experiment
		l-bromo-5-chloropentane (29 lg, 1.57 mol) was reacted with diethyl oxalate (206.5g) through Grignard reaction to obtain <strong>[78834-75-0]ethyl 7-chloro-2-oxo-heptanoate</strong> (3) and the compound (3) was reacted with (S)-2,2-dimethylcyclopropanecarboxamide to obtain ethyl (Z)-7-chloro-2-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptanoate (237g, 0.79 mol). The above-described step was performed by the procedure according to the procedure disclosed in EP 48301 (Bl).
36.4 g	With toluene-4-sulfonic acid; In water; toluene;Reflux;	25.0 g of <strong>[78834-75-0]ethyl 7-chloro-2-oxoheptanoate</strong> obtained in Example 1 (GC normalized content 98.3%, external standard content 98.5%),(+) - S-2,2-dimethylcyclopropanecarboxamide and 0.15 g of p-toluenesulfonic acid were added to 125 ml of toluene, and the mixture was heated under reflux to azeotropize toluene with water to carry out the reaction.After completion of the reaction, the reaction mixture was cooled to room temperature, and the reaction solution was washed three times with 10% dilute hydrochloric acid (100 ml x 3) and 10% sodium hydrogen sulfite solution (100 ml x 3). After the washing, the toluene layer was separated and dried over anhydrous sodium sulfate. Filtered and concentrated under reduced pressure recovered toluene to give 36.4g of brown viscous liquid, the product will not be isolated directly used in the next step.
	With toluene-4-sulfonic acid; In toluene; at 130℃; for 10h;	247.8 g of <strong>[78834-75-0]ethyl 7-chloro-2-oxoheptanoate</strong>,135.6 g of S - (+) 2,2-dimethylcyclopropylcarboxamidewith1.6 g of p-toluenesulfonic acid at 130 C1200ml toluene refluxed for 10 hours;After the reaction is completed, the toluene is concentrated and recovered;To the concentrate is added 600 ml of ethanol and 720 g of 10% sodium hydroxide solution,HPLC monitoring of the reaction process,At 45 ~ 50 for 10 hours;Then add t-butyl ether three times,Each 1000ml, discard the organic layer,Add concentrated hydrochloric acid,Adjust the pH to 3 ~ 3.5, add ethyl acetate three times,Each time 1000ml,Discard the water layer,Add anhydrous sodium sulfate drying,Concentration under reduced pressure gave (Z) -7-chloro-2- [(S) -2,2-dimethylcyclopropylcarboxamido] -2-heptenoic acid viscous liquid. Under reflux, 200 g of the above concentrate was added to 600 ml of dioxane,Then add 1260ml cyclohexane, stir,Let stand for 12 hours at room temperature, filtered,Drying in vacuo gave (Z) -7-chloro-2- [(S) -2,2-dimethylcyclopropylcarboxamido] -2-heptenoic acid as a solid; After controlling the temperature to be less than or equal to 10 DEG C, purging with nitrogen, 105.3 g of L-cysteine hydrochloride monohydrate was added, the mixture was stirred for 0.5 hours, warmed to 55-60 DEG C, the reaction was monitored by HPLC, the reaction was completed in 8 hours, Cooled to room temperature, washed three times with dichloromethane,Each 600ml, discard the organic layer,One volume of water was added to the reaction solution,Concentrated hydrochloric acid to adjust the pH to 2.5 to 3.0,Four times with dichloromethane,Each 800ml, discard the organic layer,That is included[R- [R , S (Z)]] - 7 - [(2-Amino-2- carboxyethyl) thio]2 - [[(2,2-dimethylcyclopropyl) carbonyl] amino] -2-heptenoic acid.

References: [1]Patent: WO2006/22511,2006,A1 .Location in patent: Page/Page column 10-11.
[2]Patent: CN106117060,2016,A .Location in patent: Paragraph 0007; 0123.
[3]Patent: CN107522642,2017,A .Location in patent: Paragraph 0036; 0041.

3
aqueous formalin [ No CAS ]
[ 78834-75-0 ]
[ 54512-75-3 ]
[ 497-19-8 ]
7-chloro(1-oxoethyl)heptanoic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With nitrosylsulfuric acid; sulfuric acid; In water; toluene;	Then, 230 g (0.62 mol) of the crude product of ethyl 7-chloro-2-(1-oxoethyl)heptanoate thus obtained was cooled to 5°C, to which 228 g (0.81 mol) of 44percent nitrosylsulfuric acid/sulfuric acid solution was added dropwise over 6 hours, and the mixture was further stirred at the same temperature for 4 hours. In another flask, 113 g (1.39 mol) of 37percent aqueous formalin solution and 291 g of toluene were placed and then cooled to 10°C, to which the above reaction solution was added dropwise at the same temperature over 2 hours, and the mixture was further stirred at the same temperature for 30 minutes. The reaction mixture was subjected to phase separation, and the oil layer was washed with 107 g of 5percent aqueous sodium carbonate solution and then with 107 g of water to give 508 g of a toluene solution containing <strong>[78834-75-0]ethyl 7-chloro-2-oxoheptanoate</strong>. In the toluene solution, 18.1percent by weight (72percent yield) of <strong>[78834-75-0]ethyl 7-chloro-2-oxoheptanoate</strong> and 5.4percent by weight of 1-bromo-5-chloropentane were contained.

References: [1]Patent: EP937703,1999,A1 .

4
[ 78834-75-0 ]
[ 75885-58-4 ]
[ 877758-94-6 ]
[ 1022895-93-7 ]

Yield	Reaction Conditions	Operation in experiment
		Ref. Ex. 1; Preparation of Ethyl (Z)-7-chloro-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoate (2); As described in European Patent No. 48301, 250 g of <strong>[78834-75-0]ethyl 7-chloro-2-oxoheptanoate</strong> and 141 g of (S)-2,2-dimethyl cyclopropanecarboxamid were reacted and concentrated. In result, 372.4 g of ethyl (Z)-7-chloro-((S)-2,2-dimethylcyclopropanecarboxamido)-2-hepnoate (2) containing, by gas chromatography assay, 10.5% of ethyl (E)-7-chloro-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoate (3) was obtained.

References: [1]Patent: US7371897,2008,B1 .Location in patent: Page/Page column 5-6.

5
[ 1022895-93-7 ]
[ 78834-75-0 ]
[ 75885-58-4 ]

Yield	Reaction Conditions	Operation in experiment
		Ex. 1; Preparation of (Z)-7-chloro-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid (1); 200 g (0.66 mol) of ethyl (Z)-7-chloro-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoate (2) obtained from the Ref. Ex. 1 was dissolved in 600 ml of dichloromethane. 126 g of 4-toluenesulfonic acid was added to the mixture and stirred at 20° C. When a (mol) ratio of the ethyl (Z)-7-chloro-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoate (2) to the ethyl (E)-7-chloro-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoate (3) was about 200:1 according to gas chromatography assay, the pH of the mixture was adjusted to 8-9 by adding 0.5N caustic soda solution, and an organic phase was isolated. The isolated organic phase was concentrated under reduced pressure and provided to 1,000 ml of acetonitrile. Next, 1,420 ml (0.925 mole) of 0.65N caustic soda solution was added and stirred at room temperature until ethyl (Z)-7-chloro-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoate (2) was completely reacted. Most of acetonitrile was evaporated under reduced pressure, and an aqueous phase was washed with 270 ml of dichloromethane. The pH of the aqueous phase was adjusted to 3.5 by adding hydrochloric acid and extracted from 670 ml of dichloromethane. Meanwhile, the organic phase was provided into 70 g of anhydrous magnesium sulfate, stirred, filtered and concentrated under reduced pressure. The residual was crystallized from a mixed solvent of ethyl acetate and n-hexane (about 1:4), filtered and dried in hot air at 40° C. for 10 hours to produce 101.4 g of the target compound, (Z)-7-chloro-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid (1).HPLC(C18, 40percent aqueous acetonitrile solution) purity: 99.1percent, (Z)/(E)=910H1 nmr (CDCl3, 500 MHz) ppm: 0.82-0.84 (dd, 1H), 1.15-1.23 (s, 7H), 1.43-1.46 (dd, 1H), 1.61-1.67 (m, 2H), 1.78-1.83 (m, 2H), 2.19-2.23 (m, 2H), 3.53-3.56 (t, 2H), 6.77-6.79 (t, 1H), 6.99 (s, 1H)
		Ex. 2; Preparation of (Z)-7-chloro-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid (1); 100 g (0.33 mol) of ethyl (Z)-7-chloro-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoate (2) obtained from the Ref. Ex. 1 was dissolved in 300 ml of toluene. 47 g of methyl sulfonic acid was added to the mixture and stirred at 30° C. When a (mol) ratio of the ethyl (Z)-7-chloro-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoate (2) to the ethyl (E)-7-chloro-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoate (3) was about 120:1 according to gas chromatography assay, the reaction was ended, and the mixture was stirred. The pH of the mixture was adjusted to 8-9 by adding 0.5N caustic soda solution, and an organic phase was isolated. The isolated organic phase was concentrated under reduced pressure and provided to 300 ml of ethanol. Next, 380 ml (0.46 mole) of 1.2N caustic soda solution was added and stirred at room temperature until ethyl (Z)-7-chloro-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoate (2) was completely reacted. Most of ethanol was evaporated under reduced pressure, and an aqueous phase was washed with 150 ml of dichloromethane. The pH of the aqueous phase was adjusted to 3.5 by adding 35percent hydrochloric acid and extracted from 1,500 ml of isoprophyl ether. Meanwhile, the organic phase was provided into 100 g of anhydrous magnesium sulfate, stirred, filtered and concentrated under reduced pressure. The filtrate was crystallized, filtered and dried in hot air at 40° C. for 10 hours to produce 50.5 g of the target compound, (Z)-7-chloro-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid (1).HPLC(C18, 40percent aqueous acetonitrile solution) purity: 99.3percent, (Z)/(E)=540H1 nmr (CDCl3, 500 MHz) ppm: 0.82-0.84 (dd, 1H), 1.15-1.23 (s, 7H), 1.43-1.46 (dd, 1H), 1.61-1.67 (m, 2H), 1.78-1.83 (m, 2H), 2.19-2.23 (m, 2H), 3.53-3.56 (t, 2H), 6.77-6.79 (t, 1H), 6.99 (s, 1H)

References: [1]Patent: US7371897,2008,B1 .Location in patent: Page/Page column 6.
[2]Patent: US7371897,2008,B1 .Location in patent: Page/Page column 6-7.

6
[ 78834-75-0 ]
[ 75885-58-4 ]
[ 1022895-92-6 ]

Yield	Reaction Conditions	Operation in experiment
	With toluene-4-sulfonic acid; In toluene; for 20h;Heating / reflux;	EXAMPLE 1 Preparation of 7-chloro-2-[[(1S)-2,2-dimethyl cyclopropane]carboxamide]-2-heptenoic Acid (II) (Starting Material) To the solution of S-2,2-dimethylcylopropyl carboxamide (100 gm) in toluene (500) was added Ethyl-7-chloro-2-oxo-heptanoate (270 gm) and p-toluene sulphonic acid (1.5 gm). The resulted solution was refluxed for 20 hrs azeotropically. The resulted mass was cooled to 5-10 C. and added the solution of sodium hydroxide (140 gm) in water 500 ml and the resulted two-layered solution was stirred for 8 hrs at 25-30 C. up to the complete disappearance of ester. The toluene layer was separated and the aqueous layer was washed with toluene. The pH of the aqueous layer was adjusted to 4.0 to 4.5 and extracted with toluene (1 lt). The toluene layer containing 7-chloro-2-[[(1S)-2,2-dimethyl cyclopropane]carboxamide]-2-heptenoic acid was washed with water and used as such for the next step. The ratio of Z and E isomer 90:10% was obtained.

References: [1]Patent: US2009/143614,2009,A1 .Location in patent: Page/Page column 3.

7
[ 278605-08-6 ]
[ 95-92-1 ]
[ 78834-75-0 ]

Yield	Reaction Conditions	Operation in experiment
74 - 90%		(Example 2) Example 2 was carried out in a reaction apparatus 50 shown in Figure 2. Here, each length of branch introduction flow channels 16a to 16e was set at 0.5 m, and a portion from a main flow channel 12 to 5 cm of branch introduction flow channels 16a to 16e was arranged in a thermostatic liquid tank 28. The length of an adjusting flow channel 18 was set at 1 m. Each of the flow channel lengths of a flow channel 12a between introduction points 12o and 12p in the main flow channel 12 and a flow channel 12b between introduction points 12p and 12q was set at 3 m, and each of the flow channel lengths of a flow channel 12c between introduction points 12q and 12r, a flow channel 12d between introduction points 12r and 12s and a flow channel 12e from an introduction point 12s to an edge of the thermostatic liquid tank 28 was set at 1 m. The other conditions were set at the same condition as in Example 1. A Grignard reagent: 1-bromomagnesium-5-chloropentane (0.45 mol/L) was diluted by a tetrahydrofuran solvent and the diluted solution was used as a raw material M2. Diethyl oxalate (7.4 mol/L) which had not been diluted by the solvent was used as a raw material M1. The raw material M2 and the raw material M1 were supplied to a flowing-type fine reaction flow channel 32, at 110 mL/min and 5.1 mL/min, respectively. From the above described conditions, a mixed solution of these materials stays in the flowing-type fine reaction flow channel 32 for approximately 42 seconds. The Grignard reagent and diethyl oxalate were accommodated in a supply container and controlled at 10°C and room temperature respectively, and the thermostatic liquid tank 28 accommodated methanol as a refrigerant 30 and was controlled at -15°C. The produced liquid was collected and quenched with a dilute hydrochloric acid. The target substance of ethyl-7-chloro-2-oxalic pentane was obtained in the yield of 90percent.; (Example 2') Example 2' was carried out while controlling the temperature of a thermostatic liquid tank 28 to -5°C, and setting other conditions at the same conditions as in Example 2. As a result, the yield of ethyl-7-chloro-2oxalic pentane was 86percent.; (Example 3) Example 3 was carried out in a reaction apparatus 50 shown in Figure 2. Here, a circular pipe having an inner diameter 3 mm and an outer diameter 4 mm was used for the pipe which constitutes a main flow channel 12, an introduction flow channel 14 and each of branch introduction flow channels 16a to 16e. The lengths of the respective branch introduction flow channels 16a to 16e were set at 0.5 m. The length of an adjusting flow channel 18 was set at 1 m. The flow channel lengths of a flow channel 12a between introduction points 12o and 12p in the main flow channel 12 and a flow channel 12b between introduction points 12p and 12q were each set at 3 m, and the flow channel lengths of a flow channel 12c between introduction points 12q and 12r, a flow channel 12d between introduction points 12r and 12s and a flow channel 12e from an introduction point 12s to an edge of a thermostatic liquid tank 28 were set at 1 m respectively. The other conditions were the same as in Example 1. A Grignard reagent: 1-bromomagnesium-5-chloropentane (0.45 mol/L) was diluted by a tetrahydrofuran solvent and the diluted solution was used as a raw material M2. Diethyl oxalate (7.4 mol/L) which had not been diluted by the solvent was used as a raw material M1. The raw material M2 and the raw material M1 were supplied to a flowing-type fine reaction flow channel 32, at 965 mL/min and 47 mL/min, respectively. From the above described conditions, a mixed solution of these materials stays in a flowing-type fine reaction flow channel 32 for approximately 4.9 seconds. The Grignard reagent and diethyl oxalate were accommodated in a supply container and controlled at 10°C and room temperature respectively, and the thermostatic liquid tank 28 accommodated methanol as a refrigerant 30 and was controlled at -30°C. The produced liquid was collected and quenched with a dilute hydrochloric acid. The target substance of ethyl-7-chloro-2-oxalic pentane was obtained in the yield of 88percent.; (Example 4) Example 4 was carried out in a reaction apparatus 50 shown in Figure 2. Here, a circular pipe having an inner diameter 1 mm and an outer diameter 3 mm was used for the pipe which constitutes a main flow channel 12. A circular pipe having an inner diameter 3 mm and an outer diameter 4 mm was used for the pipe which constitutes an introduction flow channel 14. A circular pipe having an inner diameter 1 mm and an outer diameter 3 mm was used for the pipe which constitutes each of branch introduction flow channels 16a to 16e. Lengths of branch introduction flow channels 16a to 16e were set at 0.5 m, 1.5 m, 2.0 m, 2.5 m and 3.0 m respectively, and portions from the main flow channel 12 to 5 cm of all branch introduction flow channels were arranged in a thermostatic liquid tank 28. The length of an adjusting flow ...

References: [1]Patent: EP2065354,2009,A1 .Location in patent: Page/Page column 12-15.

8
[ 1174680-07-9 ]
[ 78834-75-0 ]

Yield	Reaction Conditions	Operation in experiment
97%	With sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hydrogencarbonate; potassium bromide; In dichloromethane; water; at -2 - -1℃;	In a reaction flask, water (300 ml), sodium bicarbonate (31.5 g, 0.375 mol), andDichloromethane (385g), compound IV (77g, 0.37mol), TEMPO (0.77g), Potassium bromide (5.0g), the temperature was lowered to -1 -2 , and ice was formed in the flask.Started the dropwise addition of aqueous sodium hypochlorite solution (360g, effective chlorine content 10%), The addition is completed in about 1 hour, and the temperature is controlled to less than 8 C. After the addition is complete, the temperature is maintained for 2 hours, and the layers are kept still. Wash with 2-3% hydrochloric acid (120g), and 1% sodium thiosulfate (120g).Wash with water and recover methylene chloride to the end to obtain 73.9 g of 7-chloro-2-oxoheptanoic acid ethyl ester as a finished product, The yield was 97%, and the GC purity was greater than 98%.
	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;	Example 6 Synthesis of ethyl 7-chloro-2-oxoheptylate 90 g (0.43 mol) of ethyl 7-chloro-alpha-hydroxyheptylate, 440 ml of dichloromethane, 6g (0.05 mol)of potassium bromide, 1.0g (0.006mol) of TEMPO, and 660ml of saturated solution of sodium bicarbonate cooled to internal temperature of -1 to 5 C were added into a flask. The aqueous solution of 680g of (0.45mol) of sodium hypochlorite, which had be pre-cooled below 0C, was added in batch into the flask and the temperature was maintained at 0C for 2.5 h after the feed was completed. The organic layer was separated. The aqueous layer was extracted once again with 100ml of dichloromethane. The dichloromethane layer was washed firstly with 100ml of 5% solution of sodium thiosulfate and then with 200ml of water. After thorough recovering of the dichloromethane, the residue was distilled under reduced pressure and distillate cut at 90-92C/2mm Hg was collected, resulting in 77g( 0.37mol) of ethyl 7-choloro-2-oxoheptylate with 95% of chromatographic purity (GC).

References: [1]Patent: CN107344916,2019,B .Location in patent: Paragraph 0056-0058.
[2]Patent: EP2394979,2011,A1 .Location in patent: Page/Page column 7.

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[ 2009-83-8 ]
[ 78834-75-0 ]

References: [1]Patent: EP2394979,2011,A1 .

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[ 52387-36-7 ]
[ 78834-75-0 ]

References: [1]Patent: EP2394979,2011,A1 .
[2]Patent: CN107344916,2019,B .

11
[ 1174680-06-8 ]
[ 78834-75-0 ]

References: [1]Patent: EP2394979,2011,A1 .

12
[ 1174680-05-7 ]
[ 78834-75-0 ]

References: [1]Patent: EP2394979,2011,A1 .
[2]Patent: CN107344916,2019,B .

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[ 78834-75-0 ]
[ 75885-58-4 ]
[ 877674-77-6 ]
(E)-7-chloro-2[[(1S)-2,2-dimethyl cyclopropane]carboxamide]-2-heptenoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 1Preparation of 7-chloro-2-[[(1S)-2,2-dimethyl cyclopropane]carboxamide]-2-heptenoic acid (II) (starting material):To the solution of S-2, 2-dimethylcylopropyl carboxamide (100gm) in toluene (500) was added Ethyl-7-chloro-2-oxo-heptanoate (270gm) and p-toluene sulphonic acid (1.5gm).The resulted solution was refluxed for 20hrs azeotropically.The resulted mass was cooled to 5-10°C and added the solution of sodium hydroxide (140gm) in water 500 ml and the resulted two-layered solution was stirred for 8hrs at 25-30°C up to the complete disappearance of ester.The toluene layer was separated and the aqueous layer was washed with toluene.The pH of the aqueous layer was adjusted to 4.0 to 4.5 and extracted with toluene (1 lt).The toluene layer containing 7-chloro-2-[[(1S)-2,2-dimethyl cyclopropane]carboxamide]-2-heptenoic acid was washed with water and used as such for the next step.The ratio of Z and E isomer 90:10percent was obtained.

References: [1]Patent: EP2402312,2012,A1 .Location in patent: Page/Page column 5.

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[ 78834-75-0 ]
[ 82009-34-5 ]

References: [1]Patent: EP2402312,2012,A1 .
[2]Patent: EP2402312,2012,A1 .
[3]Patent: CN107522642,2017,A .

15
[ 78834-75-0 ]
[ 877674-77-6 ]

References: [1]Patent: EP2402312,2012,A1 .
[2]Patent: CN107522642,2017,A .

16
[ 78834-75-0 ]
cilastatin sodium [ No CAS ]

References: [1]Patent: EP2402312,2012,A1 .
[2]Patent: EP2402312,2012,A1 .

17
[ 78834-75-0 ]
α-Brom-δ-chlorvaleriansaeure-ethylester [ No CAS ]

References: [1]ACS Medicinal Chemistry Letters,2014,vol. 5,p. 662 - 667.

18
[ 78834-75-0 ]
[ 1235034-74-8 ]

References: [1]ACS Medicinal Chemistry Letters,2014,vol. 5,p. 662 - 667.

19
[ 78834-75-0 ]
[ 1235034-75-9 ]

References: [1]ACS Medicinal Chemistry Letters,2014,vol. 5,p. 662 - 667.

20
[ 78834-75-0 ]
C₃₂H₃₀N₄O₄S₂ [ No CAS ]

References: [1]ACS Medicinal Chemistry Letters,2014,vol. 5,p. 662 - 667.

21
[ 78834-75-0 ]
[ 1235032-77-5 ]

References: [1]ACS Medicinal Chemistry Letters,2014,vol. 5,p. 662 - 667.

22
[ 78834-75-0 ]
[ 1235035-22-9 ]