[ CAS No. 64399-27-5 ]

Name: 64399-27-5|1-(4-Chlorophenyl)cyclopropanecarbonitrile|98%
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Quality Control of [ 64399-27-5 ]

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Product Details of [ 64399-27-5 ]

CAS No. :	64399-27-5	MDL No. :	MFCD00019211
Formula :	C₁₀H₈ClN	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	BVWSEHMDAKSWQW-UHFFFAOYSA-N
M.W :	177.63 g/mol	Pubchem ID :	98666
Synonyms :

Safety of [ 64399-27-5 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 64399-27-5 ]

* 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.

Upstream synthesis route of [ 64399-27-5 ]
Downstream synthetic route of [ 64399-27-5 ]

[ 64399-27-5 ] Synthesis Path-Upstream 1~1

1
[ 64399-27-5 ]
[ 72934-37-3 ]

Yield	Reaction Conditions	Operation in experiment
95%	Reflux	The cyclopropanecarbonitrile ( 18 gm) obtained in example 1 was added to 20percent sulfuric acid (184ml). The temperature of the reaction mass was slowly raised and maintained at reflux for 10-12 hours. After 12 hours , ethyl acetate was used to extract the product. The acid product from the organic layer was then extracted into 20percent NaOH solution. The aqueous layer was then acidified to pH 2-4 with concentrated HCl. The white solid product obtained was filtered and washed with water. The product p- chlorophenylcyclopropanecarboxylic acid was dried. The yield was 90-95percent and the product had apurity of 99.4percent by HPLC. The melting point was 152-155⁰C.
90.3%	With sodium hydroxide In water; diethylene glycol for 18 h; Reflux	A stirred solution of 1-(4-chlorophenyl)cyclopropane-1-carbonitrile (step 1, 30.0 g, 169.49 mmol, 1.0 eq), sodium hydroxide (20.3 g, 508.47 mmol, 3.0 eq), diethylene glycol(120 ml) and water (35.4 ml) was refluxed for about 18 hours. TLC indicated startingmaterial was consumed and the desired product was observed. The reaction mixture was poured into water (1800 ml) and acidified to pH4.0 with concentrated HC1 (54 ml). The generated crystals were collected by filtration and dried under vacuum to obtain the desired product (30.0 g, 90.3percent yield) as a pale-brown colour solid. ‘H NMR (300 MHz, DMSO-d6):ppm 12.40 (br.s., 1H), 7.34 (m, 4H), 1.48-1.42 (m, 2H), 1.16-1.10 (m, 2H).

Reference： [1] Patent: WO2009/150660, 2009, A1, . Location in patent: Page/Page column 16
[2] Patent: WO2016/178092, 2016, A2, . Location in patent: Page/Page column 63; 64
[3] Patent: WO2017/64628, 2017, A1, . Location in patent: Page/Page column 33; 34
[4] Chemische Berichte, 1979, vol. 112, p. 3914 - 3933
[5] Patent: US2009/312558, 2009, A1, . Location in patent: Page/Page column 6
[6] Journal of the American Chemical Society, 2011, vol. 133, # 49, p. 19598 - 19601
[7] Organic Letters, 2014, vol. 16, # 24, p. 6314 - 6317
[8] Journal of the American Chemical Society, 2018, vol. 140, # 21, p. 6545 - 6549
[9] Advanced Synthesis and Catalysis, 2018, vol. 360, # 22, p. 4306 - 4311

[ 64399-27-5 ] Synthesis Path-Downstream 1~58

1
[ 64399-27-5 ]
[ 72934-37-3 ]

Yield	Reaction Conditions	Operation in experiment
95%	With sulfuric acid; water;Reflux;	The cyclopropanecarbonitrile ( 18 gm) obtained in example 1 was added to 20% sulfuric acid (184ml). The temperature of the reaction mass was slowly raised and maintained at reflux for 10-12 hours. After 12 hours , ethyl acetate was used to extract the product. The acid product from the organic layer was then extracted into 20% NaOH solution. The aqueous layer was then acidified to pH 2-4 with concentrated HCl. The white solid product obtained was filtered and washed with water. The product p- chlorophenylcyclopropanecarboxylic acid was dried. The yield was 90-95% and the product had apurity of 99.4% by HPLC. The melting point was 152-1550C.
90.3%	With sodium hydroxide; In water; diethylene glycol; for 18h;Reflux;	A stirred solution of 1-(4-chlorophenyl)cyclopropane-1-carbonitrile (step 1, 30.0 g, 169.49 mmol, 1.0 eq), sodium hydroxide (20.3 g, 508.47 mmol, 3.0 eq), diethylene glycol(120 ml) and water (35.4 ml) was refluxed for about 18 hours. TLC indicated startingmaterial was consumed and the desired product was observed. The reaction mixture was poured into water (1800 ml) and acidified to pH4.0 with concentrated HC1 (54 ml). The generated crystals were collected by filtration and dried under vacuum to obtain the desired product (30.0 g, 90.3% yield) as a pale-brown colour solid. ?H NMR (300 MHz, DMSO-d6):ppm 12.40 (br.s., 1H), 7.34 (m, 4H), 1.48-1.42 (m, 2H), 1.16-1.10 (m, 2H).
77%	With sodium hydroxide; In methanol; water; at 100 - 105℃; for 14h;Inert atmosphere;	A mixture of nitrile 11 (1.42 g, 8.0 mmol) and NaOH (6.4 g, 160 mmol) in MeOH (40mL) and water (26 mL) was stirred at 100 - 105 C for 14 h under an Ar atmosphere.The mixture was cool down to room temperature and quenched with water, whichwas washed twice with Et2O. 6 M-HCl aq. was added to adjust theseparated water phase to pH = 1. Water phase was extracted twice with AcOEt, and the combinedorganic phase was washed with water, brine, dried (Na 2SO4) and concentrated to give the desiredcarboxylic acid intermediate [4] (1.21g, 77%), which was sufficiently pure without anypurification for the next step.Pale yellow crystals: mp 153 - 155 C [lit.[1] 154 - 156 C];

With sulfuric acid; water;Reflux;

EXAMPLE 2; Preparation of p-chlorophenycyclopropane carboxylic acid; The cyclopropanecarbonitrile (18 gm) obtained in example 1 was added to 20% sulfuric acid (184 ml). The temperature of the reaction mass was slowly raised and maintained at reflux for 10-12 hours. After 12 hours, ethyl acetate was used to extract the product. The acid product from the organic layer was then extracted into 20% NaOH solution. The aqueous layer was then acidified to pH 2-4 with concentrated HCl. The white solid product obtained was filtered and washed with water. The product p-chlorophenylcyclopropanecarboxylic acid was dried. The yield was 90-95% and the product had a purity of 99.4% by HPLC. The melting point was 152-155 C.

Reference： [1]Patent: WO2009/150660,2009,A1 .Location in patent: Page/Page column 16
[2]Patent: WO2016/178092,2016,A2 .Location in patent: Page/Page column 63; 64
[3]Patent: WO2017/64628,2017,A1 .Location in patent: Page/Page column 33; 34
[4]Molecules,2019,vol. 24
[5]Chemische Berichte,1979,vol. 112,p. 3914 - 3933
[6]Patent: US2009/312558,2009,A1 .Location in patent: Page/Page column 6
[7]Journal of the American Chemical Society,2011,vol. 133,p. 19598 - 19601
[8]Organic Letters,2014,vol. 16,p. 6314 - 6317
[9]Journal of the American Chemical Society,2018,vol. 140,p. 6545 - 6549
[10]Advanced Synthesis and Catalysis,2018,vol. 360,p. 4306 - 4311
[11]Journal of the American Chemical Society,2019,vol. 141,p. 10599 - 10604

2
[ 106-93-4 ]
[ 140-53-4 ]
[ 64399-27-5 ]

Yield	Reaction Conditions	Operation in experiment
90%		To a solution of Sulfolane (250ml), p-chlorophenylacetonitrile (lOOgm) was added under stirring. Sodium hydroxide powder (13.19gm, 5.0 mole) and TEBAC (0.05% )751gm was added to the reaction mixture and stirred for 10-40 minutes.Then 1,2-dibromoethane (37.17gm, 3.0 mole) was added to the reaction mass and the temperature of the reaction was slowly raised and maintained at 50-700C for 14-16 hours. The progress of the reaction was monitored by Thin Layer chromatography (Solvent system). After 14-16 hours, the reaction mass was quenched into water (~600ml) and the organic layer was separated. The aqueous layer was washed with ethyl acetate. The organic layer was distilled under vacuum to remove the solvent and then the residue was subjected to fractional distillation at 2mm Hg vacuum at 120-1300C to yield p- chlorocyclopropanecarbonitrile product (85-90%). The purity of the product was 99.0% by HPLC and the Melting point : 140-1430C.
80%	With tetrabutylammomium bromide; potassium hydroxide; In water; at 70 - 75℃; for 24h;Inert atmosphere;	1,2-Dibromoethane (1.72 mL, 20 mmol) was added to a stirred suspension of 2-(4-chlorophenyl)acetonitrile (1.52 g, 10 mmol), tetrabuthyl ammonium bromide(TBAB) (161 mg, 0.05 eq.), and KOH (5.61 g, 100 mmol) in water (5 mL) at 70 -75 C under an Ar atmosphere, followed by being stirred at the same temperaturefor 24 h [2]. The mixture was cooled down to room temperature and reversely quenched with iceand 6 M-HCl aq., which was extracted twice with Et2O. The combined organic phase was washedwith water, brine, dried (Na2SO4) and concentrated. The obtained crude oil was purified by SiO2-column chromatography (hexane/AcOEt = 15:1) to give the desired product 1 (1.42 g, 80%).Pale yellow crystals: mp 55 - 56 C [lit.[3] 42 - 45 C];
		EXAMPLE 1; Preparation of para-chlorocyclopropanecarbonitrile; To a solution of Sulfolane (250 ml), p-chlorophenylacetonitrile (100 gm) was added under stirring. Sodium hydroxide powder (13.19 gm, 5.0 mole) and TEBAC (0.05% )751 gm was added to the reaction mixture and stirred for 10-40 minutes.Then 1,2-dibromoethane (37.17 gm, 3.0 mole) was added to the reaction mass and the temperature of the reaction was slowly raised and maintained at 50-70 C. for 14-16 hours. The progress of the reaction was monitored by Thin Layer chromatography (Solvent system). After 14-16 hours, the reaction mass was quenched into water (600ml) and the organic layer was separated. The aqueous layer was washed with ethyl acetate. The organic layer was distilled under vacuum to remove the solvent and then the residue was subjected to fractional distillation at 2mm Hg vacuum at 120-130 C. to yield p-chlorocyclopropanecarbonitrile product (85-90%).The purity of the product was 99.0% by HPLC and the Melting point: 140-143 C.

		A suspension of 55% sodium hydride (25.27 g, 1052.9 mmol, 5.3 eq) and THF (200 ml) under nitrogen atmosphere was heated to 40 C and a solution of 2-(4-chlorophenyl) acetonitrile (30.0 g, 198.67 mmol, 1.0 eq) in THF (50 ml) was added dropwise over about 30 minutes. The mixture was stirred at 40 C for about 30 minutes and a solution of 1,2- dibromoethane (74.3 g, 397.35 mmol, 2.0 eq) in THF (50 ml) was added dropwise over about 30 minutes. The reaction mixture was stirred at 40 C for about 1 hour. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was cooled to 0 C, quenched with ice water (250 ml) and extracted with ethyl acetate (3x400 ml). The combined organic extracts were washed with brine solution (400 ml), dried over sodium sulfate, filtered and evaporated under reduced pressure to obtain the desired product (30.0 g) as a semi solid, which is used as such for next step without further purification. 1H NMR (300 MHz, CDC13): δ ppm 7.33 (d, J= 8.7 Hz, 2H), 7.24 (d, J= 8.7 Hz, 2H), 1.78-1.71 (m, 2H), 1.42-1.35 (m, 2H).
30 g		A suspension of 55% sodium hydride (25.27 g, 1052.9 mmol, 5.3 eq) and THF (200 ml) under nitrogen atmosphere was heated to 40 C and a solution of 2-(4-chlorophenyl)acetonitrile (30.0 g, 198.67 mmol, 1.0 eq) in THF (50 ml) was added dropwise over 30 minutes. The mixture was stirred at 40 C for about 30 minutes and a solution of 1,2- dibromoethane (74.3 g, 397.35 mmol, 2.0 eq) in THF (50 ml) was added dropwise over 30 minutes. The reaction mixture was stirred at 40 C for about 1 hour. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture wascooled to 0 C, quenched with ice water (250 ml) and extracted with ethyl acetate (3x400 ml). The combined organic extracts were washed with brine solution (400 ml), dried over sodium sulfate, filtered and evaporated under reduced pressure to obtain the desired product (30.0 g) as a semi solid, which is used as such for next step without further purification. ‘H NMR (300 MHz, CDC13): ppm 7.33 (d, J = 8.7 Hz, 2H), 7.24 (d, J = 8.7 Hz, 2H), 1.78-1.7 1 (m, 2H),1.42-1.35 (m, 2H).

Reference： [1]Patent: WO2009/150660,2009,A1 .Location in patent: Page/Page column 15
[2]Molecules,2019,vol. 24
[3]Chemische Berichte,1979,vol. 112,p. 3914 - 3933
[4]Patent: US2009/312558,2009,A1 .Location in patent: Page/Page column 5-6
[5]Organic Letters,2015,vol. 17,p. 4944 - 4947
[6]Patent: WO2016/178092,2016,A2 .Location in patent: Page/Page column 63
[7]Patent: WO2017/64628,2017,A1 .Location in patent: Page/Page column 33
[8]Journal of the American Chemical Society,2017,vol. 139,p. 12398 - 12401
[9]Advanced Synthesis and Catalysis,2018,vol. 360,p. 4306 - 4311

3
[ 30568-32-2 ]
[ 64399-27-5 ]
[ 20401-29-0 ]
[ 100845-90-7 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; diisobutylaluminium hydride; In diethyl ether; hexane; water;	EXAMPLE 2 Preparation of 2-(p-Chlorophenyl)-2-methylpropionaldehyde STR13 Diisobutylaluminum hydride (0.236 mol, 236 mL of a 1M solution in hexane) is added over 90 minutes to a solution of p-chloro-α-methylhydratroponitrile (32.6 g, 0.181 mol) in diethyl ether under nitrogen at 0 C. After the addition is complete, water and 6N hydrochloric acid are added to the reaction mixture while maintaining the temperature below 30 C. The resultant aqueous solution is stirred overnight at room temperature and extracted with diethyl ether The organic extracts are combined, washed sequentially with 2N hydrochloric acid and water, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title product as an oil (31.1 g, 94% yield). Using essentially the same procedure, but substituting 1-(p-chlorophenyl)cyclopropanecarbonitrile for p-chloro-α-methylhydratroponitrile, 1-(p-chlorophenyl)cyclopropanecarboxaldehyde is obtained as a colorless solid, mp 38-41 C.
	With hydrogenchloride; diisobutylaluminium hydride; In diethyl ether; hexane; water;	EXAMPLE 2 Preparation of 2-(p-Chlorophenyl)-2-methylpropionaldehyde STR13 Diisobutylaluminum hydride (0.236 mol, 236 mL of a 1M solution in hexane) is added over 90 minutes to a solution of p-chloro-α-methylhydratroponitrile (32.6 g, 0.181 mol) in diethyl ether under nitrogen at 0 C. After the addition is complete, water and 6N hydrochloric acid are added to the reaction mixture while maintaining the temperature below 30 C. The resultant aqueous solution is stirred overnight at room temperature and extracted with diethyl ether. The organic extracts are combined, washed sequentially with 2N hydrochloric acid and water, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title product as an oil (31.1 g, 94% yield). Using essentially the same procedure, but substituting 1-(p-chlorophenyl)cyclopropanecarbonitrile for p-chloro-α-methylhydratroponitrile, 1-(p-chlorophenyl)cyclopropanecarboxaldehyde is obtained as a colorless solid, mp 38-41 C.
	With hydrogenchloride; diisobutylaluminium hydride; In diethyl ether; hexane; water;	EXAMPLE 9 Preparation of 2-(p-Chlorophenyl)-2-methylpropionaldehyde Diisobutylaluminum hydride (0.236 mol, 236 mL of a 1 M solution in hexane) is added over 90 minutes to a solution of p-chloro-α-methylhydratroponitrile (32.6 g, 0.181 mol) in diethyl ether under nitrogen at 0 C. After the addition is complete, water and 6 N hydrochloric acid are added to the reaction mixture while maintaining the temperature below 30 C. The resultant aqueous solution is stirred overnight at room temperature and extracted with diethyl ether. The organic extracts are combined, washed sequentially with 2 N hydrochloric acid and water, dried over anhydrous sodium sulfate, and concentrated in vacuoto give the title product as an oil (31.1 g, 94% yield). Using essentially the same procedure, but substituting 1-(p-chlorophenyl)cyclopropanecarbonitrile for p-chloro-α-methylhydratroponitrile, 1-(p-chlorophenyl)cyclopropanecarboxaldehyde is obtained as a colorless solid, mp 38-41 C.

With hydrogenchloride; diisobutylaluminium hydride; In diethyl ether; hexane; water;

EXAMPLE 9 Preparation of 2-(p-Chlorophenyl)-2-methylpropionaldehyde Diisobutylaluminum hydride (0.236 mol, 236 mL of a 1 M solution in hexane) is added over 90 minutes to a solution of p-chloro-α-methylhydratroponitrile (32.6 g, 0.181 mol) in diethyl ether under nitrogen at 0 C. After the addition is complete, water and 6 N hydrochloric acid are added to the reaction mixture while maintaining the temperature below 30 C. The resultant aqueous solution is stirred overnight at room temperature and extracted with diethyl ether. The organic extracts are combined, washed sequentially with 2 N hydrochloric acid and water, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title product as an oil (31.1 g, 94% yield). Using essentially the same procedure, but substituting 1-(p-chlorophenyl)cyclopropanecarbonitrile for p-chloro-α-methylhydratroponitrile, 1-(p-chlorophenyl)cyclopropanecarboxaldehyde is obtained as a colorless solid, mp 38-41 C.

Reference： [1]Patent: US5998673,1999,A
[2]Patent: US5849958,1998,A
[3]Patent: EP933027,1999,A1
[4]Patent: US6235754,2001,B1

4
[ 109-04-6 ]
[ 64399-27-5 ]
[1-(4-chlorophenyl)-cyclopropan-1-yl]-pyridin-2-yl-methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With n-butyllithium; In tetrahydrofuran; hexane;	a. [1-(4-chlorophenyl)-cyclopropan-1-yl]-pyridin-2-yl-methanone To a solution of 19.6 g (0.124 mol) of 2-bromopyridine in 200 ml tetrahydrofuran, a solution of 85 ml (0.141 mol) of n-butyllithium (15% in hexane) is added dropwise at -45 C. After 1 hour at -45 C. a solution of 21.2 g (0 119 mol) of <strong>[64399-27-5]1-(4-chlorophenyl)-1-cyclopropanecarbonitrile</strong> in 50 ml tetrahydrofuran is added dropwise. After heating to ambient temperature the mixture is poured onto ice water, adjusted to pH 5 with formic acid and extracted with ethyl acetate. The organic extracts are washed with sodium chloride solution, dried and concentrated by evaporation. The residue is chromatographed on silica gel and eluted with petroleum ether/ethyl acetate (19:1). The desired fractions are combined and concentrated by evaporation. Yield: 7.2 g (23% of theory), Rf value: 0.71 (silica gel; methylene chloride/ethanol=19:1).

Reference： [1]Patent: US6114532,2000,A

5
[ 137-43-9 ]
[ 64399-27-5 ]
4-[1-(cyclopentylcarbonyl)cyclopropyl]-chlorobenzene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With iodine; magnesium;	a. 4-[1-(cyclopentylcarbonyl)cyclopropyl]-chlorobenzene 2.4 g (0.1 mol) of magnesium chips are suspended in 10 ml ether. After the addition of a spatula-tip of iodine, 14.9 g (0.1 mol) of bromocyclopentane are slowly added dropwise to 40 ml of ether, the reaction being started off initially by gentle heating. After the addition has ended the mixture is refluxed for 30 minutes. Then a solution of 14.0 g (0.08 mol) of <strong>[64399-27-5]1-(4-chlorophenyl)-1-cyclopropanecarbonitrile</strong> in 75 ml ether is added and refluxed for a further 3 hours. The reaction solution is poured onto ice water, adjusted to pH 3 with hydrochloric acid and extracted with ether. The organic extracts are dried and concentrated by evaporation. The residue is chromatographed on silica gel and eluted with petroleum ether/ethyl acetate (19:1 and 15:1). Yield: 3.0 g (12% of theory), Rf value: 0.58 (silica gel; petroleum ether/ethyl acetate=4:1).

Reference： [1]Patent: US6248770,2001,B1

6
[ 64399-27-5 ]
[ 39895-55-1 ]
[ 1039766-08-9 ]

Yield	Reaction Conditions	Operation in experiment
	With dimethylaluminum chloride; In toluene; at 150℃; for 0.666667h;Microwave irradiation;	EXAMPLE 59; N-[(2-[1-(4-Chlorophenyl)cyclopropyl]-1-[4-(1,1-dimethylethyl)phenyl]methyl}-4-hydroxy-6-oxo-1,6-dihydro-5-pyrimidinyl)carbonyl]glycine; 59a) 2-[1-(4-Chlorophenyl)cyclopropyl]-3-[4-(1,1-dimethylethyl)phenyl]methyl}-6-hydroxy-4(3H)-pyrimidinone; Dimethylaluminium chloride (1.212 ml, 1.212 mmol) was added to a solution of <strong>[64399-27-5]1-(4-chlorophenyl)cyclopropanecarbonitrile</strong> (234 mg, 1.322 mmol) and 4-t-butylbenzylamine (0.194 ml, 1.102 mmol) in toluene (1.5 ml). The resulting mixture was stirred under nitrogen for 10 min. and then at 150 C. for 30 min in a Biotage Initiator microwave synthesizer. The reaction mixture was cooled and the solvent evaporated. The residue was suspended in methoxyethanol (4.0 ml). Diethylmalonate (0.668 ml, 4.41 mmol) and sodium methoxyde (1.008 ml, 4.41 mmol) were added and the mixture was stirred at reflux for 20 h. After cooling, the mixture was poured into water. The pH was adjusted to ca. 5 by the addition of 1 N HCl. The resulting precipitate was collected, washed with water, dried and purified on silica gel (0-9% MeOH in chloroform) to afford 2-[1-(4-chlorophenyl)cyclopropyl]-3-[4-(1,1-dimethylethyl)phenyl]methyl}-6-hydroxy-4(3H)-pyrimidinone (387 mg, 0.946 mmol, 84.5% yield). 1H-NMR (400 MHz, CHLOROFORM-d) d ppm 7.13-7.23 (m, 4 H), 6.97 (d, J=8.59 Hz, 2 H), 6.79 (d, J=8.34 Hz, 2 H), 5.79 (s, 1 H), 5.25 (br. s., 2 H), 1.38-1.44 (m, 2 H), 1.29-1.34 (m, 2 H), 1.27 (s, 9 H). LCMS (ES+) m/z 409 (MH-).

Reference： [1]Patent: US2008/171756,2008,A1 .Location in patent: Page/Page column 39

7
[ 5332-24-1 ]
[ 64399-27-5 ]
[ 1134916-53-2 ]

Yield	Reaction Conditions	Operation in experiment
		A solution of n-butyl lithium (1.6 M in hexanes, 1.5 ml) was added to 3-bromoquinoline (CAS Reg. No. 5332-24-1) (500 mg) in diethyl ether (16 ml) at -78 C. The mixture was stirred at -78 C. for 1 h. A solution of <strong>[64399-27-5]1-(4-chlorophenyl)-1-cyclopropanecarbonitrile</strong> (CAS Reg. No. 64399-27-5) (427 mg) in 3 ml diethyl ether was added at -78 C. to the red mixture and then stirred for 15 min at -78 C. The mixture was allowed to warm to room temperature, then poured into water (40 ml) and extracted with diethyl ether. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, ethyl acetate/heptane 0:100-20:80, then ethyl acetate/DCM 0:100-10:90) to give the title compound as a light yellow oil (100 mg). MS (m/e)=308.3 [M+H+].

Reference： [1]Patent: US2009/88425,2009,A1 .Location in patent: Page/Page column 40-41

8
[ 64399-27-5 ]
[ 676-58-4 ]
[ 1017388-59-8 ]

Yield	Reaction Conditions	Operation in experiment
34%		a) 1-[1-(4-Chloro-phenyl)-cyclopropyl]-ethanone; To a solution of <strong>[64399-27-5]1-(4-chlorophenyl)-1-cyclopropanecarbonitrile</strong> (181 mg, 1.0 mmol) in toluene (5 mL) was added drop wise at 20 C. under an atmosphere of nitrogen a 3 M solution of methylmagnesium chloride in tetrahydrofuran (0.5 mL, 1.5 mmol). The reaction was heated for 16 h to 80 C. In an ice bath 6 N aqueous hydrochloric acid solution (1.08 mL) was added carefully and the reaction was heated to reflux for 2 h. The reaction was diluted with toluene, extracted once with water, once with brine, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using heptane/ethyl acetate (9:1 v/v) as eluent to yield the title compound (67 mg, 34%) as a yellow oil.1H NMR (CDCl3, 300 MHz): δ (ppm)=7.31 (m, 4H), 2.00 (s, 3H), 1.61 (q, 2H), 1.15 (q, 2H).

Reference： [1]Patent: US2009/215759,2009,A1 .Location in patent: Page/Page column 21

9
[ 64399-27-5 ]
[ 1314760-57-0 ]

Yield	Reaction Conditions	Operation in experiment
41%	With sulfuric acid; nitric acid; at -15 - 20℃; for 2h;	General procedure: To conc H2SO4 (5.7 mL, 107 mmol) were added successively HNO3 (5.4 mL, 840 mmol) and then 13 (3.77 g, 210 mmol) at -15 C. After stirring for 2 h at room temperature, the reaction mixture was poured into ice-water, and extracted with EtOAc (×2). The combined organic layers were washed with water, brine, dried over Na2SO4 and evaporated to yield 15 (4.6 g, 97% yield) as a pale yellow solid.