CAS No. :	2012-74-0
Formula :	C₁₁H₁₃ClO₂
M.W :	212.67
SMILES Code :	CC(C)C(C(O)=O)C1=CC=C(Cl)C=C1
MDL No. :	MFCD00037763
InChI Key :	VTJMSIIXXKNIDJ-UHFFFAOYSA-N
Pubchem ID :	16197

Safety of 2-(4-Chlorophenyl)-3-methylbutyric Acid

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

Application In Synthesis of 2-(4-Chlorophenyl)-3-methylbutyric Acid

* 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 [ 2012-74-0 ]

[ 2012-74-0 ] Synthesis Path-Downstream 1~54

1
[ 2012-81-9 ]
[ 2012-74-0 ]

2
[ 2012-74-0 ]
[ 51631-50-6 ]

References: [1]Bulletin of the Academy of Sciences of the USSR Division of Chemical Science,1986,vol. 35,p. 1239 - 1242.
Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya,1986,p. 1365 - 1368.
[2]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,1990,vol. 29,p. 1034 - 1040.
[3]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 8574 - 8581.
[4]Tetrahedron Letters,2010,vol. 51,p. 2010 - 2013.
[5]Journal of Medicinal Chemistry,2010,vol. 53,p. 6003 - 6017.
[6]Asian Journal of Chemistry,2012,vol. 24,p. 2881 - 2883.

3
[ 2012-74-0 ]
(+)-2-(4-chlorophenyl)-3-methylbutanoic acid [ No CAS ]

References: [1]Agricultural and Biological Chemistry,1986,vol. 50,p. 675 - 680.

4
[ 2012-74-0 ]
(-)-2-(4-chlorophenyl)-3-methylbutanoic acid [ No CAS ]

References: [1]Agricultural and Biological Chemistry,1986,vol. 50,p. 675 - 680.

5
[ 5096-11-7 ]
[ 51631-99-3 ]
[ 2012-74-0 ]
[ 88549-73-9 ]
[ 88549-73-9 ]

References: [1]Angewandte Chemie,1984,vol. 96,p. 166 - 167.
[2]Angewandte Chemie,1984,vol. 96,p. 166 - 167.

6
[ 27854-88-2 ]
[ 51631-99-3 ]
[ 2012-74-0 ]
[ 88549-71-7 ]
[ 88549-71-7 ]

References: [1]Angewandte Chemie,1984,vol. 96,p. 166 - 167.
[2]Angewandte Chemie,1984,vol. 96,p. 166 - 167.

7
[ 74408-48-3 ]
[ 2012-74-0 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium permanganate; sulfuric acid; In toluene;	EXAMPLE 12 Preparation of 2-(4-chlorophenyl)-3-methylbutyric acid 100 g (0.49 mol) of 96.42% by weight 2-(4-chlorophenyl)-3-methylbutanal (the product of Example 11) and 558.4 g of 19.4% by weight sulfuric acid are initially introduced into a 1 liter three-necked flask fitted with a stirrer, a reflux condenser, a dropping funnel, and an internal thermometer. Thereto, 79.05 g (0.5 mol) of KMnO4 are added at 20 to 25 C. in the course of 2 hours. After an after-reaction of one hour at 20 to 25 C., 600 g of toluene are introduced. The solid is filtered off and the organic phase is separated from the aqueous phase. The organic phase is freed from the toluene on a rotary evaporator and the residue is recrystallized from cyclohexane. The yield is 86.4 g corresponding to 82.8% of theoretical (based on the aldehyde employed), and the product has a melding point of 89 to 91 C.

References: [1]Advanced Synthesis and Catalysis,2000,vol. 342,p. 498 - 501.
[2]Anales de Quimica,1996,vol. 92,p. 101 - 107.
[3]Patent: US5072037,1991,A .

8
[ 2012-74-0 ]
[ 55332-38-2 ]

References: [1]Organic Letters,2018,vol. 20,p. 2654 - 2658.
[2]Journal of Agricultural and Food Chemistry,1999,vol. 47,p. 2145 - 2155.

9
[ 2012-74-0 ]
[ 63640-09-5 ]

References: [1]Journal of Agricultural and Food Chemistry,1999,vol. 47,p. 2145 - 2155.

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 5 5.30 g of (-)-isomer rich alpha-isopropyl-4-chlorophenylacetic acid ([alpha]D24 -46.56) was mixed with 2.10 g of potassium hydroxide and 50 ml of ethylene glycol, and the resulting mixture was kept at 170 C. for 15 hours. The reaction solution was cooled to room temperature, diluted with 250 ml of water and acidified to a pH of 1 with concentrated hydrochloric acid. Thereafter, the same procedure as in Example 1 was carried out to obtain 5.19 g of racemized alpha-isopropyl-4-chlorophenylacetic acid. The rate of conversion was about 95%. [alpha]D22.0 -2.07.
		STEP D: D 2-isopropyl-2-p-chlorophenyl-acetic acid 286 ml of 2 N aqueous hydrochloric acid were added with stirring to a mixture of 143 g of the product of Step C and 286 ml of methylene chloride and the mixture was stirred for 15 minutes resulting in 2 limpid phases. The decanted aqueous phase was extracted with methylene chloride and the combined organic phases were washed with water. The aqueous wash waters were extracted with methylene chloride and the organic phases were dried and filtered. The filtrate was evaporated to dryness to obtain 91 g of D 2-isopropyl-2-p-chlorophenyl-acetic acid melting at 105 C. and having a specific rotation of [alpha]D20 =+42 (c=1% in ethanol).
		Suitable examples of the substituted phenyl-acetic acids of the formula (II) are exemplified as follows. ... 4-Methoxy-alpha-iso-propyl-phenylacetic acid 4-Chloro-alpha-ethyl-phenylacetic acid 4-Chloro-alpha-iso-propyl-phenylacetic acid 4-Bromo-alpha-iso-propyl phenylacetic acid ...

11
[ 2012-74-0 ]
[ 186347-51-3 ]
2-(4-chloro-phenyl)-<i>N</i>-[3-(4-cyano-4-<i>o</i>-tolyl-piperidin-1-yl)-propyl]-3-methyl-butyramide [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2000,vol. 10,p. 1621 - 1624.

12
[ 2012-74-0 ]
[ 69741-69-1 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 162 - 166.
[2]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 8574 - 8581.

13
[ 51630-58-1 ]
[ 2012-74-0 ]
[ 39515-47-4 ]

References: [1]Journal of Agricultural and Food Chemistry,2005,vol. 53,p. 7415 - 7420.

14
[ 67-56-1 ]
[ 2012-74-0 ]
[ 86618-06-6 ]

Yield	Reaction Conditions	Operation in experiment
100%	sulfuric acid; at 20℃;	To a solution of commercial <strong>[2012-74-0]2-(4-chlorophenyl)-3-methylbutyric acid</strong> (1 g, 4.7 mmol) in CH3OH (10 mL), few drops of cone. H2SO4 were added, and the resulting mixture was left stirring at room temperature overnight. After solvent evaporation under vacuum, CH2Cl2 (10 mL) and H2O (10 mL) were added; the two phases were separated and the organic one dried over Na2SO4, filtered and evaporated under vacuum to give the intermediate methyl 2-(4-chlorophenyl)-3-methylbutanoate as an <n="18"/>oily residue (quantitative yield). This intermediate was transformed in the related methyl 2-(4-hydroxyphenyl)-3-methylbutanoate according a known procedure3: a mixture of methyl 2-(4-chlorophenyl)-3-methylbutanoate (1.06 g, 4.7 mmol), 60% sodium hydride (0.56 g, 14.1 mmol) and H2O (85 muL, 4.7 mmol) was heated to 45C while kept at argon atmosphere for 3 days (1H-NMR analysis). The solvent was evaporated and the residue diluted with EtOAc and washed with IN HCl (2 x 5 mL); the solvent was evaporated under vacuum and the crude residue was purified by flash chromatography (CHCI3/CH3OH 85: 15) to give the pure intermediate as an oil (0.75 g, 77% yield). 1H-NMR (CDCl3) delta 7.18 (d, 2H, J = 7Hz), 6.82 (d, 2H, J = 7Hz), 5.75 (bs, IH, OH), 3.70 (s, 3H), 3.15 (d, IH, J = 14Hz), 2.55 (m, IH), 1.10 (d, 3H, J = 7Hz), 0.72 (d, 3H, J = 7Hz). The steps of insertion of the triflate group and the following hydrolysis were performed as described1 and 3-methyl-2-[4- (trifluoromethylsulfonyloxy)phenyl]butanoic acid was obtained as a colourless oil (0.91 g, 78% yield calculated from the 4-hydroxy methyl ester derivative). The optical resolution was performed as described.4 (2R)-3-methyl-2-[4- (trifluoromethylsulfonyloxy)phenyl]butanoic acid (0.32 g, 35% yield) was obtained as a white solid. [alpha]D25 (c=l, CH3OH): -50; 1H-NMR (CDCl3) delta 7.55 (d, 2H, J = 7Hz), 7.25 (d, 2H, J = 7Hz), 3.15 (d, IH, J = 14Hz), 2.55 (m, IH), 1.10 (d, 3H, J = 7Hz), 0.72 (d, 3H, J = 7Hz).

References: [1]Patent: WO2007/60215,2007,A2 .Location in patent: Page/Page column 16-17.

15
[ 2012-74-0 ]
[ 916074-16-3 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 162 - 166.

16
[ 2012-74-0 ]
C₁₁H₂₀N₃O₃(C₆H₄Cl) [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 162 - 166.

17
[ 2012-74-0 ]
C₁₆H₁₅N₄OSCl₃ [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 8574 - 8581.

18
[ 2012-74-0 ]
C₂₀H₂₅N₄O₃SCl [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 8574 - 8581.

19
2-amino-1-(4-chloro-phenyl)-3-methyl-butan-1-ol [ No CAS ]
[ 2012-74-0 ]

References: [1]Advanced Synthesis and Catalysis,2000,vol. 342,p. 498 - 501.

20
[ 2012-74-0 ]
[ 67614-32-8 ]

References: [1]Journal of Agricultural and Food Chemistry,1999,vol. 47,p. 2145 - 2155.

21
[ 2012-74-0 ]
[ 67614-33-9 ]

References: [1]Journal of Agricultural and Food Chemistry,1999,vol. 47,p. 2145 - 2155.

22
[ 2012-74-0 ]
[ 66230-05-5 ]

References: [1]Journal of Agricultural and Food Chemistry,1999,vol. 47,p. 2145 - 2155.

23
[ 2012-74-0 ]
[ 66230-04-4 ]

References: [1]Journal of Agricultural and Food Chemistry,1999,vol. 47,p. 2145 - 2155.

24
[ 2012-74-0 ]
[ 71697-10-4 ]

References: [1]Journal of Agricultural and Food Chemistry,1999,vol. 47,p. 2145 - 2155.

25
[ 2012-74-0 ]
[ 66267-77-4 ]

References: [1]Journal of Agricultural and Food Chemistry,1999,vol. 47,p. 2145 - 2155.

26
[ 2012-74-0 ]
(S)-3-[cyano[(S)-2-(4-chlorophenyl)-3-methyl-1-oxobutanoxy]methyl]phenoxyacetic acid [ No CAS ]

References: [1]Journal of Agricultural and Food Chemistry,1999,vol. 47,p. 2145 - 2155.

27
[ 2012-74-0 ]
N-[(S)-4-chloro-2-(1-methylethyl)benzeneacetyl]4-amino-L-phenylalanine [ No CAS ]

References: [1]Journal of Agricultural and Food Chemistry,1999,vol. 47,p. 2145 - 2155.

28
[ 2012-74-0 ]
[ 223905-29-1 ]

References: [1]Journal of Agricultural and Food Chemistry,1999,vol. 47,p. 2145 - 2155.

29
[ 2012-74-0 ]
(S)-cyano[3-(4-aminophenoxy)phenyl]methyl (S)-4-chloro-α-(1-methylethyl)benzeneacetate [ No CAS ]

References: [1]Journal of Agricultural and Food Chemistry,1999,vol. 47,p. 2145 - 2155.

30
[ 2012-74-0 ]
(S)-cyano[3-(4-nitrophenoxy)phenyl]methyl (S)-4-chloro-α-(1-methylethyl)benzeneacetate [ No CAS ]

References: [1]Journal of Agricultural and Food Chemistry,1999,vol. 47,p. 2145 - 2155.

31
[ 2012-74-0 ]
(R)-cyano[3-(4-nitrophenoxy)phenyl]methyl (S)-4-chloro-α-(1-methylethyl)benzeneacetate [ No CAS ]

References: [1]Journal of Agricultural and Food Chemistry,1999,vol. 47,p. 2145 - 2155.

32
[ 2012-74-0 ]
benzyl (S)-[cyano[(S)-2-(4-chlorophenyl)-3-methyl-1-oxobutanoxy]methyl]phenoxyacetate [ No CAS ]

References: [1]Journal of Agricultural and Food Chemistry,1999,vol. 47,p. 2145 - 2155.

33
[ 2012-74-0 ]
benzyl (R)-[cyano[(S)-2-(4-chlorophenyl)-3-methyl-1-oxobutanoxy]methyl]phenoxyacetate [ No CAS ]

References: [1]Journal of Agricultural and Food Chemistry,1999,vol. 47,p. 2145 - 2155.

34
[ 2012-74-0 ]
6-[(S)-3-[cyano[(S)-2-(4-chlorophenyl)-3-methyl-1-oxobutanoxy]methyl]phenoxy]hexanoic acid [ No CAS ]

References: [1]Journal of Agricultural and Food Chemistry,1999,vol. 47,p. 2145 - 2155.

35
[ 2012-74-0 ]
benzyl 6-[(S)-3-[cyano[(S)-2-(4-chlorophenyl) 3-methyl-1-ocobutanoxy]methyl]phenoxy]hexanoate [ No CAS ]

References: [1]Journal of Agricultural and Food Chemistry,1999,vol. 47,p. 2145 - 2155.

36
[ 2012-74-0 ]
benzyl 6-[(R)-3-[cyano[(S)-2-(4-chlorophenyl) 3-methyl-1-ocobutanoxy]methyl]phenoxy]hexanoate [ No CAS ]

References: [1]Journal of Agricultural and Food Chemistry,1999,vol. 47,p. 2145 - 2155.

37
[ 2012-74-0 ]
benzyl 4-[(S)-3-[cyano[(S)-2-(4-chlorophenyl)-3-methyl-1-oxobutanoxy]methyl]phenoxy]benzenepropanoate [ No CAS ]

References: [1]Journal of Agricultural and Food Chemistry,1999,vol. 47,p. 2145 - 2155.

38
[ 2012-74-0 ]
benzyl 4-[(R)-3-[cyano[(S)-2-(4-chlorophenyl)-3-methyl-1-oxobutanoxy]methyl]phenoxy]benzenepropanoate [ No CAS ]

References: [1]Journal of Agricultural and Food Chemistry,1999,vol. 47,p. 2145 - 2155.

39
[ 2012-74-0 ]
(S)-2-[(S)-2-[(S)-2-(4-Chloro-phenyl)-3-methyl-butyrylamino]-3-(4-nitro-phenyl)-propionylamino]-3-(4-nitro-phenyl)-propionic acid [ No CAS ]

References: [1]Journal of Agricultural and Food Chemistry,1999,vol. 47,p. 2145 - 2155.

40
[ 106-43-4 ]
Ni(CO)4 [ No CAS ]
[ 2012-74-0 ]

References: [1]Bulletin of the Academy of Sciences of the USSR Division of Chemical Science,1986,vol. 35,p. 1239 - 1242.
Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya,1986,p. 1365 - 1368.

41
[ 2012-74-0 ]
[ 51630-58-1 ]

References: [1]Bulletin of the Academy of Sciences of the USSR Division of Chemical Science,1986,vol. 35,p. 1239 - 1242.
Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya,1986,p. 1365 - 1368.

42
[ 622-95-7 ]
[ 2012-74-0 ]

References: [1]Bulletin of the Academy of Sciences of the USSR Division of Chemical Science,1986,vol. 35,p. 1239 - 1242.
Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya,1986,p. 1365 - 1368.

43
[ 140-53-4 ]
[ 2012-74-0 ]

44
[ 2012-74-0 ]
[ 131691-16-2 ]

References: [1]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,1990,vol. 29,p. 1034 - 1040.

45
[ 2012-74-0 ]
[ 131691-17-3 ]

References: [1]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,1990,vol. 29,p. 1034 - 1040.

46
[ 2012-74-0 ]
[ 131691-10-6 ]

References: [1]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,1990,vol. 29,p. 1034 - 1040.

47
[ 2012-74-0 ]
[ 131691-14-0 ]

References: [1]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,1990,vol. 29,p. 1034 - 1040.

48
[ 2012-74-0 ]
[ 131691-15-1 ]

References: [1]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,1990,vol. 29,p. 1034 - 1040.

49
[ 2012-74-0 ]
[ 2627-86-3 ]
[ 73591-05-6 ]
[ 71656-96-7 ]
[ 63640-09-5 ]

Yield	Reaction Conditions	Operation in experiment
	In water; butan-1-ol; at 50 - 70℃; for 6.5h;Heating / reflux;Purification / work up;	In a suitable reactor 566g of () CPA and 2430 g of 30% aqueous butanol was charged under stirring. A solution of 322g of (-) PEA in 966g of 30 % aqueous n-butanol was added to above solution at temperature ranging from 50-70C in about 60 minutes and the contents were heated to reflux for about 90 minutes. The reaction mixture was allowed to come to about 50C in about 240 minutes and filtered off. The filtrate was weighed (2507 g) and treated for recovery of R enriched (-) CPA isomer along with washings of wet cake (850g) as described in example (L LA). The cake (757 g) obtained was washed twice (2 x 390 g) with 30% aq. n-butanol and filtered off. The cake (680. 0g) was further recrystallised using 2430 g of 30 % aqueous n-butanol by heating to reflux temperature (Z90C) FOR about 120 minutes and then allowed to cool to 52C in about 150 minutes and filtered off. The weight of cake and filtrate being 527.7g and 2523 g respectively. The wet cake (527.7 g) was refined in 1562 g of 30% aqueous n-butanol by refluxing for 35 minutes at 90C and the contents were cooled to 52C in about 60 minutes, filtered and weighed. The weight of cake and filtrate obtained was 406. 3g and 1617g respectively. The cake was dried to a constant weight (306 g). The dried PEA salt (306g), distilled water (300g), toluene (900g) were charged into a suitable reactor successively and contents were stirred well. 250G of 40% H2S04 was added over a period of 10-30 minutes and mixed well for 20-30 minutes. The separated aqueous layer containing PEA-HS04 (641 g) was stored for recovery of S (-) PEA. The toluene layer is made free of traces of acid and concentrated to obtain (S+) CPA (197g). Dry weight OF S (+) CPA = 197.0 g. [A] D= +45.129 [CHC13, 6.01]

References: [1]Patent: WO2004/60850,2004,A1 .Location in patent: Page 11-12.

50
[ 2012-74-0 ]
[ 2627-86-3 ]
[ 71656-96-7 ]

Yield	Reaction Conditions	Operation in experiment
	In propan-1-ol; water; at 20 - 88℃; for 3 - 3.16667h;Heating / reflux;Purification / work up;	In a suitable reaction vessel, 42.2g of ()-CPA and 138. Og of 30% aqueous n- propanol was charged and heated to form a solution. A solution of 14.2g (-) PEA in 42g of 30% aqueous n-propanol was added to the above solution at 52C. The mixture was heated to the reflux temperature for (88C) about 60 minutes and the contents were allowed to reach to 37C under stirring in about 120 minutes. The precipitated (+) CPA- (-) PEA salt (cake) was filtered off and washed with 50g of 30% aqueous n-propanol twice separating the filtrate each time. The wet cake was dried and weighed. The general procedure followed for liberation of the (+) CPA from its amine salt was described below. A small portion of the salt (2. 0G) was extracted with 30ML of 40% Sulphuric acid. The liberated (+) CPA, was extracted with 2 x 20 ml of DCM and concentrated to obtain (+) CPA, which was dried and analysed for its optical purity by POLORIMETRY. The same procedure was followed for all the examples described below. Dry weight = 23.16 g. aD = +41. 09 [CHC13, C = 6.00]; EXAMPLE-3; To 42.2g of () CPA was added under stirring 94. 0g of 20% aqueous n-propanol to make a solution. A solution of 14.2g of (-) PEA in 71. Og of propanol-water (20%) was added to the above solution at 50C and the mixture was heated to reflux temperature for about 60- 70 minutes, allowed to cool to 30C under stirring in about 120 minutes. Precipitated salt was filtered and cake was washed with 20% aqueous n-propanol twice, separating the filtrate each time. Cake obtained was dried and weighed. Dry weight = 23.44 G. aD = + 40.56 [CHC13 ; C=6.05]; EXAMPLE-8; To 42.8g of () CPA was added under stirring 186. 0g of 30% aqueous n-propanol to form a solution. A solution of 14.2g of (-) PEA in 71. OG OF 30% aqueous n-propanol was added to the above solution at 55C in 30 minutes. The reaction mixture was heated to reflux for about 150 minutes and the contents were allowed to reach to room temperature. The precipitated salt of (+) CPA- (-) PEA was filtered off. The cake was re-dissolved in 50g of the solvent system used for resolution of (+) CPA, heated to reflux for about 30 minutes cooled and filtered off. The same procedure was repeated again and the cake obtained was dried and weighed. Dry Weight = 21. 01 G. AD = + 42.86 [CHCL3 ; C=6.04]
	In propan-1-ol; water; butan-1-ol; at 20 - 70℃; for 3.33333 - 3.83333h;Heating / reflux;Purification / work up;	To 42. 1g of () CPA was added under stirring, 155g of 21% aqueous n-butanol-n- propanol to form a homogeneous solution. A solution of 14.2 g of (-) PEA in 105 G of 21% aqueous n-butanol-n-propanol was added to the above solution at 70C in about 50 minutes and the mixture was heated to reflux for about an hour, allowed to reach to room temperature under stirring in about 90-120 minutes. Crystallized (+) CPA (-) PEA salt was filtered off and cake was washed twice with 50g of same solvent system used for reaction separating the filtrate each time. Wet cake was dried and weighed. Dry WEIGHT = 21. 17 9-AD + 41. 57 [CHC13 ; C=6.06]
	In water; butan-1-ol; at 35 - 93℃; for 1.5 - 3.58333h;Heating / reflux;Purification / work up;	To 42.26g of (+)-CPA was added under stirring 120g of 20% aqueous n-butanol to form a solution. A solution of 14.26g of (-) PEA in 40g of 20% aqueous n-butanol was added to above solution at 55C. The reaction mixture was refluxed for about 90 minutes and allowed to cool slowly to 37C in about 90-120 minutes. The precipitated CPA- (-) PEA salt (cake) was filtered off and washed with 50G of 20% aqueous butanol under stirring twice separating the filtrate each time. The wet cake was dried and weighed. Dry weight = 23.5 g. aD =+41. 14 [CHC13 ; C=6.23]; EXAMPLE-5; To 42.2g of CPA was added under stirring 45. Og of saturated solution of butanol in water to make a homogeneous solution. A solution of 14.4g (-) PEA in 114g of saturated solution of butanol in water was added to the above solution at a temperature ranging between 45-52C and the mixture was heated to reflux temperature for about 65 minutes, allowed to cool to 37C in about 150 minutes under stirring. Precipitated salt was filtered. Cake was washed with 50g of 10% aqueous butanol twice, separating the filtrate each time. Cake obtained was dried and weighed. Dry Weight = 26.71 G. aD = + 40.79 [CHC13 ; C=6. 03]; EXAMPLE-10; TO 42. 2G OF () CPA HAVING [A] D-3 was added under stirring, 138g 30% aqueous n-butanol to form a solution. A solution of 14. 2 of (-) PEA in 42.2g of above solvent system was added to the already made (+)-CPA solution at 50-60C in 30-50 minutes. The reaction mixture was refluxed for about 60-80 minutes, cooled to room temperature and filtered off. Precipitated salt (cake) was washed twice with 50g of the solvent system used for reaction, separating the filtrate each time. Wet cake was dried and weighed. Dry weight = 23. 15 g. [A] D= + 38.11 [CHCL3 ; C = 6.05]; EXAMPLE-12 The glass lined reactor equipped with stirrer, heater exchanger, dropping funnel and a thermovel is charged with 6.36kg of () CPA, 19.17kg butanol, 8.79kg water under stirring and heated to 50-60C. 2.27kg OF S (-) Phenylethylamine (PEA) is fed into the reactor over a period of 20-30 minutes. The contents are heated with steam to vigorous reflux (92-93 by circulating cold water in the heat exchanger and reflux is contd. for 60 minutes, followed by gradual cooling of the reaction mixture to 35C over a period of 120 minutes and is filtered off (28.32 kg ML-I). The (+) CPA- (-) PEA salt (cake) obtained is dried under vacuum for a period of 20-30 minutes. The cake is recharged into the reactor followed by of 6.38kg of butanol, 2.78kg of water and contents are stirred for a period of 20 minutes, filtered under vacuum to dryness to obtain 10.02kg of washings (WS-I) and 6.38kg of cake. The filtrate (ML-1) and washings (WS-1) are combined and concentrated for recovery of R enriched (-) CPA. The cake (6.38kg) obtained is charged into the reactor and recrystallized using 19.18 kg of Butanol and 8.3kg of water by heating the reaction mixture to vigorous reflux under stirring (92-93C), maintained at that temperature for 60-75 minutes and then allowed to cool to 55-60C over a period of 120minutes. RECRYSTALLIZED slurry is filtered under vacuum (120- 100mm). The filtrate obtained (27.06kg) is kept in storage tank to be used for subsequent batches of recrystallization of cake. The cake obtained (5.26kg) is further refined by charging into the reactor using 4.47kg butanol, 1.93kg of water and heating to reflux (92-93C) for 30- 40 minutes and then cooled to 45C over a period ranging from 45-60 minutes under stirring and the slurry is filtered after removing most of the solvent the cake is dried under vacuum (120-100 mm) for 10-15 minutes. The filtrate (5.3 kg) is stored and recycled to be used for refinement of further batches of the salt. The cake (3.98 kg) is dried in a jacked vacuum tray drier at 46-48C under reduced pressure till a constant wt. (3.08 kg) is obtained.

	In water; toluene; at 40℃; for 3.66667 - 3.83333h;Heating / reflux;Purification / work up;	To 42.2g of ( :) CPA was added under stirring, 85g of 3.5% aqueous toluene to form a solution. A solution of 14.2g (-) PEA in 56g of 3.5% aqueous toluene was added to above solution at 40C in 20-30 minutes and contents were heated to reflux for about 200 minutes and cooled to room temperature. Precipitated salt was filtered and cake was washed with 75g of toluene twice separating the filtrate each time. Wet cake was dried to a constant weight. Dry weight = 34. 00G. [a] D = +34. 528 [CHC13 ; C = 6. 02]
	In 2-methyl-propan-1-ol; water; at 37 - 60℃; for 3.08333h;Heating / reflux;Purification / work up;	To 42.2g of ()-CPA was added under stirring, 80.0 g of 20% aqueous isobutyl alcohol to form a solution. A solution of 14.2 g (-) PEA in 78g of 20% aqueous isobutyl alcohol was added to above solution at 60C. The reaction mixture was heated to reflux temperature for about 65 minutes and the contents were allowed to reach to 37C under stirring in about 120 minutes. The precipitated salt was filtered and cake was washed with 50g of 20% aqueous isobutylalcohol twice. The cake obtained is dried and weighed. Dry weight: 25.60g. ap = +40.78 [CHC13 ; C = 6.06]

References: [1]Patent: WO2004/60850,2004,A1 .Location in patent: Page 9-11.
[2]Patent: WO2004/60850,2004,A1 .Location in patent: Page 10-11.
[3]Patent: WO2004/60850,2004,A1 .Location in patent: Page 9-11; 13.
[4]Patent: WO2004/60850,2004,A1 .Location in patent: Page 11.
[5]Patent: WO2004/60850,2004,A1 .Location in patent: Page 10.

51
[ 2012-74-0 ]
[ 2627-86-3 ]
[ 55332-38-2 ]

References: [1]Patent: WO2004/60850,2004,A1 .Location in patent: Page 15.
[2]Patent: WO2004/60850,2004,A1 .Location in patent: Page 17.
[3]Patent: WO2004/60850,2004,A1 .Location in patent: Page 17.
[4]Patent: WO2004/60850,2004,A1 .Location in patent: Page 16-20.
[5]Patent: WO2004/60850,2004,A1 .Location in patent: Page 16.
[6]Patent: WO2004/60850,2004,A1 .Location in patent: Page 16.
[7]Patent: WO2004/60850,2004,A1 .Location in patent: Page 16.
[8]Patent: WO2004/60850,2004,A1 .Location in patent: Page 16.
[9]Patent: WO2004/60850,2004,A1 .Location in patent: Page 18.
[10]Patent: WO2004/60850,2004,A1 .Location in patent: Page 17.
[11]Patent: WO2004/60850,2004,A1 .Location in patent: Page 16.
[12]Patent: WO2004/60850,2004,A1 .Location in patent: Page 16.
[13]Patent: WO2004/60850,2004,A1 .Location in patent: Page 17.
[14]Patent: WO2004/60850,2004,A1 .Location in patent: Page 16-17.
[15]Patent: WO2004/60850,2004,A1 .Location in patent: Page 17.
[16]Patent: WO2004/60850,2004,A1 .Location in patent: Page 16.
[17]Patent: WO2004/60850,2004,A1 .Location in patent: Page 16.
[18]Patent: WO2004/60850,2004,A1 .Location in patent: Page 16.
[19]Patent: WO2004/60850,2004,A1 .Location in patent: Page 17.

52
[ 79-37-8 ]
[ 2012-74-0 ]
[ 69741-69-1 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonia; In N,N-dimethyl-formamide;	EXAMPLE 1 To a solution of 4.25 g (20 mmol) of 2-(4-chlorophenyl)-3-methylbutanoic acid in 30 ml of ether containing one drop of N,N-dimethylformamide is added dropwise 3.81 g (30 mmol) of oxalyl chloride. The solution is stirred at RT until gas evolution ceases. The solvent and excess oxalyl chloride are removed in vacuo and the residue is taken up in 30 ml of ether. This solution is then added dropwise at 0-5 to 4.86 g (40 mmol) of a 14% w/w aqueous solution of ammonia. After stirring the mixture for 30 minutes at 0-5, the aqueous layer is removed. The ethereal solution is washed with water, dried over sodium sulfate, filtered and concentrated in vacuo to obtain 2-(4-chlorophenyl)-3-methylbutyramide.

References: [1]Patent: US4254264,1981,A .

53
[ 79-37-8 ]
[ 2012-74-0 ]
N-methyl-2-(4-chlorophenyl)-3-methylbutyramide [ No CAS ]
3-phenoxybenzyl N-methyl-2-(4-chlorophenyl)-3-methylbutanimidate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 2 Following the methods of Example 1, 2-(4-chlorophenyl)-3-methylbutanoic acid is reacted with oxalyl chloride and aqueous methylamine to give N-methyl-2-(4-chlorophenyl)-3-methylbutyramide, which is then combined with 3-phenoxybenzyl bromide and AgBF4, yielding 3-phenoxybenzyl N-methyl-2-(4-chlorophenyl)-3-methylbutanimidate, MS m/e 407 (M+).

References: [1]Patent: US4254264,1981,A .

54
[ 74771-59-8 ]
[ 2012-74-0 ]
[ 74771-47-4 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In 5,5-dimethyl-1,3-cyclohexadiene;	EXAMPLE 4 Preparation of [4-(2-methylbenzyl)-1,3,4-oxadiazolin-5-on-2-yl]-methyl 2-(4-chlorophenyl)-3-methyl-butyrate (compound No. 6). A solution of 2-chloromethyl-4-(2-methylbenzyl)-1,3,4-oxadiazolin-5-one (13.3 g) in xylene (35 cc) is added in the course of 20 minutes to a solution of <strong>[2012-74-0]2-(4-chlorophenyl)-3-methyl-butyric acid</strong> (19 g) and triethylamine (11.7 cc) in xylene (175 cc) heated to 110 C. The reaction mixture is heated at the reflux temperature for 4 hours and, after cooling, is washed successively with water (100 cc), a 3.5% strength aqueous hydrochloric acid solution (100 cc), a 4% strength aqueous sodium carbonate solution (100 cc) and water (100 cc). After drying, decolorizing over animal charcoal and concentrating under reduced pressure, the residue obtained is purified by chromatography on a silica column and gives [4-(2-methylbenzyl)-1,3,4-oxadiazolin-5-on-2-yl]-methyl 2-(4-chlorophenyl)-3-methylbutyrate (11.2 g) in the form of an oil.

References: [1]Patent: US4259497,1981,A .

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CAS No.: 2012-74-0

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CAS No.: 2012-74-0

Alternative Products

Product Details of 2-(4-Chlorophenyl)-3-methylbutyric Acid

Safety of 2-(4-Chlorophenyl)-3-methylbutyric Acid

Application In Synthesis of 2-(4-Chlorophenyl)-3-methylbutyric Acid

[ 2012-74-0 ] Synthesis Path-Downstream 1~54

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