[ CAS No. 85953-29-3 ]

Name: 85953-29-3|Methyl 2-chloro-4-fluorobenzoate|98%
Brand: Ambeed
SKU: A527402
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Quality Control of [ 85953-29-3 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 85953-29-3 ]

Product Details of [ 85953-29-3 ]

CAS No. :	85953-29-3	MDL No. :	MFCD00173937
Formula :	C₈H₆ClFO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	YZDLPZNWBRBZMZ-UHFFFAOYSA-N
M.W :	188.58	Pubchem ID :	2763551
Synonyms :

Calculated chemistry of [ 85953-29-3 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.12
Num. rotatable bonds :	2
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	42.69
TPSA :	26.3 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-4.94 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.2
Log Po/w (XLOGP3) :	3.53
Log Po/w (WLOGP) :	2.69
Log Po/w (MLOGP) :	2.94
Log Po/w (SILICOS-IT) :	2.75
Consensus Log Po/w :	2.82

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-3.47
Solubility :	0.0637 mg/ml ; 0.000338 mol/l
Class :	Soluble
Log S (Ali) :	-3.77
Solubility :	0.0323 mg/ml ; 0.000171 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.37
Solubility :	0.0803 mg/ml ; 0.000426 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	2.0
Synthetic accessibility :	1.62

Safety of [ 85953-29-3 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H319	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 85953-29-3 ]

* 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 [ 85953-29-3 ]
Downstream synthetic route of [ 85953-29-3 ]

[ 85953-29-3 ] Synthesis Path-Upstream 1~8

1
[ 67-56-1 ]
[ 2252-51-9 ]
[ 85953-29-3 ]

Yield	Reaction Conditions	Operation in experiment
99%	at 20℃; for 24 h;	A mixture of 2-chloro-4-fluorobenzoic acid (6.5 g, 37 mmol) in methanol (100 mL) was treated with chlorotrimethylsilane (14.0 mL, 111 mmol), stirred 24h at room temperature and evaporated. The residue was dissolved in dichloromethane, washed with sodium bicarbonate, dried (sodium sulfate) and evaporated to provide 2-chloro-4-fluoro-benzoic acid methyl ester (7.01 g, 99percent yield) as a pale yellow oil. 1H-NMR (CDCl3, 500 MHz) 7.93 (m, 1H), 7.22 (m, 1H), 7.06 (m, 1H), 3.95 (s, 3H) ppm; MS (FIA) 189.1 (M+H); HPLC (Method A) 3.37 min.
92%	at 60℃; for 10 h;	General procedure: To a mixture of the appropriate substituted benzoic acid (8.6 mmol) in methanol (10 mL) was added sulfuric acid (0.5 mL),and the mixture was heated overnight at 60 °C. The reaction was then allowed to cool to room temperature, the solvent was reduced by evaporation, and the residue was diluted in cold water and neutralized with sodium hydrogen carbonate solution. The aqueous solution was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous MgSO₄, filtered, and concentrated in vacuo to give the title compound as oil.

Reference： [1] Patent: WO2004/46120, 2004, A2, . Location in patent: Page 175; 176
[2] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 21, p. 9524 - 9535
[3] European Journal of Medicinal Chemistry, 2015, vol. 90, p. 195 - 208
[4] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 8, p. 3130 - 3141

2
[ 1996-41-4 ]
[ 79-22-1 ]
[ 85953-29-3 ]

Reference： [1] Patent: US4670046, 1987, A,
[2] Patent: US4427438, 1984, A,
[3] Patent: US4431822, 1984, A,
[4] Patent: US4437877, 1984, A,
[5] Patent: US4452981, 1984, A,

3
[ 13324-11-3 ]
[ 85953-29-3 ]

Reference： [1] Tetrahedron Letters, 2010, vol. 51, # 14, p. 1906 - 1909
[2] Journal of Fluorine Chemistry, 1993, vol. 63, # 1-2, p. 25 - 30

4
[ 2252-51-9 ]
[ 74-88-4 ]
[ 85953-29-3 ]

Reference： [1] Patent: JP2015/54844, 2015, A, . Location in patent: Paragraph 0115-0117

5
[ 67-56-1 ]
[ 21900-54-9 ]
[ 85953-29-3 ]

Reference： [1] Journal of Medicinal Chemistry, 2018, vol. 61, # 19, p. 8670 - 8692

6
[ 85953-29-3 ]
[ 127510-96-7 ]

Yield	Reaction Conditions	Operation in experiment
73%	With copper(l) cyanide In 1-methyl-pyrrolidin-2-one at 195℃; for 1.5 h; Inert atmosphere	Example 123Exam le 123 a Methyl 2-Cyano-4-fluorobenzoate 123a123aA 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with methyl 2-chloro-4-fluorobenzoate (10.0 g, 53.0 mmol), copper (I) cyanide (5.22 g, 58.3 mmol) and 2-methylpyrolidinone (30 mL). After heating at 195 °C for 1.5 h, the reaction mixture was cooled to room temperature and poured into water (600 mL). The resulting suspension was filtered, and the filter cake was washed with water (100 mL). To the solid obtained was then added a solution of sodium cyanide (3.00 g, 61.2 mmol) in water (110 mL), and the reaction mixture was stirred at room temperature for 50 min. After this time, ethyl acetate (500 mL) was added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (2 x 10 mL), and the organic extracts were combined, dried over sodium sulfate, filtered and concentrated under CGIPHARM60WO reduced pressure. The resulting residue was purified by flash chromatography to afford 123a in 73percent yield (6.99 g) as a white solid: mp 92-93 °C; ^]H NMR (500 MHz, CDC1₃) δ 8.18 (dd, 1H, / = 9.0, 5.5 Hz), 7.50 (dd, 1H, / = 8.0, 2.5 Hz), 7.38 (m, 1H), 4.01 (s, 3H).

Reference： [1] Patent: WO2012/31004, 2012, A1, . Location in patent: Page/Page column 113-114

7
[ 544-92-3 ]
[ 85953-29-3 ]
[ 127510-96-7 ]

Reference： [1] Journal of Medicinal Chemistry, 1992, vol. 35, # 24, p. 4613 - 4627

8
[ 85953-29-3 ]
[ 1260666-80-5 ]

Reference： [1] Patent: WO2012/31004, 2012, A1,

[ 85953-29-3 ] Synthesis Path-Downstream 1~69

1
[ 13324-11-3 ]
[ 85953-29-3 ]

Reference： [1]Tetrahedron Letters,2010,vol. 51,p. 1906 - 1909
[2]Journal of Fluorine Chemistry,1993,vol. 63,p. 25 - 30

2
[ 544-92-3 ]
[ 85953-29-3 ]
[ 127510-96-7 ]

Reference： [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 4613 - 4627

3
[ 110-85-0 ]
[ 85953-29-3 ]
[ 234082-19-0 ]

Yield	Reaction Conditions	Operation in experiment
	With dimethyl sulfoxide; In water; ethyl acetate;	Intermediate 34: Methyl 2-chloro-4-(piperazin-1-yl)-benzoate Dimethyl sulfoxide (15 ml) was added to 4.5 g of piperazine to prepare a suspension, and 3.3 g of <strong>[85953-29-3]methyl 2-chloro-4-fluorobenzoate</strong> was added to the suspension. The mixture was stirred at 80 C. for one hr. The temperature of the system was then returned to room temperature. Ethyl acetate (1,000 ml) and 500 ml of water were added thereto. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under the reduced pressure to prepare 3.7 g of the title compound. Physicochemical Properties of Intermediate 34

Reference： [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 2089 - 2108
[2]Patent: US6451800,2002,B1

4
[ 85953-29-3 ]
[ 100960-18-7 ]

Reference： [1]Acta Crystallographica, Section C: Crystal Structure Communications,2006,vol. 62,p. o618-o624

5
[ 506-59-2 ]
[ 67-68-5 ]
[ 85953-29-3 ]
[ 773874-76-3 ]

Yield	Reaction Conditions	Operation in experiment
99%	With potassium carbonate;	a) 2-Chloro-4-dimethylamino-benzoic acid methyl ester (1a) To a stirred solution of 4,00g (20.6 mmol) <strong>[85953-29-3]2-chloro-4-fluoro-benzoic acid methyl ester</strong> (Apollo) and 60 ml dimethylsulphoxid are added 2.03 g (24,7 mmol) dimethylamine hydrochloride and 5,97 g (43.2 mmol) potassium carbonate. The reaction mixture is stirred over night and is reduced with high vacuum rotation evaporator at 65C. The residue is diluted with dichloromethane, washed twice with water. The combined water phases are extracted with dichloromethane. The combined dichloromethane phases are washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude product 1a is obtained in 99% yield (4,36 g, 20.4 mmol) and is used for the next step without purification. MS-ESI: 213/215 (M+ +1, 64/48).

Reference： [1]Patent: EP1897885,2008,A1

6
[ 506-59-2 ]
[ 85953-29-3 ]
[ 773874-76-3 ]

Yield	Reaction Conditions	Operation in experiment
99%	With potassium carbonate; In dimethyl sulfoxide;	To a stirred solution of 4,00g (20.6 mmol) <strong>[85953-29-3]2-chloro-4-fluoro-benzoic acid methyl ester</strong> (Apollo) and 60 ml dimethylsulphoxid are added 2.03 g (24,7 mmol) dimethylamine hydrochloride and 5,97 g (43.2 mmol) potassium carbonate. The reaction mixture is stirred over night and is reduced with high vacuum rotation evaporator at 65C. The residue is diluted with dichloromethane, washed twice with water. The combined water phases are extracted with dichloromethane. The combined dichloromethane phases are washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude product 2.3.3.a is obtained in 99% yield (4,36 g, 20.4 mmol) and is used for the next step without purification. MS-ESI: 213/215 (M+ +1, 64 / 48). Elementary analysis: Calculated: C 56.21% H 5.66% N 6.56% Determined: C 56.39% H 5,67% N 6.54%
99%	With potassium carbonate; In dimethyl sulfoxide;	Example 1a) 2-Chloro-4-dimethylamino-benzoic acid methyl ester (1a)To a stirred solution of 4,0Og (20.6 mmol) <strong>[85953-29-3]2-chloro-4-fluoro-benzoic acid methyl ester</strong> (Apollo) and 60 ml dimethylsulphoxid were added 2.03 g (24,7 mmol) dimethylamine hydrochloride and 5,97 g (43.2 mmol) potassium carbonate. The reaction mixture was stirred over night and is reduced with high vacuum rotation evaporator at 65C. The residue was diluted with dichloromethane, washed twice with water. The combined water phases were extracted with dichloromethane. The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude product 1a was obtained in 99 % yield (4,36 g,20.4 mmol) and was used for the next step without purification.MS-ESI: 213 / 215 (M+ +1 , 64 / 48). Elementary analysis:Calculated: C 56.21% H 5.66% N 6.56% Determined: C 56.39% H 5,67% N 6.54%

Reference： [1]Patent: EP1916003,2008,A1 .Location in patent: Page/Page column 21-22
[2]Patent: WO2008/28688,2008,A2 .Location in patent: Page/Page column 84

7
[ 85953-29-3 ]
[ 234082-20-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 2089 - 2108

8
[ 85953-29-3 ]
[ 234082-21-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 2089 - 2108

9
[ 85953-29-3 ]
[ 234081-34-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 2089 - 2108

10
[ 85953-29-3 ]
(S)-2-Benzenesulfonylamino-3-[2-chloro-4-(4-pyrimidin-2-yl-piperazin-1-yl)-benzoylamino]-propionic acid; compound with trifluoro-acetic acid [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 2089 - 2108

11
[ 85953-29-3 ]
[ 911312-88-4 ]

Reference： [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 4388 - 4397

12
[ 85953-29-3 ]
[ 313674-12-3 ]

Reference： [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 4388 - 4397

13
[ 85953-29-3 ]
[ 233755-70-9 ]

Reference： [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 4388 - 4397

14
[ 85953-29-3 ]
[ 220461-68-7 ]

Reference： [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 4388 - 4397
[2]Patent: US6235900,2001,B1

15
[ 85953-29-3 ]
[ 911312-93-1 ]

Reference： [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 4388 - 4397
[2]Organic Letters,2019,vol. 21,p. 4535 - 4539

16
[ 85953-29-3 ]
[ 192513-60-3 ]

Reference： [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 4388 - 4397
[2]Organic Letters,2019,vol. 21,p. 4535 - 4539

17
[ 85953-29-3 ]
[ 896723-26-5 ]

Reference： [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 4388 - 4397

18
[ 85953-29-3 ]
2-chloro-4-piperidin-1-yl-benzoyl chloride [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 4388 - 4397

19
[ 85953-29-3 ]
[ 175153-55-6 ]

Reference： [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 4388 - 4397

20
[ 85953-29-3 ]
[ 313674-11-2 ]

Reference： [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 4388 - 4397

21
[ 85953-29-3 ]
(2-chloro-4-pyrazol-1-yl-phenyl)-(2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-methanone [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 4388 - 4397

22
[ 85953-29-3 ]
OPC₂₃h [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 4388 - 4397
[2]Journal of Medicinal Chemistry,2018,vol. 61,p. 8670 - 8692

23
[ 85953-29-3 ]
(2-chloro-4-(pyrrolidine-1-yl)phenyl)(2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl) methanone [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 4388 - 4397
[2]Organic Letters,2019,vol. 21,p. 4535 - 4539

24
[ 85953-29-3 ]
(2-chloro-4-morpholin-4-yl-phenyl)-(2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-methanone [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 4388 - 4397

25
[ 85953-29-3 ]
(2-chloro-4-piperidin-1-yl-phenyl)-(2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-methanone [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 4388 - 4397

26
[ 85953-29-3 ]
(2-chloro-4-pyrrolidin-1-yl-phenyl)-(7-chloro-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-methanone [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 4388 - 4397

27
[ 85953-29-3 ]
[ 127511-00-6 ]

Reference： [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 4613 - 4627

28
[ 85953-29-3 ]
C₁₂H₉FN₂O₃ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 4613 - 4627

29
[ 85953-29-3 ]
Cyano-[6-fluoro-3-oxo-2,3-dihydro-isoindol-(1Z)-ylidene]-acetic acid ethyl ester [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 4613 - 4627

30
[ 85953-29-3 ]
[ 127511-34-6 ]

Reference： [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 4613 - 4627

31
[ 85953-29-3 ]
[ 1026423-28-8 ]

Reference： [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 4613 - 4627

32
[ 85953-29-3 ]
C₁₄H₁₁FN₂O₅ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 4613 - 4627

33
[ 1453-58-3 ]
[ 85953-29-3 ]
[ 220462-02-2 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 120℃; for 6.0h;	20.85 g of <strong>[85953-29-3]methyl 2-chloro-4-fluorobenzoate</strong> were dissolved in 150 ml of N-methylpyrrolidone, 30.68 g of potassium carbonate and 9.38 ml of 3-methylpyrazole were added thereto, and the mixture was stirred at 120 C for 3 hours.. Additionally, thereto was added 1.79 ml of 3-methylpyrazole, and the mixture was stirred at 120 C for 3 hours.. The reaction solution was cooled, mixed with water, and extracted with EtOAc. The organic layer was washed with water and brine, and then dried over magnesium sulfate.. The solvent was evaporated, and then the residue was purified by silica gel column chromatography (hexane-EtOAc (20:1)) to obtain 9.25 g of methyl 2-chloro-4-(3-metyl-1H-pyrazol-1-yl)benzoate.

Reference： [1]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 9524 - 9535
[2]Patent: EP1445253,2004,A1 .Location in patent: Page 19
[3]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 5796 - 5800
[4]Bioorganic and Medicinal Chemistry,2009,vol. 17,p. 3130 - 3141
[5]Journal of Medicinal Chemistry,2018,vol. 61,p. 8670 - 8692

34
[ 67-56-1 ]
[ 2252-51-9 ]
[ 85953-29-3 ]

Yield	Reaction Conditions	Operation in experiment
99%	With chloro-trimethyl-silane; at 20℃; for 24.0h;	A mixture of 2-chloro-4-fluorobenzoic acid (6.5 g, 37 mmol) in methanol (100 mL) was treated with chlorotrimethylsilane (14.0 mL, 111 mmol), stirred 24h at room temperature and evaporated. The residue was dissolved in dichloromethane, washed with sodium bicarbonate, dried (sodium sulfate) and evaporated to provide 2-chloro-4-fluoro-benzoic acid methyl ester (7.01 g, 99% yield) as a pale yellow oil. 1H-NMR (CDCl3, 500 MHz) 7.93 (m, 1H), 7.22 (m, 1H), 7.06 (m, 1H), 3.95 (s, 3H) ppm; MS (FIA) 189.1 (M+H); HPLC (Method A) 3.37 min.
92%	With sulfuric acid; at 60℃; for 10.0h;	General procedure: To a mixture of the appropriate substituted benzoic acid (8.6 mmol) in methanol (10 mL) was added sulfuric acid (0.5 mL),and the mixture was heated overnight at 60 C. The reaction was then allowed to cool to room temperature, the solvent was reduced by evaporation, and the residue was diluted in cold water and neutralized with sodium hydrogen carbonate solution. The aqueous solution was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give the title compound as oil.

Reference： [1]Patent: WO2004/46120,2004,A2 .Location in patent: Page 175; 176
[2]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 9524 - 9535
[3]Angewandte Chemie - International Edition,2019,vol. 58,p. 13499 - 13506
Angew. Chem.,2019,vol. 131,p. 13633 - 13640,8
[4]European Journal of Medicinal Chemistry,2015,vol. 90,p. 195 - 208
[5]Bioorganic and Medicinal Chemistry,2009,vol. 17,p. 3130 - 3141

35
[ 85953-29-3 ]
2-chloro-4-(5-methylpyrazol-1-yl)benzoic acid methyl ester [ No CAS ]
[ 220462-02-2 ]

Yield	Reaction Conditions	Operation in experiment
	In N-methyl-acetamide; 3-Methylpyrazole;	EXAMPLE 96 2-Chloro-4-(3-methyl-1H-pyrazol-1-yl)-benzoic Acid Methyl Ester and 2-Chloro-4-(5-methyl-1H-pyrazol-1-yl)-benzoic Acid Methyl Ester A suspension of hexane washed potassium hydride (0.424 g) in dimethylformamide (5 ml) was treated in one portion with 3-methyl pyrazole (0.85 ml) while stirring. After the gas evolution ceased, <strong>[85953-29-3]2-chloro-4-fluorobenzoic acid methyl ester</strong> (2.0 g, 10.6) was added to the clear solution and heated at 130 C. for 15 minutes. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and brine. The organic phase was washed with water, brine, and dried over anhydrous sodium sulfate. Removal of solvent in vacuo afforded 2.2 g of a yellow oil. (Note: 20% hydrolysis of the ester was detected by analysis of the NMR spectrum of the crude product). The desired regioisomer 2-chloro-4-(3-methyl-1H-pyrazol-1-yl)-benzoic acid methyl ester was isolated from the other isomer (described below) by flash column chromatography on silica gel (Merck 60) eluding with dichloromethane-hexane 2:1) to give 1.55 g of the title compound as a colorless solid. MS (EI m/z: 250/252 (M)+. The 5-regioisomer, namely 2-chloro-4-(5-methyl-1H-pyrazol-1-yl)-benzoic acid methyl ester was isolated from the above flash column chromatography on silica gel (Merck 60) by further eluding with dichloromethane-hexane 2:1 to give 0.20 g of the product as a colorless solid. MS (EI), m/z: 250/252 (M)+.

Reference： [1]Patent: US6511974,2003,B1

36
[ 85953-29-3 ]
[ 88054-14-2 ]
[ 220462-02-2 ]

Yield	Reaction Conditions	Operation in experiment
	In N-methyl-acetamide; 3-Methylpyrazole;	Step A. 2-Chloro-4-(3-methyl-1H-pyrazol-1-yl)-benzoic acid methyl ester Under anhydrous conditions a stirred suspension of hexane washed potassium hydride (0.424 g, 10.6 mmol) in 5 mL of dimethylformamide was treated in one portion with 3-methyl pyrazole (0.85 mL, 10.6 mmol). After the gas evolution ceased, <strong>[85953-29-3]2-chloro-4-fluorobenzoic acid methyl ester</strong> (2.0 g, 10.6 mmol) was added to the clear solution. The mixture was heated at 130 C. for 15 minutes, cooled, and partitioned between ethyl acetate and brine. The organic layer was washed with water and brine, and dried over sodium sulfate. Removal of solvent afforded 2.2 g of a yellow oil consisting of a mixture of 3-methyl and 5-methylpyrazole regioisomers. In addition, about 20% of the acid derived from hydrolysis of the ester was detected by analysis of the NMR spectrum of the crude product. The desired 3-methylpyrazole regioisomer was separated from the 5-methyl isomer of Example 22 by flash chromatography (on silica Merck-60, dichloromethane-hexane 2:1) and was isolated as a white solid (1.55 g, 56%). NMR (DMSO-d6, 400 MHz): delta 2.264 (s, 3H, CCH3), 3.845 (s, 3H, OCH3), 6.40 (d, 1H), 7.865 (dd, 1H), 7.93 (d, 1H), 8.00 (s, 1H), 8.535 (d, 1H). MS (EI, m/z): 250/252 [M]+, 219
	In N-methyl-acetamide; 3-Methylpyrazole;	Step A. 2-Chloro-4-(3-methyl-1H-pyrazol-1-yl)-benzoic acid methyl ester Under anhydrous conditions a stirred suspension of hexane washed potassium hydride (0.424 g, 10.6 mmol) in 5 mL of dimethylformamide was treated in one portion with 3-methyl pyrazole (0.85 mL, 10.6 mmol). After the gas evolution ceased, <strong>[85953-29-3]2-chloro-4-fluorobenzoic acid methyl ester</strong> (2.0 g, 10.6 mmol) was added to the clear solution. The mixture was heated at 130C for 15 minutes, cooled, and partitioned between ethyl acetate and brine. The organic layer was washed with water and brine, and dried over sodium sulfate. Removal of solvent afforded 2.2 g of a yellow oil consisting of a mixture of 3-methyl and 5-methylpyrazole regioisomers. In addition, about 20% of the acid derived from hydrolysis of the ester was detected by analysis of the NMR spectrum of the crude product. The desired 3-methylpyrazole regioisomer was separated from the 5-methyl isomer of Example 16 by flash chromatography (on silica Merck-60, dichloromethane-hexane 2:1) and was isolated as a white solid (1.55 g). NMR (DMSO-d6, 400 MHz): delta 2.26 (s, 3H), 3.84 (s, 3H), 6.40 (d, 1H), 7.86 (dd, 1H), 7.93 (d, 1H), 8.00 (s, 1H), 8.53 (d, 1H). MS (EI, m/z): 250/252 [M]+, 219
	In N-methyl-acetamide; 3-Methylpyrazole;	Step A. 2-Chloro-4-(3-methyl-1H-pyrazol-1-yl)-benzoic acid methyl ester Under anhydrous conditions a stirred suspension of hexane washed potassium hydride (0.424 g, 10.6 mmol) in 5 mL of dimethylformamide was treated in one portion with 3-methyl pyrazole (0.85 mL, 10.6 mmol). After the gas evolution ceased, <strong>[85953-29-3]2-chloro-4-fluorobenzoic acid methyl ester</strong> (2.0 g, 10.6 mmol) was added to the clear solution. The mixture was heated at 130 C. for 15 minutes, cooled, and partitioned between ethyl acetate and brine. The organic layer was washed with water and brine, and dried over sodium sulfate. Removal of solvent afforded 2.2 g of a yellow oil consisting of a mixture of 3-methyl and 5-methylpyrazole regioisomers. In addition, about 20% of the acid derived from hydrolysis of the ester was detected by analysis of the NMR spectrum of the crude product. The desired 3-methylpyrazole regioisomer was separated from the 5-methyl isomer of Example 22 by flash chromatography (on silica Merck-60, dichloromethane-hexane 2:1) and was isolated as a white solid (1.55 g, 56%). NMR (DMSO-d6, 400 MHz): delta 2.264 (s, 3H, CCH3), 3.845 (s, 3H, OCH3), 6.40 (d, 1H), 7.865 (dd, 1H), 7.93 (d, 1H), 8.00 (s, 1H), 8.535 (d, 1H). MS (EI, m/z): 250/252 [M]+, 219.

In N-methyl-acetamide; 3-Methylpyrazole;

Step A. 2-Chloro-4-(3-methyl-1H-pyrazol-1-yl)-benzoic acid methyl ester Under anhydrous conditions a stirred suspension of hexane washed potassium hydride (0.424 g, 10.6 mmol) in 5 mL of dimethylformamide was treated in one portion with 3-methyl pyrazole (0.85 mL, 10.6 mmol). After the gas evolution ceased, [85953-29-3]2-chloro-4-fluorobenzoic acid methyl ester (2.0 g, 10.6 mmol) was added to the clear solution. The mixture was heated at 130 C. for 15 minutes, cooled, and partitioned between ethyl acetate and brine. The organic layer was washed with water and brine, and dried over sodium sulfate. Removal of solvent afforded 2.2 g of a yellow oil consisting of a mixture of 3-methyl and 5-methylpyrazole regioisomers. In addition, about 20% of the acid derived from hydrolysis of the ester was detected by analysis of the NMR spectrum of the crude product. The desired 3-methylpyrazole regioisomer was separated from the 5-methyl isomer of Example 16 by flash chromatography (on silica Merck-60, dichloromethane-hexane 2:1) and was isolated as a white solid (1.55 g). NMR (DMSO-d6, 400 MHz): delta2.26 (s, 3H), 3.84 (s, 3H), 6.40 (d, 1H), 7.86 (dd, 1H), 7.93 (d, 1H), 8.00 (s, 1H), 8.53 (d, 1H). MS (EI, m/z): 250/252 [M]+, 219

Reference： [1]Patent: US6090803,2000,A
[2]Patent: EP1149096,2002,B1
[3]Patent: US6194407,2001,B1
[4]Patent: US6235900,2001,B1

38
[ 1996-41-4 ]
[ 79-22-1 ]
[ 85953-29-3 ]

Yield	Reaction Conditions	Operation in experiment
	In water;	EXAMPLE 3 Production of the nitrophenol (V) 2-Chloro-4-fluorophenol (83.4 g) was added to a solution of sodum hydroxide (27.7 g) in water (450 ml), and methyl chloroformate (69.2 g) was dropwise added thereto at a temperature below 10 C. Precipitated crystals were collected by filtration and washed with water to give methyl(2-chloro-4-fluorophenyl)formate (134.8 g). M.P., 69-71 C.
	With sodium hydroxide; In water;	EXAMPLE 7 Production of the nitrophenol (VII: X=Cl): 2-Chloro-4-fluorophenol (83.4 g) was added to a solution of sodium hydroxide (27.7 g) in water (450 ml), and methyl chloroformate (69.2 g) was dropwise added thereto at a temperature of below 10 C. Precipitated crystals were collected by filtration and washed with water to give methyl (2-chloro-4-fluorophenyl)formate (134.8 g). M.P., 69-71 C.
	With sodium hydroxide; In water;	EXAMPLE 10 Production of the nitrophenol (V: X=Cl): 2-Chloro-4-fluorophenol (83.4 g) was added to a solution of sodium hydroxide (27.7 g) in water (450 ml), and methyl chloroformate (69.2 g) was dropwise added thereto at a temperature of below 10 C. Precipitated crystals were collected by filtration and washed with water to give methyl (2-chloro-4-fluorophenyl)formate (134.8 g). M.P., 69-71 C.

	With sodium hydroxide; In water;	EXAMPLE 10 2-Chloro-4-fluorophenol (83.4 g) was added to a solution of sodium hydroxide (27.7 g) in water (450 ml), and methyl chloroformate (69.2 g) was dropwise added thereto at a temperature below 10 C. Precipitated crystals were collected by filtration and washed with water to give methyl (2-chloro-4-fluorophenyl)formate (134.8 g). M.P., 69-71 C.
	With sodium hydroxide; In water;	EXAMPLE 12 2-Chloro-4-fluorophenol (83.4 g) was added to a solution of sodium hydroxide (27.7 g) in water (450 ml), and methyl chloroformate (69.2 g) was dropwise added thereto at a temperature below 10 C. Precipitated crystals were collected by filtration and washed with water to give methyl (2-chloro-4-fluorophenyl) formate (134.8 g). M.P., 69-71 C.

Reference： [1]Patent: US4670046,1987,A
[2]Patent: US4427438,1984,A
[3]Patent: US4431822,1984,A
[4]Patent: US4437877,1984,A
[5]Patent: US4452981,1984,A

39
[ 85953-29-3 ]
[ 85953-30-6 ]

Yield	Reaction Conditions	Operation in experiment
	With conc. nitric acid; In sulfuric acid;	Methyl(2-chloro-4-fluorophenyl)formate (134.8 g) obtained above was suspended in conc. sulfuric acid (50 ml). To the suspension, a mixture of conc. sulfuric acid (50 ml) and conc. nitric acid (50 ml) was added at about 30 C., and the mixture was stirred for 1 hour at this temperature. The reaction mixture was poured into ice-water, and precipitated crystals were collected and washed with water. Methyl(2-chloro-4-fluoro-5-nitrophenyl)formate (143 g) was thus obtained. M.P., 53-55 C.
	With nitric acid; In sulfuric acid;	Methyl (2-chloro-4-fluorophenyl)formate (134.8 g) obtained above was suspended in concentrated sulfuric acid (50 ml). To the suspension, a mixture of concentrated sulfuric acid (50 ml) and concentrated nitric acid (50 ml) was added at about 30 C., and the mixture was stirred for at this temperature for 1 hour. The reaction mixture was poured into ice water, and precipitated crystals were collected and washed with water to give methyl (2-chloro-4-fluoro-5-nitrophenyl)formate (143 g). M.P., 53-55 C.
	With conc. nitric acid; In sulfuric acid;	Methyl (2-chloro-4-fluorophenyl)formate (134.8 g) obtained above was suspended in conc. sulfuric acid (50 ml). To the suspension, a mixture of conc. sulfuric acid (50 ml) and conc. nitric acid (50 ml) was added at about 30 C., and the mixture was stirred for 1 hour at this temperature. The reaction mixture was poured into ice water, and precipitated crystals were collected and washed with water. Methyl (2-chloro-4-fluoro-5-nitrophenyl)formate (143 g) was thus obtained. M.P., 53-55 C.

With conc. nitric acid; In sulfuric acid;

Methyl (2-chloro-4-fluorophenyl)formate (134.8 g) obtained above was suspended in conc. sulfuric acid (50 ml). To the suspension, a mixture of conc. sulfuric acid (50 ml) and conc. nitric acid (50 ml) was added at about 30 C., and the mixture was stirred at this temperature for 1 hour. The reaction mixture was poured into ice water, and precipitated crystals were collected and washed with water to give methyl (2-chloro-4-fluoro-5-nitrophenyl)formate (143 g). M.P., 50-55 C.

Reference： [1]Patent: US4670046,1987,A
[2]Patent: US4427438,1984,A
[3]Patent: US4431822,1984,A
[4]Patent: US4452981,1984,A

40
[ 109-01-3 ]
[ 85953-29-3 ]
[ 1059705-62-2 ]

Yield	Reaction Conditions	Operation in experiment
28.1%	With potassium carbonate; In dimethyl sulfoxide; at 120℃; for 18.0h;Inert atmosphere;	0.72 ml of <strong>[85953-29-3]methyl 2-chloro-4-fluorobenzoate</strong> was dissolved in 5 ml of dimethylsulfoxide, 0.67 ml of 1-methylpiperazine and1.041 g of potassium carbonate, and the temperature was raised to 120 C under argon. After stirring for 18 hours, the reaction was stopped and 25 ml of water was addedThe reaction solution was extracted with ethyl acetate, the organic phases were combined and washed five times with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate,The residue was purified by column chromatography (dichloromethane: methanol = 99: 1-98: 2, v / v) to give 379 mg of a yellow oil,Yield 28.1%.

Reference： [1]ACS Medicinal Chemistry Letters,2016,vol. 7,p. 629 - 634
[2]Patent: CN106146493,2016,A .Location in patent: Paragraph 0514; 0515; 0516; 0517
[3]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 9524 - 9535

41
[ 67-51-6 ]
[ 85953-29-3 ]
[ 530091-49-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 9524 - 9535

42
[ 111-49-9 ]
[ 85953-29-3 ]
[ 530091-77-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 9524 - 9535

43
[ 271-42-1 ]
[ 85953-29-3 ]
methyl 2-chloro-4-(2H-indazol-2-yl)benzoate [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 9524 - 9535

44
[ 13808-71-4 ]
[ 85953-29-3 ]
[ 530091-61-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 9524 - 9535

45
[ 2458-26-6 ]
[ 85953-29-3 ]
[ 530091-45-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 9524 - 9535

46
[ 69478-75-7 ]
[ 85953-29-3 ]
[ 1092770-23-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 9524 - 9535

47
[ 49633-25-2 ]
[ 85953-29-3 ]
[ 530091-62-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 9524 - 9535

48
[ 85953-29-3 ]
[ 765-38-8 ]
[ 530091-52-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 9524 - 9535

49
[ 69498-25-5 ]
[ 85953-29-3 ]
[ 530091-54-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2009,vol. 17,p. 8161 - 8167

50
[ 85953-29-3 ]
[ 69498-24-4 ]
[ 530091-53-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2009,vol. 17,p. 8161 - 8167

51
[ 104-01-8 ]
[ 85953-29-3 ]
[ 1183781-70-5 ]