[ CAS No. 517920-75-1 ]

Name: 517920-75-1|(3-Chloro-2-fluorophenyl)hydrazine hydrochloride|97%
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SKU: A159046
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Quality Control of [ 517920-75-1 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 517920-75-1 ]

SDS Specification

Alternatived Products of [ 517920-75-1 ]

Product Details of [ 517920-75-1 ]

CAS No. :	517920-75-1	MDL No. :	MFCD03094280
Formula :	C₆H₇Cl₂FN₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	TWYLYPMRIHFEQN-UHFFFAOYSA-N
M.W :	197.04	Pubchem ID :	25067375
Synonyms :

Calculated chemistry of [ 517920-75-1 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	2.0
Num. H-bond donors :	2.0
Molar Refractivity :	45.58
TPSA :	38.05 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.59 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	2.69
Log Po/w (WLOGP) :	2.8
Log Po/w (MLOGP) :	2.72
Log Po/w (SILICOS-IT) :	1.42
Consensus Log Po/w :	1.93

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.09
Solubility :	0.159 mg/ml ; 0.000805 mol/l
Class :	Soluble
Log S (Ali) :	-3.14
Solubility :	0.142 mg/ml ; 0.000722 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.97
Solubility :	0.209 mg/ml ; 0.00106 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.81

Safety of [ 517920-75-1 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 517920-75-1 ]

* 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 [ 517920-75-1 ]
Downstream synthetic route of [ 517920-75-1 ]

[ 517920-75-1 ] Synthesis Path-Upstream 1~1

1
[ 650578-82-8 ]
[ 517920-75-1 ]

Reference： [1] Patent: US2007/27178, 2007, A1, . Location in patent: Page/Page column 21

[ 517920-75-1 ] Synthesis Path-Downstream 1~25

1
[ 517920-75-1 ]
[ 41979-39-9 ]
7-Chloro-6-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In isopropyl alcohol; at 20 - 80℃; for 15.1667h;	Step B.; A solution of 1-<strong>[517920-75-1](3-chloro-2-fluorophenyl)hydrazine hydrochloride</strong> (3.35 g, 17.0 mmol) and 4-piperidone hydrochloride monohydrate (2.6 g, 17.0 mmol) in IPA(50.0 mL) was stirred at 20 C. for 10 min, following by stirring at 80 C. for 15 h. The reaction mixture was filtered to obtain the title compound (3.2g, 12.5 mmol) as a beige solid: MS (ES) 269.0 (M-H).

Reference： [1]Patent: US2007/27178,2007,A1 .Location in patent: Page/Page column 21

2
[ 650578-82-8 ]
[ 517920-75-1 ]

Yield	Reaction Conditions	Operation in experiment
		Example 15 7-Chloro-6-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride Step A.; A solution of sodium nitrite (12.5 g, 85.9 mmol) and H2O (21.4 mL) was added dropwise at 0 C. to a solution of 3-chloro-2-fluorobenzenamine hydrochloride (2.0 g, 8.45 mmol) in 12N HCl (203.3 mL) and TFA (23.4 mL). The reaction mixture was stirred at 0 C. for 1 h followed by the dropwise addition of a solution of tin(II)chloride (35.8 g, 188.9 mmol) in 12N HCl (51.6 mL) and H2O (6.8 mL) at 0 C. The reaction mixture stirred for 15 h at 20 C. and was filtered and placed under vacuum to give 1-(3-chloro-2-fluorophenyl)hydrazine hydrochloride as a gold solid (23.5 g, 119.0 mmol).

Reference： [1]Patent: US2007/27178,2007,A1 .Location in patent: Page/Page column 21

3
[ 517920-75-1 ]
[ 3609-53-8 ]
[ 926634-47-1 ]

Yield	Reaction Conditions	Operation in experiment
	With acetic acid; zinc(II) chloride; at 105℃; for 48h;	(3-Chloro-2-fluoro-phenyl)-hydrazine hydrochloride (Apollo Scientific, Ltd., 221 mg, 1.12 mmol) and 4-acetyl-benzoic acid methyl ester (200 mg, 1.12 mmol) are treated with anhydrous ZnCl2 (382 mg, 2.81 mmol) and acetic acid (10 mL). The reaction is heated to 105 C. for 48 hours. After cooling to room temperature, the reaction is diluted with ethyl acetate and sequentially washed with H2O (5×) followed by saturated aqueous NaCl. The organics are then dried over Na2SO4 and filtered. After concentration, the crude product is purified by preparative RP LC-MS to give 4-(6-chloro-7-fluoro-1H-indol-2-yl)-benzoic acid methyl ester as an off-white solid: ESMS m/z 304.0 (M+H+).

Reference： [1]Patent: US2008/194668,2008,A1 .Location in patent: Page/Page column 5-6

4
[ 517920-75-1 ]
[ 134653-70-6 ]
[ 1422386-21-7 ]

Yield	Reaction Conditions	Operation in experiment
28%	With triethylamine; In ethanol; at 20℃; for 0.166667h;	[00375] Intermediate 25 A. Ethyl 1 -(3 -chloro-2-fluorophenyl)-5 -methyl- lH-pyrazole- 4-carboxylate: (Reference: Herold, P. et al, Tetrahedron, 56:6497-6499 (2000)) A solution of ethyl 2-((dimethylamino)methylene)-3-oxobutanoate (0.517 g, 2.79 mmol), <strong>[517920-75-1](3-chloro-2-fluorophenyl)hydrazine hydrochloride</strong> (0.500 g, 2.54 mmol) in EtOH (2.54 mL) and TEA (0.707 mL, 5.08 mmol) was stirred at rt. After 10 min, the reaction mixture was concentrated and purified by silica gel chromatography. The desired product, ethyl 1 -(3 -chloro-2-fluorophenyl)-5 -methyl- lH-pyrazole -4-carboxylate (200 mg, 28%), was obtained as an off white solid. MS(ESI) m/z: 283.1 (M+H)+.
28%	With triethylamine; In ethanol; at 20℃; for 0.166667h;	Intermediate 15A. Ethyl l-(3-chloro-2-fluorophenyl)-5-methyl-lH-pyrazole-4- carboxylate: (Reference: Herold, P. et al, Tetrahedron, 56:6497-6499 (2000)) A solution of ethyl 2-((dimethylamino)methylene)-3-oxobutanoate (0.517 g, 2.79 mmol), <strong>[517920-75-1](3-chloro-2-fluorophenyl)hydrazine hydrochloride</strong> (0.500 g, 2.54 mmol) in EtOH (2.54 mL) and TEA (0.707 mL, 5.08 mmol) was stirred at room temperature t. After 10 min, the reaction mixture was concentrated and purified by silica gel chromatography. The desired product, ethyl l-(3-chloro-2-fluorophenyl)-5-methyl-lH-pyrazole-4-carboxylate (200 mg, 28%), was obtained as an off-white solid. MS (ESI) m/z: 283.1 (M+H)+.
28%	With triethylamine; In ethanol; at 20℃; for 0.166667h;	A solution of ethyl 2-((dimethylamino) methylene)-3-oxobutanoate (0.5 17 g, 2.79mmol), <strong>[517920-75-1](3-chloro-2-fluorophenyl)hydrazine hydrochloride</strong> (0.500 g, 2.54 mmol) inEtOH (2.54 ml) and TEA (0.707 ml, 5.08 mmol) was stirred at rt. After 10 mm, thereaction mixture was concentrated and purified by normal phase chromatography. Thedesired product, ethyl 1 -(3 -chloro-2-fluorophenyl)-5-methyl- 1 H-pyrazole-4-carboxyl ate(200 mg, 28%), was obtained as an off white solid. MS (ESI) m/z: 283.1 (M+H)t

Reference： [1]Journal of Medicinal Chemistry,2020,vol. 63,p. 784 - 803
[2]Patent: WO2013/22818,2013,A1 .Location in patent: Paragraph 00375
[3]Patent: WO2014/160668,2014,A1 .Location in patent: Page/Page column 119
[4]Patent: WO2016/205482,2016,A1 .Location in patent: Page/Page column 133

5
[ 517920-75-1 ]
[ 108-24-7 ]
[ 1422386-49-9 ]

Yield	Reaction Conditions	Operation in experiment
		[00390] Intermediate 33A. N'-(3-Chloro-2-fluorophenyl)acetohydrazide: To a solution of (3-chloro-2-fluorophenyl)hydrazine, HC1 (450 mg, 2.284 mmol) in ether (10 mL) and THF (1 mL) at 0 C was added sodium hydroxide (0.228 mL, 2.284 mmol) and stirred at room temperature for 1 h. The reaction mixture was concentrated, diluted with EtOAc and washed with brine. The crude product was then dried under vacuum and taken to the next step. To a solution of the above obtained oil in ether (10 mL) at 0 C was added dropwise a solution of acetic anhydride (0.215 mL, 2.284 mmol) in ether (5 mL) and stirred at 0 C for 30 min. The reaction mixture was concentrated, diluted with ethyl acetate and washed with brine. The organic layer was dried over MgSC^ and concentrated to yield the crude product. The crude product was then taken to the next step without further purification. MS(ESI) m/z: 203.1 (M+H)+.
		Intermediate 45 A. N'-(3-Chloro-2-fluorophenyl)acetohydrazide: To a solution of (3-chloro-2-fluorophenyl)hydrazine, HC1 (450 mg, 2.284 mmol) in ether (10 mL) and THF (1 mL) at 0 C was added sodium hydroxide (0.228 mL, 2.284 mmol) and stirred at room temperature for 1 h. The reaction mixture was concentrated, diluted with EtOAc and washed with brine. The crude product was then dried under vacuum and taken to the next step. To a solution of the above obtained oil in ether (10 mL) at 0 C was added dropwise a solution of acetic anhydride (0.215 mL, 2.284 mmol) in ether (5 mL) and stirred at 0 C for 30 min. The reaction mixture was concentrated, diluted with ethyl acetate and washed with brine. The organic layer was dried over MgS04 and concentrated to yield the crude product. The crude product was then taken to the next step without further purification. MS(ESI) m/z: 203.1 (M+H)+.

Reference： [1]Patent: WO2013/22818,2013,A1 .Location in patent: Paragraph 00390
[2]Patent: WO2014/160668,2014,A1 .Location in patent: Page/Page column 137-138

6
[ 517920-75-1 ]
[ 42466-67-1 ]
[ 1422385-89-4 ]

Yield	Reaction Conditions	Operation in experiment
78%	With sodium acetate; In water; acetic acid; at 20 - 100℃;	[00319] Intermediate 2 A. Ethyl 5-amino-l-(3-chloro-2-fluorophenyl)-lH-pyrazole-4- carboxylate: To a mixture of <strong>[517920-75-1](3-chloro-2-fluorophenyl)hydrazine hydrochloride</strong> (0.67 g, 3.40 mmol), (E)-ethyl 2-cyano-3-ethoxyacrylate (0.633 g, 3.72 mmol) and sodium acetate (0.586 g, 7.12 mmol) at rt was added AcOH and H20 to form a slurry. The reaction mixture was continued to stir at rt for 0.25 h and then heated at 100 C for overnight. After overnight stirring, the reaction mixture was quenched with H20 (200 mL) and a yellowish brown solid separated. The solids were filtered and washed thoroughly with H20. Re-dissolved the residue in DCM, dried and evaporated to a brown solid as the desired product (0.76 g, 78%). MS(ESI) m/z: 284.2 (M+H)+. 1H NMR (400 MHz, CDCls) delta 7.76 (s, 1H), 7.51 - 7.29 (m, 2H), 7.27 - 7.03 (m, 1H), 5.30 - 5.06 (m, 2H), 4.24 (q, J = 7.2 Hz, 2H), 1.38 - 1.04 (m, 3H) ppm.

Reference： [1]Patent: WO2013/22818,2013,A1 .Location in patent: Paragraph 00319

7
[ 517920-75-1 ]
[ 100-52-7 ]
[ 1422386-76-2 ]

Yield	Reaction Conditions	Operation in experiment
27%	With sodium hydroxide; In methanol; at 20℃; for 2.5h;	[00405] Intermediate 40 A. (E)-l-Benzylidene-2-(3-chloro-2-fluorophenyl)hydrazine: Using a modified procedure described by Deprez-Poulain. (Deprez-Poulain, R. et al, European Journal of Medicinal Chemistry, 46:3867 (2011).) To a clear, orange brown solution of (3-chloro-2-fluorophenyl)hydrazine, HC1 (3 g, 15.23 mmol) in methanol (60.9 ml) was added benzaldehyde (1.543 mL, 15.23 mmol) followed by the slow addition of 1.0 M NaOH (15.23 mL, 15.23 mmol). The resulting dark brown solution was stirred at rt. Over time, a precipitate formed. After 2.5 h, the reaction was stopped and the solid was collected by filtration. The solid was washed with water, air-dried, and dried under vacuum overnight to give Intermediate 40A (1.01 g, 27%) as an off- white solid. MS(ESI) m/z: 249.0 (M+H)+.

Reference： [1]Patent: WO2013/22818,2013,A1 .Location in patent: Paragraph 00405

8
[ 517920-75-1 ]
[ 1357191-82-2 ]
[ 1357191-83-3 ]

Yield	Reaction Conditions	Operation in experiment
97 mg	With trifluoroacetic acid; In ethanol; at 35℃;Cooling with ice;	To a solution of 3- [3- (dimethylamino) prop-2-enoyl] -1- [2- fluoro-4- (lH-pyrazol-l-yl) phenyl] -5-methoxypyridazin-4 (IH) -one (200 mg) in trifluoroacetic acid/ethanol (5/95, 8 mL) was added (3-chloro-2-fluorophenyl) hydrazine hydrochloride (98.8 mg) under ice-cooling. The reaction mixture was stirred at room temperature for 3 hr, water was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (97 mg) . 1H NMR (300 MHz, DMSO-d6) delta 3.80 (3H, s) , 6.57-6.71 (1H, m) , 7.12-7.22 (1H, m) , 7.23-7.32 (1H, m) , 7.38-7.49 (2H, m) , 7.55- 7.69 (1H, m) , 7.72-7.81 (1H, m) , 7.81-8.01 (3H, m) , 8.50 (1H, d, J = 1.9 Hz), 8.67 (1H, d, J = 2.6 Hz).

Reference： [1]Patent: WO2013/27845,2013,A1 .Location in patent: Paragraph 0388

9
[ 517920-75-1 ]
[ 144918-37-6 ]
[ 1422385-89-4 ]

Yield	Reaction Conditions	Operation in experiment
78%	With sodium acetate; acetic acid; In water; at 20 - 100℃;	Intermediate 13A. Ethyl 5-amino-l-(3-chloro-2-fluorophenyl)-lH-pyrazole-4- carboxylate: To a mixture of <strong>[517920-75-1](3-chloro-2-fluorophenyl)hydrazine hydrochloride</strong> (0.67 g, 3.40 mmol), (E)-ethyl 2-cyano-3-ethoxyacrylate (0.633 g, 3.72 mmol) and sodium acetate (0.586 g, 7.12 mmol) at room temperature was added AcOH and 0 to form a slurry. The reaction mixture was continued to stir at room temperature for 0.25 h and then heated at 100 C overnight. After overnight stirring, the reaction mixture was quenched with H20 (200 mL) and a yellowish brown solid separated. The solids were filtered and washed thoroughly with H20. Re-dissolved the residue in DCM, dried and evaporated to a brown solid as the desired product (0.76 g, 78%). MS (ESI) m/z: 284.2 (M+H)+. NMR (400 MHz, CDC13) delta 7.76 (s, 1H), 7.51 - 7.29 (m, 2H), 7.27 - 7.03 (m, 1H), 5.30 - 5.06 (m, 2H), 4.24 (q, J = 7.2 Hz, 2H), 1.38 - 1.04 (m, 3H) ppm.

Reference： [1]Patent: WO2014/160668,2014,A1 .Location in patent: Page/Page column 118

10
[ 517920-75-1 ]
[ 1359980-64-5 ]
[ 1359982-39-0 ]

Yield	Reaction Conditions	Operation in experiment
44%	In tert-butyl alcohol; at 90℃; for 24h;Inert atmosphere;	To a stirred solution of compound A-S (5.25 g, 22.05 mmol) in t-BuOH (200 mL) under inert atmosphere was added (3-chloro-2-fluorophenyl) hydrazine hydrochloride (6.5 g, 33.08 mmol) at RT. The reaction mixture was heated to 90 oC and stirred for 24 h. The reaction progress was monitored by TLC; after reaction completion, the reaction mixture was diluted with ice cold water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried over Na2504, filtered and concentrated under reduced pressure to obtain crude material. The crude material was purified through silica gel flash column chromatography using 3% EtOAc/ hexanes to afford mt-A (3.5 g, 44%) as an off-white solid. 1H NMR (400 MHz, CDC13): 8.52 (br s, 1H), 7.77 (s, 1H), 7.73 (d, J= 8.0 Hz, 1H), 7.25-7.17 (m, 2H), 7.12-7.05 (m, 2H), 4.32 (q, 2H), 2.53 (s, 3H), 1.34 (t,J6.8Hz,3H).

Reference： [1]Patent: WO2015/48301,2015,A1 .Location in patent: Paragraph 00405

11
[ 517920-75-1 ]
1-(3-Chloro-2-ethoxyphenyl)-1H-pyrazole-3-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		analogously to Synthesis Example 3, Step 1, starting with <strong>[517920-75-1]3-chloro-2-fluorophenylhydrazine hydrochloride</strong>: HPLC-MS: log P=1.90; mass (m/z): 212.0 (M+H)+; 1H-NMR (DMSO-D6) 5.22 (br. s, 2H), 5.82 (d, 1H), 7.25-7.30 (m, 1H), 7.36-7.40 (m, 1H), 7.67-7.71 (m, 1H), 7.90-7.10 (m, 1H). 1-(3-Chloro-2-ethoxyphenyl)-1H-pyrazole-3-amine was obtained as a by-product: HPLC-MS: log P=2.13; mass (m/z): 238.0 (M+H)+; 1H-NMR (DMSO-D6) 1.24 (t, 3H), 3.78 (q, 2H), 5.08 (br. s, 2H), 5.78 (d, 1H), 7.17-7.21 (m, 1H), 7.30-7.33 (m, 1H), 7.56-7.59 (m, 1H), 7.97 (d, 1H).

Reference： [1]Patent: US2015/239847,2015,A1

12
[ 517920-75-1 ]
[ 203186-58-7 ]
[ 1422386-21-7 ]

Yield	Reaction Conditions	Operation in experiment
91%	With triethylamine; In ethanol; at 20℃; for 5h;	Ethyl 2- acetyl-3-(dimethylamino)acrylate (4.27 g, 23.07 mmol), <strong>[517920-75-1]3-chloro-2-fluorophenylhydrazine hydrochloride</strong> (4.50 g, 22.83 mmol) of ethanol (23 ml) solution to triethylamine (6.37, 45.68 mmol) and stirred at room temperature for 5 hours. Vacuum concentration and reaction, plus ethanol in residue, filter and the resulting solid ethanol, followed by hexane washing obtained the title compound (2.58 g). In addition, filtrate liquid is evaporated and the residue and at 50 C, after stirring added to hexane, ethanol in addition to residues. Solution at room temperature until releasing chilled, then solid is obtained and filtered in hexane the ethanol, got the title compounds by washing (1.15 g). Got title compounds of compounds obtained by 5.85 g (91%)

Reference： [1]Patent: JP2015/13821,2015,A .Location in patent: Paragraph 0153-0154

13
[ 517920-75-1 ]
[ 141-97-9 ]
[ 4637-24-5 ]
[ 1422386-21-7 ]

Yield	Reaction Conditions	Operation in experiment
97%		39a) 1 -(3-chloro-2-fluoro-phenyl)-5-methyl-1 H-pyrazole -4-carboxylic acid ethyl ester A mixture of ethyl acetoacetate (2.01 mmol) and DMF-dimethyl acetal (2.01 mmol) was stirred in a microwave reactor at 130C for 15 min. After cooling, the stirred mixture was diluted with EtOH (5 mL) and treated with 3-chloro-2-fluorophenylhydrazine HCI (0.330 g, 1 .68 mmol), followed by triethylamine (0.23 mL, 1 .68 mmol) and heated at 80C for 3 h. After cooling, the mixture was concentrated to dryness and purified by silica eluting with EtOAc/petrol 10% to give the product (0.462 g, 97%). LC-MS m/z 283 (M + H) +, 1 .44 (ret. time).

Reference： [1]Patent: WO2017/60854,2017,A1 .Location in patent: Page/Page column 227; 228

14
[ 517920-75-1 ]
[ 1422386-19-3 ]

Reference： [1]Patent: WO2017/60854,2017,A1
[2]Journal of Medicinal Chemistry,2020,vol. 63,p. 784 - 803

15
[ 517920-75-1 ]
1-(3-chloro-2-fluoro-phenyl)-5-methyl-1H-pyrazole [ No CAS ]

Reference： [1]Patent: WO2017/60854,2017,A1

16
[ 517920-75-1 ]
5-cyclopropyl-1-{3-[2-fluoro-3-(5-methyl-1H-pyrazol-1-yl)phenyl]phenyl}-1H-pyrazole-4-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2017/60854,2017,A1

17
[ 517920-75-1 ]
ethyl 1-(3-chloro-2-fluorophenyl)-1H-pyrazole-4-carboxylate [ No CAS ]