129768-28-1|5-(Trifluoromethyl)-1H-pyrazole-3-carboxylic acid| Ambeed

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Quality Control of [ 129768-28-1 ] Purity: 98% SDS Specification

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Product Details of [ 129768-28-1 ]

CAS No. :	129768-28-1
Formula :	C₅H₃F₃N₂O₂
M.W :	180.08
SMILES Code :	O=C(C1=NNC(C(F)(F)F)=C1)O
MDL No. :	MFCD03094951
InChI Key :	CIVNBJPTGRMGRS-UHFFFAOYSA-N
Pubchem ID :	4193848

Safety of [ 129768-28-1 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 129768-28-1 ] Show Less

Physicochemical Properties

Num. heavy atoms	12
Num. arom. heavy atoms	5
Fraction Csp3	0.2
Num. rotatable bonds	2
Num. H-bond acceptors	6.0
Num. H-bond donors	2.0
Molar Refractivity	30.55
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	65.98 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	0.1
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	0.99
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.28
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	0.43
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	1.47
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.05

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.76
Solubility	3.15 mg/ml ; 0.0175 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.96
Solubility	1.96 mg/ml ; 0.0109 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-1.49
Solubility	5.77 mg/ml ; 0.0321 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.7 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	1.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.56

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	1.72

Application In Synthesis of [ 129768-28-1 ]

* 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 [ 129768-28-1 ]
Downstream synthetic route of [ 129768-28-1 ]

[ 129768-28-1 ] Synthesis Path-Upstream 1~3

1
[ 881693-05-6 ]
[ 129768-28-1 ]

Yield	Reaction Conditions	Operation in experiment
84%	Stage #1: Cooling with ethanol-dry ice Stage #2: With hydrogenchloride In water	Ammonia (about 50ml) was condensed into a three-neck-flask in an ethanol-dry ice bath and 2-benzyl-5-trifiuoromethyl-2H-pyrazole-3-carboxylic acid (lOOmg, 3.70mmol) was added. To the solution sodium (about 260mg, 11.3mmol) was added in small portions until the blue color stayed for more then 5 minutes. The ammonia was evaporated overnight. Water was added and acidified with 2N HCl solution. The aqueous phase was extracted twice with ethyl acetate, the combined organic phases were dried over Na₂SO₄, the solvent was evaporated in vacuum to give 560mg 5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (3.11mmol, 84percent) as a yellow solid that was used without further purification.MSr M = 179.0 (API-)
84%	Stage #1: Cooling with ethanol-dry ice	5-Trifluoromethyl-2H-pyrazole-3-carboxylic acid About 50 ml ammonia were condensed into a three-neck-flask in an ethanol-dry ice bath and 100 mg (3.70 mmol) 2-benzyl-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid were added. To the solution sodium was added in small portions until the blue color stayed for more then 5 minutes (about 260 mg, 11.3 mmol). The ammonia was evaporated overnight. Water was added and acidified with 2N HCl solution. The aqueous phase was extracted twice with ethyl acetate, the combined organic phases were dried over Na₂SO₄, the solvent was evaporated in vacuo to give 560 mg (3.11 mmol, 84percent) 5-trifluoromethyl-2H-pyrazole-3-carboxylic acid as a yellow solid that was used without further purification. MS: M=179.0 (API-)

References: [1] Patent: WO2007/68465, 2007, A1, . Location in patent: Page/Page column 30.
[2] Patent: US2006/69145, 2006, A1, . Location in patent: Page/Page column 9; 14.

2
[ 6833-82-5 ]
[ 129768-28-1 ]

References: [1] European Journal of Organic Chemistry, 2014, vol. 2014, # 12, p. 2487 - 2495.

3
[ 129768-30-5 ]
[ 129768-28-1 ]

References: [1] European Journal of Organic Chemistry, 2017, vol. 2017, # 44, p. 6566 - 6574.

[ 129768-28-1 ] Synthesis Path-Downstream 1~35

1
[ 881693-05-6 ]
[ 129768-28-1 ]

Yield	Reaction Conditions	Operation in experiment
84%		Ammonia (about 50ml) was condensed into a three-neck-flask in an ethanol-dry ice bath and 2-benzyl-5-trifiuoromethyl-2H-pyrazole-3-carboxylic acid (lOOmg, 3.70mmol) was added. To the solution sodium (about 260mg, 11.3mmol) was added in small portions until the blue color stayed for more then 5 minutes. The ammonia was evaporated overnight. Water was added and acidified with 2N HCl solution. The aqueous phase was extracted twice with ethyl acetate, the combined organic phases were dried over Na2SO4, the solvent was evaporated in vacuum to give 560mg 5-trifluoromethyl-2H-pyrazole-3-carboxylic acid (3.11mmol, 84%) as a yellow solid that was used without further purification.MSr M = 179.0 (API-)
84%		5-Trifluoromethyl-2H-pyrazole-3-carboxylic acid About 50 ml ammonia were condensed into a three-neck-flask in an ethanol-dry ice bath and 100 mg (3.70 mmol) 2-benzyl-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid were added. To the solution sodium was added in small portions until the blue color stayed for more then 5 minutes (about 260 mg, 11.3 mmol). The ammonia was evaporated overnight. Water was added and acidified with 2N HCl solution. The aqueous phase was extracted twice with ethyl acetate, the combined organic phases were dried over Na2SO4, the solvent was evaporated in vacuo to give 560 mg (3.11 mmol, 84%) 5-trifluoromethyl-2H-pyrazole-3-carboxylic acid as a yellow solid that was used without further purification. MS: M=179.0 (API-)

References: [1]Patent: WO2007/68465,2007,A1 .Location in patent: Page/Page column 30.
[2]Patent: US2006/69145,2006,A1 .Location in patent: Page/Page column 9; 14.

2
[ 129768-28-1 ]
[ 5003-71-4 ]
[ 877402-84-1 ]

Yield	Reaction Conditions	Operation in experiment
	With 1-hydroxy-7-aza-benzotriazole; N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 0.75h;	To a solution of 500 mg (2.78 mmol) of 3-(trifluoromethyl)-lNo.-pyrazole-5-carboxylicacid, 682 mg (3.05 mmol) of 3-brornopropylamine hydrobromide, and 1.4 mL (1.04 g, 8.04 mmol) ofAr,W-diisopropylethylamine in 20 mL of dichloromethane were added 1.2 g (3.06 mmol) of O-(7-azabenzotriazol-l-yl)-N,]V,Af',7V'-tetramethyluromumhexafluorophosphate (HATU) and 459 mg (3.38mmol) of l-hydroxy-7-azabenzotriazole (HOAT). After being stirred at room temperature for 45 min, thereaction mixture was partitioned between dichloromethane and saturated sodium carbonate aqueoussolution. The organic phase was washed with 5% aqueous citric acid solution, then dried over sodiumsulfate, and concentrated. The residue was leached with dichloromethane containing a little methanol.Concentration of the organic extract yielded the title compound. LC-MS 300, 302 (M+l).

References: [1]Patent: WO2006/23750,2006,A2 .Location in patent: Page/Page column 64.

3
[ 129768-28-1 ]
[ 22483-09-6 ]
[ 877402-80-7 ]

Yield	Reaction Conditions	Operation in experiment
75%		General procedure: CDI (3.90 g, 24 mmol) was added to a solution of acid 4a-d (20 mmol) in anhydrous acetonitrile (50 ml). The reaction mixture was stirred and heated at 60-70C for 3-4 h, then treated with 2,2-dimethoxyethan-1-amine (2.10 g, 20 mmol) and stirred at the same temperature for additional 2-3 h. The solvent was removed by evaporation, the residue was dissolved in ethyl acetate (60 ml), treated with aqueous 1 HCl solution (3×10 ml), the organic layer was separated, dried over anhydrous Na2SO4, evaporated, and air-dried. Products 5a-d were obtained as white crystalline powders.
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 20.0h;	A mixture of 500 mg (2.78 mmol) of 3-(trifiuoromethyl)-l//-pyrazole-5-carboxylic acid,0.333 mL (3.05 mmol) of aminoacetaldehyde dimethyl acetal, 588 mg (3.05 mmol) of l-(3-dimethylaminopropyl)-3-ethylcarbodiifnide hydrochloride (EDC), 510 mg (3.33 mmol) of 1-hydroxybenzotriazole (HOBT), 1.92 mL (11.1 mmol) of Af,Af-diisopropylethylamine, and 20 mL ofdichloromethane was stirred at room temperature for 20 h and then concentrated. Purification of theresidue by flash chromatography on silica gel (0-10% methanol in dichloromethane) afforded the titlecompound as a white solid. LC-MS 268 (M+l).

References: [1]Chemistry of Heterocyclic Compounds,2017,vol. 53,p. 1242 - 1247.
Khim. Geterotsikl. Soedin.,2017,vol. 53,p. 1242 - 1247,6.
[2]Patent: WO2006/23750,2006,A2 .Location in patent: Page/Page column 63.

4
[ 129768-28-1 ]
5,6-diamino-3,3-dimethyl-1-(3-morpholin-4-yl-propyl)-1,3-dihydro-indol-2-one [ No CAS ]
7,7-dimethyl-5-(3-morpholin-4-yl-propyl)-2-(5-trifluoromethyl-2H-pyrazol-3-yl)-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
34%		5,6-Diamino-3,3-dimethyl-l-(3-morpholin-4-yl-propyl)-l,3-dihydro-indol-2-one (198mg, 0.622mmol) and 5-trifiuoromethyl-2H-pyrazole-3-carboxylic acid (112mg, 0.622mmol) were mixed thoroughly. Polyphosphoric acid (4260mg,43.5mmol) and phosphorus pentoxide (460mg, 3.24mmol) were added and again mixed thoroughly by spatula. The mixture was heated to 1500C under a nitrogen atmosphere for 6h. After cooling to room temperature the reaction mixture was quenched with ice water (20ml) and the resulting suspension was adjusted to pH 7 - 8 by adding 25% aqueous ammonia. The aqueous phase was extracted with ethyl acetate, the combined organic phases were washed with water, dried over Na2SO4 and the solvent was evaporated in vacuo. The residue was washed with diethylether and dried in vacuum to yield 102mg 7,7-dimethyl-5-(3-morpholin-4-yl-propyl)-2- (5-trifluoromethyl-2H-pyrazol-3-yl)-5,7-dihydro-lH-imidazo[4,5-f] indol-6-one (34%). <n="34"/>MS: M = 463.1 (API+)1H-NMR (400 MHz, D.-DMSO): delta (ppm) = 1.33 (s, 6H), 1.78 (m, 2H), 2.30 (m, 6H), 3.57 (m, 4H), 3.79 (t, 2H), 7.18-7.28 (br m, 2H), 7.56 - 7.67 (br m, IH), 12.98 (br, IH), 14.64 (br, IH)

References: [1]Patent: WO2007/68465,2007,A1 .Location in patent: Page/Page column 32-33.

5
[ 129768-28-1 ]
[ 1071874-94-6 ]
[ 1071875-10-9 ]

References: [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 6471 - 6477.

6
[ 129768-28-1 ]
[ 1276653-62-3 ]
[ 1276674-08-8 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; HATU; In dichloromethane; at 20℃; for 16.0h;	A. Preparation ofN-( cis-4-fluoro-4-( 3-fluoro-5-( trifluoromethyl)phenylsulfonyl) cyclohexyl)-3 -(trifluoromethyl)- lH-pyrazole-5-carboxamide (200)[00296] Cis-4-fluoro-4-(3-fluoro-5-(trifluoromethyl)phenylsulfonyl)cyclohexanamine hydrochloride (124) (500 mg, 1.32 mmol), 3-trifluoromethyl-lH- pyrazole-5-carboxylic acid (199) (238 mg, 1.32 mmol), HATU (668 mg, 1.8 mmol), and TEA (740 mu, 5.3 mmol) were stirred in DCM (15 mL) at room temperature for 16 hours. The reaction was diluted with DCM, washed sequentially with NH4C1 saturated solution and Na2HC03 saturated solution, dried (Na2S04), and concentrated in vacuo. The residue purified by automated flash chromatography (20% EtOAc/PE) to give N-(cis-4-fluoro-4-(3-fluoro-5-(trifluoromethyl)phenylsulfonyl) cyclohexyl)-3- (trifluoromethyl)-lH-pyrazole-5-carboxamide (200) (530 mg, 82%).

References: [1]Patent: WO2011/35159,2011,A1 .Location in patent: Page/Page column 110-111.

7
[ 129768-28-1 ]
[ 1276653-62-3 ]
[ 1276674-26-0 ]

References: [1]Patent: WO2011/35159,2011,A1 .

8
[ 129768-28-1 ]
[ 1374862-87-9 ]

References: [1]Patent: WO2012/61926,2012,A1 .

9
[ 129768-28-1 ]
[ 1374864-36-4 ]

References: [1]Patent: WO2012/61926,2012,A1 .

10
[ 129768-28-1 ]
[ 1276662-70-4 ]

References: [1]Patent: WO2012/61926,2012,A1 .

11
[ 67-56-1 ]
[ 129768-28-1 ]
[ 6833-82-5 ]

Yield	Reaction Conditions	Operation in experiment
93%	With acetyl chloride; for 2.0h;Reflux;	Example 9. Procedure for the synthesis of 2-(trifluoromethyl)-5-(3-((3- (trifluo (5H)-one (34); Preparation of methyl 3-(trifluoromethyl)-lH-pyrazole-5-carboxylate (32); 3-(Trifluoromethyl)-lH-pyrazole-5-carboxylic acid (31) (1.0 g, 8.33 mmol) was stirred inMeOH (50 mL) at rt. AcCl (1.18 mL, 16.67 mmol) was added dropwise, and the reaction stirred at reflux for 2 hours. The reaction was concentrated in vacuo and partitioned between EtOAc and saturated NaHC03 solution. The organics were dried (Na2S04) and concentrated in vacuo to give methyl 3-(trifluoromethyl)-lH-pyrazole-5-carboxylate (32) (1.0 g, 93%); NMR (300 MHz, CDC13) delta 3.98 (s, 3H), 7.10 (s, 1 H). The product was used without purification.

References: [1]Patent: WO2012/61926,2012,A1 .Location in patent: Page/Page column 41.

12
[ 129768-28-1 ]
[ 481066-00-6 ]