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[ CAS No. 72537-17-8 ] {[proInfo.proName]}

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Chemical Structure| 72537-17-8
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Product Details of [ 72537-17-8 ]

CAS No. :72537-17-8 MDL No. :MFCD00191918
Formula : C6H2ClF4N Boiling Point : -
Linear Structure Formula :- InChI Key :GDSROTVTTLUHCO-UHFFFAOYSA-N
M.W : 199.53 Pubchem ID :1268075
Synonyms :

Calculated chemistry of [ 72537-17-8 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 12
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.17
Num. rotatable bonds : 1
Num. H-bond acceptors : 5.0
Num. H-bond donors : 0.0
Molar Refractivity : 34.21
TPSA : 12.89 Ų

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) : -5.53 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.82
Log Po/w (XLOGP3) : 2.8
Log Po/w (WLOGP) : 4.47
Log Po/w (MLOGP) : 2.6
Log Po/w (SILICOS-IT) : 3.46
Consensus Log Po/w : 3.03

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -3.15
Solubility : 0.143 mg/ml ; 0.000716 mol/l
Class : Soluble
Log S (Ali) : -2.73
Solubility : 0.374 mg/ml ; 0.00187 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.81
Solubility : 0.0308 mg/ml ; 0.000155 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.09

Safety of [ 72537-17-8 ]

Signal Word:Danger Class:3
Precautionary Statements:P501-P240-P210-P233-P243-P241-P242-P264-P280-P370+P378-P337+P313-P305+P351+P338-P362+P364-P303+P361+P353-P332+P313-P403+P235 UN#:1993
Hazard Statements:H225-H315-H319-H335 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 72537-17-8 ]

* 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 [ 72537-17-8 ]
  • Downstream synthetic route of [ 72537-17-8 ]

[ 72537-17-8 ] Synthesis Path-Upstream   1~15

  • 1
  • [ 75-09-2 ]
  • [ 60075-04-9 ]
  • [ 497-19-8 ]
  • [ 72537-17-8 ]
  • [ 69806-40-2 ]
Reference: [1] Patent: US5049675, 1991, A,
  • 2
  • [ 72537-17-8 ]
  • [ 85148-26-1 ]
  • [ 69045-82-5 ]
Reference: [1] Molecules, 2013, vol. 18, # 1, p. 398 - 407
  • 3
  • [ 584-08-7 ]
  • [ 72537-17-8 ]
  • [ 89402-42-6 ]
Reference: [1] Patent: US4625035, 1986, A,
[2] Patent: US4480102, 1984, A,
  • 4
  • [ 124-38-9 ]
  • [ 584-08-7 ]
  • [ 72537-17-8 ]
  • [ 89402-42-6 ]
Reference: [1] Patent: US4480102, 1984, A,
  • 5
  • [ 72537-17-8 ]
  • [ 89402-42-6 ]
Reference: [1] Patent: US2008/221327, 2008, A1, . Location in patent: Page/Page column 6
  • 6
  • [ 7440-02-0 ]
  • [ 72537-17-8 ]
  • [ 69045-84-7 ]
Reference: [1] Patent: US4546192, 1985, A,
  • 7
  • [ 72537-17-8 ]
  • [ 69045-84-7 ]
Reference: [1] Patent: US4546192, 1985, A,
  • 8
  • [ 72537-17-8 ]
  • [ 85148-26-1 ]
  • [ 69045-82-5 ]
Reference: [1] Molecules, 2013, vol. 18, # 1, p. 398 - 407
  • 9
  • [ 72537-17-8 ]
  • [ 79456-26-1 ]
YieldReaction ConditionsOperation in experiment
99.5% With ammonia In tetrahydrofuran at 35℃; for 28 h; Autoclave; Inert atmosphere EXAMPLE 1 [0048] Preparation of 2-amino, 3-chloro, 5- trifluoromethylpyridine .[0049] 35,0 grams (0,176 moles) of 2-fluoro, 3-chloro, 5- trifluoromethylpyridine and 82,8 grams (93,1 ml) of THF are put into an autoclave of 250 ml. After degassing the system with nitrogen, 6,8 grams (0,4 moles) of NH3 are loaded making it possible to achieve a pressure of about 2,6 bar at 35°C. In these conditions, total conversion is achieved in 28 hours.[0050] As the reaction progresses, there is a drop in pressure due to the consumption of ammonia by the pyridine reagent; the reaction may be considered complete when the pressure drops no further and the datum can be confirmed analytically.[0051] When the reaction has been concluded (yield 99,5percent, reagent concentration of pyridine of general formula 1 < 0,5percent), the reactor is cooled to 20°C, the excess ammonia emptied into a suitable removal system, the autoclave sterilised and the mixture obtained separated by filtration from the salt NH4F, the panel of which (6,41 grams, 0,173 moles, recovery of 99percent of the salt formed during the reaction) is washed with 194 ml (173 grams) of THF.[0052] This addition, consisting in washing solvent combined with the mixture produced in the reaction, also has the function of diluting the mixture to the necessary degree for the subsequent reaction.. A solution containing 34,1 grams (0,173 moles) of 2-Amino-3Chloro-5- Trifluoromethylpyridine is thereby obtained.
Reference: [1] Patent: WO2011/92618, 2011, A1, . Location in patent: Page/Page column 9-11
[2] Organic and Biomolecular Chemistry, 2018, vol. 16, # 41, p. 7564 - 7567
  • 10
  • [ 69045-84-7 ]
  • [ 72537-17-8 ]
YieldReaction ConditionsOperation in experiment
100% With potassium carbonate; cesium fluoride In dimethyl sulfoxide at 120℃; for 4 h; EXAMPLE 3b; Equipment:; 250 ml four-necked round bottom flask equipped with a thermometer, a mechanical stirrer a dropping funnel and an inert gas supply25 ml DMSO was evaporated at 120° C. and 25-30 mbar from a suspension of 150 ml DMSO, 2.5 g potassium carbonate (17.9 mmol) and 25.0 g cesium fluoride (162.9 mmol). The reaction mixture was treated with 25.0 g 2,3-dichloro-5-trifluoromethylpyridine (12-1, 112.3 mmol) and stirred at 120° C. for 4 h. The suspension was filtered and the product 12-3 was directly distilled out of the distillate at 95 to 115° C. and 40-60 mbar to get 12-3 in quantitative yield. GC analysis: 96.9 area-percent of 12-3.
98% With potassium carbonate; cesium fluoride In 1-methyl-pyrrolidin-2-one at 70℃; for 1 - 3 h; 4. Optimized Procedure to Difluoro Trifluoromethyl Pyridine (12-2); The synthesis of the 12-2 was elaborated starting from the corresponding dichloro compound 12-1 or from the very expensive chloro-fluoro compound 12-3. The reactivity of the chloro atom in the 2-position of 12-1 is significant higher compared with the chloro atom in the 3-position. Based on the known safety issue of DMSO in combination with bases like K2CO3 at high temperatures like 120° C., DMSO was substituted by N-methylpyrrolidinone (NMP). The heterogenic reaction is very water-sensitive. Traces of water led to longer reaction time and/or incomplete conversion. Longer reaction time (more than 17 h at 120° C.) or higher temperature led, due to the instability of the product 12-2, to several unknown by-products, ending up as a black tar in the reaction vessel. Therefore, it was necessary to work with water free solvent. A substantial amount of CsF was needed for this reaction. CsF is very hygroscopic and contaminated the reaction mixture with water. Therefore, to completely eliminate water from the reaction mixture, a defined amount of NMP was evaporated prior to the addition of dichloro compound 12-1 to the suspension of K2CO3 and CsF in NMP.
97% With potassium fluoride; N-benzyl-N,N,N-triethylammonium chloride In N,N-dimethyl acetamide at 170℃; for 5 h; 500mL glass bottle,Supporting serpentine condenser,54.0 g (0.25 mol) of 2,3-dichloro-5-trifluoromethylpyridine,DMAC 150g,Anhydrous KF 18.9 g (0.325 mol),4 g (0.018 mol) of benzyltriethylammonium chloride,The temperature of the oil bath was raised to 170 ° C,Time reaction 5h,After DMAC was recovered by distillation,2-Fluoro-3-chloro-5-trifluoromethylpyridine was collected under reduced pressure48.6g,Its content of 2-fluoro-3-chloro-5-trifluoromethylpyridine was 99.5percentYield 97percent.
93.6% With potassium fluoride In dimethyl sulfoxide at 115 - 120℃; Inert atmosphere Under a nitrogen atmosphere, a 2 L four-necked round bottom flask was charged with 178.7 g (0.827 mol) of2,3-dichloro-5-trifluoromethylpyridine, 57.6 g (0.992 mol) of anhydrous KFAnd 200 mL of DMSO, The resulting mixture is heated to 115 ° C to 120 ° C and incubated for 3 to 5 hours, cooled to room temperature.Filtered and washed with 40 mL of DMSO to give a DMSO solution of 2-fluoro-3-chloro-5-trifluoromethylpyridine. The fractions were collected by distillation under reduced pressure at 50-55C / 11 mmHg to give a colorless liquid2-Fluoro-3-chloro-5-trifluoromethylpyridine, GC purity of 98.3percent, the yield of 93.6percent.
89.2% With potassium carbonate; cesium fluoride In dimethyl sulfoxide at 120℃; for 4 h; Inert atmosphere The 1500ml DMSO, 250g 25g of potassium carbonate and cesium fluoride were added to a 5000ml reaction flask was heated in an oil bath, concentrated under reduced pressure to a 500ml DMSO; under nitrogen, was added 250g2,3--dichloro-5-trifluoromethylpyridine, The reaction at 120 4 hours; distillation under reduced pressure to give a colorless liquid 206g, a yield of 89.2percent.

Reference: [1] Patent: US2008/221327, 2008, A1, . Location in patent: Page/Page column 9-10
[2] Patent: US2008/221327, 2008, A1, . Location in patent: Page/Page column 6
[3] Patent: CN107286087, 2017, A, . Location in patent: Paragraph 0032; 0033
[4] Patent: CN106905231, 2017, A, . Location in patent: Paragraph 0077; 0078; 0079; 0080; 0081; 0082; 0083-0085
[5] Patent: EP1199305, 2002, A1, . Location in patent: Page 6
[6] Patent: CN104628679, 2018, B, . Location in patent: Paragraph 0061-0063
  • 11
  • [ 69045-83-6 ]
  • [ 72537-17-8 ]
YieldReaction ConditionsOperation in experiment
97.56%
Stage #1: for 6 h; Autoclave; Inert atmosphere
Stage #2: at -5 - 185℃; for 12 h; Autoclave
1. In a 200 mL autoclave, add 23.0 g (0.1 mol) of 2,3,-dichloro-5-trichloromethylpyridine, place a lid on the kettle, and fill it with nitrogen for 1 hour at a pressure of 10.0 MPa for 5 hours to leak the reaction kettle. After confirming that the reactor is leak-free, the pressure in the kettle is vented.The reactor was then placed in an ice-salt bath and cooled when the temperature in the kettle fell below -5°C.The kettle was charged with anhydrous HF 40.0 g (~2.0 mol), and the reaction system was heated to 180°C with stirring, and the reaction was incubated for 12 hours.2. After the reaction is completed, cool down to 25°C, exchange nitrogen in the reactor for half an hour (exchanged gas is passed into 10percent aqueous sodium hydroxide for neutralization absorption), and hydraulically introduce the reaction into a 250 mL round bottom flask. ,70 g (~1.0 mol) of a 25percent aqueous ammonia solution was added and reacted at 35°C for 12 hours under normal pressure.3. After the reaction is complete, collect the oil layer and wash three times until neutral. Add 10g of anhydrous sodium sulfate to the oily liquid and dry it for 6h. Filter the solids out and then conduct vacuum distillation to collect the fraction with a boiling point of 50-55°C/11mmHg.Obtained 16.0 g of 2-fluoro-3-chloro-5-trifluoromethylpyridine product.The content of 2-fluoro-3-chloro-5-trifluoromethylpyridine in the product was determined to be 99.95percent (GC) and the yield was 97.56percent.
Reference: [1] Patent: CN107954924, 2018, A, . Location in patent: Paragraph 0033-0036; 0037-0042
[2] Patent: CN107935920, 2018, A, . Location in patent: Paragraph 0026; 0027; 0028; 0033; 0036
  • 12
  • [ 79456-26-1 ]
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Reference: [1] Tetrahedron, 1996, vol. 52, # 1, p. 23 - 36
[2] Journal of Fluorine Chemistry, 1988, vol. 38, p. 435 - 438
  • 13
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  • [ 80194-70-3 ]
YieldReaction ConditionsOperation in experiment
89%
Stage #1: With dmap In acetone for 5 h; Reflux; Large scale
Stage #2: at 20℃; for 2.5 h; Large scale
2.745 kg of 3-chloro-2-fluoro-5-trifluoromethylpyridine was dissolved in 49.41 L of acetone,Then, 1.478 kg of 4-dimethylaminopyridine was added thereto, heated under reflux for 5 hours, cooled to 24 ° C,To obtain a reaction solution, and the resulting reaction solution was filtered to obtain a filter cake,The resulting filter cake was vacuum dried at 44 ° C for 1.5 hours to obtain an organic salt; The organic salt obtained in step (1), 0.588 kg of sodium cyanide was added to 8.232 L of chloroform and 1.029 L of water,The reaction was stirred at 20 ° C for 2.5 hours to obtain a mixed solution, and the resulting mixture was allowed to stand at room temperature to obtain an organic phase a;The obtained organic phase a was added to hydrochloric acid to adjust its pH to 3 and then allowed to stand for delamination to obtain an acid water layer and an organic layer,The resulting organic layer was washed with water to pH 6.5 to give washed water and organic phase b; The organic phase b obtained in step was distilled at atmospheric pressure to 60 ° C and then vacuum distilled to collect a vacuum of 2 mmHg,Potassium temperature of 70 ~ 120 fractions that is 3 - chloro - 2 - cyano - 5 - trifluoromethyl pyridine 1.84kg, yield 89percent.
83% at 20℃; for 5 h; Example 4
A reactor was charged with a solution of sodium cyanide (73.5 g) in water (150 ml), propionitrile (500 ml), 4-dimethylaminopyridine (16 g), and 3-chloro-2-fluoro-5-trifluoromethylpyridine (149.3 g) added over 30 minutes..
After stirring for 5 hours at 20° C., the upper organic phase was separated off and washed with water..
The lower aqueous layer was extracted with propionitrile, the two organic layers combined and solvent distilled off under vacuum at 45° C. to give an 83percent yield of 3-chloro-2-cyano-5-trifluoromethylpyridine.
74.3% With tetrabutylammomium bromide In water; dimethyl sulfoxide at 45 - 50℃; To the reaction liquid obtained in the above Example 1 was added 44.6 g (0.910 mol) of NaCN,13.4 g (0.0415 mol) of TBAB and 200 mL of water,The resulting mixture was heated at 45 ° C to 50 ° C,After stirring for 20-22 hours, water was added and extracted with dichloromethane.The resulting organic layer was concentrated,Distillation gave 127 g of 2-cyano-3-chloro-5-trifluoromethylpyridine as a light yellow liquid,Yield 74.3percent, GC purity 99.33percent.
46.7 g at 20℃; for 10 h; 500mL glass bottle,48.6 g (0.243 mol) of 2-fluoro-3-chloro-5-trifluoromethylpyridine,Dichlorohexane 200g,40.4 g (0.247 mol) of 30percent sodium cyanide,4 g (0.018 mol) of benzyltriethylammonium chloride,Warmed to 20 ° C,Timed reaction 10h,After the water treatment,After the oil phase is recovered from dichloroethane,100-110 ° C / 15 mmHg fractions were collected.46.7 g of a colorless liquid 2-cyano-3-chloro-5-trifluoromethylpyridine was obtained.The content of 2-cyano-3-chloro-5-trifluoromethylpyridine in the product was 99.6percent (GC)The total yield of the two-step reaction is 90.1percent.

Reference: [1] Patent: CN106349159, 2017, A, . Location in patent: Paragraph 0026
[2] Patent: US6699993, 2004, B1, . Location in patent: Page column 4
[3] Patent: CN106905231, 2017, A, . Location in patent: Paragraph 0086; 0087; 0088; 0089; 0090; 0091; 0092-0094
[4] Patent: CN107286087, 2017, A, . Location in patent: Paragraph 0032; 0034
  • 14
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  • [ 80194-70-3 ]
YieldReaction ConditionsOperation in experiment
84% at 30℃; for 0.833333 h; Description 115; 3-Chloro-5-trifluoromethylpvridine-2-carbonitrile; To 3-chloro-2-fluoro-5-trifluoromethylpyridine (10 g, 50 mmol) in DMSO (70 ml) was added potassium cyanide (3.6 g, 55 mmol) over 20 min, ensuring the reaction mixture temperature stayed below 30°C. The reaction mixture was stirred for a further 30 minutes then poured onto ice water (150 ml). The mixture was extracted 3 times with hexane, and the combined organic extracts were evaporated to give a solid (8. 7 g, 84percent). 1H NMR (400 MHz, CDCl3) 8.15 (1 H, d, J 1.2), 8. 88 (1 H, d, J1. O).
Reference: [1] Patent: WO2005/47279, 2005, A1, . Location in patent: Page/Page column 56
  • 15
  • [ 72537-17-8 ]
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Reference: [1] Patent: EP1199305, 2002, A1, . Location in patent: Example 2
[2] Patent: EP1199305, 2002, A1, . Location in patent: Example 3
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