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Product Details of [ 5750-76-5 ]

CAS No. :5750-76-5 MDL No. :MFCD03788200
Formula : C4HCl3N2 Boiling Point : -
Linear Structure Formula :- InChI Key :GIKMWFAAEIACRF-UHFFFAOYSA-N
M.W : 183.42 Pubchem ID :237259
Synonyms :

Calculated chemistry of [ 5750-76-5 ]

Physicochemical Properties

Num. heavy atoms : 9
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 2.0
Num. H-bond donors : 0.0
Molar Refractivity : 37.06
TPSA : 25.78 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) : -5.47 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.88
Log Po/w (XLOGP3) : 2.75
Log Po/w (WLOGP) : 2.44
Log Po/w (MLOGP) : 1.43
Log Po/w (SILICOS-IT) : 2.99
Consensus Log Po/w : 2.3

Druglikeness

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

Water Solubility

Log S (ESOL) : -3.2
Solubility : 0.115 mg/ml ; 0.000627 mol/l
Class : Soluble
Log S (Ali) : -2.95
Solubility : 0.208 mg/ml ; 0.00113 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.5
Solubility : 0.0579 mg/ml ; 0.000316 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.68

Safety of [ 5750-76-5 ]

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

Application In Synthesis of [ 5750-76-5 ]

* 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 [ 5750-76-5 ]
  • Downstream synthetic route of [ 5750-76-5 ]

[ 5750-76-5 ] Synthesis Path-Upstream   1~18

  • 1
  • [ 1820-81-1 ]
  • [ 5750-76-5 ]
YieldReaction ConditionsOperation in experiment
95% Neat (no solvent); Heating / reflux 5-Chlorouracil (4.5 g, 30.82 mmol) was dissolved in phosphorus oxychloride (100 mL) and phosphorus pentachloride (19.2 g, 92.46 mmol) was added. The reaction mixture was heated at reflux overnight; it was then cooled to RT and the solvent was evaporated under reduced pressure. The residue was cooled to 0 0C and ice flakes were carefully added. The resulting mixture was stirred for 10 minutes; it was then partitioned between water and DCM. The organic phase was separated and washed 3 times with water. The aqueous layers were combined and extracted twice with DCM. The combined organic extracts were dried over Na2SO4, filtered and evaporated under reduced pressure to give f> o fQSpercent vipid) of 2,4, 5-trichloro-pyrimidine as a yellow oil without further purifications.
81% at 110℃; for 24 h; Example 15
N4-[(trans-4-aminocyclohexyl)methyl]-5-chloro-N2-[2-(trifluoromethoxy)benzyl]pyrimidine-2,4-diamine
To a suspension of 5-chlorouracil (15.0 g, 102.4 mmol) in POCl3 (50 mL, 326.1 mmol) was added N,N-diethylaniline (7.5 mL).
The reaction mixture was heated at 110° C. for 24 h.
The reaction mixture was cooled to room temperature and concentrated in vacuo to about 25 mL.
The resulting residue was then poured into ice and stirred until all the ice melted.
The aqueous layer was extracted with ether (*3).
The combined organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo.
The resulting residue was distilled under vacuum at ~90° C. to afford 12.5 g (81percent) of 5-chloro-2,4-dichloropyrimidine.
69% at 110℃; for 3 h; Example 1; compound 1 <n="45"/>A 50OmL round bottomed flask was charged with 5-chlorouracil a (25.0 g, 170 mmol, 1.0 equiv) and phosphoryl chloride (159 mL, 1.7 mol, 10 equiv). The reaction vessel was equipped with a vigoreaux column followed by careful addition of diisopropylethylamine (59 mL, 340 mmol, 2.0 equiv) over 1 minute. Evolution of white fumes was observed during the addition of diisopropylethylamine. The reaction was then heated to 1100C and stirred for 3 h. The reaction was cooled to ambient temperature and concentrated in vacuo to crude brown oil. The residual oil was quenched by careful addition of ice chips followed by cold water (100 mL). The aqueous mixture was extracted with diethyl ether and the organic layer washed with brine. The organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to yield crude yellow oil. The crude oil was purified by silica gel chromatography, 0-10percent EtOAc/hexane, to provide 2,4,5-trichloropyrimidine b as colorless oil (21.4 g, 69percent).; Example 3; compound 78NMM, THF -780CA 500-mL round bottomed flask was charged with 5-chlorouracil a (25.0 g, 170 mmol, 1.0 equiv) and phosphoryl chloride (159 mL, 1.7 mol, 10 equiv). The reaction vessel was equipped with a vigoreaux column followed by careful addition of diisopropylethylamine (59 mL, 340 mmol, 2.0 equiv) over 1 minute. Evolution of white fumes was observed during the addition of diisopropylethylamine. The reaction was then heated to 110 0C and stirred for 3 h. The reaction was cooled to ambient temperature and concentrated in vacuo to crude brown oil. The residual oil was quenched by careful addition of ice chips followed by cold water (100 mL). The aqueous mixture was extracted with diethyl ether and the organic layer washed with brine. The organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to yield crude yellow oil. The crude oil was <n="49"/>purified by silica gel chromatography, 0-10percent EtOAc/hexane, to provide 2,4,5-trichloropyrimidine b as colorless oil (21.4 g, 69percent).; Example 4 compound 80A 500-mL round bottomed flask was charged with 5-chlorouracil a (25.0 g, 170 mmol, 1.0 equiv) and phosphoryl chloride (159 mL, 1.7 mol, 10 equiv). The reaction vessel was equipped with a vigoreaux column followed by careful addition of diisopropylethylamine (59 mL, 340 mmol, 2.0 equiv) over 1 minute. Evolution of white fumes was observed during the addition of diisopropylethylamine. The reaction was then heated to 110 0C and stirred for 3 h. The reaction was cooled to ambient temperature and concentrated in vacuo to crude brown oil. The residual oil was quenched by careful addition of ice chips followed by cold water (100 mL). The aqueous mixture was extracted with diethyl ether and the organic layer washed with brine. The organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to yield crude yellow oil. The crude oil was purified by silica gel chromatography, 0-10percent EtOAc/hexane, to provide 2,4,5-trichloropyrimidine b as colorless oil (21.4 g, 69percent).; Example 5 compound 84a bA 50OmL round bottomed flask was charged with 5-chlorouracil a (25.0 g, 170 mmol, 1.0 equiv) and phosphoryl chloride (159 mL, 1.7 mol, 10 equiv). The reaction vessel was equipped with a vigoreaux column followed by careful addition of diisopropylethylamine (59 mL, 340 mmol, 2.0 equiv) over 1 minute. Evolution of white fumes was observed during the addition of diisopropylethylamine. The reaction was then heated to 1100C and stirred for 3 h. The reaction was cooled to ambient temperature and concentrated in vacuo to crude brown oil. The residual oil was quenched by careful addition of ice chips followed by cold water (100 mL). The aqueous mixture was extracted with diethyl ether and the organic layer washed with brine. The organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to yield crude yellow oil. The crude oil was purified by silica gel chromatography, 0-10percent EtOAc/hexane, to provide 2,4,5-trichloropyrimidine b as colorless oil (21.4 g, 69percent).
69% at 110℃; for 3.01667 h; Example 10 N-(2-(2,5 -dichloropyrimidin-4-ylamino)phenyl)-cyclopropanecarboxamide; A 500 mL round bottomed flask was charged with 5-chlorouracil a (25.0 g, 170 mmol, 1.0 equiv) and phosphoryl chloride (159 mL, 1.7 mol, 10 equiv). The reaction vessel was equipped with a vigoreaux column followed by careful addition of diisopropylethylamine (59 mL, 340 mmol, 2.0 equiv) over 1 minute. Evolution of white fumes was observed during the addition of diisopropylethylamine. The reaction was then heated to 110 0C and stirred for 3 h. The reaction <n="41"/>was cooled to ambient temperature and concentrated in vacuo to crude brown oil. The residual oil was quenched by careful addition of ice chips followed by cold water (100 mL). The aqueous mixture was extracted with diethyl ether and the organic layer washed with brine. The organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to yield crude yellow oil. The crude oil was purified by silica gel chromatography, 0-10percent EtOAc/hexane, to provide 2,4,5-trichloropyrimidine b as colorless oil (21.4 g, 69percent).; A 500 mL round bottomed flask was charged with 5-chlorouracil a (25.0 g, 170 mmol, 1.0 equiv) and phosphoryl chloride (159 mL, 1.7 mol, 10 equiv). The reaction vessel was equipped with a vigoreaux column followed by careful addition of diisopropylethylamine (59 mL, 340 mmol, 2.0 equiv) over 1 minute. Evolution of white fumes was observed during the addition of diisopropylethylamine. The reaction was then heated to 110 0C and stirred for 3 h. The reaction was cooled to ambient temperature and concentrated in vacuo to crude brown oil. The residual oil was quenched by careful addition of ice chips followed by cold water (100 mL). The aqueous mixture was extracted with diethyl ether and the organic layer washed with brine. The organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to yield <n="43"/>crude yellow oil. The crude oil was purified by silica gel chromatography, 0-10percent EtOAc/hexane, to provide 2,4,5-trichloropyrimidine b as colorless oil (21.4 g, 69percent).
51% With phosphorus pentachloride In water; ethyl acetate; trichlorophosphate Method 19
2,4,5-Trichloropyrimidine
5-Chlorouracil (10.0 g, 68.5 mmol) was dissolved in phosphorus oxychloride (60 ml) and phosphorus pentachloride (16.0 g, 77 mmol) was added.
The reaction mixture was then stirred at reflux (110° C.) for 16 hrs then allowed to cool to 20° C.
The reaction mixture was then poured slowly and carefully into water (200 ml) at 25° C. with vigorous stirring.
Then stirred well for 90 minutes before addition of EtOAc (250 ml).
Organic layer separated off and aqueous layer re-extracted into EtOAc (250 ml).
The organic layers were then combined and washed with sodium bicarbonate (200 ml aqueous solution), brine (200 ml) and then evaporated to a yellow liquid.
The crude material was purified by column chromatography eluding with dichloromethane to afford the product as a yellow liquid (6.37 g, 51percent). NMR (CDCl3): 8.62 (s, 1H); MS (M+): 182, 184,186.
51% With phosphorus pentachloride In ethyl acetate; trichlorophosphate Method 3
2,4,5-Trichloropyrimidine
5-Chlorouracil (10.0 g, 68.5 mmol) was dissolved in phosphorus oxychloride (60 ml) and phosphorus pentachloride (16.0 g, 77.0 mmol) was added.
The mixture was heated under reflux for 16 hours, left to cool and then poured slowly into water (200 ml) with vigorous stirring.
The mixture was stiffed for 1.5 hours and then ethyl acetate (250 ml) was added.
The organic layer was separated and the aqueous layer was extracted with a further portion of ethyl acetate (250 ml).
The combined extracts were washed with saturated sodium bicarbonate (200 ml) and saturated sodium chloride solution (200 ml), and then dried.
Volatile material was removed by evaporation and the residue was purified by column chromatography, eluding with DCM, to give the product as a yellow liquid (6.37 g, 51percent). NMR (CDCl3): 8.62 (s, 1H); MS (MH+): 182, 184, 186.
51% With phosphorus pentachloride In ethyl acetate; trichlorophosphate Method 5
2,4,5-Trichloropyrimidine
5-Chlorouracil (10.0 g, 68.5 mmol) was dissolved in phosphorus oxychloride (60 ml) and phosphorus pentachloride (16.0 g, 77.0 mmol) was added.
The mixture was heated under reflux for 16 hours, left to cool and then poured slowly into water (200 ml) with vigorous stirring.
The mixture was stirred for 1.5 hours and then ethyl acetate (250 ml) was added.
The organic layer was separated and the aqueous layer was extracted with a further portion of ethyl acetate (250 ml).
The combined extracts were washed with saturated sodium bicarbonate (200 ml) and saturated sodium chloride solution (200 ml), and then dried.
Volatile material was removed by evaporation and the residue was purified by column chromatography, eluding with DCM, to give the product as a yellow liquid (6.37 g, 51percent). NMR (CDCl3): 8.62 (s, 1H); MS (MH+): 182, 184, 186.
51% With phosphorus pentachloride In ethyl acetate; trichlorophosphate Method 8
2,4,5-Trichloropyrimidine
5-Chlorouracil (10.0 g, 68.5 mmol) was dissolved in phosphorus oxychloride (60 ml) and phosphorus pentachloride (16.0 g, 77.0 mmol) was added.
The mixture was heated under reflux for 16 hours, left to cool and then poured slowly into water (200 ml) with vigorous stirring.
The mixture was stirred for 1.5 hours and then ethyl acetate (250 ml) was added.
The organic layer was separated and the aqueous layer was extracted with a further portion of ethyl acetate (250 ml).
The combined extracts were washed with saturated sodium bicarbonate (200 ml) and saturated sodium chloride (200 ml), and then dried.
Volatile material was removed by evaporation and the residue was purified by column chromatography, eluding with DCM, to give the product as a yellow liquid (6.37 g, 51percent). NMR (CDCl3): 8.62 (s, 1H); MS (MH+): 182, 184, 186.
51% With phosphorus pentachloride In ethyl acetate; trichlorophosphate Method 11
2,4,5-Trichloropyrimidine
5-Chlorouracil (10.0 g, 68.5 mmol) was dissolved in phosphorus oxychloride (60 ml) and phosphorus pentachloride (16.0 g, 77.0 mmol) was added.
The mixture was heated under reflux for 16 hours, left to cool and then poured slowly into water (200 ml) with vigorous stirring.
The mixture was stirred for 1.5 hours and then ethyl acetate (250 ml) was added.
The organic layer was separated and the aqueous layer was extracted with a further portion of ethyl acetate (250 ml).
The combined extracts were washed with saturated sodium bicarbonate (200 ml) and saturated sodium chloride solution (200 ml), and then dried.
Volatile material was removed by evaporation and the residue was purified by column chromatography, eluding with DCM, to give the product as a yellow liquid (6.37 g, 51percent). NMR (CDCl3): 8.62 (s, 1H); MS (MH+): 182, 184, 186.
82.9% With N,N-diethylaniline In diethyl ether; trichlorophosphate 3A Preparation of 2,4,5-trichloropyrimidine
10 g (0.068 mol) of 5-chlorouracil in 20 mL POCl3 (0.21 mol) was treated with 18 mL of N,N-diethylaniline (0.14 mol) at ambient temperature.
The stirred mixture was heated to 100° C. for 4 h.
Volatile solvents were removed in vacuo and the residue dissolved in 100 mL of diethyl ether and washed with 2*100 mL of ice cold 10percent HCl solution, dried, filtered and evaporated to yield 8.54 g (82.9percent) of 2,4,5-trichloropyrimidine as a colorless liquid. b.p. 73-75° C./3 Torr).

Reference: [1] Patent: WO2008/28860, 2008, A1, . Location in patent: Page/Page column 45
[2] Patent: US2006/25433, 2006, A1, . Location in patent: Page/Page column 108
[3] Patent: US4299961, 1981, A,
[4] Patent: WO2008/79719, 2008, A1, . Location in patent: Page/Page column 43-44; 47-48; 49; 51
[5] Patent: WO2007/120339, 2007, A1, . Location in patent: Page/Page column 39-42
[6] Patent: US2003/149064, 2003, A1,
[7] Patent: US2003/149266, 2003, A1,
[8] Patent: US2003/114473, 2003, A1,
[9] Patent: US6593326, 2003, B1,
[10] Patent: EP1161428, 2003, B1,
[11] Journal of the Chemical Society, 1955, p. 3478,3481
[12] Tetrahedron Letters, 1997, vol. 38, # 7, p. 1111 - 1114
[13] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 18, p. 2961 - 2966
[14] Patent: US6153619, 2000, A,
[15] Patent: WO2004/16597, 2004, A2, . Location in patent: Page 107
[16] Journal of Medicinal Chemistry, 2011, vol. 54, # 2, p. 510 - 524
  • 2
  • [ 1820-81-1 ]
  • [ 5750-76-5 ]
Reference: [1] Molecules, 2012, vol. 17, # 4, p. 4533 - 4544
  • 3
  • [ 10025-67-9 ]
  • [ 5750-76-5 ]
Reference: [1] Patent: US4171442, 1979, A,
  • 4
  • [ 1207557-48-9 ]
  • [ 5750-76-5 ]
  • [ 274-56-6 ]
  • [ 1224709-13-0 ]
  • [ 169557-02-2 ]
  • [ 1383675-58-8 ]
YieldReaction ConditionsOperation in experiment
59% With bis(di-tert-​butyl(4-​dimethylaminophenyl)​phosphine)​dichloropalladium(II); water; sodium carbonate In 1,2-dimethoxyethane at 85℃; for 3 h; Inert atmosphere Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (Pd(Amphos)Cl2) (4.24 g, 5.99 mmol) was added to a degassed mixture of 2,4,5-trichloropyrimidine (13.72 mL, 119.7 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (10, 24.35 g, 0.1 mol) and 2M Na2CO3 (110 mL, 219.46 mmol) in DME (500 mL) under nitrogen. The resulting mixture was stirred at 85 °C for 3 h and then allowed to cool to ambient temperature overnight. The precipitate was collected by filtration, washed with DME (150 mL) and water (3.x.250 mL) and dried under vacuum at 50 °C for 4 h to afford the title compound (8, 13.64 g) as a pale yellow solid. A precipitate developed in the aqueous filtrate, which was collected by filtration, stirred in acetone (250 mL) for .similar.5 min, filtered and dried under vacuum to afford further title compound (8, 2.01 g) as a cream solid. Overall yield 15.65 g, 59percent; δH (400 MHz, DMSO): 7.28 (1H, td, J 7, 1 Hz, ArH-6), 7.67-7.77 (1H, m, ArH-5), 8.56 (1H, d, J 9 Hz, ArH-4), 8.80 (1H, s, ArH-2), 8.96 (1H, d, J 7 Hz, ArH-7), 9.08 (1H s, pyrimidine H); δC (176 MHz, DMSO at 70 °C): 105.78, 115.21, 119.81, 124.33, 128.86, 130.09, 139.76, 143.98, 157.33, 158.13, 159.44; m/z (ES+) 265 (100, MH+); HRMS (ESI): MH+, found 265.00439. C11H7Cl2N4 requires 265.00423.
Reference: [1] Tetrahedron, 2012, vol. 68, # 27-28, p. 5434 - 5444
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  • [ 5750-76-5 ]
  • [ 22536-67-0 ]
Reference: [1] Patent: WO2008/85316, 2008, A1, . Location in patent: Page/Page column 96
[2] Patent: WO2011/19538, 2011, A1, . Location in patent: Page/Page column 65-66
[3] Patent: WO2013/74388, 2013, A1, . Location in patent: Page/Page column 43
[4] Patent: WO2013/122821, 2013, A1, . Location in patent: Page/Page column 40
[5] Patent: WO2009/129036, 2009, A1, . Location in patent: Page/Page column 44-45
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  • [ 5750-76-5 ]
  • [ 89180-51-8 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 24, p. 5446 - 5449
[2] Patent: WO2004/108704, 2004, A1, . Location in patent: Page 53
[3] Patent: WO2009/150240, 2009, A1, . Location in patent: Page/Page column 132
[4] Patent: WO2004/108710, 2004, A1, . Location in patent: Page 53
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  • [ 124-41-4 ]
  • [ 5750-76-5 ]
  • [ 5750-74-3 ]
YieldReaction ConditionsOperation in experiment
57% at 20℃; Sodium methoxide (295 mg, 5.45 mmol) was taken up in methanol (13.6 ml) and 2,4,5- trichloropyrimidine (500 mg, 2.73 mmol) was added. The mixture was stirred at roomtemperature overnight. The resulting mixture was concentrated under reduced pressure. The resulting residue was diluted with diethyl ether, washed with 1 : 1 water : saturated aqueous ammonium choride. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by Combiflash (0-10percent diethyl ether/hexanes) afforded 280 mg (1.56 mmol, 57percent) of 2,5-dichloro-4-methoxypyrimidine as a white solid.
0.98 g at 0 - 20℃; To a 250 mL round bottom flask equipped with a stir bar was added 1 g 5- chloro-2,4-dichloro- pyrimidine, and 15mL of diethyl ether. The mixture was cooled to 0°C in an ice bath and then 1 equivalent of sodium methoxide in methanol (prepared from reacting 120 mg of sodium with 4 mL of methanol at room temperature) was slowly added. The reaction was stirred over night at room temperature and checked by LCMS. The white precipitate was filtered and the solid washed with cold methanol. After drying, 0.98 g of pure 2,5-dichloro-4- methoxypyrimidine was obtained and this material was used without further purification.
0.98 g at 0 - 20℃; To a 250 mL round bottom flask equipped with a stir bar was added 1 g 5-chloro- 2,4-dichloro- pyrimidine, and l5mL of diethyl ether. The mixture was cooled to 0°C inan ice bath and then 1 equivalent of sodium methoxide in methanol (prepared from reacting 120 mg of sodium with 4 mL of methanol at room temperature) was slowly added. The reaction was stirred over night at room temperature and checked by LCMS. The white precipitate was filtered and the solid washed with cold methanol. After drying, 0.98 g of pure 2,5-dichloro-4-methoxypyrimidine was obtained and this material wasused without further purification.
Reference: [1] Tetrahedron Letters, 2006, vol. 47, # 26, p. 4415 - 4418
[2] Patent: WO2011/75560, 2011, A1, . Location in patent: Page/Page column 57
[3] Patent: WO2012/62783, 2012, A1, . Location in patent: Page/Page column 66
[4] Patent: WO2013/79493, 2013, A1, . Location in patent: Page/Page column 42-43
[5] Patent: WO2013/79494, 2013, A1, . Location in patent: Page/Page column 57-58
[6] Patent: WO2013/79505, 2013, A1, . Location in patent: Page/Page column 46-47
[7] Patent: WO2013/79495, 2013, A1, . Location in patent: Page/Page column 49
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  • [ 67-56-1 ]
  • [ 5750-76-5 ]
  • [ 5750-74-3 ]
Reference: [1] Patent: US2011/301141, 2011, A1, . Location in patent: Page/Page column 22
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  • [ 67-56-1 ]
  • [ 5750-76-5 ]
  • [ 5750-74-3 ]
Reference: [1] Patent: WO2016/107832, 2016, A1, . Location in patent: Page/Page column 121
  • 10
  • [ 5750-76-5 ]
  • [ 129271-98-3 ]
  • [ 882562-40-5 ]
YieldReaction ConditionsOperation in experiment
91% With sodium carbonate; acetonitrile In water for 1.5 h; Heating / reflux To a solution of 2,4,5-trichloropyrimidine (1.25 g) in dry MeCN/water (20 ml/10 ml) under nitrogen was added l-(phenylsulfonyl)-lH-indol-3-ylboronic acid (2.0 g) and Na2CO3 (1.4 g). The mixture was degassed 3 times before the addition of tetrakis(triphenylphosphine)palladium(0) (390 mg) took place. After degassing a further3 times, the mixture was heated at reflux for 90 min. The resulting precipitate was filtered off and washed with water and Et2O to afford the title compound as a white solid(2.48 g, 91percent). 1H NMR 300 MHz (d6-DMSO) 9.00 (1H, s), 8.80 (1H, s), 8.55 (1H, d), 8.15 (2H, d), 8.05-8.02 (1H, s), 7.75 (1H, t), 7.64 (2H, t), 7.52-7.41 (2H, m).
Reference: [1] Patent: WO2006/38001, 2006, A1, . Location in patent: Page/Page column 40
[2] Journal of the American Chemical Society, 2015, vol. 137, # 46, p. 14640 - 14652
[3] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 12, p. 3463 - 3467
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  • [ 870717-93-4 ]
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  • [ 882562-40-5 ]
Reference: [1] Journal of Medicinal Chemistry, 2013, vol. 56, # 17, p. 7025 - 7048
  • 12
  • [ 31230-17-8 ]
  • [ 5750-76-5 ]
  • [ 543712-81-8 ]
YieldReaction ConditionsOperation in experiment
89.5% With triethylamine In ethanol at 20℃; for 16 h; To a solution of 5-methyl-l /-pyrazol-3-amine (4.00 g, 41.2 mmol) in absolute EtOH (100 mL) were added Et3 (12.51 g, 123.6 mmol) and 2,4,5-trichloropyrimidine (7.56 g, 41.2 mmol). The reaction was stirred at room temperature for 16 h and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 1/1) to give the title compound as a pale yellow solid (9.00 g, 89.5percent). MS (ESI, pos. ion) m/z: 244.1 [M+H]+; NM (600 MHz, DMSO-i: δ (ppm) 12.32 (br. s, 1H), 9.70 (s, 1H), 8.33 (s, 1H), 6.28 (s, 1H), 2.25 (s, 3H).
89.5% With triethylamine In ethanol at 20℃; for 16 h; 5-methyl-1H-pyrazol-3-amine (4.00 g, 41.2 mmol) was dissolved in absolute ethanol (100 mL). Et3N (12.51 g, 123.6 mmol) and 2,4,5-trichloropyrimidine (7.56 g, 41.2 mmol) were added thereto. After the addition was completed, the reaction mixture was stirred at room temperature for 16 hours and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc / PE (v / v) = 1/1) to give the title compound as a pale yellow solid (9.00 g, 89.5percent).
76% With N-ethyl-N,N-diisopropylamine In ethanol at 20℃; for 48 h; Inert atmosphere Step 1: Compound 1a (3.64 g, 20 mmol), 3-amino-5-methyl-pyrazole (1.94 g, 20 mmol) and diisopropylethylamine (5.17 g, 40 mmol) were added to 20 mL of ethanol solution and then stirred at room temperature for 2 days. The insoluble substance was collected to obtain Compound 1b (3.7 g, Yield 76percent), MS [M + 1]+ 244.0.
76% With N-ethyl-N,N-diisopropylamine In ethanol at 20℃; for 48 h; Inert atmosphere Compound la (3.64 g. 20 mmol), 3-amino-5-me- thyl-pyrazole (1.94 g, 20 mmol) and diisopropylethylamine (5.17 g, 40 mmol) were added to 20 mE of ethanol solution and then stirred at room temperature for 2 days. The insoluble substance was collected to obtain Compound lb (3.7 g, Yield76percent), MS [M+l] 244.0.

Reference: [1] Journal of Medicinal Chemistry, 2011, vol. 54, # 1, p. 262 - 276
[2] Organic Process Research and Development, 2013, vol. 17, # 9, p. 1123 - 1130
[3] Patent: WO2015/94803, 2015, A1, . Location in patent: Paragraph 323
[4] Patent: CN104672250, 2017, B, . Location in patent: Paragraph 0762; 0763; 0764; 0765
[5] Patent: EP2754659, 2014, A1, . Location in patent: Paragraph 0061-0063
[6] Patent: US2014/378488, 2014, A1, . Location in patent: Paragraph 0093; 0094; 0095
[7] Patent: WO2009/7753, 2009, A2, . Location in patent: Page/Page column 56-57
[8] Journal of Medicinal Chemistry, 2008, vol. 51, # 15, p. 4672 - 4684
[9] Patent: WO2007/49041, 2007, A1, . Location in patent: Page/Page column 58
[10] Patent: WO2009/158431, 2009, A2, . Location in patent: Page/Page column 29-30
  • 13
  • [ 76697-50-2 ]
  • [ 5750-76-5 ]
  • [ 761440-16-8 ]
YieldReaction ConditionsOperation in experiment
72%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5 h;
Stage #2: at 0 - 20℃; for 2 h;
To a solution of 2-(isopropylsulfonyl)aniline (3.0 g,15.1 mmol) in DMF (80 mL) was added sodium hydride (1.2 g,30.1 mmol, 60percent in mineral oil) at 0 °C. After stirring for 30 min,2,4,5-trichloropyrimidine was added to the reaction mixture followedby warming the mixture to room temperature. After stirringfor 2 h, the reaction mixture was quenched with ice and dilutedwith excess water. The precipitate was filtered and the solid wasdried by blowing nitrogen gas to obtain 3c as an off-white solid(3.75 g, 72percent). 1H NMR (500 MHz, DMSO-d6) δ 9.81 (s, 1H), 8.56 (s,1H), 8.33-8.31 (m, 1H), 7.89 (dd, J = 7.9, 1.5 Hz, 1H), 7.88-7.84 (m,1H), 7.48 (td, J = 7.6, 1.2 Hz, 1H), 3.58-3.48 (m, 1H), 1.16 (d, J = 6.7,6H); LC/MS (ESI) m/z 346.18 [M+H]+.
65.6% With palladium diacetate; caesium carbonate; triphenylphosphine In toluene for 4 h; Inert atmosphere; Reflux To a stirred solution of 40 g (0.200mole) of 2-isopropylsulfonyl aniline [formula- XI] in 400 ml of toluene into a flask under nitrogen atmosphere. 49.7 g (0.27 mole) of 2,4,5-trichlropyrimidine (formula-XII), 81.7g (0.25 mole) of caesium carbonate, 4.5 g (0.02 mole) of palladium(II)acetate, 13.1 g (0.05 mole) of triphenylphosphine were added. Raised the reaction mass temperature to reflux under nitrogen and maintained for 4 hours. Checked the TLC for 2-isopropylsulfonyl aniline content by TLC. 2-isopropylsulfonyl aniline content is absent. Reaction mass was cooled to 25-30°C and filtered the mass. Washed the solid with 400 ml of ethyl acetate. Toluene and ethyl acetate were removed by distillation under vacuum at a temperature 60°C to give crude compound. Crude compound was further purified by column chromotography to 45.6 g of 2, 5-dichloro-N-(2-(isopropyl sulfonyl) phenyl) pyrimidin-4-amine [formula-XIII] as a light yellow solid product with 65.6 percent yield by theory.
63%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 1 h; Ionic liquid
Stage #2: at 20℃;
11.
Preparation of 2,5-dichloro -N- (2- (isopropylsulfonyl) phenyl) pyrimidin-4-amine
Under the protection of nitrogen, 2-(isopropylsulfonyl) aniline (0.65 g, 3.29 mmol) and anhydrous N, N-dimethylformamide (6 mL) was sequentially added into a flask, cooled to 0 °C, and sodium hydride (0.20g, 60percent, 8.24mmol) was added in batches.
Upon addition, the reaction mixture was stirred for 1 hour. 2,4,5-trichloropyrimidine (1.21 g, 6.59 mmol) in N, N-dimethylformamide (3 mL) was added dropwise, and then heated to room temperature and stirred overnight.
The reaction mixture was added into pure water to quench the reaction.
Then it was extracted with ethyl acetate for three times.
The organic layers were combined, and washed with water and brine successively, dried over anhydrous sodium sulfate, filtered and concentrated by a rotary evaporator under vacuo to give a crude product.
The crude product was purified by column chromatography to give the desired product as white soild (0.70g, 63percent).MS Calcd.: 345; MS Found: 346 (M+H)+, 368 (M+Na)+.
HNMR (CDCl3, 400 MHz) δ 10.08 (s, 1H), 8.65 (d,J=8.4 Hz, 1H), 8.32 (s, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.75 (t, J=8.4 Hz, 1H), 7.33 (t, J=8.0 Hz, 1H), 3.25-3.12 (m, 1H), 1.34 (d, 6H).
59%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5 h;
Stage #2: at 0 - 20℃;
To the suspension of NaH (4.5 g, 0.12 mol) in DMF (160 mL), 2-(isopropylsulfonyl)aniline (16.0 g, 0.08 mol) was added at 0 °C.
The mixture was stirred for 30 min at 0 °C, and then 2,4-dichloro-5-methylpyrimidine (29.3 g, 0.16 mol) diluted in DMF (6 mL)was added slowly.
The mixture was warmed to room temperature and stirred overnight.
The reaction mixture was poured into water to give a dark red precipitate which was collected by filtration.
The crude product was directly crystallized from cold CH3CN to afford 4 as a light yellow solid in a 59percent yield. M.p.:152-154 °C; MS (ESI) m/z(percent): 346.0 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 10.06 (s, 1H), 8.63 (d, J = 8.4 Hz, 1H), 8.30 (s, 1H), 7.92 (dd, J = 8.0, 1.5 Hz, 1H), 7.77-7.68 (m, 1H), 7.35-7.29 (m, 1H), 3.21 (hept, J = 6.9 Hz, 1H), 1.31 (d, J = 6.9 Hz, 6H).
52% With sodium hydride In dimethyl sulfoxide; N,N-dimethyl-formamide; mineral oil at 20℃; for 16 h; Cooling with ice 2-(Isopropylsulfonyl)aniline (2 g, 10 mmol) was dissolved ina mixed solvent of DMF (10 mL) and DMSO(1 mL).
In ice bath, NaH (600 mg, 15 mmol, 60percent) in a mixed solvent of DMF/DMSO (20/2 mL) was slowly added dropwise, and then2,4,5-trichloropyrimidine (3.66 g, 20 mmol)in a mixed solvent of DMF/DMSO(10/1 mL) was slowly added dropwise.
The resultant mixture was reacted at room temperature under stirring for 16 h.
After the reaction, 100 mL water was added.
After extraction with ethyl acetate (100 mL*2), the organic phases were combined, dried with anhydrous sodium sulphate, filtrated, and concentrated to obtain a crude product.
After purification by silica gel column chromatography (petroleum ether: ethyl acetate=20:1), the product (1.8 g, yield: 52percent) was obtained.
46% With sodium hydride In N,N-dimethyl-formamide; mineral oil at 25℃; for 12 h; 2-(isopropylsulfonyl)aniline (1g, 5.02mmol) and 2,4,5-trichloropyrimidine (1.1g, 6mmol) was dissolved in N,N-dimethylformamide (30 mL) and added sodium hydride (content 60percent, 0.4g, 10mmol) then reacted at 25°C for 12 hours. Water (20mL) was added then extracted with ethyl acetate (30mL × 3). The organic phases were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 25: 1) gave the product (0.8g, 46percent yield).
46% With sodium hydride In N,N-dimethyl-formamide; mineral oil at 25℃; for 12 h; A mixture of 2- (isopropylsulfonyl) aniline (1 g, 5 mmol)And 2,4,5-trichloropyrimidine (1.1 g, 6 mmol)Was dissolved in N, N-dimethylformamide (30 mL)Sodium hydride (60percent, 0.4 g, 10 mmol) was added,25 ° C for 12 hours.(30 mL x 3), the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated in vacuo,The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 25: 1)The product (0.8 g, yield 46percent) was obtained.
40.6%
Stage #1: With sodium hydride In dimethyl sulfoxide; N,N-dimethyl-formamide at 0℃; for 0.5 h;
Stage #2: at 0 - 20℃; for 15 h;
Sodium hydride (60.00percent, 1.219 g, 30.471 mmol) was added to a solution ofTo a solution of N, N-dimethylformamide (25 mL) / dimethylsulfoxide (2.5 mL) at 0 & lt;To the solution was added 2- (isopropylsulfonyl) aniline (2.530 g, 12.696 mmol)DMF / DMSO (10 ml, 9: 1 ratio)The dissolved solution was added dropwise at 0 ° C, and the mixture was stirred at the same temperature for 0.5 hour.To the reaction mixture was added 2,4,5-trichloropyrimidine (4.658 g, 25.393 mmol) in DMF / DMSO (10 ml, 9: 1 ratio)The solution prepared by dissolving was added dropwise at 0 deg. C, the temperature was gradually raised to room temperature, and further stirred for 15 hours.The reaction mixture was cooled in an ice bath and treated with AcOH (2 ml, ca. 33 mmol)Water (1.8 ml, 100 mmol) was slowly added to terminate the reaction. The filtrate was filtered through celite and the filtrate was poured into 50 ml of water and extracted with ethyl acetate (50 ml × 3).The combined organic layers were washed with a half-brine (100 ml) saturated sodium chloride and water mixture, and dried over anhydrous magnesium sulfateAfter filtration, the filtrate was concentrated under reduced pressure. The concentrate was purified and purified by column chromatography (SiO2, 80 g cartridge; ethyl acetate / hexane = 10percent to 20percent) to give 2,5-dichloro-N- (2- (isopropylsulfonyl) phenyl) Amin-4-amine (1.783 g, 40.6percent) as a white solid.
40%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5 h;
Stage #2: at 20℃; for 12 h;
To a suspension of NaH (1.0 g, 25 mmol) in a mixtureof DMF (30 mL) was added dropwise 2-(isopropylsulfonyl)benzenamine (1.99 g,10 mmol) in DMF (10 mL) at 0 °C. The solutionwas stirred for 30 min, and then 2,4,5-trichloropyrimidine (1.82 g,10 mmol) in DMF (10 mL) was added slowly. The solution was warmed to room temperature and stirred for 12 h. Water was added and the mixture was extracted with CH2Cl2. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purifiedby column chromatography (20percent EtOAc in petroleum ether) to afford compound 51a (1.38 g, 40percent) as a white solid. 1H NMR(400 MHz, DMSO-d6) δ 9.82 (s, 1H), 8.55 (s, 1H), 8.32 (d, J 7.2 Hz,1H), 7.90e7.85 (m, 2H), 7.47 (d, J 6.4 Hz, 1H), 3.50e3.30 (m, 1H),1.16 (d, J 6.4 Hz, 6H); 13C NMR (100 MHz, DMSO-d6) δ 157.15,157.09, 156.34, 156.34, 137.14, 135.66, 131.62, 126.63, 125.60, 124.75,115.29, 55.11, 15.27; HRMS (ESI, m/z) [M+H]+ calcd forC13H14Cl2N3O2S: 346.0184, found: 346.0186.
40%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil for 0.5 h; Cooling with ice
Stage #2: for 10 h; Cooling with ice
39.8 g (0.20 mol) of intermediate IV was added to 400 mLDried N, N-dimethylformamide (DMF)Under ice bath, 32.0 g (0.80 mol)60percent sodium hydride, ice bath for 30min,A solution of 73.4 g (0.40 mol)2,4,5-trichloropyrimidine, ice bath for 10 h. The reaction solution was poured into a large amount of ammonium chloride saturated solution,Stir for 30 min at room temperature, suction filter, brown red solid.The acetonitrile was recrystallized to give a pale yellow solid27.6 g,Yield 40.0percent.
40%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil for 0.5 h; Cooling with ice
Stage #2: for 10 h; Cooling with ice
39.8 g (0.20 mol) of intermediate IV was added to 400 mL of dry N,N-dimethylformamide (DMF).Under ice-cooling, 32,0 g (0.80 mol) of 60percent sodium hydride was added portionwise, and the mixture was stirred for 30 min under ice-cooling, and 73,4 g (0.40 mol) of 2,4,5-trichloropyrimidine was slowly added thereto, and the mixture was reacted for 10 hours under ice bath. The reaction solution was poured into a large amount of a saturated solution of ammonium chloride, stirred at room temperature for 30 min, and suction filtered to give a brown solid. The acetonitrile was recrystallized to give a pale yellow solid (27.6 g).
40%
Stage #1: With sodium hydride In N,N-dimethyl-formamide for 0.5 h; Cooling with ice
Stage #2: at 20℃; Cooling with ice
2-(isopropylsulfonyl)phenylamine (9.96 g, 50 mmol) was weighed and dissolved in N,N-dimethylformamide(DMF, 100 mL), to which sodium hydride (NaH, 2.4 g, 100 mmol) was slowly added on an ice bath and stirred for 0.5 h.A solution of 2,4,5-trichloropyrimidine (11.0 g, 60 mmol) dissolved in 20 mL of DMF was slowly added dropwise on anice bath. After the addition, the mixture was reacted overnight at room temperature, washed with water, and extractedwith ethyl acetate. After drying and concentration, the crude material was purified by column chromatography to give awhite solid 1-1 (6.9 g, 40percent). MS(ESI): m/z 346.0 (M + H)+. 1H NMR (400 MHz, CDCl3) δ 10.07(s, 1 H), 8.63 (d, J = 8.0Hz, 1 H), 8.30 (s, 1 H), 7.92 (d, J = 7.4 Hz, 1 H), 7.73 (t, J = 7.4 Hz, 1 H), 7.33 (t, J = 7.0 Hz, 1 H), 3.22 (heptet, J = 6.0Hz,1 H), 1.32 (d, J = 6.0 Hz, 6 H). 13C NMR (100 MHz, CDCl3) δ 157.8, 156.3, 155.6, 137.3, 135.2, 131.4, 124.5, 124.2,122.7, 115.2, 56.1, 15.3.
33%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.25 h;
Stage #2: at 20℃;
In Scheme 2In the synthesis of Compound 2-5,The starting material 2-fluoronitrobenzene (i.e., compound 2-1)The remaining synthetic methods were the same as those of Scheme 1 of Scheme 1,To give compound 2-5, yield: 33percent.
In the ice bath conditions,Compounds 2-4 (30.0 g,150 mmol) was dissolved in N, N-dimethylformamide (300 mL)Sodium hydride (7.3 g, 300 mmol) was added slowlyTo the reaction system,Stirred at 0 ° C for 15 minutes;2,4,5-trichloropyrimidine (33.1 g, 180 mmol) was added dropwise to the reaction system,Room temperature reaction and stirring overnight;The reaction was completed, cooled and poured into 500 mL of water,Extracted with ethyl acetate, dried,Concentrated, silica gel column chromatography,To give compound 2-5 (17.3 g),Yield: 32.0percent.
32.69%
Stage #1: With sodium hydride In N,N-dimethyl-formamide for 0.25 h; Cooling
Stage #2: at 20℃; for 16 h;
Step 4: Preparation of 2,5-dichloro-N-(2-(isopropylsulfonyl)phenyl)pyrimidin-4-amine (5); 2-(isopropylsulfonyl)aniIine (4, 3 g, 15 mmol) was taken up in DMF (30 mL) to form a mixture, and the mixture was cooled in a water bath. NaH (0.723 g, 30 mmol) was then added to the mixture in portions and the mixture was stirred for 15 min. 2,4,5-trichloropyrimidine (3.31 g, 18 mmol) was then added dropwise to the mixture and the mixture was stirred at room temperature overnight (16 h).Compound 5 was detected in the reaction mixture by LC-MS. The reaction mixture was then quenched with ice and water, and the product was extracted with ethyl acetate. The organic extract was dried over sodium sulfate and concentrated to obtain a crude product. The crude product was purified by column chromatography (silica gel 20percent ethyl acetate (EA) in Hexane) to afford 2,5-dichloro-N-(2- (isopropylsulfonyl)phenyl)pyrimidin-4-amine (5, 1 .7 g, 32.69percent). 'HNMR (CDC13): 10.05 (s, I H), 8.64- 8.60 (d, I H), 8.30 (s, I H), 7.94-7.90 (d, I H), 7.77-7.70 (t, I H), 7.37-7.30 (t, IH), 3.25-3.17 (m, I H), 1.30 (s, 6H)
32%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.25 h;
Stage #2: at 20℃;
Compound 24 (30 g, 150 mmol) was dissolved in DMF (300 mL) under ice-cooling, and sodium hydride (7. 23 g, 300 mmol) was slowly added to the reaction system at 0 ° C for 15 minutes.2, 4, 5-trichloropyrimidine(33. lg, 180 mmol) was added dropwise to the reaction system and the reaction was stirred at room temperature overnight. After cooling, pour 500mL of water, ethyl acetateThe ester was extracted and dried and concentrated by silica gel column chromatography to give compound 2-5 (17.33, yield: 32percent).
32.7%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0 - 5℃; for 0.25 h;
Stage #2: at 0 - 5℃;
The reaction flask was charged with 9 g of 2- (isopropylsulfonyl) aniline and 90 mL of N, N-dimethylformamide. The reaction liquid is coldBut to 0 ~ 5 , 2.2g sodium hydrogen was added to the reaction solution in batches, plus the end of stirring for 15 minutes. The temperature was controlled at 0-5 , 9.9g 2,4,5-trichloropyrimidine was added dropwise to the reaction solution, and the mixture was stirred for 16-20 hours while dropping to room temperature. The reaction was quenched with ice water and extracted with ethyl acetateTake, the organic phase was concentrated to give the crude product. The crude product was isolated by column chromatography to give compound 3. (5.1 g, molar yield 32.7percent).
20%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.333333 h;
Stage #2: at 0 - 20℃; for 2.5 h;
2,5-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (0440) To a solution of 1-Amino-2-(isopropylsulphonyl)benzene (0.955 g, 4.80 mmol) in 2 mL of DMF at 0° C. was added NaH (60percent in oil, 0.349 g, 8.72 mmol) in one portion. After stirring fro 20 min, 2,4,5-trichloropyrimidine was added. The mixture was stirred at 0° C. for 30 minutes, and then at room temperature for 2 h. After quenching with saturated ammonium chloride solution, the mixture was poured in water and ethyl acetate mixture. Yellow suspension was filtered as final product (0.3 g, 20percent yield). MS/ES+: m/z=346.
9.1 g
Stage #1: With sodium hydride In N,N-dimethyl acetamide at 0℃; for 1 h;
Stage #2: at 20 - 25℃; for 2 h;
A solution of 2-(isopropylsulfonyl)benzenamine (10 g) in dimethylacetamide (30 mL) was added slowly to a mixture of sodium hydride (7.43 g) in dimethyl acetamide (40 mL) at 0°C and stirred for 1 hour. A solution of 2,4,5-trichloropyrimidine (17.26 mL) in dimethylacetamide (30 mL) was added to the above reaction mixture and warmed to 20-25°C. The reaction mass was stirred for 2 hours and quenched by a saturated solution of ammonium chloride (300 mL). The reaction mass was extracted with ethyl acetate (3 x 200 mL). The combined organic layer was washed with water (3 x 150 mL) and dried over sodium sulfate. The organic layer was distilled under reduced pressure to afford the crude compound, which was purified by silica gel column chromatography using 5percent ethyl acetate in hexane to obtain the desired product. Yield: 9.1 g, Purity (by HPLC): 99.2percent
1.7 g
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.5 h; Cooling with ice
Stage #2: at 20℃; for 16 h;
2-(isopropylsulfonyl)aniline (3g, 14mmol), add DMF 30ml. Under ice-water bath add batchwise sodium hydride (0.73g, 30mmol), Addition is completed. Room temperature stirring 30min. Add 2,4,5-trichloropyrimidine (3.31g, 18mmol). Stirring at the room temperature 16h. ice water quenching of the reaction, ethyl acetate (30 ml * 3), the combined organic layer, water washing, salt is washed with water, concentrated to dryness to obtain white solid 1.7g, yield 37percent, in order to 2 - (isopropyl sulfonyl) aniline calculation.
0.5 g With sodium hydride In N,N-dimethyl-formamide at 20℃; Compound b1-4 (1 g, 5 mmol) was placed in a 100 mL three-necked flask and added to DMF (70 mL).Then NaH (0.4 g, 10.1 mmol) was added and stirred for 15 minutes, then a solution of compound b2 (1.83 g, 10.1 mmol) in DMF was added.Stir at room temperature overnight,After adding 100 mL of water, ethyl acetate was extracted, and the organic phase was washed with brine, dried over anhydrous magnesium sulfateYield 0.5 g of a white solid,

Reference: [1] European Journal of Medicinal Chemistry, 2017, vol. 136, p. 497 - 510
[2] Patent: WO2017/158619, 2017, A1, . Location in patent: Page/Page column 19
[3] Patent: EP2990405, 2016, A1, . Location in patent: Paragraph 0097; 0120; 0121
[4] Journal of Medicinal Chemistry, 2013, vol. 56, # 14, p. 5675 - 5690
[5] European Journal of Medicinal Chemistry, 2016, vol. 123, p. 80 - 89
[6] Patent: EP3202765, 2017, A1, . Location in patent: Paragraph 0182; 0183; 0209; 0210; 0236; 0237; 0257; 0258
[7] Patent: CN105524045, 2016, A, . Location in patent: Paragraph 0248; 0249; 0250
[8] Patent: CN106146525, 2016, A, . Location in patent: Paragraph 0198; 0199; 0200
[9] Patent: KR2016/147358, 2016, A, . Location in patent: Paragraph 0242-0244
[10] European Journal of Medicinal Chemistry, 2017, vol. 139, p. 674 - 697
[11] Patent: CN107151233, 2017, A, . Location in patent: Paragraph 0121; 0122
[12] Patent: CN108047204, 2018, A, . Location in patent: Paragraph 0205; 0206
[13] Patent: EP3392245, 2018, A1, . Location in patent: Paragraph 0070; 0071; 0072
[14] Patent: CN106336382, 2017, A, . Location in patent: Paragraph 0099; 0144-0146; 0162; 0176; 0177; 0182; 0185-0186
[15] Patent: WO2011/140338, 2011, A1, . Location in patent: Page/Page column 46; 48
[16] Patent: CN106146468, 2016, A, . Location in patent: Paragraph 0088; 0096; 0103; 0104
[17] Patent: CN106854200, 2017, A, . Location in patent: Paragraph 0065
[18] Patent: US2015/225436, 2015, A1, . Location in patent: Paragraph 0440
[19] Patent: US2014/128387, 2014, A1, . Location in patent: Paragraph 0628; 0629
[20] Journal of Medicinal Chemistry, 2015, vol. 58, # 1, p. 197 - 211
[21] Patent: EP2257637, 2015, B1, . Location in patent: Paragraph 0221; 0225
[22] Journal of Medicinal Chemistry, 2016, vol. 59, # 16, p. 7478 - 7496
[23] Patent: WO2016/199020, 2016, A1, . Location in patent: Page/Page column 42-43; 48
[24] Patent: CN104356112, 2017, B, . Location in patent: Paragraph 0031; 0032
[25] Patent: US2018/57457, 2018, A1, . Location in patent: Paragraph 0260; 0263
[26] Patent: CN108689994, 2018, A, . Location in patent: Paragraph 0123; 0125; 0126
  • 14
  • [ 75-16-1 ]
  • [ 5750-76-5 ]
  • [ 1192064-63-3 ]
YieldReaction ConditionsOperation in experiment
65% With iron(III)-acetylacetonate In tetrahydrofuran; NMP (N-methylpyrrolidone); diethyl ether at 0℃; for 0.5 h; Intermediate 13: 2,5-Dichloro-4-methylpyrimidine.To a solution of 2 ,4,5-trichloropyrimidine (2.52 g, 13.74 mmol) in THF/NMP (86 mL/6 mL) was added Fe(acac)3 (485 mg, 1 .37) and the mixture was cooled to 0 C. 3.0 M MeMgBr in Et2O (6.87 mL, 20.61 mmol) was added dropwise. After 30 min at 0 C, the reaction was complete and quenched with saturated aqueous NH CI solution. Et2O was added and the layers were separated and the aqueous layer was further extracted with several portions of Et2O. The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. Chromatography (Hex to 10percent EtOAc/Hex) gave the desired product as a white solid (1 .45 g, 65percent). 1 H NMR (500 MHz, CDCI3): 8.47 (s, 1 H), 2.61 (s, 3H).
45%
Stage #1: at -78℃; for 1 h;
Stage #2: With ammonium chloride In tetrahydrofuran; water
2,4,5-Trichloropyrimidine (250 mg, 1.36 mmol) and ferric acetylacetonate (24 mg, 0.07 mniol) were taken up in tetrahydroruran (2.7 ml) and the reaction was cooled to -78 °C.Methylmagnesium bromide (0.45 ml of 3 M in THF, 1.36 mmol) was added dropwise and the mixture was stirred at -78 °C for one hour. The mixture was quenched with aqueous ammonium chloride and extracted with ethyl acetate. The combined organic fractions were dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by Combiflash (0-10percent diethylether in hexanes) to provide 2,5- dichloro-4-methylpyrimidine (99 mg, 0.61 mmol, 45 percent) as a white solid. MS APCI: [M+H]+ m/z 163.0.
Reference: [1] Patent: WO2011/50202, 2011, A1, . Location in patent: Page/Page column 57
[2] Patent: WO2011/75560, 2011, A1, . Location in patent: Page/Page column 58
  • 15
  • [ 75-16-1 ]
  • [ 5750-76-5 ]
  • [ 1192064-63-3 ]
  • [ 75712-73-1 ]
Reference: [1] Patent: WO2009/129036, 2009, A1, . Location in patent: Page/Page column 80-81
  • 16
  • [ 594-27-4 ]
  • [ 5750-76-5 ]
  • [ 1192064-63-3 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 21, p. 4992 - 4999
  • 17
  • [ 1197953-47-1 ]
  • [ 5750-76-5 ]
  • [ 1197953-49-3 ]
YieldReaction ConditionsOperation in experiment
84.6% With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 4 h; 25 mL of a one-necked flask was added DMF (3 mL),2,5,6-trichloropyrimidine (0.72 g, 3.9 mmol) was added successively with stirring,2- (dimethylphosphonino) aniline (0.5 g, 3 mmol)Anhydrous potassium carbonate (0.62 g, 4.5 mmol), heated to 60 ° C and stirred for 4 h.(30 mL x 2), the organic phase was combined, washed with water (60 mL x 2), and the organic layer was dried over anhydrous sodium sulfate, and the organic layer was washed with ethyl acetate (30 mL) and water (30 mL) Filtered and concentrated, and the residue was passed through a silica gel column to give 0.8 g of a pale yellow solid in 84.6percent yield.
69% With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 5 h; (2-aminophenyl)dimethyl phosphorus oxide (8.76 g, 51.81 mmol), 2,4,5-trichloropyrimidine (14.92 g, 81.35 mmol), anhydrouspotassium carbonate (22.49 g, 162.29 mmol) and N,N-dimethylformamide (50 mL) were added in a 100 mLsingle-necked flask, and the mixture was heated to 60°C and reacted for 5 hours. After the reaction was completed, thereaction solution was cooled down to room temperature, added with water (30mL) and extracted with dichloromethane(100 mL 3 3), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered by suction, andevaporated under reduced pressure to remove the solvent. The resulting crude product was subjected to silica gelcolumn chromatography (mobile phase, dichloromethane : methanol = 40 : 1) to give (2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethyl phosphorus oxide (11.3 g, 69.0percent yield).1H-NMR (300 MHz, CDCl3) : δ = 11.55 (s, 2H), 8.67 (dd, J = 4.4, 8.5 Hz, 1H), 8.22 (s, 1H), 7.59 (dd, J = 7.7, 8.1 Hz,1H), 1.86 (s, 3H), 1.82 (s, 3H). 13C-NMR (75 MHz, CDCl3) : δ = 156.85, 155.10, 133.05, 133.03, 129.77, 129.63, 123.56,123.40, 122.18, 122.09, 19.28, 18.33.HRMS (ESI, [M+H]+) m/z: 316.0175.
68.4% With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 16 - 70℃; for 16 h; At 16 deg.C , Example 1K (2.50 g, 14.8 mmol) and 2,4,5-trichloropyrimidine (2.85 g, 15.5 mmol) in DMF (20mL) mixture was added DIPEA (3.82 g, 29.6 mmol). The reaction mixture was heated to 70 deg. C and stirred for 16 hours. TLC showed the reaction was complete. The reaction mixture was washed with water (50 mL) diluted (40mL × 3) and extracted with EtOAc. The combined organic phases were washed with saturated brine (20mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was recrystallized from ethanol to give the title compound (3.20 g, 10.1 mmol, 68.4percent yield) as a white solid.
61% With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 5 h; Step 2: Synthesis of 2:2,4,5-Trichloropyrimidine (1.57 eq), 1 (1.0 eq), and potassium carbonate (3.14 eq) in DMF were stirred at 60 °C for 5 hours and then cooled to room temperature. The mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (ISCO machine) (DCM/MeOH 20: 1 ) to give 2 as a yellow solid (61 percent yield).
61% With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 5 h; 2,4,5-Trichloropyrimidine (1.57 eq), 1 (1.0 eq), and potassium carbonate (3.14 eq) in DMF were stirred at 60 °C for 5 hours and then cooled to room temperature. The mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (ISCO machine) (DCM/MeOH 20:1) to give 2 as a yellow solid (61 percent yield).
50% for 12 h; Reflux A solution of 2,4,5-trichloropyrimidine(1.82 g, 10 mmol), (2-aminophenyl)dimethylphosphine oxide(1.69 g, 10 mmol) and N,N-diisopropylethylamine (1.94 g, 15 mmol)in propan-2-ol (25 mL) was heated under reflux for 12 h. The solvent was removed by evaporation and the residue was dissolvedin CH2Cl2 (100 mL). The solution was washed with water andsaturated sodium chloride solution and dried, filtered andconcentrated. The residuewas purified by flash chromatography onsilica gel (0e2percent MeOH in DCM) to afford compound 51l (1.60 g,50percent). 1H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 8.43 (s, 2H), 7.62(s, 2H), 7.25 (s, 1H), 1.83 (s, 3H), 1.80 (s, 3H); 13C NMR (100 MHz,DMSO-d6) d 157.01, 155.99, 142.48, 132.73, 131.47 (d, J 10 Hz),124.17 (d, J 6.0 Hz), 122.64, 122.06 (d, J 3.0 Hz), 121.73, 115.30,18.98, 18.28. HRMS (ESI, m/z) [M+H]+ calcd for C12H13Cl2N3OP:316.0173, found: 316.0175.
17 g at 75℃; for 6 h; 2-iodoaniline (17.5 g, 79.9 mmol) and dimethyl phosphine oxide (6.9 g, 88.5 mmol) were added,Palladium acetate (0.3 g, 1.3 mmol), Xantphos (0.77 g, 1.3 mmol),N,N-diisopropylethylamine (22.7 g, 175.8 mmol), DMF (50 mL),Magnetic stirring. Under nitrogen protection, heat to 100°C for 6 hours,The 2-iodoaniline consumption was monitored by thin layer chromatography. Cool to room temperature2,4,5-trichloropyrimidine (17.5 g, 95.9 mmol) was added and the reaction was heated to 75°C for 6 hours.The reaction was complete by thin layer chromatography. Cool to room temperature, add water 300mL,Adjust pH to 5 with 5percent hydrochloric acid and extract with ethyl acetate (100 mL x 3).Wash with sodium bicarbonate solution (100 mL), wash with saturated sodium chloride solution (100 mL × 2),Dry over anhydrous sodium sulfate. It is filtered with suction and concentrated to give a crude brown solid.Recrystallization with ethyl acetate/petroleum ether (volume ratio 1:2) gave an almost white solid 17g.Yield 67.3percent.
0.7 g With potassium carbonate In N,N-dimethyl-formamide at 60℃; Compound b1-1 (0.5 g, 3 mmol) was placed in a 100 mL three-necked flask, and DMF (30 mL) was added.Then, compound b2 (0.86 g, 4.7 mmol), anhydrous potassium carbonate (1.23 g, 9.5 mmol) was added, and stirred at 60 ° C overnight.TLC showed the reaction was almost complete, cooled to room temperature, and then water (100 mL)The organic phase was washed with brine and dried over anhydrous magnesium sulfate.Concentrated through the column to give 0.7 g of a yellow solid.

Reference: [1] Patent: CN106188138, 2016, A, . Location in patent: Paragraph 0094-0096; 0106; 0107
[2] Journal of Medicinal Chemistry, 2016, vol. 59, # 10, p. 4948 - 4964
[3] Patent: EP3381925, 2018, A1, . Location in patent: Paragraph 0158
[4] Patent: CN105330698, 2016, A, . Location in patent: Paragraph 0196; 0197; 0198; 0199
[5] Patent: WO2012/151561, 2012, A1, . Location in patent: Page/Page column 37-38
[6] Patent: WO2013/169401, 2013, A1, . Location in patent: Page/Page column 43-44
[7] Patent: US2015/225436, 2015, A1, . Location in patent: Paragraph 0793-0794
[8] European Journal of Medicinal Chemistry, 2017, vol. 139, p. 674 - 697
[9] Patent: WO2016/65028, 2016, A1, . Location in patent: Paragraph 00369
[10] European Journal of Medicinal Chemistry, 2017, vol. 136, p. 497 - 510
[11] Patent: CN107522742, 2017, A, . Location in patent: Paragraph 0022; 0023; 0025; 0027; 0029; 0031; 0033
[12] Patent: CN108689994, 2018, A, . Location in patent: Paragraph 0108; 0110; 0111
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  • [ 5750-76-5 ]
  • [ 1197953-49-3 ]
YieldReaction ConditionsOperation in experiment
79% With N-ethyl-N,N-diisopropylamine In ethanol at 80℃; for 18 h; Large scale o a solution of (2-aminophenyl) dimethylphosphine oxide hydrochloride (900 g, 4.16 mil) in ethanol (600 mL) was addedDIPEA (1.24 Kg, 1.67 L, 9.56 mil, 2.3 eq)It was observed that the solution became clear,Then 2,4,5-trichloropyrimidine was added(915.238,4.99 11,1,1 equivalent)The The reaction mixture was heated to 80 ° (and stirred for 18 hours.The reaction was complete and the reaction mixture was concentrated by cooling the reaction solution.Water (2 L) and DCM (2 L) were added and stirred for 0.5 h. After separation, the aqueous phase was extracted with DCM (500 mL x 3) and the combined organic phases were washed with saturated brine (2 L), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. After concentration to give a brown solid, the crude product was washed with methyl tert-butyl ether beating and filtered to give the title compound as a white solid (l.KKK, yield 79percent)
Reference: [1] Patent: CN106928275, 2017, A, . Location in patent: Paragraph 0100-0102
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