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Chemical Structure| 84163-77-9
Chemical Structure| 84163-77-9
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Product Details of [ 84163-77-9 ]

CAS No. :84163-77-9 MDL No. :MFCD03236724
Formula : C12H13FN2O Boiling Point : -
Linear Structure Formula :- InChI Key :MRMGJMGHPJZSAE-UHFFFAOYSA-N
M.W : 220.24 Pubchem ID :849421
Synonyms :

Calculated chemistry of [ 84163-77-9 ]

Physicochemical Properties

Num. heavy atoms : 16
Num. arom. heavy atoms : 9
Fraction Csp3 : 0.42
Num. rotatable bonds : 1
Num. H-bond acceptors : 4.0
Num. H-bond donors : 1.0
Molar Refractivity : 62.76
TPSA : 38.06 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : Yes
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.26 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.5
Log Po/w (XLOGP3) : 1.95
Log Po/w (WLOGP) : 2.47
Log Po/w (MLOGP) : 2.17
Log Po/w (SILICOS-IT) : 3.01
Consensus Log Po/w : 2.42

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.78
Solubility : 0.362 mg/ml ; 0.00164 mol/l
Class : Soluble
Log S (Ali) : -2.37
Solubility : 0.931 mg/ml ; 0.00423 mol/l
Class : Soluble
Log S (SILICOS-IT) : -4.41
Solubility : 0.00857 mg/ml ; 0.0000389 mol/l
Class : Moderately soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.59

Safety of [ 84163-77-9 ]

Signal Word:Warning Class:
Precautionary Statements:P280-P305+P351+P338 UN#:
Hazard Statements:H317-H319 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 84163-77-9 ]

* 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 [ 84163-77-9 ]
  • Downstream synthetic route of [ 84163-77-9 ]

[ 84163-77-9 ] Synthesis Path-Upstream   1~17

  • 1
  • [ 63234-80-0 ]
  • [ 84163-77-9 ]
  • [ 106266-06-2 ]
YieldReaction ConditionsOperation in experiment
92.8% With sodium carbonate In methanol at 73 - 75℃; for 4 - 4.5 h; Example 2; Preparation of risperidone of the formula (I) from 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido [ 1,2-a]pyrirnidine-4-one and 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole bases of the formulae (II) and (III).Starting from 11.45 g of 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole, 12.45 g of 3-(2-cWoroemyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidine-4-one and 11.8 g of dry sodium carbonate the same method as described in Example 1 is followed, to give 19.8 g (92.8 percent) of risperidone.Mp: 171-172 °C; purity is at least 99 percent, determined by HPLC
77.8% With N-ethyl-N,N-diisopropylamine In methanol at 45 - 50℃; for 70 - 100 h; 6-Fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (20.0 grams), 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (22.6 grams) and diisopropyl ethylamine (14.1 grams) were dissolved in methanol (90.0 ml). The resulting reaction mixture was maintained at 45-50° C. for about 70-100 hours. The reaction mass was then cooled to 25-35° C. and then separate solid product. The solid mass was filtered and washed with methanol (20.0 ml) followed by water (120.0 ml). The wet product was dried at 70-80° C. to get 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-A]pyrimidin-4-one. (Yield: 29.0 g; 77.8percent; purity by HPLC is 99.93percent)6-Fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (10 Kg), 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (11.3 Kg) and diisopropyl ethylamine (7 Kg) were dissolved in methanol (45 Lt). The resulting reaction mixture was maintained at 45-50° C. for about 70 to 100 hours. The reaction mass was then cooled to 25-35° C. and then separate solid product. The solid mass was filtered and washed with methanol (10 Lt) followed by water (60 Lt). The wet product was dried at 70-80° C. to get 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-A]pyrimidin-4-one. (Yield: 18 Kg, purity by HPLC is 99.93percent).
73% With sodium carbonate In water at 85 - 90℃; for 4 h; [2.27G OF 4- (6-FLUORO-1, 2-BENZISOXAZOL-3-YL) -PIPERIDINE OBTAINED IN STEP A)] and 2.26g of 3- (2-chloroethyl)-6, 7,8, 9-tetrahydro-2-methyl-4H-pyrido [1, 2- [A] PYRIMIDIN-4-ONE] obtained in Preparation Example 2 were added to a solution of 2.25g of [NA2C03] in [12ML] of water. The resulting mixture was stirred at 85 to [90 °C] for 4 hours, cooled to room temperature, and filtered. The resulting solid was added to [16ML] of N, N- dimethylformamide. The resulting suspension was heated to [80 °C,] left at that temperature for 5 minutes, and then slowly cooled to room temperature. The crystal was filtered, washed with [5ML] of water and dried to obtain 3.02g of the title compound as a white crystal (yield: 73percent). The melting point [ANDAPOS;H-NMR] data were the same as in Example 1.
Reference: [1] Patent: WO2006/5974, 2006, A1, . Location in patent: Page/Page column 7
[2] Patent: US2006/4199, 2006, A1, . Location in patent: Page/Page column 2
[3] Patent: WO2004/35573, 2004, A1, . Location in patent: Page 11
[4] Patent: US2002/115672, 2002, A1,
  • 2
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  • [ 106266-06-2 ]
YieldReaction ConditionsOperation in experiment
46% With potassium iodide; sodium carbonate In N,N-dimethyl-formamide EXAMPLE 1
A mixture of 5.3 parts of 3-(2-chloromethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one monohydrochloride, 4.4 parts of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole, 8 parts of sodium carbonate, 0.1 part of potassium iodide, and 90 parts of DMF is stirred overnight at 80°-90° C.
After cooling, the reaction mixture is poured into water.
The product is filtered off and crystallized from a mixture of DMF and 2-propanol.
The product is filtered off and dried, yielding 3.8 parts (46percent) of 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one; mp. 170.0° C.
Reference: [1] Patent: US5688801, 1997, A,
  • 3
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  • [ 106266-06-2 ]
YieldReaction ConditionsOperation in experiment
46% With potassium iodide; sodium carbonate In N,N-dimethyl-formamide EXAMPLE 5
A mixture of 5.3 parts of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one monohydrochloride, 4.4 parts of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole, 8 parts of sodium carbonate, 0.1 parts of potassium iodide and 90 parts of N,N-dimethylformamide was stirred overnight at 85°-90° C.
After cooling, the reaction mixture was poured into water.
The product was filtered off and crystallized from a mixture of N,N-dimethylformamide and 2-propanol.
The product was filtered off and dried, yielding 3.8 parts (46percent) of 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one; mp. 170.0° C. (compound 1).
Reference: [1] Patent: US4804663, 1989, A,
  • 4
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YieldReaction ConditionsOperation in experiment
75% for 4 h; Reflux 4)
Preparation of 4-(6-fluoro-1,2-benzisoxazolyl)-piperidine
2,4-difluorophenyl-(4-piperidinyl)-methanone oxime hydrochloride (5.52g,20 mmol ) is added to 25 ml of 50 percent potassium hydroxide; reflux for 4 hours, cooled to room temperature, and extracted with toluene (25 mlx2).
The combined organic phases are dried over anhydrous magnesium sulfate, filtered, evaporated to dryness under reduced pressure, and recrystallized in diethyl ether, to obtain 3.3g of a product, with a yield of 75 percent.
75% With potassium hydroxide In toluene for 4 h; Reflux 2,4-difluorophenyl-(4-piperidinyl)methanone oxime hydrochloride (5.52 g, 20 mmol)Was added to 25 ml of 50percent potassium hydroxide, refluxed for 4 hours, cooled to room temperature, extracted with toluene 25 ml * 2, the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, Evaporate to dryness and recrystallize from diethyl ether to give 3.3 g of product. Yield is 75percent.
Reference: [1] Patent: EP2322520, 2011, A1, . Location in patent: Page/Page column 16
[2] Patent: JP5714152, 2015, B2, . Location in patent: Paragraph 0089
  • 5
  • [ 84163-13-3 ]
  • [ 84163-77-9 ]
YieldReaction ConditionsOperation in experiment
40% With sodium hydroxide In water at 20℃; for 1 h; Inert atmosphere To a solution of 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazole hydrochloride (1.04 g, 4.05 mmol) in 50 mL H2O, 1 N NaOH (70 mL) was added at room temperature slowly. After the reaction mixture was stirred for 1 h at room temperature, DCM (100 mL) was added and then stirred for 30 min in additionally. The resulting solution was extracted with DCM thrice and dried over with anhydrous MgSO4. After the solvent was removed under vacuum, the desired product (1) was obtained as a white solid product without further purification (880 mg, 40percent yield). 1H NMR (400 MHz, CDCl3) δ 1.66 (m, 2H), 1.90 (m, 2H), 2.71 (m, 5H), 7.24 (dd, J = 6.4, 2.0 Hz, 1H), 7.31 (dd, J = 6.4, 4.2 Hz, 1H), 7.77 (dd, J = 4.2, 2.0 Hz, 1H). 13C NMR (400 MHz, CDCl3) δ 23.1 (2C), 27.4 (2C), 36.6, 118.0 (2C), 124.3, 148.8 (2C), 157.6, 161.8.
21 g With sodium hydroxide In water for 0.333333 h; Example-14
Preparation of Crystalline 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (formula-10)
To the suspension of 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazole hydrochloride (formula-6) (25 grams) dissolved in water (100 ml), added aqueous sodium hydroxide (4.8 g in 20 ml water).
Stirred for 20 min and extracted with dichloromethane.
Washed the organic layer with water, distilled off the solvent under reduced pressure to obtain the title compound.
Yield: 21 grams.
Reference: [1] Bulletin of the Korean Chemical Society, 2016, vol. 37, # 9, p. 1464 - 1471
[2] Patent: WO2007/93870, 2007, A2, . Location in patent: Page/Page column 7-9
[3] Patent: US2011/293889, 2011, A1,
[4] Patent: US2011/293889, 2011, A1,
[5] Patent: US8481729, 2013, B2, . Location in patent: Paragraph 22
[6] Organic Process Research and Development, 2003, vol. 7, # 4, p. 521 - 532
[7] Journal of Chemical Sciences, 2015, vol. 127, # 10, p. 1739 - 1746
  • 6
  • [ 84162-86-7 ]
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Reference: [1] Patent: US4804663, 1989, A,
  • 7
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Reference: [1] Chemical Science, 2014, vol. 5, # 4, p. 1574 - 1578
[2] Chemical Science, 2016, vol. 7, # 8, p. 5206 - 5211
  • 8
  • [ 84163-41-7 ]
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Reference: [1] Organic Process Research and Development, 2003, vol. 7, # 4, p. 521 - 532
[2] ACS Chemical Neuroscience, 2016, vol. 7, # 9, p. 1292 - 1299
  • 9
  • [ 84162-80-1 ]
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Reference: [1] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2004, vol. 43, # 9, p. 1954 - 1957
[2] Organic Process Research and Development, 2003, vol. 7, # 4, p. 521 - 532
[3] ACS Chemical Neuroscience, 2016, vol. 7, # 9, p. 1292 - 1299
  • 10
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Reference: [1] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2004, vol. 43, # 9, p. 1954 - 1957
[2] Organic Process Research and Development, 2003, vol. 7, # 4, p. 521 - 532
[3] ACS Chemical Neuroscience, 2016, vol. 7, # 9, p. 1292 - 1299
  • 11
  • [ 84163-42-8 ]
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Reference: [1] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2004, vol. 43, # 9, p. 1954 - 1957
[2] Organic Process Research and Development, 2003, vol. 7, # 4, p. 521 - 532
[3] ACS Chemical Neuroscience, 2016, vol. 7, # 9, p. 1292 - 1299
  • 12
  • [ 84163-43-9 ]
  • [ 84163-77-9 ]
Reference: [1] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2004, vol. 43, # 9, p. 1954 - 1957
[2] Organic Process Research and Development, 2003, vol. 7, # 4, p. 521 - 532
[3] ACS Chemical Neuroscience, 2016, vol. 7, # 9, p. 1292 - 1299
  • 13
  • [ 84162-94-7 ]
  • [ 84163-77-9 ]
Reference: [1] Organic Process Research and Development, 2003, vol. 7, # 4, p. 521 - 532
[2] ACS Chemical Neuroscience, 2016, vol. 7, # 9, p. 1292 - 1299
  • 14
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Reference: [1] Patent: EP2322520, 2011, A1,
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Reference: [1] Patent: EP2322520, 2011, A1,
  • 16
  • [ 84162-82-3 ]
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Reference: [1] Patent: EP2322520, 2011, A1,
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Reference: [1] Chemical Science, 2016, vol. 7, # 8, p. 5206 - 5211
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