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[ CAS No. 690632-38-3 ] {[proInfo.proName]}

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Chemical Structure| 690632-38-3
Chemical Structure| 690632-38-3
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Product Details of [ 690632-38-3 ]

CAS No. :690632-38-3 MDL No. :MFCD05865132
Formula : C18H22BrNO4 Boiling Point : -
Linear Structure Formula :- InChI Key :ZUKYLVHOLKDNGX-UHFFFAOYSA-N
M.W : 396.28 Pubchem ID :2794759
Synonyms :

Calculated chemistry of [ 690632-38-3 ]

Physicochemical Properties

Num. heavy atoms : 24
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.56
Num. rotatable bonds : 3
Num. H-bond acceptors : 4.0
Num. H-bond donors : 0.0
Molar Refractivity : 98.42
TPSA : 55.84 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : Yes
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : Yes
CYP2D6 inhibitor : Yes
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -6.35 cm/s

Lipophilicity

Log Po/w (iLOGP) : 3.64
Log Po/w (XLOGP3) : 3.33
Log Po/w (WLOGP) : 3.8
Log Po/w (MLOGP) : 2.63
Log Po/w (SILICOS-IT) : 3.42
Consensus Log Po/w : 3.37

Druglikeness

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

Water Solubility

Log S (ESOL) : -4.38
Solubility : 0.0165 mg/ml ; 0.0000415 mol/l
Class : Moderately soluble
Log S (Ali) : -4.18
Solubility : 0.0262 mg/ml ; 0.0000662 mol/l
Class : Moderately soluble
Log S (SILICOS-IT) : -4.97
Solubility : 0.00428 mg/ml ; 0.0000108 mol/l
Class : Moderately soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 3.5

Safety of [ 690632-38-3 ]

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

Application In Synthesis of [ 690632-38-3 ]

* 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 [ 690632-38-3 ]
  • Downstream synthetic route of [ 690632-38-3 ]

[ 690632-38-3 ] Synthesis Path-Upstream   1~3

  • 1
  • [ 30186-18-6 ]
  • [ 79099-07-3 ]
  • [ 690632-38-3 ]
YieldReaction ConditionsOperation in experiment
87% With pyrrolidine In methanol at 60 - 65℃; for 3 h; EXAMPLE 1; Reaction of 5-bromo-2-hydroxy acetophenone with N-Boc-4-piperidone; In a 500 ml 3-necked flask, fitted with a reflux condenser, a CaCl2 gaurd tube and a magnetic needle, 0.1 mole of N-Boc-4-piperidone (19.5 g) and 0.116 mole of pyrrolidine (8.95 g), dissolved in 100 ml of anhydrous MeOH at ambient temperature were added to 0.0837 mole 5-bromo-2-hydroxyacetophenone (18 g). The reaction mixture was stirred under reflux at 60-65° C. for about 3 hours. The reaction mixture was transferred to a rotary flask, and MeOH was distilled off to obtain an orange viscous liquid. 75 ml of water was added, and the product was extracted four times with 100 ml portions of ethyl acetate. The aqueous layer was discarded, and the organic layer was dried over anhydrous Na2SO4. Ethyl acetate was distilled off, and an orange viscous oil was obtained that was thoroughly dried in vacuo. Further purification by column chromatography with ethyl acetate/petrolether 10/90 yielded 28,7 g (87percent) of a pale yellow crystalline solid. Melting Point: 140-143° C.
Reference: [1] Patent: US2007/117823, 2007, A1, . Location in patent: Page/Page column 13
  • 2
  • [ 1450-75-5 ]
  • [ 79099-07-3 ]
  • [ 690632-38-3 ]
YieldReaction ConditionsOperation in experiment
99%
Stage #1: With pyrrolidine In methanol
Stage #2: at 80℃;
To a stirred solution of pyrrolidine (1.07g, 15 mmol) in MeOH (150 mL) was added 5-bromo-2-hydroxy acetophenone (6.45g, 30 mmol) (solution turned yellow). Then 4-t- butoxycarbonyl-piperidone (5.98g, 30 mmol) was added (solution turned brown). The reaction was heated at 80 0C overnight. The reaction mixture was concentrated and the residue was dissolved in EtOAc (300 mL). The mixture was washed with 1 N HCl (150 mL), IN NaOH (150 mL x 2), water and brine. The organic layer was dried (Na2SO4), filtered and concentrated to give compound 8A (11.7g, 99percent). 1H-NMR (CDCl3) δ 7.95 (d, J = 2.7 Hz, IH), 7.55 (dd, J = 8.7, 2.7 Hz, IH), 6.88 (d, J = 8.7 Hz, IH), 3.84 (br s, 2H), 3.21-3.13 (m, 2H), 2.03-1.95 (m, 2H), 1.64-1.55 (m, 2H), 1.44 (s, 9H).
97%
Stage #1: With pyrrolidine In toluene at 20℃; for 0.333333 h;
Stage #2: for 15 h; Reflux
Example 13Preparation of Compound 17 Step 1A mixture of compound 13a (11.1 g, 52 mmol) and pyrrolidine (5.6 mL, 67 mmol) in toluene (200 mL) was stirred at 20° C. for 20 minutes. The mixture was then treated with 1-BOC-4-piperidone 13b (13.4 g, 67 mmol) and refluxed for about 15 hours. The reaction mixture was then cooled to room temperature, washed sequentially with 10percent aqueous NaOH and H2O, dried over MgSO4, filtered and concentrated in vacuo. The residue obtained was purified using flash column chromatography (10percent EtOAc/hexanes) to provide compound 13c (20.0 g, 97percent) as a yellow solid.
94% With pyrrolidine In methanol for 11 h; Reflux Intermediate 1: (E)-3-14-Oxo-spiro[chromane-2,4'-piperidine]-6-yl}-acrylic acid methyl ester [Show Image] STEP A A mixture of 2-hydroxy-5-bromoacetophenone (10.75 g, 50 mmol), N-BOC-4-piperidone (9.96 g, 50 mmol) and pyrrolidine (2.09 ml, 25 mmol) in MeOH (80 ml) was heated to reflux for 11 h. The solvent was removed under vacuum and the crude mixture was purified by column chromatography (eluent: hexane/AcOEt 90:10 to 80:20) to give 6-bromo-4-oxo-spiro[chromane-2,4'-piperidine]-1'-carboxylic acid tert-butyl ester (18.55 g) as a yellow solid. Y=94percent LC-MS: Method A, rt=6.4 min; (ES+) MNa+: 419.8 1H-NMR (CDCl3) δ (ppm): 7.96 (s, 1H), 7.55 (d, J=8.8 Hz, 1H), 6.82 (d, J=7.6 Hz, 1H), 3.84 (m, 2H), 3.18 (t, J=11.6 Hz, 2H), 2.70 (s, 2H), 2.00 (m, 2H), 1.60 (m, 2H), 1.44 (s, 9H).
93% With pyrrolidine In methanol for 4 h; Reflux 5-bromo-2-hydroxyacetophenone(2.15 g, 10 mmol), N-Boc-4-piperidone (1.99 g, 10 mmol) was dissolved in methanol (15 mL), pyrrolidine (1 mL, 13 mmol) was added and the mixture was heated at reflux for 4 hours until the starting material disappeared. The solvent was distilled off, and the residue was dissolved in dichloromethane (100 mL), washed with 1N hydrochloric acid (50 mL) and saturated brine (50 mL) successively, the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (elution Agent: petroleum ether/ethyl acetate = 10:1 to 4:1) Compound 1-e (3.69 g, 93percent) was obtained.
92% With pyrrolidine In methanol for 12 h; Reflux j00228J 1 -(5 -Bromo-2-hydroxyphenyl)ethan- 1-one (10.0 g, 45.5 mmol), tert-butyl 4- oxopiperidine-1-carboxylate (9.27 g, 46.5 mmol) and pyrrolidine (1.91 mL, 23.3 mmol) were combined in 75 mL of MeOH and refluxed for 12 h. After cooling down to room temperature the reaction mixture was concentrated to dryness and purified by normal phase silica gel (EtOAc/hexanes gradient). After purification 17.1 g (92percent yield) of the title compound was obtained. ‘H NIVIR (300 MHz, CDC13) (ppm): 7.96 (d, J= 2.5 Hz, 1H), 7.55 (dd, Jj = 8.8 Hz, J2 = 2.5 Hz, 1H), 7.88 (d, J= 8.8 Hz, 1H), 3.86 (br s, 2H), 3.20-3.10 (m, 2H), 2.71 (s, 2H), 2.05-1.90 (m, 2H), 1.70-1.55 (m, 2H), 1.45 (s, 9H). MS: (ES, m/z): 296/298 [M-Boc].chromatography on
87% With pyrrolidine In methanol at 60 - 65℃; for 3 h; Heating / reflux Example 1 :Reaction between 5-Bromo-2-hydroxy acetophenone with N-Boc-4-piperidone; In a 500 ml 3-necked flask, fitted with a reflux condenser, a CaCI2 gaurd tube and a magnetic needle, 0.1 mol N-Boc-4-piperidone (19.5 g) and 0.1 16 mol pyrrolidine (8.95 g), dissolved in 100 ml of anhydrous MeOH at ambient temperature were added to 0.0837 mol 5-Bromo-2-hydroxyacetophenone (18 g). The reaction mixture was stirred under reflux at 60-650C for about 3 hrs. The reaction mixture was transferred to a rotary flask and MeOH was distilled off to obtain an orange viscous liquid. 75 ml of water was added and the product was extracted with ethyl acetate (4 timesl OO ml). The aqueous layer was discarded and the organic layer was dried over anhydrous Na2SO4. Ethyl acetate was distilled off and an orange viscous oil was obtained that was thoroughly dried in vacuo. Further purification by column chromatography with ethyl acetate/petrolether 10/90 yielded 28,7 g (87percent) of a pale yellow crystalline solid. Melting Point: 140 -1430C
84% With pyrrolidine In methanol at 20℃; To a solution 1-(5-bromo-2-hydroxyphenyl)ethanone (2.0 g, 9.3 mmol) in methanol (20 mL) was added pyrrolidine (0.8 mL, 9.6 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (1.91 g, 9.6 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated and purified by Biotage chromatography (4OM column, 8percent - 20percent ethyl acetate/heptane gradient) to provide tert-butyl 6-bromo-4-oxo-3,4-dihydro-1 H-spiro[chromene-2,4 -piperidine]-1 -carboxylate as a yellow solid (3.09 g, 84percent). 1H NMR (CDCI3) δ 7.96 (d, J=2.5, 1H), 7.56 (dd, J=8.7, 2.5, 1H), 6.89 (d, J=8.7, 1H), 2.70 (s, 2H), 1.44 (s, 9H).
79% With pyrrolidine In methanol for 17 h; Heating / reflux Step 1 :; Intermediate 1; Spiro[2H-1 -benzopyran-2,4'-piperidine]-1 '-carboxylic acid, 6-bromo-3,4- dihydro-4-oxo-, 1,1-dimethylethyl ester.; A mixture of 5'-bromo-2'-hydroxyacetophenone (50.0 g, 232.5 mmol), t-butyl 4-oxo-1- piperidinecaboxylate (46.3 g, 232.4 mmol) and pyrrolidine (50 ml_, 599.0 mmol) in methanol (500 mL) was refluxed for 17h, then cooled and concentrated. The red colored residue was dissolved in EtOAc (600 mL) and washed with water (2 x 200 mL), aqueous ~3M citric acid (2x 150 mL), water and brine. The organics were dried (Mg SO4) and concentrated to a thick, light orange foamy tar. Hexanes (~ 100 mL) was added and the vessel walls were scratched to induce crystallization. Another 150 mL hexanes was added and the mixture was stirred for 66 hrs, then filtered, rinsed with hexanes and air dried to afford 73.2 g (79percent) of the title compound as a dull yellow solid: NMR (CDCI3) δ 7.94 (d, J = 2.5 Hz, 1 H), 7.54 (dd, J = 8.7, 2.5 Hz, 1 H), 6.87 (d, J = 8.7 Hz, 1 H), 3.85 (br s, 2H), 3.16 (br t, J = 11.6 Hz, 2H), 2.69 (s, 2H), 1.98 (br d, J= 13.3 Hz, 2H), 1.62-1.54 (m, 2H), 1.43 (s, 9H).
42.2 g With pyrrolidine In methanol for 4 h; Reflux A solution of tert-butyl 4-oxopiperidine-1-carboxylate (21.5 g, 100 mmol), 1-(5-bromo- 2-hydroxyphenyl) ethan-1-one (20.0 g, 100 mmol), and pyrrolidine (20 mL, 270 mmol) in methanol (200 mL) was heated at reflux for 4 h until completion was confirmed by LC/MS. The methanol was concentrated, the residue was dissolved in TBME (250 mL) and washed with washed with iN HC1 (200mL), saturated NaHCO3 solution (200 mL) and brine (200 mL). The organic phase was dried (Mg504), filtered and concentrated to yield a gum. The cmde product was dissolved in hexanes (500 mL) and stirred at RT overnight to give a yellow solid, which was collected by filtration and further washed with hexanes. After drying, tert-butyl 6-bromo-4- oxospiro[chromane-2,4’-piperidinej-l’-carboxylate was obtained as a yellow solid (42.2 g).

Reference: [1] Patent: WO2009/97567, 2009, A1, . Location in patent: Page/Page column 62
[2] Patent: US2011/166124, 2011, A1, . Location in patent: Page/Page column 36
[3] Patent: EP2110377, 2009, A1, . Location in patent: Page/Page column 14
[4] Journal of Medicinal Chemistry, 2011, vol. 54, # 8, p. 3051 - 3064
[5] Patent: CN103304571, 2018, B, . Location in patent: Paragraph 0116-0118
[6] Patent: WO2016/168660, 2016, A1, . Location in patent: Paragraph 00228
[7] Patent: WO2007/54580, 2007, A1, . Location in patent: Page/Page column 30
[8] Patent: WO2008/65508, 2008, A1, . Location in patent: Page/Page column 17
[9] Patent: WO2007/88462, 2007, A1, . Location in patent: Page/Page column 17
[10] Patent: WO2007/11809, 2007, A1, . Location in patent: Page/Page column 92; 105
[11] Patent: US2008/171761, 2008, A1, . Location in patent: Page/Page column 42; 45
[12] Patent: WO2008/88692, 2008, A2, . Location in patent: Page/Page column 104
[13] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 3, p. 949 - 953
[14] Patent: WO2010/2010, 2010, A1, . Location in patent: Page/Page column 77
[15] Patent: WO2018/112204, 2018, A1, . Location in patent: Paragraph 00313
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  • [ 690632-38-3 ]
  • [ 921760-46-5 ]
Reference: [1] Patent: US2007/117823, 2007, A1, . Location in patent: Page/Page column 14
[2] Patent: WO2007/54580, 2007, A1, . Location in patent: Page/Page column 31-32
[3] Patent: US2008/171761, 2008, A1, . Location in patent: Page/Page column 42
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