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Product Details of [ 1450-75-5 ]

CAS No. :1450-75-5 MDL No. :MFCD00191850
Formula : C8H7BrO2 Boiling Point : -
Linear Structure Formula :- InChI Key :HQCCNFFIOWYINW-UHFFFAOYSA-N
M.W : 215.04 Pubchem ID :95991
Synonyms :

Calculated chemistry of [ 1450-75-5 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 11
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.12
Num. rotatable bonds : 1
Num. H-bond acceptors : 2.0
Num. H-bond donors : 1.0
Molar Refractivity : 46.36
TPSA : 37.3 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) : -5.69 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.04
Log Po/w (XLOGP3) : 2.7
Log Po/w (WLOGP) : 2.36
Log Po/w (MLOGP) : 1.86
Log Po/w (SILICOS-IT) : 2.35
Consensus Log Po/w : 2.26

Druglikeness

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

Water Solubility

Log S (ESOL) : -3.21
Solubility : 0.132 mg/ml ; 0.000614 mol/l
Class : Soluble
Log S (Ali) : -3.14
Solubility : 0.157 mg/ml ; 0.000731 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.02
Solubility : 0.207 mg/ml ; 0.000962 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.36

Safety of [ 1450-75-5 ]

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 [ 1450-75-5 ]

* 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 [ 1450-75-5 ]
  • Downstream synthetic route of [ 1450-75-5 ]

[ 1450-75-5 ] Synthesis Path-Upstream   1~21

  • 1
  • [ 1450-75-5 ]
  • [ 5676-56-2 ]
  • [ 42524-21-0 ]
YieldReaction ConditionsOperation in experiment
65% With acetylhydroxamic acid; sulfuric acid In acetonitrile at 80℃; for 0.166667 h; Microwave irradiation General procedure: 2-Hydroxy acetophenone 4a (1.0 g, 7.4 mmol), acetohydroxamic acid (0.83 g, 11.0 mmol), acetonitrile (3 ml), and conc. H2SO4 (0.2 ml) were taken into a 10 ml pressure tube and subjected to microwave heating (CEM discover, 360 W, 80 °C, 25 psi) for 8 min. Next, the reaction mixture was diluted with ethyl acetate (3 ml) and to this; saturated sodium bicarbonate solution (5 ml) was added drop-wise. The mixture was extracted with ethyl acetate (2 .x. 10 ml) and the combined organic layer was washed with saturated NaCl solution, dried over anhy. Na2SO4, and concentrated under reduced pressure. Purification of the mixture by normal column chromatography (silica gel 60-120 mesh, ethyl acetate/hexane: 1:9) gave benzoxazole 5a (0.67 g, 70percent) in the form of a yellow oil and 2-hydroxy acetophenone oxime 6a (68 mg, 6percent, mp 104-107 °C) in the form of a white powder.
Reference: [1] Tetrahedron Letters, 2011, vol. 52, # 46, p. 6103 - 6107
[2] Catalysis Letters, 2015, vol. 145, # 3, p. 939 - 946
  • 2
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Reference: [1] Journal of Organic Chemistry, 2015, vol. 80, # 17, p. 8657 - 8667
  • 3
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  • [ 5676-56-2 ]
Reference: [1] Journal of Organic Chemistry, 2015, vol. 80, # 17, p. 8657 - 8667
[2] Catalysis Letters, 2015, vol. 145, # 3, p. 939 - 946
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Reference: [1] Catalysis Letters, 2015, vol. 145, # 3, p. 939 - 946
  • 5
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  • [ 5676-56-2 ]
  • [ 6329-74-4 ]
Reference: [1] Catalysis Letters, 2015, vol. 145, # 3, p. 939 - 946
  • 6
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  • [ 14733-73-4 ]
Reference: [1] Advanced Synthesis and Catalysis, 2013, vol. 355, # 18, p. 3591 - 3596
  • 7
  • [ 118-93-4 ]
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  • [ 2491-36-3 ]
Reference: [1] Polish Journal of Chemistry, 1983, vol. 57, # 1/3, p. 49 - 56
  • 8
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  • [ 35794-84-4 ]
Reference: [1] Patent: US2002/45650, 2002, A1,
  • 9
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  • [ 35794-84-4 ]
Reference: [1] Chemical Communications, 2016, vol. 52, # 83, p. 12306 - 12309
  • 10
  • [ 1450-75-5 ]
  • [ 74-88-4 ]
  • [ 16740-73-1 ]
YieldReaction ConditionsOperation in experiment
94% With potassium carbonate In acetone 1-(5-Bromo-2-methoxy-phenyl)-ethanone
A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (10 g, 47 mmol), methyl iodide (3.5 mL, 56 mmol), and potassium carbonate (10 g, 73 mmol) in acetone (80 mL) was heated at reflux for 4 h.
The reaction mixture was cooled to room temperature and the resulting white solid filtered and washed thoroughly with ethyl acetate.
The filtrate was washed with water, brine, dried over MgSO4 and filtered.
The filtrate was concentrated in vacuo to provide the title compound (10 g, 94percent) as a white solid.
91%
Stage #1: With potassium carbonate In [(2)H6]acetone at 20℃; for 1 h;
Stage #2: at 20℃; for 20 h;
Potassium carbonate (9.6 g) was added to a solution of 1-(5-bromo-2-hydroxyphenyl)ethanone (4.98 g) in acetone (50 mL) and the suspension was stirred at rt for 1 h.
Methyl iodide (1.89 mL) was added and the reaction mixture was stirred at rt for 20 h at which time it was filtered and the volatiles were removed under reduced pressure.
The residue was diluted in Et2O and was washed with water.
The organic layer was dried and the solvent was removed under reduced pressure to yield the desired product (91percent yield).
LC-MS (Method 1): m/z [M+H]+=229.1 (MW calc.=229.07); Rt=3.30 min.
91%
Stage #1: With potassium carbonate In acetone at 20℃; for 1 h;
Stage #2: at 20℃; for 20 h;
Intermediate 7a) Potassium carbonate (9.6 g) was added to a solution of 1 -(5-bromo-2-hydroxyphenyl)ethanone (4.98 g) in acetone (50 mL) and the suspension was stirred at rt for 1 h. Methyl iodide (1.89 mL) was added and the reaction mixture was stirred at rt for 20 h at which time it was filtered and the volatiles were removed under reduced pressure. The residue was diluted in Et20 and was washed with water. The organic layer was dried and the solvent was removed under reduced pressure to yield the desired product (91 percent yield). LC-MS (Method 1): m/z [M+H]+ = 229.1 (MW calc. = 229.07); R, = 3.30 min.
89% With potassium carbonate In N,N-dimethyl-formamide at 20℃; A mixture of 5-Bromo-2-hydroxyacetophenone 2a (10g, 46.5mmol, 1 eq), potassium carbonate (9.62g, 69.75mmol, 1.5 eq) and iodomethane (5.8mL, 93mmol, 2 eq) in DMF (120mL) were stirred overnight in a sealed round bottom flask at room temperature. DMF was removed under reduced pression and the residue was partitioned between water and EtOAc. The combined EtOAc extracts were washed with brine, 0.5M NaOH and then three times with water. The organic layer was dried over MgSO4 and the solvent evaporated. The product was obtained as an off-white solid (9.5g, 89percent). m.p. 31–32°C. SM (ESI): m/z 251–253 [M+Na]+. 1H NMR (δ ppm): 2.54 (s, 3H, COCH3), 3.90 (s, 3H, OCH3), 7.18 (d, Jortho=8.9Hz, 1H, CHar), 7.66 (d, Jmeta=2.6Hz, 1H, CHar), 7.72 (dd, Jortho=8.9Hz, Jmeta=2.6Hz, 1H, CHar).
75% With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃; for 12 h; Inert atmosphere To a stirred solution of 1 -(5-bromo-2-hydroxyphenyl)ethan- 1-one 1 (10 g, 46.51 mmol) in DMF (100 mL) were added K2C03 (9.63 g, 69.77 mmol) and Mel (5.8 mL, 93.02 mmol) at 0°C under Ar. The mixture was stirred at RT for 12 h then quenched with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with brine (80 mL), dried over Na2 SO4, filtered and concentrated under reduced pressure to afford compound 2 (8.8 g, 75percent) as pale yellow liquid. ‘H NIVIR (500MHz, DMSO-d6): 7.70 (dd, J 9.0, 2.6 Hz, 1H), 7.64 (d, J= 2.6 Hz, 1H), 7.16 (d, J= 9.0 Hz, 1H), 3.88 (s, 3H), 2.52 (s, 3H); LC-MS (ESI):m/z 228.8 (M + Hf).

Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 15, p. 2561 - 2563
[2] Tetrahedron, 2001, vol. 57, # 24, p. 5027 - 5038
[3] Chemistry - A European Journal, 2016, vol. 22, # 30, p. 10415 - 10419
[4] Patent: US2003/187007, 2003, A1,
[5] Patent: US2014/194443, 2014, A1, . Location in patent: Paragraph 0427-0429
[6] Patent: WO2014/108337, 2014, A1, . Location in patent: Page/Page column 56; 57
[7] European Journal of Medicinal Chemistry, 2018, vol. 144, p. 774 - 796
[8] Journal of the Chemical Society. Perkin Transactions 1, 2002, # 8, p. 1115 - 1123
[9] Patent: WO2017/15221, 2017, A1, . Location in patent: Paragraph 00255
[10] Organic and Biomolecular Chemistry, 2005, vol. 3, # 24, p. 4432 - 4443
[11] Advanced Synthesis and Catalysis, 2018, vol. 360, # 8, p. 1634 - 1638
  • 11
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YieldReaction ConditionsOperation in experiment
15% With (difluoroboryl)dimethylglyoximatocobalt(II) bis(acetonitrile); water; 3-cyano-1-methylquinolinium cation In acetonitrile at 20℃; for 5 h; Inert atmosphere; Irradiation; Green chemistry 1-methyl-3-cyanoquinoline salt as a photosensitizer, Cobalt oxime complex 2 as a cobalt catalyst, 5mL acetonitrile was added2.69 mg (1 × 10 -2 mmol) photosensitizer and 2.80 mg (6 × 10 -3 mmol) cobalt catalyst, Replacing the atmosphere with Ar atmosphereAnd then0.2 mmol of 3'-bromoacetophenone (R1 is COCH3, R3 is Br, R2, R4 are independently H) and 2 mmol of H2O. Room temperature, high pressureMercury lamp irradiation 5h. After the reaction was completed, the H2 production was detected by GC (TCD) and the conversion of benzene by GC (FID), And then separated by column. 1H NMR and MS identified products were 3'-bromo-2-hydroxyacetophenone, 3'-bromo-4-hydroxyacetophenone and 3'-bromo-6-hydroxyacetophenone. The conversion of 3'-bromoacetophenone was 32percent, the yield of coupling products was 2percent, 15percent and 15percent, respectively, and the yield of H2 was 8percent.
Reference: [1] Patent: CN107324975, 2017, A, . Location in patent: Paragraph 0130-0131
  • 12
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  • [ 1450-75-5 ]
YieldReaction ConditionsOperation in experiment
61% With Oxone; ammonium bromide In methanol at 20℃; for 4.5 h; General procedure: Oxone (1.352 g, 2.2 mmol) was added to the well stirred solution of substrate (2 mmol) and NH4Br (0.215 g, 2.2 mmol) in methanol (10 ml) and the reaction mixture was allowed to stir at room temperature (or reflux temperature). After completion of the reaction, as monitored by TLC, the reaction mixture was quenched with aqueous sodium thiosulfate, and extracted with ethyl acetate (3.x.25 ml). Finally, the combined organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and removal of solvent in vacuo yielded a crude residue, which was further purified by column chromatography over silica gel (finer than 200 mesh) to afford pure products. All the products were identified on the basis of 1H NMR and mass spectral data.
Reference: [1] Tetrahedron Letters, 2012, vol. 53, # 2, p. 191 - 195
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YieldReaction ConditionsOperation in experiment
19 %Chromat. With N-Bromosuccinimide In acetonitrile at 20℃; for 2 h; General procedure: Reaction conditions: Thiourea (5.1 molpercent, 2 mg, 0.026 mmol) was added to an acetonitrile solution (10 mL) containing NBS (1.15 equiv, 104.4 mg, 0.587 mmol). Anisole (56.3 mg, 0.51 mmol) was added immediately to the resulting stirred solution and allowed to stir at room temperature for 10 min. The reaction was quenched by the addition of 10percent aqueous solution of Na2S2O3 (10 mL) and extracted with ethyl acetate (70 mL). The organic solution was then washed with additional 10percent Na2S2O3 (2 * 10 mL), followed by deionized water (3 * 15 mL) and brine (2 * 10 mL). The organic solution was then dried over anhydrous Na2SO4 and the solvent was evaporated in vacuo. The major product of each reaction was isolated by centrifugal thin-layer chromatography using a 2 mm thick silica gel 60GF254 coated plate (5percent CH2Cl2/hexanes). The products reported herein are known compounds and were characterised by GC-MS, IR, 1H and 13C NMR. Their spectroscopic data are in agreement with those reported in the literature.
Reference: [1] Journal of Organic Chemistry, 2012, vol. 77, # 13, p. 5823 - 5828
[2] Tetrahedron, 2017, vol. 73, # 46, p. 6564 - 6572
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  • [ 67-56-1 ]
  • [ 201230-82-2 ]
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  • [ 57009-12-8 ]
YieldReaction ConditionsOperation in experiment
83% at 100℃; A solution of l-(5-bromo-2-hydroxyphenyl)ethanone (20.0 g, 93.0 mmol, 1.00 equiv) in methanol (500 mL), Pd(dppf)2Cl2 (4 g, 4.7 mmol, 0.05 equiv) and triethylamine (20 g, 200.00 mmol, 2.00 equiv) were stirred overnight at 100°C under an atmosphere of CO (g). The reaction progress was monitored by LCMS. The resulting mixture was concentrated in vacuo. The residue was diluted with 200 mL of H20 and the resulting solution was extracted with 5x50 mL of ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate. The solids were filtered off. The resulting mixture was concentrated in vacuo and the residue was purified by silica gel column with ethyl acetate/petroleum ether (1 : 10). This resulted in 15 g (83percent) of methyl 3-acetyl-4-hydroxybenzoate as a light yellow solid. H NMR (300 MHz, CDC13): 12.68 (s, 1 H), 8.49 (d, 1H), 8.14 (dd, / = 2.1 Hz, l H), 7.02 (d, / = 9.6 Hz,l H), 3.93 (s, 3 H), 2.71 (s,3 H)
Reference: [1] Patent: WO2014/66795, 2014, A1, . Location in patent: Paragraph 0175
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  • [ 33839-11-1 ]
Reference: [1] Bulletin de la Societe Chimique de France, 1969, p. 781 - 787
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  • [ 70978-54-0 ]
YieldReaction ConditionsOperation in experiment
73% With nitric acid In tetrachloromethane 1I 5-Bromo-2-hydroxy-3-nitroacetophenone
A solution of 5-bromo-2-hydroxyacetophenone (23.7 g, 0.110 mol) in carbon tetrachloride (90 ml) was added with concentrated nitric acid (17.2 ml).
The mixture was left under stirring at 75° C. for 50 minutes, then left to cool at room temperature.
The precipitated solid was recovered by filtration washing with cold carbon tetrachloride.
After drying under vacuum, 20.9 g of the title product were obtained as a light yellow solid (73percent yield).
1 H N.M.R. (300 MHz, CDCl3) δ ppm: 2.73 (s, 3H); 8.14 (d, 1H); 8.31 (d, 1H); 12.92 (s, 1H).
Reference: [1] Patent: US5990142, 1999, A,
[2] Patent: EP1391451, 2004, A1, . Location in patent: Page 113
[3] Patent: WO2017/221002, 2017, A1, . Location in patent: Page/Page column 92
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Reference: [1] Catalysis Letters, 2015, vol. 145, # 3, p. 939 - 946
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  • [ 6329-74-4 ]
Reference: [1] Catalysis Letters, 2015, vol. 145, # 3, p. 939 - 946
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  • [ 55580-08-0 ]
Reference: [1] Patent: US2011/76291, 2011, A1,
[2] Patent: WO2012/162330, 2012, A1,
[3] Journal of Medicinal Chemistry, 2017, vol. 60, # 2, p. 627 - 640
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  • [ 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
  • 21
  • [ 1450-75-5 ]
  • [ 79099-07-3 ]
  • [ 921760-46-5 ]
YieldReaction ConditionsOperation in experiment
96%
Stage #1: With pyrrolidine In methanol at 80℃; for 16 h;
Stage #2: With hydrogenchloride In 1,4-dioxane; dichloromethane at 20℃; for 16 h;
A mixture of 5-bromo-2-hydroxyacetophenone (6.0 g, 0.027 mol) and pyrrolidine (2.7 mL, 0.033 mol) in MeOH (48 mL) was stirred at 25°C for 20 min in a sealed flask. The mixture was then treated with 1 -Boc-4-piperidone (5.55 g, 0.027 mol) and heated to 80 °C for 16 h.The reaction mixture was then concentrated in vacuo and the residue dissolved in DCM (50 mL), cooled to 15°C,treated with 4M HC1 -dioxane (30 mL) and stirred for 16 h at rt. The solid was filtered and washed with DCM to the title compound as a cream color HC1 salt (8.92 g, 96percent). Ή NMR (400 MHz, CD3OD) δ 7.93 (d, .7=2.5 Hz, 1 H), 7.71 (dd, J=8.9, 2.6 Hz, 1 H), 7.1 1 (d, .7=9.0 Hz, 1 H), 3.32 - 3.41 (m, 4 H), 2.90 (s, 2 H), 2.23 - 2.36 (m, 2 H), 1.87 - 2.05 (m, 2 H), MS ESI 297 [M + H]+, calcd for [C13H14BrN02+H]+ 297.02.
Reference: [1] Patent: WO2013/53051, 2013, A1, . Location in patent: Page/Page column 93
[2] Patent: WO2007/11809, 2007, A1, . Location in patent: Page/Page column 92
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