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Product Details of [ 16532-79-9 ]

CAS No. :16532-79-9 MDL No. :MFCD00001916
Formula : C8H6BrN Boiling Point : -
Linear Structure Formula :- InChI Key :MFHFWRBXPQDZSA-UHFFFAOYSA-N
M.W : 196.04 Pubchem ID :27914
Synonyms :

Calculated chemistry of [ 16532-79-9 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 10
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.12
Num. rotatable bonds : 1
Num. H-bond acceptors : 1.0
Num. H-bond donors : 0.0
Molar Refractivity : 43.66
TPSA : 23.79 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) : -5.7 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.89
Log Po/w (XLOGP3) : 2.53
Log Po/w (WLOGP) : 2.52
Log Po/w (MLOGP) : 2.52
Log Po/w (SILICOS-IT) : 2.81
Consensus Log Po/w : 2.45

Druglikeness

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

Water Solubility

Log S (ESOL) : -3.03
Solubility : 0.184 mg/ml ; 0.000939 mol/l
Class : Soluble
Log S (Ali) : -2.68
Solubility : 0.413 mg/ml ; 0.00211 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.74
Solubility : 0.0353 mg/ml ; 0.00018 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.16

Safety of [ 16532-79-9 ]

Signal Word:Danger Class:6.1
Precautionary Statements:P261-P280-P301+P310-P305+P351+P338 UN#:2811
Hazard Statements:H301-H312+H332-H315-H319-H335 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 16532-79-9 ]

* 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 [ 16532-79-9 ]
  • Downstream synthetic route of [ 16532-79-9 ]

[ 16532-79-9 ] Synthesis Path-Upstream   1~30

  • 1
  • [ 16532-79-9 ]
  • [ 74-88-4 ]
  • [ 42186-06-1 ]
YieldReaction ConditionsOperation in experiment
72%
Stage #1: With sodium hydride In tetrahydrofuran at 0 - 20℃; for 1 h;
Stage #2: for 14 h;
Example 649 2-(4-bromophenyl)propanenitrileTo a solution of 2-(4-bromophenyl)acetonitrile (5.0 g, 25.5 mmol) in anhydrous THF (70 mL) was cooled to 0 °C and sodium hydride (60 wt percent, 1.5 g, 38.3 mmol) added portion wise. The mixture was stirred at room temperature for 1 h. After which methyl iodide (1.8 mL, 28.1 mmol) was added and the mixture stirred for 14 h. The reaction mixture was carefully quenched with water at 0 °C and diluted with ethyl acetate (200 mL). The layers were seperated and the organic layer was dried over anhydrous sodium sulfate, filtered, concentrated and the residue purified by column chromatography (silica, 0-30percent ethyl acetate/heptane) to afford the desired product (3.8 g, 72percent) as a yellow oil: ESI MS m/z 210 [C H8BrN +H]+.
62%
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 1 h;
Stage #2: at 20℃; for 2 h;
Step 1. 2-(4-Bromophenyl)propanenitriIe (1541) [00487] into a 100-mL round-bottom flask was added 2-(4-bromophenyl)acetonitrile (3.00 g, 15.3 mmol), tetrahydrofuran (30 mL), and sodium hydride (60percent by weight; 2.60 g, 65.0 mmol). The reaction mixture was stirred for I h at RT. The reaction mixture was cooled to 0 °C then iodomethane (0.551 g, 0.242 mL, 3.88 mmol) was added and the reaction mixture was stirred at RT for an additional 2 h. The reaction was then quenched by the addition of H2O (10 mL), and then was extracted with dichloromethane (3 30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford 2-(4- bromophenyi)propanemtrile (2 g, 62percent) as a yellow solid. LCMS (ESI, m/z) 210 [M+H]+.
53.6%
Stage #1: With sodium hexamethyldisilazane In tetrahydrofuran at 0 - 20℃; Inert atmosphere
Stage #2: at 20℃; for 1 h;
Step 1: To a stirred solution of 2-(4-bromo phenyl) acetonitrile (20 g, 102.04 mmol) in dry tetrahydrofuran (200 mL) was added sodium bis(trimethylsilyl)amide (18.71 g, 102.04 mmol) at 0° C. under a nitrogen atmosphere. After stirring for 20 minutes at room temperature, methyl iodide (14.48 g, 102 mmol) was added and then stirred for 1 h at room temperature. The reaction mixture was quenched with an aqueous ammonium chloride solution and extracted with ethyl acetate (2×150 mL). The combined organic layers were washed with water (2×100 mL), a saturated aqueous sodium chloride solution (2×25 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (3-4percent ethyl acetate/hexanes) afforded 2-(4-bromo-phenyl)-propionitrile as a light yellow liquid (11.5 g, 53.6percent).
51.2% With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; In a round bottom flask, 2-(4-bromophenyl)acetonitrile (1.01 g, 5.15 mmol) was dissolved in DMF (5.15 mL). At 0°C was added 60percent sodium hydride (261 mg, 6.53 mmol, 1.27 eq) and methyl iodide (321 uL, 5.15 mmol, 1.0 eq) was added over 30 mm. After 2h stirring at RT, reaction was quenched by addition to cold water. Mixture was extracted with ethyl acetate, washed with saturated sodium chloride, dried over magnesium sulfate, filtered, evaporated. Purification by silica gel chromatography (0-50percent ethyl acetate in heptanes as eluent) yielded 2-(4-bromophenyl)propanenitrile (553.5 mg, 51.2percent yield). ‘H NMR (400 MHz, CHLOROFORM-d) ö 7.53 (d, I = 8.53 Hz, 2H), 7.25 (d, I = 8.28 Hz, 2H), 3.88 (q, I = 7.28 Hz, 1H), 1.64 (d, I = 7.28 Hz, 3H).

Reference: [1] Journal of the American Chemical Society, 2015, vol. 137, # 19, p. 6156 - 6159
[2] Patent: WO2011/123419, 2011, A1, . Location in patent: Page/Page column 386
[3] Patent: WO2017/139778, 2017, A1, . Location in patent: Paragraph 00487
[4] Patent: US2013/331375, 2013, A1, . Location in patent: Paragraph 0178
[5] Patent: WO2018/140876, 2018, A1, . Location in patent: Page/Page column 113; 115
  • 2
  • [ 16532-79-9 ]
  • [ 616-38-6 ]
  • [ 42186-06-1 ]
Reference: [1] Journal of Medicinal Chemistry, 2000, vol. 43, # 23, p. 4354 - 4358
[2] Patent: US2012/214785, 2012, A1, . Location in patent: Page/Page column 59
  • 3
  • [ 16532-79-9 ]
  • [ 42186-06-1 ]
YieldReaction ConditionsOperation in experiment
85% With potassium carbonate In ethyl acetate; carbonic acid dimethyl ester Preparation 1
2-(4-Bromophenyl)propionitrile
A solution of 50.0 g (225.0 mmol) of 4-bromophenylacetonitrile and 1.8 g (12.8 mmol) of potassium carbonate in 387 mL of dimethyl carbonate was heated to 180° C. in a sealed vessel for 16 hours.
The solution was then cooled, diluted with 200 ml of ethyl acetate and washed once with 100 ml water, once with 100 ml of 10percent aqueous sodium bisulfate and once with 100 ml brine.
The organic portion was dried (MgSO4), filtered and concentrated in vacuo.
The residue was distilled under vacuum through a short path distillation apparatus to afford 40.3 g (85percent) of the title compound.
Reference: [1] Patent: US6303816, 2001, B1,
  • 4
  • [ 16532-79-9 ]
  • [ 68-12-2 ]
  • [ 42186-06-1 ]
Reference: [1] Angewandte Chemie - International Edition, 2018, vol. 57, # 36, p. 11770 - 11775[2] Angew. Chem., 2018, vol. 130, # 36, p. 11944 - 11949,6
  • 5
  • [ 16532-79-9 ]
  • [ 876-31-3 ]
Reference: [1] European Journal of Organic Chemistry, 2016, vol. 2016, # 18, p. 3056 - 3059
  • 6
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  • [ 14191-95-8 ]
Reference: [1] Angewandte Chemie - International Edition, 2018, vol. 57, # 7, p. 1968 - 1972[2] Angew. Chem., 2018, vol. 130, p. 1986 - 1990,5
  • 7
  • [ 16532-79-9 ]
  • [ 51628-12-7 ]
Reference: [1] Journal of the American Chemical Society, 2002, vol. 124, # 50, p. 14844 - 14845
[2] Journal of the American Chemical Society, 2015, vol. 137, # 26, p. 8328 - 8331
  • 8
  • [ 75-91-2 ]
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  • [ 59247-47-1 ]
Reference: [1] RSC Advances, 2016, vol. 6, # 104, p. 102023 - 102027
  • 9
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  • [ 4654-39-1 ]
Reference: [1] Journal of Organic Chemistry, 1964, vol. 29, # 8, p. 2109 - 2116
  • 10
  • [ 64-17-5 ]
  • [ 16532-79-9 ]
  • [ 14062-25-0 ]
Reference: [1] Chemische Berichte, 1909, vol. 42, p. 1938
[2] Justus Liebigs Annalen der Chemie, 1897, vol. 296, p. 361
  • 11
  • [ 16532-79-9 ]
  • [ 75-26-3 ]
  • [ 51632-12-3 ]
YieldReaction ConditionsOperation in experiment
21.3 g
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.25 h;
Stage #2: at 20℃; for 2 h;
Synthesis of 2-(4-bromo-phenyl)-2,3-dimethylbutyronitrile
To a solution of R-1 (20.0 g, 0.102 mol) in DMF (300 mL) at 0° C. is added NaH (60percent in oil suspension, 4.28 g, 0.107 mol) slowly.
The mixture is then stirred for a further 15 minutes and 2-bromopropane (9.60 mL, 0.107 mol) is added.
The reaction mixture is allowed to warm to room temperature, stirring continued for 2 hours and then concentrated in vacuo.
The residue is partitioned between CH2Cl2 and brine.
The combined organics are dried with Na2SO4, filtered and concentrated in vacuo.
The residue is purified by flash chromatography (SiO2, 0-15percent EtOAc in heptane) to give I-1 (21.3 g); m/z 238.3, 240.2 [M/M+2H]
Reference: [1] Journal of Medicinal Chemistry, 2015, vol. 58, # 4, p. 1669 - 1690
[2] Patent: WO2012/24150, 2012, A1, . Location in patent: Page/Page column 109
[3] Patent: US2013/195879, 2013, A1, . Location in patent: Paragraph 0217; 0218
[4] Journal of the American Chemical Society, 2016, vol. 138, # 47, p. 15303 - 15306
[5] Chem.Abstr., 1974, vol. 80, # 120746,
  • 12
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  • [ 51632-12-3 ]
Reference: [1] Journal of the American Chemical Society, 2015, vol. 137, # 19, p. 6156 - 6159
  • 13
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  • [ 201230-82-2 ]
  • [ 124-41-4 ]
  • [ 52787-14-1 ]
  • [ 41841-16-1 ]
  • [ 76469-88-0 ]
Reference: [1] Russian Journal of Organic Chemistry, 1994, vol. 30, # 3.2, p. 435 - 441[2] Zhurnal Organicheskoi Khimii, 1994, vol. 30, # 3, p. 404 - 410
  • 14
  • [ 16532-79-9 ]
  • [ 201230-82-2 ]
  • [ 124-41-4 ]
  • [ 52787-14-1 ]
  • [ 41841-16-1 ]
  • [ 76469-88-0 ]
Reference: [1] Russian Journal of Organic Chemistry, 1994, vol. 30, # 3.2, p. 435 - 441[2] Zhurnal Organicheskoi Khimii, 1994, vol. 30, # 3, p. 404 - 410
  • 15
  • [ 16532-79-9 ]
  • [ 201230-82-2 ]
  • [ 124-41-4 ]
  • [ 52787-14-1 ]
  • [ 41841-16-1 ]
  • [ 76469-88-0 ]
Reference: [1] Russian Journal of Organic Chemistry, 1994, vol. 30, # 3.2, p. 435 - 441[2] Zhurnal Organicheskoi Khimii, 1994, vol. 30, # 3, p. 404 - 410
  • 16
  • [ 16532-79-9 ]
  • [ 73918-56-6 ]
YieldReaction ConditionsOperation in experiment
80%
Stage #1: With borane-THF In tetrahydrofuran at 0℃; for 24.5 h; Reflux
Stage #2: for 4 h; Reflux
General procedure: Toa solution of 2-bromobenzyl cyanide (20.0 g, 0.1 mol) in THF (100 mL) was added1M BH3·THF (200 mL, 0.2 mol) dropwise at 0 oCover 30 min and then heated to reflux for 24 h. After quenchedwith MeOH (50 mL) and 6M HCl (50 mL) at 0 oC, the reaction mixturewas heated to reflux for another 4 h and concentrated under reduced pressure.The residue was diluted with H2O (300 mL) and washed with EA (75 mL×2). The aqueous layer was then neutralized by 15percent NaOH, extracted with EA (75mL ×2). The combined organic layer was dried over Na2SO4and concentrated under reduced pressure to afford compound 2a as yellow oil (17.4 g, 85.2percent).
78%
Stage #1: With borane-THF; 5-bromoisoindoline In tetrahydrofuran at 75℃;
Stage #2: With hydrogenchloride; water In tetrahydrofuran at 20℃;
To a solution of 4-bromophenyl acetonitrile (20 g, 102 mmol) in THF (20 mL) is added a solution of borane (1 M in THF, 300 mL) under a nitrogen atmosphere. The reaction mixture is stirred at 75 C overnight. It is cooled to room temperature and treated with 6 N <n="52"/>HCl (500 mL) drop-wise and stirred further at room temperature for 5 h. The resulting mixture is washed with ethyl acetate and ethyl acetate is discarded. The aqueous layer is basified with sodium carbonate and then extracted with ethyl acetate several times. The combined organic layer is washed with water, dried (Na2SO4), and the solvent was removed under reduced pressure to obtain pale yellow oil without further purification (16 g, 78percent).
Reference: [1] Chemical Communications, 2014, vol. 50, # 40, p. 5391 - 5393
[2] Patent: US2016/145193, 2016, A1, . Location in patent: Paragraph 0052
[3] Organic Letters, 2014, vol. 16, # 4, p. 1092 - 1095
[4] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 18, p. 3050 - 3056
[5] Patent: WO2008/76954, 2008, A2, . Location in patent: Page/Page column 50-51
[6] Journal of Organic Chemistry, 1958, vol. 23, p. 1979,1980
[7] Polish Journal of Chemistry, 1979, vol. 53, p. 1025 - 1032
[8] Journal of Medicinal Chemistry, 2000, vol. 43, # 23, p. 4354 - 4358
[9] Journal of Medicinal Chemistry, 2008, vol. 51, # 21, p. 6808 - 6828
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Reference: [1] Journal of Medicinal Chemistry, 1990, vol. 33, # 7, p. 1919 - 1924
  • 18
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  • [ 74-88-4 ]
  • [ 101184-73-0 ]
YieldReaction ConditionsOperation in experiment
96% With sodium hydride In N,N-dimethyl-formamide at 0 - 10℃; for 1 h; 45 g (1100 mmol) of sodium hydride (a 60percent dispersion in a mineral oil) was added in divided portions to a solution of 100 g (510 mmol) of 4-bromophenylacetonitrile in 1500 ml of N,N-dimethylformamide at 0° C. in an argon stream with stirring.
Then, 95 ml (1500 mmol) of methyl iodide was added dropwise thereto at 0° C. with stirring and the mixture was stirred at 10° C. for 1 hour.
After the reaction was completed, the reaction solution was gradually poured into 900 g of a saturated aqueous solution of ammonium chloride, then 500 ml of water was added thereto and the mixture was extracted with 2000 ml of ethyl acetate.
The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure, whereby 110 g of the title compound was obtained as a dark brown oily substance (yield: 96percent).
Rf value: 0.78 (n-hexane:ethyl acetate=1:1 (v/v))
Mass spectrum (CI, m/z): 224, 226 (M++1)
1H-NMR spectrum (CDCl3, δppm): 1.71 (s, 6H), 7.32-7.38 (m, 2H), 7.49-7.54 (m, 2H)
96%
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 0.5 h;
Stage #2: at 40℃;
A solution of 4-Bromophenylacetonitrile (10.0 g, 51.0 mmol) in tetrahydrofuran (200 mL) was added slowly to a suspension of sodium hydride (60percent in mineral oil, 6.0 g, 153 mmol) in tetrahydrofuran (400 mL) at room temperature over 30 minutes.
After complete addition, methyl iodide (7.6 mL, 122 mmol) was added slowly over 30 minutes, maintaining the reaction temperature below 40° C. by occasional immersion into a water bath.
The reaction was then stirred overnight at room temperature.
The mixture was poured into water (500 mL) and extracted into ethyl acetate (2*300 mL).
The combine organic layers were washed with brine (2*300 mL), dried over magnesium sulfate, filtered and concentrated.
Crude purified on silica gel eluding with 2percent ethyl acetate in hexanes) to give 2-(4-bromophenyl)-2-methylpropanenitrile (11 g, 96percent) as a yellow oil.
1H NMR (300 MHz, CDCl3): δ ppm 1.70 (s, 6H), 7.35 (dd, 2H), 7.53 (dd, 2H).
96% With sodium hydride In N,N-dimethyl-formamide at 0 - 10℃; for 1 h; (Reference Example 1)
Synthesis of 1-bromo-4-(1-cyano-1-methylethyl)benzene (Reference compound 1-1)
45 g (1100 mmol) of sodium hydride (a 60percent dispersion in a mineral oil) was added in divided portions to a solution of 100 g (510 mmol) of 4-bromophenylacetonitrile in 1500 ml of N,N-dimethylformamide at 0°C in an argon stream with stirring.
Then, 95 ml (1500 mmol) of methyl iodide was added dropwise thereto at 0°C with stirring and the mixture was stirred at 10°C for 1 hour.
After the reaction was completed, the reaction solution was gradually poured into 900 g of a saturated aqueous solution of ammonium chloride, then 500 ml of water was added thereto and the mixture was extracted with 2000 ml of ethyl acetate.
The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure, whereby 110 g of the title compound was obtained as a dark brown oily substance (yield: 96percent).
Rf value: 0.78 (n-hexane: ethyl acetate = 1: 1 (v/v))
Mass spectrum (CI, m/z): 224, 226 (M++1)
1H-NMR spectrum (CDCl3, δppm): 1.71 (s, 6H), 7.32-7.38 (m, 2H), 7.49-7.54 (m, 2H)
96%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.25 h;
Stage #2: at 0 - 20℃; for 1.16667 h;
Step 1:
Preparation of 2-(4-bromophenyl)-2-methylpropanenitrile
To a solution of (4-bromophenyl)acetonitrile (3 g) in N,N-dimethylformamide (45 ml) chilled to 0° C. was added sodium hydride (55 wt percent, 1.47 g) portionwise.
The reaction mixture was stirred at the same temperature for 15 min Iodomethane (2.86 mL) was added to the mixture at 0° C. dropwise.
After being stirred at 0° C. for 10 min then at room temperature for 1 h, the reaction mixture was poured into ammonium chloride aqueous solution and extracted with diisopropyl ether (3 times) and washed with saturated sodium bicarbonate aqueous solution then brine.
The organics were dried over anhydrous sodium sulfate and concentrated under reduced pressure.
Purification by column chromatography (0-10percent ethyl acetate in hexanes) gave the product (3.29 g, 96percent).
1HNMR (CDCl3) 400 MHz δ: 7.52 (d, J=8.6 Hz, 2H), 7.35 (d, J=8.6 Hz, 2H), 1.71 (s, 6H).
87.5% With hydrogenchloride In N,N-dimethyl-formamide 4A.
2-Methyl-2-(4-bromophenyl)propionitrile
To a suspension of sodium hydride (60percent dispersion in oil, 50 g, 1.25 m) in dry N,N-dimethylformamide (400 ml under nitrogen was added with stirring a solution of 4-bromophenylacetonitrile in N,N-dimethylformamide (400 ml) keeping the temperature between 30° and 40° C. A solution of iodomethane (213 g, 1.50 m) in N,N-dimethylformamide was then added gradually keeping the temperatue between 35° C. and the mixture then stirred at ambient temperature overnight.
With ice cooling 2N aqueous hydrochloric acid (800 ml) was gradually added and then the mixture was diluted with water (1200 ml).
The product was extracted with ether and the extract washed with water, saturated sodium bicarbonate, aqueous sodium sulphite, water again and finally brine.
After drying and concentration on vacuo an orange oil was obtained which was distilled in vacuo to give the title compound as a colourless liquid (98.05 g, 87.5percent) b.pt. 98°-100°/0.4 mm.
78%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.25 h;
Stage #2: at 0 - 20℃;
To a solution of (4-bromo-phenyl)-acetonitrile (1 g, 5.10 mmol) in DMF (10 mL) is added sodium hydride (0.408 g, 10.20 mmol, 60percent in mineral oil) at 0 °C. Thereaction mixture is stirred at 0 °C for 15 minutes and then methyl iodide (0.69 mL, 11.22 mmol) is added at 0 °C. The reaction mixture is stirred at room temperature forovernight. The reaction mixture is quenched with aqueous ammonium chloride solution (5 mL) and extracted with EtOAc (2x20 mL). The combined organic extracts arewashed with water (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered, and evaporated. The crude material is purified over silica gel column chromatography(combiflash) eluting with 5-10percent EtOAc in hexanes to give an off white solid (0.9 g,78percent). 1H NMR (400 MHz, CDC13) i5 7.51 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H),1.77 (s, 3H).
78%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.333333 h;
Stage #2: at 0 - 20℃;
To a solution of (4-bromo-phenyl)-acetonitrile (1 g, 5.10 mmol) in DMF (10 mL) is added sodium hydride (0.408 g, 10.20 mmol, 60percent in mineral oil) at 0° C.
The reaction mixture is stirred at 0° C. for 15 minutes and then methyl iodide (0.69 mL, 11.22 mmol) is added at 0° C.
The reaction mixture is stirred at room temperature for overnight.
The reaction mixture is quenched with aqueous ammonium chloride solution (5 mL) and extracted with EtOAc (2*20 mL).
The combined organic extracts are washed with water (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered, and evaporated.
The crude material is purified over silica gel column chromatography (combiflash) eluting with 5-10percent EtOAc in hexanes to give an off white solid (0.9 g, 78percent).
1H NMR (400 MHz, CDCl3) δ 7.51 (d, J=8.4 Hz, 1H), 7.34 (d, J=8.4 Hz, 1H), 1.77 (s, 3H).
70%
Stage #1: With sodium hydride In dimethyl sulfoxide
Stage #2: at 0 - 25℃; for 12 h;
A solution of (4-bromophenyl)acetonitrile (Method 1; 2.1 g, 0.010 mol) in DMSO (20 ml) was treated with sodium hydride (60percent, 1.3 g, 0.032 mol, 3 eq). Methyl iodide (2.0 ml, 0.032 mol, 3.0 equiv) was then added dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was then quenched with water and extracted with EtOAc. The combined organics were dried with NaCl(sat) and then Na2SO4(S). The solvents were removed under reduced pressure. The crude product was purified by column chromatography utilizing an ISCO system (hexane-EtOAc) to give 1.6 g (70percent) of the desired product. NMR: 7.62 (d, 2H), 7.47 (d, 2H), 1.66 (s, 6H).
42% With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 18 h; Step a) intermediate 20 <n="39"/>Synthesis of 2-(4-bromophenyl)-2-methylpropanenitrile.The preparation of 2-(4-bromophenyl)-2-methylpropanenitrile is carried out as described in J. Med. Chem. (1995), no 38, page 1608-1628. Sodium Hydride (60percent susp. in oil, 6.66 g, 166.3 mmol) is added in many portions over 1 hour to 2-(4-bromophenyl)-acetonitrile (1Og, 51.0 mmol), dissolved in anhydrous DMF and methyl iodide (14.838g, 102.0 mmol) at 0 0C. This solution turns to a thick and brown orange paste. It is left stirring to slowly warm up to room temperature (18h). The organic solution is partitioned between water and ethyl acetate, separated, dried over anhydrous sodium sulfate and filtered. The solution is concentrated under reduced pressure and the resulting crude is purified on silicagel using a 0 to 20 percent ethyl acetate in hexane gradient to yield the desired compound (4.9 g, 42percent) as a clear oil. IH NMR (400 MHz, CHLOROFORM-D) δ ppm 1.71 (s, 6 H) 7.35 (d, /=8.79 Hz, 2 H) 7.52 (d, /=8.79 Hz, 2 H)
5 g With sodium hydride In tetrahydrofuran at 0 - 20℃; for 4.17 h; Methyl iodide was added to a solution of 2-(4-bromophenyl)acetonitrile (1.5 g, 2.5 m mol) in dry THF (20 mL) at 0 °C, stirred for 10 min and then added to a solution of NaH (1.2 g, 5.1 mmol) in dry THF (80 mL) at 0 °C. The reaction mixture was slowly brought to rt and stirred for 4 h. The reaction mixture was poured into crushed ice and extracted with EtOAc (2x), the combined organics were washed with H20, brine, dried over a2S04, concentrated to give 5 g of 52A as a brown liquid. XH NMR (400 MHz, CDC13) δ 7.53 (2 H, d, J= 1.2 Hz), 7.36 (2 H, d, J= 1.2 Hz), 1.72 (6 H, s) ppm
13 g
Stage #1: With potassium hexamethylsilazane In tetrahydrofuran at 0 - 3℃; for 0.666667 h;
Stage #2: at 8 - 20℃; for 20.8333 h;
To a solution of KHMDS (50 g) in THF (300 mL) cooled to 0° C. there is added slowly a solution of commercial (4-bromophenyl)acetonitrile (16 g, 81 mmoles) in THF (90 mL), the temperature being maintained below 3° C. The mixture is stirred for 40 minutes at 0° C., and then methyl iodide (11.7 mL) is added in the course of 50 minutes at a temperature below 8° C. The mixture is stirred at ambient temperature for 20 hours and then poured carefully into ice-water (1.5 L). The aqueous phase is extracted with Et2O, and the organic phase is washed with a saturated aqueous NaCl solution, dried and concentrated in vacuo. The residue is chromatographed on silica gel (eluant CH2Cl2/cyclohexane (60/40)). The expected intermediate (13 g) is obtained in the form of a white solid. 1H NMR (300 MHz, CDCl3): δ 7.52 (d, 2H), 7.36 (d, 2H), 1.75 (s, 6H) IR (cm−1): 2237

Reference: [1] Journal of Medicinal Chemistry, 2008, vol. 51, # 24, p. 7953 - 7967
[2] Patent: US2009/12123, 2009, A1, . Location in patent: Page/Page column 5
[3] Patent: US2010/197591, 2010, A1, . Location in patent: Page/Page column 29
[4] Patent: EP1870099, 2007, A1, . Location in patent: Page/Page column 7-8
[5] Patent: US2012/108574, 2012, A1, . Location in patent: Page/Page column 111
[6] Patent: WO2018/149419, 2018, A1, . Location in patent: Paragraph 00704
[7] Organic Letters, 2013, vol. 15, # 3, p. 690 - 693
[8] Patent: US4705854, 1987, A,
[9] Farmaco, 1999, vol. 54, # 9, p. 600 - 610
[10] Patent: WO2015/105779, 2015, A1, . Location in patent: Page/Page column 18; 19
[11] Patent: US2016/333005, 2016, A1, . Location in patent: Paragraph 0069-0070
[12] Journal of the American Chemical Society, 2013, vol. 135, # 50, p. 18778 - 18781
[13] Journal of Medicinal Chemistry, 1995, vol. 38, # 10, p. 1608 - 1628
[14] Patent: WO2008/20203, 2008, A1, . Location in patent: Page/Page column 70
[15] Patent: WO2008/18827, 2008, A1, . Location in patent: Page/Page column 37-38
[16] Patent: US2002/193410, 2002, A1,
[17] Patent: WO2010/10184, 2010, A1, . Location in patent: Page/Page column 61; 62; 98
[18] Patent: US2012/157383, 2012, A1, . Location in patent: Page/Page column 84
[19] Patent: US2013/109639, 2013, A1, . Location in patent: Paragraph 0407-0408
[20] Patent: WO2013/55984, 2013, A1, . Location in patent: Paragraph 00356
[21] Patent: WO2014/125408, 2014, A2, . Location in patent: Page/Page column 27
[22] Patent: US2017/137385, 2017, A1, . Location in patent: Paragraph 0230; 0231; 0232; 0233
[23] Patent: WO2018/98499, 2018, A1, . Location in patent: Page/Page column 165
  • 19
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  • [ 101184-73-0 ]
Reference: [1] Patent: US6358974, 2002, B1,
[2] Patent: US6541505, 2003, B1,
[3] Journal of Medicinal Chemistry, 2015, vol. 58, # 4, p. 1669 - 1690
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  • [ 16532-79-9 ]
  • [ 847361-67-5 ]
Reference: [1] Patent: WO2006/133559, 2006, A1,
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  • [ 16532-79-9 ]
  • [ 258515-65-0 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 18, p. 3050 - 3056
  • 22
  • [ 16532-79-9 ]
  • [ 107-04-0 ]
  • [ 345965-52-8 ]
YieldReaction ConditionsOperation in experiment
82%
Stage #1: With N-benzyl-N,N,N-triethylammonium chloride; potassium hydroxide In water at 50℃; for 3 h;
Stage #2: at 100℃; for 72 h;
A solution of 4-bromophenylacetonitrile (50.0 g, 255 mmol), 1-bromo-2-chloroethane (26.5 mL, 319 mmol), benzyltriethylammonium chloride (1.16 g, 5.10 mol), and potassium hydroxide (100 g, 1.79 mol) in water (100 mL) was stirred at 50°C for 3 h. Ethanol (400 mL) was added to the reaction mixture, and the mixture was stirred at 100°C for 3 days. The reaction mixture was neutralized by pouring it into 5 N hydrochloric acid (360 mL) with ice cooling. The reaction mixture was extracted with dichloromethane, the organic layer was dried with anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the residue, and the precipitate was collected by filtration and dried under reduced pressure to obtain the title compound (50.4 g, 82percent) as a white solid. 1H-NMR (500 MHz, CDCl3) δ: 1.23 (2H, q, J = 3.7 Hz), 1.67 (2H, q, J = 3.7 Hz), 7.22 (2H, dt, J = 8.6, 2.2 Hz), 7.43 (2H, dt, J = 8.6, 2.2 Hz)
Reference: [1] Patent: EP2700643, 2014, A1, . Location in patent: Paragraph 0200
  • 23
  • [ 16532-79-9 ]
  • [ 106-93-4 ]
  • [ 345965-52-8 ]
YieldReaction ConditionsOperation in experiment
51% With N-benzyl-N,N,N-triethylammonium chloride; sodium hydroxide In water at 70 - 150℃; for 22 h; Step 1 : Preparation of l-(4-bromophenyl)cyclopropanecarboxylic acid To a mixture of 4-bromophenylacetonitrile (5.0 g, 25.44 mmol) and benzyltriethylammonium chloride (144.9 mg, 0.63 mmol) was added 1,2-dibromoethane (7.45 mL, 86.5 mmol). The reaction mixture was heated to 70 °C followed by dropwise addition of 50percent aqueous sodium hydroxide solution (25 mL). The reaction mixture was heated at 70 °C for 7 h and then heated at 150 °C for 15 h. After the completion of reaction as confirmed by TLC, the reaction mixture was diluted with diethyl ether ( 100 mL). The aqueous layer was separated and acidified with 50percent aqueous HCl to pH 1. The crude compound was diluted with ethyl acetate (500 mL). The organic layer was separated, washed with water (2 x 10 mL), dried over Na2S04 and concentrated to afford title compound (3.1 g, 51 percent) as a solid. ESIMS (m/z): 241.5 (M-l )
51% With N-benzyl-N,N,N-triethylammonium chloride; sodium hydroxide In water at 70 - 150℃; for 22 h; Step 1:
Preparation of 1-(4-bromophenyl)cyclopropanecarboxylic acid
To a mixture of 4-bromophenylacetonitrile (5.0 g, 25.44 mmol) and benzyltriethylammonium chloride (144.9 mg, 0.63 mmol) was added 1,2-dibromoethane (7.45 mL, 86.5 mmol).
The reaction mixture was heated to 70 °C followed by dropwise addition of 50percent aqueous sodium hydroxide solution (25 mL).
The reaction mixture was heated at 70 °C for 7 h and then heated at 150 °C for 15 h.
After the completion of reaction as confirmed by TLC, the reaction mixture was diluted with diethyl ether (100 mL).
The aqueous layer was separated and acidified with 50percent aqueous HCl to pH 1.
The crude compound was diluted with ethyl acetate (500 mL).
The organic layer was separated, washed with water (2 x 10 mL), dried over Na2SO4 and concentrated to afford title compound (3.1 g, 51 percent) as a solid.
ESIMS (m/z): 241.5 (M-1)
Reference: [1] Patent: WO2013/38429, 2013, A2, . Location in patent: Page/Page column 75-76
[2] Patent: EP2755722, 2017, B1, . Location in patent: Paragraph 0180
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Reference: [1] Patent: US2011/82164, 2011, A1,
[2] Patent: WO2012/78593, 2012, A2,
[3] Patent: US2011/82181, 2011, A1,
[4] Patent: WO2012/78805, 2012, A1,
[5] Patent: US2012/258987, 2012, A1,
[6] Patent: WO2013/25733, 2013, A1,
[7] Patent: WO2013/189865, 2013, A1,
[8] Patent: EP2738174, 2014, A2,
[9] Patent: US2014/163226, 2014, A1,
[10] Advanced Synthesis and Catalysis, 2018, vol. 360, # 22, p. 4306 - 4311
  • 25
  • [ 16532-79-9 ]
  • [ 1032350-06-3 ]
Reference: [1] Patent: US2014/5185, 2014, A1,
[2] Patent: EP2868660, 2015, A1,
[3] Patent: US2015/266876, 2015, A1,
  • 26
  • [ 16532-79-9 ]
  • [ 1032528-06-5 ]
Reference: [1] Patent: US2014/5185, 2014, A1,
[2] Patent: EP2868660, 2015, A1,
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  • [ 1236357-65-5 ]
Reference: [1] Patent: WO2012/82817, 2012, A1,
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  • [ 943751-93-7 ]
Reference: [1] Patent: WO2010/17048, 2010, A1, . Location in patent: Page/Page column 35-36
  • 29
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  • [ 1215205-50-7 ]
Reference: [1] Patent: US2011/82164, 2011, A1,
[2] Patent: WO2012/78593, 2012, A2,
[3] Patent: US2011/82181, 2011, A1,
[4] Patent: WO2012/78805, 2012, A1,
[5] Patent: US2012/258987, 2012, A1,
  • 30
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  • [ 1257213-52-7 ]
Reference: [1] Patent: US2011/82164, 2011, A1,
[2] Patent: WO2012/78593, 2012, A2,
[3] Patent: US2011/82181, 2011, A1,
[4] Patent: WO2012/78805, 2012, A1,
[5] Patent: US2012/258987, 2012, A1,
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