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[ CAS No. 2675-89-0 ] {[proInfo.proName]}

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Product Details of [ 2675-89-0 ]

CAS No. :2675-89-0 MDL No. :MFCD00039360
Formula : C4H8ClNO Boiling Point : -
Linear Structure Formula :- InChI Key :XBPPLECAZBTMMK-UHFFFAOYSA-N
M.W : 121.57 Pubchem ID :75886
Synonyms :

Calculated chemistry of [ 2675-89-0 ]

Physicochemical Properties

Num. heavy atoms : 7
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.75
Num. rotatable bonds : 2
Num. H-bond acceptors : 1.0
Num. H-bond donors : 0.0
Molar Refractivity : 29.23
TPSA : 20.31 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.79 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.4
Log Po/w (XLOGP3) : 0.35
Log Po/w (WLOGP) : 0.31
Log Po/w (MLOGP) : 0.49
Log Po/w (SILICOS-IT) : 0.18
Consensus Log Po/w : 0.55

Druglikeness

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

Water Solubility

Log S (ESOL) : -0.68
Solubility : 25.3 mg/ml ; 0.208 mol/l
Class : Very soluble
Log S (Ali) : -0.34
Solubility : 55.5 mg/ml ; 0.456 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -0.91
Solubility : 14.9 mg/ml ; 0.122 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.11

Safety of [ 2675-89-0 ]

Signal Word:Danger Class:8
Precautionary Statements:P261-P280-P305+P351+P338-P310 UN#:3265
Hazard Statements:H302-H314 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 2675-89-0 ]

* 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.

  • Downstream synthetic route of [ 2675-89-0 ]

[ 2675-89-0 ] Synthesis Path-Downstream   1~83

  • 2
  • [ 75-04-7 ]
  • [ 2675-89-0 ]
  • [ 97454-95-0 ]
  • 3
  • [ 124-40-3 ]
  • [ 79-04-9 ]
  • [ 2675-89-0 ]
YieldReaction ConditionsOperation in experiment
93.1% With sodium hydrogencarbonate; In toluene; at -2 - 5℃; for 1h; In a 500 mL four-necked flask, sodium hydrogen carbonate 126.0 g (1.50 mol) and 146.8 g of toluene were added, and the mixture was stirred while cooling. The internal temperature was maintained below 5 C, 112.9 g (1.00 mol) of chloroacetyl chloride was added dropwise over 4 hours, and 49.6 g (1.10 mol) of dimethylamine gas was blown over 4 hours. After stirring at -2 to 1 C. for 1 hour, the reaction solution was filtrated under reduced pressure to remove inorganic salt crystals by filtration. The crystals were washed with 100 g of toluene, the filtrate and washings were combined. After separating and removing the aqueous layer in the filtrate washings, the toluene layer was concentrated under reduced pressure to obtain 113.2 g (0.93 mol) of oily 2-chloro-N,N-dimethylacetamide. The yield was 93.1%. The purity (GC area%) was 99.5%.
48% With potassium carbonate; In tetrahydrofuran; dichloromethane; at -20℃; for 1h; To a solution of dimethylamine 33-2 (2M in THF, 1.99 g, 44.2 mmol) in dichloromethane (40 nil.) was added K2CO3 (12.2 g, 88.5 mmol) followed by chloroacetyl chloride 33-1 (3.5 mL, 44.2 mmol) drop- wise at -20 C. The reaction mixture was allowed to stir at same temperature for Ih The reaction mass was diluted with ethyl acetate (200 mL), washed with water (2 X 150 mL), dried over sodium sulfate and concentrated under reduced pressure to give product 33-3 as a pale yellow wax 2.6 g (0931) (48%).
In benzene; for 1h;Reflux; General procedure: Chloroacetyl chloride 13 (0.06 mol, 4.0 ml) was added dropwise into the solution of imine (4a-4c) (0.06 mol) in benzene (20 ml) at 10 C. 30 min later, this mixture was refluxed gently for 1 h and then allowed to cool to room temperature. The organic layer was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by vacuum distillation to afford the imino chlorides (14a-14c) which were then used directly in the next step.
In dichloromethane; at -10 - 5℃; for 1h;pH 4 - 7; (1) 160 g of methylene chloride was first added to the reaction vessel and stirred, Cool to -10-0 C and start dropping 51g of 50% dimethylamine solution and 30 g of chloroacetyl chloride. The temperature was controlled at -10-5C and pH at 4-7. After the dropwise addition, the reaction was carried out at -10-5 C for 1 hour. Reaction process control pH5-7,After the reaction was allowed to stand for 20 min,The organic layer was concentrated under reduced pressure, and the concentration was 80 C or less. After the completion of the concentration, the mixture was distilled under reduced pressure at 130C to obtain N,N-dimethyl-2-chloroacetamide distillate.
31 g In dichloromethane; water; at 5 - 10℃; for 1.33h;pH 4 - 7; (1), 160 g of methylene chloride DCM was added to the reaction vessel and stirred, cooled and cooled to 0 to 10 C. A drop of 51 g of 50% aqueous dimethylamine was added dropwise while 30 g of chloroacetyl chloride was added dropwise; dropping the process control temperature 5 ~ 10 , the system pH control in 4-7, after the drop in the 5 - 10 reaction 1h, the reaction process pH control in 5-7, after the end of the reaction for 20min, liquid, water to 54g Dichloromethane, and the organic layer was concentrated under reduced pressure at 80 C to obtain crude N, N-dimethylchloroacetamide. The crude N, N-dimethylchloroacetamide was distilled under reduced pressure at 130 C to obtain N , N-dimethylchloroacetamide distillate; yield 31 g
With triethylamine; at 0 - 20℃; for 4h; General procedure: In a round bottom flask, primary or secondary amines (0.1 mol) and triethyl amine weredissolved in DCM and stirred at 0 C. 2-Chloroacetyl chloride (0.1 mol) was added to reaction mixture drop wise with continuous stirring on magnetic stirrer. After the addition,the ice bath was removed and the reaction mixture was stirred at room temperature for 4 h.The progress of the reaction was monitored by TLC using ethyl acetate: hexane (1:9) as asolvent system. After completion of the reaction, the reaction mixture was poured on crushedice and neutralised by adding acetic acid to it. The obtained solid intermediates of respectiveamines were filtered, dried and crystallised in ethanol.

  • 4
  • [ 122-52-1 ]
  • [ 2675-89-0 ]
  • [ 3842-86-2 ]
YieldReaction ConditionsOperation in experiment
78% at 165℃; for 5.5h;
76% at 110 - 115℃; Inert atmosphere; 7 Example 7: Diethyl f2-fdimethylamino)-2-oxoethyl)phosphonate To a 500-ml 3-neck RB flask was charged triethylphosphite (284.0 g, 1674 mmol), heated to 110°C - 115°C with N2 swept through head space. 2-Chloro-N,N- dimethylacetamide was added dropwise over 3 h to 4 h at 110-115°C. The reaction mixture was aged 2 h at this temperature then concentrated under vacuum to yield desired product (313.4 g, AY=76%) as yellow oil.
20% at 150℃; 8.1 8.1 Synthesis of Intermediate 21 8.1 Synthesis of Intermediate 21A mixture of 2-chloro-N,N-dimethylacetamide (300 mg, 2.47 mmol) and triethyl phosphite (820 mg, 4.94 mmol) was stirred at 150° C. overnight. The reaction mixture was cooled to room temperature and was purified by Prep HPLC to give intermediate 21 (105 mg, 20%).
at 140 - 190℃;
4.5 g at 160℃; for 8h; Inert atmosphere; A mixture of 2-chloro-N,N-dimethylacetamide (5.0 g, 41.1 mmol) and triethyl phosphite (6.83 g, 41.1 mmol) was degassed and purged with N2 for 3 times. The mixture was stirred at 160 °C for 8 h under N2atmosphere. The mixture was concentrated and purified by column chromatography to provide diethyl (2-(dimethylamino)-2- oxoethyl)phosphonate (I-35) (4.5 g) as a yellow oil. LCMS m/z 224.3 (M+1)+.1H NMR (400 MHz, CDCl3) ^ 4.20-4.12 (m, 4H), 3.11 (s, 3H), 3.07-3.01 (d, J = 22 Hz, 2H), 2.97 (s, 3H), 1.35-1.31 (t, J = 7.2 Hz, 6H).

  • 5
  • [ 3247-00-5 ]
  • [ 2675-89-0 ]
  • [ 41858-34-8 ]
YieldReaction ConditionsOperation in experiment
With sodium hydride In diethyl ether Ambient temperature;
  • 6
  • [ 26816-97-7 ]
  • [ 2675-89-0 ]
  • [ 23703-80-2 ]
YieldReaction ConditionsOperation in experiment
With potassium hydroxide
  • 7
  • [ 506-59-2 ]
  • [ 79-04-9 ]
  • [ 2675-89-0 ]
YieldReaction ConditionsOperation in experiment
77% With triethylamine; In dichloromethane; at 15℃; Step A: 2-Chloroacetyl chloride (3.00 g, 26.6 mmol, 1.6 eq.), dimethylamine hydrochloride (2.38 g, 29.2 mmol, 1.1eq.) and triethylamine (8.0 g, 79.7 mmol, 3.0eq.) were added to DCM (30 mL). The mixture was stirred at 15C for3 hours. The reaction mixture was poured into water (30 mL) and extracted with DCM (50 mL 3 2). The organicphase was washed with dilute hydrochloric acid (30 mL 3 2, 1 M), dried over anhydrous Na2SO4 and concentratedin vacuum to give 2-chloro-N,N-dimethylacetamide (2.5 g, 20.6 mmol, 77% yield) as a yellow oil.
62% With triethylamine; In dichloromethane; at 0℃; for 3h; General procedure: Chloroacetyl chloride (3 equiv.) was added dropwise to a stirring mixture of dimethylamine hydrochloride (1 equiv.) and triethylamine (1.1 equiv.) in an ice bath. The reaction was allowed to stir further in the ice bath for 3 h before 40 mL of water was added for quenching the reaction. The aqueous layer was extracted with 50 mL of dichloromethane (DCM) twice and the combined organic layer was washed three times with 50mL of 1M hydrochloric acid. The organic layer was concentrated in vacuo before being dispersed in diethyl ether and stirred overnight. Solid precipitate was filltered away and the organic layer was reconcentrated in vacuo to aord the purified 2-chloro-N,N-dimethylacetamide(11) as a liquid. 7-nitroindole (1 equiv.) was dissolved in a neat solution of 11 (5 equiv.). The mixture was stirred under argon in an ice bath. Phosphorus oxychloride (2 equiv.) was added dropwise into the reaction mixturein the ice bath. The reaction mixture was allowed to stir overnight at room temperature. The reaction was neutralized with 4 mL of 2M aqueous sodium hydroxide solution. The aqueous layer was extracted with 10mL of EA three times. Combined organic layers were washed with 30 mL saturated sodium bicarbonate twice. The organic layer was dried over anhydrous sodium sulphate and concentrated in vacuo. Residue obtained was purified with column chromatography (EA: Hexane = 1:100-1:4) to givepure 2-chloro-1-(7-nitro-1H-indol-3-yl)ethanone (12). 2-Chloro-N,N-dimethylacetamide (11): Dark brownish liquid, yield: 62%. 1H NMR (400 MHz, CDCl3): = 3.86 (s, 1 H), 2.81 (s, 3 H), 2.67 (s, 3 H). 13C NMR (CDCl3): = 166.06, 40.84, 36.92, 35.31.
With triethylamine; In dichloromethane; at 20℃; for 6h; Step 1 A dichlorometane (200 mL) solution of dimethylamine hydrochloride (10.2 g, 128 mmol) was added with triethylamine (35.0 mL, 251 mmol), chloroacetylchloride (10.0 mL, 126 mmol), followed by stirring st room temperature for 6 hours. The reaction mixture was filtered and the filtrate was concentrated to obtain N,N-dimethylchloroacetamide (15.2 g). 1H-NMR (270 MHz, CDCl3) delta 2.99 (s, 3H), 3.10 (s, 3H), 4.09 (s, 2H).
With triethylamine; In dichloromethane; at 0℃; for 4h; General procedure: Dimethylammonium chloride (4.08 g, 50 mmol) and triethylamine (10.1 g, 100 mmol) were dissolved in dichloromethane (50 mL). Chloroacetyl chloride (6.78 g, 60 mmol) was added dropwise under stirring at 0 C. The resulting solution was stirred at 0 C for 4 h. After washing with water (30mL×3),dryingoverNa2SO4,andremovingthesolvent,thecrudeN,N-dimethyl-2-chloroacetamide was obtained and used directly in the next step [34]. To a solution of diphenylamine (8.45 g, 50 mmol) or N-methylaniline (5.35 g, 50 mmol) in dry toluene (30 mL), chloroacetyl chloride (5.65 g, 50 mmol) was added dropwise under stirring. The resulting solution was reuxed for 4 h. After removal of solvent under reduced pressure, the crude product was obtained and used directly in the next step [34].

  • 8
  • [ 69-57-8 ]
  • [ 2675-89-0 ]
  • (2S,5R,6R)-3,3-Dimethyl-7-oxo-6-phenylacetylamino-4-thia-1-aza-bicyclo[3.2.0]heptane-2-carboxylic acid dimethylcarbamoylmethyl ester [ No CAS ]
  • 9
  • [ 23981-47-7 ]
  • [ 2675-89-0 ]
  • N,N-dimethylcarbamoylmethyl (6-methoxy-2-naphthyl)acetate [ No CAS ]
  • 10
  • [ 176022-47-2 ]
  • [ 2675-89-0 ]
  • [ 182009-51-4 ]
  • 11
  • [ 10514-70-2 ]
  • [ 2675-89-0 ]
  • 2-(2,2-Dimethyl-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-N,N-dimethyl-acetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
65% With sodium hydride In N,N-dimethyl-formamide for 3h; Ambient temperature;
  • 12
  • [ 7652-29-1 ]
  • [ 2675-89-0 ]
  • [ 26509-18-2 ]
YieldReaction ConditionsOperation in experiment
70% With sodium hydride In N,N-dimethyl-formamide for 3h; Ambient temperature;
  • 13
  • [ 81721-87-1 ]
  • [ 2675-89-0 ]
  • N,N-Dimethyl-2-(6-nitro-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-acetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
70% With sodium hydride In N,N-dimethyl-formamide for 3h; Ambient temperature;
  • 14
  • [ 85160-84-5 ]
  • [ 2675-89-0 ]
  • 2-(2,2-Dimethyl-6-nitro-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-N,N-dimethyl-acetamide [ No CAS ]
  • 15
  • [ 134997-74-3 ]
  • [ 2675-89-0 ]
  • [ 221225-63-4 ]
  • 16
  • [ 4394-00-7 ]
  • [ 2675-89-0 ]
  • N,N-dimethylcarbamoylmethyl 2-[3-(trifluoromethyl)anilino]nicotinic ester [ No CAS ]
  • 17
  • [ 6959-66-6 ]
  • [ 2675-89-0 ]
  • S-[2-(4-methyl)pyrimidinyl]thioglycolic acid, N,N-dimethylamide [ No CAS ]
  • 18
  • [ 274-47-5 ]
  • [ 109-72-8 ]
  • [ 108-18-9 ]
  • [ 2675-89-0 ]
  • [ 358780-16-2 ]
YieldReaction ConditionsOperation in experiment
62% With hydrogenchloride; In tetrahydrofuran; hexane; b) Reaction under N2 atmosphere. Tetrahydrofuran (700 ml) was cooled to -70 C. n-Butyllithium 2.5M in hexane (100 ml) was added. A solution of N-(1-methylethyl)-2-propanamine (0.22 mol) in tetrahydrofuran (100 ml) was added dropwise at -70 C., then warmed slowly to -40 C. and stirred for 30 minutes at 40 C. The reaction mixture was re-cooled to -70 C. A solution of <strong>[274-47-5]imidazo[1,5-a]pyridine</strong> (0.2 mol) in tetrahydrofuran (100 ml) was added dropwise and the reaction mixture was stirred for 2 hours, allowing the temperature to rise to +--30 C. The reaction mixture was re-cooled to -70 C. A solution of N,N-dimethyl-2-chloroacetamide (0.22 mol) in tetrahydrofuran (100 ml) was added dropwise. The cooling bath was removed and the reaction mixture was stirred until the temperature reached +-0 C. The reaction mixture was cooled, decomposed with ice and 2N HCl. The layers were separated. The water layer was extracted twice with ethyl acetate. The separated organic layer was dried, filtered and the solvent evaporated. Yield: 24 g of 2-chloro-1-(imidazo[1,5-a]pyridin-3-yl)ethanone (62%) (interm. 8).
  • 19
  • [ 224624-80-0 ]
  • [ 2675-89-0 ]
  • (R)-1-{6-[(R)-2-(dimethylcarbamoyl-methoxycarbonyl)-pyrrolidin-1-yl]-6-oxo-hexanoyl}-pyrrolidine-2-carboxylic acid dimethylcarbamoyl-methyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
190 mg (84%) With sodium iodide; triethylamine; In N-methyl-acetamide; EXAMPLE 6 (R)-1-{6-[(R)-2-(Dimethylcarbamoyl-methoxycarbonyl)-pyrrolidin-1-yl]-6-oxo-hexanoyl}-pyrrolidine-2-carboxylic acid dimethylcarbamoyl-methyl ester To a solution of 170 mg (0.5 mmol) <strong>[224624-80-0](R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]-pyrrolidine-2-carboxylic acid</strong> and 103 ml (1 mmol) 2-chloro-N,N-dimethylacetamide in 2.5 ml dimethylformamide were added 14.9 mg (0.1 mmol) sodium iodide and 139 ml (1 mmol) triethylamine. After stirring overnight at 100 C. the solvent was distilled off, the residue was taken up with dichloromethane and extracted with water. The organic extracts were dried with sodium sulfite and the solvent was distilled off to yield 190 mg (84%) of (R)-1-{6-[(R)-2-(dimethylcarbamoyl-methoxycarbonyl)-pyrrolidin -1-yl]-6-oxo-hexanoyl}-pyrrolidine-2-carboxylic acid dimethylcarbamoyl-methyl ester as a yellow oil, MS m/e (%): 511 (M+H+, 100).
  • 20
  • [ 24985-85-1 ]
  • [ 2675-89-0 ]
  • [ 380240-85-7 ]
  • 5-dimethylcarbamoylmethoxy-1H-indole-2-carboxylic acid ethyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
With caesium carbonate; In N-methyl-acetamide; Example 1 Preparation of 5-(2-dimethylamino-ethoxy)-1H-indole 2-carbaldehyde A mixture of <strong>[24985-85-1]5-hydroxy-1H-indole-2-carboxylic acid ethyl ester</strong> (2 g, 10 mmol), 2-chloro-N,N-dimethylacetamide (1.33 g, 11 mmol) and cesium carbonate (9.8 g, 30 mmol)) in dimethylformamide (20 mL) was stirred at room temperature for 16 hours. The reaction was diluted with ethyl acetate (150 mL), washed with water (5*50 mL) and brine, dried and concentrated. The residue was recrystallized from ethyl acetate and hexane to give 1.4 g of 5-dimethylcarbamoylmethoxy-1H-indole-2-carboxylic acid ethyl ester as a brown solid. 1H-NMR (300 MHz, DMSO-d6)delta 11.74 (s, br, 1H, NH), 7.33 (d, J=9.0 Hz, 1H, H-7), 7.06 (d, J=2.4 Hz, 1H, H-4), 7.01 (d, J=1.5 Hz, 1H, H-3), 6.94 (dd, J=2.4 & 9.0 Hz, 1H, H-6), 4.74 (s, 2H, OC2CON(CH3)2, 4.31 (q, J=7.1 Hz, 2H, OC2CH3), 3.0 (s, 3H, NCH3), 2.83 (s, 3H, NCH3), 1.32 (t, J=7.1 Hz, 3H, OCH2C3). MS-EI m/z 290 [M+].
  • 21
  • ethereal hydrogen chloride [ No CAS ]
  • [ 74050-98-9 ]
  • [ 2675-89-0 ]
  • [ 298696-31-8 ]
YieldReaction ConditionsOperation in experiment
With NaH In N,N-dimethyl-formamide; mineral oil 16 2-[3-{2-[4-(4Fluorobenzoyl)-1-piperidinyl]ethyl}-2,4-dioxo-3,4-dihydro-1(2H)-quinazolinyl]-N,N-dimethylacetamide hydrochloride EXAMPLE 16 2-[3-{2-[4-(4Fluorobenzoyl)-1-piperidinyl]ethyl}-2,4-dioxo-3,4-dihydro-1(2H)-quinazolinyl]-N,N-dimethylacetamide hydrochloride 3-{2-[4-(4-Fluorobenzoyl)-1-piperidinyl]ethyl}-2,4(1H,3H)-quinazolinedione was dissolved in DMF (5 ml) and NaH (60% dispersion in mineral oil) added. After 0.5 hours, 2-chloro-N,N-dimethylacetamide was added and the solution stirred at room temperature for 16 hours. Water and ethyl actetate were added, the organic phase separated, dried and concentrated to an oil. Purification by chromatography (dichloromethane:methanol 95:5) gave an oil which was treated with 1.0 M ethereal hydrogen chloride solution to give the titled product as a solid(0.015 g). MS: ESI 481.22 (M+H) 1H NMR: δ(DMSO) 8.08 (m,3H), 7.76 (t, 1H), 7.40 (t, 2H), 7.32 (m, 2H), 5.05 (s, 2H), 4.36 (m, 1H), 3.76 (m, 3H), 3.39 (m, 2H), 3.15 (s, 3H), 2.87 (s, 3H), 2.02 (m, 2H), 1.81 (m, 2H), 1.28 (m,2H)
  • 22
  • [ 5106-98-9 ]
  • [ 2675-89-0 ]
  • [ 298699-02-2 ]
YieldReaction ConditionsOperation in experiment
With caesium carbonate In water; ethyl acetate 1.v (v) (v) 2-(Dimethylamino)-2-oxoethyl 4-chloro-2-[2-(dimethylamino)-2-oxoethoxy]benzoate A mixture of 4-chloro-2-hydroxybenzoic acid (5 g), Cs2CO3 (17.5 g) and 2-chloro-N,N-dimethylacetamide (6.6 g) was stirred and heated at 70° C. for 3 hours. Water and ethyl acetate were added, the organic phase separated, dried and concentrated to a gum which was purified by chromatography (ethyl acetate:methanol, 9:1) to give the sub-titled product as a solid (8.0 g). MS: APCI(+ve) 343(M+H)
With caesium carbonate In water; ethyl acetate 1.a (a) (a) 2-(Dimethylamino)-2-oxoethyl 4-chloro-2-[2-(dimethylamino)-2-oxoethoxy]benzoate A mixture of 4-chloro-2-hydroxybenzoic acid (5 g), cesium carbonate (17.5 g) and 2-chloro-N,N-dimethylacetamide (6.6 g) was stirred and heated at 70° C. for 3 hours. Water and ethyl acetate were added, the organic phase separated, dried and concentrated to give a gum which was purified by chromatography (ethyl acetate:methanol 9:1) to give the product as a solid (8.0 g), m.p. 140-141° C. MS: APCI(+ve) 343(M+H).
  • 23
  • 3-(4-chloro-3-methoxyphenyl)-8-[4-hydroxy-2,3-dimethylbenzyl]-8-azabicyclo[3.2.1]octan-3-ol [ No CAS ]
  • [ 2675-89-0 ]
  • 2-(4-[3-(4-chloro-3-methoxyphenyl)-3-hydroxy-8-azabicyclo[3.2.1]oct-8-yl]methyl}-2,3-dimethylphenoxy)-N,N-dimethylacetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
81% With caesium carbonate;sodium iodide; In N,N-dimethyl-formamide; at 60℃; EXAMPLE 3. SYNTHESIS OF 2-(4-([3-(4-CHLORO-S-METHOXYPHENYL)^-HYDROXY-S-AZABICYCLO[3.2.1]OCT-8-YL]METHYL}-2,3-DIMETHYLPHENOXY)-N,N-DIMETHYLACETAMIDE; To a solution of 3-(4-chloro-3-memoxyphenyl)-8-(4-hydroxy-2,3-dimethylbenzyl)-8- azabicyclo[3.2.1]octan-3-ol obtained in step 4, Example 2, (20 mg, 0.05 mmol) in anhydrous DMF (1 mL) is added Cs2CO3 (24.2 mg, 0.075 mmol), followed by <strong>[2675-89-0]2-chloro-N,N-dimethylacetamide</strong> (0.06 mmol) and catalytic amounts of NaI. The mixture is heated at 6O0C overnight. The reaction is then cooled to room temperature, diluted with ethyl acetate, washed with water, brine, dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by preparative TLC (CH2Cl2/MeOH/NH4OH: 95/5/1) to furnish 2-(4-[3-(4-chloro-3-methoxyphenyl)-3-hydroxy-8- azabicyclo[3.2.1]oct-8-yl]methyl}-2,3-dimethylphenoxy)-N,N-dimethylacetamide as a yellow oil (19.7 mg, 81%): 1H NuMR (CDCl3) delta 7.21 (d, IH), 6.99-7.00 (m, 2H), 6.88 (d, IH), 6.59 (d, IH), 4.60 (s, 2H), 3.83 (s, 3H), 3.42 (s, 2H), 3.18 (s, IH), 3.03 (s, 3H), 2.91 (s, 3H), 2.28 (s, 3H), 1.68-2.34 (m, 13H); LC-MS m/z: 487.
  • 24
  • [ 175838-58-1 ]
  • [ 70384-51-9 ]
  • [ 2675-89-0 ]
  • [ 191356-31-7 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In dichloromethane; di-isopropyl ether; acetonitrile; Example 5 3.51 g (0.01 mol) of 2-(2,6-difluorophenyl)-4-(4'-hydroxybiphenyl-4-yl)-1,3-oxazoline and 1.38 g (0.01 mol) of potassium carbonate are suspended in 50 ml of acetonitrile and, after addition of three drops of tris(3,6-dioxaheptyl)amine (TDA), 1.2 g (0.01 mol) of 2-chloro-N,N-dimethyl-acetamide are added. The reaction mixture is stirred at 80° C. for 20 hours and then concentrated. The residue is taken up in 100 ml of methylene chloride and the mixture is washed with water, dried over sodium sulfate and concentrated. The residue is stirred with diisopropyl ether and the mixture is concentrated. 2.4 g (55percent of theory) of 2-(2,6-difluorophenyl)-4-(4'-dimethylaminocarbonylmethyloxy-biphenyl-4-yl)-1,3-oxazoline of melting point 78-80° C. are obtained.
  • 25
  • [ 2675-89-0 ]
  • [ 928341-71-3 ]
YieldReaction ConditionsOperation in experiment
73% NaH (1.4 eq., 60 % dispersion in mineral oil) was added to a solution of methyl 13-cyclohexyl-6-oxo-6,7- dihydro-5H-indolo[l,2-d][l,4]benzodiazepine-10-carboxylate (from Step 3) in DMF (0.15 M) and the solution was allowed to stir at RT for 45 min. Then 2-chloro-N.N-dimethylacetamide (1.1 eq.) was added and the mixture stirred at RT for 20 min. RP-HPLC analysis showed the absence of starting material with desired product as the main peak. The solution was diluted with EtOAc and washed with IN HCl. The aqueous phase was extracted with EtOAc (x3) and the combined organics washed with brine, dried over Na2SO4, filtered and the solvent evaporated in vacuo. The crude product was purified by flash chromatography (Biotage cartridge Sil2M, 9: 1 EtOAc/PE) to give the title compound (73 %). 1H NMR (400 MHz, DMSO-fik, 300 K) delta 1.15-1.23 (m, IH), 1.35-1.48 (m, 2H), 1.55-1.61 (m, IH) 1.70-1.77 (m, 2H), 1.85-2.11, (m, 4H), 2.46-2.51 (m, IH partially obscured by DMSO peak), 2.82 (s, 3H), 2.90 (s, 3H), 3.89 (s, 3H), 4.42 (d, J 16.8, IH), 4.49 (d, J 14.6, IH), 4.66 (d, J 16.8, IH), 5.20 (d, J 14.6, IH), 7.42-7.49 (m, 2H), 7.52-7.68 (m, 2H), 7.69 (d, J 8.8, IH), 7.96 (d, J 8.8, IH), 8.29 (s, IH); MS (ES+) m/z 474(M+H)+
  • 26
  • [ 1635-84-3 ]
  • [ 2675-89-0 ]
  • [ 939018-67-4 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 120 - 130℃; for 21h; A mixture of 2,4-dimethyl-6-nitroaniline (5.00 g, 30.1 mmol), 2-chloro-[Lambda][zeta]iV- dimethylacetamide (18.3 g, 150 mmol), K2CO3 (6.24 g, 45.2 mmol), and KI (499 mg, 3.01 mmol) in DMF. (100 mL) was heated at 120<0>C for 7 h, then at 130 <0>C for 14 h. The cooled mixture was quenched with H2O (200 mL) and extracted with CH2Cl2 (3 x 150 mL). The combined organic layers were dried over Na2S[theta]4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc - 100:0 to 50:50, to give the title compound. MS: mlz = 252 (M + 1).
With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 120 - 130℃; for 21h; A mixture of 2,4-dimethyl-6-nitroaniline (5.00 g, 30.1 mmol), 2-chloro-N,N- dmethylacetamide (18.3 g, 150 mmol), K2CO3 (6.24 g, 45.2 mmol), and KI (499 mg, 3.01 mmol) in DMF (100 mL) was heated at 120 0C for 7 h, then at 130 0C for 14 h. The cooled mixture was quenched with H?O (200 mL) and extracted with CH2CI2 (3 x 150 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexanerEtOAc - 100:0 to 50:50, to give the title compound. MS: m/z = 252 (M + 1).
  • 27
  • [ 56962-11-9 ]
  • [ 2675-89-0 ]
  • [ 937040-24-9 ]
YieldReaction ConditionsOperation in experiment
69% With caesium carbonate;sodium iodide; In N,N-dimethyl-formamide; at 150℃; for 0.25h;Microwave; A microwave vial was charged with <strong>[56962-11-9]2-chloro-4-hydroxybenzaldehyde</strong> (50 mg, 0.319 mmol), N,N-dimethyl-2-chloroacetamide (36 uL, 0.35 mmol), cesium carbonate (312 mg, 0.957 mmol), and a few crystals of sodium iodide [potassium carbonate and potassium iodide are good substitutes for a base and catalyst, respectively]. DMF (1.5 mL) was added and the reaction mixture was run on a Personal Chemistry microwave reactor at 150° C. for 900 seconds. Cesium carbonate was filtered and the filtrate was adsorbed directly on silica gel. Purification on silica gel with 20-100percent gradient of EtOAc/Hexane as eluent provided 53 mg of 2-(3-chloro-4-formyl-phenoxy)-N,N-dimethyl-acetamide as a clear oil (69percent yield). 1H NMR (d6-DMSO) delta 10.2 (s, 1H), 7.80 (d, 1H), 7.16 (d, 1H), 7.03 (dd, 1H), 5.03 (s, 2H), 2.97 (s, 3H), 2.84 (s, 3H).
  • 28
  • [ 756839-56-2 ]
  • [ 311-28-4 ]
  • [ 2675-89-0 ]
  • [ 765914-91-8 ]
YieldReaction ConditionsOperation in experiment
12% With potassium carbonate In dichloromethane; N,N-dimethyl-formamide 134.A Preparation of 2-(5-{2-[3-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-ureidomethyl]-4-fluorophenoxy}-indazol-1-yl)-N,N-dimethylacetamide (47d) Step A: 2-[5-(2-Cyano-4-fluorophenoxy)-indazol-1-yl]-N,N-dimethylacetamide (45d): To a solution of 5-fluoro-2-(1H-indazol-5-yloxy)-benzonitrile (44d) (0.200 g, 0.790 mmol) in DMF (6 mL) was added 2-chloro-N,N-dimethylacetamide (0.115 g, 0.948 mmol) and tetrabutyl ammonium iodide (0.088 g, 0.237 mmol), followed by K2CO3 (0.164 g, 1.19 mmol). The mixture was heated to 11 0° C. for 48 hours under N2 atmosphere. The reaction mixture was concentrated under reduced pressure and dissolved in dichloromethane. The solution was washed with 1N HCl, filtered, and chromatographed on Biotage eluding with 5% MeOH in dichloromethane to afford 0.032 g of the product (12% yield).
  • 29
  • [ 1029026-09-2 ]
  • [ 2675-89-0 ]
  • [ 1029287-90-8 ]
YieldReaction ConditionsOperation in experiment
72% Example 2E. 2-(3-Cyano-4-(2,4-dichlorophenyl)-2-methyl-5-oxo-7,8-dihydro- l,6-naphthyridin-6(5H)-yl)-N,N-dimethylacetamide; [00159] To a suspension of NaH (60% in oil, 256 mg, 6.4 mmol) in 10 mL of DMF at 00C was added Example 2D (1.06 g, 3.2 mmol) dropwise in 30 mL of DMF. After the addition, the reaction was stirred for 10 min. Then there was added 2-chloro-N,N- dimethylacetamide (0.78 g, 6.4 mmol), and the reaction was stirred at room temperature for 3 h. The reaction was diluted with EtOAc, washed with water and brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography (elution with 0-100% EtOAc/hexane) to afford 695 mg (72%) of Example 2E as an oil. 1H NMR (500 MHz, CDCl3) delta 7.49 (s, IH), 7.37 (d, IH), <n="58"/>7.16 (d, IH), 4.50 and 4.10 (ABq, 2H), 3.76-3.70 (m, 2H), 3.46-3.32 (m, 2H), 2.95 (s, 3H), 2.93 (s, 3H), 2.85 (s, 3H). LRMS (ESI): 417.2 [M + H]+.
  • 30
  • [ 1032715-18-6 ]
  • [ 2675-89-0 ]
  • [ 1032715-21-1 ]
YieldReaction ConditionsOperation in experiment
72% To a stirred solution of 40 mg (0.10 mmol) of (5-chloro-1H-indol-2-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone in DMF (3 ml) at RT was added 5 mg (0.11 mmol) of NaH (in oil, 55%). After 20 minutes, 12 mg (0.10 mmol) of 2-chloro-N,N-dimethyl-acetamide was added and stirring was continued over night. The reaction mixture was concentrated in vacuo and purification by preparative HPLC (30% CH3CN/H2O) afforded 35 mg (72%) of 2-{5-chloro-2-[4-(2,6-dimethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide as a white solid.ES-MS m/e (%): 484.3 (M+H+).
  • 31
  • [ 1032189-21-1 ]
  • [ 2675-89-0 ]
  • [ 1032189-23-3 ]
YieldReaction ConditionsOperation in experiment
82% To a stirred solution of 60 mg (0.15 mmol) of 1'-[(5-chloro-1H-indol-2-yl)carbonyl]-3H-spiro[2-benzofuran-1,4'-piperidin]-3-one in DMF (4 ml) at RT was added 7 mg (0.16 mmol) of NaH (in oil, 55%). After 20 minutes, 19 mg (0.015 mmol) of 2-chloro-N,N-dimethyl-acetamide was added and stirring was continued over night. The reaction mixture was concentrated in vacuo and purification by preparative HPLC (30% CH3CN/H2O) afforded 60 mg (82%) of 2-{5-chloro-2-[(3-oxo-1'H,3H-spiro[2-benzofuran-1,4'-piperidin]-1'-yl)carbonyl]-1H-indol-1-yl}-N,N-dimethylacetamide as a white solid.ES-MS m/e (%): 466.3 (M+H+).
  • 32
  • [ 1032189-20-0 ]
  • [ 2675-89-0 ]
  • [ 1032189-22-2 ]
YieldReaction ConditionsOperation in experiment
96% To a stirred solution of 60 mg (0.15 mmol) of 1'-[(5-chloro-1H-indol-2-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4'-piperidin]-3-one in DMF (4 ml) at RT was added 7 mg (0.16 mmol) of NaH (in oil, 55%). After 20 minutes, 18 mg (0.015 mmol) of 2-chloro-N,N-dimethyl-acetamide was added and stirring was continued over night. The reaction mixture was concentrated in vacuo and purification by preparative HPLC (30% CH3CN/H2O) afforded 70 mg (96%) of 2-{5-chloro-2-[(5-fluoro-3-oxo-1'H,3H-spiro[2-benzofuran-1,4'-piperidin]-1'-yl)carbonyl]-1H-indol-1-yl}-N,N-dimethylacetamide as a white solid.ES-MS m/e (%): 484.5 (M+H+).
  • 33
  • (3RS,4RS)-N-[3,5-bis(trifluoromethyl)benzyl]-3-(4-fluoro-2-methylphenyl)-N-methylpiperidine-4-carboxamidehydrochloride [ No CAS ]
  • [ 2675-89-0 ]
  • (3R*,4R*)-N-[3,5-bis(trifluoromethyl)benzyl]-1-[2-(dimethylamino)-2-oxoethyl]-3-(4-fluoro-2-methylphenyl)-N-methylpiperidine-4-carboxamide monohydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
73% With triethylamine; sodium iodide; In N,N-dimethyl-formamide; at 20℃; for 16h; Reference Example 62 (3R*,4R*)-N-[3,5-bis(trifluoromethyl)benzyl]-1-[2-(dimethylamino)-2-oxoethyl]-3-(4-fluoro-2-methylphenyl)-N-methylpiperidine-4-carboxamide monohydrochlorideTo a solution of (3R*,4R*)-N-[3,5-bis(trifluoromethyl)benzyl]-3-(4-fluoro-2-methylphenyl)-N-methylpiperidine-4-carboxamide monohydrochloride (256 mg), <strong>[2675-89-0]2-chloro-N,N-dimethylacetamide</strong> (77 muL) and NaI (60 mg) in DMF (10 mL) was added Et3N (174 muL), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was poured into water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH Chromatorex) (solvent; 100% ethyl acetate) to give a colorless oil. The obtained oil was treated with 1 equivalent amount of 0.4N hydrogen chloride/ethyl acetate to give the title compound (217 mg, 73%) as a white powder. MS (ESI+):562 (M-HCl+H)
  • 34
  • [ 1092977-07-5 ]
  • [ 2675-89-0 ]
  • [ 1092977-08-6 ]
YieldReaction ConditionsOperation in experiment
75% Step 3: 2-[2-(3-Butoxyphenyl)-(tert-butoxycarbonyl)ethylamino]-N,N-dimethylacetamide To a suspension of NaH (60%, 2.0 g, 51 mmol) in dry DMF (125 ml) cooled at 0 C., a solution of 2-(3-butoxyphenyl)-(tert-butoxycarbonyl)ethylamine (7.5 g, 25.5 mmol) in dry DMF (125 ml) was added dropwise. After 1 h at room temperature, <strong>[2675-89-0]2-chloro-N,N-dimethylacetamide</strong> (5.2 ml, 51 mmol) was added and the mixture was stirred for 16 h at room temperature. H2O (10 ml) was added and the solvent was evaporated under reduced pressure. The residue was dissolved in H2O (150 ml) and extracted with CH2Cl2 (2*150 ml). The collected organic phases were dried over Na2SO4, filtered and evaporated. The crude was purified by flash chromatography (petroleum ether/EtOAc 4:6) affording the title compound (7.2 g, 75%) as light yellow oil. 1H NMR (300 MHz, DMSO-d6): delta 7.1 (m, 1H), 6.79-6.71 (m, 3H), 3.97 (t, J=6.0 Hz, 2H), 3.96 (s, 2H), 3.40 (dd, J=8.7 Hz, J=7.2 Hz, 2H), 2.88 (s, 6H), 2.76 (dd, J=7.9 Hz, J=6.4 Hz, 2H), 1.76 (m, 2H), 1.46 (m, 2H), 1.37 (s, 9H), 0.95 (t, J=7.3 Hz, 3H). ESI+MS: calcd for C21H34N2O4: 378.52; found: 379.0 (MH+).
75% Step 3: 2-[2-(3-Butoxyphenyl)-(tert-butoxycarbonyl)ethylamino]-N,N-dimethylacetamide. To a suspension of NaH (60%, 2.0 g, 51 mmol) in dry DMF (125 ml) cooled at 0 C, a solution of 2-(3-butoxyphenyl)-(tert-butoxycarbonyl)ethylamine (7.5 g, 25.5 mmol) in dry DMF (125 ml) was added dropwise. After Ih at room temperature, 2-chloro-N,N- dimethylacetamide (5.2 ml, 51 mmol) was added and the mixture was stirred for 16h at room temperature. H2O (10 ml) was added and the solvent was evaporated under reduced pressure. The residue was dissolved in H2O (150 ml) and extracted with CH2Cl2 (2x150 ml). The collected organic phases were dried over Na2SO4, filtered and evaporated. The crude was purified by flash chromatography (petroleum ether/EtOAc 4:6) affording the title compound (7.2 g, 75%) as light yellow oil.1H NMR (300 MHz, DMSO-d6): delta 7.1 (m, IH), 6.79 - 6.71 (m, 3H), 3.97 (t, J = 6.0 Hz, 2H), 3.96 (s, 2H), 3.40 (dd, J = 8.7 Hz, J = 7.2 Hz, 2H), 2.88 (s, 6H), 2.76 (dd, J = 7.9 Hz, J = 6.4 Hz, 2H), 1.76 (m, 2H), 1.46 (m, 2H), 1.37 (s, 9H), 0.95 (t, J = 7.3 Hz, 3H). ESI+MS: calcd for C21H34N2O4: 378.52; found: 379.0 (MH+).
  • 35
  • [ 2138-22-9 ]
  • [ 2675-89-0 ]
  • [ 1092454-90-4 ]
  • [ 1092455-01-0 ]
YieldReaction ConditionsOperation in experiment
With triethylamine; In N,N-dimethyl-formamide; at 75℃; i) 2-(5-Chloro-2-hydroxyphenoxy)-N,N-dimethylacetamide; A mixture of 4-chlorobenzene-l,2-diol (290 mg, 2 mmol), 2-chloro-N,N- dimethylacetamide (243 mg, 2 mmol) and Et3N (0.279 ml, 2 mmol) in DMF (3 mL) was stirred at 75 0C overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography (0-50% ethyl acetate in petroleum spirit 40-60) to give sub title compound (28 mg) and 2-(4-chloro-2-hydroxy- phenoxy)-7V,7V-dimethyl-acetamide (26 mg).1H-NMR (DMSOd6, 400 MHz): for 2-(5-chloro-2-hydroxyphenoxy)-N,N- dimethylacetamide, delta 6.95 (d, J= 2.4 Hz, IH); 6.85 (dd, J= 2.4, 8.5 Hz, IH); 6.80 (s, IH); 4.80 (s, 2H); 2.98 (s, 3H); 2.92 (s, 3H). 1H-NMR (DMSOd6, 400 MHz): for 2-(4-chloro-2- hydroxy-phenoxy)-7V,7V-dimethyl-acetamide, 6.89 (d, J= 8.6 Hz, IH); 6.82 (d, J= 2.3 Hz, IH); 6.75 (dd, J= 2.3, 8.6 Hz, IH); 4.70 (s, 2H); 2.99 (s, 3H); 2.85 (s, 3H).
  • 36
  • [ 5840-01-7 ]
  • [ 2675-89-0 ]
  • [ 1094609-90-1 ]
YieldReaction ConditionsOperation in experiment
71% Step 1To an ice-cooled solution of 2-chloro-N,N-dimethyl-acetamide (10 mL, 97.5 mmol) was added POCl3 (14 mL, 149.5 mmol). The clear mixture was stirred at room temperature for 20 min. 5,6- dihydro-4H-pyrrolo[3,2,l-ij]quinoline (10.20 g, 65.0 mmol, for preparation see WO06086486A1) was added. The mixture was stirred at 80 0C for two hours. The mixture was poured on to ice (200 mL) and dichloromethane (300 mL). Aqueous sodium hydroxide was added to adjust to pH>12. The dichloromethane layer was separated, washed with water (300 mL), dried over Na2SOzI, filtered and evaporated to give a dark solid. The solid was dissolved into DCM and purified by silica gel column chromatography (eluent: 0% to 1% EtOAc in DCM). 2-Chloro- 1 -(5,6-dihydro-4H-pyrro Io [3,2,1 - ij]quinolin-l-yl)-ethanone was obtained as an off-white solid (10.82 g, 71%) after tituration with EtOAc. M.p.= 118-1 19 0C; 1H NMR (400 MHz, CDCl3) delta: 8.00 (d, J= 8.0 Hz, IH), 7.82 (s, IH), 7.23 (m, IH), 7.03 (d, J= 7.2 Hz, IH), 4.51 (s, 2H), 4.21 (t, J= 6.0 Hz, 2H), 3.01 (t, J= 6.0 Hz, 2H), 2.27 (m, 2H). LCMS: m/e 234.03 [M+H].
  • 37
  • [ 23659-87-2 ]
  • [ 2675-89-0 ]
  • [ 1146074-18-1 ]
YieldReaction ConditionsOperation in experiment
82% Stage #1: 4,6-dimethoxyindole With potassium hydroxide In dimethyl sulfoxide for 0.5h; Stage #2: 2-chloro-N,N-dimethylacetamide In dimethyl sulfoxide
  • 38
  • [ 95798-23-5 ]
  • [ 2675-89-0 ]
  • [ 1174044-48-4 ]
YieldReaction ConditionsOperation in experiment
88% With tetra(n-butyl)ammonium hydrogensulfate; sodium hydroxide; In water; toluene; at 25℃; (a) Benzyl 4-(2-(dimethylamino)-2-oxoethoxy)piperidine-1-carboxylate (81) Benzyl 4-hydroxypiperidine-1-carboxylate (5 g, 21.25 mmol), tetrabutylammonium hydrogensulfate (0.361 g, 1.06 mmol) and <strong>[2675-89-0]2-chloro-N,N-dimethylacetamide</strong> (4.13 g, 27.63 mmol) were added to toluene (50 mL) to this was added sodium hydroxide (21 g, 210.02 mmol) in water (30 mL) and the reaction was stirred at 25 C. overnight. The reaction mixture was quenched with water (100 mL), extracted with Et2O (3*75 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford the desired compound as an orange liquid (6.00 g, 88% yield); 1H NMR (400.132 MHz, CDCl3) delta 1.65-1.55 (2H, m), 1.93-1.86 (2H, m), 2.95 (3H, s), 3.03 (3H, s), 3.25-3.18 (2H, m), 3.63-3.57 (1H, m), 3.85-3.79 (2H, m), 4.17 (2H, s), 5.12 (2H, s), 7.38-7.30 (5H, m).
  • 39
  • [ 1187159-87-0 ]
  • [ 2675-89-0 ]
  • [ 1187161-35-8 ]
YieldReaction ConditionsOperation in experiment
87% With sodium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h; Example 136 2-(4-{3-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-ureido}-piperidin-1-yl)-N,N-dimethyl-acetamide 1-[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-3-piperidin-4-yl-urea (0.05 g, 0.12 mmol), <strong>[2675-89-0]2-chloro-N,N-dimethylacetamide</strong> (0.023 mg, 0.18 mmol) and sodium carbonate (0.02 g, 0.18 mmol) were stirred at ambient temperature for 16 h in N,N-dimethylformamide (3 mL). The reaction mixture was evaporated. The residue was taken up in dimethylsulfoxide (1 mL) and subjected to preparative HPLC to yield the title compound (0.053 g, 87%) as a yellow oil; MS: m/e=487.8 (M+H+).
  • 40
  • [ 1187321-43-2 ]
  • [ 207557-35-5 ]
  • [ 2675-89-0 ]
  • [ 1187321-69-2 ]
  • [ 1187320-32-6 ]
YieldReaction ConditionsOperation in experiment
Step I : Scheme: Sodium hydride (0.132 g, 0.003 mol) is added to a stirred solution of 4,5-dihydroxy-2,3-0-isopropylidene- l-[piperidine-{4-benzyloxycarbonylamino-(4-methyl)}-l-yl]-l-deoxy-beta-D-fructopyranose (1.0 g, 0.002 mol) in N,N-dimethylformamide (8 mL). 2-chloro-N,N-dimethylacetamide (0.334 g, 0.003 mol) is dissolved in N,N-dimethylformamide (2 mL) added slowly to the reaction mixture at room temperature and the reaction mixture is stirred at room temperature for 45 minutes. D. M. water (10 mL) is added to the reaction mixture and extracted with ethyl acetate (2x1 S mL). Combined organic layer is then washed with brine solution (1x10 mL) and dried over anhydrous sodium sulphate. Removal of ethyl acetate under reduced pressure gives viscous liquid which is purified by column chromatography (silica gel 230-400 mesh, dichloromethane:methanol, 95:5) to get a mixture of 4-hydroxy-2,3-O-isopropylidene-l-[piperidine- {4-benzyloxycarbonylamino-(4-methyl)}-l-yl]-5-O-(N,N-dimethylaminocarbonylmethyl)-l-deoxy-beta-D- fructopyranose and 5-hydroxy-2,3-0-isopropylidene-l-[piperidine-{4-benzyloxycarbonylamino-(4- methy I) } - 1 -y l]-4-O-(N,N-dirnethylaminocarbonylmethyl)- 1 -deoxy-beta-D-fructopyranose.Step Ii : Scheme:5% Pd/C (0.076 g, 50% wet) is added to a stirred solution of the mixture of 4-hydroxy-2,3-O- isopropylidene- l-[piperidine-{4-benzyloxycarbonylamino-(4-methyl)}-l-yl]-5-0-(N,N- dimethylaminocarbonylmethyO-l-deoxy-beta-D-fructopyranose and 5-hydroxy-2,3-O-isopropylidene-l- [piperidine-{4-benzyloxycarbonylamino-(4-methyl)}-l-yl]-4-O-(N,N-dimethylaminocarbonylmethyl)-l- <n="76"/>deoxy-beta-D-fructopyranose (0.38 g, 0.0007 mol) in ethanol (10 mL). Hydrogen gas is bubbled through the reaction mixture for 45 minutes. Reaction mixture is filtered through celite bed and washed with ethanol (2x20 mL). Removal of combined ethanol under reduced pressure furnish mixture of 4-hydroxy-2,3-O- isopropylidene- 1 -[piperidine- {4-amino-4-methyl} - 1 -yl]-5-O-(N,N-dimethylaminocarbonylrnethyl)- 1 - deoxy-beta-D-fructopyranose & 5-hydroxy-2,3-O-isopropylidene-l-[piperidine-{4-amino-4-methyl}-l-yl]-4- O-(N , N -dimethy lam inocarbonylmethy I)- 1 -deoxy-beta-D-fructopyranose..Step III : Scheme: N,N-di-isopropylethylamine (0.12 mL, 0.001 mol) is added to a stirred solution of the mixture of 4- hydroxy-2,3-0-isopropylidene-l-[piperidine-{4-arnino-4-methyl}-l-yl]-5-0-(dimethylarninocarbonylmethyl)-l-deoxy-beta-D-fructopyranose & 5-hydroxy-2,3-0-isopropylidene-l- [p iperid ine- {4-am ino-4-methy 1} - 1 -y l]-4-O-(dimethy laminocarbony lmethy I)- 1 -deoxy-beta-D-fructopyranose (0.32 g, 0.001 mol) in N,N-dimethylformamide (5 mL). l-(2-Chloroacetyl)pyrrolidine-2-(S)-carbonitriie0 (0.1 15 g, 0.001 mol) is added and reaction mixture is heated at 75 C for 3 hrs 30 minutes. Reaction mixture is concentracted under reduced pressure and the residue is purified by column chromatography (silica gel 230-400 mesh, dichloromethane:methanol, 93:7) to get a mixture of 4-hydroxy-2,3-O- isopropylidene-l-[piperidine-{4-aminoacetyl pyrrolidine-2-(S)-carbonitrile)-(4-methyl)}-l-yl]-5-O-(N,N- dimethylaminocarbonylmethyO-l-deoxy-beta-D-fructopyranose (99A) & 5-hydroxy-2,3-0-isopropylidene-l- [piperidine-{4-aminoacetyl pyrrolidine-2-(S)-carbonitrile)-(4-methyl)}-l-yl]-4-0-(N,N- dimethylaminocarbonylmethyl)-l-deoxy-beta-D-fructopyranose (99B) .
  • 41
  • [ 269410-08-4 ]
  • [ 2675-89-0 ]
  • [ 930596-20-6 ]
YieldReaction ConditionsOperation in experiment
90% With caesium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 70℃; To a solution of 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (1.00 g, 5.15 mmol) in DMF (40 mL) were added 2-chloro-N, N-dimethylacetamide (1 g, 8.2 mmol) and Cs2CO3(4.7 g, 14 mmol) and KI (0.5 g, 3 mmol) . The mixture was stirred at 70 overnight. The reaction mixture was concentrated to remove DMF. The residue was diluted with water (30 mL) . The resulting mixture was extracted with DCM (50 mL × 3) . The combined organic layers were dried over anhydrous Na2SO4and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with PE/EtOAc (v/v) 9/1 to give a yellow oily product (1.3 g, 90) .[2006]MS (ESI, pos. ion) m/z: 280.3 [M+1]+.
74% With caesium carbonate; In N,N-dimethyl-formamide; at 90℃; for 3h; Step 1: Preparation of N,N-dimethyl-2-(4-(4,4, 5 ,5-tetramethyl- 1,3 ,2-dioxaborolan-2- yl)- 1 H-pyrazol- 1 -yl)acetamide (Intermediate 25) A mixture of 4-(4,4,5 ,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)- 1 H-pyrazole(100 mg, 0.5 15 mrnol), <strong>[2675-89-0]2-chloro-N,N-dimethylacetamide</strong> (58.3 jiL, 0.567 mmol) andCs2CO3 (252 mg, 0.773 mmol) in DMF (3.0 mL) was stirred at 90 C for 3 hours.After being cooled to room temperature, the reaction mixture was treated with waterand extracted with EtOAc twice. The combined organic layers were dried overNa2SO4, filtered and concentrated in vacuo to obtain the title compound (106 mg, 74%) as a white solid, which was used for the next reaction without further purification.H-N1vIR (400 MHz, CDC13): oe 7.81 (d, J= 5.6 Hz, 2H), 4.99 (s, 2H), 3.07 (s,3H), 2.98 (s, 3H), 1.31 (s, 12H).
With caesium carbonate; In N,N-dimethyl-formamide; at 90℃; for 1h;microwave irradiation; A solution of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (0.8 g, 4.1 mmol), cesium carbonate (2.0 g, 6.2 mmol), and <strong>[2675-89-0]2-chloro-N,N-dimethylacetamide</strong> (0.47 rnL, 4.5 mmol) in DMF (14 mL) was heated in a microwave at 900C for 1 hr. The crude reaction mixtures were then diluted with water (300 mL) and extracted with ethyl acetate (3 x 50 mL). Product was purified by silica gel column using DCM/EtOAc/MeOH (8/1.5/0.5) as eluent to provide N,N-dimethyl-2-(4-(4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- 1 H-pyrazol- 1 - yl)acetamide (1.3 g) as a light yellow oil. ESI-MS:m/z 280.3 (M+H)+.
  • 42
  • [ 51478-09-2 ]
  • [ 2675-89-0 ]
  • [ 1224436-21-8 ]
YieldReaction ConditionsOperation in experiment
74% With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0 - 50℃; To a suspension of (4aR,4bS,6aS,9aS,9bR)-4a,6a-dimethyl-4,4a,4b,5,6,6a,9,9a,9b,10-decahydro-1H-indeno[5,4-f]quinoline-2,7(3H,8H)-dione (794 mg, 2.7 mmol) in anhydrous DMF (30 mL) was added NaH (60%, 324 mg, 8.1 mmol) and <strong>[2675-89-0]2-chloro-N,N-dimethylacetamide</strong> (670 mg, 5.5 mmol) at 0 C., then the reaction was stirred under 50 C. for 2 hour. Then cooled down to room temperature and partitioned between ethyl acetate (20 mL) and water (20 mL). The layers were separated and the aqueous layer extracted with ethyl acetate (25 mL×3). The combined organic layers were dried over Na2 SO4. After filtration, the organic phase was concentrated under vacuum to afford 2-((4aR,4bS,6aS,9aS,9bR)-4a,6a-dimethyl-2,7-dioxo-2,3,4,4a,4b,5,6,6a,7,8,9,9a,9b,10-tetradecahydroindeno[5,4-f]quinolin-1-yl)-N,N-dimethylacetamide as a yellow solid (760 mg, yield 74%). 1H-NMR (400 MHz, CDCl3): 4.82 (m, 1H), 4.15 (m, 1H), 3.06 (s, 3H), 2.97 (m, 3H), 2.50 (m, 3H), 2.25 (m, 1H), 2.14 (m, 1H), 1.19 (m, 12H), 1.15 (s, 3H), 0.90 (s, 3H). LC-MS (m/z) 373 [M+H]+.
  • 43
  • [ 28395-03-1 ]
  • [ 2675-89-0 ]
  • [ 885051-36-5 ]
YieldReaction ConditionsOperation in experiment
86% With triethylamine; sodium iodide; In N,N-dimethyl-formamide; at 0 - 50℃; for 10h; To a solution of bumetanide 33-4 (3 g, 8.2 mmol) in N,N- Dimethylformamide (30 mL) were added triethylamine (1.68 mL, 12.3 mmol), Nal (1.35 g, 9.0 mmol) and <strong>[2675-89-0]2-chloro-N,N-dimethylacetamide</strong> 33-3 (1.2 g, 9.8 mmol) at 0-5 C. The reaction mixture was allowed to stir at 50 C'C for I Oh. The resulting reaction mass was diluted with ethyl acetate (200 mL), washed with water (2 X 100 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude product obtained upon evaporation of volatiles was purified by silica gel (230-400 mesh) column chromatography to give product Compound 26 as a white solid 3.2 g (86%). NMR (400 MHz, DMSO-de) d 7.74 (d, J = 2 Hz, 1H), 7.47-7.35 (m, 3H), 7.27 (t, I = 8 Hz, 2H), 7 02 (t, J = 8 Hz, H I ), 6.86 (d, I = 8 Hz, 21 1 ). 5.18 (t, 1 1 1 ), 5.07 (s, 21 1 ). 3.13-3.01 (m, 2H), 2.99 (s, 3H), 2 85 (s, 3H), 1 .37 (quintet, 2H), 1.1 1 (sextet, 2H), 0.77 (t, 3H); MS m/z (0933) [ M | 450.9.
60% With triethylamine;sodium iodide; In N,N-dimethyl-formamide; at 50℃; for 10h; EXAMPLE 18; N,N-Dimethylaminocarbonylmethyl 3-Aminosulfonyl-5-butylamino-4- phenoxybenzoate (Bumetanide N,N-Dimethylglycolamido Ester); [0481] Bumetanide (1.2g, 3.29 mmol) was dissolved in dimethylformamide (DMF, 10 mL) and 2- chloro-N,N-dimethylacetamide (410 muL, 3.9 mmol) was added followed by triethylamine (0.70 mL) and sodium iodide (545 mg, 3.6 mmol). The reaction was heated to 50C for 10 hours, TLC and LC/MS indicated the reaction was complete. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate, water, and brine and dried over anhydrous magnesium sulfate. The ethyl acetate was removed under reduced pressure and the product was purified via flash chromatography on silica gel to yield 685 mg (60%) of pure N,N- dimethylaminocarbonylmethyl 3-aminosulfonyl-5-butylamino-4-phenoxybenzoate.
  • 44
  • [ 19438-10-9 ]
  • [ 2675-89-0 ]
  • [ 1240518-18-6 ]
YieldReaction ConditionsOperation in experiment
91% With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 145h; Intermediate 16Methyl 3-[2-(dimethylamino)-2-oxoethyl]oxy}benzoate; A mixture of methyl 3-hydroxybenzoate (Aldrich) (1.52 g, 10 mmol) and K2CO3 (1.38 g, 10 mmol) in DMF (10 mL) was stirred for 1 h. 2-Chloro-N,N-dimethylacetamide (Merck) (1.03 mL, 10 mmol) was added and the mixture was stirred for 1 h at RT and then stood at RT for 6 days. The mixture was then acidified with 2M HCl and extracted with EtOAc. The aqueous layer was extracted twice more with EtOAc and the combined organic solutions were washed with 2M HCl (×3), aq. sat NaHCO3, brine, dried (MgSO4) and evaporated under reduced pressure to give the title compound (2.22 g, 94%) as a white solid. LCMS (System A) RT=0.80 min, 91%, ES+ve m/z 238 (M+H)+.
  • 45
  • [ 99-76-3 ]
  • [ 2675-89-0 ]
  • [ 1208752-16-2 ]
YieldReaction ConditionsOperation in experiment
68% With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; Intermediate 19Methyl 4-[2-(dimethylamino)-2-oxoethyl]oxy}benzoate; Methyl 4-hydroxybenzoate (Fluka) (1.52 g, 10 mmol) and potassium carbonate (1.38 g, 10 mmol) in DMF (10 mL) was treated with <strong>[2675-89-0]2-chloro-N,N-dimethylacetamide</strong> (Merck) (1.03 ml, 10 mmol) and the mixture was stirred at RT overnight. The reaction mixture was worked up by partitioning between ethyl acetate and 2M hydrochloric acid, washing with HCl, brine, dried (MgSO4) and evaporating to dryness. The residue was dissolved in DMF (5 mL) and treated with potassium carbonate (1.38 g, 10 mmol) and <strong>[2675-89-0]2-chloro-N,N-dimethylacetamide</strong> (Merck) (1.03 ml, 10 mmol). The mixture was stirred at RT over the weekend, and then worked up. Partitioned between ethyl acetate and 2M HCl and the organic solution was washed with HCl (X2), brine (X3), dried (MgSO4), and evaporated to give the title compound (1.62 g, 68%) as a white solid. LCMS (System A) RT=0.73 min, ES+ve m/z 238 (M+H)+.
  • 46
  • [ 3943-74-6 ]
  • [ 2675-89-0 ]
  • [ 954252-16-5 ]
YieldReaction ConditionsOperation in experiment
25% With potassium carbonate In N,N-dimethyl-formamide at 20℃; 22 Intermediate 22 Methyl 4-[2-(dimethylamino)-2-oxoethyl]oxy}-3-(methyloxy)benzoate; Methyl 4-hydroxy-3-(methyloxy)benzoate (methyl vanillate, Aldrich) (3.85 g, 21.1 mmol) and potassium carbonate (2.92 g, 21.1 mmol) in DMF (10 mL) was treated at RT with 2-chloro-N,N-dimethylacetamide (Merck) (2.18 mL, 21.1 mmol) and the mixture was stirred over the weekend. The mixture was partitioned between ethyl acetate and 2M HCl. The organic phase was washed with, 2M HCl, saturated sodium bicarbonate solution (turns lightly coloured), acid (loses colour), brine, dried (MgSO4), and evaporated under reduced pressure, to give the product contaminated with starting material (5.0 g). The mixture was therefore re-dissolved in DMF (5 mL) and treated with potassium carbonate (1.38 g, 10 mmol) and 2-chloro-N,N-dimethylacetamide (1 mL, 10 mmol) for another day. The mixture was then partitioned between ethyl acetate and 2M HCl and treated as above. The filtrate was evaporated to give a solid (2.614 g) which was loaded in chloroform to a silica cartridge (70 g) and purified by chromatography on Flashmaster using a 0-100% ethyl acetate-cyclohexane gradient over 30 min. The appropriate fractions were combined and evaporated in vacuo to give the title compound (1.4 g, 25%) as a white solid. LCMS (System A) RT=0.69 min, ES+ve m/z 268 (M+H)+.
  • 47
  • [ 1152636-93-5 ]
  • [ 2675-89-0 ]
  • [ 1152636-97-9 ]
YieldReaction ConditionsOperation in experiment
100% With potassium carbonate; In water; N,N-dimethyl-formamide; at 20℃;Inert atmosphere; 12-(a) (N,N-dimethylaminocarbonyl)methyl (4S)-3-oxo-8-[2-(8-tert-butoxycarbonyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidin-2-yl)ethoxy]-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-4-acetate To 1 mL of a dimethylformamide solution containing 113 mg (0.200 mmol) of (4S)-3-oxo-8-[2-(8-tert-butoxycarbonyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidin-2-yl)ethoxy]-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-4-acetic acid obtained in Example 5-(a) was added 55.3 mg (0.400 mmol) of potassium carbonate, and the mixture was stirred under argon gas atmosphere at room temperature. Then, 26 muL (0.25 mmol) of <strong>[2675-89-0]2-chloro-N,N-dimethylacetamide</strong> was added to the mixture, and the resulting mixture was stirred at the same temperature for 8 hours. After completion of the reaction, the reaction mixture was poured into 10 ml of water, and extracted with 30 mL of ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then, concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (eluent; chloroform: methanol=40:1? 19:1 (V/V)), and the separated fractions containing the objective material were concentrated under reduced pressure to obtain 131 mg of the title compound as yellow oily product. (Yield: quantitative) Mass Spectrum (FAB, m/z): 652 (M++1). 1H-NMR Spectrum (CDCl3, delta ppm): 1.54 (s, 9H), 2.05-2.13 (m, 2H), 2.64 (dd, J1=17.0Hz, J2=5.5Hz, 1H), 2.84-3.17 (m, 11H), 3.82-3.98 (m, 7H), 4.15-4.26 (m, 3H), 4.64 (d, J=14.4Hz, 1H), 4.85 (d, J=14.4Hz, 1H), 5.31 (d, J=16.1Hz, 1H), 6.49 (s, 1H), 6.63 (d, J=2.7Hz, 1H), 6.80 (dd, J1=8.5Hz, J2=2.7Hz, 1H), 7.02 (d, J=8.5Hz, 1H).
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 8h;Inert atmosphere; 12-(a) (N,N-Dimethylaminocarbonyl)methyl (4S)-3-oxo-8-[2-(8-tert-butoxycarbonyt-5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidin-2-yl)ethoxy]-2-(2,2,2-trifluooroethyl)-2,3,4,5-tetrahydro-1H-2-benzazep in-4-acetate To 1 mL of a dimethylformamide solution containing 113 mg (0.200 mmol) of (4S)-3-oxo-8-[2-(8-tert-butoxycarbonyl-5,6,7,8-tetrahydroimidazo[1,2-a]plrimidin-2-yl)ethoxy]-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-4-acetic acid obtained in Example 5-(a) was added 55.3 mg (0.400 mmol) of potassium carbonate, and the resulting mixture was stirred under argon gas atmosphere at room temperature. Then, 26 muL (0.25 mmol) of <strong>[2675-89-0]2-chloro-N,N-dimethylacetamide</strong> was added to the mixture, and the resulting mixture was stirred at the same temperature for 8 hours. After completion of the reaction, the reaction mixture was poured into 10 mL of water, and extracted with 30 mL of ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (eluent; chloroform:methanol=40:1?19:1 (V/V)), and the separated fractions containing the desired product were concentrated under reduced pressure to obtain 131 mg of the title compound as yellow oil. (Yield: quantitative) Mass spectrum (FAB, m/z): 652 (M++1). 1H-NMR spectrum (CDCl3, delta ppm): 1.54 (s, 9H), 2.05-2.13 (m, 2H), 2.64 (dd, J1=17.0Hz, J2=5.5Hz, 1H), 2.84-3.17 (m, 11H), 3.82-3.98 (m, 7H), 4.15-4.26 (m, 3H), 4.64 (d, J=14.4Hz, 1H), 4.85 (d, J=14.4Hz, 1H), 5.31 (d, J=16.1Hz, 1H), 6.49 (s, 1H), 6.63 (d, J=2.7Hz, 1H), 6.80 (dd, J1=8.5Hz, J2=2.7Hz, 1H), 7.02 (d, J=8.5Hz, 1H).
  • 48
  • [ 73874-95-0 ]
  • [ 76-05-1 ]
  • [ 2675-89-0 ]
  • 2-(4-aminopiperidin-1-yl)-N,N-dimethylacetamide bis(trifluoroacetate) [ No CAS ]
YieldReaction ConditionsOperation in experiment
77% 4-(BOC-amino)piperidine (300 mg) was partitioned between DCM (75 ml) and saturated aqueous Na2CO3 solution (75 ml). The aqueous layer was separated and extracted with DCM (50 ml). The organic layers were combined, dried over MgSO4, filtered and concentrated in vacuo. The resulting white powder was dissolved in dry DMF (25 ml) under nitrogen and to this mixture was added Na2CO3 (318 mg) and 2- chloro-N,iV-dimethylacetamide (0.31 ml). The reaction mixture was stirred at room temperature for 24 hours. Water (80 ml) was added and the mixture was extracted with DCM (2 x 100 ml). The organic layers were combined, dried over MgSO4, filtered and concentrated in vacuo. The residue was suspended in dry DCM (20 ml) under nitrogen and to it was slowly added TFA. The mixture was stirred at room temperature for 5 hours. The solvent was removed in vacuo and the residue was triturated in Et2O to afford the title compound as a white solid (476 mg, 77%). 1H NMR 300 MHz (d6-DMSO) 8.25- 7.91 (4H, m, br), 7.79-7.69 (1H, m, br), 4.43-4.34 (1H, m), 3.91-3.78 (2H, m), 3.65-3.42 (2H, m), 3.20-3.01 (2H, m), 2.19-2.00 (2H, m), 1.93-1.76 (2H, m).
  • 49
  • 1-(5,6-dichloro-1H-indol-3-yl)-2,2,2-trifluoroethanone [ No CAS ]
  • [ 2675-89-0 ]
  • 2-[5,6-dichloro-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-N,N-dimethyl-acetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
78% To a stirred solution of 1-(5,6-dichloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (0.11 g) in 3 ml of DMF at 0 C., were added 18 mg (1.05 eq.) of NaH (60% in oil). The mixture was stirred for 30 min. and then 0.04 ml (1.0 eq.) of dimethylamino-acetyl chloride were added. The mixture was stirred an additional hour and then poured onto water and extracted with ethyl acetate. The combined organic phases were dried over Na2SO4 and concentrated in vacuo to afford 112 mg (78%) of 2-[5,6-dichloro-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-N,N-dimethyl-acetamide as a white solid.
  • 50
  • 1-{3-[(R)-2-[3-(phenylsulphonylamino)-phenyl]-2-hydroxy-ethylamino]-3-methyl-butyl}-1H-indole-5-carboxylic acid hydrotrifluoroacetate [ No CAS ]
  • [ 2675-89-0 ]
  • (dimethylcarbamoylmethyl) 1-{3-[(R)-2-[3-(phenylsulphonylamino)phenyl]-2-hydroxyethylamino]-3-methylbutyl}-1H-indole-5-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
76% EXAMPLE 57 (Dimethylcarbamoylmethyl) 1-{3-[(R)-2-[3-(phenylsulphonylamino)-phenyl]-2-hydroxy-ethylamino]-3-methyl-butyl}-1H-indole-5-carboxylate hydrotrifluoroacetate Potassium hydrogen carbonate (141 mg, 1.4 mmol) is added to a solution of 1-{3-[(R)-2-[3-(phenylsulphonylamino)-phenyl]-2-hydroxy-ethylamino]-3-methyl-butyl}-1H-indole-5-carboxylic acid-hydrotrifluoroacetate (Example 6; 300 mg, 0.47 mmol) in 2 ml DMF. Then the reaction mixture is stirred for 20 minutes at RT and <strong>[2675-89-0]2-chloro-N,N-dimethylacetamide</strong> (143 mg, 1.18 mmol) is added. After 90 hours stirring at RT the reaction mixture is diluted with 50 ml of water and extracted with ethyl acetate. The organic phase is dried on magnesium sulphate and the solvent is eliminated in vacuo. The residue is chromatographed on silica gel (DCM/methanol=100:0?95:5). Yield: 217 mg (76% of theory) C32H38N4O6S (606.73) Mass spectrum: (M+H)+=607 retention time (Method 1): 2.58 min
  • 51
  • [ 1282517-92-3 ]
  • [ 2675-89-0 ]
  • [ 1282513-74-9 ]
YieldReaction ConditionsOperation in experiment
38% With triethylamine;tetra-(n-butyl)ammonium iodide; In dichloromethane; at 20℃; for 72h; Example 329 2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)piperidin-1-yl)-N,N-dimethylacetamide 329 A suspension of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene hydrochloride (310 mg, 0.72 mmol) in DCM (6 mL) and TEA (0.3 mL, 2.16 mmol) was sonicated and stirred before adding N,N-dimethyl-2-chloroacetamide (98 mg, 0.8 mmol) and TBAI (28 mg, 0.072 mmol) and the reaction mixture stirred for 72 h at RT before being concentrated in vacuo. The resultant residue was partitioned between water and DCM and the aqueous extracted five times with DCM, the combined organic extracts dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 10% methanol in DCM) then triturated in diethyl ether to give 329 as a white solid (129 mg, 38%). LCMS: RT=2.71 min, [M+H]+=478. 1H NMR 400 MHz (CDCl3) delta: 8.44 (1H, d, J=8.30 Hz), 7.61 (1H, s), 7.04 (1H, d, J=8.43 Hz), 6.91 (1H, s), 5.91 (1H, t, J=6.63 Hz), 4.45 (4H, d, J=14.92 Hz), 3.39 (2H, m), 3.11 (2H, m), 3.10 (3H, s), 2.99 (1H, m), 2.98 (3H, s), 2.54 (2H, m), 2.41 (3H, s), 1.90 (4H, s), 1.57 (6H, d, J=6.65 Hz)
  • 52
  • 8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid (2-hydroxy-ethyl)-isopropyl-amide hydrochloride [ No CAS ]
  • [ 2675-89-0 ]
  • [ 1282514-09-3 ]
YieldReaction ConditionsOperation in experiment
20% With potassium carbonate;potassium iodide; In N,N-dimethyl-formamide; at 20℃; for 72h; To a stirred mixture of 8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid (2-hydroxy-ethyl)-isopropyl-amide hydrochloride (127 mg, 0.23 mmol) in DMF (2 mL) was added potassium carbonate (127 mg, 0.92 mmol), N,N-dimethyl-2-chloroacetamide (36 mg, 0.3 mmol) and KI (catalytic) and stirring continued at RT for 72 h before concentrating in vacuo. The resultant residue was diluted with ethyl acetate and washed with water followed by brine, then dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was passed down an Isolute SCX-2 cartridge eluting with DCM/methanol then 2M NH3 in methanol. Basic fractions were combined and concentrated in vacuo, the residue subjected to RPHPLC (C18 column, gradient 5 to 95% CH3CN in water+0.1% HCO2H) to give 356 as a colourless glass (22 mg, 20%). LCMS: RT=1.90 min, [M+H]+=484 1H NMR 400 MHz (CDCl3) delta: 8.42 (2H, s), 8.20 (1H, br, s), 8.34 (1H, d, J=8.32 Hz), 7.81 (1H, s), 7.04 (1H, dd, J=8.40, 1.77 Hz), 6.90 (1H, d, J=1.69 Hz), 4.63 (2H, m), 4.45-4.44 (4H, m), 3.38 (3H, m), 3.32 (2H, m), 3.16 (2H, d, J=11.21 Hz), 3.11 (3H, s), 2.99 (3H, s), 2.56 (1H, m), 2.48 (2H, m), 1.87 (4H, m), 1.42 (6H, d, J=6.46 Hz)
  • 53
  • [ 821-09-0 ]
  • [ 2675-89-0 ]
  • [ 1293379-62-0 ]
YieldReaction ConditionsOperation in experiment
94% Pentenol 3 (1.2 mL, 11.6 mmol) was added dropwise to a stirred suspension of NaH (557 mg, 60% dispersion in mineral oil, 13.9 mmol) in anhydrous THF (23 mL) at 0 C. After 1 h at the same temperature, chloroacetamide 1 (1.4 mL, 13.9 mmol) was added at 0 C and the mixture was stirred for 24 h at room temperature. The mixture was neutralized with saturated aqueous NH4Cl and THF was evaporated under reduced pressure. The residue was dissolved in EtOAc and washed with water and brine. The organic layer was dried over anhydrous MgSO4 and concentrated at reduced pressure. Purification of the residue by flash column chromatography on silica gel (hexanes/EtOAc, 1:1) afforded 6b (1.87 g, pale orange oil) in 94% yield. 1H NMR (CDCl3, 300 MHz) delta 5.89-5.74 (m, 1H), 5.07-4.93 (m, 2H), 4.13 (s, 2H), 3.52 (t, J = 6.5 Hz, 2H), 3.02 (s, 3H), 2.96 (s, 3H), 2.19-2.08 (m, 2H), 1.77-1.66 (m, 2H); 13C NMR (CDCl3, 75 MHz) delta 169.4, 138.1, 114.9, 70.9, 70.4, 36.5, 35.6, 20.3, 28.8; HRMS (EI) m/z calcd for C9H17NO2 (M+) 171.1259, found 171.1243.
94% General procedure: To a suspension of NaH (344 mg, 60% dispersion in mineral oil) in THF (17 mL) was added allyl alcohol (2) (500 mg, 8.6 mmol) at 0 C. After 1 h at the same temperature, chloroacetamide 1 (0.97 mL, 9.5 mmol) was added and the mixture was stirred for 24 h. The mixture was quenched with saturated aqueous NH4Cl and concentrated at reduced pressure. The resulting residue was dissolved in EtOAc and washed with water and brine. The organic layer was dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (hexanes/EtOAc, 3:1) to give 6a (1.05 g, pale yellow oil) in 85% yield.
  • 54
  • [ 4117-10-6 ]
  • [ 2675-89-0 ]
  • [ 1293379-63-1 ]
YieldReaction ConditionsOperation in experiment
92% To a suspension of NaH (193 mg, 60% dispersion in mineral oil) in THF (8.8 mL) was added hepteneol 4 (500 mg, 4.4 mmol) at 0 C. After 1 h at the same temperature, chloroacetamide 1 (0.50 mL, 4.8 mmol) was added and the mixture was stirred for 24 h. The mixture was neutralized with saturated aqueous NH4Cl and THF was removed at reduced pressure. The resulting residue was dissolved in EtOAc and washed with water and brine. The organic layer was dried over anhydrous MgSO4 and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (hexanes/EtOAc, 1:1) afforded 6c (803 mg, pale yellow oil) in 92% yield: 1H NMR (CDCl3, 300 MHz) delta 5.87-5.71 (m, 1H), 5.04-4.88 (m, 2H), 4.12 (s, 2H), 3.49 (t, J = 6.6, 2H), 3.10 (s, 3H), 2.95 (s, 3H), 2.10-2.01 (m, 2H), 1.68-1.57 (m, 2H), 1.48-1.30 (m, 4H); 13C NMR (CDCl3, 75 MHz) delta 169.5, 139.0, 114.4, 71.6, 70.5, 36.6, 35.6, 33.8, 29.5, 28.8, 25.7; HRMS (EI) m/z calcd for C11H21NO2 (M+) 199.1572, found 199.1576.
92% General procedure: To a suspension of NaH (344 mg, 60% dispersion in mineral oil) in THF (17 mL) was added allyl alcohol (2) (500 mg, 8.6 mmol) at 0 C. After 1 h at the same temperature, chloroacetamide 1 (0.97 mL, 9.5 mmol) was added and the mixture was stirred for 24 h. The mixture was quenched with saturated aqueous NH4Cl and concentrated at reduced pressure. The resulting residue was dissolved in EtOAc and washed with water and brine. The organic layer was dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (hexanes/EtOAc, 3:1) to give 6a (1.05 g, pale yellow oil) in 85% yield.
  • 55
  • [ 13019-22-2 ]
  • [ 2675-89-0 ]
  • [ 1293379-64-2 ]
YieldReaction ConditionsOperation in experiment
82% To a suspension of NaH (141 mg, 60% dispersion in mineral oil) in THF (6.4 mL) was added decenol 5 (500 mg, 3.2 mmol) at 0 C. After 1 h at the same temperature, chloroacetamide 1 (0.33 mL, 3.5 mmol) was added and the mixture was stirred for 24 h. The mixture was quenched with saturated aqueous NH4Cl and THF was evaporated under reduced pressure. The resulting residue was dissolved in EtOAc and washed with water and brine. The organic layer was dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (hexanes/EtOAc, 1:1) to give 6d (633 mg, pale yellow oil) in 82% yield: 1H NMR (CDCl3, 300 MHz) delta 5.89-5.73 (m, 1H), 5.04-4.89 (m, 2H), 4.13 (s, 2H), 3.49 (t, J = 6.6 Hz , 2H), 3.03 (s, 3H), 2.96 (s, 3H), 2.09-1.98 (m, 2H), 1.68-1.55 (m, 2H), 1.40-1.20 (m, 10H); 13C NMR (CDCl3, 75 MHz) delta 169.6, 139.3, 114.3, 71.7, 70.5, 36.6, 35.6, 33.9, 29.7, 29.53, 29.50, 29.2, 29.0, 26.2; HRMS (EI) m/z calcd for C14H27NO2 (M+) 241.2042, found 241.2072.
82% General procedure: To a suspension of NaH (344 mg, 60% dispersion in mineral oil) in THF (17 mL) was added allyl alcohol (2) (500 mg, 8.6 mmol) at 0 C. After 1 h at the same temperature, chloroacetamide 1 (0.97 mL, 9.5 mmol) was added and the mixture was stirred for 24 h. The mixture was quenched with saturated aqueous NH4Cl and concentrated at reduced pressure. The resulting residue was dissolved in EtOAc and washed with water and brine. The organic layer was dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (hexanes/EtOAc, 3:1) to give 6a (1.05 g, pale yellow oil) in 85% yield.
  • 56
  • [ 107-18-6 ]
  • [ 2675-89-0 ]
  • [ 78142-32-2 ]
YieldReaction ConditionsOperation in experiment
85% To a suspension of NaH (344 mg, 60% dispersion in mineral oil) in THF (17 mL) was added allyl alcohol (2) (500 mg, 8.6 mmol) at 0 C. After 1 h at the same temperature, chloroacetamide 1 (0.97 mL, 9.5 mmol) was added and the mixture was stirred for 24 h. The mixture was quenched with saturated aqueous NH4Cl and concentrated at reduced pressure. The resulting residue was dissolved in EtOAc and washed with water and brine. The organic layer was dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (hexanes/EtOAc, 1:3) to give 6a (1.05 g, pale yellow oil) in 85% yield: 1H NMR (CDCl3, 300 MHz) delta 5.90-5.84 (m, 1H), 5.35-517 (m, 2H), 4.14 (s, 2H), 4.10-4.04 (m, 2H), 3.03-2.92 (m, 6H); 13C NMR (CDCl3, 75 MHz) delta 169.2, 134.1, 117.9, 72.2, 69.1, 36.4, 35.5; HRMS (EI) m/z calcd for 7H13NO2 (M+) 143.0946, found 143.0943.
85% To a suspension of NaH (344 mg, 60% dispersion in mineral oil) in THF (17 mL) was added allyl alcohol (2) (500 mg, 8.6 mmol) at 0 C. After 1 h at the same temperature, chloroacetamide 1 (0.97 mL, 9.5 mmol) was added and the mixture was stirred for 24 h. The mixture was quenched with saturated aqueous NH4Cl and concentrated at reduced pressure. The resulting residue was dissolved in EtOAc and washed with water and brine. The organic layer was dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (hexanes/EtOAc, 3:1) to give 6a (1.05 g, pale yellow oil) in 85% yield.
  • 57
  • [ 468743-82-0 ]
  • [ 2675-89-0 ]
  • [ 1186313-12-1 ]
YieldReaction ConditionsOperation in experiment
95% With potassium carbonate; In acetonitrile; at 30 - 45℃; for 48h; The three secondary amines of the obtained monoester 5.0 are then functionalized with <strong>[2675-89-0]2-chloro-N,N-dimethylacetamide</strong> (this chlorinated reagent is preferred to its brominated analog which leads to the formation of a significant amount of quaternized products). To do this, the 11.21 g (i.e. 39.2 mmol) of the compound 5.0 obtained previously are dissolved in 100 mL of acetonitrile and this solution is added dropwise into a solution of 14.28 g (117 mmol) of <strong>[2675-89-0]2-chloro-N,N-dimethylacetamide</strong> and 35 g (252 mmol) of potassium carbonate in 900 mL of acetonitrile brought to 30 C. The reaction medium is maintained at 45 C. with stirring for 48 h.After filtration on celite and evaporation of solvent, the compound 5.1 is obtained as 20.2 g of a slightly yellow solid (yield=95%), having the following characteristics:1H NMR (500 MHz, CDCl3): 1.21 (t, 3H, OCH2CH3); 1.57 (m, 4H, CH2CH2CH2); 2.50-2.63 (m, 16H, CH2N); 2.88 (s, 9H, NCH3); 3.04 (s, 3H, NCH3); 3.07 (s, 3H, NCH3); 3.10 (s, 3H, NCH3); 3.23-3.27 (m, 8H, CH2CONH2 and CH2CO2Et); 4.09 (q, 2H, OCH2CH3).13C NMR (125 MHz, CDCl3): 14.9 (OCH2CH3); 25.2 (CH2CH2CH2); 25.4 (CH2CH2CH2); 36.1-38.1 (NCH3); 51.1-52.5 (CH2N); 56.0 (CH2CO2Et); 57.8 (CH2CONH2); 58.1 (CH2CONH2); 58.4 (CH2CONH2); 60.8 (OCH2CH3); 171.3 (CO2Et); 171.5 (CONMe2); 171.6 (CONMe2); 172.0 (CONMe2).Mass spectroscopy (MALDI-TOF) m/z: 541.8 [L]+.Elementary analysis: C, 57.93; H, 9.70; N, 17.93. (As an indication, the data calculated for C26H51N7O5 (M=541.40) are the following: C, 57.65; H, 9.49; N, 18.10).
  • 58
  • [ 1351522-60-5 ]
  • [ 2675-89-0 ]
  • [ 1351521-66-8 ]
YieldReaction ConditionsOperation in experiment
67% With triethylamine; potassium iodide; In acetonitrile; at 85℃; for 1h; To a stirred suspension of N-(4-(3-(5-tert-butylisoxazol-3- yl)ureido)phenyl)-5-(pyrrolidin-3-yloxy)picolinamide hydrochloride (150 mg, 0.30 mmol) in CH3CN (3 mL) was added TEA (126 muEpsilon, 0.90 mmol), KI (10 mg,0.060mmol), and <strong>[2675-89-0]2-chloro-N,N-dimethylacetamide</strong> (21 muEpsilon , 0.30 mmol). The resulting mixture was heated at 85 C for 1 h. LC-MS indicated that the reaction was complete. The reaction mixture was evaporated under reduced pressure and the residue was purified by reverse phase HPLC to give N-(4-(3-(5-tert-butylisoxazol-3- yl)ureido)phenyl)-5 -( 1 -(2-(dimethylamino)-2-oxoethyl)pyrrolidin-3 - yloxy)picolinamide (110 mg, 67%). LC-MS (ESI) m/z 550 (M + H)+.
  • 59
  • [ 1352948-27-6 ]
  • [ 2675-89-0 ]
  • [ 1352948-47-0 ]
YieldReaction ConditionsOperation in experiment
91% With potassium carbonate; In N,N-dimethyl-formamide; at 65℃; for 18h; fert-Butyl 3-f3-ff2-fdimethylaminoN)-2-oxoethoxyN)carbonyl benzylN)-4-oxo-l-phenyl-1.3.8- triazaspiro[4.51decane-8-carboxylate; [0119] To a solution of tert-butyl 4-oxo-l -phenyl-l,3,8-triazaspiro[4.5]decane-8-carboxylate (0.25 g, 0.54 mmol) and potassium carbonate (0.11 g, 0.81 mmol) in NN-dimethylformamide (5 mL), was added <strong>[2675-89-0]2-chloro-N,N-dimethylacetamide</strong> (0.055 mL, 0.54 mmol, d = 1.182). After stirring at 65C for 18 hours, the reaction mixture was diluted with ethyl acetate (25 mL), washed with dilute citric acid, water and brine. The organic phase was dried over MgS04, filtered and purified by Biotage flash chromatography (1-15% methanol/dichloromethane) to obtain the title compound (0.27 g, 91%); lH NMR (DMSO-i/6): delta 1.45 (s, 9H), 1.65 (d, 2H, J= 13.6 Hz), 2.41-2.48 (m, 2H), 2.82 (s, 3H), 2.96 (s, 3H), 3.45 (br, 2H), 3.90 (br, 2H), 4.63-4.66 (m, 4H), 5.03 (s, 2H), 6.68 (d, 2H, J= 8 Hz), 6.76 (t, 1H, J= 7.6 Hz), 7.17 (t, 2H, J= 8.8 Hz), 7.54-7.63 (m, 2H), 7.91-7.93 (m, 2H); MS for C3oH38N406 m/z 551.04(M+H)+.
  • 60
  • [ 1361960-94-2 ]
  • [ 2675-89-0 ]
  • [ 1361961-06-9 ]
YieldReaction ConditionsOperation in experiment
74% To a stirred solution of 4-chloro-2-(4-fluorophenylthio)-7H- pyrrolo[2,3-d]pyrimidine from Example 7 Step D) (300 mg, 1.07 mmol) in DMF (6 mL) at 0 C was added 60% sodium hydride/mineral oil (64 mg, 1.61 mmol). The mixture was stirred at 0 C for 15 min, and then a solution of 2-chloro-N,N- dimethylacetamide (260 mg, 2.14 mmol) in DMF (2 mL) was added. The mixture was stirred at 0 C for 1 h. The mixture was partitioned between EtOAc and water. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 0 to 60% EtOAc/hexanes to afford 2-(4-chloro-2-(4- fluorophenylthio)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-N,N-dimethylacetamide (288 mg, 74%) as a yellow solid. H NMR (300 MHz, DMSO-< 6) delta 7.64 - 7.70 (m, 2H), 7.56 (d, J= 3.3 Hz, 1H), 7.29 - 7.48 (m, 2H), 6.56 (d, J= 3.3 Hz, 1H), 5.01 (s, 2H), 3.00 (s, 3H), 2.83 (s, 3H). LCMS (ESI) m/z 365 (M + H)+.
  • 61
  • [ 1187450-51-6 ]
  • [ 2675-89-0 ]
  • [ 1273387-10-2 ]
YieldReaction ConditionsOperation in experiment
100% With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 4h; [Example 9] [2-(Dimethylamino)-2-oxoethyl] (6-{(pyridin-2-ylsulfonyl)[4-(thiazol-2-yl)benzyl]-aminomethyl}pyridin-2-ylamino)acetate To 1 ml of an N,N-dimethylformamide solution containing 174 mg (0.351 mmol) of (6-{(pyridin-2-ylsulfonyl)[4-(thiazol-2-yl)benzyl]aminomethyl}pyridin-2-ylamino)acetic acid obtained by the same manner as in Reference example 3-(b) were added 97 mg (0.70 mmol) of potassium carbonate and 47 mul (0.46 mmol) of<strong>[2675-89-0]2-chloro-N,N-dimethylacetamide</strong>, and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was applied to silica gel column chromatography (eluent; ethyl acetate:methanol=9:1 (V/V)), and the fractions containing the objective material were concentrated under reduced pressure to obtain 203 mg of the title compound as white foam substantially quantitatively. Mass spectrum (FAB, m/z): 581 (M++1). 1H-NMR spectrum (DMSO-d6, delta ppm): 8.67 (ddd, J=4.7, 1.8, 0.9 Hz, 1H), 7.96 (ddd, J=7.7, 7.7, 1.8 Hz, 1H), 7.92 (d, J=3.2 Hz, 1H), 7.88-7.83 (m, 2H), 7.81 (ddd, J=7.8, 1.0, 0.9 Hz, 1H), 7.78 (d, J=3.2 Hz, 1H), 7.59 (ddd, J=7.7, 4.7, 1.0 Hz, 1H), 7.38-7.33 (m, 2H), 7.21 (dd, J=8.3, 7.1 Hz, 1H), 6.92 (t, J=6.0 Hz, 0.8H), 6.35 (d, J=8.3 Hz, 1H), 6.31 (d, J=7.1 Hz, 1H), 4.77 (s, 2H), 4.73 (s, 2H), 4.27 (s, 2H), 3.98 (d, J=6.0 Hz, 2H), 2.87 (s, 3H), 2.78 (s, 3H). Rf value: 0.20 (ethyl acetate:methanol=50:1).
  • 62
  • [ 1355011-30-1 ]
  • [ 2675-89-0 ]
  • [ 1395986-73-8 ]
YieldReaction ConditionsOperation in experiment
100% A solution of methyl 6-(2,6-difluoro-4-hydroxyphenyl)-5-fluoropicolinate (1.0 equiv.) in DMF (0.17 M) was added NaH, 60% dispersion in mineral oil (1.1 equiv.). The mixture was stirred for 30 min at ambient temperature. <strong>[2675-89-0]2-chloro-N,N-dimethylacetamide</strong> (1.1 equiv.) was added in a dropwise fashion. The mixture was stirred overnight at ambient temperature. The reaction mixture was quenched by the addition of water. The mixture was extracted with ethyl acetate. The combined extracts were washed sequentially with water and brine, dried over sodium sulfate, filtered, and concentrated to give methyl 64442-(dimethylamino)-2-oxoethoxy)-2,6-difluorophenyl)-5-fluoropicolinate in 100% yield. LC/MS=369.2 (MH+), Rt=0.74 min.
  • 63
  • [ 1400703-87-8 ]
  • [ 2675-89-0 ]
  • [ 1400705-22-7 ]
YieldReaction ConditionsOperation in experiment
67% With potassium carbonate; sodium iodide; In N,N-dimethyl-formamide; at 20℃; A mixture of (S)-2-({2-[3-(lH-Indazol-4-yl)-propylamino]-4,6-dimethyl-pyrimidine-5- carbonyl}-amino)-3-[(thiophene-2-carbonyl)-amino]-propionic acid (0.05g, 0.095mmol), 2- chlorodimethyl acetamide (0.017g, 0.143mmol), sodium iodide (0.021g, 0.143mmol), and potassium carbonate (0.020g, 0.143mmol) in DMF (1ml) was stirred at rt overnight. The mixture was diluted with EtOAc, washed with brine, dried over Na2S04, filtered, concentrated the presence of silica gel and chromatographed (100% EtOAc) to give the desired product (38.8mg, 67% yield). MS m/e 607.1 (M+H+).
  • 64
  • [ 1400703-89-0 ]
  • [ 2675-89-0 ]
  • [ 1400705-07-8 ]
YieldReaction ConditionsOperation in experiment
74% With triethylamine; sodium iodide; In N,N-dimethyl-formamide; at 120℃; for 0.333333h;microwave irradiation; A mixture of (S)-2-({2-[3-(3-Hydroxy-phenyl)-propylamino]-4,6-dimethyl-pyrimidine-5- carbonyl}-amino)-3-[(thiophene-2-carbonyl)-amino]-propionic acid (200mg, 0.40mmol), 2- chlorodimethylacetamide (0.15g, 1.2mmol), sodium iodide (0.18g, 1.2mmol) and triethylamine (0.12g, 1.2mmol) in DMF (2ml) was microwaved at 120 C for 20 minutes. The mixture was diluted with EtOAc, washed with brine, dried over Na2S04, filtered, concentrated in the presence of silica gel and chromatographed (100 % EtOAc) to give the title compound (172.2mg, 74% yield). MS m/e 583.2 (M+H+).
  • 65
  • [ 229305-47-9 ]
  • [ 2675-89-0 ]
  • [ 1401719-88-7 ]
YieldReaction ConditionsOperation in experiment
69% With potassium carbonate; In N,N-dimethyl-formamide; at 45℃; for 3h; Example 6 Preparation of H-D-Gl -Trp-OCHj-CO-NfCHshl-OH, Apo894 Cbz-D-Glu(OH)-OBzl (18.57 g, 50.0 mmol), HOSu (6.04 g, 52.5 mmol) and EDCI hydrochloride (10.55 g, 55.0 mmol) were mixed in DMF (75 mL) and stirred for 2.5 h. L-Trp-OH (12.25 g, 55.0 mmol) was then added to the reaction mixture. After stirring at RT for overnight, the mixture was diluted with ethyl acetate, then washed with a 0.5N HCI solution (x2), water and brine, dried over MgS04 and filtered. The filtrate was concentrated by rotary evaporation to give Cbz-D-Glu(L-Trp-OH)-OBzl (27.5 g) as a white solid. Yield = 98%. 'H NMR (DMSO-De, 400 MHz) d ppm: 12.55 (br. s, 1H), 10.83 (br. s, 1H), 8.14 (d, J= 8.1 Hz, 1H), 7.78 (d, J= 8.1 Hz.1H), 7.51 (d, J = 7.1 Hz, 1H), 7.28 - 7.44 (m, 11 H), 7.12 (s, 1H), 7.02-7.10 (m, 1H), 6.90-7.01 (m, 1H), 5.12 (s, 2H), 4.97-5.08 (m, 2H), 4.35-4.50 (m, 1H), 4.04- 4.15 (m, 1H), 314 (dd, J = 14.7, 4.5 Hz, 1 H), 2.98 (dd, J= 14.7, 8.6 Hz, 1H), 2.12-2.27 (m, 2H), 1.87 - 2.00 (m, 1H), 1.64 - 1.81 (m, 1H). To a mixture of Cbz-D-Glu(L-Trp-OH)-OBzl (2.24 g, 4.08 mmol) with potassium carbonate (1.11 g: 8.0 mmol) in rV,/V-dimethylformamide (20 mL) warmed under a 45C temperature oil bath was added 2-chloro-W,W- dimethylacetamide (0.73 g, 6.0 mmol). After stirring for 3h, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water (x3) then brine. The product was purified by column chromatography on silica gel using a solvent mixture of ethyl acetate/hexanes {8/2, v/v) to give the desired alkylated compound Cbz-D-Glu(L-Trp-OCH2-CO-N(CH3)2)-OBzl (1.79 g) as a white foam. Yield = 69%; 1H NMR (DMSO-D6, 300 Hz} 6 ppm: 10.85 (br. s, 1 H), 8.34 (d, J = 7.5 Hz, 1 H), 7.78 (d, J = 7.5 Hz, 1H), 7.50 (d, J = 7.5 Hz, 1 H), 7.34 (br. s, 11 H), 7.19 (s, 1 H), 7.03 - 7.13 (m, 1 H), 6.93 - 7.02 (m, 1 H), 5.12 (s, 2H), 4.96 - 5.09 (m, 2H), 4.81 (q, J = 15.1 Hz, 2H), 4.49 - 4.62 (m, 1 H), 4.02 - 4.15 (m, 1H), 3.27 - 3.33 (rn, 1H), 3.01 (dd, J = 14.3, 9.8 Hz,1 H), 2.90 (s, 3H), 2.83 (s, 3H), 2.12 - 2.30 (m, 2H), 1.87 - 1.98 (m, 1 H), 1.64 - 1.80 (m, 1 H); MS (m/z): 643 [M+1f. Cbz-D-Glu(L-Trp-OCH2-CO-N(CH3)2)-OBzl (1.65 g, 2.6 mmol) and 10 % Pd-C (wet, 0.36 g) was mixed in ethanol (100 ml_). The reaction mixture was hydrogenated in a Parr apparatus for 1.5 h under an atmosphere of hydrogen.The mixture was filtered through CeiHe. The filtrate was concentrated by rotary evaporation under reduced pressure and the residue was triturated with acetonitrile. The title compound H-D-Glu(L-Trp-OCHrCO-N(CH3)2)-OH (Apo894, 1.00 g) was collected by suction filtration as a white solid. Yield = 92%; 1H NMR (DMSO-D6 + D20, 300 MHz) d ppm: 7.49 (d, J = 7.5 Hz, H), 7.34 (d, J = 7.5 Hz,1 H), 7.18 (br. s, 1 H), 6.90 - 7.12 (m, 2H), 4.79 (q, J = 15.1 Hz, 2H), 4.47 - 4.61 (m, 1 H), 3.26 - 3.39 (m, 1 H), 3.19 (t, J = 5.7 Hz, 1 H), 2.94- 3.12 (m, 1 H), 2.88 (br. s, 3H), 2.81 (br. s, 3H), 2.11 - 2.33 (m, 2H), 1.68 - 1.93 (m, 2H).
  • 66
  • [ 124-41-4 ]
  • [ 2675-89-0 ]
  • [ 4128-76-1 ]
YieldReaction ConditionsOperation in experiment
With methanol at 40℃; for 4h; Inert atmosphere; 5.1 Example 5.1Preparation of CH3-O-CH2-CONMe2 (Product 1-R1=Me)In a 1 liter reactor, initially loaded with sodium methylate in solution in methanol (25% w/w) (682 g, 3.2 mol), with nitrogen inertization, chlorodimethylacetamide (384 g, 3.2 mol) is cast within 2 hours so that the temperature of the reaction medium does not exceed +40° C. At the end of the casing, the temperature of the reaction medium is maintained at +40° C. for 2 hours. After the temperature of the reaction medium has returned to +25° C., the formed salts are removed from the mixture by filtration and the solvents are distilled under partial vacuum. The desired product of 760 g is then obtained.
  • 67
  • [ 112-30-1 ]
  • [ 2675-89-0 ]
  • [ 1296198-68-9 ]
YieldReaction ConditionsOperation in experiment
82% With sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 20h;Inert atmosphere; Example 5.3Preparation of nC10H21-O-CH2-CONMe2 (Product 3-R1=nC10H21)In a 250 mL reactor, under a nitrogen atmosphere, is introduced sodium hydride, (60% suspended in mineral oil) (5 g, 125 mmol). This product is washed with pentane (3×15 mL) and is then suspended in THF (100 g). The suspension is cooled to 0 C., n-decanol (17.4 g, 110 mmol) is introduced with a syringe. The chlorodimethylacetamide (12.1 g, 100 mmol) is then slowly added onto the mixture. The temperature of the reaction mixture is brought back to room temperature and the reaction mixture is maintained with stirring for 20 hours. The reaction mixture is neutralized with cold water (20 mL) and then this aqueous phase is extracted with dichloromethane (200 mL), the organic phase is washed with a saturated solution of NH4Cl (50 mL), a saturated solution of NaHCO3 (50 mL) and then with water (50 mL). The organic phase is dried on sodium sulfate and concentrated under reduced pressure in order to obtain 20.6 g of the expected product with a purity>98% i.e. a yield of 82%.
  • 68
  • [ 108-93-0 ]
  • [ 2675-89-0 ]
  • [ 1296198-67-8 ]
YieldReaction ConditionsOperation in experiment
72% Example 5.2Preparation of Cy-O-CH2-CONMe2 (Product 2-R1=Cy)Cyclohexanol (12.2 g, 0.11 mol) and toluene (42.2 g) are loaded In a 250 mL reactor. The temperature of this mixture is brought to 30 C. Soda (5.6 g, 0.14 mol) is then introduced with portions of about 2 g. The reaction mixture is mechanically stirred. After maintaining the stirring for ten minutes at 30 C., chlorodimethylacetamide (11.6 g, 0.09 mol) is added dropwise directly into the mass within 0.5 hour. The reaction medium is maintained with stirring at 30 C. for 5 hours. Distilled water is introduced until the totality of the salts are dissolved (about 30 mL). The organic phase is recovered and the solvents are distilled under partial pressure and the desired product is obtained, 12 g, with a yield of 72%.
  • 69
  • [ 1310704-59-6 ]
  • [ 2675-89-0 ]
  • [ 1310704-65-4 ]
YieldReaction ConditionsOperation in experiment
82% With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20 - 40℃; 7-(5-Methoxy-l//^-indol-3-yl)-l-methyl-6 osyl-l,6-dihydropyrazolo[3,4-J]pyrrolo[2,3-ft]pyridine (0.100 g, 0.212 mmol; Preparation No.P.1.1) and 60 wt% NaH (0.009 g, 0.212 mmol) were suspended in DMF (3 mL). After about 10 min, 2-chloro-A^,A^-dimethylacetamide (0.052 g, 0.424 mmol, Pfaltz-Bauer) was added and mixture was stirred at rt. After about 1 h additional 60 wt% NaH (0.005 g, 0.212 mmol) was added and the mixture was heated to about 40 C for about 16 h. The mixture was concentrated in vacuo and purified on a 4 g silica column eluting with EtOAc to provide 2-(5-methoxy-3-(l-methyl-6-tosyl-l,6-dihydropyrazolo[3,4-dJpyrrolo[2,3-bJpyridin-7- yl)-lH-indol-l-yl)-N,N-dimethylacetamide (0.097 g, 82%): LC/MS (Table 2, Method c) Rt = 1.46 min; MS m/z 557 (M+H)+.
  • 70
  • [ 1417442-65-9 ]
  • [ 2675-89-0 ]
  • [ 1417442-66-0 ]
YieldReaction ConditionsOperation in experiment
87% Step F150 mg (0.46 mmol) of N-(ieri-butoxycarbonyl)-2,2-difluoro-2-(3- butoxyphenyl)ethylamine are dissolved in dry DMF (2.5 mL) and the solution was cooled to 0C. NaH (60% in mineral oil; 22 mg; 0.55 mmol) is added and the reaction mixture stirred for 10 minutes at 0C and for further 10 minutes at room temperature. The reaction mixture is cooled again at 0C, then N,N-dimetylchloroacetamide (73 mg; 0.60 mmol) is added and stirring is continued for 24 hours at room temperature. The reaction is quenched with water, extracted three times with EtAc, washed with brine. The organic phases are dried over anhydrous Na2S04, filtered and evaporated. The residue is flash- chromatographed on silica gel (eluant: DCM/EtAc, from 98/2 to 95/5). 2-[N -(tert- butoxycarbonyl)-2,2-difluoro-2-(3-butoxyphenyl)-ethylamino]-N,N-dimethyl-acetamide (165 mg; 87%) is obtained as a white solid.
87% Step F 150 mg (0.46 mmol) of N-(tert-butoxycarbonyl)-2,2-difluoro-2-(3-butoxyphenyl)ethylamine are dissolved in dry DMF (2.5 mL) and the solution was cooled to 0 C. NaH (60% in mineral oil; 22 mg; 0.55 mmol) is added and the reaction mixture stirred for 10 minutes at 0 C. and for further 10 minutes at room temperature. The reaction mixture is cooled again at 0 C., then N,N-dimethylchloroacetamide (73 mg; 0.60 mmol) is added and stirring is continued for 24 hours at room temperature. The reaction is quenched with water, extracted three times with EtAc, washed with brine. The organic phases are dried over anhydrous Na2SO4, filtered and evaporated. The residue is flash-chromatographed on silica gel (eluant: DCM/EtAc, from 98/2 to 95/5). 2-[N'-(tert-butoxycarbonyl)-2,2-difluoro-2-(3-butoxyphenyl)-ethylamino]-N,N-dimethyl-acetamide (165 mg; 87%) is obtained as a white solid.
  • 71
  • [ 1417442-70-6 ]
  • [ 2675-89-0 ]
  • [ 1417442-71-7 ]
YieldReaction ConditionsOperation in experiment
58% With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃;Inert atmosphere; Step FA solution of iert-butyl 2-(3-butoxyphenyl)-2-fluoroethylcarbamate (136 mg; 0.44 mmol) in dry DMF (4 mL) under nitrogen atmosphere is cooled to 0C and sodium hydride (22.7 mg; 0.57 mmol) is added. The mixture is stirred at RT for 10 min, then is cooled again to 0C and 2-chloro-N,N-dimethyl-acetamide (0.054 mL; 0.524 mmol) is added. The reaction mixture is stirred at RT for 4 hours. An LC/MS shows very low conversion. Additional sodium hydride (38 mg; 0.96 mmol) is added followed after 10 min by 2-chloro-N,N- dimethyl-acetamide (0.09 mL; 0.87 mmol). Stirring is continued for 12 hours. An LC/MS shows almost complete conversion. The solvent is evaporated, EtAc is added and the solution is washed with brine, then dried over anhydrous Na2S04, filtered and evaporated. The crude residue is purified by flash-chromatography (DCM/EtAc from 96/4 to 95/5) yielding iert-butyl N- [2-(3-butoxyphenyl)-2-fluoroethyl]-N- [(2-dimethylamino)-2- oxoethyl)] -carbamate (100 mg; 0.25 mmol; 58%) as a colourless oil.
58% Step F A solution of tert-butyl 2-(3-butoxyphenyl)-2-fluoroethylcarbamate (136 mg; 0.44 mmol) in dry DMF (4 mL) under nitrogen atmosphere is cooled to 0 C. and sodium hydride (22.7 mg; 0.57 mmol) is added. The mixture is stirred at RT for 10 min, then is cooled again to 0 C. and 2-chloro-N,N-dimethyl-acetamide (0.054 mL; 0.524 mmol) is added. The reaction mixture is stirred at RT for 4 hours. An LC/MS shows very low conversion. Additional sodium hydride (38 mg; 0.96 mmol) is added followed after 10 min by 2-chloro-N,N-dimethyl-acetamide (0.09 mL; 0.87 mmol). Stirring is continued for 12 hours. An LC/MS shows almost complete conversion. The solvent is evaporated, EtAc is added and the solution is washed with brine, then dried over anhydrous Na2SO4, filtered and evaporated. The crude residue is purified by flash-chromatography (DCM/EtAc from 96/4 to 95/5) yielding tert-butyl N-[2-(3-butoxyphenyl)-2-fluoroethyl]-N-[(2-dimethylamino)-2-oxoethyl)]-carbamate (100 mg; 0.25 mmol; 58%) as a colourless oil.
  • 72
  • [ 26621-44-3 ]
  • [ 2675-89-0 ]
  • [ 1343183-73-2 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In acetonitrile; at 60℃; for 48h; A solution of <strong>[26621-44-3]3-nitropyrazole</strong> (300mg, 2.65mmol), potassium carbonate (2eq) and 2-chloro- N,N-dimethylacetamide (l . leq) in acetonitrile (lOmL) was heated at 60C for 48h. After cooling to rt the mixture was filtered and the filtrate diluted with DCM then washed with H20. The organic phase was collected, dried (hydrophobic frit) and concentrated in vacuo. The crude residue was dissolved in methanol (lOmL), palladium on carbon (50mg) was added and the reaction was stirred under a balloon of hydrogen for 18h. The resulting mixture was filtered through Celite and the filtrate concentrated in vacuo to give 2-(3-amino-lH-pyrazol-l- yl)-N,N-dimethylacetamide.
  • 73
  • [ 14430-23-0 ]
  • [ 2675-89-0 ]
  • [ 81633-43-4 ]
YieldReaction ConditionsOperation in experiment
40% With trichlorophosphate; at 0 - 20℃; for 2.5h; General procedure: Phoshorus oxychloride (0.913 mL, 10 mmol) was added dropwise at 0 C to a solution of the appropriate indole (8-10) (177 mg, 1 mmol) in dimethylamide of chloroacetic acid (3.08 mL, 30 mmol) and the mixture was stirred for 2.5 h at room temperature. The reaction mixture was neutralized by NaOH 2 N aqueous solution (4 mL), extracted with EtOAc (3 x 10 mL) and washed with NaHCO3 saturated aqueous solution (2 x 10 mL). The organic layer was dried over dry Na2SO4 and after evaporation of the solvent under reduced pressure, the residue was crystallized from DCM. Spectral data for compounds 13-14 were in accordance with literature.13,14
  • 74
  • [ 2675-89-0 ]
  • [ 73664-43-4 ]
YieldReaction ConditionsOperation in experiment
53% With sodium iodide; In acetonitrile; at 60℃; for 2h; Preparation of 2-iodo-N,N-dimethylacetamide After <strong>[2675-89-0]2-chloro-N,N-dimethylacetamide</strong> (1.3 g, 10.69 mmol) was dissolved in acetonitrile (33 mL), sodium iodide (7.23 g, 48 mmol) was added thereto, and the mixture was stirred for 2 hours at 60 C. Water (30 mL) was added to the reaction material and the result was extracted with ethyl acetate (30 mL*2). The organic layer was dried with anhydrous magnesium sulfate, and concentrated under reduced pressure to give a target compound (1.2 g, 53%). 1H-NMR (300 MHz, CDCl3) delta 2.96 (s, 3H), 3.05 (s, 3H), 3.74 (m, 2H)
53% With sodium iodide; In acetonitrile; at 60℃; for 2h; After <strong>[2675-89-0]2-chloro-N,N-dimethylacetamide</strong> (1.3 g, 10.69 mmol) was dissolved in acetonitrile (33 mL), sodium iodide (7.23 g, 48 mmol) was added thereto, and the mixture was stirred for 2 hours at 60C. Water (30 mL) was added to the reaction material and the result was extracted with ethyl acetate (30 mLx2). The organic layer was dried with anhydrous magnesium sulfate, and concentrated under reduced pressure to give a target compound (1.2 g, 53%). 1H-NMR (300 MHz, CDCl3) delta 2.96 (s, 3H), 3.05 (s, 3H), 3.74 (m, 2H).
  • 75
  • [ 1306763-31-4 ]
  • [ 2675-89-0 ]
  • [ 1306763-46-1 ]
YieldReaction ConditionsOperation in experiment
Stage #1: tert-butyl N-[(1S)-4-cyano-2,3-dihydro-1H-inden-1-yl]carbamate With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 3h; Stage #2: 2-chloro-N,N-dimethylacetamide In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 1.5h; (S)-tert-butyl 4-cyano-2, 3-dihydro-lH-inden-l-yl(2-(dimethylamino)-2- oxoeth l)-carbamate Prepared using General Procedure 9. To a solution of (5)-tert-butyl 4- cyano-2,3-dihydro-7H-inden-l-ylcarbamate INT-9 (3.0 g, 1.16 mmol) in DMF (20 mL) was added NaH (1.39 g of 60%> dispersion in mineral oil, 34.8 mmol) at 0°C with stirring for 3 h before the addition of 2-chloro-N,N-dimethylacetamide (2.82 g, 23.2 mmol). The reaction mixture was stirred at 0°C for 0.5 h and then warmed to room temperature for 1 h. The reaction mixture was quenched with water (3 mL) slowly at 0°C. The mixture was partitioned between EA (3 x 20 mL) and water (50 mL). The combined organic layers were concentrated and purified by chromatography (DCM / MeOH) to provide product 3.82 g (96.0 %) of (5)-tert-butyl 4-cyano-2,3-dihydro-7H- inden-l-yl(2-(dimethylamino)-2-oxoethyl)carbamate as a light brown solid. LCMS-ESI (m/z) calculated for Ci9H25ClN606; 343.4; found 366.1 [M+Na]+, tR = 3.16 min.
  • 76
  • tert-butyl (E)-(2S,3S)-2-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-carboxy-ethylcarbamoyl]-11-(2-heptyl-[1,3]dioxolan-2-yl)-2-hydroxy-undec-4-enoate [ No CAS ]
  • [ 2675-89-0 ]
  • C51H84N2O11Si [ No CAS ]
YieldReaction ConditionsOperation in experiment
>= 99% With tetra-(n-butyl)ammonium iodide; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 50℃; for 12h;Inert atmosphere; (S)-2-{(E)-(S)-1-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-diethylcarbamoylmethoxycarbonyl-ethylcarbamoyl]-10-oxo-heptadec-2-enyl}-2-hydroxy-succinate No. 5459786: Compound I (11.21 g, 13.279 mmol) was dissolved in dichloromethane (33 mL), and 2-chloro-N, N-dimethylacetamide (1.5 mL, 14.6 mmol), tetrabutylammonium iodide (980 mg, 2.66 mmol), N,N-diisopropylethylamine (2.5 mL) were added in order. The reaction mixture was stirred at 50 C for 12 hours, cooled to room temperature, then diluted in ethyl acetate (100 mL), and washed with a saturated aqueous solution of ammonium chloride (100 mL). The separated organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain No. 5459787: Compound O (12.4 g, yield 99% or more, ESI (LC/MS positive mode) m/z 930 (M+H); Rt 4.59 min.).
  • 77
  • [ 3481-09-2 ]
  • [ 2675-89-0 ]
  • [ 13648-32-3 ]
  • 78
  • [ 62-53-3 ]
  • [ 2675-89-0 ]
  • [ 587-65-5 ]
YieldReaction ConditionsOperation in experiment
81% With [2,2]bipyridinyl; boron trifluoride diethyl etherate; oxygen; palladium diacetate; Trimethylacetic acid; In toluene; at 120℃; for 24h; General procedure: Under molecular oxygen atmosphere, to a mixture of Pd(OAc)2 (1.3 mg, 0.006 mmol) and bpy (0.9 mg, 0.006 mmol), toluene (2.0 mL) was added. Then aniline (0.2 mmol), amide (2.0 mmol), PivOH (40.9 mg, 0.4 mmol), and BF3Et2O (42.6 mg, 0.3 mmol) were added to the mixture. The mixture was heated to 120 C and it stirred at 120 C for 24 h. After completion, the mixture was cooled to room temperature and diluted with ethyl acetate. Washed withaq NaHCO3, water, and aq NaCl. Dried over MgSO4 and filtered. Aftere vaporation of the solvent, the residue was purified by preparative thin-layer chromatography on silica gel with PE/EtOAc (1/1) as aneluent to give the product 3.
  • 79
  • 9-ethyl-6,6-dimethyl-11-oxo-8-(1H-pyrazol-4-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile [ No CAS ]
  • [ 2675-89-0 ]
  • 2-(4-(3-cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl)-1H-pyrazol-1-yl)-N,N-dimethylacetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
71% With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 55 - 80℃; for 48h; General procedure: A mixture of compound 18d (0.1 mmol), a corresponding chlo-ride (0.15 mmol), K2CO3 (0.3 mmol) and KI (0.05 mmol) in DMF (3 mL) was heated at 55 o Ce80 o C for 2 days. The mixture wasdiluted with EtOAc (120 mL), washed with brine and then dried over with Na2SO4, ltered, and evaporated. The crude product was puried by chromatograph (CHCl3/MeOH) to give the correspond-ing product. 5.22.1 2-(4-(3-Cyano-9-ethyl-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol -8-yl)-1H-pyrazol-1-yl)-N,N-dimethylacetamide (21a). White solid (71% yield) 1H NMR (400 MHz, CDCl3 + CD3OD) delta 8.41 (d, J = 8.0 Hz, 1H), 8.22 (s, 1H), 7.72 (s, 1H), 7.65 (s, 1H), 7.63 (s, 1H), 7.50 (s, 1H), 7.47 (d, J = 8.4 Hz, 1H), 5.03 (s, 2H), 3.10 (s, 3H), 2.97 (s, 3H), 2.76 (q, J = 7.7 Hz, 2H), 1.70 (s, 6H), 1.21 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, CDCl3 + CD3OD) delta 180.9, 166.6, 159.9, 145.2, 140.6, 139.3, 135.9, 135.9, 130.5, 130.3, 128.3, 127.3, 126.6, 125.2, 122.5, 121.9, 120.4, 116.1, 110.7, 105.4, 53.1, 36.8, 36.4, 36.0, 30.2, 26.2, 15.1. MS (ESI) m/z 464 [M - H]-. HRMS: calcd for C28H26N5O2 [M - H]-, 464.2087; found 464.2100.
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; Compound 5-2 and 2 eq of compound <strong>[2675-89-0]2-chloro-N,N-dimethylacetamide</strong> were dissolved in dimethylformamide (DMF), 4 eq of potassium carbonate was added, and the mixture was heated to 80 C. overnight.After the reaction was completed, the reaction solution was cooled, slowly poured into ice-water mixture, extracted twice with ethyl acetate, and the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate and mixed with silica gel, CHCl 3 :MeOH=100: Compounds S5 were obtained from 1 to 30:1.
  • 80
  • 6-chloro-3-iodonaphthalen-2-ol [ No CAS ]
  • [ 2675-89-0 ]
  • 2-(6-chloro-3-iodonaphthalen-2-yloxy)-N,N-dimethylacetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
89.8% With potassium carbonate; In N,N-dimethyl-formamide; at 30℃; for 2h; A mixture of 6-chloro-3-iodonaphthalen-2-ol (1 g, 3.29 mmol), <strong>[2675-89-0]2-chloro-N,N-dimethylacetamide</strong> (0.37 mL, 3.62 mmol), potassium carbonate (914 mg, 6.58 mmol) in DMF was stirred at 30 C for 2 hr, then quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SC>4, and concentrated under reduced pressure. The residue was purified by column chromatography (eluted with PE/ EtOAc =1/1) to give 2-(6-chloro-3-iodonaphthalen-2-yloxy)-N,N- dimethylacetamide (1.15 g, 89.8% yield). LC-MS: m z 390 (M+H)+.
  • 81
  • [ 23872-36-8 ]
  • [ 2675-89-0 ]
  • 4-chloro-1-dimethylcarbamoylmethyl-1H-indole-3-carboxylic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
426 mg With barium(II) hydroxide octahydrate; In N,N-dimethyl-formamide; at 50℃; Step 1 Preparation of 4-Chloro-1-dimethylcarbamoylmethyl-1H-indole-3-carboxylic acid 2-chloro-N,N-dimethylacetamide (0.19 ml; 1.84 mmol; 1.20 eq.) was added to a solution of 4-Chloro-1H-indole-3-carboxylic acid (300.00 mg; 1.53 mmol; 1.00 eq.) and barium hydroxide octahydrate (967.67 mg; 3.07 mmol; 2.00 eq.) in DMF (15.63 ml; 202.65 mmol; 132.13 eq.) at 50° C. The reaction mixture was stirred overnight. The reaction mixture was diluted with DMSO (1 ml) and water (1 ml) then submitted to MPLC purification (Yamazen, Interchim 100 g polymeric Reverse Phase column, basic buffer) to afford the desired product 4-Chloro-1-dimethylcarbamoylmethyl-1H-indole-3-carboxylic acid (426.00 mg; 1.52 mmol) as a white solid. 1H NMR (400 muMHz, MeOD) delta 7.42 (s, 1H), 6.89-6.79 (m, 1H), 6.78-6.64 (m, 2H), 4.73 (s, 2H), 2.73 (s, 3H), 2.57-2.49 (m, 4H) ppm; [M+H]+ 281.1. LC-MS (254 nm) tR=3.47 min; HPLC (254 nm) Purity: >99percent; tR=2.68 min.
  • 82
  • [ 156-38-7 ]
  • [ 2675-89-0 ]
  • [ 59721-16-3 ]
YieldReaction ConditionsOperation in experiment
Ca. 45 g With sodium hydrogensulfite; triethylamine In water at 40 - 95℃; 2 N, N-dimethyl-2-chloroacetamide prepared in the step (1) and 9 g of triethylamine were added to the reaction vessel with stirring at low speed, and then 0.4 g of sodium bisulfite and 40g p-hydroxyphenylacetic acid were added. 17.6g of triethylamine was droped at 40-95°C. After dropping, keep at 80-95 °C. The reaction was carried out for 3 hours. 90 g of sodium hydrogen sulfite solution (0.05 g of NaHSO3 + 90 g of H2O) was added, the starting temperature was 70°C or higher, the final temperature of addition was 48°C or more, and the resultant mixture was cooled and crystallized (cooling temperature: 0-5°C, crystallization time: 2 hours). To the reaction vessel was added 20.2 g of sodium hydrogen sulfite solution (0.2 g of NaHSO3 + 20 g of H2O), followed by the addition of crude (2-(dimethylamino)-2-oxoethyl)-2-(4-hydroxyphenyl)acetate(Crystallization temperature of 0-5°C, crystallization time of 1 hour), suction filtration, filter cake with 10mL of water (10mL), and the mixture was washed with water Washed, dried and then washed with 20 mL of ethyl acetate, drained, dried under reduced pressure (60 ± 3 ° C for 2 hours), and finally dried (Crystallization temperature 0-5 , the crystallization time of 1 hour), filtration, the filter cake to 17mL acetonitrile washing, drained, and then washed with acetone, Dried under reduced pressure (60 ± 3 ° C, 2 hours) to give (2-(dimethylamino)-2-oxoethyl)-2-(4-hydroxyphenyl)acetate with a yield of about 45g.
45 g With sodium hydrogensulfite; triethylamine In water at 70 - 95℃; for 3h; 2 A method for the preparation of Camostat mesilate intermediates comprising the steps of: (2), 30.6 g of N, N-dimethylchloroacetamide, 9 g of triethylamine TEA, 0.4 g of sodium bisulfite and 40 g of p-hydroxyphenylacetic acid were sequentially charged into a reaction vessel for low-speed stirring, (0.05gNaHSO3 + 90gH2O) was added to the reaction temperature, and the starting temperature was above 70 . After the reaction was carried out, the reaction mixture was stirred at 80-95 ° C for 3 hours. After the reaction, the aqueous solution of sodium bisulfite , Add the end of the temperature above 48 , after the completion of cooling, cooling at 40 , adding the seed crystal, keep the cooling temperature 0-5 , crystallization 2h, crystallization after filtration, filter cake 100g purified water washing, P-hydroxyphenylacetic acid-N, N-dimethylcarbamoylmethyl ester, 50 mL of ethyl acetate was added to a solution of sodium bisulfite (0.2 GNaHSO3 + 20gH2O) dissolved in the solution, after cooling, crystallization crystallization, to maintain the crystallization temperature of 0-5 , crystallization time 1h, crystallization after filtration, filter cake washed with 10mL water, dried and then 20mL acetic acid Ethyl ester washing, drying and then at 60 ± 3 under reduced pressure drying 2h, the p-hydroxyphenylacetic acid -N, N-dimethyl carbamoyl methyl ester dry products; yield of about 47g; (3), 47 g of p-hydroxyphenylacetic acid-N, N-dimethylcarbamoylmethyl ester concentrate was added to 30 mL of acetonitrile and dissolved by heating. After completion of the dissolution, the temperature was cooled to 0-5 ° C, After the end of the crystal, the filter was filtered and the filter cake was washed with 17 mL of acetonitrile and dried at 60 ± 3 ° C for 2 hours under reduced pressure to give the Camostat mesilate intermediate, p-hydroxyphenylacetic acid, N, N-dimethylamino Formyl methyl ester, yield about 45g.
  • 83
  • 4-(5-((((R)-2-((R)-1-(N-(benzyloxy)formamido)propyl)heptanamido)methyl)carbamoyl)furan-2-yl)benzoic acid [ No CAS ]
  • [ 2675-89-0 ]
  • 2-(dimethylamino)-2-oxoethyl 4-(5-((((R)-2-((R)-1-(N-(benzyloxy)formamido)propyl)heptanamido)methyl)carbamoyl)furan-2-yl)benzoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
75% With triethylamine; sodium iodide; In N,N-dimethyl-formamide; at 20℃; for 96h; INTERMEDIATE 122: 2-(dimethylamino)-2-oxoethyl 4-(5-((((R)-2-((R)-1 -(N- (benzyloxy)formamido)propyl)heptanamido)methyl)carbamoyl)furan-2-yl)benzoate To a solution containing 4-(5-((((R)-2-((R)-1-(N- (benzyloxy)formamido)propyl)heptanamido)methyl)carbamoyl)furan-2-yl)benzoic acid (100 mg, 0.177 mmol), sodium iodide (31.9 mg, 0.213 mmol) and 2-chloro-N, N- dimethylacetamide (0.036 mL, 0.355 mmol) in DMF (1 mL) was added TEA (0.124 mL, 0.887 mmol). The reaction mixtures were stirred at RT for 65 h. Additional 2-chloro-N,N- dimethylacetamide (0.036 mL, 0.355 mmol), sodium iodide (31.9 mg, 0.213 mmol) and TEA (0.124 mL, 0.887 mmol) was added and stirred for 96 h RT. The reaction mixture was diluted with EtOAc and washed with water. The organic phase was washed with water 2x and the combined aqueous layers were washed with EtOAc. The combined organic layer was passed through a hydrophobic frit and concentrated. Purification by Si (0-10% MeOH/EtOAc) afforded the title compound as an yellow solid. (86 mg, 75 % yield). MS (m/z) 649.2 (M+H)+
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