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[ CAS No. 405939-39-1 ] {[proInfo.proName]}

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Chemical Structure| 405939-39-1
Chemical Structure| 405939-39-1
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Quality Control of [ 405939-39-1 ]

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Product Details of [ 405939-39-1 ]

CAS No. :405939-39-1 MDL No. :MFCD07368614
Formula : C8H11BrN2O2S Boiling Point : -
Linear Structure Formula :- InChI Key :OIBKBVFFZYCBAQ-UHFFFAOYSA-N
M.W : 279.15 Pubchem ID :21300388
Synonyms :

Calculated chemistry of [ 405939-39-1 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 14
Num. arom. heavy atoms : 5
Fraction Csp3 : 0.5
Num. rotatable bonds : 4
Num. H-bond acceptors : 3.0
Num. H-bond donors : 1.0
Molar Refractivity : 60.06
TPSA : 79.46 ?2

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : Yes
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.96 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.5
Log Po/w (XLOGP3) : 2.88
Log Po/w (WLOGP) : 3.06
Log Po/w (MLOGP) : 1.4
Log Po/w (SILICOS-IT) : 2.48
Consensus Log Po/w : 2.47

Druglikeness

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

Water Solubility

Log S (ESOL) : -3.39
Solubility : 0.115 mg/ml ; 0.000412 mol/l
Class : Soluble
Log S (Ali) : -4.21
Solubility : 0.0173 mg/ml ; 0.0000619 mol/l
Class : Moderately soluble
Log S (SILICOS-IT) : -3.1
Solubility : 0.224 mg/ml ; 0.000804 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 0.0
Synthetic accessibility : 2.9

Safety of [ 405939-39-1 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H332-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 405939-39-1 ]

* 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 [ 405939-39-1 ]

[ 405939-39-1 ] Synthesis Path-Downstream   1~11

  • 1
  • [ 405939-39-1 ]
  • (S)-2-(Naphthalene-2-sulfonylamino)-pent-4-ynoic acid cyclopentyl-methyl-amide [ No CAS ]
  • {5-[4-(cyclopentyl-methyl-carbamoyl)-4-(naphthalene-2-sulfonylamino)-but-1-ynyl]-thiazol-2-yl}-carbamic acid <i>tert</i>-butyl ester [ No CAS ]
  • 2
  • [ 3034-22-8 ]
  • [ 24424-99-5 ]
  • [ 405939-39-1 ]
YieldReaction ConditionsOperation in experiment
73% With dmap; triethylamine; In dichloromethane; at 20℃; for 2h;Inert atmosphere; To a solution of 5-bromothiazol-2-amine (4.46 g, 24.9 mmol), di-ferf-butyl dicarbonate (6.52 g, 30 mmol) and 4-dimethylaminopyridine (0.304 g, 2.5 mmol) in dichloromethane (120 ml_) at room temperature was added triethylamine (6.3 g, 62.3 mmol) dropwise under nitrogen. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with dichloromethane (200 ml_) and washed with 1 N hydrochloric acid solution (50 ml_ x 2). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 10/1 ) to give ferf-butyl 5-bromothiazol-2-ylcarbamate as a white solid (4.04 g, 1 8.1 mmol, 73%); LCMS (ESI) m/z: 223.0 [M+H]+.
64% With potassium carbonate; In dichloromethane; at 20℃; for 16h; Example 15, Step E [00157] To a solution of 15_1 (58 g, 0.223 mol) in DCM (580 mL) was added Boc20 (58.3 g, 0.268 mol) and K2C03 (62.0 g, 0.446 mol). The reaction solution was stirred at 20 C for 16 hours, filtered, concentrated in vacuo and purified by chromatography on silica gel to afford compound 15_2 (40 g, 64%) as a white solid.
64% With potassium carbonate; In dichloromethane; at 20℃; for 16h; Example 15, Step E[00157] To a solution of 15_1 (58 g, 0.223 mol) in DCM (580 mL) was added Boc20 (58.3 g, 0.268 mol) and K2C03 (62.0 g, 0.446 mol). The reaction solution was stirred at 20 C for 16 hours, filtered, concentrated in vacuo and purified by chromatography on silica gel to afford compound 15_2 (40 g, 64%) as a white solid.
40% With dmap; In tetrahydrofuran; at 20℃; for 48h; To a solution of 153 5-bromothiazol-2-amine (46) (105g, 403.1mmol) in 154 THF (500mL) was added 155 DMAP (2.41g, 20mmol) and the solution became turbid. Then a solution of Boc2O (105.6g, 484.6mmol) in THF (50mL) was added to the above mixture slowly and the resulting mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated and the crude product was purified by silica gel flash chromatography (eluting with ethyl acetate in 74 petroleum ether 10-17%) to give 156 47 as an off-white solid (45.1g, yield=40%). 1H NMR (400MHz, CDCl3) delta 11.75 (br, 1H), 7.24 (s, 1H), 1.58 (s, 9H); LC/MS (ESI, m/z) 222.98 [M+H-56]+.
52.1 mmol With dmap; In tetrahydrofuran; at 20℃; for 6h; Step a. To a solution of 2-amino-5-bromothiazole (73.06 mmol) and DMAP (3.6mmol) in THF (130 ml) was added (BOC)20 (73.06 mmol) at rt. The reaction mixture was stirred at rt for 6 h. Excess THF was removed under reduced pressure and the resulting residue was purified by column chromatography (0-5% EtOAc in Hexane) yielding tert-butyl (5- bromothiazol-2-yl)carbamate (52.1mmol). MS: ES+ 279.08; 1H MR (400 MHz, DMSO-d6) delta ppm 11.75 (s, 1H), 7.44 (s, 1H), 1.48 (s, 9H).
14.5 g With dmap; In tetrahydrofuran; at 20℃; for 6h; To a solution of 2 -amino-5 -bromothiazole (13 g, 72.62 mmol) and DMAP (0.44 g, 3.63 mmol) in THF (130 ml) was added (Boc)20 (15.83 g, 72.62 mmol) at rt. The reaction mixture was stirred at rt for 6 h. Excess THF was removed under reduced pressure and the resulting residue was purified by column chromatography (0-5% EtOAc in Hexane) yielding tert-butyl (5-bromothiazol-2- yl)carbamate (14.5 g, 52.16 mmol). LCMS: Method C, 2.28 min, MS: ES+ 279.08; NMR (400 MHz, DMSO-d6) 5 ppm 11.75 (s, 1H), 7.44 (s, 1H), 1.48 (s, 9H).

  • 3
  • [ 89031-84-5 ]
  • [ 405939-39-1 ]
  • [ 405939-40-4 ]
  • 4
  • [ 170961-15-6 ]
  • [ 405939-39-1 ]
YieldReaction ConditionsOperation in experiment
73.9% With N-Bromosuccinimide; In tetrahydrofuran; at 20℃; for 12h; tert-Butyl 5-bromothiazol-2-ylcarbamate 3. A suspension of NBS (6.2 g, 34.6 mmol, 1.1 equiv) and tert-butyl thiazol-2-ylcarbamate (6.3 g, 31.5 mmol, 1.0 equiv) in THF (100 mL) was stirred at room temperature for 12 hours. Then, the reaction mixture was filtrated and purified by column chromatography to give target compound (6.5 g, 73.9%).
With N-Bromosuccinimide; In tetrahydrofuran; at 20℃; Terf-butyl 1 ,3-thiazol-2-ylcarbamate (90 g, 449.8 mmol, 1 eq.) is taken in THF (1 .4 L) to which is added /V-bromosuccinimide (88.06 g, 494.8 mmol, 1 .1 eq.) portion wise. The reaction mixture is then stirred at RT overnight. The reaction mass is concentrated to remove THF. The crude is purified by column chromatography to get the titled product.1H NMR(DMSO-d6, 400 MHz): delta 1 1 .73 (bs, 1 H), 7.42 (s, 1 H), 1.46 (s, 9H).
  • 5
  • [ 824-94-2 ]
  • [ 405939-39-1 ]
  • [ 881402-27-3 ]
YieldReaction ConditionsOperation in experiment
66% With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 1h;Inert atmosphere; 7-Butyl (5-bromothiazol-2-yl)carbamate was dissolved in DMF (40 mL). To the solution were added CS2CO3 (18.0 g, 56.0 mmol) followed by 4-methoxybenzyl chloride (5.1 g, 33.0 mmol). The mixture was stirred at 80 C for 1 h. The reaction mixture was cooled to 25 C, quenched with water (100 mL), and extracted with Et20 (3 x 100 mL). The organic extracts were dried over MgSCL, filtered, and concentrated under reduced pressure. The product, purified by flash column chromatography (hexane: EtOAc; 1 :0 to 7:3), was obtained as a colorless oil (8.7 g, 66 %). (0298) 111 NMR (500 MHz, Chloroform-d) iJtppm); 7.36 (s, 1H), 7.28 - 7.33 (m, 2H), 6.82 - 6.88 (m, 2H), 5.22 (s, 2H), 3.80 (s, 3H), 1.60 (s, 9H); (0299) 13C NMR (126 MHz, Chloroform-d) d (ppm) 161.6, 159.2, 153.3, 138.4, 129.8, 129.4, 113.9, 103.6, 84.1, 55.4, 49.0, 28.4; (0300) HRMS calcd for CieHzoBr^CbS [M+H]+ 399.0373, found 399.0371.
52.4% With 1,8-diazabicyclo[5.4.0]undec-7-ene; In dichloromethane; at 20℃; To a solution of <strong>[405939-39-1]tert-butyl (5-bromothiazol-2-yl)carbamate</strong> (LXII) (1.3 g, 4.66 mmol) in DCM (23 mL) was added DBU (2.1 mL, 14.04 mmol) was followed by 1-(chloromethyl)-4-methoxybenzene (LXIII) (0.95 mL, 7.01 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (24 g) (0?10% EtOAc/hexanes) to produce tert-butyl (5-bromothiazol-2-yl)(4-methoxybenzyl)carbamate (LXIV) as an off-white solid (974 mg, 2.44 mmol, 52.4% yield). ESIMS found for C16H19BrN2O3S m/z 399.1 (M+H).
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In dichloromethane; To a single necked round bottom flask (5-Bromo-thiazol-2-yl)-carbamic acid tert-butyl ester (1.4 g, 5.01 mmol) was dissolved in 25 ml dry DCM. To it 1,8-Diazabicyclo[5.4.0]undec-7-ene(DBU) (2.24 ml, 15.03 mmol) was added followed by 1-Chloromethyl-4-methoxy-benzene (1.02 ml, 7.52 mmol) addition was done and reaction mixture was stirred for overnight. Reaction was quenched by addition of water (20 ml), extracted with DCM (25 ml), Organic layer was separated and washed with brine (30 ml) and dried over anhydrous sodium sulfate, sodium sulfate was filtered and washed with DCM (20 ml) and solvent was evaporated on rotavapour to get required product. The crude material was purified by silica-gel column chromatography, eluding with 4% acetone in hexane. (1.4 g). 1H NMR (400 MHz, CDCl3): delta 1.44(s, 9H), 3.70(s, 3H), 5.11(s, 2H), 6.74 (d, J=8.2 Hz, 2H), 7.21 (d, J=7.9 Hz, 2H), 7.22 (s, 1H). MS (EI) m/z: 400.8 (M+1).
  • 6
  • [ 405939-39-1 ]
  • [ 405939-42-6 ]
  • 7
  • [ 67-63-0 ]
  • [ 405939-39-1 ]
  • [ 905300-50-7 ]
YieldReaction ConditionsOperation in experiment
90% With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 0 - 20℃; [00157] To a solution of tert-butyl 5 -bromothiazol-2-ylcarbamate (3 g, 10.7 mmol), isopropanol (6.40 g, 107.4 mmol) and triphenylphosphine (5.63 g, 21.5 mmol) in THF (30 mL) was added diethyl azodicarboxylate dropwise at O0C. The mixture was stirred at O0C and slowly warmed up to room temperature overnight. The solvent was evaporated. The residue was redissolved in dichloromethane (20 mL) and filtered to <n="55"/>get rid of the undissolved solid. The filtrate was concentrated and purified by column chromatography on silica gel using 100% hexane to give a light yellow oil (3.1O g, 90% yield). LCMS (Conditions C): 4.19 min (RT); (M+H)+ = 267.01 (100%), 265.01 (95%), 224.95 (60%), 222.95 (60%). 1H NMR, 400 MHz, CDCl3: delta 7.34 (s, 1 H), 5.29 (m, 1 H), 1.59 (s, 9 H), 1.45 (d, 6.8 Hz, 6 H).
90% With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 0 - 20℃; To a solution of tert-butyl 5 -bromothiazol-2-ylcarbamate (3 g, 10.7 mmol), isopropanol (6.40 g, 107.4 mmol) and triphenylphosphine (5.63 g, 21.5 mmol) in THF (30 mL) was added diethyl azodicarboxylate dropwise at O0C. The mixture was stirred at O0C and slowly warmed up to room temperature overnight. The solvent was evaporated. The residue was redissolved in dichloromethane (20 mL) and filtered to <n="65"/>get rid of the undissolved solid. The filtrate was concentrated and purified by column chromatography on silica gel using 100% hexane to give a light yellow oil (3.1O g, 90% yield). LCMS (Conditions C): 4.19 min (RT); (M+H)+ = 267.01 (100%), 265.01 (95%), 224.95 (60%), 222.95 (60%). 1H NMR, 400 MHz, CDCl3: delta 7.34 (s, 1 H), 5.29 (m, 1 H), 1.59 (s, 9 H), 1.45 (d, 6.8 Hz, 6 H).
79% Step 2: Preparation 18b; To a solution of Preparation 18a (10 g, 36 mmol), triphenylphosphine (14.1 g, 54 mmol), and isopropanol (4.1 mL, 54 mmol) in THF (75 mL) at rt was slowly added diethyl azodicarboxylate (8.4 mL, 54 mmol) over 10 min causing a slight exothermic reaction. After stirring for 2.5 h at rt, the reaction was concentrated in vacuo to remove the THF and the remaining material was dissolved in ethyl acetate (150 mL). The solution was washed with 1 N aq. HCl (3×100 mL), water (50 mL), and satd. Aq. sodium bicarbonate (50 mL), then dried over anhyd sodium sulfate, filtered, and concentrated in vacuo to afford a thick reddish-brown oil. Approximately 50 mL of ethyl acetate was added causing a precipitate to form from the solution. The solution was filtered to remove the solid and the resulting clear solution was concentrated. To the resulting material was then added diethyl ether (200 mL) and a 20% aq. solution of Oxone was added and the mixture was stirred vigorously at rt for ?16 h. Ethyl acetate (200 mL) was added and the resulting layers were separated. The organic layer was concentrated and the resulting oil was purified by flash chromatography on silica gel using a gradient elution from 5% to 10% ethyl acetate in hexanes as the eluant. Fractions containing the product were collected and concentrated to afford 9.2 g (79%) of a grey solid as Preparation 18b. HPLC Ret. time: 4.20 min.
5.0 g With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 75℃; for 3.16667h;Inert atmosphere; A mixture of <strong>[405939-39-1]tert-butyl (5-bromothiazol-2-yl)carbamate</strong> (5.0g, 18.0 mmol), PPh3 (10.37 g, 39.57 mmol) and IPA (3.2 g, 54.0 mmol) in THF (50 ml) was cooled at 0C under N2 atmosphere. DIAD (7.70 ml, 39.6 mmol) was added dropwise to the reaction mixture at 0C. The reaction mixture was stirred at rt for 10 min and then heated to 75 C for 3 h. The resulting reaction mixture cooled to rt and was concentrated under reduced pressure. The residue was purified by column chromatography (2-5% EtOAc in hexane) yielding tert-butyl (5-bromothiazol-2-yl)(isopropyl)carbamate (5.0 g, 15.62 mmol). LCMS: Method C, 3.11 min, MS: ES+ 321.1, 323.1(M + 2); NMR (400 MHz, CDC13) delta ppm 7.36 (s, 1, 1H), 5.26 - 5.33 (m, 1H), 1.61 (s, 9H), 1.45 (d, J=7.2 Hz, 6H).

  • 8
  • [ 24424-99-5 ]
  • [ 61296-22-8 ]
  • [ 405939-39-1 ]
YieldReaction ConditionsOperation in experiment
91% With dmap; triethylamine; In tetrahydrofuran; at 0℃; Di-tert-butyl dicarbonate [(Boc)20, 100.7 g, 0.461 mol, 1.2 eq] was added to a flask containing a mixture of 2-amino-5-bromothiazole monohydrobromide (la?, 100 g, 0.385 mol, 1.0 eq) and 4-(dimethylamino)pyridine (DMAP, 1.18 g, 9.7 mmol, 0.025 eq) in900 mL of THF and 135 mL of Et3N and cooled to 0 C using an ice bath. The reaction mixture was stirred at r.t. overnight and then concentrated in vacuo. The residue was stirred in EtOAc/Heptane (1:10, 250 ml) at rt overnight and then filtered. The filtrate was washed with brine, dried, filtered, and concentrated in vacuo to furnish intermediate lb? as a yellow solid (91% yield).
78% 4.2 Synthesis of tert-butyl (5-bromo-1,3-thiazol-2-yl)carbamate (506) 5-bromo-1,3-thiazol-2-amine hydrobromide (505, 6.5150 g, 25.062 mmol) and 4-dimethylaminopyridine (69.9 mg, 0.572 mmol) were combined under an atmosphere of dry N2, and tetrahydrofuran (40 mL) and triethylamine (15 mL) were added to form a thick off-white suspension. A solution of di-tert-butyldicarbonate (6.0546 g, 27.742 mmol) in tetrahydrofuran (24 mL) was added to the above suspension, and the resulting slurry was stirred at room temperature for 4 h. The reaction mixture was then poured onto water (100 mL), and the aqueous was extracted with ethyl acetate. The combined organics were washed with saturated NaHCO3 solution, brine, dried over MgSO4, filtered, and the solvent was removed in vacuo. The crude product was adsorbed onto silica gel, and eluted through a plug of silica gel with 9:1 hexanes:ethyl acetate. The eluent was collected, and evaporated to give 506 (5.42 g, 78%) as a colorless crystalline solid. Data for 506: 1H NMR (400 MHz, DMSO-d6) d 12.75 (br s, 1 H), 7.44 (s, 1 H), and 1.48 (s, 9 H) ppm. 13C NMR (100 MHz, DMSO-d6) d 160.1, 152.9 (br), 139.0, 100.5, 81.7, and 27.8 ppm. MS (ESI+) m/z (rel. intensity): 225.1 (100, M81Br-(CH3)2C=CH2+), 223.1 (100, M79Br-(CH3)2C=CH2+).
78% With dmap; triethylamine; In tetrahydrofuran; at 20℃; for 4h;Inert atmosphere; 5-Bromo-1,3-thiazol-2-amine hydrobromide (505, 6.52 g, 25.1 mmol) and 4-dimethylaminopyridine (69.9 mg, 0.572 mmol) were combined under an atmosphere of dry N2, and tetrahydrofuran (40 mL) and triethylamine (15 mL) were added to form a thick off-white suspension. A solution of di-tert-butyldicarbonate (6.06 g, 27.7 mmol) in tetrahydrofuran (24 mL) was added to the above suspension, and the resulting slurry was stirred at room temperature for 4 h. The reaction mixture was then poured onto water (100 mL), and the aqueous was extracted with ethyl acetate. The combined organics were washed with saturated NaHCO3 solution, brine, dried over MgSO4, filtered, and the solvent was removed in vacuo. The crude product was adsorbed onto silica gel, and eluted through a plug of silica gel with 9:1 hexanes:ethyl acetate. The eluent was collected, and evaporated to give 506 (5.42 g, 78%) as a colorless crystalline solid.Data for 506: 1H NMR (400 MHz, DMSO-d6) d 12.75 (br s, 1H), 7.44 (s, 1H), and 1.48 (s, 9H) ppm. 13C NMR (100 MHz, DMSO-d6) d 160.1, 152.9 (br), 139.0, 100.5, 81.7, and 27.8 ppm. MS (ESI+) m/z (rel. intensity): 225.1 (100, M81Br-(CH3)2CCH2+), 223.1 (100, M79Br-(CH3)2CCH2+).
74.9% With pyridine; at 20℃; for 2h; A mixture of 5-bromothiazol-2-amine hydrobromide (LXI) (1.99 g, 7.66 mmol) and Boc2O (2.21 g, 10.1 mmol) in pyridine (6 mL) was stirred at room temperature for 2 h. The solvent was removed, and the residue was purified by silica gel column chromatography (40 g) (0?50% EtOAc/hexanes) to produce tert-butyl (5-bromothiazol-2-yl)carbamate (LXII) as a white solid (1.6 g, 5.73 mmol, 74.9% yield). ESIMS found for C8H11BrN2O2S m/z 222.9 (81BrM+H-tBu).
67% With pyridine; at 20℃; for 16h; Synthesis 39 (5-Bromo-thiazol-2-yl)-carbamic acid tert-butyl ester To a stirred slurry of 2-amino-5-bromothiazole monohydrobromide (18.5 mmol, 4.81 g) in pyridine (50 ml) at room temperature was added, portionwise, di-tert-butyl dicarbonate (20.3 mmol, 4.43 g). The mixture was left to stir at room temperature for 16 hours. The solvent was removed by evaporation under reduced pressure. Water (150 ml_) was added to the slurry and the crude product was extracted with ethyl acetate (2x100 ml_). The organic phase was collected, washed with 1 M hydrochloric acid, then washed with saturated sodium bicarbonate solution. The organic phase was dried over MgSCU, filtered and evaporated under reduced pressure to yield the title compound as a brown/pink powder. Yield: 3.5 g, 67%. LCMS, analytical method 1 , TR=4.82 mins, 100%, MI=222/224 (-tert- Bu). H NMR (300 MHz, CDCI3) delta: 7.23 (1 H, s), 1.58 (9H, s).
63% With pyridine; at 20℃; [00156] Di-tert-butyl dicarbonate (28.90 g, 132.4 mmol) was added portionwise to a suspension of 2-amino-5-bromothiazole monohydrobromide (28.64 g, 110.3 mmol) in pyridine (100 mL) over 20 minutes at room temperature. The mixture was stirred at room temperature overnight. The solvent was evaporated. The residue was extracted between 0.5 N HCl (200 mL) and ethyl acetate (200 mL). The organic layer was separated and concentrated. The residue was filtered through a pad of silica gel using 10% ethyl acetate/hexane as a solvent. The filtrate was concentrated to give tert-butyl-5-bromothiazol-2-ylcarbamate (19.5 g, 63% yield) as a white solid. LCMS (Conditions A): 3.40 min (RT); (M+H)+ = 225.12 (100%), 223.12 (95%). 1H NMR, 400 MHz, CDCl3: delta 7.27 (s, 1 H), 1.60 (s, 9 H).
63% With pyridine; at 20℃; Di-tert-butyl dicarbonate (28.90 g, 132.4 mmol) was added portionwise to a suspension of 2-amino-5-bromothiazole monohydrobromide (28.64 g, 110.3 mmol) in pyridine (100 mL) over 20 minutes at room temperature. The mixture was stirred at room temperature overnight. The solvent was evaporated. The residue was extracted between 0.5 N HCl (200 mL) and ethyl acetate (200 mL). The organic layer was separated and concentrated. The residue was filtered through a pad of silica gel using 10% ethyl acetate/hexane as a solvent. The filtrate was concentrated to give tert-butyl-5-bromothiazol-2-ylcarbamate (19.5 g, 63% yield) as a white solid. LCMS (Conditions A): 3.40 min (RT); (M+H)+ = 225.12 (100%), 223.12 (95%). 1H NMR, 400 MHz, CDCl3: delta 7.27 (s, 1 H), 1.60 (s, 9 H).
62% With pyridine; at 20℃; for 16.25h; Step 1: Preparation 18a; To a slurry of 2-amino-5-bromo-thiazole monohydrobromide (25 g, 96 mmol) in 75 mL of pyridine at rt was added (Boc)2O (23.1 g, 106 mmol) in three portions over 15 min and the resulting mixture was allowed to stir at rt for ?16 h. The mixture was concentrated in vacuo and partitioned between water (200 mL) and ethyl acetate (200 mL). The aqueous layer containing a significant amount of undissolved solids was further extracted with warm ethyl acetate (3×150 mL). The combined organic extracts were then washed with 1 N aq. HCl (3×150 mL), sat'd aq. sodium bicarbonate (2×100 mL), and brine (100 mL), then dried over anhyd sodium sulfate, filtered, and concentrated to afford 16.7 g (62%) of Preparation 18a as a tan solid. HPLC Ret. time: 3.71 min
49% Example 462(S)-tert-butyl (5-[5-([methyl(oxo)phenyl-lambda6-sulfanylidene]amino}carbonyl)pyridin-3- yljethynyl} - 1 ,3-thiazol-2-yl)carbamate Step 1 tert-buiyl (5-bromo-l,3-thiazol-2-yl)carbamate <n="75"/>The title compound was prepared by a modification of the procedure described in J. Med. Chem. 2005, 48, 1886-1900. A mixture of 2-amino-6-bromothiazole monohydrobromide (390 mg, 1.5 mmol) and NaHCO3 (441 mg, 5.3 mmol) in 6.0 mL tert-butyl alcohol was heated for 1 minute at near reflux, then cooled to room temperature. To this mixture was added DMAP (18 mg, 0.15 mmol) and di-tert-butyl dicarbonate (1.0 M in THF, 1.65 mL) and the reaction stirred at room temperature for 16 hours. In order to drive reaction to completion, additional di-tert-butyl dicarbonate (1.0 M in THF, 0.5 mL) was added, the reaction heated at 50 0C for 2 hours, then di- tert-butyl dicarbonate (1.0 M in THF, 1.0 mL) and 100 mg NaHCO3 added and continued heating at 50 0C an additional 2 hours. The mixture was filtered and rinsed with EtOAc, then the EtOAc filtrate washed with H2O, dilute aqueous HCl, saturated NaHCO3 solution, brine, dried with anhydrous anhydrous Na2SO4 and rotary evaporated. The brown solid was chromatographed eluting with hexane/EtOAc and the product triturated with hexane to give the title compound as a cream solid (204 mg, 49%).
46% With pyridine; In acetonitrile; at 22℃; for 22h; tert- Butyl 5-bromothiazol-2-ylcarbamate: A suspension of 5- bromothiazol-2-amine hydrobromide (325 g, 1250 mmol) in acetonitrile (3.0 L) was stirred at room temperature (22 0C) and treated with pyridine (506 mL, 6251 mmol) followed by di-tert-butyl dicarbonate (435 mL, 1875 mmol, Aldrich). The reaction mixture was stirred at room temperature for 22 hours. The solvent was reduced in vacuo and the mixture was partitioned between EtOAc and 1 N HCl. The aqueous layer was extracted again with EtOAc and the combined organic phases were washed with 1 N HCl, saturated NaHCtheta3, and saturated NaCl. The organic layer was then dried over Na2Stheta4 and filtered. The reaction mixture was concentrated, loaded onto silica, and purified by flash chromatography (0 - 25 %, EtOAc in hexanes). The fractions were concentrated in vacuo to provide tert-butyl 5-bromothiazol-2-ylcarbamate (160 g, 46 %) as a white crystalline solid.
40% With dmap; In tetrahydrofuran; for 48h; 5-bromothiazol-2-amine hydrobromide (105 g, 403 mmol) was suspended in 500 mL of tetrahydrofuran, and dimethylaminopyridine (2.41 g, 20 mmol) was added to form a white turbidity. A solution of di-tert-butyl dicarbonate (105.6 g, 484.6 mmol) in tetrahydrofuran was slowly added dropwise. The mixture was reacted for two days. Then the reaction solution was concentrated, dissolved in dichloromethane (300mL), mixed with silica gel and isolated by column (eluted with petroleum ether / ethyl acetate = 10/1 - 6/1 gradient) to give 45 g of tert-butyl 5-bromothiazol-2-ylcarbamate as an off-white solid, yield 40%, MS(ESI): m/z 278.98 (M + H)+.
With pyridine; at 20℃; for 1h; To a stirred suspension of 2-amino-5-bromothiazole hydrobromide (2.5 g, 9.617 mmol) in pyridine (7.5 ml) was added Di-tert-butyl dicarbonate (2.31 g, 10.584 mmol) and the reaction was stirred for 1 hr at room temperature. Pyridine was removed under reduced pressure and the residue was pardoned between water (100 ml) and ethyl acetate (100 ml). The layers were separated, the organic layer was washed with 1N HCl followed by Sat. sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to get (5-bromo-thiazol-2-yl)-carbamic acid tert-butyl ester (1.8 g). 1H NMR (400 MHz, CDCl3): delta 1.58 (s, 9H), 7.24 (s, 1H), 10.94(bs, 1H). MS (El) m/z: 279.0 (M+1).
5-bromothiazol-2-amine hydrobromide (8.58 g, 33 mmol) was shaken with saturated aqueous solution of NaHCCh (50 mL) and EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried over MgSCE, filtered, concentrated under reduced pressure and dried under high vacuum. The residue was dissolved in CH2CI2 (40 mL). To the solution were added DMAP (40 mg, 0,33 mmol) and di- tert-butyl dicarbonate (8.0 g, 36.0 mmol). The mixture was stirred at 25 C for 24 hours. The solvent was evaporated and the resulting /^/7-butyl (5-bromothiazol-2-yl)carbamate was directly used in the next step without purification.

  • 9
  • [ 405939-39-1 ]
  • [ 944804-88-0 ]
YieldReaction ConditionsOperation in experiment
100% With lithium diisopropyl amide; In tetrahydrofuran; hexane; water; at 20℃; for 12.25h; Diisopropylamine (2.3 mL, 16 mmol) was taken up in 30 mL of THF and chilled to 0 C. Butyllithium, 2.5M in hexane (6.4 mL, 16 mmol), was added to the reaction mixture, and the mixture was stirred for 20 minutes. tert-Butyl 5-bromothiazol-2-ylcarbamate (1.5 g, 5.4 mmol) was then added slowly in 8 mL of THF. After 15 minutes, approximately 2 mL of water was added, and the mixture was warmed to room temperature and stirred for 12 hours. The mixture was diluted with 30 mL of 1/2 saturated aqueous NH4Cl and transferred to a separatory funnel. The mixture was extracted twice with 5 mL of EtOAc, and the combined organic extracts were washed with brine and dried over MgSO4. Filtration and concentration under reduced pressure afforded tert-butyl 4-bromothiazol-2-ylcarbamate (1.5 g, 100% yield) as a brown solid.
100% With n-butyllithium; diisopropylamine; In tetrahydrofuran; hexane; at 20℃; t-Butyl 4-bromothiazol-2-ylcarbamate: Diisopropylamine (2.3 mL, 16 mmol, Aldrich) was taken up in 30 mL of THF, and the mixture was chilled to 0 0C. Butyllithium (2.5 M in hexane (6.4 mL, 16 mmol, Aldrich)) was added to the reaction mixture, and the mixture was stirred for 20 minutes. tert-Butyl 5-bromothiazol-2- ylcarbamate (1.5 g, 5.4 mmol, prepared as shown in Scheme 2) was then added slowly in 8 mL of THF. After 15 minutes, approximately 2 mL of water was added, and the mixture was warmed to room temperature and stirred for 12 hours. The mixture was diluted with 30 mL of 1/2 saturated aqueous NH4Cl and transferred to a separatory funnel. The mixture was extracted twice with 5 mL of EtOAc, and the combined organic extracts were washed with brine and dried over MgSO4. Filtration and concentration under reduced pressure afforded tert-butyl 4-bromothiazol-2-ylcarbamate (1.5 g, 100 %) as a brown solid
96% With lithium diisopropyl amide; In tetrahydrofuran; hexanes; water; at 0 - 7℃; for 0.6h; 4.3 Synthesis of tert-butyl (4-bromo-1,3-thiazol-2-yl)carbamate (507) Tetrahydrofuran (160 mL) and N,N-diisopropylamine (14 mL, 97 mmol) were combined in a 3-neck 500 mL RBF equipped with a stirbar, septum, and an internal temperature probe. The resulting solution was cooled to 0.8 C., and n-butyllithium in hexanes (2.50 M, 38 mL, 95 mmol) was added slowly over ca. 5 min to produce a light yellow solution (Tint max=10 C.), which was stirred and allowed to re-cool to near 0 C. A solution of tert-butyl (5-bromo-1,3-thiazol-2-yl)carbamate, 506 (8.74 g, 31.3 mmol) in tetrahydrofuran (30.0 mL) was added dropwise to the above solution over 16 min (Tit varied from 0.9 C. to a maximum of 7 C.). The now deep brown reaction mixture was stirred for 15 min before being quenched with water (13 mL), and stirred for an additional 5 minutes. Aqueous saturated NH4Cl (250 mL) and ethyl acetate (250 mL) were added, and the layers were separated. The aqueous was extracted with ethyl acetate, and the combined organics were washed with brine, dried with MgSO4, filtered, and concentrated in vacuo. The crude material was adsorbed onto silica gel with ethyl acetate, and elute through a plug of silica gel with 2 liters of 9:1 hex:EtOAc The eluent was collected, and the solvents were removed to give 507 (8.41 g, 96%) as a colorless solid. Data for 507: 1H NMR (400 MHz, DMSO-d6) d 12.75 (br s, 1 H), 7.24 (s, 1 H), and 1.48 (s, 9 H) ppm. 13C NMR (400 MHz, CDCl3) d 160.6, 152.7 (br), 119.8, 110.6, 81.7, and 27.9 ppm. MS (ESI+) m/z (rel. intensity): 225.1 (100, M81Br-(CH3)2C=CH2+), 223.1 (100, M79Br-(CH3)2C=CH2+).
96% Tetrahydrofuran (160 mL) and N,N-diisopropylamine (14 mL, 97 mmol) were combined in a 3-neck 500 mL RBF equipped with a stirbar, septum, and an internal temperature probe. The resulting solution was cooled to 0.8 C., and n-butyllithium in hexanes (2.50 M, 38 mL, 95 mmol) was added slowly over ca. 5 min to produce a light yellow solution (Tint max=10 C.), which was stirred and allowed to re-cool to near 0 C. A solution of tert-butyl (5-bromo-1,3-thiazol-2-yl)carbamate, 506 (8.74 g, 31.3 mmol) in tetrahydrofuran (30.0 mL) was added dropwise to the above solution over 16 min (Tint varied from 0.9 C. to a maximum of 7 C.). The now deep brown reaction mixture was stirred for 15 min before being quenched with water (13 mL), and stirred for an additional 5 minutes. Aqueous saturated NH4Cl (250 mL) and ethyl acetate (250 mL) were added, and the layers were separated. The aqueous was extracted with ethyl acetate, and the combined organics were washed with brine, dried with MgSO4, filtered, and concentrated in vacuo. The crude material was adsorbed onto silica gel with ethyl acetate, and elute through a plug of silica gel with 2 liters of 9:1 hex:EtOAc The eluent was collected, and the solvents were removed to give 507 (8.41 g, 96%) as a colorless solid. Data for 507: 1H NMR (400 MHz, DMSO-d6) d 12.75 (br s, 1H), 7.24 (s, 1H), and 1.48 (s, 9H) ppm. 13C NMR (400 MHz, CDCl3) d 160.6, 152.7 (br), 119.8, 110.6, 81.7, and 27.9 ppm. MS (ESI+) m/z (rel. intensity): 225.1 (100, M81Br-(CH3)2CCH2+), 223.1 (100, M79Br-(CH3)2CCH2+).
78% With n-butyllithium; diisopropylamine; In tetrahydrofuran; at 0℃; for 2h;Inert atmosphere; To a solution of 158 diisopropylamine (64mL, 446mmol) in 154 THF (100mL) was added dropwise 159 n-BuLi (2.5M, 173mL) under N2 atmosphere at 0C. After that a solution of 156 47 (40g, 143.9mmol) in THF (400mL) was added dropwise at 0C. The reaction mixture was stirred at the same temperature for 2h, and then quenched with sat. 160 NH4Cl (500mL) and extracted with ethyl acetate (3×300mL). The combined organic layers were washed with brine (100mL) and dried over anhydrous Na2SO4. The organic layers were evaporated to dryness and the crude product was purified by silica gel flash chromatography (eluting with ethyl acetate in 74 petroleum ether 1-30%) to give the 20 title compound 48 as a white solid (31.2g, yield=78%). 1H NMR (400MHz, CDCl3) delta 8.05 (br, 1H), 6.78 (s, 1H), 1.56 (s, 9H); LC/MS (ESI, m/z) 222.98 [M+H-56]+.
77.5% With n-butyllithium; diisopropylamine; In tetrahydrofuran; at 0℃; for 2h;Inert atmosphere; A solution of diisopropylamine (64 ml, 446 mmol) in 200 mL of tetrahydrofuran was added to a dry three-neck bottle, which was protected under nitrogen, and cooled to 0 C, and then n-butyllithium (2.5M, 173ml, 431.7mmol) was added. The reaction was conducted for 1 hour after addition was completed. A solution of <strong>[405939-39-1]tert-butyl 5-bromothiazol-2-ylcarbamate</strong> in 400 mL of tetrahydrofuran was added dropwise at 0 C, and the reaction was conducted for 2 hours after addition was completed. TLC showed the reaction was completed. At 0 C, the reaction was quenched by slow addition of ice water (5 mL), stirred for 30 min, then saturated ammonium chloride (500mL) aqueous solution was added, and separated. The aqueous layer was extracted with dichloromethane (2 × 300 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was recrystallized with petroleum ether : ethyl acetate = 30:1 to give 31g of tert-butyl 4-bromothiazol-2-ylcarbamate as a white solid, yield 77.5%, MS(ESI): m/z 278.98 (M + H)+.

  • 10
  • [ 405939-39-1 ]
  • [ 731018-54-5 ]
  • 11
  • [ 405939-39-1 ]
  • [ 1064678-19-8 ]
YieldReaction ConditionsOperation in experiment
72% To a solution of tert-butyl N-(5-bromo-l,3-thiazol-2-yl)carbamate (5 g, 17.9 mmol) in tetrahydrofuran (100 ml) was added dropwise LDA (29.4 ml, 2 mol/L) at -78 C, and the resulting mixture was stirred for 1 h at -78C. Then the mixture was added a solution of hexachloroethane (14 g, 59.1 mmol) in tetrahydrofuran (50 ml) at -78 C. The reaction was stirred for additional 15 h at room temperature. The reaction was quenched by water, then extracted with dichloromethane and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/petroleum ether (1/9) to afford tert-butyl N-(4-bromo-5-chloro-l,3-thiazol-2-yl)carbamate (4.07 g , 72%) as brown oil. LCMS (ESI): M+H+ = 313.0.
Lithium diisopropylamide (1.8 M in THF, 19.8 mL, 35.6 mmol) was added dropwise to a stirred solution of <strong>[405939-39-1](5-bromo-thiazol-2-yl)-carbamic acid tert-butyl ester</strong> (Kuo, Gee-Hong; et al. J. Med. Chem. 2005; 6; 1886 - 1900) (3.00 g, 10.8 mmol) in anhydrous THF (75 mL) at00C. After stirring for 30 min at 0C, a solution of 1,1,1,2,2,2-hexachloro-ethane (8.43 g, 35.6 mmol) in anhydrous THF (45 mL) was added dropwise at -900C. The reaction mixture was allowed to warm to -10C and was then quenched by the addition of concentrated aqueous NH4CI (15 mL). The mixture was concentrated in vacuo and the residue was partitioned between DCM (100 mL) and water (30 mL). The aqueous layer was extracted with DCM (2 x50 mL) and the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution withDCM/hexane 2:1) to give the title compound. MS (m/z): 314.6 [IVB-H+].
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; ;