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[ CAS No. 96-50-4 ] {[proInfo.proName]}

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Chemical Structure| 96-50-4
Chemical Structure| 96-50-4
Structure of 96-50-4 * Storage: {[proInfo.prStorage]}
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Product Details of [ 96-50-4 ]

CAS No. :96-50-4 MDL No. :MFCD00005325
Formula : C3H4N2S Boiling Point : -
Linear Structure Formula :- InChI Key :RAIPHJJURHTUIC-UHFFFAOYSA-N
M.W : 100.14 Pubchem ID :2155
Synonyms :
2-Aminothiazole;2-Thiazolylamine;NSC 1900;Basedol

Calculated chemistry of [ 96-50-4 ]

Physicochemical Properties

Num. heavy atoms : 6
Num. arom. heavy atoms : 5
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 1.0
Num. H-bond donors : 1.0
Molar Refractivity : 26.52
TPSA : 67.15 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) : -6.64 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.02
Log Po/w (XLOGP3) : 0.38
Log Po/w (WLOGP) : 0.73
Log Po/w (MLOGP) : -0.65
Log Po/w (SILICOS-IT) : 1.67
Consensus Log Po/w : 0.63

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.32
Solubility : 4.83 mg/ml ; 0.0482 mol/l
Class : Very soluble
Log S (Ali) : -1.36
Solubility : 4.42 mg/ml ; 0.0441 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -0.86
Solubility : 14.0 mg/ml ; 0.139 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.97

Safety of [ 96-50-4 ]

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

Application In Synthesis of [ 96-50-4 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Upstream synthesis route of [ 96-50-4 ]
  • Downstream synthetic route of [ 96-50-4 ]

[ 96-50-4 ] Synthesis Path-Upstream   1~33

  • 1
  • [ 96-50-4 ]
  • [ 3034-48-8 ]
Reference: [1] Journal fuer Praktische Chemie (Leipzig), 1974, vol. 316, p. 349 - 352
  • 2
  • [ 96-50-4 ]
  • [ 3034-52-4 ]
YieldReaction ConditionsOperation in experiment
45% With hydrogenchloride; sodium chloride; sodium nitrite In water at 20℃; for 1 h; A solution of 2-aminothiazole (101) (20.0 g, 200.0 mmol) in saturated aqueous NaCl (20 mL) and HCl (60 mL) was maintained in a room-temperature bath. It was then treated with NaNO2 (250 mmol) in H2O (50 mL) and concentrated HCl (20 mL) dropwise simultaneously. The reaction was stirred at room temperature for 1 hour, extracted with ether and concentrated at 1 atm. The product was obtained by distilled under vacuum to give 102 as a pale yellow liquid (10.7 g, 45percent): 1H NMR(CDCl3 ) δ 12A ( d, J= 3.6 Hz, IH ) , 7.57 ( d, J= 3.3 Hz,lH).
Reference: [1] Patent: WO2008/33746, 2008, A2, . Location in patent: Page/Page column 56
[2] Patent: US5498630, 1996, A,
[3] Patent: US2004/54186, 2004, A1, . Location in patent: Page 133
  • 3
  • [ 96-50-4 ]
  • [ 3034-52-4 ]
YieldReaction ConditionsOperation in experiment
49% With sodium chloride; phosphoric acid; nitric acid; sodium nitrite In water A.
2-chlorothiazole (Prepared by the Literature Procedure: V. Genapathi. Indian Academy of Science Section A, 1945, 362-378)
Phosphoric acid (57 mL) was added slowly dropwise to a flask containing 2-aminothiazole (15 g, 0.15 mol).
The resulting exothermic brown solution was cooled to ~5° C. and nitric acid (30 mL) was added slowly dropwise, while maintaining the temperature below 15° C.
The reaction mixture was then cooled to about -5° C. and a solution of sodium nitrite (12 g) in water (40 mL) was added over 30 min.
After the resulting orange solution was stirred at 0° C. for 40 min, the cold reaction mixture was then added to a solution of copper sulfate (25 g) and sodium chloride (25 g) in water (100 mL) at 10° C.
The resulting mixture was stirred for 30 min in an ice bath followed by 1 h at room temperature, then was steam distilled.
The product was separated from the water co-distillate, dried over Na2SO4 and filtered to yield 2-chlorothiazole (8.72 g, 49percent yield).
Reference: [1] Patent: US2002/161237, 2002, A1,
  • 4
  • [ 96-50-4 ]
  • [ 3034-53-5 ]
YieldReaction ConditionsOperation in experiment
85.8%
Stage #1: With sulfuric acid; nitric acid; sodium nitrite In water at 2 - 10℃; for 1 h;
Stage #2: With copper(II) sulfate; sodium bromide In water at 6℃; for 8.5 h;
2-Amino-thiazol 0.25mol 150ml45percent sulfuric acid was dissolved in 500ml reaction flask and stirred to dissolve 2-aminothiazol-section and cooled to 2 , 50ml of concentrated nitric acid 65percent was added dropwise, maintaining the internal temperature should not exceed 10 . Then 50ml solution of sodium nitrite was slowly dropped 5mol / l, the addition was completed, stirring was continued for 1h, controlling the temperature below 7 . The reaction was continued with a dropping funnel, the red-brown diazonium salt solution was added dropwise 200ml solution containing 74g of sodium bromide and 40g copper sulfate carried bromination, maintained at 6 , dropping time of about 1.5h, after the addition was complete 7H, N2 so excluded; after cooling the solution was added 20percent NaOH and the solution was adjusted pH of 6 to 7, then washed with water steam distillation to collect the aqueous solution containing the 2-bromothiazole, dried over MgSO4 solution by distillation, vacuum distillation collect bp71 ~ 73 / 2.4kPa fraction, 2-bromothiazole 35.2g, a yield of 85.8percent, showing that the reaction temperature is maintained at the present application 0 ~ 10 , the reaction rate is faster, while also reducing side reactions, the reaction yield has been greatly improved.
2.5 g
Stage #1: for 0.166667 h;
Stage #2: With sodium nitrite In water at 0℃; for 1 h;
Stage #3: With copper(II) sulfate; sodium bromide In water at 0 - 20℃; for 22 h;
To a cool solution of thiazol-2-amine (5.0 g, 50 mmol) in 85percent H3P04 was added conc. nitricacid and stirred the reaction mixture for iO mins followed by addition of aq.NaNO2 (4. i4 g,60 mmol), continued stirring for i h at 0°C.Then added aq.Cu504 (6.36 g, 40 mmol) & NaBr(i4.49 g,i45 mmol).The reaction mass was further stirred at 0°C for 6 h then at ft for i6 h.The reaction mass was basified with KOH & Na2CO3 up to pH-9 and extracted with DCM.The organic layers were separated and concentrated to afford 2.5 g of title compound . ‘HNMR (300 MHz, DMSO-d6): 7.62-7.6i (d, J = 3.0 Hz, iH), 7.3 i-7.30 (d, J = 3.3 Hz, iH)
Reference: [1] Synthesis, 2012, vol. 44, # 7, p. 1026 - 1029
[2] Patent: CN105348216, 2016, A, . Location in patent: Paragraph 0048; 0049
[3] Recueil des Travaux Chimiques des Pays-Bas, 1934, vol. 53, p. 77,78
[4] Recueil des Travaux Chimiques des Pays-Bas, 1962, vol. 81, p. 554 - 564
[5] Patent: WO2016/55947, 2016, A1, . Location in patent: Page/Page column 142
[6] Journal of Organic Chemistry, 2017, vol. 82, # 11, p. 5947 - 5951
  • 5
  • [ 420-04-2 ]
  • [ 4124-63-4 ]
  • [ 141-46-8 ]
  • [ 4570-45-0 ]
  • [ 96-50-4 ]
Reference: [1] Journal of the American Chemical Society, 2012, vol. 134, # 33, p. 13889 - 13895
  • 6
  • [ 96-50-4 ]
  • [ 75-17-2 ]
  • [ 10200-59-6 ]
Reference: [1] Chemische Berichte, 1957, vol. 90, p. 2372,2377
  • 7
  • [ 96-50-4 ]
  • [ 3034-22-8 ]
YieldReaction ConditionsOperation in experiment
75% at 0 - 30℃; for 2 h; (a)at 0 ° C2-Aminothiazole (400 mg, 4 mmol) was dissolved in 16 mLAcetic acid solution,Bromine (408 μL, 8 mmol) was slowly added dropwise.The mixture was further stirred at room temperature for 2 hours,TLC reaction was monitored until the reaction was completed,The pH was adjusted to 7-8 with saturated NaHCO3,Ethyl acetate (20 mL x 3), washed with saturated saline and the organic layer was mixed,Dry over anhydrous sodium sulfate, filter and concentrate and purify by column chromatography5-Bromothiazol-2-amine(520 mg, 75percent yield).
Reference: [1] Patent: CN107286150, 2017, A, . Location in patent: Paragraph 0354; 0355; 0356
[2] Journal of the American Chemical Society, 2016, vol. 138, # 42, p. 14129 - 14137
[3] Journal of the American Chemical Society, 1946, vol. 68, p. 453,457
[4] Recueil des Travaux Chimiques des Pays-Bas, 1954, vol. 73, p. 325,329
[5] Helvetica Chimica Acta, 1945, vol. 28, p. 985,988
[6] Patent: US2537592, 1945, ,
[7] Patent: US2457078, 1944, ,
[8] Svensk Kemisk Tidskrift, 1945, vol. 57, p. 229,232
[9] Patent: US2537592, 1945, ,
[10] Patent: US2457078, 1944, ,
[11] Bulletin de la Societe Chimique de France, 1962, p. 2075 - 2078
[12] Journal of Organic Chemistry, 2017, vol. 82, # 11, p. 5947 - 5951
  • 8
  • [ 96-50-4 ]
  • [ 624-92-0 ]
  • [ 99171-11-6 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 22, p. 5521 - 5525
  • 9
  • [ 96-50-4 ]
  • [ 121-66-4 ]
Reference: [1] Proceedings - Indian Academy of Sciences, Section A, 1945, # 22, p. 362,376
[2] Galenica Acta, 1959, vol. 12, p. 249,252
[3] Journal of Organic Chemistry, 1955, vol. 20, p. 499,505
[4] Tetrahedron Letters, 1997, vol. 38, # 12, p. 2085 - 2086
[5] Russian Journal of General Chemistry, 2010, vol. 80, # 12, p. 2572 - 2589
  • 10
  • [ 96-50-4 ]
  • [ 625-58-1 ]
  • [ 121-66-4 ]
Reference: [1] Annali di Chimica Applicata, 1948, vol. 38, p. 449,454
  • 11
  • [ 96-50-4 ]
  • [ 540-72-7 ]
  • [ 23056-10-2 ]
YieldReaction ConditionsOperation in experiment
55%
Stage #1: With bromine; sodium bromide In methanol at -10 - 0℃; for 3 h;
Stage #2: With ammonia In methanol; water
Preparation of 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester:2-Aminothiazole (35 g, 350 mmol) and sodium thiocyanate (89 g, 1 .08 mol) in MeOH (400 ml_) was stirred at -10 0C. Bromine (18.0 ml_, 350 mmol) dissolved in MeOH (100 ml_) saturated with with NaBr was slowly added keeping the internal temperature between -10 and 0 0C. After the addition the mixture was stirred at 0 0C for 3 h and the reaction mixture was poured into ice water (1500 ml_). Aqueous NH4OH was added to pH ca 8.5 causing precipitation of light yellow crystals which were isolated by filtration, washed with ice water and dried in a vacuum oven to give 30 g (55percent) 5-thiocyanato-thiazol-2-ylamine as light yellow crystals.
55%
Stage #1: With bromine; sodium bromide In methanol at -10 - 0℃; for 3 h;
Stage #2: With ammonia; water In methanol
Step 1 :2-Aminothiazole (35 g, 350 mmol) and sodium thiocyanate (89 g, 1.08 mol) in MeOH (400 ml.) was stirred at -10 A°C. Bromine (18.0 ml_, 350 mmol) dissolved in MeOH (100 ml.) saturated with with NaBr was slowly added keeping the internal temperature between -10 and 0 A°C. After the addition the mixture was stirred at 0 A°C for 3h and the reaction mixture was poured into ice water (1500 ml_). Aqueous NH4OH was added to pH ca 8.5 causing precipitation of light yellow crystals which were isolated by filtration, washed with ice water and dried in a vacuum oven to give 30 g (55percent) 5-thiocyanato-thiazol-2-ylamine as light yellow crystals.1 H NMR (400 MHz, DMSO-d6) ppm 7.83 (br. s., 2 H) 7.44 (s, 1 H)
55%
Stage #1: With bromine; sodium bromide In methanol at -10 - 0℃; for 3 h;
:Step i :2-Aminothiazole (35 g, 350 mmol) and sodium thiocyanate (89 g, 1.08 mol) in MeOH (400 ml.) was stirred at -10 °C. Bromine (18.0 ml_, 350 mmol) dissolved in MeOH (100 ml.) saturated with with NaBr was slowly added keeping the internal temperature between -10 and 0 °C. After the addition the mixture was stirred at 0 °C for 3h and the reaction mixture was poured into ice water (1500 ml_). Aqueous NH4OH was added to pH ca 8.5 causing precipitation of light yellow crystals which were isolated by filtration, washed with ice water and dried in a vacuum oven to give 30 g (55percent) 5-thiocyanato-thiazol-2-ylamine as light yellow crystals.1H NMR (400 MHz, DMSO-d6) (ppm) 7.83 (br. s., 2H) 7.44 (s, 1 H) Step 2:
Reference: [1] Patent: WO2007/6814, 2007, A1, . Location in patent: Page/Page column 93; 156
[2] Patent: WO2008/84043, 2008, A1, . Location in patent: Page/Page column 45
[3] Patent: WO2008/84044, 2008, A1, . Location in patent: Page/Page column 60
  • 12
  • [ 96-50-4 ]
  • [ 23056-10-2 ]
YieldReaction ConditionsOperation in experiment
57% With bromine In methanol; water D.
Preparation of 2-amino-5-thiocyanatothiazole
2-Aminothiazole (41 g, 410 mM) and sodium thiocyanate (60 g, 740 mM, dried in a vacuum oven at 130° C. overnight) was dissolved in 450 mL of anhydrous methanol and the solution was cooled in a cold water bath.
Here was added bromine (23 mL, 445 mM) dropwise with good stirring.
After the addition it was stirred for 4 h at rt.
To the mixture 500 mL of water was added and it was stirred for 5 minutes, filtered through a celite bed and washed the bed with water.
The pH of the filtrate solution was about 1.
Most of the methanol was removed under the reduced pressure and pH of the solution was adjusted to about 7 by adding aq. sodium carbonate slowly with stirring.
The precipitated solid was filtered and washed with water to obtain 37 g (57percent) of the dark brown colored desired product after drying, mp 140-143° C. 1 H NMR (CD3 OD) δ7.33 (s, 1 H); MS (CI/NH3) m/e 179 (M+Na)+, 158 (M+H)+.
57% With bromine In methanol; water D.
Preparation of 2-amino-5-thiocyanatothiazole
2-Aminothiazole (41 g, 410 mM) and sodium thiocyanate (60 g, 740 mM, dried in a vacuum oven at 130° C. overnight) was dissolved in 450 mL of anhydrous methanol and the solution was cooled in a cold water bath.
Here was added bromine (23 mL, 445 mM) dropwise with good stirring.
After the addition it was stirred for 4 h at rt.
To the mixture 500 mL of water was added and it was stirred for 5 minutes, filtered through a celite bed and washed the bed with water.
The pH of the filtrate solution was about 1.
Most of the methanol was removed under the reduced pressure and pH of the solution was adjusted to about 7 by adding aq. sodium carbonate slowly with stirring.
The precipitated solid was filtered and washed with water to obtain 37 g (57percent) of the dark brown colored desired product after drying, mp 140-143° C.
1H NMR (CD3OD) δ 7.33 (s, 1H); MS (CI/NH3) m/e 179 (M+Na)+, 158(M+H)+.
Reference: [1] Patent: US6040321, 2000, A,
[2] Patent: US6262096, 2001, B1,
  • 13
  • [ 96-50-4 ]
  • [ 333-20-0 ]
  • [ 23056-10-2 ]
Reference: [1] Journal of Medicinal Chemistry, 2004, vol. 47, # 7, p. 1719 - 1728
  • 14
  • [ 96-50-4 ]
  • [ 1147550-11-5 ]
  • [ 23056-10-2 ]
Reference: [1] Journal of the American Chemical Society, 1949, vol. 71, p. 4007,4009
[2] Annali di Chimica Applicata, 1948, vol. 38, p. 449,454
[3] Yakugaku Zasshi, 1951, vol. 71, p. 1367,1369[4] Chem.Abstr., 1952, p. 8099
  • 15
  • [ 96-50-4 ]
  • [ 163276-49-1 ]
  • [ 23056-10-2 ]
Reference: [1] Synlett, 2018, vol. 29, # 14, p. 1902 - 1908
  • 16
  • [ 96-50-4 ]
  • [ 121-60-8 ]
  • [ 72-14-0 ]
Reference: [1] European Journal of Medicinal Chemistry, 2017, vol. 136, p. 63 - 73
  • 17
  • [ 96-50-4 ]
  • [ 24939-24-0 ]
  • [ 72-14-0 ]
Reference: [1] Journal of Medicinal Chemistry, 1994, vol. 37, # 3, p. 329 - 331
  • 18
  • [ 96-50-4 ]
  • [ 98-60-2 ]
  • [ 72-14-0 ]
Reference: [1] Patent: CH210779, 1938, ,
[2] DRP/DRBP Org.Chem.,
  • 19
  • [ 96-50-4 ]
  • [ 5694-39-3 ]
  • [ 116-43-8 ]
Reference: [1] Journal of the American Chemical Society, 1942, vol. 64, p. 1572,1573, 1574
  • 20
  • [ 96-50-4 ]
  • [ 1113-59-3 ]
  • [ 53572-98-8 ]
Reference: [1] Organic Letters, 2010, vol. 12, # 3, p. 412 - 415
  • 21
  • [ 96-50-4 ]
  • [ 70-23-5 ]
  • [ 64951-04-8 ]
YieldReaction ConditionsOperation in experiment
38.27% at 20℃; for 8 h; To a solution of 2-aminothiazole (0.500 g, 5 mmol)In tetrahydrofuran was added ethyl bromopyruvate (90percent, 1.625 g, 7.5 mmol) dropwise,After 8h reaction at room temperature, the resulting precipitate was filtered,The filter cake was washed with tetrahydrofuran.The filter cake was then dissolved in hot ethanol and at 80 under reflux 8h,After cooling, the solvent was distilled off,The residual solid was washed with cold water and filtered,After vacuum drying, the intermediate body weight was 0.375 g,Yield 38.27percent
Reference: [1] Journal of Medicinal Chemistry, 2003, vol. 46, # 18, p. 3914 - 3929
[2] Journal of Medicinal Chemistry, 2015, vol. 58, # 6, p. 2764 - 2778
[3] Patent: CN105985356, 2016, A, . Location in patent: Paragraph 0117; 0118
[4] Farmaco, Edizione Scientifica, 1977, vol. 32, # 10, p. 735 - 746
[5] Patent: US2010/249071, 2010, A1, . Location in patent: Page/Page column 45
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  • [ 96-50-4 ]
  • [ 70-23-5 ]
  • [ 64951-04-8 ]
  • [ 244258-92-2 ]
Reference: [1] Journal of Chemical Research, Miniprint, 1999, # 7, p. 1750 - 1760
  • 23
  • [ 96-50-4 ]
  • [ 609-15-4 ]
  • [ 57626-37-6 ]
YieldReaction ConditionsOperation in experiment
82% at 90℃; for 6 h; 2-Aminothiazole (3.00 g, 29.99 mmol) and 2-chloroethylacetoacetate(4.96 mL, 35.99 mmol) were taken in 1,2-dimethoxyethane(30 mL) and heated at 90 C for 6 h. The reactionmixture was concentrated under reduced pressure, diluted withEtOAc (80 mL), washed the organic layer with H2O (3 30 mL).The separated organic layer was dried over anhyd Na2SO4 and concentratedunder vacuo to get crude compound. The crude compoundwas purified by column chromatography using 20percent EtOAcin Hexanes as eluent to get ethyl 6-methylimidazo[2,1-b]thiazole-5-carboxylate (2a) (5.20 g, 82percent) as an Off-white solid. ESIMSshowed 211 [M+H]+ and carried to next step.
26% at 80℃; for 24 h; [001195] (i) Production of ethyl 6-methylimidazo[2,l-b][l,3]thiazole-5-carboxylate[001196] A mixture of l,3-thiazol-2-amine (10 g, 100 mmol), ethyl 2-chloro-3-oxobutanoate (16 g, 100 mmol) and ethanol (100 mL) was stirred at 800C for 1 day. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium bicarbonate solution was added to the obtained residue, and the mixture was extracted with ethyl acetate. The collected organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80- 50/50) and washed with diisopropyl ether to give the title compound (5.5 g, 26percent) as a colorless solid.[001197] 1H-NMR (DMSO-d6, 300 MHz) 5 1.34 (3H, t, J = 7.2 Hz), 2.51 (3H, s), 4.33 (2H, q, J = 7.2Hz), 7.44 (IH, d, J = 4.3 Hz), 8.08 (IH, d, J = 4.3 Hz).
Reference: [1] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 6, p. 1298 - 1307
[2] European Journal of Medicinal Chemistry, 1994, vol. 29, # 12, p. 981 - 983
[3] Patent: WO2010/90716, 2010, A1, . Location in patent: Page/Page column 328
[4] Farmaco, Edizione Scientifica, 1983, vol. 38, # 7, p. 533 - 545
[5] Archiv der Pharmazie, 1976, vol. 309, # 12, p. 959 - 965
[6] Patent: US2010/152192, 2010, A1, . Location in patent: Page/Page column 10
[7] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 24, p. 5916 - 5919
[8] Patent: WO2010/70452, 2010, A1, . Location in patent: Page/Page column 23
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  • [ 96-50-4 ]
  • [ 84911-18-2 ]
  • [ 57626-37-6 ]
Reference: [1] European Journal of Medicinal Chemistry, 1975, vol. 10, # 1, p. 59 - 64
[2] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1992, # 15, p. 2029 - 2032
[3] Tetrahedron Letters, 2017, vol. 58, # 37, p. 3662 - 3666
  • 25
  • [ 84911-18-2 ]
  • [ 96-50-4 ]
  • [ 57626-37-6 ]
Reference: [1] European Journal of Medicinal Chemistry, 1982, vol. 17, # 3, p. 271 - 274
  • 26
  • [ 96-50-4 ]
  • [ 431-35-6 ]
  • [ 109113-98-6 ]
Reference: [1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1988, vol. 27, # 1-12, p. 1051 - 1053
[2] Journal of Heterocyclic Chemistry, 1986, vol. 23, # 4, p. 1031 - 1034
[3] Patent: WO2008/81399, 2008, A2, . Location in patent: Page/Page column 71
[4] Patent: WO2009/16560, 2009, A2, . Location in patent: Page/Page column 43; 81-82
[5] Patent: US2010/16401, 2010, A1, . Location in patent: Page/Page column 47
  • 27
  • [ 96-50-4 ]
  • [ 169260-95-1 ]
  • [ 109113-98-6 ]
Reference: [1] Journal of Fluorine Chemistry, 1995, vol. 73, # 1, p. 83 - 86
  • 28
  • [ 96-50-4 ]
  • [ 2314-97-8 ]
  • [ 169260-97-3 ]
YieldReaction ConditionsOperation in experiment
67% With sodium dithionite; sodium hydrogencarbonate In water; acetonitrile at 5 - 10℃; Inert atmosphere General procedure: Sodium dithionite (1.0 mmol) was added in one portion to a mixture of 2-aminothiazole (1.0 mmol), NaHCO3 (1.0 mmol) and polyfluoroalkyl iodide (1.5 mmol) in acetonitrile/water (4:1/v:v) at 5-10 °C under Ar atmosphere. The mixture was stirred until complete conversion of starting material as indicated by TLC analysis. Acetonitrile was removed under reduced pressure and water (5 mL) was added. The mixture was extracted with ethyl acetate (4.0 mL .x. 3) and the combined organic layers were dried over Na2SO4. The solvent was removed under vacuum and the residue was purified by column chromatography on silica gel (petroleum/ethyl acetate) to give the product.
Reference: [1] Journal of Fluorine Chemistry, 2012, vol. 133, p. 115 - 119
  • 29
  • [ 96-50-4 ]
  • [ 75-63-8 ]
  • [ 169260-97-3 ]
YieldReaction ConditionsOperation in experiment
61% With sodium dithionite; sodium phosphate dibasic dodecahydrate In water; acetonitrile at 80℃; for 3 h; Autoclave Sodium dithionite (70 g, 0.4 mol), 2-aminothiazole (20 g, 0.2 mol) and Na2HPO4*12H2O (76 g, 0.1 mol) in 150 mL acetonitrile/180 mL water was added into a 1.0 L autoclave, and then it was sealed and evacuated followed with the introduction of CF3Br (90 g, 0.6 mmol). The reaction mixture was heated to 80 °C for 3 h. The work up was the same as that aforementioned to give 5-(trifluoromethyl)thiazol-2-amine in 61percent yield.
Reference: [1] Journal of Fluorine Chemistry, 2012, vol. 133, p. 115 - 119
  • 30
  • [ 96-50-4 ]
  • [ 24424-99-5 ]
  • [ 170961-15-6 ]
YieldReaction ConditionsOperation in experiment
96% at 20℃; for 16 h; To tetrahydrofuran solution (20 ml) of 46 (10.0 g, 99.9 mmol), (Boc) 20 (27.5 ml, 119.9 mmol) was added, and stirred at room temperature for 16 hours. The solvent of the reaction mixture was evaporated to dryness under reduced pressure, and the obtained crystal was pulverized in n-hexane, to obtain 47 (19.25 g, 96percent) of colorless crystal. mp 181.5.similar.182.5° C, 1H NMR(300MHz,CDCl3)δ 1.60(9H,s),6.88(1H,d,J=3.7Hz),7.38(1H,d,J=3.7Hz),11.9(1H,s) IR(Nujol) 1713 cm-1, APCI-MS m/z 201[M+H]+
90% With dmap In acetonitrile at 20℃; To a suspension of 2-aminothiazole (50 g, 499 mmol, 1 eq.) and 4-dimethylaminopyridine (0.1 g) in acetonitrile (125 mL) is added boc anhydride (130.6 g, 599 mmol, 1.2 eq.) over a period of 30 min at RT. The reaction mixture is then stirred at RT overnight. The reaction mass is then concentrated and partitioned between EtOAc and water by which time solid precipitated and is filtered to get 40 g of the product. The organic layer is washed with brine, separated and dried over sodium sulfate and concentrated to get the product (50 g) which is mixed with the initially obtained product to give 90 g (90percent) of the title compound. 1H NMR (DMSO-c/6, 400 MHz): δ 1 1 .41 (bs, 1 H), 7.34-7.33 (d, J = 3.56 Hz, 1 H), 7.13-7.12 (d, J = 3.56 Hz, 1 H), 1 .46 (s, 9H).
86% at 20℃; EXAMPLE 108; N-{1-methyl-3-[2-(4-phenoxy)phenoxy)-1,3-thiazol-5-yl]prop-2-ynyl}-1,3-thiazol-2-amine; EXAMPLE 108A; Thiazol-2-yl-carbamic acid tert-butyl ester; A mixture of 2-aminothiazole (5.0 g, 0.05 mol), Boc anhydride (11.35 g, 0.052 mol) and DMAP (10 mg) was stirred at RT overnight. The precipitate was collected by filtration, washed with hexane, air-dried to give 4.8 g of product as a white solid. The filtrate was concentrated and partitioned between ethyl acetate and water. Organic layer was washed with brine, dried over magnesium sulfate and concentrated. The crude was triturated with ethyl acetate/hexane to give 3.8 g of more product (total 8.6 g, 86percent yield). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.48 (s, 9H) 3.33 (s, 1H) 7.14 (d, J=3.68 Hz, 1H) 7.36 (d, J=3.68 Hz, 1H) 11.41 (s, 1H). MS (ESI), M/Z 201. (+H)+.
83% at 20℃; for 16 h; to a solution of 2-amino thiazole (30 g, 300 mmol) in THF (300 mL) was added Boc2O (79 mL, 360 mmol) and the reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was concentrated under reduced pressure, and the precipitated solid was washed with pet. -ether to afford tert-butyl thiazol-2-ylcarbamate (50 g, 83 percent). MS (APCI); m/z 201 (MH).
80% With dmap; triethylamine In tetrahydrofuran at 0℃; for 16 h; Step 1 Compound [55] (5.0 g, 50 mmol) was dissol ved in THF ( 100 ml) and cooled to 0 °C. TEA ( 1 1.99 g, 55 mmol) was added dropwise. The mixture was stirred at 0°C for 16 hrs. After completion of the reaction, 100 ml of water was added, and the reaction mass was extracted with 3 X 100 ml EtOAc (3. X 100 ml). The EtOAc layers were combined then washed with . brine, dried over anhydrous and concentrated to give crude. The product was purified with column silica gel chromatography with DCM to obtain compound [97] as a pale yellow solid (8.0 g, 80 percent yield). ESIMS: 201 (M+ + 1 )
78% With dmap; triethylamine In tetrahydrofuran at 20℃; for 4.5 h; Inert atmosphere 2-Aminothiazole (600 mg, 5.99 mmol), DMAP (600 μg, 4.90 μmol), Boc2O (1.51 mL, 6.59mmol) and Et3N (1.00 mL, 7.19 mmol) were suspended in anhydrous THF (3 mL), and stirredat rt for 4.5 h under argon atmosphere. After completion of the reaction, the reaction mixture was diluted with CH2Cl2 (5 mL), and washed with 0.1 N HCl (5 mL) and water (5 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated by rotary evaporation. Purification by column chromatography (10:1 hexanes/EtOAc) yielded S1s (930mg, 78percent) as a white solid.
76.4%
Stage #1: With dmap; triethylamine In tetrahydrofuran at 0 - 20℃; for 0.166667 h;
Stage #2: at 20℃; for 3 h;
A mixture of compound 14 (5.00 g, 49.93 mmol) and THF (50 mL) was added and the mixture was stirred at 0 ° C and then triethylamine (10.10 g, 99.81 mmol) and DMAP (30 mg, 0.25 mmol) were added. After 10 min, (Boc) 2O (13.08 g, 59.93 mmol) was added dropwise to the flask.Drop finished, remove the ice bath, rose to room temperature, continue to stir 3h, TLC detection reaction is complete, dropping distilled water quenching. The filtrate was spin-dried, combined with the filter cake, diluted with 100 mL of methylene chloride, washed with saturated citric acid solution (100 mL) for 3-5 times,The organic phase was washed 1-2 times with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate and concentrated to give compound 15 (white solid, 7.65 g). The yield was 76.4percent.
72% With dmap; triethylamine In tetrahydrofuran at 20 - 25℃; for 18 h; [00174] tert-Butyl thiazol-2-ylcarbamate/sV-NHBocTo a solution of 2-aminothiazole (20.0 g, 199.7 mmol) and (Boc)2O (48.0 g, 219.7 mmol) in anhydrous THF (100 mL) were added DMAP (20 mg) and Et3N (36.0 mL, 260.0 mmol). The reaction mixture was stirred at 250C for 18 h, diluted with CH2Cl2 and washed with 0.1 N HCl (X 1), brine (X 1) and H2O (X 1). The organic layer was separated from the aqueous layer, dried over Na2SO4 and concentrated. The crude product was purified by column chromatography (0- 40percent EtOAc/Hexane) to provide tert-butyl thiazol-2-ylcarbamate as a white solid (20.7 g, 72percent). 1H-NMR (400 MHz, CDCl3) ? 11.44 (s, IH), 7.38 (d, J = 3.6 Hz, IH), 6.89 (d, J = 3.6 Hz, IH), 1.58 (s, 9H). HPLC ret. time 2.61 min, 10-99percentCH3CN, 5 min run; ESI-MS 145.1 m/z (MH+). [00197] tert-Butyl thiazol-2-ylcarbamateTo a solution of aminothiazole (20.0 g, 199.7 mmol) and (Boc)2O (48.0 g, 219.7 mmol) in anhydrous THF (100 mL) were added DMAP (20 mg) and Et3N (36.0 mL, 260.0 mmol). The reaction mixture was stirred at room temperature for 18 h, diluted with DCM and washed with 0.1 N HCl, H2O and brine. The organic layer was separated from the aqueous layer, dried over Na2SO4 and concentrated. The crude product was purified by column chromatography (0-40percent EtOAc/Hexane) to provide tert-butyl thiazol-2-ylcarbamate as a white solid (20.7 g, 72percent). 1H- NMR (400 MHz, CDCl3) ? 11.44 (s, IH), 7.38 (d, J = 3.6 Hz, IH), 6.89 (d, J = 3.6 Hz, IH), 1.58 (s, 9H); HPLC ret. time 2.61 min, 10-99percentCH3CN, 5 min run; ESI-MS 145.1 m/z (MH+).
68% With triethylamine In tetrahydrofuran at 20℃; for 16 h; tert-Butyl thiazol-2-ylcarbamate: 2-Aminothiazole (10.0 g, 100 mmol,Aldrich) was dissolved in THF (50 mL) and di-tert-butyl dicarbonate was added (24 g, 110 mmol, Aldrich) followed by TEA (17 mL, 120 mmol). The resulting mixture was then stirred at ambient temperature for 16 hours. The solids were filtered and washed with ether to afford tert-butyl thiazol-2-ylcarbamate (13.5 g, 68 percent). LCMS (API-ES) m/z: 201 (M+H+).
64%
Stage #1: With dmap; triethylamine In tetrahydrofuran at 0℃; for 0.166667 h;
Stage #2: at 20℃; for 3 h;
To a stirring solution of compound 3 (1.00 g10 mmolin 15 ml THF, was added Et3N (2.04 g, 20 mmol) and DMAP (0.12 g, 1 mmol) at 0 °C, respectively. 10 min later, (Boc)2O2.40 g11 mmolwas dropwise added to the mixture and the mixture was stirred at ambient temperature for 3 h until compound 3 was not observed. The reaction was quenched by adding distilled water. The solvent was evaporated to give a precipitate. The precipitate was ltered and the residue was dissolved with 25 ml CH2Cl2, the organic phase was washed with Citric acid solution (2 × 5 ml) and saturated salt water (2 ×5 ml), the organic phase was dried over Na2SO4, ltered, and concentrated to give compound 4 (1.28g64percentas a white solid. 1H NMR (400 MHz, CDCl3): δ ppm 12.71 (bs, 1H), 7.41 (d, J = 3.5 Hz, 1H), 6.90 (d, J = 3.5 Hz, 1H), 1.61 (s, 9H)13C NMR (100 MHz, CDCl3) δ 162.17, 153.13, 136.67,111.94, 81.73, 28.33MS: [M+H]+ 201.01.
47.5% at 20℃; for 16 h; (Boc) 20 (52.305 g, 240 mmol) was added dropwise to a solution of thiazol-2-amine (20.0 g, 200 mmol) in tetrahydrofuran solution (150 mL) followed by stirring at room temperature for 16 h. The solvent was removed in vacuo to afford crude product, which was pulverized in EtOAc and filtered. 19.0 g (47.5percent) of the title compound as a white solid was obtained.
NMR (400 MHz, CDC13) δ 12.20 (s, 1H), 7.38 (d, J= 3.6 Hz, 1H), 6.88 (d, J= 3.6 Hz, 1H), 1.59 (s, 9H).
39% With triethylamine In tetrahydrofuran for 4 h; Di-tert-butyl dicarbonate (2.40 g; 11.00 mmol) was added to a solution of 2-aminothiazole (1.00 g; 9.99 mmol) in THF (5 mL). TEA (1.67 mL; 11.98 mmol) was added followed by a catalytic amount of 4-DMAP (2.0 mg). After 4 h the reaction mixture was concentrated in vacuo. The residue was partitioned between EtOAc (20 mL) and 0.1 N aqueous HCl (15 mL).The organic phase was washed with brine (15 mL), dried (MgSO4) and concentrated in vacuo. The crude product was chromatographed (SiO2; continuous gradient from 0 to 100percent solvent B over 25 min; hold at 100percent solvent B for 5 min, where solvent A=hexanes and solvent B=EtOAc) to give Part E compound (0.77 g; 39percent) as a white solid.
31.5% With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 50℃; for 12 h; tert-Butyl thiazol-2-ylcarbamate 2. A solution of thiazol-2-amine (10.0 g, 0.10 mol, 1.0 equiv), (BoC2)O (26.2 g, 0.12 mol, 1.2 equiv), and DIPEA (25.8 g, 0.20 mol, 2.0 equiv) in THF (150 mL) was stirred at 50 0C for 12 hours. The reaction mixture was concentrated in vacuum and EtOAc (300 mL) was added. Then, the organic layer was washed by water (250 mLx2) and brine (250 mLx2), dried (MgSO4), filtrated, concentrated in vacuum to give target product (6.3 g, 31.5percent). [M+l]: 201.1.
28% at 20℃; for 2 h; To a solution of thiazol-2-amine (500.0 mg, 5.0 mmol) in pyridine (5 mL) wasadded Boc2O (1.3 g, 6.0 mmol). The resulting mixture was stirred at it for 2 h. The mixture wasconcentrated under reduced pressure and the residue was purified by silica gel chromatography,eluting with petroleum ether/EtOAc (4:1), to afford tert-butyl thiazol-2-ylcarbamate as a solid(280 mg, 28percent). ‘H NIVIR (300 MHz, DM50-c/6) 6 11.38 (br s, 1 H), 7.35 (d, J 3.6 Hz, 1H),7.14 (d, J 3.6 Hz, 1H), 1.44 (s, 9H).
390 mg at 20℃; for 17 h; Example 10
tert-butyl thiazol-2-ylcarbamate
To a solution of thiazol-2-amine (200 mg) in N-methylpyrrolidone (2.3 mL) was added di-tert-butyl dicarbonate (480 mg) and the reaction mixture was stirred at room temperature for 17 hours.
The reaction mixture was added with water (10 mL).
The precipitated solid was collected by filtration.
The solid was washed and dried to give the titled compound (390 mg) having the following physical data.
TCL : Rf 0.52 (Hexane : Ethyl Acetate = 4 : 1).

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YieldReaction ConditionsOperation in experiment
60%
Stage #1: With pyridine In dichloromethane at 0 - 20℃; Sonographic reaction
Stage #2: With hydrogenchloride In water at 20℃; for 1 h;
3-Cyano-4-fluorobenzenesulfonyl chloride (10 g, 45.53 mmol) was added portion wise to a solution of 2-aminothiazole (5 g, 50.13 mmol) in dichloromethane (50 mL) and pyridine (18.4 mL, 228 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature. After 1 hour a precipitate was observed. The mixture was stirred for 18 hours at room temperature. The mixture was sonicated for 2.5 hours until the solid had dissolved, then left to stir at room temperature for 18 hours. The reaction mixture was then concentrated in vacuo and azeotropically dried with toluene (2.x.100 mL). The residue was diluted carefully with a 1M aqueous solution of hydrogen chloride and stirred for 1 hour at room temperature whereupon a precipitate formed. The brown solid was collected by filtration and triturated with dichloromethane to afford the title compound as a brown solid (7.8 g, 60percent).1HNMR (d6-DMSO): δ 6.90 (m, 1H), 7.30 (m, 1H), 7.65 (t, 1H), 8.15 (m, 1H), 8.30 (m, 1H), 12.90 (br s, 1H).LCMS Rt=2.18 minutes MS m/z 284 [MH]+, 282 [MH]-
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