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Product Details of [ 22483-09-6 ]

CAS No. :22483-09-6 MDL No. :MFCD00008135
Formula : C4H11NO2 Boiling Point : -
Linear Structure Formula :- InChI Key :QKWWDTYDYOFRJL-UHFFFAOYSA-N
M.W : 105.14 Pubchem ID :89728
Synonyms :

Calculated chemistry of [ 22483-09-6 ]

Physicochemical Properties

Num. heavy atoms : 7
Num. arom. heavy atoms : 0
Fraction Csp3 : 1.0
Num. rotatable bonds : 3
Num. H-bond acceptors : 3.0
Num. H-bond donors : 1.0
Molar Refractivity : 26.22
TPSA : 44.48 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) : -7.54 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.3
Log Po/w (XLOGP3) : -0.85
Log Po/w (WLOGP) : -0.44
Log Po/w (MLOGP) : -0.66
Log Po/w (SILICOS-IT) : -0.59
Consensus Log Po/w : -0.25

Druglikeness

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

Water Solubility

Log S (ESOL) : 0.24
Solubility : 183.0 mg/ml ; 1.74 mol/l
Class : Highly soluble
Log S (Ali) : 0.4
Solubility : 262.0 mg/ml ; 2.49 mol/l
Class : Highly soluble
Log S (SILICOS-IT) : -0.16
Solubility : 72.9 mg/ml ; 0.693 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.43

Safety of [ 22483-09-6 ]

Signal Word:Danger Class:3,8
Precautionary Statements:P280-P305+P351+P338-P310 UN#:2924
Hazard Statements:H226-H314 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 22483-09-6 ]

* 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 [ 22483-09-6 ]
  • Downstream synthetic route of [ 22483-09-6 ]

[ 22483-09-6 ] Synthesis Path-Upstream   1~34

  • 1
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Reference: [1] Journal of Pharmaceutical Sciences, 1981, vol. 70, # 12, p. 1322 - 1324
  • 2
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  • [ 42398-73-2 ]
YieldReaction ConditionsOperation in experiment
66%
Stage #1: at 90℃;
Stage #2: With chloroformic acid ethyl ester; triethyl phosphite In chloroform at 0 - 20℃; for 24 h;
Stage #3: With titanium tetrachloride In chloroform at 0 - 20℃; Reflux
Para-tolualdehyde (53 mL, 0.486 mol) was stirred in a solvent of chloroform (900 mL). Aminoacetaldehyde dimethyl acetal (59.3 mL, 0.486 mol) was slowly added thereto, followed by stirring at 90° C. until about one-half of the reaction solution was evaporated. The reaction solution was cooled to room temperature, and the resulting yellow reaction solution was dissolved in chloroform (400 mL), followed by cooling the solution to 0° C. or below. Ethyl chloroformate (48 mL, 0.486 mol) and triethylphosphite (104 mL, 0.583 mol) were slowly added to the reaction solution. The reaction solution was stirred for 24 hours at room temperature. The reaction solution was cooled to 0° C. or below, slowly added with titanium tetrachloride (213.6 mL, 1.94 mol), and refluxed for 12 hours or more. The reaction solution was cooled to room temperature, and stirred for 12 hours or more. The reaction mixture was poured to an ice water to separate the organic layer and the aqueous layer, and the aqueous layer was washed with dichloromethane. A saturated sodium tartrate solution was added to the aqueous layer, adjusted to pH 9 by adding ammonia water, and subjected to extraction with dichloromethane. The obtained organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (46.3 g, 66percent). 1H-NMR Spectrum (300 MHz, DMSO-d6): δ 9.23 (s, 1H), 8.45 (d, 1H), 8.02 (d, 1H), 7.72 (d, 2H), 7.54 (d, 1H), 2.49 (s, 3H)
66%
Stage #1: at 90℃;
Stage #2: With chloroformic acid ethyl ester; triethyl phosphite In chloroform at 0 - 20℃; for 24 h;
Stage #3: With titanium tetrachloride In chloroform at 0℃; for 12 h; Reflux
p-Tolualdehyde (53 mL, 0.486 mol) was stirred in a solvent of chloroform (900 mL), slowly added with aminoacetaldehyde dimethyl acetal (59.3 mL, 0.486 mol), and stirred at 90°C until about a half of the reaction solution had evaporated.
The reaction solution was cooled to room temperature, and the yellow reaction solution was dissolved in chloroform (400 mL), followed by cooling to 0°C or lower.
The reaction solution was slowly added with ethyl chloroformate (48 mL, 0.486 mol) and triethyl phosphite (104 mL, 0.583 mol), followed by stirring for 24 hours at room temperature.
The reaction solution was cooled to 0°C or lower, slowly added with titanium tetrachloride (213.6 mL, 1.94 mol), and refluxed for 12 hours or more.
The temperature of the reaction solution was adjusted to room temperature and stirred for over 12 hours.
The reaction mixture was poured over an ice water to separate the organic layer and the aqueous layer, and the aqueous layer was washed with dichloromethane.
The aqueous layer was poured into a saturated potassium sodium tartrate solution, and adjusted to have a pH value of 9 by adding an aqueous ammonia solution, and then extracted with dichloromethane.
The combined organic layer thus obtained was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (46.3 g, 66 percent).
1H-NMR Spectrum (300 MHz, DMSO-d6): δ 9.23(s, 1H), 8.45(d, 1H), 8.02(d, 1H), 7.72(d, 2H), 7.54(d, 1H), 2.49(s, 3H)
66%
Stage #1: at 90℃;
Stage #2: With chloroformic acid ethyl ester; triethyl phosphite In chloroform at 0 - 20℃; for 24 h;
Stage #3: With titanium tetrachloride In chloroform at 0℃; Reflux
p-Tolualdehyde (53 mL, 0.486 mol) was stirred in a solvent of chloroform (900 mL), slowly added with aminoacetaldehyde dimethyl acetal (59.3 mL, 0.486 mol), and stirred at 90° C. until about a half of the reaction solution had evaporated.
The reaction solution was cooled to room temperature, and the yellow reaction solution was dissolved in chloroform (400 mL), followed by cooling to 0° C. or lower.
The reaction solution was slowly added with ethyl chloroformate (48 mL, 0.486 mol) and triethyl phosphite (104 mL, 0.583 mol), followed by stirring for 24 hours at room temperature.
The reaction solution was cooled to 0° C. or lower, slowly added with titanium tetrachloride (213.6 mL, 1.94 mol), and refluxed for 12 hours or more.
The temperature of the reaction solution was adjusted to room temperature and stirred for over 12 hours.
The reaction mixture was poured over an ice water to separate the organic layer and the aqueous layer, and the aqueous layer was washed with dichloromethane.
The aqueous layer was poured into a saturated potassium sodium tartrate solution, and adjusted to have a pH value of 9 by adding an aqueous ammonia solution, and then extracted with dichloromethane.
The combined organic layer thus obtained was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (46.3 g, 66percent).
1H-NMR Spectrum (300 MHz, DMSO-d6): δ 9.23 (s, 1H), 8.45 (d, 1H), 8.02 (d, 1H), 7.72 (d, 2H), 7.54 (d, 1H), 2.49 (s, 3H)
Reference: [1] Patent: US2014/371219, 2014, A1, . Location in patent: Paragraph 0216; 0217
[2] Patent: EP2876107, 2015, A1, . Location in patent: Paragraph 0072
[3] Patent: US2015/191450, 2015, A1, . Location in patent: Paragraph 0143; 0144
  • 3
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YieldReaction ConditionsOperation in experiment
78%
Stage #1: at 22 - 65℃;
Stage #2: With triethyl phosphite In chloroform at -3 - 20℃; for 23 h;
Stage #3: With titanium tetrachloride In chloroform at 52℃; for 10.5 h;
Aminoacetaldehyde dimethyl acetal (8.83 mL, 81.1 mmol) was added over 1 min to a stirred solution of p-tolualdehyde (9.88 mL, 81.1 mmol) in chloroform (150 mL) at 22 0C. An exotherm was noted. The reaction was heated to reflux (65 0C) and half the solvent was removed (azeotropically to remove water). The heat was removed and the yellow solution was cooled to r.t. NMR showed the imine was formed smoothly, however, a trace of aldehyde was observed. The yellow solution was diluted with chloroform to bring the volume back to -100 mL, cooled to -3 0C and ethyl chloroformate (7.99 mL, 81.1 mmol) was added dropwise over 5 min followed by triethyl phosphite (17.4 mL, 97.3 mmol) over 10 minutes. The clear yellow solution was then allowed to warm to RT. A reflux condenser added to reaction vessel. After 23 h, titanium tetrachloride (35.6 mL, 324 mmol) was added very slowly (strong exotherm and white fumes observed) and the reaction began to gently reflux (50 °C). Color changed from yellow to dark red to dark brown. Once addition was complete, the dark brown solution was heated to reflux (52 0C) for 10.5 h. After allowing to cool to RT overnight, the dark brown solution was poured onto ice (filled a 2 L beaker with approximately 1 L of ice), the organic layer was separated off, and the aqueous layer was washed with DCM (2 x 100 mL). The aqueous layer (now orange in color) was poured into a solution of potassium sodium tartrate tetrahydrate (183 g, 648 mmol) in water (300 mL), basified to pH 9 with 28-30 percent ammonium hydroxide (a white ppt crashed out) and then extracted with DCM (3 x 200 mL). The organic layer was separated, dried over sodium sulfate, filtered and the solvent was evaporated in vacuo to yield 6-methylisoquinoline (9.02 g, 78percent yield) as a light tan amorphous solid. Found MS (ESI, pos. ion) m/z: 144.1 [M+H]+
Reference: [1] Patent: WO2008/153947, 2008, A2, . Location in patent: Page/Page column 53
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Reference: [1] Patent: US2007/254879, 2007, A1, . Location in patent: Page/Page column 29; 30
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  • [ 7651-83-4 ]
Reference: [1] Chemical Communications, 2005, # 17, p. 2208 - 2210
[2] Journal of the American Chemical Society, 2011, vol. 133, # 32, p. 12451 - 12453
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Reference: [1] Patent: US2007/254879, 2007, A1, . Location in patent: Page/Page column 29; 30
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Reference: [1] Patent: US2018/215731, 2018, A1, . Location in patent: Paragraph 1054; 1055; 1056; 10567
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  • [ 407-25-0 ]
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YieldReaction ConditionsOperation in experiment
84% With hydrogenchloride; ammonia; trifluoroborane diethyl ether In toluene 85a.
7-Methoxy-isoquinoline
Aminoacetaldehyde dimethyl acetal (81.9 mL) was added to a solution of 60.8 mL of 3-methoxy-benzaldehyde in 600 mL of toluene.
The mixture was refluxed for 5 h using a Dean-Stark trap and subsequently cooled to 5° C. In a nitrogene atmosphere trifluoroacetic acid anhydride (209 mL) and borontrifluoride etherate (185 mL) were added in succession at such a rate, that the internal temperature was kept below 10° C.
After stirring for 3 days at room temperature the the reaction mixture was poured on ice, 250 mL 2 N hydrochloric acid added and the organic layer extracted with 1 N hydrochloric acid.
The pH value of the combined aqueous extracts was adjusted to pH 9 by adding concentrated aqueous ammonia.
Extraction with ethyl acetate, followed by drying and removal of the solvent in vacuo gave 66.9 g (84percent) of the title compound as a light brownish oil. EI-MS: 159 (M+).
Reference: [1] Patent: US6194409, 2001, B1,
  • 9
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  • [ 872-35-5 ]
Reference: [1] Patent: US4391808, 1983, A,
  • 10
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Reference: [1] Patent: WO2009/156951, 2009, A2, . Location in patent: Page/Page column 46
  • 11
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YieldReaction ConditionsOperation in experiment
73%
Stage #1: at 20℃;
Stage #3: With potassium carbonate In ethanol; water
Step b: 2-tert-butyl-lH- imidazole [0464] A solution of ethyl pivalimidate hydrochloride (4.2 g, 25.2 mmol) andaminoacetaldehyde dimethyl acetal (3.2 g, 30.45 mmol) in methanol (8.0 mL) was stirred at room temperature overnight. The mixture was concentrated and concentrated HC1 (5.0 mL) was added. The mixture was concentrated again and water (10.0 mL) was added. The mixture was adjusted to pH=l 1 with K2CO3 solution and ethanol (10.0 mL) was added. The resulting mixture was filtered and the filtrate was concentrated. The residue was purified by flash column chromatography on silica gel (DCM/MeOH = 100: 1 to 50: 1) to afford 2.3 g of the title compound as a white solid (73percent yield).
Reference: [1] Patent: WO2012/178015, 2012, A2, . Location in patent: Page/Page column 116-117
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YieldReaction ConditionsOperation in experiment
36%
Stage #1: at -20 - 20℃;
Stage #2: at 20℃;
EXAMPLE 81 2-tert-Butyl-4-(5-methylfuran-2-yl)-1-(tetrahydrofuran-4-ylmethyl)-1H-imidazole (Compound 81); Step 1 Trimethylacetonitrile (18.3 g, 0.22 mol) was dissolved in ethanol (12.8 mL, 0.22 mol), and hydrochloric acid gas was blown into the mixture at -20°C until the mixture was saturated with hydrochloric acid gas, and then, the mixture was stirred overnight at room temperature. The mixture was concentrated, and the obtained crude crystals were washed with isopropyl ether to give ethyl-tert-butyl-imidate (16.24 g, 98 mmol, yield: 45percent). The thus obtained ethyl-tert-butyl imidate (16.24 g, 98 mmol) was dissolved in methanol (17.5 mL), and aminoacetaldehyde =dimethyl acetal (11.7 mL, 0.11 mol) was added thereto, and then, the mixture was stirred overnight at room temperature. The mixture was concentrated, and to the residue, concentrated hydrochloric acid (26.2 mL) and water (17.5 mL) were added. The solvent was evaporated under reduced pressure, and the residue was dissolved in water (9 mL), and the pH of the mixture was adjusted to 10 with potassium carbonate, and then, the solvent was evaporated under reduced pressure. The residue was dissolved in ethanol (175 mL), and the solvent was evaporated under reduced pressure. The obtained residue was washed with diisopropyl ether to give 2-tert-butyl-1H-imidazole (9.7 g, 78.2 mmol, yield: 36percent).
Reference: [1] Patent: EP2090570, 2009, A1, . Location in patent: Page/Page column 65
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YieldReaction ConditionsOperation in experiment
62%
Stage #1: With sodium methylate In methanol at 40℃; for 1 h; Inert atmosphere
Stage #2: With acetic acid In methanol for 1 h; Inert atmosphere; Reflux
2-Pyridinecarbonitrile (10.4 g, 100 mmol) was added to a solutionof NaOMe (0.54 g, 10.0 mmol) in abs. MeOH (40 ml). The mixture was stirred for 1 h at 40 °C before it was allowed to cool down. 2,2-Dimethoxyethylamine (10.5 g, 100 mmol) and glacial acetic acid (11 ml) was added drop wise and the resulting mixture was refluxed for 1 h and was afterwards allowed to cool down before MeOH (50 ml) and 6 M HCl (50 ml) was added. The mixture was then refluxed for further 4 h before the solvent was removed under reduced pressure. The residue was digested in a solution of K2CO3(50 g) in H2O (50 ml) before DCM (50 ml) was added to the resulting suspension. The mixture was filtered and the organic phase separated .The aqueous phase was extracted several times with DCM and the combined organic layers were dried over Na2SO4 before removal of the solvent under reduced pressure and recrystallisation of the residue from ethyl acetate (50 ml) gave a tan amorphous powder of I. Yield: 62percent. 1H NMR (200.13 MHz, DMSO-d6): δ = 12.77 (bs, 1 H, 1-imH), 8.58 (d, 1 H, 6-pyH), 8.04 (d, 1 H, 3-pyH), 7.87 (ddd, 1 H, 4-pyH), 7.34 (ddd, 1 H, 5-pyH), 7.22 (s, 1 H,5-imH or 4-imH), 7.08 (s, 1 H, 5-imH or 4-imH) ppm. 13C NMR (50.33 MHz, DMSO-d6): δ = 149.2 (2-pyC), 148.9 (6-pyC), 145.5 (2-imC), 137.1 (4-pyC), 129.5 (4-imC or 5-imC), 123.0 (5-pyC), 119.4 (3-pyC), 118.7 (4-imC or 5-imC) ppm. EI-MS (MeOH) m/z (rel. abundance, fragment) = 145.0 (100percent, I+). IR (diamond, ATR): ~v = 3046, 2983, 2887, 2821, 2743, 1594 (s), 1568, 1479 (vs), 1458 (vs), 1415, 1382, 1308, 1139, 1109 (s), 992, 954 (s), 909, 786 (vs), 758,736 (vs), 706 (vs), 630 (s), 621, 504, 464, 403 cm-1. Elemental analysis(percent) Anal. Calc. for C8H7N3 (145.16 g mol1): C, 66.19; H, 4.86 N,28.95. Found: C, 65.89, H, 4.97; N, 29.09percent.
Reference: [1] European Journal of Inorganic Chemistry, 2017, vol. 2017, # 3, p. 609 - 615
[2] Polyhedron, 2015, vol. 93, p. 28 - 36
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Reference: [1] Journal of the American Chemical Society, 1955, vol. 77, p. 6640
[2] Patent: US4137268, 1979, A,
[3] Patent: US4137268, 1979, A,
[4] Patent: US4137268, 1979, A,
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  • [ 97-97-2 ]
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Reference: [1] Journal of the American Chemical Society, 1953, vol. 75, p. 3398
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  • [ 27328-34-3 ]
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Reference: [1] Pharmaceutical Chemistry Journal, 1989, vol. 23, # 3, p. 231 - 234[2] Khimiko-Farmatsevticheskii Zhurnal, 1989, vol. 23, # 3, p. 299 - 302
  • 17
  • [ 81956-67-4 ]
  • [ 60193-28-4 ]
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Reference: [1] Journal of the American Chemical Society, 1982, vol. 104, # 15, p. 4117 - 4124
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  • [ 81956-81-2 ]
  • [ 778519-97-4 ]
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Reference: [1] Journal of the American Chemical Society, 1982, vol. 104, # 15, p. 4117 - 4124
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  • [ 22483-09-6 ]
Reference: [1] Organic Letters, 2011, vol. 13, # 23, p. 6156 - 6159
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  • [ 7252-83-7 ]
  • [ 56548-04-0 ]
  • [ 22483-09-6 ]
Reference: [1] Journal of the Chemical Society, 1922, vol. 121, p. 1896
[2] Journal of the Chemical Society, 1922, vol. 121, p. 1896
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Reference: [1] Tetrahedron Asymmetry, 2008, vol. 19, # 23, p. 2682 - 2692
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Reference: [1] Journal of Organic Chemistry, 1970, vol. 35, p. 340 - 344
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YieldReaction ConditionsOperation in experiment
22%
Stage #1: at 120℃; Dean-Stark
Stage #2: at 160℃; for 0.5 h;
General procedure: Aminoacetaldehyde dimethylacetal (3.0 eq.) was added to a solution of bromobenzaldehyde13b or 13c (1.0 eq.) in toluene (30 mL). Each reaction mixture was refluxed (Dean–Stark apparatus)at 120 °C. After consumption of the starting material, each reaction mixture was concentrated todryness, then dissolved in conc. H2SO4 (2 mL) and added to a cold solution of P2O5 in conc. H2SO4(0.5 mL). Each reaction mixture was heated at 160 °C for 30 min, allowed to cool to RT, neutralizedwith NaOH (10 M), extracted with EtOAc, and concentrated to dryness. Each residue was subjected toFCC to afford 6-bromoisoquinoline (14b, 30 mg, 0.14 mmol, 14percent) and 7-bromoisoquinoline (14c, 99 mg,0.47 mmol, 22percent) [20,21]. Ethylchloroformate (1.0 eq.) was added to a solution of isoquinoline 14b or14c (1.0 eq.) in DCM at 0 °C and stirred at the same temperature for 30 min, followed by additionof 2-trimethylsilylthiazole (1.0 eq.). Each reaction mixture was stirred at RT for 3 h, concentratedto dryness, and each residue was subjected to FCC. Each product was dissolved in benzene (5 mL),o-chloranil (1.0 eq.) was added, and each reaction mixture was refluxed for 5 h. Each reaction mixturewas diluted with 5percent NaOH (10 mL), extracted with DCM, and concentrated to dryness. Each reactionmixture residue was subjected to FCC to afford the products 9b and 9c.
Reference: [1] Molecules, 2017, vol. 22, # 8,
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Reference: [1] Patent: US2018/215731, 2018, A1, . Location in patent: Paragraph 1054; 1055; 1056; 10567
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Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 22, p. 6378 - 6382
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YieldReaction ConditionsOperation in experiment
49.8%
Stage #1: for 3 h; Inert atmosphere; Reflux; Dean-Stark
Stage #2: With aluminum (III) chloride In dichloromethane at 0 - 45℃; for 2 h; Inert atmosphere
A mixture of 2-bromobenzaldehyde (50 g, 270 mmol) , aminoacetaldehyde dimethyl acetal (28.4 g, 270 mmol) and toluene (400 mL) was refluxed under argon. Dehydration was carried out using dean stark for 2.0 hours. After removal of calculated amount of water, the reflux was continued for 1.0 hour. The toluene was evaporated under reduced pressure, the residue was dissolved in dichloromethane (600 mL) , and the solution was cooled to 0°C. To the cooled solution was slowly added aluminium chloride (118.9 g, 891.7 mmol) under argon. The reaction mixture was stirred at 45°C for 2.0 hours. After the completion of the reaction was confirmed by TLC, the mixture was cooled to room temperature and slowly poured into an ice water. The mixture was basified with 10percent sodium hydroxide solution, and the dichloromethane layer was separated. The aqueous layer was re-extracted with dichloromethane (2 x 100 mL) . The combined dichloromethane layers were washed with brine, and dried over sodium sulfate. The dichloromethane was evaporated, and the residue was purified by silica gel (100-200 mesh) column chromatography 5 with 8-12percent. ethyl acetate in hexane as a mobile phase to give the title compound as an off-white solid (28 g, 49.8percent). MS(ESI)m/z: 208 [M (79Br)+l] ,210 [M (81Br)+l]; XH NMR (400 MHz, DMSO-d5) : δ 7.17 (t, J= 7.8 Hz, 1H) ; 7.91 (d, J= 6.0 Hz, 1H) ; 8.02 (d, J = 8.4 Hz, 1H) ; 8.05 (d, J = 8.8 Hz, 1H) ; 8.65 10 (d, J = 5.2 Hz, 1H) 9.48 (s, IH) .
Reference: [1] Patent: WO2016/21742, 2016, A1, . Location in patent: Paragraph 0222; 0223
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Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 22, p. 6378 - 6382
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YieldReaction ConditionsOperation in experiment
35%
Stage #1: for 12 h; Reflux; Dean-Stark
Stage #2: With chloroformic acid ethyl ester In tetrahydrofuran at -10℃; for 0.166667 h;
A mixture of 4-bromobenzaldehyde (300.0 g, 1620.0 mmol) and amino acetaldehyde dimethyl acetal (170.4 g, 1620 mmol) in anhydrous toluene (1.5 L) was refluxed under a Dean-Stark condenser for 12 h. The solution was concentrated under vacuum. The residue was dissolved in anhydrous THF and cooled to -10 °C. Ethyl chloroformate (193.3 ml_, 1782 mmol) was added and stirred for 10 min at -10 °C, and then allowed to warm to room temperature. Subsequently trimethyl phosphite (249.6 ml_, 1782.0 mmol) was added dropwise to the reaction mixture and stirred for 10 h at room temperature. The solvent was evaporated under vacuum and the residue was dissolved in anhydrous DCM (1.5 L) and stirred for 30 minutes. The reaction mixture was cooled to 0 °C, and titanium tetrachloride (1.2 L, 6480 mmol) was added dropwise. The reaction mixture was stirred at 40 °C for 6 days. The reaction mixture was poured into ice and pH was adjusted to 8 - 9 with aqueous 6N NaOH solution. The suspension was extracted three times with EtOAc. The organic layer was extracted with 3 M HCI. The acidic aqueous solution was adjusted to pH to 7 - 8 with 3N NaOH solutions and extracted two times with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide the product. Crude compound was dissolved in minimum amount of DCM and mixed with pentane to get compound A1 as light brown solid. Yield: 90 g (35percent). Rf: 0.6 (30percent EtOAc in petroleum ether). LCMS m/z = 209 (M + 1 ). 1H NMR (400 MHz, cf6-DMSO): δ 7.82 (m, 2H), 8.1 1 (d, J = 8.8 Hz, 2H), 8.30 (br s, 1 H), 8.56 (d, J = 6.0 Hz, 1 H), 9.35 (s, 1 H).
14%
Stage #1: at 120℃; Dean-Stark
Stage #2: at 160℃; for 0.5 h;
General procedure: Aminoacetaldehyde dimethylacetal (3.0 eq.) was added to a solution of bromobenzaldehyde13b or 13c (1.0 eq.) in toluene (30 mL). Each reaction mixture was refluxed (Dean–Stark apparatus)at 120 °C. After consumption of the starting material, each reaction mixture was concentrated todryness, then dissolved in conc. H2SO4 (2 mL) and added to a cold solution of P2O5 in conc. H2SO4(0.5 mL). Each reaction mixture was heated at 160 °C for 30 min, allowed to cool to RT, neutralizedwith NaOH (10 M), extracted with EtOAc, and concentrated to dryness. Each residue was subjected toFCC to afford 6-bromoisoquinoline (14b, 30 mg, 0.14 mmol, 14percent) and 7-bromoisoquinoline (14c, 99 mg,0.47 mmol, 22percent) [20,21]. Ethylchloroformate (1.0 eq.) was added to a solution of isoquinoline 14b or14c (1.0 eq.) in DCM at 0 °C and stirred at the same temperature for 30 min, followed by additionof 2-trimethylsilylthiazole (1.0 eq.). Each reaction mixture was stirred at RT for 3 h, concentratedto dryness, and each residue was subjected to FCC. Each product was dissolved in benzene (5 mL),o-chloranil (1.0 eq.) was added, and each reaction mixture was refluxed for 5 h. Each reaction mixturewas diluted with 5percent NaOH (10 mL), extracted with DCM, and concentrated to dryness. Each reactionmixture residue was subjected to FCC to afford the products 9b and 9c.6-Bromo-1-(2-thiazolyl)isoquinoline (9b): 6-Bromoisoquinoline (14b, 30 mg, 0.14 mmol) was synthesizedstarting from 4-bromobenzaldehyde (13c, 200 mg, 1.08 mmol) in 14percent yield. Compound 9b wassynthesized starting from 6-bromoisoquinoline (14b, 100 mg, 0.48 mmol) in 15percent yield over two steps(21 mg, 0.07 mmol), obtained as an orange powder, m.p. 103–105 °C.
Reference: [1] Patent: WO2015/181676, 2015, A1, . Location in patent: Page/Page column 132-133
[2] Dalton Transactions, 2015, vol. 44, # 18, p. 8552 - 8563
[3] Molecules, 2017, vol. 22, # 8,
[4] Journal of the Chemical Society. Perkin Transactions 2, 1998, # 2, p. 437 - 447
  • 29
  • [ 22483-09-6 ]
  • [ 456-48-4 ]
  • [ 456-47-3 ]
Reference: [1] Tetrahedron, 2008, vol. 64, # 51, p. 11783 - 11788
  • 30
  • [ 22483-09-6 ]
  • [ 456-48-4 ]
  • [ 1099778-01-4 ]
  • [ 456-47-3 ]
  • [ 56766-81-5 ]
Reference: [1] Tetrahedron, 2008, vol. 64, # 51, p. 11783 - 11788
  • 31
  • [ 541-41-3 ]
  • [ 22483-09-6 ]
  • [ 71545-60-3 ]
YieldReaction ConditionsOperation in experiment
100% With sodium hydroxide In dichloromethane; water at 20℃; Ethyl chloroformate (4.37 mL, 45.77 mmol) was added drop wise to an ice cooled solution of aminoacetaldehyde dimethyl acetale (5 mL, 45.77 mmol) and NaOH (2.05 g, 51.26 mmol) in a mixture of DCM/H20 (25/12 mL) keeping the internal temperature below 10 °C. After addition ceased the reaction mixture was vigorously stirred at RT ON. The two phases wereseparated and the organic one was washed with brine, then dried and evaporated to afford 8.1 g of the title compound (p6S, y= quant) as colourless oil. MS (m/z): 178.1 [IVIH]t
83% With sodium hydroxide In water; toluene at 0 - 20℃; Large scale A solution of NaOH (578.4 g, 14.46 mol) in H2O (2 L) was added to a solution of 2,2-dimethoxyethanamine (800 g, 7.6 mol) in toluene (2 L) and the resulting mixture was cooled to 0°C using an ice bath. Ethyl chloroformate (825 g, 7.6 mol) was added dropwise while keeping the temperature near 10°C. The mixture was then stirred at r.t. overnight. The phases were then separated and the aqueous solution was saturated with solid NaCl. This solution was then extracted with toluene (1.25 L x 3). The combined organic solutions were dried (Na2SO4) and concentrated in vacuo to give the title compound (1.123 kg, 83percent) as colorless oil; 1H NMR: (CDCl3) 1.17 (3H, t), 3.14 (2H, s), 3.32 (6H, s), 4.02-4.07 (2H, m), 4.30 (1H, t).
Reference: [1] Patent: WO2017/21920, 2017, A1, . Location in patent: Paragraph 0625; 0626
[2] Patent: WO2013/14448, 2013, A1, . Location in patent: Page/Page column 99; 100
[3] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 17, p. 2491 - 2496
[4] Patent: US4990517, 1991, A,
[5] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 11, p. 2891 - 2894
  • 32
  • [ 22483-09-6 ]
  • [ 103-80-0 ]
  • [ 89314-87-4 ]
Reference: [1] Journal of Medicinal Chemistry, 1990, vol. 33, # 5, p. 1496 - 1504
[2] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 7, p. 1871 - 1875
  • 33
  • [ 52328-05-9 ]
  • [ 22483-09-6 ]
  • [ 1450-93-7 ]
Reference: [1] Tetrahedron Letters, 2002, vol. 43, # 4, p. 593 - 595
  • 34
  • [ 19847-12-2 ]
  • [ 22483-09-6 ]
  • [ 119165-68-3 ]
Reference: [1] Chemical Communications, 2015, vol. 51, # 12, p. 2425 - 2428
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