[ CAS No. 3336-43-4 ] {[proInfo.proName]}

Name: 3336-43-4|1-Chloroisoquinolin-4-ol|98%
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SKU: A470882
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2D 3D

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Quality Control of [ 3336-43-4 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 3336-43-4 ]

SDS Specification

Alternatived Products of [ 3336-43-4 ]

Product Details of [ 3336-43-4 ]

CAS No. :	3336-43-4	MDL No. :	MFCD03425941
Formula :	C₉H₆ClNO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	JEVLGPVFFYUBRI-UHFFFAOYSA-N
M.W :	179.60	Pubchem ID :	4281882
Synonyms :

Calculated chemistry of [ 3336-43-4 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	10
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	48.78
TPSA :	33.12 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.47 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.74
Log Po/w (XLOGP3) :	2.71
Log Po/w (WLOGP) :	2.59
Log Po/w (MLOGP) :	1.76
Log Po/w (SILICOS-IT) :	2.6
Consensus Log Po/w :	2.28

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-3.28
Solubility :	0.0948 mg/ml ; 0.000528 mol/l
Class :	Soluble
Log S (Ali) :	-3.06
Solubility :	0.157 mg/ml ; 0.000873 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.74
Solubility :	0.0327 mg/ml ; 0.000182 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.51

Safety of [ 3336-43-4 ]

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

Application In Synthesis of [ 3336-43-4 ]

* 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 [ 3336-43-4 ]
Downstream synthetic route of [ 3336-43-4 ]

[ 3336-43-4 ] Synthesis Path-Upstream 1~4

1
[ 3336-60-5 ]
[ 3336-43-4 ]

Reference： [1] Patent: WO2003/99274, 2003, A1, . Location in patent: Page 310-312

2
[ 30081-72-2 ]
[ 3336-43-4 ]

Reference： [1] Synthesis, 2008, # 16, p. 2551 - 2560

3
[ 824-72-6 ]
[ 30081-72-2 ]
[ 3336-43-4 ]

Reference： [1] Journal of the American Chemical Society, 1958, vol. 80, p. 5481

4
[ 3336-43-4 ]
[ 18107-18-1 ]
[ 3336-60-5 ]

Yield	Reaction Conditions	Operation in experiment
46.4%	at 0 - 20℃; for 2 h;	Step 1: Preparation of 1-chloro-4-methoxyisoquinoline (0151) To a solution of 1-chloroisoquinolin-4-ol (5.0 g, 27.8 mmol) in acetonitrile (50 mL) was added TMS-diazomethane (12.73 g, 111.2 mmol) at 0° C. The reaction mixture was allowed to come to room temperature and stirred for 2 h. Solvent was evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get 1-chloro-4-methoxyisoquinoline (2.5 g, 46.4percent) as off-white solid. ¹H NMR (400 MHz, CD₃OD): δ ppm 8.29-8.17 (m, 2H), 7.97 (s, 1H), 7.91-7.82 (m, 2H), 4.05 (s, 3H); MS: MS m/z 194.7 (M⁺+1).
46.4%	at 0 - 20℃; for 2 h;	To a solution of 1-chloroisoquinolin-4-ol (5.0 g, 27.8 mmol) in acetonitrile (50 mL) was added TMS-diazomethane (12.73 g, 111.2 mmol) at 0° C. The reaction mixture was allowed to come to room temperature and stirred for 2 h. Solvent was evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get 1-chloro-4-methoxyisoquinoline (2.5 g, 46.4percent) as off-white solid.¹H NMR (400 MHz, CD₃OD): δ ppm 8.29-8.17 (m, 2H), 7.97 (s, 1H), 7.91-7.82 (m, 2H), 4.05 (s, 3H); MS: MS m/z 194.7 (M⁺+1).
46.4 % (2.5 g)	at 0℃;	Step 1: Preparation of 1-chloro-4-methoxyisoquinoline To a solution of 1-chloroisoquinolin-4-ol (5.0 g, 27.8 mmol) in acetonitrile (50 mL) was added TMS-diazomethane (12.73 g, 111.2 mmol) at 0° C. The reaction mixture was allowed to come to room temperature and stirred for 2 h. Solvent was evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get 1-chloro-4-methoxyisoquinoline (2.5 g, 46.4percent) as off-white solid. ¹H NMR (400 MHz, CD₃OD): δ ppm 8.29-8.17 (m, 2H), 7.97 (s, 1H), 7.91-7.82 (m, 2H), 4.05 (s, 3H); MS: MS m/z 194.7 (M⁺+1).

Reference： [1] Patent: US2015/284409, 2015, A1, . Location in patent: Paragraph 0150; 0151
[2] Patent: US9527885, 2016, B2, . Location in patent: Page/Page column 561
[3] Patent: US2013/115190, 2013, A1, . Location in patent: Page/Page column
[4] Patent: US2015/376233, 2015, A1,
[5] Patent: US2013/142754, 2013, A1, . Location in patent: Page/Page column

[ 3336-43-4 ] Synthesis Path-Downstream 1~72

1
[ 824-72-6 ]
[ 30081-72-2 ]
[ 3336-43-4 ]

Reference： [1]Journal of the American Chemical Society,1958,vol. 80,p. 5481

2
[ 110-91-8 ]
[ 50-00-0 ]
[ 3336-43-4 ]
[ 3336-50-3 ]

Reference： [1]Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences,1965,vol. 261,p. 1339 - 1342

3
[ 50-00-0 ]
[ 3336-43-4 ]
[ 106488-48-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid;Miyoko Toyama and Hirotaka Otomasu reaction;	6-Chloro-1, 3-Oxazino [5,6-c] isoquinoline was prepared by the procedure of Miyoko Toyama and Hirotaka Otomasu starting from1-chloro-4-hydroxy isoquinoline. The starting material: 1-chloro-4-hydroxy isoquinoline (Example 226c) was prepared by the synthetic sequence shown above. MCPBA oxidation of 4-methoxy isoquinoline (Example 222a) was carried as usual to give 79.1% of the corresponding N-oxide (Example 226a). The material was converted into the 1-chloro derivative immediately afterward in POCI3 to give the chloride (Example 226b) in essentially quantitative yield. The crudel-chloro-4-methoxy isoquinoline was de-methylated in BBr3 at room temperature to give the corresponding 1-chloro-4-hydroxy isoquinoline (Example 226c) after treating the crude BBr3 mixture with anhydrous methanol at room temperature, followed by evaporation to get rid of excess of borate residues. The reaction of Miyoko Toyama and Hirotaka Otomasu gave 266mg of 6-chloro-1, 3- oxazino [5,6-c] isoquinoline (Example 226d, 62.3%) overall yield from 300mg of 4- methoxy isoquinoline in 4 steps. LC/MS Rt-min([M-HCHO] H+) [method D]: 2.45(192).'H NMR (400 MHz, CHLOROFORM-D)8 ppm 5.02 (s, 2 H) 5.41 (s, 2 H) 7.68 (m, 1 H) 7.77 (ddd, J=8. 25,6. 91,1. 22 Hz, 1 H) 8.10 (d, J=8. 31 Hz, 1 H) 8.26 (d, J=8. 56 Hz,1 H). The chloride was found to be unreactive under the alkylation protocol of Example 184. The corresponding 6-fluoro-1, 3-oxazino [5,6-c] isoquinoline (Example 226) was prepared by the method of [Uchibori, Y.; Umeno, M.; Yoshiokai, H.; Heterocycles, 1992,34 (8),1507-1510] cited earlier. The reaction was not allowed to go to completion, and the crude reaction mixture was recovered as a mixture of ratio of 1: 2.4 (Cl : F). Without further purification, the chloride/fluoride mixture was alkylated with the tripeptide using the procedure of Example 184 to give 66mg (50.0%) of BOCNH-P3(L-t-BuGly)-P2 [ (4R)- ( 1, 3-oxazino [5,6-c] isoquinoline-6-oxo)-S-proline]-P1 (lR, 2S VinylAcca)-CONHSO2Cyclopropane after preparative HPLC purification. LC/MS Rt-min(MNa+) [method D]: 3.03(764).'H NMR (400 MHz, CD30D)8 ppm 1.01 (s, 9 H) 1.06 (dd, J=8. 07,1. 96 Hz, 2 H) 1.22 (s, 10 H) 1.34 (d, J=6. 11 Hz,1 H) 1.42 (m, 1 H) 1.86 (dd, J=8. 07,5. 38 Hz,1 H) 2.23 (m, 2 H) 2.59 (dd,J=13. 82,6. 97 Hz,1 H) 2.93 (m,1 H) 4.03 (dd,J=11. 86,3. 06 Hz,1 H) 4.23 (s, 1 H) 4.41 (d,J=11. 98 Hz,1 H) 4.50 (dd, J=9. 66,6. 97 Hz,1 H) 4.87 (m, 2 H) 5.11 (d, J=10. 52 Hz, 1 H) 5.28 (d,J=17. 12 Hz,1 H) 5.34 (s, 2 H) 5.74 (m, 2 H) 7.51 (t, J=7. 46 Hz,1 H) 7.70 (t, J=7. 58 Hz,1 H) 7.95 (d, J=8. 31 Hz, 1 H) 8.12 (d, J=8. 31 Hz,1 H).

Reference： [1]Chemical and Pharmaceutical Bulletin,1985,vol. 33,p. 5543 - 5546
[2]Patent: WO2003/99274,2003,A1 .Location in patent: Page 310-312

4
[ 3336-43-4 ]
[ 75-39-8 ]
[ 106488-50-0 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1985,vol. 33,p. 5543 - 5546

5
[ 50-00-0 ]
[ 3336-43-4 ]
[ 124-40-3 ]
[ 106488-57-7 ]
[ 106488-55-5 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1985,vol. 33,p. 5543 - 5546

6
[ 50-00-0 ]
[ 3336-43-4 ]
[ 62-53-3 ]
[ 106488-49-7 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1985,vol. 33,p. 5543 - 5546

7
[ 50-00-0 ]
[ 3336-43-4 ]
[ 74-89-5 ]
[ 106507-91-9 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1985,vol. 33,p. 5543 - 5546

10
1.4-dioxy-isoquinoline [ No CAS ]
[ 3336-43-4 ]
[ 15298-58-5 ]

Reference： [1]Chemische Berichte,1900,vol. 33,p. 987
Chemische Berichte,1901,vol. 34,p. 1654

11
[ 3336-43-4 ]
[ 74-88-4 ]
methanol. KOH-solution [ No CAS ]
[ 3336-60-5 ]

Reference： [1]Chemische Berichte,1900,vol. 33,p. 987
Chemische Berichte,1901,vol. 34,p. 1654

12
[ 3336-43-4 ]
[ 39684-80-5 ]
[ 953421-69-7 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In dimethyl sulfoxide; at 20℃;	<strong>[3336-43-4]1-chloro-4-hydroxyisoquinoline</strong> (50 mg, 0.28 mmol, 1.0 equiv), Cs2CO3 (454 mg, 1.39 mmol, 5.0 equiv.), and tert-butyl (2-bromoethyl)carbamate (2-2) (94 mg, 0.42 mmol, 1.5 equiv.) were suspended in anhydrous DMSO (2 mL) and stirred at room temperature. When LCMS indicated the reaction was complete, the crude reaction mixture was purified with reverse phase HPLC (H2O/CH3CN gradient w/0.1% TFA present) to yield the product (2-3). LRMS m/z (M+H) 323.1 found, 323.1 required.

Reference： [1]Patent: US2007/254879,2007,A1 .Location in patent: Page/Page column 28

13
[ 3336-60-5 ]
[ 3336-43-4 ]

Yield	Reaction Conditions	Operation in experiment
	With boron tribromide; In methanol; dichlromethane; at 20℃;	6-Chloro-1, 3-Oxazino [5,6-c] isoquinoline was prepared by the procedure of Miyoko Toyama and Hirotaka Otomasu starting from1-chloro-4-hydroxy isoquinoline. The starting material: 1-chloro-4-hydroxy isoquinoline (Example 226c) was prepared by the synthetic sequence shown above. MCPBA oxidation of 4-methoxy isoquinoline (Example 222a) was carried as usual to give 79.1percent of the corresponding N-oxide (Example 226a). The material was converted into the 1-chloro derivative immediately afterward in POCI3 to give the chloride (Example 226b) in essentially quantitative yield. The crudel-chloro-4-methoxy isoquinoline was de-methylated in BBr3 at room temperature to give the corresponding 1-chloro-4-hydroxy isoquinoline (Example 226c) after treating the crude BBr3 mixture with anhydrous methanol at room temperature, followed by evaporation to get rid of excess of borate residues. The reaction of Miyoko Toyama and Hirotaka Otomasu gave 266mg of 6-chloro-1, 3- oxazino [5,6-c] isoquinoline (Example 226d, 62.3percent) overall yield from 300mg of 4- methoxy isoquinoline in 4 steps. LC/MS Rt-min([M-HCHO] H+) [method D]: 2.45(192).'H NMR (400 MHz, CHLOROFORM-D)8 ppm 5.02 (s, 2 H) 5.41 (s, 2 H) 7.68 (m, 1 H) 7.77 (ddd, J=8. 25,6. 91,1. 22 Hz, 1 H) 8.10 (d, J=8. 31 Hz, 1 H) 8.26 (d, J=8. 56 Hz,1 H). The chloride was found to be unreactive under the alkylation protocol of Example 184. The corresponding 6-fluoro-1, 3-oxazino [5,6-c] isoquinoline (Example 226) was prepared by the method of [Uchibori, Y.; Umeno, M.; Yoshiokai, H.; Heterocycles, 1992,34 (8),1507-1510] cited earlier. The reaction was not allowed to go to completion, and the crude reaction mixture was recovered as a mixture of ratio of 1: 2.4 (Cl : F). Without further purification, the chloride/fluoride mixture was alkylated with the tripeptide using the procedure of Example 184 to give 66mg (50.0percent) of BOCNH-P3(L-t-BuGly)-P2 [ (4R)- ( 1, 3-oxazino [5,6-c] isoquinoline-6-oxo)-S-proline]-P1 (lR, 2S VinylAcca)-CONHSO2Cyclopropane after preparative HPLC purification. LC/MS Rt-min(MNa+) [method D]: 3.03(764).'H NMR (400 MHz, CD30D)8 ppm 1.01 (s, 9 H) 1.06 (dd, J=8. 07,1. 96 Hz, 2 H) 1.22 (s, 10 H) 1.34 (d, J=6. 11 Hz,1 H) 1.42 (m, 1 H) 1.86 (dd, J=8. 07,5. 38 Hz,1 H) 2.23 (m, 2 H) 2.59 (dd,J=13. 82,6. 97 Hz,1 H) 2.93 (m,1 H) 4.03 (dd,J=11. 86,3. 06 Hz,1 H) 4.23 (s, 1 H) 4.41 (d,J=11. 98 Hz,1 H) 4.50 (dd, J=9. 66,6. 97 Hz,1 H) 4.87 (m, 2 H) 5.11 (d, J=10. 52 Hz, 1 H) 5.28 (d,J=17. 12 Hz,1 H) 5.34 (s, 2 H) 5.74 (m, 2 H) 7.51 (t, J=7. 46 Hz,1 H) 7.70 (t, J=7. 58 Hz,1 H) 7.95 (d, J=8. 31 Hz, 1 H) 8.12 (d, J=8. 31 Hz,1 H).

Reference： [1]Patent: WO2003/99274,2003,A1 .Location in patent: Page 310-312

14
[ 3336-43-4 ]
[ 851679-55-5 ]
[ 851679-54-4 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydroxide; In DMF (N,N-dimethyl-formamide); at 20℃; for 12h;	The mixture of 1-chloroisoquinolin4-ol (0.5 g, 2.8 mmol) and [6-([tert- butyl (dimethyl) silyl] oxy} methyl) pyridin-2-yl] methyl methanesulfonate (0.9 g, 2.8 mmol) in anhydrous DMF (15 mL) was treated with potassium hydroxide (0.16 g, 2.8 mmol) at rt. After 12, the mixture was partitioned between saturated aqueous NaHC03 (10 mL) and EtOAc (20 mL). The phases were separated and the aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated. The residue was purified on silica gel (20: 1 hexane-ethyl acetate) to provide 4-{ [6-({ [tert-butyl (dimethyl) silyl] oxy} methyl) pyridin-2-yl] methoxy}-1-chloroisoquinoline as an orange oil : LRMS (ESI) m/z 416 (416 calcd for C22H27ClN202Si, M+H).

Reference： [1]Patent: WO2005/41971,2005,A1 .Location in patent: Page/Page column 97-98

15
[ 3336-43-4 ]
[ 4903-73-5 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide;	(1) 1-Chloro-4-(phenylmethoxy)isoquinoline To a mixture of <strong>[3336-43-4]1-chloroisoquinolin-4-ol</strong> (2.33 g, 13 mmol) and potassium carbonate (3 g) in anhydrous DMF (50 mL) is added benyl bromide (1.73 mL, 14.5 mmole) dropwise at room temperature. The resulting solution is stirred at room temperature for 48 hours, and then poured into ice water. The precipitate is collected by filtration and washed with water and hexanes, and dried to give the desired product as a white solid (3.25 g, yield: 93%). m.p. 97-98 C.

Reference： [1]Patent: US2002/19410,2002,A1

16
[ 33252-28-7 ]
[ 3336-43-4 ]
[ 1087351-31-2 ]