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Chemical Structure| 630423-36-8 Chemical Structure| 630423-36-8

Structure of 630423-36-8

Chemical Structure| 630423-36-8

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Product Details of [ 630423-36-8 ]

CAS No. :630423-36-8
Formula : C10H7Cl2NO
M.W : 228.08
SMILES Code : COC1=CN=C(Cl)C2=C1C=CC(Cl)=C2
English Name :1,7-Dichloro-4-methoxyisoquinoline
MDL No. :MFCD17012717
InChI Key :HOBCGPSQZNVUSJ-UHFFFAOYSA-N
Pubchem ID :22250249

Safety of [ 630423-36-8 ]

Computational Chemistry of [ 630423-36-8 ] Show Less

Physicochemical Properties

Num. heavy atoms 14
Num. arom. heavy atoms 10
Fraction Csp3 0.1
Num. rotatable bonds 1
Num. H-bond acceptors 2.0
Num. H-bond donors 0.0
Molar Refractivity 58.26
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

22.12 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

2.56
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

3.66
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

3.55
Log Po/w (MLOGP)?

MLOGP: Topological method implemented from
Moriguchi I. et al. 1992 Chem. Pharm. Bull.
Moriguchi I. et al. 1994 Chem. Pharm. Bull.
Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.

2.6
Log Po/w (SILICOS-IT)?

SILICOS-IT: Hybrid fragmental/topological method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

3.68
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

3.21

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-4.02
Solubility 0.0217 mg/ml ; 0.000095 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Moderately soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-3.81
Solubility 0.035 mg/ml ; 0.000154 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble
Log S (SILICOS-IT)?

SILICOS-IT: Fragmental method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-5.07
Solubility 0.00195 mg/ml ; 0.00000855 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Moderately soluble

Pharmacokinetics

GI absorption?

Gatrointestinal absorption: according to the white of the BOILED-Egg

High
BBB permeant?

BBB permeation: according to the yolk of the BOILED-Egg

Yes
P-gp substrate?

P-glycoprotein substrate: SVM model built on 1033 molecules (training set)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

No
CYP1A2 inhibitor?

Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.83 / AUC=0.90
External: ACC=0.84 / AUC=0.91

Yes
CYP2C19 inhibitor?

Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.80 / AUC=0.86
External: ACC=0.80 / AUC=0.87

Yes
CYP2C9 inhibitor?

Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set)
and tested on 2075 molecules (test set)
10-fold CV: ACC=0.78 / AUC=0.85
External: ACC=0.71 / AUC=0.81

No
CYP2D6 inhibitor?

Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set)
and tested on 1068 molecules (test set)
10-fold CV: ACC=0.79 / AUC=0.85
External: ACC=0.81 / AUC=0.87

No
CYP3A4 inhibitor?

Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)
and tested on 2579 molecules (test set)
10-fold CV: ACC=0.77 / AUC=0.85
External: ACC=0.78 / AUC=0.86

No
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-5.09 cm/s

Druglikeness

Lipinski?

Lipinski (Pfizer) filter: implemented from
Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev.
MW ≤ 500
MLOGP ≤ 4.15
N or O ≤ 10
NH or OH ≤ 5

0.0
Ghose?

Ghose filter: implemented from
Ghose AK. et al. 1999 J. Comb. Chem.
160 ≤ MW ≤ 480
-0.4 ≤ WLOGP ≤ 5.6
40 ≤ MR ≤ 130
20 ≤ atoms ≤ 70

None
Veber?

Veber (GSK) filter: implemented from
Veber DF. et al. 2002 J. Med. Chem.
Rotatable bonds ≤ 10
TPSA ≤ 140

0.0
Egan?

Egan (Pharmacia) filter: implemented from
Egan WJ. et al. 2000 J. Med. Chem.
WLOGP ≤ 5.88
TPSA ≤ 131.6

0.0
Muegge?

Muegge (Bayer) filter: implemented from
Muegge I. et al. 2001 J. Med. Chem.
200 ≤ MW ≤ 600
-2 ≤ XLOGP ≤ 5
TPSA ≤ 150
Num. rings ≤ 7
Num. carbon > 4
Num. heteroatoms > 1
Num. rotatable bonds ≤ 15
H-bond acc. ≤ 10
H-bond don. ≤ 5

0.0
Bioavailability Score?

Abbott Bioavailability Score: Probability of F > 10% in rat
implemented from
Martin YC. 2005 J. Med. Chem.

0.55

Medicinal Chemistry

PAINS?

Pan Assay Interference Structures: implemented from
Baell JB. & Holloway GA. 2010 J. Med. Chem.

0.0 alert
Brenk?

Structural Alert: implemented from
Brenk R. et al. 2008 ChemMedChem

1.0 alert: heavy_metal
Leadlikeness?

Leadlikeness: implemented from
Teague SJ. 1999 Angew. Chem. Int. Ed.
250 ≤ MW ≤ 350
XLOGP ≤ 3.5
Num. rotatable bonds ≤ 7

No; 1 violation:MW<2.0
Synthetic accessibility?

Synthetic accessibility score: from 1 (very easy) to 10 (very difficult)
based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties,
trained on 12'782'590 molecules and tested on 40 external molecules (r2 = 0.94)

1.89

Application In Synthesis of [ 630423-36-8 ]

* 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 [ 630423-36-8 ]

[ 630423-36-8 ] Synthesis Path-Downstream   1~14

YieldReaction ConditionsOperation in experiment
71%
  • 2
  • [ 1028252-14-3 ]
  • [ 3061741-76-9 ]
  • [ 630423-36-8 ]
YieldReaction ConditionsOperation in experiment
In methanol; hexanes; acetonitrile at 0 - 20℃; 6.1.8 To a slurry of the product of Step 7 (16 g, 75.5 mmol) in MeOH-MeCN (30 mL/300 mL) at 0° C. was added dropwise 60 mL of 2 M solution of TMSCHN2 in hexanes (120 mmol). The reaction mixture was allowed to warm to room temperature; then it was stirred for 14 h. The solution was then concentrated and the resulting solid was recrystallized from EtOAc (about 50 mL) to give 8.1 g of the desired product which was washed with 25% EtOAc in hexanes (3×20 mL). The mother liquors were concentrated and purified by flash column chromatography (SiO2, eluted with 16% EtOAc in hexanes) to provide 3.2 g of the desired product as a solid. 1H NMR (400 MHz, CDCl3) δ ppm 4.05 (s, 3H), 7.67 (dd, J=9.06, 2.01 Hz, 1H), 7.80 (s, 1H), 8.16 (d, J=8.81 Hz, 1H), 8.23 (d, J=2.01 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ ppm 56.68, 122.70, 123.99, 124.14, 126.67, 127.83, 131.43, 134.10, 139.75, 149.94; LC-MS, MS m/z 229 (M++H).
In methanol; hexanes; acetonitrile at 0 - 20℃; 2.8 Step 8: To a slurry of the product of Step 7, Example 2 (16 g, 75.5 mmol) in MeOH-MeCN (30 mL/300 mL) at 0 0 C was added dropwise 60 ml of 2 M solution of TMSCHN2 in hexanes (120 mmol). The reaction mixture was allowed to warm to room temperature, then stirred for 14 h. The solution was then concentrated and the resulting solid was recrystallized from EtOAc (about 50 mL) to give 8.1 g of the desired product which was washed with 25% EtOAc in hexances; 20×3 times. The mother liquid was concentrated and purified by Biotage (elution with 16% EtOAc in hexanes) to provide 3.2 g of the desired product as a solid. 1H NMR (400 MHz, CDCl3) δ ppm 4.05 (s, 3H), 7.67 (dd, J=9.06, 2.01 Hz, 1H), 7.80 (s, 1H), 8.16 (d, J=8.81 Hz, 1H), 8.23 (d, J=2.01 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ ppm 56.68, 122.70, 123.99, 124.14, 126.67, 127.83, 131.43, 134.10, 139.75, 149.94; LC-MS, MS m/z 229.
In methanol; hexanes; acetonitrile at 0 - 20℃; for 14h; 22.8 Step 8:; To a slurry of the product of Step 7 (16 g, 75.5 mmol) in MeOH-MeCN (30 mL/300 mL) at 0° C. was added dropwise 60 ml of 2 M solution of TMSCHN2 in hexanes (120 mmol). The reaction mixture was allowed to warm to room temperature, then stirred for 14 h. The solution was then concentrated and the resulting solid was recrystallized from EtOAc (about 50 mL) to give 8.1 g of the desired product which was washed with 25% EtOAc in hexances; 20×3 times. The mother liquid was concentrated and purified by Biotage (elution with 16% EtOAc in hexanes) to provide 3.2 g of the desired product as a solid.1H NMR (400 MHz, CDCl3) δ ppm 4.05 (s, 3H), 7.67 (dd, J=9.06, 2.01 Hz, 1H), 7.80 (s, 1H), 8.16 (d, J=8.81 Hz, 1H), 8.23 (d, J=2.01 Hz, 1H); 13C NMR (100 MHz, DMSO-D6) δ ppm 56.68, 122.70, 123.99, 124.14, 126.67, 127.83, 131.43, 134.10, 139.75, 149.94; LC-MS, MS m/z 229.
  • 3
  • [ 630423-36-8 ]
  • [ 13726-69-7 ]
  • [ 1028252-15-4 ]
YieldReaction ConditionsOperation in experiment
58.9% Stage #1: 1,7-dichloro-4-methoxyisoquinoline; (2S,4R)-4-hydroxy-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid With potassium <i>tert</i>-butylate In dimethyl sulfoxide at 36℃; for 1h; Stage #2: With hydrogenchloride In water; dimethyl sulfoxide; ethyl acetate at 11.2 - 14.6℃; 4 Preparation of Compound CDMSO (264 ml) was added to a mixture of Compound A (6 g, 26.31 mmol, 1.0 eq, 96.5% potency), Compound B (6.696 g, 28.96 mmol, 1.1 eq) and KOtBu (8.856 g, 78.92 mmol, 3 eq) under nitrogen and stirred at 36 0C for 1 h. After cooling the dark solution to 16 0C, it was treated with water (66 ml) and EtOAc (132 ml). The resulting biphasic mixture was acidified to pH 4.82 with IN HCl (54 ml) at 11.2-14.6 0C. The phases were separated. The aqueous phase was extracted once with EtOAc (132 ml). The organic phases were combined and washed with 25% brine (2x 132 ml). Rich organic phase (228 ml) was distilled at 30-40 °C/50 mbar to 37.2 ml. A fresh EtOAc (37.2 ml) was added and distilled out to 37.2 ml at 30-35 °C/50 mbar. After heating the final EtOAc solution (37.2 ml) to 50 0C3 heptane ((37.2 ml) was added at 46-51 0C and cooled to 22.5 0C over 2 h. It was seeded with 49 mg of Compound C and held at 23 0C for 15 min to develop a thin slurry. It was cooled to 0.5 0C in 30 min and kept at 0.2-0.5 0C for 3 h. After the filtration, the cake was washed with heptane (16.7 ml) and dried at 47 °C/80 mm/15.5 h to give Compound C as beige colored solids (6.3717 g, 58.9% corrected yield, 99.2% potency, 97.4 AP).
Stage #1: 1,7-dichloro-4-methoxyisoquinoline; (2S,4R)-4-hydroxy-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid With potassium <i>tert</i>-butylate In dimethyl sulfoxide at 20℃; for 4h; Stage #2: With hydrogenchloride In water; dimethyl sulfoxide 6.2.1 The product of Step 8, Scheme 1, Example 6 (0.452 g, 1.98 mmol), Boc-HYP-OH (0.508 g, 2.20 mmol), and potassium tert-butoxide (0.672 g, 6.0 mmol) in DMSO (20 mL) was stirred at room temperature for 4 hours. The mixture was quenched with water and neutralized with 1.0M aqueous HCl. The mixture was extracted with ethyl acetate and the organic was washed with brine, dried over anhydrous MgSO4, filtered and concentrated to give a crude solid (0.844 g, quantitative) which was used in the next step without further purification.
Stage #1: 1,7-dichloro-4-methoxyisoquinoline; (2S,4R)-4-hydroxy-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid With potassium <i>tert</i>-butylate In dimethyl sulfoxide at 10℃; for 3.5h; Stage #2: With hydrogenchloride; water In dimethyl sulfoxide 2.9 Step 9: To a mixture of 1,7-dichloro-4-methoxyisoquinoline (4.52 g, 20 mmol), Boc-L-Hyp-OH (5.08 g, 22 mmol) and t-BuOK (6.72 g, 60 mmol) was added DMSO (200 mL) with stirring at 10° C. and then the resulting slurry was sonicated for 30 min in order to quickly obtain a homogeneous solution at rt. The resulting solution was stirred for 3 h. The reaction mixture was then cooled to 0° C. and quenched with 50 ml of water. The resulting mixture was neutralized/acidified to a final pH of 5 by the addition of 1 N HCl. The resulting mixture was extracted with EtOAc (400 mL), and the organic layer was then washed with brine (200 mL), water (200 mL×2), dried over MgSO4, filtered, and then concentrated in vacuo to provide a crude solid (8.36 g). This material was used in the next step without further purification. 1H NMR (400 MHz, CD3OD) δ ppm 2.34-2.47 (m, 1H), 2.62-2.77 (m, 1H), 3.70-3.92 (m, 2H), 4.42-4.59 (m, 1H), 5.65 (brs, 1H), 7.54 (s, 1H), 7.68 (dd, J=8.81, 2.01 Hz, 1H), 8.02-8.13 (m, 2H); 13C NMR (125 MHz, DMSO-d6) (the observed peaks are more than carbon numbers due to Boc rotamers) δ ppm 13.90, 14.04, 20.71, 22.02, 27.84, 27.98, 30.91, 35.00, 35.87, 51.84, 52.08, 56.21, 57.49, 57.80, 59.70, 73.32, 73.87, 79.14, 79.19, 119.11, 119.77, 122.38, 123.35, 128.50, 130.95, 132.25, 145.70, 151.94, 153.25, 153.71, 173.51, 173.98; LC-MS, MS m/z 423.
With potassium <i>tert</i>-butylate In dimethyl sulfoxide at 10 - 20℃; 1001.6 Step 6To a mixture of the product of Step 5, Example 1001, l,7-dichloro-4- methoxyisoquinoline (4.52 g, 20 mmol), (25',4R)-l-(tert-butoxycarbonyl)-4- hydroxypyrrolidine-2-carboxylic acid (5.08 g, 22 mmol) and t-BuOK (6.72 g, 60 mmol) was added DMSO (200 mL) with stirring at 10°C. The resulting slurry was sonicated for 30 min to provide a homogeneous solution which was stirred at room temperature for 3 h. The reaction mixture was cooled to 0 °C and quenched by the addition of H2O (50 ml). The mixture was neutralized, then acidified, to a final pH of 5 by the careful addition of 1 N aqueous HC1. The mixture was extracted with EtOAc (400 mL), and the organic layer washed with brine (200 mL), H2O (200 mLx2) before being dried over MgS04 and concentrated in vacuo to provide 8.36 g of crude solid (2S,4R)- 1 -(tert-butoxycarbonyl)-4-(7-chloro-4-methoxyisoquinolin- 1 - yloxy)pyrrolidine-2-carboxylic acid. This material was used in the next step without further purification. XH NMR (400 MHz, CD3OD) δ ppm 2.34 - 2.47 (m, 1 H), 2.62 - 2.77 (m, 1 H), 3.70 - 3.92 (m, 2 H), 4.42 - 4.59 (m, 1 H), 5.65 (brs, 1 H), 7.54 (s, 1 H), 7.68 (dd, J=8.81, 2.01 Hz, 1 H), 8.02 - 8.13 (m, 2 H); 13C NMR (126 MHz, DMSO-D6) δ ppm 13.90, 14.04, 20.71, 22.02, 27.84, 27.98, 30.91, 35.00, 35.87, 51.84, 52.08, 56.21, 57.49, 57.80, 59.70, 73.32, 73.87, 79.14, 79.19, 1 19.11, 1 19.77, 122.38, 123.35, 128.50, 130.95, 132.25, 145.70, 151.94, 153.25, 153.71, 173.51, 173.98; MS (M+H)+ 423.
8.36 g With potassium <i>tert</i>-butylate In dimethyl sulfoxide at 10 - 20℃; for 3.5h; Sonication; Inert atmosphere;

  • 4
  • [ 630423-35-7 ]
  • [ 630423-36-8 ]
YieldReaction ConditionsOperation in experiment
87% With trichlorophosphate In acetonitrile at 30℃; Inert atmosphere; Reflux; 4 To a 250 ml 3-neck round-bottom flask (Flask A) equipped with a stir bar, nitrogen inlet, temperature probe, heating mantle and reflux condenser were charged the following reagents respectively:1) starting isocarbostyril 2) acetonitrile 3) POCl3 (maintained temperature during addition below 30° C.) Began heating to reflux and followed conversion by LC analysis.In a separate, 3-neck round-bottom flask (Flask B) equipped with a stir bar, temperature probe, and cooling capabilities were charged the following reagents respectively:1) water-inverse quench 2) potassium phosphate, tribasic, N-hydrate Upon complete conversion the reaction solution was cooled to room temperature.The contents of Flask A were then transferred to Flask B maintaining the temperature below 10° C. during the inverse addition.Upon complete transfer, the resulting slurry was aged between 0-10° C. for 30 minutes.The following solvents were then charged to begin extractive workup:1) Tetrahydrofuran2) TolueneThe combined biphasic solution, Vmax=45 mL/g-bulk-LR, was stirred for 30 minutes as the temperature of the combined mixture increased to room temperature.Agitation was stopped and the layers were given time to separate.The layers were split and the aqueous layer was discarded,The organic layer was subjected to carbon treatment (10 wt % charge wrt Bulk-LR) for 1 hour with agitation.MgSO4 (1:1 charge wrt Bulk-LR) was then charged and the solution was again agitated for 1 hour.The solids were then filtered off and the resulting cake was washed with Tetrahydrofuran-Carbon cake wash.Organic layers were then combined and solvent-switched to n-Heptane in order to crystallize product from solution.After switching to n-Heptane, the resulting slurry is held at 50° C. with agitation for approximately 1 hour prior to cooling to 7° C.The resulting ‘cold’ slurry was then aged with agitation for an additional hour.The slurry was filtered and the solid washed with n-Heptane.Typical results range from 77-87% isolated yield; 98% LCAP (250 nm wavelength).
  • 6
  • [ 630423-36-8 ]
  • [ 1367552-70-2 ]
  • [ 1367554-41-3 ]
YieldReaction ConditionsOperation in experiment
82% Stage #1: (2S,3S,4R)-1-boc-4-hydroxy-3-methylproline With potassium <i>tert</i>-butylate In dimethyl sulfoxide at 0℃; for 0.25h; Stage #2: 1,7-dichloro-4-methoxyisoquinoline In dimethyl sulfoxide for 18h; 6 Compound 2K-32K-1 2K-3[0559] To a solution of compound 2K-1 (500 mg, 2.03 mmol, 1.05 eq) in 10 mL of DMSO was added KOi-Bu (683 mg, 6.09 mmol, 3.15 eq) at 0°C. The suspension was stirred for 15min at 0°C. After that, compound 2K-2 (439 mg, 1.93 mmol, 1 eq) was added into the flask. The resulting mixture was stirred for another 18h. TLC analysis showed the reaction completed. The reaction mixture was diluted with water, adjusted to pH=5-6 with aq. HC1 (2 N), extracted with EA (50 mLx3). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by prep-TLC (DCM: MeOH=13:l) gave compound 2K-3 (690 mg, yield 82%). MS (ESI) m / z (M+H)+ 437.1.
  • 7
  • [ 26386-88-9 ]
  • [ 630423-36-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: triethylamine / benzene / 2 h 1.2: 3.5 h / 90 °C / Reflux 2.1: N-Bromosuccinimide / acetonitrile / Reflux 3.1: trichlorophosphate / 5 h / Reflux 3.2: -35 °C / pH 8 4.1: n-butyllithium; Triisopropyl borate / hexane; tetrahydrofuran / 0.75 h / -78 - -65 °C 4.2: 1.17 h / -60 - 20 °C 4.3: 0 °C / pH 6 5.1: diazomethyl-trimethyl-silane / hexane; acetonitrile / 14 h / 0 - 20 °C
  • 8
  • [ 24188-74-7 ]
  • [ 630423-36-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: N-Bromosuccinimide / acetonitrile / Reflux 2.1: trichlorophosphate / 5 h / Reflux 2.2: -35 °C / pH 8 3.1: n-butyllithium; Triisopropyl borate / hexane; tetrahydrofuran / 0.75 h / -78 - -65 °C 3.2: 1.17 h / -60 - 20 °C 3.3: 0 °C / pH 6 4.1: diazomethyl-trimethyl-silane / hexane; acetonitrile / 14 h / 0 - 20 °C
  • 9
  • [ 630423-36-8 ]
  • [ 630420-16-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: potassium <i>tert</i>-butylate / dimethyl sulfoxide / 10 - 20 °C 2: N-ethyl-N,N-diisopropylamine; HATU / 16 h 3: hydrogenchloride / water; methanol / 2 h / Reflux 4: N-ethyl-N,N-diisopropylamine; HATU / dichloromethane / 16 h / 0 - 20 °C
Multi-step reaction with 3 steps 1: potassium <i>tert</i>-butylate / dimethyl sulfoxide / 3.5 h / 10 - 20 °C / Sonication; Inert atmosphere 2: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane / 16 h / Inert atmosphere 3: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane / 16 h / 20 °C / Inert atmosphere
  • 10
  • [ 630423-36-8 ]
  • [ 1028252-17-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: potassium <i>tert</i>-butylate / dimethyl sulfoxide / 10 - 20 °C 2: N-ethyl-N,N-diisopropylamine; HATU / 16 h
Multi-step reaction with 2 steps 1: potassium <i>tert</i>-butylate / dimethyl sulfoxide / 3.5 h / 10 - 20 °C / Sonication; Inert atmosphere 2: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dichloromethane / 16 h / Inert atmosphere
  • 11
  • [ 630423-36-8 ]
  • [ 1192148-58-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: potassium <i>tert</i>-butylate / dimethyl sulfoxide / 10 - 20 °C 2: N-ethyl-N,N-diisopropylamine; HATU / 16 h 3: hydrogenchloride / water; methanol / 2 h / Reflux 4: N-ethyl-N,N-diisopropylamine; HATU / dichloromethane / 16 h / 0 - 20 °C 5: hydrogenchloride / 1,4-dioxane; water / 3 h / 25 °C
  • 12
  • [ 630423-36-8 ]
  • [ 1028252-18-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: potassium <i>tert</i>-butylate / dimethyl sulfoxide / 10 - 20 °C 2: N-ethyl-N,N-diisopropylamine; HATU / 16 h 3: hydrogenchloride / water; methanol / 2 h / Reflux
  • 13
  • [ 953421-74-4 ]
  • [ 630423-36-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: n-butyllithium; Triisopropyl borate / hexane; tetrahydrofuran / 0.75 h / -78 - -65 °C 1.2: 1.17 h / -60 - 20 °C 1.3: 0 °C / pH 6 2.1: diazomethyl-trimethyl-silane / hexane; acetonitrile / 14 h / 0 - 20 °C
Multi-step reaction with 2 steps 1.1: n-butyllithium / hexane; tetrahydrofuran / 0.75 h / 65 °C / Inert atmosphere 1.2: 0.75 h / 65 °C / Inert atmosphere 1.3: 0.5 h / -60 - -40 °C 2.1: diazomethyl-trimethyl-silane / hexane; acetonitrile / 14 h / 0 - 20 °C / Inert atmosphere
Multi-step reaction with 2 steps 1.1: n-butyllithium / hexane; tetrahydrofuran / 0.75 h / 65 °C / Inert atmosphere 1.2: 0.75 h / 65 °C / Inert atmosphere 1.3: 0.5 h / -60 - -40 °C 2.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 4 °C / Inert atmosphere
Multi-step reaction with 2 steps 1.1: n-butyllithium / tetrahydrofuran; hexanes / 0.75 h / -78 - -65 °C 1.2: 0.67 h / -78 - -65 °C 2.1: methanol; hexanes; acetonitrile / 14 h / 0 - 20 °C

References: [1]Current Patent Assignee: BRISTOL MYERS SQUIBB - WO2012/166459, 2012, A1.
[2]Scola, Paul M.; Sun, Li-Qiang; Wang, Alan Xiangdong; Chen, Jie; Sin, Ny; Venables, Brian L.; Sit, Sing-Yuen; Chen, Yan; Cocuzza, Anthony; Bilder, Donna M.; D'Andrea, Stanley V.; Zheng, Barbara; Hewawasam, Piyasena; Tu, Yong; Friborg, Jacques; Falk, Paul; Hernandez, Dennis; Levine, Steven; Chen, Chaoqun; Yu, Fei; Sheaffer, Amy K.; Zhai, Guangzhi; Barry, Diana; Knipe, Jay O.; Han, Yong-Hae; Schartman, Richard; Donoso, Maria; Mosure, Kathy; Sinz, Michael W.; Zvyaga, Tatyana; Good, Andrew C.; Rajamani, Ramkumar; Kish, Kevin; Tredup, Jeffrey; Klei, Herbert E.; Gao, Qi; Mueller, Luciano; Colonno, Richard J.; Grasela, Dennis M.; Adams, Stephen P.; Loy, James; Levesque, Paul C.; Sun, Huabin; Shi, Hong; Sun, Lucy; Warner, William; Li, Danshi; Zhu, Jialong; Meanwell, Nicholas A.; McPhee, Fiona [Journal of Medicinal Chemistry, 2014, vol. 57, # 5, p. 1730 - 1752].
[3]Scola, Paul M.; Sun, Li-Qiang; Wang, Alan Xiangdong; Chen, Jie; Sin, Ny; Venables, Brian L.; Sit, Sing-Yuen; Chen, Yan; Cocuzza, Anthony; Bilder, Donna M.; D'Andrea, Stanley V.; Zheng, Barbara; Hewawasam, Piyasena; Tu, Yong; Friborg, Jacques; Falk, Paul; Hernandez, Dennis; Levine, Steven; Chen, Chaoqun; Yu, Fei; Sheaffer, Amy K.; Zhai, Guangzhi; Barry, Diana; Knipe, Jay O.; Han, Yong-Hae; Schartman, Richard; Donoso, Maria; Mosure, Kathy; Sinz, Michael W.; Zvyaga, Tatyana; Good, Andrew C.; Rajamani, Ramkumar; Kish, Kevin; Tredup, Jeffrey; Klei, Herbert E.; Gao, Qi; Mueller, Luciano; Colonno, Richard J.; Grasela, Dennis M.; Adams, Stephen P.; Loy, James; Levesque, Paul C.; Sun, Huabin; Shi, Hong; Sun, Lucy; Warner, William; Li, Danshi; Zhu, Jialong; Meanwell, Nicholas A.; McPhee, Fiona [Journal of Medicinal Chemistry, 2014, vol. 57, # 5, p. 1730 - 1752].
[4]Current Patent Assignee: BRISTOL MYERS SQUIBB - US2008/119461, 2008, A1.
  • 14
  • [ 67-56-1 ]
  • [ 1028252-14-3 ]
  • [ 630423-36-8 ]
YieldReaction ConditionsOperation in experiment
66% With diazomethyl-trimethyl-silane In hexane; acetonitrile at 0 - 20℃; for 14h; 1001.5 Step 5Preparation of 1, 7-dichloro-4-methoxyisoquinoline:To a slurry of the product of Step 4, Example 1001, 1,7-dichloroisoquinolin- 4-ol (16 g, 75.5 mmol) in MeOH/CH3CN (30 mL/300 mL) maintained at 0 °C was added dropwise a 2 M solution of TMSCHN2 in hexanes (60 ml , 120 mmol). The reaction mixture was warmed to room temperature and stirred for 14 h. The solution was concentrated and the residual solid recrystallized from EtOAc (about 50 mL) to give 8.1 g of l,7-dichloro-4-methoxyisoquinoline which was washed with 25% EtOAc in hexanes. The mother liquid was concentrated and purified by Biotage (16 % EtOAc in hexanes) to provide an additional 3.2 g of l,7-dichloro-4- methoxyisoquinoline as a solid. In total, 11.3 g (66%) of l,7-dichloro-4- methoxyisoquinoline was obtained. XH NMR (400 MHz, CDC13) δ ppm 4.05 (s, 3 H), 7.67 (dd, J=9.06, 2.01 Hz, 1 H), 7.80 (s, 1 H), 8.16 (d, J=8.81 Hz, 1 H), 8.23 (d, j=2.01 Hz, 1 H); 13C NMR (101 MHz, DMSO-D6) δ ppm 56.68, 122.70, 123.99, 124.14, 126.67, 127.83, 131.43, 134.10, 139.75, 149.94; LC/MS, MS m/z (M+H)+ 228.
66% With diazomethyl-trimethyl-silane In hexane; acetonitrile at 0 - 20℃; for 14h; Inert atmosphere;
 

Historical Records

Technical Information

Categories

Pharmaceutical Intermediates of
[ 630423-36-8 ]

Asunaprevir Related Intermediates

Chemical Structure| 24188-74-7

[24188-74-7]

7-Chloroisoquinolin-1-ol

Chemical Structure| 159622-10-3

[159622-10-3]

(1R,2S)-1-((tert-Butoxycarbonyl)amino)-2-vinylcyclopropanecarboxylic acid

Chemical Structure| 13726-69-7

[13726-69-7]

Boc-Hyp-OH

Chemical Structure| 940-62-5

[940-62-5]

(E)-3-(4-Chlorophenyl)acrylic acid

Chemical Structure| 259217-95-3

[259217-95-3]

(1R,2S)-Ethyl 1-((tert-butoxycarbonyl)amino)-2-vinylcyclopropanecarboxylate

Related Functional Groups of
[ 630423-36-8 ]

Chlorides

Chemical Structure| 3336-60-5

A304245 [3336-60-5]

1-Chloro-4-methoxyisoquinoline

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