[ CAS No. 141196-38-5 ]

Name: 141196-38-5|(S)-2-(Methoxymethyl)morpholine hydrochloride|95%
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Quality Control of [ 141196-38-5 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 141196-38-5 ]

SDS Specification

Alternatived Products of [ 141196-38-5 ]

Product Details of [ 141196-38-5 ]

CAS No. :	141196-38-5	MDL No. :	MFCD16294688
Formula :	C₆H₁₄ClNO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	NBPHWKGEMABLPV-RGMNGODLSA-N
M.W :	167.63 g/mol	Pubchem ID :	53338717
Synonyms :

Calculated chemistry of [ 141196-38-5 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	0
Fraction Csp3 :	1.0
Num. rotatable bonds :	2
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	44.69
TPSA :	30.49 Å²

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) :	-7.22 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	0.14
Log Po/w (WLOGP) :	0.04
Log Po/w (MLOGP) :	-0.31
Log Po/w (SILICOS-IT) :	0.82
Consensus Log Po/w :	0.14

Druglikeness

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

Water Solubility

Log S (ESOL) :	-0.84
Solubility :	24.5 mg/ml ; 0.146 mol/l
Class :	Very soluble
Log S (Ali) :	-0.34
Solubility :	77.2 mg/ml ; 0.461 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.05
Solubility :	15.0 mg/ml ; 0.0897 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.37

Safety of [ 141196-38-5 ]

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

Application In Synthesis of [ 141196-38-5 ]

* 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 [ 141196-38-5 ]

[ 141196-38-5 ] Synthesis Path-Downstream 1~11

1
[ 132305-88-5 ]
[ 141196-38-5 ]
[ 141196-36-3 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; boron trifluoride diethyl etherate; acetic anhydride; triethylamine Yield given. Multistep reaction;

Reference： [1]Jinbo; Kondo; Taguchi; Inoue; Sakamoto; Tsukamoto [Journal of Medicinal Chemistry, 1994, vol. 37, # 17, p. 2791 - 2796]

2
[ 141196-43-2 ]
[ 141196-38-5 ]

Yield	Reaction Conditions	Operation in experiment
78%	With hydrogenchloride; hydrogen In 1,4-dioxane; ethanol at 40℃; for 6h;
	With hydrogenchloride In 1,4-dioxane; ethanol	R.11.3 (3) (3) (2S)-2-methoxymethylmorpholine hydrochloride (2S)-4-Benzyl-2-methoxymethylmorpholine (3 g) is dissolved in ethanol (50 ml) and thereto are added 4N hydrogen chloride/dioxane (3.4 ml) and 10% palladium-carbon (0.3 g), and the mixture is stirred under hydrogen pressure of 5 kg/cm2 at 40° C. for 6 hours. After removing palladium-carbon, the solvent is distilled off under reduced pressure. The residue is recrystallized from ethyl acetate-methanol to give the title compound (1.8 g). M.p. 141°-142° C. NMR (CDCl3) δ: 3.0-3.2 (2H, m), 3.4 (3H, s), 3.3-3.6 (4H, m), 4.0 4.2 (3H, m), 10.0 (2H, br).

Reference： [1]Jinbo; Kondo; Taguchi; Inoue; Sakamoto; Tsukamoto [Journal of Medicinal Chemistry, 1994, vol. 37, # 17, p. 2791 - 2796]
[2]Current Patent Assignee: KANEBO LTD - US5166203, 1992, A

3
[ 52520-62-4 ]
[ 141196-38-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 56 percent / methanol / 18 h / Heating 2: 78 percent / H₂, HCl / 10percent Pd/C / dioxane; ethanol / 6 h / 40 °C / 3677.5 Torr

Reference： [1]Jinbo; Kondo; Taguchi; Inoue; Sakamoto; Tsukamoto [Journal of Medicinal Chemistry, 1994, vol. 37, # 17, p. 2791 - 2796]

4
[ CAS Unavailable ]
[ 141196-38-5 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; triethylamine In ethanol; dimethyl sulfoxide	21 Preparation of 9,1-(methylimino)methano-7-fluoro-8-[(2S)-2-methoxymethylmorpholino)-5-oxo-5H-thiazolo[3,2-a] -quinoline-4-carboxylic acid [compound (I) in which Z is (2S)-2-methoxymethylmorpholino] EXAMPLE 21 Preparation of 9,1-(methylimino)methano-7-fluoro-8-[(2S)-2-methoxymethylmorpholino)-5-oxo-5H-thiazolo[3,2-a] -quinoline-4-carboxylic acid [compound (I) in which Z is (2S)-2-methoxymethylmorpholino] A mixture of difluoro [9,1-(methylimino)methano7,8-difluoro-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxy]-borane (cf. Example 27 hereinafter) (2.5 g), (2S)-2-methoxymethylmorpholine hydrochloride (cf. Reference Example 11) (1.7 g), triethylamine (3.5 ml) and dimethylsulfoxide (30 ml) is stirred at 55°-60° C. for 18 hours. The reaction mixture is concentrated under reduced pressure, and thereto is added ethanol (60 ml). The precipitated crystal is separated by filtration, and thereto are added ethanol (20 ml) and 2N aqueous sodium hydroxide (15 ml), and the mixture is stirred at 80° C. for 2 hours. The insoluble materials are filtered off and the filtrate is adjusted to pH 3 with 2N hydrochloric acid. The precipitated crystal is separated by filtration and recrystallized from dimethylsulfoxide-ethanol to give the title compound (1.9 g). M.p. decomposed at around 220° C. NMR (DMSO-d6) δ: 2.8 (3H, s), 3.0-3.1 (1H, m), 3.2-3.5 (5H, m), 3.3 (3H, s), 3.7-3.8 (2H, m), 3.9-4.0 (1H, m), 4.5 (2H, s), 7.6 (1H, s), 7.7 (1H, d, J=12.5Hz), 15.9 (1H, s). IR (KBr) νmax cm-1: 1694, 1614, 1490.

Reference： [1]Current Patent Assignee: KANEBO LTD - US5166203, 1992, A

5
[ 959983-22-3 ]
[ 141196-38-5 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
82%	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine In dimethyl sulfoxide at 22℃; for 1h;	51 EXAMPLE 51 (+/-)-8-cyclohexyl-N-[(dimethylamino)sulfonyl]-1,1a,2,12b-tetrahydro-1a-[[(cis)-(S)-2-methoxymethyl-4-morpholinyl]carbonyl]-cycloprop[d]indolo[2,1-a][2]benzazepine-5-carboxamide. TBTU (120 mg, 0.374 mmol) was added to a stirred solution at 22° C. of (+/-)-8-cyclohexyl-5-[[[(dimethylamino)sulfonyl]amino]carbonyl]-1,12b-dihydro-11-methoxy cycloprop[d]indolo[2,1-a][2]benzazepine-1a(2H)-carboxylic acid, (164.4 mg, 0.298 mmol), (2S)-2-(methoxymethyl)morpholine hydrochloride (63 mg, 0.376 mmol), and TEA (152 mg, 1.50 mmol) in DMSO (1 mL). The mixture was stirred for 1 hr and was diluted with water. The solution was acidified with dilute HCl to precipitate the product which was collected, washed with cold water, and dried in vacuo over phosphorous pentoxide to afford a mixture of diastereoisomers (162 mg, 82% yield). A portion of this material was purified on a Shimadzu preparative liquid chromatograph using an XTerra 30100 mm reverse phase column and a gradient of methanol-water containing 1% TFA. The methanol was removed from the product containing fractions. The precipitated product was extracted into ethyl acetate. The organic layer was washed (water, brine), dried (sodium sulfate), and concentrated to a pale yellow solid. LC/MS: m/z 665 (MH+), rt 2.382 min. Phenomenex-Luna 4.650 mm S10 column.

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2007/60565, 2007, A1 Location in patent: Page/Page column 91

6
[ 1127235-90-8 ]
[ 141196-38-5 ]
[ 1127236-07-0 ]

Yield	Reaction Conditions	Operation in experiment
81%	Stage #1: 5-[13-cyclohexyl-3-methoxy-10-[[[(2-methylpropyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-1H-pyrazole-4-carboxylic acid With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 20℃; for 0.25h; Stage #2: (2S)-2-(methoxymethyl)morpholine hydrochloride In dimethyl sulfoxide at 20℃; for 3h;	7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy- 6-[4-[[(2S)-2-(methoxymethyl)-4-morpholinyl] carbonyl] -l-methyl-lH-pyrazol-5-yl] - N-[(2-methylpropyl)sulfonyl]-; To a solution of lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-10-[[[(2-methylpropyl)sulfonyl]amino]carbonyl]-7H-indolo[2, 1 -a] [2]benzazepin-6- yl]-l -methyl- (30 mg, 0.048 mmol) in DMSO (1 mL), TBTU (22.91 mg, 0.071 mmol) and DIPEA (0.042 mL, 0.238 mmol) were added. The reaction mixture was stirred at RT for 15 min. (S)-2-(methoxymethyl)morpholine, HCl (11.96 mg, 0.071 mmol) was then added and the resultant solution was stirred at RT for 3 hours. LC/MS analysis then showed the reaction had progressed to completion. The reaction mixture was then purified by preparative ηPLC using Cη3CN-η2O-TFA as solvent system. Homogeneous fractions were combined and concentrated under vacuum. The title compound was obtained as a yellow colored solid, (28.6 mg, 0.038 mmol, 81 % yield).MS m/z 742(M-H"), Retention time: 1.598 min.(basic)IH NMR (500 MHz, MeOD) δ ppm 1.16 (d, J=6.71 Hz, 6 H) 1.22 - 1.65 (m,4 H) 1.75 - 2.24 (m, 6 H) 2.28 - 2.42 (m, 1 H) 2.88 - 3.63 (m, 15 H) 3.81 (s, 3 H) 3.95(s, 3 H) 4.61 - 4.72 (m, 1 H) 5.02 - 5.14 (m, 1 H) 7.11 (s, 1 H) 7.17 (d, J=2.44 Hz, 1 H) 7.20 (dd, J=8.55, 2.44 Hz, 1 H) 7.56 - 7.65 (m, 2 H) 7.66 (s, 1 H) 7.93 (s, 1 H)7.96 - 8.03 (m, 1 H).

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2009/29384, 2009, A2 Location in patent: Page/Page column 97

7
[ 1127237-80-2 ]
[ 141196-38-5 ]
[ 1127237-91-5 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 5-[13-cyclohexyl-3-methoxy-10-[[[(cyclobutyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-1H-pyrazole-4-carboxylic acid With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate In N,N-dimethyl-formamide at 20℃; for 1.25h; Stage #2: (2S)-2-(methoxymethyl)morpholine hydrochloride With dmap In N,N-dimethyl-formamide at 20℃;	7H-indolo[2, 1-a] [2]benzazepine-10-carboxamide, N-(cyclobutylsulfonyl)-13- cyclohexyl-3-methoxy-6-[4-[[(2S)-2-(methoxymethyl)-4-morpholinyl]carbonyl]-l- methyl-lH-pyrazol-5-yl]-; Into a 2 dram vial place 787ul of a stock solution containing lH-pyrazole-4- carboxylic acid, 5-[ 10-[[(cyclobutylsulfonyl)amino]carbonyl]- 13-cyclohexyl-3- methoxy-7H-indolo[2,l-a][2]benzazepin-6-yl]-l-methyl- (0.091M) (0.787 mL, 0.072 mmol) and TBTU (0.213M) (0.787 mL, 0.168 mmol) which was pre-mixed for 1.25hr at room temperature. To the reaction mixture add DMAP (48.0 mg, 0.393 mmol), then add the amine reagent then add the amine reagent, in this case, (S)-2-(methoxymethyl)morpholine hydrochloride (30.4 mg, 0.181 mmol). Cap the reaction under a nitrogen atmosphere and stir at room temperature overnight. The reaction is diluted with acetonitrile and purified by reverse phase Prep HPLC.IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.19 (m, 1 H) 1.31 - 1.54 (m, 3 H) 1.79 (d, J=10.38 Hz, 2 H) 1.90 - 2.20 (m, 7 H) 2.23 - 2.55 (m, 3 H) 2.58 - 2.82 (m, 4 H) 2.82 - 3.13 (m, 6 H) 3.11 - 3.49 (m, 5 H) 3.90 (s, 3 H) 3.94 (s, 3 H) 4.51 - 4.67 (m, 2 H) 4.78 - 4.96 (m, 1 H) 6.85 (s, 1 H) 6.95 (s, 1 H) 7.12 (dd, J=8.55, 2.44 Hz, 1 H) 7.56 (d, J=8.55 Hz, 1 H) 7.59 (d, J=7.63 Hz, 1 H) 7.63 - 7.74 (m, 2 H) 7.90 (t, J=9.00 Hz, 1 H) 10.09 (s, 0.3 H) 10.41 (s, 0.6 H). LC-MS retention timel.62 min; 740 m/z (MH-). LC data was recorded on aShimadzu LC-IOAS liquid chromatograph equipped with a Waters Xterra MS 7u C18 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 2 min, and an analysis time of 5 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2009/29384, 2009, A2 Location in patent: Page/Page column 193-194

8
[ CAS Unavailable ]
[ 141196-38-5 ]
[ CAS Unavailable ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
45.2%	Stage #1: 5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-(1-methyl-4-piperidinyl)-1H-pyrazole-4-carboxylic acid hydrochloride With HATU In N,N-dimethyl-formamide at 20℃; for 2h; Inert atmosphere; Stage #2: (2S)-2-(methoxymethyl)morpholine hydrochloride With dmap In N,N-dimethyl-formamide at 20℃; for 16h; Inert atmosphere; Stage #3: trifluoroacetic acid In dichloromethane	1H-Pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-(1-methyl-4-piperidinyl)-*HCl salt (71.9 mg, 0.098 mmol) in was dissolved in DMF (1.0 ml) and HATU (82 mg, 0.215 mmol) added to the reaction. The reaction was capped under a nitrogen atmosphere and stirred at room temperature for 2 hours. DMAP (46.6 mg, 0.381 mmol), was added to the reaction followed by the amine reagent, (S)-2-(methoxymethyl)morpholine hydrochloride (35.4 mg, 0.211 mmol). The reaction was again capped under a nitrogen atmosphere and stirred at room temperature overnight (16 hr).The product was purified on a Shimadzu high pressure liquid chromatography system employing DISCOVERY VP software interfaced with a SCL-10A controller, SIL-10A autosampler and FRC-10A fraction collector. The reaction mixture was diluted with acetonitrile to 2 ml and purified using a Waters XTERRA Prep MS C18 OBD, 5 uM, 30 mm×100 mm column and monitored using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 40 mL/min, a gradient of 80% solvent A/20% solvent B to 0% solvent A/100% solvent B, a gradient time of 20 minutes with a run time of 20 minutes using % A=10 mM Ammonium Acetate in 95:5 Water/Acetonitrile % B=10 mM Ammonium Acetate in 5:95 Water/Acetonitrile solvent system. The product exhibited rotomeric like splitting with retention time s of 9.3 and 9.6 minutes. The product fractions were combined and volatiles removed in vacuo using a rotary evaporator. The product was dried in vacuo for approximately 1 hr then dissolved in dichloromethane (4 ml) and filtered through an ACRODISC 0.45 uM syringe filter using a norm jet syringe which was pre-rinsed using dichloromethane. TFA (30 μL, 0.389 mmol) was added to the solution and the volatiles were removed in vacuo using a rotary evaporator. The product was dried in vacuo at room temperature yielding 40.9 mg (45.2%) as an amorphous orange solid.1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.00-1.30 (m, 2.7H) 1.30-1.61 (m, 8.9H) 1.79 (d, J=9.16 Hz, 2.3H) 1.88-2.16 (m, 5.8H) 2.24-2.65 (m, 3.9H) 2.66-2.99 (m, 6.3H) 2.98-3.53 (m, 9.3H) 3.61 (s, 3.0H) 3.90-3.95 (m, 3.0H) 3.96-4.14 (m, 2.1H) 4.59 (d, J=118.62 Hz, 2.0H) 4.68-5.09 (m, 6.1H) 6.75-6.85 (m, 1.1H) 6.87-6.99 (m, 1.2H) 7.12 (t, J=7.02 Hz, 1.1H) 7.46-7.77 (m, 3.9H) 7.82-8.01 (m, 1.3H) 10.24 (s, 0.8H) 11.30 (s, 1.1H).LC-MS retention time 1.60 min; 811 m/z (MH-). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a MICROMASS Platform for LC in electrospray mode.

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2009/280083, 2009, A1 Location in patent: Page/Page column 15-16

9
[ 1195782-36-5 ]
[ 141196-38-5 ]
[ CAS Unavailable ]
[ 1195778-09-6 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-(3-methyl-4-pyridinyl)-1H-pyrazole-4-carboxylic acid hydrochloride With HATU In N,N-dimethyl-formamide at 20℃; for 2h; Inert atmosphere; Stage #2: (2S)-2-(methoxymethyl)morpholine hydrochloride With dmap In N,N-dimethyl-formamide at 20℃; for 65h; Inert atmosphere; Stage #3: trifluoroacetic acid In water; acetonitrile	1H-Pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-(3-methyl-4-pyridinyl)-*HCl (65.0 mg, 0.089 mmol) was dissolved in DMF (890 μL) and HATU (77 mg, 0.203 mmol) added to the reaction. The reaction was capped under a nitrogen atmosphere and stirred at room temperature for 2 hr. DMAP (49.4 mg, 0.404 mmol) was added to the reaction followed by the amine reagent, (S)-2-(methoxymethyl)morpholine hydrochloride (34.7 mg, 0.207 mmol). The reaction was capped under a nitrogen atmosphere and stirred at room temperature over weekend (65 hrs). The product was purified on a Shimadzu high pressure liquid chromatography system employing DISCOVERY VP software interfaced with a SCL-10A controller, SIL-10A autosampler and FRC-10A fraction collector. The reaction was diluted to 2 ml with acetonitrile and purified using a Waters Sunfire Prep C18 OBD, 5 uM 19 mm×100 mm column and monitored using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 25 mL/min, a gradient of 80% solvent A/20% solvent B to 0% solvent A/100% solvent B, a gradient time of 20 minutes with a run time of 20 minutes using % A=10% acetonitrile, 90% water, 0.1% TFA % B=90% acetonitrile, 10% water, 0.1% TFA solvent system. Retention time of product was 10.4 minutes. Remove volatiles for product fractions in vacuo using a SPEED VAC with heat on low setting. The title compound (56.2 mg) was isolated as a amorphous yellow solid trifluoroacetic acid salt.1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.10-1.29 (m, 1H) 1.32-1.44 (m, 2H) 1.52 (dd, J=21.82, 6.87 Hz, 6H) 1.73-1.87 (m, 2H) 1.88-2.12 (m, 4H) 2.32-2.45 (m, 3H) 2.82 (t, J=11.75 Hz, 2H) 3.12-3.42 (m, 5H) 3.50 (s, 1H) 3.68 (s, 1H) 3.86 (s, 3H) 3.99-4.12 (m, 1H) 4.48 (d, J=14.95 Hz, 1H) 4.72-4.92 (m, 1H) 5.66 (d, J=1.53 Hz, 2H) 6.41-6.89 (m, 2H) 6.96 (s, 1H) 7.05 (dd, J=8.70, 2.59 Hz, 1H) 7.45 (d, J=8.55 Hz, 2H) 7.53 (s, 1H) 7.80-7.92 (m, 2H) 8.56 (s, 1H) 9.90 (s, 1H).LC-MS retention time 1.61 min; 805 m/z (MH-). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a MICROMASS Platform for LC in electrospray mode.

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2009/280083, 2009, A1 Location in patent: Page/Page column 20

10
[ 1195778-76-7 ]
[ 141196-38-5 ]
[ 1195779-80-6 ]

Yield	Reaction Conditions	Operation in experiment
79%	With 4-methyl-morpholine; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate In N,N-dimethyl-formamide for 1h;	7H-Indolo[2,1-a][2]benzazepine-10-carboxamide, 6-[1-cyclobutyl 4-[[(2S)-2-(methoxymethyl)-4-morpholinyl]carbonyl]-1H-pyrazol-5-yl]-13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]- A 2 dram vial was charged with 1H-pyrazole-4-carboxylic acid, 1-cyclobutyl-5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-(70 mg, 0.107 mmol), DMF (1 mL), (R)-2-(methoxymethyl)morpholine, HCl (35.7 mg, 0.213 mmol), 4-methylmorpholine (0.035 mL, 0.320 mmol) and o-Benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) (37.6 mg, 0.117 mmol). The rxn was stirred for 1 hour. It was diluted with ether, washed with saturated ammonium chloride then brine, dried (MgSO4) and evaporated giving a yellow foam. The foam was dissolved in DCM, the solution was added to a Thompson silica gel cartridge and it was eluted with ethyl acetate/methanol (0% to 10%). The appropriate fractions (TLC) were combined and evaporated giving a light yellow film. The film was dissolved in DCM, re-evaporated, the residue triturated in hexane/ether (5%) and filtered giving the product (66 mg, 0.084 mmol, 79% yield) as light a yellow powder. HPLC: 98.0% pure, 22.52 minutes. LCMS: 770.32 at 3.96 minutes, mp: 176-178° C. HRMS: calculated-770.3582, found 770.3583. 1H NMR: (400 Mz, CD3OD) δ 1.23-1.26 (td, J=7 Hz & 3.5 Hz, 2H), 1.35-1.44 (m, 4H), 1.46-1.48 (d, J=6 Hz, 2H), 1.52-1.53 (d, J=6 Hz, 3H), 1.68 (bs, 1H), 1.77-1.80 (d, J=10 Hz, 3H), 1.84 (bs, 1H), 1.92-2.01 (m, 3H), 2.03 (s, 1H), 2.08-2.16 (bm, 3 h), 2.28 (bs, 1H), 2.28 (bs, 2H), 2.44 (bs, 1H), 2.70-2.74 (t, J=10 Hz, 2H), 2.79 (s, 1H), 2.84-2.89 (m, 2H), 2.97 (bs, 2H), 3.04 (bs, 1H), 3.19 (bs, 2H), 3.24 (s, 2H), 3.38 (bs, 1H), 3.95 (s, 3H), 4.06-4.13 (m, 1H), 4.55-4.59 (dd, J=15 Hz & 5 Hz, 1H), 4.77 (bs, 1H), 4.83-4.90 (t, J=15 Hz, 1H), 6.73-6.75 (d, J=8 Hz, 1H), 6.94 (s, 1H), 7.11-7.12 (d, J=8 Hz, 1H), 7.56-7.66 (m, 3H), 7.71 (s, 1H), 7.88-7.92 (t, J=8 Hz, 1H) & 10.5 (bs, 1H).

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2009/280083, 2009, A1 Location in patent: Page/Page column 52

11
[ 2374782-77-9 ]
[ 141196-38-5 ]
[ 2791475-62-0 ]

Yield	Reaction Conditions	Operation in experiment
88%	With methanesulfonato(2-bis(3,5-di(trifluoromethyl)phenylphosphino)-3,6-dimethoxy-2',6'-bis(dimethylamino)-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II); Cs₂CO₃ In 1,4-dioxane at 85℃; for 20h; Inert atmosphere;	Intermediate 187: tert-Butyl 6-((3S,5R)-3,5-dimethylmorpholino)quinoline-4- carboxylate General procedure: A mixture of tert-butyl 6-bromoquinoline-4-carboxylate (149 mg, 0.48 mmol), Cs2CO3 (473 mg, 1.45 mmol), Pd Catalyst [CAS: 1810068-35-9] (55 mg, 0.05 mmol), (3S,5R)-3,5-dimethylmorpholine hydrochloride (96 mg, 0.63 mmol) and dioxane (1.2 mL) under N2 (g) was stirred at 85°C for 60 h. After cooling to rt the reaction mixture was diluted to 3.5 mL with EtOAc and was filtered through a pad of Celite 521. The filter pad was washed with EtOAc and the combined filtrates were concentrated. The residue was purified by straight phase flash chromatography on silica (gradient: 0-75% EtOAc in heptane) to afford the title compound (73 mg, 41%) as a yellow oil; MS (ESI) m/z [M+H]+ 343.3.
88%	With methanesulfonato(2-bis(3,5-di(trifluoromethyl)phenylphosphino)-3,6-dimethoxy-2',6'-bis(dimethylamino)-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II); Cs₂CO₃ In 1,4-dioxane at 85℃; for 20h; Inert atmosphere;	Intermediate 187: tert-Butyl 6-((3S,5R)-3,5-dimethylmorpholino)quinoline-4- carboxylate General procedure: A mixture of tert-butyl 6-bromoquinoline-4-carboxylate (149 mg, 0.48 mmol), Cs2CO3 (473 mg, 1.45 mmol), Pd Catalyst [CAS: 1810068-35-9] (55 mg, 0.05 mmol), (3S,5R)-3,5-dimethylmorpholine hydrochloride (96 mg, 0.63 mmol) and dioxane (1.2 mL) under N2 (g) was stirred at 85°C for 60 h. After cooling to rt the reaction mixture was diluted to 3.5 mL with EtOAc and was filtered through a pad of Celite 521. The filter pad was washed with EtOAc and the combined filtrates were concentrated. The residue was purified by straight phase flash chromatography on silica (gradient: 0-75% EtOAc in heptane) to afford the title compound (73 mg, 41%) as a yellow oil; MS (ESI) m/z [M+H]+ 343.3.

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2022/130270, 2022, A1 Location in patent: Page/Page column 218; 221
[2]Current Patent Assignee: ASTRAZENECA PLC - WO2022/130270, 2022, A1 Location in patent: Page/Page column 218; 221

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H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
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H242	Heating may cause a fire
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H261	In contact with water releases flammable gas
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H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
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H311	Toxic in contact with skin
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H316	Causes mild skin irritation
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H319	Causes serious eye irritation
H320	Causes eye irritation
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H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
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H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 141196-38-5 ]

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[ 141196-38-5 ] Synthesis Path-Downstream 1~11

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Ethers

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Aliphatic Heterocycles

Morpholines

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[ 141196-38-5 ]

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[ 141196-38-5 ]