[ CAS No. 137977-97-0 ] {[proInfo.proName]}

Name: 137977-97-0|1-(4-Amino-2-methylbenzoyl)-7-chloro-3,4-dihydro-1H-benzo[b]azepin-5(2H)-one|98%
Brand: Ambeed
SKU: A147201
Rating: 97 (35 reviews)

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Quality Control of [ 137977-97-0 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 137977-97-0 ]

Product Details of [ 137977-97-0 ]

CAS No. :	137977-97-0	MDL No. :	MFCD19440799
Formula :	C₁₈H₁₇ClN₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	FLJCJPKXJWRZJB-UHFFFAOYSA-N
M.W :	328.79	Pubchem ID :	19608232
Synonyms :

Calculated chemistry of [ 137977-97-0 ]

Physicochemical Properties

Num. heavy atoms :	23
Num. arom. heavy atoms :	12
Fraction Csp3 :	0.22
Num. rotatable bonds :	2
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	95.76
TPSA :	63.4 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-6.11 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.47
Log Po/w (XLOGP3) :	3.09
Log Po/w (WLOGP) :	3.48
Log Po/w (MLOGP) :	2.83
Log Po/w (SILICOS-IT) :	3.59
Consensus Log Po/w :	3.09

Druglikeness

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

Water Solubility

Log S (ESOL) :	-4.08
Solubility :	0.0274 mg/ml ; 0.0000833 mol/l
Class :	Moderately soluble
Log S (Ali) :	-4.09
Solubility :	0.0268 mg/ml ; 0.0000815 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-5.82
Solubility :	0.000502 mg/ml ; 0.00000153 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	2.47

Safety of [ 137977-97-0 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280	UN#:	N/A
Hazard Statements:	H302-H312-H332	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 137977-97-0 ]

* 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 [ 137977-97-0 ]
Downstream synthetic route of [ 137977-97-0 ]

[ 137977-97-0 ] Synthesis Path-Upstream 1~2

1
[ 137977-97-0 ]
[ 150683-30-0 ]

Reference： [1] Bioorganic and Medicinal Chemistry, 1999, vol. 7, # 8, p. 1743 - 1754
[2] Patent: US2013/190490, 2013, A1,

2
[ 933-88-0 ]
[ 137977-97-0 ]
[ 137973-76-3 ]

Yield	Reaction Conditions	Operation in experiment
96%	Stage #1: With magnesium hydroxide In dichloromethane; water at 10℃; for 0.5 h; Stage #2: for 3 h;	To a 3 L reactor was added 1- (4-amino-2-methylbenzoyl) -7-chloro-5-oxo-2,3,4,5-tetrahydro- 1 H- 1 -benzazepine (70. 0 g, 212.90 mmol), dichloromethane (560 ml) and distilled water (140 ml), and the mixture was stirred for 1 hour. Magnesium hydroxide (14.90 g, 14.90 mmol) was added to the reaction mixture at 10 ° C. or lower, and the mixture was stirred for 30 minutes. 2-Methylbenzoyl chloride (30.42 ml) was gradually added to the reaction mixture, followed by stirring for 3 hours. The reaction mixture was filtered to remove magnesium hydroxide and the pH of the reaction mixture was adjusted to pH 8 to 9 using aqueous sodium hydroxide solution and then the organic layer was separated. The obtained organic layer was dried with sodium sulfate (Na 2 SO 4), filtered and concentrated under reduced pressure to give 7-chloro-1- [2-methyl-4 - [(2-methylbenzoyl) amino] benzoyl] -5 - oxo-2,3,4,5-tetrahydro-1 H-1-benzazepine 91.35 g was obtained (yield: 96percent).
90.6%	With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 2 h;	Compound (IX) (14.0g, 42.58mmol) was dissolved in dichloromethane (350 mL of) was added diisopropylethylamine (11.0g, 85.16mmol), stirred for 15min, then was added portionwise o-methylbenzoic chloride (7.90g, 51.10mmol), at RT for 2h, TLC detection, the reaction was complete. The reaction mixture was poured into water (200 mL), the organic phase washed with water twice (200mlx2), dried over anhydrous sodium sulfate, and methylene chloride to give a spin product 2-methyl-4- (2-methyl-benzoylamino) benzene acid (17.24g, 90.6percent).
88%	With triethylamine In dichloromethane at 20℃; for 2.25 h;	The compound (IX) (18.0 g, 54.75 mmol) was dissolved in dichloromethane (150 mL)Triethylamine (15.22 mL, 109.49 mmol) was added, stirred for 15 min,Then, 2-methylbenzoyl chloride (10.16 g, 65.70 mmol) was slowly added dropwise and reacted for 2 h at room temperature. The reaction was complete by TLC. The reaction solution was poured into water (100 mL), and the organic phase water was washed successively with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, removal of the dichloromethane gave the product compound (X) (21.53 g, 88percent).

88.2%	With pyridine In dichloromethane at 0 - 10℃; for 2 h;	The intermediate 10.0g,Pyridine 3.5g, 150ml dichloromethane into 500ml reaction flask,Stirring, dropping 4.9 g of 2-methylbenzoyl chloride in dichloromethane under the condition of 0 DEG C,The reaction was heated to 10 ° C for 2h, followed by TLC sampling, showing no starting material and the reaction was completed.The pH was adjusted to 2 with 6N aqueous hydrochloric acid, the layers were separated and the organic layer was concentrated under reduced pressure to give a light yellow solid,Recrystallization by addition of methanol and cyclohexane afforded 12g as an off-white solid in 88.2percent yield with an HPLC purity of 99.5percent.
86.1%	With pyridine In dichloromethane at 20 - 30℃;	To a 250 ml reaction flask was added 50 ml of dichloromethane, 5.6 ml of pyridine, and the compound of the formula III was added with stirring, then 3.5 g of o-methylbenzoyl chloride was added, and the reaction was completed at 20 to 30 ° C with stirring. Filtered 6.95g crude tolvaptan, purity95.39percent, impurity M 0.56percent.The solid obtained in the above step was added to a solvent of 32 g of ethyl acetate/dichloromethane/isopropyl ether (volume ratio 1:4:1), heated to 50 ° C to 60 ° C, stirred and dissolved, cooled and crystallized, and filtered to obtain a white solid 6.1 g. , yield: 86.1percent, purity: 99.51percent, impurity M content 0.04percent.
185 g	With sodium hydrogencarbonate In dichloromethane; water at 0 - 5℃;	Example 4 Preparation of 7-chloro-1-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine 1-(4-Amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (185 gm) as obtained in example 3 was dissolved in methylene chloride (4000 ml) and then added sodium bicarbonate solution (10percent, 47.3 gm). The reaction mass was cooled to 0 to 5° C. and then added 2-methyl benzoyl chloride (95.7 gm) slowly. The pH of the reaction mass was adjusted to 7.0 to 8.0 with aqueous sodium bicarbonate solution (120 ml). The separated aqueous layer was extracted with methylene chloride and then concentrated to obtain a residual solid of 7-chloro-1-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (185 gm).

Reference： [1] Patent: JP2018/12690, 2018, A, . Location in patent: Paragraph 0029; 0030
[2] Patent: CN105315169, 2016, A, . Location in patent: Paragraph 0170; 0224; 0225
[3] Patent: CN105753735, 2016, A, . Location in patent: Paragraph 0181; 0217; 0218
[4] Patent: CN106883175, 2017, A, . Location in patent: Paragraph 0017; 0018
[5] Patent: CN108503586, 2018, A, . Location in patent: Paragraph 0044; 0045; 0054; 0055; 0056
[6] Bioorganic and Medicinal Chemistry, 1999, vol. 7, # 8, p. 1743 - 1754
[7] Tetrahedron Asymmetry, 2010, vol. 21, # 19, p. 2390 - 2393
[8] Patent: WO2012/46244, 2012, A1, . Location in patent: Page/Page column 9
[9] Patent: US2013/190490, 2013, A1, . Location in patent: Paragraph 0064; 0065

[ 137977-97-0 ] Synthesis Path-Downstream 1~31

1
[ 933-88-0 ]
[ 137977-97-0 ]
[ 137973-76-3 ]

Yield	Reaction Conditions	Operation in experiment
96%		To a 3 L reactor was added 1- (4-amino-2-methylbenzoyl) -7-chloro-5-oxo-2,3,4,5-tetrahydro- 1 H- 1 -benzazepine (70. 0 g, 212.90 mmol), dichloromethane (560 ml) and distilled water (140 ml), and the mixture was stirred for 1 hour. Magnesium hydroxide (14.90 g, 14.90 mmol) was added to the reaction mixture at 10 C. or lower, and the mixture was stirred for 30 minutes. 2-Methylbenzoyl chloride (30.42 ml) was gradually added to the reaction mixture, followed by stirring for 3 hours. The reaction mixture was filtered to remove magnesium hydroxide and the pH of the reaction mixture was adjusted to pH 8 to 9 using aqueous sodium hydroxide solution and then the organic layer was separated. The obtained organic layer was dried with sodium sulfate (Na 2 SO 4), filtered and concentrated under reduced pressure to give 7-chloro-1- [2-methyl-4 - [(2-methylbenzoyl) amino] benzoyl] -5 - oxo-2,3,4,5-tetrahydro-1 H-1-benzazepine 91.35 g was obtained (yield: 96%).
90.6%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 2h;	Compound (IX) (14.0g, 42.58mmol) was dissolved in dichloromethane (350 mL of) was added diisopropylethylamine (11.0g, 85.16mmol), stirred for 15min, then was added portionwise o-methylbenzoic chloride (7.90g, 51.10mmol), at RT for 2h, TLC detection, the reaction was complete. The reaction mixture was poured into water (200 mL), the organic phase washed with water twice (200mlx2), dried over anhydrous sodium sulfate, and methylene chloride to give a spin product 2-methyl-4- (2-methyl-benzoylamino) benzene acid (17.24g, 90.6%).
88%	With triethylamine; In dichloromethane; at 20℃; for 2.25h;	The compound (IX) (18.0 g, 54.75 mmol) was dissolved in dichloromethane (150 mL)Triethylamine (15.22 mL, 109.49 mmol) was added, stirred for 15 min,Then, 2-methylbenzoyl chloride (10.16 g, 65.70 mmol) was slowly added dropwise and reacted for 2 h at room temperature. The reaction was complete by TLC. The reaction solution was poured into water (100 mL), and the organic phase water was washed successively with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, removal of the dichloromethane gave the product compound (X) (21.53 g, 88%).

88.2%	With pyridine; In dichloromethane; at 0 - 10℃; for 2h;	The intermediate 10.0g,Pyridine 3.5g, 150ml dichloromethane into 500ml reaction flask,Stirring, dropping 4.9 g of 2-methylbenzoyl chloride in dichloromethane under the condition of 0 DEG C,The reaction was heated to 10 C for 2h, followed by TLC sampling, showing no starting material and the reaction was completed.The pH was adjusted to 2 with 6N aqueous hydrochloric acid, the layers were separated and the organic layer was concentrated under reduced pressure to give a light yellow solid,Recrystallization by addition of methanol and cyclohexane afforded 12g as an off-white solid in 88.2% yield with an HPLC purity of 99.5%.
86.1%	With pyridine; In dichloromethane; at 20 - 30℃;	To a 250 ml reaction flask was added 50 ml of dichloromethane, 5.6 ml of pyridine, and the compound of the formula III was added with stirring, then 3.5 g of o-methylbenzoyl chloride was added, and the reaction was completed at 20 to 30 C with stirring. Filtered 6.95g crude tolvaptan, purity95.39%, impurity M 0.56%.The solid obtained in the above step was added to a solvent of 32 g of ethyl acetate/dichloromethane/isopropyl ether (volume ratio 1:4:1), heated to 50 C to 60 C, stirred and dissolved, cooled and crystallized, and filtered to obtain a white solid 6.1 g. , yield: 86.1%, purity: 99.51%, impurity M content 0.04%.
	With sodium hydrogencarbonate; In dichloromethane; at 0 - 5℃;pH 7 - 8;	Preparation of 7-chloro-l-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-dxo- 2,3,4,5-tetrahydro-lH-l-benzazepine1 -(4-Amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3 ,4,5-tetrahydro- 1 H- 1 - benzazepine (185 gm) as obtained in example 3 was dissolved in methylene chloride (4000 ml) and then added sodium bicarbonate solution (10%, 47.3 gm). The reaction mass was cooled to 0 to 5C and then added 2-methyl benzoyl chloride (95.7 gm) slowly. -The pH of the reaction mass was adjusted to 7.0 to 8.0 with aqueous sodium bicarbonate solution (120 ml). The separated aqueous layer was extracted with methylene chloride and then concentrated to obtain a residual solid of 7-chloro-l-[2- methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro- 1 H- 1 - benzazepine (185 gm).
185 g	With sodium hydrogencarbonate; In dichloromethane; water; at 0 - 5℃;pH 7.0 - 8.0;	Example 4 Preparation of 7-chloro-1-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine 1-(4-Amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (185 gm) as obtained in example 3 was dissolved in methylene chloride (4000 ml) and then added sodium bicarbonate solution (10%, 47.3 gm). The reaction mass was cooled to 0 to 5 C. and then added 2-methyl benzoyl chloride (95.7 gm) slowly. The pH of the reaction mass was adjusted to 7.0 to 8.0 with aqueous sodium bicarbonate solution (120 ml). The separated aqueous layer was extracted with methylene chloride and then concentrated to obtain a residual solid of 7-chloro-1-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (185 gm).

Reference： [1]Patent: JP2018/12690,2018,A .Location in patent: Paragraph 0029; 0030
[2]Patent: CN105315169,2016,A .Location in patent: Paragraph 0170; 0224; 0225
[3]Patent: CN105753735,2016,A .Location in patent: Paragraph 0181; 0217; 0218
[4]Patent: CN106883175,2017,A .Location in patent: Paragraph 0017; 0018
[5]Patent: CN108503586,2018,A .Location in patent: Paragraph 0044; 0045; 0054; 0055; 0056
[6]Bioorganic and Medicinal Chemistry,1999,vol. 7,p. 1743 - 1754
[7]Tetrahedron Asymmetry,2010,vol. 21,p. 2390 - 2393
[8]Patent: WO2012/46244,2012,A1 .Location in patent: Page/Page column 9
[9]Patent: US2013/190490,2013,A1 .Location in patent: Paragraph 0064; 0065

2
[ 137982-91-3 ]
[ 137977-97-0 ]

Yield	Reaction Conditions	Operation in experiment
97.5%	With indium(III) chloride; palladium on activated carbon; hydrogen; In methanol; at 30℃; under 2250.23 Torr; for 6h;Autoclave; Industrial scale; Green chemistry;	Add 3.0 kg of compound II, 0.3 kg of lithium chloride to a 50 L autoclave, 0.3kg mass fraction is 10wt% Palladium on carbon catalyst and 25 L of methanol. Hydrogen was replaced 3 times, stirring was started, and the pressure of the reactor was adjusted to 0.3 MPa. The reaction temperature was controlled at 30 ± 2 C for 6 h. After TLC showed that the reaction was completed, the mixture was filtered, and the filter cake was washed with methanol, and the filtrate was combined and concentrated under reduced pressure. The residue was added to ethyl acetate 25 L at room temperature for 1 h, and filtered. 2.56 kg of Compound I as a white solid powder were obtained in a yield of 96.4%. The HPLC purity was 99.3% and no byproduct III was detected
95.6%	With ammonium sulfate; sulfuric acid; iron; In ethanol; at 60℃; for 5h;	Was prepared in a 100 mL four-necked round bottom flask equipped with a magnetic stirrer and a thermometer,Chloro-1- (2-methyl-4-nitrobenzoyl) -5-Oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (compound of formula (II)),Iron powder 1.60g, 98% concentrated sulfuric acid 4.20g,20.0 g of ammonium sulfate and 50 mL of ethanol.60 C for 5 hours,TLC showed complete reaction after filtration,Ethanol filter cake, combined filtrate after vacuum distillation steam,The resulting product was added to 50 mL of dichloromethane,Slowly add saturated sodium bicarbonate solution, adjust the pH7 ~ 8,The organic phase was washed with brine,Dried over anhydrous magnesium sulfate, filtered and the solvent was distilled off,To give 4.10 g of the compound of formula (II), a pale yellow foamy solid,Mp 190 to 191 C in a yield of 95.6%.
90.9%	With iron; ammonium chloride; In methanol; water; at 35 - 40℃; for 6h;	15.0g of intermediate II, 7.0g of iron powder, 8.9g of ammonium chloride, 80.0ml of methanol and 80.0ml of water were added into 250mL four-neck reaction flask and the temperature was raised to 35-40 C and reacted for 6 hours. TLC traces the reaction at the same time and disappearance of intermediate II terminates the reaction. The mixture was cooled and filtered to remove iron powder. The mixture was extracted with dichloromethane and separated into layers. The methylene chloride layer was evaporated to give a yellow solid, which was dried in vacuo at 60 C for 6 hours to give 12.5 g. The yield was 90.9% and the HPLC purity was 99.5%.

89.7%	With methanol; tin(II) chloride dihdyrate; at 10℃; for 23h;	To a 2 L reactor, 7-chloro-1- (2-methyl-4-nitrobenzoyl) -5-oxo-2,3,4,5-tetrahydro- 1 H- 1 -benzazepine (140 g, 390.21 mmol)And methanol (300 ml), and the mixture was stirred at room temperature for 1 hour.Tin chloride dihydrate (338.99 g, 1502.31 mmol) was dissolved in methanol (600 ml) while stirring the reaction mixture at 10 C. or less, and the mixture was gradually added. After 23 hours, the pH of the reaction mixture was adjusted to pH 8 to 9 using aqueous sodium hydroxide solution, dichloromethane (200 ml) was added and stirred, then filtered to remove reaction byproducts. Dichloromethane (3 L) and distilled water (2 L) were added to the obtained filtrate, and the layers were separated to obtain an organic layer. The obtained organic layer was dried with sodium sulfate (Na 2 SO 4), filtered, and concentrated under reduced pressure to give 1- (4-amino-2-methylbenzoyl) -7-chloro- , 5-tetrahydro-1 H-1-benzazepine115.09 g was obtained (yield: 89.70%).
81.3%	With hydrogenchloride; tin(II) chloride dihdyrate; In ethanol; at 20℃; for 4h;	To compound () (20.0g, 55.75mmol) in concentrated hydrochloric acid (70mL) and ethanol (140mL) suspension was added in portions SnCl2 · 2H2O (37.74g, 167.23mmol), at room temperature after the addition was complete the reaction 4h. TLC, the reaction was completed, ethanol was removed under reduced rotation, the remaining reaction solution was stored in a refrigerator overnight refrigeration, a large number of solid was precipitated, suction filtered, the filter cake washed with a small amount of water, the dissolved and then 150ml water, was added dropwise with stirring hydroxide 20% sodium solution was adjusted to pH = 9, was filtered, the filter cake with ethanol and recrystallized to give a pale yellow solid, compound () (14.90g, 81.3%).
81%	With hydrogenchloride; tin(II) chloride dihdyrate; In ethanol; water; at 20℃; for 3h;	To a suspension of the compound (VIII) (25.0 g, 69.68 mmol) in concentrated hydrochloric acid (75 mL) and ethanol (140 mL) was added SnCl2.2H2O (47.17 g, 209.04 mmol) in portions and the mixture was reacted at room temperature for 3.0 h. After completion of the reaction with TLC, the reaction solution was poured into water (200 mL) and adjusted to pH 9 to 10 by adding 20% sodium hydroxide solution. Ethanol was recovered and extracted with dichloromethane (3 x 200 mL)The organic phase was combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, suction-filtered and spin-dried to obtain the compound (IX) (18.56 g, 81%).
	With tin(ll) chloride; In methanol; at 20℃; for 16h;	Example 3:Preparation of l-(4-amino-2-methylbenzoyl)-7-chIoro-5-oxo-2,3,4,5-tetrahydro-lH- 1-benzazepine7-Chloro- 1 -(2-methyl-4-nitrobenzoyl)-5-oxo-2,3 ,4,5-tetrahydro- 1 H- 1 - benzazepine (250 gm) as obtained in example 2 was dissolved in methanol (575 ml) and then added a solution of tin chloride (630 gm) in methanol (1130 ml). The reaction mixture was stirred for 16 hours at room temperature and then poured to the ice water. The pH of the reaction mass was adjusted to 8.0 to 9.0 with sodium hydroxide solution (1250 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate. The solvent was distilled off under vacuum to obtain a residual solid of l-(4- amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro- 1 H- 1 -benzazepine (185 gm).
185 g	With tin(IV) chloride; In methanol; at 20℃; for 16h;	Example 3 Preparation of 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine 7-Chloro-1-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (250 gm) as obtained in example 2 was dissolved in methanol (575 ml) and then added a solution of tin chloride (630 gm) in methanol (1130 ml). The reaction mixture was stirred for 16 hours at room temperature and then poured to the ice water. The pH of the reaction mass was adjusted to 8.0 to 9.0 with sodium hydroxide solution (1250 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate. The solvent was distilled off under vacuum to obtain a residual solid of 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (185 gm).
	With tin(II) chloride dihdyrate; In methanol; at 20℃; for 24h;	A 3 L reactor was charged with 7-chloro-1- (2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-1 H-1-benzazepine (220 g, 613.19 mmol)And methanol (440 ml) were added,And the mixture was stirred at room temperature for 1 hour.While stirring the reaction mixture at 10 C. or lower,Tin chloride dihydrate (532.70 g, 2360.78 mmol) was dissolved in methanol (1 L) and gradually added. After 23 hours,After adjusting the pH of the reaction mixture to pH 8 to 9 with an aqueous solution of sodium hydroxide,Dichloromethane (200 ml) was added, stirred and filtered to remove reaction byproducts.Dichloromethane (3 L) and distilled water (2 L) were added to the resulting filtrate, the layers were separated and the organic layer was removed.The obtained organic layer was dried over sodium sulfate (Na 2 SO 4), filtered and concentrated under reduced pressure to give163 g of 1- (4-amino-2-methylbenzoyl) -7-chloro-5-oxo-2,3,4,5-tetrahydro- 1 H- 1 -benzazepine was obtained (HPLC purity: 96.57%).The product obtained is used as crude 1- (4-amino-2-methylbenzoyl) -7-chloro-5-oxo-2,3,4,5-tetrahydro- 1 H-1 -benzazepine
	With hydrogenchloride; tin(II) chloride dihdyrate; In methanol; at 50 - 60℃;Large scale;	60 kg of methanol, 40 kg of tetrahydrofuran and 40 kg of concentrated hydrochloric acid were added to the reaction vessel, and 10.4 kg was added by stirring.7-Chloro-1,2,3,4-tetrahydro-1-(2-methyl-4-nitrobenzoyl)-5H-1-benzazepine-5-one (compound of formula IV) .25 kg of dihydrate and stannous chloride were dissolved in 40 kg of methanol, added to the above system, heated to 50 to 60 C, and the reaction time was 2 to 2.5 hours, and the reaction was completed. The organic solvent was removed by concentration under reduced pressure, and the material was placed in a material bucket and chilled overnight. The mixture was pulverized and beaten with tetrahydrofuran, and filtered to dryness to give a compound of formula III.

Reference： [1]Patent: CN108341780,2018,A .Location in patent: Paragraph 0019-0021; 0022
[2]Patent: CN103373960,2017,B .Location in patent: Paragraph 0033; 0034; 0035; 0036; 0037; 0038; 0039-0044
[3]Patent: CN106883175,2017,A .Location in patent: Paragraph 0015
[4]Patent: JP2018/12690,2018,A .Location in patent: Paragraph 0027; 0028
[5]Patent: CN105315169,2016,A .Location in patent: Paragraph 0170; 0222; 0223
[6]Patent: CN105753735,2016,A .Location in patent: Paragraph 0181; 0217; 0218
[7]Bioorganic and Medicinal Chemistry,1999,vol. 7,p. 1743 - 1754
[8]Tetrahedron Asymmetry,2010,vol. 21,p. 2390 - 2393
[9]Patent: WO2012/46244,2012,A1 .Location in patent: Page/Page column 8-9
[10]Patent: US2013/190490,2013,A1 .Location in patent: Paragraph 0061; 0062; 0063
[11]Patent: JP2018/24637,2018,A .Location in patent: Paragraph 0020
[12]Patent: CN108503586,2018,A .Location in patent: Paragraph 0041; 0042

3
[ 5202-89-1 ]
[ 137977-97-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: 85 percent / pyridine / 20 °C 2.1: 94 percent / K₂CO₃ / dimethylformamide / 4 h / 120 °C 3.1: t-BuOK / toluene / 0.5 h / Heating 3.2: 60 percent / conc. HCl / acetic acid / 5 h / Heating 4.1: 81 percent / polyphosphoric acid / 1.5 h / 80 - 100 °C 5.1: 32 percent / Et₃N / CH₂Cl₂ / 2 h / 20 °C 6.1: 39 percent / SnCl₂*2H₂O; conc. HCl / ethanol / 20 °C
	Multi-step reaction with 5 steps 1: sodium carbonate / acetonitrile / 5 h / 80 °C 2: N-ethyl-N,N-diisopropylamine / dichloromethane / 4 h / 20 °C 3: potassium <i>tert</i>-butylate / toluene / 1 h / 120 °C 4: acetic acid; hydrogenchloride / water / 6 h / 100 °C 5: hydrogenchloride; tin(II) chloride dihdyrate / ethanol / 4 h / 20 °C

Reference： [1]Kondo, Kazumi; Ogawa, Hidenori; Yamashita, Hiroshi; Miyamoto, Hisashi; Tanaka, Michinori; Nakaya, Kenji; Kitano, Kazuyoshi; Yamamura, Yoshitaka; Nakamura, Shigeki; Onogawa, Toshiyuki; Mori, Toyoki; Tominaga, Michiaki [Bioorganic and Medicinal Chemistry, 1999, vol. 7, # 8, p. 1743 - 1754]
[2]Current Patent Assignee: SHANGHAI TIANCI BIOLOG VALLEY BIOLOG ENGINEERING - CN105315169, 2016, A

4
[ 2516-95-2 ]
[ 137977-97-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 1.1: 100 percent / K₂CO₃ / acetone / 0.5 h / Heating 2.1: SnCl₂2H₂O; conc. HCl / ethanol / 20 °C 3.1: 85 percent / pyridine / 20 °C 4.1: 94 percent / K₂CO₃ / dimethylformamide / 4 h / 120 °C 5.1: t-BuOK / toluene / 0.5 h / Heating 5.2: 60 percent / conc. HCl / acetic acid / 5 h / Heating 6.1: 81 percent / polyphosphoric acid / 1.5 h / 80 - 100 °C 7.1: 32 percent / Et₃N / CH₂Cl₂ / 2 h / 20 °C 8.1: 39 percent / SnCl₂2H₂O; conc. HCl / ethanol / 20 °C

5
[ 30459-70-2 ]
[ 137977-97-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 32 percent / Et₃N / CH₂Cl₂ / 2 h / 20 °C 2: 39 percent / SnCl₂*2H₂O; conc. HCl / ethanol / 20 °C
	Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / dichloromethane; water / pH 7 - 8 2: tin(ll) chloride / methanol / 16 h / 20 °C
	Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / water; dichloromethane / 0 - 5 °C / pH 7.0 - 8.0 2: tin(IV) chloride / methanol / 16 h / 20 °C

Multi-step reaction with 2 steps 1.1: magnesium hydroxide / acetonitrile / 0.5 h / 10 °C 1.2: 5 h 2.1: methanol; tin(II) chloride dihdyrate / 23 h / 10 °C

Reference： [1]Kondo, Kazumi; Ogawa, Hidenori; Yamashita, Hiroshi; Miyamoto, Hisashi; Tanaka, Michinori; Nakaya, Kenji; Kitano, Kazuyoshi; Yamamura, Yoshitaka; Nakamura, Shigeki; Onogawa, Toshiyuki; Mori, Toyoki; Tominaga, Michiaki [Bioorganic and Medicinal Chemistry, 1999, vol. 7, # 8, p. 1743 - 1754]
[2]Current Patent Assignee: HETERO DRUGS LIMITED - WO2012/46244, 2012, A1
[3]Current Patent Assignee: HETERO DRUGS LIMITED - US2013/190490, 2013, A1
[4]Current Patent Assignee: HEXAPHARMATEC - JP2018/12690, 2018, A

6
[ 1975-51-5 ]
[ 137977-97-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: SOCl₂ 2: 32 percent / Et₃N / CH₂Cl₂ / 2 h / 20 °C 3: 39 percent / SnCl₂*2H₂O; conc. HCl / ethanol / 20 °C

7
[ 51282-49-6 ]
[ 137977-97-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry,1999,vol. 7,p. 1743 - 1754

8
[ 160129-45-3 ]
[ 137977-97-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry,1999,vol. 7,p. 1743 - 1754
[2]Patent: WO2012/46244,2012,A1
[3]Patent: US2013/190490,2013,A1
[4]Patent: CN106883175,2017,A
[5]Patent: JP2018/12690,2018,A

9
[ 247237-38-3 ]
[ 137977-97-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: 94 percent / K₂CO₃ / dimethylformamide / 4 h / 120 °C 2.1: t-BuOK / toluene / 0.5 h / Heating 2.2: 60 percent / conc. HCl / acetic acid / 5 h / Heating 3.1: 81 percent / polyphosphoric acid / 1.5 h / 80 - 100 °C 4.1: 32 percent / Et₃N / CH₂Cl₂ / 2 h / 20 °C 5.1: 39 percent / SnCl₂*2H₂O; conc. HCl / ethanol / 20 °C

10
[ 193686-76-9 ]
[ 137977-97-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 81 percent / polyphosphoric acid / 1.5 h / 80 - 100 °C 2: 32 percent / Et₃N / CH₂Cl₂ / 2 h / 20 °C 3: 39 percent / SnCl₂*2H₂O; conc. HCl / ethanol / 20 °C

11
[ 137977-97-0 ]
[ 150683-30-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry,1999,vol. 7,p. 1743 - 1754
[2]Patent: US2013/190490,2013,A1

12
[ 247237-43-0 ]
[ 137977-97-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: t-BuOK / toluene / 0.5 h / Heating 1.2: 60 percent / conc. HCl / acetic acid / 5 h / Heating 2.1: 81 percent / polyphosphoric acid / 1.5 h / 80 - 100 °C 3.1: 32 percent / Et₃N / CH₂Cl₂ / 2 h / 20 °C 4.1: 39 percent / SnCl₂*2H₂O; conc. HCl / ethanol / 20 °C

13
[ 207742-73-2 ]
[ 137977-97-0 ]
[ 1296212-29-7 ]

Yield	Reaction Conditions	Operation in experiment
94%	With triethylamine; HATU In N,N-dimethyl-formamide at 65℃; for 4h; Inert atmosphere;	7 Hexafluorophosphoric 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium (3.04 g) was added to a solution of 1-(4-amino-2-methylbenzoyl)-7-chloro-2,3,4-trihydro-1H-benzo[b]azepin-5(2H)-one (2.39 g), 3,4,5,6-tetradeutero-2-trideutero methylbenzoic acid (1.04 g) and triethylamine (1.4 mL, 10 mmol) in dimethylformamide (24 mL). The mixture was then stirred at 65°C under a nitrogen atmosphere for 4 hours. After concentrating the reaction mixture, 0.1 N hydrochloric acid (100 mL) was added thereto, followed by extraction with ethyl acetate (100 mL). The organic layer was sequentially washed with saturated sodium bicarbonate water and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled off and the resulting residue was purified by medium pressure silica gel column chromatography (dichloromethane→dichloromethane/ethyl acetate = 3/1) to obtain 3.1 g of N-{4-(7-chloro-5-oxo-2,3,4-trihydro-1H-benzo[b]azepine-1-carbonyl)-3-methylphenyl}-3,4,5,6-tetradeutero-2-trideutero methylbenzamide in the form of a yellowish-brown amorphous solid. Properties: yellowish-brown amorphous powder 1H-NMR (300 MHz, CDCl3) δppm 1.86-2.31 (2H, m), 2.40 (3H, s), 2.87 (2H, t, J=6.3 Hz), 3.16-5.04 (2H, br), 6.42-7.41 (4H, m), 7.45-7.70 (2H, m), 7.76 (1H, br.s).

Reference： [1]Current Patent Assignee: OTSUKA HOLDINGS CO LTD - EP2495236, 2012, A1 Location in patent: Page/Page column 12-13

14
C₁₃H₁₆ClNO₄ [ No CAS ]
[ 137977-97-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine / dichloromethane / 4 h / 20 °C 2: potassium <i>tert</i>-butylate / toluene / 1 h / 120 °C 3: acetic acid; hydrogenchloride / water / 6 h / 100 °C 4: hydrogenchloride; tin(II) chloride dihdyrate / ethanol / 4 h / 20 °C

Reference： [1]Current Patent Assignee: SHANGHAI TIANCI BIOLOG VALLEY BIOLOG ENGINEERING - CN105315169, 2016, A

15
C₂₁H₂₁ClN₂O₇ [ No CAS ]
[ 137977-97-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: potassium <i>tert</i>-butylate / toluene / 1 h / 120 °C 2: acetic acid; hydrogenchloride / water / 6 h / 100 °C 3: hydrogenchloride; tin(II) chloride dihdyrate / ethanol / 4 h / 20 °C

Reference： [1]Current Patent Assignee: SHANGHAI TIANCI BIOLOG VALLEY BIOLOG ENGINEERING - CN105315169, 2016, A

16
C₂₀H₁₇ClN₂O₆ [ No CAS ]
[ 137977-97-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: acetic acid; hydrogenchloride / water / 6 h / 100 °C 2: hydrogenchloride; tin(II) chloride dihdyrate / ethanol / 4 h / 20 °C

Reference： [1]Current Patent Assignee: SHANGHAI TIANCI BIOLOG VALLEY BIOLOG ENGINEERING - CN105315169, 2016, A

17
C₁₈H₁₆Cl₂N₂O₄ [ No CAS ]
[ 137977-97-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: dichloromethane / 4.5 h / 20 °C / Reflux 2: hydrogenchloride; tin(II) chloride dihdyrate / water; ethanol / 3 h / 20 °C