[ CAS No. 230615-51-7 ] {[proInfo.proName]}

Name: 230615-51-7|1-(4,5-Dihydro-1H-1,5-methanobenzo[d]azepin-3(2H)-yl)-2,2,2-trifluoroethanone|97%
Brand: Ambeed
SKU: A102768
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Quality Control of [ 230615-51-7 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 230615-51-7 ]

Product Details of [ 230615-51-7 ]

CAS No. :	230615-51-7	MDL No. :	MFCD11042282
Formula :	C₁₃H₁₂F₃NO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	LMOTUASGGOAXPT-UHFFFAOYSA-N
M.W :	255.24	Pubchem ID :	21864732
Synonyms :

Calculated chemistry of [ 230615-51-7 ]

Physicochemical Properties

Num. heavy atoms :	18
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.46
Num. rotatable bonds :	2
Num. H-bond acceptors :	4.0
Num. H-bond donors :	0.0
Molar Refractivity :	63.38
TPSA :	20.31 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.05 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.31
Log Po/w (XLOGP3) :	2.55
Log Po/w (WLOGP) :	3.54
Log Po/w (MLOGP) :	2.72
Log Po/w (SILICOS-IT) :	2.75
Consensus Log Po/w :	2.77

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.14
Solubility :	0.183 mg/ml ; 0.000718 mol/l
Class :	Soluble
Log S (Ali) :	-2.62
Solubility :	0.607 mg/ml ; 0.00238 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.49
Solubility :	0.082 mg/ml ; 0.000321 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	2.61

Safety of [ 230615-51-7 ]

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 [ 230615-51-7 ]

* 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 [ 230615-51-7 ]
Downstream synthetic route of [ 230615-51-7 ]

[ 230615-51-7 ] Synthesis Path-Upstream 1~3

1
[ 230615-52-8 ]
[ 407-25-0 ]
[ 230615-51-7 ]

Reference： [1] Patent: US2009/318695, 2009, A1, . Location in patent: Page/Page column 9
[2] Patent: WO2010/23561, 2010, A1, . Location in patent: Page/Page column 16-17
[3] Patent: US2003/60624, 2003, A1,

2
[ 69718-72-5 ]
[ 407-25-0 ]
[ 230615-51-7 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 22, p. 4889 - 4897

3
[ 407-25-0 ]
[ 357425-93-5 ]
[ 230615-51-7 ]

Reference： [1] Patent: WO2009/65872, 2009, A2, . Location in patent: Page/Page column 10-11; 15-16

[ 230615-51-7 ] Synthesis Path-Downstream 1~21

1
[ 230615-51-7 ]
[ 1493-13-6 ]
[ 230615-53-9 ]

Yield	Reaction Conditions	Operation in experiment
	With nitric acid; In dichloromethane; at 0 - 20℃;	Trifluoromethane sulfonic acid (19.8g) was dissolved in CH2CI2 (275ml) and cooled to 00C. Fuming HNO3 (2.8ml) was added dropwise. The solution was cloudy for a brief period, then went to a clear yellow solution again. In a separate vessel, 3-(trifluoroacetyl)-2,3,4,5- tetrahydro-1 H-1 ,5-methano-3-benzazepine (15.3g) was dissolved in CH2CI2 (350ml) and transferred to an addition funnel. This solution was added dropwise over ~1 hour. The reaction temperature was maintained at 0-50C throughout the addition. Once addition was complete, the pot was kept at 0-50C for 2 hours, slowly warmed to room temperature, then stirred overnight. After TLC (eluent = 1 :1 EtOAc:Hex) confirmed that the reaction was complete, the reaction mixture was slowly added to ice water to quench the reaction, and stirred 20 minutes. The biphasic system was transferred to a separatory funnel for phase separation. The CH2CI2/ product solution was collected, simultaneously treated with Na2SO4 and Darco KB-B, filtered through a pad of celite and rinsed with CH2CI2. The filtrate was collected and vacuum stripped to a dark yellow oil, which solidified to a waxy yellow solid on standing. The solid was allowed to dry in a vacuum oven at 45C overnight. This afforded crude product as a yellow solid (17.9g of 90% pure as determined by HPLC). <n="12"/>The crude product (17.9g) was taken up in EtOH (90ml) and brought to reflux, which resulted in a clear yellow solution. The solution was allowed to slowly cool to room temperature and stir overnight. This gave a cream-colored slurry. The slurry was filtered onto a No.2 Whatman paper filter and rinsed with EtOH. The solid was then allowed to dry overnight in a vacuum oven at 45C. This afforded 14.6g (81.1 % yield) of a cream-colored solid.

Reference： [1]Patent: WO2007/110730,2007,A2 .Location in patent: Page/Page column 10-11

2
aluminum chloride (AlCl₃) [ No CAS ]
[ 230615-51-7 ]
[ 75-34-3 ]
[ 230615-80-2 ]

Yield	Reaction Conditions	Operation in experiment
	With acetyl chloride;	A 1-(4-Acetyl-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone 1-(10-Aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone (253 mg, 1.0 mmol) and AcCl (0.68 mL, 10 mmol) were dissolved in DCE (3 mL) and treated with aluminum chloride (AlCl3) (667 mg, 5.0 mmol). The resulting yellow mixture was stirred for 30 minutes then poured over ice and saturated aqueous NaHCO3 solution. After stirring 20 minutes the mixture was extracted with CH2Cl2 (3*30 mL). The organic layer was dried through a cotton plug then concentrated to a orange-yellow oil (255 mg, 86%).

Reference： [1]Patent: US2003/60624,2003,A1

3
[ 230615-52-8 ]
[ 407-25-0 ]
[ 230615-51-7 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; at 0 - 20℃;Product distribution / selectivity;	A suspension of 10-Aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene hydrochloride (500 g) and MDC (8 l) was stirred at 0 to 5 C., and treated with triethylamine (621.4 g). To this solution, tri-fluoro acetic anhydride (645 g) was added at 0 to 5 C. over 30 to 40 minutes. The resulting solution was allowed to warm to room temperature, and stirred for 2 hours. The progress of the reaction was checked by HPLC. The reaction was quenched by addition of DM water (3.75 l) at 5 to 10 C., and stirred for 1.0 hour. The layers were separated, and the aqueous layer was extracted with MDC (1 l). The organic layer was washed with 1N HCl (3×3 l) and 10 percent aqueous sodium chloride solution (2 l). Concentration of the organic layer to 2 l provided a 1-(10-Aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene-10-yl)-2,2,2-trifluoro ethenone product, which was further processed as described below stage (HPLC purity 98.12 percent).
	With pyridine; In dichloromethane; at 0℃; for 0.166667h;	10-Aza-tricyclo[6.3.1.02 7]dodeca-2(7),3,5-triene hydrochloride salt (60 g) was stirred in methylene chloride (600 ml) at 25-30C, the mixture was cooled to 0C, and then treated with pyridine (61.68 g), followed by the addition of trifluoroacetic anhydride (TFAA) (81.39 g) over 10 minutes. Aqueous hydrochloric acid solution (600 ml) was added to the resulting mass followed by the separation of layers. The aqueous layer was extracted with methylene chloride (2 x 300 ml) and the combined organic layer was washed with aqueous hydrochloric acid solution (300 ml), water (2 x 600 ml) and saturated aqueous sodium bicarbonate solution (600 ml). The resulting solution was dried over sodium sulfate followed by concentration under vacuum at below 40C to afford a clear oil which was then crystallized to give 66 g of l-(10-aza-tricyclo[6.3.1.02 7]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone as white needles (Purity by HPLC: 99.33%).
	With pyridine; In dichloromethane;	A 1-(10-Aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone 10-Aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene hydrochloride salt (12.4 g, 63.9 mmol) was stirred in CH2Cl2 (200 mL). This was cooled (ice bath) and treated with pyridine (12.65 g, 160 mmol) followed by trifluoroacetic anhydride (TFAA) (16.8 g, 11.3 mL, 80 mmol) from an addition funnel over 10 minutes. After ~3 hours, the solution was poured into 0.5N aqueous HCl (200 mL) and the layers separated. The aqueous layer was extracted with CH2Cl2 (350 mL) and the combined organic layer was washed with 0.5N aqueous HCl (50 mL), H2O (250 mL) and saturated aqueous NaHCO3 solution (50 mL). This solution was dried through a cotton plug, then diluted with ~3% ethyl acetate and filtered through a 2 inch Silica pad eluted with ~3% ethyl acetate/CH2Cl2. Concentration afforded a clear oil which crystallized to give white needles (15.35 g, 60.2 mmol, 94%). (TLC 30% ethyl acetate/hexanes Rf 0.53). 1H NMR (400 MHz, CDCl3) delta7.18 (m, 4H), 4.29 (br d, J=12.6 Hz, 1H), 3.84 (br d, J=12.6 Hz, 1H), 3.51 (dd, J=12.6, 1.5 Hz, 1H), 3.21 (br s, 1H), 3.10 (br s, 1H), 3.10 (br d, J=12.6 Hz, 1H), 2.37 (m, 1H), 1.92 (d, J=10.8 Hz, 1H). GCMS m/e 255 (M+). M.p. 67-68 C.

Reference： [1]Patent: US2009/318695,2009,A1 .Location in patent: Page/Page column 9
[2]Patent: WO2010/23561,2010,A1 .Location in patent: Page/Page column 16-17
[3]Patent: US2003/60624,2003,A1

4
[ 230615-51-7 ]
[ 230615-53-9 ]

Yield	Reaction Conditions	Operation in experiment
94%	With nitric acid; In trifluoroacetic acid; at 0℃; for 2.16667h;	A solution of 1-(10-Aza-tricyclo[6.3.1.02l7]dodeca-2(7),3,5-trien- 10-yl)-2,2,2-trifluoro-ethanone (49.9g, 196 mmol) (4) (see O'Donnell et al., JOC, 2004 (69,7), 5756-59 and International Publication Nos. WO 04/063164 and WO 99/35131) and in trifluoroacetic acid (TFA) (100 mL) was cooled in an acetone/ice bath and treated drop-wise with fuming HNO3 over 10 minutes. The resultant reaction mixture was stirred for 1 hour as the ice bath temperature increased to 0C and then for an additional 1 hour. The ice bath was removed, excess NO2 was removed under a stream of nitrogen, and TFA was removed <n="84"/>under reduced pressure. The resultant residue was poured into 300 ml of ice water and extracted with 3 x 200 ml CH2CI2. The combined organic phases were washed with saturated NaCI (1 x 100 ml) and saturated NaHCO3. (1 x 100 ml). The organic phase was dried over MgSO4 and passed through a 200 g plug of silica gel (230-400 mesh) eluting with CH2CI2 (2000 ml). The resultant eluent was concentrated under reduce pressure to provide C17 as a pale yellow solid (55.4 g, 184 mmol, 94% yield). 1H NMR (400 MHz, DMSO-D6) delta ppm 2.1 (d, (d, J=4.6 Hz, 2 H) 3.7 (m, 1 H) 3.8 (m, 1 H) 4.1 (d, J=12.9 Hz, 1 H) 7.5 (t, J=8.5 Hz, 1 H) 8.1 (d, J=7.9 Hz, 1 H) 8.2 (dd, J=10.8, 2.1 Hz, 1 H) ppm.
78%	With trifluorormethanesulfonic acid; nitric acid; In dichloromethane;	B 1-(4-Nitro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone (Based on the method described by Coon, C. L.; Blucher, W. G.; Hill, M. E. J. Org. Chem. 1973, 25, 4243.) To a solution of trifluoromethanesulfonic acid (2.4 ml, 13.7 mmol) in CH2Cl2 (10 ml) stirred at 0 C. was slowly added nitric acid (0.58 ml, 27.4 mmol) generating a white precipitate. After 10 minutes the resulting mixture was cooled to -78 C. and treated with <strong>[230615-51-7]1-(10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone</strong> (3.5 g, 13.7 mmol) in CH2Cl2 (15 ml) dropwise from an addition funnel over 5 minutes. The reaction was stirred at -78 C. for 30 minutes then warmed to 0 C. for 1 hour. The reaction mixture was poured into a vigorously stirred ice (100 g). The layers were separated and the aqueous layer extracted with CH2Cl2 (330 ml). The organic layer was combined and washed with H2O (3 30 ml). The combined organic layer was washed with saturated aqueous NaHCO3 solution (20 mL) and H2O (20 mL) then dried through a cotton plug and concentrated to give an orange oil that solidified on standing (4.2 g). Chromatography yielded pure product as a crystalline solid (3.2 g, 78%). (TLC 30% ethyl acetate/hexanes Rf 0.23). 1H NMR (400 MHz, CDCl3) delta8.12 (br d, J=8.0 Hz, 1H), 8.08 (br s, 1H), 7.37 (br d, J=8.0 Hz, 1H), 4.38 (br d, J=12.6 Hz, 1H), 3.94 (br d, J=12.6 Hz, 1H), 3.59 (br d, J=12.6 Hz, 1H), 3.43-3.35 (m, 2H), 3.18 (br d, J=12.6 Hz, 1H), 2.48 (m, 1H), 2.07 (d, J=10.8 Hz, 1H). GCMS m/e 300 (M+).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 4889 - 4897
[2]Patent: WO2007/72158,2007,A2 .Location in patent: Page/Page column 81-82
[3]Patent: US2003/60624,2003,A1

Yield	Reaction Conditions	Operation in experiment
		A 1-(10-Aza-tricyclo[6.3.1.02.7]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone 10-Aza-tricyclo[6.3.1.02.7]dodeca-2(7),3,5-triene hydrochloride salt (12.4 g, 63.9 mmol) was stirred in CH2Cl2 (200 mL). This was cooled (ice bath) and treated with pyridine (12.65 g 160 mmol) followed by trifluoroacetic anhydride (TFAA) (16.8 g, 11.3 mL, 80 mmol) from an addition funnel over 10 minutes. After ~3 hours, the solution was poured into 0.5N aqueous HCl (200 mL) and the layers separated. The aqueous layer was extracted with CH2Cl2 (350 mL) and the combined organic layer was washed with 0.5N aqueous HCl (50 mL), H2O (250 mL) and saturated aqueous NaHCO3 solution (50 mL). This solution was dried through a cotton plug, then diluted with ~3% EtOAc and filtered through a 2 inch Silica pad eluted with ~3% EtOAc/CH2Cl2. Concentration afforded a clear oil which crystallized to give white needles (15.35 g, 60.2 mmol. 94%). (TLC 30% EtOAc/hexanes Rf 0.53). 1H NMR (400 MHz. CDCl3) delta 7.18 (m, 4H), 4.29 (br d. J=12.6 Hz, 1H), 3.84 (br d, J=12.6 Hz, 1 H), 3.51 (dd, J=12.6,1.5 Hz, 1H), 3.21 (br s, 1H), 3.10 (br s, 1H), 3.10 (br d, J=12.6 Hz, 1H), 2.37 (m, 1H), 1.92 (d, J=10.8 Hz, 1H). GCMS m/e 255 (M+) mp 67-68 C.

6
aluminum chloride (AICl₃) [ No CAS ]
[ 230615-51-7 ]
[ 75-34-3 ]
[ 230615-80-2 ]

Yield	Reaction Conditions	Operation in experiment
	With acetyl chloride;	A 1-(4-Acetyl-10-aza-tricyclo[6.3.1.02.7]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro Ethanone 1-(10-Aza-tricyclo[6.3.1.02.7]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone (253 mg, 1.0 mmol) and AcCl (0.68 mL, 10 mmol) were dissolved in DCE (3 mL) and treated with aluminum chloride (AICl3) (667 mg, 5.0 mmol). The resulting yellow mixture was stirred for 30 minutes then poured over ice and saturated aqueous NaHCO3 solution. After stirring 20 minutes the mixture was extracted with CH2Cl2 (3*30 mL). The organic layer was dried through a cotton plug then concentrated to a orange-yellow oil (255 mg, 86%).

Reference： [1]Patent: US2002/72524,2002,A1

7
[ 230615-51-7 ]
[ 230615-89-1 ]

Yield	Reaction Conditions	Operation in experiment
87%	With chlorosulfonic acid;	A 10-Trifluoroacetyl-10-aza-tricyclo[6.3.1.02.7]dodeca-2(7),3,5-triene-4-sulfonyl Chloride 1-(10-Aza-tricyclo(6.3.1.02.7]dodeca-2(7),3,5-trien-10-yl)-2.2,2-trifluoro-ethanone (530 mg. 2.1 mmol) was added to chlorosulfonic acid (2 mL, 30 mmol) and stirred for 5 minutes. The mixture was quenched with ice, extracted with EtOAc, dried (Na2SO4), filtered and concentrated to provide an oil (640 mg, 87%) (TLC 30% EtOAc/hexanes Rf 0.15).
87%	With chlorosulfonic acid;	A 10-Trifluoroacetyl-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene-4-sulfonyl Chloride 1-(10-Aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone (530 mg, 2.1 mmol) was added to chlorosulfonic acid (2 mL, 30 mmol) and stirred for 5 minutes. The mixture was quenched with ice, extracted with ethyl acetate, dried (Na2SO4), filtered and concentrated to provide an oil (640 mg, 87%). (TLC 30% ethyl acetate/hexanes Rf 0.15).

Reference： [1]Patent: US2002/72524,2002,A1
[2]Patent: US6605610,2003,B1

8
aluminum chloride (AlCl₃) [ No CAS ]
[ 230615-51-7 ]
[ 230615-80-2 ]

Yield	Reaction Conditions	Operation in experiment
	With acetyl chloride;	A 1-(4-Acetyl-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone 1-(10-Aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone (253 mg, 1.0 mmol) and AcCl (0.68 mL, 10 mmol) were dissolved in DCE (3 mL) and treated with aluminum chloride (AlCl3) (667 mg, 5.0 mmol). The resulting yellow mixture was stirred for 30 minutes then poured over ice and saturated aqueous NaHCO3 solution. After stirring 20 minutes the mixture was extracted with CH2Cl2 (3*30 mL). The organic layer was dried through a cotton plug then concentrated to a orange-yellow oil (255 mg, 86%).

Reference： [1]Patent: US6605610,2003,B1

9
[ 230615-51-7 ]
C₁₃H₁₁ClF₃NO₂S [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 4889 - 4897

10
[ 230615-51-7 ]
3-(trifluoroacetyl)-6,8-dinitro-2,3,4,5-tetrahydro-1H-1,5-methano-3-benzazepine [ No CAS ]
[ 230615-59-5 ]

Yield	Reaction Conditions	Operation in experiment
	With trifluorormethanesulfonic acid; nitric acid; In dichloromethane; at 0 - 15℃;Product distribution / selectivity;	On the other hand, a 500 mL round bottom flask with thermometer, condenser, addition funnel and magnetic stirring was charged with CF3SO3H (25.9 g, 172.5 mmol), CH2Cl2 (110 mL) and cooled to 0-5 0C. At this temperature, fuming nitric acid (5.4 g, 86.25 mmol) was added slowly. To the resulting slurry at 0-5 0C, the solution obtained in the previous step was slowly added, maintaining the temperature < 15 0C. After the addition, the reaction mixture was stirred overnight. The complete dinitration was confirmed by GC. The crude reaction mixture was poured into water (60 mL) an ice (80 g) and stirred. The phases were separated and the aqueous phase was extracted with CH2Cl2 (3 x 50 mL) . The mixture of the organic phases was washed with aqueous saturated NaHCO3, dried over Na2SO4 and volatiles evaporated under vacuum to obtain 11.9 g of a solid that was suspended and stirred for 2 hours in AcOEt (12 mL) and hexanes (24 mL) . The solid was filtered and washed with hexanes to <n="13"/>obtain the compound of formula (III), 9.1g with a purity of 88.9% by GC (9.8% of meta-dimtrocompound impurity) .

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 4889 - 4897
[2]Patent: WO2009/65872,2009,A2 .Location in patent: Page/Page column 11-12

11
[ 230615-51-7 ]
[ 75-36-5 ]
[ 230615-80-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 4889 - 4897

12
[ 69718-72-5 ]
[ 407-25-0 ]
[ 230615-51-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 4889 - 4897

13
[ 407-25-0 ]
[ 357425-93-5 ]
[ 230615-51-7 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; at 0 - 15℃; for 1.0h;Product distribution / selectivity;	A) Preparation of compound of formula (III)This example is based on U.S. Patent No. 6,410,550.A 250 mL round bottom flask with thermometer, condenser, addition funnel and magnetic stirring was <n="12"/>charged with 10-aza-tricyclo [ 6.3.1. O2'7] dodeca-2, 4, 6- triene para-toluene sulfonic acid salt (12.4g, 37.5 mmol) and 44 mL of CH2Cl2. Triethylamine (8.3 g, 82.5 mmol) was added to the slurry and the resulting solution was cooled to 0-5 0C. The addition funnel was charged with a solution of (CF3CO)2O (8.1q, 41.25 mmol) in 19 mL of CH2Cl2. This solution was slowly added to the reaction mixture, maintaining the temperature < 15 0C. The resulting mixture was stirred for 1 hour, and the complete conversion was monitored by GC. The crude reaction mixture was washed with water (2 * 40 mL) and brine (40 mL) . The organic phase was used in the next step without further purification. Example 1: Preparation of 7, 8, 9, lO-tetrahydro-6, 10- methano-6H-pyrazmo [2, 3-h] [3] benzazepine L-tartrate(i.e. vareniclme L-tartrate)A) Preparation of compound of formula (III) <n="17"/>This example is based on U.S. Patent No. 6,410,550, except for the purification step, which is the object of the present invention (i.e. crystallization in toluene) .A 500 mL round bottom flask with thermometer, condenser, addition funnel and magnetic stirring was charged with 10-aza-tricyclo [ 6.3.1. O2'7] dodeca-2, 4, 6- t?ene para-toluene sulfonic acid salt (32.5g, 98.2 mmol) and 115 mL of CH2Cl2. Triethylamine (21.8 g, 216 mmol) was added to the slurry and the resulting solution was cooled to 0-5 0C. The addition funnel was charged with a solution of (CF3CO)2O (22.7 g, 108 mmol) in 50 mL of CH2Cl2. This solution was slowly added to the reaction mixture, maintaining the temperature < 15 0C. The resulting mixture was stirred for 1 hour, and the complete conversion was monitored by GC. The crude reaction mixture was washed with water (2 x 100 mL) and brine (100 mL) . The organic phase was used in the next step without further purification.

Reference： [1]Patent: WO2009/65872,2009,A2 .Location in patent: Page/Page column 10-11; 15-16

14
[ 230615-51-7 ]
[ 230615-59-5 ]

Yield	Reaction Conditions	Operation in experiment
68.9%	With trifluorormethanesulfonic acid; nitric acid; In dichloromethane; at 0 - 30℃;Product distribution / selectivity;	Example 10Procedure for Preparation of 1-(4,5-Dinitro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene-10-yl)-2,2,2-trifluoro-ethanone (IX); Fuming nitric acid (390.2 g) was added over 25 to 35 minutes at 0 to 5 C. to a solution of tri-fluoro methane sulfonic acid (1.7 kg) in MDC (2.52 l). The mixture was stirred for 10-15 minutes. To this resulting organic layer, <strong>[230615-51-7]1-(10-Aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene-10-yl)-2,2,2-trifluoro-ethanone</strong> in MDC was added over 1.0 to 1.5 hours at 0 to 5 C. After completion of addition, the temperature was immediately raised to 25 to 30 C. The reaction mass was stirred at 25 to 30 C. for 2.0 hours. The progress of the reaction was checked by HPLC. The reaction mixture was quenched in DM water (6.5 l) at 0 to 5 C. The layers were separated, and the aqueous layer was extracted with MDC (2×1.26 l). The combined organic layer was washed with DM water (3×3.2 l), and then with an 8 percent aqueous NaHCO3 solution (1×3.2 l) and DM water (1×2.5 l). The organic layer was concentrated to provide crude 1-(4,5-Dinitro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene-10-yl)-2,2,2-trifluoro-ethanone. This was triturated with ethyl acetate (1.30 l) at 55 to 60 C. for 2 hours. The solid was filtered and washed with chilled ethyl acetate (630 ml) to provide pure 1-(4,5-Dinitro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene-10-yl)-2,2,2-trifluoro-ethanone having a yield of 68.9 percent and an HPLC purity of 99.55 percent.
	With trifluorormethanesulfonic acid; nitric acid; In dichloromethane; at 0 - 15℃;Product distribution / selectivity;	A l L round bottom flask with thermometer, condenser, addition funnel and magnetic stirring was charged with CF3SO3H (67.8 g, 452 mmol), CH2Cl2 (280 mL) and cooled to 0-5 0C. At this temperature, fuming nitric acid (14.2 g, 226 mmol) was slowly added. To the resulting slurry at 0-5 0C, the solution obtained in the previous step was slowly added, maintaining the temperature < 15 0C. After the addition, the reaction mixture was stirred overnight. The complete dinitration was confirmed by GC. The crude reaction mixture was poured into water (150 mL) an ice (200 g) and stirred. The phases were separated and the aqueous phase was extracted with CH2Cl2 (100 mL) . The mixture of the organic phases was washed with aqueous saturated NaHCO3 <n="18"/>(2x100 mL) , water (100 mL) , dried over Na2SO4 and volatiles evaporated under vacuum to obtain 30.5 g of a solid with a 83.6% purity by GC (12.5% of meta- dinitrocompound impurity) . 20 g of this solid were crystallized in toluene (100 mL) to obtain the compound of formula (III), 15 g of a pale brown solid with a 98.5 % purity by GC (meta-dinitrocompound impurity not detected) .
	With sulfuric acid; nitric acid; In dichloromethane; at 0 - 30℃; for 7.0h;	Fuming nitric acid (39 g) was slowly added to a solution concentrated sulfuric acid (126.17 g) in methylene chloride (450 ml) followed by stirring at O0C to generate a white precipitate. This step was followed by drop wise addition of a solution of l-(10-aza- tricyclo[6.3.1.02 7]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone (65 g) in methylene chloride (100 ml) through an addition funnel over 30 minutes. The reaction mixture was stirred for 2 hours 30 minutes at 00C and then stirred for 4 hours at 25-30C. The resulting mass was poured into a vigorously stirred mixture of water (650 ml) at 15-200C. The resulting layers were separated and the aqueous layer was extracted with methylene chloride (I x 325 ml). The organic layers were combined and washed with water (3 x 650 ml) and then dried over sodium sulfate and concentrated to afford a solid. The resulting solid was slurried with methanol (325 ml), filtered and dried to yield 60 g of l-(4,5-dinitro-10-aza- tricyclo[6.3.1.02 7]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone as off-white solid (Purity by HPLC: 99.5%).

Reference： [1]Patent: US2009/318695,2009,A1 .Location in patent: Page/Page column 9-10
[2]Patent: WO2009/65872,2009,A2 .Location in patent: Page/Page column 16-17
[3]Patent: WO2010/23561,2010,A1 .Location in patent: Page/Page column 17

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Reference： [1]Patent: US2003/60624,2003,A1

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Reference： [1]Patent: US2003/60624,2003,A1

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Reference： [1]Patent: US2003/60624,2003,A1

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Reference： [1]Patent: US2003/60624,2003,A1

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Reference： [1]Patent: US2003/60624,2003,A1

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Reference： [1]Patent: US2003/60624,2003,A1

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Reference： [1]Patent: US2003/60624,2003,A1

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H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
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H204	Fire or projection hazard
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H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
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H316	Causes mild skin irritation
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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. 230615-51-7 ] {[proInfo.proName]}

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[ 230615-51-7 ] Synthesis Path-Upstream 1~3

[ 230615-51-7 ] Synthesis Path-Downstream 1~21

Pharmaceutical Intermediates of [ 230615-51-7 ]

Varenicline Intermediates

Related Functional Groups of [ 230615-51-7 ]

Fluorinated Building Blocks

Amides

Trifluoromethyls

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Other Aromatic Heterocycles

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[ 230615-51-7 ]

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[ 230615-51-7 ]