[ CAS No. 167484-18-6 ] {[proInfo.proName]}

Name: 167484-18-6|Benzyl spiro[indoline-3,4'-piperidine]-1'-carboxylate|97%
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Quality Control of [ 167484-18-6 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 167484-18-6 ]

CAS No. :	167484-18-6	MDL No. :	MFCD11007805
Formula :	C₂₀H₂₂N₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	XJUPGFXGJQIYQG-UHFFFAOYSA-N
M.W :	322.40	Pubchem ID :	10914256
Synonyms :

Calculated chemistry of [ 167484-18-6 ]

Physicochemical Properties

Num. heavy atoms :	24
Num. arom. heavy atoms :	12
Fraction Csp3 :	0.35
Num. rotatable bonds :	4
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	101.12
TPSA :	41.57 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-5.7 cm/s

Lipophilicity

Log Po/w (iLOGP) :	3.15
Log Po/w (XLOGP3) :	3.62
Log Po/w (WLOGP) :	2.68
Log Po/w (MLOGP) :	3.14
Log Po/w (SILICOS-IT) :	3.14
Consensus Log Po/w :	3.15

Druglikeness

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

Water Solubility

Log S (ESOL) :	-4.23
Solubility :	0.0192 mg/ml ; 0.0000595 mol/l
Class :	Moderately soluble
Log S (Ali) :	-4.18
Solubility :	0.0213 mg/ml ; 0.000066 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-6.02
Solubility :	0.000306 mg/ml ; 0.000000951 mol/l
Class :	Poorly soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	3.5

Safety of [ 167484-18-6 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H317	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 167484-18-6 ]

* 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 [ 167484-18-6 ]

[ 167484-18-6 ] Synthesis Path-Downstream 1~81

1
[ 124-63-0 ]
[ 167484-18-6 ]
[ 184289-84-7 ]

Yield	Reaction Conditions	Operation in experiment
81%	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0 - 20℃;	Compound A (3.03 g, 9.4 mmol) was dissolved in tetrahydrofuran (30 mL) and cooled to 0C. diisopropylethylamine (1.8 mL, 10.3 mmol) and methanesulfonyl chloride (0. 8 mL, 10.3 mmol) were added slowly. The reaction was stirred over night at room temperature. The solvent was removed under vacuum and the crude material was dissolved in dichloromethane, washed successively with aqueous HC1 (1N), saturated aqueous NaHC03 and brine. The organic layer was dried over Na2S04. The dichloromethane was removed by evaporation and the crude material was crystallised from hot ethanol and a drop of acetic acid to give 3.06g (81 %) of B as a beige solid.
81%	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃;	Synthesis of B:; Compound A (3.03 g, 9.4 mmol) was dissolved in tetrahydrofuran (30 mL) and cooled to 0C. diisopropylethylamine (1.8 mL, 10.3 mmol) and methanesulfonyl chloride (0.8 mL, 10.3 mmol) were added slowly. The reaction was stirred over night at room temperature. The solvent was removed under vacuum and the crude material was dissolved in dichloromethane, washed successively with aqueous HCI (IN), saturated aqueous NaHC03 and brine. The organic layer was dried over Na2S04. The dichloromethane was removed by evaporation and the crude material was crystallised from hot ethanol and a drop of acetic acid to give 3.06g (81 %) of B as a beige solid.
68%	With triethylamine; In dichloromethane; at 0 - 25℃; for 3h;	Methanesulfonyl chloride (0.145 mL, 1.861 mmol) was added to a solution of benzyl spiro[indoline-3,4?-piperidine]-l?-carboxylate (Compound of step 1 of Example 116, 0.5 g, 0. 1.55 1 mmol) and triethylamine (0.648 mL, 4.65 mmol) in DCM (20 mL) at 0-5 C. The reaction mixture was stirred at RT for 3h. After completion of reaction, water (20 mL) and DCM (20 mL) was added to the reaction mixture. The organic layer was separated and dried over Na2504. The solvent was evaporated and the residue was purified by flash column chromatography (silica gel column, 1-70% EtOAc/petroleum ether as eluent) to obtain the title compound (0.42 g). Yield: 68%; 1H NMR (DMSO-d6, 300 MHz): 5 1.60 (s, 3H), 1.70- 1.74 (m, 2H), 2.93 (s, 3H), 2.97-3.02 (m, 1H), 3.87 (s, 2H), 4.25 (br s, 2H), 5.19 (s, 2H), 7.09 (t, J = 7.2 Hz, 1H), 7.15 (d, J = 7.2 Hz, 1H), 7.25 (d, J = 7.2 Hz, 1H), 7.40 (brs, 6H); MS (mlz): [M] 400.1.

Reference： [1]Patent: WO2005/46682,2005,A1 .Location in patent: Page/Page column 90
[2]Patent: WO2005/97788,2005,A2 .Location in patent: Page/Page column 86
[3]Patent: WO2015/28960,2015,A1 .Location in patent: Page/Page column 151
[4]Tetrahedron,1997,vol. 53,p. 10983 - 10992
[5]Chinese Chemical Letters,2012,vol. 23,p. 661 - 664

2
[ 184289-85-8 ]
[ 167484-18-6 ]

Reference： [1]Tetrahedron,1997,vol. 53,p. 10983 - 10992
[2]Chinese Chemical Letters,2012,vol. 23,p. 661 - 664

3
[ 13139-17-8 ]
[ 171-75-5 ]
[ 167484-18-6 ]

Yield	Reaction Conditions	Operation in experiment
69%	In tetrahydrofuran; at 20℃; for 1h;	To a stirred solution of 49a (0.90 g, 4.78 mmol) in dry THF (25 mL) was added (N-benzyloxycarbonyloxy)-succinimide (1.2 g, 4.8 mmol) in THF (5 mL) over a 2-min period of time at rt under N2. The resulting mixture was stirred at rt for 1 h. EtOAc was added. It was washed with sat'd NaHCO3, H2O, brine, dried over MgSO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, hexanes/EtOAc) to give pure 49b as colorless crystals (0.96 g, yield: 69%). LC-MS ESI 323.15 (M+H)+(tR=2.62 min, 10%-90% MeOH in H2O in a 4-min run).
69%	In tetrahydrofuran; at 20℃; for 1.03333h;	6b. Spiro[3H-indole-3,4'-piperidine]-1'-carboxylic acid, 1,2-dihydro-, Phenylmethyl Ester:; To a stirred solution of 6a (0.90 g, 4.78 mmol) in dry THF (25 mL) was added (N-benzyloxycarbonyloxy)-succinimide (1.2 g, 4.8 mmol) in THF (5 mL) over a 2-min period of time at rt under N2. The resulting mixture was stirred at rt for 1 h. EtOAc was added. It was washed with saturated NaHCO3, H2O, brine, dried over MgSO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, hexanes/EtOAc) to give pure 6b as colorless crystals (0.96 g, yield: 69%). LC-MS ESI 323.15 (M+H)+(tR=2.62 min, 10%-90% MeOH in H2O in a 4-min run).

Reference： [1]Tetrahedron,2004,vol. 60,p. 4875 - 4878
[2]Patent: US2005/261244,2005,A1 .Location in patent: Page/Page column 54
[3]Patent: US2006/293281,2006,A1 .Location in patent: Page/Page column 73
[4]Journal of Medicinal Chemistry,2013,vol. 56,p. 9275 - 9295

4
[ 252002-43-0 ]
[ 167484-18-6 ]

Reference： [1]Tetrahedron,2004,vol. 60,p. 4875 - 4878

5
[ 726198-18-1 ]
[ 167484-18-6 ]

Reference： [1]Tetrahedron,2004,vol. 60,p. 4875 - 4878

6
[ 498-94-2 ]
[ 167484-18-6 ]

Reference： [1]Tetrahedron,1997,vol. 53,p. 10983 - 10992
[2]Chinese Chemical Letters,2012,vol. 23,p. 661 - 664

7
[ 10314-98-4 ]
[ 167484-18-6 ]

Reference： [1]Tetrahedron,1997,vol. 53,p. 10983 - 10992

8
[ 138163-08-3 ]
[ 167484-18-6 ]

Reference： [1]Tetrahedron,1997,vol. 53,p. 10983 - 10992
[2]Chinese Chemical Letters,2012,vol. 23,p. 661 - 664

9
[ 501-53-1 ]
(+-)-2.3-diamino-propionic acid [ No CAS ]
[ 167484-18-6 ]

Reference： [1]Tetrahedron,1997,vol. 53,p. 10983 - 10992

10
[ 10314-99-5 ]
[ 167484-18-6 ]

Reference： [1]Tetrahedron,1997,vol. 53,p. 10983 - 10992

11
[ 100-63-0 ]
1.4-diphenyl-butanedione-(2.3) [ No CAS ]
[ 167484-18-6 ]

Reference： [1]Tetrahedron,1997,vol. 53,p. 10983 - 10992

12
[ 167484-18-6 ]
[ 159634-47-6 ]

Reference： [1]Tetrahedron,1997,vol. 53,p. 10983 - 10992

13
[ 167484-18-6 ]
[ 178261-41-1 ]

Reference： [1]Tetrahedron,1997,vol. 53,p. 10983 - 10992
[2]Chinese Chemical Letters,2012,vol. 23,p. 661 - 664
[3]Patent: WO2015/28960,2015,A1

14
[ 167484-18-6 ]
[ 180465-67-2 ]

Reference： [1]Tetrahedron,1997,vol. 53,p. 10983 - 10992
[2]Chinese Chemical Letters,2012,vol. 23,p. 661 - 664

15
[ 167484-18-6 ]
[ 180465-66-1 ]

Reference： [1]Tetrahedron,1997,vol. 53,p. 10983 - 10992
[2]Chinese Chemical Letters,2012,vol. 23,p. 661 - 664

16
[ 167484-18-6 ]
[ 159634-87-4 ]

Reference： [1]Tetrahedron,1997,vol. 53,p. 10983 - 10992
[2]Chinese Chemical Letters,2012,vol. 23,p. 661 - 664

17
[ 167484-18-6 ]
MK-677 [ No CAS ]

Reference： [1]Tetrahedron,1997,vol. 53,p. 10983 - 10992
[2]Chinese Chemical Letters,2012,vol. 23,p. 661 - 664

18
[ 138163-08-3 ]
[ 100-63-0 ]
[ 167484-18-6 ]

Yield	Reaction Conditions	Operation in experiment
84%		Preparation 1; Benzyl spiro[in line-3,4'-piperidine]- 1 '-carboxylateA solution of phenyl hydrazine (1.29 g, 12.0 mmol) and trifluoroacetic acid (3.0 mL) in a 49/1 solution of toluene/acetonitrile (50 mL) is heated at 35 C. 4-Formyl- piperidine- l -carboxylic acid benzyl ester (2.7 g, 10.91 mmol) is dissolved in a 49/1 solution of toluene/acetonitrile (10 mL) and added dropwise to the mixture(WO2005046682). The mixture is stirred at 35 C overnight. The resulting solution is cooled to 0 C, and methanol (5 mL) is added. NaBFLt (0.619 g, 16.38 mmol) is added slowly to the solution and the mixture is stirred for 45 min. The mixture is washed with aqueous NH4OH (6%, 25 mL) and brine (30 mL), dried over sodium sulfate, and evaporated to dryness to give a yellow solid. The crude solid is recrystallised from EtOAc to give a pale yellow solid (1.25 g, 1st crop). The mother liquor is evaporated and purified by flash chromatography, eluting with hexane:ethyl acetate (8:2) to give the title compound as a pale yellow solid (1.2 g, 2n crop) with a total yield (2.4 g, 84%). ESI/MS m/z 323 (M+H)+.
76%		Preparation 1Benzyl spiro[indoline-3,4'-piperidine]-1'-carboxylate A solution of phenyl hydrazine (1.29 g, 12.0 mmol) and trifluoroacetic acid (3.0 mL) in a 49:1 solution of toluene:acetonitrile (50 mL) is heated at 35 C. 4-Formyl-piperidine-1-carboxylic acid benzyl ester (2.7 g, 10.91 mmol) is dissolved in a 49:1 solution of toluene:acetonitrile (10 mL) and added dropwise to the mixture (WO2005046682). The mixture is stirred at 35 C. overnight. The resulting solution is cooled to 0 C., and methanol (5 mL) is added. NaBH4 (0.619 g, 16.38 mmol) is added portion wise to the solution and the mixture is stirred for 45 min. The reaction mixture is washed with aqueous NH4OH (6%, 25 mL) and brine (30 mL), dried over sodium sulfate, and evaporated to dryness to give a yellow solid. The crude solid is recrystallised from EtOAc to give a yellow solid (1.25 g, 1st crop). The mother liquor is evaporated and purified by silica gel chromatography, eluting with hexane:ethyl acetate (8:2) to give the title compound as a pale yellow solid (1.2 g, 2nd crop) with a total yield of (2.4 g, 76%). ESI/MS m/z 323 (M+H)+.
75%		A solution of phenylhydrazine (2.38 g, 22 mmol) and trifluoroacetic acid (5 mL) in Toluene/acetonitrile (49/1) (100 mL) was heated at 35C. N-benzyloxycarbonyl 4- formylpiperidine (4.94 g, 20 mmol) was dissolved in 20 mL of toluene/acetonitrile (49/1) and added dropwise to the mixture, which was stirred at 35C overnight. The resulting solution was then cooled to 0C, and methanol (10 mL) was added. NaBH4 (1.13 g, 30 mmol) was added very slowly to the solution which was stirred for a further 45 min. The reaction mixture was washed with aqueous NH40H 6% (40 mL). Methanol (2 mL) was added and the organic layer was washed with brine (40 mL) then dried over Na2S04 and evaporated. The crude material was purified by column chromatography on silica gel, eluting with ethyl acetate/cyclohexane (1/1) to give 4.85 g (75%) of A as a pale yellow solid.

75%		Synthesis of advanced intermediate E Synthesis of A:; A solution of phenylhydrazine (2.38 g, 22 mmol) and trifluoroacetic acid (5 mL) in Toluene/acetonitrile (49/1) (100 mL) was heated at 35C. N-benzyloxycarbonyl 4- formylpiperidine (4.94 g, 20 mmol) was dissolved in 20 mL of toluene/acetonitrile (49/1) and added dropwise to the mixture, which was stirred at 35C overnight. The resulting solution was then cooled to 0C, and methanol (10 mL) was added. NaBH4 (1.13 g, 30 mmol) was added very slowly to the solution which was stirred for a further 45 min. The reaction mixture was washed with aqueous NH40H 6% (40 mL). Methanol (2 mL) was added and the organic layer was washed with brine (40 mL) then dried over Na2S04 and evaporated. The crude material was purified by column chromatography on silica gel, eluting with ethyl acetate/cyclohexane (1/1) to give 4.85 g (75%) of A as a pale yellow solid.
74%		A solution of phenyl hydrazine (5.96 mmol) and trifluoroacetic acid (1.5 mL) in a solvent system of toluene: acetonitrile (49:1) (25 mL) was stirred at 35 C. To this reaction mixture, a solution of benzyl 4-formylpiperidine- 1 -carboxylate (5.46 mmol) in a solvent system of toluene: acetonitrile (49:1) (5 mL) was added drop wise. The reaction mixture was stirred overnight at 35 C. The reaction mixture was then cooled in ice bath and MeOH (2.5 mL) was added, followed by the addition of sodium borohydride (8.16 mmol) in portions. The reaction mixture was then stirred for 45 minutes. After the completion of reaction, the reaction mixture was diluted with ethyl acetate (25 mL), washed with 5% aqueous ammonia, brine, dried over Na2504 and concentrated. The residue was purified by flash column chromatography (silica gel column, 10%-20% ethyl acetate/ petroleum ether). Yield: 74%; 1H NMR (CDC13, 300 MHz): 7.391 (m, 5H), 7.100 (m, 2H), 6.789 (t, J= 7.5, 1H), 6.686 (d, J = 7.5, 1H), 5.182 (s, 2H), 4.153 (bs, 2H), 3.501 (s, 2H), 3.067 (t, J = 14.1, 2H), 1.895 (m, 4H); MS (mlz): 323.1 (M+H) and 345.1 (M+Na).
49%		To a solution of phenylmethyl 4-formyl-1-piperidinecarboxylate (81 mmol) in 200 mL of DCM cooled in an ice bath was added phenylhydrazine (81 mmol). After stirring for approximately 15 min, TFA (202.5 mmol) was added over a period of 5 min. The mixture was allowed to slowly warm to room temperature and stir overnight. The mixture was then cooled in and ice bath and NaBH4 (121.5 mmol) was added in small portions over 15 min. The resulting solution was allowed to warm to room temperature and stir for one hour, whereupon a 10% solution of NH4OH (~100 mL) was added. After stirring for 30 min, the mixture was separated, and the aqueous layer extracted with DCM. The combine organic solutions were dried over Na2SO4 and concentrated. The residue was purified by column chromatography eluding with 0-10% MeOH in DCM. 12.72 g (39.4 mmol, 49% yield) of the desired product phenylmethyl 1,2-dihydro-1'H-spiro[indole-3,4'-piperidine]-1'-carboxylate was obtained. MS (ES) m/e 323 [M+H]+.
487 mg		(Reference Example 33) 1'-benzyloxycarbonyl-1-tert-butyloxycarbonylspiro[indoline-3,4'-piperidine] <Step 1> First, 1-benzyloxycarbonyl-4-formylpiperidine (514.5 mg) was dissolved in chloroform (10 mL), phenylhydrazine (0.245 mL) and trifluoroacetic acid (0.478 mL) were added thereto, and the mixture was stirred at 35C for 14 hours. After that, sodium triacetoxyborohydride (881.9 mg) was added thereto, and the mixture was further stirred at room temperature for 1 hour. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried with anhydrous magnesium sulfate and was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane = 50/50) to obtain 1'-benzyloxycarbonylspiro[indoline-3,4'-piperidine] (487.0 mg). MS (ESI)m/z:323[M+H]+.

Reference： [1]Patent: WO2011/66183,2011,A1 .Location in patent: Page/Page column 11
[2]Patent: US2011/92531,2011,A1 .Location in patent: Page/Page column 8
[3]Patent: WO2005/46682,2005,A1 .Location in patent: Page/Page column 89; 90
[4]Patent: WO2005/97788,2005,A2 .Location in patent: Page/Page column 85
[5]Patent: WO2015/28960,2015,A1 .Location in patent: Page/Page column 86; 149; 150
[6]Tetrahedron,2010,vol. 66,p. 573 - 577
[7]Patent: US2008/318990,2008,A1 .Location in patent: Page/Page column 22
[8]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 3359 - 3363
[9]Patent: EP3480198,2019,A1 .Location in patent: Paragraph 0237; 0238

19
[ 1493-27-2 ]
[ 167484-18-6 ]
[ 870072-74-5 ]

Yield	Reaction Conditions	Operation in experiment
91%	at 175℃; for 8h;	6c. Spiro[3H-indole-3,4'-piperidine]-1'-carboxylic acid, 1,2-dihydro-1-(2-nitrophenyl)-, Phenylmethyl Ester:; To 6b (200 mg, 0.62 mmol, 10025-B) was added 2-fluoro-nitrobenzene (400 mg, 2.8 mmol). The reaction was stirred at 175 C. for 8 h. The desired compound was purified by column chromatography using 0% to 40% EtOAc in hexanex as eluting gradient to afford 6c (250 mg, 91%). MS (ES) m/z 444 [M+H]+.
70%	at 200 - 220℃; for 0.5h;microwave;	49b (0.25 g) and ortho-fluoronitrobenzene (0.40 mL) was heated with stirring at 200-220 C. for 30 min under microwave irradiation. The resulting mixture was purified via flash chromatography (silica gel, hexanes:EtOAc=1:0 to 1:1) to give 49c (0.24 g, yield: 70%). LC-MS (ESI) 444.

Reference： [1]Patent: US2006/293281,2006,A1 .Location in patent: Page/Page column 74
[2]Patent: US2005/261244,2005,A1 .Location in patent: Page/Page column 55
[3]Journal of Medicinal Chemistry,2013,vol. 56,p. 9275 - 9295

20
[ 121-44-8 ]
[ 75-36-5 ]
[ 167484-18-6 ]
[ 167484-19-7 ]

Yield	Reaction Conditions	Operation in experiment
2.93 g (77%)	With acetic acid;palladium-carbon; In ethanol; dichloromethane;	1-Acetyl-spiro(indoline-3,4'-piperidine) Acetyl chloride (1.4 mL, 19.9 mmol) was added to a solution of 5.35 g (16.6 mmol) of <strong>[167484-18-6]1'-benzyloxycarbonyl-spiro(indoline-3,4'-piperidine)</strong> in 33 mL of CH2 Cl2 and 3.2 mL (23.2 mmol) of Et3 N keeping the temperature between 0-5 C. by cooling in ice bath. After 10 min the cold bath was removed and reaction was stirred for 30 min at which time a TLC indicated complete reaction. The solution was diluted with CH2 Cl2 and washed with water, brine and dried over Na2 SO4. The filtrate was concentrated to a thick oil and the oil was dissolved in 40 mL of EtOH. Acetic acid (3 mL) and 0.8 g of 10% Pd/C were added to the solution and the resulting mixture was hydrogenated on a Parr apparatus for 3 h. The catalyst was filtered and washed with EtOAc and the combined filtrate was concentrated. The residue was partitioned between CH2 Cl2 and water and 2N NaOH was added to this mixture until the aqueous layer was basic. The layers were separated and the aqueous layer was extracted with CH2 Cl2. The combined organic layer was washed with brine, dried over Na2 SO4 and the filtrate was concentrated to give 2.93 g (77%) of the title compound sufficiently pure for use in the next reaction.
2.93 g (77%)	With acetic acid;palladium-carbon; In ethanol; dichloromethane;	1-Acetyl-spiro(indoline-3,4'-piperidine) Acetyl chloride (1.4 mL, 19.9 mmol) was added to a solution of 5.35 g (16.6 mmol) of <strong>[167484-18-6]1'-benzyloxycarbonyl-spiro(indoline-3,4'-piperidine)</strong> in 33 mL of CH2 Cl2 and 3.2 mL (23.2 mmol) of Et3 N keeping the temperature between 0-5 C. by cooling in ice bath. After 10 min the cold bath was removed and reaction was stirred for 30 min at which time a TLC indicated complete reaction. The solution was diluted with CH2 Cl2 and washed with water, brine and dried over Na2 SO4. The filtrate was concentrated to a thick oil and the oil was dissolved in 40 mL of EtOH. Acetic acid (3 mL) and 0.8 g of 10% Pd/C were added to the solution and the resulting mixture was hydrogenated on a Parr apparatus for 3 h. The catalyst was filtered and washed with EtOAc and the combined filtrate was concentrated. The residue was partitioned between CH2 Cl2 and water and 2N NaOH was added to this mixture until the aqueous layer was basic. The layers were separated and the aqueous layer was extracted with CH2 Cl2. The combined organic layer was washed with brine, dried over Na2 SO4 and the filtrate was concentrated to give 2.93 g (77%) of the title compound sufficiently pure for use in the next reaction.

Reference： [1]Patent: US5962462,1999,A
[2]Patent: US6013652,2000,A

22
[ 24391-41-1 ]
[ 167484-18-6 ]
benzyl 1-(5-cyano-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,2-dihydro-1'H-spiro[indole-3,4'-piperidine]-1'-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With potassium dihydrogenphosphate; phosphoric acid; In dimethyl sulfoxide; at 80℃; for 12h;	A solution of <strong>[24391-41-1]4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile</strong> (1.0 g, 5.6 mmol), benzyl 1 ,2-dihydro-1'H-spiro[indole-3,4'-piperidine]-1'-carboxylate (1.80 g, 5.6 mmol), phosphoric acid (0.11g, 1.1 mmol), and potassium dihydrogen phosphate (0.76 g, 5.6 mmol) in 3 mL of dimethyl sulfoxide has heated at 8O0C for 12 h. The mixture was poured into 25% sodium bicarbonate in water (by weight) and extracted 3x with ethyl acetate. The combined organics were dried over sodium sulfate. Chromatography on silica gel, eluting with 62-65% ethyl acetate / hexanes afforded 1.94 g (74%) of benzyl 1-(5-cyano-7H-pyrrolo[2,3-d]pyrimidin- 4-yl)-1 ,2-dihydrc-1Eta-spiro[indole-3,4'-piperidine]-r-carboxylate; TR 7.54 min (HPLC Conditions H).

Reference： [1]Patent: WO2006/90261,2006,A1 .Location in patent: Page/Page column 63
[2]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 3359 - 3363

23
[ 1618-36-6 ]
[ 167484-18-6 ]
benzyl 1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,2-dihydro-1'H-spiro[indole-3,4'-piperidine]-1'-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51%	In ethyl acetate; at 100℃; for 48h;	A suspension of 4-Chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (0.05 g, 0.30 mmol) and benzyl 1 ,2-dihydro-1'H-spiro[indole-3,4'-piperidine]-1'-carboxylate (0.0961 g, 0.3 mmol) in ethyl acetate was heated to 1000C, boiling off the ethyl acetate. The mixture was heated at 1000C for 48 h. The cooled reaction was taken up in ethyl acetate and saturated sodium bicarbonate. The layers were separated and the aqueous layer was extracted three times with ethyl acetate, and the combined organics were washed with brine, dried over sodium sulfate and evaporated. The crude material was absorbed on silica gel and chromatographed with 1:1 ethyl acetate/ hexanes to afford 0.693 g (51%) of benzyl 1-(5-methyl-7H-pyrrolo[2,3- dlpyrimidin^-yO-i ^-dihydro-i'H-spirotindole-S^'-piperidinel-i'-carboxylate; TR 7.80 min (HPLC conditions H).

Reference： [1]Patent: WO2006/90261,2006,A1 .Location in patent: Page/Page column 61
[2]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 3359 - 3363

24
[ 167484-18-6 ]
[ 55052-28-3 ]
[ 908287-33-2 ]

Yield	Reaction Conditions	Operation in experiment
52%	With trifluoroacetic acid; In N,N-dimethyl-formamide; at 65℃; for 48h;	Benzyl 1 ,2-dihydro-1Eta-spiro[indole-3,4'-piperidine]-1'-carboxylate (2 g, 6.2 mmol) is mixed with 4-chloro-1H-pyrrolo[2,3-b]pyridine (prepared as described in WO 2003000690), DMF (1 mL) and TFA (0.478 mL). The suspension is heated to 650C for 2 days. The reaction is then cooled to room temperature and partitioned between EtOAc and a solution of saturated sodium bicarbonate in water. The EtOAc layer is removed and the water layer is extracted twice more. The combined organics are dried over sodium sulfate, filtered, and the solvent is removed in vacuo. The resulting solid is then purified by column chromatography (99% EtOAc + 1 % Et3N) to provide 1.41g (52% yield) of benzyl 1-(1 H-pyrrolo[2,3-b]pyridin-4-yl)- 1 ,2-dihydro-1Eta-spiro[indole-3,4'-piperidine]-1'-carboxylate as an orange solid. 1H NMR (500 EPO <DP n="75"/>MHz, DMSOd6) delta 11.56 (1H, br. s), 8.05 (1H1 d, J = 6.0 Hz), 7.38-7.40 (4H, m), 7.31-7.35 (2H, m), 7.27 (1 H, br. d, J = 7.0 Hz), 7.12 (1H1 td, J = 8.0, 1.0 Hz), 7.05 (1H, d, J = 8.0 Hz), 6.92 (1H1 d, J = 6.0 Hz), 6.85 (1H, t, J = 7.8 Hz)1 6.43-6.44 (1H, m), 5.11 (2H, br. s), 4.18 (2H, s), 3.98- 4.06 (2H, m), 2.98-3.19 (2H, m), 1.81 (2H, dt, J = 12.9, 4.7 Hz), 1.67-1.75 (2H, m); LRMS (M+): 439.2; HPLC retention time: 1.99 min. (HPLC method I).

Reference： [1]Patent: WO2006/90261,2006,A1 .Location in patent: Page/Page column 73-74

25
[ 3680-69-1 ]
[ 167484-18-6 ]
[ 908283-37-4 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 100℃; for 25.67h;	4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (0.4 M, 300 ul, 120 umol) and benzyl 1,2-dihydro- I'H-spirotindole-S^'-piperidinel-r-carboxylate (0.4 M, 300 ul, 120 umol) in DMSO were mixed together. DIEA (neat, 75 ul, 431 umol) was added. The contents were concentrated to dryness in a Genevac and the reaction vial was capped and heated at 1000C for 25 h, 40 min to form benzyl 1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1 ,2-dihydro-1Eta-spiro[indole-3,4'-piperidine]-1'- carboxylate. THF (0.5 ml) was added to the mixture, followed by lithium aluminum hydride (1 M in THF, 0.24 ml, 240 umol). The resulting solution was shaken at room temperature for 2 h, 20 min. Water (2 ml) and dichloroethane (2 ml) were added to the reaction mixture and the layers EPO <DP n="71"/>were separated. The aqueous layer was re-extracted with dichloroethane (2 ml). The combined organic layers were concentrated to dryness to afford 27.5 mg of a crude product. The material was dissolved in DMSO (1 ml) and purified by HPLC to afford 9.4 mg of the title compound as a TFA salt (18% overall yield after two steps). APCI LCMS: Observed mass: 320.13 (M+1). Retention time: 1.9 min (Method E).

Reference： [1]Patent: WO2006/90261,2006,A1 .Location in patent: Page/Page column 69
[2]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 3359 - 3363

26
[ 871335-85-2 ]
[ 167484-18-6 ]
benzyl 1-(3-methyl-1H-pyrazolo[2,3-d]pyrimidin-4-yl)-1,2-dihydro-1'H-spiro[indole-3,4'-piperidine]-1'-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53%	In ethyl acetate; at 100℃; for 4h;	A mixture of 4-chloro-3-methyl-1 H-pyrazolo[3,4-d]pyrimidine (1.30 g, 7.7 mmol) and benzyl 1 ,2-dihydro-1'H-spiro[indole-3,4'-piperidine]-1'-carboxylate (2.48 g, 7.7 mmol) in ethyl acetate was heated to 100 0C, boiling off the ethyl acetate. The mixture was heated at 1000C for 4 h and then cooled to rt. The mixture was taken up in 4:1 dichloromethane/ methanol and 2M ammonia in methanol was added until neutral. The mixture was evaporated to dryness and chromatographed on silica gel, eluting with 60-90 % ethyl acetate/ hexanes to afford 1.86 g (53%) of benzyl 1-(3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-1 ,2-dihydro-1'H-spiro[indole-3,4'- piperidine]-1'-carboxylate; TR 7.35 min (HPLC conditions H).

Reference： [1]Patent: WO2006/90261,2006,A1 .Location in patent: Page/Page column 79

27
5-benzyl-4-chloro-7H-pyrrolo[2,3-d]pyrimidine [ No CAS ]
[ 167484-18-6 ]
benzyl 1-(5-benzyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,2-dihydro-1'H-spiro[indole-3,4'-piperidine]-1'-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	In ethyl acetate; at 100℃; for 24h;	A suspension of 5-benzyl-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.0683 g, 0.28 mmol) and benzyl i^-dihydro-i'H-spirotindole-S^'-piperidineJ-i'-carboxylate (0.0904 g, 0.28 mmol) in ethyl acetate was heated to 10O0C, boiling off the ethyl acetate. The mixture was heated at 1000C for 24 h. The mixture was taken up in 4:1 dichloromethane/ methanol and 2M ammonia in methanol was added until neutral. The mixture was evaporated to dryness and chromatographed on silica gel, eluting with 2-2.3 % methanol/ methylene chloride to afford 0.075 g (50%) of benzyl 1-(5-benzyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1 ,2-dihydro-1'H- spiro[indole-3,4'-piperidine]-1'-carboxylate; TR 8.62 min (HPLC conditions H).

Reference： [1]Patent: WO2006/90261,2006,A1 .Location in patent: Page/Page column 65
[2]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 3359 - 3363

28
[ 541-41-3 ]
[ 167484-18-6 ]
[ 937255-10-2 ]

Yield	Reaction Conditions	Operation in experiment
31%	With triethylamine; In dichloromethane; at 20℃; for 18h;	Preparation 1251 '-benzyl 1-ethyl 1'H-spiro?ndole-3.4'-piperidinel-1 ,1'(2H)-dicarboxylateBenzyl 1 ,2-dihydro-1eta-spiro[indole-3,4'-piperidine]-r-carboxylate [described in J. Xie et al., Tetrahedron, 2004, 60, 4875-4878] (251 mg, 0.78 mmol), ethyl chloroformate (93 mg, 0.86 mmol) and triethylamine (0.15 ml, 0.97 mmol) were stirred in dichloromethane (5 ml) at room temperature for 18 hours. The organic phase was washed with saturated aqueous sodium hydrogen carbonate (5 ml), dried (MgSO4), and loaded onto a silica gel column. Gradient elution with cydohexane:Et2O (90:10 - 50:50) yielded the title compound as a colourless gum (95 mg, 0.24 mmol, 31 %). MS m/z (APCI) 395 [MH]+

Reference： [1]Patent: WO2007/57775,2007,A1 .Location in patent: Page/Page column 183

29
[ 79-22-1 ]
[ 167484-18-6 ]
[ 937255-09-9 ]

Yield	Reaction Conditions	Operation in experiment
29%	With triethylamine; In dichloromethane; at 20℃; for 18h;	Preparation 1241'-benzyl 1-methyl 1'H-spiro?ndole-3,4'-piperidine1-1 ,1'(2H)-dicarboxylateBenzyl i ^-dihydro-i'H-spiroIindole-S^'-piperidineJ-i'-carboxylate [described in J. Xie et al., Tetrahedron, 2004, 60, 4875-4878] (251 mg, 0.78 mmol), methyl chloroformate (81 mg, 0.86 mmol) and triethylamine (0.15 ml, 0.97 mmol) were stirred in dichloromethane (5 ml) at room <n="184"/>temperature for 18 hours. The organic phase was washed with saturated aqueous sodium hydrogen carbonate (5 ml), dried (MgSO4), and loaded onto a silica gel column. Gradient elution with cyclohexane:Et2O (90:10 - 50:50) yielded the title compound as a colourless gum (85 mg, 0.22 mmol, 29%).MS m/z (APCI) 381 [MH]+

Reference： [1]Patent: WO2007/57775,2007,A1 .Location in patent: Page/Page column 182-183

30
[ 108-23-6 ]
[ 167484-18-6 ]
[ 937255-11-3 ]

Yield	Reaction Conditions	Operation in experiment
20%	With triethylamine; In dichloromethane; at 20℃; for 18h;	Preparation 126 1 '-Benzyl 1-isopropyl 1 'H-spirorindole-3,4'-piperidinel-1.1 '(2H)-dicarboxylate <n="185"/>Benzyl i^-dihydro-i'H-spiropndole-S^'-piperidineJ-i'-carboxylate [described in J. Xie et al., Tetrahedron, 2004, 60, 4875-4878] (251 mg, 0.78 mmol), isopropyl chloroformate (95 mg, 0.86 mmol) and triethylamine (0.15 ml, 0.97 mmol) were stirred in dichloromethane (5 ml) at room temperature for 18 hours. The organic phase was washed with saturated aqueous sodium hydrogen carbonate (5 ml), dried (MgSO4), and loaded onto a silica gel column. Gradient elution with cyclohexane/Et2O (90:10 - 50:50) yielded the title compound as a colourless gum (65 mg, 0.16 mmol, 20%). MS m/z (APCI) 409 [MH]+.

Reference： [1]Patent: WO2007/57775,2007,A1 .Location in patent: Page/Page column 183-184

31
[ 167484-18-6 ]
[ 171-75-5 ]

Yield	Reaction Conditions	Operation in experiment
78%	With palladium on activated charcoal; ammonium formate; In methanol; for 2h;Reflux;	Benzyl spiro[indoline-3,4?-piperidine] -1 ?-carboxylate (Compound of step 1 of Example 116, 0.7 g, 2.171 mmol) and ammonium formate (0.685 g, 10.86 mmol) were added to a suspension of Pd/C (0.231 g, 2.171 mmol) in MeOH (20 mL) at RT. The reaction mixture was refluxed for 2 h. After completion of reaction, the reaction mixture was filtered over celite bed. The filtrate was concentrated and the residue was purified by flash column chromatography (0-3 % MeOH chloroform with 0.5% aqueous ammonia as eluent, silica gel column) to obtain the title compound (0.32 g). Yield: 78%; H NMR (CDC13, 300 MHz):1.71-1.88 (m, 4H), 1.76 (t, J = 12.0 Hz, 2H), 3.09 (d, 12.0 Hz, 2H), 3.50 (s, 2H), 6.66 (d, J =7.2 Hz, 1H), 6.77 (t, J= 7.5 Hz, 1H), 7.05 (a, J= 7.5 Hz, 1H), 7.11 (a, J= 7.2 Hz, 1H); MS(mlz): [M+H]+ 189.1.
68%	With hydrogen;palladium 10% on activated carbon; In methanol; at 20℃;	A solution of <strong>[167484-18-6]phenylmethyl 1,2-dihydro-1'H-spiro[indole-3,4'-piperidine]-1'-carboxylate</strong> (12.72 g, 39.4 mmol) in 200 mL of MeOH in a 500-mL flask was purged with N2 for 15 min, after which time 10% Pd/C (5 g, approx 50% water) was added. The reaction flask was then purged with H2 and fitted with a balloon charged with H2. The reaction was allowed to stir at room temperature overnight. The mixture was then filtered through celite and the filtrate was concentrated. The celite/Pd/C mixture was stirred in 500 mL of MeOH for 30 min to extract remaining product that may have precipitated out of the reaction. The mixture was filtered through additional celite and the filtrate combined with the previous filtrate and concentrated. 5.05 g (26.7 mmol, 68% yield) of the desired product 1,2-dihydrospiro[indole-3,4'-piperidine] was obtained. MS (ES) m/e 189 [M+H]+.

Reference： [1]Patent: WO2015/28960,2015,A1 .Location in patent: Page/Page column 152; 153
[2]Patent: US2008/318990,2008,A1 .Location in patent: Page/Page column 22

32
[ 115093-90-8 ]
[ 167484-18-6 ]
[ 908283-43-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 3359 - 3363

33
[ 594-44-5 ]
[ 167484-18-6 ]
[ 1185762-10-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2009,vol. 17,p. 5015 - 5026

34
[ 167484-18-6 ]
[ 74-88-4 ]
[ 1093956-87-6 ]

Yield	Reaction Conditions	Operation in experiment
40%		A 0 C. solution of <strong>[167484-18-6]phenylmethyl 1,2-dihydro-1'H-spiro[indole-3,4'-piperidine]-1'-carboxylate</strong> (100 mg, 0.3 mmol) in DMF (3 mL) was treated with NaH (95%, 10 mg, 0.4 mmol) and stirred at room temperature for 30 min. The solution was cooled to 0 C. and treated with CH3I (0.019 mL, 0.31 mmol) and stirred at room temperature overnight. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic layers were combined, concentrated and purified by FCC (0-25% EtOAc/hexanes) to afford the product (40 mg, 40%), MS (ES) m/e 337 [M+H]+.

Reference： [1]Patent: US2008/318990,2008,A1 .Location in patent: Page/Page column 28-29

35
[ 167484-18-6 ]
[ 208932-96-1 ]

Reference： [1]Patent: US2011/92531,2011,A1
[2]Patent: WO2011/66183,2011,A1
[3]Patent: WO2015/28960,2015,A1

36
[ 167484-18-6 ]
[ 1292291-54-3 ]

Reference： [1]Patent: US2011/92531,2011,A1

37
[ 167484-18-6 ]
[ 1292290-66-4 ]

Reference： [1]Patent: US2011/92531,2011,A1

38
[ 108-86-1 ]
[ 167484-18-6 ]
[ 1292290-90-4 ]

Yield	Reaction Conditions	Operation in experiment
86.48%	With caesium carbonate;palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 0 - 100℃;Inert atmosphere;	Preparation 14Benzyl 1-phenylspiro[indoline-3,4'-piperidine]-1'-carboxylate To a solution of <strong>[167484-18-6]benzyl spiro[indoline-3,4'-piperidine]-1'-carboxylate</strong> (1.5 g, 4.65 mmol) in 1-4, dioxane (5 mL) is added bromobenzene (0.803 g, 5.115 mmol), 4,5-(diphenyl-phosphino)-9,9-dimethyl xanthene (0.807 g, 1.395 mmol) and cesium carbonate (4.54 g, 13.95 mmol) at 0 C. The reaction mixture is purged with nitrogen gas for 15 minutes and palladium acetate (0.062 g, 0.279 mmol) is added. The mixture is stirred at 100 C. for 5 hours, filtered, diluted with ammonium chloride solution, extracted with EtOAc, dried with sodium sulphate, and concentrated under reduced pressure. The crude material is purified by silica gel chromatography, eluting with hexane:ethyl acetate (9.0:1.0) to give the title compound (1.6 g, 86.48%). ESI/MS m/z 399.4 (M+H)+.

Reference： [1]Patent: US2011/92531,2011,A1 .Location in patent: Page/Page column 9

39
[ 50-00-0 ]
[ 167484-18-6 ]
[ 1093956-87-6 ]

Yield	Reaction Conditions	Operation in experiment
98.3%		Preparation 2; Benzyl 1 -methylspiro[indoline-3,4'-piperidine]- 1 '-carboxylate To a 0 C solution of benzyl l,2-dihydro- H-spiro[indole-3,4'-piperidine]- - carboxylate (315 g, 977.5 mmol), formaldehyde (40 % aqueous solution, 138 mL, 4.9 mol) and acetic acid (279 mL, 4.9 mol) in methanol (6.0 L), is added sodiumcyanoborohydride (184 g, 2.9 mol) in portions over a period of 2 h (some effervescence is observed). The reaction mixture is allowed warm to room temperature and stirred for 6 h. The pH of the mixture is adjusted to about 8 with 10% NaHC(¾ solution and extracted with EtOAc (3 x 5.0 L). The combined extracts are washed with water (2 x 2.5 L) and brine (2.5 L), dried over sodium sulfate, and evaporated to dryness to give the title compound as a pale yellow solid (310 g, 98.3%). ESI/MS m/z 337 (M+H)+.
92%	With sodium cyanoborohydride; acetic acid; In methanol; at 0 - 25℃;	Sodium cyanoborohydride (6.23 mmol) was added to the reaction mixture of benzyl spiro[indoline-3,4?-piperidine]-l?-carboxylate (compound of step 1, 2.078 mmol), acetic acid (10.39 mmol) and formaldehyde (8.31 mmol) in MeOH (20 mL) at 0 C. The reaction mixture was stirred overnight at RT. After the completion of reaction, the reaction mixture was poured into ice-cold water (100 mL) and basified by 10% sodium bicarbonate to obtain the crude product, which was filtered and washed with water to obtain the title compound. Yield: 92%; 1H NMR (CDC13, 300 MHz): 1.60 (s, 2H), 1.75 (bs, 2H), 2.78 (s, 3H), 3.03 (bs, 2H), 3.26 (s, 2H), 4.15 (bs, 2H), 5.18 (s, 2H), 6.53 (d, J= 7.5 Hz, 1H), 6.73 (t, J= 7.2 Hz, 1H), 7.03 (d, J = 7.2 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H), 7.28-7.41 (m, 5H); MS: (mlz) 338.3 (M+H).
75%		Preparation 7Benzyl 1-methylspiro[indoline-3,4'-piperidine]-1'-carboxylateTo a 0 C. solution of <strong>[167484-18-6]benzyl spiro[indoline-3,4'-piperidine]-1'-carboxylate</strong> (1.15 g, 3.56 mmol), formaldehyde (37% aqueous solution, 1.44 mL, 17.83 mmol) and acetic acid (1.02 mL, 17.83 mmol) in methanol (25 mL) is added sodium cyanoborohydride (0.67 g, 10.68 mmol). The reaction mixture is allowed to warm to room temperature overnight. The pH of the mixture is adjusted to approximately 8 with 10% NaHCO3 solution and extracted with EtOAc (3×50 mL). The combined extracts are washed with water (50 mL) and brine (50 mL), dried, filtered, and evaporated to dryness. The crude material is purified by silica gel chromatography, eluting with hexane:ethyl acetate (85:15) to give the title compound as an off-white solid (0.9 g, 75%). ESI/MS m/z 337.2 (M+H)+.

Reference： [1]Patent: WO2011/66183,2011,A1 .Location in patent: Page/Page column 11
[2]Patent: WO2015/28960,2015,A1 .Location in patent: Page/Page column 86; 87
[3]Patent: US2011/92531,2011,A1 .Location in patent: Page/Page column 8

40
[ 167484-18-6 ]
[ 1309436-41-6 ]

Reference： [1]Patent: WO2011/66183,2011,A1

41
[ 6457-49-4 ]
[ 167484-18-6 ]

Reference： [1]Chinese Chemical Letters,2012,vol. 23,p. 661 - 664

42
[ 100-63-0 ]
[ 167484-18-6 ]

Reference： [1]Chinese Chemical Letters,2012,vol. 23,p. 661 - 664

43
[ 122860-33-7 ]
[ 167484-18-6 ]

Reference： [1]Chinese Chemical Letters,2012,vol. 23,p. 661 - 664

44
[ 823-85-8 ]
[ 138163-08-3 ]
[ 167484-18-6 ]

Yield	Reaction Conditions	Operation in experiment
		To a mixture of 4-fluorophenylhydrazine hydrochloride (13.36 mmol,1.93 g), trifluoroacetic acid (40.06 mmol, 2.97 mL) in acetonitrile:toluene (49: 1, 25 mL), a solution of benzyl 4-formylpiperidine-l-carboxylate (12.14 mmol, 3 g) in acetonitrile:toluene (49:1, 10 mL) was added drop wise at room temperature. The reaction mixture was stirred at 35 C for 16 hr followed by 5 hr at 50 C. Then the reaction mixture cooled to 0 C, diluted with 3 mL MeOH, added NaBH4 (18.21 mmol, 688 mg) and continued stirring at room temperature for 3 hr. The reaction mixture was then diluted with sat. aq. NaHC03 solution, extracted with ethyl acetate, dried over anhydrous Na2S04, evaporated under reduced pressure and the residue was purified by flash column chromatography. The product eluted at 1 :2 hexane:ethyl acetate solvent mixture.

Reference： [1]Patent: WO2012/177782,2012,A1 .Location in patent: Page/Page column 106-107

45
[ 24424-99-5 ]
[ 167484-18-6 ]
[ 676607-30-0 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of spiroindole (3.32 mmol, 1.07 g) in DMF (5 mL) at 0C, NaH (4.98 mmol, 119 mg) added and stirred for 10 min. Then to the mixture boc- anhydride (4.31 mmol, 942 mg) was added and stirred for 4 hr. The reaction mixture diluted with water (50 mL), extracted with ethylacetate (2 x 50 mL), the ethylacetate layer was washed with brine, dried over Na2S04, evaporated under reduced pressure and the crude was purified by flash column chromatography.
587.3 mg	With dimethylaminopyridine; In chloroform; at 20℃; for 1h;	The 1?-benzyloxycarbonylspiro[indoline-3,4?-piperidine] (487.0 mg) was dissolved in chloroform (15 mL), ditert-butyl dicarbonate (0.416 mL) and dimethylaminopyridine (221.5 mg) were added thereto, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried with anhydrous magnesium sulfate and was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane = 25/75) to obtain the title compound (587.3 mg). 1H-NMR (400MHz,CDCl3) delta: 1.58(br.s,9H),1.77-1.88(m,2H),2.90-3.03(m,2H),3.80-3.93(m,2 H),4.16-4.29(m,2H),5.17(s,2H),6.95-6.99(m,1H),7.06-7.09(m,1 H),7.16-7.22(m,1H),7.30-7.96(m,6H). MS (ESI)m/z:423[M+H]+.

Reference： [1]Patent: WO2012/177782,2012,A1 .Location in patent: Page/Page column 108
[2]Patent: EP3480198,2019,A1 .Location in patent: Paragraph 0237; 0239

46
[ 167484-18-6 ]
[ 676607-31-1 ]

Reference： [1]Patent: WO2012/177782,2012,A1

47
[ 167484-18-6 ]
[ 1416892-49-3 ]

Reference： [1]Patent: WO2012/177782,2012,A1

48
[ 167484-18-6 ]
[ 1416892-51-7 ]

Reference： [1]Patent: WO2012/177782,2012,A1

49
C₂₅H₂₇F₂N₃O₂ [ No CAS ]
[ 167484-18-6 ]