790667-49-1|(S)-tert-Butyl 2-methyl-4-oxopiperidine-1-carboxylate| Ambeed

Structure of 790667-49-1

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Quality Control of [ 790667-49-1 ] Purity: 98% SDS Specification

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Product Details of [ 790667-49-1 ]

CAS No. :	790667-49-1
Formula :	C₁₁H₁₉NO₃
M.W :	213.27
SMILES Code :	O=C(N1[C@@H](C)CC(CC1)=O)OC(C)(C)C
MDL No. :	MFCD09832895
InChI Key :	HQMYWQCBINPHBB-QMMMGPOBSA-N
Pubchem ID :	11401606

Safety of [ 790667-49-1 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 790667-49-1 ] Show Less

Physicochemical Properties

Num. heavy atoms	15
Num. arom. heavy atoms	0
Fraction Csp3	0.82
Num. rotatable bonds	3
Num. H-bond acceptors	3.0
Num. H-bond donors	0.0
Molar Refractivity	61.6
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	46.61 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.54
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	1.0
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.59
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	1.05
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	1.23
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.48

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.59
Solubility	5.43 mg/ml ; 0.0255 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.57
Solubility	5.77 mg/ml ; 0.0271 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-1.56
Solubility	5.91 mg/ml ; 0.0277 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.89 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	2.56

Application In Synthesis of [ 790667-49-1 ]

* 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 [ 790667-49-1 ]

[ 790667-49-1 ] Synthesis Path-Downstream 1~41

1
[ 71322-99-1 ]
[ 24424-99-5 ]
[ 790667-43-5 ]
[ 790667-49-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; In diethyl ether; water; at 20℃; for 3h;	Step 1 A solution of 0.52 g of 7-Methyl-1,4-dioxa-8-aza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester), prepared according to the method of Beak at al. (J. Org. Chem. 1993,58,1109-1117), in 6 ml acetic acid and 2.5 ml concentrated HCl was stirred overnight at room temperature. The mixture was diluted with ethyl acetate and washed with 1N sodium hydroxide. The organic layer was dried over sodium sulfate and evalorated to give 0.29 g of a yellow oil. This was dissolved in 15 ml ether and treated with 5 ml 1N NaOH and 72 g (2.57 mmol) boc anhydride. The mixture was stirred for 3 hours at room temperature then diluted with ether and washed with 1N NaOH, water, and brine. The organic layer was dried over sodium sulfate and evaporated. The residue was purified by column chromatography over silica gel, eluding with 20% ethyl acetate in hexane to give 0.18 g of 1-tert-butoxycarbonyl-2-methyl-4-oxo-piperidine as a mixture of diastereomers.

References: [1]Patent: US2005/4121,2005,A1 .Location in patent: Page/Page column 12.

2
[ 790667-49-1 ]
[ 850083-26-0 ]
[ 850083-75-9 ]

Yield	Reaction Conditions	Operation in experiment
46%		Preparation 58. (2S, 4S)-4- (3- (2-Chloro-4-fluoro-benzoylamino)-phenylamino)-2-methyl- piperidine-1-carboxylic acid tert-butyl ester; Dissolve N- (3-amino-phenyl)-2-chloro-4-fluoro-benzamide (Preparation 1,200 mg, 0.756 mmol) and (2S)-2-methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (161 mg, 0.756 mmol) in tetrahydrofuran (5 mL). Add acetic acid (52 uL, 0.907 mmol) and sodium triacetoxyborohydride (192 mg, 0.907 mmol) and stir at room temperature for 18 hr. Heat the reaction to 45C for 4 hr. Cool the reaction to room temperature and load onto an SCX column with methanol. Wash the column with methanol, flush with 2M ammonia in methanol, and concentrate in vacuo. Purify by column chromatography (20%-75% ethyl acetate/hexane) to yield 161 mg (46%) of the title compound. Mass spectrum (ion spray): m/z 462.4 (M+1) ; 1H NMR : 8 (CDC13, ppm) 7.76 (m, 2H), 7.20 (m, 1H), 7.15 (m, 1H), 7.10 (m, 1H), 6.70 (d, J = 7.6 Hz, 1H), 6.40 (d, J= 8. 4 Hz, 1H), 4.20 (m, 1H), 3.82 (m, 2H), 3.67 (bs, 1H), 3.20 (m, 1H), 2.00 (m, 2H), 1.65 (m, 2H), 1.47 (s, 9H), 1.27, (m, 4H).

References: [1]Patent: WO2005/35499,2005,A1 .Location in patent: Page/Page column 69-70.

3
[ 24424-99-5 ]
[ 89467-36-7 ]
[ 790667-49-1 ]

Yield	Reaction Conditions	Operation in experiment
55%	With 10 wt% Pd(OH)2 on carbon; hydrogen; In tetrahydrofuran; at 20℃; under 2585.81 Torr; for 16h;	[00239] A mixture of Core-2b_A4b (200 mg, 0.92 mmol), Boc20 (301 mg, 1.38 mmol) and Pd(OH)2/C (50 mg, cat.) in THF (30 ml.) was hydrogenated at 20 C under H2 (50 psi) for 16 h. The reaction was filtered, and the filtrate was concentrated. The residue was purified by column chromatography (PE:EtOAc=4:1) to afford Core-2b_B1 (1 10 mg, yield 55%) as white solid; 1H NMR (400 MHz, CDCI3) d4.64 (brs, 1H), 4.19 - 4.14 (m, 1H), 3.28 - 3.25 (m, 1H), 2.63 - 2.58 (m, 1H), 2.41 - 2.39 (m, 1H), 2.29 - 2.25 (m, 1H), 2.20 - 2.16 (m, 1H), 1.48 (s, 9H), 1.1 1 (d, J = 8Hz, 3H).
15%	With hydrogen;palladium 10% on activated carbon; In tetrahydrofuran; at 50℃; under 2250.23 Torr;	Dissolve 2-Methyl-4-piperidinone hydrochloride (200 g, estimated 1.2855 mole free base content) in water (500 ml). Add the solution to a mixture of methylene dichloride (1 L) and aqueous NAHC03 (180 g in 1.2 L water) at room temperature. Add a solution of di-tert-butyl dicarbonate (280 g, 1.28 mole) in methylene dichloride (500 ML) and stir the reaction mixture overnight at 20C. Separate the water layer and extract twice with methylene dichloride (500ml). Combine the organic layers, wash with water (500 ML), dry over MGS04 (60 g), filter and concentrate under vacuum (276.5 g as red oil). Dissolve the oil in cyclohexane (1 L) and plug-filter through silicagel (300 g). Elute the silicagel with cyclohexane (2L) and 50/50 CYCLOHEXANE/ETHYL acetate (1L). Concentrate the filtrates under vacuum to obtain the title compound as a yellow residue (261 g, 95). Alternatively, N-TERT-BUTYLOXYCARBONYL-2-S-METHYL-4-PIPERIDINONE is prepared in a one-pot synthesis from N- (S)-L-PHENYIETHYI-2-S-METHYI-4-PIPERIDINONE as follows: Dissolve N- (S)-L-PHENYLETHYL-2-S-METHYL-4-PIPERIDINONE (200 g, 0.9208 mole) in THF (200 ml), Add a solution OF DI-TERI-BUTYL DICARBONATE (214. 7g, 0.9838 mole) in THF (200 ML). Place the reaction mixture under a nitrogen flow and add PD/C (10% content, dry catalyst, 10 g). Pressurize the reactor three times with N2, followed by three times with H2. Heat the reaction mixture to 50C and hydrogenate overnight with STIRRING (3 bar H2, ~43. 5 PSI,-300KPA, 300 rpm). Determine the end of the reaction by TLC analysis (silica plate, CYCLOHEXANE/ETHYLACETATE 50/50, complete disappearance of the starting product). Cool the reaction mixture to room temperature and purge the reator by pressurizing three times with N2. Filter off the catalyst using a celite pad and wash with THF (200 ML). Remove the solvent by evaporation (40C, vacuum) to obtain the crude product as a yellow oil (183.5 gram, 93%). Dissolve the crude product in n-hexane (200 ML) and stir overnight at 20C. Filter off the solid, wash with n-hexane (50 ML), and dry under vacuum at 20C to obtain the title compound (78 g, 39%). Concentrate the mother liquors under vacuum to 140 g residual. Cool the solution and stir overnight at 20C. Cool the resulting suspension to 5C and stir for 15 minutes. Filter off the solid, wash with n-hexane (20M1) and dry under vacuum at 20C to obtain additional title compound (30.6 g, 15%).
	With hydrogen; palladium(II) hydroxide; In tetrahydrofuran; at 20℃;Inert atmosphere;	In a 2 neckroundbottomflask (S)-2-methyl-1-((S)-1-phenyl-ethyl)-piperidin-4-one (33) (0.8 g, 3.68 mmol) was dissolved in 18 ml of THF. Boc2O (964 mg, 4.42 mmol) was added under argon. Pd(OH)2 (130 mg, 0.184 mmol) was added and the reaction mixture was hydrogenated overnight at rt. The mixture was filtered over celite, rinsed with THF and evaporated. The crude product was purified by flash chromatography (silica gel, EtOAc/cyclohexane, 10-20%) which furnished the product as white solid. MS (ESI): 214 [M+H]+, 1H-NMR (CDCl3, 400 MHz) delta (ppm): 4.71 (m, 1H), 4.24 (ddd, 1H), 3.32 (ddd, 1H), 2.68 (dd, 1H), 2.48 (ddd, 1H), 2.35 (m, 1H), 2.26 (m, 1H), 1.50 (s, 9H), 1.19 (d, 3H).

References: [1]Patent: WO2019/244047,2019,A1 .Location in patent: Paragraph 00239.
[2]Patent: WO2004/94380,2004,A1 .Location in patent: Page 28; 31-32.
[3]Patent: US2012/252778,2012,A1 .Location in patent: Paragraph 0340-0341.

4
[ 790667-45-7 ]
[ 24424-99-5 ]
[ 790667-49-1 ]

Yield	Reaction Conditions	Operation in experiment
95%	With sodium hydrogencarbonate; In dichloromethane; water; at 20℃;	Dissolve 2-Methyl-4-piperidinone hydrochloride (200 g, estimated 1.2855 mole free base content) in water (500 ml). Add the solution to a mixture of methylene dichloride (1 L) and aqueous NAHC03 (180 g in 1.2 L water) at room temperature. Add a solution of di-tert-butyl dicarbonate (280 g, 1.28 mole) in methylene dichloride (500 ML) and stir the reaction mixture overnight at 20C. Separate the water layer and extract twice with methylene dichloride (500ml). Combine the organic layers, wash with water (500 ML), dry over MGS04 (60 g), filter and concentrate under vacuum (276.5 g as red oil). Dissolve the oil in cyclohexane (1 L) and plug-filter through silicagel (300 g). Elute the silicagel with cyclohexane (2L) and 50/50 CYCLOHEXANE/ETHYL acetate (1L). Concentrate the filtrates under vacuum to obtain the title compound as a yellow residue (261 g, 95). Alternatively, N-TERT-BUTYLOXYCARBONYL-2-S-METHYL-4-PIPERIDINONE is prepared in a one-pot synthesis from N- (S)-L-PHENYIETHYI-2-S-METHYI-4-PIPERIDINONE as follows: Dissolve N- (S)-L-PHENYLETHYL-2-S-METHYL-4-PIPERIDINONE (200 g, 0.9208 mole) in THF (200 ml), Add a solution OF DI-TERI-BUTYL DICARBONATE (214. 7g, 0.9838 mole) in THF (200 ML). Place the reaction mixture under a nitrogen flow and add PD/C (10% content, dry catalyst, 10 g). Pressurize the reactor three times with N2, followed by three times with H2. Heat the reaction mixture to 50C and hydrogenate overnight with STIRRING (3 bar H2, ~43. 5 PSI,-300KPA, 300 rpm). Determine the end of the reaction by TLC analysis (silica plate, CYCLOHEXANE/ETHYLACETATE 50/50, complete disappearance of the starting product). Cool the reaction mixture to room temperature and purge the reator by pressurizing three times with N2. Filter off the catalyst using a celite pad and wash with THF (200 ML). Remove the solvent by evaporation (40C, vacuum) to obtain the crude product as a yellow oil (183.5 gram, 93%). Dissolve the crude product in n-hexane (200 ML) and stir overnight at 20C. Filter off the solid, wash with n-hexane (50 ML), and dry under vacuum at 20C to obtain the title compound (78 g, 39%). Concentrate the mother liquors under vacuum to 140 g residual. Cool the solution and stir overnight at 20C. Cool the resulting suspension to 5C and stir for 15 minutes. Filter off the solid, wash with n-hexane (20M1) and dry under vacuum at 20C to obtain additional title compound (30.6 g, 15%).

References: [1]Patent: WO2004/94380,2004,A1 .Location in patent: Page 28; 31-32.

5
[ 190906-92-4 ]
[ 790667-43-5 ]
[ 790667-49-1 ]

Yield	Reaction Conditions	Operation in experiment
33%; 35%	Resolution of racemate;	Resolve racemic 2-methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (15.0 g) using a CHIRALPAK ADTM (4.6 x 250nm) column, eluting with absolute ethanol at a flow rate of 1.0 ML/MINUTE (UV=220nm) to obtain isomer 1 (5.28 g, 35%) and isomer 2 (5.01 g, 33%). 1H NMR (CDCl3) : 4.7 (m, 1H), 4.2 (m, 1H), 3.3 (m, 1H), 2.7 (m, 1H), 2.5 (m, 1H), 2.3 (m, 1H), 2.2 (m, 1H), 1.5 (s, 9H), 1.2 (d, 3H); identical for both isomers.

References: [1]Patent: WO2004/94380,2004,A1 .Location in patent: Page 26-27.

6
[ 790667-49-1 ]
[ 790667-91-3 ]
[ 790667-99-1 ]

Yield	Reaction Conditions	Operation in experiment
30%; 52%	With sodium tetrahydroborate; In ethanol; for 2h;	Combine 2-METHYL-4-OXO-PIPERIDINE-1-CARBOXYLIC acid tert-butyl ester isomer l (10.0 g, 46.89 mmol), absolute ethanol (200 mL), and sodium borohydride (2.66 g, 70.33 mmol) with stirring. After 2 hr. , concentrate the reaction mixture and then partition the residue between water (100 mL) and 1 : 1 hexane: ethyl acetate (100 mL). Separate the aqueous layer and wash with 1: 1 hexane: ethyl acetate (4X100 mL), combine the organic layers, wash with aqueous NACI solution, dry over sodium sulfate, filter and concentrate. Purify the residue by silica gel flash chromatography eluting with 7: 3 hexane : ethyl acetate to obtain the resolved trans isomer 1 (3.03 g, 30%) and cis isomer 1 (5.2 g, 52%). Trans isomer 1 :'H NMR (CDCl3) : 4.5 (m, 1H), 4.05 (m, 1H), 3.95 (M, 1H), 2.9 (M, 1H), 1.9 (m, 1H), 1.8 (m, 1H), 1.5 (m, 1H), 1.45 (s, 9H), 1.4 (m, 1H), 1.35 (m, 1H), 1.1 (d, 3H). cis isomer 1 :] H NMR (CDC13) : 4.25 (m, 1H), 4.15 (M, 1H), 3.8 (m, 1H), 3.25 (m, 1H), 1.8 (M, 1H), 1.65 (m, 3H), 1. 4 (s, 9H), 1.3 (d, 3H).
41%; 49%	With methanol; sodium tetrahydroborate; In tetrahydrofuran; at 0℃; for 1h;	General procedure: A flask was charged with t-butyl (3aR,6aS)-5-oxohexahydrocyclopenta[c]pyrrole-2(lH)- carboxylate (1.00 g, 4.44 mmol, 1.00 equiv) and MeOH (15 mL). Sodium borohydride (0.507 g, 13.4 mmol, 3.00 equiv) was added at 0 C. The resulting solution was stirred for 2 h at room temperature and quenched with water (20 mL). The resulting solution was extracted with DCM (3 x 30 mL) and the organic layers were combined, washed with brine (1 x 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide 0.950 g (94% yield) of t-butyl tra5-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(lH)-carboxylate as a yellow oil. LCMS (ESI, m/z): 228 [M+H]+.

References: [1]Patent: WO2004/94380,2004,A1 .Location in patent: Page 27.
[2]Patent: WO2018/217805,2018,A1 .Location in patent: Paragraph 00335; 00393; 00400.

7
[ 790667-49-1 ]
[ 1730-25-2 ]
(S)-4-allyl-4-hydroxy-2-methylpiperidine-1-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In diethyl ether; at 0℃; for 2h;	In a argon flushed dry 25 ml 2-neckoundbottomflask (S)-2-methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (34) (0.6 g, 2.81 mmol) was dissolved in 10 ml of ether. A 1M solution of allylmagnesiumbromide in Et2O (3.66 ml, 3.66 mmol) was added dropwise at 0 C. The reaction mixture was stirred at 0 C. for 2 h. The mixture was quenched with NH4Cl solution and extracted with ether. The organic layer was washed with brine, dried over Na2 SO4 and evaporated. The crude product was purified by flash chromatography (silica gel, 20-30% EtOAc/cyclohexane) which furnished the product as white solid MS (ESI): 256 [M+H]+, 1H-NMR (DMSO-d6, 400 MHz) delta (ppm): 5.85 (m, 1H), 5.05 (d, 1H), 5.0 (d, 1H), 4.18 (m, 1H), 3.7 (dd, 1H), 3.1 (dd, 1H), 2.1 (d, 2H), 1.35 (s, 9H), 1.3-1.5 (m, 5H), 1.2 (d, 3H).

References: [1]Patent: US2012/252778,2012,A1 .Location in patent: Paragraph 0342-0343.

8
[ 10575-36-7 ]
[ 790667-49-1 ]

References: [1]Patent: US2012/252778,2012,A1 .

9
[ 921599-74-8 ]
[ 24424-99-5 ]
[ 790667-49-1 ]

Yield	Reaction Conditions	Operation in experiment
100%	With palladium on activated charcoal; hydrogen; In tetrahydrofuran; ethanol; under 775.743 Torr; for 18h;	Step 1. Synthesis of tert-butyl (2S)-2-methyl-4-oxopiperidine-1-carboxylate (C19) A mixture of benzyl (2S)-2-methyl-4-oxopiperidine-1-carboxylate (6.00 g, 24.3 mmol), palladium on carbon (1.03 g), ethanol (50 mL) and tetrahydrofuran (50 mL) was treated with di-tert-butyl dicarbonate (5.82 g, 26.7 mmol) and subjected to Parr hydrogenation at 15 psi for 18 hours. The reaction was filtered through Celite and the filter cake was washed with ethanol (3*150 mL). The combined filtrates were concentrated in vacuo, yielding an oily residue that crystallized when placed under high vacuum. The product was obtained as a solid. Yield: 5.52 g, 25.9 mmol, quantitative. APCI m/z 114.0 [(M-tert-BOC)+1]. 1H NMR (400 MHz, CDCl3) delta 4.67-4.75 (m, 1H), 4.20-4.27 (m, 1H), 3.32 (ddd, J=13.9, 11.2, 4.0 Hz, 1H), 2.68 (dd, J=14.5, 6.7 Hz, 1H), 2.48 (br ddd, J=15.3, 11.3, 6.9 Hz, 1H), 2.31-2.38 (m, 1H), 2.25 (ddd, J=14.5, 2.7, 1.8 Hz, 1H), 1.49 (s, 9H), 1.18 (d, J=6.8 Hz, 3H).

References: [1]Patent: US2013/150376,2013,A1 .Location in patent: Paragraph 0270.
[2]Journal of Organic Chemistry,2017,vol. 82,p. 12246 - 12256.

10
[ 790667-49-1 ]
[ 1338821-12-7 ]

References: [1]Patent: US2013/150376,2013,A1 .
[2]Journal of Organic Chemistry,2017,vol. 82,p. 12246 - 12256.

11
[ 790667-49-1 ]
[ 1338821-13-8 ]

References: [1]Patent: US2013/150376,2013,A1 .
[2]Journal of Organic Chemistry,2017,vol. 82,p. 12246 - 12256.
[3]Journal of Organic Chemistry,2017,vol. 82,p. 12246 - 12256.

12
[ 790667-49-1 ]
[ 1338821-14-9 ]

References: [1]Patent: US2013/150376,2013,A1 .
[2]Journal of Organic Chemistry,2017,vol. 82,p. 12246 - 12256.
[3]Journal of Organic Chemistry,2017,vol. 82,p. 12246 - 12256.

13
[ 790667-49-1 ]
[ 1338821-15-0 ]

References: [1]Patent: US2013/150376,2013,A1 .
[2]Journal of Organic Chemistry,2017,vol. 82,p. 12246 - 12256.
[3]Journal of Organic Chemistry,2017,vol. 82,p. 12246 - 12256.

14
[ 790667-49-1 ]
[ 1338821-16-1 ]

References: [1]Patent: US2013/150376,2013,A1 .
[2]Journal of Organic Chemistry,2017,vol. 82,p. 12246 - 12256.
[3]Journal of Organic Chemistry,2017,vol. 82,p. 12246 - 12256.

15
[ 790667-49-1 ]
[ 1338821-47-8 ]

References: [1]Patent: US2013/150376,2013,A1 .

16
[ 790667-49-1 ]
[ 1338821-49-0 ]

References: [1]Patent: US2013/150376,2013,A1 .

17
[ 790667-49-1 ]
[ 1338819-94-5 ]

References: [1]Patent: US2013/150376,2013,A1 .

18
[ 790667-49-1 ]
[ 1338821-11-6 ]

References: [1]Patent: US2013/150376,2013,A1 .
[2]Journal of Organic Chemistry,2017,vol. 82,p. 12246 - 12256.

19
[ 790667-49-1 ]
[ 5927-18-4 ]
[ 1338821-09-2 ]

Yield	Reaction Conditions	Operation in experiment
		Step 2. Synthesis of tert-butyl (2S,4E)- and tert-butyl (2S,4Z)-4-(2-methoxy-2-oxoethylidene)-2-methylpiperidine-1-carboxylate (C20) Sodium hydride (60% in mineral oil, 1.35 g, 33.6 mmol) was washed with hexanes (25 mL), suspended in N,N-dimethylformamide (40 mL) and cooled to 0 C. Methyl (dimethoxyphosphoryl)acetate (4.66 mL, 32.3 mmol) was added to the reaction in a drop-wise manner, and the mixture was held at 0 C. with vigorous stirring for 20 minutes. A solution of <strong>[790667-49-1]ter<strong>[790667-49-1]t-butyl (2S)-2-methyl-4-oxopiperidine-1-carboxylate</strong></strong> (C19) (5.52 g from the previous experiment, ?24.3 mmol) in N,N-dimethylformamide (10 mL) was added drop-wise, and the resulting solution was allowed to warm to room temperature over 16 hours. The reaction was then diluted with diethyl ether (400 mL) and washed with water (300 mL). The aqueous layer was extracted with diethyl ether (200 mL) and the combined organic layers were washed with water (4200 mL) and saturated aqueous sodium chloride solution (200 mL), then dried over magnesium sulfate, filtered and concentrated under reduced pressure. The product was obtained as a colorless oil, composed of a roughly 1:1 mixture of olefin isomers. Yield: 6.63 g, 24.6 mmol, quantitative. 1H NMR (400 MHz, CDCl3) delta 5.83 and 5.72 (2 br s, 1H), 4.44-4.61 (m, 1H), 3.98-4.14 (m, 1H), 3.71 and 3.70 (2 s, 3H), 3.58-3.70 (m, 1H), 2.93-3.03 (m, 1H), 2.06-2.11, 2.18-2.33 and 2.53-2.59 (multiplets, total 3H), 1.47 (2 s, 9H), 1.08 (d, J=6.7 Hz) and 1.07 (d, J=6.9 Hz, total 3H).

References: [1]Journal of Organic Chemistry,2017,vol. 82,p. 12246 - 12256.
[2]Patent: US2013/150376,2013,A1 .Location in patent: Paragraph 0271.

20
[ 37595-74-7 ]
[ 790667-49-1 ]
(S)-tert-butyl 2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate [ No CAS ]
(S)-tert-butyl 6-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A solution of (S)-tert-butyl-2-methyl-4-oxopiperdine-l-carboxylate (5 g, 23.44 mmol) in tetrahydrofuran (100 mL) was cooled to -78C and lithium bis(trimethylsilyl)amide (1M in hexanes, 28.1 mL, 28.1 mmol) was added dropwise. The mixture was stirred at -78C for 30 minutes and a solution of l,l,l-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl) methanesulfonamide (10.89 g, 30.5 mmol) in tetrahydrofuran (25 mL) was added dropwise. The mixture was allowed to warm to room temperature and after 24 hours, the reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate. The extracts were dried over sodium sulfate, filtered, and concentrated. Purification by flash chromatography on silica gel eluting with 0-40% ethyl acetate-hexanes gave an oil as a mixture of enol isomers. This material also contained 25% by weight 1 , 1 , 1 -trifluoro-N- phenylmethanesulfonamide. The mixture was carried on in the next step without any further purification. MS (ESI) m/e 246.0 (M-BOC)+.

References: [1]Patent: WO2014/139328,2014,A1 .Location in patent: Page/Page column 478; 479.

21
[ 37595-74-7 ]
[ 790667-49-1 ]
4-(5-fluoro-2-methoxyphenyl)-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine [ No CAS ]
(S)-tert-butyl 4-(4-(5-fluoro-2-methoxyphenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-methyl-5,6-dihydropyridine-1(2H)-carboxylate [ No CAS ]
(S)-tert-butyl 4-(4-(5-fluoro-2-methoxyphenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-6-methyl-5,6-dihydropyridine-1(2H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 258D (S)-fert-butyl 4-(4-(5-fluoro-2-methoxyphenyl)-l-tosyl-lH-pyrrolo[2,3-b]pyridin-2-yl)-2-methyl-5,6- dihydropyridine- 1 (2H)-carboxylate and (S)-fert-butyl 4-(4-(5-fluoro-2-methoxyphenyl)-l-tosyl-lH- pyrrolo[2,3-b]pyridin-2-yl)-6-methyl-5,6-dihydropyridine-l(2H)-carboxylate (4: 1) A mixture of Example 258A (1.75 g, 6.89 mmol), bis(diphenylphosphino)ferrocene] dichloropalladium(II)-dichloromethane adduct (0.235 g, 0.287 mmol), 4,4,4',4',5,5,5',5'-octamethyl- 2,2'-bi(l,3,2-dioxaborolane) (1.75 g, 28.7 mmol), and potassium acetate (2.82 g, 28.7 mmol) in dioxane (40 mL) was degassed and heated at reflux for 90 minutes. After cooling to room temperature, Example 258C (3 g, 5.74 mmol), additional bis(diphenylphosphino) ferrocene]dichloropalladium(II)-dichloromethane adduct (0.235 g, 0.287 mmol) and a solution of sodium carbonate (3.35 g, 31.6 mmol) in water (0.5 mL) was added and the mixture was heated to 65C for 24 hours. The mixture was partitioned between water and ethyl acetate and the organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by flash chromatography on silica gel eluting with 0-30% ethyl acetate in heptanes over 50 minutes provided the title compound as a mixture of regioisomers which was used in the next step without any further purification. MS (ESI) m/e 592.1 (M+l)+. A mixture of Example 258A (1.75 g, 6.89 mmol), bis(diphenylphosphino)ferrocene] dichloropalladium(II)-dichloromethane adduct (0.235 g, 0.287 mmol), 4,4,4',4',5,5,5',5'-octamethyl- 2,2'-bi(l,3,2-dioxaborolane) (1.75 g, 28.7 mmol), and potassium acetate (2.82 g, 28.7 mmol) in dioxane (40 mL) was degassed and heated at reflux for 90 minutes. After cooling to room temperature, Example 258C (3 g, 5.74 mmol), additional bis(diphenylphosphino) ferrocene]dichloropalladium(II)-dichloromethane adduct (0.235 g, 0.287 mmol) and a solution of sodium carbonate (3.35 g, 31.6 mmol) in water (0.5 mL) was added and the mixture was heated to 65C for 24 hours. The mixture was partitioned between water and ethyl acetate and the organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by flash chromatography on silica gel eluting with 0-30% ethyl acetate in heptanes over 50 minutes provided the title compound as a mixture of regioisomers which was used in the next step without any further purification. MS (ESI) m/e 592.1 (M+l)+.

References: [1]Patent: WO2014/139328,2014,A1 .Location in patent: Page/Page column 480.

22
[ 37595-74-7 ]
[ 790667-49-1 ]
4-(5-fluoro-2-methoxyphenyl)-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine [ No CAS ]
(S)-tert-butyl 4-(4-(5-fluoro-2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-methyl-5,6-dihydropyridine-1(2H)-carboxylate [ No CAS ]
(S)-tert-butyl 4-(4-(5-fluoro-2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-6-methyl-5,6-dihydropyridine-1(2H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 258D (S)-fert-butyl 4-(4-(5-fluoro-2-methoxyphenyl)-l-tosyl-lH-pyrrolo[2,3-b]pyridin-2-yl)-2-methyl-5,6- dihydropyridine- 1 (2H)-carboxylate and (S)-fert-butyl 4-(4-(5-fluoro-2-methoxyphenyl)-l-tosyl-lH- pyrrolo[2,3-b]pyridin-2-yl)-6-methyl-5,6-dihydropyridine-l(2H)-carboxylate (4: 1) A mixture of Example 258A (1.75 g, 6.89 mmol), bis(diphenylphosphino)ferrocene] dichloropalladium(II)-dichloromethane adduct (0.235 g, 0.287 mmol), 4,4,4',4',5,5,5',5'-octamethyl- 2,2'-bi(l,3,2-dioxaborolane) (1.75 g, 28.7 mmol), and potassium acetate (2.82 g, 28.7 mmol) in dioxane (40 mL) was degassed and heated at reflux for 90 minutes. After cooling to room temperature, Example 258C (3 g, 5.74 mmol), additional bis(diphenylphosphino) ferrocene]dichloropalladium(II)-dichloromethane adduct (0.235 g, 0.287 mmol) and a solution of sodium carbonate (3.35 g, 31.6 mmol) in water (0.5 mL) was added and the mixture was heated to 65C for 24 hours. The mixture was partitioned between water and ethyl acetate and the organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by flash chromatography on silica gel eluting with 0-30% ethyl acetate in heptanes over 50 minutes provided the title compound as a mixture of regioisomers which was used in the next step without any further purification. MS (ESI) m/e 592.1 (M+l)+. A mixture of Example 258A (1.75 g, 6.89 mmol), bis(diphenylphosphino)ferrocene] dichloropalladium(II)-dichloromethane adduct (0.235 g, 0.287 mmol), 4,4,4',4',5,5,5',5'-octamethyl- 2,2'-bi(l,3,2-dioxaborolane) (1.75 g, 28.7 mmol), and potassium acetate (2.82 g, 28.7 mmol) in dioxane (40 mL) was degassed and heated at reflux for 90 minutes. After cooling to room temperature, Example 258C (3 g, 5.74 mmol), additional bis(diphenylphosphino) ferrocene]dichloropalladium(II)-dichloromethane adduct (0.235 g, 0.287 mmol) and a solution of sodium carbonate (3.35 g, 31.6 mmol) in water (0.5 mL) was added and the mixture was heated to 65C for 24 hours. The mixture was partitioned between water and ethyl acetate and the organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by flash chromatography on silica gel eluting with 0-30% ethyl acetate in heptanes over 50 minutes provided the title compound as a mixture of regioisomers which was used in the next step without any further purification. MS (ESI) m/e 592.1 (M+l)+. To a solution of Example 258D (3.06 g, 5.17 mmol) in dioxane (29.6 mL) was added a solution of sodium hydroxide (0.724 g, 18.1 mmol) in water (3.62 mL) and the mixture was heated at 90C for 24 hours. The mixture was cooled to room temperature, diluted with saturated sodium bicarbonate and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered, and concentrated. Purification by flash chromatography on silica gel eluting with 0-50% methanol in dichloromethane provided the title compound as a mixture of regioisomers which was used in the next step without any further purification. MS (ESI) m/e 438.1 (M+l)+.

References: [1]Patent: WO2014/139328,2014,A1 .Location in patent: Page/Page column 480.

23
[ 37595-74-7 ]
[ 790667-49-1 ]
4-(5-fluoro-2-methoxyphenyl)-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine [ No CAS ]
(S)-4-(5-fluoro-2-methoxyphenyl)-2-(6-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 258D (S)-fert-butyl 4-(4-(5-fluoro-2-methoxyphenyl)-l-tosyl-lH-pyrrolo[2,3-b]pyridin-2-yl)-2-methyl-5,6- dihydropyridine- 1 (2H)-carboxylate and (S)-fert-butyl 4-(4-(5-fluoro-2-methoxyphenyl)-l-tosyl-lH- pyrrolo[2,3-b]pyridin-2-yl)-6-methyl-5,6-dihydropyridine-l(2H)-carboxylate (4: 1) A mixture of Example 258A (1.75 g, 6.89 mmol), bis(diphenylphosphino)ferrocene] dichloropalladium(II)-dichloromethane adduct (0.235 g, 0.287 mmol), 4,4,4',4',5,5,5',5'-octamethyl- 2,2'-bi(l,3,2-dioxaborolane) (1.75 g, 28.7 mmol), and potassium acetate (2.82 g, 28.7 mmol) in dioxane (40 mL) was degassed and heated at reflux for 90 minutes. After cooling to room temperature, Example 258C (3 g, 5.74 mmol), additional bis(diphenylphosphino) ferrocene]dichloropalladium(II)-dichloromethane adduct (0.235 g, 0.287 mmol) and a solution of sodium carbonate (3.35 g, 31.6 mmol) in water (0.5 mL) was added and the mixture was heated to 65C for 24 hours. The mixture was partitioned between water and ethyl acetate and the organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by flash chromatography on silica gel eluting with 0-30% ethyl acetate in heptanes over 50 minutes provided the title compound as a mixture of regioisomers which was used in the next step without any further purification. MS (ESI) m/e 592.1 (M+l)+. A mixture of Example 258A (1.75 g, 6.89 mmol), bis(diphenylphosphino)ferrocene] dichloropalladium(II)-dichloromethane adduct (0.235 g, 0.287 mmol), 4,4,4',4',5,5,5',5'-octamethyl- 2,2'-bi(l,3,2-dioxaborolane) (1.75 g, 28.7 mmol), and potassium acetate (2.82 g, 28.7 mmol) in dioxane (40 mL) was degassed and heated at reflux for 90 minutes. After cooling to room temperature, Example 258C (3 g, 5.74 mmol), additional bis(diphenylphosphino) ferrocene]dichloropalladium(II)-dichloromethane adduct (0.235 g, 0.287 mmol) and a solution of sodium carbonate (3.35 g, 31.6 mmol) in water (0.5 mL) was added and the mixture was heated to 65C for 24 hours. The mixture was partitioned between water and ethyl acetate and the organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by flash chromatography on silica gel eluting with 0-30% ethyl acetate in heptanes over 50 minutes provided the title compound as a mixture of regioisomers which was used in the next step without any further purification. MS (ESI) m/e 592.1 (M+l)+. To a solution of Example 258D (3.06 g, 5.17 mmol) in dioxane (29.6 mL) was added a solution of sodium hydroxide (0.724 g, 18.1 mmol) in water (3.62 mL) and the mixture was heated at 90C for 24 hours. The mixture was cooled to room temperature, diluted with saturated sodium bicarbonate and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered, and concentrated. Purification by flash chromatography on silica gel eluting with 0-50% methanol in dichloromethane provided the title compound as a mixture of regioisomers which was used in the next step without any further purification. MS (ESI) m/e 438.1 (M+l)+. To a solution of Example 258E (0.600 g, 1.37 mmol) in 4 mL 1 : 1 methanol: ethyl acetate was added 2M hydrogen chloride in diethyl ether (5 mL) and the mixture was stirred at 40C for 2 hours and concentrated. Purification by reverse phase-HPLC (Sunfire 5muMu, 50 X 250 mm) eluting with 5- 40% acetonitrile in water (containing 0.1% trifluoroacetic acid), provided the title compound as trifluoroacetate salt. To a solution of this salt in methanol was added 2M hydrogen chloride in diethyl ether. Concentration afforded the title compound as the hydrochloride salt. MS (ESI) m/e 338.1 (M+l)+.

References: [1]Patent: WO2014/139328,2014,A1 .Location in patent: Page/Page column 480; 481.

24
[ 790667-49-1 ]
5-cyclopropyl-N-[(2S,4S)-2-methyl-1-(4-methylpiperazine-1-sulfonyl) piperidin-4-yl]-1,2-oxazole-3-carboxamide [ No CAS ]