1211534-25-6|4-Bromo-5-chloro-2-methoxypyridine| Ambeed

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Quality Control of [ 1211534-25-6 ] Purity: 98% SDS Specification

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Product Details of [ 1211534-25-6 ]

CAS No. :	1211534-25-6
Formula :	C₆H₅BrClNO
M.W :	222.47
SMILES Code :	COC1=NC=C(Cl)C(Br)=C1
MDL No. :	MFCD16609882
InChI Key :	RSSHUQXUQXYECT-UHFFFAOYSA-N
Pubchem ID :	70700260

Safety of [ 1211534-25-6 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H332-H335
Precautionary Statements:	P261-P280-P305+P351+P338

Computational Chemistry of [ 1211534-25-6 ] Show Less

Physicochemical Properties

Num. heavy atoms	10
Num. arom. heavy atoms	6
Fraction Csp3	0.17
Num. rotatable bonds	1
Num. H-bond acceptors	2.0
Num. H-bond donors	0.0
Molar Refractivity	43.44
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	22.12 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.32
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	2.48
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.51
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.	1.92
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	2.67
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.38

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.16
Solubility	0.154 mg/ml ; 0.000692 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-2.59
Solubility	0.573 mg/ml ; 0.00258 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	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	-3.63
Solubility	0.0524 mg/ml ; 0.000236 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	Yes
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.	-5.9 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)	1.89

Application In Synthesis of [ 1211534-25-6 ]

* 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 [ 1211534-25-6 ]

[ 1211534-25-6 ] Synthesis Path-Downstream 1~36

1
[ 67-56-1 ]
[ 1187449-01-9 ]
[ 1211534-25-6 ]

Yield	Reaction Conditions	Operation in experiment
84%		[00253j 27B. 4-Bromo-5-chloro-2-methoxypyridine: To MeOH (390 mL) at 0 °C was added TMS-C1 (49.0 mL, 386 mmol). The reaction mixture was warmed to rt and stirred for 30 mm. To this solution was added 27A (20.0 g, 96.0 mmol). The reaction mixturewas stirred for 15 mill and then NaNO2 (2.74 g, 39.8 mmol) was added to the mixture at rt. The reaction mixture was stirred at 50 °C for 3 h. The reaction mixture was concentrated. The residue was diluted with EtOAc and then basified to pH = 11-13 with 1 N aq. NaOH and extracted with EtOAc (3x). The combined organic layers wereconcentrated. Purification by recrystallization from MeOH and water afforded 27B as white needles (18.0 g, 81.0 mmol, 84percent yield). LC-MS Anal. Calc?d for C6H5BrC1NO:220.92, found [M+H] 223.9.
84%		81B. 4-Bromo-5-chloro-2-methoxypyridine To MeOH (390 mL) was added chlorotrimethylsilane (49 mL, 386 mmol) at 0° C., and the solution was warmed to rt and stirred for 30 min. To the resulting solution was added 4-bromo-5-chloropyridin-2-amine (20 g, 96 mmol), and the mixture was stirred for 15 min. To the reaction mixture was added sodium nitrite (2.7 g, 40 mmol) and the solution was stirred at 50° C. for 3 h. The reaction mixture was evaporated in vacuo, and the residue was diluted with EtOAc. The pH of the aqueous layer was adjusted to pH=?12 via addition of 1 N NaOH, and the solution was extracted 3* with EtOAc. The combined organic layers were concentrated, and the residue was purified via recrystallization from MeOH and H2O to give 4-bromo-5-chloro-2-methoxypyridine as white crystalline needles (18 g, 81 mmol, 84percent yield). LC-MS Anal. Calc'd for C6H5BrClNO 222.92. found [M+H] 223.9. 1H NMR (400 MHz, CDCl3) delta 8.18 (s, 1H), 7.08 (s, 1H), 3.94 (s, 4H).

References: [1]Patent: WO2014/78609,2014,A1 .Location in patent: Paragraph 00253.
[2]Patent: US9133163,2015,B2 .Location in patent: Page/Page column 90.

2
[ 1211534-25-6 ]
(3,4-cis)-1-(5-chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-ol [ No CAS ]

References: [1]Patent: WO2014/78609,2014,A1 .

3
[ 1211534-25-6 ]
[ 1610033-94-7 ]

References: [1]Patent: WO2014/78609,2014,A1 .

4
[ 1211534-25-6 ]
[ 1610034-00-8 ]

References: [1]Patent: WO2014/78609,2014,A1 .
[2]Patent: US9133163,2015,B2 .

5
[ 1211534-25-6 ]
2-((2R)-1-(4-(((3,4-trans)-1-(5-chloro-2-methoxypyridin-4-yl)-3-fluoropiperidin-4-yl)oxy)phenyl)-4-(trifluoromethyl)pyrrolidin-2-yl)acetonitrile [ No CAS ]

References: [1]Patent: WO2014/78609,2014,A1 .

6
[ 1211534-25-6 ]
(3,4-cis)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-1-(5-chloro-2-methoxypyridin-4-yl)piperidin-4-ol [ No CAS ]

References: [1]Patent: WO2014/78609,2014,A1 .

7
[ 1211534-25-6 ]
methyl 2-((2R,4R)-1-(4-(((3,4-trans)-3-(((tertbutyldiphenylsilyl)oxy)methyl)-1-(5-chloro-2-methoxypyridin-4-yl)piperidin-4-1-(5-chloro-2-methoxypyridin-4-yl)piperidin-4-yl)oxy)phenyl)-4-methoxypyrrolidin-2-yl)acetate [ No CAS ]

References: [1]Patent: WO2014/78609,2014,A1 .

8
[ 1211534-25-6 ]
[ 1610035-71-6 ]

References: [1]Patent: WO2014/78609,2014,A1 .

9
[ 1211534-25-6 ]
(3,4-cis)-4-((tert-butyldimethylsilyl)oxy)-3-methylpiperidine [ No CAS ]
4-((3,4-cis)-4-((tert-butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-5-chloro-2-methoxypyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With potassium carbonate; In dimethyl sulfoxide; at 110℃;	[00257j 27F. 4-((3 ,4-cis)-4-((tert-Butyldimethylsilyl)oxy)-3 -methylpiperidin- l-yl)-5 - chloro-2-methoxypyridine: A mixture of 27B (9.70 g, 43.6 mmol), 27E (10.0 g, 43.6mmol), and K2C03 (12.0 g, 87.0 mmol) in DMSO (14.5 mL) was vigorously stirred at110 °C overnight. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water and brine, dried (MgSO4), and concentrated. Purification via silica chromatography gave 27F as an oil (14.3 g, 77percent yield). LC-MS Anal. Calc?d for C18H31C1N2O2Si: 370.18, found [M+H] 371.2.

References: [1]Patent: WO2014/78609,2014,A1 .Location in patent: Paragraph 00257.

10
[ 1211534-25-6 ]
[ 1610033-98-1 ]
[ 1610033-99-2 ]

Yield	Reaction Conditions	Operation in experiment
58%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; lithium hexamethyldisilazane; In tetrahydrofuran; at 70℃; for 2h;Inert atmosphere;	[00266j 28F. 4-(4-(Qert-Butyldimethylsilyl)oxy)-3 -fluoropiperidin- 1 -yl)-5 -chloro-2- methoxypyridine: A mixture of 28E (194 mg, 0.830 mmol), 27B (185 mg, 0.830 mmol) and SPhos precatalyst (6.0 mg, 8.3 jimol) in THF (1.7 mL) was purged with argon and a 1 M solution of LHMDS in THF (1.0 mL, 1.0 mmol) was added. The reaction mixturewas heated to 70 °C for 2 h and then cooled to rt. Sat. aq. NaHCO3 (10 mL) was added slowly to the reaction mixture. The mixture was then extracted with EtOAc (2 x 10 mL) and the combined organic extracts were washed with water (20 mL) and brine (20 mL), dried (Na2504), filtered, and concentrated. Purification by silica chromatography gave 28F (182 mg, 0.490 mmol, 58percent yield). LC-MS Anal. Calc?d for C17H28C1FN2O2Si:374.16,found[M+H] 374.9.
58%	With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; lithium hexamethyldisilazane; In tetrahydrofuran; at 70℃; for 2h;Inert atmosphere;	A mixture of 4-((tert-butyldimethylsilyl)oxy)-3-fluoropiperidine (194 mg, 0.83 mmol), <strong>[1211534-25-6]4-bromo-5-chloro-2-methoxypyridine</strong> (185 mg, 0.83 mmol) and Sphos pre.cat. (6 mg, 8 mumol) in THF (1.7 mL) was purged with argon and lithium bis(trimethylsilyl)amide (1 mL, 1.0 mmol) was added. The reaction mixture was heated at 70° C. for 2 h. Sat. aqueous NaHCO3 (10 mL) was added slowly to the reaction mixture. The mixture was extracted with EtOAc (2*10 mL), and the combined organic extracts were washed with water (20 mL) and brine (20 mL), and dried (Na2SO4), filtered, and concentrated. Purification via silica gel chromatography gave 4-(4-((tert-butyldimethylsflyl)oxy)-3-fluoropiperidin-1-yl)-5-chloro-2-methoxypyridine (182 mg, 0.49 mmol, 58percent yield). LC-MS Anal. Calc'd for C17H28ClFN2O2Si 374.16. found [M+H] 374.9.

References: [1]Patent: WO2014/78609,2014,A1 .Location in patent: Paragraph 00266.
[2]Patent: US9133163,2015,B2 .Location in patent: Page/Page column 78.

11
[ 1211534-25-6 ]
2-((2S,4R)-4-methoxy-1-(4-(((3,4-trans)-3-methylpiperidin-4-yl)oxy)phenyl)pyrrolidin-2-yl)acetonitrile hydrochloride [ No CAS ]
2-((2S,4R)-1-(4-(((3,4-trans)-1-(5-chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-methoxypyrrolidin-2-yl)acetonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In dimethyl sulfoxide; at 110℃;	[003811 84D. 2-((2S,4R)- 1 -(4-(((3 ,4-trans)- 1 -(5 -Chloro-2-methoxypyridin-4-yl)-3 - methylpiperidin-4-yl)oxy)phenyl)-4-methoxypyrrolidin-2-yl)acetonitrile, Isomer 1 andIsomer 2: To a solution of 84C (100 mg, 0.273 mmol) in DMSO (91 jiL), K2C03 (189 mg, 1.37 mmol) was added followed by 27B (60.8 mg, 0.273 mmol). The reaction mixture was heated to 110 °C overnight. The reaction mixture was diluted with EtOAc and washed with water and brine, dried (Na2SO4), and concentrated. The crude productwas purified by RP-Prep. HPLC followed by chiral SFC to recover 84D, Isomer 1 and Isomer 2 as single isomers. 84D, Isomer 1 (22 mg, 0.047 mmol, 17percent yield) was isolated as a pale yellow oil. LC-MS Anal. Calc?d for C25H31C1N403: 470.99, found [M+H]471.0. 1H NMR (400 MHz, CDC13) oe 7.96 (s, 1H), 6.89 - 6.91 (m, 2H), 6.50 - 6.54 (m,2H), 6.26 (s, 1H), 4.05 - 4.13 (m, 2H), 3.88 (s, 3H), 3.80 (td, J=8.66, 4.08 Hz, 1H), 3.58 -3.65 (m, 2H), 3.51 (d, J10.60 Hz, 1H), 3.36 - 3.41 (m, 4H), 2.88 - 2.96 (m, 1H), 2.68 -2.79 (m, 3H), 2.31 - 2.37 (m, 1H), 2.15 - 2.25 (m, 1H), 2.01 - 2.15 (m, 2H), 1.69 - 1.80 (m, 1H), 1.12 (d, J=6.71 Hz, 3H). 84D, Isomer 2 (24 mg, 0.05 1 mmol, 19percent yield) pale yellow oil. LC-MS Anal. Calc?d for C25H31C1N403: 470.99, found [M+H] 471.0. 1H NMR (400 MHz, CDC13) oe 7.96 (s, 1H), 6.89 - 6.91 (m, 2H), 6.50 - 6.54 (m, 2H), 6.26 (s,1H),4.06 - 4.13 (m, 2H), 3.87 (s, 3H), 3.80 (td, J=8.64, 4.17 Hz, 1H), 3.58 - 3.65 (m, 2H),3.48 - 3.53 (m, 1H), 3.35 - 3.41 (m, 4H), 2.89 - 2.96 (m, 1H), 2.68 - 2.79 (m, 3H), 2.31 -2.37 (m, 1H), 2.02 - 2.25 (m, 3H), 1.70 - 1.80 (m, 1H), 1.12 (d, J=6.71 Hz, 3H).

References: [1]Patent: WO2014/78609,2014,A1 .Location in patent: Paragraph 00381.

12
[ 1211534-25-6 ]
(3,4-cis)-3-(hydroxymethyl)piperidin-4-ol trifluoroacetate [ No CAS ]
(3,4-cis)-1-(5-chloro-2-methoxypyridin-4-yl)-3-(hydroxymethyl)piperidin-4-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%	With potassium carbonate; In dimethyl sulfoxide; at 110℃; for 16h;	[00401j 93E. (3,4-cis)-1-(5-Chloro-2-methoxypyridin-4-yl)-3- (hydroxymethyl)piperidin-4-ol: To a solution of 93D (1.55 g, 4.32 mmol) and K2C03(2.69 g, 19.4 mmol) in DMSO (14.4 mL) was added 27B (1.01 g, 4.54 mmol). The reaction mixture was stirred at 110 °C for 16 h. The reaction mixture was diluted with EtOAc and the organic layer was washed with water and brine, dried over Na2SO4, and concentrated. The crude product was purified by silica chromatography to provide 93E (0.680 g, 2.49 mmol, 58percent yield) as a colorless oil. LC-MS Anal. Calc?d forC12H17C1N203: 272.1, found: [M+H] 273.1. 1H NMR (400 MHz, CDC13) oe 7.95 (s,1H), 6.30 (s, 1H), 4.28 - 4.20 (m, 1H), 3.93 (d, J=4.8 Hz, 2H), 3.87 (s, 3H), 3.23 - 3.14 (m, 4H), 2.97 (d, J=6.6 Hz, 1H), 2.71 (br. s, 1H), 2.13 - 2.06 (m, 1H), 1.98 - 1.88 (m, 2H).

References: [1]Patent: WO2014/78609,2014,A1 .Location in patent: Paragraph 00401.

13
[ 1211534-25-6 ]
[ 1610035-83-0 ]
[ 1610035-80-7 ]

References: [1]Patent: WO2014/78609,2014,A1 .

14
[ 1211534-25-6 ]
[ 1610035-83-0 ]
[ 1610035-84-1 ]

Yield	Reaction Conditions	Operation in experiment
37%	With potassium carbonate; In dimethyl sulfoxide; at 90℃;	[00425j 1 02D. Methyl 2-((2R,4R)- 1 -(4-(( 1 -(5 -chloro-2-methoxypyridin-4-yl)piperidin- 4-yl)methyl)phenyl)-4-methoxypyrrolidin-2-yl)acetate: A solution of 102C (48 mg, 0.14 mmol), 27B (37 mg, 0.17 mmol), and K2C03 (57.4 mg, 0.416 mmol) in DMSO (1.5 mL) was heated to 90 °C overnight. The reaction was quenched with sat. aq. NaHCO3 andextracted with EtOAc (2x). The combined organic extracts were washed with brine, dried (Na2SO4), and concentrated. The crude product was purified by silica chromatography to provide 102D (25 mg, 0.051 mmol, 37percent yield) as yellow oil. LC-MS Anal. Calc?d for C26H34C1N304: 487.1, found [M+H] 488.2.

References: [1]Patent: WO2014/78609,2014,A1 .Location in patent: Paragraph 00425.

15
[ 5382-16-1 ]
[ 1211534-25-6 ]
[ 1610036-07-1 ]

Yield	Reaction Conditions	Operation in experiment
88%	With potassium carbonate; In dimethyl sulfoxide; at 110℃; for 14h;	[00443j 1 12A. 1-(5-Chloro-2-methoxypyridin-4-yl)piperidin-4-ol: To a round bottom flask was added 27B (2.8 g, 13 mmol), piperidin-4-ol (1.40 g, 13.8 mmol), K2C03 (8.70g, 62.9 mmol) and DMSO (30 mL). The reaction mixture was stirred at 110 °C for 14 h. The reaction mixture was partitioned between water (150 mL) and EtOAc (150 mL). The organic layer was separated, washed with water (2 x 100 mL) and brine (100 mL), dried over Mg504, filtered, and concentrated. The residue was purified by silica chromatography to give 1 12A (2.7 g, 11 mmol, 88percent yield) as a colorless oil. LC-MSAnal. Calc?d for C11H15C1N202: 242.70, found [M+H] 243.1, 245.0. ?HNMR(400 MHz, CDC13) oe 7.97 (s, 1H), 6.27 (s, 1H), 3.94 - 3.84 (m, 4H), 3.51 - 3.37 (m, 2H), 2.90 (ddd,J=12.3, 9.2, 3.0 Hz, 2H), 2.07- 1.95 (m, 2H), 1.84- 1.66 (m, 2H).
88%	With potassium carbonate; In dimethyl sulfoxide; at 110℃; for 14h;	solution of 1 J (2.80 g, 12.6 mmol), piperidin-4-ol (1.40 g, 13.8 mmol), and K2C03 (8.70 g, 62.9 mmol) in DMSO (30 mL) was stirred at 110 °C for 14 h. The reaction mixture was partitioned between water (150 mL) and EtOAc (150 mL). The organic layer was separated, washed with water (2 x 100 mL) and brine (100 mL), dried over MgS04, filtered, and concentrated. The residue was purified by silica chromatography to give 4A (2.70 g, 11.1 mmol, 88percent yield) as a colorless oil. LC-MS Anal. Calc'd for CnHi5CiN202: 242.70 found [M+H] 243.0. 1H NMR (400 MHz, CDC13) delta 7.97 (s, IH), 6.27 (s, IH), 3.94 - 3.84 (m, 4H), 3.51 - 3.37 (m, 2H), 2.90 (ddd, J=12.3, 9.2, 3.0 Hz, 2H), 2.07 - 1.95 (m, 2H), 1.84 - 1.66 (m, 2H).

References: [1]Patent: WO2014/78609,2014,A1 .Location in patent: Paragraph 00443.
[2]Patent: WO2015/171722,2015,A1 .Location in patent: Page/Page column 85.
[3]Journal of Medicinal Chemistry,2018,vol. 61,p. 681 - 694.

16
[ 84249-14-9 ]
[ 1211534-25-6 ]

References: [1]Patent: WO2014/78609,2014,A1 .
[2]Patent: US9133163,2015,B2 .

17
[ 1211534-25-6 ]
rac-1-(5-chloro-2-methoxypyridin-4-yl)-3-cis-methylpiperidin-4-ol [ No CAS ]

References: [1]Patent: US9133163,2015,B2 .
[2]Patent: WO2015/171722,2015,A1 .

18
[ 1211534-25-6 ]
methyl 2-((4S,5S)-1-(4-((1-(5-chloro-2-methoxypyridin-4-yl)-3-trans-methylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetate [ No CAS ]