[ CAS No. 884495-36-7 ] {[proInfo.proName]}

Name: 884495-36-7|6-Chloro-2-methylnicotinaldehyde|97%
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SKU: A115501
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Quality Control of [ 884495-36-7 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 884495-36-7 ]

Product Details of [ 884495-36-7 ]

CAS No. :	884495-36-7	MDL No. :	MFCD07368876
Formula :	C₇H₆ClNO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	BLLSRSWUYXEXNF-UHFFFAOYSA-N
M.W :	155.58	Pubchem ID :	44754867
Synonyms :

Calculated chemistry of [ 884495-36-7 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	1
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	39.6
TPSA :	29.96 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.06 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.53
Log Po/w (XLOGP3) :	1.68
Log Po/w (WLOGP) :	1.86
Log Po/w (MLOGP) :	0.73
Log Po/w (SILICOS-IT) :	2.58
Consensus Log Po/w :	1.67

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-2.24
Solubility :	0.893 mg/ml ; 0.00574 mol/l
Class :	Soluble
Log S (Ali) :	-1.92
Solubility :	1.85 mg/ml ; 0.0119 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.96
Solubility :	0.17 mg/ml ; 0.00109 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.49

Safety of [ 884495-36-7 ]

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

Application In Synthesis of [ 884495-36-7 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 884495-36-7 ]
Downstream synthetic route of [ 884495-36-7 ]

[ 884495-36-7 ] Synthesis Path-Upstream 1~2

1
[ 132606-40-7 ]
[ 68-12-2 ]
[ 884495-36-7 ]

Yield	Reaction Conditions	Operation in experiment
71%	Stage #1: With n-butyllithium In diethyl ether at -78 - -70℃; for 0.5 h; Stage #2: at -78 - 20℃; for 1.5 h;	To a 3 L 3-neck flask was added Et₂O followed by 2-chloro-6-methyl-5- bromopyridine (56.97 g, 0.28 mol). The mixture was cooled to -78 ⁰C and n-BuLi (132 mL, 0.33 mol) was added dropwise with an addition funnel while maintaining the pot temperature below -70 ⁰C. The mixture was agitated at -78 ⁰C for 30 min, DMF (43 mL, 0.56 mol) was added dropwise at -78 ⁰C then the cooling bath was removed and the reaction was agitated at rt for 1.5 h and quenched with brine (300 mL). The layers were separated and the aqueous layer was extracted with Et₂O (150 mL). The combined organic layers were neutralized with cone. HCl to pH -3-4 followed by saturated aqueous NaHCO₃ (300 mL). The layers were separated and the organic layer was concentrated to dryness. The product was recrystallized from Et₂O/hexane (200 mL, 1 : 1) to afford a light yellow crystalline solid (19 g). The filtrate was concentrated and purified by column chromatography (EtOAc/hexane, 1 :9) to give another crop of product (13 g). Combined yield was 71percent. ¹H NMR (CDCl₃) δ 2.87 (s, 3H), 7.35 (d, IH, J= 9.0 Hz), 8.07 (d, IH, J= 9.0 Hz), 10.31 (s, IH).

Reference： [1] Patent: WO2007/22371, 2007, A2, . Location in patent: Page/Page column 50
[2] Patent: WO2014/28669, 2014, A1, . Location in patent: Paragraph 00328

2
[ 66909-36-2 ]
[ 884495-36-7 ]

Reference： [1] Patent: WO2009/58923, 2009, A1, . Location in patent: Page/Page column 16

[ 884495-36-7 ] Synthesis Path-Downstream 1~24

1
[ 884495-36-7 ]
[ 91361-92-1 ]
[ 926296-40-4 ]

Yield	Reaction Conditions	Operation in experiment
99%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h;	A mixture of <strong>[884495-36-7]6-chloro-2-methyl-pyridine-3-carbaldehyde</strong> (491 mg, 3.16 mmol), methyl 4-mercaptophenylacetate (575 mg, 3.16 mmol), and K2CO3 (436 mg, 3.15 mmol) in DMF (6.3 mL) was stirred at room temperature for 2 h then filtered and concentrated. The residue was dissolved in EtOAc (40 mL) and washed with brine (4 x 10 mL) then dried (MgSO4) and concentrated to give [4-(5-formyl-6-methyl-pyridin-2-ylsulfanyl)-phenyl]-acetic acid methyl ester as a yellow oil (941 mg, 99%). 1H NMR (CDCl3) delta 2.82 (s, 3H), 3.70 (s, 2H), 3.74 (s, 3H), 6.73 (d, IH, J= 8.1 Hz), 7.40 (d, 2H, J= 8.1 Hz), 7.58 (d, 2H, J= 8.1 Hz), 7.81 (d, IH, J= 8.1 Hz), 10.20 (s, IH).

Reference： [1]Patent: WO2007/22371,2007,A2 .Location in patent: Page/Page column 59

2
[ 884495-36-7 ]
[ 637-89-8 ]
C₁₃H₁₁NO₂S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h;	A mixture of 6-chloro-2-methylpyridine-3-carboxaldehyde (3.00 g, 19.3 mmol), A- mercaptophenol (90% pure, 2.7Og, 19.3 mmol) and K2CO3 (1.66 g, 12.0 mmol) in DMF (20 mL) was stirred at room temperature for 16 h. Bromoacetic acid tert-butyl ester (6.00 g, 30.8 mmol) and K2CO3 (3.40 g, 24.6 mmol) were added, and the mixture was stirred for another 4 h. Aqueous work-up and purification by flash chromatography on silica gel (EtOAc/hexanes, 1 :4 in v/v) afforded 4-(5-fo?nyl~6-methyl-rhoyridin-2-ylsulfanyl)-benzoic acid tert-butyl ester as EPO <DP n="61"/>a pale yellow solid (7.40 g, 100%). 1H NMR (CDCl3) delta 1.50 (s, 9H), 2.81 (s, 3H)5 4.57 (s, 2H), 6.66 (d, IH, J= 8.1 Hz), 6.97-7.01 (m, 2H), 7.51-7.55 (m, 2H), 7.79 (d, IH, J= 8.1 Hz), 10.19 (s, IH).

Reference： [1]Patent: WO2007/22371,2007,A2 .Location in patent: Page/Page column 59-60

3
[ 884495-36-7 ]
[ 135996-16-6 ]
[ 926305-03-5 ]

Yield	Reaction Conditions	Operation in experiment
13%	With potassium carbonate; In N,N-dimethyl-formamide; at 125℃; for 1h;	A mixture of 6-chloro-2-methylpyridine-3-carboxaldehyde (1.87 g, 12.0 mmol), (4- hydroxy-phenylsulfanyl)-acetic acid tert-butyl ester (2.48 g, 10.7 mmol) and K2CO3 (0.830 g, EPO <DP n="70"/>6.00 mmol) in DMF (20 mL) was heated at 125 C for 1 h. The mixture was cooled to room temperature and DMF was removed. Aqueous work-up and purification by flash chromatography on basic Al2O3 gel (CH2Cl2/hexanes, 1 :1 in v/v) afforded [4-(5-formyl-6- methyl-pyridin-2-yloxy)-phenylsulfanyl]-acetic acid tert-butyi ester as a pale yellow solid (0.481 g, 13%). 1H NMR (CDCl3) delta 1.42 (s, 9H), 2.72 (s, 3H), 3.56 (s, 2H), 6.78 (d, IH, J= 8.4 Hz), 7.09-7.13 (m, 2H), 7.46-7.50 (m, 2H), 8.11 (d, IH, J= 8.4 Hz), 10.24 (s, IH).

Reference： [1]Patent: WO2007/22371,2007,A2 .Location in patent: Page/Page column 68-69

4
[ 884495-36-7 ]
[ 14395-51-8 ]
[ 926303-58-4 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; for 1h;	To a suspension of 4-bromo-2-methylaniline (5.40 g, 29.0 mmol) in aqueous (6 N, 14 mL) cooled at 0 0C was added a solution OfNaNO2 (2.27 g, 36.2 mmol) in water (5 mL) slowly. After addition the mixture was stirred at 0 0C for 30 min to give a clear solution. The solution was then added very slowly using a pipette to a solution of O-ethylxanthic acid potassium salt (5.81 g, 36.2 mmol) in water (10 mL) preheated at 40 0C [cautions, potential explosion hazard). After addition the mixture was stirred at 45 0C for 20 min, cooled to room temperature and extracted with Et2O (3 x 50 mL). The combined extract was washed with aqueous NaOH (2 N, 40 mL) and water (2 X 30 mL), and dried over anhydrous Na2SO4. After filtration the solvent was removed to give a brown oil. The oil was dissolved in ethanol (30 mL) and heated to 70 0C. KOH (7 g) was then added and the mixture was heated at reflux for 16 h. The mixture was then cooled to room temperature, washed with Et2O (30 fnL) and acidified with 6 N HCl to pH = 3. Extraction with EtOAc (3 x 30 mL) was followed by drying over anhydrous Na2SO4. After filtration the solvent was removed, and the residue was stirred with 6-chloro-2-memylrhoyridine-3-carboxaldehyde (2.00 g, 12.8 mmol) and K2CO3 (2.00 g, EPO <DP n="64"/>14.5 mmol) in DMF (20 niL) for 1 h. The mixture was concentrated and aqueous HCl (1 N3 15 mL) and water (20 mL) were added. Extraction with EtOAc (3 X 30 mL) was performed and the extracts were dried over anhydrous Na2SO4. After filtration the solvent was removed, and the residue was purified by flash chromatography on basic Al2O3 gel (EtOAc/hexanes, 1 :4 in v/v) to afford 6-(4-bromo-2-methyl-phenylsulfanyl)-2-methyl-pyridine-3-carbaldehyde as a yellow oil (2.91 g, 70%).

Reference： [1]Patent: WO2007/22371,2007,A2 .Location in patent: Page/Page column 62-63

5
[ 860298-71-1 ]
[ 884495-36-7 ]
[ 926305-17-1 ]

Yield	Reaction Conditions	Operation in experiment
63%	With potassium carbonate; In N,N-dimethyl-formamide; at 105℃; for 2h;	A mixture of 2-methyl-6-chloropyridine-3-carboxaldehyde (0.850 g, 4.25 mmol), N-cyclopropyl-4-hydroxy-benzarnide (0.765 g, 4.32 mmol) and K2CO3 (0.414 g, 2.55 mmol) in DMF (8 mL) was stirred at 105 C for 2 h. The mixture was cooled to room temperature and DMF was removed. Methanol (20 mL) and water (20 mL) were added and the mixture was stirred for 10 min. Methanol was then removed and the residual mixture was extracted with EPO <DP n="72"/>CH2Cl2 (3 x 40 mL). The combined extracts were dried over anhydrous Na2SO4. After filtration the solvent was removed, and the residue was purified by flash chromatography on silica gel (MeOHZCH2Cl2, 1 :50 v/v) followed by recrystallization from EtOAc/hexanes, affording iV-cyclopropyl-4-(5-formyl-6-methyl-pyridin-2-yloxy)-benzamide as a white solid (0.79 g, 63%). 1H NMR (CDCl3) delta 0.60-0.66 (m, 2H), 0.86-0.92 (m, 2H)3 2.71 (s, 3H), 2.88- 2.95 (m, IH), 6.23 (br s, IH), 6.84 (d, IH, J= 8.7 Hz), 7.18-7.23 (m, 2H), 7.77-7.82 (m, 2H), 8.13 (d, IH, J= 8.7 Hz), 10.24 (s, IH).

Reference： [1]Patent: WO2007/22371,2007,A2 .Location in patent: Page/Page column 70-71

6
[ 66909-36-2 ]
[ 884495-36-7 ]

Yield	Reaction Conditions	Operation in experiment
		Intermediate 10; theta-chloro^-methyl-S-pyridinecarbaldehyde; Dibal-H 10At 0 0C, to a stirred solution of 6-chloro-2-methyl-3-pyridinecarbonitrile ([Singh et al., (1991) Synthesis pp. 894-896) (1.53g, lOmmol) in dichloro??ethane (3OmL) was added dibal-H (12mL, 1Wl in CH2C12). The resulting mixture was stirred for one hour before it was quenched with saturated citric acid solution. Stirring was continued for additional one hour. The reaction mixture was then diluted with dichloromethane (10OmL) and washed with saturated sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate. After evaporation of solvents, the crude product was purified by column chromatography (silical gel, 0 to 30% ethyl acetate in hexane) to afford 950mg (61%) of 6-chloro-2-methyl-3-pyridi?ecarbaldehyde. 1 H NMR (400 MHz, CHLOROFORM-d) delta ppm 10.28 (s, 1 H), 8.04 (d, J=8.07 Hz, 1 H), 7.33 (d, J=8.07 Hz, 1 H), 2.84 (s, 3 H).

Reference： [1]Patent: WO2009/58923,2009,A1 .Location in patent: Page/Page column 16

7
[ 122374-27-0 ]
[ 884495-36-7 ]
[ 1150617-08-5 ]

Yield	Reaction Conditions	Operation in experiment
53%	With caesium carbonate; In N,N-dimethyl-formamide; at 60℃; for 2h;	Preparation of intermediate 11, N-{4-[(5-formyl-6-methyl-2-pyridinyl)thio]phenyl} metha?esulfonamide; To a stirred solution of N-(4-mercaptophenyl)methanesulfonamide intermediate 9 (1.0g,4.9mmol) in N, N-dimethylformamide (3OmL) were added 6-chloro-2-methyl-3- pyridinecarbaldehyde intermediate 10 (0.763g, 4.9mmol) and cesium carbonate (1.6g, 4.9mmol)). The resulting mixture was heated to 600C for two hours. After completion of the reaction, the mixture was diluted with ethyl acetate (10OmL) and washed with sodium bicarbonate solution. The organic phase was then dried over anhydrous sodium sulfate. After evaporation of solvents, the crude product was purified by column chromatography (silica gel, 0 to 50% ethyl acetate in hexane) to give 844 mg (53%) of N-{4-[(5-formyl-6-methyl-2- pyridinyl)thio]phenyl}methanesulfonamide intermediate 11 as solid. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 10.21 (s, 1 H), 7.83 (d, J=8.43 Hz, 1 H), 7.60 (m, 2 H), 7.31 (m, 2 H), 7.02 (s, 1 H), 6.75 (d, J=8.43 Hz, 1 H), 3.12 (s, 3 H), 2.80 (s, 3 H).

Reference： [1]Patent: WO2009/58923,2009,A1 .Location in patent: Page/Page column 18

8
[ 884495-36-7 ]
[ 1150617-11-0 ]
[ 1150617-12-1 ]

Yield	Reaction Conditions	Operation in experiment
43%	With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); DavePhos; In 1,2-dimethoxyethane; at 90℃;	Preparation of N-[2-(ethyloxy)ethyl]-4-[(5-formyl-6-methyl-2-pyridinyl)amino]-3- methylbenzamide, intermediate 25; beta-Chloro^-methyl-S-pyridinecarbaldehyde intermediate 10 (156mg, 1mmol) and 4- amino-N-[2-(ethyloxy)ethyl]-3-methylbenzamide intermediate 24 (266mg, 1.2mmol) were mixed in a sealed tube followed by additions of cesium carbonate (975mg, 3mmol), Pd2(dba)3 (46mg, O.Odeltammol), 2-dicyclohexylphosphino-2'-(N, N'- dimethylaminojbiphenyl (40mg, O.immol) and dimethoxyethane (5mL). The resulting mixture was purged with N2 (3X) before being heated to 90 0C overnight. After cooled down to room temperature, the reaction mixture was diluted with ethyl acetate (10OmL) and washed with saturated sodium bicarbonate solution. The organic phase was then dried over anhydrous sodium sulfate. After evaporation of solvents, the crude product was purified by column chromatography (silical gel, 0 to 80% ethyl acetate in hexane) to afford 145mg (43%) of N-[2-(ethyloxy)ethyl]-4-[(5-formyl-6- methyl-2-pyridinyl)amino]-3-methylbenzamide intermediate 25 as solid. 1H NMR (400 WIHz, CHLOROFORM-d) delta ppm 10.12 (s, 1 H), 7.92 (d, J=8.80 Hz, 1 H), 7.73 (s, 1 H), 7.62 (m, 1 H), 6.83 (s, 1 H), 6.63 (m, 2 H), 6.53 (s, 1 H), 3.60 (m, 6 H), 2.75 (s, 3 H), 2.34 (S, 3 H), 1.23 (m, 3 H). LCMS m/z (M+H)+ calcd: 342, obsd: 342.1.

Reference： [1]Patent: WO2009/58923,2009,A1 .Location in patent: Page/Page column 31

9
[ 132606-40-7 ]
[ 68-12-2 ]
[ 884495-36-7 ]

Yield	Reaction Conditions	Operation in experiment
71%		To a 3 L 3-neck flask was added Et2O followed by 2-chloro-6-methyl-5- bromopyridine (56.97 g, 0.28 mol). The mixture was cooled to -78 0C and n-BuLi (132 mL, 0.33 mol) was added dropwise with an addition funnel while maintaining the pot temperature below -70 0C. The mixture was agitated at -78 0C for 30 min, DMF (43 mL, 0.56 mol) was added dropwise at -78 0C then the cooling bath was removed and the reaction was agitated at rt for 1.5 h and quenched with brine (300 mL). The layers were separated and the aqueous layer was extracted with Et2O (150 mL). The combined organic layers were neutralized with cone. HCl to pH -3-4 followed by saturated aqueous NaHCO3 (300 mL). The layers were separated and the organic layer was concentrated to dryness. The product was recrystallized from Et2O/hexane (200 mL, 1 : 1) to afford a light yellow crystalline solid (19 g). The filtrate was concentrated and purified by column chromatography (EtOAc/hexane, 1 :9) to give another crop of product (13 g). Combined yield was 71%. 1H NMR (CDCl3) delta 2.87 (s, 3H), 7.35 (d, IH, J= 9.0 Hz), 8.07 (d, IH, J= 9.0 Hz), 10.31 (s, IH).
		Step 1: Under nitrogen atmosphere, to a solution of compound 8-1 (1.0 g, 5 mmol) in dry THF (30 mL) was added ri-But.yllithium, 2.5 M solution in THF (3 mL, 7.5 mmol) dropwise under minus 78 degree. The solution was stirred at -78 degree for 10 min, followed by addition of dry DMF (0.73 g, 10 mmol). The mixture was stirred for 30 min at this temperature and then quenched with H20 (30 mL), extracted with EA (30 mL x 2). The combined organic layer was dried over anhydrous Na2S04 and concentrated to give product 8-2 as yellow oil. LC-MS: m/z = 156.1 [M+H]+.

Reference： [1]Patent: WO2007/22371,2007,A2 .Location in patent: Page/Page column 50
[2]Patent: WO2014/28669,2014,A1 .Location in patent: Paragraph 00328

10
[ 884495-36-7 ]
(trans-4-{5-[5-(1H-benzimidazol-2-yl)-6-methyl-pyridin-2-yl]-pyrimidin-2-yloxy}-cyclohexyl)-acetic acid methyl ester [ No CAS ]

Reference： [1]Patent: WO2013/74387,2013,A1

11
[ 884495-36-7 ]
(trans-4-{5-[5-(1H-benzimidazol-2-yl)-6-methyl-pyridin-2-yl]-pyrimidin-2-yloxy}-cyclohexyl)-acetic acid trifluoroacetate [ No CAS ]

Reference： [1]Patent: WO2013/74387,2013,A1

12
[ 884495-36-7 ]
{cis-4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrimidin-2-yloxy]-cyclohexyl}-acetic acid methyl ester [ No CAS ]
{cis-4-[5-(5-formyl-6-methyl-pyridin-2-yl)-pyrimidin-2-yloxy]-cyclohexyl}-acetic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.4 g	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; ethanol; water; at 120℃; for 1.5h;Sealed tube; Microwave irradiation; Inert atmosphere;	6-Cl-2-Methylpyridine-3-carbaldehyde (0.227g, 1.462 mmol, 1.1 equiv.), {4-[5-(4,4,5,5-Tetramethyl-l ,3,2-dioxaborolan-2-yl)-pyrimidin-2-yloxy]-cyclohexyl}-acetic acid methyl ester (0.5 g, 1.329 mmol, 1 equiv.), Tetrakis(PPh3)Pd(0) (0.23 g, 0.199 mmol, 0.15 equiv.), and 2M Na2C03 (aq) (2.66 mL, 5.32 mmol, 4equiv.) were placed in DME (3.56 mL) / EtOH (1.75 mL) and stirred at room temperature in a sealed microwave reaction vial. The reaction was placed under vacuum for 5 min (until no continuing gas evolution was detected) and then N2(g) was bubbled into the reaction suspension for 25 min. The reaction suspension was heated at 120C under microwave conditions for 1 hr30 min. The reaction was concentrated to a residue which was then dissolved in EtOAc / brine. The EtOAc phase was dried over Na2S04, filtered, and concentrated to an oil,0.189 g. Purification with Biotage SP-1 [ hexanes:EtOAc 0>12% 2CV; 12>100% 10CV; 100% 5CV ] isolated 0.4 g. LC-MS (ES, m/z): C20H23N3O4: 369; Found: 370 [M+H]+.

Reference： [1]Patent: WO2013/74387,2013,A1 .Location in patent: Page/Page column 110; 111

13
[ 884495-36-7 ]
{cis-4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrimidin-2-yloxy]-cyclohexyl}-acetic acid methyl ester [ No CAS ]
(cis-4-{5-[5-(5-fluoro-1H-benzimidazol-2-yl)-6-methyl-pyridin-2-yl]-pyrimidin-2-yloxy}-cyclohexyl)-acetic acid methyl ester [ No CAS ]

Reference： [1]Patent: WO2013/74387,2013,A1

14
[ 884495-36-7 ]
{trans-4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrimidin-2-yloxy]-cyclohexyl}-acetic acid methyl ester [ No CAS ]
{trans-4-[5-(5-formyl-6-methyl-pyridin-2-yl)-pyrimidin-2-yloxy]-cyclohexyl}-acetic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.4 g	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; ethanol; water; at 120℃; for 1.5h;Sealed tube; Microwave irradiation; Inert atmosphere;	6-Cl-2-Methylpyridine-3-carbaldehyde (0.227g, 1.462 mmol, 1.1 equiv.), {4-[5- (4,4,5,5-Tetramethyl-l ,3,2-dioxaborolan-2-yl)-pyrimidin-2-yloxy]-cyclohexyl}-acetic acid methyl ester (0.5 g, 1.329 mmol, 1 equiv.), Tetrakis(PPh3)Pd(0) (0.23 g, 0.199 mmol, 0.15 equiv.), and 2M Na2C03 (aq) (2.66 mL, 5.32 mmol, 4equiv.) were placed in DME (3.56 mL) / EtOH (1.75 mL) and stirred at room temperature in a sealed microwave reaction vial. The reaction was placed under vacuum for 5 min (until no continuing gas evolution was detected) and then N2(g) was bubbled into the reaction suspension for 25 min. The reaction suspension was heated at 120C under microwave conditions for 1 hr30 min. The reaction was concentrated to a residue which was then dissolved in EtOAc / brine. The EtOAc phase was dried over Na2S04, filtered, and concentrated to an oil.Purification with Biotage SP-1 [ FLASH 25 cartridge. Hexanes:EtOAc 0> 12% 2CV; 12> 100% 10CV; 100% 5CV ] isolated 0.4 g. LC-MS (ES, m/z): CzoEbNsC : 369; Found: 370 [M+H]+.

Reference： [1]Patent: WO2013/74387,2013,A1 .Location in patent: Page/Page column 109

15
[ 884495-36-7 ]
[ 1093879-95-8 ]