[ CAS No. 81606-47-5 ] {[proInfo.proName]}

Name: 81606-47-5|2-(3-Bromophenyl)-2-methylpropanoic acid|96%
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SKU: A181664
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Quality Control of [ 81606-47-5 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 81606-47-5 ]

Product Details of [ 81606-47-5 ]

CAS No. :	81606-47-5	MDL No. :	MFCD11036929
Formula :	C₁₀H₁₁BrO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	PZQVCFYGWRPVLE-UHFFFAOYSA-N
M.W :	243.10	Pubchem ID :	12805128
Synonyms :

Calculated chemistry of [ 81606-47-5 ]

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.3
Num. rotatable bonds :	2
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	55.18
TPSA :	37.3 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.65 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.89
Log Po/w (XLOGP3) :	3.01
Log Po/w (WLOGP) :	2.81
Log Po/w (MLOGP) :	2.99
Log Po/w (SILICOS-IT) :	2.59
Consensus Log Po/w :	2.66

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-3.45
Solubility :	0.0857 mg/ml ; 0.000352 mol/l
Class :	Soluble
Log S (Ali) :	-3.46
Solubility :	0.0847 mg/ml ; 0.000348 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.45
Solubility :	0.0859 mg/ml ; 0.000353 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.74

Safety of [ 81606-47-5 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 81606-47-5 ]

* 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 [ 81606-47-5 ]
Downstream synthetic route of [ 81606-47-5 ]

[ 81606-47-5 ] Synthesis Path-Upstream 1~6

1
[ 53086-52-5 ]
[ 74-88-4 ]
[ 81606-47-5 ]

Yield	Reaction Conditions	Operation in experiment
91%	Stage #1: With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene at 0℃; for 1.25 h; Stage #2: for 15.1667 h; Stage #3: With hydrogenchloride; water In tetrahydrofuran; n-heptane; ethylbenzene	Step 2: To a solution of lithium diisopropylamide in tetrahydrofuran/n-heptane/ethylbenzene (1.8 M, 17 mL) at 0° C. is added a solution of 2-(3-bromo-phenyl)-propionic acid (3 g, 13.9 mmol) in tetrahydrofuran (5 mL) dropwise during 15 minutes. The mixture is stirred for 1 hour, followed by addition of methyl iodide (4.93 g, 34.8 mmol) in tetrahydrofuran (5 mL) dropwise during 10 min. The reaction mixture is stirred for 15 hours, quenched with 2 N HCl, concentrated in vacuo, and diluted with ether (150 mL). The ether layer is washed with 2 N HCl, extracted three times with 2 N NaOH (50 mL). The combined NaOH layers are acidified with 6 N HCl to pH=1 and extracted three times with ether (75 mL). The combined organic layers are washed with brine, dried over sodium sulfate and concentrated to obtain 2-(3-bromo-phenyl)-2-methyl-propionic acid as a solid (3.08 g, 91percent), which is used without further purification. LC/MS: 243 (M+H).
91%	Stage #1: With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene at 0℃; for 1.25 h; Stage #2: for 15.1667 h;	To a solution of LDA in THF/n-heptane/ethylbenzene (1.8 M, 17 mL) at O⁰C is added a solution of 2-(3-bromo-phenyl)-propionic acid [3 g, 13.9 mmol, Intermediate (69)] in THF (5 mL) dropwise during 15 minutes. Stir for 1 hour, followed by addition of methyl iodide (4.93 g, 34.8 mmol) in THF (5 mL) dropwise during 10 min. The reaction mixture is stirred for 15 hours, quenched with 2N hydrochloric acid, concentrated in vacuo, and diluted with ether (150 mL). The ether layer is washed with 2N hydrochloric acid, extracted three times with 2N sodium hydroxide (50 mL), Combined sodium hydroxide layers are acidified with 6 N hydrochloric acid to pH=l and extracted three times with ether (75 mL). Combined organic layers are washed with brine, dried over sodium <n="174"/>sulfate and concentrated to obtain 2-(3-bromo-phenyl)-2-methyl-propionic acid as a solid (3.08 g, 91percent yield), which is used without further purification. LC/MS: 243 (M+H)
91%	Stage #1: With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene at 0℃; for 1.25 h; Stage #2: for 15.1667 h;	To a solution of LDA in THF/n-heptane/ethylbenzene (1.8 M, 17 mL) at O⁰C is added a solution of 2-(3-bromo-phenyl)-propionic acid [3 g, 13.9 mmol, Intermediate (69)] in THF (5 mL) dropwise during 15 minutes. Stir for 1 hour, followed by addition of methyl iodide (4.93 g, 34.8 mmol) in THF (5 mL) dropwise during 10 min. The reaction mixture is stirred for 15 hours, quenched with 2N hydrochloric acid, concentrated in vacuo, and diluted with ether (150 mL). The ether layer is washed with 2N hydrochloric acid, extracted three times with 2N sodium hydroxide (50 mL), Combined sodium hydroxide layers are acidified with 6 N hydrochloric acid to pH=l and extracted three times with ether (75 mL). Combined organic layers are washed with brine, dried over sodium <n="174"/>sulfate and concentrated to obtain 2-(3-bromo-phenyl)-2-methyl-propionic acid as a solid (3.08 g, 91percent yield), which is used without further purification. LC/MS: 243 (M+H)

Reference： [1] Patent: US2008/194600, 2008, A1, . Location in patent: Page/Page column 7
[2] Patent: WO2008/39882, 2008, A1, . Location in patent: Page/Page column 172-173
[3] Patent: WO2008/39882, 2008, A1, . Location in patent: Page/Page column 172-173

2
[ 74-88-4 ]
[ 81606-47-5 ]

Yield	Reaction Conditions	Operation in experiment
91%	Stage #1: With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene at 0℃; for 1.25 h; Stage #2: for 15 h;	b) Step 1. To a solution of LDA in THF/n-heptane/ethylbenzene (1.8 M, 17 mL) at 0°C is added a solution of 2-(3-bromo-phenyl)-propionic acid [3 g, 13.9 mmol, Intermediate (69)] in THF (5 mL) dropwise during 15 minutes. Stir for 1 hour, followed by addition of methyl iodide (4.93 g, 34.8 mmol) in THF (5 mL) dropwise during 10 min. The reaction mixture is stirred for 15 hours, quenched with 2N hydrochloric acid, concentrated in vacuo, and diluted with ether (150 mL). The ether layer is washed with 2N hydrochloric acid, extracted three times with 2N sodium hydroxide (50 mL), Combined sodium hydroxide layers are acidified with 6 N hydrochloric acid to pH=l and extracted three times with ether (75 mL). Combined organic layers are washed with brine, dried over sodium sulfate and concentrated to obtain 2-(3 -bromo-phenyl)-2-methyl-propionic acid as a solid (3.08 g, 91percent yield), which is used without further purification. LC/MS: 243 (M+H)

Reference： [1] Patent: WO2006/44732, 2006, A2, . Location in patent: Page/Page column 173-174
[2] Patent: WO2007/121280, 2007, A1, . Location in patent: Page/Page column 31-32

3
[ 251458-15-8 ]
[ 81606-47-5 ]

Yield	Reaction Conditions	Operation in experiment
68%	Stage #1: With methanol; sodium hydroxide In tetrahydrofuran for 2 h; Reflux Stage #2: With hydrogenchloride In water	INTERMEDIATE 82-(3 -Bromophenyl)-2-methylpropionic acidSodium hydroxide (2M, 20 mL) was added to a solution of Intermediate 7 (6.5 g) in MeOH (20 mL) and THF (20 mL). The resulting mixture was refluxed for 2 h. The mixture was evaporated, and the residue partitioned between water and DCM (100 mL each). The aqueous phase was acidified (2M hydrochloric acid) and extracted with DCM (100 mL then 50 mL). The combined organic phases were dried (MgSO₄) and the solvent removed in vacuo to give the title compound (4.55 g, 68percent over two steps) as a cream solid. δ_H (CDCl₃) 7.54 (s, IH), 7.40 (d, IH), 7.33 (d, IH), 7.21 (t, IH), 1.59 (s, 6H).

Reference： [1] Patent: WO2010/52448, 2010, A2, . Location in patent: Page/Page column 37
[2] Patent: WO2004/48374, 2004, A1, . Location in patent: Page 47

4
[ 81606-46-4 ]
[ 81606-47-5 ]

Yield	Reaction Conditions	Operation in experiment
86%	Stage #1: Heating / reflux Stage #2: With hydrogenchloride In water	A6.1c: 2-(3-bromophenyl)-2-methylpropanoic acid; To a solution of A6.1b (22 g, 0.081 mol) in ethanol (220 ml) was added sodium hydroxide (9.7 g, 0.405 mol) and heated to reflux over night. The reaction mixture was concentrated to remove ethanol. The crude product was dissolved in water (200 ml) and washed with ether (2.x.150 ml). The aqueous later was acidified with 6N HCl and extracted with ethyl acetate. Combined organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated to give 17 g (86percent) of A6.1c as white solid. ¹H NMR (300 MHz, CDCl₃) 1.6 (s, 6H), 7.27 (dd, 1H), 7.35 (d, 1H), 7.4 (d, 1H), 7.55 (s, 1H).

Reference： [1] Patent: US2006/106051, 2006, A1, . Location in patent: Page/Page column 29

5
[ 90433-20-8 ]
[ 81606-47-5 ]

Reference： [1] Patent: WO2008/76427, 2008, A2, . Location in patent: Page/Page column 151

6
[ 1878-67-7 ]
[ 81606-47-5 ]

Reference： [1] Patent: WO2008/39882, 2008, A1,

[ 81606-47-5 ] Synthesis Path-Downstream 1~28

1
[ 81606-47-5 ]
[ 885068-00-8 ]

Yield	Reaction Conditions	Operation in experiment
		Step 2; A solution of 2-(3~bromo-phcoyI>-2-metbyl-propialphanic acid (2. 8 nimol ) in anhydrous ether (2i) .mL? is added ^n'-butyl lithium ( 1.7 M in pemane. 5.4 mL. 9.16 mmon dropwise :u -78V'(S and this ?ixturc is stirred tor 30 mhiuies (reared with tributyl borate (2.34 mL, 8.72 mnsoi). The reaction mixture is itHowed io wrirm up to room stnpeTamre, stirred for 15 hours, diluted with ether, and quenched with 1 M UjPO.;. A Tier stirring for 30 minutes the ether layer is .separated and extracted with 2 N aqueous sodium hvdroxkappak- {3 x 20 mL}. The combined sodium hydroxide extracts are acidified with 6 N hydrochloric acid io pH ?-? 1 and extracted three tiines wish efher (50 mL). The combined organic extracts are washed with brinepsilon. dried over sodium suHate a«d cortcentrated Io obtain 3rU^ajixi,x.y- J -methy l-ethv\|j-pbeuyi hororiic acid, which is used vv-ahou fmther purification.

Reference： [1]Patent: WO2007/121280,2007,A1 .Location in patent: Page/Page column 32

2
[ 81606-47-5 ]
[ 701263-25-4 ]
[ 702639-54-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In propan-1-ol; water; at 70 - 90℃; for 3h;	A mixture of NAPHTHYRIDINONE 3 (1.0 eq), acid from step 2 (1.5 eq), NA2C03 (3. 5eq. ; 2M in H20) and Pd (Ph3) 4 or PDC12 (dppf) or Pd (OAc) 2 (Ph3P) 3 (0.05 eq) in n-propanol (0. 1M) was stirred at 70-90C for 3h. The mixture was cooled to rt, quenched with HCI and diluted with EtOAc. The combined organic extracts were washed with brine, dried over MGS04, filtered and concentrated. Flash chromatography (CH2CL2 : MeOH, 99: 1) afforded the title compound as a white solid. 'H NMR (500 MHz, acetone-d6) : d 11.0 (s, OH), 9.76 (s, NH), 8.95 (s, 1H), 8.74 (dd, 1H), 8.71 (dd, 1H), 8.02 (s, 1H), 7.88 (d, 1H), 7.81 (s, 1H), 7.72 (t, 1H), 7.65 (m, 2H), 7.58 (dd, 1H), 7.46 (d, 1H), 2.94 (m, 1H), 1.61 (s, 6H), 0.77 (m, 2H), 0.58 (m, 2H). MS +ESI Q1 (M+L) 468.3
	With sodium carbonate;Pd(OAc)2(PPh3)3; In propan-1-ol; water; at 70 - 90℃; for 3h;	A mixture of NAPHTHYRIDINONE 3 (1.0 eq), acid from step 2 (1.5 eq), NA2C03 (3. 5eq. ; 2M in H20) and Pd (Ph3) 4 or PDC12 (dppf) or Pd (OAc) 2 (Ph3P) 3 (0.05 eq) in n-propanol (0. 1M) was stirred at 70-90C for 3h. The mixture was cooled to rt, quenched with HCI and diluted with EtOAc. The combined organic extracts were washed with brine, dried over MGS04, filtered and concentrated. Flash chromatography (CH2CL2 : MeOH, 99: 1) afforded the title compound as a white solid. 'H NMR (500 MHz, acetone-d6) : d 11.0 (s, OH), 9.76 (s, NH), 8.95 (s, 1H), 8.74 (dd, 1H), 8.71 (dd, 1H), 8.02 (s, 1H), 7.88 (d, 1H), 7.81 (s, 1H), 7.72 (t, 1H), 7.65 (m, 2H), 7.58 (dd, 1H), 7.46 (d, 1H), 2.94 (m, 1H), 1.61 (s, 6H), 0.77 (m, 2H), 0.58 (m, 2H). MS +ESI Q1 (M+L) 468.3
	With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In propan-1-ol; water; at 70 - 90℃; for 3h;	A mixture of NAPHTHYRIDINONE 3 (1.0 eq), acid from step 2 (1.5 eq), NA2C03 (3. 5eq. ; 2M in H20) and Pd (Ph3) 4 or PDC12 (dppf) or Pd (OAc) 2 (Ph3P) 3 (0.05 eq) in n-propanol (0. 1M) was stirred at 70-90C for 3h. The mixture was cooled to rt, quenched with HCI and diluted with EtOAc. The combined organic extracts were washed with brine, dried over MGS04, filtered and concentrated. Flash chromatography (CH2CL2 : MeOH, 99: 1) afforded the title compound as a white solid. 'H NMR (500 MHz, acetone-d6) : d 11.0 (s, OH), 9.76 (s, NH), 8.95 (s, 1H), 8.74 (dd, 1H), 8.71 (dd, 1H), 8.02 (s, 1H), 7.88 (d, 1H), 7.81 (s, 1H), 7.72 (t, 1H), 7.65 (m, 2H), 7.58 (dd, 1H), 7.46 (d, 1H), 2.94 (m, 1H), 1.61 (s, 6H), 0.77 (m, 2H), 0.58 (m, 2H). MS +ESI Q1 (M+L) 468.3

Reference： [1]Patent: WO2004/48374,2004,A1 .Location in patent: Page 48
[2]Patent: WO2004/48374,2004,A1 .Location in patent: Page 48
[3]Patent: WO2004/48374,2004,A1 .Location in patent: Page 48

3
[ 251458-15-8 ]
[ 81606-47-5 ]

Yield	Reaction Conditions	Operation in experiment
68%		INTERMEDIATE 82-(3 -Bromophenyl)-2-methylpropionic acidSodium hydroxide (2M, 20 mL) was added to a solution of Intermediate 7 (6.5 g) in MeOH (20 mL) and THF (20 mL). The resulting mixture was refluxed for 2 h. The mixture was evaporated, and the residue partitioned between water and DCM (100 mL each). The aqueous phase was acidified (2M hydrochloric acid) and extracted with DCM (100 mL then 50 mL). The combined organic phases were dried (MgSO4) and the solvent removed in vacuo to give the title compound (4.55 g, 68% over two steps) as a cream solid. deltaH (CDCl3) 7.54 (s, IH), 7.40 (d, IH), 7.33 (d, IH), 7.21 (t, IH), 1.59 (s, 6H).
	With lithium hydroxide; In tetrahydrofuran; methanol; at 50℃; for 1h;Alkaline conditions;	To a solution of ester from step 1 in THF-MeOH (4: 1,0. 5M) was added LIOH (3 eq, 2M) and the mixture was stirred at 50C for 1h. The organic solvent evaporated, aqueous was acidified with HCl IN and the acid extracted with EtOAc (3X). The organic was washed with brine, dried and solvent evaporated to afford the acid.

Reference： [1]Patent: WO2010/52448,2010,A2 .Location in patent: Page/Page column 37
[2]Patent: WO2004/48374,2004,A1 .Location in patent: Page 47

4
[ 81606-47-5 ]
[ 541-41-3 ]
C₁₃H₁₅BrO₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; at 0℃; for 1h;	A6.1d:Benzyl 2-(3-bromophenyl)propan-2-ylcarbamate; To solution of A6.1c (11 g, 0.045 mol) in dichloromethane (110 ml) was added triethylamine (5.85 g, 0.057 mol) and cooled to 0 C. under N2. Ethylchloroformate (5.65 g, 0.05 mol) was added drop wise and stirred at 0 C. for 1 h. Sodium azide (3.24 g, 0.049 mol) was added and the mixture was stirred at RT over night. Reaction mixture was filtered to remove triethylamine-hydrochloride salt. The organic layer was concentrated to provide 1-azido-2-(3-bromophenyl)-2-methylpropan-1-one which was dissolved in toluene (60 mL) and heated to 100 C. for 30 min. The toluene was removed under vacuum to provide 1-bromo-3-(2-isocyanatopropan-2-yl)benzene. A mixture of 1-bromo-3-(2-isocyanatopropan-2-yl)benzene, pyridine (30 ml) and benzyl alcohol (12.2 g, 0.113 mol) was heated to 100 C. for 2 h under nitrogen. The reaction mixture was cooled to RT, quenched with 1.5 N HCl and extracted with ethyl acetate (3×50 ml). The combined organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated. Product was purified by column chromatography to give 7 g (45%) of A6.1d. 1H NMR (300 MHz, CDCl3) 1.65 (s, 6H), 5.03 (s, 2H), 5.1 (bs, 1H), 7.2 (dd, 1H), 7.35 (m, 6H), 7.54 (s, 1H). LCMS (M-H)+=350.

Reference： [1]Patent: US2006/106051,2006,A1 .Location in patent: Page/Page column 30

5
[ 81606-46-4 ]
[ 81606-47-5 ]

Yield	Reaction Conditions	Operation in experiment
86%		A6.1c: 2-(3-bromophenyl)-2-methylpropanoic acid; To a solution of A6.1b (22 g, 0.081 mol) in ethanol (220 ml) was added sodium hydroxide (9.7 g, 0.405 mol) and heated to reflux over night. The reaction mixture was concentrated to remove ethanol. The crude product was dissolved in water (200 ml) and washed with ether (2×150 ml). The aqueous later was acidified with 6N HCl and extracted with ethyl acetate. Combined organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated to give 17 g (86%) of A6.1c as white solid. 1H NMR (300 MHz, CDCl3) 1.6 (s, 6H), 7.27 (dd, 1H), 7.35 (d, 1H), 7.4 (d, 1H), 7.55 (s, 1H).

Reference： [1]Patent: US2006/106051,2006,A1 .Location in patent: Page/Page column 29

7
[ 74-88-4 ]
[ 81606-47-5 ]

Yield	Reaction Conditions	Operation in experiment
91%		b) Step 1. To a solution of LDA in THF/n-heptane/ethylbenzene (1.8 M, 17 mL) at 0C is added a solution of 2-(3-bromo-phenyl)-propionic acid [3 g, 13.9 mmol, Intermediate (69)] in THF (5 mL) dropwise during 15 minutes. Stir for 1 hour, followed by addition of methyl iodide (4.93 g, 34.8 mmol) in THF (5 mL) dropwise during 10 min. The reaction mixture is stirred for 15 hours, quenched with 2N hydrochloric acid, concentrated in vacuo, and diluted with ether (150 mL). The ether layer is washed with 2N hydrochloric acid, extracted three times with 2N sodium hydroxide (50 mL), Combined sodium hydroxide layers are acidified with 6 N hydrochloric acid to pH=l and extracted three times with ether (75 mL). Combined organic layers are washed with brine, dried over sodium sulfate and concentrated to obtain 2-(3 -bromo-phenyl)-2-methyl-propionic acid as a solid (3.08 g, 91% yield), which is used without further purification. LC/MS: 243 (M+H)
		Bxaniple 7:pyrimidin-4-yI } -.phe»yi)v2-trtethvl-propiQnvli-amtde <n="33"/>Step L: To a solution of LDA in ITiWn-heptane/ethyibenxene (IM M I"? mi..} at O0C is added a solution of 2K-Vhroroo-phenySVprapk)mc acid (3 g) in THF {5 mLj dropwise during 15 mhtauiik:s. The rnixHsrs is stirred for i hour followed by addition of methyl iodide (4.93 g) in THF (5 otLj dropwise during 10 r?irs. "The reaction mixture Ls stirred for 15 hours, quenched with 2N hydrochloric aei. concentrated /« v«r »?lambda and dilated with ether ( 150 mL). The ether layer is washed with 2N hydrochloric acid, and extracted three times with 2N scxliusr; hydroxide (50 mL}, The combined sodium hydroxide layers are acidified with 6 N isydrochkfrlc ncid io pH ~ 1 and exiraeted three tti?es with ether (75 ml.). The combined organic layers are washed with brine, dried over sodium sulfate and concentrated to obtain ~;:/.3-bchio?;itvghejij.Jj-2^vjejh^ B'.QlMtheta]cil?k1 ;ss ;s solid (3.08 g), which is used without further purification. T.X7MS: 243 {M4-I1}

Reference： [1]Patent: WO2006/44732,2006,A2 .Location in patent: Page/Page column 173-174
[2]Patent: WO2007/121280,2007,A1 .Location in patent: Page/Page column 31-32

8
[ 90433-20-8 ]
[ 81606-47-5 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; water; In 1,4-dioxane;	Step B: Preparation of 2-(3-Bromophenyl)-2-methylpropanoic acid; [0663] 2-(3-Bromophenyl)-2-methylpropanenitrile (14.0 g, 62.47 mmol) was heated in dioxane (150 mL) and 60% H2SO4 (150 mL) for 16 hours, cooled to room temperature, and partitioned between DCM and water. The layers were separated, and the aqueous layer was extracted with DCM (2x). The combined organic layers were washed with water (2x) and brine, dried (MgSO4), and concentrated in vacuo to give the product as an oil that solidified upon standing (14.75 g).

Reference： [1]Patent: WO2008/76427,2008,A2 .Location in patent: Page/Page column 151

9
[ 81606-47-5 ]
[ 878743-65-8 ]

Yield	Reaction Conditions	Operation in experiment
	With oxalyl dichloride; In dichloromethane; at 20℃; for 18.5h;	INTERMEDIATE 92-(3 -Bromophenyl)-2-methyl- 1 -(pyrrolidin- 1 -vDpropan- 1 -one Oxalyl chloride (3 mL) was added to a solution of Intermediate 8 (1.6 g, 6.58 mmol) in DCM (20 mL) at r.t. The mixture was stirred for 30 minutes and then allowed to stand for 18 h. The mixture was concentrated in vacuo, adding DCM (2 x 10 mL) to assist removal of oxalyl chloride. Half this residue was dissolved in DCM (10 mL) and added to a stirred solution of pyrrolidine (257 mg, 3.62 mmol) and triethylamine (366 mg, 3.62 mmol) in DCM (10 mL), pre-cooled in an ice-water bath. The mixture was allowed to warm to r.t., and after 15 minutes the mixture was partitioned between water (20 mL) and DCM (10 mL). The aqueous phase was extracted with further DCM (10 mL), and the combined organic phases dried (MgSO4) and concentrated in vacuo to give the title compound (980 mg, essentially quantitative) as a pale yellow-orange solid. 5H (CDCl3) 7.41 (t, IH), 7.34-7.38 (dt, IH), 7.12-7.23 (m, 2H), 3.52 (t, 2H), 2.75 (t, 2H), 1.56-1.80 (m, 4H), 1.52 (s, 6H). LCMS (ES+) 297 (M+H)+, RT 3.67 minutes.
	With oxalyl dichloride;N,N-dimethyl-formamide; In tetrahydrofuran; at 20℃; for 1h;	To a solution of 2- (3-bromophenyl) -2-methylpropionic acid (89 mg, 0.361 mmol) in tetrahydrofuran (1 mL) were added oxalyl chloride (40 muL, 0.466 mmol) and N,N-dimethylformamide (10 muL) , and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N, N- dimethylacetamide (1 mL) . N- [6- (3-Aminophenoxy) -7-cyano-l, 3- benzothiazol-2-yl] acetamide (100 mg, 0.308 mmol) produced in Example 12 (ii) was added to the solution, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate (12 mL) , washed successively with 5% aqueous sodium hydrogen carbonate solution (6 mL) and saturated brine (6 mL) , and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=30/70?80/20) , and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethanol to give the title compound (136 mg, 81%) as a white powder.1H-NMR (DMSO-de, 300 MHz) delta 1.53 (6H, s), 2.25 (3H, s) , 6.72 - 6.93 (IH, m) , 7.14 (IH, d, J = 9.1 Hz), 7.22 - 7.41 (3H, m) , 7.48 (4H, dt, J = 11.8, 1.8 Hz), 8.03 (IH, d, J = 9.1 Hz), 9.29 (IH, s) , 12.70 (IH, s)
	With thionyl chloride; at 75℃; for 2.5h;	Thionyl chloride (50 mL) was added to 2-(3-bromophenyl)-2- methylpropanoic acid (10.63 g, 43.7 mmol). The reaction mixture was stirred at 75C for 2.5 hours. The mixture was then concentrated in vacuo to give the acid chloride.

Reference： [1]Patent: WO2010/52448,2010,A2 .Location in patent: Page/Page column 37
[2]Patent: WO2010/64722,2010,A1 .Location in patent: Page/Page column 125-126
[3]Patent: WO2008/76427,2008,A2 .Location in patent: Page/Page column 152

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[ 74-88-4 ]
[ 81606-47-5 ]

Yield	Reaction Conditions	Operation in experiment
91%		Step 2: To a solution of lithium diisopropylamide in tetrahydrofuran/n-heptane/ethylbenzene (1.8 M, 17 mL) at 0 C. is added a solution of 2-(3-bromo-phenyl)-propionic acid (3 g, 13.9 mmol) in tetrahydrofuran (5 mL) dropwise during 15 minutes. The mixture is stirred for 1 hour, followed by addition of methyl iodide (4.93 g, 34.8 mmol) in tetrahydrofuran (5 mL) dropwise during 10 min. The reaction mixture is stirred for 15 hours, quenched with 2 N HCl, concentrated in vacuo, and diluted with ether (150 mL). The ether layer is washed with 2 N HCl, extracted three times with 2 N NaOH (50 mL). The combined NaOH layers are acidified with 6 N HCl to pH=1 and extracted three times with ether (75 mL). The combined organic layers are washed with brine, dried over sodium sulfate and concentrated to obtain 2-(3-bromo-phenyl)-2-methyl-propionic acid as a solid (3.08 g, 91%), which is used without further purification. LC/MS: 243 (M+H).
91%		To a solution of LDA in THF/n-heptane/ethylbenzene (1.8 M, 17 mL) at O0C is added a solution of 2-(3-bromo-phenyl)-propionic acid [3 g, 13.9 mmol, Intermediate (69)] in THF (5 mL) dropwise during 15 minutes. Stir for 1 hour, followed by addition of methyl iodide (4.93 g, 34.8 mmol) in THF (5 mL) dropwise during 10 min. The reaction mixture is stirred for 15 hours, quenched with 2N hydrochloric acid, concentrated in vacuo, and diluted with ether (150 mL). The ether layer is washed with 2N hydrochloric acid, extracted three times with 2N sodium hydroxide (50 mL), Combined sodium hydroxide layers are acidified with 6 N hydrochloric acid to pH=l and extracted three times with ether (75 mL). Combined organic layers are washed with brine, dried over sodium <n="174"/>sulfate and concentrated to obtain 2-(3-bromo-phenyl)-2-methyl-propionic acid as a solid (3.08 g, 91% yield), which is used without further purification. LC/MS: 243 (M+H)

Reference： [1]Patent: US2008/194600,2008,A1 .Location in patent: Page/Page column 7
[2]Patent: WO2008/39882,2008,A1 .Location in patent: Page/Page column 172-173

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