[ CAS No. 123254-58-0 ] {[proInfo.proName]}

Name: 123254-58-0|(R)-2-((tert-Butoxycarbonyl)amino)-2-methylbutanoic acid|95%
Brand: Ambeed
SKU: A121822
Rating: 98 (35 reviews)

,{[proInfo.pro_purity]}

Cat. No.: {[proInfo.prAm]}

DV 2D 3D

3d Animation Molecule Structure of 123254-58-0

Structure of 123254-58-0 * Storage: {[proInfo.prStorage]}

Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Search after Editing

* Storage: {[proInfo.prStorage]}

For Research Only 110K+ Compounds Competitive Price 1-2 Day Shipping

Quality Control of [ 123254-58-0 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 123254-58-0 ]

SDS Specification

Alternatived Products of [ 123254-58-0 ]

Product Details of [ 123254-58-0 ]

CAS No. :	123254-58-0	MDL No. :	MFCD12963786
Formula :	C₁₀H₁₉NO₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	SHZXLTCEPXVCSV-SNVBAGLBSA-N
M.W :	217.26	Pubchem ID :	14284791
Synonyms :

Calculated chemistry of [ 123254-58-0 ]

Physicochemical Properties

Num. heavy atoms :	15
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.8
Num. rotatable bonds :	6
Num. H-bond acceptors :	4.0
Num. H-bond donors :	2.0
Molar Refractivity :	56.51
TPSA :	75.63 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.46 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.13
Log Po/w (XLOGP3) :	1.64
Log Po/w (WLOGP) :	1.76
Log Po/w (MLOGP) :	1.13
Log Po/w (SILICOS-IT) :	0.5
Consensus Log Po/w :	1.43

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.82
Solubility :	3.26 mg/ml ; 0.015 mol/l
Class :	Very soluble
Log S (Ali) :	-2.84
Solubility :	0.313 mg/ml ; 0.00144 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-1.44
Solubility :	7.87 mg/ml ; 0.0362 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.71

Safety of [ 123254-58-0 ]

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 [ 123254-58-0 ]

* 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 [ 123254-58-0 ]
Downstream synthetic route of [ 123254-58-0 ]

[ 123254-58-0 ] Synthesis Path-Upstream 1~10

1
[ 3059-97-0 ]
[ 24424-99-5 ]
[ 123254-58-0 ]

Yield	Reaction Conditions	Operation in experiment
97%	With triethylamine In tetrahydrofuranInert atmosphere	Under nitrogen protection,(R) -2-amino-2-methylbutanoic acid (2.05 g, 17.50 mmol)Triethylamine (7.01 mL, 50.20 mmol)Di-tert-butyl dicarboxylate (5.70 g, 26.00 mmol)Added together, and then added tetrahydrofuran (20 mL), warmedThe reaction was cooled to room temperature, extracted with ethyl acetate (50 mL x 3), dried over anhydrous Na2SO4, and the solvent was removed. Column separation (dichloromethane / methanol (v / v) = 10/1) To give 3.60 g of a colorless oil, yield: 97.0percent.

Reference： [1] Patent: CN106336413, 2017, A, . Location in patent: Paragraph 0471; 0472; 0473

2
[ 24424-99-5 ]
[ 73473-40-2 ]
[ 123254-58-0 ]

Reference： [1] Tetrahedron Asymmetry, 2015, vol. 26, # 1, p. 1 - 5

3
[ 252953-43-8 ]
[ 123254-58-0 ]

Reference： [1] Journal of Organic Chemistry, 1999, vol. 64, # 22, p. 8220 - 8225

4
[ 188476-24-6 ]
[ 123254-58-0 ]

Reference： [1] Journal of Organic Chemistry, 1999, vol. 64, # 22, p. 8220 - 8225

5
[ 219567-09-6 ]
[ 123254-58-0 ]

Reference： [1] Journal of Organic Chemistry, 1999, vol. 64, # 22, p. 8220 - 8225

6
[ 219567-00-7 ]
[ 123254-58-0 ]

Reference： [1] Journal of Organic Chemistry, 1999, vol. 64, # 22, p. 8220 - 8225

7
[ 252953-41-6 ]
[ 123254-58-0 ]

Reference： [1] Journal of Organic Chemistry, 1999, vol. 64, # 22, p. 8220 - 8225

8
[ 252953-36-9 ]
[ 123254-58-0 ]

Reference： [1] Journal of Organic Chemistry, 1999, vol. 64, # 22, p. 8220 - 8225

9
[ 252953-42-7 ]
[ 123254-58-0 ]

Reference： [1] Journal of Organic Chemistry, 1999, vol. 64, # 22, p. 8220 - 8225

10
[ 123254-58-0 ]
[ 944842-54-0 ]

Reference： [1] Journal of Medicinal Chemistry, 2015, vol. 58, # 18, p. 7195 - 7216

[ 123254-58-0 ] Synthesis Path-Downstream 1~50

1
[ 100-39-0 ]
[ 123254-58-0 ]
[ 141345-74-6 ]

Reference： [1]Journal of the American Chemical Society,1992,vol. 114,p. 4095 - 4106

2
[ 123254-58-0 ]
(S)-2-({(S)-1-[2-((S)-2-Amino-4-methyl-pentanoylamino)-2-methyl-propionyl]-pyrrolidine-2-carbonyl}-amino)-4-methyl-pentanoic acid methyl ester; compound with trifluoro-acetic acid [ No CAS ]
(S)-2-[((S)-1-{2-[(S)-2-((R)-2-tert-Butoxycarbonylamino-2-methyl-butyrylamino)-4-methyl-pentanoylamino]-2-methyl-propionyl}-pyrrolidine-2-carbonyl)-amino]-4-methyl-pentanoic acid methyl ester [ No CAS ]

Reference： [1]Journal of the Chemical Society. Perkin transactions I,1997,p. 1587 - 1594

3
[ 123254-58-0 ]
[ 73473-40-2 ]

Reference： [1]Journal of Organic Chemistry,1999,vol. 64,p. 8220 - 8225

4
[ 252953-43-8 ]
[ 123254-58-0 ]

Reference： [1]Journal of Organic Chemistry,1999,vol. 64,p. 8220 - 8225

5
[ 188476-24-6 ]
[ 123254-58-0 ]

Reference： [1]Journal of Organic Chemistry,1999,vol. 64,p. 8220 - 8225

6
[ 219567-09-6 ]
[ 123254-58-0 ]

Reference： [1]Journal of Organic Chemistry,1999,vol. 64,p. 8220 - 8225

7
[ 219567-00-7 ]
[ 123254-58-0 ]

Reference： [1]Journal of Organic Chemistry,1999,vol. 64,p. 8220 - 8225

8
[ 252953-42-7 ]
[ 123254-58-0 ]

Reference： [1]Journal of Organic Chemistry,1999,vol. 64,p. 8220 - 8225

9
[ 252953-41-6 ]
[ 123254-58-0 ]

Reference： [1]Journal of Organic Chemistry,1999,vol. 64,p. 8220 - 8225

10
[ 252953-36-9 ]
[ 123254-58-0 ]

Reference： [1]Journal of Organic Chemistry,1999,vol. 64,p. 8220 - 8225

11
[ 123254-58-0 ]
[ 141345-80-4 ]

Reference： [1]Journal of the American Chemical Society,1992,vol. 114,p. 4095 - 4106

12
[ 123254-58-0 ]
[ 141345-79-1 ]

Reference： [1]Journal of the American Chemical Society,1992,vol. 114,p. 4095 - 4106

13
[ 123254-58-0 ]
[ 141345-91-7 ]

Reference： [1]Journal of the American Chemical Society,1992,vol. 114,p. 4095 - 4106

14
[ 123254-58-0 ]
[ 141345-89-3 ]

Reference： [1]Journal of the American Chemical Society,1992,vol. 114,p. 4095 - 4106

15
[ 123254-58-0 ]
[ 141345-76-8 ]

Reference： [1]Journal of the American Chemical Society,1992,vol. 114,p. 4095 - 4106

16
[ 123254-58-0 ]
[ 141434-05-1 ]

Reference： [1]Journal of the American Chemical Society,1992,vol. 114,p. 4095 - 4106

17
[ 123254-58-0 ]
[ 141345-75-7 ]

Reference： [1]Journal of the American Chemical Society,1992,vol. 114,p. 4095 - 4106

18
[ 123254-58-0 ]
[ 141345-78-0 ]

Reference： [1]Journal of the American Chemical Society,1992,vol. 114,p. 4095 - 4106

19
[ 123254-58-0 ]
[ 141345-77-9 ]

Reference： [1]Journal of the American Chemical Society,1992,vol. 114,p. 4095 - 4106

20
[ 2127-03-9 ]
[ 123254-58-0 ]
S-2-pyridinyl (2R)-2-([(1,1-dimethylethyl)oxy]carbonyl}amino)-2-methylbutanethioate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triphenylphosphine; In tetrahydrofuran; at 20℃; for 3h;	Intermediate 139 5-2-pyridinyl (2/?)-2-([(l,l-dimethylethyl)oxylcarbonyl}amino)-2-methylbutanethioateTo a solution of N-[(l,l-dimethylethyl)oxy]carbonyl}-D-isovaline (100 mg, 0.460 mmol) in dry tetrahydrofuran (THF) (10 ml) 2,2'-dithiodipyridine (254 mg, 1.151 mmol) and triphenylphosphine (302 mg, 1.151 mmol) were added. The mixture was stirred at room temperature for 3 hours. THF was evaporated under vacuum. The residue was purified by flash chromatography on silica gel using a 25g the title compound (78 mg, 0.251 mmol) as a white solid.XH NMR (400MHz, DMSO-d6) delta ppm 8.59 (1H, d), 7.87 (1H, t), 7.70 (1H, br.s.), 7.51 (1H, d), 7.41 (t, 1H), 2.02-1.84 (1H, m), 1.74-1.60 (1H, m), 1.43 (9H, s), 1.33 (3H, s), 0.81 (3H, t).UPLCJPQC: 1.01 min, 311 [M+H]+.
78 mg	With triphenylphosphine; In tetrahydrofuran; at 20℃; for 3h;	Intermediate 139 [0903] S-2-pyridinyl (2R)-2-([(1,1-dimethylethyl)oxy]carbonyl}amino)-2-methylbutanethioate [0904] To a solution of <strong>[123254-58-0]N-[(1,1-dimethylethyl)oxy]carbonyl}-D-isovaline</strong> (100 mg, 0.460 mmol) in dry tetrahydrofuran (THF) (10 ml) 2,2?-dithiodipyridine (254 mg, 1.151 mmol) and triphenylphosphine (302 mg, 1.151 mmol) were added. The mixture was stirred at room temperature for 3 hours. THF was evaporated under vacuum. The residue was purified by flash chromatography on silica gel using a 25 g the title compound (78 mg, 0.251 mmol) as a white solid. [0905] 1H NMR (400 MHz, DMSO-d6) delta ppm 8.59 (1H, d), 7.87 (1H, t), 7.70 (1H, br.s.), 7.51 (1H, d), 7.41 (t, 1H), 2.02-1.84 (1H, m), 1.74-1.60 (1H, m), 1.43 (9H, s), 1.33 (3H, s), 0.81 (3H, t). [0906] UPLC_IPQC: 1.01 min, 311 [M+H]+.

Reference： [1]Patent: WO2012/76877,2012,A1 .Location in patent: Page/Page column 135-136
[2]Patent: US2013/267510,2013,A1 .Location in patent: Paragraph 0903-0906

21
[ 123254-58-0 ]
[ 1380698-36-1 ]

Reference： [1]Patent: WO2012/76877,2012,A1
[2]Patent: US2013/267510,2013,A1

22
[ 123254-58-0 ]
[ 1380698-37-2 ]

Reference： [1]Patent: WO2012/76877,2012,A1
[2]Patent: US2013/267510,2013,A1

23
[ 123254-58-0 ]
[ 1380699-10-4 ]

Reference： [1]Patent: WO2012/76877,2012,A1
[2]Patent: US2013/267510,2013,A1

24
[ 123254-58-0 ]
[ 1380699-11-5 ]

Reference： [1]Patent: WO2012/76877,2012,A1
[2]Patent: US2013/267510,2013,A1

25
[ 123254-58-0 ]
[ 1380696-36-5 ]

Reference： [1]Patent: WO2012/76877,2012,A1
[2]Patent: US2013/267510,2013,A1

26
[ 123254-58-0 ]
[ 1380696-55-8 ]
[ 1380696-56-9 ]

Reference： [1]Patent: WO2012/76877,2012,A1

27
[ 1311139-85-1 ]
[ 123254-58-0 ]
[ 1380697-78-8 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 48h;	Intermediate 92 l.l-dimethylethyl [(l/?)-l-methyl-l-([6-(spiro[l-benzofuran-3,l'-cyclopropanl-4-yloxy)-3- pyridinyllaminolcarbonvDpropyllcarbamate6-(spiro[l-benzofuran-3,l'-cyclopropan]-4-yloxy)-3-pyridinamine (Intermediate 91, 127 mg), N-[(1,1- dimethylethyl)oxy]carbonyl}-D-isovaline (Nagase & Co Ltd,109 mg, 0.499 mmol), DIPEA (0.131 mL, 0.749 mmol) and HATU (247 mg, 0.649 mmol) were dissolved in dry N,N-dimethylformamide (3 ml) and the mixture obtained was stirred at room temperature for 2 days. A saturated aqueous NaHC03 solution was then added and the mixture was extracted twice with diethyl ether. The organic phase was washed with brine, dried over sodium sulphate and concentrated under vacuum to give 300mg of crude. This was purified by flash chromatography (Biotage KP-Sil 25g SNAP column, eluant cyclohexane/ethyl acetate from 90/10 to 20/80 in 12CV) to give 106 mg of the title compound as a brown solid.XH NM (400MHz, CDCI3): delta ppm 8.13-8.18 (2H, m), 7.06 (1H, t), 6.85 (1H, d), 6.66 (1H, d), 6.45 (1H, d), 4.85 (1H, br.s), 4.48 (2H, s), 1.90-2.11 (2H, m), 1.53 (3H, s), 1.48 (9H, s), 1.42-1.47 (2H, m), 0.97 (3H, t), 0.81-0.86 (2H, m); UPLC: 1.19 min, 454 [M+H]+.

Reference： [1]Patent: WO2012/76877,2012,A1 .Location in patent: Page/Page column 106-107

28
[ 1311138-07-4 ]
[ 123254-58-0 ]
[ 1311138-52-9 ]

Yield	Reaction Conditions	Operation in experiment
		Reference Intermediate R7 l,l-dimethylethyl((l/?)-l-methyl-l-{r(6-{r4-methyl-3-(methyloxy)phenylloxy}-3- pyridinvDaminolcarbonyllpropyDcarbamateTo a solution of A/-[(l,l-dimethylethyl)oxy]carbonyl}-D-isovaline (94 mg, 0.434 mmol) in dry N,N-Dimethylformamide (1 mL) DIPEA (0.114 mL, 0.651 mmol) and HATU (165 mg, 0.434 mmol) were added. The reaction was stirred at room temperature for 15 minutes. 6-[4-methyl-3-(methyloxy)phenyl]oxy}-3- pyridinamine (Reference Intermediate R4, 50 mg) was then added. After 1 hour of stirring at room temperature the mixture was heated at 50C and stirred at that temperature for 4 hours, it was then cooled down to room temperature and stirred overnight at that temperature. The mixture was quenched with brine (2 mL) and extracted with ethyl acetate (3x2 mL). Combined organic layers were dried over sodium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using a lOg SNAP column and cyclohexane/ethyl acetate as eluents from 100/0 to 60/40 (Biotage system) to afford the title compound as a white solid (65 mg). XH NMR (400 MHz, DMSO-c/6): delta ppm 9.60 (1H, br s), 9.10 (1H, br s), 8.31 (1H, br. s.), 8.03 (1H, br s), 7.12 (1H, d), 6.93 (1H, d), 6.69 (1H, d), 6.53 (1H, dd), 3.74 (3H, s), 2.11 (3H, s), 1.72-1.86 (1H, m), 1.60-1.72 (1H, m), 1.41 (9H, s), 1.33 (3H, s), 0.78 (3H, t); UPLC: 0.87 min, 430 [M+H]+
65 mg		Reference Intermediate R7 1,1-dimethylethyl((1R)-1-methyl-1-[(6-[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)amino]carbonyl}propyl)carbamate [1391] <strong>[123254-58-0]N-[(1,1-dimethylethyl)oxy]carbonyl}-D-isovaline</strong> (94 mg, 0.434 mmol) in dry N,N-Dimethylformamide (1 mL) DIPEA (0.114 mL, 0.651 mmol) and HATU (165 mg, 0.434 mmol) were added. The reaction was stirred at room temperature for 15 minutes. 6-[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinamine (Reference Intermediate R4, 50 mg) was then added. After 1 hour of stirring at room temperature the mixture was heated at 50 C. and stirred at that temperature for 4 hours, it was then cooled down to room temperature and stirred overnight at that temperature. The mixture was quenched with brine (2 mL) and extracted with ethyl acetate (3×2 mL). Combined organic layers were dried over sodium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using a 10 g SNAP column and cyclohexane/ethyl acetate as eluents from 100/0 to 60/40 (Biotage system) to afford the title compound as a white solid (65 mg). [1393] 1H NMR (400 MHz, DMSO-d6): delta ppm 9.60 (1H, br s), 9.10 (1H, br s), 8.31 (1H, br. s.), 8.03 (1H, br s), 7.12 (1H, d), 6.93 (1H, d), 6.69 (1H, d), 6.53 (1H, dd), 3.74 (3H, s), 2.11 (3H, s), 1.72-1.86 (1H, m), 1.60-1.72 (1H, m), 1.41 (9H, s), 1.33 (3H, s), 0.78 (3H, t); UPLC: 0.87 min, 430 [M+H]+

Reference： [1]Patent: WO2012/76877,2012,A1 .Location in patent: Page/Page column 225
[2]Patent: US2013/267510,2013,A1 .Location in patent: Paragraph 1391-1393

29
[ 1380698-11-2 ]
[ 123254-58-0 ]
[ 1380698-44-1 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃;	Intermediate 146 tert-butyl N-[(lR)-l-methyl-l-[[6-(3-methylchroman-5-yl)oxy-3-pyridyllcarbamoyllpropyllcarbamate In a 8 mL 6-[(3-methyl-3,4-dihydro-2H-chromen-5-yl)oxy]-3-pyridinamine (Intermediate 119, 82.4 mg, 0.0305 mmol), <strong>[123254-58-0](2R)-2-(tert-butoxycarbonylamino)-2-methyl-butanoic acid</strong> (59.7 mg, 0.275 mmol) and DIPEA (0.080 mL, 0.458 mmol) were dissolved in Nu,Nu-Dimethylformamide (DMF) (2 mL) to give a pale yellow solution. HATU (151 mg, 0.397 mmol) was added. The reaction mixture was stirred at room temperature over week-end. The reaction mixture was evaporated in vacuo and the residue was purified by flash chromatography on silica gel using a column SNAP 25g and cyclohexane/ethyl acetate from 3:1 to 1:2 as eluents affording the title compound (55.8 mg) as white solid.XH NMR (400 MHz, CDCI3) delta ppm 8.08 - 8.16 (2H, m), 7.10 (1H, t), 6.84 (1H, d), 6.70 (1H, d), 6.59 (1H, d), 6.13 (1H, br. s.), 4.90 (1H, br. s.), 4.12 -4.22 (1H, m), 3.59 - 3.75 (1H, m), 2.59 - 2.92 (1H, m), 1.85 - 2.25 (3H, m), 1.69 - 1.84 (1H, m), 1.51 (3H, s), 1.45 (9H, s), 0.91 - 1.05 (6H, m). UPLCjpqc: 1.22 min, 456 [M+H]+.

Reference： [1]Patent: WO2012/76877,2012,A1 .Location in patent: Page/Page column 139-140

30
[ 1380699-15-9 ]
[ 123254-58-0 ]
[ 1380699-16-0 ]

Yield	Reaction Conditions	Operation in experiment
		Intermediate 224l.l-dimethylethyl [(lR)-l-([2-(2,3-dihvdrospiro[chromene-4,l'-cyclopropanl-5-yloxy)-5- pyrimidinyllaminolcarbonvD-l-methylpropyllcarbamateTo a solution of (2 )-2-(tert-butoxycarbonylamino)-2-methyl-butanoic acid (105 mg, 0.483 mmol) in dry N,N-Dimethylformamide (2 mL) DIPEA (0.101 mL, 0.579 mmol) and HATU (184 mg, 0.483 mmol) were added. The reaction mixture was stirred at r.t. for 15 minutes, then it was added to a solution of 2-(2,3- dihydrospiro[chromene-4,l'-cyclopropan]-5-yloxy)-5-pyrimidinamine (Intermediate 223, 52 mg, 0.193 mmol) in dry DMF (0.5 mL). The mixture was heated at 40QC overnight, it was then warmed to 60QC and stirred at that temperature for 4 hours. After cooling the reaction was quenched with water (5 mL) and extracted with ethyl acetate (3x5 mL). Combined organic layers were washed with brine (3x5 mL), dried (Na2S04), filtered and evaporated. The residue was purified by flash chromatography on silica gel using a column SNAP 25g and toluene to toluene/ethyl acetate 60:40 as eluents affording the title compound (10 mg) as a white solid.UPLC_B: 1.15 min, 469 [M+H]+.
10 mg		Intermediate 224 1,1-dimethylethyl[(1R)-1-([2-(2,3-dihydrospiro[chromene-4,1?-cyclopropan]-5-yloxy)-5-pyrimidinyl]amino}carbonyl)-1-methylpropyl]carbamate [1161] [1162] To a solution of <strong>[123254-58-0](2R)-2-(tert-butoxycarbonylamino)-2-methyl-butanoic acid</strong> (105 mg, 0.483 mmol) in dry N,N-Dimethylformamide (2 mL) DIPEA (0.101 mL, 0.579 mmol) and HATU (184 mg, 0.483 mmol) were added. The reaction mixture was stirred at r.t. for 15 minutes, then it was added to a solution of 2-(2,3-dihydrospiro[chromene-4,1?-cyclopropan]-5-yloxy)-5-pyrimidinamine (Intermediate 223, 52 mg, 0.193 mmol) in dry DMF (0.5 mL). The mixture was heated at 40 C. overnight, it was then warmed to 60 C. and stirred at that temperature for 4 hours. After cooling the reaction was quenched with water (5 mL) and extracted with ethyl acetate (3×5 mL). Combined organic layers were washed with brine (3×5 mL), dried (Na2SO4), filtered and evaporated. The residue was purified by flash chromatography on silica gel using a column SNAP 25 g and toluene to toluene/ethyl acetate 60:40 as eluents affording the title compound (10 mg) as a white solid. [1163] UPLC_B: 1.15 min, 469 [M+H]+.

Reference： [1]Patent: WO2012/76877,2012,A1 .Location in patent: Page/Page column 182
[2]Patent: US2013/267510,2013,A1 .Location in patent: Paragraph 1161-1163

31
[ 1380699-19-3 ]
[ 123254-58-0 ]
[ 1380699-20-6 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃;	Intermediate 227 tert-butyl N-[(lR)-l-[[6-(l,la,2,7b-tetrahvdrocvclopropa[clchromen-7-yloxy)-3-pyridyllcarbamoyll-l- methyl-propyllcarbamateIn a 8 mL vial tube 6-(l,la,2,7btetrahydrocyclopropa[c]chromen-7-yloxy)-3-pyridinamine (Intermediate 226, 84 mg, 0.0305 mmol), <strong>[123254-58-0](2R)-2-(tert-butoxycarbonylamino)-2-methyl-butanoic acid</strong> (59.7 mg, 0.275 mmol) and DIPEA (0.080 mL, 0.458 mmol) were dissolved in Nu,Nu-Dimethylformamide (DMF) (2 mL) to give a pale yellow solution. HATU (151 mg, 0.397 mmol) was added. The reaction mixture was stirred at room temperature over week-end. The reaction mixture was evaporated in vacuo and the residue was purified by flash chromatography on silica gel using a column SNAP 25g and cyclohexane/ethyl acetate from 3:1 to 1:2 as eluents affording the title compound (74 mg) as white solid. XH NMR (400 MHz, CDCI3) delta ppm 8.14 - 8.18 (1H, m), 8.09 - 8.14 (1H, m), 7.04 (1H, t), 6.85 (1H, d), 6.64 - 6.72 (2H, m), 6.30 (1H, br. s.), 4.91 (1H, br. s.), 4.31 (1H, dd), 3.94 (1H, dd), 1.83 - 2.17 (3H, m), 1.70 - 1.83 (1H, m), 1.51 (3H, s), 1.45 (9H, s), 0.91 - 1.05 (5H, m). UPLCjpqc: 1.17 min, 454 [M+H]+.
74 mg	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃;	Intermediate 227 tert-butyl N-[(1R)-1-[[6-(1,1a,2,7b-tetrahydrocyclopropa[c]chromen-7-yloxy)-3-pyridyl]carbamoyl]-1-methyl-propyl]carbamate [1170] [1171] In a 8 mL vial tube 6-(1,1a,2,7btetrahydrocyclopropa[c]chromen-7-yloxy)-3-pyridinamine (Intermediate 226, 84 mg, 0.0305 mmol), <strong>[123254-58-0](2R)-2-(tert-butoxycarbonylamino)-2-methyl-butanoic acid</strong> (59.7 mg, 0.275 mmol) and DIPEA (0.080 mL, 0.458 mmol) were dissolved in N,N-Dimethylformamide (DMF) (2 mL) to give a pale yellow solution. HATU (151 mg, 0.397 mmol) was added. The reaction mixture was stirred at room temperature over week-end. The reaction mixture was evaporated in vacuo and the residue was purified by flash chromatography on silica gel using a column SNAP 25 g and cyclohexane/ethyl acetate from 3:1 to 1:2 as eluents affording the title compound (74 mg) as white solid. [1172] 1H NMR (400 MHz, CDCl3) delta ppm 8.14-8.18 (1H, m), 8.09-8.14 (1H, m), 7.04 (1H, t), 6.85 (1H, d), 6.64-6.72 (2H, m), 6.30 (1H, br. s.), 4.91 (1H, br. s.), 4.31 (1H, dd), 3.94 (1H, dd), 1.83-2.17 (3H, m), 1.70-1.83 (1H, m), 1.51 (3H, s), 1.45 (9H, s), 0.91-1.05 (5H, m). UPLC_ipqc: 1.17 min, 454 [M+H]+.

Reference： [1]Patent: WO2012/76877,2012,A1 .Location in patent: Page/Page column 184
[2]Patent: US2013/267510,2013,A1 .Location in patent: Paragraph 1170-1172

32
[ 1311139-89-5 ]
[ 123254-58-0 ]
[ 1380697-78-8 ]

Yield	Reaction Conditions	Operation in experiment
106 mg	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 48h;	Intermediate 92 1,1-dimethylethyl[(1R)-1-methyl-1-([6-(spiro[1-benzofuran-3,1?-cyclopropan]-4-yloxy)-3-pyridinyl]amino}carbonyl)propyl]carbamate [0756] [0757] 6-(spiro[1-benzofuran-3,1?-cyclopropan]-4-yloxy)-3-pyridinamine (Intermediate 91, 127 mg), <strong>[123254-58-0]N-[(1,1-dimethylethyl)oxy]carbonyl}-D-isovaline</strong> (Nagase & Co Ltd, 109 mg, 0.499 mmol), DIPEA (0.131 mL, 0.749 mmol) and HATU (247 mg, 0.649 mmol) were dissolved in dry N,N-dimethylformamide (3 ml) and the mixture obtained was stirred at room temperature for 2 days. A saturated aqueous NaHCO3 solution was then added and the mixture was extracted twice with diethyl ether. The organic phase was washed with brine, dried over sodium sulphate and concentrated under vacuum to give 300 mg of crude. This was purified by flash chromatography (Biotage KP-Sil 25 g SNAP column, eluant cyclohexane/ethyl acetate from 90/10 to 20/80 in 12CV) to give 106 mg of the title compound as a brown solid. [0758] 1H NMR (400 MHz, CDCl3): delta ppm 8.13-8.18 (2H, m), 7.06 (1H, t), 6.85 (1H, d), 6.66 (1H, d), 6.45 (1H, d), 4.85 (1H, br.s), 4.48 (2H, s), 1.90-2.11 (2H, m), 1.53 (3H, s), 1.48 (9H, s), 1.42-1.47 (2H, m), 0.97 (3H, t), 0.81-0.86 (2H, m); UPLC: 1.19 min, 454 [M+H]+.

Reference： [1]Patent: US2013/267510,2013,A1 .Location in patent: Paragraph 0756-0758

33
[ 123254-58-0 ]
[ 1380696-55-8 ]

Reference： [1]Patent: US2013/267510,2013,A1

34
[ 24424-99-5 ]
[ 73473-40-2 ]
[ 123254-58-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; In isopropyl alcohol; at 40℃; for 5.5h;pH 11.0;	At first, CsAM transformed E. coli was cultured at 30C for 10h in a test tube containing 5mL of 2-YT medium. The seed culture (1mL) was then inoculated in a 500-mL Sakaguchi flask containing 50mL of 2-YT medium. After 20h of incubation at 30C with reciprocal shaking (at 130rpm), the cultured cells were collected by centrifugation from 1.0L of the cultured broth (from twenty-one Sakaguchi flasks) and were suspended in 1.0L of water. Next, 2-ethyl-2-methyl-malonamide (80g, 0.55mol) and the cultured cell suspensions (860mL) were stirred at 30C for 22h. The pH of the reaction mixture was maintained at 7.0 with 30% sodium hydroxide solution. The resulting mixture was centrifuged, and the supernatant was adjusted to pH 12.0 with 30% sodium hydroxide solution. The ammonia in the mixture was removed by evaporation under reduced pressure and concentrated to give the crude mixture (272.6g), which contains (S)-2-ethyl-2-methyl-malonamic acid. A solution of 13% hypochlorous acid (481g, 0.83mol), 48% sodium hydroxide solution (138g, 1.65mol), crude mixture (272.6g), which contains (S)-2-ethyl-2-methyl-malonamic acid, and water (10g) were stirred at 0C for 2h. The mixture was heated to 20C and stirred for 2.5h. Subsequently, the pH of the mixture was adjusted to 4.0 with concentrated hydrochloric acid (238.3g, 2.28mol) and stirred at 20C for 25h to give crude (R)-isovaline hydrochloride. The resulting mixture, sodium hydroxide (23.0g, 0.56mol), 2-propanol (168.8g), and di-tert-butyl dicarbonate (143.0g, 0.65mol) were stirred at 40C for 3.5h, while the pH was maintained at 11.0 by the addition of sodium hydroxide (68.5g, 1.66mol). The resulting mixture was stirred at 40C for 2h and then cooled to 0C and stirred for 15h. Concentrated hydrochloric acid (235.0g, 2.26mol) was added to the resulting mixture and the mixture was heated to 18C. The organic layer was separated and evaporated under reduced pressure. Toluene (423.0g) and water (212.0g) were added to the concentrate and the organic layer (560.0g) was separated and evaporated under reduced pressure to give the crude concentrate containing (R)-N-Boc-isovaline (117.5g, 0.54mol). Crude (R)-N-Boc-isovaline was dissolved in dichloromethane (1175g), and methanesulfonic acid (62.4g, 0.65mol) was added. The mixture was stirred at 24C for 5h. The resulting mixture was evaporated under reduced pressure to give the crude concentrate containing (R)-isovaline mesylate. Crude (R)-isovaline mesylate was dissolved in acetone (1175g), and triethylamine (68.4g, 0.68mol) was added. The mixture was stirred at 24C for 4h. The solid matter was precipitated and filtered, washed with acetone, and dried to give (R)-isovaline (48.7g, 0.42mol) as a white solid in 74.9% yield. Characterization of (R)-isovaline:11 1H NMR (500MHz, D2O) delta (ppm): 1.74 (m, 1H), 1.59 (m, 1H), 1.30 (s, 3H), 0.75 (t, 3H, J=7.5Hz). [alpha]D25=-8.2 (c 1.0, H2O).

Reference： [1]Tetrahedron Asymmetry,2015,vol. 26,p. 1 - 5

35
[ 123254-58-0 ]
[ 3059-97-0 ]

Yield	Reaction Conditions	Operation in experiment
48.7 g		At first, CsAM transformed E. coli was cultured at 30C for 10h in a test tube containing 5mL of 2-YT medium. The seed culture (1mL) was then inoculated in a 500-mL Sakaguchi flask containing 50mL of 2-YT medium. After 20h of incubation at 30C with reciprocal shaking (at 130rpm), the cultured cells were collected by centrifugation from 1.0L of the cultured broth (from twenty-one Sakaguchi flasks) and were suspended in 1.0L of water. Next, 2-ethyl-2-methyl-malonamide (80g, 0.55mol) and the cultured cell suspensions (860mL) were stirred at 30C for 22h. The pH of the reaction mixture was maintained at 7.0 with 30% sodium hydroxide solution. The resulting mixture was centrifuged, and the supernatant was adjusted to pH 12.0 with 30% sodium hydroxide solution. The ammonia in the mixture was removed by evaporation under reduced pressure and concentrated to give the crude mixture (272.6g), which contains (S)-2-ethyl-2-methyl-malonamic acid. A solution of 13% hypochlorous acid (481g, 0.83mol), 48% sodium hydroxide solution (138g, 1.65mol), crude mixture (272.6g), which contains (S)-2-ethyl-2-methyl-malonamic acid, and water (10g) were stirred at 0C for 2h. The mixture was heated to 20C and stirred for 2.5h. Subsequently, the pH of the mixture was adjusted to 4.0 with concentrated hydrochloric acid (238.3g, 2.28mol) and stirred at 20C for 25h to give crude (R)-isovaline hydrochloride. The resulting mixture, sodium hydroxide (23.0g, 0.56mol), 2-propanol (168.8g), and di-tert-butyl dicarbonate (143.0g, 0.65mol) were stirred at 40C for 3.5h, while the pH was maintained at 11.0 by the addition of sodium hydroxide (68.5g, 1.66mol). The resulting mixture was stirred at 40C for 2h and then cooled to 0C and stirred for 15h. Concentrated hydrochloric acid (235.0g, 2.26mol) was added to the resulting mixture and the mixture was heated to 18C. The organic layer was separated and evaporated under reduced pressure. Toluene (423.0g) and water (212.0g) were added to the concentrate and the organic layer (560.0g) was separated and evaporated under reduced pressure to give the crude concentrate containing <strong>[123254-58-0](R)-N-Boc-isovaline</strong> (117.5g, 0.54mol). Crude <strong>[123254-58-0](R)-N-Boc-isovaline</strong> was dissolved in dichloromethane (1175g), and methanesulfonic acid (62.4g, 0.65mol) was added. The mixture was stirred at 24C for 5h. The resulting mixture was evaporated under reduced pressure to give the crude concentrate containing (R)-isovaline mesylate. Crude (R)-isovaline mesylate was dissolved in acetone (1175g), and triethylamine (68.4g, 0.68mol) was added. The mixture was stirred at 24C for 4h. The solid matter was precipitated and filtered, washed with acetone, and dried to give (R)-isovaline (48.7g, 0.42mol) as a white solid in 74.9% yield. Characterization of (R)-isovaline:11 1H NMR (500MHz, D2O) delta (ppm): 1.74 (m, 1H), 1.59 (m, 1H), 1.30 (s, 3H), 0.75 (t, 3H, J=7.5Hz). [alpha]D25=-8.2 (c 1.0, H2O).

Reference： [1]Tetrahedron Asymmetry,2015,vol. 26,p. 1 - 5

36
[ 123254-58-0 ]
C₇H₁₃F₃N₂O*C₂HF₃O₂ [ No CAS ]