Boc-Thr(Me)-OH | Carbamates

CAS No. :	48068-25-3
Formula :	C₁₀H₁₉NO₅
M.W :	233.26
SMILES Code :	C(=O)(OC(C)(C)C)N[C@@H]([C@H](OC)C)C(=O)O
MDL No. :	MFCD00076990
InChI Key :	VWSUOKFUIPMDDX-RQJHMYQMSA-N
Pubchem ID :	15460346

Safety of [ 48068-25-3 ]

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

Computational Chemistry of [ 48068-25-3 ] Show Less

Physicochemical Properties

Num. heavy atoms	16
Num. arom. heavy atoms	0
Fraction Csp3	0.8
Num. rotatable bonds	7
Num. H-bond acceptors	5.0
Num. H-bond donors	2.0
Molar Refractivity	57.55
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	84.86 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.01
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	0.84
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.0
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.	0.32
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	0.09
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	0.85

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.35
Solubility	10.3 mg/ml ; 0.0443 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-2.2
Solubility	1.46 mg/ml ; 0.00624 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	-0.82
Solubility	34.9 mg/ml ; 0.15 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	No
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-7.13 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.	0.56

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)	3.27

Application In Synthesis of [ 48068-25-3 ]

* 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 [ 48068-25-3 ]

[ 48068-25-3 ] Synthesis Path-Downstream 1~54

1
[ 2592-18-9 ]
[ 74-88-4 ]
[ 48068-25-3 ]

References: [1]Journal of Organic Chemistry,1979,vol. 44,p. 2299 - 2300.

2
[ 48068-25-3 ]
[ 64698-98-2 ]
[ 102979-58-8 ]

References: [1]Journal of Medicinal Chemistry,1986,vol. 29,p. 1281 - 1284.

3
[ 48068-25-3 ]
(S)-2-{(2S,3R)-3-Methoxy-2-[(pyrazine-2-carbonyl)-amino]-butyrylamino}-3,3-dimethyl-butyric acid [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 5007 - 5011.

4
[ 48068-25-3 ]
(S)-2-{(2S,3R)-3-Methoxy-2-[(pyrazine-2-carbonyl)-amino]-butyrylamino}-3,3-dimethyl-butyric acid methyl ester [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 5007 - 5011.

5
[ 48068-25-3 ]
(S)-2-((2S,3R)-2-Amino-3-methoxy-butyrylamino)-3,3-dimethyl-butyric acid methyl ester; hydrochloride [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 5007 - 5011.

6
[ 48068-25-3 ]
(1S,3aR,6aS)-2-((S)-2-{(2S,3R)-3-Methoxy-2-[(pyrazine-2-carbonyl)-amino]-butyrylamino}-3,3-dimethyl-butyryl)-octahydro-cyclopenta[c]pyrrole-1-carboxylic acid [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 5007 - 5011.

7
[ 48068-25-3 ]
(1S,3aR,6aS)-2-((S)-2-{(2S,3R)-3-Methoxy-2-[(pyrazine-2-carbonyl)-amino]-butyrylamino}-3,3-dimethyl-butyryl)-octahydro-cyclopenta[c]pyrrole-1-carboxylic acid ethyl ester [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 5007 - 5011.

8
[ 48068-25-3 ]
(1S,3aR,6aS)-2-((S)-2-{(2S,3R)-3-Methoxy-2-[(pyrazine-2-carbonyl)-amino]-butyrylamino}-3,3-dimethyl-butyryl)-octahydro-cyclopenta[c]pyrrole-1-carboxylic acid (1-cyclopropylaminooxalyl-butyl)-amide [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 5007 - 5011.

9
[ 48068-25-3 ]
(1S,3aR,6aS)-2-((S)-2-{(2S,3R)-3-Methoxy-2-[(pyrazine-2-carbonyl)-amino]-butyrylamino}-3,3-dimethyl-butyryl)-octahydro-cyclopenta[c]pyrrole-1-carboxylic acid [1-(cyclopropylcarbamoyl-hydroxy-methyl)-butyl]-amide [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 5007 - 5011.

10
[ 48068-25-3 ]
(E)-(S)-4-[(2S,3R)-3-Methoxy-2-((S)-3-methyl-2-methylamino-3-phenyl-butyrylamino)-butyryl]-methyl-amino}-2,5-dimethyl-hex-2-enoic acid [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 4329 - 4332.

11
[ 48068-25-3 ]
(E)-(S)-4-[((2S,3R)-2-Amino-3-methoxy-butyryl)-methyl-amino]-2,5-dimethyl-hex-2-enoic acid ethyl ester; hydrochloride [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 4329 - 4332.

12
[ 48068-25-3 ]
(E)-(S)-4-({(2S,3R)-2-[(S)-2-(tert-Butoxycarbonyl-methyl-amino)-3-methyl-3-phenyl-butyrylamino]-3-methoxy-butyryl}-methyl-amino)-2,5-dimethyl-hex-2-enoic acid [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 4329 - 4332.

13
[ 48068-25-3 ]
(E)-(S)-4-({(2S,3R)-2-[(S)-2-(tert-Butoxycarbonyl-methyl-amino)-3-methyl-3-phenyl-butyrylamino]-3-methoxy-butyryl}-methyl-amino)-2,5-dimethyl-hex-2-enoic acid ethyl ester [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 4329 - 4332.

14
[ 48068-25-3 ]
[ 102979-62-4 ]

References: [1]Journal of Medicinal Chemistry,1986,vol. 29,p. 1281 - 1284.

15
[ 48068-25-3 ]
[ 102979-66-8 ]

References: [1]Journal of Medicinal Chemistry,1986,vol. 29,p. 1281 - 1284.

16
[ 48068-25-3 ]
[ 102979-70-4 ]

References: [1]Journal of Medicinal Chemistry,1986,vol. 29,p. 1281 - 1284.

17
[ 2592-18-9 ]
hexane-diethyl ether [ No CAS ]
[ 101-83-7 ]
[ 74-88-4 ]
[ 48068-25-3 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; methanol; ethyl acetate;	[Process 1] Boc-Thr(Me)-OH In a THF solution containing 0.8 g of Boc-Thr-OH, 100 mg of sodium hydride (60% in oil) was added under ice cooling and the resultant mixture was stirred for 30 min at room temperature. Further, 2.8 ml of methyl iodide was added and the obtained reaction mixture was stirred overnight at room temperature. The reaction mixture was evaporated under reduced pressure and the resultant residue was redissolved in ethyl acetate, washed with 5% sodium hydrogensulfite aqueous solution, water and saturated sodium chloride aqueous solution, successively, and dried over anhydrous sodium sulfate. The dried solution was evaporated under reduced pressure, dissolved in methanol, mixed with DCHA and reevaporated. Ether-hexane was added to the residue to give 0.55 g of the title compound as its DCHA salt.

References: [1]Patent: US6313094,2001,B1 .

18
[ 48068-25-3 ]
(2S,4S)-4-fluoropyrrolidine-2-carboxamide hydrochloride [ No CAS ]
(2S,4S)-2-(aminocarbonyl)-1-[(2S,3R)-2-(tert-butoxycarbonylamino)-3-methoxybutanoyl)-4-fluoropyrrolidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		(1) Synthesis of (2S,4S)-2-(aminocarbonyl)-1-[(2S,3R)-2-(tert-butoxycarbonylamino)-3-methoxybutanoyl)-4-fluoropyrrolidine According to the manner similar to that of Example 1(3), the title compound (2.28 g) was obtained as a colorless amorphous substance from (2S,4S)-2-(aminocarbonyl)-4-fluoropyrrolidine hydrochloride (1.18 g) and <strong>[48068-25-3](2S,3R)-2-(tert-butoxycarbonylamino)-3-methoxybutanoic acid</strong> (1.63 g). MS(ESI pos.)m/z: 370([M+Na]+), (ESI neg.)m/z: 346([M-H]-).

References: [1]Patent: EP1333025,2003,A1 .
[2]Chemical and Pharmaceutical Bulletin,2008,vol. 56,p. 1110 - 1117.

19
[ 1003961-25-8 ]
[ 48068-25-3 ]
[ 1174654-27-3 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution containing Boc-L-Thr(Mc)- OH (105 mg, 0.45 mmol) in NMP (4 mL) at 0 0C was added HATU (169 mg, 0.44 mmol) followed by DIPEA (0.1 mL, 0.57 mmol). After 5 min, amine 59 (124 mg, 0.45 mmol) in NMP (5 mL) was added in a dropwise fashion. The reaction mixture was allowed to warm to ambient temperature. After 1 h, the solution was diluted with EtOAc, washed with IM HCl, saturated aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 260 mg of amide 60 as an orange-colored oil that was used without further purification.

References: [1]Patent: WO2009/94287,2009,A1 .Location in patent: Page/Page column 56.

20
[ 1003961-41-8 ]
[ 48068-25-3 ]
[ 1174654-15-9 ]

Yield	Reaction Conditions	Operation in experiment
48%	With N-ethyl-N,N-diisopropylamine; HATU; In 1-methyl-pyrrolidin-2-one; at 0 - 20℃; for 6h;	To a solution containing crude 49 (0.3 g, 1.1 mmol) and <strong>[48068-25-3]Boc-Thr(Me)-OH</strong> (0.31 g, 1.3 mmol) in NMP (5 mL) at 0 0C was added DIPEA (0.25 mL, 1.44 mmol) followed by HATU (0.5 g, 1.3 mmol) and the reaction mixture was stirred at ambient temperature for 6 h. The reaction mixture was diluted with EtOAc and washed successively with dilute aqueous HCl, water, saturated aqueous NaHCO3, water, and brine. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated. The product was purified by reverse-phase HPLC (Cl 8; 50-100% ACN/watcr v/v 0.1% AcOH). The product-containing fractions were concentrated in vacuo to afford 0.28 g (48%) of 50 as a white solid. 1H NMR (CDCl3. 300 MHz): delta 8.2 (s, IH), 7.8-7.5 (m, IH), 7.05 (m, 2H), 6.92 (m, IH), 5.6 (d, J= 10.7 Hz, IH), 4.6 (m, IH), 4.1 (m, IH), 3.6 (m, 3H), 3.4 (s, 3H), 3.35 (m, IH), 2.6 (m, IH), 2.1 (m, 2H), 1.7 (m, I H), 1.48 (m, H) 1.45 (s, 9H), 1.21 (d, ./ = 6.45 Hz, 3 H, major rotamer), 1.14 (d, J = 6.45 Hz, minor rotamer), 0.90 (d, J = 7.03 Hz, minor rotamer), 0.76 (d, J= 6.45 Hz, 3H, major rotamer) ppm. Mass spectrum, m/z = [447.7] (M)+.

References: [1]Patent: WO2009/94287,2009,A1 .Location in patent: Page/Page column 49.

21
[ 1174654-54-6 ]
[ 48068-25-3 ]
[ 1174654-55-7 ]

Yield	Reaction Conditions	Operation in experiment
38%	With N-ethyl-N,N-diisopropylamine; HATU; In 1-methyl-pyrrolidin-2-one; at 0 - 20℃; for 2h;	To a solution containing amine 66 (225 mg, 0.72 mmol), <strong>[48068-25-3]Boc-Thr(Me)-OH</strong> (177 mg, 0.75 mmol), and HATU (289 mg, 0.76 mmol) in NMP (4 mL) at 0 C was added DIPEA (110 mg, 0.86 mmol). The reaction mixture was allowed to warm to ambient temperature. After 2 h, reaction mixture was diluted with diethyl ether and washed successively with dilute aqueous HCl, water (5X), aqueous NaHCO3, water (2X), then brine. The organic phase was dried with anhydrous Na2SO4, filtered, and concentrated to afford the crude product which was purified by flash silica gel chromatography (1 :1 hexanes/EtOAc) to afford 146 mg (38%) of 67 as a tan-colored foam. Mass spectrum, m/z = [526.0] (M)+.

References: [1]Patent: WO2009/94287,2009,A1 .Location in patent: Page/Page column 61.

22
[ 1174653-58-7 ]
[ 48068-25-3 ]
[ 1174653-59-8 ]

Yield	Reaction Conditions	Operation in experiment
61%	With N-ethyl-N,N-diisopropylamine; HATU; In 1-methyl-pyrrolidin-2-one; at 0 - 20℃; for 12h;	To a solution containing crude 9 (0.33 g, 1.27 mmol) and Boc-L-Thr(Me)-OH (0.30 g, 1.27 mmol) in NMP ( 10 mL) at 0 0C was added DIPEA (0.22 mL, 1.27 mmol) followed by HATU (0.48 g, 1.27 mmol) and the reaction mixture was stirred to ambient temperature over 12 h at which point TLC analysis revealed the complete consumption of 9 [1 : 1 EtOAc/hexanes; Ri(9) = 0.01, Rf(IO) = 0.4]. The reaction mixture was diluted with diethyl ether and washed successively with dilute aqueous HCl, water, saturated aqueous NaHCO3, water (5X), brine, and dried over anhydrous Na2SO4, filtered, and concentrated to afford 0.5 g of <n="25"/>crude 10 which was purified by flash silica gel chromatography (20% EtOAc/hexancs) to provide 0.37 g (61%) of 10 as a white solid. 1H NMR (CDCl3, 300 MHz): delta 9.2 (s, IH), 8.4-8.2 ( m, 2H), 7.1 (s, IH), 5.6 (d, J= 10.7 Hz, IH), 5.3 (s, IH), 4.6-4.4 (m, 2H), 4.0 (m, 2h), 3.9 (m, IH), 3.6 (m, IH), 3.4 (s, 3H), 2.8 (dd, J = 16 Hz, 10 Hz). 2.1 (s, 3H), 1.4(s, 9H), 1.1 (d, J = 10.7 Hz, 3H) ppm.

References: [1]Patent: WO2009/94287,2009,A1 .Location in patent: Page/Page column 23-24.

23
[ 48068-25-3 ]
[ 543-27-1 ]
[ 537697-19-1 ]

Yield	Reaction Conditions	Operation in experiment
		Part A. ((lR,2R)-l-Hydroxymethyl-2-methoxy-propyl)-carbamic acid tert-butyl ester To a cold solution (-15C) of BocThr(Me)OH (5.14 g, 22 mmol) in dichloroethane (22 mL) were successively added N-methyl morpholine (2.44 mL, 22 mmol) and isobutyl chloroformate (2.99 mL, 22 mmol). After one min, the precipitate was filtered and washed with dichloroethane (5 x 4mL). The filtrate and washings were combined in a large three neck flask in an ice-salt bath. A solution of NaBH4 (1.26 g, 33 mmol) in H2O (11 mL) was added at once, proceeding a strong evolution of gas, followed by H20 (500 mL). The mixture was then extracted with EtOAc (5 x 150 mL). The combined EtOAc was dried ( a2S04) and concentrated to give the titled compound (5 g). MS (MH+ 220).

References: [1]Patent: WO2011/44212,2011,A1 .Location in patent: Page/Page column 55.

24
[ 48068-25-3 ]
[ 1287206-14-7 ]

References: [1]Patent: WO2011/44212,2011,A1 .

25
[ 48068-25-3 ]
[ 1287206-15-8 ]

References: [1]Patent: WO2011/44212,2011,A1 .
[2]Journal of Medicinal Chemistry,2018,vol. 61,p. 6748 - 6758.

26
[ 48068-25-3 ]
[ 1287206-16-9 ]

References: [1]Patent: WO2011/44212,2011,A1 .

27
[ 48068-25-3 ]
[ 1287206-17-0 ]

References: [1]Patent: WO2011/44212,2011,A1 .

28
[ 48068-25-3 ]
trans-2-pyrazin-2-ylcyclopropanecarboxylic acid ((2R,3R)-2-amino-3-methoxybutyl)-(4'-propylbiphenyl-4-yl)amide ditrifluoroacetate [ No CAS ]

References: [1]Patent: WO2011/44212,2011,A1 .

29
[ 48068-25-3 ]
[ 124-40-3 ]
[ 1355149-26-6 ]

Yield	Reaction Conditions	Operation in experiment
78%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;	Preparation of Compound 57Step 1: Tert-butyl ((2S,3R)-l-(dimethylamino)-3-methoxy-l-oxobutan-2-yl)carbamate. A solution of <strong>[48068-25-3](2S,3R)-2-(tert-butoxycarbonylamino)-3-methoxy-butanoic acid</strong> (400 mg, 1.7 mmol) in DMF (3 mL) was added DIEA (665 mg, 0.9 mL, 5.1 mmol) , HBTU (976mg, 2.6 mmol) and N-methylmethanamine (580 mg, 0.62 mL of 40 %w/w, 5.1 mmol) and stirred overnight at RT. The mixture was diluted with EtOAc (20 mL), washed with H20 (15 mL), brine (15 mL), dried over Na2S04 and concentrated. The residue was purified by silica gel chromatography, eluting with 0-60% EtOAc in hexane to afford tert-butyl ((2S,3R)-l-(dimethylamino)-3-methoxy-l-oxobutan-2-yl)carbamate (350 mg, 1.3 mmol, 78%). To resulting tert-butyl ((2S,3R)-l-(dimethylamino)-3-methoxy-l-oxobutan-2- yl)carbamate (350 mg, 1.3 mmol) was added HC1 (5 mL of 4.0 M, 20 mmol) in dioxane and stirred for 2 h at RT. The solution was concentrated and used directly in next step.

References: [1]Patent: WO2012/6055,2012,A2 .Location in patent: Page/Page column 207-208.

30
[ 48068-25-3 ]
[ 1355041-29-0 ]

References: [1]Patent: WO2012/6055,2012,A2 .

31
[ 48068-25-3 ]
[ 1355041-28-9 ]

References: [1]Patent: WO2012/6055,2012,A2 .

32
[ 48068-25-3 ]
C₂₇H₄₀N₂O₅S [ No CAS ]

References: [1]Patent: WO2012/6055,2012,A2 .

33
[ 48068-25-3 ]
C₂₆H₃₈N₂O₅S [ No CAS ]

References: [1]Patent: WO2012/6055,2012,A2 .

34
[ 123-75-1 ]
[ 48068-25-3 ]
[ 1380104-08-4 ]

Yield	Reaction Conditions	Operation in experiment
95%		Compound Gl: Tert-butyl (2S,3R)-3-methoxy-l-oxo-l-(pyrrolidin-l-yl)butan-2- ylcarbamate; (2S,3R)-2-(Tert-butoxycarbonylamino)-3-methoxybutanoic acid (643 mg, 2.76 mmol), which is commercially available, and DIPEA (1.440 mL, 8.27mmol) was mixed in DCM (10 mL). The mixture was cooled to 0 C. TBTU (974 mg, 3.03 mmol) was added and the mixture stirred at rt for 10 min. Pyrrolidine (0.274 mL, 3.31 mmol) was added and the resultant mixture was stirred at rt for 16 h. The mixture was diluted with DCM (10 mL). The organic phase was washed with NaHCC^ (8% in aq. solution) and brine, filtered through a phase separator and concentrated under reduced pressure. The residue was purified via Biotage (gradient; DCM / iso-propanol, 99:1 to 95:5, KP-SIL 340g column). The solvent was removed under reduced pressure to give the title compound (0.704 g, 95%). .H NMR (400 MHZ, CD3OD) delta 1.15, 1.44, 1.82 - 2.05, 3.33, 3.35 - 3.52, 3.54 - 3.65, 3.66 - 3.79, 4.36. Total no of protons: 25. LCMS (M+H)+: 287.

References: [1]Patent: WO2012/74469,2012,A1 .Location in patent: Page/Page column 56-57.

35
[ 48068-25-3 ]
[ 124-40-3 ]
[ 1355041-27-8 ]

Yield	Reaction Conditions	Operation in experiment
2.02 g	With N-ethyl-N,N-diisopropylamine; HATU; In water; N,N-dimethyl-formamide; at 20℃;	To a solution of N- (tert-butoxycarbonyl) -O-methyl-L- threonine (2.33 g) , 50% aqueous dimethylamine solution (1.08 g) and N-ethyl-N- (1-methylethyl) propan-2-amine (2.58 g) in D F (30 mL) was added 0- (7-azabenzotriazol-l-yl) -Nu,Nu,Nu' ,Nu'- tetramethyluronium hexafluorophosphate (4.18 g) under ice- cooling. The reaction mixture was stirred at room temperature overnight, the reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.02 g) .XH NMR (300 MHz, DMSO-d6) delta 1.01 (3H, d, J = 6.1 Hz), 1.37 (9H, s), 2.83 (3H, s), 3.06 (3H, s) , 3.23 (3H, s) , 3.49 (1H, qd, J = 6.1, 6.1 Hz), 4.42 (1H, dd, J = 8.4, 6.1 Hz), 6.56 (1H, d, J = 8.4 Hz) .

References: [1]Patent: WO2013/18929,2013,A1 .Location in patent: Paragraph 0710.

36
[ 48068-25-3 ]
[ 1422128-54-8 ]

References: [1]Patent: WO2013/18929,2013,A1 .

37
[ 48068-25-3 ]
[ 1355149-26-6 ]

References: [1]Patent: WO2013/18929,2013,A1 .

38
[ 48068-25-3 ]
[ 1422129-97-2 ]

References: [1]Patent: WO2013/18929,2013,A1 .

39
[ 48068-25-3 ]
[ 1575-37-7 ]
[ 1449473-62-4 ]

References: [1]Patent: WO2013/114250,2013,A1 .

40
[ 48068-25-3 ]
[ 1575-37-7 ]
C₁₆H₂₃N₃O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 77 2-{2-[( 1 R,2R)-1 -Amino-2-methoxypropyl1-1 H-benzimidazol-5-yl)benzonitrile To 4-bromo-1 ,2-benzenediamine (2.3 g, 12.3 mmol) and N-boc-O-methyl-L-threonine (2.9 g, 12.3 mmol) was added DCM (100 ml_) followed by DIEA (3 ml_, 17.5 mmol) and HATU (4.7 g, 12.3 mmol). The reaction was stirred at 30C for 16 hours before concentrating in vacuo. To the residue was added AcOH (120 ml_) and the reaction heated to 50C for 2 hours. The reaction was cooled, concentrated in vacuo and diluted with a 2M solution of LiOH in water (250 ml_). The aqueous layer was extracted with EtOAc (2 x 150 ml_), the organic layers combined, dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in dioxane to obtain a 0.075M solution. To an aliquot of this solution (1 ml_) was added cesium carbonate (75 mg, 225 pmol), 2-cyanophenylboronic acid (1 12.5 muomicronIota), water (30 muIota_), and nitrogen was bubbled through for 30 seconds. Pd(dppf)CI2 (6 mg, 7.5 pmol) was then added and the reaction shaken at 90C for 16 hours before cooling and filtering. MeOH (200muIota_) was then added followed by 4M HCI in dioxane (300 muIota_) and the reaction shaken at 30C for 16 hours. The reaction was concentrated in vacuo and purified using preparative HPLC (Boston Symmetrix ODS-H; 150 x 30 mm x 5 mu; mobile phase A: Acetonitrile, mobile phase B: 0.225% TFA in water; eluting with a gradient of 22-52% organic, over 10 minutes with a flow rate of 30 mL/min) to afford the title compound as the TFA salt. LCMS Rt = 2.42 minutes MS m/z 307 [M+H]+

References: [1]Patent: WO2013/114250,2013,A1 .Location in patent: Page/Page column 87; 88.

41
[ 48068-25-3 ]
[ 1575-37-7 ]
[ 1449476-01-0 ]

Yield	Reaction Conditions	Operation in experiment
96%		Preparation 23 tert-Butyl {(1 S,2R)-1 -[(2-amino-4-bromophenyl)carbamoyl1-2- methoxypropyDcarbamate To a solution of N-(fe/t-butoxycarbonyl)-O-methyl-L-threonine (Preparation 51 , 4 g, 17.15 mmol) in anhydrous THF (150 mL) was added NMM (2.43 g, 24.01 mmol) and isobutyl chloroformate (2.58 g, 18.86 mmol) at -78C and the reaction was stirred at this temperature for 1 hour. This solution was then added to a solution of 4- bromophenyl-1 ,2-diamine (3.85 g, 20.58 mmol) in THF ( 50 mL) at -78C and the reaction was stirred warming to room temperature for 18 hours. The reaction was quenched by the addition of water and extracted with EtOAc (3 x 50 mL). The organic layers were combined, dried over Na2SO4 and concentrated in vacuo. The residue was purified using reverse phase column chromatography eluting with 0-60% acetonitrile in 0.1 % formic acid in water to afford the title compound (6.60 g, 96%). 1H NMR (400MHz, MeOD): delta ppm 0.95-1 .20 (m, 3H), 1 .45 (s, 9H), 3.38 (s, 3H), 3.85 (m, 1 H), 4.20 (m, 1 H), 6.60-7.20 (m, 3H).

References: [1]Patent: WO2013/114250,2013,A1 .Location in patent: Page/Page column 150.

42
[ 1449475-35-7 ]
[ 48068-25-3 ]
[ 543-27-1 ]
C₂₃H₂₅FN₄O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 91 4-{2-[( 1 R,2R)-1 -Amino- -methoxypropyl1-6-fluoro-1 H-benzimidazol-5-yl)benzonitrile Isobutylchloroformate (0.17 g, 0.125 mmol) was added to a cooled mixture of N-(tert- butoxycarbonyl)-O-methyl-L-threonine (Preparation 51 , 0.28 g, 0.12 mmol) and NMM (0.137 g, 0.135 mmol) in THF (10 ml_) at -78C. The reaction was stirred at this temperature for 1 hour and then added dropwise to a cooled solution of 4',5'-diamino- 2'-fluorobiphenyl-4-carbonitrile (Preparation 76, 0.28 g, 0.12 mmol) at -78C and stirred at this temperature for 3 hours. The reaction was partitioned between EtOAc (70 ml_) and saturated aqueous NaHCO3 solution (30 ml_), the organic layer was collected and concentrated in vacuo to afford a brown residue that was dissolved in AcOH (5 ml_) and heated to 40C for 2 days followed by 50C for 1 day. The reaction was concentrated in vacuo and purified using silica gel column chromatography to afford a beige solid that was dissolved in TFA DCM (0.2 mL/3 ml_) and stirred at room temperature for 5 hours. The reaction was partitioned between saturated aqueous Na2CO3 solution (10 ml_) and EtOAc (30 ml_). The organic layer was collected and concentrated in vacuo. The residue was purified using reverse phase column chromatography eluting with a gradient of acetonitrile in 0.5% formic acid in water followed by elution through an SCX cartridge to afford the title compound that contains some of the other diastereomer. 1H NMR (400MHz, MeOD): delta ppm 1 .08 (m, 3H), 3.22 (s, 3H), 3.82 (m, 1 H), 4.36-4.50 (m, 1 H), 7.42 (m, 1 H), 7.69 (m, 1 H), 7.76 (m, 2H), 7.82 (m, 2H), 8.40 (br s, 1 H). LCMS (4.5 minute run) Rt = 1 .80 minutes MS m/z 325 [M+H]+

References: [1]Patent: WO2013/114250,2013,A1 .Location in patent: Page/Page column 96; 97.

43
[ 471240-59-2 ]
[ 48068-25-3 ]
[ 543-27-1 ]
C₂₃H₂₆N₄O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 92 4-{2-[(1 R,2R)-1 -Amino- -methoxypropyl1-1 H-benzimidazol-5-yl)benzonitrile To a stirred solution of N-(terf-butoxycarbonyl)-O-methyl-L-threonine (Preparation 51 , 1 .696 g, 7.27 mmol) in acetonitrile (25 mL) at 0C was added NMM (1 .12 mL, 10.2 mmol) followed by isobutylchloroformate (0.943 mL, 7.27 mmol) dropwise. The reaction was stirred at 0C for 35 minutes forming a white precipitate (NMM.HCI salt). This suspension was added dropwise filtering through a cotton wool plug to a solution of 3',4'-diaminobiphenyl-4-carbonitrile (Preparation 82, 1 .521 g, 7.271 mmol) in acetonitrile (25 mL) and the reaction stirred at room temperature for 18 hours. The reaction was diluted with EtOAc (100 mL) and 5% aqueous citric acid (50 mL). The organic layer was separated, washed further with 5% aqueous citric acid (50 mL), brine, dried over MgSO4 and concentrated in vacuo. The residue was dissolved in AcOH (20 mL) and stirred at room temperature for 4 days. The reaction was concentrated to dryness and partitioned between saturated aqueous NaHCO3 solution (50 mL) and EtOAc (100 mL). The organic layer was collected, dried over Na2SO and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 0-50% EtOAc in heptanes to afford an orange/brown foam that was dissolved in 4M HCI in dioxane (30 mL) and stirred at room temperature for 2 hours. The reaction was concentrated in vacuo and diluted with 4M NaOH to pH=9. The aqueous solution was extracted with EtOAc (2 x 40 mL), the organic layers were combined and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 95:5:0.5 DCM:MeOH:NH3 to afford the title compound (1 g, 46%). 1H NMR (400MHz, CDCI3): delta ppm 1 .20 (d, 3H), 3.40 (s, 3H), 3.90 (m, 1 H), 4.25 (m, 1 H), 7.45 (d, 2H), 7.60-7.75 (m, 6H). LCMS (5 minute run) Rt = 1 .44 minutes MS m/z 307 [M+H]+

References: [1]Patent: WO2013/114250,2013,A1 .Location in patent: Page/Page column 97; 98.

44
[ 1449475-35-7 ]
[ 48068-25-3 ]
[ 1449473-82-8 ]

References: [1]Patent: WO2013/114250,2013,A1 .

45
[ 1449475-37-9 ]
[ 48068-25-3 ]
[ 1449473-87-3 ]

Yield	Reaction Conditions	Operation in experiment
15%		General procedure: Example 96 (1 R,2R)-1 -[5-(2,2-Dimethylpropyl)-5-fluoro-1 H-benzimidazol-2-yl1-2-methoxypropan-1 - amine Method 3 To a suspension of <strong>[48068-25-3]Boc-Thr(Me)-OH</strong> (23.8 mg, 0.102 mmol) in acetonitrile (0.4 mL) was added 4-methylmorpholine (0.025 mL, 0.23 mmol) and isobutyl chloroformate (0.014 mL, 0.11 mmol). After stirring for 45 minutes 4-fluoro-5- neopentylbenzene-1 ,2-diamine (Preparation 73, 22 mg, 0.1 1 mmol) was added and the reaction was stirred for 18 hours. The solution was concentrated in vacuo, redissolved in acetic acid (0.4 mL, 7 mmol) and heated to 65C for 5 hours. After cooling, the solution was concentrated in vacuo, redissolved in methylene chloride and washed with aqueous saturated sodium hydrogen carbonate solution (2x). The organic layer was dried over anhydrous magnesium sulphate, filtered, and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with a 0-100% ethyl acetate/hexanes gradient to afford the protected benzimidazole as a clear oil. The oil was dissolved in methylene chloride (3 mL) and treated with trifluoroacetic acid (0.5 mL, 6 mmol). After stirring for 2 hours, the solution was concentrated in vacuo, redissolved in methylene chloride and treated with saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted with methylene chloride (2x). The organic layers were combined, dried over anhydrous magnesium sulphate, filtered, and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with a 0-100% CMA80/methylene chloride gradient to afford the title compound (15 mg, 15%) as a white solid. 1H NMR (400MHz, DMSO-d6): delta ppm 0.93 (s, 9H), 1 .00 (d, 3H), 2.61 (s, 2H), 3.25 (s, 3H), 3.68 (m, 1 H), 3.97 (d, 1 H), 7.27 (m, 2H). LCMS Rt = 1 .16 minutes MS m/z 294 [M+H]+

References: [1]Patent: WO2013/114250,2013,A1 .Location in patent: Page/Page column 99; 100.

46
[ 1449475-51-7 ]
[ 48068-25-3 ]
[ 1449474-14-9 ]

References: [1]Patent: WO2013/114250,2013,A1 .

47
[ 1449475-51-7 ]
[ 48068-25-3 ]
C₂₃H₂₄ClFN₄O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 120 4-{2-[( 1 R,2R)-1 -Amino-2-.methoxypropyl1-4-chloro-1 H-benzimidazol-5-yl)-2- fluorobenzonitrile Method 4 Step 1 To a solution of N-(terf-butoxycarbonyl)-O-methyl-L-threonine (Preparation 51 , 280 mg, 1 .20 mmol) in DMF (15 ml_) was added NMM (175 mg, 1 .73 mmol) and HATU (525 mg, 1 .38 mmol) at 0C. The reaction was stirred at 0C for 2 hours before a solution of 3',4'-diamino-2'-chloro-3-fluorobiphenyl-4-carbonitrile (Preparation 80, 300 mg, 1 .15 mmol) in DMF (5 ml_) was added with heating to 50C for 18 hours. The reaction was diluted with water (80 ml_) and brine (80 ml_), and extracted into EtOAc (3 x 30 mL). The organic layers were combined, washed with brine (2 x 100 mL), dried over Na2SO4 and concentrated in vacuo to afford a brown oil that was dissolved in DMSO (1 mL) and purified using reverse phase column chromatography eluting with 0-100% acetonitrile in 0.1 % formic acid in water over 30 minutes to afford a pale brown foam. Step 2 The foam was dissolved in AcOH (15 mL) and heated to 40C for 18 hours. The reaction was concentrated in vacuo aeotroping with DCM. The residue was purified using silica gel column chromatography eluting with 0-15% EtOAc in DCM to afford a brown solid. Step 3 The solid was dissolved in 4M HCI in dioxane (3 mL) and stirred at room temperature for 3 hours. The solvent was removed in vacuo and the residue was dissolved in MeOH (1 mL) and 0.7N NH3 (10 mL). The solvents were removed in vacuo and the residue purified using silica gel column chromatography eluting with DCM:MeOH:NH3 (99:1 :0.1 to 96:4:0.1 ) to afford a white solid (49 mg, 45%). 1H NMR (400MHz, MeOD): delta ppm 1 .16 (d, 3H), 3.35 (s, 3H) 3.68-3.74 (m, 1 H), 4.09 (d, 1 H), 7.28 (d, 1 H), 7.49-7.53 (m, 2H), 7.59 (d, 1 H), 7.84 (dd, 1 H). LCMS (4.5 minute run) Rt = 1 .90 minutes MS m/z 359 [M+H]+

References: [1]Patent: WO2013/114250,2013,A1 .Location in patent: Page/Page column 115; 116.

48
[ 1449475-73-3 ]
[ 48068-25-3 ]
[ 1449474-39-8 ]

References: [1]Patent: WO2013/114250,2013,A1 .

49
[ 1449475-73-3 ]
[ 48068-25-3 ]
C₂₁H₃₁N₃O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 145 (1 R,2R)-1 -(5-Cvclopentyl-1 H-benzo[d1imidazol-2-yl)-2-methoxypropan-1 -amine To a solution of <strong>[48068-25-3]Boc-Thr(Me)-OH</strong> (1 13 mg, 0.48 mmol) in N,N-dimethylformamide (3.0 mL) was added HATU (225 mg, 0.592 mmol). The mixture was stirred for 30 minutes and then 4-cyclopentylbenzene-1 ,2-diamine (Compound 84, 1 18 mg, 0.669 mmol) was added. After stirring for 2 days, the solution was diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulphate, filtered, and concentrated in vacuo. To the resulting residue was added acetic acid (3 mL, 50 mmol) and the mixture allowed to stir for 2 days. The reaction mixture was then concentrated in vacuo and purified by silica gel column chromatography eluting with 0-100% ethyl acetate in hexanes. The resulting brown oil was dissolved in methylene chloride (5 mL) and treated with trifluoroacetic acid (0.5 mL, 6 mmol). After stirring for 3 hours, the reaction mixture was concentrated in vacuo, redissolved in methylene chloride, and washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0-100% methylene chloride/CMA80 gradient to afford the title compound (10.4 mg, 8%) as a white solid. 1H NMR (300 MHz, DMSO-d6): delta ppm 1 .06 (d, 3H), 1 .65 (m, 4H), 1 .80 (m, 2H), 2.08 (m, 2H), 3.15 (m, 1 H), 3.24 (s, 3H), 3.65 (m, 1 H), 3.96 (d, 1 H), 7.05 (m, 1 H), 7.47 (m, 2H), 1 1 .80 (m, 1 H). LCMS Rt = 1 .08 minutes MS m/z 275 [M+H]+

References: [1]Patent: WO2013/114250,2013,A1 .Location in patent: Page/Page column 128; 129.

50
[ 48068-25-3 ]
[ 1449473-70-4 ]

References: [1]Patent: WO2013/114250,2013,A1 .

51
[ 48068-25-3 ]
[ 1449475-32-4 ]

References: [1]Patent: WO2013/114250,2013,A1 .

52
[ 48068-25-3 ]
C₂₃H₂₅ClN₄O₃ [ No CAS ]

References: [1]Patent: WO2013/114250,2013,A1 .

53
[ 48068-25-3 ]
[ 1449473-81-7 ]

References: [1]Patent: WO2013/114250,2013,A1 .

54
[ 48068-25-3 ]
tert-butyl ((1R,2R)-1-(5-(4-cyano-2-fluorophenyl)-1H-benzo[d]imidazol-2-yl)-2-methoxypropyl)carbamate [ No CAS ]

References: [1]Patent: WO2013/114250,2013,A1 .

Historical Records

Technical Information

• Acyl Group Substitution • Bouveault-Blanc Reduction • Catalytic Hydrogenation • Complex Metal Hydride Reductions • Ester Cleavage • Reactions with Organometallic Reagents • Specialized Acylation Reagents-Carbodiimides and Related Reagents

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Code	Phrase
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P401
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H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

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CAS No.: 48068-25-3

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CAS No.: 48068-25-3

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[ 48068-25-3 ] Synthesis Path-Downstream 1~54

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