159622-10-3|(1R,2S)-1-((tert-Butoxycarbonyl)amino)-2-vinylcyclopropanecarboxylic acid| Ambeed

Structure of 159622-10-3

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Quality Control of [ 159622-10-3 ] Purity: 95% SDS Specification

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Product Details of [ 159622-10-3 ]

CAS No. :	159622-10-3
Formula :	C₁₁H₁₇NO₄
M.W :	227.26
SMILES Code :	O=C([C@]1(NC(OC(C)(C)C)=O)[C@H](C=C)C1)O
MDL No. :	MFCD11042412
InChI Key :	RFAQWADNTLIWMG-RDDDGLTNSA-N
Pubchem ID :	10376443

Safety of [ 159622-10-3 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302
Precautionary Statements:	P280-P305+P351+P338

Computational Chemistry of [ 159622-10-3 ] Show Less

Physicochemical Properties

Num. heavy atoms	16
Num. arom. heavy atoms	0
Fraction Csp3	0.64
Num. rotatable bonds	6
Num. H-bond acceptors	4.0
Num. H-bond donors	2.0
Molar Refractivity	58.73
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	75.63 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.3
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	1.41
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.54
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.	0.93
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	0.86
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.41

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.74
Solubility	4.12 mg/ml ; 0.0181 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.	-2.6
Solubility	0.567 mg/ml ; 0.0025 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	-1.25
Solubility	12.9 mg/ml ; 0.0566 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.	-6.69 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	1.0 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)	3.38

Application In Synthesis of [ 159622-10-3 ]

* 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 [ 159622-10-3 ]

[ 159622-10-3 ] Synthesis Path-Downstream 1~36

1
[ 159622-10-3 ]
[ 159700-60-4 ]

Yield	Reaction Conditions	Operation in experiment
49%	With 10 wt% Pd(OH)2 on carbon; hydrogen; In tert-butyl methyl ether; under 760.051 Torr; for 3h;	2 was prepared by a modification of the procedure published in the literature (J. Org. Chem., 2005, 70, 5869). 1 (1.004 g, 4.40 mmol) was dissolved in TI3ME (25 ml) and hydrogenated (1 atm hydrogen gas) over 20percent Pd(OH)2/C (150 mgs)for 3 hours. The suspension was then filtered on celite and thecrude concentrated under reduced pressure. The crude is crystallized from water-ethanol. The crude is taken in 100 ml water and heated to 70° C. and ethanol is added drop wise until the solution becomes cleat The solution is lefi overnight to cool and the solids are filtered to get the pure product 2 (494 mgs, 2.155 mmol, 49percent yield). The pure product is dried under vacuum.
42%	With hydrogen;palladium hydroxide on carbon; In tert-butyl methyl ether; at 20℃; under 760.051 Torr; for 5h;Product distribution / selectivity;	Compound 23; (1R,2R )-1-(tert-butoxycarbonylamino)-2-ethy]cyclopropanecarboxylic acid; (1R,2S)-1-(tert-butoxycarbonyl)-2-vinylcyclopropanecarboxyhc acid (10 0 g, 44 0 mmol, prepared as described in WO2005037214) was dissolved m MTBE (250 mL) and hydrogenated (1 atm H2) over Pd(OH)2/C (1 24 g, 8.80 mmol) for 5 h at rt The reaction was then stopped, filtered and concentrated down to 30 mL, followed by addition of 300 mL hexanes while stirring vigorously After 60 mm, the fine white precipitate was filtered, yielding the titled compound as a fine off-white powder (4 2 g, 42 percent yield) 1H-NMR (400 MHz, d6-DMSO) delta 12 2 (s, 1 H), 7 41 (s, 1 H), 1.29 - 1 54 (m, 3 H), 1 36 (s, 9 H), 1 18 - 1 21 (m, 1 H), 0 96 - 0 98 (m, 1 H), 0 90 (t, 3 H); (1R,2R)-1-(tert-butoxycarbonylamino)-2-ethylcyclopropanecarboxylic acid; (li,25)-1-(tert-butoxycarbonyl)-2-vinyIcyclopropanecarboxylic acid (10.0 g, 44.0 mmol, prepared as described in WO2005037214) was dissolved in MTBE (250 mL) and hydrogenated (1 atm H2) over Pd(OH)2/C (1.24 g, 8.80 mmol) for 5 h at rt. The reaction was then stopped, filtered and concentrated down to 30 mL, followed by addition of 300 mL hexanes while stirring vigorously. After 60 min, the fine white precipitate was filtered, yielding the titled compound as a fine off-white powder (4.2 g, 42 percent yield). 1H-NMR (400 MHz, d6-DMSO) delta 12.2 (s, 1 H), 7.41 (s, 1 H), 1.29 - 1.54 (m, 3 H), 1.36 (s, 9 H), 1.18 - 1.21 (m, 1 H), 0.96 - 0.98 (m, 1 H), 0.90 (t, 3 H).

References: [1]Patent: US9206232,2015,B2 .Location in patent: Page/Page column 64; 65.
[2]Patent: WO2008/141227,2008,A1 .Location in patent: Page/Page column 105; 149.
[3]Synthetic Communications,1994,vol. 24,p. 2873 - 2876.

2
[ 159622-09-0 ]
[ 159622-10-3 ]

Yield	Reaction Conditions	Operation in experiment
100%		The vinylcyclopropyl ester 1c (9.23 g, 38.3 mmol) was dissolved in THF (127 mL) and MeOH (127 mL). Aqueous lithium hydroxide solution (1.5 N, 127 mL, 202 mmol) was added at a fast dropwise pace. After 2 h at room temperature, more lithium hydroxide (4.6 g, 202 mmol) was added, and the suspension was stirred at room temperature for an additional 17 h. The suspension was cooled to 0° C. and acidified to pH 5 with 1N HCl, whereupon ethyl acetate (300 mL) was added. It was further acidified to pH 1 and extracted with ethyl acetate (2.x.300 mL). The combined organic layers were washed with brine (200 mL), dried over magnesium sulfate, and concentrated in vacuo to afford 8.91 g of the acid 1d in quantitative yield.
98%	With lithium hydroxide monohydrate; water; In tetrahydrofuran; methanol; at 45℃;	Ste 1: (lR,2S)-l-((tert-butoxycarbonyl)amino)-2-vin lcyclopropanecarboxylic A round-bottom flask was charged with (lR,2S)-ethyl l-((tert- butoxycarbonyl)amino)-2-vinylcyclopropanecarboxylate (4 g, 15.67 mmol) and lithium hydroxide monohydrate (2.63 g, 62.7 mmol). Methanol (52.2 ml), THF (52.2 ml) and water (52.2 ml) were added. The mixture was heated (oil bath at 45°C) overnight. The reaction mixture was concentrated to half-its volume in rotavap and the pH of the mixture was adjusted to pH = 2-3 with aq 1M HC1. The mixture was extracted with dichloromethane (3 x 150 mL). The combined organic extracts were washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated in rotavap to give the title compound (3.5 g, 15.40 mmol, 98 percent yield) as a white powder. No further purification was carried out.

References: [1]Patent: US2009/47252,2009,A1 .Location in patent: Page/Page column 33-34.
[2]Patent: WO2013/74386,2013,A2 .Location in patent: Page/Page column 73.
[3]Synthetic Communications,1994,vol. 24,p. 2873 - 2876.

3
[ 98-10-2 ]
[ 159622-10-3 ]
[ 905994-17-4 ]

References: [1]Bioorganic and Medicinal Chemistry,2007,vol. 15,p. 1448 - 1474.

4
[ 159622-10-3 ]
C₁₁H₁₈N₂O₃ [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry,2007,vol. 15,p. 4057 - 4068.

5
[ 613-94-5 ]
[ 159622-10-3 ]
C₁₈H₂₃N₃O₄ [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry,2007,vol. 15,p. 4057 - 4068.

6
[ 80-17-1 ]
[ 159622-10-3 ]
C₁₇H₂₃N₃O₅S [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry,2007,vol. 15,p. 4057 - 4068.

7
[ 159622-10-3 ]
C₄₆H₄₉N₅O₉S [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry,2007,vol. 15,p. 1448 - 1474.

8
[ 159622-10-3 ]
C₁₂H₁₄N₂O₃S*HCl [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry,2007,vol. 15,p. 1448 - 1474.

9
[ 159622-10-3 ]
[ 928162-28-1 ]

References: [1]Bioorganic and Medicinal Chemistry,2007,vol. 15,p. 1448 - 1474.

10
[ 159622-10-3 ]
C₃₆H₃₂N₄O₆S*HCl [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry,2007,vol. 15,p. 1448 - 1474.

11
[ 159622-10-3 ]
C₄₇H₅₁N₅O₉S [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry,2007,vol. 15,p. 1448 - 1474.

12
[ 17447-60-8 ]
[ 159622-10-3 ]

References: [1]Synthetic Communications,1994,vol. 24,p. 2873 - 2876.

13
[ 159622-08-9 ]
[ 159622-10-3 ]

References: [1]Synthetic Communications,1994,vol. 24,p. 2873 - 2876.

14
[ 159700-59-1 ]
[ 159622-10-3 ]

References: [1]Synthetic Communications,1994,vol. 24,p. 2873 - 2876.

15
[ 259217-95-3 ]
[ 159622-10-3 ]

Yield	Reaction Conditions	Operation in experiment
99%	With sulfuric acid; In water;pH 2;	To an aqueous solution of sodium phosphate buffer (0.1 M, 4.25 liter ("L"), pH 8) housed in a 12 Liter jacked reactor, maintained at 39° C., and stirred at 300 rpm was added 511 grams of Alcalase 2.4 L (about 425 mL) (Novozymes North America Inc.). When the temperature of the mixture reached 39° C., the pH was adjusted to 8.0 by the addition of a 50percent NaOH in water. A solution of the racemic N-Boc-(1R,2S)/(1S,2R)-1-amino-2-vinylcyclopropane carboxylic acid ethyl ester (85 g) in 850 mL of DMSO was then added over a period of 40 min. The reaction temperature was then maintained at 40° C. for 24.5 h during which time the pH of the mixture was adjusted to 8.0 at the 1.5 h and 19.5 h time points using 50percent NaOH in water. After 24.5 h, the enantio-excess of the ester was determined to be 97.2percent, and the reaction was cooled to room temperature (26° C.) and stirred overnight (16 h) after which the enantio-excess of the ester was determined to be 100percent. The pH of the reaction mixture was then adjusted to 8.5 with 50percent NaOH and the resulting mixture was extracted with MTBE (2.x.2 L). The combined MTBE extract was then washed with 5percent NaHCO3 (3.x.100 mL), water (3.x.100 mL), and evaporated in vacuo to give the enantiomerically pure N-Boc-(1R,2S)/-1-amino-2-vinylcyclopropane carboxylic acid ethyl ester as light yellow solid (42.55 g; purity: 97percent (210 nm, containing no acid; 100percent enantiomeric excess ("ee"). The aqueous layer from the extraction process was then acidified to pH 2 with 50percent H2SO4 and extracted with MTBE (2.x.2 L). The MTBE extract was washed with water (3.x.100 mL) and evaporated to give the acid as light yellow solid (42.74 g; purity: 99percent (210 nm, containing no ester).
98%		A round-bottom flask was charged with (1R,2S)-ethyl 1-((tert-butoxycarbonyl)amino)-2-vinylcyclopropanecarboxylate (4 g, 15.67 mmol) and lithium hydroxide monohydrate (2.63 g, 62.7 mmol). Methanol (52.2 ml), THF (52.2 ml) and water (52.2 ml) were added. The mixture was heated (oil bath at 45° C.) overnight. The reaction mixture was concentrated to half-its volume in rotavap and the pH of the mixture was adjusted to pH=2-3 with aq 1M HCl. The mixture was extracted with dichloromethane (3×150 mL). The combined organic extracts were washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated in rotavap to give the title compound (3.5 g, 15.40 mmol, 98percent yield) as a white powder. No further purification was carried out.
90%		To a solution of 1-t-butoxycarbonylamino-2-vinyl-cyclopropanecarboxylic acid ethyl ester (0.34 g, 1.3 mmol) in THF (5 mL) and methanol (5 mL) was added a suspension of LiOH (0.13 g, 5.3 mmol) in water (1.4 mL). After being stirred overnight at room temperature, the reaction was quenched with 10percent HCl (2 mL) and the solvent was removed under vacuum. The resultant solid powder was washed with water (10 mL) to give compound I-1 (0.27 g, 90percent). MS m/z 249.9 (M++23); 1H NMR (CDCl3) delta 10.35 (brs, 1H), 5.84-5.71 (m, 1H), 5.29 (d, J=17.4 Hz, 1H), 5.12 (d, J=10.2 Hz, 1H), 2.23-2.14 (m, 1H), 1.87-1.65 (m, 1H), 1.58-1.41 (m, 1H), 1.43 (s, 9H).

90%		Example 1Synthesis of {4-Cyclopropanesulfonylaminocarbonyl-2,15-dioxo-18-[2-(4-trifluoromethyl-phenyl)-benzo[4,5]furo[3,2-d]pyrimidin-4-yloxy]-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-14-yl}-carbamic acid cyclopentyl ester (Compound 1)Compound I-3 was first prepared from commercially available 1-t-butoxycarbonylamino-2-vinyl-cyclopropanecarboxylic acid ethyl ester via the route shown below:To a solution of 1-t-butoxycarbonylamino-2-vinyl-cyclopropanecarboxylic acid ethyl ester (0.34 g, 1.3 mmol) in THF (5 mL) and methanol (5 mL) was added a suspension of LiOH (0.13 g, 5.3 mmol) in water (1.4 mL). After being stirred overnight at room temperature, the reaction was quenched with 10percent HCl (2 mL) and the solvent was removed under vacuum. The resultant solid powder was washed with water (10 mL) to give compound I-1 (0.27 g, 90percent). MS m/z 249.9 (M++23); 1H NMR (CDCl3) delta 10.35 (brs, 1H), 5.84-5.71 (m, 1H), 5.29 (d, J=17.4 Hz, 1H), 5.12 (d, J=10.2 Hz, 1H), 2.23-2.14 (m, 1H), 1.87-1.65 (m, 1H), 1.58-1.41 (m, 1H), 1.43 (s, 9H).A solution of compound I-1 (0.52 g, 2.3 mmol), 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluoro-phosphate methanaminium (HATU, 1.74 g, 4.6 mmol), and 4-dimethylaminopyridine (1.39 g, 11.6 mmol) in CH2Cl2 (40 mL) was stirred at room temperature for 1 hour, followed by slow addition of cyclopropanesulfonamide (0.57 g, 4.7 mmol), diisopropylethylamine (1.81 mL, 14.0 mmol), and 1,8-diazabicyclo[5,4,0]undec-7-ene (1.80 g, 11.7 mmol) over 15 minutes. After the reaction mixture was stirred at room temperature overnight, the solvent was removed under vacuum. The residue was purified by silica gel column chromatography to give compound I-2 (0.51 g, 66percent). MS m/z 353.1 (M++423); 1H NMR (CDCl3) delta 9.75 (brs, 1H), 5.64-5.51 (m, 1H), 5.30 (d, J=17.4H), 5.16 (d, J=10.2 Hz, 1H), 2.95-2.89 (m, 1H), 2.19-2.10 (m, 1H), 1.93-1.88 (m, 1H), 1.47 (s, 9H), 1.46-1.38 (m, 1H), 1.32-1.23 (m, 2H), 1.15-1.00 (m, 2H).To a solution of compound I-2 (0.50 g, 1.5 mmol) in MeOH (8 mL) was added SOCl2 (0.26 g, 2.2 mmol) at room temperature. After the reaction mixture was refluxed for 1 hour, MeOH and SOCl2 was removed under vacuum. The residue was triturated from pentane and filtered to give intermediate I-3 as an off-white solid (0.32 g, 91percent). MS m/z (M++1); 1H NMR (CD3COD) delta 5.77-5.65 (m, 1H), 5.43 (d, J=17.4 Hz, 1H), 5.32 (d, J=10.2 Hz, 1H), 3.06-2.97 (m, 1H), 2.45 (dd, J=17.4 Hz, J=7.8, 1H), 2.16 (dd, J=8.0 Hz, J=7.8 Hz, 1H), 1.75 (dd, J=10.1 Hz, J=7.8 Hz, 1H), 1.32-0.86 (m, 4H).Compound 1 was prepared via the route shown below:A solution of 3-amino-benzofuran-2-carboxylic acid amide (1.00 g, 5.7 mmol) and pyridine (1 mL, 12.26 mmol) in THF (25 mL) was stirred at 0° C. for 10 min. To the resulting solution was slowly added 4-trifluoromethyl-benzoyl chloride (1.48 g, 7.1 mmol). Then the temperature was raised to room temperature and the mixture was stirred for 12 h. After the solvent was removed under reduced pressure, the resulting solid was collected, washed with water, and air-dried to yield I-4 (1.92 g, 96.0percent). MS: m/z 349.0 (M++1).To a suspension of I-4 (1.92 g, 5.5 mmol) and 2N NaOH (13 mL) in EtOH (25 mL) was heated at 85° C. for 12 h. After cooled, the mixture was acidified and then EtOH was removed. The resulting solid was collected, filtrated, washed with water, and dried to afford I-5 (1.71 g, 95.0percent). MS m/z 331 (M++1).A solution of I-5 (1.71 g, 5.2 mmol) and excess phosphorus oxychloride (POCl3) was refluxed for 2 hours. After cooled and thoroughly concentrated, the mixture was subjected to extraction with methylene chloride and 10percent sodium hydroxide. The organic layer was dried over MgSO4, concentrated, and crystallized from CH2Cl2 and n-hexane to give compound I-6 (1.49 g, 82percent). MS m/z 348.8, 350.9 (M++1); 1H NMR (CDCl3) delta 8.70 (d, 2H), 8.34 (d, 1H), 7.82-7.75 (m, 4H), 7.57 (ddd, 1H).To a suspension of boc-trans-4-hydroxy-L-proline (0.53 g, 2.3 mmol) in DMSO (25 mL) was added t-BuOK (0.82 g, 5.1 mmol) at 0° C. After the mixture was allowed to warm to room temperature and stirred for 1 hour, compound I-6 (0.81 g, 2.3 mmol) was added slowly at 10° C. Stirring was continued overnight. Iodomethane (1.02 g, 6.9 mmol) was added and the reaction mixture was stirred at room temperature for additional 30 minutes. The reaction mixture was neutralized to pH 6-7 by 10percent HCl aqueous solution and subjected to extraction with methylene chloride. The organic layer was dried over MgSO4, evaporated under vacuum, and purified by silica gel column chromatography to give compound I-7 (1.12 g, 86percent). MS m/z 557.8 (M++1); 1H NMR (CDCl3) delta 8.63 (d, 2H), 8.28 (d, 1H), 7.80-7.74 (m, 2H), 7.70 (d, 2H), 7.51 (ddd, 1H).To a solution of compound I-7 (1.13 g, 2.0 mmol) in MeOH (20 mL) was added SOCl2 (1.21 g, 9.8 mmol) at room temperature. The reaction mixture was refluxed for 1 hour, and MeOH and SOCl2 were removed. The residue was triturated in penta...
90%		Compound 1-3 was first prepared from commercially available 1 -t- butoxycarbonylamino-2-vinyl-cyclopropanecarboxylic acid ethyl ester via the route shown below:To a solution of l-i-butoxycarbonylamino-2-vinyl-cyclopropanecarboxylic acid ethyl ester (0.34 g, 1.3 mmol) in THF (5 mL) and methanol (5 mL) was added a suspension of LiOH (0.13 g, 5.3 mmol) in water (1.4 mL). After being stirred overnight at room temperature, the reaction was quenched with 10percent HCI (2 mL) and the solvent was removed under vacuum. The resultant solid powder was washed with water (10 mL) to give compound I-l (0.27 g, 90percent). MS m/z 249.9 (M++23); 1H NMR (CDC13) d 10.35 (brs, 1H), 5.84-5.71 (m, 1H), 5.29 (d, J = 17.4 Hz, 1H), 5.12 (d, J = 10.2 Hz, 1H), 2.23-2.14 (m, 1H), 1.87-1.65 (m, 1H), 1.58-1.41 (m, 1H), 1.43 (s, 9H).
87%	With lithium hydroxide; water; In tetrahydrofuran; methanol;Product distribution / selectivity;	III. Preparation of P1'-P1 Intermediates 1a. Preparation of cyclopropanesulfonic acid (1-(R)-amino-2-(S)-vinyl-cyclopropanecarbonyl)amide HCl salt Step 1: Preparation of 1(R)-tert-butoxycarbonylamino-2(S)-vinyl-cyclopropanecarboxylic acid To a solution of 1(R)-tert-butoxycarbonylamino-2(S)-vinyl-cyclopropanecarboxylic acid ethyl ester (3.28 g, 13.2 mmol) in THF (7 mL) and methanol (7 mL) was added a suspension of LiOH (1.27 g, 53.0 mmol) in water (14 mL). The mixture was stirred overnight at room temperature and quenched with 1N NaOH (15 mL) and water (20 mL). The resulting mixture was washed with ethyl acetate (20 mL), and the organic phase was extracted with 20 mL 0.5N NaOH. The combined aqueous phases were acidified with 1N HCl until pH 4 and extracted with ethyl acetate (3.x.40 mL). The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated to yield the title compound as a white solid (2.62 g, 87percent). 1H NMR: (DMSO-d6) delta 1.22-1.26 (m, 1H), 1.37 (s, 9H), 1.50-1.52 (m, 1H), 2.05 (q, J=9 Hz, 1H), 5.04 (d, J=10 Hz, 1H), 5.22 (d, J=17 Hz, 1H), 5.64-5.71 (m, 1H), 7.18, 7.53 (s, NH (rotamers), 12.4 (br s, 1H)); LC-MS (retention time: 1.67 minutes, method B), MS m/z 228 (M++H).; Example 7 To a solution of 1 (R)-tert-butoxycarbonylamino-2(S)-vinyl-cyclopropanecarboxylic acid ethyl ester (prepared by the procedure described in WO 03/099274, 3.28 g, 13.2 mmol) in THF (7 mL) and methanol (7 mL) was added a suspension of LiOH (1.27 g, 53.0 mmol) in water (14 mL). The mixture was stirred overnight at room temperature and quenched with 1N NaOH (15 mL) and water (20 mL). The resulting mixture was washed with ethyl acetate (20 mL), and the organic phase was extracted with 20 mL 0.5N NaOH. The combined aqueous phases were acidified with 1N HCl to pH 4 and extracted with ethyl acetate (3.x.40 mL). The combined organic extracts were washed with brine, dried (MgSO4), filtered, and concentrated to provide the desired compound as a white solid (2.62 g, 87percent). 1H NMR (DMSO-d6) delta 1.22-1.26 (m, 1H), 1.37 (s, 9H), 1.50-1.52 (m, 1H), 2.05 (q, J=9 Hz, 1H), 5.04 (d, J=10 Hz, 1H), 5.22 (d, J=17 Hz, 1H), 5.64-5.71 (m, 1H), 7.18, 7.53 (s, NH (rotamers), 12.4 (br s, 1H); LC/MS (MH+, 228).
87%		To a solution of 1(R)-tert-butoxycarbonylamino-2(S)-vinyl-cyclopropanecarboxylic acid ethyl ester (3.28 g, 13.2 mmol) in THF (7 mL) and methanol (7 mL) was added a suspension of LiOH (1.27 g, 53.0 mmol) in water (14 mL). The mixture was stirred overnight at room temperature and quenched with 1N NaOH (15 mL) and water (20 mL). The resulting mixture was washed with ethyl acetate (20 mL), and the organic phase was extracted with 20 mL 0.5N NaOH. The combined aqueous phases were acidified with 1N HCl to pH 4 and extracted with ethyl acetate (3*40 mL). The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated to provide the desired compound as a white solid (2.62 g, 87percent). 1H-NMR: (DMSO-d6) delta 1.22-1.26 (m, 1H), 1.37 (s, 9H), 1.50-1.52 (m, 1H), 2.05 (q, J=9 Hz, 1H), 5.04 (d, J=10 Hz, 1H), 5.22 (d, J=17 Hz, 1H), 5.64-5.71 (m, 1H), 7.18, 7.53 (s, NH (rotamers), 12.4 (br s, 1H)); LC-MS (retention time: 1.67 minutes, method B), MS m/z 228 (M++H).
87%		To a solution of 1(R)-tert-butoxycarbonylamino-2(S)-vinyl-cyclopropanecarboxylic acid ethyl ester (3.28 g, 13.2 mmol) in THF (7 mL) and methanol (7 mL) was added a suspension of LiOH (1.27 g, 53.0 mmol) in water (14 mL). The mixture was stirred overnight at room temperature and quenched with 1N NaOH (15 mL) and water (20 mL). The resulting mixture was washed with ethyl acetate (20 mL), and the organic phase was extracted with 20 mL 0.5 N NaOH. The combined aqueous phases were acidified with 1N HCl until pH 4 and extracted with ethyl acetate (3.x.40 mL). The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated to yield the title compound as a white solid (2.62 g, 87percent). 1H NMR: (DMSO-d6) delta 1.22-1.26 (m, 1H), 1.37 (s, 9H), 1.50-1.52 (m, 1H), 2.05 (q, J=9 Hz, 1H), 5.04 (d, J=10 Hz, 1H), 5.22 (d, J=17 Hz, 1H), 5.64-5.71 (m, 1H), 7.18, 7.53 (s, NH (rotamers), 12.4 (br s, 1H)); MS m/z 228 (M++H).
87%		To a solution ofl (R)-tert-butoxycarbonylamino-2 (S)-vinyl- cyclopropanecarboxylic acid ethyl ester, the product of Step 6a (3.28 g, 13.2 mmol) in THF (7 mL) and methanol (7 mL) was added a suspensionof LiOH (1.27 g, 53.0 mmol) in water (14 mL). The mixture was stirred overnight at room temperature and quenched with IN NaOH (15mL) and water (20 mL). The resulting mixture was washed with EtOAc (20 mL), and the organic phase was extracted with 20 mL 0.5N NaOH. The combined aqueous phases were acidified with IN HCI until pH 4 and extracted with EtOAc (3 x 40mL). The combined organic extracts were washed with brine and dried(MgS04) to yield the title compound as a white solid (2.62 g, 87percent). 'H NMR :(DMSO-d6)b 1.22-1. 26 (m, 1H), 1.37 (s, 9H), 1.50-1. 52 (m, 1H), 2.05 (q, J=9 Hz,1H), 5.04 (d, J=10 Hz, 1H), 5.22 (d, J=17 Hz,1H), 5.64-5. 71(m, 1H), 7.18, 7.53 (s, NH (rotamers), 12.4 (br s,1H)) ; LC-MS (retention time: 1.67 min, method B), MS7rl/z 228 (M++H).
87%		To a solution of 1(R)-tert-butoxycarbonylamino-2(S)-vinyl-cyclopropanecarboxylic acid ethyl ester (3.28 g, 13.2 mmol) in THF (7 mL) and methanol (7 mL) was added a suspension of LiOH (1.27 g, 53.0 mmol) in water (14 mL). The mixture was stirred overnight at room temperature. To the mixture was added 1.0M NaOH (15 mL), water (20 mL) and ethyl acetate (20 mL). The mixture was shaken, the phases were separated, and the organic phase was again extracted with 20 mL 0.5M NaOH. The combined aqueous phases were acidified with 1.0M HCl until pH=4 and extracted with ethyl acetate (3.x.40 mL). The combined organic extracts were washed with brine, dried (MgSO4), and filtered to provide the desired product as a white solid (2.62 g, 87percent). 1H NMR: (DMSO-d6) delta1.22-1.26 (m, 1H), 1.37 (s, 9H), 1.50-1.52 (m, 1H), 2.05 (q, J=9 Hz, 1H), 5.04 (d, J=10 Hz, 1H), 5.22 (d, J=17 Hz, 1H), 5.64-5.71 (m, 1H), 7.18, 7.53 (s, NH (rotamers), 12.4 (br s, 1H)); LC-MS MS m/z 228 (M++H).
87%		Step 1: Preparation of 1 (R)-tert-butoxycarbonylamino-2(S)-vinyl- cyclopropanecarboxylic acid; <n="66"/>To a solution of l(R)-tert-butoxycarbonylamino-2(S)-vinyl- cyclopropanecarboxylic acid ethyl ester (3.28 g, 13.2 mmol) in THF (7 mL) and methanol (7 mL) was added a suspension of LiOH (1.27 g, 53.0 mmol) in water (14 mL). The mixture was stirred overnight at room temperature and quenched with IN NaOH (15 mL) and water (20 mL). The resulting mixture was washed with ethyl acetate (20 mL), and the organic phase was extracted with 20 mL 0.5N NaOH. The combined aqueous phases were acidified with IN HCl until pH 4 and extracted with ethyl acetate (3 x 4OmL). The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated to yield the title compound as a white solid (2.62 g, 87percent). 1H NMR: (DMSO-d6) delta 1.22-1.26 (m, IH), 1.37 (s, 9H), 1.50-1.52 (m, IH), 2.05 (q, J=9 Hz, IH), 5.04 (d, J=IO Hz, IH), 5.22 (d, J=Il Hz, IH), 5.64- 5.71 (m, IH), 7.18, 7.53 (s, NH (rotamers), 12.4 (br s, IH) ); MS m/z 228 (M++H).
87%		To a solution of 1(R)-tert-butoxycarbonylamino-2(S)-vinyl-cyclopropanecarboxylic acid ethyl ester (3.28 g, 13.2 mmol) in THF (7 mL) and methanol (7 mL) was added a suspension of LiOH (1.27 g, 53.0 mmol) in water (14 mL). The mixture was stirred overnight at room temperature and quenched with 1N NaOH (15 mL) and water (20 mL). The resulting mixture was washed with ethyl acetate (20 mL), and the organic phase was extracted with 20 mL 0.5N NaOH. The combined aqueous phases were acidified with 1N HCl until pH 4 and extracted with ethyl acetate (3*40 mL). The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated to yield the title compound as a white solid (2.62 g, 87percent). 1H NMR: (DMSO-d6) 1.22-1.26 (m, 1H), 1.37 (s, 9H), 1.50-1.52 (m, 1H), 2.05 (q, J=9 Hz, 1H), 5.04 (d, J=10 Hz, 1H), 5.22 (d, J=17 Hz, 1H), 5.64-5.71 (m, 1H), 7.18, 7.53 (s, NH (rotamers), 12.4 (br s, 1H)); MS m/z 228 (M++H).
87%		Step 1: Preparation of 1(R)-tert-butoxycarbonylamino-2(S)-vinyl-cyclopropanecarboxylic acid To a solution of 1(R)-tert-butoxycarbonylamino-2(S)-vinyl-cyclopropanecarboxylic acid ethyl ester (3.28 g, 13.2 mmol) in THF (7 mL) and methanol (7 mL) was added a suspension of LiOH (1.27 g, 53.0 mmol) in water (14 mL). The mixture was stirred overnight at room temperature and quenched with 1N NaOH (15 mL) and water (20 mL). The resulting mixture was washed with ethyl acetate (20 mL), and the organic phase was extracted with 20 mL 0.5N NaOH. The combined aqueous phases were acidified with 1N HCl until pH 4 and extracted with ethyl acetate (3*40 mL). The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated to yield the title compound as a white solid (2.62 g, 87percent). 1H NMR: (DMSO-d6) delta 1.22-1.26 (m, 1H), 1.37 (s, 9H), 1.50-1.52 (m, 1H), 2.05 (q, J=9 Hz, 1H), 5.04 (d, J=10 Hz, 1H), 5.22 (d, J=17 Hz, 1H), 5.64-5.71 (m, 1H), 7.18, 7.53 (s, NH (rotamers), 12.4 (br s, 1H)); MS m/z 228 (M++H).
87%	With lithium hydroxide; water; In tetrahydrofuran; methanol; at 20℃;	To a solution of 1(R)-tert-butoxycarbonylamino-2(S)-vinyl-cyclopropanecarboxylic acid ethyl ester (3.28 g, 13.2 mmol) in THF (7 mL) and methanol (7 mL) was added a suspension of LiOH (1.27 g, 53.0 mmol) in water (14 mL). The mixture was stirred overnight at room temperature and quenched with 1N NaOH (15 mL) and water (20 mL). The resulting mixture was washed with ethyl acetate (20 mL), and the organic phase was extracted with 20 mL 0.5N NaOH. The combined aqueous phases were acidified with 1N HCl until pH 4 and extracted with ethyl acetate (3.x.40 mL). The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated to yield the title compound as a white solid (2.62 g, 87percent). 1H NMR: (DMSO-d6) 1.22-1.26 (m, 1H), 1.37 (s, 9H), 1.50-1.52 (m, 1H), 2.05 (q, J=9 Hz, 1H), 5.04 (d, J=10 Hz, 1H), 5.22 (d, J=17 Hz, 1H), 5.64-5.71 (m, 1H), 7.18, 7.53 (s, NH (rotamers), 12.4 (br s, 1H)); MS m/z 228 (M++H).
87%	With lithium hydroxide; water; In tetrahydrofuran; methanol; at 20℃;	To a solution of 1(R)-tert-butoxycarbonylamino-2(S)-vinyl-cyclopropanecarboxylic acid ethyl ester (3.28 g, 13.2 mmol) in THF (7 mL) and methanol (7 mL) was added a suspension of LiOH (1.27 g, 53.0 mmol) in water (14 mL). The mixture was stirred overnight at room temperature and quenched with 1N NaOH (15 mL) and water (20 mL). The resulting mixture was washed with ethyl acetate (20 mL), and the organic phase was extracted with 20 mL 0.5N NaOH. The combined aqueous phases were acidified with 1N HCl until pH 4 and extracted with ethyl acetate (3.x.40 mL). The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated to yield the title compound as a white solid (2.62 g, 87percent). 1H NMR: (DMSO-d6)
87%		III. Preparation of P1'-P1 Intermediates; 12. Preparation of P1-P1'; Step 1:; To a solution of 1(R)-tert-butoxycarbonylamino-2(S)-vinyl-cyclopropanecarboxylic acid ethyl ester (3.28 g, 13.2 mmol) in THF (7 mL) and methanol (7 mL) was added a suspension of LiOH (1.27 g, 53.0 mmol) in water (14 mL). The mixture was stirred overnight at room temperature. To the mixture was added 10M NaOH (15 mL), water (20 mL) and ethyl acetate (20 mL). The mixture was shaken, the phases were separated, and the organic phase was again extracted with 20 mL 0.5M NaOH. The combined aqueous phases were acidified with 1.0M HCl until pH=4 and extracted with ethyl acetate (3.x.40 mL). The combined organic extracts were washed with brine, dried (MgSO4), and filtered to provide the desired product as a white solid (2.62 g, 87percent). 1H NMR: (DMSO-d6) delta1.22-1.26 (m, 1H), 1.37 (s, 9H), 1.50-1.52 (m, 1H), 2.05 (q, J=9 Hz, 1H), 5.04 (d, J=10 Hz, 1H), 5.22 (d, J=17 Hz, 1H), 5.64-5.71 (m, 1H), 7.18, 7.53 (s, NH (rotamers), 12.4 (br s, 1H)); LC-MS MS m/z 228 (M++H).
87%		To a solution of l(R)-tert-butoxycarbonylamino-2(S)-vinyl- cyclopropanecarboxylic acid ethyl ester (3.28 g, 13.2 mmol) in THF (7 mL) and methanol (7 mL) was added a suspension of LiOH (1.27 g, 53.0 mmol) in water (14 mL). The mixture was stirred overnight at room temperature and quenched with IN NaOH (15 mL) and water (20 mL). The resulting mixture was washed with ethyl acetate (20 mL), and the organic phase was extracted with 20 mL 0.5N NaOH. The combined aqueous phases were acidified with IN HCl until pH 4 and extracted with ethyl acetate (3 x 4OmL). The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated to yield the title compound as a white solid (2.62 g, 87percent). 1H NMR: (DMSO-d6) delta 1.22-1.26 (m, IH), 1.37 (s, 9H), 1.50-1.52 (m, IH), 2.05 (q, J=9 Hz, IH), 5.04 (d, J=IO Hz, IH), 5.22 (d, J=17 Hz, IH), 5.64- 5.71 (m, IH), 7.18, 7.53 (s, NH (rotamers), 12.4 (br s, IH) ); MS m/z 228 (M++H).
71.44 g (54.0 g, 100%, corrected for residual solvent)	With hydrogenchloride; lithium hydroxide; lithium hydroxide monohydrate; In tetrahydrofuran; cyclohexane; water;	Stage 1a: (1R,2S)-1-(tert-butoxycarbonylamino)-2-vinyl-cyclopropane-1-carboxylic acid (452) Ethyl (1R,2S)-1-(tert-butoxycarbonylamino)-2-vinyl-cyclopropane-1-carboxylate (61 g, 0.239 mol, 1.0 eq.) and tetrahydrofuran (700 mL) were charged into a 2 L round bottom flask placed in ice/water bath. Lithium hydroxide monohydrate (30 g, 0.714 mol, 3.0 eq.) was dissolved in water (800 mL) and added slowly to the mixture. The reaction mixture was heated at 50° C. for 18 hours. Monitoring the reaction conversion by LCMS showed some residual starting material so lithium hydroxide (20 g, 0.476 mol, 2 eq.) was added. The reaction was stirred further for 5 hours and then stirred at room temperature for 2 days. Monitoring the reaction conversion by LCMS showed complete conversion. The reaction mixture was acidified to pH 3 by slow addition of 1M hydrochloric acid then extracted with ethyl acetate (4*900 mL). The organic extracts were pooled, washed with brine (600 mL), dried over sodium sulfate, filtered and concentrated to dryness. Cyclohexane (100 mL) was added to the dried crude material and concentrated to give 71.44 g (54.0 g, 100percent, corrected for residual solvent) of the title compound as a pale yellow solid which contained residual cyclohexane (24.5percent w/was calculated from 1H-NMR). The compound was used in the next step without further purification. 1H NMR (500 MHz, CHLOROFORM-d) delta ppm 5.79 (dt, J=17.01, 9.65 Hz, 1H) 5.27 (br. s., 1H) 5.30 (d, J=17.09 Hz, 1H) 5.14 (d, J=10.38 Hz, 1H) 2.20 (q, J=8.85 Hz, 1H) 1.70-1.90 (m, 1H) 1.52-1.63 (m, 1H) 1.45 (s, 9H)
	With lithium hydroxide; In tetrahydrofuran; methanol; water; at 20℃; for 1h;	Intermediate C6: tert-butyl (1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamate Following the procedure in Scheme III, Intermediate C5 (6.0 g, 23.5 mmol) was added in a solution of LiOH (3.0 g, 73.5 mmol) in THF/MeOH/H2O (20 mL/20 mL/10 mL). After 1 h at r.t., the pH was adjusted to ?4 with 1N HCl, aqueous layer was separated, EA was added, and the mixture was extracted with EA twice. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give the yellow oil, which was used directly in the next reaction without further purification. Then the intermediate (5.6 g, 24.2 mmol) and CDI (5.2 g, 31.5 mmol) were dissolved in THF (20 mL). After refluxed for 1 h, the mixture was cooled to r.t. and then a solution of cyclopropanesulfonamide (3.8 g, 31.5 mmol) in DCM (30 mL) was added followed by adding DBU (5.2 mg, 34.0 mmol). The mixture was stirred overnight at the room temperature, concentrated and extracted with EA twice. The combined organic layer was washed with brine, dried over Na2SO4, filtered, concentrated and purified by flash column chromatography to give the title compound C6 (2.8 g, 36.4percent) as white solid. 1H NMR (400 MHz, CDC3) delta 9.52 (s, 1H), 5.66-5.57 (m, 1H), 5.32 (d, J=13.2 Hz, 1H), 5.17 (dd, J=10.4, 0.8 Hz, 1H), 2.94-2.87 (m, 1H), 2.17 (q, J=8.4 Hz, 1H), 1.92-1.89 (m, 1H), 1.48 (s, 9H), 1.45-1.39 (m, 1H), 1.32-1.25 (m, 2H), 1.13-1.00 (m, 2H).

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16
hydroxymethylbenzamide [ No CAS ]
[ 159622-10-3 ]
C₁₉H₂₃N₂O₅Pol [ No CAS ]

References: [1]Patent: US2005/153877,2005,A1 .Location in patent: Page/Page column 93.

17
[ 159622-10-3 ]
[ 630111-73-8 ]

Yield	Reaction Conditions	Operation in experiment
78%	With diazomethane;palladium diacetate; In diethyl ether; at 20℃; for 19h;	II. Preparation of N-Boc- (1R, 2S)-l-amino-2-cyclopropylcyclopropane carboxylic acid ethyl ester H O H 0 N N\\-O'CH2N2. -N IR Pd (OAc) 2 ZNR 0 N 10 2s X ether, rt x (1) (2) 9 A solution of N-Boc-(lR, 2S)-l-amino-2-vinylcyclopropal1e carboxylic acid (255 mg, 1.0 mmol) in ether (10 mL) was treated with palladium acetate (5 mg, 0.022 mmol). The orange/red solution was placed under an atmosphere of N2. An excess of diazomethane in ether was added dropwise over the course of 1 h. The resulting solution was stirred at rt for 18 h. The excess diazomethane was removed using a stream of nitrogen. The resulting solution was concentrated by rotary evaporation to give the'crude product. Flash chromatography (10percent EtOAc/hexane) provided 210 mg (78percent) of N-Boc-(1R, 2S)-l-amino-2-cyclopropylcyclopropane carboxylic acid ethyl ester as a colorless oil. LC-MS (retention time: 2.13, similar to method A except: gradient time 3 min, Xterra MS C18 S7 3.0 x 50mm column), MS m/e 270 (M++I).

References: [1]Patent: WO2005/46712,2005,A1 .Location in patent: Page/Page column 67.

18
[ 154743-05-2 ]
[ 159622-10-3 ]
[ 1028251-26-4 ]

Yield	Reaction Conditions	Operation in experiment
	With 1,1'-carbonyldiimidazole; lithium hexamethyldisilazane; In tetrahydrofuran; hexane; at 20℃; for 3.75h;Heating / reflux;	Step 1 of Example 19 To a solution of (1R, 2S) l-tert-butoxycarbonylamino-2-vinyl- cyclopropanecarboxylic acid (217 mg, 1.194 mmol) in THF (5 mL), CDI (290 mg, 1. 791 mmol) was added and the reaction mixture was heated under reflux for 45 min. In another round-bottomed flask, LiHMDS (1.0 M solution in hexanes, 2.4 mL, 2.4 mmol) was added to a solution of N-ethylmethylsulfamide (330 mg, 2.388 mmol) in THF (5 mL) and the reaction mixture was stirred at rt for lh. Two reaction mixtures were added together and stirred at rt for 2h. Water was added to quench the reaction and the reaction solution was extracted with EtOAc. The oraganic layer was separated and dried over MgS04. Evaporation of solvent gave crude product which was purified by Prep. HPLC to afford desired N-acylsulfamide. N-acylsulfamide was then dissolved in 4N HC1 solution in dioxane (2mL) and stirred at rt for 4h. Evaporation of solution give brownish oil as HCl salt. (112mg, 33percent yield). 1H NMR (400Mz, CD30D) delta 1. 16 (t, J=7. 21 Hz, 3 H), 1.68 (dd, J=10. 03,7. 83 Hz, 1 H), 2.15 (m, 1 H), 2.37 (m, 1 H), 2.89 (s, 3 H), 3.30 (m, 2 H), 5.31 (d, J=10. 27 Hz, 1 H), 5.42 (d, J=17. 12 Hz, 3 H), 5.68 (m, 1 H). LC-MS (retention time: 0.883 min. ), MS m/z 270 (M+Na+).
		13. Preparation of P1-P1' Sulfamide Derivative; To a solution of (1R,2S) 1-tert-butoxycarbonylamino-2-vinyl-cyclopropanecarboxylic acid (217 mg, 1.194 mmol) in THF (5 mL), was added CDI (290 mg, 1.791 mmol) and the reaction mixture was heated to reflux for 45 minutes. In another round-bottomed flask, LiHMDS (1.0M solution in hexanes, 2.4 mL, 2.4 mmol) was added to a solution of N-ethylmethylsulfamide (330 mg, 2.388 mmol) in THF (5 mL) and the reaction mixture was stirred at room temperature for 1 hour. The two reaction mixtures were combined and stirred at room temperature for 2 hours. Water was added to quench the reaction and the reaction solution was extracted with ethyl acetate. The organic layer was separated and dried over MgSO4. Filtration and concentration gave crude product which was purified by preparative HPLC to provide the desired N-Boc protected N-acylsulfamide. The Boc protecting group was then removed as the compound was dissolved in 4N HCl solution in dioxane (2 mL) and stirred at room temperature for 4 hours. Concentration provided a brownish oil as the HCl salt. (112 mg, 33percent yield). 1H NMR (400Mz, CD3OD) delta 1.16 (t, J=7.21 Hz, 3H), 1.68 (dd, J=10.03, 7.83 Hz, 1H), 2.15 (m, 1H), 2.37 (m, 1H), 2.89 (s, 3H), 3.30 (m, 2H), 5.31 (d, J=10.27 Hz, 1H), 5.42 (d, J=17.12 Hz, 3H), 5.68 (m, 1H). LC-MS (retention time: 0.883 minutes.), MS m/z 270 (M+Na+).

References: [1]Patent: WO2005/46712,2005,A1 .Location in patent: Page/Page column 84.
[2]Patent: US2008/119461,2008,A1 .Location in patent: Page/Page column 36.

19
[ 530-62-1 ]
[ 159622-10-3 ]
C₁₄H₁₉N₃O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; for 0.75 - 0.833333h;Heating / reflux;Product distribution / selectivity;	Step 2: Preparation of cyclopropanesulfonic acid (1-(R)-tert-butoxycarbonylamino-2-(S)-vinylcyclopropanecarbonyl)-amide A solution of the product of Step 1 (2.62 g, 11.5 mmol) and CDI (2.43 g, 15.0 mmol) in THF (40 mL) was heated at reflux for 50 minutes under nitrogen. The solution was cooled to room temperature and transferred by cannula to a solution of cyclopropylsulfonamide (1.82 g, 15.0 mmol) in THF (10 mL). To the resulting solution was added DBU (2.40 mL, 16.1 mmol) and stirring was continued for 20 hours. The mixture was quenched with 1N HCl to pH 1 and THF was concentrated in vacuo. The suspension was extracted with ethyl acetate (2.x.50 mL) and the combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification by recystallization from hexanes-ethyl acetate (1:1) afforded the title compound (2.4 g) as a white solid. The mother liquor was purified by a Biotage 40S column (eluted 9percent acetone in dichloromethane) to give a second batch of the title compound (1.1 g). Both batches were combined (total yield 92percent). 1H NMR (DMSO-d6) delta 0.96-1.10 (m, 4H), 1.22 (dd, J=5.5, 9.5 Hz, 1H), 1.39 (s, 9H), 1.70 (t, J=5.5 Hz, 1H), 2.19-2.24 (m, 1H), 2.90 (m, 1H), 5.08 (d, J=10 Hz, 1H), 5.23 (d, J=17 Hz, 1H), 5.45 (m, 1H), 6.85, 7.22 (s, NH (rotamers); LC-MS (retention time: 1.70 minutes, method B), MS m/z 331 (M++H).; 1b. Preparation of P1-P1' sulfamide derivative To a solution of (1R,2S) 1-tert-butoxycarbonylamino-2-vinyl-cyclopropanecarboxylic acid (217 mg, 1.194 mmol) in THF (5 mL), was added CDI (290 mg, 1.791 mmol) and the reaction mixture was heated under reflux for 45 minutes. In another round-bottomed flask, LiHMDS (1.0M solution in hexanes, 2.4 mL, 2.4 mmol) was added to a solution of N-ethylmethylsulfamide (330 mg, 2.388 mmol) in THF (5 mL) and the reaction mixture was stirred at room temperature for 1 hour. Two reaction mixtures were added together and stirred at room temperature for 2 hours. Water was added to quench the reaction and the reaction solution was extracted with ethyl acetate. The organic layer was separated and dried over MgSO4. Filtration and concentration of the solvent gave crude product which was purified by preparative HPLC to afford desired N-Boc protected N-acylsulfamide. The Boc protecting group was then removed as the compound was dissolved in 4N HCl solution in dioxane (2 mL) and stirred at room temperature for 4 hours. Evaporation of solution give brownish oil as the HCl salt. (112 mg, 33percent yield). 1H NMR (400 Mz, CD3OD) delta 1.16 (t, J=7.21 Hz, 3H), 1.68 (dd, J=10.03, 7.83 Hz, 1H), 2.15 (m, 1H), 2.37 (m, 1H), 2.89 (s, 3H), 3.30 (m, 2H), 5.31 (d, J=10.27 Hz, 1H), 5.42 (d, J=17.12 Hz, 3H), 5.68 (m, 1H). LC-MS (retention time: 0.883 minutes.), MS m/z 270 (M+Na+).; A solution of the product of Step 7a (2.62 g, 11.5 mmol) and CDI (2.43 g, 15.0 mmol) in THF (40 mL) was heated at reflux for 50 minutes under nitrogen. The solution was cooled to room temperature and transferred by cannula to a solution of cyclopropanesulfonic acid amide (1.82 g, 15.0 mmol) in THF (10 mL). To the resulting solution was added DBU (2.40 mL, 16.1 mmol) and stirring was continued for 20 hours. The mixture was quenched with 1N HCl to pH 1 and the THF was evaporated in vacuo. The suspension was extracted with ethyl acetate (2.x.50 mL) and the combined organic extracts dried (Na2SO4), filtered, and concentrated. Purification by recystallization from hexanes-ethyl acetate (1:1) provided the desired compound (2.4 g) as a white solid. The mother liquor was purified by a Biotage 40 S column (eluted 9percent acetone in dichloromethane) to provide a second batch of the desired compound (1.1 g). Both batches were combined (total yield 92percent). 1H NMR (DMSO-d6) delta 0.96-1.10 (m, 4H), 1.22 (dd, J=5.5, 9.5 Hz, 1H), 1.39 (s, 9H), 1.70 (t, J=5.5 Hz, 1H), 2.19-2.24 (m, 1H), 2.90 (m, 1H), 5.08 (d, J=10 Hz, 1H), 5.23 (d, J=17 Hz, 1H), 5.45 (m, 1H), 6.85, 7.22 (s, NH (rotamers); LC/MS (MH+, 331).;
	In tetrahydrofuran; at 20℃; for 3h;Product distribution / selectivity;	Example 58 Preparation of Compound 58 Step 1. To a solution N-Boc-vinylcyclopropane carboxylic acid, the product of step 7a, Example 7, (1.83 g, 8.05 mmol) and THF (32 mL) was added 1,1'-carbonyldiimidazole (1.44 g, 8.86 mmol). After stirring at room temperature for 3 hours, the reaction mixture was treated with N,N-dimethylsulfamide (1.0 g, 8.05 mmol) followed by DBU (2.45 g, 16.1 mmol) and it was stirred at room temperature for an additional 15 hours. The reaction was then diluted with EtOAc (50 mL) and was washed with 2.x.25 mL 1N aqueous HCl. The aqueous layer was extracted with 2.x.50 mL EtOAc. The combined organic portion was washed with H2O (25 mL) and brine, dried over MgSO4, filtered, and concentrated to a light yellow solid (2.6 g, 97percent yield) which was used without further purification. LC-MS, MS m/z 356 (M++Na).
	In tetrahydrofuran; for 0.833333h;Heating / reflux;	Preparation of 1(R)-tert-butoxycarbonylamino-2(S)-vinyl-cyclopropanecarboxylic acid To a solution of 1(R)-tert-butoxycarbonylamino-2(S)-vinyl-cyclopropanecarboxylic acid ethyl ester (3.28 g, 13.2 mmol) in THF (7 mL) and methanol (7 mL) was added a suspension of LiOH (1.27 g, 53.0 mmol) in water (14 mL). The mixture was stirred overnight at room temperature and quenched with 1N NaOH (15 mL) and water (20 mL). The resulting mixture was washed with ethyl acetate (20 mL), and the organic phase was extracted with 20 mL 0.5N NaOH. The combined aqueous phases were acidified with 1N HCl until pH 4 and extracted with ethyl acetate (3.x.40 mL). The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated to yield the title compound as a white solid (2.62 g, 87percent). 1H NMR: (DMSO-d6) delta 1.22-1.26 (m, 1H), 1.37 (s, 9H), 1.50-1.52 (m, 1H), 2.05 (q, J=9 Hz, 1H), 5.04 (d, J=10 Hz, 1H), 5.22 (d, J=17 Hz, 1H), 5.64-5.71 (m, 1H), 7.18, 7.53 (s, NH (rotamers), 12.4 (br s, 1H)); MS m/z 228 (M++H).

In tetrahydrofuran; for 1 - 2h;Heating / reflux;Product distribution / selectivity;

Step 1; [(lR,2S)-l-(2-Amino-benzenesulfonylaminocarbonyl)-2-vinyl-cyclopropyl]-carbamic acid tert-butyl ester; To a solution of 6.3 g (28 mmol) (lR,2S)-l-tert-Butoxycarbonylamino-2-vinyl-cyclopropane- <n="155"/>carboxylic acid (prepared according to WO 2000009558 Al) in 90 mL abs. THF is added 6.95 g (42 mmol) CDI and the mixture is refluxed for 2 h. After cooling to rt 5.1 g (29 mmol) 2-Aminobenzenesulfonamide and 6.5 g (42 mmol) DBU is added and stirring is continued for 45 min. The reaction mixture is diluted with 250 mL EtOAc and washed with 100 mL 0.5 N HCl and brine. The organic phase is dried with Na2SO4, filtered and the solvent is removed in vacuo. The residue is purified by FC on silica (eluent: CH2Cl2/Me0H 98:2) to give the title compound as a colorless solid. HPLC (method A) tR = 3.99 min TLC, Rf (CH2Cl2/Me0H 19:1) = 0.35 MS (method D): 382 [M+H]; Step 7; 12-{l-[((lR,2S)-l-tert-Butoxycarbonylamino-2-vinyl-cyclopropanecarbonyl)-su.famoyl]- cyclopropylj-dodecanoic acid methyl ester; <n="256"/>A mixture of 610 mg (2.7 mmol) (lR,2S)-l-tert-Butoxycarbonylamino-2-vinyl- cyclopropane-carboxylic acid and 687 mg (4.0 mmol) CDI in 20 mL THF is refluxed for 1 h. The reaction mixture is cooled to RT and 0.6 mL (4.0 mmol) DBU and a mixture of 806 mg (2.4 mmol) 12-(l-Sulfamoyl-cyclopropyl)-dodecanoic acid methyl ester in 5 mL THF is added. The mixture is stirred at RT overnight, concentrated in vacuo, taken up in EtOAc and washed with 0.1 M aq. HCl. The combined organic phases are dried over Na2SO4 and concentrated in vacuo. The residue is purified by FC on silica (Eluent: EtOAc/hexane 1:3) to give the title compound.LC-MS (method E) tR = 5.132 min, M-H = 543.3 HPLC (method C) tR = 4.472 min; Step 4; Methyl 12-[[({(lR,2S)-l-[(tert-butoxycarbonyl)amino]-2- vinylcyclopropyl}carbonyl)amino]-sulfonyl}(methyl)amino]dodecanoate; A mixture of 1.41 g (6.2 mmol) (lR,2S)-l-tert-Butoxycarbonylamino-2-vinyl-cyclopropane- carboxylic acid and 1.52 mg (9.31 mmol) CDI in 30 mL THF is refluxed for 1 h. In a second flask to a mixture of 3.0 g (9.31 mmol) of the title compound obtained in step 3 in 30 mL THF 9.3 mL (9.3 mmol) LiHMDS (1 M in THF) is added at 0°C and the mixture is stirred for 30 min. Both mixtures are combined and stirred at RT overnight. Water is added and the mixture is extracted with DCM (3x). The combined organic layers are dried over Na2SO4 and concentrated in vacuo. The residue is purified by FC (silica gel, eluent: EtOAc/hexane 1 :3) to give the title compound. LC-MS (method E) tR = 4.728 min, M-H = 530.2

References: [1]Patent: US2006/183694,2006,A1 .Location in patent: Page/Page column 33; 44-45.
[2]Patent: US2006/183694,2006,A1 .Location in patent: Page/Page column 56.
[3]Patent: US2007/99825,2007,A1 .Location in patent: Page/Page column 36.
[4]Patent: WO2008/101665,2008,A1 .Location in patent: Page/Page column 153-154; 254-255; 260.

20
C₂HF₃O₂*C₁₁H₁₈N₂O₃S [ No CAS ]
[ 159622-10-3 ]
C₄₄H₅₉N₇O₉S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 4-methyl-morpholine; HATU; In N,N-dimethyl-formamide; at 20℃; for 14h;	To a solution of cyclic acylsulfonamide (92 mg) in QHbCb (4.0 mL) wasadded TFA (2.0 (mL). The reaction mixture was stirred at rt for 3 hr. Solventwas removed under vacuum. The residue was azeotroped with PhMe threetimes. The crude TFA salt was diluted with DMF (2.0 mL), to this solutionwas added acid (100 mg, 0.15 mmol), HATU (87 mg, 0.23 mmol) and NMM(62 mg, 0.61 mmol). The resulting reaction mixture was stirred at rt for 14 hr.Diluted with EtOAc and washed with saturated NlHUCl, brine and dried overNa2SO4. The drying agent was filtered off and the solvent was evaporated.The crude product was purified by HPLC to give compound 109 as a yellowsolid (38 mg, 16percent). HNMR (300 MHz, CDCls): 8 9.8 (s, 1H), 8.66 (s, 1H), 8.13(d, J = 9.4 Hz, 1H), 7.76-7.7 (m, 2H), 5.76 (s, 1H), 5.7-5.62 (m, 1H), 5.31 (dd, J =16.5, 7.3 Hz, 1H), 5.18 (s, 1H), 5.04 (s, 1H), 4.75-4.63 (m, 2H), 4.12-4.04 (m, 1H),3.95 (s, 3H), 3.56-3.54 (m, 1H), 2.9-2.67 (m, 2H), 2.05-1.21 (m, 8H), 0.93 (s, 9H).

References: [1]Patent: WO2006/20276,2006,A2 .Location in patent: Page/Page column 360-361.

21
(1R,2S)-1-amino-2-vinylcyclopropane carboxylic acid methyl ester tosylate salt [ No CAS ]
[ 24424-99-5 ]
[ 159622-10-3 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 4B; Synthesis of P1-P1' fragment (4B3); Step A; To a solution of compound 4B1 (12 g, 38.29 mmol) in a mixture of THF (50 mL) and 1 N aq. NaOH (85 mL, 85.00 mmol) was added Boc anhydride (1O g, 45.95 mmol). The reaction mixture was stirred at RT for 4 days. The pH was periodically adjusted to 9 by adding more NaOH. The THF was then removed in vacuo and the aqueous layer was washed with ether (3 X 150 mL) and then cooled to 00C for the slow addition of 1 N EPO <DP n="45"/>aq. HCI until pH 3-4 was obtained. The aqueous layer was then extracted with EtOAc (3 X 150 ml_) and the combined organic extracts were successively washed with water (3 X 100 ml.) and brine. After drying over MgSO4, filtration and concentration, 5.16 g of the desired Boc-protected intermediate 4B2 was isolated.

References: [1]Patent: WO2007/9227,2007,A1 .Location in patent: Page/Page column 43-44.

22
[ 154350-29-5 ]
[ 159622-10-3 ]
[ 630421-48-6 ]

Yield	Reaction Conditions	Operation in experiment
92%		A solution of the product of Step 1 (2.62 g, 11.5 mmol) and CDI (2.43 g, 15.0 mmol) in THF (40 mL) was heated at reflux for 50 minutes under nitrogen. The solution was cooled to room temperature and transferred by cannula to a solution of cyclopropylsulfonamide (1.82 g, 15.0 mmol) in THF (10 mL). To the resulting solution was added DBU (2.40 mL, 16.1 mmol) and stirring was continued for 20 hours. The mixture was quenched with 1N HCl to pH 1 and THF was concentrated in vacuo. The suspension was extracted with ethyl acetate (2.x.50 mL) and the combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification by recystallization from hexanes-ethyl acetate (1:1) afforded the title compound (2.4 g) as a white solid. The mother liquor was purified by a Biotage 40S column (eluted 9percent acetone in dichloromethane) to give a second batch of the title compound (1.1 g). Both batches were combined (total yield 92percent). 1H NMR (DMSO-d6) delta 0.96-1.10 (m, 4H), 1.22 (dd, J=5.5, 9.5 Hz, 1H), 1.39 (s, 9H), 1.70 (t, J=5.5 Hz, 1H), 2.19-2.24 (m, 1H), 2.90 (m, 1H), 5.08 (d, J=10 Hz, 1H), 5.23 (d, J=17 Hz, 1H), 5.45 (m, 1H), 6.85, 7.22 (s, NH (rotamers); MS m/z 331 (M++H).
92%		A solution of the product of Step 6 (2.62 g, 11.5 mmol) and CDI (2.43 g, 15.0 mmol) in THF (40mL) was heated at reflux for 50 min under nitrogen. The solution was cooled to room temperature and transferred by cannula to a solution of cyclopropylsulfonamide (1.82 g, 15.0 mmol) in THF (10 mL). To the resulting solution was added DBU (2.40 mL, 16.1 mmol) and stirring was continued for 20 h. The mixture was quenched with IN HCI to pH1 and THF was evaporated in vacuo. The suspension was extracted with EtOAc (2 x 50 mL) and the combined organic extracts dried(Na2S04). Purification by recystallization from hexanes-EtOAc (1: 1) afforded the title compound (2.4 g) as a white solid. The mother liquor was purified by a Biotage 40S column (eluted 9percent acetone in DCM) to give a second batch of the title compound(1.1 g). Both batches were combined (total yield 92percent). 'H NMR : (DMSO-d6)8 0.96-1. 10 (m, 4H), 1.22 (dd, J=5.5, 9.5 Hz, 1H), 1.39 (s, 9H), 1.70 (t, J=5.5 Hz, 1H), 2.19-2. 24(m, 1H), 2.90(m, 1H), 5.08 (d, J=10 Hz, 1H), 5.23 (d,J=17 Hz,1H), 5.45(m,1H), 6.85, 7.22 (s, NH (rotamers); LC-MS (retention time: 1.70 min, method B), MS m/z 331 (M++H).
92%		A solution of the product of Step 1 (2.62 g, 11.5 mmol) and CDI (2.43 g, 15.0 mmol) in THF (40 mL) was heated at reflux for 50 minutes under nitrogen. The solution was cooled to room temperature and transferred by cannula to a solution of cyclopropylsulfonamide (1.82 g, 15.0 mmol) in THF (10 mL). To the resulting solution was added DBU (2.40 mL, 16.1 mmol) and stirring was continued for 20 hours. The mixture was quenched with 1.0M HCl to pH=1, and THF was evaporated in vacuo. The suspension was extracted with ethyl acetate (2.x.50 mL) and the organic extracts were combined and dried (Na2SO4). Filtration, concentration, and purification by recrystallization from hexanes-ethyl acetate (1:1) provided the desired product (2.4 g) as a white solid. The mother liquor was purified by flash column chromatography (SiO2, eluted 9percent acetone in dichloromethane) to give a second batch of the desired product (1.1 g). Both batches were combined (total yield 92percent). 1H NMR: (DMSO-d6) delta 0.96-1.10 (m, 4H), 1.22 (dd, J=5,5, 9.5 Hz, 1H), 1.39 (s, 9H), 1.70 (t, J=5.5 Hz, 1H), 2.19-2.24 (m, 1H), 2.90 (m, 1H), 5.08 (d, J=10 Hz, 1H), 5.23 (d, J=17 Hz, 1H), 5.45 (m, 1H), 6.85, 7.22 (s, NH (rotamers)); LC-MS, MS m/z 331 (M++H).

92%		Step 2: Preparation of cyclopropanesulfonic acid (l-(R)-tert-butoxycarbonylamino- 2-(S)-vinylcyclopropanecarbonyl)-amide; A solution of the product of Step 1 (2.62 g, 11.5 mmol) and CDI (2.43 g, 15.0 mmol) in THF (40 mL) was heated at reflux for 50 minutes under nitrogen. The solution was cooled to room temperature and transferred by cannula to a solution of cyclopropylsulfonamide (1.82 g, 15.0 mmol) in THF (10 mL). To the resulting solution was added DBU (2.40 mL, 16.1 mmol) and stirring was continued for 20 hours. The mixture was quenched with IN HCl to pH 1 and THF was concentrated in vacuo. The suspension was extracted with ethyl acetate (2 x 50 mL) and the combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification by recystallization from hexanes-ethyl acetate (1: 1) afforded the title compound (2.4 g) as a white solid. The mother liquor was purified by a Biotage 4OS column (eluted 9percent acetone in dichloromethane) to give a second batch of the title compound (1.1 g). Both batches were combined (total yield 92percent). 1H NMR <n="67"/>(DMSO-d6) delta 0.96-1.10 (m, 4H), 1.22 (dd, J=S.5, 9.5 Hz, IH), 1.39 (s, 9H), 1.70 (t, J=5.5 Hz, IH), 2.19-2.24 (m, IH), 2.90 (m, IH), 5.08 (d, J=IO Hz, IH), 5.23 (d, J=Yl Hz, IH), 5.45 (m, IH), 6.85, 7.22 (s, NH (rotamers); MS mk 331 (M++H).
92%		A solution of the product of Step 1 (2.62 g, 11.5 mmol) and CDI (2.43 g, 15.0 mmol) in THF (40 mL) was heated at reflux for 50 minutes under nitrogen. The solution was cooled to room temperature and transferred by cannula to a solution of cyclopropylsulfonamide (1.82 g, 15.0 mmol) in THF (10 mL). To the resulting solution was added DBU (2.40 mL, 16.1 mmol) and stirring was continued for 20 hours. The mixture was quenched with 1N HCl to pH 1 and THF was concentrated in vacuo. The suspension was extracted with ethyl acetate (2*50 mL) and the combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification by recystallization from hexanes-ethyl acetate (1:1) afforded the title compound (2.4 g) as a white solid. The mother liquor was purified by a Biotage 40S column (eluted 9percent acetone in dichloromethane) to give a second batch of the title compound (1.1 g). Both batches were combined (total yield 92percent). 1H NMR (DMSO-d6) delta 0.96-1.10 (m, 4H), 1.22 (dd, J=5.5, 9.5 Hz, 1H), 1.39 (s, 9H), 1.70 (t, J=5.5 Hz, 1H), 2.19-2.24 (m, 1H), 2.90 (m, 1H), 5.08 (d, J=10 Hz, 1H), 5.23 (d, J=17 Hz, 1H), 5.45 (m, 1H), 6.85, 7.22 (s, NH (rotamers); MS m/z 331 (M++H).
92%		A solution of <strong>[159622-10-3](1R,2S)-1-((tert-butoxycarbonyl)amino)-2-vinylcyclopropanecarboxylic acid</strong> (2.62 g, 11.5 mmol) and CDI (2.43 g, 15.0 mmol) in THF (40 mL) was heated at reflux for 50 min under nitrogen. The solution was cooled to room temperature and transferred by cannula to a solution of cyclopropylsulfonamide (1.82 g, 15.0 mmol) in THF (10 mL). To the resulting solution was added DBU (2.40 mL, 16.1 mmol) and stirring was continued for 20 h. The mixture was quenched with 1N HCl to pH 1 and THF was evaporated in vacuo. The suspension was extracted with EtOAc (2×50 mL) and the combined organic extracts dried (Na2SO4). Purification by recrystallization from hexanes-EtOAc (1:1) afforded the title compound (2.4 g) as a white solid. The mother liquor was purified by a Biotage 40S column (eluted 9percent acetone in DCM) to give a second batch of the compound tert-butyl ((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamate (1.1 g). Both batches were combined (total yield 92percent). (0146) 1H NMR: (DMSO-d6) delta ppm 0.96-1.10 (m, 4H), 1.22 (dd, J=5.5, 9.5 Hz, 1H), 1.39 (s, 9H), 1.70 (t, J=5.5 Hz, 1H), 2.19-2.24 (m, 1H), 2.90 (m, 1H), 5.08 (d, J=10 Hz, 1H), 5.23 (d, J=17 Hz, 1H), 5.45 (m, 1H), 6.85, 7.22 (s, NH (rotamers); LC-MS MS m/z 331 (M++H).
92%		A solution of the product of Step 1 (2.62 g, 11.5 mmol) and CDI (2.43 g, 15.0 mmol) in THF (40 mL) was heated at reflux for 50 minutes under nitrogen. The solution was cooled to room temperature and transferred by cannula to a solution of cyclopropylsulfonamide (1.82 g, 15.0 mmol) in THF (10 mL). To the resulting solution was added DBU (2.40 mL, 16.1 mmol) and stirring was continued for 20 hours. The mixture was quenched with 1N HCl to pH 1 and THF was concentrated in vacuo. The suspension was extracted with ethyl acetate (2.x.50 mL) and the combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification by recystallization from hexanes-ethyl acetate (1:1) afforded the title compound (2.4 g) as a white solid. The mother liquor was purified by a Biotage 40S column (eluted 9percent acetone in dichloromethane) to give a second batch of the title compound (1.1 g). Both batches were combined (total yield 92percent). 1H NMR (DMSO-d6) delta 0.96-1.10 (m, 4H), 1.22 (dd, J=5.5, 9.5 Hz, 1H), 1.39 (s, 9H), 1.70 (t, J=5.5 Hz, 1H), 2.19-2.24 (m, 1H), 2.90 (m, 1H), 5.08 (d, J=10 Hz, 1H), 5.23 (d, J=17 Hz, 1H), 5.45 (m, 1H), 6.85, 7.22 (s, NH (rotamers); MS m/z 331 (M++H).
92%		A solution of the product of Step 1 (2.62 g, 11.5 mmol) and CDI (2.43 g, 15.0 mmol) in THF (40 mL) was heated at reflux for 50 minutes under nitrogen. The solution was cooled to room temperature and transferred by cannula to a solution of cyclopropylsulfonamide (1.82 g, 15.0 mmol) in THF (10 mL). To the resulting solution was added DBU (2.40 mL, 16.1 mmol) and stirring was continued for 20 hours. The mixture was quenched with 1N HCl to pH 1 and THF was concentrated in vacuo. The suspension was extracted with ethyl acetate (2.x.50 mL) and the combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification by recrystallization from hexanes-ethyl acetate (1:1) afforded the title compound (2.4 g) as a white solid. The mother liquor was purified by a Biotage 40S column (eluted 9percent acetone in dichloromethane) to give a second batch of the title compound (1.1 g). Both batches were combined (total yield 92percent). 1H NMR (DMSO-d6) delta 0.96-1.10 (m, 4H), 1.22 (dd, J=5.5, 9.5 Hz, 1H), 1.39 (s, 9H), 1.70 (t, J=5.5 Hz, 1H), 2.19-2.24 (m, 1H), 2.90 (m, 1H), 5.08 (d, J=10 Hz, 1H), 5.23 (d, J=17 Hz, 1H), 5.45 (m, 1H), 6.85, 7.22 (s, NH (rotamers); MS m/z 331 (M++H).
92%		Step 2:; A solution of the product of Step 1 (2.62 g, 11.5 mmol) and CDI (2.43 g, 15.0 mmol) in THF (40 mL) was heated at reflux for 50 minutes under nitrogen. The solution was cooled to room temperature and transferred by cannula to a solution of cyclopropylsulfonamide (1.82 g, 15.0 mmol) in THF (10 mL). To the resulting solution was added DBU (2.40 mL, 16.1 mmol) and stirring was continued for 20 hours. The mixture was quenched with 1.0M HCl to pH=1, and THF was evaporated in vacuo. The suspension was extracted with ethyl acetate (2.x.50 mL) and the organic extracts were combined and dried (Na2SO4). Filtration, concentration, and purification by recrystallization from hexanes-ethyl acetate (1:1) provideed the desired product (2.4 g) as a white solid. The mother liquor was purified by a Biotage 40S column (eluted 9percent acetone in dichloromethane) to give a second batch of the desired product (1.1 g). Both batches were combined (total yield 92percent). 1H NMR: (DMSO-d6) delta 0.96-1.10 (m, 4H), 1.22 (dd, J=5.5, 9.5 Hz, 1H), 1.39 (s, 9H), 1.70 (t, J=5.5 Hz, 1H), 2.19-2.24 (m, 1H), 2.90 (m, 1H), 5.08 (d, J=10 Hz, 1H), 5.23 (d, J=17 Hz, 1H), 5.45 (m, 1H), 6.85, 7.22 (s, NH (rotamers)); LC-MS, MS m/z 331 (M++H).
85%		A solution of the acid 1d (8.70 g, 38.3 mmol) and carbonyldiimidazole (8.0 g, 50 mmol) in THF (125 mL) was refluxed for 1 h. To a slurry of cyclopropylsulfonamide 1b (6.03 g, 49.8 mmol) in THF (20 mL) was added at room temperature the above solution via cannular, followed by DBU (8.3 mL, 55.5 mmol). The mixture was stirred for 17 h whereupon it was acidified to pH 7 with 1N HCl. The organic solvent was removed in vacuo and ethyl acetate (200 mL) was added. The aqueous layer was further acidified to pH 1, and the organic layer drawn off. The aqueous layer was extracted with ethyl acetate (2.x.150 mL) and the combined organic layers were washed with brine (110 mL), dried over sodium sulfate, and concentrated in vacuo. The crude solid was purified by silica gel chromatography (ethyl acetate/hexanes) to afford 11.0 g of the product 1e in 85percent yield. 1H NMR (300 MHz, CD3OD): delta 5.64-5.52 (m, 1H), 5.29 (d, J=17.1 Hz, 1H), 5.12 (d, J=10.5 Hz, 1H), 2.95 (bs, 1H), 2.29-2.15 (m, 1H), 1.88-1.82 (m, 1H), 1.47 (s, 9H), 1.33-1.00 (m, 5H).
82%		Step B; To a solution of acid 4B2 (567 mg, 2.49 mmol), in THF (20 mL), was added CDI (515 mg, 3.17 mmol). The resulting solution was stirred for 30 min, refluxed for 30 min and allowed to cool down to RT. Cyclopropylsulfonamide 4A4 (455 mg, 3.76 mmol) was added followed by the addition of DBU (0.75 mL, 5.02 mmol) and the reaction was stirred 12 h. The THF was removed in vacuo and the residue was diluted with EtOAc, washed with 1 M HCI (2 X 100 mL) and brine, dried (MgSO4) and purified by flash chromatography (elution conditions: 70:30 hexane/EtOAc) to afford 682 mg (82percent) of compound 4B3 as a white solid.
66%		A solution of compound I-1 (0.52 g, 2.3 mmol), 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluoro-phosphate methanaminium (HATU, 1.74 g, 4.6 mmol), and 4-dimethylaminopyridine (1.39 g, 11.6 mmol) in CH2Cl2 (40 mL) was stirred at room temperature for 1 hour, followed by slow addition of cyclopropanesulfonamide (0.57 g, 4.7 mmol), diisopropylethylamine (1.81 mL, 14.0 mmol), and 1,8-diazabicyclo[5,4,0]undec-7-ene (1.80 g, 11.7 mmol) over 15 minutes. After the reaction mixture was stirred at room temperature overnight, the solvent was removed under vacuum. The residue was purified by silica gel column chromatography to give compound I-2 (0.51 g, 66percent). MS m/z 353.1 (M\|+23); 1H NMR (CDCl3) delta 9.75 (brs, 1H), 5.64-5.51 (m, 1H), 5.30 (d, J=17.4 H), 5.16 (d, J=10.2 Hz, 1H), 2.95-2.89 (m, 1H), 2.19-2.10 (m, 1H), 1.93-1.88 (m, 1H), 1.47 (s, 9H), 1.46-1.38 (m, 1H), 1.32-1.23 (m, 2H), 1.15-1.00 (m, 2H).
66%		Example 1Synthesis of {4-Cyclopropanesulfonylaminocarbonyl-2,15-dioxo-18-[2-(4-trifluoromethyl-phenyl)-benzo[4,5]furo[3,2-d]pyrimidin-4-yloxy]-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-14-yl}-carbamic acid cyclopentyl ester (Compound 1)Compound I-3 was first prepared from commercially available 1-t-butoxycarbonylamino-2-vinyl-cyclopropanecarboxylic acid ethyl ester via the route shown below:To a solution of 1-t-butoxycarbonylamino-2-vinyl-cyclopropanecarboxylic acid ethyl ester (0.34 g, 1.3 mmol) in THF (5 mL) and methanol (5 mL) was added a suspension of LiOH (0.13 g, 5.3 mmol) in water (1.4 mL). After being stirred overnight at room temperature, the reaction was quenched with 10percent HCl (2 mL) and the solvent was removed under vacuum. The resultant solid powder was washed with water (10 mL) to give compound I-1 (0.27 g, 90percent). MS m/z 249.9 (M++23); 1H NMR (CDCl3) delta 10.35 (brs, 1H), 5.84-5.71 (m, 1H), 5.29 (d, J=17.4 Hz, 1H), 5.12 (d, J=10.2 Hz, 1H), 2.23-2.14 (m, 1H), 1.87-1.65 (m, 1H), 1.58-1.41 (m, 1H), 1.43 (s, 9H).A solution of compound I-1 (0.52 g, 2.3 mmol), 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluoro-phosphate methanaminium (HATU, 1.74 g, 4.6 mmol), and 4-dimethylaminopyridine (1.39 g, 11.6 mmol) in CH2Cl2 (40 mL) was stirred at room temperature for 1 hour, followed by slow addition of cyclopropanesulfonamide (0.57 g, 4.7 mmol), diisopropylethylamine (1.81 mL, 14.0 mmol), and 1,8-diazabicyclo[5,4,0]undec-7-ene (1.80 g, 11.7 mmol) over 15 minutes. After the reaction mixture was stirred at room temperature overnight, the solvent was removed under vacuum. The residue was purified by silica gel column chromatography to give compound I-2 (0.51 g, 66percent). MS m/z 353.1 (M++423); 1H NMR (CDCl3) delta 9.75 (brs, 1H), 5.64-5.51 (m, 1H), 5.30 (d, J=17.4H), 5.16 (d, J=10.2 Hz, 1H), 2.95-2.89 (m, 1H), 2.19-2.10 (m, 1H), 1.93-1.88 (m, 1H), 1.47 (s, 9H), 1.46-1.38 (m, 1H), 1.32-1.23 (m, 2H), 1.15-1.00 (m, 2H).To a solution of compound I-2 (0.50 g, 1.5 mmol) in MeOH (8 mL) was added SOCl2 (0.26 g, 2.2 mmol) at room temperature. After the reaction mixture was refluxed for 1 hour, MeOH and SOCl2 was removed under vacuum. The residue was triturated from pentane and filtered to give intermediate I-3 as an off-white solid (0.32 g, 91percent). MS m/z (M++1); 1H NMR (CD3COD) delta 5.77-5.65 (m, 1H), 5.43 (d, J=17.4 Hz, 1H), 5.32 (d, J=10.2 Hz, 1H), 3.06-2.97 (m, 1H), 2.45 (dd, J=17.4 Hz, J=7.8, 1H), 2.16 (dd, J=8.0 Hz, J=7.8 Hz, 1H), 1.75 (dd, J=10.1 Hz, J=7.8 Hz, 1H), 1.32-0.86 (m, 4H).Compound 1 was prepared via the route shown below:A solution of 3-amino-benzofuran-2-carboxylic acid amide (1.00 g, 5.7 mmol) and pyridine (1 mL, 12.26 mmol) in THF (25 mL) was stirred at 0° C. for 10 min. To the resulting solution was slowly added 4-trifluoromethyl-benzoyl chloride (1.48 g, 7.1 mmol). Then the temperature was raised to room temperature and the mixture was stirred for 12 h. After the solvent was removed under reduced pressure, the resulting solid was collected, washed with water, and air-dried to yield I-4 (1.92 g, 96.0percent). MS: m/z 349.0 (M++1).To a suspension of I-4 (1.92 g, 5.5 mmol) and 2N NaOH (13 mL) in EtOH (25 mL) was heated at 85° C. for 12 h. After cooled, the mixture was acidified and then EtOH was removed. The resulting solid was collected, filtrated, washed with water, and dried to afford I-5 (1.71 g, 95.0percent). MS m/z 331 (M++1).A solution of I-5 (1.71 g, 5.2 mmol) and excess phosphorus oxychloride (POCl3) was refluxed for 2 hours. After cooled and thoroughly concentrated, the mixture was subjected to extraction with methylene chloride and 10percent sodium hydroxide. The organic layer was dried over MgSO4, concentrated, and crystallized from CH2Cl2 and n-hexane to give compound I-6 (1.49 g, 82percent). MS m/z 348.8, 350.9 (M++1); 1H NMR (CDCl3) delta 8.70 (d, 2H), 8.34 (d, 1H), 7.82-7.75 (m, 4H), 7.57 (ddd, 1H).To a suspension of boc-trans-4-hydroxy-L-proline (0.53 g, 2.3 mmol) in DMSO (25 mL) was added t-BuOK (0.82 g, 5.1 mmol) at 0° C. After the mixture was allowed to warm to room temperature and stirred for 1 hour, compound I-6 (0.81 g, 2.3 mmol) was added slowly at 10° C. Stirring was continued overnight. Iodomethane (1.02 g, 6.9 mmol) was added and the reaction mixture was stirred at room temperature for additional 30 minutes. The reaction mixture was neutralized to pH 6-7 by 10percent HCl aqueous solution and subjected to extraction with methylene chloride. The organic layer was dried over MgSO4, evaporated under vacuum, and purified by silica gel column chromatography to give compound I-7 (1.12 g, 86percent). MS m/z 557.8 (M++1); 1H NMR (CDCl3) delta 8.63 (d, 2H), 8.28 (d, 1H), 7.80-7.74 (m, 2H), 7.70 (d, 2H), 7.51 (ddd, 1H).To a solution of compound I-7 (1.13 g, 2.0 mmol) in MeOH (20 mL) was added SOCl2 (1.21 g, 9.8 mmol) at room temperature. The reaction mixture was refluxed for 1 hour, and MeOH and SOCl2 were removed. The residue was triturated in penta...
66%		A solution of compound 1-1 (0.52 g, 2.3 mmol), 2-(lH-7-azabenzotriazol-l-yl)- 1,1 ,3,3-tetramethyl uronium hexafluoro -phosphate methanaminium (HATU, 1.74 g, 4.6 mmol), and 4-dimethylaminopyridine (1.39 g, 1 1.6 mmol) in CH2CI2 (40 mL) was stirred at room temperature for 1 hour, followed by slow addition ofcyclopropanesulfonamide (0.57 g, 4.7 mmol), diisopropylethylamine (1.81 mL, 14.0 mmol), and l ,8-diazabicyclo[5,4,0]undec-7-ene (1.80 g, 11.7 mmol) over15 minutes. After the reaction mixture was stirred at room temperature overnight, the solvent was removed under vacuum. The residue was purified by silica gel column chromatography to give compound 1-2 (0.51 g, 66percent). MS m/z 353.1 (M++23); !H NMR (CDCI3) d 9.75 (brs, 1H), 5.64-5.51 (m, 1H), 5.30 (d, J = 17.4 H), 5.16 (d, J = 10.2 Hz, 1H), 2.95-2.89 (m, 1H), 2.19-2.10 (m, 1H), 1.93-1.88 (m, 1H), 1.47 (s, 9H), 1.46-1.38 (m, 1H), 1.32-1.23 (m, 2H), 1.15-1.00 (m, 2H).
		To a solution of Boc-D-beta-vinyl cyclopropane amino acid (4.5g) in DMF was added CDI (3.97g). The reaction mixture was stirred at 4O0C for Ih and then added cyclopropylsulfonamide (4.66g) and DBU (5.78ml). The reaction mixture was stirred overnight at 4O0C. The reaction mixture was extracted with EtOAc. The organic extracts were washed with IM NaHCO3, brine, dried over Na2SO4, filtered and concentrated. The residue was desolved in 4NHCL/Dioxane. The reaction was stirred at RT for lhour and then concentrated in vacuo. The resulted solid was carrired out to next step without further purification. MS (ESI): m/z = 231.10 [M+H].
	With hydrogenchloride; 1,8-diazabicyclo[5.4.0]undec-7-ene; 1,1'-carbonyldiimidazole; In tetrahydrofuran; [(2)H6]acetone;	Step 1: tert-butyl ((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamate A solution of <strong>[159622-10-3](1R,2S)-1-((tert-butoxycarbonyl)amino)-2-vinylcyclopropanecarboxylic acid</strong> (2.62 g, 11.5 mmol) and CDI (2.43 g, 15.0 mmol) in THF (40 mL) was heated at reflux for 50 min under nitrogen. The solution was cooled to room temperature and transferred by cannula to a solution of cyclopropylsulfonamide (1.82 g, 15.0 mmol) in THF (10 mL). To the resulting solution was added DBU (2.40 mL, 16.1 mmol) and stirring was continued for 20 h. The mixture was quenched with 1N HCl to pH 1 and THF was evaporated in vacuo. The suspension was extracted with EtOAc (2*50 mL) and the combined organic extracts dried (Na2SO4). Purification by recystallization from hexanes-EtOAc (1:1) afforded the title compound (2.4 g) as a white solid. The mother liquor was purified by a Biotage 40S column (eluted 9percent acetone in DCM) to give a second batch of the compound tert-butyl ((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamate (1.1 g).
2.8 g		Intermediate C6: tert-butyl (1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamate (0154) (0155) Following the procedure in Scheme III, Intermediate C5 (6.0 g, 23.5 mmol) was added in a solution of LiOH (3.0 g, 73.5 mmol) in THF/MeOH/H2O (20 mL/20 mL/10 mL). After 1 h at r.t., the pH was adjusted to 4 with 1N HCl, aqueous layer was separated, EA was added, and the mixture was extracted with EA twice. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give the yellow oil, which was used directly in the next reaction without further purification. (0156) Then the intermediate (5.6 g, 24.2 mmol) and CDI (5.2 g, 31.5 mmol) were dissolved in THF (20 mL). After refluxed for 1 h, the mixture was cooled to r.t. and then a solution of cyclopropanesulfonamide (3.8 g, 31.5 mmol) in DCM (30 mL) was added followed by adding DBU (5.2 mg, 34.0 mmol). The mixture was stirred overnight at the room temperature, concentrated and extracted with EA twice. The combined organic layer was washed with brine, dried over Na2SO4, filtered, concentrated and purified by flash column chromatography to give the title compound C6 (2.8 g, 36.4percent) as white solid. (0157) 1H NMR (400 MHz, CDC3) delta 9.52 (s, 1H), 5.66-5.57 (m, 1H), 5.32 (d, J=13.2 Hz, 1H), 5.17 (dd, J=10.4, 0.8 Hz, 1H), 2.94-2.87 (m, 1H), 2.17 (q, J=8.4 Hz, 1H), 1.92-1.89 (m, 1H), 1.48 (s, 9H), 1.45-1.39 (m, 1H), 1.32-1.25 (m, 2H), 1.13-1.00 (m, 2H).

References: [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 1708 - 1729.
[2]Patent: US2008/107625,2008,A1 .Location in patent: Page/Page column 32.
[3]Patent: WO2003/99274,2003,A1 .Location in patent: Page 75.
[4]Patent: US2009/274652,2009,A1 .Location in patent: Page/Page column 26-27.
[5]Patent: WO2008/64061,2008,A1 .Location in patent: Page/Page column 65.
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[9]Patent: US2008/107624,2008,A1 .Location in patent: Page/Page column 32.
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23
[ 3984-14-3 ]
[ 159622-10-3 ]
[ 905994-12-9 ]

Yield	Reaction Conditions	Operation in experiment
97%		Example 16; Preparation of Compound 16: N-(4,6-dimethyl-2-pyridinyl)valyl-(4R)-N-((1R,2S)-1-((dimethylsulfamoyl)carbamoyl)-2-vinylcyclopropyl)-4-((6-methoxy-1-isoquinolinyl)oxy)-L-prolinamide; Step 1:; To a solution of N-Boc-vinylcyclopropane carboxylic acid (1.83 g, 8.05 mmol) and THF (32 mL) was added 1,1'-carbonyldiimidazole (1.44 g, 8.86 mmol). After stirring at room temperature for 3 hours, the reaction mixture was treated with N,N-dimethylsulfamide (1.0 g, 8.05 mmol) followed by DBU (2.45 g, 16.1 mmol) and was stirred at room temperature for an additional 15 hours. The reaction was then diluted with ethyl acetate (50 mL) and washed with 1.0M aqueous HCl (2.x.25 mL). The aqueous layer was extracted with ethyl acetate (2.x.50 mL). The combined organic portion was washed with H2O (25 mL) and brine, dried over MgSO4, filtered, and concentrated to a light yellow solid (2.6 g, 97percent yield) which was used without further purification. LC-MS, MS m/z 356 (M++Na).

References: [1]Patent: US2008/119461,2008,A1 .Location in patent: Page/Page column 55.

24
C₃H₉N₂O₂S^(1-)*Li⁽¹⁺⁾ [ No CAS ]
[ 159622-10-3 ]
[ 1028251-26-4 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of (1R,2S) 1-tert-butoxycarbonylamino-2-vinyl-cyclopropanecarboxylic acid (217 mg, 1.194 mmol) in THF (5 mL), was added CDI (290 mg, 1.791 mmol) and the reaction mixture was heated to reflux for 45 minutes. In another round-bottomed flask, LiHMDS (1.0M solution in hexanes, 2.4 mL, 2.4 mmol) was added to a solution of N-ethylmethylsulfamide (330 mg, 2.388 mmol) in THF (5 mL) and the reaction mixture was stirred at room temperature for 1 hour. The two reaction mixtures were combined and stirred at room temperature for 2 hours. Water was added to quench the reaction and the reaction solution was extracted with ethyl acetate. The organic layer was separated and dried over MgSO4. Filtration and concentration gave crude product which was purified by preparative HPLC to provide the desired N-Boc protected N-acylsulfamide. The Boc protecting group was then removed as the compound was dissolved in 4N HCl solution in dioxane (2 mL) and stirred at room temperature for 4 hours. Concentration provided a brownish oil as the HCl salt. (112 mg, 33percent yield). 1H NMR (400 Mz, CD3OD) delta 1.16 (t, J=7.21 Hz, 3H), 1.68 (dd, J=10.03, 7.83 Hz, 1H), 2.15 (m, 1H), 2.37 (m, 1H), 2.89 (s, 3H), 3.30 (m, 2H), 5.31 (d, J=10.27 Hz, 1H), 5.42 (d, J=17.12 Hz, 3H), 5.68 (m, 1H). LC-MS, MS m/z 270 (M+Na+).
		EXAMPLE 2; Specific procedure for the preparation of an acylsulfamide intermediate; To a solution of (IR, 2S) l-tert-butoxycarbonylamino-2-vinyl- cyclopropanecarboxylic acid (217 mg, 1.194 mmol) in THF (5 mL), CDI (290 mg, 1.791 mmol) was added and the reaction mixture was heated under reflux for 45 min. In another round-bottomed flask, LiHMDS (1.0 M solution in hexanes, 2.4 mL, 2.4 mmol) was added to a solution of N-ethylmethylsulfamide (330 mg, 2.388 mmol) in THF (5 mL) and the reaction mixture was stirred at rt for Ih. Two reaction mixtures were added together and stirred at rt for 2h. Water was added to quench the reaction and the reaction solution was extracted with EtOAc. The oraganic layer was separated and dried over MgSO4. Evaporation of solvent gave crude product which was purified by Prep. HPLC to afford desired N-acylsulfamide. N-acylsulfamide was then dissolved in 4N HCl solution in dioxane (2mL) and stirred at rt for 4h.Evaporation of solution give brownish oil as HCl salt. (112mg, 33percent yield). 1H NMR (400Mz, CD3OD) delta 1.16 (t, J=7.21 Hz, 3 H), 1.68 (dd, J=10.03, 7.83 Hz, 1 H), 2.15 (m, 1 H), 2.37 (m, 1 H), 2.89 (s, 3 H), 3.30 (m, 2 H), 5.31 (d, J=10.27 Hz, 1 H), 5.42 (d, J=17.12 Hz, 3 H), 5.68 (m, 1 H). LC-MS (retention time: 0.883 min.), MS m/z 270 (M+Na+).
		To a solution of (1R, 2S) 1-tert-butoxycarbonylamino-2-vinyl-cyclopropanecarboxylic acid (217 mg, 1.194 mmol) in THF (5 mL), CDI (290 mg, 1.791 mmol) was added and the reaction mixture was heated under reflux for 45 min. In another round-bottomed flask, LiHMDS (1.0 M solution in hexanes, 2.4 mL, 2.4 mmol) was added to a solution of N-ethylmethylsulfamide (330 mg, 2.388 mmol) in THF (5 mL) and the reaction mixture was stirred at rt for 1 h. Two reaction mixtures were added together and stirred at rt for 2 h. Water was added to quench the reaction and the reaction solution was extracted with EtOAc. The oraganic layer was separated and dried over MgSO4. Evaporation of solvent gave crude product which was purified by Prep. HPLC to afford desired N-acylsulfamide. N-acylsulfamide was then dissolved in 4N HCl solution in dioxane (2 mL) and stirred at rt for 4 h. Evaporation of solution give brownish oil as HCl salt. (112 mg, 33percent yield). 1H NMR (400 Mz, CD3OD) 1.16 (t, J=7.21 Hz, 3 H), 1.68 (dd, J=10.03, 7.83 Hz, 1 H), 2.15 (m, 1 H), 2.37 (m, 1 H), 2.89 (s, 3 H), 3.30 (m, 2 H), 5.31 (d, J=10.27 Hz, 1 H), 5.42 (d, J=17.12 Hz, 3 H), 5.68 (m, 1 H). LC-MS (retention time: 0.883 min.), MS m/z 270 (M+Na+).

To a solution of (IR, 2S) l-tert-butoxycarbonylamino-2-vinyl- cyclopropanecarboxylic acid (217 mg, 1.194 mmol) in THF (5 mL), CDI (290 mg, 1.791 mmol) was added and the reaction mixture was heated under reflux for 45 min. In another round-bottomed flask, LiHMDS (1.0 M solution in hexanes, 2.4 mL, 2.4 mmol) was added to a solution of N-ethylmethylsulfamide (330 mg, 2.388 mmol) in THF (5 mL) and the reaction mixture was stirred at room temperature for 1 hour. Two reaction mixtures were added together and stirred at room temperature for 2 h. Water was added to quench the reaction and the reaction solution was extracted with EtOAc. The oraganic layer was separated and dried over MgSO4. Evaporation of solvent gave crude product which was purified by Prep. HPLC to afford desired N- acylsulfamide. N-acylsulfamide was then dissolved in 4N HCl solution in dioxane (2mL) and stirred at rt for 4h. Evaporation of solution give brownish oil as HCl salt. (112mg, 33percent yield). 1H NMR (400Mz, CD3OD) delta 1.16 (t, J=I.21 Hz, 3 H), 1.68 (dd, J=10.03, 7.83 Hz, 1 H), 2.15 (m, 1 H), 2.37 (m, 1 H), 2.89 (s, 3 H), 3.30 (m, 2 H), 5.31 (d, J=10.27 Hz, 1 H), 5.42 (d, J=17.12 Hz, 3 H), 5.68 (m, 1 H). LC-MS (retention time: 0.883 min.), MS m/z 270 (M+Na+).

References: [1]Patent: US2009/274652,2009,A1 .Location in patent: Page/Page column 27.
[2]Patent: WO2008/64061,2008,A1 .Location in patent: Page/Page column 37.
[3]Patent: US2007/93414,2007,A1 .Location in patent: Page/Page column 33.
[4]Patent: WO2008/64057,2008,A1 .Location in patent: Page/Page column 35-36.

25
[ 669008-34-8 ]
[ 159622-10-3 ]
[ 681809-18-7 ]

Yield	Reaction Conditions	Operation in experiment
100%		A solution of 1(R)-tert-butoxycarbonylamino-2(S)-vinyl-cyclopropanecarboxylic acid (4.45 g, 19.6 mmol) and 1,1'-carbonyldiimidazole (3.97 g, 24.5 mmol) in dry THF (60 mL) was heated to boiling under reflux for 90 min. Upon cooling to rt, the mixture was treated sequentially with the product from Example 100, Step 2 (5.17 g, 24.5 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (6.26 g, 41.1 mmol). The resulting mixture was stirred at rt for 72h, and was then concentrated in vacuo to a viscous brown oil. The residue was dissolved in ethyl acetate (300 mL) and was washed with 1N HCl (3.x.75 mL) and then with brine (75 mL). The organic was dried over anhydrous magnesium sulfate, filtered, and concentrated. Purification by flash silica gel chromatography (DCM, then 1percent MeOH in DCM) gave 8.4 g (quantitative yield) of the desired product as an off-white solid: MS m/z 443 ((M+Na)+).
100%		A solution of 1 (R)-tert-butoxycarbonylamino-2 (S)-vinyl-cyclopropanecarboxylic acid (4.45 g, 19.6 mmol) and 1, 1'-carbonyldiimidazole (3.97 g, 24.5 mmol) in dry THF (60 mL) was heated to boiling under reflux for 90 min. Upon cooling to rt, the mixture was treated sequentially with the product from Example 200, Step 2 (5.17 g, 24.5 mmol) and 1, 8-diazabicyclo [5.4. 0] undec-7-ene (6.26 g, 41.1 mmol). The resulting mixture was stirred at rt for 72h, and was then concentrated i71 vacuo to a viscous brown oil. The residue was dissolved in ethyl acetate (300 mL) and was washed with IN HC1 (3 x 75 mL) and then with brine (75 mL). The organic was dried over anhydrous magnesium sulfate, filtered, and concentrated. Purification by flash silica gel chromatography (DCM, then 1percent MeOH in DCM) gave 8.4 g (quantitative yield) of the desired product as an off-white solid: MS m/z 443 ).

References: [1]Patent: US2004/77551,2004,A1 .Location in patent: Page/Page column 111.
[2]Patent: WO2005/51410,2005,A1 .Location in patent: Page/Page column 109.

26
1-cyclopropylmethyl-cyclopropanesulfonic acid amide [ No CAS ]
[ 159622-10-3 ]
[ 681809-25-6 ]

Yield	Reaction Conditions	Operation in experiment
98%		Step1. [0732] To a solution of 1R-tert-butoxycarbonylamino-2S-vinyl-cyclopropanecarboxylic acid (2.1 g, 9.24 mmol) in THF (26 mL) was added CDI (1.87 g, 11.6 mmol) and was heated to 78° C. for 45 min. After let cool to rt, the reaction mixture was treated with Example 16 (2.11 g, 12.01 mmol) and DBU (2.95 g, 19.4 mmol). After stirring at rt for 14 h, the reaction was diluted with EtOAc (50 mL) and washed with 4.x.50 mL 1N HCl. The combined aqueous layer was extracted with 3.x.50 mL EtOAc. The combined organic layer was with brine, dried over MgSO4 and concentrated to a light brown solid product (3.48 g, 98percent). The product was used as crude. 1H NMR (500 MHz, CD3OD, 500 MHz) delta 0.07 (q, J=4.88 Hz, 2H) 0.44-0.48 (m, 2H) 0.68-0.72 (m, 1 H) 1.14 (s, 2H) 1.28 (dd, J=9.46, 5.19 Hz, 1 H) 1.43 (d, J=7.02 Hz, 1 H) 1.46 (s, 9H) 1.49-1.53 (m, 2H) 1.81 (dd, J=7.78, 5.34 Hz, 1 H) 1.86 (s, 2H) 2.16-2.20 (m, 1 H) 5.08 (dd, J=10.38, 1.22 Hz, 1 H) 5.27 (dd, J=17.24, 1.37 Hz, 1 H) 5.51-5.55 (m, 1 H).
98%		To a solution of lR-tert-butoxycarbonylamino-2S-vinyl-cyclopropanecarboxylic acid (2.1 g, 9.24 mmol) in THF (26 mL) was added CDI (1. 87 g, 11.6 mmol) and was heated to 78 °C for 45 min. After let cool to rt, the reaction mixture was treated with 1-cyclopropylmethyl-cyclopropanesulfonic acid amide (2.11 g, 12.01 mmol) and DBU (2.95 g, 19.4 mmol). After stirring at rt for 14 li, the reaction was diluted with EtOAc (50 mL) and washed with 4x50 mL IN HC1. The combined aqueous layer was extracted with 3x50 mL EtOAc. The combined organic layer was with brine, dried over MgS04 and concentrated to a light brown solid product (3.48 g, 98percent). The product was used as crude. 1H NMR (500 MHz, CD3OD) 8 0. 07 (q, J=4.88 Hz, 2 H) 0.44-0. 48 (m, 2 H) 0. 68-0.72 (m, 1 H) 1.14 (s, 2 H) 1. 28 (dd, J=9. 46,5. 19 Hz, 1 H) 1.43 (d, J=7. 02 Hz, 1 H) 1 46 (s, 9 H) 1.49-1. 53 (m, 2 H) 1.81 (dd, J=7. 78,5. 34 Hz, 1 H) 1.86 (s, 2 H) 2.16-2. 20 (m, 1 H) 5. 08 (dd, J=10. 38, 1.22 Hz, 1 H) 5.27 (dd, J=17. 24,1. 37 Hz, 1 H) 5.51-5. 55 (m, 1 H).

References: [1]Patent: US2004/77551,2004,A1 .Location in patent: Page/Page column 120.
[2]Patent: WO2005/51410,2005,A1 .Location in patent: Page/Page column 148-149.

27
[ 154350-29-5 ]
[ 159622-10-3 ]
(1R,2S)-1-amino-N-(cyclopropylsulfonyl)-2-vinylcyclopropane-1-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Step 1f:; To a solution of Boc-D-beta-vinyl cyclopropane amino acid (4.5) in DMF was added CDI (3.97 g). The reaction mixture was stirred at 40° C. for 1 h and then added cyclopropylsulfonamide (4.66 g) and DBU (5.78 ml). The reaction mixture was stirred overnight at 40° C. The reaction mixture was extracted with EtOAc. The organic extracts were washed with 1M NaHCO3, brine, dried over Na2SO4, filtered and concentrated. The residue was desolved in 4NHCL/Dioxane. The reaction was stirred at RT for 1 hour and then concentrated in vacuo. The resulted solid was carried out to next step without further purification.MS (ESI): m/z=231.10 [M+H].

References: [1]Patent: US2009/142299,2009,A1 .Location in patent: Page/Page column 37.

Yield	Reaction Conditions	Operation in experiment
99%		Step A: Synthesis of (1R,2S)-1-(tert-butoxycarbonylamino)-2-vinylcyclopropanecarboxylic acid 121. Compound 120 (51 g) was dissolved in THF (170 mL) at room temperature. Sodium hydroxide in water (1.47 eq. in 170 mL) was added. The reaction mixture was stirred at room temperature for 15 hrs, warmed to 50° C. for 1.5 hrs, and then cooled before neutralizing with 5 M HCl. After neutralizing with 5 M HCl, the reaction mixture was extracted with DCM. The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated under vacuum to yield compound 121 (47.7 g) as a thick, yellow oil in 99percent yield.

29
[ 159622-10-3 ]
[ 630421-48-6 ]

Yield	Reaction Conditions	Operation in experiment
87%	With CDI; 1,8-diazabicyclo[5.4.0]undec-7-ene; In tetrahydrofuran;	Step A: Synthesis of tert-butyl (1R,2S)-1-(cyclopropylsulfonyl-carbamoyl)-2-vinylcyclopropylcarbamate 130. Compound 121 (47.75 g) was dissolved in THF (480 mL) at room temperature. CDI (1.3 eq.) was added and the reaction mixture was refluxed for 30 min. After the reaction mixture was cooled to 20° C., sulfonamide (1.5 eq.) was added, followed by the addition of DBU (2 eq.). After stirring at room temperature for 15 hrs, the reaction mixture was diluted with DCM, neutralized with 5 M HCl, and washed with saturated brine to pH 7. The organics were dried over sodium sulfate and concentrated to give an off-white solid in 65 g. Crystallization from methanol/water gave compound 130 (60.17 g) as a white solid in 87percent yield.

References: [1]Patent: US2009/202480,2009,A1 .

30
[ 159622-10-3 ]
[ 853269-57-5 ]

Yield	Reaction Conditions	Operation in experiment
77%	With CDI; 1,8-diazabicyclo[5.4.0]undec-7-ene; In tetrahydrofuran;	Step B: Synthesis of tert-butyl (1R,2S)-1-(1-methylcyclopropylsulfonyl-carbamoyl)-2-vinylcyclopropylcarbamate 122. Compound 121 (104.6 g) was dissolved in THF (1.0 L) at room temperature under argon. CDI (1.5 eq.) was added and the reaction mixture was refluxed for 20 min. After the reaction mixture was cooled to 4-6° C., sulfonamide (1.5 eq.) was added, followed by the addition of DBU (2 eq.). After stirring at room temperature for 64 hrs, the reaction mixture was diluted with DCM, neutralized with 1M HCl, and washed with saturated brine to pH 7. The organics were dried over sodium sulfate and concentrated to give an off-white solid in 106.4 g. Crystallization from methanol/water gave compound 122 (91 g) as a white solid in 77percent yield.

References: [1]Patent: US2009/202480,2009,A1 .

31
[ 669008-26-8 ]
[ 159622-10-3 ]
[ 853269-57-5 ]

Yield	Reaction Conditions	Operation in experiment
79%		To a solution of lR-tert-butoxycarbonylamino-2S-vinyl-cyclopropanecarboxylic acid (2.3 g, 10.1 mmol) in THF (40 mL) was added CDI (1.80 g, 11.6 mmol) and was heated to 85 °C for 30 min. After let cool to rt, the reaction mixture was treated with 1-methyl-cyclopropanesulfonam (1.64 g, 12.1 mmol) and DBU (3.08 g, 20.2 mmol). After stirring at rt for 16 h, the reaction was diluted with EtOAc (160 mL) and washed with 2x25 mL IN HC1. The combined aqueous layer was extracted with 1x50 mL EtOAc. The combined organic layer was washed with H20 (50 mL), brine, dried over MgS04 and concentrated to a light yellow solid product (2.75 g, 79percent). The product was used as crude. MS m/z 367 (M+Na).
74.2%		General procedure: Step 2: tert-butyl ((lR,2S)-l-(((l-methylcyclopropyl)sulfonyl)carbamoyl)-2- vinylcyclopropyl)carbamate A round-bottom flask was charged with the carboxylic acid product of step 1 (2 g, 8.80 mmol) and Iota,Gamma-carbonyldiimidazole (2.141 g, 13.20 mmol). Dry THF (44.0 ml) was added under anhydrous conditions and the mixture was heated (oil bath at 85°C) for 2 hours with exclusion of moisture. The mixture was cooled to room temp and a solution of 1- methylcyclopropane-1 -sulfonamide (2.379 g, 17.60 mmol) in dry THF (10 mL) was added followed by l,8-diazabicyclo[5.4.0]undec-7-ene (2.63 ml, 17.60 mmol). The mixture was heated (oil bath at 75°C) overnight. The reaction mixture was treated with aq 1M HC1 (20 mL) and water (50 mL). The product was extracted into ethyl acetate (400 mL). Upon separation, the organic layer was washed with aq 1M HCl/water (1 :2, 80 mL), and brine (80 mL), dried over magnesium sulfate, filtered and concentrated in rotavap. The residue was purified on a gold cap RediSep® (120 g) silica gel column (gradient: 0 to 25percent ethyl acetate in dichloromethane) to give the the title compound (2.25 g, 6.53 mmol, 74.2 percent yield) as a white powder.
74.2%		A round-bottom flask was charged with the carboxylic acid product of step 1 (2 g, 8.80 mmol) and 1,1?-carbonyldiimidazole (2.141 g, 13.20 mmol). Dry THF (44.0 ml) was added under anhydrous conditions and the mixture was heated (oil bath at 85° C.) for 2 hours with exclusion of moisture. The mixture was cooled to room temp and a solution of 1-methylcyclopropane-1-sulfonamide (2.379 g, 17.60 mmol) in dry THF (10 mL) was added followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (2.63 ml, 17.60 mmol). The mixture was heated (oil bath at 75° C.) overnight. The reaction mixture was treated with aq 1M HCl (20 mL) and water (50 mL). The product was extracted into ethyl acetate (400 mL) Upon separation, the organic layer was washed with aq 1M HCl/water (1:2, 80 mL), and brine (80 mL), dried over magnesium sulfate, filtered and concentrated in rotavap. The residue was purified on a gold cap RediSep® (120 g) silica gel column (gradient: 0 to 25percent ethyl acetate in dichloromethane) to give the title compound (2.25 g, 6.53 mmol, 74.2percent yield) as a white powder.

65%		Carbonyldiimidazole (1.75 g, 1.3 eq.) was added to a solution of compound 32B (1.89 g, 1 eq.) in anhydrous THF (20 mL) at room temperature. The reaction mixture was refluxed for 2 hrs and allowed to cooled down to room temperature. Methyl cyclopropyl sulfonamide (1.68 g, 1.5 eq.) and DBU (1.68 g, 1.5 eq.) were then added at 0 0C and the mixture was stirred at room temperature for 16 hrs.Solvent was removed in vacuo and the residue was dissolved in EtOAc, washed sequentially with IN HCl and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to yield compound 32Ca as a white powder in 65percent yield. 1H NMR (CDCl3, 400 MHz) delta (ppm) 1.01-1.05 (m, 2H), 1.25-1.28 (m, 2H), 1.35-1.40 (m, 2H), 1.45 (s, 9H), 1.50 (s, 3H), 1.77-1.80 (m, IH), 4.90(d, J= 10.60 Hz, IH), 5.04 (d, J= 17.32 Hz, IH), 5.42 (m, IH).
58%		To a solution of <strong>[159622-10-3](1R,2S)-1-(tert-butoxycarbonylamino)-2-vinylcyclopropanecarboxylic acid</strong> (25 g, 110 mmol) in THF (300 mL) was added CDI (205 g, 127 mmol) and the reaction mass was heated at 85° C. for 1 h. The reaction mass was cooled to rt and to this reaction mass was added 1-methylcyclopropane-1-sulfonamide (17.7 g, 131 mmol) followed by DBU (33.2 mL, 33.5 mmol). The reaction mixture was stirred at rt for 18 h. The solvent was evaporated under reduced pressure and the residue was diluted with water and acidified to pH ?2 by using aq. 1.5 N HCl solution. The precipitated solid was isolated via filtration and washed with water to get desired compound (22 g, 58percent) as off-white solid. 1H NMR (400 MHz, DMSO-d6) delta ppm 11.01-11.17 (m, 1H), 7.17-7.33 (m, 1H), 5.35-5.51 (m, 1H), 5.18-5.29 (m, 1H), 4.99-5.09 (m, 1H), 2.21 (s, 1H), 1.69 (dd, J=7.78, 5.27 Hz, 1H), 1.40 (d, J=3.01 Hz, 14H), 1.20 (dd, J=9.29, 5.27 Hz, 1H), 0.82-0.96 (m, 2H). MS: MS m/z 343 (M++1).
		Step 4: tert-butyl [(lR,2S)-2-ethenyl-l~[(l-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl] carbamate; To a solution of (li?,2<S)-l-[(ter/-butoxycarbonyl)amino)-2- ethenylcyclopropanecarboxylic acid (4.35 g, 19.1 mmol) in THF (75 mL), carbonyldiimidazole (4.0 g, 24.88 mmol) was added, and the solution was then heated to reflux for 1 hour. The mixture was then cooled to T, and the product from step 3 (4.35 g, 19.14 mmol) was then added followed by DBU (4.0 mL, 26.8 mmol). After stirring for 20 hours, 1 N HC1 was added until acidic, and the mixture was extracted with EtO Ac 2x. The combined organic layers were dried over Na2S04, and the solvent was removed in vacuo. 1 : 1 EtOAc/hexanes (100 mL) was then added, and the resulting solid was filtered. The filtrate was concentrated and the 1 : 1 EtOAc hexanes was added again to produce more solid. The combined solids were dried to yield the title compound as a solid (5 g). LCMS (ES+) m/z 289.3 ((M-/-Bu) +H)+.
	With hydrogenchloride; 1,8-diazabicyclo[5.4.0]undec-7-ene; 1,1'-carbonyldiimidazole; In tetrahydrofuran;	Preparation of tert-butyl ((1R,2S)-1-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamate To a solution of <strong>[159622-10-3](1R,2S)-1-(tert-butoxycarbonylamino)-2-vinylcyclopropanecarboxylic acid</strong> (25 g, 110 mmol) in THF (300 mL) was added CDI (205 g, 127 mmol) and the reaction mass was heated at 85° C. for 1 h. The reaction mass was cooled to rt and to this reaction mass was added 1-methylcyclopropane-1-sulfonamide (17.7 g, 131 mmol) followed by DBU (33.2 mL, 33.5 mmol). The reaction mixture was stirred at rt for 18 h. The solvent was evaporated under reduced pressure and the residue was diluted with water and acidified to pH ?2 by using aq. 1.5 N HCl solutions. The precipitated solid was isolated via filtration and washed with water to get desired compound (22 g, 58percent) as off-white solid. 1H NMR (400 MHz, DMSO-d6) delta ppm 11.01-11.17 (m, 1H), 7.17-7.33 (m, 1H), 5.35-5.51 (m, 1H), 5.18-5.29 (m, 1H), 4.99-5.09 (m, 1H), 2.21 (s, 1H), 1.69 (dd, J=7.78, 5.27 Hz, 1H), 1.40 (d, J=3.01 Hz, 14H), 1.20 (dd, J=9.29, 5.27 Hz, 1H), 0.82-0.96 (m, 2H). MS:MS m/z 343 (M++1).

References: [1]Patent: WO2005/51410,2005,A1 .Location in patent: Page/Page column 126.
[2]ChemMedChem,2015,vol. 10,p. 727 - 735.
[3]Patent: WO2013/74386,2013,A2 .Location in patent: Page/Page column 73; 74.
[4]Patent: US9328138,2016,B2 .Location in patent: Page/Page column 94; 95.
[5]Patent: WO2011/17389,2011,A1 .Location in patent: Page/Page column 130.
[6]Patent: US9643999,2017,B2 .Location in patent: Page/Page column 68; 70.
[7]Patent: WO2012/40040,2012,A1 .Location in patent: Page/Page column 36.
[8]Patent: US2015/376233,2015,A1 .

32
[ 681808-56-0 ]
[ 159622-10-3 ]
[ 853269-46-2 ]

Yield	Reaction Conditions	Operation in experiment
32%		A mixture of 1(R)-N-Boc-amino-2(S)-vinyl-cyclopropanecarboxylic acid (3. 41 g, 15 mmol) and CDI (2.46 g, 16.5 mmol) in THF (40 ml) was refluxed for 1 h. The solution was cooled to room temperature and transferred into a solution of 1-ethyl- cyclopropylsulfonamide (2.46 g, 16.5 mmol) in THF (10 ml). DBU (2.7 ml, 18 mmol) was added and the resulting mixture was stirred at room temperature overnight. The reaction was quenched with IN HCl to pH 1 and the solvent was evaporated in vacuo. The residue was extracted with EtOAc (3 x 100 ml). The combined organic extracts were washed with brine, dried over MgS04 and concentrated in vacuo. The crude product was purified by flash column chromatograph (Biotage Flash 40M) eluted with EtOAc to give the desired product (1.72 g, 32percent). 1H NMR (400 MHz, CD30D) 8 ppm 0.92 (m, 2 H), 0.98 (t, J=7. 46 Hz, 3 H), 1.27 (dd, J=9. 54, 5.38 Hz, 1 H), 1.47 (m, 11 H), 1. 81 (dd, J=7. 83, 5.62 Hz, 1 H), 1.91 (m, 2 H), 2.18 (m, 1 H), 5.09 (dd, J=10. 27,1. 47 Hz, 1 H), 5.27 (dd, J=17. 24,1. 59 Hz, 1 H), 5.53 (m, 1 H) ; MS 359 (M+H) +.

References: [1]Patent: WO2005/51410,2005,A1 .Location in patent: Page/Page column 85-86.

33
[ 1229248-10-5 ]
[ 159622-10-3 ]
[ 1233399-93-3 ]

Yield	Reaction Conditions	Operation in experiment
88%	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 72h;	Preparation of (IR, 2S)~l-amino-2-vinylcyclopropanecarbonyl)-sulfamic acid 1-methylcyclopropyl ester hydrochloride; Step 1: (IR, 2S)-[2-Vinyl-l-(l- methylcyclopropoxysulfonylaminocarbonypcyclopropylj-carbamic acid tert- butyl ester; To a solution of (IR, 2S)-l-tert-butoxycarbonylamino-2-vinyl- cyclopropanecarboxylic acid (Wang, et al. WO2003/ 099274; 1.00 g, 4.40 mmol) in CH2CI2 (22 niL) was added sulfamic acid 1-methylcyclopropyl ester (0.328 g, 2.20 mmol), HATU (1.85 g, 4.84 mmol) and DIPEA (3.8 mL, 22 mmol). The reaction mixture was stirred at room temperature for 3 days before dilution with CH2CI2. The solution was washed twice with aqueous HCl (IM) and once with brine. The aqueous layers were backextracted with CH2CI2. The organic layers were combined, dried over Na2SO4, and concentrated in vacuo. The crude sulfamate was purified by column chromatography (20 -+100percent EtOAc/hexanes) to provide (IR, 2S)-[2-vinyl-l-(l -methyl- cyclopiOpoxysulfonylamino-carbonyl)-cyclopropyl]~carbamic acid ferf-butyl ester (1.39 g, 88percent). (LC/MS: m/z 382.9 (M+Na)+). 1H-NMR (CDCl3, 400 MHz) d 5.64-5.52 (m, IH), 5.32-5.28 (m, 2H), 5.17 (dd, IH), 2.14 (q, IH), 1.89 (dd, IH), 1.69 (s, 3H), 1.48 (s, 9H), 1.34-1.28 (m, 3H), 0.68-0.64 (m, 2H).

References: [1]Patent: WO2010/75127,2010,A1 .Location in patent: Page/Page column 93-94.

34
[ 681808-68-4 ]
[ 159622-10-3 ]
[ 1013925-93-3 ]

Yield	Reaction Conditions	Operation in experiment
	With CDI; 1,8-diazabicyclo[5.4.0]undec-7-ene; In tetrahydrofuran;	Step 5 tert-butyl [(1R,2S)-1-[(1-non-8-en-1-ylcyclopropyl)sulfonyl]carbamoyl}-2-vinylcyclopropyl]carbamate A mixture of 1.3 g (5.6 mmol) (1R,2S)-1-tert-Butoxycarbonylamino-2-vinyl-cyclopropane-carboxylic acid and 1.4 g (8.4 mmol) CDI in 40 mL THF is heated under reflux for 1 h. After cooling to rt, 1.3 mL (8.4 mmol) DBU and a solution of 1.4 g (5.8 mmol) 1-non-8-enyl-cyclopropanesulfonic acid amide in 5 mL THF is added and the mixture is stirred at rt overnight. After concentration under reduced pressure, the residue is partitioned between EtOAc and 1 N HCl. The aq. layer is extracted with EtOAc and the combined organic layers are dried over Na2SO4 and concentrated. The crude is purified by flash chromatography (silica gel, DCM/MeOH 98:2) to give the title compound. LC-MS (method A): Rt=4.99 min, M+H=455.2

References: [1]Patent: US2010/204159,2010,A1 .

35
[ 955138-46-2 ]
[ 159622-10-3 ]
[ 955138-47-3 ]

Yield	Reaction Conditions	Operation in experiment
	With CDI; 1,8-diazabicyclo[5.4.0]undec-7-ene; In tetrahydrofuran; ethyl acetate;	acid 2-trimethylsilanyl-ethyl ester To a solution of 8.6 g (37.8 mmol) (1R,2S)-1-tert-Butoxycarbonylamino-2-vinyl-cyclopropanecarboxylic acid in 120 mL THF is added 9.69 g (56.8 mmol) CDI and the mixture is stirred at 70° C. for 2 hours. The mixture is allowed to cool to RT and 12.8 g (40.5 mmol) (2-Sulfamoyl-phenyl)-carbamic acid 2-trimethylsilanyl-ethyl ester and 8.6 mL (56.8 mmol) DBU are added. The reaction mixture is stirred at RT for 12 hours. 400 mL EtOAc are added and the mixture is washed twice with 150 mL 0.5 N HCl each: The organic layer is dried with MgSO4 and concentrated in vacuo. The residue is chromatographed on SiO2 (hexanes/EtOAc 6:1 to EtOAc) to give [2-[((1R,2S)-1-tert-Butoxycarbonylamino-2-vinyl-cyclopropanecarbonyl)-sulfamoyl]-phenyl]-carbamic acid 2-trimethylsilanyl-ethyl ester as a colorless oil. LC-MS (Method A): Rt=4.97 min; M+Na=548.2, M-1=524.2

References: [1]Patent: US2010/204159,2010,A1 .

36
[ 1013925-64-8 ]
[ 159622-10-3 ]
[ 1013925-65-9 ]

Yield	Reaction Conditions	Operation in experiment
	With CDI; 1,8-diazabicyclo[5.4.0]undec-7-ene; In tetrahydrofuran; ethyl acetate;	acid tert-butyl ester To a solution of 300 mg (1.32 mmol) (1R,2S)-1-tert-Butoxycarbonylamino-2-vinyl-cyclopropanecarboxylic acid in 3 mL THF is added 338 mg (1.98 mmol) CDI and the mixture is stirred at 70° C. for 2 hours. The mixture is allowed to cool to room temperature and 449 mg (1.58 mmol) 3-Oct-7-enyloxy-benzenesulfonamide and 0.30 mL (1.98 mmol) DBU are added. The reaction is stirred at room temperature for 12 hours. 10 mL EtOAc are added and the mixture is washed with 5 mL 1 N HCl. The organic layer is dried with MgSO4 and concentrated in vacuo. The residue is purified by preparative reverse phase HPLC (Method E) to afford ((1R,2S)-1-(3-Oct-7-enyloxy-benzenesulfonylaminocarbonyl)-2-vinyl-cyclopropyl)-carbamic acid tert-butyl ester as an off-white solid. HPLC (Method C): Rt=4.42 min; LC-MS (Method A): M-H=491.5

References: [1]Patent: US2010/204159,2010,A1 .

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Technical Information

• Acyl Group Substitution • Bouveault-Blanc Reduction • Catalytic Hydrogenation • Complex Metal Hydride Reductions • Ester Cleavage • Halogenation • Heat of Combustion • Reactions of Amines • Reactions of Benzene and Substituted Benzenes • Reactions with Organometallic Reagents • Specialized Acylation Reagents-Carbodiimides and Related Reagents

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CAS No.: 159622-10-3

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CAS No.: 159622-10-3

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