42303-42-4|H-Acpc-OEt.HCl| Ambeed

Structure of 42303-42-4

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Quality Control of [ 42303-42-4 ] Purity: 95% SDS Specification

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Product Details of [ 42303-42-4 ]

CAS No. :	42303-42-4
Formula :	C₆H₁₂ClNO₂
M.W :	165.62
SMILES Code :	Cl.C(C)OC(=O)C1(CC1)N
MDL No. :	MFCD00190747
InChI Key :	XFNUTZWASODOQK-UHFFFAOYSA-N
Pubchem ID :	386203

Safety of [ 42303-42-4 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315
Precautionary Statements:	P280

Computational Chemistry of [ 42303-42-4 ] Show Less

Physicochemical Properties

Num. heavy atoms	10
Num. arom. heavy atoms	0
Fraction Csp3	0.83
Num. rotatable bonds	3
Num. H-bond acceptors	3.0
Num. H-bond donors	1.0
Molar Refractivity	39.84
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	52.32 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	0.0
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	0.72
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	0.78
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.	0.35
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	0.51
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	0.47

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.12
Solubility	12.5 mg/ml ; 0.0754 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.	-1.4
Solubility	6.64 mg/ml ; 0.0401 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-0.78
Solubility	27.3 mg/ml ; 0.165 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	Yes
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.	-6.8 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	1.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	1.38

Application In Synthesis of [ 42303-42-4 ]

* 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 [ 42303-42-4 ]

[ 42303-42-4 ] Synthesis Path-Downstream 1~54

1
[ 50-00-0 ]
[ 42303-42-4 ]
[ 99478-48-5 ]

References: [1]Phosphorus and Sulfur and the Related Elements,1984,vol. 20,p. 313 - 322.

2
[ 64-17-5 ]
[ 22059-21-8 ]
[ 42303-42-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	With thionyl chloride; at 0℃; for 2h;Reflux; Green chemistry;	The compound of the formula II (500.0 g, 4.95 mol) was added to ethanol (10 L) at room temperature, and thionyl chloride(883.4g, 7.43 mol) was added dropwise at 0 C, and the reaction mixture was heated to reflux and stirred for 2 h. The solution was cooled to room temperature, concentrated, and washed three times with THF (1L×3) to give the compound of formula III, 819.8 g, yield 100%.
80.6%	With thionyl chloride; at 0 - 70℃; for 20h;	Thionyl chloride (150 mL, 2.056 mol) was added slowly below 0 C to a suspension of 1- aminocyclopropanecarboxylic acid (100 g, 0.989 mol) in anhydrous ethanol (1 L). The mixture was stirred at 70 C for 20 h. TLC (methanol, f = 0.4) showed that most of the starting material was consumed. Then the solution was concentrated to give 210 g of crude product. The residue was dissolved in water and adjusted to a pH between 9 and 10 with potassium carbonate. The aqueous layer was extracted with dichloromethane (1 L x 3). The combined organic layers were concentrated to dryness. The residue was dissolved in ethyl acetate (300 mL) and hydrochloride in ethyl acetate (250 mL, 4M) was added slowly to the solution below -30 C. It was stirred for 30 min at 0 C. A solid precipitated and it was filtered under nitrogen atmosphere to give ethyl 1- aminocyclopropanecarboxylate hydrochloride (132 g, 80.6% yield) as a white solid. The following 1H-NMR is from the free amine. 1H-NMR (400MHz, chloroform-di): delta [ppm] = 0.91-1.02 (m, 2H), 1.15-1.30 (m, 5H), 2.17 (s, 2H), 4.10 (d, 2H).
80.6%		Thionyl chloride (150 mL, 2.056 mol) was added slowly below 0 C to a suspension of 1- aminocyclopropanecarboxylic acid (100 g, 0.989 mol) in anhydrous ethanol (1 L). The mixture was stirred at 70 C for 20 h. TLC (methanol, Rf = 0.4) showed that most of the starting material wasconsumed. Then the solution was concentrated to give 210 g of crude product. The residue was dissolved in water and adjusted to a pH between 9 and 10 with potassium carbonate. The aqueous layer was extracted with dichloromethane (1 L x 3). The combined organic layers were concentrated to dryness. The residue was dissolved in ethyl acetate (300 mL) and hydrochloride in ethyl acetate (250 mL, 4M) was added slowly to the solution below -30C. It was stirred for 30 mm at 0C. A solid precipitated and it was filtered under nitrogen atmosphere to give ethyl 1-aminocyclopropanecarboxylate hydrochloride (132 g, 80.6% yield) as a white solid.The following ?H-N MR is from the free amine.?H-NMR (400MHz, chloroform-d,): 6 [ppm] = 0.91-1.02 (m, 2H), 1.15-1.30 (m, 5H), 2.17 (s, 2H), 4.10 (d, 2H).

With thionyl chloride; for 8h;Heating / reflux;

a) A suspension of 6.15 g of 1-aminocyclopropanecarboxylic acid in 100 ml of ethanol is prepared and 6.5 ml of thionyl chloride are added gradually. The reaction mixture is refluxed gently for 8 hours and then concentrated under reduced pressure, toluene being added to drive off the ethanol. This gives 10 g of the hydrochloride of the ethyl ester of the starting acid.

References: [1]Patent: CN108863958,2018,A .Location in patent: Paragraph 0073; 0074; 0075; 0076.
[2]Journal of Medicinal Chemistry,1986,vol. 29,p. 1840 - 1846.
[3]Patent: WO2014/147021,2014,A2 .Location in patent: Page/Page column 129.
[4]Patent: WO2015/140195,2015,A1 .Location in patent: Page/Page column 92; 93.
[5]Patent: US2006/25589,2006,A1 .Location in patent: Page/Page column 9.

3
[ 42303-42-4 ]
[ 501-53-1 ]
[ 85452-41-1 ]

References: [1]Journal of Medicinal Chemistry,1986,vol. 29,p. 1840 - 1846.

4
[ 42303-42-4 ]
[ 70-11-1 ]
[ 957122-42-8 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; In N,N-dimethyl-formamide; at 20℃; for 18h;	A mixture of <strong>[42303-42-4]ethyl <strong>[42303-42-4]1-aminocyclopropanecarboxylate hydrochloride</strong></strong> (1.0 g, 7.74 mmol), 2-bromoacetophenone (3.08 g, 15.5 mmol), and NaHCO3 (1.30 g, 15.5 mmol) in DMF (20 mL) was stirred at ambient temperature for 18 h. H2O (20 mL) was added and the mixture was extracted with EtOAc (2×75 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H-90:10:0.1 to 5:95:0.1. The product-containing fractions were combined, adjusted to pH 10 by addition of saturated aqueous Na2CO3 and extracted with EtOAc (2×75 nL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound. MS: m/z=248 (M+1).

References: [1]Patent: US2007/265225,2007,A1 .Location in patent: Page/Page column 58.

5
[ 107259-05-2 ]
[ 42303-42-4 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In ethyl acetate; at 20℃; for 1h;	Step 3: 1-Ethoxycarbonyl-cyclopropyl-ammonium chloride A saturated solution of HCl in ethyl acetate (20 mL) was added under nitrogen to a solution of 1-[[(1,1-dimethylethoxy)carbonyl]amino]cyclopropane carboxylic acid ethyl ester (10.07 g, 43.9 mmol), prepared in the previous step, in 20 mL of ethyl acetate at room temperature. After the addition, the reaction was stirred at room temperature for 1 h. The solid present was collected by filtration, rinsed with ethyl acetate and dried under reduced pressure to give 1-ethoxycarbonyl-cyclopropyl-ammonium chloride as a white solid.

References: [1]Patent: US2008/45556,2008,A1 .Location in patent: Page/Page column 22.

6
[ 42303-42-4 ]
[ 65679-14-3 ]
[ 1007583-09-6 ]

Yield	Reaction Conditions	Operation in experiment
36%	With triethylamine; In ethanol; at 65℃; for 96h;	Step 4: Ethyl 1-[4-(4-bromophenyl)-1,3-thiazol-2-yl]amino}cyclopropane carboxylate Triethylamine (3.1 mL, 22.3 mmol) was added under nitrogen to a mixture of 2-(4-bromophenyl)-2-oxoethyl thiocyanate (5.2024 g, 20.3 mmol), prepared in step 1 of Example 1, and 1-ethoxycarbonyl-cyclopropyl-ammonium chloride (3.7001 g, 22.3 mmol), prepared in the previous step, in 400 mL of absolute ethanol. After the addition, the reaction was stirred at 65 C. for 4 days. The reaction was concentrated under reduced pressure to remove the ethanol. The residue was taken up in methylene chloride, applied to a Biotage FLASH 25+ cartridge and the methylene chloride allowed to evaporate. Purification of the residue on the samplet on a Horizon Flash Collector (the Biotage FLASH 25+ cartridge) using a linear gradient of 5% ethyl acetate-hexane to 100% ethyl acetate gave ethyl 1-[4-(4-bromophenyl)-1,3-thiazol-2-yl]amino}cyclopropane carboxylate (2.66 g, 36%) as a light yellow solid, mp 152-154 C.; MS m/z 367.

References: [1]Patent: US2008/45556,2008,A1 .Location in patent: Page/Page column 22.

7
[ 42303-42-4 ]
[ 99478-49-6 ]

References: [1]Phosphorus and Sulfur and the Related Elements,1984,vol. 20,p. 313 - 322.

8
[ 7732-18-5 ]
[ 42303-42-4 ]
[ 194086-61-8 ]
1-(6-Chloro-1,4-dihydro-1,1-dioxo-thieno[3,2-e]-1λ6,2,4-thiadiazin-3-ylamino)-cyclopropanecarboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
354 mg (28%)	With triethylamine; In sodium hydroxide; ethanol;	Example 8 1-(6-Chloro-1,1-dioxo-1,4-dihydro-thieno[3,2-e]-1lambda6,2,4-thiadiazin-3-ylamino)-cyclopropanecarboxylic acid A mixture of 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (1.0 g, 3.9 mmol), <strong>[42303-42-4]1-aminocyclopropanecarboxylic acid ethyl ester hydrochloride</strong> (1.29 g, 7.8 mmol) and triethylamine (1.1 ml, 7.8 mmol) in ethanol (6 ml) was stirred for 23 h at 120C in a sealed flask.. The cooled solution was concentrated in vacuo and the residue was triturated with water followed by adjustment to PH <2 with 4M hydrochloric acid.. The resulting crude dark material was isolated by filtration and boiled in 1 N sodium hydroxide followed by treatment with decolourising charcoal.. After filtration, the solution was acidified to PH <2 with 4M hydrochloric acid and the precipitate was filtered off and recrystallized from ethanol to give 354 mg (28 %) of the title compound; mp 299-300C (dec.); 1H-NMR (DMSO-d6): delta 1.17 (br s, 2H), 1.49 (br s, 2H), 7.09 (s, 1H), 8.1 (br s, 1H), 11.15 (br s, 1H), 12.7 (br s, 1H); MS: m/e 303/305 (M-H2O)+.

References: [1]Patent: EP1338600,2003,A1 .

9
[ 42303-42-4 ]
[ 194086-61-8 ]
1-(6-Chloro-1,4-dihydro-1,1-dioxo-thieno[3,2-e]-1λ6,2,4-thiadiazin-3-ylamino)-cyclopropanecarboxylic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
151 mg (11%)	With triethylamine; In ethanol;	Example 7 1-(6-Chloro-1,4-dihydro-1,1-dioxo-thieno[3,2-e]-1lambda6,2,4-thiadiazin-3-ylamino)-cyclopropanecarboxylic acid ethyl ester A mixture of 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (1.0 g, 3.9 mmol), <strong>[42303-42-4]1-aminocyclopropanecarboxylic acid ethyl ester hydrochloride</strong> (1.29 g, 7.8 mmol) and triethylamine (1.1 ml, 7.8 mmol) in ethanol (6 ml) was stirred for 23 h at 120C in a sealed flask.. The cooled solution was concentrated in vacuo and the residue was triturated with water followed by adjustment to PH <2 with 4M hydrochloric acid.. The resulting crude dark material was isolated by filtration and purified by chromatography (ethyl acetate) to give 151 mg (11 %) of the title compound; mp 190-194C (dec.); 1H-NMR (DMSO-d6): delta 1.15 (t, 3H), 1.22 (m, 2H), 1.50 (m, 2H), 4.09 (q, 2H), 7.06 (s, 1H), 8.14 (br s, 1H), 11.14 (br s, 1H); MS: m/e 349/351 (M+).
151 mg (11%)	With triethylamine; In ethanol;	EXAMPLE 7 1-(6-Chloro-1,4-dihydro-1,1-dioxo-thieno[3,2-e]-1lambda6,2,4-thiadiazin-3-ylamino)-cyclopropanecarboxylic acid ethyl ester A mixture of 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (1.0 g, 3.9 mmol), <strong>[42303-42-4]1-aminocyclopropanecarboxylic acid ethyl ester hydrochloride</strong> (1.29 g, 7.8 mmol) and triethylamine (1.1 ml, 7.8 mmol) in ethanol (6 ml) was stirred for 23 h at 120C in a sealed flask. The cooled solution was concentrated in vacuo and the residue was triturated with water followed by adjustment to pH <2 with 4M hydrochloric acid. The resulting crude dark material was isolated by filtration and purified by chromatography (ethyl acetate) to give 151 mg (11 %) of the title compound; mp 190-194C (dec.); 1H-NMR (DMSO-d6): delta 1.15 (t, 3H), 1.22 (m, 2H), 1.50 (m, 2H), 4.09 (q, 2H), 7.06 (s, 1H), 8.14 (br s, 1H), 11.14 (br s, 1H); MS: m/e 349/351 (M+).
151 mg (11%)	With triethylamine; In ethanol;	Example 7 1-(6-Chloro-1,4-dihydro-1,1-dioxo-thieno[3,2-e]-1lambda6,2,4-thiadiazin-3-ylamino)-cyclopropanecarboxylic acid ethyl ester A mixture of 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (1.0 g, 3.9 mmol), <strong>[42303-42-4]1-aminocyclopropanecarboxylic acid ethyl ester hydrochloride</strong> (1.29 g, 7.8 mmol) and triethylamine (1.1 ml, 7.8 mmol) in ethanol (6 ml) was stirred for 23 h at 120 C. in a sealed flask. The cooled solution was concentrated in vacuo and the residue was triturated with water followed by adjustment to pH <2 with 4M hydrochloric acid. The resulting crude dark material was isolated by filtration and purified by chromatography (ethyl acetate) to give 151 mg (11%) of the title compound; mp 190-194 C. (dec.); 1H-NMR (DMSO-d6): delta1.15 (t, 3H), 1.22 (m, 2H), 1.50 (m, 2H), 4.09 (q, 2H), 7.06 (s, 1H), 8.14 (br s, 1H), 11.14 (br s, 1H); MS: m/e 349/351 (M+).

References: [1]Patent: EP1338600,2003,A1 .
[2]Patent: EP1140945,2003,B1 .
[3]Patent: US6329367,2001,B1 .

10
[ 42303-42-4 ]
[ 120-92-3 ]
[ 755039-57-7 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium acetate; sodium tris(acetoxy)borohydride; In dichloromethane;	25.0 g (0.19 mol) of ethyl l-aminocyclopropane-l-carboxylate x HCl and 16.8 g (0.20 mol) of cyclopentanone are dissolved in 300 mL of dichloromethane and combined with 16.4 g (0.20 mol) of sodium acetate and 61.7 g (0.29 mol) of sodium triacetoxyborohydride. It is stirred overnight and the reaction mixture is then poured onto 400 mL of 10% sodium hydrogen carbonate solution. The aqueous phase is extracted with dichloromethane. The combined organic phases are dried over Na2SO4 and evaporated down. Yield: 34.5 g of a compound Z4a (colourless oil)
	With sodium acetate; sodium tris(acetoxy)borohydride; In dichloromethane;	25.0 g (0.19 mol) ethyl 1-aminocyclopropane-1-carboxylate×HCl and 16.8 g (0.20 mol) cyclopentanone are dissolved in 300 mL dichloromethane and combined with 16.4 g (0.20 mol) sodium acetate and 61.7 g (0.29 mol) sodium triacetoxyborohydride. The mixture is stirred overnight and the reaction mixture is then poured onto 400 mL 10% sodium hydrogen carbonate solution. The aqueous phase is extracted with dichloromethane. The combined organic phases are dried over Na2SO4 and evaporated down. Yield: 34.5 g of a compound Z4a (colourless oil)
	With sodium acetate; sodium tris(acetoxy)borohydride; In dichloromethane;	25.0 g (0.19 mol) of ethyl 1-aminocyclopropane-1-carboxylate×HCl and 16.8 g (0.20 mol) of cyclopentanone were dissolved in 300 mL of dichloromethane and combined with 16.4 g (0.20 mol) of sodium acetate and 61.7 g (0.29 mol) of sodium triacetoxyborohydride. It was stirred overnight and the reaction mixture was then poured onto 400 mL of 10% sodium hydrogen carbonate solution. The aqueous phase was extracted with dichloromethane. The combined organic phases were dried over Na2SO4 and evaporated down. Yield: 34.5 g of a compound Z4a (colourless oil)

References: [1]Patent: WO2006/18182,2006,A1 .Location in patent: Page/Page column 60.
[2]Patent: US2006/35903,2006,A1 .Location in patent: Page/Page column 15.
[3]Patent: US2004/176380,2004,A1 .Location in patent: Page/Page column 10.
[4]Patent: WO2004/76454,2004,A1 .Location in patent: Page/Page column 30.

11
[ 4595-61-3 ]
[ 42303-42-4 ]
[ 845829-97-2 ]

Yield	Reaction Conditions	Operation in experiment
95%		1a) ethyl 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylate A solution of 15.74 g (126.9 mmol) pyrimidine-5-carboxylic acid, 43.57 mL (312.6 mmol) triethylamine and 44.61 g (138.9 mmol) TBTU in 460 mL THF was stirred for 30 minutes at ambient temperature. Then 9.11 g (127.3 mmol) ethyl 1-amino-cyclopropane-carboxylate hydrochloride were added and the mixture was stirred further overnight. Then the mixture was evaporated down and the residue was combined with 200 mL water, made alkaline with dilute potassium carbonate solution and extracted with ethyl acetate. The intermediate product was purified by column chromatography (silica gel, dichloromethane+0-4% methanol). Yield: 95% of theory C11H13N3O3 (235.24) Rt=1.23 min. method 1
88%		1a) ethyl 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylateA solution of 6.80 g (54.8 mmol) of pyrimidine-5-carboxylic acid, 18.82 mL (135 mmol) of triethylamine and 19.27 g (60 mmol) of TBTU in 200 mL THF was stirred for 30 minutes at ambient temperature. Then 9.11 g (55 mmol) of ethyl 1-amino-cyclopropanecarboxylate hydrochloride were added and the mixture was stirred further overnight. Then the mixture was evaporated down, the residue was stirred with 200 mL water and the crude product was extracted with ethyl acetate. The intermediate product was purified by column chromatography (silica gel, dichloromethane+0-4% methanol).Yield: 88% of theoryC11H13N3O3 (235.24)Mass spectrum: [M+H]+=236
	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; for 16h;	Reference Example 3: Preparation of L-[(PYRIMIDIN-5-YLCARBONYL) amino] cyclopropanecarboxylic acid compound with chlorolithium (1: 1). Triethylamine (7.026g, 69.44 mmol) was added to a suspension of 1- (ethoxycarbonyl) cyclopropanaminium chloride (11. 50g, 69. 44 mmol), PYRIMIDINE-5-CARBOXYLIC acid (8.617g, 69.44 mmol), EDC (13.312g, 69.44 mmol), and HOAT (0.945g, 69.44 mmol) in CH2C12 (125mL) and allowed to stir for 16 hours. The reaction was adsorbed onto silica and purified by silica gel chromatography and eluted with ethyl acetate to yield ethyl 1- [ (PYRIMIDIN-5-YLCARBONYL) AMINO]- cyclopropanecarboxylate as a white solid. Low resolution mass spectrometry: (M+H+) = 236.2.

References: [1]Patent: US2010/240669,2010,A1 .Location in patent: Page/Page column 135.
[2]Patent: US2011/263626,2011,A1 .Location in patent: Page/Page column 44.
[3]Patent: WO2005/16886,2005,A1 .Location in patent: Page/Page column 29.

12
[ 677798-15-1 ]
[ 42303-42-4 ]
[ 677798-14-0 ]

Yield	Reaction Conditions	Operation in experiment
24%	With triethylamine;copper; In dichloromethane; at 20℃;	b) 1.25 g of the ester hydrochloride obtained above are mixed with 6.25 g of diacetyltri(4-phenoxyphenyl)bismuth in 20 ml of dichloromethane, and 1.1 ml of triethylamine and 22 mg of copper powder are added. The reaction mixture is stirred at room temperature overnight and then chromatographed on silica gel using a dichloromethane/cyclohexane mixture (8/2; v/v) as the eluent to give 0.47 g of the expected product (yield=24%). M.p.=80 C.

References: [1]Patent: US2006/25589,2006,A1 .Location in patent: Page/Page column 9.

13
2-carboxymethyl-1-(4-isopropoxyphenyl)-5-(4-trifluoromethylphenoxy)-indole-3-carboxylic acid ethyl ester [ No CAS ]
[ 42303-42-4 ]
[ 902169-69-1 ]

Yield	Reaction Conditions	Operation in experiment
	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In acetonitrile; at 20℃; for 24h;	Et3N (54 mg, 0.532 mmol) was added to a mixture of 2-carboxymethyl-l-(4-iso- propoxyphenyl)-5-(4-trifluoromethylphenoxy)indole-3-carboxylic acid ethyl ester (144 mg, 0.266 mmol, see step (d) above), 1 -amino- 1 -eye lopropanecarboxy lie acid ethyl ester hydrochloride (44 mg, 0.266 mmol), HBTU (101 mg, 0.266 mmol) and anhydrous MeCN (10 mL). The mixture was stirred at rt for 24 h. NaHCO3 (aq, sat, 10 mL) was added and the mixture was extracted with EtOAc. The organic layer was washed with saturated NaHCO3 (aq, sat, 10 mL) and brine (15 mL), dried (Na2SO4) and concentrated to give the sub-title compound which was used in the next step without further purification.

References: [1]Patent: WO2006/77365,2006,A1 .Location in patent: Page/Page column 94.

14
[ 42303-42-4 ]
[ 107017-72-1 ]

Yield	Reaction Conditions	Operation in experiment
98%		Example 67; 5-Cvano-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carboxylic acid (1- hvdroxymethylcvclopropyDamide1-Amino-cyclopropanecarboxylic acid ethyl ester hydrochloride (350mg, 2.11mmol) was dissolved in anhydrous THF (15ml) and cooled to 00C under argon. A 1.0M solution of lithium aluminium hydride in THF (2.5ml, 2.50mmol) was added dropwise and the reaction allowed to warm to room temperature and stirred for 17 h. The reaction was quenched by EPO <DP n="51"/>cautious addition of sodium sulfate decahydrate until evolution of hydrogen had ceased. The suspension was stirred for 2 h, filtered through Dicalite and the residue washed thoroughly with ether. The filtrate and washings were combined and concentrated to yield (i-amino-cyclopropyl)methanol (180mg, 98%) as a colourless oil.
95%	With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 2h;Inert atmosphere;	To a stirred solution of lithium aluminum hydride (1.3 g, 36.23 mmol) in THF (30 mL) under an argon atmosphere was added <strong>[42303-42-4]ethyl 1-aminocyclopropane-1-carboxylate hydrochloride</strong> (3 g, 18.11 mmol) at 0 oC and stirred for 2 h. After consumption of starting material (monitored by TLC), the reaction mixture was quenched with a saturated sodium sulfate solution (100 mL) and stirred for 1 h. The reaction mixture was filtered and washed with 20% MeOH: CH2Cl2. The filtrate was concentrated in vacuo to obtain (1- aminocyclopropyl) methanol (1.5 g, 95%) as a colorless liquid used in the next step without further purification. TLC: EtOAc (Rf: 0.1).

References: [1]Patent: WO2006/100208,2006,A1 .Location in patent: Page/Page column 48-49.
[2]Patent: WO2015/109109,2015,A1 .Location in patent: Paragraph 1163.

15
petroleum [ No CAS ]
[ 652-39-1 ]
[ 42303-42-4 ]
2-(1'-Ethoxycarbonylcyclopropyl)-1,3-dioxo-4-fluoroisoindoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran; chloroform;	PREPARATION 6 2-(1'-Ethoxycarbonylcyclopropyl)-1,3-dioxo-4-fluoroisoindoline 3-Fluorophthalic anhydride (2.0 g), ethyl 1-aminocyclopropane carboxylate hydrochloride (4.0 g) and triethylamine (4 ml) were stirred in chloroform (30 ml) for 0.5 h. Volatile material was evaporated and the residue was heated at 210 for 0.25 h in a nitrogen atmosphere; the residue was dissolved in THF (insoluble triethylame hydrochloride was discarded) and the ethereal solution was evaporated to dryness. This residue was recrystallized from dichloromethane/light petroleum (40-60) to give the title compound m.p. 164.

References: [1]Patent: US4351842,1982,A .

16
[ 59882-98-3 ]
[ 42303-42-4 ]
2-(1'-Hydroxymethylcyclopropyl)benz[e]isoindoline hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In tetrahydrofuran; chloroform; water;	EXAMPLE 49 2-(1'-Hydroxymethylcyclopropyl)benz[e]isoindoline hydrochloride Ethyl <strong>[42303-42-4]1-aminocyclopropanecarboxylate hydrochloride</strong> (16 g) in chloroform (50 ml) was added to 1,2-bis(bromomethyl)naphthalene (40 g) and potassium carbonate (40 g) in chloroform (200 ml) kept at 60. The reaction mixture was refluxed for a further 6 hr and then filtered; the filtrate was evaporated to dryness and the residue [i.e. crude 2-(1'-carbethoxycyclopropyl)benz[e]isoindoline] was dissolved in THF (150 ml) and added to lithium aluminium hydride (10 g) in THF (100 ml) over 0.5 h. Water was then added and the resultant slurry was filtered and the filtrate was evaporated to dryness; the residue was partitioned between ether and water and the ether layer was extracted with concentrated hydrochloric acid. The acidic extract was evaporated to dryness to give a residue which was recrystallized from iso-propanol/ethyl acetate to give the title compound (5.9 g. m.p.192).

References: [1]Patent: US4351842,1982,A .

17
(1R*,2S*)-N,N-bis(tert-butoxycarbonyl)-4-oxo-1,2-cyclohexanediamine [ No CAS ]
[ 42303-42-4 ]
(1R*,2S*)-N,N-Bis(tert-butoxycarbonyl)-4-[(1-ethoxycarbonyl)cyclopropan-1-yl]amino-1,2-cyclohexanediamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium tris(acetoxy)borohydride; sodium hydrogencarbonate; In dichloromethane;	[Referential Example 239] (1R,2S)-N,N-Bis(tert-butoxycarbonyl)-4-[(1-ethoxycarbonyl)cyclopropan-1-yl]amino-1,2-cyclohexanediamine (Stereoisomer A and Stereoisomer B): Ethyl <strong>[42303-42-4]1-aminocyclopropanecarboxylate hydrochloride</strong> (1.63 g) was dissolved in dichloromethane (60 ml), and (1R,2S)-N,N-bis(tert-butoxycarbonyl)-4-oxo-1,2-cyclohexanediamine (3.0 g) and sodium triacetoxyborohydride (2.51 g) were added to stir the mixture at room temperature for 3 hours. An aqueous solution of sodium hydrogencarbonate was added to separate an organic layer. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate = 3:1 ? 1:1) to obtain the title compounds (Stereoisomer A: 1.43 g and Stereoisomer B: 2.17 g) as colorless amorphous solids. Stereoisomer A: 1H-NMR (CDCl3) delta: 0.90-1.00(1H,m), 1.05-1.15(1H,m), 1.20-1.85(29H,m), 2.00-2.10(1H,m), 3.20-3.35(2H,m), 3.65-3.75(1H,m) 4.11(2H,q,J=7.1Hz), 4.75-4.95(2H,m). MS (FAB) m/z: 442(M+H)+. Stereoisomer B: 1H-NMR (CDCl3) delta: 0.90-1.70(29H,m), 1.85-1.95(1H,m), 1.95-2.10(1H,m), 2.20-2.30(1H,m), 2.85-2.95(1H,m) 3.20-3.45(2H,m), 4.13(2H,q,J=7.1Hz), 4.80-4.95(2H,m). MS (FAB) m/z: 442(M+H)+.

References: [1]Patent: EP1270557,2003,A1 .

18
[ 42303-42-4 ]
[ 194086-61-8 ]
1-(6-Chloro-1,4-dihydro-1,1-dioxo-thieno[3,2-e]-1λ6,2,4-thiadiazin-3-ylamino)-cyclopropanecarboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
354 mg (28%)	With triethylamine; In sodium hydroxide; ethanol;	Example 8 1-(6-Chloro-1,1-dioxo-1,4-dihydro-thieno[3,2-e]-1lambda6,2,4-thiadiazin-3-ylamino)-cyclopropanecarboxylic acid A mixture of 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (1.0 g, 3.9 mmol), <strong>[42303-42-4]1-aminocyclopropanecarboxylic acid ethyl ester hydrochloride</strong> (1.29 g, 7.8 mmol) and triethylamine (1.1 ml, 7.8 mmol) in ethanol (6 ml) was stirred for 23 h at 120 C. in a sealed flask. The cooled solution was concentrated in vacuo and the residue was triturated with water followed by adjustment to pH <2 with 4M hydrochloric acid. The resulting crude dark material was isolated by filtration and boiled in 1N sodium hydroxide followed by treatment with decolourising charcoal. After filtration, the solution was acidified to pH <2 with 4M hydrochloric acid and the precipitate was filtered off and recrystallized from ethanol to give 354 mg (28%) of the title compound; mp 299-300 C. (dec.); 1H-NMR (DMSO-d6): delta1.17 (br s, 2H), 1.49 (br s, 2H), 7.09 (s, 1H), 8.1 (br s, 1H), 11.15 (br s, 1H), 12.7 (br s, 1H); MS: m/e 303/305 (M-H2O)+.

References: [1]Patent: US6329367,2001,B1 .

19
[ 39494-19-4 ]
[ 42303-42-4 ]
[ 99127-13-6 ]