27741-65-7|Ethyl 2-cyclobutylideneacetate| Ambeed

Structure of 27741-65-7

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Quality Control of [ 27741-65-7 ] Purity: 97% SDS Specification

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Product Details of [ 27741-65-7 ]

CAS No. :	27741-65-7
Formula :	C₈H₁₂O₂
M.W :	140.18
SMILES Code :	O=C(OCC)/C=C1CCC\1
MDL No. :	MFCD11977311
InChI Key :	FGCGWHVDPBOFJE-UHFFFAOYSA-N
Pubchem ID :	15724666

Safety of [ 27741-65-7 ]

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

Computational Chemistry of [ 27741-65-7 ] Show Less

Physicochemical Properties

Num. heavy atoms	10
Num. arom. heavy atoms	0
Fraction Csp3	0.62
Num. rotatable bonds	3
Num. H-bond acceptors	2.0
Num. H-bond donors	0.0
Molar Refractivity	39.27
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	26.3 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.38
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	1.4
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.66
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.	1.46
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	1.98
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.78

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.39
Solubility	5.67 mg/ml ; 0.0404 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.	-1.56
Solubility	3.89 mg/ml ; 0.0278 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	-1.47
Solubility	4.72 mg/ml ; 0.0337 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.	-6.16 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	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)	2.43

Application In Synthesis of [ 27741-65-7 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 27741-65-7 ]
Downstream synthetic route of [ 27741-65-7 ]

[ 27741-65-7 ] Synthesis Path-Upstream 1~5

1
[ 867-13-0 ]
[ 1191-95-3 ]
[ 27741-65-7 ]

Yield	Reaction Conditions	Operation in experiment
79%	Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0 - 10℃; for 1.16667 h; Inert atmosphere Stage #2: at 0 - 10℃; for 2.5 h; Inert atmosphere	To a slurry of NaH (8.0 g, 60percent in oil) in THF (150mL), was added triethyl phosphonoacetate (44.8 g)in 25 mL of THF dropwise at 0-10 ^oC over 40 min. The reactionmixture was stirred at 0-10 ^oC for another 0.5 h. Then cyclobutanone(5, 14.0 g) in 25 mL of THF was added dropwise at 0-10 ^oCover 30 min. The reaction mixture was stirred at 0-10 ^oC for 2 h. Atotal of 50 mL of water was then added slowly at 20-30 ^oC. Theorganic solvent was removed under reduced pressure followed by addition of 150mL of water. The aqueous solution was extracted with MTBE (3 x 100 mL). Thecombined organic phase was washed with water (100 mL). It was then dried overanhydrous MgSO₄. Filtration followed by evaporation gave the crudeproduct, which was purified by fractional distillation at 81-82 ^oC/19mbar to give 22.2 g (79percent yield) of Compound 9 as a colorless liquid. ¹HNMR (500 MHz,CDCl₃) δ 5.58 (m, 1H), 4.13(q, 2H, J = 7.1 Hz), 3.15-3.12 (m, 2H),2.85-2.82 (m, 2H),2.12-2.06 (m, 2H),1.26 (t, 3H, J = 7.1 Hz); ¹³C NMR (125 MHz, CDCl₃) δ 167.60, 166.60, 112.38, 59.53, 33.75, 32.32, 17.66, 14.36; MS (m/z)140.1; ESI-HRMS m/zcalcd for C₈H₁₂O₂ [M + H]⁺ 141.0910, found 141.0911.
79%	Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0 - 10℃; for 1.16667 h; Stage #2: at 0 - 10℃; for 2.5 h;	To a slurry of NaH (8.0 g, 60 in oil) in THF (150 mL) , was added triethyl phosphonoactate (44.8 g) in 25mL of THF dropwise at 0-10 over 40 min. The reaction mixture was stirred at 0-10 for another 0.5 h. Then cyclobutanone (14.0 g) in 25 mL of THF was added dropwise at 0-10 over 30 min. The reaction mixture was stirred at 0-10 for 2 h. A total of 50 mL of water was then added slowly at 20-30 . The organic solvent was removed under reduced pressure followed by addition of 150 mL of water. The aqueous solution was extracted with MTBE (3 x 100 mL) . The combined organic phase was washed with water (100 mL) . It was then dried over anhydrous MgSO₄. Filtration followed by evaporation gave the crude product, which was purified by fractional distillation at 81-82 /19 mbar to give 22.2 g (79 yield, 99 purity) of Compound 12 as a colorless liquid.¹HNMR(400 MHz, CDCl₃) δ 5.56 (m, 1H) , 4.13 (q, 2H, J 7.2 Hz) , 3.12 (m, 2H) , 2.81 (m, 2H) , 2.08 (m, 2H) , 1.25 (t, 3H, J 7.2 Hz) ¹³CNMR(100 MHz, DMSO-d₆) δ167.2, 165.3, 111.8, 58.9, 33.3, 31.8, 17.1, 14.0 MS (m/z) 140.1.
75%	Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 0.166667 h; Stage #2: at 20℃; for 4 h;	(0203) Triethyl phosphonoacetate (3.32 g, 1.0 equiv) was dissolved in abs. tetrahydrofuran and added to a suspension, cooled down to 0° C., of sodium hydride (0.58 g, 1.02 equiv, 60percent dispersion) in abs. tetrahydrofuran (5 mL). The resulting reaction mixture was stirred at a temperature of 0° C. for 10 minutes and then admixed with a solution of cyclobutanone (1.0 g, 1.0 equiv) in abs. tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for a further 4 h. After the cautious addition of water, the reaction mixture was concentrated under reduced pressure and admixed with dichloromethane. The aqueous phase was then repeatedly extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), ethyl cyclobutylideneacetate (1.5 g, 75percent of theory) was isolated. Ethyl cyclobutylideneacetate (1.0 g, 1.0 equiv) was dissolved in methanol and admixed with a 1 M solution of KOH in aq. methanol. The resulting reaction mixture was stirred at room temperature for 16 h, then neutralized with dil. HCl, admixed with water, concentrated under reduced pressure and then admixed with dichloromethane. The aqueous phase was then repeatedly extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), cyclobutylideneacetic acid (0.40 g, 51percent of theory) was isolated. Aniline (0.26 g, 1 equiv.) was dissolved in dichloromethane (5 mL) and cooled down to a temperature of 0° C., and diisopropylethylamine (1.98 mL, 4.0 equiv.), cyclopentylideneacetic acid (0.30 g, 1.0 equiv.) and N,N,N′,N′-tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate (0.97 g, 1.1 equiv.) were added. The resulting reaction mixture was stirred at room temperature for 3 h, and water and dichloromethane were then added. The aqueous phase was then repeatedly extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), 2-cyclobutylidene-N-phenylacetamide (0.27 g, 54percent of theory) was isolated. In the next step, aluminum trichloride (0.42 g, 3.0 equiv.) was initially charged in abs. dichloroethane (5 mL) under argon in a baked-out round-bottom flask and then, while cooling with ice, a solution of 2-cyclobutylidene-N-phenylacetamide (0.20 g, 1.0 equiv.) in abs. dichloroethane (5 mL) was added. The resulting reaction mixture was stirred at room temperature for a further 4 h and then added cautiously to ice-water. After adding aqueous HCl and dichloromethane, the aqueous phase was extracted repeatedly with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated cautiously under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), 1′H-spiro[cyclobutyl-1,4′-quinolin]-2′(3′H)-one was isolated as a colorless solid. 1′H-Spiro[cyclobutyl-1,4′-quinolin]-2′(3′H)-one (0.2 g, 1 equiv.) was added to conc. acetic acid (1.5 mL) and then cautiously admixed at 0° C. with fuming nitric acid (0.5 mL). The resulting reaction mixture was then stirred at 90° C. for 2 h and, after cooling to room temperature, cautiously diluted with ice-water. The aqueous phase was then repeatedly extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), 6′-nitro-1′H-spiro[cyclobutyl-1,4′-quinolin]-2′(3′H)-one (100 mg, 78percent of theory) was isolated as a colorless solid. 6′-Nitro-1′H-spiro[cyclobutyl-1,4′-quinolin]-2′(3′H)-one (100 mg, 1.0 equiv.) was dissolved under argon in abs. dioxane (2 mL) and admixed with fine cesium carbonate powder (400 mg, 3.0 equiv.). After stirring at room temperature for 5 min, cyclobutylmethyl bromide (110 mg, 2.0 equiv.) and potassium iodide (35 mg, 0.1 equiv.) were added at room temperature. The resulting reaction mixture was stirred at 150° C. under microwave conditions for 1 h and, after cooling to room temperature, water and ethyl acetate were added. The aqueous phase was then repeatedly extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), 1-(cyclopropylmethyl)-6′-nitro-1′H-spiro[cyclobutyl-1,4′-quinolin]-2′(3′H)-one (70 mg, 60percent of theory) was isolated as a colorless solid. In the next step, 1-(cyclopropylmethyl)-6′-nitro-1′H-spiro[cyclobutyl-1,4′-quinolin]-2′(3′H)-one (50 g, 1 equiv.) was added together with zinc dust (55 mg, 5 equiv.) and ammonium chloride (90 mg, 10 equiv.) to methanol/water (5:1) and the mixture was stirred under argon at a temperature of 70° C. for 2 h. After cooling to room temperature, the reaction mixture was poured onto ice-water and then adjusted to pH 12 with 6 N NaOH. The aqueous phase was then repeatedly extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), 6′-amino-1-(cyclopropylmethyl)-1′H-spiro[cyclobutyl-1,4′-quinolin]-2′(3′H)-one (35 mg, 70percent of theory) was isolated as a colorless solid. 6′-Amino-1-(cyclopropylmethyl)-1′H-spiro[cyclobutyl-1,4′-quinolin]-2′(3′H)-one (100 mg, 1.0 equiv.) was dissolved together with 4-methylphenylsulfonyl chloride (81 mg, 1.1 equiv) in abs. dichloromethane (5 mL) in a baked-out round-bottom flask under argon, then pyridine (0.15 mL, 5 equiv.) was added and the mixture was stirred at room temperature for 1 h. The reaction mixture was then concentrated under reduced pressure, the remaining residue was admixed with dil. HCl and dichloromethane, and the aqueous phase was extracted repeatedly with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), 4-methyl-N-[1′-(cyclopropylmethyl)-2′-oxo-2′,3′-dihydro-1′H-spiro[cyclobutyl-1,4′-quinolin]-6′-yl]phenylsulfonamide (70 mg, 43percent of theory) was isolated as a colorless solid. ¹H-NMR (400 MHz, d₆-DMSO δ, ppm) 10.05 (s, 1H, NH), 7.62 (d, 2H), 7.36 (d, 2H), 7.12 (m, 2H), 6.96 (m, 1H), 3.76 (m, 2H), 2.61 (s, 2H), 2.33 (s, 3H), 2.03-1.92 (m, 5H), 1.79 (m, 1H), 0.97 (m, 1H), 0.36 (m, 2H), 0.22 (m, 2H).

16%	Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 0.0833333 h; Stage #2: at 27℃; for 2 h;	To a stirred suspension of 60percent NaH (1.23 g, 51.35 mmol) in THF (50 mL), ethyl 2-(diethoxyphosphoryl)acetate (6.23 mL, 31.38 mmol) in 10 mL THF was added at 0°C and stirred for 5 mm at same temperature. Then cyclobutanone 75 (2 g, 28.53 mmol) in THF (10 mL) was added to it and allowed to stir at room temperature for 2h. Then the reaction mixture was quenched with cold water and extracted with ethyl acetate. The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain ethyl 2-cyclobutylideneacetate 76 as colorless liquid (0.65 g, 16percent yield). 1HNMR (400 MHz, CDC13): ö 5.57 (s, 1H), 4.13 (q, 2H), 3.12 (t, 2H), 2.82 (t, 2H), 2.12-2.04 (m, 2H), 1.26 (t, 3H).
96%	With NaH In tetrahydrofuran	Synthesis of Cyclobutylidene-acetic acid ethyl ester (2) NaH (60percent dispersion in oil, 1.80 g, 44.94 mmol) was suspended in dry tetrahydrofuran (80 mL) and cooled to 0° C. Triethylphosphonoacetate (9.33 mL, 47.08 mmol) was added and the mixture stirred at 0° C. for 15 minutes. Cyclobutanone (1) (3.0 g, 42.8 mmol) in THF (20 mL) was then added and the mixture allowed to warm to room temperature. After 2 hours, the mixture was partitioned between diethyl ether (200 mL) and water (150 mL). The organic phase was separated, washed with brine, dried (MgSO₄), and the solvent removed in vacuo at 600 mm Hg. The residue was purified by flash chromatography (silica, ethyl acetate:pentane 1:19) to give 5.81 g (96percent) of (2) as a colorless oil. ¹H NMR, 400 MHz (CDCl₃): δ1.27 (3H, t, J=6 Hz), 2.09 (2H, m), 2.82 (2H, m,) 3.15 (2H, m), 4.14 (2H, q, J=6 Hz), 5.58 (1H, s). MS (ES+) m/e: 141 ([MH⁺], 100percent). IR (film) ν cm^-1: 1088, 1189, 1336, 1673, 1716, 2926.
80%	With ammonium chloride; sodium hexamethyldisilazane In tetrahydrofuran	Step A Ethyl 3,3-trimethylene acrylate A solution of triethylphosphonoacetate (17 mL, 85.6 mmol), in 150 mL dry THF was cooled to -78° C. A solution of sodium hexamethyldisilazide (86 mL, 1.0M in THF, 86 mmol) was added. The mixture was warmed to 0 C for 30 min and cyclobutanone (5 grams, 71.3 mmol) was added. The mixture was warmed to room temperature and stirred overnight. Sat'd ammonium chloride was added and the mixture was extracted with ethyl acetate. The organic was dried over sodium sulfate and concentrated. Flash chromatography (30/1 hexane/ether) afforded 8.0 grams (80percent) of the desired compound. ¹H NMR (300 MHz, CDCl₃). δ1.25 (t, 3H), 2.0-2.2 (p, 2H), 2.8-2.9 (t, 2H), 3.1-3.2 (t, 2H), 4.1-4.2 (q, 2H), 5.58 (s, 1H).

References: [1] Journal of Organic Chemistry, 2016, vol. 81, # 3, p. 1057 - 1074.
[2] Journal of the Chemical Society. Perkin Transactions 2, 1999, # 5, p. 937 - 945.
[3] Tetrahedron Letters, 2015, vol. 56, # 45, p. 6287 - 6289.
[4] Patent: WO2016/37534, 2016, A1, . Location in patent: Page/Page column 19.
[5] Patent: US2017/27172, 2017, A1, . Location in patent: Paragraph 0203.
[6] Patent: WO2015/25197, 2015, A1, . Location in patent: Paragraph 000149.
[7] Journal of Medicinal Chemistry, 2005, vol. 48, # 15, p. 5025 - 5037.
[8] Patent: US6635673, 2003, B1, .
[9] Patent: US6248755, 2001, B1, .
[10] European Journal of Organic Chemistry, 2017, vol. 2017, # 31, p. 4530 - 4542.
[11] Molecules, 2018, vol. 23, # 11, .

2
[ 1191-95-3 ]
[ 1099-45-2 ]
[ 27741-65-7 ]

Yield	Reaction Conditions	Operation in experiment
70%	at 125 - 140℃; for 24 h;	Cyclobutanone (0.5 g, 7.14 mmol) and (ethoxycarbonylmethylen)-triphenylphosphorane (2.7 g, 7.75 mmol) were heated to 125 to 140° C. in seal tube for 24 h. Reaction mixture was cooled to room temperature; 50 mL of pentane was added and stirred for 20 min. Then reaction mixture was filtered. Pentane layer was evaporated without applying pressure. Crude product was purified by column chromatography (silica gel 60-120 mesh, diethyl ether and n-pentane was used as eluent) afforded colorless oil. Yield: 0.7 g, 70percent.¹H NMR (400 MHz, CDCl₃): δ 1.27 (t, J=7.0 Hz, 3H), 2.04-2.13 (m, 2H), 2.83 (t, J=8.0 Hz, 2H), 3.13 (t, J=8.0 Hz, 2H), 4.10-4.17 (m, 2H), 5.58 (t, J=2.2 Hz, 1H)

References: [1] Patent: US2012/295874, 2012, A1, . Location in patent: Page/Page column 245.
[2] Journal of the American Chemical Society, 1973, vol. 95, # 6, p. 1849 - 1859.

3
[ 71032-10-5 ]
[ 27741-65-7 ]

References: [1] Journal of the American Chemical Society, 2006, vol. 128, # 5, p. 1472 - 1473.

4
[ 1191-95-3 ]
[ 27741-65-7 ]

References: [1] Patent: EP1443046, 2004, A1, . Location in patent: Page 176.
[2] Patent: US2006/128790, 2006, A1, . Location in patent: Page/Page column 81; 97.

5
[ 867-13-0 ]
[ 27741-65-7 ]

References: [1] Patent: US2006/128790, 2006, A1, . Location in patent: Page/Page column 67.

[ 27741-65-7 ] Synthesis Path-Downstream 1~35

1
[ 71032-10-5 ]
[ 27741-65-7 ]

References: [1]Journal of the American Chemical Society,2006,vol. 128,p. 1472 - 1473.

2
[ 27741-65-7 ]
[ 1026636-78-1 ]

References: [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 5025 - 5037.

3
[ 27741-65-7 ]
[ 229330-47-6 ]

References: [1]Journal of the Chemical Society. Perkin Transactions 2 (2001),1999,p. 937 - 945.

4
[ 27741-65-7 ]
[ 229330-48-7 ]

References: [1]Journal of the Chemical Society. Perkin Transactions 2 (2001),1999,p. 937 - 945.

5
[ 27741-65-7 ]
methanesulfonic acid 1-oxa-spiro[2.3]hex-2-ylmethyl ester [ No CAS ]

References: [1]Journal of the Chemical Society. Perkin Transactions 2 (2001),1999,p. 937 - 945.

6
[ 1191-95-3 ]
[ 27741-65-7 ]

Yield	Reaction Conditions	Operation in experiment
		To an ice-cooled suspension of 60% sodium hydride (0.68 g) in N,N-dimethylformamide (20 mL) was added triethyl phosphonoacetate (3.4 mL) dropwise over 5 minutes. After stirring the suspension under ice cooling for 30 minutes, cyclobutanone (1.1 mL) was added dropwise over 5 minutes. The solution was stirred under ice cooling for additional 1 hour. The reaction solution was poured into saturated aqueous ammonium chloride solution, and it was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by chromatography [silica gel, hexane-ethyl acetate (20:1)] to give the title compound (1.27 g).1H-NMR (CDCl3) delta: 1.27 (t, 3H, J=6.8 Hz), 2.04-2.13 (m, 2H), 2.82-2.85 (m, 2H), 3.10-3.15(m, 2H), 4.14 (q, 2H, J=6.8 Hz), 5.56-5.59 (m, 1H).
		Step 1: Cyclobutylidene-acetic acid ethyl ester To a stirred solution of triethyl phosphonoacetate (25.7 g) in 150 mL of anhydrous THF at 0 C. was added slowly NaH (4.6 g, 60% in mineral oil). After 10 min., cyclobutanone (7.3 g) was added to the mixture, and the reaction was allowed to stir at room temperature for 2 hours. After the reaction was quenched by adding water, the mixture was extracted 3 times with ethyl acetate. The organic layer was separated and dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography eluted with 10% ethyl acetate in hexane to give 12.0 g of cyclobutylidene-acetic acid ethyl ester as a colorless liquid. 1H-NMR (300 MHz, CDCl3,) delta=5.54 (m, 1H, =CH), 4.11 (q, 2H, OCH2), 3.09 (t, 2H, CH2), 2.79 (t, 2H, CH2), 2.06 (m, 2H, CH2), 1.23 (t, 3H, CH3) ppm. 13C-NMR (75 MHz, CDCl3) delta=167.0, 166.5, 112.4, 59.5, 33.7, 32.3, 17.6, 14.3 ppm. Step 1: Ethyl 2-cyclobutylideneacetate To a solution of triethyl phosphono acetate (35.2 g) in 100 mL THF, at 0 C., was added slowly via a syringe a solution of NaH (6.2 g) in 60 mL THF. The mixture was stirred at 0 C. for 10 minutes, cyclobutanone (10 g) was added by a syringe, and the resulting mixture was stirred at room temperature for 2 hours, followed by addition of distilled water to quench the reaction. The aqueous solution was extracted by ethyl acetate (3*20 mL), the combined organic layers were dried over Na2SO4 and the solvent was removed by evaporation. The crude residue was eluted by column chromatography (10% ethyl acetate/hexane), to give ethyl 2-cyclobutylideneacetate (20 g). 'H-NMR (300 MHz, CDCl3) delta=5.57 (s, 1H), 4.13 (q, 2H), 3.11 (m, 2H), 2.81 (m, 2H), 2.08(m, 2H), 1.26 (t) ppm. MS: m/z 370 (100, M+H)+

References: [1]Patent: EP1443046,2004,A1 .Location in patent: Page 176.
[2]Patent: US2006/128790,2006,A1 .Location in patent: Page/Page column 81; 97.

7
[ 67-56-1 ]
[ 27741-65-7 ]
[ 43132-86-1 ]
[ 891188-23-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; trimethyl orthoformate; for 96h;Heating / reflux;	Step 2: 6'-Hydroxy-5,7'-dimethylspiro[cyclobutane-1,2'-thiochromen]-4'(3'H)-one To a solution of 4-mercapto-2,6-dimethylphenol (2.5 g) in anhydrous methanol (40 mL) containing trimethyl orthoformate (3 mL), was added <strong>[27741-65-7]cyclobutylidene-acetic acid ethyl ester</strong> (7.6 g) and then 5 drops of concentrated sulfuric acid. The solution was deoxygenated by bubbling with nitrogen, and was allowed to reflux for 4 days. The mixture was concentrated, washed with saturated NaHCO3 and extracted with ethyl acetate. After concentrated in vacuo, the residue was purified by flash chromatography eluted with 10-20% ethyl acetate in hexane to give 3.1 g of methyl {1-[(4-hydroxy-3,5-dimethylphenyl)thio]cyclobutyl}acetate as a white solid. The above addition product (3.1 g) was suspended in 200 mL of 1N NaOH in MeOH and water (1:1, v/v), and the mixture was allowed to stir for 1 hour. The reaction mixture was then acidified with 1N HCl and extracted 3 times with ethyl acetate. The organic layer was washed with water and dried over anhydrous Na2SO4, and concentrated in vacuo.

References: [1]Patent: US2006/128790,2006,A1 .Location in patent: Page/Page column 81.

8
[ 867-13-0 ]
[ 27741-65-7 ]

Yield	Reaction Conditions	Operation in experiment
		Step 1: Cyclobutylidene-acetic acid ethyl ester. To a stirred solution of cyclobutanone (5.0 g) in 150 mL of anhydrous THF at 0 C. was slowly added NaH (3.1 g, 60% in mineral oil). After 10 min, triethyl phosphonoacetate (17.6 g) was added to the mixture, and the reaction was allowed to stir at room temperature for 2 hours. After the reaction was quenched by addition of water, the mixture was extracted 3 times with ethyl acetate. The organic layer was separated and dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography eluted with 10% ethyl acetate in hexane to give 7.0 g of cyclobutylidene-acetic acid ethyl ester. 1H-NMR (300 MHz, CDCl3) delta=5.54 (m, 1H), 4.11 (q, 2), 3.09 (t, 2H), 2.79 (t, 2H), 2.06 (m, 2H), 1.23 (t, 3H) ppm. 13C-NMR (75 MHz, CDCl3) delta=167, 166.5, 112.4, 59.5, 33.7, 32.3, 17.6, 14.3 ppm.

References: [1]Patent: US2006/128790,2006,A1 .Location in patent: Page/Page column 67.

9
[ 27741-65-7 ]
[ 39785-37-0 ]
ethyl 2-(1-(4-methoxy-3,5-dimethylphenylamino)cyclobutyl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In 1,4-dioxane; toluene; for 72h;Heating / reflux;	Step 4: Ethyl 2-(1-(4-methoxy-3,5-dimethylphenylamino)cyclobutyl)acetate To a solution of 4-methoxy-3,5-dimethylaniline (5 g) and <strong>[27741-65-7]ethyl 2-cyclobutylideneacetate</strong> (10 g) in 6 mL toluene, under nitrogen was added by syringe 1mL HCl (4M in dioxane). After refluxing the solution for 3 days, the mixture was concentrated, water was added, and the solution was extracted with ethyl acetate (3*20 mL). The combined organic layers were dried over Na2SO4 and the solvent was removed by evaporation. The crude compound was purified by column chromatography (10% ethyl acetate/hexane), giving ethyl 2-(1-(4-methoxy-3,5-dimethylphenylamino)-cyclobutyl)acetate (1 g) as a while solid. 1H-NMR (300 MHz, CDCl3) delta=6.21 (s, 2H), 4.10(q, 2H), 3.67 (s, 3H), 2.90 (s, 2H), 2.33 (m, 2H), 2.19 (m, 8H), 1.95 (m, 2H), 1.24 (t, J =6.9 Hz, 3H) ppm. MS: m/z 293 (100, M+H)+

References: [1]Patent: US2006/128790,2006,A1 .Location in patent: Page/Page column 97.

10
[ 27741-65-7 ]
[ 85460-73-7 ]
[ 149-73-5 ]
[ 891188-02-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; In methanol; for 96h;Heating / reflux;	Step 2: 6'-Hydroxy-5',7',8'-trimethylspiro[cyclobutane-1,2'-thiochromen]-4'(3'H)-one 4-Mercapto-2,3,6-trimethyl-phenol (1.8 g) was dissolved in anhydrous methanol (30 mL) containing trimethyl orthoformate (2 mL). To this solution was added <strong>[27741-65-7]cyclobutylidene-acetic acid ethyl ester</strong> (4.0 g) and then 5 drops of concentrated sulfuric acid. The solution was deoxygenated by bubbling with nitrogen, and was allowed to reflux for 4 days. The mixture was concentrated, washed with NaHCO3 and extracted with ethyl acetate. After concentration in vacuo, the residue was purified by flash chromatography eluted with 10-20% ethyl acetate in hexane to give 2.26 g of [1-(4-Hydroxy-2,3,5-trimethyl-phenylsulfanyl)-cyclobutyl]-acetic acid methyl ester as a white solid.

References: [1]Patent: US2006/128790,2006,A1 .Location in patent: Page/Page column 67.

11
[ 27741-65-7 ]
[ 25021-04-9 ]

Yield	Reaction Conditions	Operation in experiment
62%	With lithium hydroxide monohydrate; water; In tetrahydrofuran; methanol; at 20℃; for 16h;	In 1:1:0.5 THF/water/Methanol (10:10:5 mL each), <strong>[27741-65-7]ethyl 2-cyclobutylideneacetate</strong> (1.2 g, 8.57 mmol) and lithium hydroxide monohydrate (2.15 g, 51.4 mmol) was added at room temperature. Reaction mixture was allowed to stir at room temperature for 16 h. TLC showed absence of starting material (Rf=0.4, 30% ethyl acetate/n-hexane). THF and Methanol was removed under reduced pressure. Aqueous layer was acidified with citric acid and extracted with ethyl acetate. Crude product was purified by column chromatography (silica gel 60-120 mesh ethyl acetate/n-hexane as eluent) to afford white solid. [0505] Yield: 0.6 g (62%) [0506] 1H NMR (400 MHz, CDCl3): delta 2.02-2.20 (m, 2H). 2.86 (t, J=7.8 Hz, 2H), 3.14 (t, J=7.8 Hz, 2H), 5.59 (t, J=2 Hz, 1H).
62%	With water; sodium hydroxide; In ethanol; at 27℃; for 12h;	To a solution of 25% NaOH in H20 (1.5 mL) and EtOH (1.5 mL) was added <strong>[27741-65-7]ethyl 2-cyclobutylideneacetate</strong> 76 (0.20 g, 1.42 mmol) and stirred for 12h at room temperature, reaction mixture was concentrated to one third and acidified with iN HC1 to pH 2-3 and extracted with ethyl acetate (2 x 50 mL), organic layer was washed with water, dried over Na2SO4 and concentrated to obtain pure compound 2- cyclobutylideneacetic acid precursor-44 as off white solid (0.10 g, 62% Yield). 1IETNMR (400 MHz, CDC13): oe 5.59 (t, 111), 3.14 (t, 2H), 2.86 (t, 2H), 2.13-2.05 (m, 2H).
54%	With lithium hydroxide; In tetrahydrofuran; water; at 20℃; for 18h;	A solution of LiOH · H2O (4.20 g, 100 mmol) in water (25 mL) was added to a solution of raw221 ethyl cyclobutylidenacetat (1.40 g, 10 mmol) in THF (25 mL). The mixture was stirred for 18 h at room222 temperature. TLC showed very little conversion. THF, water and MeOH (10 mL each), were added223 and the mixture was stirred for further three days. No starting material was visible in TLC. The224 mixture was concentrated under reduced pressure to about 30 mL, washed with ether (2 x 10 mL),225 acidified with conc. HCl (ca. 8 mL) and extracted with Et2O (3 x 10 mL). This extract was dried over226 anhydrous Na2SO4 and evaporated. 580 mg of the raw product (0.99 g) were purified by CC (silica,227 cyclohexane / EtOAc = 3:1 to 2:1) resulting in 352 mg cyclobutylideneacetic acid (2a) (54%).

51%	With potassium hydroxide; In methanol; water; at 20℃; for 16h;	(0203) Triethyl phosphonoacetate (3.32 g, 1.0 equiv) was dissolved in abs. tetrahydrofuran and added to a suspension, cooled down to 0 C., of sodium hydride (0.58 g, 1.02 equiv, 60% dispersion) in abs. tetrahydrofuran (5 mL). The resulting reaction mixture was stirred at a temperature of 0 C. for 10 minutes and then admixed with a solution of cyclobutanone (1.0 g, 1.0 equiv) in abs. tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for a further 4 h. After the cautious addition of water, the reaction mixture was concentrated under reduced pressure and admixed with dichloromethane. The aqueous phase was then repeatedly extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), <strong>[27741-65-7]ethyl cyclobutylideneacetate</strong> (1.5 g, 75% of theory) was isolated. Ethyl cyclobutylideneacetate (1.0 g, 1.0 equiv) was dissolved in methanol and admixed with a 1 M solution of KOH in aq. methanol. The resulting reaction mixture was stirred at room temperature for 16 h, then neutralized with dil. HCl, admixed with water, concentrated under reduced pressure and then admixed with dichloromethane. The aqueous phase was then repeatedly extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), cyclobutylideneacetic acid (0.40 g, 51% of theory) was isolated. Aniline (0.26 g, 1 equiv.) was dissolved in dichloromethane (5 mL) and cooled down to a temperature of 0 C., and diisopropylethylamine (1.98 mL, 4.0 equiv.), cyclopentylideneacetic acid (0.30 g, 1.0 equiv.) and N,N,N?,N?-tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate (0.97 g, 1.1 equiv.) were added. The resulting reaction mixture was stirred at room temperature for 3 h, and water and dichloromethane were then added. The aqueous phase was then repeatedly extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), 2-cyclobutylidene-N-phenylacetamide (0.27 g, 54% of theory) was isolated. In the next step, aluminum trichloride (0.42 g, 3.0 equiv.) was initially charged in abs. dichloroethane (5 mL) under argon in a baked-out round-bottom flask and then, while cooling with ice, a solution of 2-cyclobutylidene-N-phenylacetamide (0.20 g, 1.0 equiv.) in abs. dichloroethane (5 mL) was added. The resulting reaction mixture was stirred at room temperature for a further 4 h and then added cautiously to ice-water. After adding aqueous HCl and dichloromethane, the aqueous phase was extracted repeatedly with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated cautiously under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), 1?H-spiro[cyclobutyl-1,4?-quinolin]-2?(3?H)-one was isolated as a colorless solid. 1?H-Spiro[cyclobutyl-1,4?-quinolin]-2?(3?H)-one (0.2 g, 1 equiv.) was added to conc. acetic acid (1.5 mL) and then cautiously admixed at 0 C. with fuming nitric acid (0.5 mL). The resulting reaction mixture was then stirred at 90 C. for 2 h and, after cooling to room temperature, cautiously diluted with ice-water. The aqueous phase was then repeatedly extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), 6?-nitro-1?H-spiro[cyclobutyl-1,4?-quinolin]-2?(3?H)-one (100 mg, 78% of theory) was isolated as a colorless solid. 6?-Nitro-1?H-spiro[cyclobutyl-1,4?-quinolin]-2?(3?H)-one (100 mg, 1.0 equiv.) was dissolved under argon in abs. dioxane (2 mL) and admixed with fine cesium carbonate powder (400 mg, 3.0 equiv.). After stirring at room temperature for 5 min, cyclobutylmethyl bromide (110 mg, 2.0 equiv.) and potassium iodide (35 mg, 0.1 equiv.) were added at room temperature. The resulting reaction mixture was stirred at 150 C. under microwave conditions for 1 h and, after cooling to room temperature, water and ethyl acetate were added. The aqueous phase was then repeatedly extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), 1-(cyclopropylmethyl)-6?-nitro-1?H-spiro[cyclobutyl-1,4?-quinolin]-2?(3?H)-one (70 mg, 60% of theory) was isolated as a colorless solid. In the next step, 1-(cyclopropylmethyl)-6?-nitro-1?H-spiro[cyclo...
		Step 1: Cyclobutylideneacetic acid To a solution of <strong>[27741-65-7]ethyl 2-cyclobutylideneacetate</strong> (5.5 g) in 40 mL EtOH was added an aqueous NaOH solution (10 g NaOH in 40 mL H2O). The mixture was stirred at room temperature overnight. The volume of the reaction mixture was reduced to one third and the pH was modified to 2-3. The solid present was collected by filtration and dried under high vacuum, giving the pure cyclobutylideneacetic acid as an off-white solid (3.5 g) 1H-NMR (300 MHz, CDCl3) delta=5.57 (s, 1H); 4.13 (q, J=7.05 Hz, 2H); 3.11 (m, 2H); 2.81 (m, 2H); 2.08 (m, 2H); 1.26 (t, J=6.97 Hz) ppm. MS: (m/z)=113 (100, M+H)+.

References: [1]Patent: US2014/194383,2014,A1 .Location in patent: Paragraph 0503-0506.
[2]Patent: WO2015/25197,2015,A1 .Location in patent: Paragraph 000150.
[3]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 827 - 831.
[4]Molecules,2018,vol. 23.
[5]Patent: US2017/27172,2017,A1 .Location in patent: Paragraph 0203.
[6]Patent: US2006/128790,2006,A1 .Location in patent: Page/Page column 98.

12
[ 27741-65-7 ]
[ 100-46-9 ]
[ 1223573-54-3 ]

References: [1]Organic Letters,2010,vol. 12,p. 1944 - 1947.

13
[ 27741-65-7 ]
[ 1290056-77-7 ]

References: [1]Patent: US2012/295874,2012,A1 .
[2]Patent: US2014/194383,2014,A1 .
[3]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 827 - 831.

14
[ 27741-65-7 ]
[ 1290056-78-8 ]

References: [1]Patent: US2012/295874,2012,A1 .
[2]Patent: US2014/194383,2014,A1 .
[3]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 827 - 831.

15
[ 27741-65-7 ]
[ 1290056-79-9 ]

References: [1]Patent: US2012/295874,2012,A1 .
[2]Patent: US2014/194383,2014,A1 .
[3]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 827 - 831.

16
[ 27741-65-7 ]
[ 1290056-92-6 ]

References: [1]Patent: US2012/295874,2012,A1 .

17
[ 27741-65-7 ]
[ 1290056-91-5 ]

References: [1]Patent: US2012/295874,2012,A1 .

18
[ 27741-65-7 ]
[ 1290056-80-2 ]

References: [1]Patent: US2012/295874,2012,A1 .
[2]Patent: US2014/194383,2014,A1 .
[3]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 827 - 831.

19
[ 27741-65-7 ]
[ 623-51-8 ]
[ 1422354-53-7 ]

Yield	Reaction Conditions	Operation in experiment
		(step a) intermediate 1 -17.4 ml_ (64.2 mmol) Mercapto acetic acid ethyl ester and 0.6 ml_ (6.4 mmol) piperidine are mixed together in ethanol (1 13 ml_). After addition of 9.0 gcyclobutyliden acetic acid ethyl ester (64.2 mmol) the mixture is stirred for 20 h.A total of 2.7 g (1 15.6 mmol) sodium metal is added carefully in portions. After complete addition the reaction mixture is heated to reflux for one hour and then left to stirr for 5 days. After cooling to 0-5C 8.4 ml_ (144.5 mmol) acetic acid is added carefully. Then the reaction mixture is concentrated in vacuo to give crude product that is purified by MPLC (silica gel, CH/Ethyl acetate 9:1 ).CioHi4O3S (214.28)Mass spectrometry (ESI+): m/z = 215 [M+H]+ HPLC (Method A): Retention time = 0.62 min.
		7.4 mL (64.2 mmol) Mercapto acetic acid ethyl ester and 0.6 mL (6.4 mmol) piperidine are mixed together in ethanol (113 mL). After addition of 9.0 g cyclobutyliden acetic acid ethyl ester (64.2 mmol) the mixture is stirred for 20 h. A total of 2.7 g (115.6 mmol) sodium metal is added carefully in portions. After complete addition the reaction mixture is heated to reflux for one hour and then left to stir for 5 days. After cooling to 0-5 C. 8.4 mL (144.5 mmol) acetic acid is added carefully. Then the reaction mixture is concentrated in vacuo to give crude product that is purified by MPLC (silica gel, CH/Ethyl acetate 9:1). C10H14O3S (214.28) Mass spectrometry (ESI+): m/z=215 [M+H]+ HPLC (Method A): Retention time=0.62 min.

References: [1]Patent: WO2013/20992,2013,A1 .Location in patent: Page/Page column 55.
[2]Patent: US2013/196988,2013,A1 .Location in patent: Paragraph 0257-0260.

20
[ 27741-65-7 ]
[ 1422354-54-8 ]