65338-28-5|Ethyl 1-methylcyclobutanecarboxylate| Ambeed

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Quality Control of [ 65338-28-5 ] Purity: 98+% SDS Specification

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Product Details of [ 65338-28-5 ]

CAS No. :	65338-28-5
Formula :	C₈H₁₄O₂
M.W :	142.20
SMILES Code :	O=C(C1(C)CCC1)OCC
MDL No. :	MFCD20527466
InChI Key :	ZLUCBLOVYOJREX-UHFFFAOYSA-N
Pubchem ID :	57538409

Safety of [ 65338-28-5 ]

GHS Pictogram:
Signal Word:	Danger
Hazard Statements:	H315-H319-H225
Precautionary Statements:	P210-P233-P240-P241+P242+P243-P264-P280-P302+P352+P332+P313+P362+P364-P305+P351+P338+P337+P313-P370+P378-P403+P235-P501
Class:	3
UN#:	1993
Packing Group:	Ⅱ

Application In Synthesis of [ 65338-28-5 ]

* 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 [ 65338-28-5 ]

[ 65338-28-5 ] Synthesis Path-Downstream 1~17

2
[ 14924-53-9 ]
[ 74-88-4 ]
[ 65338-28-5 ]

Yield	Reaction Conditions	Operation in experiment
	With lithium diisopropyl amide; In tetrahydrofuran;	1-Methyl-cyclobutanecarboxylic acid ethyl ester 1 was prepared from ethyl cyclobutanecarboxylate by the method described in J. Am. Chem. Soc, Vol. 103 No.2 1981 436-442.
	With potassium hexamethylsilazane; In tetrahydrofuran; toluene; at -78 - 20℃;	Step A; Ethyl 1-Methylcyclobutanecarboxylic Acid; To a solution of ethyl cyclobutanecarboxylate (1.0 g, 7.8 mmol) and methyl iodide (2.4 mL, 39 mmol) in 20 mL of anhydrous tetrahydrofuran at -78C was added potassium hexamethyldisilazide (0.5 M in toluene, 23 mL, 12 mmol), and the reaction was allowed to warm to room temperature overnight. After quenching with saturated ammonium chloride (10 mL), the resulting mixture was partitioned between water (100 mL) and ethyl acetate (100 mL). The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness to give the title compound, which was used without further purification. *H NMR (500 MHz, CD3OD): delta 4.12 (q,2H), 2.5-1.8 (m, 6H), 1.48 (s, 3H), 1.25 (t, 3H).
	With lithium diisopropyl amide; In tetrahydrofuran;	1-Methyl-cyclobutanecarboxylic acid ethyl ester 1 was prepared from ethyl cyclobutanecarboxylate by the method described in J. Am. Chem. Soc, Vol. 103 No.2 1981 436-442.1-Methyl-cyclobutanecarboxylic acid ethyl ester 1 (1eq) was stirred under a nitrogen atmosphere at O0C in anhydrous THF. To this solution was added portionwise lithium aluminium hydride (1.5eq) and the suspension was stirred at room temperature for 3 hours. The reaction mixture was cooled on ice, treated with 1 M HCI (aq) and stirred at O0C 20 minutes. The solution was passed through a pad of celite and the filtrate extracted into diethyl ether. The organic phases were dried over MgSO4, filtered and concentrated in vacuo to give (i-methyl-cyclobutyl)-methanol, 2.Pyridinium chlorochromate (1.25eq) and the same weight of celite were taken up as a suspension in anhydrous dichloromethane. To this was added dropwise a solution of compound 2 (1eq) in anhydrous dichloromethane and the resulting heterogeneous mixture was stirred at room temperature for 3 hours. The reaction mixture was passed through a pad of silica, eluting with 19:1 isohexanes: ethyl acetate to give 1- methylcyclobutanecarboxaldehyde, 3.Compound 3 (1eq) was dissolved with stirring in anhydrous dichloromethane, and to this was added Boc-phosphoglycine trimethyl ester (0.5eq) and 1 ,8- EPO <DP n="120"/>diazabicyclo[5.4.0]undec-7-ene (1.2eq). The resulting solution was stirred at ambient temperature under nitrogen overnight. The reaction mixture was partitioned between dichloromethane and successively 1 M HCI (aq), sat. NaHCO3 (aq) and sat. NaCI (aq). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography, eluting with 1%methanol in dichloromethane to give 2-tert-butoxycarbonylamino-3-(1-methyl-cyclobutyl)-acrylic acid methyl ester, 4.Compound 4 was dissolved in anhydrous methanol and degassed with nitrogen. (+)- 1 ,2-bis (2S,5S)-diethylphosphonolanbenzene (cyclooctadiene)rhodium (I) triflate was added and degassing was continued for a further 10 minutes. The reaction was shaken under a hydrogen atmosphere (4 bar) for 48 hours. The solution was concentrated, in vacuo and purified by flash chromatography, eluting with dichloromethane, to give 2S- tert-butoxycarbonylamino-3-(1-methyl-cyclobutyl)-propionic acid methyl ester, 5.HPLC retention time 5.88min (monitored at 215 and 254 nm) HPLC using Synergy Max RP 80 mum 50x4.6mm column, 10?90% 6 min gradient of solution B (solution A = 0.1% TFA in water and solution B = 10% A in acetonitrile) at flow rate of 2ml/min.MS [M+H]+ 272.08 (20%) [M-Boc+H]+ 172.06 (100%)Electrospray ionisation, eluting with acetonitrile / ammonium formate buffer.1H NMR (400 MHz, CDCI35 4.83.79 (1 H, m) 4.33-4.27 (1 H, m) 3.71 (3H, s) 1.98-1.62 (8H, m) 1.42 (9H, s) 1.22 (3H, s)

	With lithium diisopropyl amide; In tetrahydrofuran; at -78 - 20℃;	Formation of ethyl 1-methylcyclobutanecarboxylate (111a)A solution of ethyl cyclobutanecarboxylate (20.0 g, 156.0 mmol) in THF (160 mL) was added dropwise to a cold (-78 C) solution of LDA (164 mmol of 2M solution) in THF (40 mL). The solution was warmed to 0 C and then cooled again to -40 C before the addition of iodomethane (10.2 mL, 163.8 mmol). The solution was slowly warmed to room temperature and stirred overnight. The reaction was quenched with an aqueous saturated solution of ammonium chloride and ether was added. The layers were separated and the aqueous layer was washed with ether. The combined organic layers were washed with IN HC1 then dried over MgS04. The product was purified by distillation: 1H NMR (400 MHz, MeOD) delta 4.20 - 4.05 (m, 2H), 2.57 - 2.33 (m, 2H), 2.08 - 1.94 (m, 1H), 1.94 - 1.77 (m, 3H), 1.40 (s, 3H), 1.27 (tt, J = 7.1, 1.5 Hz, 3H).
		Formation of ethyl 1-methylcyclobutanecarboxylate (22a) A solution of ethyl cyclobutanecarboxylate (20.0 g, 156.0 mmol) in THF (160 mL) was added dropwise to a cold (-78 C) solution of LDA (164 mmol of 2M solution) in THF (40 mL). The solution was warmed to 0 C and then cooled again to -40 C before the addition of iodomethane (10.2 mL, 163.8 mmol). The solution was slowly warmed to room temperature and stirred overnight. The reaction was quenched with an aqueous saturated solution of ammonium chloride and ether was added. The layers were separated and the aqueous layer was washed with ether. The combined organic layers were washed with IN HC1 then dried over MgS04. The product was purified by distillation: XH NMR (400 MHz, MeOD) delta 4.20 - 4.05 (m, 2H), 2.57 - 2.33 (m, 2H), 2.08 - 1.94 (m, 1H), 1.94 - 1.77 (m, 3H), 1.40 (s, 3H), 1.27 (tt, J= 7.1, 1.5 Hz, 3H) ppm.

References: [1]Patent: WO2007/6716,2007,A1 .Location in patent: Page/Page column 57.
[2]Patent: WO2006/41797,2006,A2 .Location in patent: Page/Page column 48.
[3]Patent: WO2007/6714,2007,A1 .Location in patent: Page/Page column 118-119.
[4]Patent: WO2013/19828,2013,A1 .Location in patent: Page/Page column 96-97.
[5]Journal of the American Chemical Society,2013,vol. 135,p. 6030 - 6032.
[6]Patent: WO2013/184985,2013,A1 .Location in patent: Paragraph 00265.
[7]ACS Medicinal Chemistry Letters,2017,vol. 8,p. 256 - 260.

3
[ 65338-28-5 ]
[ 38401-41-1 ]

Yield	Reaction Conditions	Operation in experiment
		1-Methyl-cyclobutanecarboxylic acid ethyl ester 1 (1eq) was stirred under a nitrogen atmosphere at O0C in anhydrous THF. To this solution was added portionwise lithium aluminium hydride (1.5eq) and the suspension was stirred at EPO <DP n="59"/>room temperature for 3 hours. The reaction mixture was cooled on ice, treated with 1 M HCI (aq) and stirred at O0C 20 minutes. The solution was passed through a pad of celite and the filtrate extracted into diethyl ether. The organic phases were dried over MgSO4, filtered and concentrated in vacuo to give (1- methyl-cyclobutyl)-methanol, 2.
	With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 3h;	Example 5 Preparation of 1-methylcvclobutylalanine building block: 1-Methyl-cyclobutanecarboxylic acid ethyl ester 1 was prepared from ethyl cyclobutanecarboxylate by the method described in J. Am. Chem. Soc, Vol. 103 No.2 1981 436-442.1-Methyl-cyclobutanecarboxylic acid ethyl ester 1 (1eq) was stirred under a nitrogen atmosphere at O0C in anhydrous THF. To this solution was added portionwise lithium aluminium hydride (1.5eq) and the suspension was stirred at room temperature for 3 hours. The reaction mixture was cooled on ice, treated with 1 M HCI (aq) and stirred at O0C 20 minutes. The solution was passed through a pad of celite and the filtrate extracted into diethyl ether. The organic phases were dried over MgSO4, filtered and concentrated in vacuo to give (1 -methyl- cyclobutyl)-methanol, 2.Pyridinium chlorochromate (1.25eq) and the same weight of celite were taken up as a suspension in anhydrous dichloromethane. To this was added dropwise a solution of compound 2 (1eq) in anhydrous dichloromethane and the resulting heterogeneous mixture was stirred at room temperature for 3 hours. The reaction mixture was passed through a pad of silica, eluting with 19:1 isohexanes: ethyl acetate to give 1-methylcyclobutanecarboxaldehyde, 3.Compound 3 (1eq) was dissolved with stirring in anhydrous dichloromethane, and to this was added Boc-phosphoglycine trimethyl ester (0.5eq) and 1 ,8-diazabicyclo[5.4.0]undec-7-ene (1.2eq). The resulting solution was stirred at ambient temperature under nitrogen overnight. The reaction mixture was partitioned between dichloromethane and successively 1M HCI (aq), sat. NaHCO3 (aq) and sat. NaCI (aq). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography, eluting EPO <DP n="42"/>with 1%methanol in dichloromethane to give 2-tert-butoxycarbonylamino-3-(1-methyl- cyclobutyl)-acrylic acid methyl ester, 4.Compound 4 was dissolved in anhydrous methanol and degassed with nitrogen. (+)-1 ,2-bis (2S,5S)-diethylphosphonolanbenzene (cyclooctadiene)rhodium (I) triflate was added and degassing was continued for a further 10 minutes. The reaction was shaken under a hydrogen atmosphere (4 bar) for 48 hours. The solution was concentrated, in vacuo and purified by flash chromatography, eluting with dichloromethane, to give 2S-tert-butoxycarbonylamino-3-(1- methyl-cyclobutyl)-propionic acid methyl ester, 5.HPLC retention time 5.88min (monitored at 215 and 254 nm) HPLC using Synergy Max RP 80 mum 50x4.6mm column, 10?90% 6 min gradient of solution B (solution A = 0.1 % TFA in water and solution B = 10% A in acetonitrile) at flow rate of 2ml/min.MS [M+H]+ 272.08 (20%) [M-Boc+H]+ 172.06 (100%)Electrospray ionisation, eluting with acetonitrile / ammonium formate buffer.1H NMR (400 MHz, CDCI3) delta 4.89-4.79 (1H, m) 4.33-4.27 (1H, m) 3.71 (3H, s) 1.98-1.62 (8H, m) 1.42 (9H, s) 1.22 (3H, s)
		1-Methyl-cyclobutanecarboxylic acid ethyl ester 1 was prepared from ethyl cyclobutanecarboxylate by the method described in J. Am. Chem. Soc, Vol. 103 No.2 1981 436-442.1-Methyl-cyclobutanecarboxylic acid ethyl ester 1 (1eq) was stirred under a nitrogen atmosphere at O0C in anhydrous THF. To this solution was added portionwise lithium aluminium hydride (1.5eq) and the suspension was stirred at room temperature for 3 hours. The reaction mixture was cooled on ice, treated with 1 M HCI (aq) and stirred at O0C 20 minutes. The solution was passed through a pad of celite and the filtrate extracted into diethyl ether. The organic phases were dried over MgSO4, filtered and concentrated in vacuo to give (i-methyl-cyclobutyl)-methanol, 2.Pyridinium chlorochromate (1.25eq) and the same weight of celite were taken up as a suspension in anhydrous dichloromethane. To this was added dropwise a solution of compound 2 (1eq) in anhydrous dichloromethane and the resulting heterogeneous mixture was stirred at room temperature for 3 hours. The reaction mixture was passed through a pad of silica, eluting with 19:1 isohexanes: ethyl acetate to give 1- methylcyclobutanecarboxaldehyde, 3.Compound 3 (1eq) was dissolved with stirring in anhydrous dichloromethane, and to this was added Boc-phosphoglycine trimethyl ester (0.5eq) and 1 ,8- EPO <DP n="120"/>diazabicyclo[5.4.0]undec-7-ene (1.2eq). The resulting solution was stirred at ambient temperature under nitrogen overnight. The reaction mixture was partitioned between dichloromethane and successively 1 M HCI (aq), sat. NaHCO3 (aq) and sat. NaCI (aq). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography, eluting with 1%methanol in dichloromethane to give 2-tert-butoxycarbonylamino-3-(1-methyl-cyclobutyl)-acrylic acid methyl ester, 4.Compound 4 was dissolved in anhydrous methanol and degassed with nitrogen. (+)- 1 ,2-bis (2S,5S)-diethylphosphonolanbenzene (cyclooctadiene)rhodium (I) triflate was added and degassing was continued for a further 10 minutes. The reaction was shaken under a hydrogen atmosphere (4 bar) for 48 hours. The solution was concentrated, in vacuo and purified by flash chromatography, eluting with dichloromethane, to give 2S- tert-butoxycarbonylamino-3-(1-methyl-cyclobutyl)-propionic acid methyl ester, 5.HPLC retention time 5.88min (monitored at 215 and 254 nm) HPLC using Synergy Max RP 80 mum 50x4.6mm column, 10?90% 6 min gradient of solution B (solution A = 0.1% TFA in water and solution B = 10% A in acetonitrile) at flow rate of 2ml/min.MS [M+H]+ 272.08 (20%) [M-Boc+H]+ 172.06 (100%)Electrospray ionisation, eluting with acetonitrile / ammonium formate buffer.1H NMR (400 MHz, CDCI35 4.83.79 (1 H, m) 4.33-4.27 (1 H, m) 3.71 (3H, s) 1.98-1.62 (8H, m) 1.42 (9H, s) 1.22 (3H, s)

	With lithium aluminium tetrahydride; In diethyl ether; at 0℃; for 2h;	Formation of (l-methylcyclobutyl)methanol (112a)Lithium aluminum hydride (2.1 g, 59.4 mmol) was suspended in ether (150 mL) and cooled to 0 C. A solution of <strong>[65338-28-5]ethyl 1-methylcyclobutanecarboxylate</strong>, 111a, (13.0 g, 91.4 mmol) in ether (60 mL) was added dropwise to the LiAlH4 suspension. The mixture was stirred 2 hours in an ice bath then quenched slowly with IN HC1. The layers were separated and the aqueous layer was washed with ether. The combined organic layers were washed with brine and the volatiles were removed with a gentle stream of nitrogen to afford the desired product that was used without further purification: 1H NMR (400 MHz, CDC13) delta 3.54 - 3.39 (m, 4H), 1.99 - 1.74 (m, 8H), 1.74 - 1.62 (m, 4H), 1.46 - 1.18 (m, 3H), 1.13 (d, J = 1.7 Hz, 6H).
	With lithium aluminium tetrahydride; In diethyl ether; at 0℃; for 2h;	Formation of (l-methylcyclobutyl)methanol (23a) Lithium aluminum hydride (2.1 g, 59.4 mmol) was suspended in ether (150 mL) and cooled to 0 C. A solution of <strong>[65338-28-5]ethyl 1-methylcyclobutanecarboxylate</strong>, 22a, (13.0 g, 91.4 mmol) in ether (60 mL) was added dropwise to the LiAlH4 suspension. The mixture was stirred 2 hours in an ice bath then quenched slowly with IN HC1. The layers were separated and the aqueous layer was washed with ether. The combined organic layers were washed with brine and the volatiles were removed with a gentle stream of nitrogen to afford the desired product that was used without further purification: XH NMR (400 MHz, CDCI3) delta 3.54 - 3.39 (m, 4H), 1.99 - 1.74 (m, 8H), 1.74 - 1.62 (m, 4H), 1.46 - 1.18 (m, 3H), 1.13 (d, J = 1.7 Hz, 6H) ppm.

References: [1]Patent: WO2007/6716,2007,A1 .Location in patent: Page/Page column 57-58.
[2]Patent: WO2006/64286,2006,A1 .Location in patent: Page/Page column 39-41.
[3]Patent: WO2007/6714,2007,A1 .Location in patent: Page/Page column 118-119.
[4]Patent: WO2013/19828,2013,A1 .Location in patent: Page/Page column 96-97.
[5]Patent: WO2013/184985,2013,A1 .Location in patent: Paragraph 00265.
[6]ACS Medicinal Chemistry Letters,2017,vol. 8,p. 256 - 260.

4
[ 65338-28-5 ]
[ 32936-76-8 ]

Yield	Reaction Conditions	Operation in experiment
		Step B; 1 -Methylcyclobutanecarboxylic Acid; To a solution of ethyl l-methylcyclobutanecarboxylate (Step A, 1.0 g, 7.0 mmol) in water (10 mL) and dioxane (10 mL) was added lithium hydroxide monohydrate (2 g, 48 mmol), and the mixture was heated at 1000C for 2 days. After cooling to room temperature, the reaction was quenched with 2 M hydrochloric acid to pH = 2, and the resulting mixture was partitioned between water (100 mL) and ethyl acetate (100 mL). The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness to give the title compound, which was used without further purification. 1H NMR (500 MHz, CD3OD): delta 2.5-1.8 (m, 6H), 1.39 (s, 3H).

References: [1]Patent: WO2006/41797,2006,A2 .Location in patent: Page/Page column 48.
[2]Journal of the American Chemical Society,2013,vol. 135,p. 6030 - 6032.
[3]Chemical Communications,2015,vol. 51,p. 7863 - 7866.

5
[ 65338-28-5 ]
[ 65338-30-9 ]

References: [1]Patent: WO2013/19828,2013,A1 .
[2]Patent: WO2013/184985,2013,A1 .
[3]ACS Medicinal Chemistry Letters,2017,vol. 8,p. 256 - 260.

6
[ 65338-28-5 ]
methyl 3-(1-methylcyclobutyl)acrylate [ No CAS ]

References: [1]Patent: WO2013/19828,2013,A1 .
[2]Patent: WO2013/184985,2013,A1 .
[3]ACS Medicinal Chemistry Letters,2017,vol. 8,p. 256 - 260.

7
[ 65338-28-5 ]
[ 1422052-22-9 ]

References: [1]Patent: WO2013/19828,2013,A1 .
[2]Patent: WO2013/184985,2013,A1 .
[3]ACS Medicinal Chemistry Letters,2017,vol. 8,p. 256 - 260.

8
[ 65338-28-5 ]
[ 1422052-23-0 ]

References: [1]Patent: WO2013/19828,2013,A1 .
[2]Patent: WO2013/184985,2013,A1 .
[3]ACS Medicinal Chemistry Letters,2017,vol. 8,p. 256 - 260.

9
[ 65338-28-5 ]
[ 1429896-61-6 ]

References: [1]Journal of the American Chemical Society,2013,vol. 135,p. 6030 - 6032.
[2]Chemical Communications,2015,vol. 51,p. 7863 - 7866.

10
[ 65338-28-5 ]
[ 21890-82-4 ]

References: [1]Journal of the American Chemical Society,2013,vol. 135,p. 6030 - 6032.
[2]Chemical Communications,2015,vol. 51,p. 7863 - 7866.

11
[ 65338-28-5 ]
1-((phenylthio)methyl)-N-(quinolin-8-yl)cyclobutanecarboxamide [ No CAS ]

References: [1]Chemical Communications,2015,vol. 51,p. 7863 - 7866.

12
[ 65338-28-5 ]
[ 1422052-79-6 ]