137638-05-2|Methyl 3-cyclobutyl-3-oxopropanoate| Ambeed

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Quality Control of [ 137638-05-2 ] Purity: 97% SDS Specification

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Product Details of [ 137638-05-2 ]

CAS No. :	137638-05-2
Formula :	C₈H₁₂O₃
M.W :	156.18
SMILES Code :	O=C(OC)CC(C1CCC1)=O
MDL No. :	MFCD11974606
InChI Key :	VOLSRTAMKIBBTQ-UHFFFAOYSA-N
Pubchem ID :	52911251

Safety of [ 137638-05-2 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H315-H319-H335-H227
Precautionary Statements:	P210-P261-P264-P271-P280-P302+P352-P304+P340-P305+P351+P338-P312-P332+P313-P337+P313-P362-P370+P378-P403+P233-P403+P235-P405-P501

Application In Synthesis of [ 137638-05-2 ]

* 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 [ 137638-05-2 ]

[ 137638-05-2 ] Synthesis Path-Downstream 1~35

1
[ 108-24-7 ]
[ 137638-05-2 ]
(R)-3-Acetoxy-3-cyclobutyl-propionic acid methyl ester [ No CAS ]
(S)-3-Acetoxy-3-cyclobutyl-propionic acid methyl ester [ No CAS ]

References: [1]Bulletin of the Chemical Society of Japan,2002,vol. 75,p. 355 - 363.

2
[ 137638-05-2 ]
(R)-methyl 3-cyclobutyl-3-hydroxypropanoate [ No CAS ]
(S)-methyl 3-cyclobutyl-3-hydroxypropanoate [ No CAS ]

References: [1]Bulletin of the Chemical Society of Japan,2002,vol. 75,p. 355 - 363.

3
[ 67-56-1 ]
[ 2033-24-1 ]
[ 5006-22-4 ]
[ 137638-05-2 ]

Yield	Reaction Conditions	Operation in experiment
88%		Example 44 Synthesis of l-[l-(4-chlorophenyl)-5-cyclobutyl-pyrazol-4-yl]-3-[2-methyl-4- (trifluoromethyl)imidazol-l-yl]pyrrolidin-2-one [0216] a) Pyridine (20.46 mL, 253 mmol) was added to a solution of cyclobutanecarboxylic acid chloride (10.0 g, 84.3 mmol) and isopropylidene malonate (12.16 g, 84.3 mmol) in (( (100 mL) at 0 C and the mixture was stirred at room temperature for 1.5 h. Methanol (100 mL) was then added and the resulting mixture was stirred at reflux for 3 h, cooled to room temperature, and partitioned between aqueous HCl (1 M, 200 mL) and EtOAc (500 mL). The organic layer was separated, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by flash chromatography (S1O2, 0 - 20% EtOAc/hexanes gradient elution) to give methyl 3-cyclobutyl-3-oxo-propanoate (11.6 g, 88% yield). [0217] b) A mixture of methyl 3-cyclobutyl-3-oxo-propanoate (5.8 g, 37.2 mmol) and N,N-dimethylformamide dimethyl acetal (25 g, 210 mmol) was stirred at 100 C for 1 h. After cooling to room temperature, the mixture was concentrated in vacuo to give an oily residue that was directly carried to the next step. [0218] c) A mixture of the intermediate (~ 37.2 mmol) obtained in step b, 4- chlorophenylhydrazine hydrochloride (6.67 g, 37.2 mmol) and K2CO3 (10.3 g, 74.4 mmol) in DMF (50 mL) was stirred at 100 C for 1 h. After cooling to room temperature the mixture was diluted with aqueous HCl (200 mL) and extracted with EtOAc (500 mL). The organic layer was separated, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by flash chromatography (S1O2, 0 - 10% EtOAc/CH2Cl2 gradient elution) to give methyl 1- (4-chlorophenyl)-5-cyclobutyl-pyrazole-4-carboxylate (8.3 g, 76% yield). [0219] d) A mixture of methyl l-(4-chlorophenyl)-5-cyclobutyl-pyrazole-4-carboxylate (8.3 g, 28.5 mmol) and lithium hydroxide monohydrate (3.6 g, 85.6 mmol) in MeOH (25 mL), THF (25 mL) and FLO (12 mL) was stirred at 80 C for 1 h. After cooling to room temperature the mixture was acidified with 1 M aqueous HCl and extracted with EtOAc (400 mL). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated in vacuo to yield l-(4-chlorophenyl)-5-cyclobutyl-pyrazole-4-carboxylic acid (6.92 g, 87% yield). [0220] e) To a mixture of l-(4-chlorophenyl)-5-cyclobutyl-pyrazole-4-carboxylic acid (4.0 g, 14.4 mmol) in CH2CI2 (100 mL) was added oxalyl chloride (3.78 mL, 43.4 mmol) and DMF (0.06 mL). After 2 h at room temperature, the reaction mixture was concentrated in vacuo, re-dissolved in 40 mL of acetone, and added to a 0 C solution of a 3 (3.75 g, 57.8 mmol) in H2O (40 mL). Brine (150 mL) and EtOAc (350 mL) were then added. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was stirred in 100 mL of toluene at 95 C for 1 h, cooled to room temperature, and then treated with 150 mL of 6 M aqueous HCl at 1 10 C for 1 h. After cooling to room temperature, the mixture was basified with dilute NH4OH and extracted with EtOAc (500 mL). The organic layer was separated, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by flash chromatography (Si02, 0 - 100% EtOAc/CH2Cl2 gradient elution) to yield l-(4-chlorophenyl)-5-cylocbutyl-pyrazol-4-amine (2.9 g, 81% yield). [0221] f) A mixture of l-(4-chlorophenyl)-5-cylocbutyl-pyrazol-4-amine (0.080 g, 0.32 mmol) and 3-[2-methyl-4-(trifluoromethyl)imidazol-l-yl]tetrahydrofuran-2-one (0.080 g, 0.34 mmol) in 1,2-dichloroethane (2 mL) was treated with MesAl (0.32 mL, 0.64 mmol, 2 M/toluene) at room temperature for 1.5 h. The reaction mixture was then quenched with saturated aqueous aHC03 solution and extracted with EtOAc (100 mL). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the desired alcohol intermediate. [0222] g) A 0 C solution of the alcohol intermediate (-0.32 mmol) obtained in step f and Et3 (0.067 mL, 0.48 mmol) in CH2C12 (1.5 mL) was treated with methanesulfonyl chloride (0.027 mL, 0.35 mmol) for 10 min. The mixture was then basified with saturated aqueous aHC03 solution and extracted with EtOAc (500 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated in vacuo to afford the desired mesylate. [0223] h) A mixture of the mesylate (~ 0.032 mmol) obtained in step g and Ets (0.15 mL, 1.07 mmol in 1,2-dichloroethane (3 mL) was stirred at 75 C for 3 h. After cooling to room temperature the reaction mixture was directly purified by flash chromatography (Si02, 0 - 100% EtOAc/CH2Cl2), followed by reverse phase HPLC (CI 8 column, acetonitrile-H20 with 0.1% TFA as eluent) to afford the titled compound (0.060 g, 40% yield, free form). XH NMR (400 MHz, CDCI3) δ 7.57 (s, 1 H), 7.43 (m, 2 H), 7.36 (m, 2 H), 7.23 (d, J= 1.2 Hz, 1 H), 4.95 (dd, J= 9.2, 8.4 Hz, 1 H), 3.86 (m, 2 H), 3.71 (m, 1 H), 2.84 (m, 1 H), 2.50 (s, 3 H), 2.36 (m, 1 H), 1.99 (m, 6 H); MS: (ES) m/z calculated for C22H21C1F3 50 [M + H]+...
88%		Pyridine (20.46 mL, 253 mmol) was added to a solution of cyclobutanecarboxylic acid chloride (10.0 g, 84.3 mmol) and isopropylidene malonate (12.16 g, 84.3 mmol) in CH2Cl2 (100 mL) at 0 C. and the mixture was stirred at room temperature for 1.5 h. Methanol (100 mL) was then added and the resulting mixture was stirred at reflux for 3 h, cooled to room temperature and partitioned between aqueous HCl (1 M, 200 mL) and EtOAc (500 mL). The organic layer was separated, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by flash chromatography (SiO2, 0-20% EtOAc/hexanes gradient elution) to give methyl 3-cyclobutyl-3-oxo-propanoate (11.6 g, 88% yield).
		a.1.1 : Methyl^-cyclobutanoyl-acetate; 22 g of meldrum's acid (2,2-dimethyl-1 ,3-dioxane-4,6-dione) (152.7 mmol) and 36.9 ml of pyridine (457.2 mmol) were dissolved in 200 ml of dichloromethane. 18.1 g of cyclobutylcarbonic acid chloride were added at 0 to 10C. The reaction mixture was stirred overnight at room temperature, washed with 1 N HCI and extracted with dichloromethane. The organic layer was washed with water, dried over magnesium sulfate, filtered, and then concentrated to dryness. The oily residue was dissolved in 300 ml of methanol and heated under reflux for 2h. The reaction mixture was concentrated to dryness and the residue purified via silica gel chromatography with ethyl acetate as eluent. Yield: 21.2 gMS (ESI) m/z: 157.1 [M+H]+1H-NMR (CDCI3): δ [ppm] 3.7 (s, 3H), 3.4 (s, 2H), 3.3-3.4 (m, 1 H), 2.2-2.4 (m, 2H), 2.1-2.25 (m, 2H), 1.9-2.1 (m, 1H), 1.8-1.9 (m, 1 H).

2, 2-dimethyl-l, 3-dioxane-4, 6-dione (54.2 g, 376 mmol) was dissolved in CHCI3 (400 mL), then pyridine (50.6 mL, 625 mmol, 1.83 eq) was added to the mixture. A solution of cyclobutanecarbonyl chloride (40.5 g, 342 mmol) in CHCI3 (160 mL) was added dropwise to the reaction at a temperature of between 5-10 0 C while cooling in an ice-bath. Then the reaction mixture was stirred at 0 0 C for 1 hour, and at room temperature for 1 hour. The reaction mixture was then cooled to 0 0 C, and IN aqueous HC1 (400 mL) was added. Then the reaction mixture was extracted with CHCI3 (300 mL x 3). The combined organic layers were washed with water, and dried over anhydrous Na2SC"4, followed by concentration under reduced pressure. Then MeOH (400 ml) was added to the residue and the solution was heated under reflux for 3 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure and the resulting residue was distilled to give methyl 3-cyclobutyl-3-oxopropanoate. 1H NMR (400 MHz, CDC13) £3.68 (s, 3H), 3.36 (s, 2H), 2.27-2.10 (m, 4H), 1.99-1.75 (m, 2H), 1.25-1.19 (m, 1H).

References: [1]Patent: WO2014/89495,2014,A1 .Location in patent: Paragraph 0215; 0216.
[2]Patent: US2014/179733,2014,A1 .Location in patent: Paragraph 0199; 0200.
[3]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 6836 - 6840.
[4]Patent: WO2006/58753,2006,A1 .Location in patent: Page/Page column 18.
[5]Patent: WO2014/130608,2014,A1 .Location in patent: Page/Page column 130.

4
[ 870-46-2 ]
[ 137638-05-2 ]
C₁₃H₂₂N₂O₄ [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 6836 - 6840.

5
[ 18202-73-8 ]
[ 137638-05-2 ]
2-tert-butyl-4-hydroxy-6-cyclobutyl-pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85.7%	With sodium methylate; In methanol; at 10 - 20℃;	a.1.2: 2-terf-Butvl-4-hvdroxv-6-cvclobutvl-pvrimidine; 9.2 g of tert-butyl amidinium chloride (67.3 mmol, Maybridge) and 12.6 g of methyl-2-cyclobutanoyl acetate (80.7 mmol) were dissolved/suspended in 100 ml of methanol. 14.5 g of sodium methanolate (268.4 mmol) were added in portions to the solution at 10C. The suspension was then stirred at room temperature overnight. The reaction mixture was concentrated to roughly half the volume and filtered. The filtrate was extracted with water and dichloromethane. The organic phase was dried over magnesium sulfate, filtered, and then concentrated to dryness. The residue was stirred with acetone and the precipitate was collected by filtration. Yield: 11.9 g (85.7 %).MS (ESI) m/z: 207.2 [M+H]+
85.7%	With sodium methylate; In methanol; at 10 - 20℃;	a.1.2: 2-terf-Butyl-4-hydroxy-6-cyclobutyl-pyrimidine; 9.2 g of te/t-butyl amidinium chloride (67.3 mmol, Maybridge) and 12.6 g of methyl-2- cyclobutanoyl acetate (80.7 mmol) were dissolved/suspended in 100 ml of methanol. 14.5 g of sodium methanolate (268.4 mmol) were added in portions to the solution at 1O0C. The suspension was then stirred at room temperature overnight. The reaction mixture was concentrated to roughly half the volume and filtered. The filtrate was ex- traded with water and dichloromethane. The organic phase was dried over magnesium sulfate, filtered, and then concentrated to dryness. The residue was stirred with acetone and the precipitate was collected by filtration. Yield: 1 1.9 g (85.7 %). EPO <DP n="20"/>MS (ESI) m/z: 207.2 [M+H]+

References: [1]Patent: WO2006/15842,2006,A1 .Location in patent: Page/Page column 34.
[2]Patent: WO2006/58753,2006,A1 .Location in patent: Page/Page column 18-19.

6
[ 2033-24-1 ]
[ 5006-22-4 ]
[ 137638-05-2 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; In dichloromethane; at 0 - 20℃;	I.Intermediates:; a. Preparation of 4-r4-(3-chloro-propvD-piperazin-1 -yll-pyrimidines; a. 1 2-terf-Butyl-4-r4-(3-chloro-propyl)-piperazin-1 -vll-6-cvclobutvl-pyrimidine; a.1.1: Methvl-2-cyclobutanoyl-acetate; 22 g of meldrum's acid (2,2-dimethyl-1,3-dioxane-4,6-dione) (152.7 mmol) and 36.9 ml of pyridine (457.2 mmol) were dissolved in 200 ml of dichloromethane. 18.1 g of cyclobutylcarbonic acid chloride were added at 0 to 10C. The reaction mixture was stirred overnight at room temperature, washed with 1 N HCI and extracted with dichloromethane. The organic layer was washed with water, dried over magnesium sulfate, filtered, and then concentrated to dryness. The oily residue was dissolved in 300 ml of methanol and heated under reflux for 2h. The reaction mixture was concentrated to dryness and the residue purified via silica gel chromatography with ethyl acetate as eluent. Yield: 21.2 gMS (ESI) m/z: 157.1 [M+H]+1H-NMR (CDCI3): 5 [ppm] 3.7 (s, 3H), 3.4 (s, 2H), 3.3-3.4 (m, 1H), 2.2-2.4 (m,2H), 2.1-2.25 (m, 2H), 1.9-2.1 (m, 1H), 1.8-1.9 (m, 1H).

References: [1]Patent: WO2006/15842,2006,A1 .Location in patent: Page/Page column 34.

7
[ 4637-24-5 ]
[ 137638-05-2 ]
[ 1191094-90-2 ]

Yield	Reaction Conditions	Operation in experiment
61.8%	In 1,4-dioxane; at 100℃; for 4h;Inert atmosphere;	N,N-Dimethylformamide dimethyl acetal (5.62 mL, 42.26 mmol) was added in one portion to <strong>[137638-05-2]methyl 3-cyclobutyl-3-oxopropanoate</strong> (5.5 g, 35.22 mmol) in dioxane (50 mL) at room temperature under nitrogen. The resulting solution was stirred at 100 C. for 4 hours. The reaction mixture was evaporated, to afford crude product. The crude product was purified by flash silica (120 g) chromatography, elution gradient 50 to 80% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (Z)-methyl 2-(cyclobutanecarbonyl)-3-(dimethylamino)acrylate (4.60 g, 61.8%) as a yellow oil.1H NMR (400.132 MHz, CDCl3) δ 1.72-1.82 (1H, m), 1.85-1.97 (1H, m), 2.06-2.13 (2H, m), 2.18-2.29 (2H, m), 3.02 (6H, s), 3.68-3.75 (1H, m), 3.73 (3H, s), 7.62 (1H, s)m/z (ESI+) (M+Na)+=234; HPLC tR=1.42 min.
	at 100℃; for 1h;	Example 44 Synthesis of l-[l-(4-chlorophenyl)-5-cyclobutyl-pyrazol-4-yl]-3-[2-methyl-4- (trifluoromethyl)imidazol-l-yl]pyrrolidin-2-one [0216] a) Pyridine (20.46 mL, 253 mmol) was added to a solution of cyclobutanecarboxylic acid chloride (10.0 g, 84.3 mmol) and isopropylidene malonate (12.16 g, 84.3 mmol) in (( (100 mL) at 0 C and the mixture was stirred at room temperature for 1.5 h. Methanol (100 mL) was then added and the resulting mixture was stirred at reflux for 3 h, cooled to room temperature, and partitioned between aqueous HCl (1 M, 200 mL) and EtOAc (500 mL). The organic layer was separated, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by flash chromatography (S1O2, 0 - 20% EtOAc/hexanes gradient elution) to give methyl 3-cyclobutyl-3-oxo-propanoate (11.6 g, 88% yield). [0217] b) A mixture of methyl 3-cyclobutyl-3-oxo-propanoate (5.8 g, 37.2 mmol) and N,N-dimethylformamide dimethyl acetal (25 g, 210 mmol) was stirred at 100 C for 1 h. After cooling to room temperature, the mixture was concentrated in vacuo to give an oily residue that was directly carried to the next step. [0218] c) A mixture of the intermediate (~ 37.2 mmol) obtained in step b, 4- chlorophenylhydrazine hydrochloride (6.67 g, 37.2 mmol) and K2CO3 (10.3 g, 74.4 mmol) in DMF (50 mL) was stirred at 100 C for 1 h. After cooling to room temperature the mixture was diluted with aqueous HCl (200 mL) and extracted with EtOAc (500 mL). The organic layer was separated, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by flash chromatography (S1O2, 0 - 10% EtOAc/CH2Cl2 gradient elution) to give methyl 1- (4-chlorophenyl)-5-cyclobutyl-pyrazole-4-carboxylate (8.3 g, 76% yield). [0219] d) A mixture of methyl l-(4-chlorophenyl)-5-cyclobutyl-pyrazole-4-carboxylate (8.3 g, 28.5 mmol) and lithium hydroxide monohydrate (3.6 g, 85.6 mmol) in MeOH (25 mL), THF (25 mL) and FLO (12 mL) was stirred at 80 C for 1 h. After cooling to room temperature the mixture was acidified with 1 M aqueous HCl and extracted with EtOAc (400 mL). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated in vacuo to yield l-(4-chlorophenyl)-5-cyclobutyl-pyrazole-4-carboxylic acid (6.92 g, 87% yield). [0220] e) To a mixture of l-(4-chlorophenyl)-5-cyclobutyl-pyrazole-4-carboxylic acid (4.0 g, 14.4 mmol) in CH2CI2 (100 mL) was added oxalyl chloride (3.78 mL, 43.4 mmol) and DMF (0.06 mL). After 2 h at room temperature, the reaction mixture was concentrated in vacuo, re-dissolved in 40 mL of acetone, and added to a 0 C solution of a 3 (3.75 g, 57.8 mmol) in H2O (40 mL). Brine (150 mL) and EtOAc (350 mL) were then added. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was stirred in 100 mL of toluene at 95 C for 1 h, cooled to room temperature, and then treated with 150 mL of 6 M aqueous HCl at 1 10 C for 1 h. After cooling to room temperature, the mixture was basified with dilute NH4OH and extracted with EtOAc (500 mL). The organic layer was separated, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by flash chromatography (Si02, 0 - 100% EtOAc/CH2Cl2 gradient elution) to yield l-(4-chlorophenyl)-5-cylocbutyl-pyrazol-4-amine (2.9 g, 81% yield). [0221] f) A mixture of l-(4-chlorophenyl)-5-cylocbutyl-pyrazol-4-amine (0.080 g, 0.32 mmol) and 3-[2-methyl-4-(trifluoromethyl)imidazol-l-yl]tetrahydrofuran-2-one (0.080 g, 0.34 mmol) in 1,2-dichloroethane (2 mL) was treated with MesAl (0.32 mL, 0.64 mmol, 2 M/toluene) at room temperature for 1.5 h. The reaction mixture was then quenched with saturated aqueous aHC03 solution and extracted with EtOAc (100 mL). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the desired alcohol intermediate. [0222] g) A 0 C solution of the alcohol intermediate (-0.32 mmol) obtained in step f and Et3 (0.067 mL, 0.48 mmol) in CH2C12 (1.5 mL) was treated with methanesulfonyl chloride (0.027 mL, 0.35 mmol) for 10 min. The mixture was then basified with saturated aqueous aHC03 solution and extracted with EtOAc (500 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated in vacuo to afford the desired mesylate. [0223] h) A mixture of the mesylate (~ 0.032 mmol) obtained in step g and Ets (0.15 mL, 1.07 mmol in 1,2-dichloroethane (3 mL) was stirred at 75 C for 3 h. After cooling to room temperature the reaction mixture was directly purified by flash chromatography (Si02, 0 - 100% EtOAc/CH2Cl2), followed by reverse phase HPLC (CI 8 column, acetonitrile-H20 with 0.1% TFA as eluent) to afford the titled compound (0.060 g, 40% yield, free form). XH NMR (400 MHz, CDCI3) δ 7.57 (s, 1 H), 7.43 (m, 2 H), 7.36 (m, 2 H), 7.23 (d, J= 1.2 Hz, 1 H), 4.95 (dd, J= 9.2, 8.4 Hz, 1 H), 3.86 (m, 2 H), 3.71 (m, 1 H), 2.84 (m, 1 H), 2.50 (s, 3 H), 2.36 (m, 1 H), 1.99 (m, 6 H); MS: (ES) m/z calculated for C22H21C1F3 50 [M + H]+...
	at 100℃; for 1h;	A mixture of methyl 3-cyclobutyl-3-oxo-propanoate (5.8 g, 37.2 mmol) and N,N-dimethylformamide dimethyl acetal (25 g, 210 mmol) was stirred at 100 C. for 1 h. After cooling to room temperature the mixture was concentrated in vacuo to give an oily residue that was directly carried to the next step.

References: [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 10652 - 10661.
[2]Patent: US2009/264401,2009,A1 .Location in patent: Page/Page column 62.
[3]Patent: WO2014/89495,2014,A1 .Location in patent: Paragraph 0215; 0217.
[4]Patent: US2014/179733,2014,A1 .Location in patent: Paragraph 0199; 0201.

8
guanidine hydrochloride salt [ No CAS ]
[ 137638-05-2 ]
[ 199863-73-5 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of methyl S-cyclobutyl-S-oxopropanoate (6.5 g, 41.6 mmol) and guanidine hydrochloride (4.77 g, 49.9 mmol) in CH3OH (80 ml.) at room temperature was added potassium te/t-butoxide (25.2 g) portionwise over 15 minutes with vigorous stirring and the reaction warmed automatically. Then the reaction was cooled to room temperature and stirred overnight. The precipitated salt was removed by filtration, and the filtrate was concentrated under reduce pressure to approximately 10 ml_, then diluted with 10 ml. of water and the pH adjusted to 5 by the addition of 6N HCI. The precipitate was separated by filtration to afford the title compound (6.6 g) as a white solid. 1H NMR: δ 10.647 (br, 1H), 6.5 (br, 2 H), 5.35 (s, 1 H), 3.11-3.20 (m, 1 H), 1.86-2.13 (m, 4 H), 1.71-1.77 (m, 2 H).

References: [1]Patent: WO2010/120854,2010,A1 .Location in patent: Page/Page column 121.

9
[ 67-56-1 ]
[ 134302-13-9 ]
[ 137638-05-2 ]

Yield	Reaction Conditions	Operation in experiment
	for 3h;Reflux;	2,2-Dimethyl-1 ,3-dioxane-4,6-dione (10.5 g, 72.9 mmols) was dissolved in CHCI3 (1 10 ml_), and pyridine (10.9 ml_, 133.4 mmols) was added. Then a solution of cyclobutanecarbonyl chloride (9.5 g, 80.1 mmols) in CHCI3 (40 ml.) was added dropwise thereto at a temperature of 10 0C or lower while cooling in an ice-bath. After completion of the dropwise addition, the reaction mixture was stirred for 1 hour at 0 0C, then at room temperature for 1 hour. The mixture was cooled at 0 0C, and 1 N aqueous HCI (100 ml.) was added thereto. The reaction product was extracted with CHCI3, washed with water, and dried over anhydrous Na2SO4, followed by concentrating under reduced pressure. CH3OH (100 ml.) was added thereto to dissolve the residue and the solution was heated for 3 hours under reflux. After cooling to room temperature, the mixture was concentrated under reduced pressure and the residue was distilled to afford the title compound (6.5 g) as a colorless liquid.

References: [1]Patent: WO2010/120854,2010,A1 .Location in patent: Page/Page column 124.

10
[ 929903-21-9 ]
[ 137638-05-2 ]
[ 1260236-04-1 ]

References: [1]ACS Medicinal Chemistry Letters,2011,vol. 2,p. 171 - 176.

11
[ 3721-95-7 ]
[ 38330-80-2 ]
[ 137638-05-2 ]

Yield	Reaction Conditions	Operation in experiment
59 g		10300] Under argon 64.1 g cabonyldiimidazol (396 mmol) was added to 31.5 mL cyclobutanecarboxylic acid (330 mmol) in 300 mL THF within 10 minutes at tt. After 25 minutes 226 mL DCM, 77 g potassium 3-methoxy-3-oxopro- panoate (494 mmol) and 37.7 g magnesium chloride (396 mmol) were added subsequently, heated up to 56 C. within 2.5 hours, and stirred for another 3.5 hours. The resulting suspension was cooled to tt., 600 mL 2N aqueous hydrochloric acid was added to reach pH 2, another 800 mL water was added and the resulting biphasic solution was separated. The aqueous phase was extracted twice with 250 mL DCM, the combined organic phases were washed with half concentrated aqueous sodium chloride solution, dried over sodium sulfate, filtered and evaporated. The resulting methyl 3-cy- clobutyl-3-oxopropanoate (59 g, used for the next step without purification) was dissolved in 10 mL methanol, 378 mL 2M aqueous sodium hydroxide solution was added and the mixture was stirred for one hour. 100 mL TI3ME was added, the aqueous phase twice extracted with 50 mL TEME, combined aqueous phases filtered and cooled to 5 C. To that solution 65.1 mL concentrated aqueous hydrochloric acid was added to reach pH <1. 167 g solid sodium chloride was added and the mixture was four times extracted with 100 mLethyl acetate, organic phases washed with water, dried over sodium sulfate, and evaporated to yield 3-cyclobutyl-3-oxo- propanoic acid (43 g, used for the next step without purification) as a slightly yellow oil. This oil was dissolved in 508 mL THF and 53.1 g carbonyldiimidazol (328 mmol) were added carefully and stirred for 6 hours. To the resulting solution 50 mL water was added, the THF evaporated under reduced pressure, 200 mL DCM added and washed with 400 mL 2M aqueous hydrochloric acid, 200 mL 0.5M aqueous hydrochloric acid, 200 mL water. Aqueous phases were extracted with 100 mL DCM and combined organic phases were dried over sodium sulfate, filtered and evaporated. The suiting orange oil was purified by liquid chromatography over silica gel with DCM/methanol as eluent. Target fractions were combined and evaporated to yield 22 g 3-(cyclobutanecarbonyl)- 6-cyclobutyl-4-hydroxy-2H-pyran-2-one (89 mmol, 53%) as a slowly crystallizing oil.

References: [1]ACS Medicinal Chemistry Letters,2011,vol. 2,p. 171 - 176.
[2]Patent: US2015/344476,2015,A1 .Location in patent: Paragraph 0299; 0300.

12
[ 4637-24-5 ]
[ 137638-05-2 ]
[ 1191094-91-3 ]

Yield	Reaction Conditions	Operation in experiment
62%	In 1,4-dioxane; at 100℃; for 4h;	DMF dimethyl acetal (5.62 mL, 42.3 mmol) was added in one portion to <strong>[137638-05-2]methyl 3-cyclobutyl-3-oxopropanoate</strong> (5.5 g, 35.2 mmol) in dioxane (50 mL) at RT. The resulting solution was stirred at 100 C. for 4 h. The reaction mixture was concentrated and the resulting crude product was purified by FCC, eluting with 59-80% EtOAc/isohexane, to afford the title compound (4.60 g, 62%); 1H NMR (400 MHz, CDCl3) 1.72-1.82 (1H, m), 1.85-1.97 (1H, m), 2.06-2.13 (2H, m), 2.18-2.29 (2H, m), 3.02 (6H, s), 3.68-3.75 (1H, m), 3.73 (3H, s), 7.62 (1H, s); m/z [M+Na]+=234; HPLC tR=1.42 min.

References: [1]Patent: US2011/92526,2011,A1 .Location in patent: Page/Page column 15.

13
[ 137638-05-2 ]
[ 1191095-44-9 ]

References: [1]Patent: US2011/92526,2011,A1 .
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 10652 - 10661.

14
[ 137638-05-2 ]
[ 1292289-41-8 ]

References: [1]Patent: US2011/92526,2011,A1 .
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 10652 - 10661.

15
[ 137638-05-2 ]
[ 1292289-42-9 ]

References: [1]Patent: US2011/92526,2011,A1 .
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 10652 - 10661.

16
[ 137638-05-2 ]
[ 1292289-43-0 ]

References: [1]Patent: US2011/92526,2011,A1 .
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 10652 - 10661.

17
[ 137638-05-2 ]
4-cyclobutyl-N-(5-hydroxy-2-adamantyl)-2-[[(3S)-tetrahydrofuran-3-yl]amino]pyrimidine-5-carboxamide [ No CAS ]

References: [1]Patent: US2011/92526,2011,A1 .

18
[ 137638-05-2 ]
[ 1292289-39-4 ]

References: [1]Patent: US2011/92526,2011,A1 .
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 10652 - 10661.

19
[ 137638-05-2 ]
[ 1292289-40-7 ]

References: [1]Patent: US2011/92526,2011,A1 .
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 10652 - 10661.

20
[ 137638-05-2 ]
[ 1191095-45-0 ]