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Structure of 20249-17-6

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Quality Control of [ 20249-17-6 ] Purity: 97% SDS Specification

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Product Details of [ 20249-17-6 ]

CAS No. :	20249-17-6
Formula :	C₅H₇NO
M.W :	97.12
SMILES Code :	OC1CC(C1)C#N
English Name :	3-Hydroxycyclobutanecarbonitrile
MDL No. :	MFCD13659429

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Application In Synthesis of [ 20249-17-6 ]

* 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 [ 20249-17-6 ]

[ 20249-17-6 ] Synthesis Path-Downstream 1~14

1
[ 20249-17-6 ]
[ 167081-42-7 ]

Yield	Reaction Conditions	Operation in experiment
		9.c c c 3-Aminomethyl-cyclobutanol A mixture of 24.28 g (0.25 mol) of 3-cyano-cyclobutanol [J. Am. Chem. Soc. 93,110 (1971)], 550 ml of an approximately 8 % ethanolic ammonia solution and 10.9 g of Raney nickel is hydrogenated at 35° C. After the end of the uptake of hydrogen, the catalyst is filtered off and the filtrate is evaporated in vacuo. The title compound, obtained as a crystalline residue, melts at 72° C.

References: [1]Current Patent Assignee: NOVARTIS - US5516806, 1996, A.

2
[ 15760-35-7 ]
[ 20249-17-6 ]

Yield	Reaction Conditions	Operation in experiment
73%	Stage #1: 3-methylenecyclobutanecarbonitrile With ozone In methanol; dichloromethane at -78℃; Stage #2: With sodium tetrahydroborate In methanol; dichloromethane at -78 - 20℃; for 12h; Stage #3: With water In ethyl acetate	5 Example 5Trans 2-Chloro-iV-[l-cyclopropylmethyl-3-[methyl-(propane-l-sulfonyl)-amino]- cyclobutylmethyl]-4- trifluoromcthyl-bcnzamidc (compound 5):3-(4-Methoxy-benzyloxy)-cyclobutanecarbonitrile: Ozone was bubbled into a solution of S-methylenecyclobutanecarbonitrile (2.00 g, 0.0215 mol) in methanol (150 mL) and methylene chloride (150 mL) at -78 0C until a blue colour persisted. Oxygen followed by nitrogen was bubbled through the solution then sodium borohydride (4.1 g, 0.108 mol) was added and the reaction mixture allowed to warm to ambient temperature over 12 hours. The solvent was evaporated and the residue partitioned between ethyl acetate and water. The organic phase was separated and the aqueous phase re-extracted with ethyl acetate twice. The combined organic phase was washed with brine, dried (magnesium sulfate), filtered, and the solvent evaporated to leave a pale yellow liquid (1.53 g, 73%) that was used in the next step without further purification.A solution of S-hydroxy-cyclobutanecarbonitrile in DMF (150 mL) was added dropwise to a suspension of sodium hydride (60% dispersion in oil) (1.26 g, 0.0315 mol) in DMF (50 mL) cooled in an ice bath. On completion of the addition, the ice bath was removed and the reaction mixture stirred at ambient temperature for 0.5 hours. A solution of p-methoxybenzyl chloride (4.25 mL, 0.0315 mol) and tetrabutylammonium iodide (2.91 g, 0.0079 mol) in DMF (50 mL) was added. The reaction mixture was stirred at ambient temperature for 12 hours then quenched with saturated ammonium chloride solution and extracted with diethyl ether (3X). The combined organic phase was washed with brine, dried (magnesium sulfate), filtered, and evaporated to leave a pale yellow liquid. The liquid was purified using the Horizon Chromatography system (silica column) eluting with 0-50% ethyl acetate-hexane to give a colourless liquid (2.95 g, 86%) 1H NMR (400 MHz, CDC13): δ 7.22 (2H, d, J 8.4), 6.88 (2H, d, J 8.4), 4.35 (2H, s), 4.00- 3.91 (IH, m), 3.81 (3H, s), 2.67-2.55 (3H, m), 2.42-2.30 (2H, m).
	Multi-step reaction with 2 steps 1: sodium periodate; ruthenium trichloride / water; dichloromethane; acetonitrile / 0 - 20 °C 2: sodium tetrahydroborate / methanol / 2 h / 0 - 20 °C
	Multi-step reaction with 2 steps 1: sodium periodate; rhodium(III) chloride hydrate / dichloromethane; acetonitrile; water / 8 h 2: methanol; sodium tetrahydroborate / 0.5 h / 0 °C

	Multi-step reaction with 2 steps 1: ozone / dichloromethane / 0.17 h / -78 °C / Inert atmosphere 2: sodium tetrahydroborate; methanol / 20 °C
	Multi-step reaction with 2 steps 1: ruthenium(III) trichloride hydrate; sodium periodate / dichloromethane; water; acetonitrile / 2.25 h / 25 °C 2: water; sodium tetrahydroborate / tetrahydrofuran / 1 h / -70 °C
	Multi-step reaction with 2 steps 1: ruthenium(III) trichloride hydrate; sodium periodate / dichloromethane; water; acetonitrile / 2.25 h / 10 - 25 °C 2: sodium tetrahydroborate / water; tetrahydrofuran / -70 °C / Cooling with liquid nitrogen
	Multi-step reaction with 2 steps 1: ruthenium(III) trichloride hydrate; sodium periodate / dichloromethane; water; acetonitrile / 2 h / 10 - 25 °C 2: sodium tetrahydroborate / water; tetrahydrofuran / 1 h / -70 °C
	Multi-step reaction with 2 steps 1: ruthenium trichloride; sodium periodate / dichloromethane; water; acetonitrile / 0 - 20 °C 2: sodium tetrahydroborate / methanol / 2 h / 0 - 20 °C
	With ruthenium trichloride; sodium periodate In dichloromethane; water; acetonitrile for 12h;	7.1 3-Oxocyclobutane-1-carbonitrile (8b) 3-Methylene cyclobutane-1-carbonitrile 8a (13.97 g, 150 mmol), ruthenium trichloride (311 mg, 1.5 mmol), sodium periodate (12.83 g, 600 mmol), dichloromethane (200 mL), acetonitrile (200 mL), and water (300 mL) were mixed. After stirring for 12 hours, the mixture was filtered, and then extracted with dichloromethane (3 × 200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain the target product 8b (14.27 g, crude product). This product was used directly in the next reaction without further purification.

References: [1]Current Patent Assignee: MERCK - WO2007/60484, 2007, A1 Location in patent: Page/Page column 23; 36-37.
[2]Current Patent Assignee: MERCK SHARP DOHME - US9181236, 2015, B2.
[3]Current Patent Assignee: NORTHEASTERN UNIVERSITY IN BOSTON MASSACHUSETTS - WO2015/179190, 2015, A1.
[4]Current Patent Assignee: PFIZER - WO2016/24185, 2016, A1.
[5]Current Patent Assignee: PROTEOSTASIS THERAPEUTICS - WO2015/196071, 2015, A1.
[6]Current Patent Assignee: PROTEOSTASIS THERAPEUTICS - WO2016/115090, 2016, A1.
[7]Current Patent Assignee: PROTEOSTASIS THERAPEUTICS - WO2017/40606, 2017, A1.
[8]Current Patent Assignee: MERCK SHARP DOHME - WO2013/28670, 2013, A1.
[9]Current Patent Assignee: BEIJING INNOCARE PHARMA TECHNOLOGY - WO2025/214476, 2025, A1 Location in patent: Page/Page column 50.

3
[ 20249-17-6 ]
[ 824-94-2 ]
[ 938064-64-3 ]

Yield	Reaction Conditions	Operation in experiment
86%	Stage #1: 3-hydroxycyclobutane-1-carbonitrile With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5h; Stage #2: p-methoxybenzyl chloride With tetra-(n-butyl)ammonium iodide In N,N-dimethyl-formamide at 20℃; for 12h;	5 Example 5Trans 2-Chloro-iV-[l-cyclopropylmethyl-3-[methyl-(propane-l-sulfonyl)-amino]- cyclobutylmethyl]-4- trifluoromcthyl-bcnzamidc (compound 5):3-(4-Methoxy-benzyloxy)-cyclobutanecarbonitrile: Ozone was bubbled into a solution of S-methylenecyclobutanecarbonitrile (2.00 g, 0.0215 mol) in methanol (150 mL) and methylene chloride (150 mL) at -78 0C until a blue colour persisted. Oxygen followed by nitrogen was bubbled through the solution then sodium borohydride (4.1 g, 0.108 mol) was added and the reaction mixture allowed to warm to ambient temperature over 12 hours. The solvent was evaporated and the residue partitioned between ethyl acetate and water. The organic phase was separated and the aqueous phase re-extracted with ethyl acetate twice. The combined organic phase was washed with brine, dried (magnesium sulfate), filtered, and the solvent evaporated to leave a pale yellow liquid (1.53 g, 73%) that was used in the next step without further purification.A solution of S-hydroxy-cyclobutanecarbonitrile in DMF (150 mL) was added dropwise to a suspension of sodium hydride (60% dispersion in oil) (1.26 g, 0.0315 mol) in DMF (50 mL) cooled in an ice bath. On completion of the addition, the ice bath was removed and the reaction mixture stirred at ambient temperature for 0.5 hours. A solution of p-methoxybenzyl chloride (4.25 mL, 0.0315 mol) and tetrabutylammonium iodide (2.91 g, 0.0079 mol) in DMF (50 mL) was added. The reaction mixture was stirred at ambient temperature for 12 hours then quenched with saturated ammonium chloride solution and extracted with diethyl ether (3X). The combined organic phase was washed with brine, dried (magnesium sulfate), filtered, and evaporated to leave a pale yellow liquid. The liquid was purified using the Horizon Chromatography system (silica column) eluting with 0-50% ethyl acetate-hexane to give a colourless liquid (2.95 g, 86%) 1H NMR (400 MHz, CDC13): δ 7.22 (2H, d, J 8.4), 6.88 (2H, d, J 8.4), 4.35 (2H, s), 4.00- 3.91 (IH, m), 3.81 (3H, s), 2.67-2.55 (3H, m), 2.42-2.30 (2H, m).l-Cyclopropylmethyl-3-(4-methoxy-benzyloxy)-cyclobutanecarbonitrile:Potassium bis(trimethylsilyl)amide solution (0.5M in toluene) (13.2 mL, 6.6 mmol) was added slowly dropwise to a stirred solution of 3-(4-methoxy-benzyloxy)-cyclobutanecarbonitrile (1.20 g, 5.52 mmol) and cyclopropylmethyl bromide (0.642 mL, 6.62 mmol) in THF (20 mL) at -78 0C. The yellow solution was allowed to warm slowly to ambient temperature over 12 hours then quenched with saturated ammonium chloride solution and extracted with ethyl acetate (3X). The combined organic phase was washed with brine, dried (magnesium sulfate), filtered, and evaporated to leave a colourless oil. The oil was purified using the Horizon Chromatography System (silica column) eluting with 0-40% ethyl acetate-hexane to give a colourless oil (1.14 g, 76%) as a 1:1 mixture of cis and trans isomers 1H NMR (500 MHz, CDC13): δ 7.27-7.21 (2H, m), 6.88 (2H, d, J 7.7), 4.36 (IH, s), 4.35 (IH, s), 4.26 (0.5H, quin, J 7.3), 4.06 (0.5H, quin, J 7.3), 3.81 (3H, s), 2.79-2.75 (IH, m), 2.55-2.45 (2H, m), 2.10-2.04 (IH, m), 1.64 (IH, d, J 7.4), 1.59 (IH, d, J 7.0), 0.84-0.76 (IH, m), 0.57-0.50 (2H, m), 0.22-0.16 (2H, m).
10 g	With sodium hydride In N,N-dimethyl-formamide at 0℃; for 2.5h;	21.3 To a suspension of NaH (2.7 g, 68 mmol) in DMF (60 mL) at 0 °C was added compound 21-3 (5 g, 52 mmol). The mixture was stirred for 30 min, and then PMBC1 (9.7 g, 62 mmol) in DMF (10 mL) was added slowly. The reaction mixture was stirred at 0 °C for 2 h and then quenched with water. The aqueous layer was separated and extracted with EtOAc. The combined organic layers were washed with brine, dried over a2S04 and filtered. The filtrate was concentrated and purified by silica gel chromatography (PE: EA = 10: 1) to give 10 g of compound 21-4. 1H NMR (400 MHz, CDC13): δ 7.23 (d, J= 8.0 Hz, 2 H), 6.85 (d, J= 8.0 Hz, 2 H), 4.33 (s, 2 H), 3.90 - 3.94 (m, 1 H), 3.78 (s, 3 H), 2.56 - 2.62 (m, 3 H), 2.31 - 2.35 (m, 2 H).
10 g	Stage #1: 3-hydroxycyclobutane-1-carbonitrile With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5h; Stage #2: p-methoxybenzyl chloride In N,N-dimethyl-formamide at 0℃; for 2h;	3 Step 3 (0732) To a suspension of NaH (2.7 g, 68 mmol) in DMF (60 mL) at 0° C. was added compound 21-3 (5 g, 52 mmol). The mixture was stirred for 30 min, and then PMBCl (9.7 g, 62 mmol) in DMF (10 mL) was added slowly. The reaction mixture was stirred at 0° C. for 2 h and then quenched with water. The aqueous layer was separated and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated and purified by silica gel chromatography (PE: EA=10:1) to give 10 g of compound 21-4. 1H NMR (400 MHz, CDCl3): δ 7.23 (d, J=8.0 Hz, 2H), 6.85 (d, J=8.0 Hz, 2H), 4.33 (s, 2H), 3.90-3.94 (m, 1H), 3.78 (s, 3H), 2.56-2.62 (m, 3H), 2.31-2.35 (m, 2H).

References: [1]Current Patent Assignee: MERCK - WO2007/60484, 2007, A1 Location in patent: Page/Page column 23; 36-37.
[2]Current Patent Assignee: MERCK SHARP DOHME - WO2013/28670, 2013, A1 Location in patent: Page/Page column 115.
[3]Current Patent Assignee: MERCK SHARP DOHME - US9181236, 2015, B2 Location in patent: Page/Page column 139.

4
[ 20249-16-5 ]
[ 20249-17-6 ]

Yield	Reaction Conditions	Operation in experiment
92%	With methanol; sodium tetrahydroborate at 0℃; for 0.5h;	107.2 Step 2. 3-Hydroxycyclobutane-l-carbonitrile. Step 2. 3-Hydroxycyclobutane-l-carbonitrile. Sodium borohydride (597 mg, 15.8 mmol) was added in portions into a cold (0 °C) mixture of 3-oxocyclobutane-l- carbonitrile (1.0 g, 10.52 mmol) and anhydrous methanol (10 mL). After the addition the mixture stirred for 30 minutes, and then it was carefully poured into ice water. The mixture was extracted with ethyl acetate and the organic extracts washed with water and brine and dried over anhydrous MsS04. The solvents were removed under vacuum and the residue was purified on silica gel (Biotage; eluting solvents hexanes: EtOAc 2/1 ratio) to afford 3- hydroxycyclobutane-l-carbonitrile, 8: 1 isomeric mixture, as oil (920 mg, 92% yield): XH NMR (500MHz, CDCh) δ ppm [4.62 (m), 4.26 (m), 1H], [3.06 (m), 2.75 (m), 2H], [5.65 (m), 2.33 (m), 2H], 2.6 (m, 1), 2.31 (m, 1H).
66%	With sodium tetrahydroborate; water In tetrahydrofuran at -70℃; for 1h;	41.1a [0499] Step la: 3-hydroxycyclobutane-1-carbonitrile: NaBH4 (2.4 g, 63.45 mmol, 0.50 eq.) was added slowly to a -70°C solution of 3 -oxocyclobutane- 1 -carbonitrile (12 g, 126.18 mmol, 1.00 eq., prepared according example 33, step 1) in THF (100 mL) and water (5 mL). The resulting solution was stirred for 1 hour at -70°C in a liquid nitrogen bath. The reactionwas then quenched by the addition of 50 mL of water/ice. The resulting solution was extracted with ethyl acetate (3x100 mL) and the organic layers combined. The resulting mixture was washed with brine (3x50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to give 8.13 g (66%) of 3-hydroxycyclobutane-1-carbonitrile as colorless oil.
66%	With sodium tetrahydroborate In tetrahydrofuran; water at -70℃; Cooling with liquid nitrogen;	41.1a Step la: 3-hydroxycyclobutane-l-carbonitrile: NaBH4 (2.4 g, 63 45 mmol, 0 50 eq.) was added slowly to a -70°C solution of 3-oxocyclobutane-l-carbonitrile (12 g, 126.18 mmol, 1.00 eq., prepared according example 33, step 1) in THF (100 mL) and water (5 mL). The resulting solution was stirred for 1 hour at -70°C in a liquid nitrogen bath. The reaction was then quenched by the addition of 50 mL of water/ice. The resulting solution was extracted with ethyl acetate (3x100 mL) and the organic layers combined. The resulting mixture was washed with brine (3x50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to give 8.13 g (66%) of 3-hydroxycyclobutane-l-carbonitrile as colorless oil.

66%	With sodium tetrahydroborate In tetrahydrofuran; water at -70℃; for 1h;	41.1a 3-hydroxycyclobutane-1-carbonitrile NaBH4 (2.4 g, 63.45 mmol, 0.50 eq.) was added slowly to a -70°C solution of 3-oxocyclobutane-l-carbonitrile (12 g, 126.18 mmol, 1.00 eq., prepared according example 33, step 1) in THF (100 mL) and water (5 mL). The resulting solution was stirred for 1 hour at -70°C in a liquid nitrogen bath. The reaction was then quenched by the addition of 50 mL of water/ice. The resulting solution was extracted with ethyl acetate (3x100 mL) and the organic layers combined. The resulting mixture was washed with brine (3x50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to give 8.13 g (66%) of 3-hydroxycyclobutane-l-carbonitrile as colorless oil.
59%	With methanol; sodium tetrahydroborate for 0.5h; Inert atmosphere;
4.8 g	With sodium tetrahydroborate In methanol at 0 - 20℃; for 2h;	21.2 To a solution of compound 21-2 (5 g, 53 mmol) in 50 mL of MeOH was added NaBEL; (3 g, 79 mmol) at 0 °C, and the mixture was stirred at room temperature for 2 h. The solvent was removed from the reaction mixture in vacuo, and EtOAc (150 mL) and water (100 mL) were added to the residue. The organic layer was separated, washed with water and brine, dried over MgS04, filtered, and concentrated to give 4.8 g of compound 21-3. XH NMR (400 MHz, CDCI3): δ 4.18 - 4.22 (m, 1 H), 2.69 - 2.73 (m, 3 H), 2.53 - 2.58 (m, 1 H), 2.23 - 2.34 (m, 2 H).
4.8 g	With sodium tetrahydroborate In methanol at 0 - 20℃; for 2h;	2 Step 2 (0731) To a solution of compound 21-2 (5 g, 53 mmol) in 50 mL of MeOH was added NaBH4 (3 g, 79 mmol) at 0° C., and the mixture was stirred at room temperature for 2 h. The solvent was removed from the reaction mixture in vacuo, and EtOAc (150 mL) and water (100 mL) were added to the residue. The organic layer was separated, washed with water and brine, dried over MgSO4, filtered, and concentrated to give 4.8 g of compound 21-3. 1H NMR (400 MHz, CDCl3): δ 4.18-4.22 (m, 1H), 2.69-2.73 (m, 3H), 2.53-2.58 (m, 1H), 2.23-2.34 (m, 2H).
6.5 g	With methanol; sodium tetrahydroborate at 20℃;	45.2; 46.2 Step 2: 3-Hydroxycyclobutane-1-carbonitrile To a solution of 3-oxocyclobutane-1 -carbonitrile in methanol (150 mL) was added sodium boro- hydride (4.44 g, 11 6.84 mmol) at room temperature. The reaction mixture was stirred overnight and quenched using saturate aqueous ammonium chloride (100 mL). The organic layer was removed using a rotary evaporator and aqueous phase was extracted with dichloromethane (2 x 100 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to give title compound (6.5 g, 100%) as oil.1H NMR (400 MHz, CDCl3): 4.25- 4.17 (m, 1 H), 2.67-2.78 (m, 2H), 2.50-2.61 (m, 1 H), 2.24-2.38 (m, 2H).
	With sodium tetrahydroborate In tetrahydrofuran at 0 - 20℃; for 1h;	106.1 Step 1. 3-Cyanocyclobutyl methanesulfonate (106b) NaBH4(600 mg, 15.78 mmol) was added to a solution of 106a (1 g, 10.52 mmol) in tetrahydrofuran (50 mL) at 0 . The mixture was stirred at room temperature for 1 hour. The mixture was filtered. Triethyl amine (2.12 g, 21.04 mmol) and MsCl (1.45 g, 12.62 mmol) were added to the filtrate. The mixture was stirred at room temperature for 4 hours. Then the reaction mixture was quenched with 50 mL saturated aq. ammonium chloride solution. The resultant mixture was extracted with dichloromethane (50 mL x 3) . The combined organic layers were washed with brine (50 mL) , dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness. The residue was purified by silica gel column chromatography (PE: EtOAc = 20: 1 to 10: 1) to afford the desired product as light yellow oil (440 mg, 24%yield) .1H NMR (400 MHz, CDCl3) δ 5.00 -4.91 (m, 0.9H) , 4.80 -4.72 (m, 0. 1H) , 3.04 (s, 3H) , 2.95 -2.88 (m, 2H) , 2.84 -2.76 (m, 3H) .
	With methanol; sodium tetrahydroborate at 20℃; for 2h; Inert atmosphere;
57 %	With methanol; sodium tetrahydroborate at 20℃; Cooling with ice;	8.1 The first step: the synthesis of compound 9-2 Under ice-cooling, sodium borohydride (200 mg, 5 mmol) was slowly added to a solution of compound 9-1 (1 g, 10 mmol) in methanol (15 mL). The reaction was stirred at room temperature for 3 hours. After the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1) to obtain compound 9-2 (560 mg, yield: 57%).
57 %	With methanol; sodium tetrahydroborate at 20℃; Cooling with ice;	8.1 The first step: the synthesis of compound 9-2 Under ice-cooling, sodium borohydride (200 mg, 5 mmol) was slowly added to a solution of compound 9-1 (1 g, 10 mmol) in methanol (15 mL). The reaction was stirred at room temperature for 3 hours. After the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (petroleum ether/ethyl acetate=10/1) to obtain compound 9-2 (560 mg, yield: 57%).
62.31 %	With methanol; sodium tetrahydroborate at 20℃;	18.1 Step 1: Synthesis of 3-hydroxycyclobutanenitrile To a solution of 3-oxocyclobutanenitrile (3.30 g, 34.70 mmol) in methanol (70 mL) was added sodium borohydride (1.97 g, 52.05 mmol) in portions. After the addition was completed, the system reacted at room temperature overnight, and then saturated ammonium chloride (70 mL) was added to the reaction system to quench the reaction. Most of the methanol was removed under reduced pressure. Water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (100 mL × 4). The organic phases were combined and spin-dried under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain a colorless liquid (2.10 g, yield 62.31%).
62.31 %	With methanol; sodium tetrahydroborate at 20℃;	18.1 Step 1: Synthesis of 3-hydroxycyclobutanenitrile To a solution of 3-oxocyclobutanenitrile (3.30 g, 34.70 mmol) in methanol (70 mL) was added sodium borohydride (1.97 g, 52.05 mmol) in portions. After the addition was completed, the system reacted at room temperature overnight, and then saturated ammonium chloride (70 mL) was added to the reaction system to quench the reaction. Most of the methanol was removed under reduced pressure. Water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (100 mL × 4). The organic phases were combined and spin-dried under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain a colorless liquid (2.10 g, yield 62.31%).
87.48 %	With methanol; sodium tetrahydroborate at 20℃;
5 g	With methanol; sodium tetrahydroborate In dichloromethane at 0 - 25℃; for 2h;	A76.1 Step 1: To a stirred solution of 3-cyanocyclobutanone (1, 5 g, 52.6 mmol) in MeOH (50 mL), was added sodium borohydride (1.193 g, 31.5 mmol) over a period of 10 min at 0 , and the reaction mixture stirred at 25 °C for 2 h. The reaction mixture was cooled to 0 , quenched with ice cold water (5 mL) and stirred for 30 min. This was concentrated under reduced pressure. The crude residue, thus obtained was dissolved in 10% MeOH in DCM (100 mL), washed with water (5 mL), brine solution (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 2 as a pale-brown semi-solid. The crude product was taken to the next step without any purification. Yield: 5 g (crude product weight)
	With sodium tetrahydroborate In tetrahydrofuran; methanol at 0 - 20℃; for 1h;	8.A Step A. 3-Hydroxycyclobutane-1-carbonitrile Sodium borohydride (73 mg, 1.82 mmol) was added to a solution of 3-oxocyclobutane-1-carbonitrile (100 mg, 1.05 mmol) in tetrahydrofuran/methanol (5 mL/5 mL) at 0°C. The reaction solution was stirred at room temperature for 1 h, quenched with ammonium chloride, and extracted with ethyl acetate (20 mL×3). The organic phases were combined and washed with saturated brine, dried over sodium sulfate, and concentrated. The crude product was directly used for the next reaction.

References: [1]Current Patent Assignee: NORTHEASTERN UNIVERSITY IN BOSTON MASSACHUSETTS - WO2015/179190, 2015, A1 Location in patent: Paragraph 0332.
[2]Current Patent Assignee: PROTEOSTASIS THERAPEUTICS - WO2015/196071, 2015, A1 Location in patent: Paragraph 0499.
[3]Current Patent Assignee: PROTEOSTASIS THERAPEUTICS - WO2016/115090, 2016, A1 Location in patent: Paragraph 0490.
[4]Current Patent Assignee: PROTEOSTASIS THERAPEUTICS - WO2017/40606, 2017, A1 Location in patent: Paragraph 0444.
[5]Tissot, Matthieu; Body, Nathalie; Petit, Sylvain; Claessens, Jehan; Genicot, Christophe; Pasau, Patrick [Organic Letters, 2018, vol. 20, # 24, p. 8022 - 8025].
[6]Current Patent Assignee: MERCK SHARP DOHME - WO2013/28670, 2013, A1 Location in patent: Page/Page column 115.
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[ 1425507-35-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C 1.2: 2 h / 0 °C 2.1: Lithium 1,1,1,3,3,3-hexamethyldisilazide / tetrahydrofuran / 4 h / -78 °C
	Multi-step reaction with 2 steps 1: sodium hydride / N,N-dimethyl-formamide / 2.5 h / 0 °C 2: Lithium 1,1,1,3,3,3-hexamethyldisilazide / tetrahydrofuran / 4 h / -78 °C