* 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.
Product from Step A (4. 8G, 17 mmol) was stirred with 20percent HC1 (20 ML) at reflux for 60 h before being cooled to room temperature. Ether was added and the solution was vigorously stirred for 24 hours. The ether layer was removed and the aqueous layer was extracted with ether (3x). The combined organic layers were dried over anhydrous MGS04 and concentrated in vacuo to yield Intermediate 1 (1.84g, 96.8percent). The crude product was used on next step. NMR (400 MHz, CDC13) 8 3.52-3. 26 (m, 5H).
84.78%
for 60 h; Reflux
Diisopropyl 3,3-dimethoxycyclobutane-1,1-dicarboxylate (31 g, 0.11 mol) was heated with 78 mL of 20percent HCl at reflux for 60 h. After cooling, the solution was continuously extracted with ether for 18 h. The ether was removed at a reduced pressure, leaving a yellow oil, which crystallized on standing to give the titled acid (10.4 g, 84.78percent).
80%
Stage #1: at 20℃; for 4 h; Stage #2: With hydrogenchloride In water for 24 h; Reflux
(2.5 g) of 3,3-dimethoxycyclobutane-1,1-dicarboxylic acid diisopropyl ester was added to a solution of 2.5 equivalents of KOH (3.0 g) in (15 mL) and stirred at room temperature for 4 hours Rear,20 mL of concentrated hydrochloric acid was slowly added (the concentration of hydrochloric acid in the reaction solution was about 25percent), heated to reflux, reacted for 24 hours, and the reaction was completed.Cooled to room temperature and extracted with ethyl acetate three times. The organic phase was dried over anhydrous sodium sulfate and the organic solvent was distilled off under reduced pressure. The crude product was recrystallized to obtain 0.79 g of white crystals in 80percent yield.
65 g
With hydrogenchloride In water at 60℃; Reflux
Compound 29.3 (150 g, 0.52 mol) was added to a solutionof 10 M HCI (400 ml), andthe reaction mixture was heated to reflux for 60 hr.The reactionmixture was cooledto rt, extracted with Et20 (10 x 1 L) and the combinedorganic layers were dried, filteredand concentrated under reduced pressureto give compound 29.4 (65 g) as a yellow oil, which was5 carriedthrough to the next step withoutfurther purification..
Reference：
[1] Journal of Organic Chemistry, 1988, vol. 53, # 16, p. 3841 - 3843
[2] Patent: WO2004/82682, 2004, A1, . Location in patent: Page 35-36
[3] Synlett, 2009, # 11, p. 1827 - 1829
[4] Chemistry - A European Journal, 2011, vol. 17, # 2, p. 468 - 480
[5] Patent: US2009/233903, 2009, A1, . Location in patent: Page/Page column 46
[6] Patent: CN106866405, 2017, A, . Location in patent: Paragraph 0010; 0011; 0012; 0013
[7] Patent: WO2005/97800, 2005, A1, . Location in patent: Page/Page column 338-339
[8] Patent: US2009/298894, 2009, A1, . Location in patent: Page/Page column 44
[9] Patent: WO2014/165075, 2014, A1, . Location in patent: Page/Page column 105
[10] Patent: WO2008/119720, 2008, A1, . Location in patent: Page/Page column 46
2
[ 15760-36-8 ]
[ 23761-23-1 ]
Reference：
[1] Journal of the American Chemical Society, 1958, vol. 80, p. 5837,5839
[2] Patent: WO2012/58187, 2012, A1, . Location in patent: Page/Page column 52; 53
3
[ 115118-67-7 ]
[ 23761-23-1 ]
Yield
Reaction Conditions
Operation in experiment
70%
for 50 h; Heating / reflux
3,3-Dimethoxy-cyclobutane-1,1-dicarboxylic acid diethyl ester (4.72 g, 18.15 mmol) was stirred with 20percent hydrochloric acid (50 ml) at reflux for 50 h. After cooling, the solution was continuously extracted with ether for 20 h. The ether was removed at reduced pressure and the residue was treated with hexanes and cooled. Filtration and wash with hexanes afforded 3-oxo-cyclobutanecarboxylic acid (1.4 g, 70percent) as a brown solid.
Concentrated sulfuric acid (0.2 mL) was added dropwise to a solution of 3-oxocyclobutanecarboxylic acid (1 g, 8.77 mmol) in methanol, and the mixture was refluxed at 75°C. After the starting materials were reacted completely, the reaction was quenched by adding sodium bicarbonate, and the solvent was removed. The resulting residue was extracted to give methyl 3-oxocyclobutanecarboxylate (1.1g, 99percent yield). 1HNMR (400MHz, CDCl3) δ 3.22-3.34 (m, 3H), 3.40-3.47 (m, 2H), 3.78 (s, 3H).
96%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃;
A mixture of 3-oxocyclobutanecarboxylic acid (50 g, 438 mmol), methanol (17.75 mL; 438 mmol), 4-Λr,7V-dimethylaminopyridine (5.37 g, 43.7 mmol) and N-[3-(dimethylamino)propyl]- iV'-ethylcarbodiimide hydrochloride (126 g, 657 mmol) in dichloromethane (2500 mL) was stirred overnight at room temperature. The mixture was washed with water (3*200 mL) and the combined aqueous phase was back extracted with dichloromethane (2* 100 mL). The combined organic phase was washed with 0.5M hydrochloric acid (200 mL), half saturated sodium hydrogen carbonate (100 mL), water (100 mL) and brine (100 mL). The mixture was dried over sodium sulfate and concentrated to dryness in vacuo to afford methyl 3- oxocyclobutanecarboxylate (1) (54 g; 421 mmol; 96percent), which was used without further purification.
92.2%
With sulfuric acid In water at 75℃;
To a solution of 3-oxocyclobutanecarboxylic acid (20.1 g, 176 mmol) in MeOH (500mL) was added H2S04 aqueous solution (9.5 mL, 17.48 mmol, 1.84 M). The mixture was stirredat 75 oc overnight and concentrated in vacuo. The residue was adjusted to pH= 10 withsaturated NaHC03 aqueous solution, the resulting solution was extracted with DCM (200 mL x3). The combined organic layers were washed with brine (100 mL) and dried over anhydrousNa2S04, filtered and then concentrated in vacuo to give the title compound as yellow oil (20.8 g,yield 92.2percent).1HNMR (400 MHz, CDCh) 8 (ppm): 3.76(s, 3H), 3.46-3.36 (m, 2H), 3.33-3.20 (m, 3H).
90%
at 0℃; for 4 h; Reflux
Steps 3: synthesis of methyl 3-oxocyclobutylcarboxylate In 100 ml round-bottom flask is added 3-oxobutane-1-carboxylic acid in (1-4) (10.0g, 0 . 088mol) the CH3OH (50 ml) solution, 0 °C dropping slowly added under stirring SOCl2(3.1 ml, 0 . 045mol), after adding the reaction liquid reflux 4.0h, the reaction liquid to remove the solvent under reduced pressure, the residue is purified with silica gel column chromatography (eluant: PE: EtOAc=10:1) to obtain a target compound 10.0g, colorless oily liquid, yield > 90percent.
90%
at 0℃; for 4 h; Reflux
0C and stirring, SOCl2 (3.1mL, 0.045mol, 0.5eq.) Was slowly added dropwise to 3-oxo-cyclobutane carboxylic acid (10.0g, 0.09mol) inCH3OH (50mL) solution and the reaction mixture was refluxed for 4.0h. After the reaction, the reaction solution was concentrated under reduced pressure, the residue was purified by silica gel chromatography (eluent:PE / EtOAc (V / V) = 10/1) to give the title compound as a colorless oil (10.0g, 90percent).
90%
at 0℃; for 4 h; Reflux
0° C and, SOCl 2 (3.1ml, 0.045mol) was slowly added dropwise 3-oxo-cyclobutane-carboxylic acid (1-1) (10.0g, 0.088mol) in CH 3 OH (50ml) ,, Solution addition was complete, the reaction was refluxed of 4.0h, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (eluent: PE: EtOAc (V: V) = 10: 1) to give colorless, oily liquid (10.0g, 90percent).
89%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 25℃;
The 3-oxo-cyclobutane carboxylic acid (25.0g, 0.220mmol), methanol (14mL) and N, N- dimethyl-4-aminopyridine (3.00g, 353mmol) was dissolved in methylene chloride (a 500 mL) , at 25 °C with stirring, slowly added dropwise 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (64.0g, 340mmol), stirred overnight. The reaction was washed with aqueous hydrochloric acid (1.5N, 72mL), water (150mLx2) and saturated brine (75mLx2) and washed. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to give the product 3-oxo-cyclobutanoic acid methyl ester (25g, yellow liquid). Yield: 89percent
89%
at 0℃; for 4 h; Reflux
In a 100 mL round bottom flask was added 3-oxocaproic acid (10.0 g, 0.088 mol, 1. Oeq)Of methanol(50 mL)0 & gt; C, thionyl chloride (3. lmL, 0.045mOl, 0.5 eq) was slowly added dropwise with stirring at 0 &. After the addition was complete, the reaction solution was refluxed for 4.0 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent:? /? 89percent.
86%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃;
47A. Methyl 3-oxocyclobutanecarboxylate [00209] To a mixture of 3-oxocyclobutanecarboxylic acid (2.5 g, 21.9 mmol), EDC (6.3 g, 32.9 mmol) and DMAP (0.27 g, 2.19 mmol) in DCM (100 mL) was added MeOH (0.98 mL, 24.1 mmol). The mixture was stirred at rt overnight, then was concentrated in vacuo to give a crude oil, which was chromatographed (SiC^; 80 g; continuous gradient from 0 to 25percent Solvent B over 30 min, hold at 25percent Solvent B for 10 min, where Solvent A = Hexanes and Solvent B = 10percent EtOAc) to give the title compound (2.41 g, 18.81 mmol, 86percent yield) as a colorless oil. lH NMR (500 MHz, CDC13) δ 3.77 (s, 3H), 3.47 - 3.40 (m, 2H), 3.34 - 3.21 (m, 3H).
83%
With thionyl chloride In chloroform at 0 - 20℃; for 15 h;
To a stirring solution of29.4 (65g, 0.57 mol) inCH30H (650 ml)at 0°C was added dropwiseSOCb (65 ml)and the reactionwas stirred with warming to rt for15 hr. The solvent was removed under reduced pressure,and the residue was dilutedwith water (200 ml), and extractedwith DCM (3 x 200 ml). The combinedorganic layers were dried,filtered and concentrated under reduced pressure to give a crude,which was purified by flash15 chromatography (silicagel/ PE/EA 20: 1 to 50:1) to yield compound29.5 (50 g, 83percent) as a yellow oil.
80.64%
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 24 h;
A solution of N,N'-dicyclohexylcarbodiimide (7.17 g, 0.0347 mol) in methylene chloride (8 mL, 0.1 mol) was added dropwise to a stirred mixture of 3-oxocyclobutanecarboxylic acid (3.6 g, 0.032 mol), methanol (2.6 mL, 0.063 mol) and 4-dimethylaminopyridine (3.08 g, 0.0252 mol) in methylene chloride (20 mL, 0.2 mol). The mixture was stirred at rt for 24 h, then filtered through Celite. The filtrate was washed with 0.5 M HCl and sat. sodium bicarbonate, dried and concentrated to dry. The residue was purified on silica gel, eluding with 0 to 40percent EtOAc in hexane, to give the desired ester (3.26 g, 80.64percent). 1H NMR (CDCl3, 400 MHz): δ 3.78 (s, 3H), 3.43-3.20 (5H, m) ppm.
16.49 g
With dmap; diisopropyl-carbodiimide In dichloromethane at 20℃; for 72 h;
With dmap; 1,2-dichloro-ethane In dichloromethane at 25℃; for 18 h;
A mixture of 3-oxocyclobutanecarboxylic acid (10.0 g), MeOH (3.6 mL), DMAP (1.1 g) and EDO (25.2 g) in DCM (100 mL) was stirred at 25°C for 18 hours. The mixture was washed with water (8x200 mL). The combined aqueous phases were extracted with DCM (3x300 mL).The combined organ ics were dried, filtered and concentrated to methyl 3- oxocyclobutanecarboxylate (10.0 g).
10.0 g
at 0℃; for 4 h;
To a solution of 3-oxocyclobutanecarboxylic acid (10.0 g, 0.088 mol) in methanol (50 mL) at 0 ° C was slowly added dropwise a solution of SOCl2(3.1 mL, 0.045 mol). After refluxing, the reaction solution was refluxed for 4 hours.The reaction mixture was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10/1) to give the title compound as a colorless oily liquid (10.0 g,> 90percent)
To a solution of 3-oxocyclobutanecarboxylic acid (20.1 g, 176 mmol) in methanol (500 mL) was added aqueous H2SO4 (9.5 mL, 17.48 mmol, 1.84 M).The reaction system was heated to 75 ° C,Stir overnight,After the reaction,Concentrated under reduced pressure.The resulting residue was adjusted to pH = 10 with saturated aqueous sodium bicarbonate solution,The mixture was extracted with DCM (200 mL x 3).The combined organic phases were washed with saturated brine (100 mL)Then dried over anhydrous sodium sulfate,filter,Concentration under reduced pressure gave the title compound as a yellow oil (20.8 g, yield 92.2percent).
Reference：
[1] Patent: CN106478651, 2017, A, . Location in patent: Paragraph 1109; 1110; 1111
10
[ 23761-23-1 ]
[ 18107-18-1 ]
[ 695-95-4 ]
Yield
Reaction Conditions
Operation in experiment
98%
at 0℃; for 1.5 h;
Step A - Synthesis of Intermediate Compound 4b To a solution of compound 4a (4.0 g, 35.1 mmol) in DCM (50 ml) and MeOH (5 mL) was added TMSCH2N2 (30 mL, 60.0 mmol) at 0 °C. The solution was allowed to stir at 0°C for 1.5 h. The solvent was evaporated in vacuo to provide the compound 4b (4.4 g, 98percent yield) as an oil.
triethyl orthoacetate (24.25 g, 104 mmol) was added to a solution of 3-oxo-cyclobutanecarboxylic acid (5.0 g, 34.7 mmol) in toluene (100 mL) and the reaction mixture was heated to reflux for 5h. The reaction mixture was cooled to 0°C and quenched with iN HC1. Organic layer was separated off and the aq.phase was extracted with ethyl acetate (2 x 20 mL). Combined organic layer was washed with saturated NaHCO3 solution followed by water (50 mL) and dried over Na2SO4. Solvent removal under reduced pressure afforded the product (5.8 g, 93.5 percent) as a pale yellow oil. ‘HNMR (400 MHz, CDC13): ö 4.20 (q, J= 7.1 Hz, 2H), 3.44-3.37 (m, 2H), 3.31 -3.17 (m, 3H,), 1.28 (t, J= 7.1 Hz, 3H).
93.5%
for 5 h; Reflux
Step 1 : ethyl 3-oxocyclobutane-l-carboxylate: triethyl orthoacetate (24.25 g, 104 mmol) was added to a solution of 3-oxo-cyclobutanecarboxylic acid (5.0 g, 34.7 mmol) in toluene (100 mL) and the reaction mixture was heated to reflux for 5h. The reaction mixture was cooled to 0°C and quenched with IN HC1. Organic layer was separated off and the aq. phase was extracted with ethyl acetate (2 x 20 mL). Combined organic layer was washed with saturated NaHC03 solution followed by water (50 mL) and dried over Na2S0 . Solvent removal under reduced pressure afforded the product (5.8 g, 93.5 percent) as a pale yellow oil. NMR (400 MHz, CDC13): δ 4.20 (q, J= 7.1 Hz, 2H), 3.44 - 3.37 (m, 2H), 3.31 - 3.17 (m, 3H,), 1.28 (t, J= 7.1 Hz, 3H)
93.5%
at 110℃; for 5 h;
triethyl orthoacetate (24.25 g, 104 mmol) was added to a solution of 3-oxo-cyclobutanecarboxylic acid (5.0 g, 34.7 mmol) in toluene (100 mL) and the reaction mixture was heated to reflux for 5h. The reaction mixture was cooled to 0°C and quenched with IN HC1. Organic layer was separated off and the aq. phase was extracted with ethyl acetate (2 x 20 mL). Combined organic layer was washed with saturated NaHC03 solution followed by water (50 mL) and dried over Na2S04. Solvent removal under reduced pressure afforded the product (5.8 g, 93.5 percent) as a pale yellow oil. XH NMR (400 MHz, CDC13): δ 4.20 (q, J = 7.1 Hz, 2H), 3.44 - 3.37 (m, 2H), 3.31 - 3.17 (m, 3H,), 1.28 (t, J= 7.1 Hz, 3H).
93.5%
at 110℃; for 5 h;
triethyl orthoacetate (24.25 g, 104 mmol) was added to a solution of 3-oxo-cyclobutanecarboxylic acid (5.0 g, 34.7 mmol) in toluene (100 mL) and the reaction mixture was heated to reflux for 5h. The reaction mixture was cooled to 0°C and quenched with IN HC1. Organic layer was separated off and the aq. phase was extracted with ethyl acetate (2 x 20 mL). Combined organic layer was washed with saturated NaHCC solution followed by water (50 mL) and dried over Na2S04. Solvent removal under reduced pressure afforded the product (5.8 g, 93.5 percent) as a pale yellow oil. XH NMR (400 MHz, CDC13): δ 4.20 (q, J= 7.1 Hz, 2H), 3.44 - 3.37 (m, 2H), 3.31 - 3.17 (m, 3H,), 1.28 (t, J= 7.1 Hz, 3H).
85%
for 6 h; Reflux
triethyl orthoacetate (21.31 g,0.13 1 mol) was added to a solution of 3-oxocyclobutane-1-carboxylic acid (5.0 g, 0.043 mol) intoluene (100 mL) and the reaction mixture was refluxed for 6 h. The reaction mixture wasquenched with a IN HCI solution and the layers were separated off. The organic layer waswashed with saturated NaHCO3 solution (2 x 50 mL), brine (2 x 50 mL), dried over anhydroussodium sulfate and concentrated under reduced pressure to get the product (5.3 g, 85percent) as a yellow liquid. ‘H NMR (400 MHz, CDC13): ö 4.23-4.17 (q, J 7.0 Hz, 2H), 3.44-3.37 (m, 2H), 3.32-3.16 (m, 3H), 1.30-1.26 (t, J 7.0 Hz, 3H).
80%
at 110℃; for 5 h;
1A. 3-Oxo-cyclobutanecarboxylic acid ethyl ester A solution of 3-oxo-cyclobutanecarboxylic acid (6.0 g, 52.4 mmol; J. Org. Chem. 1988 53, 3841-3843), triethylorthoacetate (28.8 mL, 157 mmol) and toluene (120 mL) was heated at 110° C. for 5 hours. The reaction mixture was cooled to room temperature and quenched with 1.0 N HCl (120 mL). The organic phase was separated, washed with a saturated NaHCO3 and brine, dried (Na2SO4), filtered and concentrated in vacuo to provide the title compound (6.5 g, 80percent yield) as an oil. 1H NMR (400 MHz, DMSO-d4) 1.23 (t, 3H), 3.30 (m, 5H), 4.14 (q, 2H).
69%
at 110℃; for 5 h;
A solution of 3-oxo-cyclobutanecarboxylic acid (0.5 g, 4.38 mmol), triethylorthoacetate (2.4 mL, 13.1 mmol) and toluene (10 mL) was heated at 110°C for 5 hours. The reaction mixture was cooled to room temperature and quenched with 1.0 N HCI. The organic phase was separated, washed with a saturated NaHC034percent and brine, dried, filtered and concentrated in vacuo to provide the title compound (0.43 g, 69percent yield) as an oil.H NMR (400 MHz, cdcl3) δ 4.22 (q, J = 7.1 Hz, 2H), 3.49 - 3.36 (m, 2H), 3.35 - 3.17 (m, 3H), 1.30 (t. J = 7.1 Hz, 3H).
Ethyl 3 -oxocyclobutanecarboxylate [00217] To a -78 °C solution of 3-oxocyclobutanecarboxylic acid (2.0 g, 17.5 mmol) in EtOH (20 mL) was bubbled HC1 gas for 3 min. The solution was then warmed to rt and stirred at rt for 18 h. Volatiles were concentrated in vacuo and the residue was chromatographed (S1O2; 10percent EtOAc:hexanes) to afford the title compound (2.15 g, 82percent yield) as a clear oil. lR NMR (400 MHz, CDC13) δ 4.23 (q, J (m, 2H), 3.18 - 3.34 (m, 3H), 1.30 (t, J = 7.2 Hz, 3H).
A solution of 3-oxo-cyclobutanecarboxylic acid (6.0 g, 52.4 mmol; J. Org. Chem. 1988 53, 3841-3843), triethylorthoacetate (28.8 mL, 157 mmol) and toluene (120 mL) was heated at 110°C for 5 hours. The reaction mixture was cooled to room temperature and quenched with 1.0 N HCI (120 mL). The organic phase was separated, washed with a saturated NaHCO3 and brine, dried (Na2SO4), filtered and concentrated in vacuo to provide the title compound (6.5 g, 80percent yield) as an oil.1H NMR (400 MHz, DMSO-d4) 51.23 (t, 3H), 3.30 (m, 5H), 4.14 (q, 2H).
With dicyclohexyl-carbodiimide In dichloromethane at 20℃;
To a solution of commercially available 3-oxocyclobutanecarboxylic acid (11.4 g, 100 mmol) in anhydrous DCM (100 mL) was added DCC (31 g, 150 mmol) and 2 methylpropan-2-ol (8.9 g, 120 mmol), then the mixture was stirred at room temperature overnight. The mixture was quenched withaqueous H20, extracted with DCM, the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column to give reagent R-28b (15.1 g, 89percent yield).
250 g
With dmap; dicyclohexyl-carbodiimide In tetrahydrofuran at 10 - 35℃; for 16.5 h;
To a solution of 3-oxocyclobutanecarboxylic acid (250 g) in THF (1.5 L) were added tert-butanol (228 g) and 4-dimethylaminopyridine (148 g) at room temperature, and a solution of N,N'-dicyclohexylcarbodiimide (497 g) in THF (0.5 L) was added dropwise thereto over 30 min, and the reaction mixture was stirred at room temperature for 16 hr. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate, and the mixture was washed with 1M hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was diluted with petroleum ether, the mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound (250 g). 1H NMR (500 MHz, CDCl3) δ 1.48 (9H, s), 3.12-3.14 (1H, m), 3.21-3.27 (2H, m), 3.33-3.35 (2H, m).
Reference：
[1] Patent: WO2014/131855, 2014, A1, . Location in patent: Page/Page column 77
[2] Journal of Medicinal Chemistry, 2016, vol. 59, # 19, p. 8967 - 9004
[3] Journal of Organic Chemistry, 1993, vol. 58, # 1, p. 100 - 110
[4] Journal of Medicinal Chemistry, 2017, vol. 60, # 2, p. 627 - 640
[5] Patent: US2009/298894, 2009, A1, . Location in patent: Page/Page column 44
[6] Patent: US2017/283406, 2017, A1, . Location in patent: Paragraph 0685; 0686
Stage #1: With diphenylphosphoranyl azide; N-ethyl-N,N-diisopropylamine In toluene at 60℃; for 3 h; Inert atmosphere Stage #2: at 60℃;
Compound 8: l-(3-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methyl)(methyl)amino)cyclobutyl)-3-(4-(tert- butyl)phenyl)ureaBenzyl (3-oxocyclobutyl)carbamate[0665] To a solution of 3-oxocyclobutanecarboxylic acid (1.0 g, 8.77 mmol) and DIEA (1.92 g, 14.92 mmol) in toluene (8 mL) was added DPPA (2.89 g, 10.52 mmol) at rt. The mixture was heated to 60 °C under Argon for 3 h, then benzyl alcohol (1.14 g, 10.52 mmol) was added. The mixture was stirred at 60 °C overnight. The reaction was concentrated, the residue was purified by SGC (PE : EA = 8 : 1) to afford the desired compound (240 mg, yield 50percent). 1H NMR (500MHz, CDC13): δΗ 7.38-7.33 (m, 5H), 5.12 (d, / = 7.5 Hz, 2H), 4.34-4.33 (brs, 1 H), 3.44-3.39 (m, 2H), 3.10-3.07 (brs, 2H) ppm; ESI-MS (m/z): 220.2 [M+l]+.
25%
Stage #1: With diphenyl phosphoryl azide; triethylamine In toluene at 60℃; for 3 h; Stage #2: at 60℃; for 3 h;
Step A: (3-Oxo-cyclobutyl)-carbamic acid benzyl ester. A solution of 3-Oxo- cyclobutanecarboxylic acid (1.01 g, 8.8 mmol) and Et3N (1.5ml, 10.5mmol) in THF/Toluene (1: 1, 30ml) was treated with DPPA (1.9 ml, 8.8 mmol). The mixture was stirred for 3 hours at 60°C and then BnOH (1 ml, 9.7mmol) added. The reaction mixture was stirred for another 3 hours at the same temperature. The resulting mixture was concentrated under vacuum to remove most THF and then diluted with EtOAc (50 20 ml). This so-obtained mixture was washed with saturated NaHC03 solution, brine, dried over Na2S04 and filtered. The solvent was evaporated and the residue was purified via chromatography eluted with PE/EtOAc (4: 1) to give the desired product as a white solid (yield: 0.48g, 25percent yield). 1H NMR (400 MHz, CDC13): δ 7.35 (m, 5H), 5.12 (m, 3H), 4.33 (m, 1H), 3.41 (m, 2H), 3.07 (m, 2H).
With potassium osmate(VI) dihydrate; sodium periodate; In tetrahydrofuran; water; at 28℃;Industry scale;
To a solution of crude 3-methylenecyclobutane-carboxylic acid (280 g, 2.25 mol), water (5.5 L), THF (2.5 L) and potassium osmate dihydrate (2.11 g; 5.7 mmol), was charged portion-wise sodium periodate (1.1 kg, 5.14 mol) over a 1.5 h period. The inner temperature was kept below 28 C. To complete conversion additional potassium osmate dihydrate (0.5 g; 1,35 mmol) and sodium periodate (0.45 kg; 2.1 mol) were added. After 2 h stirring, the solids were removed via filtration and were subsequently washed with THF (1 L). The resulting filtrate was extracted with CH2C12 (7 x 1.5 L and 5 x 2 L) and EtOAc (9 2 L). The first 1.5 L CH2CI2 extract was set aside because of the relative large amount of by-product present. The other organic phases were combined and concentrated under reduced pressure. The solid material (approximately 140 g) was redissolved in CH2CI2 and was treated with charcoal (7 g). The charcoal was removed by filtration over Celite and the resulting filtrate was concentrated under reduced pressure, yielding a crystalline mass. This material was redissolved in toluene (150 mL) and to the solution was dosed hexane (1 0 mL). This yielded 52 g light yellowish/brown crystals, which darkened upon standing. Concentration of the mother liquor and recrystallization of the solid mass (70 g) from toluene (150 mL) yielded 48 g yellowish/brown material. The first CH2C12 extract which was set aside, was concentrated yielding 70 g of residue. To the residue CH2CI2 (30 mL) was added and the remaining solution was stored at -15C, which initiated crystallization. From this slurry, 55 g of dark grey/black needle-like crystals were recovered. All crystalline material was combined and was dissolved in EtOAc (750 mL) upon heating, charcoal (7.5 g) was added and the mixture was stirred for 1 h at ambient temperature. The charcoal was removed by filtration over Celite. Approximately 500 mL of EtOAc were removed under reduced pressure. At that point the product started to crystallize and severe foaming was observed. Hexane (500 mL) was added and the mixture was rotated on the rotary evaporator for 1 h. Filtration of the crystalline mass yielded pure product. Anal. Calcd. for C5H6O3: C, 52.63; H, 5.30. Found: C, 52.67; H, 5.31. MS (FIA/ES; negative ionization mode): m/e 430 [M-H] NMR (CDC13): δ 11.47 (br s, 1 H); 3.2-3.5 (m, 5 H). 13C NMR (CDC13): δ 203.1; 180.1; 51.5; 27.2.
With hydrogenchloride; water; for 60h;Heating / reflux;
Product from Step A (4. 8G, 17 mmol) was stirred with 20% HC1 (20 ML) at reflux for 60 h before being cooled to room temperature. Ether was added and the solution was vigorously stirred for 24 hours. The ether layer was removed and the aqueous layer was extracted with ether (3x). The combined organic layers were dried over anhydrous MGS04 and concentrated in vacuo to yield Intermediate 1 (1.84g, 96.8%). The crude product was used on next step. NMR (400 MHz, CDC13) 8 3.52-3. 26 (m, 5H).
92.2%
(1) <strong>[115118-68-8]3,3-dimethoxycyclobutane-1,1-dicarboxylic acid diisopropyl ester</strong> (1000 kg) having a purity greater than 97%, methanol, and sodium hydroxide was added to the jacketed stainless steel hydrolyzer at a molar ratio of 1:10:1.2. add 10kg of alkaline lipase, start stirring, rotate at 80 rpm/min, stir for 30 minutes to make it evenly mixed; and use 45 C hot water to pass the jacket to heat the material for preliminary reaction for 6 hours; then use 90 C hot water to the jacket to heat the material, keep the temperature at 80 ± 2 C for hydrolysis reaction, The reaction was stabilized by heating with hot water, and the reaction was kept for 18 hours; (2) After 24 hours of hydrolysis reaction, the sample was detected, and the residual of the main raw material was not detected. The circulating system was used to cool the material system to 32-35 C through a jacket, and a large amount of solid was precipitated for 2 hours. when no more solids are precipitated, the intermediate is obtained by filtration and centrifugation, and the wet weight is 1150 kg; (3) taking the above intermediate into the tank, adding 1000 kg of water and an amount of hydrochloric acid equivalent to the amount of sodium hydroxide added in the previous period, and 8 kg of sarcosine, and raising the temperature to 100 C with steam under stirring for 30 hours; After the reaction is completed, sample after moderate cooling, It is qualified to use the GC to detect 1.0% residual of the intermediate; (4) Turn on the circulating water to cool to 30±5C, add 10kg of activated carbon, decolorize and stir at this temperature for 2 hours, filter out the activated carbon, collect the clear liquid, and use steam.Concentrated under reduced pressure to a vacuum degree ? 0.09 MPa until the liquid is discharged; (5) Then the reaction system was cooled to 15 ± 2 C, and 1000 kg of dichloromethane was added to the system until no more solids were precipitated, the solid waste was treated by filtration, and the organic phase (filtrate) was collected with 40 C hot water. Distill off the dichloromethane phase, make sure to distill the methylene chloride as clean as possible; then add 500kg of industrial grade toluene to the system and stir at 25 C for 2 hours. The solid is separated by centrifugation and dried under vacuum until the water content is less than 1.0%. That is, the desired 3-oxocyclobutanecarboxylic acid was weighed to have a finished product weight of 364.9 kg, and the yield was calculated to be 92.2%.
84.78%
With hydrogenchloride; water; for 60h;Reflux;
Diisopropyl 3,3-dimethoxycyclobutane-1,1-dicarboxylate (31 g, 0.11 mol) was heated with 78 mL of 20% HCl at reflux for 60 h. After cooling, the solution was continuously extracted with ether for 18 h. The ether was removed at a reduced pressure, leaving a yellow oil, which crystallized on standing to give the titled acid (10.4 g, 84.78%).
80%
(2.5 g) of <strong>[115118-68-8]3,3-dimethoxycyclobutane-1,1-dicarboxylic acid diisopropyl ester</strong> was added to a solution of 2.5 equivalents of KOH (3.0 g) in (15 mL) and stirred at room temperature for 4 hours Rear,20 mL of concentrated hydrochloric acid was slowly added (the concentration of hydrochloric acid in the reaction solution was about 25%), heated to reflux, reacted for 24 hours, and the reaction was completed.Cooled to room temperature and extracted with ethyl acetate three times. The organic phase was dried over anhydrous sodium sulfate and the organic solvent was distilled off under reduced pressure. The crude product was recrystallized to obtain 0.79 g of white crystals in 80% yield.
With hydrogenchloride; water; for 60h;Heating / reflux;
3-Oxo-cyclobutanecarboxylic acid; [1244] 3,3-Dimethoxy-cyclobutane-1,1-dicarboxylic acid diisopropyl ester (0.1 mmol, 30 g) was refluxed in 20% HCI aqueous solution for 60 h. Part of the HCI aqueous solution was evaporated under high vacuum and light brown color oil remained. The oil was dissolved by EtOAc and washed by brine. The organic layer was dried by NaS04, filtered, and evaporated under vacuum. The title compound was obtained as an off-white solid after recrystallization from chloroform.
With hydrogenchloride; water; for 96h;Reflux;
Reference Example 3 3-Oxocyclobutane carboxylic acid To <strong>[115118-68-8]diisopropyl 3,3-dimethoxycyclobutane-1,1-dicarboxylate</strong> (760 g) obtained from Reference example 2, 20% of hydrochloric acid solution (3.2 L) was added and the mixture was refluxed for four days. After that, the reaction solution was extracted with ethyl acetate, and then the organic layer was dried over magnesium sulfate. Solids were removed, the filtrate was dried under reduced pressure to obtain the title product (700 g). 1H-NMR (CDCl3): 11.2 (1H, s), 3.41 (5H, m).
65 g
With hydrogenchloride; In water; at 60℃;Reflux;
Compound 29.3 (150 g, 0.52 mol) was added to a solutionof 10 M HCI (400 ml), andthe reaction mixture was heated to reflux for 60 hr.The reactionmixture was cooledto rt, extracted with Et20 (10 x 1 L) and the combinedorganic layers were dried, filteredand concentrated under reduced pressureto give compound 29.4 (65 g) as a yellow oil, which was5 carriedthrough to the next step withoutfurther purification..
With hydrogenchloride; water; at 100℃; for 84h;
A mixture of diisopropyl 3,3-dimethoxycyclobutane-1 ,1-dicarboxylate (D1 , 17g) and 5M hydrochloric acid (100ml) was heated for 84h at 100C, then concentrated under vacuum and partitioned between ethyl acetate and brine. Drying and evaporation gave the title compound (4.1g).
With dicyclohexyl-carbodiimide; In dichloromethane; at 20℃;
To a solution of commercially available 3-oxocyclobutanecarboxylic acid (11.4 g, 100 mmol) in anhydrous DCM (100 mL) was added DCC (31 g, 150 mmol) and 2 methylpropan-2-ol (8.9 g, 120 mmol), then the mixture was stirred at room temperature overnight. The mixture was quenched withaqueous H20, extracted with DCM, the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column to give reagent R-28b (15.1 g, 89percent yield).
With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 20h;
Reference Example 4 Tert-butyl 3-oxocyclobutane carboxylate To dichloromethane solution (1.6 L) comprising 3-oxocyclobutane carboxylic acid obtained from Reference example 3, tert-butanol (429 g), 4-dimethylaminopyridine (283 g), dichloromethane solution (700 mL) comprising DCC (656 g) was added and the mixture was stirred at room temperature for twenty hours. Upon the completion of stirring, the reaction solution was filtered using Celite, and washed with 1N hydrochloric acid solution. The organic layer was washed with saturated sodium bicarbonate solution, and then dried over magnesium sulfate. Solids were removed, and the filtrate was dried under reduced pressure to obtain the title compound (530 g). 1H-NMR (CDCl3): 3.28 (4H, m), 1.48 (9H, s).
250 g
With dmap; dicyclohexyl-carbodiimide; In tetrahydrofuran; at 10 - 35℃; for 16.5h;
To a solution of 3-oxocyclobutanecarboxylic acid (250 g) in THF (1.5 L) were added tert-butanol (228 g) and 4-dimethylaminopyridine (148 g) at room temperature, and a solution of N,N'-dicyclohexylcarbodiimide (497 g) in THF (0.5 L) was added dropwise thereto over 30 min, and the reaction mixture was stirred at room temperature for 16 hr. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate, and the mixture was washed with 1M hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was diluted with petroleum ether, the mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound (250 g). 1H NMR (500 MHz, CDCl3) delta 1.48 (9H, s), 3.12-3.14 (1H, m), 3.21-3.27 (2H, m), 3.33-3.35 (2H, m).
A solution of 3-oxocyciobutanecarboxylic acid (10.5 g, 92.0 mmoi) andptoluenesulfonic acid monohydrate (0.700 g, 3.68 mmol) in MeOH (300 mL) was heated at refiux overnight. After this time, the reaction mixture was cooled to rt, concentrated to a small volume in vacuo. and diluted with water. The resultingmixture was extracted with DCM (2X). The organic layer was dried over MgSO4, filtered and concentrated in vacuo to give methyl 3,3-dimethoxycyclobutanecarboxylate (14 g, 80 mmoi, 87 % yield).
With toluene-4-sulfonic acid;Heating / reflux;
A solution of 3- oxocyclobutanecarboxylic acid (20) (3.5 g, 31 mmol) and p-toluenesulfonic acid (0.04 equiv, 233 mg, 1.2 mmol) in MeOH (100 ml) was refluxed overnight. The reaction mixture was concentrated down to a small volume and diluted with water and extracted with dichloromethane. The orgnic layer was dried and concentrated down to provide the title compound (5.03 g) as a colorless oil. 1H NMR (400MHz, CDCI3) δ 3.69 (s, 3H, CO2Me), 3.16 (S, 3H), 3.14 (s, 3H), 2.88 (p, 1 H), 2.43 (m, 4H)
With toluene-4-sulfonic acid; at 55℃; for 72h;
[0143] Using the method described in J. Org. Chem. (2006) 61, 2174-2178, 3- oxocyclobutanecarboxylic acid (11.4 g, 100 mmol) was dissolved in MeOH (133 mL) and treated with p-toluenesulfonic acid hydrate (0.38 g, 2.0 mmol). The mixture was heated 55 C for 3 days, cooled to room temperature and concentrated in vacuo to ~l/5 volume. The resulting solution was diluted with H20, extracted with dichloromethane (3 x), washed with saturated aqueous sodium chloride and concentrated in vacuo to give the crude product (15.2 g) which was used without further purification. Rf 0.41 (20% ethyl acetate in heptane). 1H NMR (CDCI3, 300 MHz) δ 1H-NMR: 2.50 - 2.30 (m, 4 H); 2.89 (quint, J = 8.6 Hz, 1 H), 3.14 (s, 3 H); 3.17 (s, 3 H); 3.69 (s, 3 H).
15.1 [0274] Step 1: ethyl 3-oxocyclobutane-1-carboxylate:
triethyl orthoacetate (24.25 g, 104 mmol) was added to a solution of 3-oxo-cyclobutanecarboxylic acid (5.0 g, 34.7 mmol) in toluene (100 mL) and the reaction mixture was heated to reflux for 5h. The reaction mixture was cooled to 0°C and quenched with iN HC1. Organic layer was separated off and the aq.phase was extracted with ethyl acetate (2 x 20 mL). Combined organic layer was washed with saturated NaHCO3 solution followed by water (50 mL) and dried over Na2SO4. Solvent removal under reduced pressure afforded the product (5.8 g, 93.5 %) as a pale yellow oil. ‘HNMR (400 MHz, CDC13): ö 4.20 (q, J= 7.1 Hz, 2H), 3.44-3.37 (m, 2H), 3.31 -3.17 (m, 3H,), 1.28 (t, J= 7.1 Hz, 3H).
93.5%
In toluene for 5h; Reflux;
1 Step 1 : ethyl 3-oxocyclobutane-l-carboxylate
Step 1 : ethyl 3-oxocyclobutane-l-carboxylate: triethyl orthoacetate (24.25 g, 104 mmol) was added to a solution of 3-oxo-cyclobutanecarboxylic acid (5.0 g, 34.7 mmol) in toluene (100 mL) and the reaction mixture was heated to reflux for 5h. The reaction mixture was cooled to 0°C and quenched with IN HC1. Organic layer was separated off and the aq. phase was extracted with ethyl acetate (2 x 20 mL). Combined organic layer was washed with saturated NaHC03 solution followed by water (50 mL) and dried over Na2S0 . Solvent removal under reduced pressure afforded the product (5.8 g, 93.5 %) as a pale yellow oil. NMR (400 MHz, CDC13): δ 4.20 (q, J= 7.1 Hz, 2H), 3.44 - 3.37 (m, 2H), 3.31 - 3.17 (m, 3H,), 1.28 (t, J= 7.1 Hz, 3H)
93.5%
In toluene at 110℃; for 5h;
15.1 Step 1: ethyl 3-oxocyclobutane-l-carboxylate:
triethyl orthoacetate (24.25 g, 104 mmol) was added to a solution of 3-oxo-cyclobutanecarboxylic acid (5.0 g, 34.7 mmol) in toluene (100 mL) and the reaction mixture was heated to reflux for 5h. The reaction mixture was cooled to 0°C and quenched with IN HC1. Organic layer was separated off and the aq. phase was extracted with ethyl acetate (2 x 20 mL). Combined organic layer was washed with saturated NaHC03 solution followed by water (50 mL) and dried over Na2S04. Solvent removal under reduced pressure afforded the product (5.8 g, 93.5 %) as a pale yellow oil. XH NMR (400 MHz, CDC13): δ 4.20 (q, J = 7.1 Hz, 2H), 3.44 - 3.37 (m, 2H), 3.31 - 3.17 (m, 3H,), 1.28 (t, J= 7.1 Hz, 3H).
93.5%
In toluene at 110℃; for 5h;
15.1 ethyl 3-oxocyclobutane-1-carboxylate
triethyl orthoacetate (24.25 g, 104 mmol) was added to a solution of 3-oxo-cyclobutanecarboxylic acid (5.0 g, 34.7 mmol) in toluene (100 mL) and the reaction mixture was heated to reflux for 5h. The reaction mixture was cooled to 0°C and quenched with IN HC1. Organic layer was separated off and the aq. phase was extracted with ethyl acetate (2 x 20 mL). Combined organic layer was washed with saturated NaHCC solution followed by water (50 mL) and dried over Na2S04. Solvent removal under reduced pressure afforded the product (5.8 g, 93.5 %) as a pale yellow oil. XH NMR (400 MHz, CDC13): δ 4.20 (q, J= 7.1 Hz, 2H), 3.44 - 3.37 (m, 2H), 3.31 - 3.17 (m, 3H,), 1.28 (t, J= 7.1 Hz, 3H).
90%
In toluene at 110℃; for 5h;
Ethyl 3-Oxocyclobutanecarboxylate (22)
A solution of 3-oxo-cyclobutanecarboxylic acid (60.0 g, 0.524 mol) and triethyl orthoacetate (288 mL, 1.57 mol) in toluene (1.2 L) was heated at 110 °C for 5 h. The reaction mixture was cooled to r.t. and quenched with 1 M aq HCl (1 L). The organic phase was separated, washed with sat. aq NaHCO3 (3 × 350 mL) and brine (3 × 250 mL), dried over Na2SO4, filtered, and evaporated in vacuo to give ester 22. Yield: 67.4 g (90%); clear colorless oil.
85%
In toluene for 6h; Reflux;
10.1 Step 1: ethyl 3-oxocyclobutane-1-carboxylate
triethyl orthoacetate (21.31 g,0.13 1 mol) was added to a solution of 3-oxocyclobutane-1-carboxylic acid (5.0 g, 0.043 mol) intoluene (100 mL) and the reaction mixture was refluxed for 6 h. The reaction mixture wasquenched with a IN HCI solution and the layers were separated off. The organic layer waswashed with saturated NaHCO3 solution (2 x 50 mL), brine (2 x 50 mL), dried over anhydroussodium sulfate and concentrated under reduced pressure to get the product (5.3 g, 85%) as a yellow liquid. ‘H NMR (400 MHz, CDC13): ö 4.23-4.17 (q, J 7.0 Hz, 2H), 3.44-3.37 (m, 2H), 3.32-3.16 (m, 3H), 1.30-1.26 (t, J 7.0 Hz, 3H).
80%
In toluene at 110℃; for 5h;
1.A
1A. 3-Oxo-cyclobutanecarboxylic acid ethyl ester A solution of 3-oxo-cyclobutanecarboxylic acid (6.0 g, 52.4 mmol; J. Org. Chem. 1988 53, 3841-3843), triethylorthoacetate (28.8 mL, 157 mmol) and toluene (120 mL) was heated at 110° C. for 5 hours. The reaction mixture was cooled to room temperature and quenched with 1.0 N HCl (120 mL). The organic phase was separated, washed with a saturated NaHCO3 and brine, dried (Na2SO4), filtered and concentrated in vacuo to provide the title compound (6.5 g, 80% yield) as an oil. 1H NMR (400 MHz, DMSO-d4) 1.23 (t, 3H), 3.30 (m, 5H), 4.14 (q, 2H).
69%
In toluene at 110℃; for 5h;
147
A solution of 3-oxo-cyclobutanecarboxylic acid (0.5 g, 4.38 mmol), triethylorthoacetate (2.4 mL, 13.1 mmol) and toluene (10 mL) was heated at 110°C for 5 hours. The reaction mixture was cooled to room temperature and quenched with 1.0 N HCI. The organic phase was separated, washed with a saturated NaHC034% and brine, dried, filtered and concentrated in vacuo to provide the title compound (0.43 g, 69% yield) as an oil.H NMR (400 MHz, cdcl3) δ 4.22 (q, J = 7.1 Hz, 2H), 3.49 - 3.36 (m, 2H), 3.35 - 3.17 (m, 3H), 1.30 (t. J = 7.1 Hz, 3H).
In toluene Reflux; Inert atmosphere;
52.1; 53.1 Step 1 : Ethyl 3-oxocyclobutane-1-carboxylate
A mixture of oxocyclobutane-1 -carboxylic acid (99.52 g, 0.90 mol) and triethyl orthoacetate (285 g, 1.76 mol) in toluene (2 L) was refluxed overnight. The toluene was removed under reduced pressure; the residue was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (2 x 500 mL). The combined organic layer was washed with brine (500 mL), dried over sodium sulfate, filtered and concentrated as brown oil. No purification was done before next step.1H NMR (400 MHz, CDCl3) - 3.47 (m, 2 H), 3.1 5 - 3.34 (m, 3 H), 1.12 - 1 .36 (t, 3 H)
In toluene for 6h; Reflux;
1 Preparation 1 : ethyl 3-oxocyclobutane-1-carboxylate
Triethyl orthoacetate (95 mL, 516 mmol) was added to a solution of 3-oxocyclobutane-1- carboxylic acid (20 g, 172 mmol) in toluene (400 mL) and the reaction was refluxed for 6h. The reaction mixture was cooled down to RT, quenched with a 1 N solution of HCI (100 mL x 2) and the layers were separated. The organic phase was washed with s.s. of NaHC03 (100 mL) and Brine (100 mL). HCI and NaHCOs aqueous phases were back- extracted several times with DCM until complete disappearance of the desired product (check by TLC, Cy/EtOAC 8/2, Ninhydrin). Combined organics were dried over Na2S04, filtered and concentrated under vacuum affording ethyl 3-oxocyclobutane-1-carboxylate (p1 , 23.3 g) as yellow oil that was used as crude without further purification. NMR (1H, Chloroform-d): δ 4.24 (q, 1 H) 3.39 - 3.50 (m, 2 H) 3.18 - 3.37 (m, 3 H) 1.29 - 1.36 (m, 3 H)
In toluene at 110℃; for 5h;
1.1 Step 1: Preparation of Ethyl 3-oxocyclobutanecarboxylate
In a 1000 mL single-necked flask, 3-oxocyclobutanecarboxylic acid (25.0 g, 219.1 mmol) was dissolved in toluene (500 mL) and triethyl orthoacetate (106.6 g, 657.3 mmol) was added. The mixture was stirred under heating at 110° C. for 5 h. After the completion of the reaction, the mixture was cooled to room temperature. The reaction was quenched with diluted hydrochloric acid (1.0 M, 20 mL). The organic layer was separated, washed with a saturated aqueous solution of sodium carbonate and a saturated aqueous solution of sodium chloride once in sequence, dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated to obtain 24.9 g of the title compound, which was directly used in the next reaction without purification.
toluene-4-sulfonic acid; In methanol; for 2h;Heating / reflux;
To the solution of 3-oxo-cyclobutanecarboxylic acid (1.0 g, 8.77 mmol) in methanol (12 ml) was added trimethyl orthoformate (6 ml, 58.29 mmol) and a catalytic amount of p-toluenesulfonic acid monohydrate. The reaction was stirred at reflux for 2 h. After such a time it was cooled and concentrated in vacuo to remove the methanol. The remaining residue was dissolved in ether and then washed with a saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated in vacuo to afford 3,3-dimethoxy-cyclobutanecarboxylic acid methyl ester (1.48 g, 97%) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ ppm 2.33-2.51 (m, 4 H, 2×CH2), 2.82-2.97 (m, 1 H, CH), 3.16 (s, 3 H, OCH3), 3.18 (s, 3 H, OCH3), 3.71 (s, 3 H, CO2CH3).
33%
With toluene-4-sulfonic acid; In methanol; for 2h;Reflux;
To a solution of 3-oxocyclobutanecarboxylic acid (1.3 g, 11.39 mmol) in methanol (15 mL) was added trimethylorthoformate (7.5 mL, 67.8 mmol). To this was added p-toluenesulfonic acid monohydrate (2.17 g, 11.4 mmol). The reaction was warmed to reflux and held there for 2 h. The reaction was cooled to room temperature, concentrated to remove most of the methanol, diluted with ether, washed with saturated sodium bicarbonate, dried over sodium sulfate, filtered, and concentrated on the rotovap (no heat, allowing flask to get quite cold, to minimize loss due to potential volatility) to afford 0.65 g (33%). Material was used without purification.
With potassium carbonate; In acetone; for 16h;Reflux;
A mixture of 3-oxocyclobutanecarboxylic acid (5 g, 44 mmol), potassium carbonate (12 g, 88 mmol) and benzyl bromide (11.2 g, 66 mmol) in acetone (50 mL) was refluxed for 16 hr. Solvent was then removed under reduced pressure and the residue was partitioned between ethyl acetate and water. Combined organic layers were dried over anhydrous MgSO/t, filtered and concentrated. The residue was purified with silica gel chromatography eluting with a gradient of 100% hexane to 96% hexane / EtOAc to give the desired compound (8.1 g, 90% yield). 1H NMR (400 MHz, CDC13): delta 7.45 - 7.27 (m, 5H), 5.19 (s, 2H), 3.55 - 3.36 (m, 2H), 3.33 - 3.11 (m, 3H).
90%
With potassium carbonate; In [(2)H6]acetone; hexane;
Step A: Benzyl 3-oxocyclobutanecarboxylate A mixture of 3-oxocyclobutanecarboxylic acid (5 g, 44 mmol), potassium carbonate (12 g, 88 mmol) and benzyl bromide (11.2 g, 66 mmol) in acetone (50 mL) was refluxed for 16 hr. Solvent was then removed under reduced pressure and the residue was partitioned between ethyl acetate and water. Combined organic layers were dried over anhydrous MgSO4, filtered and concentrated. The residue was purified with silica gel chromatography eluting with a gradient of 100% hexane to 96% hexane/EtOAc to give the desired compound (8.1 g, 90% yield). 1H NMR (400 MHz, CDCl3): delta 7.45-7.27 (m, 5H), 5.19 (s, 2H), 3.55-3.36 (m, 2H), 3.33-3.11 (m, 3H).
53%
With triethylamine; In tetrahydrofuran; at 20℃; for 2h;
Example 261 : 2-N-Methyl-6-[5-(3-phenoxycyclobutyl)-1 ,2,4-oxadiazol-3-yl]-2-N-phenyl- 1 ,3,5-triazine-2,4-diamineTriethylamine (2 mL, 14.04 mmol) and benzyl bromide (1.2 mL, 10.0 mmol) were added to a solution of 3-oxocyclobutane-1-carboxylic acid (1.0 g, 8.77 mmol) in THF (10 mL) and the mixture was stirred at room temperature for 2 h. EtOAc (10 mL) was added and the mixture was washed with water followed by 1 M hydrochloric acid and then brine. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified by FCC, eluting with a gradient of 0-15% EtOAc in hexane to afford benzyl 3-oxocyclobutane-1-carboxylate (0.938 g, 53%). A portion of benzyl 3- oxocyclobutane-1-carboxylate (0.800 g, 3.92 mmol) was dissolved in a mixture of THF (2.5 mL) and water (2.5 mL) and cooled to 0 C. Sodium borohydride (0.051 g, 1.96 mmol) was added and the mixture was stirred at room temperature for 1 h. The mixture was concentrated under vacuum and EtOAc (10 mL) was added. This was washed with water and then brine and the organic layer was then dried over sodium sulfate and concentrated. The residue was purified by FCC, eluting with a gradient of 0-10% EtOAc in hexane to afford benzyl 3-hydroxycyclobutane-1-carboxylate (0.715 g, 88%). A portion of benzyl 3-hydroxycyclobutane-1-carboxylate (0.400 g, 1.94 mmol) was dissolved in THF (10 mL) and phenol (0.547 g, 5.83 mmol) and triphenylphosphine (0.662 g, 2.52 mmol) were added. Diethyl azodicarboxylate (0.4 mL, 2.52 mmol) was added gradually and the mixture was stirred at room temperature for 24 h. The mixture was evaporated and then extracted with EtOAc (3 x 10 mL). The organic layer was washed with brine and concentrated under vacuum. The residue was purified by FCC, eluting with a gradient of0- 15% EtOAc in hexane to afford benzyl 3-phenoxycyclobutane-1-carboxylate (0.450 g, 82%). A portion of benzyl 3-phenoxycyclobutane-1-carboxylate (0.400 g, 1.42 mmol) was dissolved in EtOH (10 mL) and 10% palladium on carbon (0.010 g) was added. The mixture was stirred under an atmosphere of hydrogen at room temperature for 2 h. The mixture was filtered and the filtrate was evaporated. The residue was purified by FCC, eluting with a gradient of 0-10% EtOAc in hexane to afford 3-phenoxycyclobutane-1- carboxylic acid (0.245 g, 95%). 2-N-Methyl-6-[5-(3-phenoxycyclobutyl)-1 ,2,4-oxadiazol-3- yl]-2-N-phenyl-1 ,3,5-triazine-2,4-diamine was then prepared from 3-phenoxycyclobutane-1- carboxylic acid (0.190 g, 0.985 mmol) and 4-amino-N-hydroxy-6- [methyl(phenyl)amino]-1 ,3,5-triazine-2-carboximidamide (prepared in an analogous manner to Intermediate 1 , 0.150 g, 0.579 mmol) according to the method described for Example 209. The residue was purified by FCC, eluting with 10% MeOH in hexane to afford the title compound as a mixture of isomers (0.095 g, 42%).
41.9%
With potassium carbonate; In acetone; for 10h;Reflux;
3-Oxocyclobutanecarboxylic acid(3.0 g, 26.3 mmol), benzyl bromide(6.7 g, 39.4 mmol) and potassium carbonate(7.3 g, 52.6 mmol) was dissolved in acetone(30 mL), and then heated to reflux for 10 hours. After TLC showed that the reaction was completed, the reaction mixture was concentrated under reduce pressure to remove the solvent, added water (20 mL), and extracted with ethyl acetate (150 mL*2). The combined organic phase was washed with saturated salt water(50 mL), dried with anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified through silica gel column chromatography (petroleum ether/ethyl acetate=10:1) to give benzyl 3-oxocyclobutane-carboxylate (2.5 g, 41.9% yield) as a colorless liquid. MS (ESI) Calcd. for C12H12O3 [M+H]+ 205, Found 205.
36.7%
With caesium carbonate; In acetonitrile; at 20℃; for 20h;Inert atmosphere;
To a mixture of commercially available 3-oxocyclobutanecarboxylic acid (13.50 g,118.32 mmol) and Cs2003 (46.26 g, 141.98 mmol) in CH3CN (120 mL), was added bromomethylbenzene (21 .25 g, 124.24 mmol) in one portion at r.t. under N2. The mixture was stirred at r.t. for 20 hours. LCMS and TLC showed the reaction was completed. The residue was poured into water and stirred for 20 mm. The aqueous phase was extracted with EtOAc (120 mL). Thecombined organic phase was washed with saturated brine (140 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography to afford reagent KR-Si (8.86 g, 36.7%).
With triethylamine; In tetrahydrofuran; at 20℃; for 2h;
Triethylamine (2.0 mL) and benzyl bromide (1.2 mL) were added to a solution of 3-oxocyclobutanecarboxylic acid (J. Org. Chem., vol. 53, pp. 3841-3843 (1981)) (995 mg) in tetrahydrofuran (5.0 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, and was sequentially washed with 1N aqueous HCl, saturated aqueous sodium hydrogencarbonate, and saturated brine, followed by drying over sodium sulfate anhydrate. The solvent was distilled away under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate : hexane = 1:6), to thereby give the title compound (886 mg).1H-NMR(CDCl3) delta:3.22-3.33(3H, m), 3.37-3.48(2H, m), 5.19(2H, s), 7.31-7.42(5H, m).MS(FAB)m/z:205(M+H+).
With sodium hydrogencarbonate; triethylamine; In tetrahydrofuran;
REFERENTIAL EXAMPLE 150 Benzyl 3-oxocyclobutanecarboxylate: Triethylamine (2.0 ml) and benzyl bromide (1.2 ml) were added to a solution of 3-oxocyclobutanecarboxylic acid (J. Org. Chem., Vol. 53, pp. 3841-3843, 1981) (995 mg) in tetrahydrofuran (5.0 ml), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, and washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure, and the resultant residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:6) to obtain the title compound (886 mg). 1H-NMR (CDCl3) delta: 3.22-3.33(3H,m), 3.37-3.48(2H,m), 5.19(2H,s), 7.31-7.42(5H,m).
Step A:3-Oxocyclobutanecarboxylic acid (2-A) (1.0 g, 10.0 mmol) was dissolved in anhydrous ethanol (25 ml), and cesium carbonate (1.66 g, 5.1 mmol) was added. After stirring at room temperature under nitrogen for 4 hours, the reaction mixture was concentrated. The residue was redissolved in anhydrous acetonitrile (50 ml) and treated with benzyl bromide (1.2 ml, 10.0 ml). The mixture was allowed to stir at room temperature under nitrogen for 12 hours. Solvent was then removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The crude product was purified with silica gel chromatography eluting with a gradient of 100% hexane to 96% hexane/ethyl acetate to give 2-B.
With triethylamine; In tetrahydrofuran; at 20℃; for 2h;
[Referential Example 150] benzyl 3-oxocyclobutanecarboxylate: triethylamine (2.0 ml) and benzyl bromide (1.2 ml) were added to a solution of 3-oxocyclobutanecarboxylic acid (J. Org. Chem., Vol. 53, pp. 3841-3843, 1981) (995 mg) in tetrahydrofuran (5.0 ml), and the mixture was stirred at room temperature for 2 hours.. The reaction mixture was diluted with ethyl acetate, and washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline and dried over anhydrous sodium sulfate.. The solvent was then distilled off under reduced pressure, and the resultant residue was purified by column chromatography on silica gel (ethyl acetate:hexane = 1:6) to obtain the title compound (886 mg).1H-NMR (CDCl3) delta: 3.22-3.33(3H,m), 3.37-3.48(2H,m), 5.19(2H,s), 7.31-7.42(5H,m). MS (FAB) m/z: 205(M+H+).
With potassium carbonate; In acetonitrile; at 20℃; for 24h;
BnBr was added to the mixture of compound 1 and K2CO3 in acetonitrile 150 mL. The mixture was stirred at room temperature over 24 h and the solid was filtered. The solvent was removed and the residue was purified by column chromatography to give compound 2.
With potassium carbonate; In acetonitrile; at 20℃; for 24h;
Step 1: benzyl 3-oxocyclobutanecarboxylate (2) Referring to Scheme 6A, BnBr was added to the mixture of compound 1 and K2CO3 in acetonitrile 150 mL. The mixture was stirred at room temperature over 24 h and the solid was filtered. The solvent was removed and the residue was purified by column chromatography to give compound 2.
With potassium carbonate; In [(2)H6]acetone; hexane;
Step A: Benzyl 3-oxocyclobutanecarboxylate A mixture of 3-oxocyclobutanecarboxylic acid (5 g, 44 mmol), potassium carbonate (12 g, 88 mmol) and benzyl bromide (11.2 g, 66 mmol) in acetone (50 mL) was refluxed for 16 h. The solvent was then removed under reduced pressure and the residue was partitioned between ethyl acetate and water. Combined organic layers were dried over anhydrous MgSO4, filtered and concentrated. The residue was purified with silica gel chromatography eluting with a gradient of 100% hexane to 96% hexane/EtOAc to give the desired compound. 1H NMR (400 MHz, CDCl3): delta 7.45-7.27 (m, 5H), 5.19 (s, 2H), 3.55-3.36 (m, 2H), 3.33-3.11 (m, 3H).
With potassium carbonate; In acetone; for 16h;Reflux;
Method Step A: Benzyl 3-oxocyclobutanecarboxylate. A mixture of 3-oxocyclobutanecarboxylic acid (5 g, 44 mmol), potassium carbonate (12 g, 88 mmol) and benzyl bromide (1 1.2 g, 66 mmol) in acetone (50 mL) was refluxed for 16 h. The solvent was then removed under reduced pressure and the residue was partitioned between ethyl acetate and water. Combined organic layers were dried over anhydrous MgS04, filtered and concentrated. The residue was purified with silica gel chromatography eluting with a gradient of 100% hexane to 96% hexane / EtOAc to give the desired compound. FontWeight="Bold" FontSize="10" H NMR (400 MHz, CDC13): delta 7.45 - 7.27 (m, 5H), 5.19 (s, 2H), 3.55 - 3.36 (m, 2H), 3.33 - 3.11 (m, 3H).
To a solution of commercially available 3-oxocyclobutanecarboxylic acid (14.9 g) in DMF (210 mL) were added potassium carbonate (27.07 g) and benzyl bromide (18.6 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added acetic acid (22.4 mL) over 12 min, and the mixture was stirred at room temperature for 10 min. Water (350 mL) was added, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed 4 times with saturated brine, dried over magnesium sulfate and concentrated. [1411] Toluene was added and the mixture was concentrated to give a crude product of compound 3-1. The obtained crude product of compound 3-1 was directly used in the next step.
With potassium carbonate; In acetone; for 16h;Reflux;
A mixture of 3-oxocyclobutanecarboxylic acid (5g, 44 mmol), potassium carbonate (12 g, 88 mmol) and benzyl bromide (11.2 g, 66 mmol) in acetone (50 mL) was refluxed for 16 h. The solvent was then removed under reduced pressure and the residue was partitioned between ethyl acetate and water. Combined organic layers were driedover anhydrous MgSO4, filtered and concentrated. The residue was purified with silica gel chromatography eluting with a gradient of 100% hexane to 96% hexane EtOAc to givethedesired compound. ?H NMR (400 MHz, CDC13): 7.45 - 7.27 (m, 511), 5.19 (s, 211), 3.55-3.36 (m, 211), 3.33 -3.11 (m, 311).
With potassium carbonate; In acetone; for 16h;Reflux;
Step A: Benzyl 3-oxocyclobutanecarboxylate. A mixture of 3-oxocycIobutanecarboxylic acid (5 g, 44 mmol), potassium carbonate ( 12 g, 88 mmol) and benzyl bromide (1 1.2 g, 66 mmol) in acetone (50 mL) was refluxed for 1 h. The solvent was then removed under reduced pressure and the residue was partitioned between ethyl acetate and water. Combined organic layers were dried over anhydrous MgSC , filtered and concentrated. The residue was purified with silica gel chromatography eluting with a gradient of 100% hexane to 96% hexane / EtOAc to give the desired compound. NMR (400 MHz, CDC13): delta 7.45 - 7.27 (m, 5H), 5.19 (s, 2H), 3.55 - 3.36 (m, 2H), 3.33 - 3.1 1 (m, 3H).
Step 1: 3-tert-Butoxycarbonylmethylene-cyclobutanecarboxylic acid A mixture of 1.2 g of cyclobutanone-3-carboxylic acid (Pigou, P. E.; Shiesser, C. H.; J. Org. Chem.53, 3841-3, 1988), 2.8 g of tert-butyl-dimethyl phosphono-acetate, 1.0 g of lithium hydroxide which had been dried at 120° C. for 30 min under vacuum, 6 g of activated 4A (heated in microwave oven then dried under vacuum for 1 h) molecular sieve dust and 50 mL of THF was heated to reflux under nitrogen for 24 h, cooled, diluted with 100 mL of ethyl acetate and 100 mL of 1N HCl and filtered through diatomaceous earth. The layers were separated and the aqueous layer extracted 4*mL of ethyl acetate. The combined organic extracts were diluted with 50 mL of toluene and concentrated under reduced pressure. Drying under vacuum overnight gave 2 g of product as a white crystalline solid: 1H NMR (400 MHz, CDCl3) 5.5 (s, 1H), 3.9-3.0 (complex m, 4H), 1.42 (s, 9H).
With toluene-4-sulfonic acid; In toluene; for 3h;Heating;
To 3-oxocyclobutanecarboxylic acid (10 g, 87,6 mmol) in dry toluene (100 mL) was added benzyl alcohol (9,1 mL, 87,6 mmol) and p-toluenesulphonic acid (0,4 g, 2,1 mmol). The reaction was heated under Dean-Stark conditions for 3 h. The reaction was concentrated to dryness in vacuo to afford the crude product. Purification using silica chromatography (ethyl acetate/hexane, 0-100% gradient) gave benzyl 3-oxocyclobutanecarboxylate (6) (16 g; 89%) as a colourless oil.1H NMR CDCl3: delta ppm 7.30 (s, 5H), 5.10 (s, 2H), 3.43-3.29 (m, 2H), 3.28-3.13 (m, 3H).
84%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride;dmap; In dichloromethane; at 20℃; for 18h;
Intermediate 1 (3. 5g, 30.7 mmol), benzyl alcohol (3.17 ml, 30.7 mmol), DMAP (375mg, 3.07 mmol), EDC (8.8g, 46.0 mmol) and DCM (100 ml) were mixed together and stirred at room temperature for 18 hours. The reaction mixture was washed with water (3x). The combined aqueous layer was extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous MGS04, and concentrated IN VACUO. Crude product was purified by MPLC (30: 70, ethyl acetate: hexanes) to yield Intermediate 3 (5.25g, 84.0%). NMR (400 MHz, CDC13) 8 7.39 (m, 4H), 5.21 (s, 2H), 3.49-3. 41 (m, 2H), 3.36-3. 28 (m, 3H).
66%
Slowly add carbonyldiimidazole (42.6 g, 263 mmol) to a solution of 3-oxo- cyclopropane carboxylic acid (25.0 g, 219 mmol) in DCM (500 mL), stir at RT for 2 h, add benzyl alcohol (24.17 g, 223 mmol) and stir at RT for 16 h. Add water, extract with DCM (2x), wash the combined organics with brine, dry over Na2S04, concentrate to dryness and purify by silica gel chromatography (EtOAc/Hex) to afford the title compound (29.5 g, 66%) as a colorless syrup. 1H NMR (400 MHz, DMSO-d6): delta 7.38- 7.35 (m, 5 H); 5.14 (s, 2 H); 3.62 (m, 5 H); MS (ESI) m/z: 227.1 (M+Na+).
66%
Example 1 Carbonyldiimidazole (42.6 g, 263 mmol) was slowly added to a solution of 3-oxo-cyclopropane carboxylic acid (25.0 g, 219 mmol) in DCM (500 mL), stirred at RT for 2 h, treated with benzyl alcohol (24.17 g, 223 mmol) and stirred at RT for 16 h. The mixture was diluted with water, extracted with DCM (2*) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified by silica gel chromatography (EtOAc/Hex) to afford benzyl 3-oxocyclobutanecarboxylate (29.5 g, 66%) as a colorless syrup. 1H NMR (400 MHz, DMSO-d6): delta 7.38-7.35 (m, 5H); 5.14 (s, 2H); 3.62 (m, 5H); MS (ESI) m/z: 227.1 (M+Na+).
3.15 g
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 18h;
A mixture of 3-oxocyclobutanecarboxylic acid (2.15 g, 18.84 mmol), benzyl alcohol (2.145 mL, 20.73 mmol) and Nl-((ethylimino)methylene)-N3,N3- dimethylpropane- 1,3 -diamine, HC1 (5.42 g, 28.3 mmol) in DCM (100 mL) was stirred at room temperature for 18 hours. The reaction mixture was washed with water (3x) and the combined aqueous layers were extracted with DCM. The combined organic layesr were washed with brine, dried over anhydrous MgS04, and concentrated in vacuo. Crude product was purified by FCC (0% to 35% EtOAc- Hexanes) to yield the desired product Cap W-25/Cap W-26 Step A (3.15 g) as a colorless oil.1HNMR (400 MHz, CDC13) delta 7.39 (m, 5H), 5.21 (s, 2H), 3.49-3. 41 (m, 2H), 3.36-3. 28 (m, 3H).
With sulfuric acid; magnesium sulfate; In dichloromethane; at 20℃; for 60h;
A Concentrated sulfuric acid (5 ML, 90 mmol) was added to a vigorously stirred suspension of anhydrous MGS04 (42 g, 350 mmol) in DCM (250 mL). The mixture was stirred for 15 minutes before Intermediate 1 (10 g, 88 mmol) was added followed by tert-butanol (42.5 ML, 438 mmol). The reaction flask was stoppered tightly and stirred at room temperature for 60 hours. Saturated NaHC03 solution was added and the resulting mixture was stirred until the reaction mixture became clear as all MGS04 dissolved. The organic layer was separated and washed with brine, dried over anhydrous MGS04, and concentrated in vacuo. The crude product was used in next step.
Concentrated sulfuric acid (0.2 mL) was added dropwise to a solution of 3-oxocyclobutanecarboxylic acid (1 g, 8.77 mmol) in methanol, and the mixture was refluxed at 75C. After the starting materials were reacted completely, the reaction was quenched by adding sodium bicarbonate, and the solvent was removed. The resulting residue was extracted to give methyl 3-oxocyclobutanecarboxylate (1.1g, 99% yield). 1HNMR (400MHz, CDCl3) delta 3.22-3.34 (m, 3H), 3.40-3.47 (m, 2H), 3.78 (s, 3H).
96%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;
A mixture of 3-oxocyclobutanecarboxylic acid (50 g, 438 mmol), methanol (17.75 mL; 438 mmol), 4-Lambdar,7V-dimethylaminopyridine (5.37 g, 43.7 mmol) and N-[3-(dimethylamino)propyl]- iV'-ethylcarbodiimide hydrochloride (126 g, 657 mmol) in dichloromethane (2500 mL) was stirred overnight at room temperature. The mixture was washed with water (3*200 mL) and the combined aqueous phase was back extracted with dichloromethane (2* 100 mL). The combined organic phase was washed with 0.5M hydrochloric acid (200 mL), half saturated sodium hydrogen carbonate (100 mL), water (100 mL) and brine (100 mL). The mixture was dried over sodium sulfate and concentrated to dryness in vacuo to afford methyl 3- oxocyclobutanecarboxylate (1) (54 g; 421 mmol; 96%), which was used without further purification.
96.7%
With diazomethyl-trimethyl-silane; In dichloromethane; for 2h;Inert atmosphere; Cooling with ice;
Under nitrogen protection,Starting material compound 83a (4.0 g, 35.1 mmol) was dissolved in 40 mL dichloromethane and 5 mL methanol.2M TMSCHN2 (30 mL, 59.6 mmol) was added dropwise under ice-water bath.Stir in an ice water bath for 2 h.The reaction was quenched by dropwise addition of 1 mL of glacial acetic acid, and the solvent was evaporated to dryness.The compound methyl 3 -oxocyclobutane-1-carboxylate (83b) (4.4 g, 34.3 mmol) was obtained.Yield: 96.7%.
92.2%
With sulfuric acid; In water; at 75℃;
To a solution of 3-oxocyclobutanecarboxylic acid (20.1 g, 176 mmol) in MeOH (500mL) was added H2S04 aqueous solution (9.5 mL, 17.48 mmol, 1.84 M). The mixture was stirredat 75 oc overnight and concentrated in vacuo. The residue was adjusted to pH= 10 withsaturated NaHC03 aqueous solution, the resulting solution was extracted with DCM (200 mL x3). The combined organic layers were washed with brine (100 mL) and dried over anhydrousNa2S04, filtered and then concentrated in vacuo to give the title compound as yellow oil (20.8 g,yield 92.2%).1HNMR (400 MHz, CDCh) 8 (ppm): 3.76(s, 3H), 3.46-3.36 (m, 2H), 3.33-3.20 (m, 3H).
> 90%
With thionyl chloride; at 0℃; for 4h;Reflux;
Steps 3: synthesis of methyl 3-oxocyclobutylcarboxylate In 100 ml round-bottom flask is added 3-oxobutane-1-carboxylic acid in (1-4) (10.0g, 0 . 088mol) the CH3OH (50 ml) solution, 0 C dropping slowly added under stirring SOCl2(3.1 ml, 0 . 045mol), after adding the reaction liquid reflux 4.0h, the reaction liquid to remove the solvent under reduced pressure, the residue is purified with silica gel column chromatography (eluant: PE: EtOAc=10:1) to obtain a target compound 10.0g, colorless oily liquid, yield > 90%.
90%
With thionyl chloride; at 0℃; for 4h;Reflux;
0C and stirring, SOCl2 (3.1mL, 0.045mol, 0.5eq.) Was slowly added dropwise to 3-oxo-cyclobutane carboxylic acid (10.0g, 0.09mol) inCH3OH (50mL) solution and the reaction mixture was refluxed for 4.0h. After the reaction, the reaction solution was concentrated under reduced pressure, the residue was purified by silica gel chromatography (eluent:PE / EtOAc (V / V) = 10/1) to give the title compound as a colorless oil (10.0g, 90%).
90%
With thionyl chloride; at 0℃; for 4h;Reflux;
0 C and, SOCl 2 (3.1ml, 0.045mol) was slowly added dropwise 3-oxo-cyclobutane-carboxylic acid (1-1) (10.0g, 0.088mol) in CH 3 OH (50ml) ,, Solution addition was complete, the reaction was refluxed of 4.0h, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (eluent: PE: EtOAc (V: V) = 10: 1) to give colorless, oily liquid (10.0g, 90%).
90%
With thionyl chloride; at 0℃; for 4h;Reflux;
0 C and stirring,SOCl2 (3.1 mL, 0.045 mol, 0.5 eq.)Add to 3-oxocyclobutanecarboxylic acid (10.0 g, 0.09 mol, 1.0 eq.)In a solution of CH3OH (50 mL),The reaction solution was refluxed for 4.0 h and concentrated under reduced pressure.The residue was subjected to silica gel column chromatography (eluent: PE/EtOAc (V/V)The title compound (10.0 g, 90%) was obtained.
89%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 25℃;
The 3-oxo-cyclobutane carboxylic acid (25.0g, 0.220mmol), methanol (14mL) and N, N- dimethyl-4-aminopyridine (3.00g, 353mmol) was dissolved in methylene chloride (a 500 mL) , at 25 C with stirring, slowly added dropwise 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (64.0g, 340mmol), stirred overnight. The reaction was washed with aqueous hydrochloric acid (1.5N, 72mL), water (150mLx2) and saturated brine (75mLx2) and washed. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to give the product 3-oxo-cyclobutanoic acid methyl ester (25g, yellow liquid). Yield: 89%
89%
With thionyl chloride; at 0℃; for 4h;Reflux;
In a 100 mL round bottom flask was added 3-oxocaproic acid (10.0 g, 0.088 mol, 1. Oeq)Of methanol(50 mL)0 & gt; C, thionyl chloride (3. lmL, 0.045mOl, 0.5 eq) was slowly added dropwise with stirring at 0 &. After the addition was complete, the reaction solution was refluxed for 4.0 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent:? /? 89%.
87%
With thionyl chloride; at 0 - 70℃; for 4h;
To a solution of 3-oxocyclobutanecarboxylic acid AA26 (20.0 g, 175 mmol) , in methanol (200 mL) was added thionyl chloride (25.0 g, 210 mmol) at 0 . After stirred at 70 for 4 hours, the mixture was allowed to cool down to room temperature and concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (petroleum ether : ethyl acetate = 10 : 1) to afford the title compound (19.5 g, 87 %yield) as colorless oil.1H NMR (300 MHz, CDCl3) delta 3.82 -3.60 (m, 3H) , 3.48 -3.09 (m, 5H) .
86%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;
47A. Methyl 3-oxocyclobutanecarboxylate [00209] To a mixture of 3-oxocyclobutanecarboxylic acid (2.5 g, 21.9 mmol), EDC (6.3 g, 32.9 mmol) and DMAP (0.27 g, 2.19 mmol) in DCM (100 mL) was added MeOH (0.98 mL, 24.1 mmol). The mixture was stirred at rt overnight, then was concentrated in vacuo to give a crude oil, which was chromatographed (SiC^; 80 g; continuous gradient from 0 to 25% Solvent B over 30 min, hold at 25% Solvent B for 10 min, where Solvent A = Hexanes and Solvent B = 10% EtOAc) to give the title compound (2.41 g, 18.81 mmol, 86% yield) as a colorless oil. lH NMR (500 MHz, CDC13) delta 3.77 (s, 3H), 3.47 - 3.40 (m, 2H), 3.34 - 3.21 (m, 3H).
83%
With thionyl chloride; In chloroform; at 0 - 20℃; for 15h;
To a stirring solution of29.4 (65g, 0.57 mol) inCH30H (650 ml)at 0C was added dropwiseSOCb (65 ml)and the reactionwas stirred with warming to rt for15 hr. The solvent was removed under reduced pressure,and the residue was dilutedwith water (200 ml), and extractedwith DCM (3 x 200 ml). The combinedorganic layers were dried,filtered and concentrated under reduced pressure to give a crude,which was purified by flash15 chromatography (silicagel/ PE/EA 20: 1 to 50:1) to yield compound29.5 (50 g, 83%) as a yellow oil.
80.64%
With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 24h;
A solution of N,N'-dicyclohexylcarbodiimide (7.17 g, 0.0347 mol) in methylene chloride (8 mL, 0.1 mol) was added dropwise to a stirred mixture of 3-oxocyclobutanecarboxylic acid (3.6 g, 0.032 mol), methanol (2.6 mL, 0.063 mol) and 4-dimethylaminopyridine (3.08 g, 0.0252 mol) in methylene chloride (20 mL, 0.2 mol). The mixture was stirred at rt for 24 h, then filtered through Celite. The filtrate was washed with 0.5 M HCl and sat. sodium bicarbonate, dried and concentrated to dry. The residue was purified on silica gel, eluding with 0 to 40% EtOAc in hexane, to give the desired ester (3.26 g, 80.64%). 1H NMR (CDCl3, 400 MHz): delta 3.78 (s, 3H), 3.43-3.20 (5H, m) ppm.
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride;dmap; In dichloromethane; at 20℃;
A solution of Intermediate 1 (2.0 g, 18 mmol), MeOH (710 UL, 17.5 mmol), DMAP (215 mg, 1.75 mmol), EDC (5.04 g, 26.3 mmol) and DCM (100 mL) were mixed and stirred at room temperature overnight. The reaction mixture was washed with water (3x). Combined aqueous layer was extracted with DCM. Combined organic layer was washed with brine, dried over anhydrous MGS04, and concentrated in vacuo to yield the desired product.. 1H NMR (400 MHz, CDC13) 8 3.79 (s, 3H), 3.48-3. 25 (m, 5H).
With dicyclohexyl-carbodiimide;dmap; In dichloromethane; at 20℃;
Example 1: Synthesis of l-((3-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2- yl)methyl) (methyl) amino)cyclobutyl)methyl) - 3 -(4- (tert- butyl)phenyl)urea (Compound 110)Step 1: Synthesis of methyl 3-oxocyclobutanecarboxylate[0608] To a solution of DCC (5.96 g, 28.95 mmol) in DCM (20 ml) was added dropwise a mixture of 3-oxocyclobutanecarboxylic acid (3.0 g, 26.31 mmol), MeOH (1.68 g, 52.62 mmol) and DMAP (2.57 g, 21.05 mmol) in DCM (30 ml). The reaction mixture was stirred at RT overnight. The mixture was filtrated. The filtrate was washed with 0.5 M HC1 solution (50 ml). The organic layer was dried over Na2S04 and concentrated. The residue was purified by SGC (PE : EA = 5 : 1) to obtain the title compound (4.0 g). 1H N.R (500 MHz, CDCls): delta 3.77 (s, 3H), 3.42-3.26 (m, 5H) ppm.
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 15 - 25℃; for 24h;
Step A: Methyl 3-oxocvclobutanecarboxylate3-Oxocyclobutanecarboxylic acid 1 (350 g, 3.06 mol), methanol (190 mL, 4.69 mol), l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (885 g, 4.69 mol), 4- dimethylaminopyridine (37 g, 0.30 mol) and dichloromethane (6 L) were stirred at ambient temperature for 24 hours. After the completion of the reaction, it was taken in a separating funnel and washed with 1.5 N HC1 solution (1 L), water (2 L x 2) and brine (1 L x 2). The organic layer was dried over anhydrous Na2S04 and concentrated in vacuo. The residue was taken to the next step without further purification. 1H NMR (300 MHz, CDC13): delta 3.23-3.25 (m, 2H), 3.27-3.32 (m, 2H), 3.33-3.42 (m, 1H), 3.76 (s, 3H). GC- + mlz = 128.
16.49 g
With dmap; diisopropyl-carbodiimide; In dichloromethane; at 20℃; for 72h;
To a stirring solution of 3-oxocycobutanecarboxyiio acid {27 ) (15 gs 131 mmo) in dichloromethane (70 mL) was added methanol (10,66 mL, 263 mmoi), followed by the dropwise addition of a solution of A/,iV-dimeihypyridin-4-amine (1 .85 g, 105 mmol) and /v-methan:ediylideRebis(propan FontWeight="Bold" FontSize="10" 2 FontWeight="Bold" FontSize="10" amne) (22,39 mL, 145 mmol) in dichoromethan (20 mi s and the reaction mixture was stirred for 3 days al room temperature. The dicyciohexylurea precipitate {16.94g ; 1 i 7.5mmole) was removed by filtraiion, dichloromethane was added and the organic layer was washed with 0.5 HGt, saturated NaHC02> saturated NaCL dried over sodium sulfate, filtered and concentrated under reduced pressure to give a crude (TLC: EtOAc/hex 1 :1 Rf 0.57}, which was purified by flash chromatography (silica gel/25-50% ethyl acetate hexanes) to yield the desired product 27.2 ( 6.49 g). H N R (400 MHz, DM0-d6) 5 3.66 (s, 3H), 3.28 (m, 5H).
10 g
With dmap; 1,2-dichloro-ethane; In dichloromethane; at 25℃; for 18h;
A mixture of 3-oxocyclobutanecarboxylic acid (10.0 g), MeOH (3.6 mL), DMAP (1.1 g) and EDO (25.2 g) in DCM (100 mL) was stirred at 25C for 18 hours. The mixture was washed with water (8x200 mL). The combined aqueous phases were extracted with DCM (3x300 mL).The combined organ ics were dried, filtered and concentrated to methyl 3- oxocyclobutanecarboxylate (10.0 g).
10.0 g
With thionyl chloride; at 0℃; for 4h;
To a solution of 3-oxocyclobutanecarboxylic acid (10.0 g, 0.088 mol) in methanol (50 mL) at 0 C was slowly added dropwise a solution of SOCl2(3.1 mL, 0.045 mol). After refluxing, the reaction solution was refluxed for 4 hours.The reaction mixture was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10/1) to give the title compound as a colorless oily liquid (10.0 g,> 90%)
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;
To a stirred solution of compound (XIX, 100 g) in dichloromethane (500 mL) was added 4-dimethylaminopyridine (DMAP ,10 g), followed by addition of methanol (65 mL). Finally 1 -(3 -dimethylaminopropyl)-3-ethylcarbodiimide.hydrochloride (EDAC. HC1 250 g)was added in small portions and it was stirred overnight at room temperature. After completion of reaction, water (100 mL) was added to quench the reaction. Organic phase was separated, dried over anhydrous Na2504 and was concentrated under reduced pressureto get compound (XX).
With thionyl chloride; at 0 - 20℃; for 2h;
To a mixture of 3-oxocyclobutanecarboxylic acid (16.00 g, 140.00 mmol) in MeOH (100 mL) was added SOCl2 (16.38 mL, 224.00 mmol) at 0C. The resulting mixture was stirred at 20C for 2 h. TLC indicated the reaction was complete. The reaction mixture was concentrated in vacuo and the residue was purified by chromatography (SiO2, PE: EtOAc =100:1 to 10:1 gradient) to give the title compound.1H NMR (CDCl3, 400 MHz): ^3.73 (s, 3H), 3.22-3.40 (m, 5H).
With dimethylsulfide borane complex In tetrahydrofuran at -78 - 20℃; for 0.5h; Cooling with acetone-dry ice;
23
In a 25 mL flask with 3-oxocyclobutanecarboxylic acid (0.1 g, 0.88 mmol) inside, 3 mL dry THF was added. This was cooled to -780C, after 30 min, borane- dimethyl sulfide (2 M in THF, 0.53 mL, 1.06 mmol) was added dropwisely. After 5 min, the dry ice-acetone bath was removed and the reaction mixture was allowed to warm up to room temperature. After stirring for overnight, the reaction mixture was quenched by adding 3 mL dry MeOH. The volatile were removed and the reaction mixture was subsequently purified by silica gel flash chromatography purification. (0.065 g, 74%) (CH2Cl2: MeOH= 8:1, Rf=0.25). 1H NMR (CDCl3, 400 MHz): δ 2.70 (m, IH), 2.84-2.92 (m, 2H), 3.08-3.18 (m, 2H), 3.59 (d, J = 6.4, 2H). 13C NMR (CDCl3, 100 MHz): δ 30.43, 49.57, 65.50, 208.17.
Multi-step reaction with 4 steps
1: dmap; diisopropyl-carbodiimide / dichloromethane / 72 h / 20 °C
2: toluene-4-sulfonic acid / benzene / 3 h / Dean-Stark; Reflux
3: lithium aluminium tetrahydride / diethyl ether / 3 h / 20 °C / Inert atmosphere; Reflux
4: hydrogenchloride; water / tetrahydrofuran / 2 h / 55 °C
With dimethylsulfide borane complex In tetrahydrofuran at -15 - 20℃;
1 Intermediate 21-b
To a solution of 3-oxocyclobutanecarboxylic acid 21-a (6.2 g, 54.8 mmol) in THF (78 ml)cooled to -15°C was slowly addec BH3.Me2S (38.3 ml, 77.0 mmol), the reaction mixture was slowly warmed to room temperature, and stirred overnight. Methanol was slowly added and volatiles were removed under reduced pressure. Purification by silica gel chromatography provided Intermediate 21-b as a colorless oil.
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 0℃; for 20h;
Intermediate 36; 3-[4-(methylsulfonyl)piperazin-1-yl]carbonyl}cyclobutanone. BOP (4.43 g, 10 mmol) was poured some more to a solution of 3-oxo-cyclobutanecarboxylic acid (1.14 g, 10 mmol), intermediate 35, 1-(Methanesulphonyl)piperazine (1.64 g, 10 mmol), and triethylamine (4.1USERSDOCSLA21952LPJWA5D2T01 . DOC / 250229 / PC3252S JWA Foreign filing 04-27-06 EPO <DP n="159"/>mL, 30 mmol) in DMF (10 ml_) in argon under stirring at O 0C. The mixture was stirred for 20 h, evaporated, and the residue was dried at 0.5 mmHg. The residue was subjected to chromatography on SiO2 (200 g, 40-63 mum, CHCI3/hexane 8;2, 9:1 , 9.5:0.5 ? CHCI3 ? CHCI3//-PrOH 99:1 ? 95:5) to give the title compound as white crystals in 2.2 g yield. GCMS data: M+ 260 (Calculated for C10H16N2O4S 260.31), 93.5%, r.t. 14.64 min. 1H-NMR data (dmso-d6): 3.56 - 3.64 (m, 4H), 3.50 (ddd, 1H, J = 7.1 Hz, J = 9 Hz, J = 15 Hz), 3.20 - 3.29 (m, 4H), 3.08 - 3.15 (m, 4H), 2.89 (s, 3H).
To a 1 L Chemglass reactor equipped with mechanical stirrer, reflux condenser, argon inlet and thermocouple with Tjacket = 22 C was added compound F (1.0 equiv.), p-toluenesulfonic acid monohydrate (0.03 equiv.), Methanol HPLC Plus 99.9% (5 volumes) and Trimethylorthoformate (1.25 volumes). The resulting solution was heated at reflux (Tbatch = 52-53 C) with Tjacket = 65 C for 1-2 hours. A sample after 1 h reflux analyzed by ‘H-NMR (0.075 mL rxn sample diluted with 1.5 mL d6-DMSO) showed complete conversion. Distilled trimethyl orthoformate and methanol at 50 C/<200 torr until no more solvent came off. Diluted with methyl tert-butyl ether (5 volumes) and washed organic layer with 5% Na2CO3 (2.5 volumes) twice and once with aq. 3% NaC1 (2.5 volumes). The organic layer was concentrated at 50 C/<200 torr to give compound Fl as a yellow oil in 90-95% yield.
With sulfonic acid type-ion exchange resin; In dichloromethane; at 20℃; for 18h;
A mixture of 3-oxocyclobutanecarboxylic acid (D2, 4.1g), methanol (20ml), dichloromethane (20ml), trimethyl orthoformate (20ml), and polymer supported p- toluenesulphonic acid (1g, 4mmol/g) was stirred at room temperature for 18h, then filtered and evaporated to give the title compound (5.5g).
71.5 g
With toluene-4-sulfonic acid; for 5h;Reflux;
To a 500 ml three-necked flask was added 3-oxocyclobutanecarboxylic acid (45.0 g, 395 mmol) and methanol (250 mL); trimethyl orthoformate (75 ml, 713 mmol) was added at room temperature; p-toluenesulfonic acid Monohydrate (2.0 g, 10.5 mmol). After heating and refluxing for 5 hours, the reaction solution was cooled to room temperature, and most of the methanol was rotated, and saturated sodium bicarbonate solution (500 mL) was added thereto, and ethyl acetate (300 mL*2) was added for extraction, and the organic phase was separated, respectively. (300 mL) and saturated brine (300 ml) were washed and dried over anhydrous sodium sulfate. The filtrate was triturated to give the title compound 1 (71.5 g, 411 mmol, 104%).
With Amberlyst-l5 ion exchange resin; at 55℃; under 150.015 Torr; for 6h;Inert atmosphere; Large scale;
A reactor was vacuumed to 0.02 MPa and less and then inerted with nitrogen to atmosphere for three times. MeOH (339.00 kg), 3-oxocyclobutanecarboxylic acid (85.19 kg, 746.6 mol, 1.0 eq.), Amberlyst-l5 ion exchange resin (8.90 kg, 10% w/w), and (0244) trimethoxymethane (196.00 kg, 1847.3 mol, 2.5 eq.) were charged into the reactor and the resulting mixture was heated to 55±5C and reacted for 6 hours to give methyl 3,3- dimethoxycyclobutane-l-carboxylate solution in MeOH. 1H NMR (CDCl3, 400 MHz) d 3.70 (s, 3H), 3.17 (s, 3H), 3.15 (s, 3H), 2.94-2.85 (m, 1H), 2.47-2.36 (m, 4H).
Example 75Preparation of Compounds 399, 400, 401 and 403403 iS/ep A - Synthesis of Compound 75 ATo a solution of compound 7OA (1.0 g, 8.78 mmol) in 65 mL toluene and 16 mL methanol was added TMS-CH2N2 (2M in hexanes, 6.6 mL, 13.2 mmol). The reaction was stirred for 1 hour, then concentrated in vacuo and the residue obtained was diluted in 60 mL methanol and the resulting solution was cooled to -100C and sodium borohydride (350 mg, 9.66 mmol) was added. After stirring for 1 hour, the reaction was quenched with saturated <n="203"/>aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried over MgStheta4, filtered and concentrated to provide a yellow oil which was diluted in 80 mL DMF and to the resulting solution was added TBDPSCl (3.62 g, 13.2 mmol) and imidazole (1.5 g, 22.0 mmol). The reaction was allowed to stir for 16 hours, then quenched with water and extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and and concentrated in vacuo to provide a crude residue which was diluted in 100 mL THF and to the resulting solution was added LAH (IM in THF, 13.26 mL, 13.26 mmol) and the reaction was stirred for 16 hours, then quenched carefully with 2.0 mL water. The resulting solution was treated with 2.0 mL IN NaOH and then diluted with 6.0 mL water. The mixture was cooled to 00C and allowed to stir at this temperature for 30 minutes then was filtered and the filtrate concentrated in vacuo. The residue obtained was washed with hexanes and the resulting filtrate was concentrated in vacuo and the crude product purified using flash column chromatography (10% acetone in hexanes) to provide compound 75 A (2.4 g).
Compound 8: l-(3-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methyl)(methyl)amino)cyclobutyl)-3-(4-(tert- butyl)phenyl)ureaBenzyl (3-oxocyclobutyl)carbamate[0665] To a solution of 3-oxocyclobutanecarboxylic acid (1.0 g, 8.77 mmol) and DIEA (1.92 g, 14.92 mmol) in toluene (8 mL) was added DPPA (2.89 g, 10.52 mmol) at rt. The mixture was heated to 60 C under Argon for 3 h, then benzyl alcohol (1.14 g, 10.52 mmol) was added. The mixture was stirred at 60 C overnight. The reaction was concentrated, the residue was purified by SGC (PE : EA = 8 : 1) to afford the desired compound (240 mg, yield 50%). 1H NMR (500MHz, CDC13): deltaEta 7.38-7.33 (m, 5H), 5.12 (d, / = 7.5 Hz, 2H), 4.34-4.33 (brs, 1 H), 3.44-3.39 (m, 2H), 3.10-3.07 (brs, 2H) ppm; ESI-MS (m/z): 220.2 [M+l]+.
25%
Step A: (3-Oxo-cyclobutyl)-carbamic acid benzyl ester. A solution of 3-Oxo- cyclobutanecarboxylic acid (1.01 g, 8.8 mmol) and Et3N (1.5ml, 10.5mmol) in THF/Toluene (1: 1, 30ml) was treated with DPPA (1.9 ml, 8.8 mmol). The mixture was stirred for 3 hours at 60C and then BnOH (1 ml, 9.7mmol) added. The reaction mixture was stirred for another 3 hours at the same temperature. The resulting mixture was concentrated under vacuum to remove most THF and then diluted with EtOAc (50 20 ml). This so-obtained mixture was washed with saturated NaHC03 solution, brine, dried over Na2S04 and filtered. The solvent was evaporated and the residue was purified via chromatography eluted with PE/EtOAc (4: 1) to give the desired product as a white solid (yield: 0.48g, 25% yield). 1H NMR (400 MHz, CDC13): delta 7.35 (m, 5H), 5.12 (m, 3H), 4.33 (m, 1H), 3.41 (m, 2H), 3.07 (m, 2H).
Step 1 : A solution of (3-oxo-cyclobutyl)-carboxylic acid (20 g, 175 mmol) and triethylamine (30 mL, 215 mmol) in 1 : 1 THF -toluene (150 mL) was treated with diphenyl phosphoryl azide (38 mL, 175 mmol). The solution was warmed to 60 C over 45 minutes, at which point nitrogen evolution was noted. After 3 hours, benzyl alcohol (18 mL, 175 mmol) was added and the solution was kept at 60 C for 4 hours. After cooling to room temperature, the solution was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, 0.5 M HC1 (2x), saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was recrystalized from ethyl acetate and petroleum ether to afford benzyl (3-oxocyclobutyl)carbamate.
1.A
A solution of 3-oxo-cyclobutanecarboxylic acid (6.0 g, 52.4 mmol; J. Org. Chem. 1988 53, 3841-3843), triethylorthoacetate (28.8 mL, 157 mmol) and toluene (120 mL) was heated at 110°C for 5 hours. The reaction mixture was cooled to room temperature and quenched with 1.0 N HCI (120 mL). The organic phase was separated, washed with a saturated NaHCO3 and brine, dried (Na2SO4), filtered and concentrated in vacuo to provide the title compound (6.5 g, 80% yield) as an oil.1H NMR (400 MHz, DMSO-d4) 51.23 (t, 3H), 3.30 (m, 5H), 4.14 (q, 2H).
With bromine; mercury(II) oxide; In tetrachloromethane; at 80℃; for 2h;
The synthesis of 2-(4-amino-l-(3-mophiholinocyclobutyl)-lH-pyrazolo [3, 4-d]pyrimidin-3- yl)-lH-indol-5-ol (Compound 12-6) is described in Scheme 12. Bromocyclobutanone is produced from compound 12-1 by reaction with mercuric oxide and bromine, which is coupled with pyrazolopyrimidine iodide, compound 2-2, to yield compound 12-3. Reductive amination with morpholine affords compound 12-4. Compound 12-4 is then coupled with a boronic acid derivative to produce compound 12-6.
With bromine; mercury(II) oxide; In tetrachloromethane; at 70℃;
A solution of bromine (0.51 ml_, 10 mmol) in CCI4 (20 ml.) was heated to 70 0C, then a mixture of 3-oxocyclobutanecarboxylic acid (1.14 g, 10 mmol) and red mercuric oxide (1.56 g, 7.9 mmol) was added over 30 min. After 1 h, the reaction mixture became colorless. The solids were filtered off and solvent was removed at 30 0C using rotary evaporator (product is volatile, 22 °C/0.5 mmHg). The residue was dissolved in hexanes and filtered through a silica gel pad and concentrated to give 3-bromocyclobutane, which contains CCI4. 1H NMR (CDCI3, 300 MHz): delta = 3.44-3.50 (m, 2 H), 3.72-3.80 (m, 2 H), 4.51-4.55 (m, 1 H).
With bromine; mercury(II) oxide; In tetrachloromethane; at 70℃; for 1.5h;
3-BromocyclobutanoneA solution of bromine (0.51 mL, 10 mmol) in CCl4 (20 mL) was heated to 70° C. and a mixture of 3-oxocyclobutanecarboxylic acid (1.14 g, 10 mmol) and red mercuric oxide (1.56 g, 7.9 mmol) was added over 30 min.After 1 h, the reaction mixture became colorless.The solids were filtered off and solvent was removed at 30° C. using rotary evaporator (product is volatile, 22° C./0.5 mm).The residue was dissolved in hexanes and filtered through silica and concentrated to give the title compound containing CCl4.It was used directly in the next step. 1H NMR (300 MHz, CDCl3): delta=3.44-3.50 (m, 2H), 3.72-3.80 (m, 2H), 4.51-4.55 (m, 1H).
(2R)-1-(4-bromo-2-chlorobenzyl)-2-methylpyrrolidine[ No CAS ]
[ 23761-23-1 ]
[ 25150-61-2 ]
[ 935866-84-5 ]
Yield
Reaction Conditions
Operation in experiment
63%
A 2.7 M solution of n-BuLi in heptane (3.6 mL, 9.6 mmol) was added for 5 min to a solution of intermediate 4, (2i?)-l-(4-bromo-2-chlorobenzyl)-2- methylpyrrolidine. (2.52 g, 8.8 mmol) in absolute THF (20 ml) in a flow of argon at - 78 to -80 0C. The reaction mixture was stirred at -78 to -80 0C for 15 min. Then a solution of 3-oxocyclobutanecarboxylic acid (500 mg, 4.4 mmol) in absolute THF (4 mL) was added drop wise over 5 min at -80 0C. The mixture was warmed to 0 0C for 1 h and evaporated to dryness. The residue was dissolved in DMF (10 mL), Intermediate 5, pyrrolidine HCl (520 mg, 4.8 mmol) was added. Then BOP (2.2 g, 4.8 mmol) was added in portions under cooling in an ice bath for 16 h at room temperature. The disappearance of the starting hydroxy acid was monitored by LC/MS. The reaction mass was evaporated to dryness under 1 mmHg. Water (100 mL), EtOAc (50 mL), and a saturated solution OfK2CO3 (to pH 10) were added. The layers were separated, and the aqueous one was subjected to extraction with EtOAc (2 x 50 mL). The combined organic layer was washed with water (50 mL), brine, dried with Na2SO4, and evaporated. The residue was purified by chromatography (60 mL of silica gel 63/100 μm, hexane/CHCl3 20:80 → 0:100, then CHCl3MeOH <n="33"/>100:0 → 90:10). The product-containing fraction were collected and concentrated to give the title compound (1.03 g, 63%). LC/MS data: 377.2 and 379.2 (M)+ (calculated for C2iH29ClN2O2 376.93). IH NMR data (DMSO-d6): δ 7.51 (s, IH, Ar- H); 7.42-7.49 (m, 2H, Ar-H), 5.75 (s, IH, OH); 3.96 (d, IH, J=13.7 Hz)5 3.25-3.35 (m, ?H+H20); 2.78-2.90 (m, 2H); 2.53-2.60 (m, 2H); 2.43-2.52 (m, 7H+DMSO); 2.06-2.16 (m, IH); 1.88-1.97 (m, IH); 1.80-1.87 (m, 2H); 1.72-1.79 (m, 2H); 1.57- 1.67 (m, 2H); 1.29-1.40 (m, IH); 1.11 (d, 3H, J=5.8 Hz, CH3)
Stage #1: cyclobutanone-3-carboxylic acid With diphenyl phosphoryl azide; triethylamine In tetrahydrofuran; toluene at -5 - 0℃; for 16h;
Stage #2: <i>tert</i>-butyl alcohol at 90 - 100℃; for 16h;
5.1 Step 1 : tert-butyl (3-oxocyclobutyl)carbamate
DPPA (4.0 g, 1.1 eq.) was added dropwise to a cold (-5-5 °C) solution of 3-oxocyclobutanecarboxylic acid (1.5 g, 1.0 eq.) and TEA (1.5 g, 1.1 eq.) in toluene (30 mL), and the mixture was stirred at -5-0 °C for 16 h. The reaction mixture was washed with NaHC03 (2 x 9 mL), water (1 x 9 mL) and NaCl aq. (1 x 4.5 mL) at 0-10 °C. The combined organic layer was dried over Na2S04, filtered, and t-BuOH (7.5 mL) added to the filtrate. The reaction mixture was heated at 90-100 °C for 16 h. The mixture was concentrated under vacuum at 60-70 °C, suspended in TBME (4.5 mL), filtered, and the solid dried over air to give 1.15 g (purity: 98.5%, yield: 47.2%) of product as a white solid
47.2%
Stage #1: cyclobutanone-3-carboxylic acid With diphenyl phosphoryl azide; triethylamine In toluene at -5 - 5℃; for 16h;
Stage #2: <i>tert</i>-butyl alcohol at 90 - 100℃; for 16h;
12.1 Step 1: tert-butyl (3-oxocyclobutyl)carbamate:
DPPA (4.0 g, 1.1 eq.) is added dropwise to a cold (-5--5 °C) solution of 3-oxocyclobutanecarboxylic acid (1.5 g, 1.0 eq.) and TEA (1.5 g, 1.1 eq.) in toluene (30 mL), and the mixture is stirred at -5--0 °C for 16 h. Thereaction mixture is washed with NaHCO3 (2*9 mE), water (1*9 mE) and NaC1 aq. (1*4.5 mL) at 0l 0 °C. The organic phase is dried over Na2SO4, filtered and t-BuOH (7.5 mL) is added to the filtrate. The reaction mixture is heated at 90-1 00 °C for 16 h. The mixture is concentrated under vacuum at 6070 °C and then suspended in TBME (4.5 mL), filtered and the solid isdried over air to give 1.15 g (purity: 98.5%, yield: 47.2%) of product as a white solid.
47.2%
Stage #1: cyclobutanone-3-carboxylic acid With diphenyl phosphoryl azide; triethylamine In toluene at -5 - 5℃; for 16h;
Stage #2: <i>tert</i>-butyl alcohol at 90 - 100℃; for 16h;
5.1 Step 1: tert-butyl (3-oxocyclobutyl)carbamate:
DPPA (4.0 g, 1.1 eq.) was added dropwise to a cold (-55 °C) solution of 3-oxocyclobutanecarboxylic acid (1.5 g, 1.0 eq.) and TEA (1.5 g, 1.1 eq.) in toluene (30 mL), and the mixture stirred at -50 °C for 16 h. Thereaction mixture was washed with NaHCO3 (2 x 9 mL), water (1 x 9 mL) and NaC1 aq. (1 x 4.5 mL) at 010 °C. The organic phase was dried over Na2SO4, filtered and t-BuOH (7.5 mL) added to the filtrate. The reaction mixture was heated at 90100 °C for 16 h. The mixture was concentrated under vacuum at 6070 °C and then suspended in TBME (4.5 mL), filtered and the solid dried in air to give 1.15 g (purity: 98.5%, yield: 47.2%) of product as a white solid.
47.2%
Stage #1: cyclobutanone-3-carboxylic acid With diphenyl phosphoryl azide In toluene at -5 - 5℃; for 16h;
Stage #2: <i>tert</i>-butyl alcohol at 90 - 100℃; for 16h;
5.1 Step 1: tert-butyl (3-oxocyclobutyl)carbamate
Step 1: tert-butyl (3-oxocyclobutyl)carbamate: DPPA (4.0 g, 1.1 eq.) was added dropwise to a cold (-5-5 °C) solution of 3-oxocyclobutanecarboxylic acid (1.5 g, 1.0 eq.) and TEA (1.5 g, 1.1 eq.) in toluene (30 mL), and the mixture was stirred at -5-0 °C for 16 h. The reaction mixture was washed with NaHCC (2 x 9 mL), water (1 x 9 mL) and NaCl aq. (1 x 4.5 mL) at 0-10 °C. The combined organic layer was dried over Na2SC>4, filtered, and t-BuOH (7.5 mL) added to the filtrate. The reaction mixture was heated at 90-100 °C for 16 h. The mixture was concentrated under vacuum at 60-70 °C, suspended in TBME (4.5 mL), filtered, and the solid dried over air to give 1.15 g (purity: 98.5%, yield: 47.2%) of product as a white solid
30%
Stage #1: cyclobutanone-3-carboxylic acid With diphenyl phosphoryl azide; triethylamine In toluene at 10 - 20℃; Inert atmosphere;
Stage #2: <i>tert</i>-butyl alcohol Reflux; Inert atmosphere;
4.A.1
A 22 L three neck flask was charged with 3 -oxocyclobutanecarboxylic acid (630 g, 5.52 mol, 1.0 equiv), toluene (12 L), and triethylamine (850 mL, 6.07 mol, 1.1 equiv). The acid dissolved in toluene after the addition of triethylamine. The solution was cooled below 10°C and diphenylphosphoryl azide (DPPA) (1.32 L, 6.07 mol, 1.1 equiv) was added dropwise over 15 minutes under N2. The solution was then warmed up to RT and stirred overnight. The reaction mixture was then transferred to 22 L separatory funnel, washed with aqueous NaHCC^ (2 x 4 L), water (4 L), brine (2 L), dried over MgS04 and filtered. The filtrate was then transferred to a 22 L three neck flask and to it was added tert-butanol (1260 mL, 13.2 mol, 2.4 equiv). The resultant reaction mixture was then heated at reflux overnight. Upon completion, the reaction mixture was cooled to RT and concentrated under reduced pressure. Another 70 g batch was combined prior to the column purification. The crude residue thus obtained was then purified using column chromatography eluting with ethyl acetate/hexanes (25 :75 to 40:60) to afford 350g of tert-butyl (3-oxocyclobutyl)carbamate (30% yield).
20.5%
Stage #1: cyclobutanone-3-carboxylic acid With diphenylphosphoranyl azide; triethylamine In toluene at -5 - 0℃; for 16h;
Stage #2: <i>tert</i>-butyl alcohol at 100℃; for 16h;
2.1 Step 1:
Step 1: Tert-butyl (3-oxocyclobutyl)carbamate 3-Oxocyclobutane-1-carboxylic acid (1.5 g, 13.2 mmol), triethylamine (2.0 mL, 14.5 mmol) and toluene (30 mL) were added to a 100 mL eggplant-shaped flask successively. Diphenylphosphoryl azide (4.0 g, 14.5 mmol) was slowly added at -5°C to 0°C. The reaction solution was stirred at 0°C for 16 hours. The reaction solution was washed with saturated aqueous sodium bicarbonate solution (30 mL*1) and saturated aqueous sodium chloride solution (30 mL*1) at 0°C, and the organic phase was dried over anhydrous sodium sulfate. Tert-butanol (7.5 mL, 74.8 mmol) was added to the organic phase, and the reaction solution was heated to 100°C and stirred for 16 hours. The reaction solution was concentrated to dryness by rotary evaporation to obtain the crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate: 5/1) to obtain tert-butyl (3-oxocyclobutyl)carbamate (500 mg, yield: 20.5%). 1H NMR (400 MHz, CDCl3) δ 4.86 (s, 1H), 4.27 (s, 1H), 3.50 - 3.33 (m, 2H), 3.11 - 2.97 (m, 2H), 1.46 (s, 9H).
20.5%
Stage #1: cyclobutanone-3-carboxylic acid With diphenylphosphoranyl azide; triethylamine In toluene at -5 - 0℃; for 16h;
Stage #2: <i>tert</i>-butyl alcohol at 100℃; for 16h;
2.1 Step 1:
Step 1: Tert-butyl (3-oxocyclobutyl)carbamate 3-Oxocyclobutane-1-carboxylic acid (1.5 g, 13.2 mmol), triethylamine (2.0 mL, 14.5 mmol) and toluene (30 mL) were added to a 100 mL eggplant-shaped flask successively. Diphenylphosphoryl azide (4.0 g, 14.5 mmol) was slowly added at -5°C to 0°C. The reaction solution was stirred at 0°C for 16 hours. The reaction solution was washed with saturated aqueous sodium bicarbonate solution (30 mL*1) and saturated aqueous sodium chloride solution (30 mL*1) at 0°C, and the organic phase was dried over anhydrous sodium sulfate. Tert-butanol (7.5 mL, 74.8 mmol) was added to the organic phase, and the reaction solution was heated to 100°C and stirred for 16 hours. The reaction solution was concentrated to dryness by rotary evaporation to obtain the crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate: 5/1) to obtain tert-butyl (3-oxocyclobutyl)carbamate (500 mg, yield: 20.5%). 1H NMR (400 MHz, CDCl3) δ 4.86 (s, 1H), 4.27 (s, 1H), 3.50 - 3.33 (m, 2H), 3.11 - 2.97 (m, 2H), 1.46 (s, 9H).
Stage #1: cyclobutanone-3-carboxylic acid With dichloro sulfoxide In dichloromethane for 1.5h; Reflux;
Stage #2: With Caswell No. 744A In lithium hydroxide monohydrate at 0℃;
Stage #3: <i>tert</i>-butyl alcohol In toluene at 90℃;
3.1 Step 1: Preparation of tert-butyl (3-hydroxycyclobutyl)carbamate
Compound r was obtained through a three-step reaction using SOCl2, NaN 3, and t-BuOH as a starting material, compound q. Then, the compound s was obtained by reduction with alcohol using L-Selectride, subsequently, p-nitrobenzoic acid and triphenylphosphine, compound t was obtained using DEAD. This was reacted again with K2CO3 to give compound u.
Step A - Synthesis of Intermediate Compound 4b To a solution of compound 4a (4.0 g, 35.1 mmol) in DCM (50 ml) and MeOH (5 mL) was added TMSCH2N2 (30 mL, 60.0 mmol) at 0 C. The solution was allowed to stir at 0C for 1.5 h. The solvent was evaporated in vacuo to provide the compound 4b (4.4 g, 98% yield) as an oil.
In methanol; hexanes; dichloromethane; at 25℃; for 2h;Inert atmosphere;
Trimethylsilyldiazomethane (21.0 mL of a 2 M solution in hexanes, 42.1 mmol) was added to a stirred solution of 3-oxocyclobutanecarboxylic acid (3.00 g5 26.3 mmol) in dry MeOH (11.1 mL) and dry CH2C12 (100 mL) at 25 C under N2. The reaction was stirred at 25 C for 2 h. The reaction mixture was concentrated in vacuo to afford methyl 3-oxocyclobutanecarboxylate, as an oil. lH NMR (500 MHz, CHCl3): delta 3.75 (s, 3 H); 3.44-3.37 (m, 2 H); 3.31-3.17 (m, 3 H).
Compound 18: (lR,25,3R,5R)-3-{4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-5-({methyl[(3-[5-(trifluoromethyl)-lH-l,3-benzodiazol-2- yl]methyl}cyclobutyl)methyl]amino}methyl)cyclopentane-l,2-diolStep 1: 3-[2-(benzyloxy)-2-oxoethylidene]cyclobutane-l-carboxylic acid[0683] A mixture of cyclobutaneone-3-carboxylic acid (5 g, 43.82 mmol), benzyl-2- (dimethoxyphosphoryl)acetate (13.58 g, 52.59 mmol), LiOH (4.20 g, 23.95 mmol) and 3A activated molecular sieves (25 g, powder form) in THF (250 ml) was heated to reflux under nitrogen for 4 h. The reaction was allowed to cool to RT and EtOAc (100 ml) followed by HC1 (IN, 100 ml) were added. This mixture was filtered through celite. The phases were separated and the aqueous layer was extracted with EtOAc (4 x 50 ml). The combined organic layers were dried over Na2S04, filtered and concentrated to yield a colorless oil. Dry flash chromatography over Si02, eluting with Hept : EtOAc from 7:3 to 1:1 gave the desired product as a colorless oil (5.2 g, 39 %); MS (ESI1") for Ci4Hi404 m/z 269.05 [M+Na]+; MS (ESP) for Ci4Hi404 m/z 245.15 [M-H] ; HPLC purity 81% (ret. time, 1.85 min); 1H NMR (250 MHz, CHLOROFORM-d) δΗ ppm 2.95 - 3.62 (5 H, m), 4.96 - 5.31 (2 H, m), 5.75 (1 H, t, 7=2.21 Hz), 7.27 - 7.45 (5 H, m).
Multi-step reaction with 3 steps
1.1: thionyl chloride / dichloromethane / 1.5 h / 0 °C / Reflux
2.1: sodium azide / acetone; water / 1 h / 0 °C
3.1: toluene / 90 °C
3.2: 90 °C
Multi-step reaction with 3 steps
1: thionyl chloride / dichloromethane / 0 °C / Reflux
2: sodium azide / acetone; water / 1 h / 0 °C
3: toluene / 90 °C / Inert atmosphere
With thionyl chloride; sodium azide In [(2)H6]acetone; water; ethyl acetate; toluene; Petroleum ether; <i>tert</i>-butyl alcohol
A Step A:
Step A: Tert-butyl 3-oxocyclobutylcarbamate To a solution of 3-oxocyclobutanecarboxylic acid (10 g, 88 mmol) in dry DCM (60 mL) at 0° C., SOCl2 (20 mL) was added dropwise. The mixture was heated to reflux for 1.5 h and then evaporated in vacuo. The resulting mixture was co-evaporated twice with toluene (2*8 mL) and the residue was dissolved in acetone (30 mL), followed by adding dropwise to a solution of NaN3 (12 g, 185.0 mmol) in H2O (35 mL) at 0° C. After addition, the mixture was stirred for another 1 h and then quenched with ice (110 g). The resulting mixture was extracted with Et2O (2*100 mL). Combined organic layers were washed with brine, dried over anhydrous Mg2SO4 and concentrated to about 15 mL solution. Toluene (2*30 mL) was added into the residue and the mixture was co-evaporated twice to remove Et2O (about 30 mL solution left each time to avoid explosion). The resulting toluene solution was heated to 90° C. until the evolution of N2 ceased. Next, 40 mL of t-BuOH was added into the reaction mixture and the resulting mixture was stirred overnight at 90° C. The mixture was cooled and concentrated. The residue was purified by column chromatography using petroleum ether/EtOAc (V:V, 7:1 to 5:1) as eluent to afford the desired product as a white solid. MS: 186.1 (M+1)+.
Multi-step reaction with 3 steps
1: thionyl chloride / dichloromethane / 1.5 h / 0 °C / Reflux
2: sodium azide / acetone; water / 1 h / 0 °C
3: toluene / 90 °C
Multi-step reaction with 3 steps
1: thionyl chloride / dichloromethane / 1.5 h / Reflux
2: sodium azide / dichloromethane; water / 1 h / 0 °C
3: 90 °C
With thionyl chloride; sodium azide In [(2)H6]acetone; water; ethyl acetate; toluene; Petroleum ether; <i>tert</i>-butyl alcohol
A Step A:
Step A: tert-Butyl 3-oxocyclobutylcarbamate To a solution of 3-oxocyclobutanecarboxylic acid (10 g, 88 mmol) in dry DCM (60 mL) at 0° C., SOCl2 (20 mL) was added dropwise. The mixture was heated to reflux for 1.5 h and then evaporated in vacuo. The resulting mixture was co-evaporated twice with toluene (2*8 mL) and the residue was dissolved in acetone (30 mL), followed by adding dropwise to a solution of NaN3 (12 g, 185.0 mmol) in H2O (35 mL) at 0° C. After addition, the mixture was stirred for another 1 h and then treated with ice (110 g). The resulting mixture was extracted with Et2O (2*100 mL). Combined organic layers were washed with brine, dried over anhydrous Mg2SO4 and concentrated to about 15 mL solution. Toluene (2*30 mL) was added into the residue and the mixture was co-evaporated twice to remove Et2O (about 30 mL solution left each time to avoid explosion). The resulting toluene solution was heated to 90° C. until the evolution of N2 had ceased. 40 mL of t-BuOH was added into the reaction mixture and the resulting mixture was stirred overnight at 90° C. The mixture was cooled and concentrated. The residue was purified by flash column using petroleum ether/EtOAc (V:V, 7:1 to 5:1) as eluent to afford the desired product as a white solid (7.0 g, yield: 43%). MS: 186.1 (M+1)+.
Multi-step reaction with 3 steps
1: thionyl chloride / dichloromethane / 0 °C / Reflux
2: sodium azide / water; acetone / 0 °C
3: toluene / 90 °C / Inert atmosphere
With diphenylphosphoranyl azide; triethylamine
2.1 Step 1:
Step 1: Tert-butyl (3-oxocyclobutyl)carbamate 3-Oxocyclobutane-1-carboxylic acid (1.5 g, 13.2 mmol), triethylamine (2.0 mL, 14.5 mmol) and toluene (30 mL) were added to a 100 mL eggplant-shaped flask successively. Diphenylphosphoryl azide (4.0 g, 14.5 mmol) was slowly added at -5°C to 0°C. The reaction solution was stirred at 0°C for 16 hours. The reaction solution was washed with saturated aqueous sodium bicarbonate solution (30 mL*1) and saturated aqueous sodium chloride solution (30 mL*1) at 0°C, and the organic phase was dried over anhydrous sodium sulfate. Tert-butanol (7.5 mL, 74.8 mmol) was added to the organic phase, and the reaction solution was heated to 100°C and stirred for 16 hours. The reaction solution was concentrated to dryness by rotary evaporation to obtain the crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate: 5/1) to obtain tert-butyl (3-oxocyclobutyl)carbamate (500 mg, yield: 20.5%). 1H NMR (400 MHz, CDCl3) δ 4.86 (s, 1H), 4.27 (s, 1H), 3.50 - 3.33 (m, 2H), 3.11 - 2.97 (m, 2H), 1.46 (s, 9H).
With dmap; triethylamine; In dichloromethane; at 0℃; for 1h;
To a mixture of 3-oxocyclobutanecarboxylic acid (175 mmol) and TEA (20.4 g, 202 mmol) in DCM (300 ml) at 0C added benzyl chloroformate (3 1.4 g, 184 mmol) slowly. After the addition, DMAP (2.14 g, 17.53 mmol) added. The reaction mixture stirred at 0C for one hour. Then concentrated under vacuum to get 35.8 g (100%) of benzyl 3-oxocyclobutanecarboxylate as colorless oil. LC-MS (ES, m/z) C12H12O3 : 204; Found: 205 [M+H]+.
Example 113 4- ( (4-Fluorobenzyl) oxy) -1- ( l-methyl-2- (3-oxocyclobutyl) -1H- benzimidazol-6-yl) pyridin-2 (1H) -one A) N- ( 4-Bromo-2- (methylamino) henyl) -3- oxocyclobutanecarboxamide To a stirred solution of 3-oxocyclobutanecarboxylic acid (1.1 g) in DMF (50 ml) were added HATU (5.7 g) and N,N- diisopropylethylamine (4.2 ml) at 0C. The mixture was allowed to warm to room temperature and stirred for 30 min. A solution of 4-bromo-N2-methylbenzene-l, 2-diamine (2.0 g) in DMF (2 ml) was added, and the resultant mixture was stirred at the same temperature for 18 h. The mixture was then concentrated in vacuo, and the residue was diluted with DCM (200 ml) and washed with saturated NH4C1 (100 ml), saturated NaHC03. (60 ml), water (100 ml) and brine (100 ml) . The DCM layer was then dried over Na2S04 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (2.7 g) as an off-white solid. MS (ESI+) : [M+H]+ 297.2.
53.53A Ethyl 3 -oxocyclobutanecarboxylate
Ethyl 3 -oxocyclobutanecarboxylate [00217] To a -78 °C solution of 3-oxocyclobutanecarboxylic acid (2.0 g, 17.5 mmol) in EtOH (20 mL) was bubbled HC1 gas for 3 min. The solution was then warmed to rt and stirred at rt for 18 h. Volatiles were concentrated in vacuo and the residue was chromatographed (S1O2; 10% EtOAc:hexanes) to afford the title compound (2.15 g, 82% yield) as a clear oil. lR NMR (400 MHz, CDC13) δ 4.23 (q, J (m, 2H), 3.18 - 3.34 (m, 3H), 1.30 (t, J = 7.2 Hz, 3H).
57.5%
With diphenyl phosphoryl azide; triethylamine at 50℃; for 16h;
Stage #1: 3-oxocyclobutanecarboxylic acid With thionyl chloride In dichloromethane for 3h; Reflux; Cooling with ice;
Stage #2: With sodium azide In water; acetone at 0℃; for 1.5h;
Stage #3: With hydrogenchloride In water; toluene at 0 - 90℃; for 16h;
1.1 [0130] Step 1: 3-Amino-cyclobutan-1-one:
soc2 (15.6 g, 131.46 mmol) was added dropwise to an ice-cooled solution of 3-oxocyclobutane carboxylic acid (5.0 g, 43.82 mmol) in dry DCM (30 mL) and the reaction mixture was refluxed for 3h. The reaction mixture was cooled to room temperature and the volatiles were removed under reduced pressure to get thecrude compound which was azeotropically distilled with toluene (20 mL x 2) to remove acidic traces. The crude compound was dissolved in dry acetone (15 mL) and to the resulting solution was added a solution of NaN3 (5.69 g, 87.64 mmol) in water (20 mL) at 0 °c over 30 mm. The reaction mixture was stirred for lh at 0 °c and crushed ice was added to the reaction mixture. The aq. phase was extracted with ether (3 x 50 mL), dried over sodium sulfate and concentratedto 1/4th volume. Then the reaction mixture was added to toluene (70 mL) and heated to 90°c, until evolution of N2 ceased (-30 mm). To the resulting reaction mixture was added 20% HC1 (50 mL) at 0 °c and the reaction mixture was gently heated to 90 °c for 16h. Organic layer was separated off and washed with water (50 mL). The aqueous layer was concentrated under vacuum to get the compound (5g, crude) as a brown solid. ‘H-NMR (400 MHz, cDcl3) ö8.75 (br, 3H), 3.92-3.86 (m obscured by solvent signal, 2H), 3.38-3.3 1 (m, 3H).
Stage #1: 3-oxocyclobutanecarboxylic acid With thionyl chloride In dichloromethane for 3h; Cooling with ice; Reflux;
Stage #2: With sodium azide In water at 0℃; for 1.5h;
Stage #3: With hydrogenchloride In water; toluene at 0 - 90℃; for 16h;
1 Step 1 : 3-Amino-cyclobutan-l-one
Step 1 : 3-Amino-cyclobutan-l-one: SOCl2 (15.6 g, 131 .46 mmol) was added dropwise to an ice-cooled solution of 3-oxocyclobutane carboxylic acid (5.0 g, 43.82 mmol) in dry DCM (30 mL) and the reaction mixture was refluxed for 3h. The reaction mixture was cooled to room temperature and the volatiles were removed under reduced pressure to get the crude compound which was azeotropically distilled with toluene (20 mL x 2) to remove acidic traces. The crude compound was dissolved in dry acetone (15 mL) and to the resulting solution was added a solution of NaN3 (5.69 g, 87.64 mmol) in water (20 mL) at 0 °C over 30 min. The reaction mixture was stirred for l h at 0 °C and crushed ice was added to the reaction mixture. The aq. phase was extracted with ether (3 x 50 mL), dried over sodium sulfate and concentrated to ~ 1 /4th volume. Then the reaction mixture was added to toluene (70 mL) and heated to 90 °C, until evolution of N2 ceased (~30 min). To the resulting reaction mixture was added 20% HCI (50 mL) at 0 °C and the reaction mixture was gently heated to 90 °C for 16h. Organic layer was separated off and washed with water (50 mL). The aqueous layer was concentrated under vacuum to get the compound (5g, crude) as a brown solid. 1 H-NMR (400 MHz, CDC13) δ 8.75 (br, 3H), 3.92-3.86 (m obscured by solvent signal, 2H), 3.38-3.31 (m, 3H).
Stage #1: 3-oxocyclobutanecarboxylic acid With thionyl chloride In dichloromethane for 3h; Cooling with ice; Reflux;
Stage #2: With sodium azide In water; acetone at 0℃; for 1.5h;
Stage #3: With hydrogenchloride In toluene at 0 - 90℃; for 16h; Inert atmosphere;
1 Step 1: 3-Amino-cyclobutan-l-one
SOCl2 (15.6 g, 131.46 mmol) was added dropwise to an ice-cooled solution of 3-oxocyclobutane carboxylic acid (5.0 g, 43.82 mmol) in dry DCM (30 mL) and the reaction mixture was refluxed for 3h. The reaction mixture was cooled to room temperature and the volatiles were removed under reduced pressure to get the crude compound which was azeotropically distilled with toluene (20 mL x 2) to remove acidic traces. The crude compound was dissolved in dry acetone (15 mL) and to the resulting solution was added a solution of NaN3 (5.69 g, 87.64 mmol) in water (20 mL) at 0 °C over 30 min. The reaction mixture was stirred for 1 h at 0 °C and crushed ice was added to the reaction mixture. The aq. phase was extracted with ether (3 x 50 mL), dried over sodium sulfate and concentrated to ~l/4th volume. Then the reaction mixture was added to toluene (70 mL) and heated to 90 °C, until evolution of N2 ceased (-30 min). To the resulting reaction mixture was added 20% HC1 (50 mL) at 0 °C and the reaction mixture was gently heated to 90 °C for 16 h. The organic layer was separated and washed with water (50 mL). The aqueous layer was concentrated under vacuum to afford the product (5 g, crude) as a brown solid. -NMR (400 MHz, CDC13) 5 8.75 (br, 3H), 3.92-3.86 (m obscured by solvent signal, 2H), 3.38-3.31 (m, 3H).
Stage #1: 3-oxocyclobutanecarboxylic acid With thionyl chloride In dichloromethane for 3h; Reflux;
Stage #2: With sodium azide In water; acetone at 0℃; for 1.5h;
Stage #3: With hydrogenchloride In toluene at 0 - 90℃; for 16h;
1.1 3-aminocyclobutan-1-one
SOCI2 (15.6 g, 131.46 mmol) was added dropwise to an ice-cooled solution of 3-oxocyclobutane carboxylic acid (5.0 g, 43.82 mmol) in dry DCM (30 mL) and the reaction mixture was refluxed for 3h. The reaction mixture was cooled to room temperature and the volatiles were removed under reduced pressure to get the crude compound which was azeotropically distilled with toluene (20 mL x 2) to remove acidic traces. The crude compound was dissolved in dry acetone (15 mL) and to the resulting solution was added a solution of NaN3 (5.69 g, 87.64 mmol) in water (20 mL) at 0 °C over 30 min. The reaction mixture was stirred for lh at 0 °C and crushed ice was added to the reaction mixture. The aq. phase was extracted with ether (3 x 50 mL), dried over sodium sulfate and concentrated to ~l/4th volume. Then the reaction mixture was added to toluene (70 mL) and heated to 90 °C, until evolution of N2 ceased (-30 min). To the resulting reaction mixture was added 20% HC1 (50 mL) at 0 °C and the reaction mixture was gently heated to 90 °C for 16h. Organic layer was separated off and washed with water (50 mL). The aqueous layer was concentrated under vacuum to get the compound (5g, crude) as a brown solid. ^-NMR (400 MHz, CDCI3) δ 8.75 (br, 3H), 3.92-3.86 (m obscured by solvent signal, 2H), 3.38-3.31 (m, 3H).
To a solution of 3-oxocyclobutanecarboxylic acid (20.1 g, 176 mmol) in methanol (500 mL) was added aqueous H2SO4 (9.5 mL, 17.48 mmol, 1.84 M).The reaction system was heated to 75 C,Stir overnight,After the reaction,Concentrated under reduced pressure.The resulting residue was adjusted to pH = 10 with saturated aqueous sodium bicarbonate solution,The mixture was extracted with DCM (200 mL x 3).The combined organic phases were washed with saturated brine (100 mL)Then dried over anhydrous sodium sulfate,filter,Concentration under reduced pressure gave the title compound as a yellow oil (20.8 g, yield 92.2%).
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 1h;
In tetrahydrofuran at -55 - 22℃; for 7h; Large scale; stereoselective reaction;
eparation of 3-Hydroxy-3-methylcyclobutane-1-carboxylic acid(20)
To the 1000 L reactor was charged 10 kg (88.0 mol) of 3-oxocyclobutanecarboxylicacid 19 followed by 280 kg of THF. The slurrywas stirred at 25 C for 1 h until all the solids dissolved. The solutionwas then cooled to 55 C and 65.2 kg (193.0 mol) of a 3 Msolution of methylmagnesium chloride was added over 2 h. Uponcompletion of the addition, the reaction mixture was warmed to 22 C. After stirring for 7 h, the reaction mixture was cooled to5 C and quenched by the addition of 210 kg of a 1 M aqueousphosphoric acid solution over a period of 2.5 h. The temperaturewas increased to 22 C and the mixture was stirred for 45 min.The layers were separated and the aqueous layer was extractedwith 180 kg of 2-MeTHF. The organic extracts were combined,washed with 65 kg of a 25% aqueous sodium chloride solutionand concentrated under reduced pressure at 50 C. An azeotropicvacuum distillation was then performed by the continuous distillationwith MTBE (approximately 111 kg MTBE used for the distillation)at 50 C until the water level reached <1% by KF analysis. Tothe resulting slurry was then added 22 kg of MTBE and the slurrywas heated to 52 C for 4 h. Upon dissolving the crude solid, themixture was then cooled to 22 C over the course of 5 h and heldat the same temperature for 7 h. The slurry was filtered, washedwith 6.7 kg of MTBE and dried under vacuum overnight at 40 Cto afford 7.1 kg (61%) of 3-hydroxy-3-methylcyclobutanecarboxylicacid 20. The trans-isomer was found to be <1% by NMRanalysis. 1H NMR (500 MHz, Methanol-d4) d 2.68 (p, J = 8.9 Hz,1H), 2.31 (td, J = 9.4, 2.4 Hz, 2H), 2.24 (td, J = 8.7, 2.5 Hz, 2H), 1.36(s, 3H). 13C NMR (126 MHz, Methanol-d4) d 177.43, 67.58, 40.40,28.38, 25.54.
With dmap; In tert-butyl alcohol; at 0 - 20℃;Inert atmosphere;
To a solution of 3 -oxocyclobutanecarboxylic acid (8.0 g, 70 mmol) and di-tert-butylpyrocarbonate (31.0 g, 140 mmol) in tert-butanol (150 mL) was added 4-dimethylaminopyridine (3.4 g, 28 mmol) at 0 °C under nitrogen atmosphere. After stirred at room temperature overnight, the mixture was quenched with water (80 mL), then concentrated under reduced pressure to remove the volatile, extracted with ethylacetate (200 mL) for three times. The combined organic layers were washed with 2 M hydrochloride aqueous solution (100 mL), dried over Na2SO4() and concentrated to give a residue, which was purified by silica gel column chromatography (petroleum ether : ethyl acetate = 10 : 1) to afford the title compound (10 g, 70 percent yield) as lightyellow oil. ?H NIVIR (300 1VIHz, CDC13) 3.34 - 2.96 (m, 5H), 1.40 (s, 9H).
(S)-N-(1-(3-(3-chloro-4-isocyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-oxocyclobutanecarboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71.6%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; Inert atmosphere;
(S)-3-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)- 1H-pyrazole-5-carboxamide (1c)
General procedure: 3-Acetyl-1Hpyrazole-5-carboxylic acid (0.75 g, 4.8 mmol), (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (1.00 g,3.8 mmol) and DIPEA (994.8 mg, 7.6 mmol) were dissolved in dryDCM (100 ml). Under nitrogen atmosphere, HOBt (271.0 mg,1.9 mmol) and EDCI (920.2 mg, 4.8 mmol) were added. The reactionwas stirred overnight at RT. The resulting mixture was diluted withDCM and washed with water. Combined organic phase was driedover Na2SO4, filtered and evaporated to dryness. Pure compound 1cwas obtained as a white solid (1.2 g, yield 79.5%) after flash columnchromatography using a solvent of 50% ethyl acetate in hexanes.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
