* 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.
EXAMPLE 1; 2,3A9-Tetrahydro-lff-earbazole-2-earboxylic acid [Compound No. 11H; 3-Oxocyclohexanecarboxylic acid (200 mg, 1.407 mmol) was dissolved in acetic acid (3 mL) to which a solution of phenylhydrazine (160 mg, 1.480 mmol) in acetic acid (2 mL) was added at room temperature, with stirring. The reaction mixture was heated until reflux for 2 hours. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate and extracted with brine. The organic layers were collected and dried (Na2SO4), and the solvent was removed under reduced pressure. The crude product was re-crystallised from ethyl acetate/n-hexane to give a light brown microcrystalline solid (191 mg, 63percent), m.p.235-238°C [c.f. Asselin, A. A., et al, J, Med. Chem. , 1976, 19, 787-792, m.p.239-2410C; Allen, et al, J. Heterocyclic Chem. , 1970, 7, 239-241, m.p.233-235°C]. IR (KBr): 3416, 3048, 2923, 2844, 1689, 1465, 1444, 1415, 1288, 1264, 1226, 935, 740 cm."1 1H NMR (DMSO^6): δ 12.27(1H, s), 1O.66(1H, s), 7.33(1H, d, J=7.6Hz), 7.24(1H, d, J=7.6Hz), 6.98(1H, dt, J=I.2Hz and J=6.8Hz), 6.91(1H, dt, J=1.2Hz and J=6.8Hz), 2.89-2.62(5H, m), 2.17(1H, m), 1.87-1.81(1H, m).
With toluene-4-sulfonic acid In tolueneInert atmosphere; Reflux
2. Preparation of Intermediates of the InventionUnless specified otherwise, all starting materials and reagents were obtained from commercial suppliers, such as Sigma-Aldrich (St. Louis, Mo., USA) and its subsidiaries, and used without further purification.Intermediate 17-Amino-2-(3-chloro-phenyl)-2-aza-spiro[4.5]decan-1-one Intermediate 1 was prepared via the process of Scheme 3, supra, as follows:Step 13-Oxo-cyclohexanecarboxylic acid ethyl ester To a round bottom flask was added 3-oxo-1-cyclohexanecarboxylic acid (3.85 g, 27.1 mmol), ethanol (7.91 mL), p-toluenesulfonic acid (0.097 g, 0.56 mmol) and toluene (65.9 mL). The mixture was refluxed with Dean-star trap overnight. The reaction mixture was cooled down and concentrated under reduced pressure to afford 4.61 g (100percent) of the title compound, 3-oxo-cyclohexanecarboxylic acid ethyl ester, as a yellow oil, which was used in the next step without further purification.
75%
at 15 - 20℃;
To a solution of 3-oxocyclohexane carboxylic acid (63.0g, 0.443mol) in ethanol (950mL), SOCl2 (38.8mL, 0.532mol) was added at 15°C. The reaction mixture was stirred at rt overnight, and then evaporated under reduced pressure. The residue was dissolved in CHCl3 (500mL) and stirred with saturated aq NaHCO3 (200mL) for 30min. The layers were separated, and the aqueous layer was extracted with CHCl3 (2×50mL). The combined organic phases were dried over Na2SO4 and evaporated in vacuo. The residue was distilled under reduced pressure to give 23. Yield 56.3g, 75percent. Colorless oil. Bp 90°C/1.8mbar (lit. [21][21c] Bp 80–83°C/0.6Torr). 1H NMR (CDCl3, 400MHz): δ=4.14 (q, J=7.1Hz, 2H), 2.83–2.72 (m, 1H), 2.53 (d, J=8.2Hz, 2H), 2.41–2.26 (m, 2H), 2.16–2.01 (m, 2H), 1.89–1.66 (m, 2H), 1.25 (t, J=7.1Hz, 3H). 13C NMR (CDCl3, 101MHz): δ=208.6, 173.1, 60.6, 43.0, 42.9, 40.7, 27.5, 24.3, 14.0. MS (EI): m/z=170 (M+), 97(M+–CO2Et). Anal. Calcd for C9H14O3: C, 63.51; H, 8.29. Found: C, 63.14; H, 8.12.
7.5 g
With toluene-4-sulfonic acid In tolueneReflux
A solution of 3-oxocyclohexane-l-carboxylic acid (8.7 g, 61.20 mmol, 1.00 equiv) and ethanol (21 mL) in toluene (150 mL) was added /?-toluenensulfonic acid (250 mg) at room temperature and the resulting solution was heated to reflux overnight in presence of a Dean- Stark. After cpmpletion, the resulting mixture was concentrated under vacuum and the residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 :4) to give the desired ethyl 3-oxocyclohexane-l-carboxylate (7.5 g, 72percent) as white oil.
7.5 g
With toluene-4-sulfonic acid In tolueneReflux; Dean-Stark
[00356] Synthesis of compound 30.4. A solution of 30.3 (8.7 g, 61.20 mmol, 1.00 equiv) and ethanol (21 mL) in toluene (150 mL) was added /?-toluenensulfonic acid (250 mg) at room temperature and the resulting solution was heated to reflux overnight in presence of a Dean- Stark. After completion, the resulting mixture was concentrated under vacuum and the residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 :4) to give the desired 30.4 (7.5 g, 72percent) as white oil.
Reference：
[1] Patent: US2011/98299, 2011, A1, . Location in patent: Page/Page column 23
[2] Journal of Fluorine Chemistry, 2017, vol. 199, p. 60 - 66
[3] Journal of the Chemical Society, 1909, vol. 95, p. 2016
[4] Patent: WO2014/11902, 2014, A1, . Location in patent: Paragraph 00284-00285
[5] Patent: WO2014/194242, 2014, A2, . Location in patent: Paragraph 00353; 00356
4
[ 606488-94-2 ]
[ 16205-98-4 ]
Yield
Reaction Conditions
Operation in experiment
8.7 g
With chromium(VI) oxide; sulfuric acid In water; acetone at 0 - 20℃; for 2.5 h;
The Jones oxidation reagent was prepared from sulfuric acid (30 mL), Cr03 (8.1 g) and H20 (30 mL) in an ice/water bath. A solution of 3-hydroxycyclohexane-l-carboxylic acid (11 g, 76.3 mmol, 1.00 equiv) in acetone (150mL) was added slowly the prepared Jones reagent at 0 °C in 30 min. After addition, the resulting solution was stirred for 2 h at room temperature and the solids were filtered out. The resulting solution was extracted with DCM (3 xlOO mL). The combined organic layers were washed with brine and dried over sodium sulfate and concentrated under vacuum to give the desired 3-oxocyclohexane-l-carboxylic acid (8.7 g, crude) as a yellow oil.
Reference：
[1] Bulletin de la Societe Chimique de France, 1989, # 1, p. 95 - 97
15
[ 10265-41-5 ]
[ 16205-98-4 ]
Reference：
[1] Journal of Organic Chemistry, 1993, vol. 58, # 3, p. 759 - 762
16
[ 17983-30-1 ]
[ 16205-98-4 ]
[ 90865-33-1 ]
[ 90865-32-0 ]
Reference：
[1] Organic Process Research and Development, 2018, vol. 22, # 7, p. 871 - 879
[2] Organic Process Research and Development, 2018, vol. 22, # 7, p. 871 - 879
17
[ 21531-47-5 ]
[ 16205-98-4 ]
[ 21531-47-5 ]
Reference：
[1] Organic Process Research and Development, 2018, vol. 22, # 7, p. 871 - 879
Reference：
[1] Organic Process Research and Development, 2018, vol. 22, # 7, p. 871 - 879
[2] Organic Process Research and Development, 2018, vol. 22, # 7, p. 871 - 879
22
[ 81143-48-8 ]
[ 16205-98-4 ]
Reference：
[1] Liebigs Annalen der Chemie, 1982, # 2, p. 240 - 249
23
[ 81143-49-9 ]
[ 16205-98-4 ]
Reference：
[1] Liebigs Annalen der Chemie, 1982, # 2, p. 240 - 249
With toluene-4-sulfonic acid; In toluene;Inert atmosphere; Reflux;
2. Preparation of Intermediates of the InventionUnless specified otherwise, all starting materials and reagents were obtained from commercial suppliers, such as Sigma-Aldrich (St. Louis, Mo., USA) and its subsidiaries, and used without further purification.Intermediate 17-Amino-2-(3-chloro-phenyl)-2-aza-spiro[4.5]decan-1-one Intermediate 1 was prepared via the process of Scheme 3, supra, as follows:Step 13-Oxo-cyclohexanecarboxylic acid ethyl ester To a round bottom flask was added <strong>[16205-98-4]3-oxo-1-cyclohexanecarboxylic acid</strong> (3.85 g, 27.1 mmol), ethanol (7.91 mL), p-toluenesulfonic acid (0.097 g, 0.56 mmol) and toluene (65.9 mL). The mixture was refluxed with Dean-star trap overnight. The reaction mixture was cooled down and concentrated under reduced pressure to afford 4.61 g (100%) of the title compound, <strong>[16205-98-4]3-oxo-cyclohexanecarboxylic acid</strong> ethyl ester, as a yellow oil, which was used in the next step without further purification.
75%
With thionyl chloride; at 15 - 20℃;
To a solution of <strong>[16205-98-4]3-oxocyclohexane carboxylic acid</strong> (63.0g, 0.443mol) in ethanol (950mL), SOCl2 (38.8mL, 0.532mol) was added at 15C. The reaction mixture was stirred at rt overnight, and then evaporated under reduced pressure. The residue was dissolved in CHCl3 (500mL) and stirred with saturated aq NaHCO3 (200mL) for 30min. The layers were separated, and the aqueous layer was extracted with CHCl3 (2×50mL). The combined organic phases were dried over Na2SO4 and evaporated in vacuo. The residue was distilled under reduced pressure to give 23. Yield 56.3g, 75%. Colorless oil. Bp 90C/1.8mbar (lit. [21][21c] Bp 80-83C/0.6Torr). 1H NMR (CDCl3, 400MHz): delta=4.14 (q, J=7.1Hz, 2H), 2.83-2.72 (m, 1H), 2.53 (d, J=8.2Hz, 2H), 2.41-2.26 (m, 2H), 2.16-2.01 (m, 2H), 1.89-1.66 (m, 2H), 1.25 (t, J=7.1Hz, 3H). 13C NMR (CDCl3, 101MHz): delta=208.6, 173.1, 60.6, 43.0, 42.9, 40.7, 27.5, 24.3, 14.0. MS (EI): m/z=170 (M+), 97(M+-CO2Et). Anal. Calcd for C9H14O3: C, 63.51; H, 8.29. Found: C, 63.14; H, 8.12.
7.5 g
With toluene-4-sulfonic acid; In toluene;Reflux;
A solution of 3-oxocyclohexane-l-carboxylic acid (8.7 g, 61.20 mmol, 1.00 equiv) and ethanol (21 mL) in toluene (150 mL) was added /?-toluenensulfonic acid (250 mg) at room temperature and the resulting solution was heated to reflux overnight in presence of a Dean- Stark. After cpmpletion, the resulting mixture was concentrated under vacuum and the residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 :4) to give the desired ethyl 3-oxocyclohexane-l-carboxylate (7.5 g, 72%) as white oil.
7.5 g
With toluene-4-sulfonic acid; In toluene;Reflux; Dean-Stark;
[00356] Synthesis of compound 30.4. A solution of 30.3 (8.7 g, 61.20 mmol, 1.00 equiv) and ethanol (21 mL) in toluene (150 mL) was added /?-toluenensulfonic acid (250 mg) at room temperature and the resulting solution was heated to reflux overnight in presence of a Dean- Stark. After completion, the resulting mixture was concentrated under vacuum and the residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 :4) to give the desired 30.4 (7.5 g, 72%) as white oil.
With acetic acid; at 20℃; for 2h;Heating / reflux;
EXAMPLE 1; 2,3A9-Tetrahydro-lff-earbazole-2-earboxylic acid [Compound No. 11H; 3-Oxocyclohexanecarboxylic acid (200 mg, 1.407 mmol) was dissolved in acetic acid (3 mL) to which a solution of phenylhydrazine (160 mg, 1.480 mmol) in acetic acid (2 mL) was added at room temperature, with stirring. The reaction mixture was heated until reflux for 2 hours. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate and extracted with brine. The organic layers were collected and dried (Na2SO4), and the solvent was removed under reduced pressure. The crude product was re-crystallised from ethyl acetate/n-hexane to give a light brown microcrystalline solid (191 mg, 63%), m.p.235-238C [c.f. Asselin, A. A., et al, J, Med. Chem. , 1976, 19, 787-792, m.p.239-2410C; Allen, et al, J. Heterocyclic Chem. , 1970, 7, 239-241, m.p.233-235C]. IR (KBr): 3416, 3048, 2923, 2844, 1689, 1465, 1444, 1415, 1288, 1264, 1226, 935, 740 cm."1 1H NMR (DMSO^6): delta 12.27(1H, s), 1O.66(1H, s), 7.33(1H, d, J=7.6Hz), 7.24(1H, d, J=7.6Hz), 6.98(1H, dt, J=I.2Hz and J=6.8Hz), 6.91(1H, dt, J=1.2Hz and J=6.8Hz), 2.89-2.62(5H, m), 2.17(1H, m), 1.87-1.81(1H, m).
1. 1,2,3,4-tetrahydrocarbazole-2-carboxylic acid STR66 A mixture of 3-ketocyclohexanecarboxylic acid (4.78 g, 33.9 mmol) and phenyihydrazine (3.66 g, 40 mmol) in 35 mL of acetic acid was heated under reflux for one hour, then cooled, diluted with water and acidified with HCl. The resultant solid was collected by filtration, washed with water and dried to give 5.5 g of the title compound as a crystalline solid.
EXAMPLE 14 Nalpha -(3-Oxocyclohexanecarbonyl)-L-histidyl-L-prolinamide (Compound 14) By the same method as in Example 1, the title compound (103 mg) was obtained as powders from <strong>[16205-98-4]3-oxocyclohexanecarboxylic acid</strong> [R. D. Allan, G. A. R. Johnston and B. Twitchin, Aust. J. Chem., 34, 2231 (1981)] (172 mg) and L-histidyl-L-prolinamide dihydrobromide (500 mg). NMR (CD3 OD): deltappm: 1.25-2.09 (8H, m), 2.16-2.42 (3H, m), 2.42-2.57 (1H, m), 2.71-2.82 (1H, m), 2.94 (1H, dd, J=7Hz and 14Hz), 3.07 (1H, dd, J=7Hz and 14Hz), 3.78 (1H, q, J=8Hz), 4.40-4.48 (1H, m), 4.72-4.85 (1H, m), 4.91-5.02 (1H, m), 6.98 (1H, s), 7.66 (1H, s). CIMS m/z: 376 (M+1)+.
With acetic acid; In sodium hydroxide; P2 O5; ethanol; water;
EXAMPLE 1 Preparation of 6-chloro-1,2,3,4-tetrahydrocarbazole-2-carboxylic acid STR16 A mixture of 50 g. of p-chlorophenylhydrazine hydrochloride (formula II), 500 ml. of 80 percent acetic acid and 42 g. of <strong>[16205-98-4]cyclohexanone-3-carboxylic acid</strong> (formula III) was placed in a 1 liter round-bottomed, three-necked flask equipped with stirrer and reflux condenser. The mixture was stirred for 2 hours at room temperature under nitrogen and then heated to reflux. After stirring under reflux for 2.5 hours, the mixture was poured into a stirred mixture of 1 kg. of ice and 1 liter of water and stirred until the ice melted. Following filtration of the aqueous mixture, the filter cake was washed with water (4 * 100 ml.). Following removal of as much water as possible by filtration, the filter cake was placed in a vacuum oven and dried for 12 hours at 120 over sodium hydroxide pellets in vacuo. The dried filter cake (66 g.) was dissolved in 500 ml. of boiling ethanol, filtered through a heated funnel, and the filtrate concentrated to 400 ml. under a nitrogen atmosphere. When the solution cooled to room temperature, the mixture was set in a refrigerator at 5 C. for 72 hours to complete the crystallization. The crystalline product was collected by filtration and the filter cake was washed with cooled ethanol (2 * 30 ml.). There was obtained 40 g. (58 percent) of 6-chloro-1,2,3,4-tetrahydrocarbazole-2-carboxylic acid as a yellowish-tan powder which melted at 249-250 when dried in vacuo over P2 O5. Concentration of the mother liquors in a Swisco under nitrogen to 150 ml. gave an additional 10.4 g. (m.p. 242-246). This second crop melted at 247-248 when recrystallized from 80 ml. of ethanol. In an analogous manner to Example 1, when the phenylhydrazine of formula II was replaced, as hereinafter set forth, the corresponding 1,2,3,4-tetrahydrocarbazole-2-carboxylic acids were obtained: The compound of Example 11 was separated from the compound of Example 12 by fractional crystallization of ethanol solutions of the mixture obtained in the reaction. The compound of Example 12 was separated from the compound of Example 15 by fractional crystallization of a methanol solution of the mixture of products obtained from the reaction. In an analogous manner to Example 1, when the cyclohexanone of formula II was replaced, as hereinafter set forth, the corresponding cyclopenta[b]indole or 1,2,3,4-tetrahydrocarbazole was obtained.
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; for 18h;
A stirred mixture of <strong>[16205-98-4]3-oxo-cyclohexanecarboxylic acid</strong> (1.50 g, 10.6 mmol) and benzyl bromide (1 .38 mL, 11 .6 mmol) in dry MeCN (20 mL) was treated with DBU (1 .66 mL, 11 .1 mmol). After 18 h, the mixture was concentrated under vacuum and then diluted with EtOAc. The organic phase was washed with saturated NaHCO3, then 1 N HCI, water andthen brine before it was dried (MgSO4), filtered, and concentrated to dryness under vacuum. Purification by silica column, 50 g SNAP, eluting 5-40 % EtOAc in petrol to gave the product (2.11 g, 86%). LC-MS m/z 250 (M + NH4) , 1.31 (ret. time).
46%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
To a solution of <strong>[16205-98-4]3-oxocyclohexanecarboxylic acid</strong> AA55 (13.2 g, 93.0 mmol) in N, N-dimethylformamide (100 mL) was added potassium carbonate (19.2 g, 139 mmol) and benzyl bromide (23.8 g, 139 mmol) at room temperature. After stirred at room temperature overnight, the mixture was poured into water (200 mL) and extracted with ethyl acetate (100 mL) for three times. The combined organic phases were washed with water (100 mL) twice followed by brine (100 mL) , dried over Na2SO4 (s), filtered and concentrated to give a residue, which was purified by silica gel column chromatography (petroleum ether : ethyl acetate = 15 : 1 to 8 : 1) to give the title compound (14.3 g, 46 %yield) as colorless oil.1H NMR (300 MHz, CDCl3) delta 7.42 -7.29 (m, 5H) , 5.15 (s, 2H) , 2.91 -2.81 (m, 1H) , 2.57 (d, J = 8.1 Hz, 2H) , 2.43 -2.26 (m, 2H) , 2.19 -2.00 (m, 2H) , 1.92 -1.80 (m, 1H) , 1.75 -1.69 (m, 1H) .
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃; for 5h;
To a solution of <strong>[16205-98-4]3-oxocyclohexanecarboxylic acid</strong> (0.90 g, 0.0063 mol) in acetonitrile (12 mL) was added benzyl bromide (0.83 mL, 0.0070 mol) at room temperature, followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (0.994 mL, 0.00665 mol). The mixture was stirred at room temperature for 5 h. After removal of solvent, the residue was diluted with ethyl acetate. The organic phase was washed with aqueous NaHCO3 solution (7.5%), 1N HCl solution, water, and brine, and dried over MgSO4. After filtration, the filtrate was concentrated. The residue was purified by flash column to afford benzyl 3-oxocyclohexanecarboxylate. LCMS: (M+H)+=233.1.
To a mixture of <strong>[16205-98-4]3-oxocyclohexanecarboxylic acid</strong> (1.00 g, 0.00703 mol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (3.27 g, 0.00739 mol) in N,N-dimethylformamide (10.0 mL) was added cyclohexanamine (0.885 mL, 0.00774 mol) at 0 C. After stirring at 0 C. for 10 min, to the reaction mixture was added N,N-diisopropylethylamine (1.84 mL, 0.0106 mol). The resultant mixture was stirred at RT for 2 h, then diluted with EtOAc, washed with aq. sodium bicarbonate, water, brine, and dried with magnesium sulfate. After evaporation to dryness, the resultant crude product was used directly in next step. LCMS (M+H)+=224.2.
To a cooled (-20 C.) solution of <strong>[16205-98-4]3-oxocyclohexanecarboxylic acid</strong> (0.2 g, 0.001 mol) in tetrahydrofuran (1 mL) was added a solution of p-anisyl magnesium bromide in tetrahydrofuran (0.5 M, 6 mL) with stirring. The mixture was gradually warmed up to RT over 1 h. The mixture was quenched with water, and extracted with ethyl acetate. The organic phase was washed with water and brine successively, dried over Na2SO4, and filtered. The filtrate was concentrated to give the crude product (quantitative yield) which was directly used in next step reaction without further purification. LCMS: (M+H)+=273.0.
To a solution of 3-oxo-l-cyclohexane carboxylic acid (1.8 g) in 1,2-dichlorethane (60 ml.) were added (+)-(R)-l-naphthalen-l-yl-ethylamine (2.2 g), glacial AcOH (1 eq., 0.75 mL) and NaBH(OAc)3 (1.5 eq., 4.1 g). The mixture was stirred at r.t. for 48 h before removal of the solvent. The residue was treated with IN NaOH (ca 100 mL) and pH was adjusted to 7 by addition of 4N HCI. The mixture was brought to reflux. The solid formed upon cooling was filtered and washed with boiling EtOH to afford the title compound as a fine powder. The filtrate was concentrated in vacuo. The residue was dissolved in hot MeCN and little MeOH. The solid formed upon cooling was filtered and washed with MeCN to afford the title compound.
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 5h;
4-Isopropoxyaniline (117 mg, 0.774 mmol), HATU (294 mg, 0.774 mmol) and diisopropylethylamine (0.27 mL, 1.548 mmol) were added in that order to a DMF (3 mL) solution of <strong>[16205-98-4]3-oxo-1-cyclohexanecarboxylic acid</strong> (100 mg, 0.703 mmol), and stirred at room temperature for 5 hours. Ethyl acetate was added to the reaction liquid, and washed with distilled water and saturated brine. The organic layer was dried with magnesium sulfate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography to give the intended product (194 mg, 100%).
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride;dmap; In dichloromethane; at 20℃; for 1h;
To a solution of <strong>[16205-98-4]3-oxocyclohexane carboxylic acid</strong> (1.5 g, 10.6 mmol) in CH2C12 (35 mL) were added DMAP (0.129 g, 1.06 mmol), EDC (4.05 g, 21.1 mmol), and BnOH (1.2 mL, 11.6 mmol). The reaction was maintained at ambient temperature for 1 h. The reaction was further diluted with CH2C12, and then washed with saturated aqueous NaHC03, followed by brine. The organic layer was separated, dried with MgS04, filtered, and concentrated. The resulting crude product was used in the next step without further purification, LCMS: calculated for C14Hi603 232.28, observed m/e 233.1 (M+H)+ 255.0 (M+Na) (Rt 1.74/4min).
Racemic <strong>[16205-98-4]3-oxocyclohexanecarboxylic acid</strong> (1.0 g, 7.03 mmol) was dissolved in THF (27.1 mL). To this solution was added triethylamine (1.9 mL, 13.5 mmol) followed by pivaloyl chloride (0.8 mL, 6.5 mmol) at -20C. The resulting mixture was stirred at -20C for 1 h. After that, LiCl (0.252 g, 5.9 mmol) and (4R,5S)-4-methyl-5- phenyloxazolidin-2-one (0.959 g, 5.4 mmol) were added to the solution at -20C. The reaction mixture was warmed to room temperature and stirred overnight, before the reaction was quenched with 0.2 N HCl. The THF was removed and the resulting mixture was partitioned by 0.2 N HCl and EtOAc. The organic layer was collected and washed with brine, dried (MgS04) and concentrated. The resulting residue was purified by preparative HPLC (PHENOMENEX Luna 5u C 18 21.2 x 250 mm, isocratic elution with Method 1 -MeOH/water containing 0.1% trifluoroacetic acid as defined above, 51%B over 30 min, 25 mL/min, 220 nM: the first peak (retention time = 15.3 min) was (4R,5S)-4-methyl-3-((S)-3-oxocyclohexanecarbonyl)-5-phenyloxazolidin-2-one, Int-8A, (LCMS = 302.0 [M+H]+), and the second peak (retention time = 19.6 min) was (4R,5S)- 4-methyl-3-((R)-3-oxocyclohexanecarbonyl)-5-phenyloxazolidin-2-one, Int-8B, LCMS = 324.1 [M+Na]+ by comparison to the R-<strong>[16205-98-4]3-oxocyclohexanecarboxylic acid</strong> case (Aust. J. Chem., 34:2231 (1981)).
With sodium tris(acetoxy)borohydride; In dichloromethane; at 20℃; for 18h;
To a stirred solution of the crude (i?)-2-chloro-N-(l-(2,4-dichlorophenyl)ethyl)- 5-(l,2,3,6-tetrahydropyridin-4-yl)aniline (0.65 g, 0.17 mmol) and 3- oxocyclohexanecarboxylic acid (0.036 g, 0.26 mmol) in dichloromethane (4 mL) was added sodium triacetoxyborohydride (NaBH(OAc)3) (0.054 g, 0.25 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was quenched with aqueous saturated sodium bicarbonate and extracted with dichloromethane. The organic layer was dried (Na2S04), filtered, and concentrated in vacuo. The resulting crude was purified by flash chromatography (Si02, 10^40% ethyl acetate in hexanes) to afford 3-(4-(4-chloro-3- ((J¾)-l-(2,4-dichlorophenyl)ethylamino)phenyl)-5,6-dihydropyridin-l(2H)- yl)cyclohexanecarboxylic acid as the desired product (0.064 g, 0.13 mmol, 74%).
With sodium tris(acetoxy)borohydride; In dichloromethane; at 20℃; for 18h;
To a stirred solution of (i?)-2-chloro-N-( 1 -(2,4-dichlorophenyl)ethyl)-5- (piperazin-l-yl)aniline (prepared as illustrated in example 13 using 5-bromo-2-chlorophenol as starting material, 0.20 g, 0.54 mmol) and <strong>[16205-98-4]3-oxocyclohexanecarboxylic acid</strong> (0.15 g, 1.1 mmol) in dichloromethane (4 mL) was added NaBH(OAc)3 (0.153 g, 1.1 mmol). The reaction mixture was stirred at room temperature for 18 h, and quenched with diluted with aqueous saturated sodium bicarbonate. The aqueous layer was extracted withdichloromethane. The organic layer was dried (Na2S04), filtered, and concentrated in vacuo. The resulting crude was purified by flash chromatography (Si02, 10-50% ethyl acetate in hexanes) to afford the desired product (0.092 g, 0.18 mmol, 33%).
With acetic acid; at 80℃; for 3h;Inert atmosphere;
3-Oxocyclohexanecarboxylic acid (27.2 mg, 0.19 mmol) was added to a stirred solution of 4-chloro-/V-(4- methoxyphenyl)benzohydrazide hydrochloride (50 mg, 0.16 mmol) in acetic acid (0.5 mL), the mixture was heated at 80 C under nitrogen for 3 h, then it was allowed to cool to ambient temperature and stirred overnight. Ice-water (2 mL) was poured into the cold reaction mixture and the formed precipitate was collected by filtration, carefully washed with water and dried in vacuo to yield the title compound (50 mg, 82%) as an off-white solid. C2iH 8CIN04, MuLambda = 383.82; 1H NMR (400 MHz, DMSO-d6) d: 1.79-1.87 (m, 1 H), 2.11-2.14 (m, 1 H), 2.57-2.75 (m, 5H), 6.73 (dd, J=2.8/9.0 Hz, 1 H), 6.97 (d, J=2.8 Hz, 1 H), 7.06 (d, J=9.2 Hz, 1 H), 7.62-7.69 (m, 4H); LCMS (ESI) fR: 2.82 min (>99%, ELSD), m/z: 384.0 [M+1]+.
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