* 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.
Reference：
[1] Journal of Medicinal Chemistry, 1992, vol. 35, # 23, p. 4334 - 4343
[2] Patent: US5571832, 1996, A,
2
[ 98303-20-9 ]
[ 15883-20-2 ]
Reference：
[1] European Journal of Medicinal Chemistry, 1998, vol. 33, # 1, p. 23 - 31
3
[ 24424-99-5 ]
[ 4043-87-2 ]
[ 98303-20-9 ]
Yield
Reaction Conditions
Operation in experiment
99%
Stage #1: With potassium carbonate In water; acetone at 20℃; Stage #2: With hydrogenchloride In water; acetone
A solution of DL-pipecolinic acid (13 g, 100 mmol), potassium carbonate (55.2 g, 400 mmol), di-tert-butyl dicarbonate (28. 4 g, 130 mmol) in acetone (30 mL) and water (100 mL) was stirred at room temperature overnight. The reaction mixture was brought to [PH-] 3 using hydrochloric acid (1 N aqueous) and then extracted with ethyl acetate (350 mL). The organic phase was separated, sequentially washed with water (200 mL) and brine (200 mL), dried (sodium sulfate), filtered and concentrated in vacuo. The isolated solid was triturated with hexanes to yield 22.7 g (99percent) of the title compound as a white [SOLID. LH-] NMR [(CDC13),] [8] [(PPM)] : 9.3 (bs, 1H), 4.84 (bd, 1H), 3.94 (m, 1H), 2.93 (m, 1H), 2.22 (m, 1H), 1.67 (m, 3H), 1.45 (m, [11H).]
70%
Stage #1: With triethylamine In 1,4-dioxane; water for 0.166667 h; Stage #2: at 20℃; for 24 h;
To a suspension of pipecolinic acid (1.0 mmol) in dioxane:water (4.5:1.5 mL) , Et3N (1.0 mmol) was added and the resulting mixture was stirred for 10 min. Then, a solution of (BOC)2O (1.10 mmol) in 1 mL of dioxane was added dropwise and the mixture was stirred at room temperature for 24 h. The solvent was evaporated under reduced pressure, and the residue was dissolved in EtOAc (30 mL). The solution was washed with 5percent HCl (15 mL), and brine (3 x 15 mL). After the last washing procedure the pH of the aqueous layer has to be >5. The organic phase was dried over MgSO4, filtered and concentrated in vacuum. The product, 1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (white solid, 70percent yield)2 was used to the next step without further purification.
57%
With hydrogenchloride; sodium hydrogencarbonate In water
EXAMPLE 9 1-(tertButoxycarbonyl)-2-piperidinecarboxylic acid A mixture of pipecolinic acid (48.43 g, 375 mmol), di-tertbutyl dicarbonate (98.2 g, 450 mmol, 1.2 eq) and NaHCO3 (126 g, 1500 mmol, 4.0 eq) in water (1000 mL) was stirred overnight at rt. Crushed ice (200 g) was added to the reaction mixture which was then treated dropwise with a solution of 120 mL of 12M HCl made up to 500 mL with water. The pH was adjusted to ca. 3.5 by addition of a further amount of HCl. The solution was extracted with EtOAc (2*500 mL) and the combined organic extract was back washed with water (2*500 mL) and evaporated in vacuo to give the product (48.7 g, 57percent) as a beige crystalline solid: mp 123°-124° C.; 1 H-NMR (CDCl3) dd;4.93 (58percent), 4.78 (42percent) (m, 1H), 3.96 (m, 1H), 2.96 (m, 1H), 2.22 (m, 1H), 1.68 (complex m, 3H), 1.23-1.50 (m, 2H), 1.46 (s, 9H); CIMS (MH+ calcd for C&11 H19 NO4): 230. Found (MH+): 230; Anal. (calcd for C11 H19 NO4): C,H,N.
73.0%
With triethylamine In 1,4-dioxane; water
Piperidine-1,2-dicarboxylic acid 1-tert-butyl ester (1). To a solution of 10.0 g (77.42 mmol) of piperidine-2-carboxylic acid in H2O/Dioxane (2OOmL, 1:1) was added 18.59g (85.16 mmol) of di-tert-butyl dicarbonate followed by 8.62g (85.16 mmol) of triethylamine, and the mixture was stirred for 16 hrs at ambient temperature. The solution was evaporated to remove excess dioxane, diluted with H2O (100 mL) and extracted with CH2Cl2 (2*200 mL). The organic phase was dried (MgSO4) and the evaporated to give a yellow oil which was subjected to column chromatography (CHCl3/MeOH/AcOH, 9:.8:.2) to yield 12.9g (73.0percent) of 1 as a yellow oil. TLC Rf=0.7 (CHCl3/MeOH/AcOH, 9:.8:.2)
73.0%
With triethylamine In 1,4-dioxane; water
Piperidine-1,2-dicarboxylic acid 1-tert-butyl ester (1). To a solution of 10.0 g (77.42 mmol) of piperidine-2-carboxylic acid in H2O/Dioxane (200 mL, 1:1) was added 18.59 g (85.16 mmol) of di-tert-butyl dicarbonate followed by 8.62 g (85.16 mmol) of triethyl amine, and the mixture was stirred for 16 hrs at ambient temperature. The solution was evaporated to remove excess dioxane, diluted with H2O (100 mL) and extracted with CH2Cl2 (2*200 mL). The organic phase was dried (MgSO4) and the evaporated to give a yellow oil which was subject to column chromatography (CHCl3/MeOH/AcOH, 9:0.8:0.2) to yield 12.9 g (73.0percent) of 1 as a yellow oil. TLC Rf=0.7 (CHCl3/MeOH/AcOH, 9:0.8:0.2)
Reference：
[1] Tetrahedron Letters, 1996, vol. 37, # 20, p. 3441 - 3444
[2] Patent: WO2004/14902, 2004, A2, . Location in patent: Page 45
[3] Organic Letters, 2013, vol. 15, # 4, p. 824 - 827
[4] Journal of Organic Chemistry, 2005, vol. 70, # 15, p. 5954 - 5963
[5] Journal of Organic Chemistry, 1999, vol. 64, # 6, p. 1993 - 2002
[6] Journal of Organic Chemistry, 2002, vol. 67, # 13, p. 4414 - 4422
[7] Journal of Medicinal Chemistry, 2009, vol. 52, # 21, p. 6672 - 6684
[8] Journal of Organic Chemistry, 1990, vol. 55, # 2, p. 738 - 741
[9] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 20, p. 5547 - 5554
[10] Journal of Medicinal Chemistry, 1992, vol. 35, # 23, p. 4334 - 4343
[11] Patent: US5571832, 1996, A,
[12] European Journal of Organic Chemistry, 1998, # 6, p. 1143 - 1153
[13] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 15, p. 4013 - 4017
[14] Patent: US2002/42377, 2002, A1,
[15] Patent: US2002/52410, 2002, A1,
[16] Patent: EP1593681, 2005, A1, . Location in patent: Page/Page column 43
[17] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 6, p. 1832 - 1837
[18] Chemical Communications, 2017, vol. 53, # 74, p. 10299 - 10302
EXAMPLE 10 1-Methyl-2-piperidinemethanol The title compound of Example 9 (23.2 g, 101 mmol) in dry THF (100 mL) was added dropwise to a 1.0M solution of LiAlH4 in THF (405 mL, 405 mmol, 4eq) and the reaction mixture was refluxed overnight and the product was isolated as described in Example 6 to give the product (13.1 g, quantative) as a colorless oil. The fumarate salt crystallized from 2-propanol: mp 118°-120° C.; 1 H-NMR (CDCl3) dd;3.85 (dd, J=gem=11 Hz, J=3.9 Hz, 1H), 3,39 (dd, J=gem=11 Hz, J=2.2 Hz, 1H), 2.89 (m, 1H), 2.30 (s, 3H), 2.15 (m, 1H), 1.97 (m, 1H), 1.76 (m, 1H), 1.42-1.68 (complex m, 4H), 1.28 (m, 1H); CIMS (MH+ calcd for C7 H15 NO): 130. Found (MH+): 130; Anal. (C11 H19 NO5): C,H,N.
With pyridine; di-tert-butyl dicarbonate; ammonium bicarbonate; In 1,4-dioxane; at 20℃;
To a mixture of 410.6g (leq.) of l-tert-Butoxycarbonyl-2-piperidinecarboxylic acid, 228.8g (1.62eq.) of ammonium bicarbonate and 605.9g (2.77eq.) of Boc20 377.9 g (2.67eq.) of pyridine and 2000mL of dioxane were added. Reaction mixture stirred overnight at ambient temperature and 1653.3g of 3N HC1 aqueous solution was added drop wise followed by addition of 2100mL of DCM, stirring and phase separation. Organic phase was concentrated and 1700mL of n-heptane were added to the residue and stirred at ambient temperature. Precipitated white solid was filtered off with suction, filter cake washed with n-heptane and dried in vacuum to give 304.5g of the title product (99% HPLC peak area) with a yield of 88.2%.
77%
With ammonium carbonate; triethylamine; 1,1'-carbonyldiimidazole; In acetonitrile; at 20℃; for 24h;
General procedure: To a solution of 20 g (93 mmol) of Boc-proline 5a in 150 mL of anhydrous acetonitrile were added successively 19.5 g (120 mmol) of 1,1'-carbonyldiimidazole, 21.0 mL (150 mmol) of trimethylamine, and 19.2 g (200 mmol) of ammonium carbonate. The reaction mixture was stirred at room temperature for 24 h. After the reaction completion the mixture was poured into a saturated solution of potassium carbonate (250 mL) and extracted with dichloromethane (3 × 250 mL). The combined organic extracts were washed with water (2 × 150 mL) and dried with sodium sulfate. After removal of the solvent the reaction product was purified by flash chromatography on silica gel using hexane-ethyl acetate (100 : 0 ? 1 : 1).
74%
Piperidine-1, 2-dicarboxylic acid-1-tert-butyl ester (12.8 g, 55.6 mmol) and THF (170 mL) were added to a 500 mL round bottom flask equipped with stir bar. The solution was cooled to-20C and triethylamine (10.1 mL, 72.3 mmol) was added followed by ethyl [CHLOROFORMATE] (5.32 mL, 55.6 [MMOL).] The resulting white precipitate was left stirring at- [10C] for 1 h. Aqueous ammonia (22.6 mL, 1168 mmol) was added to the above reaction mixture and the clear reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the isolated residue was dissolved in ethyl acetate (300 [ML).] The organic phase was successively washed with water (300 mL) and brine (200 mL), dried (sodium sulfate), filtered and concentrated in vacuo to isolate a clear gum. The gum was triturated with hexanes to isolate the title compound (9.4 g, [74%)] as a white [SOLID. LH-NMR (CDC13), 6] (ppm): 6.03 (bs, 1H), 5.55 (bs, 1H), 4.77 (bs, 1H), 4.05 (bs, 1H), 2.81 (t, 1H), 2.27 (bs, 1H), 1.47 (m, 14H). Acetonitrile (220 mL) and DMF (3.82 mL, 49.4 mmol) were added to a 500 [ML] round bottom flask equipped with stir bar. Cooled the mixture down to-5C and to it added oxalyl chloride (24.7 mL, 49.4 mmol, 2 M dichloromethane). The resulting mixture was stirred for 15 min. This was followed by addition of solution of 2-carbamoyl-piperidine-1- carboxylic acid tert-butyl ester (9.4 g, 41.2 mmol) in acetonitrile (50 [ML)] and pyridine (8.3 mL, 103 [MMOL).] Reaction mixture was left stirring at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (300 mL). The organic phase was successively washed with water (300 [ML)] and brine (200 mL), dried (sodium sulfate), filtered and concentrated in vacuo to isolate the title compound (8.44 g, 97%) as a yellow [SOLID. LH-NMR (CDC13), 6 (PPM)] : 5.23 (bs, 1H), 4.03 (bs, 1H), 2.93 (t, 1H), 1.75 (m, [5H),] 1.46 (m, 10H).
To a solution of l-(tert- butoxycarbonyl)piperidine-2-carboxylic acid 1 (5.0 g, 21.8 mmol) in dry THF (100 mL) was added TEA (3.30 g, 32.7 mmol), isobutyl carbonochloridate (3.27 g, 23.99 mmol) at 0C and the resulting solution was stirred for 20 min. NH3-H2O was added and stirred at rt for 2 h. The mixture was diluted with ethyl acetate (30 mL), and washed with sat. aq. Na2C03 (2 x 20 mL) and sat. aq. citric acid (2 x 20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give crude product (3.6 g, 72%) as white solid. MS (ESI): m/z = 173.0 [M - 55]+.
2-[1-(3-chloro-phenyl)-ethylcarbamoyl]-piperidine-1-carboxylic acid <i>tert</i>-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Stage #1: 1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid With 4-methyl-morpholine; isobutyl chloroformate In tetrahydrofuran at 0 - 5℃; for 0.0833333h;
Stage #2: 1-(3-Chloro-phenyl)-ethylamine In tetrahydrofuran at 20℃; for 1h;
2-[1-(3-trifluoromethyl-phenyl)-ethylcarbamoyl]-piperidine-1-carboxylic acid <i>tert</i>-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Stage #1: 1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid With 4-methyl-morpholine; isobutyl chloroformate In tetrahydrofuran at 0 - 5℃; for 0.0833333h;
Stage #2: 1-(3-(trifluoromethyl)phenyl)ethan-1-amine In tetrahydrofuran at 20℃; for 1h;
2-[1-(3,4-dimethoxy-phenyl)-ethylcarbamoyl]-piperidine-1-carboxylic acid <i>tert</i>-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Stage #1: 1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid With 4-methyl-morpholine; isobutyl chloroformate In tetrahydrofuran at 0 - 5℃; for 0.0833333h;
Stage #2: 1-(3',4'-Dimethoxyphenyl)ethylamine In tetrahydrofuran at 20℃; for 1h;
Stage #1: 1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid With 4-methyl-morpholine; isobutyl chloroformate In N,N-dimethyl-formamide
Stage #2: N'-hydroxy-3-methoxybenzenecarboximidamide In N,N-dimethyl-formamide
Stage #3: With tetrabutyl ammonium fluoride at 0℃; for 3h;
With polyphosphoric acid In N,N-dimethyl-formamide at 160℃; for 18h;
128.i 6-chloro-2-[1-(3,4-dimethyl-benzyl)-piperidin-2-yl]-3H-imidazo[4,5-b]pyridine
5-Chloro-2,3-diaminopyridine (300 mg, 98%, 2.05 mmol) and tert Butoxycarbonylpiperidine-2-carboxylic acid (540 mg, 2.36 mmol) was dissolved in Polyphosphoric acid (1.5 ml) and stirred 18 h at 160°C. The mixture was poured on ice and extracted with Ethyl acetate/butanol twice. The combined organic layer was dried with MgS04, filtered and evaporated to dryness. The residue was identified as compound 11 and was used without further purification (462 mg, 1.95 mmol, 95%).
95%
With Polyphosphoric acid at 160℃; for 18h;
128.i
i. 5-Chloro-2,3-diaminopyridine (300 mg, 98%, 2.05 mmol) and 1-tert. autoxycarbonylpiperidine-2-carboxylic acid (540 mg, 2.36 mmol) was dissolved in Polyphosphoric acid (1.5 niL) and stirred 18 h at 1 60 C.. The mixture was poured on ice and extracted with Ethyl acetate/butanol twice. The combined organic layer was dried with MgSO4, filtered and evaporated to dryness. The residue was identified as compound 11 and was used without further purification (462 mg, 1.95 mmol, 95%).
106.l 6-chloro-5-methyl-2-[1-(3-methyl-benzyl)-piperidin-2-yl]-1 H- benzoimidazole
I. 4-Chloro-5-methylbenzene-1 ,2-diamine (2.00 g, 95%, 12.1 mmol) and 1- tert.Butoxycarbonylpiperidine-2-carboxylic acid (2.78 g, 12.1 mmol) was dissolved in Polyphosphoric acid (11.9 g, 121 mmol) and stirred 12 h at 170°C. The mixture was poured on ice and extracted with Ethyl acetate/butanol twice. The combined organic layer was dried with MgS04, filtered and evaporated to dryness. The residue was identified as compound 14 and was used without further purification (2.00 g, 8.01 mmol, 66%).
66%
With Polyphosphoric acid at 170℃; for 12h;
106.l
1. 4-Chloro-5-methylbenzene-1,2-diamine (2.00 g, 95%, 12.1 mmol) and 1-tert. Butoxycarbonylpiperidine-2-carboxylic acid (2.78 g, 12.1 mmol) was dissolved in Polyphosphoric acid (11.9 g, 121 mmol) and stirred 12 hat 170 C..The mixture was poured on ice and extracted with Ethyl acetate/butanol twice. The combined organic layer was dried with MgSO4, filtered and evaporated to dryness. The residue was identified as compound 14 and was used without further purification (2.00 g, 8.01 mmol, 66%).
tert-butyl 2-(4-oxochroman-2-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With dipotassium hydrogen phosphate; [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine-N1,N1′]bis{3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-κN]phenyl-κC}iridium(III) hexafluorophosphate In N,N-dimethyl-formamide Irradiation;
Preparation of Trans-phenyl-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-4-oxo-6-phenylpiperidine-1-carboxylate (12).
General procedure: According the the general procedure, reaction of 200 mg (10.68 mmol)of dihydropyridone 5 with 294 mg (1.36 mmol) of N-Boc-L-proline 11 in the presence of 238 mg (1.36 mmol) of HK2PO4 and 10 mg (0.012 mmol) of (Ir[dF(CF3)ppy]2(dtbpy))PF6 provided 260 mg (82%) of compound 12 as a colorless oil and as inseparable 1:1 mixture of diastereomers and rotamers:
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