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CAS No. :13139-17-8 MDL No. :MFCD00005513
Formula : C12H11NO5 Boiling Point : -
Linear Structure Formula :C7H7CO2NC2O2C2H4O InChI Key :MJSHDCCLFGOEIK-UHFFFAOYSA-N
M.W : 249.22 Pubchem ID :83172
Synonyms :

Safety of [ 13139-17-8 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H332-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 13139-17-8 ]

* 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.

  • Upstream synthesis route of [ 13139-17-8 ]
  • Downstream synthetic route of [ 13139-17-8 ]

[ 13139-17-8 ] Synthesis Path-Upstream   1~60

  • 1
  • [ 13139-17-8 ]
  • [ 88501-00-2 ]
  • [ 13500-53-3 ]
Reference: [1] Journal of Organic Chemistry, 2004, vol. 69, # 23, p. 8077 - 8085
  • 2
  • [ 13139-17-8 ]
  • [ 73-22-3 ]
  • [ 7432-21-5 ]
Reference: [1] Russian Journal of Bioorganic Chemistry, 1999, vol. 25, # 5, p. 283 - 287[2] Bioorganicheskaya Khimiya, 1999, vol. 25, # 5, p. 323 - 328
  • 3
  • [ 498-94-2 ]
  • [ 13139-17-8 ]
  • [ 10314-98-4 ]
YieldReaction ConditionsOperation in experiment
22% With sodium carbonate In water; acetonitrile at 20℃; for 16 h; To a solution of piperidine-4-carboxylic acid (10.0 g, 77.4 mmol) and Na2CO3 (8.21 g, 77.4 mmol) in water (100 mL) was added a solution of benzyl 2,5-dioxopyrrolidin-1-yl carbonate (19.3 g, 77.4 mmol) in MeCN (100 mL). The reaction was stirred at ambient temperature for about 16 h and then concentrated under reduced pressure. The resulting aqueous solution was quenched with NH4Cl and was then extracted with EtOAc (2.x.100 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 1-(benzyloxycarbonyl)piperidine-4-carboxylic acid as a white solid (4.56 g, 22percent): LC/MS (Table 2, Method a) Rt=1.93 min; MS m/z: 262 (M-H)-.
Reference: [1] Patent: US2009/312338, 2009, A1, . Location in patent: Page/Page column 60
  • 4
  • [ 13139-17-8 ]
  • [ 51052-79-0 ]
  • [ 63845-33-0 ]
Reference: [1] Organic Process Research and Development, 2003, vol. 7, # 6, p. 866 - 872
  • 5
  • [ 13139-17-8 ]
  • [ 51052-79-0 ]
  • [ 63845-33-0 ]
Reference: [1] Organic Process Research and Development, 2003, vol. 7, # 6, p. 866 - 872
  • 6
  • [ 13139-17-8 ]
  • [ 344-25-2 ]
  • [ 6404-31-5 ]
Reference: [1] Journal of Organic Chemistry, 2004, vol. 69, # 11, p. 3849 - 3856
  • 7
  • [ 13139-17-8 ]
  • [ 4299-70-1 ]
  • [ 2717-76-2 ]
Reference: [1] Chemical and Pharmaceutical Bulletin, 2008, vol. 56, # 3, p. 260 - 265
  • 8
  • [ 110-91-8 ]
  • [ 13139-17-8 ]
  • [ 25070-73-9 ]
Reference: [1] RSC Advances, 2015, vol. 5, # 78, p. 63407 - 63420
  • 9
  • [ 6066-82-6 ]
  • [ 501-53-1 ]
  • [ 13139-17-8 ]
Reference: [1] Bulletin des Societes Chimiques Belges, 1987, vol. 96, # 10, p. 775 - 782
[2] Bulletin of the Chemical Society of Japan, 1987, vol. 60, # 7, p. 2409 - 2418
[3] Chemical and Pharmaceutical Bulletin, 1999, vol. 47, # 10, p. 1489 - 1490
[4] Organic Preparations and Procedures International, 2002, vol. 34, # 5, p. 531 - 537
[5] Patent: US3974137, 1976, A,
  • 10
  • [ 74124-79-1 ]
  • [ 100-51-6 ]
  • [ 13139-17-8 ]
Reference: [1] European Journal of Medicinal Chemistry, 1999, vol. 34, # 7-8, p. 625 - 638
[2] Patent: WO2008/64218, 2008, A2, . Location in patent: Page/Page column 72; 83-85; 86-87; 98-99; 125
  • 11
  • [ 82911-72-6 ]
  • [ 501-53-1 ]
  • [ 13139-17-8 ]
Reference: [1] Canadian Journal of Chemistry, 1982, vol. 60, p. 976 - 980
  • 12
  • [ 5382-16-1 ]
  • [ 13139-17-8 ]
  • [ 95798-23-5 ]
Reference: [1] Tetrahedron, 1998, vol. 54, # 46, p. 13981 - 13996
[2] Organic and Biomolecular Chemistry, 2012, vol. 10, # 2, p. 293 - 304
[3] Tetrahedron, 2000, vol. 56, # 43, p. 8433 - 8441
  • 13
  • [ 694-05-3 ]
  • [ 13139-17-8 ]
  • [ 66207-23-6 ]
YieldReaction ConditionsOperation in experiment
100% With triethylamine In dichloromethane at 20℃; To a solution of 1,2,3,6-tetrabydropyridine (1.66 g, 20.0 mmol) in dry CH2Cl2 (10 mL) was added triethyl amine (3.35 mL, 24.0 mmol), followed by a solution of N-(benzyloxycarbonyloxy)succinimide (5.23 g, 21.0 mmol) in dry CH2Cl2 (10 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with CH2Cl2 (50 mL) and washed with 10percent citric acid, sat'd NaHCO3, brine and dried over anhydrous Na2SO4. Concentration under reduced pressure afforded 4.34 g of Compound 135A: (100percent) as an oil. Analytical HPLC retention time = 2.996 min. (Chromolith SpeedROD column 4.6 x 50 mm, 10-90percent aqueous methanol containing 0.1percent TFA over 4 minutes, 4 mL/min, monitoring at 254 nm). 1H-NNM (CDCl3): 7.20-7.35 (m, 5H), 5.88 (bs, 1H), 5.60-5.78 (m, 1H), 5.18 (s, 2H), 3.99 (t, J = 2.64, 2H), 3.59 (t, J = 5.69, 2H), 2.18 (m, 2H).
Reference: [1] Patent: WO2005/66176, 2005, A1, . Location in patent: Page/Page column 62-63
[2] Patent: US2014/200227, 2014, A1, . Location in patent: Paragraph 0720; 0721
  • 14
  • [ 13139-17-8 ]
  • [ 13734-28-6 ]
  • [ 2389-45-9 ]
YieldReaction ConditionsOperation in experiment
91.9% With sodium hydrogencarbonate In tetrahydrofuran; water at 0 - 30℃; for 16 h; (2S)-6-(benzyloxycarbonylamino)-2-(tert-butoxycarbonylamino)hexanoic acid (ii)
To a solution of (2S)-6-amino-2-(tert-butoxycarbonylamino)hexanoic acid (100.00 g, 406.01 mmol, 1.00 eq), NaHCO3 (102.33 g, 1.22 mol, 3.00 eq) in THF (1000 mL) and H2O (1000 mL) was added CbzOSu (101.19 g, 406.01 mmol, 1.00 eq) at 0° C.
Then the mixture was stirred at 30° C. for 16 hr.
The mixture was adjusted to pH=5-6 with 1N HCl, extracted with EA (600 mL*3), dried over Na2SO4, concentrated to give (2S)-6-(benzyloxycarbonylamino)-2-(tert-butoxycarbonylamino)hexanoic acid (142.00 g, 373.26 mmol, 91.9percent yield) as a yellow oil.
Reference: [1] Patent: US2016/96830, 2016, A1, . Location in patent: Paragraph 0368-0369
  • 15
  • [ 13139-17-8 ]
  • [ 109-76-2 ]
  • [ 46460-73-5 ]
Reference: [1] Journal of Medicinal Chemistry, 1994, vol. 37, # 19, p. 2991 - 3007
[2] Patent: US5389647, 1995, A,
  • 16
  • [ 13139-17-8 ]
  • [ 141-43-5 ]
  • [ 77987-49-6 ]
Reference: [1] Journal of the American Chemical Society, 2006, vol. 128, # 6, p. 1995 - 2004
[2] Chemistry - A European Journal, 2003, vol. 9, # 20, p. 4887 - 4899
[3] RSC Advances, 2015, vol. 5, # 78, p. 63407 - 63420
[4] Journal of Medicinal Chemistry, 2000, vol. 43, # 5, p. 769 - 771
[5] Journal of Medicinal Chemistry, 2002, vol. 45, # 11, p. 2160 - 2172
[6] Patent: CN108129404, 2018, A, . Location in patent: Paragraph 0068; 0074; 0075; 0100; 0101
  • 17
  • [ 13139-17-8 ]
  • [ 338-69-2 ]
  • [ 26607-51-2 ]
Reference: [1] Organic Letters, 2006, vol. 8, # 2, p. 239 - 242
  • 18
  • [ 13139-17-8 ]
  • [ 2177-62-0 ]
  • [ 3160-47-2 ]
Reference: [1] Tetrahedron, 1995, vol. 51, # 31, p. 8525 - 8544
  • 19
  • [ 13139-17-8 ]
  • [ 1499-55-4 ]
  • [ 4652-65-7 ]
Reference: [1] Tetrahedron, 1995, vol. 51, # 31, p. 8545 - 8554
  • 20
  • [ 13139-17-8 ]
  • [ 60-34-4 ]
  • [ 37519-04-3 ]
Reference: [1] Tetrahedron Letters, 1996, vol. 37, # 2, p. 183 - 186
  • 21
  • [ 13139-17-8 ]
  • [ 4048-33-3 ]
  • [ 17996-12-2 ]
YieldReaction ConditionsOperation in experiment
83% With triethylamine In dichloromethane at 20℃; for 1 h; Inert atmosphere 00568] Compound 1001 - Starting compound 1000 (10 g, 85.38 mmol) was added to the reaction flask, evacuated and purged with argon. The starting material was dissolved in dichloromethane and triethylamine (23.79 rriL, 170.7 mmol) was added via syringe. N- (Benzyloxycarbonyloxy)succinimide (31.9 g, 128 mmol) was dissolved in anhydrous dichloromethane and then added to the reaction mixture via syringe. The reaction was stirred at room temperature for 1 hour. The reaction was checked by TLC (50percent EtOAc/hexanes) and the reaction was concentrated under reduced pressure. The residue was dissolved in dichloromethane, added to separation funnel and organic layer was washed with 10percent citric acid solution. The organic layer was separated and washed with a brine solution. The organic layer was separated and dried with sodium sulfate. The solid was filtered off and the mother liquor was concentrated. The residue was purified by flash chromatography on silica gel (10percent to 100percent EtOAc/hexanes) and the product fractions combined and concentrated on reduced pressure to yield 17.9g, (83percent) of 1001. NMR (400 MHz, DMSO-de): δ 7.40 - 7.25 (m, 4H), 7.21 (t, J = 5.7 Hz, 1H), 4.99 (s, 2H), 4.31 (t, J = 5.1 Hz, 1H), 3.36 (m, 2H), 2.96 (q, J = 6.7 Hz, 2H), 1.38 (m, 4H), 1.32 - 1.17 (m, J = 5.2, 4.6 Hz, 4H).
Reference: [1] Patent: WO2018/136620, 2018, A2, . Location in patent: Paragraph 00568
[2] Patent: US4550163, 1985, A,
  • 22
  • [ 13139-17-8 ]
  • [ 2491-18-1 ]
  • [ 56762-93-7 ]
Reference: [1] Organic and Biomolecular Chemistry, 2017, vol. 15, # 16, p. 3507 - 3518
  • 23
  • [ 13139-17-8 ]
  • [ 62-57-7 ]
  • [ 15030-72-5 ]
YieldReaction ConditionsOperation in experiment
97.8% With sodium carbonate In tetrahydrofuran; water at 20℃; for 16 h; Step 1.
Cbz-OSu (57 g, 0.23 mol) in THF (150 mL) was added a mixture of aq Na2C03 (82 g, 0.78 mol) and 80-1 (20 g, 0.19 mol). After it was stirred at r.t. for 16 h, it was adjusted to pH > 10 and washed with EtOAc (400 mL x 2). The aqueous layer was pooled and acidified to pH < 1 with cone. HC1. It was extracted with EtOAc (500 mL x 2). The organic layer was dried over Na2S04 and evaporated to give 80-2 (45 g, 97.8percent).
72%
Stage #1: With sodium hydrogencarbonate In tetrahydrofuran; water at 0 - 20℃; for 12 h;
Stage #2: at 0℃;
Synthesis of Compound S.2. To S.1 (10 g, 0.0969 mol) in THF (60 ml) and water (60 mL) at 0° C. was added sodium bicarbonate (16.27 g, 0.193 mole) followed by N-(benzyloxy carbonyloxy) succinimide (60.37 g, 0.242 mol). The reaction mixture was stirred at RT for 12 hr. The THF was removed under vacuum and the aqueous phase was washed with ether (2.x.100 mL). The aqueous phase was cooled to 0° C. and acidified to pH=2 with 5N HCL (50 mL). The reaction mixture was extracted with ethyl acetate (2.x.100 mL); the combined organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (1percent MeOH in dichloromethane) to give S.2 (16 g, 72percent). 1H NMR (CDCl3, 200 MHz) δ 7.45-7.32 (m, 5H), 5.40 (bs, 1H,) 5.12 (s, 2H), 1.82 (s, 6H); MS: m/z 238 [M+1]+.
72%
Stage #1: With sodium hydrogencarbonate In tetrahydrofuran; water at 0 - 20℃; for 12 h;
Stage #2: With hydrogenchloride In water
To S.1 (10 g, 0.0969 mol) in THF (60 ml) and water (60 mL) at 0° C. was added sodium bicarbonate (16.27 g, 0.193 mole) followed by N-(benzyloxy carbonyloxy) succinimide (60.37 g, 0.242 mol). The reaction mixture was stirred at RT for 12 hr. The THF was removed under vacuum and the aqueous phase was washed with ether (2.x.100 mL). The aqueous phase was cooled to 0° C. and acidified to pH=2 with 5N HCL (50 mL). The reaction mixture was extracted with ethyl acetate (2.x.100 mL); the combined organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography (1percent MeOH in dichloromethane) to give S.2 (16 g, 72percent). 1H NMR (CDCl3, 200 MHz) δ 7.45-7.32 (m, 5H), 5.40 (bs, 1H,) 5.12 (s, 2H), 1.82 (s, 6H); LCMS: m/z 238 [M+1]+.
Reference: [1] Patent: WO2015/95227, 2015, A2, . Location in patent: Page/Page column 215
[2] Patent: US2009/5359, 2009, A1, . Location in patent: Page/Page column 48-49
[3] Patent: US2009/36419, 2009, A1, . Location in patent: Page/Page column 93
[4] Chemical Communications, 2013, vol. 49, # 86, p. 10133 - 10135
[5] Journal of Organic Chemistry, 2004, vol. 69, # 11, p. 3849 - 3856
  • 24
  • [ 13139-17-8 ]
  • [ 60-32-2 ]
  • [ 1947-00-8 ]
Reference: [1] Patent: US4550163, 1985, A,
  • 25
  • [ 13139-17-8 ]
  • [ 2418-95-3 ]
  • [ 2389-60-8 ]
Reference: [1] Chemical and Pharmaceutical Bulletin, 1999, vol. 47, # 10, p. 1489 - 1490
  • 26
  • [ 13139-17-8 ]
  • [ 107-97-1 ]
  • [ 39608-31-6 ]
Reference: [1] Journal of Medicinal Chemistry, 2012, vol. 55, # 5, p. 2212 - 2226
[2] Journal of Inorganic Biochemistry, 2012, vol. 117, p. 248 - 260
  • 27
  • [ 13139-17-8 ]
  • [ 20859-02-3 ]
  • [ 62965-10-0 ]
YieldReaction ConditionsOperation in experiment
100% With triethylamine In methanol at 20℃; for 14 h; Step A: 2S-Benzyloxycarbonylamino-3,3-dimethyl-butyric acid; To a suspension of L-tert-leucine (11.88 g, 90.7 mmol) in methanol (200 ml) were added triethylamine (26.56 ml, 190 mmol) and N-(benzyloxycarbonyl- oxy)-succinimide (24.88 g, 99.8 mmol). The reaction mixture was stirred at room temperature for 14 h. Methanol was removed in vacuo to afford a viscous pale yellow oil, which was dissolved in ethyl acetate (100 ml). The organic layer was washed with 1M hydrochloric acid (15 ml) and brine, dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuo to fumish the title compound as an oil (24 g, quant.). 1H-NMR; δ(CDCl3), 7.43-7.36 (5H, m), 5.36 (1H, d, J = 9.4 Hz), 5.12 (2H, br s), 4.20 (1H, d, J = 9.6 Hz) and 1.02 (9H, s). LRMS: +ve ion 266 [M+H], -ve ion 264 [M-H], 529 [2M-H].
Reference: [1] Patent: EP1210330, 2005, B1, . Location in patent: Page/Page column 9-10
  • 28
  • [ 13139-17-8 ]
  • [ 16338-48-0 ]
  • [ 78553-51-2 ]
YieldReaction ConditionsOperation in experiment
100% With water; triethylamine In 1,4-dioxane To a suspension of L-2-amino-4-pentenoic acid (2.0 g) in Dioxane (80 mL) at RT was added triethylamine (4. 3 g), water (2.0 mL), and N- (BENZYLOXYCARBONYLOXY) succinimide (9.1 g). The reaction mixture was stirred overnight at RT, concentrated in vacuo, diluted with saturated NaHCO3 and extracted with ether (3x). The basic aqueous layer was acidified to pH 2 with 2N HCl and extracted with EtOAc (3x). The combined EtOAc layer was washed with brine, dried (NA2S04), filtered and evaporated, then concentrated from Toluene (2x) to give a viscous oil (4. 51 g, QUANTITATIVE). LH NMR (300 MHz, DMSO-d6) 6 2.31-2. 50 (M, 2H), 4. 00-4. 06 (m, 1H), 5.03 (s, 2H), 5.05-5. 12 (m, 2H), 5.71-5. 84 (m, 1H), 7.35 (M, 5H), 7.53 (d, 1H), 12.57 (bs, 1H). MS APCI, m/z = 250 (M+1). LC/MS 2.30 min. , Method A.
95%
Stage #1: With sodium hydroxide In water; acetone
Stage #2: With sodium hydrogencarbonate In water; acetone for 20 h;
To a stirred solution of NaOH (700mg, 17.4mmol) in water (40mL) was added l-allyl (glycine)–OH (2.00g, 17.4mmol). N-(Benzyloxycarbonyloxy)-succinimide (4.30g, 17.4mmol) in acetone (25mL) was added in one portion with vigorous stirring. After the addition was complete, NaHCO3 (1.50g, 17.4mmol) was added and stirring was continued for 20h. The reaction mixture was extracted once with Et2O (50mL) to remove any excess neutral organic compounds and the aqueous layer was acidified to pH 2 with 5M aq HCl. The aqueous layer was extracted with EtOAc (3×25mL) and dried (MgSO4) and evaporated in vacuo to give 14 as a brown oil (4.10g, 95percent yield), with spectra identical to those of an authentic sample.
Reference: [1] Patent: WO2004/80983, 2004, A1, . Location in patent: Page 47
[2] Tetrahedron, 2013, vol. 69, # 30, p. 6275 - 6284
[3] Organic Letters, 2006, vol. 8, # 2, p. 239 - 242
[4] Patent: WO2011/15241, 2011, A1, . Location in patent: Page/Page column 187; 398
[5] Patent: US2012/270881, 2012, A1, . Location in patent: Page/Page column 116
[6] Patent: CN105294732, 2016, A, . Location in patent: Paragraph 0782; 1408
[7] Patent: JP2015/155430, 2015, A, . Location in patent: Paragraph 0106; 0111
  • 29
  • [ 13139-17-8 ]
  • [ 107-15-3 ]
  • [ 72080-83-2 ]
YieldReaction ConditionsOperation in experiment
80% for 1 h; Step 1
To a solution of 2-aminoethylamine LVIII (150 mL; 2.25 mol) in chloroform (1.5 L), cooled to 0° C. was added a solution of carbobenzoxy N-hydroxysuccinimide (112.14 g; 0.45 mol) in water (0.5 L) with vigorously stirring for one hour.
The solid was filtered and the solution was washed with brine (3*), once with water and dried over anhydrous MgSO4.
The solvent was evaporated under reduced pressure and the residue was purified on a silica gel column (100:1-->30:1 DCM:MeOH) to yield benzyl 2-aminoethylcarbamate LIX as a colorless viscous oil (350 g; 1.80 mol; 80percent yield).
1H NMR (CDCl3) 2.79-2.83 (m, 2H), 3.21-3.28 (m, 2H), 5.10 (s, 2H), 5.19 (brs, 1H), 7.29-7.34 (m, 1H), 7.35-7.38 (m, 4H); ESIMS found for C10H14N2O2 m/z 195.2 (M+H).
Reference: [1] Patent: US2008/318957, 2008, A1, . Location in patent: Page/Page column 57; 58
[2] Chemical Communications, 2011, vol. 47, # 33, p. 9330 - 9332
[3] Organic Letters, 2012, vol. 14, # 17, p. 4450 - 4453
[4] Patent: WO2016/102562, 2016, A1, . Location in patent: Page/Page column 52
  • 30
  • [ 13139-17-8 ]
  • [ 3417-91-2 ]
  • [ 13512-31-7 ]
Reference: [1] Journal of Medicinal Chemistry, 2004, vol. 47, # 16, p. 4041 - 4053
[2] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 24, p. 5449 - 5460
  • 31
  • [ 13139-17-8 ]
  • [ 1080-06-4 ]
  • [ 13512-31-7 ]
Reference: [1] Synthesis, 2009, # 22, p. 3765 - 3768
  • 32
  • [ 13139-17-8 ]
  • [ 27489-62-9 ]
  • [ 27489-63-0 ]
YieldReaction ConditionsOperation in experiment
90%
Stage #1: at 0 - 20℃; for 24 h;
Stage #2: With hydrogenchloride In water
To a stirred solution of trans-4-aminocyclohexanol (35.5 g, 306.6 mmol) in methanol (621 mL) at 0° C. under nitrogen was added N-(benzyloxycarbonyloxy)succinimide (72.8 g, 291.9 mmol).
The reaction mixture was slowly warmed to room temperature and after 1 d, poured into 0.25 M aqueous hydrochloric acid solution (2.13 L).
The resulting slurry was stirred vigorously for 1 h and then filtered.
The filtered solid was washed with water to obtain the title compound (65.65 g, 90percent) as a white solid. 13C NMR (400 MHz, (CD3)2SO) δ 155.3, 137.2, 128.3, 127.7, 127.6, 68.1, 65.0, 49.1, 33.9, 30.3. 1H NMR (400 MHz, (CD3)2SO) δ 7.29 (m, 5H), 7.10 (d, J=7.9 Hz, 1H), 4.96 (d, J=2.3 Hz, 2H), 4.76 (d, J=4.0 Hz, 1H), 3.29 (s, 1H), 3.17 (br s, 1H), 1.71 (m, 4H), 1.22 (t, J=9.7 Hz, 4H).
Reference: [1] Patent: US2006/111338, 2006, A1, . Location in patent: Page/Page column 29
  • 33
  • [ 13139-17-8 ]
  • [ 59830-60-3 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 24, p. 5449 - 5460
  • 34
  • [ 13139-17-8 ]
  • [ 2640-58-6 ]
Reference: [1] Organic Preparations and Procedures International, 2002, vol. 34, # 5, p. 531 - 537
  • 35
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  • [ 24424-99-5 ]
  • [ 3184-13-2 ]
  • [ 7733-29-1 ]
Reference: [1] Organic Preparations and Procedures International, 2002, vol. 34, # 5, p. 531 - 537
  • 36
  • [ 13139-17-8 ]
  • [ 2576-47-8 ]
  • [ 53844-02-3 ]
Reference: [1] Patent: WO2005/30209, 2005, A1, . Location in patent: Page/Page column 50
  • 37
  • [ 13139-17-8 ]
  • [ 63219-70-5 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 24, p. 5449 - 5460
  • 38
  • [ 13139-17-8 ]
  • [ 22059-21-8 ]
  • [ 84677-06-5 ]
YieldReaction ConditionsOperation in experiment
53 g With sodium hydrogencarbonate In tetrahydrofuran; water at 20℃; for 16 h; Cooling with ice Step A: intermediate VI A solution of benzyl (2,5-dioxopyrrolidin-1-yl) carbonate (83 g, 334 mmol) in tetrahydrofuran (THF) (500 ml) was added to a solution of 1-aminocyclopropanecarboxylic acid (25 g, 247 mmol) in water (500 ml). At ice temperature, a solution of sodium bicarbonate (91 g, 1088 mmol) in water (500 ml) was poured into the mixture. After the addition, the reaction was allowed to warm to room temperature and was stirred for 16 h. The solvent was removedunder reduced pressure. The residue was suspended in200 mL of methylene chloride and extracted with water (500 mL). The water solution was acidified with acetic acid and the precipitate was filtered yielding 1- (((benzyloxy)carbonyl)amino)cyclopropanecarboxyiic acid (53 g, 171 mmol, 69.2 percent yield) as a white solid. Used crude in next reaction. LC/MS: m/z calculated 235.1 , found 258.0 ( +Na)+.
Reference: [1] Synlett, 2004, # 14, p. 2489 - 2492
[2] Patent: WO2013/20245, 2013, A1, . Location in patent: Paragraph 00105
[3] Patent: WO2015/95227, 2015, A2, . Location in patent: Page/Page column 220; 221
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  • [ 13139-17-8 ]
  • [ 68781-13-5 ]
  • [ 84677-06-5 ]
Reference: [1] Canadian Journal of Chemistry, 1992, vol. 70, # 5, p. 1328 - 1337
[2] Patent: WO2011/112769, 2011, A1, . Location in patent: Page/Page column 49; 50
  • 40
  • [ 13139-17-8 ]
  • [ 2508-29-4 ]
  • [ 87905-98-4 ]
Reference: [1] Tetrahedron, 2000, vol. 56, # 43, p. 8433 - 8441
  • 41
  • [ 13139-17-8 ]
  • [ 18807-71-1 ]
YieldReaction ConditionsOperation in experiment
68%
Stage #1: With ethylenediamine In dichloromethane for 2.5 h;
Stage #2: With hydrogenchloride In diethyl ether; hexane
Solid Phase Synthetic protocol: A solution of N-(benzyloxycarbonyloxy)succinimide (ZOSu, 100 g, 401 mmol) in dichloromethane (500 ml) was added dropwise over 2 hours to a solution of 5 ethylenediamine (1, 189 ml, 2.81 mol) in dichloromethane (750 ml). After 30 minutes the suspension was filtered and solids washed with dichloromethane. The filtrate was evaporated to dryness and the residue diluted with toluene (1.00 L) and water (0.50 L). The resulting mixture was filtered and the filtrate was separated to afford two phases. The aqueous phase contained the product; therefore it was extracted with 10 dichloromethane (2 x 250 ml). All organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was diluted with toluene (750 ml) and extracted with 2 M aqueous hydrochloric acid (500 ml) and 1 M aqueous hydrochloric acid (100 ml). Acidic aqueous phases were combined and basified with a solution of sodium hydroxide (60.0 g, 1.50 mol) in water (90 ml). The resulting mixture 15 was extracted with dichloromethane (4 x 200 ml), dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and diluted with hexanes (200 ml). 4 M Solution of hydrogen chloride in ether (100 ml, 400 mmol) was added to the solution, the resulting suspension was concentrated in vacuo and diluted with hexanes (1.00 L). The precipitated solid was filtered, washed with hexanes and dried in vacuo to give (2-amino20 ethyl)-carbamic acid benzyl ester hydrochloride as white powder. 25 Yield: 62.62 g (68percent). RF (Si02, dichloromethane/methanol 4: 1): 0.25 (free base). 1H NMR spectrum (300 MHz, Ac0D-d4, 80 °C, dH): 7.42-7.26 (m, 5 H); 5.16 (s, 2 H); 3.60 (t, J=5.7 Hz, 2 H); 3.32 (t, J=5.7 Hz, 2 H).
Reference: [1] Patent: WO2017/220706, 2017, A1, . Location in patent: Page/Page column 52; 53
  • 42
  • [ 13139-17-8 ]
  • [ 5003-71-4 ]
  • [ 39945-54-5 ]
YieldReaction ConditionsOperation in experiment
92% With triethylamine In dichloromethane at 0 - 20℃; TEA ( 6.91 g, 68.5 mmol) was added dropwise to an ice-cooled mixture of 3- bromopropylamine.hydrobromide (10.Og, 45.6 mmol) and N-(Benzyloxycarbonyloxy)- succinimide (11.22g, 47.9 mmol) in DCM (200 mL). The stirred mixture was allowed to warm to room temperature overnight, then washed with water (3x), brine, dried (MgSO4), filtered and concentrated, providing 11.43 g (92percent) of N-(Benzyloxycarbonyl)- 3-bromopropylamine, as a pale yellow oil .
Reference: [1] Patent: WO2007/82331, 2007, A1, . Location in patent: Page/Page column 100-101
  • 43
  • [ 13139-17-8 ]
  • [ 672-15-1 ]
  • [ 35677-88-4 ]
Reference: [1] Patent: US5508272, 1996, A,
  • 44
  • [ 13139-17-8 ]
  • [ 76985-09-6 ]
  • [ 143218-10-4 ]
Reference: [1] Journal of Medicinal Chemistry, 1992, vol. 35, # 18, p. 3364 - 3369
  • 45
  • [ 13139-17-8 ]
  • [ 1758-80-1 ]
  • [ 62234-40-6 ]
Reference: [1] Patent: WO2017/218922, 2017, A2, . Location in patent: Page/Page column 168; 169
  • 46
  • [ 13139-17-8 ]
  • [ 152120-62-2 ]
  • [ 152120-55-3 ]
Reference: [1] Tetrahedron Letters, 1993, vol. 34, # 21, p. 3389 - 3392
  • 47
  • [ 13139-17-8 ]
  • [ 58632-95-4 ]
  • [ 150407-69-5 ]
Reference: [1] Patent: WO2010/23480, 2010, A1, . Location in patent: Page/Page column 41
  • 48
  • [ 13139-17-8 ]
  • [ 74163-81-8 ]
  • [ 79261-58-8 ]
Reference: [1] Journal of Medicinal Chemistry, 1997, vol. 40, # 19, p. 3100 - 3108
  • 49
  • [ 13139-17-8 ]
  • [ 929-06-6 ]
  • [ 145881-74-9 ]
YieldReaction ConditionsOperation in experiment
40 g With triethylamine In dichloromethane at 20℃; To 2-(2-aminoethoxyl)ethanol (20 g) dissolved in dichloromethane (200 ml) was added stepwise triethylamine (26.5 ml) and benzyloxy(carbonyloxy)succinimide (47.47 g). The reaction mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure and the residue was dissolved in deionized water (500 ml). The insoluble layer was separated, and the aqueous layer was mixed with 50 g of NaCl and the pH adjusted to 5.0 with 5percent H3PO4. The product was extracted with dichloromethane (100 ml, 50 ml, and 50 ml) and the extract was dried with MgSO4, filtered, and evaporated to dryness under reduced pressure. The residue was dried under vacuum overnight, then combined with the previously separated insoluble layer and dissolved in dichloromethane (300 ml). The solution was washed with 5-percent aqueous NaCl solution (3×50 ml) and dried with MgSO4. The solvent was distilled under reduced pressure, and the residue was dried overnight under vacuum, giving 40 g of the desired product.
Reference: [1] Patent: US9173951, 2015, B2, . Location in patent: Page/Page column 125
  • 50
  • [ 1126-09-6 ]
  • [ 13139-17-8 ]
  • [ 160809-38-1 ]
Reference: [1] Synthetic Communications, 1996, vol. 26, # 24, p. 4699 - 4710
  • 51
  • [ 13139-17-8 ]
  • [ 183673-71-4 ]
  • [ 288154-16-5 ]
Reference: [1] Patent: US2004/38998, 2004, A1,
[2] Patent: US2004/53928, 2004, A1,
  • 52
  • [ 13139-17-8 ]
  • [ 7144-05-0 ]
  • [ 157023-34-2 ]
Reference: [1] Patent: US2003/119811, 2003, A1,
[2] Patent: US2002/165241, 2002, A1,
[3] Patent: US2002/165241, 2002, A1,
  • 53
  • [ 6457-49-4 ]
  • [ 13139-17-8 ]
  • [ 122860-33-7 ]
YieldReaction ConditionsOperation in experiment
96% With sodium hydrogencarbonate In tetrahydrofuran; water at 20℃; for 1 h; Piperidin-4-ylmethanol (5.2 g, 45.1 mmol) was dissolved in 60 mE of THF and 60 mE of saturated NaHCO3 aq and then benzyl (2,5-dioxopyrrolidin- 1 -yl) carbonate (11.25 g, 45.1 mmol) added portionwise. The mixture was stirred for 1 h at RT, partitioned between AcOEt and water, washed twice with 1M HClaq and saturated NaClaq. Organic layer was dried over Na2504, evaporated under reduced pressure to afford the title compound (10.77 g, 43.2 mmol, 96percent yield). The product obtained was used in the following steps without thrther purifications. UPLC-MS: 0.80 mm, 250.2 [M+H]+, method 1.
Reference: [1] Patent: US2016/235734, 2016, A1, . Location in patent: Paragraph 0706; 0707; 0708
  • 54
  • [ 13139-17-8 ]
  • [ 160706-62-7 ]
YieldReaction ConditionsOperation in experiment
85%
Stage #1: With sodium hydroxide In water at 5℃;
Stage #2: at 5 - 20℃; for 1 h;
Stage #3: With hydrogenchloride In water
R (-) [ETHYINIPECONATE] tartaric acid salt (117 g, 382 [MMOL)] was dissolved in 2N [NAOH] (1200 ml, 2.40 mol) and cooled to 5 [°C.] [Z-OSU] (100 g, 401 [MMOL)] dissolved in 100 [ML] THF was added to the chilled reaction. The mixture was allowed to stir at 5 [°C] for 1 h. and at RT overnight. Approx. 100 ml of solvent was removed by rotary evaporation in vacuo, and the remaining solution was acidified to pH 2-3 with conc. HCI (app. 75 [ML).] The resulting crystal were isolated by filtration and dried in vacuo overnight. Yield 86 g (85 percent) 1H-NMR (dmso-d6,400 MHz) [D :] 12.5 (s broad, 1H), (7.42-7. 30 (m, 5H), 5.1 (s, 2H), 4.0 (s, [1H),] 3. [80] (s, 1H), 3.12 (m, [1H),] 2.92 (t, 1H), 2.36 (m, 1H), 1.92 (m, 1H), 1.7-1. 48 (m, 2H), 1.48-1. 30 (m, [1 H).] HPLC-MS (Method B): [MILZ =] 264 (M+1), Rt = 3.30 min.
Reference: [1] Patent: WO2004/33455, 2004, A2, . Location in patent: Page 26
  • 55
  • [ 13139-17-8 ]
  • [ 36476-78-5 ]
  • [ 97628-92-7 ]
YieldReaction ConditionsOperation in experiment
99%
Stage #1: With sodium hydrogencarbonate In tetrahydrofuran; water at 20℃;
Stage #2: With hydrogenchloride In water
Preparation of Intermediate 1 (Int. l); (Z)-tert-Butyl 1 -(4-(N'-hydroxycarbamimidoyl)-benzyl)azetidine-3 -carboxylate; Int.1-A. l-(Benzyloxycarbonyl)azetidine-3-carboxylic acid [00103] To a solution of azetidine-3-carboxylic acid (88 g, 0.871 mol) and sodium bicarbonate (161 g, 1.92 mol) in water (1.75 L) at room temperature was added a solution of benzyl 2,5-dioxopyrrolidin-l-ylcarbonate (239 g, 0.959 mol) in tetrahydrofuran (3.5 L). The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the aqueous layer was washed with ethyl acetate (2 x 500 mL). The aqueous layer was acidified with a 1.0 N aqueous solution of hydrochloric acid and was then extracted with ethyl acetate (3 x 750 mL). The organic layer was washed with water, followed by brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded 1- (benzyloxycarbonyl) azetidine-3-carboxylic acid as colorless oil (202 g, 99percent yield). The compound had an HPLC retention time = 2.27 min. - Column: YMC COMBISCREEN.(R). ODS-A 4.6 x 50 mm (4 min.); Solvent A = 10percent MeOH, 90percent H2O, 0.1percent TFA; Solvent B = 90percent MeOH, 10percent H2O, 0.1percent TFA. LC/MS M+1 = 236.15. 1H NMR (400 MHz, CDCl3) δ ppm 3.39 - 3.49 (m, IH), 4.22 (d, J=7.28 Hz, 4H), 5.11 (s, 2H), and 7.29 - 7.39 (m, 5H).
99%
Stage #1: With sodium hydrogencarbonate In tetrahydrofuran at 20℃;
Stage #2: With hydrogenchloride In water
Preparation of Intermediate 1 (Int. l); tert-Butyl 1 -(4-(N'-hydroxycarbamimidoyl)-benzyl)azetidine-3 -carboxylate; Int.1-A. l-(Benzyloxycarbonyl)azetidine-3-carboxylic acid; [00109] To a solution of azetidine-3-carboxylic acid (88 g, 0.871 mol) and sodium bicarbonate (161 g, 1.92 mol) in water (1.75 L) at room temperature was added a solution of benzyl 2,5-dioxopyrrolidin-l-ylcarbonate (239 g, 0.959 mol) in tetrahydrofuran (3.5 L). The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the aqueous layer was washed with ethyl acetate (2 x 500 mL). The aqueous layer was acidified with a 1.0 N aqueous hydrochloric acid solution and was then extracted with ethyl acetate (3 x 750 mL). The organic layer was washed with water, followed by brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded 1- (benzyloxycarbonyl) azetidine-3-carboxylic acid as colorless oil (202 g, 99percent yield). The compound had an HPLC retention time = 2.27 min. - Column: YMC COMBISCREEN.(R). ODS-A 4.6 x 50 mm (4 min.); Solvent A = 10percent MeOH, 90percent H2O, 0.1percent TFA; Solvent B = 90percent MeOH, 10percent H2O, 0.1percent TFA. LC/MS M+1 = 236.15. 1H NMR (400 MHz, CDCl3) δ ppm 3.39 - 3.49 (m, IH), 4.22 (d, J=7.28 Hz, 4H), 5.11 (s, 2H), and 7.29 - 7.39 (m, 5H).
99%
Stage #1: With sodium hydrogencarbonate In tetrahydrofuran; water at 20℃;
Stage #2: With hydrogenchloride In water; ethyl acetate
Preparation 25A: l-(Benzyloxycarbonyl)azetidine-3 -carboxylic acidCbZlM^-CO2Hv (25A) [00262] To a solution of azetidine-3-carboxylic acid (88 g, 0.871 mol) and sodium bicarbonate (161 g, 1.92 mol) in water (1.75 L) at room temperature was added a solution of benzyl 2,5-dioxopyrrolidin-l-ylcarbonate (239 g, 0.959 mol) in tetrahydrofuran (3.5 L). The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the aqueous layer was washed with ethyl acetate (2 x 500 mL). The aqueous layer was acidified with a 1.0 N aqueous hydrochloric acid solution and was then extracted with ethyl acetate (3 x 750 mL). The organic layer was washed with water, followed by brine, and dried over anhydrous sodium sulfate.Concentration under reduced pressure afforded l-(benzyloxycarbonyl) azetidine-3- carboxylic acid as colorless oil (202 g, 99percent yield). The compound had an HPLC retention time = 2.27 min. - Column: YMC COMBISCREEN.(R). ODS-A 4.6 x 50 mm (4 min.); Solvent A = 10percent MeOH, 90percent H2O, 0.1percent TFA; Solvent B = 90percent MeOH, 10percent H2O, 0.1percent TFA. LC/MS M+1 = 236.15. 1H NMR (400 MHz, CDCl3) δ ppm 3.39 - 3.49 (m, IH), 4.22 (d, J=7.28 Hz, 4H), 5.11 (s, 2H), and 7.29 - 7.39 (m, 5H).
99% With sodium hydrogencarbonate In tetrahydrofuran; water at 20℃; INTERMEDIATE 6tert-Butyl azetidine-3 -carboxylate acetic acid saltStep A: l-(Benzyloxycarbonyl)azetidine-3-carboxylic acidCbzN-C°2H (I-6A)[00202] To a solution of azetidine-3 -carboxylic acid (88 g, 0.871 mol) and sodium bicarbonate (161 g, 1.92 mol) in water (1.75 L) at room temperature was added a solution of benzyl 2,5-dioxopyrrolidin-l-ylcarbonate (239 g, 0.959 mol) in THF (3.5 L). The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the aqueous layer was washed with ethyl acetate (2 x 500 mL). The aqueous layer was acidified with a 1.0 N aqueous hydrochloric acid solution and was then extracted with ethyl acetate (3 x 750 mL). The organic layer was washed with water, followed by brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded l-(benzyloxycarbonyl) azetidine-3 -carboxylic acid as colorless oil (202 g, 99percent yield). The compound had an HPLC retention time = 2.27 min (condition B); LC/MS M+1 = 236.15. XH NMR (400 MHz, CDC13) δ ppm 3.39 - 3.49 (m, 1H), 4.22 (d, J=7.28 Hz, 4H), 5.1 1 (s, 2H), and 7.29-7.39 (m, 5H).
99% With sodium hydrogencarbonate In tetrahydrofuran; water at 20℃; 1-A: l-(Benzyloxycarbonyl)azetidine-3 -carboxylic acid[0119] To a solution of azetidine-3 -carboxylic acid (88 g, 0.871 mol) and sodium bicarbonate (161 g, 1.92 mol) in water (1.75 L) at room temperature was added a solution of benzyl 2,5-dioxopyrrolidin-l-ylcarbonate (239 g, 0.959 mol) in tetrahydrofuran (3.5 L). The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the aqueous layer was washed with ethyl acetate (2 x 500 mL). The aqueous layer was acidified with a 1.0 N aqueous solution of hydrochloric acid and extracted with ethyl acetate (3 x 750 mL). The organic layer was washed with water, washed with brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded l-(benzyloxycarbonyl) azetidine-3 -carboxylic acid as colorless oil (202 g, 99percent yield). The compound had an HPLC retention time = 2.27 min. - Column: Column: YMC Combiscreen ODS-A 4.6 x 50 mm (4 min.); Solvent A = 10percent MeOH, 90percent H20, 0.1percent TFA; Solvent B = 90percent MeOH, 10percent H20, 0.1percent TFA. LC/MS M+1 = 236.15. XH-NMR (400 MHz, CDC13) δ ppm 3.39-3.49 (m, 1H), 4.22 (d, J=7.28 Hz, 4H), 5.11 (s, 2H), and 7.29-7.39 (m, 5H).
99%
Stage #1: With sodium hydrogencarbonate In tetrahydrofuran; water at 20℃;
Stage #2: With hydrogenchloride In water
Preparation of Intermediate 1 (Int. l); tert-Butyl 1 -(4-(N'-hydroxycarbamimidoyl)-benzyl)azetidine-3 -carboxylate; Int. l-A. l-(Benzyloxycarbonyl)azetidine-3-carboxylic acid; [00101] To a solution of azetidine-3-carboxylic acid (88 g, 0.871 mol) and sodium bicarbonate (161 g, 1.92 mol) in water (1.75 L) at room temperature was added a solution of benzyl 2,5-dioxopyrrolidin-l-ylcarbonate (239 g, 0.959 mol) in tetrahydrofuran (3.5 L). The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the aqueous layer was washed with ethyl acetate (2 x 500 mL). The aqueous layer was acidified with a 1.0 N aqueous solution of hydrochloric acid and extracted with ethyl acetate (3 x 750 mL). The organic layer was washed with water, washed with brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded 1- (benzyloxycarbonyl) azetidine-3-carboxylic acid as colorless oil (202 g, 99percent yield). The compound had an HPLC retention time = 2.27 min. - Column: YMC COMBISCREEN.(R). ODS-A 4.6 x 50 mm (4 min.); Solvent A = 10percent MeOH, 90percent H2O, 0.1percent TFA; Solvent B = 90percent MeOH, 10percent H2O, 0.1percent TFA. LC/MS M+1 =236.15. 1H NMR (400 MHz, CDCl3) δ ppm 3.39 - 3.49 (m, IH), 4.22 (d, J=7.28 Hz, 4H), 5.11 (s, 2H), and 7.29 - 7.39 (m, 5H).

Reference: [1] Patent: WO2010/85584, 2010, A1, . Location in patent: Page/Page column 38-39
[2] Patent: WO2010/85581, 2010, A1, . Location in patent: Page/Page column 42-43
[3] Patent: WO2011/17578, 2011, A1, . Location in patent: Page/Page column 125-126
[4] Patent: WO2011/59784, 2011, A1, . Location in patent: Page/Page column 86-87
[5] Patent: WO2012/12477, 2012, A1, . Location in patent: Page/Page column 44-45
[6] Patent: WO2010/85582, 2010, A1, . Location in patent: Page/Page column 38
[7] Patent: WO2011/95556, 2011, A1, . Location in patent: Page/Page column 69
[8] Journal of Medicinal Chemistry, 2016, vol. 59, # 6, p. 2820 - 2840
  • 56
  • [ 13139-17-8 ]
  • [ 54288-70-9 ]
  • [ 166953-64-6 ]
YieldReaction ConditionsOperation in experiment
98% at 20℃; for 16 h; To a solution of 4-bromopiperidine hydrobromide (3.0 g, 12.2 mmol) in tetrahydrofuran (30 ml) were added 1-[(benzyloxy)carbonyl]oxy}-2,5-pyrrolidinedione (3.20 g, 12.9 mmol), N-methylmorpholine (1.62 ml, 14.7 mmol) and 4-N,N-dimethylaminopyridine (30 mg) at room temperature, and stirred at room temperature for 16 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with a 1N-aqueous hydrochloric acid solution, dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent, and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate = 1/1) to obtain benzyl 4-bromo-1-piperidinecarboxylate (3.58 g, 98percent).
Reference: [1] Patent: EP1403255, 2004, A1, . Location in patent: Page 89
  • 57
  • [ 13139-17-8 ]
  • [ 151004-93-2 ]
  • [ 151004-88-5 ]
Reference: [1] Patent: WO2005/7164, 2005, A1, . Location in patent: Page 55
  • 58
  • [ 13139-17-8 ]
  • [ 850033-67-9 ]
Reference: [1] Patent: WO2008/83347, 2008, A1,
  • 59
  • [ 2762-32-5 ]
  • [ 13139-17-8 ]
  • [ 58632-95-4 ]
  • [ 149057-19-2 ]
YieldReaction ConditionsOperation in experiment
80%
Stage #1: With sodium hydroxide In 1,4-dioxane; water at 20℃; for 0.75 h;
Stage #2: at 20℃; for 17 h;
Stage #3: With hydrogenchloride In 1,4-dioxane; water
54a. 4-((Benzyloxy)carbonyl)-1 -(tert-butoxycarbonyl)piperazine-2- carboxylic acidThe tile compound was prepared according to the procedure of [Kempf, D. J.; Norbeck, D. W.; Sham, H. L U.S. Patent 5,455,351 , Oct 3, 1995]. Piperazine-2-carboxylic acid (10.0 g, 77.0 mmol) was dissolved in a 1 :1 solution of 1 ,4-dioxane:water (100 mL) at room temperature with vigorous stirring. The clear solution was adjusted to pH 11 by the addition of an aqueous solution of sodium hydroxide (80 mL of a 1Λ/ solution). The pH was monitored in situ with a pH meter throughout the reaction. The reaction flask was fitted with an addition funnel that contained a solution of Λ/-α- (benzyloxycarbonyloxy) succinamide (13.6 g, 55 mmol) in 1 ,4-dioxane (50 mL). The Λ/-α-(benzyloxycarbonyloxy) succinamide solution was added over 45 minutes at room temperature and the pH was kept above 10 by the periodic addition of 1 Λ/ sodium hydroxide. The pH of the solution was adjusted to 9.5 and 2-(teAf-butoxycarbonyloxyimino)-2-phenylacetonitrile (13.4 g, 55 mmol) was added as a solution in 1 ,4-dioxane (50 mL) over 10 minutes. The pH was maintained at 9.5 and the solution was stirred at room temperature for 17 hours. The solution was then acidified to pH 2 and the aqueous solution was washed with diethyl ether (3 x 150 mL). The aqueous solution was cooled to O0C and acidified by adding of concentrated hydrochloric acid. The acidic solution was extracted with ethyl acetate (5 x 150 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with a 1 :1 solution of dichloromethane: hexanes (150 mL) and the solvent was removed in vacuo to provide the product as a viscous yellow oil (15.7 g, 43 mmol, 80percent). Rf = 0.60 (66:34 dichloromethane: ethyl acetate + 0.1percent (v/v acetic acid); 1H-NMR (400 MHz, DMSO) δ 13.0 (br s, 1 H), 7.37-7.36 (m, 5H), 5.05 (s, 2H), 4.54-4.33 (m, 2H), 3.90-3.66 (m, 2H), 3.07-2.81 (m, 4H), 1.38 (s, 9H); Mass spectrum (ESI +ve) m/z 365.1 (MH+).
Reference: [1] Patent: WO2010/147653, 2010, A1, . Location in patent: Page/Page column 117-118
  • 60
  • [ 13139-17-8 ]
  • [ 287953-54-2 ]
Reference: [1] Patent: EP1403255, 2004, A1,
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