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Chemical Structure| 60-32-2
Chemical Structure| 60-32-2
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Product Details of [ 60-32-2 ]

CAS No. :60-32-2 MDL No. :MFCD00008238
Formula : C6H13NO2 Boiling Point : -
Linear Structure Formula :H2N(CH2)5COOH InChI Key :SLXKOJJOQWFEFD-UHFFFAOYSA-N
M.W : 131.17 Pubchem ID :564
Synonyms :
EACA;Epsilon-Amino-n-caproic Acid;Hepin;Capracid;Aminocaproic acid;NSC 400230;NSC 212532;NSC 26154;ε-Aminocaproic Acid;(6-)ε-​Aminocaproic acid;6-Aminohexanoic acid
Chemical Name :6-Aminocaproic Acid

Calculated chemistry of [ 60-32-2 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 9
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.83
Num. rotatable bonds : 5
Num. H-bond acceptors : 3.0
Num. H-bond donors : 2.0
Molar Refractivity : 35.44
TPSA : 63.32 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -9.19 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.2
Log Po/w (XLOGP3) : -2.95
Log Po/w (WLOGP) : 0.59
Log Po/w (MLOGP) : 0.39
Log Po/w (SILICOS-IT) : 0.19
Consensus Log Po/w : -0.12

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : 1.54
Solubility : 4500.0 mg/ml ; 34.3 mol/l
Class : Highly soluble
Log S (Ali) : 2.18
Solubility : 19900.0 mg/ml ; 151.0 mol/l
Class : Highly soluble
Log S (SILICOS-IT) : -0.88
Solubility : 17.2 mg/ml ; 0.131 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.12

Safety of [ 60-32-2 ]

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

Application In Synthesis of [ 60-32-2 ]

* 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 [ 60-32-2 ]

[ 60-32-2 ] Synthesis Path-Upstream   1~48

  • 1
  • [ 60-32-2 ]
  • [ 54-95-5 ]
Reference: [1] European Journal of Organic Chemistry, 2016, vol. 2016, # 14, p. 2383 - 2387
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  • [ 6066-82-6 ]
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  • [ 55750-63-5 ]
Reference: [1] Chemistry - A European Journal, 2012, vol. 18, # 41, p. 13091 - 13096
[2] Journal of Medicinal Chemistry, 2012, vol. 55, # 9, p. 4516 - 4520
[3] Synthesis (Germany), 2014, vol. 46, # 22, p. 3085 - 3096
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  • [ 60-32-2 ]
  • [ 55750-63-5 ]
Reference: [1] Journal of Organic Chemistry, 2011, vol. 76, # 21, p. 9169 - 9174
[2] Patent: WO2015/95953, 2015, A1,
[3] Patent: WO2016/41082, 2016, A1,
[4] International Journal of Molecular Sciences, 2017, vol. 18, # 9,
[5] Patent: CN107789630, 2018, A,
[6] Patent: WO2018/178060, 2018, A1,
[7] Patent: CN108743968, 2018, A,
  • 4
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  • [ 55750-63-5 ]
Reference: [1] Journal of Organic Chemistry, 2011, vol. 76, # 21, p. 9169 - 9174
  • 5
  • [ 108-31-6 ]
  • [ 60-32-2 ]
  • [ 55750-53-3 ]
YieldReaction ConditionsOperation in experiment
80% at 120℃; To 30 ml of glacial acetic acid was added 6-aminocaproic acid 3.9 g (0.03 mol) and 1.2 eq of maleic anhydride 3.5 g(0.036 mol).The reaction was stirred at 120° C. for 4-6 h.After the reaction is completed,Stop heating,Cool naturally to room temperature.It is concentrated under reduced pressure at 60°C to remove most of the acetic acidThe resulting brown-yellow viscous liquid is poured into water.Then add ethyl acetate 20ml×3 extraction,Combine the organic layers.The organic layer is watered in that orderSaturated saline wash,Drying with anhydrous sodium sulfate,filter,The filtrate was concentrated under reduced pressure to give a brown-yellow oil.Add 50ml water to stir,There are white solids precipitated,filter,50° C. vacuum drying target product 5.08g,Yield 80percent.
80% at 120℃; To 30 ml of glacial acetic acid, 3.9 g (0.03 mol) of 6-aminocaproic acid and 1.2 g of maleic anhydride 3.5 g (0.036 mol) were added. The reaction solution was stirred at 120 ° C for 4-6 h.After the reaction was completed, the heating was stopped and naturally cooled to room temperature.Most of the acetic acid was removed by concentration under reduced pressure at 60 °C. The resulting brownish yellow viscous liquid is poured into the water.Add ethyl acetate 20 ml × 3 for extraction.Combine the organic layers. The organic layer was washed successively with water and saturated brine.Dry over anhydrous sodium sulfate, filter,The filtrate was concentrated under reduced pressure to give a brown oil.An off-white solid precipitates, is filtered,The target product was dried under reduced pressure at 50 ° C, 5.08 g, yield 80percent.
77.4% at 20℃; for 10 h; Reflux Compound 1 (150 g, 1.53 mol) was added to a stirred solution of Compound 2 (201 g, 1.53 mol) in HOAc (1000 mL). After the mixture was stirred at r.t. for 2 h, it was heated at reflux for 8 h. The organic solvents were removed under reduced pressure and the residue was extracted with EtOAc(500 mL x 3), washed with H20. The combined organic layers was dried over Na2SO4 and concentrated to give the crude product. It was washed with petroleum ether to give compound 3 as white solid (250 g, 77.4 percent).
77.4% at 20℃; for 10 h; Reflux Compound 1 (150 g, 1.53 mol) was added to a stirred solution of Compound 2 (201 g, 1.53 mol) in HOAc (1000 mL). After the mixture was stirred at r.t. for 2 h, it was heated at reflux for 8 h. The organic solvents were removed under reduced pressure and the residue was extracted with EtOAc (500 mL × 3), and washed with H2O. The combined organic layers were dried over Na2SO4 and concentrated to give the product. The resulting product was washed with petroleum ether to give compound 3 as white solid (250 g, 77.4 percent).
77.4% at 20℃; for 10 h; Reflux Maleic anhydride, furan-2,5-dione (150 g, 1.53 mol) was added to a stirred solution of 6-aminohexanoic acid (201 g, 1.53 mol) in HOAc (1000 mL). After the mixture was stirred at r.t. for 2 h, it was heated at reflux for 8 h. The organic solvents were removed under reduced pressure and the residue was extracted with EtOAc (500 mL x 3), washed with 10. The combined organic layers was dried over Na2SC>4 and concentrated to give the crude product. It was washed with petroleum ether to give 6-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l- yl)hexanoic acid as white solid (250 g, 77.4 percent).
77.4% at 20℃; for 10 h; Reflux Maleic anhydride, furan-2,5 -dione (150 g, 1.53 mol) was added to a stirred solution of 6-aminohexanoic acid (201 g, 1.53 mol) in HOAc (1000 mL). After the mixture was stirred at r.t.for 2 h, it was heated at reflux for 8 h. The organic solvents were removed under reduced pressure and the residue was extracted with EtOAc (500 mL x 3), washed with H20. The combined organic layers was dried over Na2504 and concentrated to give the crude product. It was washed with petroleum ether to give 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoic acidas white solid (250 g, 77.4 percent). DPPA (130 g, 473 mmol) and TEA (47.9 g, 473 mmol) was added to a solution of 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoic acid (100 g, 473 mmol) in t-BuOH (200 mL). The mixture was heated at reflux for 8 h under N2. The mixture was concentrated, and the residue was purified by column chromatography on silica gel (PE:EtOAc= 3:1) to give tert-butyl 5-(2,5-dioxo-2,5-dihydro-1 H-pyrrol- 1 -yl)pentylcarbamate (13 g, 10 percent).To a solution of tert-butyl 5-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)pentylcarbamate (28 g, 992 mmol) in anhydrous EtOAc (30 mL) was added HC1/EtOAc (50 mL) dropwise. After the mixture was stirred at r.t. for 5 h, it was filtered and the solid was dried to give 1-(5- aminopentyl)-1H-pyrrole-2,5-dione hydrochloride lOa (16 g, 73.7 percent). ‘H NMR (400 MHz, DMSO-d6): 5 8.02 (s, 2H), 6.99 (s, 2H), 3.37-3.34 (m, 2H), 2.71-2.64 (m, 2H), 1.56-1.43 (m,4H), 1.23-1.20 (m, 2H)
77.4% With trifluoroacetic acid In acetic acid at 20℃; for 10 h; Reflux [00338] Maleic anhydride (furan-2,5-dione) la (150 g, 1.53 mol) was added to a stirred solution of 6-aminohexanoic acid lb (201 g, 1.53 mol) in HOAc (1000 mL). After the mixture was stirred at r.t. (room temperature) for 2 h, it was heated at reflux for 8 h. The organic solvents were removed under reduced pressure and the residue was extracted with EtOAc (500 mL χ 3), washed with H2O. The combined organic layers was dried over Na2S04 and concentrated to give the crude product. It was washed with petroleum ether to give 6-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l- yl)hexanoic acid lc as white solid (250 g, 77.4 percent).
77.4% at 20℃; for 10 h; Reflux Maleic anhydride, furan-2,5-dione (150 g, 1.53 mol) was added to a stirred solution of6-aminohexanoic acid (201 g, 1.53 mol) in HOAc (1000 mL). After the mixture was stirred atr.t. for 2 h, it was heated at reflux for 8 h. The organic solvents were removed under reduced pressure and the residue was extracted with EtOAc (500 mL x 3), washed with H20. The combined organic layers was dried over Na2504 and concentrated to give the crude product. It was washed with petroleum ether to give 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoic acid as white solid (250 g, 77.4 percent). DPPA (130 g, 473 mmol) and TEA (47.9 g,473 mmol) was added to a solution of 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoic acid(100 g, 473 mmol) in t-BuOH (200 mL). The mixture was heated at reflux for 8 h under N2.The mixture was concentrated, and the residue was purified by column chromatography onsilica gel (PE:EtOAc= 3:1) to give tert-butyl 5-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)pentylcarbamate (13 g, 10 percent). To a solution of tert-butyl 5-(2,5-dioxo-2,5-dihydro-1H- pyrrol-1-yl)pentylcarbamate (28 g, 992 mmol) in anhydrous EtOAc (30 mL) was added HC1/EtOAc (50 mL) dropwise. After the mixture was stirred at r.t. for 5 h, it was filtered and the solid was dried to give 1-(5-aminopentyl)-1H-pyrrole-2,5-dione hydrochloride lOa (16 g, 73.7 percent). ‘H NMR (400 MI-Tz, DMSO-d6): 5 8.02 (s, 2H), 6.99 (s, 2H), 3.37-3.34 (m, 2H),2.7 1-2.64 (m, 2H), 1.56-1.43 (m, 4H), 1.23-1.20 (m, 2H).
57% With acetic anhydride In acetic acid for 1 h; Reflux Maleic anhydride (2.94g, 30mmol) and 6-aminocaproic acid (3.94g, 30mmol) were refluxed in AcOH (70mL) overnight. Ac2O (2.83mL, 30mmol) was added dropwise and reflux continued for a further 1h. The acetic acid was co-evaporated with toluene in vacuo to yield yellow syrup. The material was purified over SiO2 (DCM:MeOH, 10:0.7) affording a cream crystalline solid in 57percent yield (3.58g): Rf (DCM/MeOH, 10:0.7)=0.50; ESI-MS (C10H13NO4, 211.1): m/z=212.0 [M+H+] (calcd 212.1), 423.1 [M+2H+] (calcd 423.2); 1H NMR: δ=6.95 (2H, s, CH=CH), 3.35 (2H, t, J 7.4Hz, NCH2), 2.15 (2H, t, J 7.2Hz, CH2COO), 1.45 (4H, m, 2CH2), 1.18 (2H, m, CH2).
19%
Stage #2: With triethylamine In toluene for 5 h; Dean-Stark; Reflux
To a stirred solution of 6-aminocaproic acid (10.0 g, 76.2 mmol, 1.0 eq) in acetic acid (75 mL), maleic anhydride (7.85 g, 80.0 mmol, 1.05 eq) was added. The solids took a few minutes todissolve, then after ca. 5 mm, white solids began to crash out. After an hour, the suspension thickened to a white cake. This material was scooped onto a fitted funnel and washed with toluene and dried in vacuo with heating to remove all traces of acetic acid.The intermediate powder was taken up in toluene (250 mL), triethylamine (21.3 mL, 152mmol, 2.0 eq) was added, and the mixture heated to reflux with a Dean—Stark trap. After 5 h of reflux,the mixture was cooled and the clear toluene layer was decanted from the rest of the sticky residue in the flask. The toluene was removed in vacuo to yield the a triethylamine salt of 6-(2,5-dioxo-2,5-dihydro- 1H-pyrrol- 1 -yl)hexanoate. The salt was redissolved in toluene, and a small amount of acetic acid was added, then concentrated. Next, the mixture was taken up in 50percent saturated sodiumbicarbonate, and 1 M HC1 was added to adjust the pH to 3, forming a milky precipitate. This wasextracted three times with EtOAc, combined organics dried over sodium sulfate, filtered, andconcentrated in vacuo to yield pure 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-l-yl)hexanoate (3.08 g, 19percent).

Reference: [1] Patent: CN107789630, 2018, A, . Location in patent: Paragraph 0061; 0062; 0063
[2] Patent: CN108743968, 2018, A, . Location in patent: Paragraph 0004; 0005; 0006
[3] Patent: WO2015/95223, 2015, A2, . Location in patent: Page/Page column 67
[4] Patent: WO2016/90050, 2016, A1, . Location in patent: Page/Page column 61-62
[5] Patent: WO2016/90038, 2016, A1, . Location in patent: Page/Page column 123
[6] Patent: WO2016/90040, 2016, A1, . Location in patent: Page/Page column 89
[7] Patent: WO2016/205176, 2016, A1, . Location in patent: Paragraph 00337; 00338
[8] Patent: WO2017/214024, 2017, A1, . Location in patent: Page/Page column 81
[9] Journal of Medicinal Chemistry, 2013, vol. 56, # 24, p. 9955 - 9968
[10] International Journal of Molecular Sciences, 2017, vol. 18, # 9,
[11] Drug Delivery and Translational Research, 2018, vol. 8, # 5, p. 1162 - 1170
[12] Synthesis, 2008, # 8, p. 1316 - 1318
[13] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 17, p. 4848 - 4854
[14] Patent: US6669951, 2003, B2, . Location in patent: Drawing sheet 23
[15] Organic and Biomolecular Chemistry, 2014, vol. 12, # 37, p. 7261 - 7269
[16] Patent: WO2016/41082, 2016, A1, . Location in patent: Page/Page column 97
[17] Patent: EP1382600, 2004, A1, . Location in patent: Page 5
[18] Organic and Biomolecular Chemistry, 2009, vol. 7, # 17, p. 3400 - 3406
[19] Australian Journal of Chemistry, 2011, vol. 64, # 6, p. 779 - 789
[20] Patent: US2017/106094, 2017, A1, . Location in patent: Paragraph 0066
[21] Patent: CN106632272, 2017, A, . Location in patent: Paragraph 0034; 0035; 0036
[22] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 9, p. 2599 - 2609
[23] Bioconjugate Chemistry, 2018, vol. 29, # 6, p. 1852 - 1858
[24] Patent: CN108164512, 2018, A, . Location in patent: Paragraph 0037; 0038; 0039
[25] Patent: CN108309938, 2018, A, . Location in patent: Paragraph 0018; 0021; 0056-0059; 0062-0064
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YieldReaction ConditionsOperation in experiment
77.4% at 20℃; for 10 h; Reflux Compound 1 (150 g, 1.53 mol) was added to a stirred solution of Compound 2 (201 g, 1.53 mol) in HOAc (1000 mL). After the mixture was stirred at r.t. for 2 h, it was heated at reflux for 8 h. The organic solvents were removed under reduced pressure and the residue was extracted with EtOAc (500 mL x 3), washed with H20. The combined organic layers was dried over Na2S04 and concentrated to give the crude product. It was washed with petroleum ether to give compound 3 as white solid (250 g, 77.4 percent).
Reference: [1] Patent: WO2015/95227, 2015, A2, . Location in patent: Page/Page column 261; 262
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Reference: [1] Patent: EP665020, 1995, A3,
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Reference: [1] Dalton Transactions, 2005, # 24, p. 3886 - 3897
[2] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 1996, vol. 35, # 3, p. 184 - 186
[3] Journal of Medicinal Chemistry, 1996, vol. 39, # 8, p. 1692 - 1703
[4] Tetrahedron Letters, 1994, vol. 35, # 35, p. 6515 - 6516
[5] Patent: US2014/249319, 2014, A1,
[6] Patent: WO2015/38493, 2015, A1,
[7] Patent: WO2015/95953, 2015, A1,
[8] Patent: WO2018/178060, 2018, A1,
  • 9
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  • [ 4048-33-3 ]
YieldReaction ConditionsOperation in experiment
96%
Stage #1: at 40℃; for 0.333333 h; Sonication
Stage #2: at 90℃; for 16.5 h; Reflux
Stage #3: With water In ethylene glycol
(1) By volume ratio, 1 part of 6-aminohexanoic acid was added to the reactor containing 15 parts of diethyl ether or dry toluene solution, At 40 deg.C constant temperature, At 1500rpm / min speed, rapidly inject 2 parts of a solution of sodium borohydride. At 250W, ultrasonic treatment 20min. Then add dropwise under reflux 8 parts of ethylene glycol solution. Dropwise addition time was 30min. Finally at 90 deg.C and at a rate of 800rpm/min, maintain temperature under stirring and react for 16 h to obtain the reaction crude product.(2) By the amount of parts count, step (1) preparation of 1 part of the reaction crude was added 6 parts water for hydrolysis. Undrego vacuum distillation, collecting 125 deg.C fraction, to obtain 6-amino-1-hexanol product .
Reference: [1] Patent: CN105669471, 2016, A, . Location in patent: Paragraph 0038; 0039; 0040
[2] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 22, p. 6346 - 6349
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  • [ 4224-70-8 ]
Reference: [1] Patent: WO2007/117404, 2007, A2, . Location in patent: Page/Page column 21; 27-28
[2] Patent: CN106632474, 2017, A,
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  • [ 2014-58-6 ]
Reference: [1] Faserforsch. Textiltech., 1954, vol. 5, p. 145,153
[2] Chemische Berichte, 1957, vol. 90, p. 320,328
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  • [ 5834-64-0 ]
  • [ 2014-58-6 ]
  • [ 5776-78-3 ]
Reference: [1] Journal of Molecular Catalysis B: Enzymatic, 2010, vol. 64, # 1-2, p. 81 - 88
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  • [ 27219-07-4 ]
Reference: [1] Journal of Medicinal Chemistry, 2014, vol. 57, # 24, p. 10290 - 10303
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YieldReaction ConditionsOperation in experiment
100% at 20℃; for 16 h; To a solution of 6-aminoheptanoic acid (2 0 g, 15 3 mmol) in dichloromethane (30 mL) was added di-tert- butyl dicarbonate (3 67 g, 16 8 mmol) The reaction was stirred at room temperature for 16 hours, filtered and the solvent removed under reduced pressure The crude product was dried under high vacuum to afford 408 g (115percent) of the desired product 400 MHz 1H NMR (DMSOd6) δ 2 85 (q, J= 13 2, 6 8 Hz, 2H), 2 15 (t, J= 1 2 Hz, 2H), 1 47- 1 43 (m, 4H), 1 34 (s, 9H), 1 22-1 18 (m, 2H) LCMS=232 [M+H]
98% With triethylamine In water; acetone at 20℃; for 4 h; A solution of 9 (1.31 g, 10.0 mmol) and Et3N (2.8 ml, 20.0 mmol) in acetone-water(1:1, 20 ml), di-tert-butyl dicarbonate ((Boc)2O, 2.5 ml,11.0 mmol) was added and the reaction mixture was stirred for 4h at room temperature. The organic component of the solvent was removed under vacuum and the aqueous residue was acidified with dilute HCl until pH 4–5. The solution was extracted with EtOAc, and the combined organic phases were washed with brine, dried over anhydrous Na2SO4, and thenconcentrated in vacuo to give 9a (2.29 g, 98percent, white solid under 4°C). Rf 0.52(CH2Cl2 : CH3OH = 9:1); 1H NMR (400 MHz, CDCl3) δ 4.61 (s, 1H), 3.12 (d, J = 5.9Hz, 2H), 2.35 (t, J = 7.4 Hz, 2H), 1.72 – 1.57 (m, 2H), 1.56 – 1.41 (m, 12H), 1.41 –1.29 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 178.85, 156.12, 79.18, 40.32, 33.96,29.63, 28.37, 26.19, 24.34; HR-MS(m/z) Calcd for C11H21NO4: 254.1368 [M + Na]+,found: 254.1356 [M + Na]+.
98% With triethylamine In water; acetone at 20℃; Compound 1 (13.0 g) was added to the flask,Di-tert-butyl dicarbonate (25 ml) and moderate amount of triethylamine,Acetone-water (v:v 1:1) as a solvent,Room temperature until the reaction is complete.Dilute hydrochloric acid to adjust the pH to acidic, ethyl acetate extraction, combined organic phase, washed with saturated sodium chloride solution,Drying over anhydrous sodium sulfate, vacuum drying,2N-tert-Butoxycarbonyl-6-aminocaproic acid (22.6 g, 98percent) was obtained as a white solid.
97% With triethylamine In water; acetone at 20℃; for 4 h; To a solution of 6-aminohexanoic acid (1.31 g, 10.0 mmol) and triethylamine (2.8 mL, 20.0 mmol) in acetone-water (1:1, 20 mL), di-tert-butyl dicarbonate ((Boc)2O, 2.5 mL, 11.0 mmol) was added and the reaction mixture was stirred for 4 hrs at room temperature. After completion of the reaction, the solution was concentrated under vacuum and the residual aqueous suspension was acidified with 1 M HCl to pH 4-5. The solution was extracted with CH2Cl2, and the combined organic phases were washed with brine, dried with anhydrous Na2SO4, and the solvent was removed by rotary evaporation to give the compound 1 (2.25 g, 97percent) as a white solid under 4 °C and as a colorless oil at room temperature. 1H NMR (300 MHz, CDCl3) δ 4.57 (s, CONH, 1H), 3.10 (d, NHCH2, J = 3.11, 2H), 2.34 (t, COCH2, J = 2.34, 2H), 1.64 (m, NHCH2CH2, J = 1.64, 2H), 1.43 (m, CH2&CH3, 13H). 13C NMR (75 MHz, CDCl3) δ 179.28, 156.42, 79.48, 40.65, 34.26, 29.97, 28.69, 26.50, 24.65.
96.55%
Stage #1: With sodium hydrogencarbonate In water for 0.166667 h;
Stage #2: at 0 - 5℃;
Stage #3: With hydrogenchloride In water
EXAMPLE 42; Synthesis of 6-{4-[2-(1,3-Benzothiozol-2-ylamino)-2-oxoethyl]piperazin-1-yl}-N-[2-amino-4-(methylthio)butanoyl]amino}hexanamide; Step-I; Synthesis of 6-[(t-Butoxycarbonyl)amino]hexanoic acid; Aminocaproic acid (3 g, 22.87 mmol) taken in to water (25 ml), added sodium bicarbonate, stirred for 10 minutes and cooled to 0-5° C. In another flask BOC-anhydride was taken into 1,4-dioxane (25 ml), cooled to 0-5° C., added to the above reaction mixture and stirred the reaction mixture overnight. Extracted with ethylacetate (150 ml.x.1). The aqueous layer acidified with 1:1 aqueous. Hydrochloric acid up to pH 2 and extracted with ethylaceate (250 ml.x.2). The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford a concentrate (5.1 g, 96.55percent), which was used further for the next reaction.
96.55%
Stage #1: With sodium hydrogencarbonate In water for 0.166667 h;
Stage #2: at 0 - 5℃;
Aminocaproic acid (3g, 22.87mmol) taken in to water (25ml), added sodium bicarbonate, stirred for 10 minutes and cooled to 0-5°C. In another flask BOC- anhydride was taken into 1,4-dioxane (25ml), cooled to 0-5°C, added to the above reaction mixture and stirred the reaction mixture overnight. Extracted with ethylacetate (150ml x 1). The aqueous layer acidified with 1:1 aqueous. Hydrochloricacid up to pH 2 and extracted with ethylaceate (250ml x 2). The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford a concentrate (5.1g, 96.55percent), which was used further for the next reaction.
94% With sodium hydroxide In 1,4-dioxane; water at 20℃; for 24 h; To 2.62 g (20 mmol) of amino-n-hexanoic acid and 30 mLAdd 5.23g (Boc) 2O and 30mL to the solution of distilled watera solution of dioxane,The resulting reaction solution was adjusted to pH 9 with a 2N aqueous NaOH solution.Stir at room temperature for 24 h,During the period, the pressure is continuously reduced.The reaction compound was adjusted to pH 7 with a KHSO 4 aqueous solution.The dioxane was removed by concentration under reduced pressure.The residual solution was continued to adjust the pH to 2 with KHSO4.The residual solution was extracted with 100 mL of ethyl acetate.Dry with anhydrous NaSO4 for 8 h.Filtered, and the filtrate was concentrated under reduced pressure.4.36 g (94percent) of the title compound are obtained.
90% at 0 - 20℃; Protected aminocaproic acid: 6-aminocaproic acid (1.12 g, 8 54 mmol) was dissolved in 2 M aqueous sodium hydroxide solution (7 mL) was added 1,4-dioxane (14 mL), and (Boc) 20 was added dropwise under ice-cooling. The mixture was allowed to warm to room temperature and stirred overnight. The organic phase was dried over anhydrous sodium sulphate and dried to give 3.76 g (90percent yield) of a colorless oily liquid, which was purified by flash chromatography on silica gel eluting with water.
89% With sodium hydroxide In 1,4-dioxane; water at 0 - 20℃; for 16 h; 6-Aminohexanoic acid (3.1 g, 23.63 mmol, 1 equiv.) was stirred in dioxane/H20 (1:1, 75 mL) at 0°C with sodium hydroxide (1.05 g, 23.63 mmol). To this solution was added Boc anhydride (5.2 g, 21.27 mmol, 0.9 equiv.) and <n="54"/>the reaction left to warm to rt for 16 h. The reaction mixture was acidified with 1 M aqueous hydrochloric acid to pH5. The mixture was extracted with CH2Cl2 (3 x 50 mL) and the combined organic phases were dried over MgSCU and concentrated in vacuo to give 31 as a colourless oil (4.5 g, 89percent) which was used without further purification.1H NMR (CDCl3, 300 MHz) δ 1.42 (m, 4H, (CH2J2)/ 1-44 (s, 9H, (CH3J3), 1.65 (m, 2H, CH2), 2.35 (t, 2H, J = 7.4 Hz, CH2), 3.10 (m, 2H, CH2), 4.55 (s, (br) , IH, NH).
89% With sodium hydroxide In 1,4-dioxane; water at 20℃; Di-fert-butyloxycarbonyl, (Boc)20 (1.99 g, 9.14 mmol) was added to a solution of 6-aminohexanoic acid (1 g, 7.61 mmol) and NaOH (10percent aqueous solution) in 1,4- dioxane. The reaction mixture was then stirred overnight at room temperature. The solvent was evaporated and the mixture was acidified using IN HC1. The acidified mixture was then extracted with dichloromethane (DCM). The organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated. The crude material was then purified using column chromatography to give the pure product 2 (1.57 g, 89percent).
89% With sodium hydroxide In 1,4-dioxane; water at 20℃; for 0.5 h; Cooling with ice 0.26g (2.0mmol) with stirringAmino-n-hexanoic acid5mL0.58g (2.6 mmol) of distilled water solution(Boc) a solution of 2O with 5 mL of dioxane.The resulting solution was adjusted to pH 9 with an aqueous solution of NaOH (2M).After stirring for 30 minutes in an ice bath, it was stirred at room temperature and pumped with a water pump.Monitor the pH during mixing and keep it at 9,The reaction was completed until TLC (dichloromethane/methanol, 3/1).Under the ice bath,The reaction mixture was adjusted to pH 7 with a saturated aqueous solution of KHSO4.Concentrate under reduced pressure.The aqueous phase was adjusted to pH 2 with a saturated aqueous solution of KHSO4.Wash well three times with 10 mL of ethyl acetate.Wash the solution to pH 7 with 10 mL of saturated NaCl aqueous solution.It was dried over anhydrous Na 2 SO 4 for 12 hours.Filter to remove Na2SO4,The filtrate was concentrated under reduced pressure.0.41 g (89percent) of the title compound are obtained.It is a colorless solid.
85% With sodium hydroxide In tetrahydrofuran; water at 0℃; for 4.25 h; To a solution of 5 g 6-aminohexanoic acid (1 eq.), dissolved in 120 ml THF, 125 ml of 1N aqueous NaOH solution was added at 0° C., followed by 34 ml Boc anhydride (1.3 eq.), sequentially using additional funnel, over a period of 15 min. The resulting solution was stirred at room temperature for 4 hours. Progress of the reaction was monitored by TLC (10percent MeOH in CHCl3; Rf: 0.5). Reaction mass was quenched with 5percent HCl (100 ml) and then EtOAc (150 ml) was added. Organic layer was separated and the aqueous layer was washed with EtOAc (2×100 ml). Combined organic layer was concentrated under reduced pressure to get gummy liquid. Quantity produced, 22.4 g; yield, 85percent.
85% With sodium hydroxide In tetrahydrofuran; water at 0 - 20℃; for 4 h; To a solution of 5 g 6-aminohexanoic acid (1 eq.), dissolved in 120 ml THF, 125 ml of 1N aqueous NaOH solution was added at 0° C., followed by 34 ml Boc anhydride (1.3 eq.), sequentially using additional funnel, over a period of 15 min. The resulting solution was stirred at room temperature for 4 hours.
Progress of the reaction was monitored by TLC (10percent MeOH in CHCl3; Rf: 0.5). Reaction mass was quenched with 5percent HCl (100 ml) and then EtOAc (150 ml) was added. Organic layer was separated and the aqueous layer was washed with EtOAc (2×100 ml). Combined organic layer was concentrated under reduced pressure to get gummy liquid. Quantity produced, 22.4 g; yield, 85percent.
84%
Stage #1: With sodium hydrogencarbonate In 1,4-dioxane; water
Stage #2: With hydrogenchloride In water
To a vigorously stirred solution of 6-aminohexanoic acid (2.93 g, 25.0 mmol) and NaHCO3 (5.26 g, 62.5 mmol) in water (50 mL) was added di-tert-butyl dicarbonate (6.55 g, 30.0 mmol) in 1,4-dioxane (50 mL), and stirring was continued overnight. The resulting mixture was extracted with diethyl ether (50 mL, discarded) and carefully acidified (pH 2) with 2 M hydrochloric acid. The aqueous layer was extracted with ethyl acetate (3 .x. 30 mL), and the combined extracts were washed with brine and dried over anhydrous Na2SO4. The volatiles were removed under reduced pressure and the residue was crystallized from diethyl ether/n-pentane to afford a white solid (4.84 g, 84percent); mp 35-37 °C; 1H NMR (300 MHz, CDCl3): δ (ppm) = 1.44 (s, 9H), 1.32-1.55 (m, 4H), 1.75 (q, 2H, 3J = 7.4 Hz), 2.36 (t, 2H, 3J = 7.4 Hz), 3.12 (m, 2H), 4.55 (m, 1H); MS (CI, NH3): m/z 249 [M+NH4]+, 232 [M+H]+, 193 [M-C4H8+NH4]+; C11H21NO4 (231.3).
81% With sodium hydrogencarbonate In tetrahydrofuran; water at 20℃; 6-Aminohexanoic acid (1.00 g, 7.26 mmol) was added to a solution of THF: To a solution of saturated NaHCO3 aqueous solution (1: 1)Was dissolved in the co-solvent and a solution of di-tert-butyl dicarbonate (2.00 g, 9.15 mmol) in THF was added dropwise to the solution at room temperature. After completion of the reaction was confirmed by TLC, the THF was removed by rotary evaporation and the resulting solution was acidified to pH 1-2. The mixture was extracted several times with DCM. The organic phases were combined, washed with deionized brine, dried over MgSO4 and concentrated by rotary evaporation.The pure compound N-Boc-aminohexanoic acid (Compound 6 was obtained as an opaque crystal (yield: 81percent).
72% With triethylamine In methanol at 60℃; for 12 h; NH2-(CH2)5-COOH (5.00 g, 38.2 mmol), (BOC)2O (9.16 g, 42.0 mmol) and triethylamine (4.24 g, 42.0 mmol) were dissolved in 200 mL of methanol, and the mixture was stirred at 60° C. for 12 hours.
After the reaction completed, methanol was removed under reduced pressure, and the obtained material was redissolved in 100 mL of ethyl acetate.
Then, the solution was subjected to separation using 0.2 mol/l HCl (twice) and water (twice), and dehydrating was carried out with anhydrous sodium sulfate.
After that, recrystallization with hexane at 4° C. and collection using a glass filter (G6) were performed, thereby obtaining Boc-NH-(CH2)5-COOH (6.35 g, 27.5 mmol, yield: 72percent).
61.6% With sodium hydroxide In tetrahydrofuran at 0 - 20℃; for 24.5 h; 6-Aminocapraic acid (2.00 g, 15.25 mmol) was dissolvedin 40 mL NaOH solution (0.62 mol/L). Then (Boc)2O (3.66 g,16.77 mmol) in 22 mL tetrahydrofuran (THF) was added dropwiseinto the flask at 0°C. The mixture was stirring for 30 minat 0°C and then reacted at room temperature for 24 h. A rotaryevaporator was used to remove the THF. Then 100 mL Et2Owas applied to extract the unreacted (Boc)2O. One mol/literHCl was added dropwise into the aqueous phase until thepH was approximately 3. The aqueous phase was then extractedwith 150 mL CH2Cl2 and washed with deionized waterfor 3 times. Organic solvent was evaporated under reducedpresure and the product was dried in a vaccum oven (45°C)to afford yellowish thick liquid, 2.13 g, yield: 61.6percent. MS m/zelectronspray ionization (ESI)+: 232 (M)+. IR (KBr) cm−1:3348, 2978, 2939, 2719, 2646, 1670, 1651, 1504, 1273, 1173,864, 779. 1H-NMR (CDCl3) δ: 1.38–1.34 (2H, t, J=7.8 Hz),1.43 (9H, s), 1.53–1.47 (2H, m), 1.68–1.61 (2H, m), 2.37–2.33(2H, t, J=7.4 Hz), 3.12–3.09 (2H, t, J=6.1 Hz), 4.56–4.55 (1H,d, J=0.6 Hz).

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  • [ 58632-95-4 ]
  • [ 60-32-2 ]
  • [ 6404-29-1 ]
YieldReaction ConditionsOperation in experiment
97% With triethylamine In 1,4-dioxane; water at 20℃; for 23 h; Inert atmosphere Step A. Synthesis of jY-Boc-amino acid alkyl chains (Boc-aa, m = 5 or 10)[0092] A solution of a commercially available aminoacid alkyl chain (7.77 mmol) in water and dioxane was stirred at room temperature. Trielthyamine (11.65 mmol) was added slowly followed by Boc-ON (8.54 mmol). The solution was kept for 23 h under nitrogen. Afterwards, the mixture was diluted with diethyl ether and water and then washed with water (6x). The aqueous layers were then combined and a few drops of 10percent aqueous HCl solution were slowly added in order to reach pH 2.5. The resulting solution was then washed with dichloromethane (3x). The organic layers were washed with saturated sodium chloride salt solution. The organic phase was dried with magnesium sulfate, filtered and evaporated. Flash chromatography (hexanes: acetone, 4:1) was performed to yield a colorless yellow viscous oil in 97percent yield.6-Boc-amino-hexanoic acid (Boc-aa, m = 5)IR (NaCl, vmax, cm"1) : 3339 (N-H), 2860-3100 (O-H), 1711 (2x C=O), 1527 and 1250 (C-N-H), 1173 (C-O-C).1H-NMR (CDCl3, Jppm) : 8.91 (IH, br s, COOH), 4.74 (IH, s, NH), 3.02 (2H, m, CH2NH), 2.27 (2H, t, J = 7.4 Hz, CH2COOH), 1.24-1.68 (6H, No.m, 3 x CH2), 1.37 (s, 9H, 3 x CH3).13C-NMR (CDCl3, .pound.ppm) : 178.7 (COOH), 156.4 (OCONH), 79.4 ((CH3)3C), 40.5 (NHCH2), 34.1 (CH2COOH), 29.8 (NHCH2CH2), 28.6 (3 x CH3), 26.4 (CH2CH2CH2CH2CH2), 24.5 (CH2CH2COOH).ESI+ HRMS: [M + Na]+ calculated for C11H2JNNaO4 = 254.1363; found = 254.1360.
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  • 16
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YieldReaction ConditionsOperation in experiment
91% With sodium hydroxide In 1,4-dioxane; water; ethyl acetate 7.1.
PREPARATION OF N-BOC-6 AMINOCAPROIC ACID
A 250 ml round bottom flask was charged with 2.62 g (0.02 mol) of 6-aminocaproic acid (Aldrich), 40 ml of dioxane, 25 ml of water and 25 ml of 1.0N sodium hydroxide solution.
The reaction solution was cooled to 0° C. and 4,583 g (0,021 mol) of di-tert-butyldicarbonate (BOC2 O) (Aldrich) was added.
The reaction mixture was allowed to stir at 0° C. for 1.5 h and then most of the solvents were removed under vacuum to leave a liquid residue.
This residue was dissolved in 30 ml of ethyl acetate, cooled to 0° C. for 10 min, and then 5percent potassium hydrogen phosphate solution (approximately 50-60 ml) was added to bring the pH of the solution to between 2 and 3.
The reaction solution was added to 50 ml of water and 30 ml of ethyl acetate.
The aqueous layer was separated from the organic layer, and the aqueous layer was extracted with three 30 ml portions of ethyl acetate.
The organic layers were combined, washed with two 75 ml portions of water, dried over NaSO4, filtered, and the solvents were removed at reduced pressure to give 4.22 g (0.0182 mol, 91percent yield) of N-BOC-6-aminocaproic acid as a thick yellow oil. 1 H NMR (CDCl3) showed the peaks usually observed for 6-aminocaproic acid in addition to a large singlet at 1.48 ppm (tBu group).
91% With sodium hydroxide In 1,4-dioxane; water; ethyl acetate 7.1.
PREPARATION OF N-BOC-6 AMINOCAPROIC ACID, 7
A 250 ml round bottom flask was charged with 2.62 g (0.02 mol) of 6-aminocaproic acid, 6, (Aldrich), 40 ml of dioxane, 25 ml of water and 25 ml of 1.0N sodium hydroxide solution.
The reaction solution was cooled to 0° C. and 4.583 g (0.021 mol) of di-tert-butyldicarbonate (BOC2 O) (Aldrich) was added.
The reaction mixture was allowed to stir at 0° C. for 1.5 h and then most of the solvents were removed under vacuum to leave a liquid residue.
This residue was dissolved in 30 ml of ethyl acetate, cooled to 0° C. for 10 min, and then 5percent potassium hydrogen phosphate solution (approximately 50-60 ml) was added to bring the pH of the solution to between 2 and 3.
The reaction solution was added to 50 ml of water and 30 ml of ethyl acetate.
The aqueous layer was separated from the organic layer, and the aqueous layer was extracted with three 30 ml portions of ethyl acetate.
The organic layers were combined, washed with two 75 ml portions of water, dried over NaSO4, filtered, and the solvents were removed at reduced pressure to give 4.22 g (0.0182 mol, 91percent yield) of N-BOC-6-aminocaproic acid, 7, as a thick yellow oil. 1 H NMR (CDCl3, TMS) showed the peaks usually observed for 6-aminocaproic acid in addition to a large singlet at 1.48 ppm (BOC group).
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YieldReaction ConditionsOperation in experiment
48.1% With triethylamine In 1,4-dioxane; water Example 6
Synthesis of 6-tert-butoxycarbonylamimnohexanoic acid (L5).
Prepared as described for L3 from stirring 6-aminohexanoic acid (3.49 g, 26.7 mmol) in 50percent aqueous dioxane with triethylamine (5.5 mL, 39.5 mmol) and BOC-ON (7.45 g, 30.2 mmol) to yield a pale yellow solid (2.96 g, 48.1percent).
1H NMR (d6-DMSO, 300 MHz): δ 1.2 (m, 2H, CH2), 1.3 (m, 2H, CH2), 1.36 (s, 9H, CH3), 1.46 (m, 2H, CH2), 2.16 (t, 2H, CH2), 2.87 (m, 2H, CH2), 6.74 (t, 1H, NH).
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  • [ 501-53-1 ]
  • [ 60-32-2 ]
  • [ 1947-00-8 ]
YieldReaction ConditionsOperation in experiment
99% With potassium carbonate In tetrahydrofuran at 20℃; To a stirred suspension of 8-aminocaproic acid (1 g, 7.62 mmol) and K2CO3 (2.1 g, 15.2 mmol) inTHF (20 mL), benzyl-chloroformate (1.63 ml, 11.45 mmol) was added slowly. The mixture wasstirred at room temperature for 16 h. The reaction was quenched with AcOEt and H2O. Aqueousphase was separated and the pH of aqueous phase was adjusted to 2 by addition of HCl 4N andextracted twice with AcOEt (10 mL). Combined organic phases were then dried over anhydrousNa2SO4, filtered and evaporated in vacuum. The product 18 was used in the next step without anyfurther purification. Yield 99percent.
94.1%
Stage #1: With chloro-trimethyl-silane; triethylamine In dichloromethane for 2 h; Reflux
Stage #2: at 20℃; for 5 h; Cooling with ice
To a stirred suspension of finely powdered 6-aminocaproic acid (32.79 g, 0.25 mol) in dichloromethane (500 ml), triethylamine (63.24 g, 0.625 mol) was added. Then, trimethylchlorosilane (54.32 g, 0.5 mol) was added dropwise with vigorous stirring and the resulting mixture was refluxed for 2 h. The reaction mixture was then cooled on an ice bath and benzyl chloroformate (95percent, 53.31 g, 0.313 mol) was added. The resulting mixture was stirred on ice for 60 min and at room temperature for 4 h. After removal of the solvent, the residue was distributed between 1000 ml of 4percent (v/w) solution of sodium hydrogen carbonate and 500 ml of methyl tert-butyl ether. The aqueous layer was separated, acidified to pH 2.0 with 2N hydrochloric acid and extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated to yield clear oil (62.4 g, 94.1 percent) corresponding to target carboxylic acid 3* that was homogeneous by LC/MS and TLC, and was used in the next step with no further purification. MS m/z 265.33 (M+1)+ (265.13 calculated).
89% With sodium hydroxide In tetrahydrofuran at 0 - 20℃; for 5.5 h; Inert atmosphere To a solution of 6-aminocaproic acid (1.0 g, 7.6 minol) and sodium hydroxide (0.6 g, 15.2 minol) in water (5 mL) at 0 °C was added dropwise a solution of benzyl chloroformate (1.6 g, 9.2 minol) in tetrahydrofuran (4 mL), and the mixture stirred at 0 °C for 30 min, thenroom temperature for 5 h. The mixture was then concentrated by half in vacuo, acidified to pH 3 with aqueous citric acid (1 M), extracted with dichloromethane (3 x), the combined organic layers dried over anhydrous magnesium sulfate and solution concentrated in vacuo to afford the title compound 74 (1.8 g, 89percent) as a white solid, which was used without further purification. m.p. 47-50 °C (Lit 56 oc34). 1H NMR (400 MHz, CDCI3) ö 1.33-1.40 (2H,m, H-4), 1.48-1.55 (2H, m, H-5), 1.61-1.68 (2H, m, H-3), 2.34 (2H, t, J = 7.3 Hz, H-2),3.17-3.22 (2H, m, H-6), 4.80-4.84 (1H, m, NH), 5.09 (2H, s, CH2Ph), 7.26-7.38 (5H, m,Ph); 13C NMR (100 MHz, CDCI3) ö 24.3 (CH2, C-4), 26.1 (CH2, C-3), 29.6 (CH2, C-5), 33.8(CH2, C-2), 40.8 (CH2, C-6), 66.7 (CH2, CH2Ph), 128.1 (3 x CH, Ph), 128.5 (2 x CH, Ph),136.6 (C, Ph), 156.5 (C, Cbz), 178.8 (C, C-i); vmax (cm1) 3331, 2944, 1687, 1527, 1252,1140, 945.
83% With sodium hydroxide In water A solution of 6-aminocaproic acid (32.8 g, 0.25M) in 75 mL of H2 O and 42 mL of 6N NaOH was cooled in a salt-ice bath to below 10° C. With stirring, benzyl chloroformate, 46.9 g, 0.275M) and 2N NaOH (138 mL) were alternatively added in small portions over 90 min.
After the addition was complete, the solution was brought to room temperature, and stirring was continued for an additional 1 hr.
The product was precipitated by lowering the pH to 2 with concentrated HCL, and H2 O was added as required to keep the suspension stirring.
The white precipitate was filtered, then resuspended and triturated with 1 liter of water.
The solid was filtered, washed with water, compressed and then washed with hexane.
The solid was then thoroughly dried in a vacuum desiccator to yield 55 grams (83percent yield) of N-benzyloxycarbonyl-6-aminocaproic acid.
82% With sodium hydroxide In water for 0.633333 h; Cooling with ice Under ice-cooling, respectively, to the 6-aminocaproic acid (3.28g, 25mmol) in NaOH solution (3N, 10ml) Was added dropwise NaOH (4N, 10ml), CbzCl, basically the same rate, About 8min dropcomplete. 30min later,The reaction was stopped.The aqueous layer was extracted with ethyl acetate,Diversion layer pH = 3,Solid precipitated,filter,The filter cake was washed with ice water As a white solid,Vacuum dried overnight. 5.43g, yield 82percent
81% With sodium hydroxide In 1,4-dioxane; water at 0 - 20℃; for 48 h; [00271j Synthesis of 6-(((benzyloxy)carbonyl)amino)hexanoic acid. 6-Aminohexanoic acid (4.61 g, 35.17 mmol) was dissolved in a mixture of 15percent aqueous NaOH (100 mL) and dioxane (100 mL). After the mixture was cooled to 0°C, benzyl chloroformate (10 mL, 70.34 mmol) was added with vigorous stirring. The mixture was then stirred at room temperature for 2 days. The solvent was removed, the product mixture dissolved in water and acidified with acetic acid, and the product extracted into methylene chloride. The organic layer was dried with Na2SO4, filtered, and the solvent was removed. The product was purified by flash column chromatography using a gradient of heptane/ethyl acetate to give 81 percent (7.62 g).
81% With sodium hydroxide In water at 0 - 20℃; for 0.5 h; General procedure: To a cooled (0°C) solution of the appropriate amino acid (1 eq) in NaOH 2N, a solution of benzyl chloroformate (1.1 eq) was added dropwise. The mixture was kept under vigorous stirring for 30 min. The solution was then washed with Et2O, acidified to pH=2 with HCl 3 N and extracted with EtOAc. The organic phase was dried over Na2SO4 and evaporated under vacuo to give 8–12. 4.1.4.4
6-(((benzyloxy)carbonyl)amino)hexanoic acid (11)
White solid: 81percent yield, 1H NMR (400 MHz, DMSO) δ 1.35-1.42 (m, 2H), 1.50-1.58 (m, 2H), 1.63-1.70 (m, 2H), 2.36-2.39 (m, 2H), 3.21 (m, 2H, J = 7.4 Hz), 4.87 (brs, 1H, exch D2O), 5.13 (s, 2H), 7.33-7.39 (m, 5H), 9.36 (brs, 1H, exch D2O); ESI-MS (m/z): 266 [M+H]+.

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YieldReaction ConditionsOperation in experiment
97.3% at 0 - 20℃; Thionyl chloride (1.4equiv) was added dropwise to a stirred methanol suspension of amide linker 4 (1equiv) at 0°C. The resulting solution was stirred overnight at room temperature. The solvent and thionyl chloride in excess were removed under reduced pressure.
97% at 20℃; Reflux General procedure: To a solution of the amino acid 1a–1e (22.45 mmol, 1 mol equiv) in 20–30 cm3 of dry methanol in a two-neck flask with a reflux condenser 2.3 cm3 thionyl chloride (31.43 mmol,1.4 mol equiv) was added drop-wise over 5–10 min. After the addition was complete, the mixture was heated to reflux for 3 h. The reaction mixture was left to stir over night at room temperature. After the reaction was complete, the solvent was removed by evaporation (RVE). The white or light-yellow solid was washed with n-hexane(2 9 50 cm3), and evaporated with another portion of n-hexane. The product was dried at low pressure.
96% at 0 - 20℃; for 2 h; Cooling with ice General procedure: To a solution of amino substituted fatty acid derivatives 10a-10d (10 mmol) in 20 mL methanol was added thionyl chloride (20 mmol) dropwise under ice bath. After stirring at room temperature for about 2 h, the solution was evaporated to give the desired products 11a-11d.
95.6% at 0 - 20℃; for 7 h; 6-Aminocaproic acid (5.0 g, 38.0 mmol) was dissolved in dry methanol (100 mL).To this solution SOCl2 (6.92mL, 95.0 mmol) was addeddrop-wise at time interval of 2 h, maintaining the temperatureat 0C. The reaction was further stirred for5 h at room temperature. The methanol was evaporatedunder vacuum and resulting solid was co-evaporatedwith diethyl ether several times to isolate the compound 9 as white solid, (6.59 g, 95.6percent yield). 1H NMR(300 MHz) (CDCl3): δ 1.44 (quintuplet, J1 = 6.6 Hz,J2 = 14.7 Hz, 2H, CH2), 1.66 (quintuplet, J1 = 7.2 Hz,J2 = 14.7 Hz, 2H, CH2); 1.80 (broad quintuplet, J =6.3 Hz, 2H, CH2); 2.33 (t, J = 8.7 Hz, 2H, CH2); 3.01,(bt, 2H, CH2); 3.66 (s, 3H, OCH3); 8.26 (bs, 3H, NH+3 )ppm. 13C NMR (75 MHz) (CDCl3): δ 24.04, 25.78,27.01, 33.48, 39.66, 51.43, 173.74 ppm. LC-MS m/z259.2 [M + TFA]+.
94%
Stage #1: at -15 - -10℃;
Stage #2: at 20℃; for 19 h;
Thionyl chloride (114 mmol, 8.30 mL) was slowly added to dry MeOH (90 mL) at -15 °C and the resulting solution was stirred for 10 min at -10 °C. 6-Aminohexanoic acid (22.9 mmol, 3.00 g) was added and the mixture was stirred for 19 h at room temperature. The solution was concentrated, the residue was redissolved in MeOH (20 mL), cooled to -20°C and Et2O (80 mL) was added. Filtration afforded methyl ester hydrochloride (3.91 g, 94percent) as white crystals; mp 118-120 °C; 1H-NMR (CD3OD): δ = 1.37-1.47 (m, 2H), 1.61-1.74 (m, 4H), 2.37 (t, J = 7.3 Hz, 2H), 2.93 (t, J = 7.6 Hz, 2H), 3.66 (s, 3H), 4.96 (bs, 1H); 13C-NMR (CD3OD): δ = 25.4, 26.9, 28.2, 34.4, 40.6, 52.1, 175.6.
94% at 0 - 75℃; for 5 h; General procedure: Compound 5 (1.5 g, 10 mmol) was dissolved in 200 mL MeOH, thenacetyl chloride (2.4 g, 30 mmol) was added dropwise at 0 °C; themixed solution was refluxed at 75 °C for 5 h. The solvent wasevaporated under vacuum, the product was washed by diethylether to give compound 6, a white solid powder (1.7 g, 93percent).
90% at 0℃; General procedure: Thionyl chloride (10 mL) was slowly added to a cold suspension solution of the appropriate aminoacid (50 mmol) in methanol (50 mL) at 0 °C. The reaction mixture was stirred for 8–10 h and thenconcentrated on a rotary evaporator. The white precipitate formed was washed with anhydrous etherand then dried under vacuum. All data agreed with the reported data [43,44].

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  • 35
  • [ 60-32-2 ]
  • [ 1926-80-3 ]
YieldReaction ConditionsOperation in experiment
99% With hydrogen chloride (gas) In methanol 1.
Preparation of methyl 6-aminocaproate hydrochloride.
Hydrogen chloride (gas) was added to a solution of 20.0 g (152 mmol) of 6-aminocaproic acid in 250 ml of methanol via rapid bubbling for 2-3 minutes.
The mixture was stirred at 15-25° C. for 3 hours and then concentrated to afford 27.5 g of the product as a white solid (99percent):
H-NMR (DMSO) 9.35 (1 H, broad t), 3.57 (3H, s), 3.14 (2H, quartet), 2.28 (2H, t), 1.48 (4H, multiplet), and 1.23 ppm (2H, multiplet).
99% With hydrogen chloride (gas) In methanol 1.
Preparation of methyl 6-aminocaproate hydrochloride.
Hydrogen chloride (gas) was added to a solution of 20.0 g (152 mmol) of 6-aminocaproic acid in 250 ml of methanol via rapid bubbling for 2-3 minutes.
The mixture was stirred at 15-25° C. for 3 hours and then concentrated to afford 27.5 g of the product as a white solid (99percent):
H-NMR (DMSO) 9.35 (1 H, broad t), 3.57 (3H, s), 3.14 (2H, quartet), 2.28 (2H, t), 1.48 (4H, multiplet), and 1.23 ppm (2H, multiplet).
99% With hydrogen chloride (gas) In methanol 1.
Preparation of methyl 6-aminocaproate hydrochloride
Hydrogen chloride (gas) was added to a solution of 20.0 g (152 mmol) of 6-aminocaproic acid in 250 ml of methanol via rapid bubbling for 2-3 minutes.
The mixture was stirred at 15°-25° C. for 3 hours and then concentrated to afford 27.5 g of the product as a white solid (99percent):
H-NMR (DMSO) 9.35 (1 H, broad t), 3.57 (3H, s), 3.14 (2H, quartet), 2.28 (2H, t), 1.48 (4H, multiplet), and 1.23 ppm (2H, multiplet).
99% With hydrogen chloride (gas) In methanol 1.
Preparation of methyl 6-aminocaproate hydrochloride.
Hydrogen chloride (gas) was added to a solution of 20.0 g (152 mmol) of 6-aminocaproic acid in 250 ml of methanol via rapid bubbling for 2-3 minutes.
The mixture was stirred at 15°-25° C. for 3 hours and then concentrated to afford 27.5 g of the product as a white solid (99percent):
H-NMR (DMSO) 9.35 (1H, broad t), 3.57 (3H, s), 3.14 (2H, quartet), 2.28 (2H, t), 1.48 (4H, multiplet), and 1.23 ppm (2H, multiplet).
99% With hydrogen chloride (gas) In methanol 1.
Preparation of methyl 6-aminocaproate hydrochloride.
Hydrogen chloride (gas) was added to a solution of 20.0 g (152 mmol) of 6-aminocaproic acid in 250 ml of methanol via rapid bubbling for 2-3 minutes.
The mixture was stirred at 15-25° C. for 3 hours and then concentrated to afford 27.5 g of the product as a white solid (99percent):
H-NMR (DMSO) 9.35 (1 H, broad t), 3.57 (3H, s),
3.14 (:2H, quartet), 2.28 (2H, t), 1.48 (4H,
multiplet), and 1.23 ppm (2H, multiplet).

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  • [ 82911-69-1 ]
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  • [ 88574-06-5 ]
YieldReaction ConditionsOperation in experiment
71% With sodium hydrogencarbonate In water; acetone at 20℃; for 3 h; To a solution of 389 mg (2.96 mmol) 6-aminohexanoic acid in 20 mL acetone/water (1:1), 1.00 g(2.96 mmol) FmocOSuc and 250 mg (2.96 mmol) NaHCO3 were added. The suspension was stirred at rt for 3 h. Acetone was removed at reduced pressure and 20 mL of DCM were added to the residue. The precipitated solid was removed by filtration. The organic phase was washed with 10 mL of 0.1 M HCl and 10 mL ofwater. The solution was dried over Na2SO4, the solvent removed at reduced pressure and the residue was dried in vacuo, yielding 747 mg (71percent) of a colourless solid.
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  • [ 28920-43-6 ]
  • [ 60-32-2 ]
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YieldReaction ConditionsOperation in experiment
81%
Stage #1: With sodium carbonate In 1,4-dioxane; water for 12 h;
Stage #2: With hydrogenchloride In 1,4-dioxane; water
6-Amino-hexanoic acid (13.1 g, 100 mmoL) was dissolved in 10percent aqueous Na2CO3 solution (300 mL), then dioxane (200 mL) was added to the above solution. Fmoc-CI (26 g, 110 mmoL) was added to the above mixture portion-wise, and the resultant reaction mixture was stirring for 12h. The mixture was extracted with ether (150 mL X 2), and the aqueous portion was acidified by 6N HCI. The mixture was filtered, and the solid was washed with water and dried to give 6- (9H-Fluoren-9-ylmethoxycarbonylamino)-hexanoic acid as a white solid (31 g, 81 percent). 6- (9H-Fluoren-9-ylmethoxycarbonylamino)-hexanoic acid (9.17 g, 25 mmoL) and 0- (2, 4- dimethoxy-benzyl)-hydroxylamine (36 g, 26 mmoL) were dissolved in DCM (250 mL), then DCC (6.18 g, 30 mmoL) was added ortion-wise. The resultant mixture was stirred for 3h at room temperature, then cooled to 0°C, filtered, and washed with DCM. The organic solution was evaporated to dryness to give the crude [5- (2, 4-dimethoxy- benzyloxycarbamoyl)-pentyl]-carbamic acid 9H-fluoren-9-ylmethyl ester. The crude ester was reacted with piperidine (5 mL) in MeOH (150 mL) at room temperature for12 h. The solution was evaporated and the residue was purified by flash chromatography (silica, EtOAc: MeOH = 5: 1). 6-Amino-hexanoic acid (2,4-dimethoxy- benzyloxy)-amide was obtained as a white solid (4.15 g, 56percent).
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  • [ 72040-64-3 ]
Reference: [1] Journal of the American Chemical Society, 2004, vol. 126, # 44, p. 14411 - 14418
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YieldReaction ConditionsOperation in experiment
1.455 g With sodium hydrogencarbonate In water; N,N-dimethyl-formamide at 20℃; for 16 h; ε-Aminocaproic acid (966mg, 8.4mmol) was dissolved in 30mL 1M aqueous NaHCO3 solution. Then N-hydroxysuccinimidobiotin (3.09g) in 35mL DMF was added dropwise to the solution and the mixture was stirred at room temperature for 16h. The solution was concentrated under reduced pressure to remove partial solvent and 150mL aqueous citric acid (100g/L) was then added and stirred at 60°C for 30min. The precipitate was collected by filtration and washed with distilled water. The precipitate was dissolved in a mixture of isopropanol and water (8:2, v/v) and kept at 4°C to give pure 3 (1.455g, 50percent) as a yellowish crystal; IR cm−1 (KBr): 3200–3500, 3070, 2932, 2859, 1696, 1644, 1543, 1475, 1391, 1324, 1265, 1118; 1H NMR (600MHz, DMSO-d6): δ 7.75 (1H, t, J=5.4Hz, C6–NH), 6.45 (1H, s, C13–NH), 6.38 (1H, s, C14–NH), 4.35–4.27 (1H, m, H-14), 4.12 (1H, m, H-13), 3.09 (1H, m, H-12), 3.00 (1H, m, H-6) 2.82 (1H, dd, J=12.4, 5.1Hz, H-15a), 2.57 (1H, d, J=12.4Hz, H-15b), 2.19 (2H, t, J=7.4Hz, H-2), 2.04 (2H, t, J=7.3Hz, H-8), 1.20–1.67 (14H, m). 13C NMR (150MHz, DMSO-d6): δ 171.84 (C-1, C-7), 162.74 (C-16), 61.06 (C-13), 59.20 (C-14), 55.44 (C-12), 39.68 (C-15), 38.25 (C-6), 35.21 (C-8), 29.05 (C-2), 28.92, 28.21, 28.04, 26.04, 25.73, 25.36.
Reference: [1] Chemical Communications, 2009, # 33, p. 5030 - 5032
[2] European Journal of Medicinal Chemistry, 2014, vol. 71, p. 219 - 228
[3] RSC Advances, 2018, vol. 8, # 57, p. 32775 - 32793
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Reference: [1] Patent: US2012/232262, 2012, A1, . Location in patent: Page/Page column 3
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  • [ 72040-64-3 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 15, p. 3591 - 3594
  • 47
  • [ 60-32-2 ]
  • [ 159857-81-5 ]
Reference: [1] International Journal of Molecular Sciences, 2017, vol. 18, # 9,
[2] Patent: CN107789630, 2018, A,
[3] Patent: CN108743968, 2018, A,
  • 48
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  • [ 1215493-56-3 ]
Reference: [1] Patent: US2012/94971, 2012, A1,
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