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Chemical Structure| 107-95-9
Chemical Structure| 107-95-9
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Product Details of [ 107-95-9 ]

CAS No. :107-95-9 MDL No. :MFCD00008200
Formula : C3H7NO2 Boiling Point : -
Linear Structure Formula :- InChI Key :UCMIRNVEIXFBKS-UHFFFAOYSA-N
M.W : 89.09 Pubchem ID :239
Synonyms :
2-Carboxyethylamine;3-Aminopropanoic acid;beta-Alanine

Calculated chemistry of [ 107-95-9 ]

Physicochemical Properties

Num. heavy atoms : 6
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.67
Num. rotatable bonds : 2
Num. H-bond acceptors : 3.0
Num. H-bond donors : 2.0
Molar Refractivity : 21.01
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) : -9.01 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.5
Log Po/w (XLOGP3) : -3.05
Log Po/w (WLOGP) : -0.58
Log Po/w (MLOGP) : -0.85
Log Po/w (SILICOS-IT) : -0.87
Consensus Log Po/w : -0.97

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 3.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : 1.66
Solubility : 4080.0 mg/ml ; 45.8 mol/l
Class : Highly soluble
Log S (Ali) : 2.28
Solubility : 17100.0 mg/ml ; 192.0 mol/l
Class : Highly soluble
Log S (SILICOS-IT) : 0.4
Solubility : 221.0 mg/ml ; 2.48 mol/l
Class : Soluble

Medicinal Chemistry

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

Safety of [ 107-95-9 ]

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 [ 107-95-9 ]

* 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 [ 107-95-9 ]
  • Downstream synthetic route of [ 107-95-9 ]

[ 107-95-9 ] Synthesis Path-Upstream   1~39

  • 1
  • [ 368-16-1 ]
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  • [ 584-85-0 ]
Reference: [1] The Journal of biological chemistry, 1959, vol. 234, p. 3210 - 3218
[2] Biochimica et biophysica acta, 1959, vol. 31, # 1, p. 47 - 55
  • 2
  • [ 368-16-1 ]
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  • [ 584-85-0 ]
Reference: [1] The Journal of biological chemistry, 1959, vol. 234, p. 3210 - 3218
[2] Biochimica et biophysica acta, 1959, vol. 31, # 1, p. 47 - 55
  • 3
  • [ 61076-89-9 ]
  • [ 107-95-9 ]
  • [ 694-32-6 ]
  • [ 99645-98-4 ]
Reference: [1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1985, p. 1255 - 1264
[2] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1985, p. 1255 - 1264
  • 4
  • [ 95-54-5 ]
  • [ 107-95-9 ]
  • [ 29518-68-1 ]
YieldReaction ConditionsOperation in experiment
66% With hydrogenchloride In water for 5 h; Reflux General procedure: General procedure for the synthesis of (1H-benzimidazole-2-yl)alkylamines was adapted from the Phillips procedure.18 L-Amino acid was added to a stirred solution of 4-nitro-o-phenylendiamine and aqueous HCl (5.5 M). The mixture was heated under reflux for 5 h. The blue reaction mixture was cooled to room temperature. The mixture was allowed to stand for overnight where upon the desired (1H-benzimidazole-2-yl)alkylamine was crystallized in its HCl salt form. The free base was obtained by neutralization of the reaction mixture with 1M K2CO3 solution followed by extraction with ethyl acetate. The extract was evaporated to dryness and recrystallized from an ethanol.
Reference: [1] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 1, p. 550 - 558
[2] Bulletin de la Societe Chimique de France, 1991, p. 255 - 259
[3] Collection of Czechoslovak Chemical Communications, 1950, vol. 15, p. 196,200
  • 5
  • [ 75-15-0 ]
  • [ 79-08-3 ]
  • [ 107-95-9 ]
  • [ 7025-19-6 ]
YieldReaction ConditionsOperation in experiment
45%
Stage #1: With potassium hydroxide In water at 20 - 25℃; for 3 h;
Stage #2: at 20℃; for 3 h;
Stage #3: With sulfuric acid In water at 20℃;
3-(4-Oxo-2-thioxothiazolidin-3-yl)propanoic acid (33). To a solution of β-alanine 32 (3.4 g, 38.1 mmol) in 17 mL of 22percent KOH solution, CS2 2.5 mL (42 mmol) was added dropwise making sure the temperature of the reaction did not exceed 25 °C. The mixture was allowed to stir at r.t. for approximately 3 hours and then bromoacetic acid (5.3 g, 38.1 mmol) was added portionwise over 20 minutes. The reaction mixture was stirred at room temperature for additional 3 hours during which time a precipitate was formed. The pH of the reaction mixture was adjusted to 3-4 using cone. H2S04 and the resulting solution was stirred overnight at room temperature. The precipitate was filtered off and washed with water thus obtaining the desired pure compound 33 (3.52 g, yield 45percent) as a yellow solid. Mp 155-156 °C. 1H NMR (400 MHz, MeOD- 1/4) δ (ppm) 5.00 (brs, 1H), 4.22 (t, J = 7.5, 2H), 4.11 (s, 1H), 2.64 (t, J = 7.6, 2H). 13C NMR (100 MHz, MeOD- 1/4) δ (ppm) 202.58, 174.37, 172.87, 39.64, 35.08, 30.28. MS (ESI) m/z: 204.1 [M-H]\\ Anal. Calcd for (C6H7N03S2): C, 35.11; H, 3.44; N, 6.82. Found: C, 35.10; H, 3.48; N, 6.88.
Reference: [1] ChemMedChem, 2014, vol. 9, # 11, p. 2538 - 2547
[2] Patent: WO2011/39735, 2011, A2, . Location in patent: Page/Page column 149-150
[3] ChemMedChem, 2014, vol. 9, # 11, p. 2538 - 2547
  • 6
  • [ 75-15-0 ]
  • [ 7748-25-6 ]
  • [ 107-95-9 ]
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Reference: [1] Journal of Medicinal Chemistry, 2016, vol. 59, # 24, p. 10917 - 10928
  • 7
  • [ 107-10-8 ]
  • [ 6168-72-5 ]
  • [ 632-12-2 ]
  • [ 56-40-6 ]
  • [ 107-95-9 ]
Reference: [1] Tetrahedron Letters, 1981, vol. 22, p. 769 - 772
[2] Tetrahedron Letters, 1981, vol. 22, p. 769 - 772
[3] Tetrahedron Letters, 1981, vol. 22, p. 769 - 772
  • 8
  • [ 107-10-8 ]
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  • [ 632-12-2 ]
  • [ 56-40-6 ]
  • [ 156-87-6 ]
  • [ 107-95-9 ]
Reference: [1] Tetrahedron Letters, 1981, vol. 22, p. 769 - 772
  • 9
  • [ 108-31-6 ]
  • [ 6066-82-6 ]
  • [ 107-95-9 ]
  • [ 55750-62-4 ]
YieldReaction ConditionsOperation in experiment
80%
Stage #1: at 70℃; Inert atmosphere
Stage #2: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In acetonitrile at 0 - 70℃;
EXAMPLE 1N-Maleimidopropionic acid NHS ester[0083] Maleic anhydride, β-alanine (1 mol eq.), and acetonitrile (ACN, 25 volumes) were charged to a vessel. The slurry was stirred under nitrogen and heated to 70 0C. The temperature was maintained at 70 0C for a further 5 to 8 hours. After cooling to 5 0C, NHS (1 mol eq.) was charged, followed by Λ/-(3-dimethylaminopropyl)-Λf'-ethylcarbodiimide hydrochloride (EDCI, 1 mol eq.). The temperature was maintained at 0 - 5 0C for 1 hour before adding a further charge of EDCI (1 mol eq.). The mixture was heated to 70 0C and maintained at this temperature for 7 hours. The reaction mixture was cooled to 200C and concentrated under vacuum at a maximum temperature of 45°C until the rate of solvent distillation was negligible. Dichloromethane (DCM, 40 volumes) was added to the residue, which was stirred until a solution was formed. This solution was washed with aqueous ammonium chloride (12 percent w/w, 25 wt eq.) then with aqueous sodium chloride (24 percent w/w, 25 wt eq.). The organic solution was dried by stirring with magnesium sulphate (1 wt eq.) at ambient temperature for 1 to 2 hours. The inorganics were filtered off under vacuum and the filter cake was washed with DCM (4 volumes). The filtrates were concentrated under vacuum, whilst gradually replacing DCM with isopropylacetate (IPAC). The residual slurry was cooled and stirred at ambient temperature for 1 hour before filtering under vacuum. The product filter cake was washed with IPAC (4 volumes) and then dried to constant mass under vacuum with slow rotation at 40 0C to yield the desired compound as an off white solid. The typical yield is 60 to 80 percent of the maximum theoretical yield.[0084] The product was characerised by NMR as follows: 1H NMR (400MHz, d6-DMSO): δ 2.80 (4H, br s), δ 3.05 (2H, t, J ~ 7Hz), δ 3.75 (2H, t J ~ 7Hz), δ 7.05 (2H, s).
60%
Stage #1: at 20℃; for 2.5 h;
Stage #2: With dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 0 - 20℃;
To a solution of maleic anhydride (2.00 g, 20.4 mmol) in 24 mL of DMF was added β-alanine (1.82 g, 20.4 mmol)and the mixture was stirred for 2.5 h at room temperature in which the solid was gradually dissolved to afford clear solution. The reaction was cooled in an ice bath and N-hydroxysuccinimide (HOSu) (2.88 g, 25 mmol) andN,N'-dicyclohexylcarbodiimide (8.24 g. 40.0 mmol) were successively added to the solution. After 30 min, the reaction was warmed to room temperature and stirred for 14 h. The reaction mixture was filtered through a cottonplug and the residue was washed with DCM and water. The filtrates were gathered and the organic layer was washed with satd NaHCO3 (three times) and brine, dried over Na2SO4 and concentrated to afford 1 (3.20 g, 60percent) as a white solid. 1H NMR (400 MHz, d6-DMSO): 2.78 (s, 4H), 3.03 (t, J = 6.9 Hz, 2H), 3.73 (t, J = 6.9 Hz, 2H),7.02 (s, 2H); 13C NMR (100 MHz, d6-DMSO): 25.4, 29.0, 32.7, 134.6, 166.7, 169.9, 170.5.
25% With dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 0 - 20℃; for 1 h; On a solution of N-hydroxysuccinimide (12.6 mmol) and dicyclohexylcarbodiimide (20.3 mmol) at 0° C., corresponding acid (6 mmol) was added and allowed to react for 4 hours at room temperature. In the case of compound VIa, a solution of maleic anhydride (10 mmol) and β-alanine was added in N,N-dimethylformamide, which has been previously made react for 1 hour. After 4 hours, mixture was evaporated at reduced pressure and the crude was dissolved in dichloromethane and washed with water. Organic extracts were dried with anhydrous magnesium sulfate, filtered and evaporated to dryness. Resulting residue was recrystallized to give desired compound. [0112] Using this methodology, and corresponding acid, the following compounds were prepared: [0113] 3-succinimidyl maleimidopropionate (VIa, 25percent yield). 1H NMR (CDCl3) δ ppm: 2.82 (4H, s), 3.02 (2H, t, J=7.07 Hz), 3.94 (2H, t, J=7.07 Hz), 6.74 (2H, s); 13C NMR (CDCl3) δ ppm: 25.5 (2C, s), 29.7 (1C, s), 32.9 (1C, s), 134.3 (2C, s), 166.0 (1C, s), 168.7 (2C, s), 170.1 (2C, s).
Reference: [1] Patent: WO2011/23680, 2011, A2, . Location in patent: Page/Page column 13-14
[2] Angewandte Chemie - International Edition, 2015, vol. 54, # 35, p. 10198 - 10201[3] Angew. Chem., 2015, vol. 127, p. 10336 - 10339
[4] Journal of the American Chemical Society, 2013, vol. 135, # 29, p. 10582 - 10585
[5] Journal of the American Chemical Society, 2004, vol. 126, # 3, p. 734 - 735
[6] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 5, p. 1721 - 1728
[7] Macromolecular Bioscience, 2012, vol. 12, # 9, p. 1209 - 1219
[8] Patent: US2013/273581, 2013, A1, . Location in patent: Paragraph 0111-0113
[9] Synthesis, 1991, # 10, p. 819 - 821
[10] Patent: WO2011/9047, 2011, A2, . Location in patent: Page/Page column 13
[11] Patent: US2013/157375, 2013, A1, . Location in patent: Paragraph 0103; 0104
[12] Chemical Communications, 2014, vol. 50, # 26, p. 3473 - 3475
[13] Patent: WO2014/100762, 2014, A1, . Location in patent: Paragraph 248
[14] Chemical Communications, 2015, vol. 51, # 53, p. 10758 - 10761
[15] Angewandte Chemie - International Edition, 2017, vol. 56, # 9, p. 2356 - 2360[16] Angew. Chem., 2017, vol. 129, # 9, p. 2396 - 2400,5
  • 10
  • [ 108-31-6 ]
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YieldReaction ConditionsOperation in experiment
67% at 170 - 180℃; for 1.5 h; First, 3-maleimidopropionic acid was synthesized according todescribed literature methods with modification [26,27]. A suspensionof maleic anhydride (3.21 g, 32.78 mmol) and β-alanine (3 g,33.67 mmol) in glacial AcOH (30 mL) was heated to reflux (bath temperature:170–180 °C) for 90min. The solutionwas cooled to roomtemperatureand the solvent was evaporated in vacuo. Residual AcOH wasremoved by coevaporation with toluene under vacuum (2 × 50 mL).The residue was treated with water (100 mL) and EtOAc (200 mL).The organic layer was separated while the aqueous layer was extractedwith EtOAc (2 × 100 mL). The combined organic extracts were dried(Na2SO4) and evaporated in vacuo. The crude product was purified bysilica gel column chromatography, eluting with 50percent ethyl acetate inhexanes, to afford 3-maleimidopropionic acid (3.7 g, 21.88 mmol, 67percentyield), the spectroscopic data of which was consistent with reporteddata.(27) 1H NMR (CDCl3) δ 8.93 (br s, 1H), 6.71 (s, 2H), 3.80 (t, J =7.2 Hz, 2H), 3.62–3.66 (m, 24H), 2.67 (t, J = 7.2 Hz, 2H).
Reference: [1] International Journal of Molecular Sciences, 2017, vol. 18, # 9,
[2] Journal of Medicinal Chemistry, 2013, vol. 56, # 24, p. 9955 - 9968
[3] Journal of Controlled Release, 2015, vol. 220, p. 660 - 670
[4] Chemistry - A European Journal, 2015, vol. 21, # 38, p. 13186 - 13190
[5] Journal of the American Chemical Society, 2013, vol. 135, # 11, p. 4333 - 4363
[6] Synthesis, 2008, # 8, p. 1316 - 1318
[7] Chemical Communications, 2017, vol. 53, # 5, p. 959 - 962
[8] RSC Advances, 2018, vol. 8, # 5, p. 2818 - 2823
[9] Organic and Biomolecular Chemistry, 2009, vol. 7, # 16, p. 3308 - 3318
[10] Tetrahedron Letters, 1998, vol. 39, # 38, p. 6987 - 6990
[11] Organic Letters, 2010, vol. 12, # 9, p. 1920 - 1923
[12] Journal of the American Chemical Society, 2005, vol. 127, # 9, p. 2966 - 2973
[13] Tetrahedron Letters, 2001, vol. 42, # 12, p. 2377 - 2380
[14] Organic Letters, 2004, vol. 6, # 20, p. 3561 - 3564
[15] Organic and Biomolecular Chemistry, 2009, vol. 7, # 17, p. 3400 - 3406
[16] Chemical Communications, 2011, vol. 47, # 25, p. 7068 - 7070
[17] Chemistry - A European Journal, 2011, vol. 17, # 46, p. 13059 - 13067
[18] Patent: US2014/56810, 2014, A1, . Location in patent: Paragraph 0181
[19] Organic and Biomolecular Chemistry, 2014, vol. 12, # 34, p. 6624 - 6633
[20] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 2, p. 162 - 167
[21] Patent: WO2015/196167, 2015, A1, . Location in patent: Paragraph 0269; 0277
[22] Patent: CN104147619, 2018, B, . Location in patent: Paragraph 0045; 0046
[23] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 9, p. 2599 - 2609
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Reference: [1] European Journal of Inorganic Chemistry, 2013, # 8, p. 1381 - 1389
  • 12
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YieldReaction ConditionsOperation in experiment
95.4% at 60℃; for 5 h; In a 250 mL reaction flask,Add 180 mL of chloroform,30 g of β-alanine (0.337 mol)37.8 g of acetic anhydride (0.371 mol),Heating up to 60 ,Reaction for 5 hours,Sampling ninhydrin does not develop color,Cooling to 4 ,Stirring for 1 hour,Filter to get solid,Dried to give the product (I) 42 g,The yield was 95.4percentHPLC purity ≥99.3percent.
Reference: [1] European Journal of Organic Chemistry, 2012, # 29, p. 5774 - 5788,15
[2] European Journal of Organic Chemistry, 2012, # 29, p. 5774 - 5788
[3] Journal of the American Chemical Society, 2017, vol. 139, # 39, p. 13596 - 13599
[4] Patent: CN105461632, 2016, A, . Location in patent: Paragraph 0030
[5] Journal of Polymer Science, 11946>124,
[6] Journal of Medicinal Chemistry, 1987, vol. 30, # 3, p. 567 - 574
[7] Journal of Medicinal Chemistry, 1985, vol. 28, # 1, p. 9 - 12
[8] New Journal of Chemistry, 2016, vol. 40, # 6, p. 5209 - 5220
  • 13
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YieldReaction ConditionsOperation in experiment
95.7% at 50℃; for 5 h; In a 1000 mL reaction flask,360 mL of toluene was added,120 g beta-alanine (1.348 mol)111.2 g of acetyl chloride (1.417 mol)Heating up to 50 ,Reaction for 5 hours,Sampling ninhydrin does not develop color,Cooling to -3 ,Stirring for 1 hour,Filter to get solid,Dried to give 169.0 g of product (I)The yield was 95.7percent and the HPLC purity was ≥99.3percent.
Reference: [1] Patent: CN105461632, 2016, A, . Location in patent: Paragraph 0032
  • 14
  • [ 64-19-7 ]
  • [ 107-95-9 ]
  • [ 3025-95-4 ]
YieldReaction ConditionsOperation in experiment
93.4% at 45℃; for 3 h; In a 500 mL reaction flask,Adding dichloromethane to 360 mL,60 g of β-alanine (0.674 mol)48.5 g acetic acid (0.808 mol),Heating up to 45 ,Reaction for 3 hours,Sampling ninhydrin does not develop color,Cooling to 4 ,Stirring for 1 hour,Filter to get solid,Dried to give 82.5 g of product (I)The yield was 93.4percentHPLC purity ≥99.3percent.
Reference: [1] Patent: CN105461632, 2016, A, . Location in patent: Paragraph 0031
  • 15
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YieldReaction ConditionsOperation in experiment
60% With acetic anhydride In sodium hydrogencarbonate; acetonitrile Example 19
Preparation of N-Acetyl-β-alanine(4a)
To a solution of β-alanine (2,25 g, 25 mmol) in aq. NaHCO3(15 mL) was added acetonitrile (15 mL) and acetic anhydride (2.55 g, 25 mmol).
The reaction mixture was stirred at room temperature for 3 h.
Acetic anhydride (2.55 g, 25 mmol) was added and after 2 h and pH was adjusted to 4-5 by addition of NaH2PO4.
The product was extracted into EtOAc (3*50 mL), dried (Na2SO4), and evaporated to dryness under vacuum to afford 1.96 g (60percent)
Reference: [1] Patent: US2003/143561, 2003, A1,
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  • [ 557-24-4 ]
Reference: [1] Patent: US2003/60441, 2003, A1,
[2] Patent: US4980482, 1990, A,
  • 17
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  • [ 2304-94-1 ]
YieldReaction ConditionsOperation in experiment
60% With sodium hydroxide In ethanol; water at 0℃; for 3.5 h; To a mixture of 0.1 mol corresponding amino acid (3-aminopropanoic acid, 4-aminobutanoic acid, 6-aminohexanoic acid, 8-aminooctanoic acid etc.) in ethanol (25 ml) in round-bottom flask (250 mol) equipped with a magnetic stirrer and dropped funnel, a solution of NaOH (8.8 g., 0.22 mol) in 100 ml water is added and the mixture is stirred by magnetic stirrer until fully dissolved. The obtained solution is cooled to 0° C. in an ice-water bath, and benzyl chloroformate (27.4 g, 0.15 mol) is added drop wise over 30 min. The reaction mixture is stirred for 3 hours at 0° C. Subsequently, about 100 ml water is added to the reaction solution and the mixture is poured into separated funnel. The water solution is extracted with diethyl ether (3.x.50 ml). The water phase is separated and acidified with HCl (3N) to pH=1 while cooling in an ice-water bath. If a precipitate is formed, it is filtered, washed with water and dissolved in 100 ml chloroform. The chloroform solution is dried with sodium sulfate for two hours. Then the sodium sulfate is separated from the chloroform solution by filtration and the solvent is evaporated in evaporator under vacuum. The residue is washed with hexane, and dried overnight in vacuum over phosphorus pentoxide (P2O5). [00089] If a precipitate is not formed, or in order to maximize the product yield, the acidified aqueous fraction is washed with chloroform (2.x.50 ml). The chloroform extracts are combined and washed with water (50 ml). The following operations with this solution are the same as for the above-described chloroform solution of the precipitate, namely, drying with sodium sulfate for two hours, then separating the sodium sulfate from the chloroform solution by filtration and evaporating the solvent in evaporator under vacuum. The residue is then washed with hexane, and dried overnight in vacuum over phosphorus pentoxide. [00090] All products were analyzed on TLC as follows: TLC analysis. Silica gel 60 on aluminium sheet. Eluent is chloroform-methanol (4:1 v/v). Indicator is a spray of the composition: 4-methoxybenzaldehyde (10 ml), absolute ethanol (200 ml), 98percent sulfuric acid (10 ml) and gracial acetic acid (2 ml). The chromatogram is sprayed with the indicator and then charred at 150-180° C. [00091] The following are specific intermediate products obtained at the end of stage 1 of the synthesis procedure: [00092] 3-[N-(Benzyloxycarbonyl)amino]propanoic acid. C6CH5-CH2-O-C(O)-NH-CH2-CH2-COOH. [00093] White solid. Yield 60percent. TLC analysis: One spot Rf0.7. 1H NMR (CD3OD). δ (ppm): 2.46-2.52 (t, 2H, α-CH2 group of alanine), 3.29-3.39 (t, 2H, γ-CH2 group of alanine) 5.06 (s, 2H, benzylic CH2 group), 7.27-7.32 (m, 5H, C6H5 group). [00094] 4[N-(Benzyloxycarbonyl)amino]butanoic acid C6H5CH2-O-C(O)-NH-(CH2)3-COOH. [00095] White solid. Yield 60percent. TLC analysis: One spot. Rf0.7. 1H NMR (CD3OD). δ (ppm): 1.71-1.82 (m, 2H), 2.28-2.34 (m, 2H), 3.10-3.17 (t 2H), 5.06 (s, 2H), 7.26-7.34 (m, 5H). [00096] 5-[N-(Benzyloxycarbonyl)amino]valeric acid C6H5CH2-O-C(O)-NH-(CH2)4-COOH. [00097] White solid. Yield 60percent. TLC analysis: One spot. Rf=0.7. 1H NMR (CD3OD) δ (ppm): 1.45-1.50 (m 2H), 1.56-1.62 (m, 2H), 2.25-2.31 (t, 2H) 3.08-3.13 (t, 2H), 5.05 (s, 2H), 7.26-7.34 (m, 5H). [00098] 6-[N-(Benzyloxycarbonyl)amino]hexanoic acid C6H5CH2-O-C(O)-NH-(CH2)2-COOH. [00099] White solid. Yield 50percent. TLC analysis: One spot. Rf0.7. 1H NMR (CD3OD). δ (ppm): 1.30-1.63 (m, 6H), 2.24-2.30 (t, 2H), 3.07-3.13 (t, 2H), 5.05 (s, 2H), 7.29-7.34 (m, 5H). [00100] 8-[N-(Benzyloxycarbonyl)amino]octanoic acid C6H5CH2-O-C(O)-NH-(CH2)2-COOH. [00101] White solid. Yield 50percent. TLC analysis: One spot. Rf0 7. 1H NMR (CD3OD). δ (ppm): 1.32 (bs, 6H), 1.47-1.50 (m, 2H), 1.53-1.59 (m, 2H), 2.23-2.29 (t, 2H), 3.06-3.12 (t, 2H), 5.05 (s, 2H), 7.29-7:34 (m, 5H).
52% 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. 4.1.4.1
3-(((benzyloxy)carbonyl)amino)propanoic acid (8)
White solid: 52percent yield, 1H-NMR (400 MHz, CDCl3) δ 2.51-2.59 (m, 2H), 3.44 (t, 2H, J = 5.7 Hz), 5.07 (s, 2H), 5.28 (brs, 1H, exch D2O), 7.23-7.32 (m, 5H), 11.97 (brs, 1H, exch D2O); ESI-MS (m/z): 224 [M+H]+.
Reference: [1] Journal of Organic Chemistry, 2007, vol. 72, # 16, p. 6162 - 6170
[2] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 2, p. 533 - 548
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YieldReaction ConditionsOperation in experiment
99% at 65 - 70℃; Inert atmosphere (3-Amino-1-hydroxypropane-1 ,1-diyl)bis(phosphonic acid) (pamidronic acid) A mixture of 3-aminopropionic acid (1.00 g, 1 1.2 mmol, 1 equiv.) and phosphorous acid (0.920 g, 1 1.2 mmol, 1 equiv.) in methanesulfonic acid (4.7 mL) was heated at 65 °C. Phosphorus trichloride (2.06 ml_, 23.6 mmol, 2.1 equiv.) was added slowly under stirring. After completion of the addition, the temperature was raised to 70 °C and the reaction mixture was stirred overnight under an argon atmosphere at the same temperature. The clear, colorless solution was cooled to 25 °C and quenched at 0-5 °C with water (4 mL) under vigorous stirring. The mixture was then refluxed for 5 h. The solution was cooled to 20 °C and the pH was adjusted to 2 with 1 N sodium hydroxide solution. Methanol was added to the mixture and a precipitate was formed. The mixture aged overnight at 4 °C. The precipitate was filtered off and washed with methanol. The white solid was then solubilized in water and loaded onto a cation exchange column (Si- Tosic acid 40-63 μηι, 0.55 mmol/g) which was beforehand rinsed with 100percent MeOH and then 100percent water. It was eluted with water and the resulting solution was then freeze- dried to get pamidronic acid as a free acid (2.619 g, 99percent) as a white solid. 1H NMR (D20, 400 MHz) δ 3.30 (t, 2H, J = 6.9 Hz), 2.33-2.22 (m, 2H); 13C NMR (D20, 151 MHz) δ 71.7 (t, Jc-p = 140 Hz), 35.3 (t, JC-p = 7.40 Hz), 30.0; 31 P NMR (D20, 162 MHz) δ 17.6; HRMS m/z calcd for C3H12NO7P2 [M+H]+ 236.0084, found 236.0081.
82% With phosphonic Acid; phosphorus trichloride In chlorobenzene at 100℃; for 3 h; Inert atmosphere In a 1,000 mL three-neck flask provided with magnetic stirring, surmounted with a condenser and with nitrogen inertization and placed in a thermostated oil bath and connected to a vacuum pump, 91 g (1 mole) of 3-aminopropionic acid, 123 g (1.5 moles) of phosphorous acid and 500 mL of anhydrous chlorobenzene are added.
The mixture is brought to a temperature of 100° C. with stirring.
The formation of a homogeneous solution is observed. 206 g (1.5 moles) of phosphorus trichloride (PCl3) are then slowly introduced into the medium.
The reaction mixture is maintained at 100° C. for a further three hours and then left to cool at room temperature.
The obtained solid residue is washed with chlorobenzene and then dissolved in 500 mL of water and brought to boiling with reflux for 1 hour.
After cooling, the solution is treated with active carbon and then filtered.
The raw acid precipitates by addition of an excess of hot methanol and after separation, the product is recrystallized from one liter of water at 100° C. The yield is 82percent of 1-hydroxy-3-amino-propylene-1,1-bisphosphonic acid. The reaction product was characterized with 31P NMR (CDCl3), 1H NMR (CDCl3) and 13C NMR.
72%
Stage #1: at 75℃; for 3.5 h; Ionic liquid
Stage #2: at 105℃; for 1 h; Ionic liquid
2.2 g (0.025 mol) of β-Alanine (1) and 4.3 g (0.053 mol) phosphorous acid were added into 3 mL (0.015 mol) of 1-butyl-3-methylimidazolium hexafluorophosphate on stirring. Then, 7 mL (0.080 mol) of phosphorous trichloride was added dropwise in ca. 30 min, and the contents of the flask were stirred at 75 °C for 3 h. After cooling the mixture to 26 °C, 10 mL (0.53 mol) of water was added and the mixture was stirred further at 105 °C for 1 h. Then, the mixture was stirred at 26 °C for 12 h, and finally at 0-5 °C for 3 h. The precipitate was removed by filtration to give ~5 g of the crude product that was suspended in 15 mL of methanol, and the mixture was digested by stirring at 65 °C for 30 min. The solid product was filtered off to furnish 4.2 g (72percent) of pamidronic acid (2) in a purity of >99percent. 31P NMR (D2O) δ:17.6, δ [16]: 17.6; 13C NMR (D2O) δ: 72.8 (t, J = 132.8, PCP), 36.5 (t, J = 7.5, NCH2CH2), 30.8 (s, NCH2), δ [16]: 75.3 (t, J = 133.0, PCP), 39.0 (t, J = 7.7, NCH2CH2), 33.3 (s, NCH2).
72%
Stage #1: at 75℃; for 3 h;
Stage #2: at 0 - 105℃;
2.2 g (0.025 mol) of β-Alanine (1) and 4.3 g (0.053 mol) phosphorous acid were added into 3 mL (0.015 mol) of 1-butyl-3-methylimidazolium hexafluorophosphate on stirring. Then, 7 mL (0.080 mol) of phosphorous trichloride was added dropwise in ca. 30 min, and the contents of the flask were stirred at 75 °C for 3 h. After cooling the mixture to 26 °C, 10 mL (0.53 mol) of water was added and the mixture was stirred further at 105 °C for 1 h. Then, the mixture was stirred at 26 °C for 12 h, and finally at 0-5 °C for 3 h. The precipitate was removed by filtration to give ~5 g of the crude product that was suspended in 15 mL of methanol, and the mixture was digested by stirring at 65 °C for 30 min. The solid product was filtered off to furnish 4.2 g (72percent) of pamidronic acid (2) in a purity of >99percent. 31P NMR (D2O) δ: 17.6, δ [16]: 17.6; 13C NMR (D2O) δ: 72.8 (t, J = 132.8, PCP), 36.5 (t, J = 7.5, NCH2CH2), 30.8 (s, NCH2), δ [16]: 75.3 (t, J = 133.0, PCP), 39.0 (t, J = 7.7, NCH2CH2), 33.3 (s, NCH2).
62.7%
Stage #1: With phosphorous acid In sulfolane at 75℃; for 0.5 h;
Stage #2: With phosphorus trichloride In sulfolane at 35 - 67℃; for 3 h;
Stage #3: With water In sulfolane at 0 - 100℃; for 8 h;
Preparation of pamidronic acid A suspension of 3-aminopropionic acid (25g, 0. 280mol) and phosphorous acid (34. 5g, 0. 421mol) in sulfolan (90ml) is heated to 75° C for 30 min. The mixture is cooled to 35- 40° C and then gradually introduced phosphorous trichloride (83ml, 0. 954mol) while maintaining the temperature at 35-45° C. The mixture is heated to 63-67° C for 3 hrs, whereby white solid results. It is then cooled to 0-5° C and quenched by slow addition of water (250ml) at 0-5° C over a period of 1 hr. The resulting clear solution is charcoalized and is heated at 100° C for 3 hrs, cooled to ambient temperature. Cooled the charcoalized solution and stirred for 4hrs at 0-5° C. The crystallized product is filtered, washed sequentially with chilled water (100mol), rectified spirit (75ml) and dried in air oven at 55-60° C until water content is less than 0.5percent w/w. Yield 41.4g, (62.7percent), appearance: white crystalline solid, purity >99.0percent.
53%
Stage #1: With phosphoric acid; phosphorus trichloride In chlorobenzene at 105 - 110℃; for 2 h;
Stage #2: at 60 - 65℃; for 0.25 h;
To a mixture of 12.3 g (0.15 mol) phosphoric acid, 8.9 g (0.9 mol) beta-aminopropyonic acid and 50 ml chlorobenzene 33.0 g (0.24 mol) PCl3 was added by dropping under stirring at 100° C. The two-layer mixture was heated at 105-110° C. for 2 h. nder those conditions the bottom layer became thick and finally became solid. The reaction mixture was cooled down to 60-65° C. At this temperature 20 ml of water was added drop by drop. The layers were stirred for 15 mm., cooled down to room temperature and then they were separated. The bottom aqueous layer was filtered through paper filter. To the solution was added to 100 ml isopropanol drop by drop (60-65° C.) under stirring. The warm solution was filtered and 100 ml of ethanol was added. After 12 hours at room temperature, precipitate was filtered off generating a yield 12.7 g (62percent) t.m. 232-234° C. To obtain a homogeneous product the solid material was boiled with 50 ml of water and insoluble substance was filtered off yield 10.8 g (53percent) m.p. 234-236° C.

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YieldReaction ConditionsOperation in experiment
81%
Stage #1: With sodium carbonate In 1,4-dioxane; water at 0 - 20℃; for 4 h;
Stage #2: With hydrogenchloride In water
β-Alanine (β-Ala) (0.5 g, 6.61 mmole) was dissolved in 10percent NaCO3 (12 ml) under stirring in a 50 ml flask.
To the resulting solution, which had been put into an ice bath, Fmoc-Cl (1.45 g, 5.61 mmol) in dioxane (10 ml) was gradually added.
The reaction mixture was stirred at room temperature for 4 hours, and water (80 ml) was then added.
The aqueous phase layer was separated from the reaction mixture and stripped with ether three times (75 ml*3).
The stripped aqueous layer was acidified with 2N HCl aqueous solution to a pH value of 2, followed by extraction with ethyl acetate three times (75 ml*3).
The organic phase layer was recovered and concentrated to obtain crude product of 1.50 g.
The crude product was recrystallized in a mixed solvent of ethyl acetate:hexane=1:2 (30 ml), and white solid denoted as Fmoc-β-Ala was obtained after filtration at a reduced pressure. Yield: 1.41 g (81percent).
NMR (CDCl3) δ 2.60 (t, 2H, NHCH2C2COOH), 3.47 (d, 2H, J=7.0 Hz, NHC2CH2COOH), 4.19 (t, 1H, J=6.0 Hz, Fmoc-C), 4.39 (d, 2H, J=7.0 Hz, Fmoc-C2), 7.29 (t, 2H, J=7.3 Hz, Ar-), 7.38 (t, 2H, J=7.3 Hz, Ar-), 7.56 (d, 2H, J=7.0 Hz, Ar-), 7.74 (d, 2H, J=7.5 Hz, Ar-).
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YieldReaction ConditionsOperation in experiment
100%
Stage #1: for 1 h; Cooling with ice
Stage #2: at 20 - 66℃; for 6.5 h;
Under ice bath, 100 ml round-bottom flask was added with 60 ml of methanol, and then slowly added with 4 ml of SOCl2 through constant pressure dropping funnel (with a drying tube on the top), and NaOH solution was used to absorb exhaust.
After stirring for 1 h, 8 mmol of β-alanine was added and stirred at room temperature for 30 min, and then refluxed at 66° C. for 6 h.
The reaction was tracked by TLC until the raw material disappears, with a solution of 2percent ninhydrin in ethanol as chromogenic reagent.
The solvent was evaporated out to obtain β-alanine methyl ester hydrochloride. Yield: 100percent.
98% 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.
85% 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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YieldReaction ConditionsOperation in experiment
87% at -10℃; for 2 h; Reflux Freshly distilled thionyl chloride (250 mL) was added drop-wise to stirring absolute EtOH (400 mL) at –10 ºC. After 20 min at –10 ºC, β-alanine (82.56 g, 0.93 mol) was slowly added to the thionyl chloride/EtOH solution. This mixture was refluxed for 2 h. Excess thionyl chloride was distilled off and the volume of the solution was reduced by half under vacuum. The white precipitate that crystallized from the reduced solution was filtered and washed with cold diethylether to give β-alanine ethyl ester hydrochloride as a white crystalline powder (124.34 g, 87percent).
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