Schönenberger, Helmut and Vogel, H. and Bamann, E. (1965) Synthesis of local anesthetics. Archiv der Pharmazie und Berichte der Deutschen Pharmazeutischen Gesellschaft 298 (6), pp. 371-378.
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The prepns. are described of the local anesthetic compds. MeO2CCH2CHRNHCHRCH2CH2OBz and the N-methyl derivs. 3-Amino-1-butanol (I), b11 63-5 Deg, was prepd. in 37.8% yield by dropwise addn. of a suspension of 28.5 g. LiAlH4 in 900 ml. abs. Et2O to an abs. Et2O soln. (500 ml.) of 0.4 mole methyl acetoacetate oxime (II), and stirring the gently boiling mixt. for 5 hrs. Me beta -[(3-hydroxy-1-methylpropyl)amino]crotonate (III), b0.01 125-6 Deg, was prepd. in 85.5% yield by mixing 23.2 g. Me acetoacetate and 8.9 g. I, adding anhyd. (ignited) Na2SO4, and shaking. Me beta -[(3-hydroxy-1-methylpropyl)amino] butyrate (IV), b0.06 90-1 Deg was prepd. in 69% yield by H-Pt redn. of 14.04 g. III in 100 ml. of abs. MeOH. Dropwise addn. of 2.8 g. BzCl in 20 ml. abs. Et2O to 40 ml. abs. Et2O contg. 3.8 g. IV and refluxing the stirred soln. for 1 hr. yielded 8.5% MeO2CCH2CHMeNHCHMeCH2CH2OBz (V), b0.01 144-5 Deg, purified by countercurrent extn. with 12:28:40 MeOH-2% HCl-CHCl3. V also was prepd. by dropwise addn. of 1.9 g. IV (in 10 ml. abs. Et2O) to Et2O satd. with HCl gas, and evapg. the Et2O from the mixt. in vacuo. The residue was dissolved in 100 ml. 1:1 1,2,4-trichlorobenzene-CHCl3. BzCl (1.4 g.) was added, and the soln. was refluxed for 24 hrs. to give 19.2% V, b0.1 144-8 Deg. Me beta -methylaminobutyrate (VI) was prepd., at 1 atm., by mixing 105 ml. 8.7% MeNH2 in MeOH with 30 g. Me crotonate and allowing the mixt. to stand 1 day at 25 Deg. Alc. MeNH2 was prepd. by adding aq. 33% MeNH2 to solid NaOH, and absorbing the MeNH2 in abs. MeOH. The reaction of Me crotonate and MeNH2 in MeOH also was performed at >1 atm. by heating the mixt. for 3 hrs. at 60 Deg in a 1-1. autoclave. After distg. MeOH, the residue was distd. in vacuo, giving 30.1 g. (at 1 atm.) or 50 g. (at >1 atm.) VI, b12 53 Deg. 3-Methylamino-1-butanol (VII), b13 77-9 Deg, was prepd. in 83.2% yield by redn. of 26.2 g. VI in 400 ml. abs. Et2O with 19 g. LiAlH4 suspended in 800 ml. abs. Et2O. Me beta -[N-methyl-N-(3-hydroxy-1-methylpropyl)amino] butyrate (VIII), b0.01 94-5 Deg, was prepd. by 28.6% yield by mixing 10.3 g. VII in 10 ml. abs. MeOH with 10 g. Me crotonate, and allowing the soln. to stand for 14 days at 25 Deg. Dropwise addn. of 1.4 g. BzCl in 20 ml. abs. Et2O to a stirred soln. of 2 g. VIII and 1 g. Et3N in 20 ml. abs. Et2O and keeping .apprx.1 hr. gave MeO2CCH2CHMeNMeCHMeCH2CH2OBz, b0.01 162-4 Deg, in 45.6% yield. 21 references.
|Additional information (public):||CAN 63:45925 35 Noncondensed Aromatic Compounds 2704-50-9; 2704-58-7 (Derived from data in the 7th Collective Formula Index (1962-1966); 2704-56-5P Role: SPN (Synthetic preparation), PRP (Properties), PREP (Preparation) (Synthesis of local anesthetics); 2704-57-6 (Butyric acid, 3-[(3-hydroxy-1-methylpropyl)amino]-, methyl ester, benzoate (ester); 859038-85-0 (Butyric acid, 3-[(3-hydroxy-1-methylpropyl)methylamino]-, benzoate (ester) (as anesthetic); 2704-49-6P (Crotonic acid, 3-[(3-hydroxy-1-methylpropyl)amino]-, methyl ester); 2704-51-0P (Butyric acid, 3-(methylamino)-, methyl ester); 2704-55-4P (1-Butanol, 3-(methylamino)-); 2866-77-5P (Butyric acid, 3-[(3-hydroxy-1-methylpropyl)amino]-, methyl ester); 2867-59-6P (1-Butanol, 3-amino-); 2867-64-3P (1-Butanol, 3-chloro-, benzoate); 2867-65-4P (1,3-Butanediol, dibenzoate); 2867-66-5P (1-Butanol, 3-bromo-, benzoate); 2867-67-6P (1-Butanol, 3-bromo-, acetate); 856615-55-9P (Butyric acid, 3-[(3-hydroxy-1-methylpropyl)methylamino]-, acetate (ester) Role: PREP (Preparation) (prepn. of)|
|Institutions:||Chemistry and Pharmacy > Institute of Pharmacy > Retired Professors > Prof. Schönenberger|
|Keywords:||Anesthetics (3-[(3-hydroxy-1-methylpropyl)amino]butyric acid derivs. as local)|
|Subjects:||500 Science > 540 Chemistry & allied sciences|
|Refereed:||Yes, this version has been refereed|
|Created at the University of Regensburg:||Unknown|
|Deposited On:||19 Nov 2010 07:06|
|Last Modified:||19 Nov 2010 07:06|