Method of separating d,l-alanine, 3-fluoro-d,l-alanine or 2-deutero-3-fluoro-d,l-alanine

专利摘要:
DL-Alanine, 3-fluoro-DL-alanine and 2-deutero-3-fluoro-DL-alanine, are resolved by reaction with a resolving base and a beta -dicarbonyl compound. The resulting azomethine diastereomeric salts which are easily separated, the masking group is readily removed under mildly acidic conditions.
公开号:SU786887A3
申请号:SU772454448
申请日:1977-02-22
公开日:1980-12-07
发明作者:Мартин Чемерда Джон；Гэл Джордж
申请人:Мерк Энд Ко, Инк (Фирма)；
IPC主号:

专利说明:

Union of Soviet
Socialist
Republics
DESCRIPTION OF THE INVENTION
TO PATENT (61) Supplementary to patent (22) Declared 02.22.77 (21) 2454448 / 23-04
01) 786887 (51) M. Cl. ^{1 * 3} (23) Priority (32) 03.03.76
S 07 S 101/08
C 07 C 99/12 (31) 664 328 (33) USA
Published December 7, 1980. Bulletin No. 45
Date of publication of the description 10.12.80 (53) UDC 547.466.
.23.07 (088.8) (72) The inventors
Foreigners
John Martin Chemerda and George Gal (USA) (71) Applicant
Foreign company Merck And Co., Inc. (USA)
(54) METHOD FOR SEPARATING D, L-ALANINE, 3-fluoro-D, l-alanine, or 2-deutero-3-fluoro-o, l-alanine
The invention relates to a new method for the separation of D _; L-alanine, 3-fluoro-D, L-alanine or 2-deutero-Zfluoro-D, L-alanine, which are potent antibacterial agents in the fight against pathogenic bacteria.
A known method for the separation of amino acid racemates using their benzenesulfonates into individual 10 optical isomers of £ 1J.
In addition, a method for the separation of Z-fluoro-D, L-alanine is known, which consists in the fact that Z-fluoro-D, L-alanine is dissolved in a polar solvent, 15 the solution is supersaturated and the crystalline of the L-isomer is introduced, then the crystalline L- isomer. D-isomer crystals are introduced into the mother liquor and 3-fluoro-D-alanine £ 2} is separated by filtration. 20
The disadvantage of this method is the complexity of its hardware design.
However, in the literature there is no known method for the separation of D, L-alanine and its derivatives into the optically active 25 isomers using quinine and 2,4-pentanedione.
The aim of the invention is to develop a new method for producing D, Lalanine, 3-fluoro-D, L-alanine, or 2 to 30 deutero-3-fluoro-D, L-alanine and to simplify the process.
The goal is achieved in that they interact with equimolecular amounts of the substances to be separated, the quinine and 2,4-pentanedione base in a solution of lower alkanol when heated and the diastereomeric salts are separated by crystallization followed by separate treatment with alkali metal hydroxide and then with mineral acid.
Separation of 2-deutero-3-fluoro-0 ₍ Ealanina.
Racemic 2-deutero-2-fluoroalanine (100 g, 0.935 I) 2,4-pentanedione (103 g 1.03 M) and quinine (320 g, 0.99 M) in 1870 mp anhydrous methanol are heated under reflux under a nitrogen atmosphere in for 1 h. After cooling and stirring for 1 h at 20 ° C, the quinine and M- (1-methyl-2-acetylvinyl) -2-deutero-3-fluoro-L-alanine-solvated methanol-soluble salt was collected, washed with cold methanol and dried under vacuum at room temperature with a final yield of 176 g. £ 0 /) ^ = -89.6 * (with 2.0, 95% EtOH); 143-144 ° C.
s 786887
Found,%: C 63.78 H, 7.30 '' J ^- 3.69; N7.90.
2c ^ 36 ^^ s * s n s o n
Calculated,%: from 63.83; H 7.38,
F 3.38; N 7.70.
Removal of solvent from 5 .ta filtration and washing solution followed by crystallization of the residue from EtOAC gives mp 500 at 0 ° C of the second fraction - 55.2 g Yield analytically Numbers ¹ · ies 1st and 2nd fraction is (Q 96 , 6%. An anhydrous form is obtained after drying the sample at 50 ° C for
h
Found,%: c 65.66; H 7.46;
F 3.77; N, 8.23. ..
'C _2e ^H _% F№ ₃ ° ₅ ..' 5 ”Calculated,%: C 65.48; H 7.07;
F 3.70; N, 8.18.
The residue after the second fraction is dissolved in 360 ml of water and an alkaline medium is created by adding 450 mp 1.2N (0.54 M) sodium hydroxide with stirring at 10-15 ° C. The isolated quinine is removed by extraction with chloroform, and the aqueous phase is acidified with stirring - 500 ml of 2N. HC1 at 15-20 ° C. After 15 minutes, the protecting group is removed, as evidenced by the dissolution of the precipitated N- (1-methyl-2-acetylvinyl) -2-deutero-3-fluoro-D-alanine. After extraction with chloroform to remove 2,4-pentanedione, the aqueous phase is clarified with activated carbon and the filter * · t is passed through 1.1 L of Dowex 50wx * resin (H ⁺ form). The column is washed with chlorine-free water, 35 then the product is eluted with 0.5 N ammonium hydroxide, ninhydrin-positive fractions are collected and concentrated until the product crystallizes (^ 150 ml). The cooling mixture, 4Q, was given up to 5 ° C, · it was incubated for several hours and crystalline 2-deutero-3-fluoro-D-alanne was separated, washed with cold water. After drying in vacuo at 40 ° C, the yield is 28.5 g (57%), so pl. 174-175 ° C. Ld. 3 V = -10.4 °. ⁴⁵ Found,%: C 22.41; H 3.74;
N, 12.96; F .17.53.
c ^ h ₆ no ₂ f.
Calculated,%: C 33.41; H 5.74, *
N, 12.96; F 17.53. ^fifty
2-Deutero-3-fluoro-1.-alanine is separated from crystalline quinine-N- (1-methyl-2-acet.ilvinyl) -2-deutero-3 ^ -fluoro-L-alaninate a (231.5 g) according to the method. described above for its anti-55 hearth. In this way receive 35.5 g (68%) of 2-deutero-3-fluoro-L-alanine, so pl. 174-175 ° C. [XI = + 10.3 °.
Found,%: C 33.45; H 5.78;
N, 13.01; F 17.77. <0 c ₃ h ₆ no ₂ f.
Calculated,%: C 33.65 ', H 5.65, ’N 13.08; F 17.74.
Potassium N- (1-methyl-2-acetylvinyl) -3-fluoro-0, L-alaninate. 45
To the suspension of 10.71 g (100 mmol)
3-fluoro-D, L-alanine in 40 ml of 90% methanol add a solution of 5.61 g (100 mmol) of potassium hydroxide in 20 ml of 90% MeOH, after which a solution of 10.1 g (100 mmol) is added ) 2,4-pentanedione in 60 ml of methanol. The mixture was refluxed for 20 minutes and concentrated in vacuo. The product was obtained by recrystallization from isopropanol (300 ml) in 17.6 g (78%) yield.
Found,%: C 42.30 H 4.88; N, 6.23; F, 8.11. ^c gH _u N0 ₅ FK.
Calculated,%: C 42.27 ·; H 4.87; N, 6.16; F 8.35.
Ή NMR (D _t 0): b 1.97 (S, 3, CH ₉ ), 2.02 (S, 3, CH ₃ ), 6 4.4 (m, 1, CH, G _n ^ 31Hz) S 4.8 (m, 2, CH ₂ F, 3 _Ht <t46 Hz).
Separation of 3-fluoro-D, L-alanine starting from potassium-N- (1-methyl-2-acetylvinyl) -3-fluoro-D, L-alanine.
To a solution of 22.72 g (100 mmol) of potassium-N- (1-methyl-2-acetylvinyl) -3-fluoro-D, L-alaninate in 200 ml of methanol, 40.5 g (102.5 mol) are added. quinine hydrochloride · 2HgO. The mixture was refluxed for 1 hour. Using the separation and purification method described above, 3-fluoro-0-alanine with Coclp = -10.4 ° and 3 fluoro-E-alanine with £ oP p = + 10.4 ° are obtained with yields of 54.2 and 64%, respectively .
Separation 0, L-alanine ..
Using the method described above, quinintH- (1-methylt2 / -acetylvinyl) -L-alaninate is obtained in a yield of 93%, and so on. 142-143 ° C and = -73.8 °.
Found,%: C 66.45; H 7.80;
N8.10.
^With 20 ^N ET N 0 _f * l / 2 H ₂ O.
Calculated,%: C 66.64) H 7.59)
N, 8.33.
_w L- Alanine is obtained from crystalline imaminquinine salt by the method described above for fluoroalanine with a yield of 76% AND [os] K = + 12.80 ° (5% 5n-HCl)

权利要求:
Claims (2)
[1]
1. S.Jamada et.al. Optical Reso-
[2]
2. USSR author's certificate
lution of 0, L-amtnoac {ds by preferen-603334, cl. C 07 C 101 / 08.01.02.

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US3381031A|1962-04-18|1968-04-30|Univ Australian|Resolution of racemic amino acids|DE2749203C2|1977-11-03|1981-12-17|Riedel-De Haen Ag, 3016 Seelze|Process for the resolution of DL-alpha-aminocarboxylic acids and diastereomeric salts|

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法律状态:

优先权:

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US05/664,328|US4048224A|1976-03-05|1976-03-05|Process for resolving alanine, 3-fluoro and 2-deutero-3-fluoro-DL-alanine|

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