SU648082A3 - Metho of obtaining amino acid deriva]ves, their salts, racemates or optically active antipodes - Google Patents

Metho of obtaining amino acid deriva]ves, their salts, racemates or optically active antipodes

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Publication number
SU648082A3
SU648082A3 SU762362204A SU2362204A SU648082A3 SU 648082 A3 SU648082 A3 SU 648082A3 SU 762362204 A SU762362204 A SU 762362204A SU 2362204 A SU2362204 A SU 2362204A SU 648082 A3 SU648082 A3 SU 648082A3
Authority
SU
USSR - Soviet Union
Prior art keywords
water
mmol
acid
benzyl
racemates
Prior art date
Application number
SU762362204A
Other languages
Russian (ru)
Inventor
Фойер Ласло
Фурка Арпад
Шебештьен Ференц
Херчел Иолан
Бендефь Эржебет
Original Assignee
Хиноин Дьедьсер Еш Ведьесети Термекек Дьяра Рт (Инопредприятие)
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to HU74FE00000928A priority Critical patent/HU171576B/en
Application filed by Хиноин Дьедьсер Еш Ведьесети Термекек Дьяра Рт (Инопредприятие) filed Critical Хиноин Дьедьсер Еш Ведьесети Термекек Дьяра Рт (Инопредприятие)
Application granted granted Critical
Publication of SU648082A3 publication Critical patent/SU648082A3/en

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Description

I
The invention relates to a method for the preparation of derivatives not described in the literature of amino acid derivatives of the general formula
HjU-CJi-ciboH (H4 „
СО-21- (СН) р- (СНг) лГ-В
I j
R r
where C - atrm of hydrogen vp alksht S.,
in - SOgOH, - 0 $ fN or ORO (6K R - hydrogen or group - COOH; P - integer 2 or 3,
p + tn - 2 or 3, with p- O or 1; as well as their salts, racemates or optically active antipodes with valuable biological properties.
The described method is based on the known peptide bond formation reaction. At the same time, the derivative of cL vminodicarboxylic acid, substituted in the amnor- or amino- and carboxyl group
not protected by a group, via a W-carboxy strong group, combined, eg, with 2-aminoethanesulfonic acid, 3-aminopropanesulfonic acid, or 2-phosphonoethanolamine. The most suitable combination method is the activated ethers method ± 1.
The aim of the invention is to expand the range of biologically active compounds.
In accordance with the invention, a method is described for the preparation of amino acid derivatives of formula 1, concluded that the compound of formula II
R-11H- / N-CO - A
{#) "
gO where the R is a C-al-eoxycarbonyl group which may be substituted with a halogen, C-alkoxy or nitro, C-j, j-aralkoxycarbonyl group or phenoxycarbonyl group. A - arapkoksngruppa, predominantly; o benzyloxy group, substituted aralcock: Igruppa, predominantly petoxyphenoxypexy or p-vitrobenzyloxype; . HW- (CH) p - (: tH2) -B f RR p, m and b have the indicated J value of a mixture of pyridine and water, and in the resulting: single group, the protective groups of the jL-amino group and the -carboxylic group are removed or successively by acidification, alkaline hydrolysis or hydrogenol followed by isolation of the target product in the free 5ide, in the form of a salt, the host optic of the active antipode. Example 1: 5.42 (11 mmol) with, -benzyl) -5-l-nitrophenyl & sarbobenzyloxane U-glutamic acid is dissolved in 50 ml of pyridine. The solution is cooled to 0 ° C and a solution of 1.25 g (1O mmop): aurine in 2O ml of water is boiled over an intensive displacement during the AO 1A. Then the mixture of cm kicked off with 3.08 ml (H2 mol) of triethyla 1a, stopped cooling and stirred for a month and left to stand at room temperature for 72 hours, then you are evaporated in vacuo. The remainder of the solution in 5O ml of water and 1N hydrochloric acid is added to the yellow color solution until it becomes discolored. ; To remove p-nitrophenol, rast. or shake 10 times with ether, each time 50 ml of ether. The water was evaporated under vacuum. 5.9 g of triethylammonium salt of carbobenylSHioxy- - (c-benzyl) -L -glugamyltarine are obtained. The substance is catalytically hydrogenated and the solvent is removed by evaporation in vacuo. JC, in order to remove the tritylamine, the substance is dissolved in a non-painful YuM amount of water and introduced into a 2x4 O cm column, - filled with HUTC 50x2. Eluirutat. water Collect about 12 O ml of zljuat and evaporate it in vacuo at 35 ° C. Crystallization and isolation of the product take place. 1.72 g of y-C-glutamyl taurine is obtained, which corresponds to a yield of 68% relative to taurine. Example 2. 1.083 g (2.2 mmol) of (oi-benzyl) -carbobenzyloxy-1-y-p-nitrophenyl ester of glutamic acid is dissolved in 6 ml of a 2: 1 mixture of pyridine and water. First, 278 mg (2 mmol) of homotaurin is added to the solution, then 0.59 ml (4.2 mmol) of triethylamine. The yellow-colored solution is kept at room temperature for 72 hours and then evaporated in vacuo. The oily residue is dissolved in water, neutralized with hydrochloric acid, and then extracted to remove the p-ntrophenol by extraction in ether for 8 hours to extract the extractor. The aqueous phase is evaporated in vacuo. 1.68 g of carbobenzyloxy-5- (c1-benzyl) -L-glutam ilgomotaurin is obtained. Example 3. The entire amount of the substance prepared according to Example 2 (1.68 g) was dissolved in 10 ml of aqueous ethanol, then 0.3 g of 1O% palladium coal was added and hydrogen was passed through the suspension for 4 hours. Then the solution is filtered and evaporated in vacuo. The rest of the qzt solution in 1-2 ml of water and to remove triethylamine is introduced into a 1x35 cm column filled with gas in a foam {Domex 50x2 resin. Elute with water. Collect 5 O ml of the eluate and then evaporate in vacuo. As a residue, 44O ml of U -I-glutamgomotaurin is used, which corresponds to & 82% yield. Electrophoresis carried out at pH 6j5 shows an insignificant impurity due to partially neutral, partially acidic substances (homotaurin, respectively, glutamic acid). The product can be purified, for example, by preparative electrophoresis. With electrophoresis carried out both at pH 6.5 and at pH l, 8, the substance moves in the direction of the cathode. Its relative mobility to cysteic acid is at pH 6.5 O, 68, at pH 1.8: O, 50. R, (n-butanol: pyridine: ice and acetic acid: water - 15: 10: 3: 12) 0.19. Example 4.1.083 g (2.2, mmol) of (c3-benzyl) -5-p-introfenyl carboxy nziloxy-and-glutamic acid ester using the method described in example 2, entering into the reaction with 278 mg (2 mmol) of M-methyl taurine. 1.59 g of carbobenzyloxy-f- (oC-benzyl) -L-glut mil- 4-methylturine, Ex. 5, is obtained. The entire amount of the substance (1.59 g) obtained according to Example 4 is catalytically hydrogenated as described in the example 3 way. I get 423 mg of rj-l-lutamyl-M-methyl-tetrafine, which corresponds to a yield of 79%. The substance moves both at pH 6.5 and .. at a pH of 1.8 when electrophore-. on paper in the direction of the cathode. Relative mobility with respect to cysteic acid at pH 6.5:: 0.68; pH 1.8: 0.49, K s (n-butanol: pyridine: ice on acetic acid: water 15: 10: 3: 12) -0.16, Example 6, 2.87 g (6.6 mmol { 4 - benzyl) - 1p-p-nitrophenyl ester of carbobenzyloxy-L-glutamic acid. Dissolve in 2 ml of pyridine and mix with a solution of 1.25 g (6 mmol) of monohydrate | -cysteic acid in a mixture of 17 mn of water and 17 ml of pirvdina. After DETAIL 2.6 ml (18.6 mmol) of triethylamine, the reaction mixture is kept at room temperature for 72 hours. Then the pactBop is evaporated in vacuo at 30 ° C. The residue is dissolved in 20 ml of water, acidified with concentrated hydrochloric acid and The mixture is then shaken 15 times, each time in 10 ml, with Cnc. The aqueous phase is evaporated in vacuo at. Carbobenzyloxy-5- (c1, -benz1) -U -glutamyl-L -cysteines y acid is obtained. Example 7- The product obtained according to Example 6 was dissolved in 2 O ml of water, and decanted from 0.3 g of 10% palladium on activated carbon and hydrogen was passed through the suspension for 3 hours. The reaction mixture is treated as described in Example 3. 7G — Ji-rnyTaManHHc-faic acid, which melts at 187®G, is obtained. Relative mobility with respect to iysteic acid by chromatography on paper — at pH 6.5: 1.21; at pH 1.8: 0.54, Example. 1.083 g (2.2 mmol) of (o1-benzsh1) - -n-n of carbobenzyloxy-L-glutamic acid trofenster ester is dissolved in 6 MP prepared in a ratio of 2: 1 mixture of pyridine and water. First, 282 g (2 mmol) of cholaminophosphate and 826 then 0.87 ml (6.2 mmol) of triethnlamine are added to the solution. The reaction mixture is held at room temperature for 72 hours and then evaporated in vacuo. Further processing is carried out by the method described in Example 2. 1.25 g of carbobenzyloxy -} - (cC-benzyl) -b-glutamylcholamine phosphate are obtained. Example 9, The entire amount of the product obtained in Example 8 (1.25 g) was catalytically hydrogenated to remove the protective caps. Hydrogenation as well as purification using ion exchange is carried out in the manner described in Example 3. 470 mg of J-L, glutaminyl phosphate, are obtained, which corresponds to a yield of 91%. The product contains (as shown by electrophoresis on paper) as an impurity of about 15-20% xo aminophosphate. Electrophoresis is selected as the cleaning method. In paper electrophoresis, both at pH 6.5 and at pH: 1.8 moves towards the cathode. The relative mobility with respect to cysteic acid is at pH 6.5: 0.75; pH 1.8:: 0.36, Pr (n-butanol: pyridine: ice on acetic acid: vada 15: 10: 3: 12) 0.18, Example 10.26 ml (1.1 mmol) ("i-benzyl ) - {- -nivrophenyl carbobenzyloxy-L-aspartic acid ester is dissolved in 5 ml of pyridine. The solution is cooled to 0 ° C and then a solution of 125 ml (1 mmol) of taurine in 2 ml of water, then 0.28 ml (2 mmol) of triethylamine is added in small portions. The reaction mixture is kept at room temperature for 48 hours and then evaporated in vacuo. The residue is dissolved in 50 ml of water and the initially yellow colored solution is mixed with 1N. hydrochloric acid until it decolorizes. To remove p-nitrophenol, a solution of 1O was shaken with ether, taking 5 ml of ether each time. The aqueous phase is evaporated in vacuo. 478 g of carbobenzyloxy-J5- (oL-benzyl) -C-aspargiltaurin are obtained. Example 11. The whole amount of the product obtained in Example 10 is dissolved in 6 ml of 50% aqueous ethano. The solution is mixed with 10 mg of 10% palladium on activated carbon and then hydrogenated with hydrogen gas for 4 hours. After filtration and evaporation in vacuum, triethylamine is removed from the product by ion exchange, as. 6 in Example 3. 172 mg of jb-l-pargiltaurin is obtained, which corresponds to a yield of 71%. The product is contaminated with an unspecified amount of Tz-url, which can be removed by electrophoresis. With electrophoresis on paper, either at pH 6.5 or pH 1.8, it moves towards the cathode. Relative mobility with respect to cysteic acid - at pH 6.5: 0.77 pH s 1.8: 0.58. R (n-butanol: pyridine: le -. D on acetic acid: water 15: 10: 3:: 12) OD6.:. Example 12. 525 g (1.1 mmol) (sC-benzyl) -, | Carbobenzyloxy-t-aspartic acid 5-p-nitrophenic ester and 139 g (1 mmol) of homotourin are reacted in the manner described in Example 1. Carbobenzyloxy-} b- (o1-benzyl) -U-aspargylgomo. Taurine is obtained. Example 13. The gender of a scientist according to Example 12 is the product catalytically hydrogenated by the method described in Example 3. A 2 OZ g (84%) is obtained (bL-ac pargilgomotaursh. When electrophoresed on paper, the substance moves towards the cathode both at pH 6.5 and at pH 1.8. Relative mobility with respect to cysteic acid is at pH a 6.5:: 0.72; pH s. 1.8: O, 53. 1 (n-butanol:: pyridine: ice for acetic acid: water 15: 10: 3: 12) 0.17. and M.p. 14, (c-Benzyl) -L-p-itro-phenyl ester of carbobenzipoxy-U-aspartic acid and cholamyiphosphate are reacted in the manner described in Example 8. Carbobenz {shoxy - - (oC-benzyl) - U-acpargilkholaminofosfag. P. and m er 15. Received according In Example 14, the substance is catalytically hydrogenated by the method described in Example 3. 1J - U -aspargylcholamine phosphate is obtained. When electrophoresed on paper, the substance moves both at pH 6.5 and at pH 1.8 towards relative to the cathode. , mobility in relation to cyst 1 SHOWER kipote - at pH 6.5: 0.81; pH a 1, -8: 0.40. U (n-butanol: pyridine: ice on acetic acid: water a 15: 10: 3 : 12j: 0.14. Example 16. In the manner described above, from carbo-benzyloxy-B-glutaam oC-benzyl-β-p-nitrophenyl ester: p-P-gluta 2 tdljS miltaurin is obtained. M.p. 219-220 ° C; -13.9. Example 17. 7.38 g (15 mmol) of 1-Benzyl - (- carbobenzyloxy-C-glutamic acid p-nitrophenyl ester is reacted with 1.41 g (10 mmol) of chloramine sulfate. Treatment of the reaction mixture, removal of the protective groups by catalytic hydrogenation and purification; the product proceeds as described in example 5; 1.75 g (64.7%) of T-1 -glutami-chloro-aminosulphate is obtained, which melts at 164-166 ° C. Example 18.2.63 g (5.5 mmol) P-N-nitrophenyl ester of carboxybenzyloxy-1 -aspartic acid is reacted with 696 mg (6 mmol) of N-methyl taurine. The resulting product is peracrystallized from a mixture of acetone and water. 1.6 g (78%) of | b - 1 ' -aspargyl-N-metEltaurin monohydrate are obtained, which melt at 188-189s of HG + 10.4 (s 1, water). Example 19. 26.32 g (55 mmol) of carbobenzenepoxy-. ((. -bangsch) - i -glutamine taurine is dissolved in 50 ml of glacial acetic acid. 4 mol of hydrogen bromide 1 dissolved in 50 MP of glacial acetic acid can be added to the solution of L5YiB. The reaction mixture is kept at room temperature 2 hours and then evaporated in vacuo at 30 ° C. The oily residue is dissolved in 170 ml of water and extracted five times with shaking each time with 7 O ml of ether. The aqueous phase is evaporated in vacuo to give 20.42 g of Y - (o1-basyl ) -1-glutamine, which is recrystallized ayut from 90% ethanol. Pf (n-butanol:: pyridine: ice on acetic acid: water: L5: 10: 3: 12) and 0.53. Ri (n-butanol: ice on acetic acid: water 4: 1: 1) -0.39, 20.42 y- (s, -benzyl) -and-glutamidtaurin is dissolved in 150 ml of 1N potassium hydroxide, the solution is kept at room temperature for 4 hours and then injected eluted with water. 300 ml of eluate is collected before being washed. This eluate is evaporated in vacuo at 35 ° C. The oily residue is crystallized by adding 8-1 O ml of water and about 100 ml of ethanol. After filtration, washing with alcohol and drying
SU762362204A 1974-04-29 1976-05-26 Metho of obtaining amino acid deriva]ves, their salts, racemates or optically active antipodes SU648082A3 (en)

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Application Number Priority Date Filing Date Title
HU74FE00000928A HU171576B (en) 1974-04-29 1974-04-29 Process for the isolation of gamma-l-glutamyl-taurine

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SU752129107A SU638243A3 (en) 1974-04-29 1975-04-28 Method of purifying gamma-alpha-glutamyltaurine
SU762356005A SU670214A3 (en) 1974-04-29 1976-05-14 Method of producing derivatives of amino acids, salts, racemates or optically active antipodes thereof
SU762362204A SU648082A3 (en) 1974-04-29 1976-05-26 Metho of obtaining amino acid deriva]ves, their salts, racemates or optically active antipodes
SU762362206A SU673176A3 (en) 1974-04-29 1976-05-26 Method of producing derivatives of amino acids, their salts, racemates or optically active antipodes

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SU762356005A SU670214A3 (en) 1974-04-29 1976-05-14 Method of producing derivatives of amino acids, salts, racemates or optically active antipodes thereof

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AR (1) AR207243A1 (en)
AU (1) AU497133B2 (en)
CS (1) CS185685B2 (en)
DD (1) DD119580A2 (en)
DK (1) DK182675A (en)
ES (1) ES437046A2 (en)
FI (1) FI53269C (en)
HU (1) HU171576B (en)
IL (1) IL47117A (en)
IN (11) IN141368B (en)
NZ (1) NZ177337A (en)
PL (2) PL108181B1 (en)
SU (4) SU638243A3 (en)
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JPS6233877U (en) * 1985-08-19 1987-02-27
JPH01108884U (en) * 1988-01-18 1989-07-24
JPH0245880U (en) * 1988-09-24 1990-03-29
JP3592497B2 (en) * 1997-09-08 2004-11-24 日本ブレーキ工業株式会社 Heat bonding method and apparatus
HK1077154A2 (en) 2003-12-30 2006-02-03 Vasogen Ireland Ltd Valve assembly
JP2006336072A (en) * 2005-06-02 2006-12-14 Nakabohtec Corrosion Protecting Co Ltd Simple corrosion-preventing device
US7803139B2 (en) 2005-07-06 2010-09-28 Icu Medical, Inc. Medical connector with closeable male luer
US7998134B2 (en) 2007-05-16 2011-08-16 Icu Medical, Inc. Medical connector
US9168366B2 (en) 2008-12-19 2015-10-27 Icu Medical, Inc. Medical connector with closeable luer connector
JP6553357B2 (en) 2011-09-09 2019-07-31 アイシーユー・メディカル・インコーポレーテッド Medical connector with fluid-resistant mating interface

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IN148247B (en) 1980-12-20
IN142471B (en) 1977-07-16
IN141368B (en) 1977-02-19
HU171576B (en) 1978-02-28
JPS6011024B2 (en) 1985-03-22
FI53269B (en) 1977-12-30
JPS58131960A (en) 1983-08-06
JPS5198312A (en) 1976-08-30
SU638243A3 (en) 1978-12-15
SU670214A3 (en) 1979-06-25
JPS6043360B2 (en) 1985-09-27
FI53269C (en) 1978-04-10
JPS58131955A (en) 1983-08-06
ZA7502394B (en) 1976-03-31
AU497133B2 (en) 1978-11-30
JPS6335635B2 (en) 1988-07-15
YU37477B (en) 1984-08-31
YU109075A (en) 1983-04-27
PL108181B1 (en) 1980-03-31
JPS6011026B2 (en) 1985-03-22
SU673176A3 (en) 1979-07-05
JPS58131961A (en) 1983-08-06
JPS6089488A (en) 1985-05-20
JPS58131952A (en) 1983-08-06
FI751271A (en) 1975-10-30
JPS6011025B2 (en) 1985-03-22
JPS58131962A (en) 1983-08-06
IN148249B (en) 1980-12-20
CS185685B2 (en) 1978-10-31
JPS6049629B2 (en) 1985-11-02
IN148248B (en) 1980-12-20
IN148243B (en) 1980-12-20
JPS58131956A (en) 1983-08-06
JPS6041657A (en) 1985-03-05
IL47117A (en) 1978-03-10
PL110477B1 (en) 1980-07-31
JPS60120995A (en) 1985-06-28
JPS6039647B2 (en) 1985-09-06
IN148242B (en) 1980-12-20
JPS6133816B2 (en) 1986-08-04
JPS6124377B2 (en) 1986-06-10
AU8032075A (en) 1976-10-21
IN146299B (en) 1979-04-21
NZ177337A (en) 1978-04-03
JPS6133817B2 (en) 1986-08-04
DD119580A2 (en) 1976-05-05
IN148244B (en) 1980-12-20
JPS58131959A (en) 1983-08-06
JPS6041658A (en) 1985-03-05
IN148245B (en) 1980-12-20
ES437046A2 (en) 1977-05-16
JPS6111943B2 (en) 1986-04-05
AR207243A1 (en) 1976-09-22
IN148246B (en) 1980-12-20
DK182675A (en) 1975-10-30
JPS6041656A (en) 1985-03-05

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