IE41927B1 - Preparation of 3-fluoro-dl-alanine salts - Google Patents
Preparation of 3-fluoro-dl-alanine saltsInfo
- Publication number
- IE41927B1 IE41927B1 IE2405/75A IE240575A IE41927B1 IE 41927 B1 IE41927 B1 IE 41927B1 IE 2405/75 A IE2405/75 A IE 2405/75A IE 240575 A IE240575 A IE 240575A IE 41927 B1 IE41927 B1 IE 41927B1
- Authority
- IE
- Ireland
- Prior art keywords
- salt
- fluoro
- alanine
- hydrate
- solution
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
- C07C227/06—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid
- C07C227/08—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid by reaction of ammonia or amines with acids containing functional groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/185—Saturated compounds having only one carboxyl group and containing keto groups
- C07C59/21—Saturated compounds having only one carboxyl group and containing keto groups containing halogen
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
1480989 Preparing 3 - fluoro- DL - alanine and salts thereof MERCK & CO Inc 27 Oct 1975 [8 Nov 1974] 44183/75 Heading C2C 3 - Fluoro - DL - alanine or a salt thereof is prepared by subjecting a salt of 3-fluoropyruric acid, or hydrate thereof, to reductive amination using aqueous ammonia to form a salt of 2-imino-3-fluoro-propionic acid, or hydrate thereof, and an alkali metal borohydride as reducing agent, optionally in the presence of NaCl or LiCl as catalyst. In examples, lithium fluoropyrurate hydrate is reacted with concentrated aqueous NH 4 OH at c. 37‹ C. to provide a solution containing about 95 parts of 2- hydroxy-2-amino-3-fluoropropionate to about 5 parts of 2,2-dihydroxy-3-fluoropropionate and, after cooling, NaBH 4 is added. The reaction mixture is distilled under reduced pressure to remove ammonia, acidified with HCl, stirred with activated charcoal, filtered, passed through a cation-exchange resin followed by elution with NH 4 OH, and the eluate recrystallized to provide 3-fluoro-DL-alanine.
Description
This invention is concerned with the production of the racemate of 3-fluoro-alanine, which is valuable as an intermediate for preparing 3-fluoro-D-alanine, its salts and esters which are potent antibacterial agents effective in inhibiting the growth of pathogenic bacteria of both the gram positive and gram negative type.
In accordance with the present invention, 3-fluoroDI·-alanine or a salt thereof is produced by subjecting a salt of 3-fluoropyruvic acid, or hydrate thereof, to reductive amination using aqueous ammonia, to form a salt of 2-imino-3-fluoropropionic acid or hydrate thereof, and an alkali metal borohydride as reducing agent, thereby forming 3-fluoro-DL-alanine or a salt thereof.
This reductive amination reaction is conveniently conducted by first equilibrating a salt of fluoropyruvic acid hydrate (e.g. lithium 2,2-dihydroxy-3-fluoro-propionate) in aqueous ammoniacal solution with formation of the corresponding salt of 2-imino-3-fluoro-propionic acid hydrate (e.g. lithium, sodium or ammonium 2-hydroxy-2-amino-3fluoro-propionate); the equilibrium ratio of the hydrated imine thus formed to hydrated pyruvate starting material (i.e. 2,2-dihydroxy-3-fluoro-propionate) is a function of ammonia concentration and, in concentrated aqueous ammonium hydroxide (13N), the ratio is approximately 95 to 5 on a weight basis. Although not ordinarily preferred, lower aqueous ammonia concentrations may be used, for example with 6.5N aqueous ammonium hydroxide, the equilibrium ratio is approximately 90 to 10. Upon reduction, this mixture would necessarily result in a reduced yield of equilibrium 3-fluoro-DL-alanine and increased amount of 3-fluoro lactate by-product. The equilibrium at 37°C. is a pseudo-first-order reaction with half-life of 15 minutes; equilibration at 37°C. for 90 minutes provides six half-lives, and an effective ratio of hydrated imine to hydrated pyruvate of 95 to 5. Although the hydrated 2-imino-3-fluoro-propionate salt is not isolated from the ammonia solution, its presence, in a purity of 95%,is readily demonstrated by NMR (nuclear magnetic resonance) measurement.
The hydrated imine (the 2-hydroxy-2-amino-3-fluoropropionate) is itself in equilibrium, by loss of water, with a minor proportion of the 2-imine (the 2-imino-3-fluoropropionate); and the hydrated pyruvate (the 2,2-dihydroxy3-fluoro-propionate) is likewise in equilibrium, by loss of water, with a minor proportion of carbonyl or 2-ketone (i.e. the fluoro-pyruvate or 2-keto-3-fluoro-propionate).
In the alkali metal borohydride reduction operation,it is the 2-imine and carbonyl (not the hydrated forms) which undergo reduction; as imine and carbonyl are reduced, the hydrated imine and hydrated carbonyl are rapidly converted to the imine and carbonyl, respectively. The discovery that the 2-imine can be efficiently reduced to the 2-amine using an alkali metal borohydride, and particularly that this reduction can be conducted in aqueous solution and even in the presence of concentrated aqueous ammonia, was indeed surprising.
Moreover, the desired reduction of the imine group to form 3-fluoro-alanine proceeds more slowly than does the reduction of carbonyl to form 3-fluoro-lactate. Accordingly, concentrated aqueous ammonia is ordinarily used in the initial equilibration reaction to achieve the highest ratio of hydrated imine to hydrated pyruvate (i.e. 95:5), and the reduction reaction is preferably conducted as rapidly as possible, relative to the rate of reverse equilibration of the hydrated imine to hydrated pyruvate. This reversal of hydrated imine to hydrated pyruvate necessarily occurs when the carbonyl group, due to its more rapid reduction, is preferentially removed from the reaction solution. Rapid reduction is conveniently accomplished by using a large (up to five-fold) excess of alkali metal borohydride reducing agent.
It is preferred, however, to use only a small (i.e. 50%) excess of borohydride reducing;agent; under such circumstances, the rate of reduction of imine would be reduced, the reverse equilibration could occur to a very considerable degree, and formation of the unwanted by-product 3-fluoro-lactate would be substantially increased. It is preferred that this unwanted reverse equilibration be minimized while using only a 50% excess of borohydride reducing agent. This is achieved by adding the borohydride reducing agent to the equilibrium solution, and then rapidly evaporating excess of ammonia from the solution; at the resulting reduced pH (corresponding to substantial removal of excess of ammonia) the borohydride reduction is extremely rapid. It is a feature of the invention that the evaporative removal of the ammonia be accomplished sufficiently rapidly so that the thereby greatly accelerated borohydride reduction effectively reduces all imine to amine before there can occur any substantial reverse equilibration of hydrated imine to hydrated pyruvate (which would otherwise result from this reduced ammonia concentration). While, with flash evaporating equipment, the parameters above indicated can be readily achieved at room temperature or above, it has been found convenient in batch operations to freeze the equilibrium at 95 parts hydrated imine to 5 parts hydrated pyruvate in concentrated aqueous ammonia by cooling the mixture to 10°C., at which temperature the equilibrium half-life (which is 15 minutes at 37°C) is increased to approximately five hours; the borohydride reducing agent is then added to the cold solution. Although, in this concentrated aqueous ammonia solution at 1Q°C., the rate of borohydride reduction of imine is relatively slow, the rate of reduction (using this low temperature and small excess of borohydride reducing agent) is greatly increased (so that the reduction of imine to amine occurs in a period of only ten minutes) by evaporation removal of excess of ammonia; such evaporation is conducted under reduced pressure while maintaining the temperature at about 10°C. This reaction may be catalysed, and the yield of 3-fluoro-DL5 alanine appreciably increased, by addition of salts such as lithium or sodium salts, as for example lithium chloride or sodium chloride, to the reduction reaction mixture.
Thus, the preferred procedure in accordance with the present invention, which effectively combines the above-noted features, involves (a) equilibration of a 3-fluoropyruvate salt, preferably an alkali metal or alkaline earth metal salt, or an ammonium salt, e.g. ammonium fluoropyruvate, sodium fluoropyruvate or lithium fluoropyruvate hydrate, preferably at about 37°C., in concentrated aqueous ammonia at which temperature there is obtained at 95:5 ratio hydrated imine:hydrated pyruvate in about 90 minutes; it is particularly advantageous to use lithium fluoropyruvate hydrate, since the latter, in contrast to other alkali metal fluoropyruvates, is relatively insoluble in water and is readily prepared in pure'form and high yield; (b) addition of alkali metal borohydride, such as sodium borohydride or lithium borohydride; after cooling to 10°C., if desired, to freeze the equilibrium; (c) evaporative removal of excess of ammonia sufficiently rapidly so that accelerated borohydride reduction effectively reduces imine to amine before substantial reverse equilibration occurs to form hydrated pyruvate; at the preferred 10°C.temperature, equilibration half-life is increased to five hours, whereas complete reduction of imine to amine occurs in only about 10 minutes. The reduction reaction may be conducted, if desired, at room temperature or above without evaporating excess of ammonia from the concentrated aqueous ammonia solution, but this procedure results in poorer yields.
Salts, such as lithium chloride or sodium chloride, which catalyse the reduction and increase the yield of 3-fluoro-DL-alanine, may be incorporated in the reaction mixture if desired.
Following the reductive amination reaction, the reaction mixture is evaporated in vacuo until water distils, thereby substantially removing all ammonia present, since residual ammonium ions are transferred in the ion-exchange column purification. The substantially ammonia-free reaction solution is then acidified with an aqueous mineral acid, such as aqueous hydrochloric acid, thereby cleaving the boron complex of 3-fluorO-alanine formed during the reductive amination reaction. The acidified reaction mixture, which is conveniently freed Of coloured impurities that may be present by treatment with activated charcoal, is then passed through a column containing an acid pre-washed strongly acidic cation-exchange resin such as those sold under the trade marks Dowex 5OW-X4, which is a strongly acidic, cation-exchange resin consisting of a sulfonated styrene-divinyl-benzene copolymer containing 4% divinylbenzene, having a mesh size 20-50 mesh based on the U.S. standard screen, or Dowex 5OW-X8, which is similar to Dowex 5OW-X4 except that it contains 8% divinylbenzene in the sulfonated styrene-divlnylbenzene copolymer, thereby separating the desired 3-fluoro-alanine from the by-product fluorolactic acid and metallic cations. The ion exchange column containing the adsorbed 3-fluoroalanine is washed with de-ionized water until the eluate is no longer acidic, and the column is then eluated with dilute aqueous ammonium hydroxide solution whereupon ammonium ion replaces the 3-fluoro-alanine on the resin column.
- 7 41927
The eluate is thqn evaporated in vacuo, thereby removing any ammonia present in the eluate; the colored solution is de-colorized with activated charcoal; the decolorized solution is evaporated in vacuo; and the residual material is crystallized from aqueous alkanol, preferably aqueous isopropanol to give the 3-fluoro-alanine in substantially pure form.
The following examples, in which the words Darco and Supercel are trade marks, illustrate methods of carrying out the present invention, but it is to be understood that these examples are given for purposes of illustration and not of limitation. Example 1 illustrates the preparation of a starting material.
EXAMPLE 1
A mixture of 400 ml of ethyl ether and 240 ml. of 5N aqueous hydrochloric aoid is cooled to a temperature of about -15 to -20°C. To this mixture is added, with good stirring and under a nitrogen atmosphere, about 138 grams of lump-free sodium 1,2-di(ethoxycarbonyl)-2fluoro-ether-l-olate, EtOOC-CP=C(ONa)-COOEt, at a steady rate such that the temperature remains between -15°C and -20°C. When addition is complete, the mixture is warmed to room temperature, diluted with 240 ml. of water, and the aqueousethereal mixture is heated at atmospheric pressure and the ether distilled until the temperature of the aqueous solution reaches 1O2-1O5°C. The resulting aqueous solution is then heated under reflux for a period of about 4 hours. The reaction solution is cooled to room temperature, stirred with about 6 grams of activated charcoal (Darco G-60) and filtered through acid-prewashed diatomaceous silica (Supercel),
- 8 41927 and the Insoluble material on the filter washed with a minimum of water. The filtered solution is cooled to 0-5°C; neutralized with pH control, by addition of solid lithium hydroxide hydrate (about 47 grams of LiOH.^O required) to a final pH of 6.0 to 6.5; and the resulting neutralized slurry is allowed to stand at about 0°C for a period of approximately 15 hours. The precipitated material is recovered by filtration, washed with a minimum of cold water, then with two 200 ml. portions of methanol, and then with two 200-ml.portions of acetone. The resulting material is air-dried to give about 56 grams of lithium fluoropyruvate hydrate.
EXAMPLE 2
About 26 grams of lithium fluoropyruvate hydrate is added, with good agitation and at room temperature, to about 300 ml. of concentrated (25-28%) aqueous ammonium hydroxide. The resulting suspension is heated to about 37°C.(whereupon substantially all of the solid material dissolves) and the solution is maintained at that temperature for a period of about 1.5 hours. The resulting dark solution, which contains about 95 parts of 2-hydroxy-2-amino3-fluoro-propionate to about 5 parts of 2,2-dihydroxy-3-fluoropropionate, is cooled to about 25°C. and placed under a nitrogen atmosphere, and about 7.6 grams ( a four-fold excess) of sodium borohydride is added. The reaction, which occurs, is exothermic, and the temperature rises to about 30°C. The reaction mixture is then heated to about 37°C. and maintained at that temperature for a period of about hours, at the end of which time the reductive amination reaction is substantially complete.
The reaction mixture is distilled under reduced pressure until about 50 ml. of water has been evaporated from the mixture, thereby ensuring substantially complete removal of ammonia, and the residual solution is cooled to about 0°C. To this solution is added, with stirring and cooling to maintain the temperature at about 0-5°C., about 165 ml. of 2.5 N aqueous hydrochloric acid solution. The acidified reaction solution is warmed to room temperature, stirred with 1.3 grams of activated charcoal (Darco G-60) for about 15 minutes, and filtered.
The filtered solution is diluted with an equal volume Of water, and slowly passed through a column containing 800 ml. of an acid pre-washed, strongly acidic, cation-exchange resin (Dowex 50 WX4). The column is washed with de-ionized water until the eluate is no longer acidic (about 4 liters water required), and the column is then eluted with 0.5 N aqueous ammonium hydroxide solution. The 3-fluoro-DL-alanine comes off immediately before the ammonia breakthrough; the elution is monitored with ninhydrin reagent spray on a test spot on a thin layer chromatogram plate. The ammonia front oan be detected as a warm band proceeding down the column.
The end of the 3-fluoro-DL-alanine elution customarily trails into the ammonia breakthrough. The eluate (volume approximately 1200 ml.) is evaporated in vacuo, at a temperature not exceeding 25°C., to form a slurry of about 75 ml. volume, and the precipitated material is redissolved by heating the slurry to about 60°C. To the resulting slurry (at 6O°C.) is added about 50 ml. of preheated isopropanol (also at 60°C), whereupon the mixture becomes cloudy, and the aqueous isopropanol solution is allowed to cool to room temperature. The slurry thus obtained is cooled to about 0°C., allowed to stand at this temperature for about one to two hours, and the resulting crystalline slurry is filtered. The crystalline material is filtered, washed with two 20 ml. portions of cold 90% isopropanol, and vacuum dried at 40°C. to give about 11 grams of 3-fluoro-DL-alanine.
EXAMPLE 3
To about 150 ml. of concentrated aqueous ammonium hydroxide is added, with good agitation and at room temperature, 18.35 grams of lithium fluoro-pyruvate. The resulting suspension is heated to about 35-37°c. (whereupon substantially all of the solid material dissolves), and the solution is maintained at that temperature for a period of about 1.5 hours; the resulting solution, which contains about 95 parts of hydrated imine to 5 parts of hydrated pyruvate and which may contain dark-colored impurities, is cooled to about 10°C., and to this cold solution is added about 8.5 grams of solid lithium chloride and 1.785 grams of sodium borohydride. The resulting solution is placed under vacuum with stirring and vigorous subsurface nitrogen flow to remove dissolved ammonia. Temperature of the solution is maintained at 10-13°C, for a period of about 1 hour, then gradually raised to about 25°C, over a 1 hour period, and held at 28-33°C. for a period of about 1.5 hours . The reaction solution is evaporated in vacuo at 35°C. until water distils and solution is essentially free of ammonia, and the resulting solution is then acidified with about 80 ml. of 2.5 N aqueous hydrochloric acid solution. The acidified reaction solution is stirred with about 2.5 grams of activated charcoal (Darco KB) for about 15 minutes and filtered.
- 11 41927
The filtered solution is slowly passed through a column containing 850 ml. of acid pre-washed, strongly acidic, cation-exchange resin (Dowex 50 WX4). The column is washed with de-ionized water until the eluate is no longer acidic (about 4 liters water required), and the column is then eluted with 0.5 N aqueous ammonium hydroxide solution. The ninhydrin-positive fractions are combined, and evaporated in vacuo at a temperature not exceeding 30°C., to give about 400 ml of an ammonium-free solution. This solution is stirred at room temperature with 2.5 grams of activated charcoal (Darco KB); the charcoal is removed by filtration, the filtered solution is again stirred with an additional
1.5 grams of activated charcoal, and the slurry is again filtered. The filtered solution is evaporated to dryness in vacuo at a temperature not exceeding 30°C. to give about 7.3 grams of crude material.
This material is dissolved in 33 ml. of water at a temperature of about 60°C.; about 27 ml. of isopropanol (preheated to 60°C.) is added; the aqueous isopropanol solution is seeded with crystals of 3-fluoro-DL-alanine; and the resulting mixture is cooled slowly first to room temperature and then to about 0°C. The crystalline slurry is allowed to stand at 0°C. for about 1-2 hours, the slurry is filtered, and the crystalline material on the filter is washed with two 5-ml portions of 90% aqueous isopropanol, then with two 5-ml.portions of isopropanol, and finally with hexane.
The washed material is dried in vacuo at a temperature of 5O-6O°C. to give about 5.6 grams of 3-fluoro-DL-alanine.
Claims (7)
1. CLAIMS :1. The process that comprises subjecting a salt of 3-fluoropyruvic acid, or hydrate thereof, to reductive amination using aqueous ammonia, to form a salt of 2-imino-3-fluoropropionic acid or hydrate thereof, and an alkali metal borohydride as reducing agent, thereby forming 3-fluoro-DL-alanine or a salt thereof.
2. A process as claimed in claim 1, that comprises reacting an alkali metal or alkaline earth metal salt of 3-fluoropyruvic acid, or hydrate thereof, with concentrated aqueous ammonium hydroxide thereby forming a salt of 2-imino-3-fluoro-propionic acid hydrate, and reacting the latter with an alkali metal borohydride to produce 3-fluoro-DL-alanine or a salt thereof.
3. A process as claimed in claim 1 or 2 in which the starting salt is reacted with concentrated aqueous ammonium hydroxide for a time sufficient to convert it substantially completely to a salt of hydrated 2-imino3-fluoro-proplonic acid, the resulting solution is cooled to a temperature of about 10°C to stabilize the 2-imino-3-fluoropropionic acid component against reconversion to a 3-fluoropyruvic acid compound, alkali metal borohydride is added to this cold aqueous ammoniacal solution and the resulting solution is distilled under reduced pressure while maintaining the temperature at about 1O°C until substantially all of the excess of ammonia has been evaporated from said solution, and the resulting solution is maintained at 10°C for a period of about 10 minutes at the end of which time the reduction of the 2-imino substituent is 41937 substantially complete to form 3-fluoro-DL-alanine or a salt thereof.
4. A process as claimed in claim 3, in which the starting salt is lithium 3-fluoropyruvate hydrate and it is reacted with concentrated aqueous ammonium hydroxide at a temperature of about 37°C. for a period of about 90 minutes thereby forming an equilibrium solution containing about 95 parts by weight of hydrated 2-imino-3-fluoro-propionate salt and about 5 parts by weight of hydrated 3-fluoro-pyruvate salt.
5. A process as claimed in claim 3 or 4, in which about 1.5 equivalents of sodium borohydride per equivalent of starting pyruvate salt is used as reducing agent.
6. A process that produces 3-fluoro-DL·-alanine or a salt thereof, substantially as hereinbefore described in Example 2 or 3.
7. 3-Fluoro-DL-alanine, and its salts, when prepared by a process as claimed in any one of the preceding claims.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US52218474A | 1974-11-08 | 1974-11-08 |
Publications (2)
Publication Number | Publication Date |
---|---|
IE41927L IE41927L (en) | 1976-05-08 |
IE41927B1 true IE41927B1 (en) | 1980-04-23 |
Family
ID=24079793
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IE2405/75A IE41927B1 (en) | 1974-11-08 | 1975-11-05 | Preparation of 3-fluoro-dl-alanine salts |
Country Status (12)
Country | Link |
---|---|
JP (1) | JPS5170721A (en) |
AT (1) | AT344675B (en) |
BE (1) | BE835357A (en) |
DE (1) | DE2550109A1 (en) |
DK (1) | DK474475A (en) |
FR (1) | FR2290417A1 (en) |
GB (1) | GB1480989A (en) |
IE (1) | IE41927B1 (en) |
IT (1) | IT1048053B (en) |
LU (1) | LU73733A1 (en) |
NL (1) | NL7512382A (en) |
SE (1) | SE7511733L (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NZ194348A (en) * | 1979-07-26 | 1982-09-14 | Merrell Toraude & Co | Fluorinated methyl-beta-alanine derivatives and pharmaceutical compositions |
EP3293167A1 (en) | 2016-09-09 | 2018-03-14 | Université Catholique De Louvain | [18f]-labelled lactate derivative as pet radiotracer |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NL7300577A (en) * | 1972-02-03 | 1973-08-07 |
-
1975
- 1975-10-20 SE SE7511733A patent/SE7511733L/en unknown
- 1975-10-22 DK DK474475A patent/DK474475A/en unknown
- 1975-10-22 NL NL7512382A patent/NL7512382A/en not_active Application Discontinuation
- 1975-10-27 GB GB44183/75A patent/GB1480989A/en not_active Expired
- 1975-10-31 IT IT52035/75A patent/IT1048053B/en active
- 1975-11-04 AT AT838675A patent/AT344675B/en active
- 1975-11-05 FR FR7533778A patent/FR2290417A1/en active Granted
- 1975-11-05 IE IE2405/75A patent/IE41927B1/en unknown
- 1975-11-06 LU LU73733A patent/LU73733A1/xx unknown
- 1975-11-07 JP JP50133149A patent/JPS5170721A/en active Pending
- 1975-11-07 DE DE19752550109 patent/DE2550109A1/en not_active Withdrawn
- 1975-11-07 BE BE161681A patent/BE835357A/en unknown
Also Published As
Publication number | Publication date |
---|---|
AT344675B (en) | 1978-08-10 |
NL7512382A (en) | 1976-05-11 |
IE41927L (en) | 1976-05-08 |
JPS5170721A (en) | 1976-06-18 |
FR2290417A1 (en) | 1976-06-04 |
ATA838675A (en) | 1977-12-15 |
DK474475A (en) | 1976-05-09 |
LU73733A1 (en) | 1976-09-06 |
GB1480989A (en) | 1977-07-27 |
FR2290417B1 (en) | 1979-01-05 |
DE2550109A1 (en) | 1976-05-13 |
SE7511733L (en) | 1976-05-10 |
BE835357A (en) | 1976-05-07 |
IT1048053B (en) | 1980-11-20 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US3972921A (en) | Synthesis of racemic 2-deutero-3-fluoro-alanine and its salts | |
JPS5836399A (en) | Production of human insulin derivative | |
KR100399509B1 (en) | Process for purifying valine | |
IE41927B1 (en) | Preparation of 3-fluoro-dl-alanine salts | |
US4149012A (en) | Synthesis of racemic 3-fluoro-alanine and its salts | |
US4667054A (en) | Process for producing optically active valine | |
US3381031A (en) | Resolution of racemic amino acids | |
US2873276A (en) | Antibiotic purification and complex compounds | |
US3994962A (en) | Method of manufacturing optically active p-hydroxyphenylglycine | |
US3527776A (en) | Optical resolution of dl-lysine | |
US3532684A (en) | Molecular compounds of inosine and tryptophan | |
KR101979836B1 (en) | Process for the preparation of calcobutrol | |
US2859244A (en) | Resolution of dl-lysine with d-camphoric acid | |
US2846469A (en) | Method of preparing synthetic dl-3 monoamide of 1-aminoglutaric acid (dl-glutamine) | |
HU176009B (en) | Process for producing amino-acids | |
US3627824A (en) | Process for crystallizing{65 -alkylmercaptolysine dihydrochloride | |
US3279989A (en) | Process for crystallizing actino-spectacin sulfate | |
US2881183A (en) | Resolution of dl-lysine | |
US3287452A (en) | Synthesis of adenine and of 4, 5-dicyanoimidazole | |
US3402199A (en) | Method for producing threonine | |
US4484003A (en) | Preparation process of β-chloroalanine | |
EP0357029B1 (en) | Method for the production of (-) 2-difluoromethyl-ornithine | |
US2870139A (en) | Purification of d(-) galactamine | |
US3374223A (en) | Crystalline sodium 5'-guanylate pentahydrate and method of producing the same | |
US3804858A (en) | Process of recovering spectinomycin |