IE41498B1 - Resolution of 2-deutero-3-fluroalanine - Google Patents
Resolution of 2-deutero-3-fluroalanineInfo
- Publication number
- IE41498B1 IE41498B1 IE1592/75A IE159275A IE41498B1 IE 41498 B1 IE41498 B1 IE 41498B1 IE 1592/75 A IE1592/75 A IE 1592/75A IE 159275 A IE159275 A IE 159275A IE 41498 B1 IE41498 B1 IE 41498B1
- Authority
- IE
- Ireland
- Prior art keywords
- solution
- fluoro
- deutero
- alanine
- isomer
- Prior art date
Links
- 238000000034 method Methods 0.000 claims abstract description 18
- 239000000203 mixture Substances 0.000 claims abstract description 15
- 239000012452 mother liquor Substances 0.000 claims abstract description 13
- 239000013078 crystal Substances 0.000 claims abstract description 7
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 7
- 230000001131 transforming effect Effects 0.000 claims abstract description 5
- UYTSRQMXRROFPU-VMNATFBRSA-N 2-amino-2-deuterio-3-fluoropropanoic acid Chemical class FCC(N)([2H])C(O)=O UYTSRQMXRROFPU-VMNATFBRSA-N 0.000 claims abstract 3
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 claims description 22
- 229940077388 benzenesulfonate Drugs 0.000 claims description 22
- 229960003767 alanine Drugs 0.000 claims description 12
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 11
- 238000002425 crystallisation Methods 0.000 claims description 10
- 230000008025 crystallization Effects 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- XOXBTKOKBQADJP-DWXPJDSVSA-N (2s)-2-amino-2-deuterio-3-fluoropropanoic acid;benzenesulfonic acid Chemical compound FC[C@](N)([2H])C(O)=O.OS(=O)(=O)C1=CC=CC=C1 XOXBTKOKBQADJP-DWXPJDSVSA-N 0.000 claims description 5
- UYTSRQMXRROFPU-LIIDHCAMSA-N (2s)-2-amino-2-deuterio-3-fluoropropanoic acid Chemical class FC[C@](N)([2H])C(O)=O UYTSRQMXRROFPU-LIIDHCAMSA-N 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 238000010924 continuous production Methods 0.000 claims description 3
- 229950010030 dl-alanine Drugs 0.000 claims description 2
- 239000000243 solution Substances 0.000 claims 17
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 6
- 230000000875 corresponding effect Effects 0.000 claims 6
- 150000008534 L-alanines Chemical class 0.000 claims 1
- 239000012047 saturated solution Substances 0.000 claims 1
- UYTSRQMXRROFPU-MYSWAXPFSA-N (2r)-2-amino-2-deuterio-3-fluoropropanoic acid Chemical compound FC[C@@](N)([2H])C(O)=O UYTSRQMXRROFPU-MYSWAXPFSA-N 0.000 abstract 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000002002 slurry Substances 0.000 description 6
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 5
- 235000004279 alanine Nutrition 0.000 description 5
- 239000002178 crystalline material Substances 0.000 description 4
- XOXBTKOKBQADJP-NGRIDVMYSA-N 2-amino-2-deuterio-3-fluoropropanoic acid;benzenesulfonic acid Chemical compound FCC(N)([2H])C(O)=O.OS(=O)(=O)C1=CC=CC=C1 XOXBTKOKBQADJP-NGRIDVMYSA-N 0.000 description 3
- 238000011109 contamination Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000007790 solid phase Substances 0.000 description 3
- 244000052616 bacterial pathogen Species 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000005086 pumping Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- RTAPYDYQORHWRY-UHFFFAOYSA-N 2-aminopropanoic acid;benzenesulfonic acid Chemical compound CC(N)C(O)=O.OS(=O)(=O)C1=CC=CC=C1 RTAPYDYQORHWRY-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 101100367123 Caenorhabditis elegans sul-1 gene Proteins 0.000 description 1
- QNAYBMKLOCPYGJ-UWTATZPHSA-N D-alanine Chemical compound C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N D-alpha-Ala Natural products CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 238000010956 selective crystallization Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
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
- C07C227/30—Preparation of optical isomers
- C07C227/34—Preparation of optical isomers by separation of optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/20—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Analytical Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Peptides Or Proteins (AREA)
Abstract
1472396 2-Deutero-3-fluoroalanine MERCK & CO Inc 28 July 1975 [31 July 1974] 31488/75 Heading C2C A process for resolving a DL-mixture of a 2- deutero-3-fluoro-DL-alanine salt, comprises preparing a saturated C 1-6 alkanolic solution of said DL-mixture in a solution zone; transforming the said solution into a supersaturated solution of the DL-mixture; contacting the supersaturated solution with crystals of one of the corresponding individual isomers, thereby crystallizing the said isomer from the said solution ; and recovering the other individual isomer from the resulting mother liquor.
Description
The invention is concerned with the preparation of 2-deutero
3-fluoro-D-alkanine, which is a potent antibacterial, agent valuable in inhibiting the growth of. pathogenic bacteria of both the gram-positive and gram-negative types.
in accordance with the present invention, a BL-mixture of
2-deutoro-3-fluoro-DL-alanine salt such as an organic sul 1’onate salt, e.g. 2-deutoro-3-fluoiO-DL-alanine benzene sulfonate,
2- deutcro-3-fluoro-DL-alanine p-toluensulfonate; ox- 2-deutero3- fluoro-DL-alanine 2-naphthalene-sulfonate, is resolved by preparing a saturated alkanolic solution of said DLmixfcure in a solution zone; transforming the said .solution into a supersaturated solution ol' the DL-mixture; contacting the supersaturated solution with crystals of one of the corresponding individual isomers, thereby crystallizing the said isomer from said solution; and recovering the other individual isomer from the resulting mother liqor. The alkanol used is preferably ethanol or propanol. The supersaturated solution is conveniently formed by raising the temperature in the solution zone to about 30°C. and maintaining approximately a 5°C.
differential between the temperature in the dissolver and that in the crystallizer. In accordance with a preferred embodiment of this procedure, a solution of 2-deutero-3-fluoro-B£-alanine benzene sulfonate in propanol, prepared in a dissolver, is 1 transformed into a supersaturated propanolic solution, the latter is then contacted with crystalline seed of 2-deutcro3-fluoro-L-alanine benzene sulfonate, and the mother liquor is separated from the crystalline material that separates.
It is ordinarily preferred <1498 to first crystallize the unwanted L-isomer, since greater chance of contamination occurs in this initial crystallizing step. The said mother liquor, with or without increase in supersaturation, is then contacted with crystalline seed of 2-deutero-3-fluoro-B~alanine benzene sulfonate, and the crystalline D-isomer,which precipitates,is separated from the mother liquor; the propanolic mother liquor from this second crystallization is returned to the dissolver. In the continuous operation of this process, the mother liquor from the second crystallization (i.e. of the D-isomer) is recycled into the dissolver, and the crystallized D- and L-isomers are withdrawn from each crystallizer continuously or intermittently.
Similarly, a solution of the 2-deutero~3-fluoro-DL15 alanine benzene sulfonate in ethanol, prepared in the dissolver, is transformed into a supersatured ethanol solution, the latter is then contacted with crystalline seed of 2-deutero-3-fluoro-L-alanine benzene sulfonate, the mother liquor is separated from the crystalline material which separates, and is then contacted with crystalline seed of 2-deutero-3-fluoro-D-alanine benzene sulfonate; the crystalline D-isomer which precipitates,is separated, and the ethanolic mother liquor from this second crystallization is returned to the dissolver.
Although it is preferred to conduct the continuous process as a series operation, it can be carried out in parallel if desired, i.e. by dividing the solution from the dissolver into two equal parts, forming a supersaturated solution with each part, contacting one part _ with seed of D^isomer and contacting the other with seed
44488 of L-isomer, and recycling both mother liquors to the dissolver, Lhe crystallized P- and L-isomern being isolated from their respective slurries continuously or intermittently.
Alternatively, this continuous direct resolution may be carried out in a process involving only two steps, i.e. a solution step and a crystallization step. In a preferred embodiment of this two-step method, a saturated propanolic solution of 2-deutero-3-fluoro10 . DL-alanine benzene sulfonate is prepared in the dissolver, and the solution is transferred to a crystallization 2one where the solution is rendered supersaturated, preferably by reducing i.ts temperature . The supersaturated propanol solution of 2-deutero-3-fluoro-DL15 alanine benzene sulfonate is seeded with crystals of the corresponding D-isomcr, thereby effecting selective crystallization of the said D-isomer in substantially pure form, and this crystalline 2-deutero-3-fluoro-D-alanine benzene sulfonate is then recovered by filtration or centrifugation. The mother liquors are then returned to the dissolver and the temperature is elevated to the temperature of the original solution in the dissolver.
The resulting solution is then contacted with additional 2-deutero-3-fluoro-d3L-alanine benzene sulfonate, thereby selectively dissolving the P-isomer. leaving the _Lr isomer undissolved in substantially pure form, thus continuously effecting selective separation of one of the enantiomorphs constituting the DL-mixture in the solution zone (i.e. the L-isomer), and effecting separation of tiie other enantiomorph (i.e. the. D-isomer) in the crystallization
41488 zone, said D- and L-isomers being removed from the crystallization and solution zones in a continuous or intermittent fashion as they are formed.
As noted hereinabove, the 2-deutero-3-fluoro-D5 alanine is a potent and useful antibacterial agent, and is useful in inhibiting the growth of pathogenic bacteria of both gram-positive and gram-negative genera.
The following examples 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
An apparatus .consisting of three vessels, each equipped with a stirrer and a means of temperature control, which are connected in a circle by delivery lines, each of which begins in an internal filter and passes through a pump to the next vessel. Additional filters are also inserted after each pump. The first vessel in the circuit, the dissolver, is further equipped f°v the addition of solid 2-deutero-3-fluoro-DL-alanine benzenesulfonate and solvent. The other two vessels are the D and L crystallizers, respectively. The operation of the equipment is a follows.
Two liters of propanol is charged to the dissolver 25 and 400 grams of 2-deutero-3-fluoro-DL-alanine benzenesulfonate is added. The slurry is equilibrated at 25°C for one hour and then pumping is started to the L-crystallizer.
When the volume in the L-crystallizer reaches 500 ml., the pump between the L- and D-crystallizers is started, and the rate is adjusted to maintain the 500 ml volume in the L-crystallizer. When lhe volume in l.iie D-crystallizer reaches 500 ml, the pump between the D-crystallizer and the dissolver is started, and the rate is adjusted to maintain the volume constant. An additional one liter of propanol and 170 grams of 2-deutero-3-fluoroDL-alanine benzene sulfonate are added to the dissolver, and the system equilibrated at 25°C. by pumping from vessel to vessel.
grams of 2-deutero-3-fluoro-L-alanine benzenesulfonate is added to the L-crystallizer and grams of 2-deutero-3-fluoro-D-alanine benzenesulfonate is added to the D-crystallizer.
Tho temperature is then raised in the dissolver to 30°C which develops a supersaturation in the crystallizers, which are maintained at 25°C. Additional solid 2-deuter'o-3-fluoro-DL-alanine benzenesulfonate is added to the dissolver to maintain a solid phase.
The solid phase in each of the crystallizers is maintained approximately constant by occasionally 2θ removing some of the crystalline slurry from each crystallizer. Filtration of the propanol slurry from the L-crystallizer gives substantially pure 2-deutero-3• fluoro-L-alanine benzenesulfonate; filtration of slurry from the D-crystallizer gives substantially pure
2-deutero-3-fluoro-D-alanine benzenesulfonate. The filtrates are returned to the dissolver.
Productivity can be increased by raising the temperature of the dissolver and maintenance of solid phase. However, the risk of contamination and production
,.. of less pure 2-deutero-3-fluoro-IP-&lanine benzenesulfonate
41438 increases with higher supersaturation. In the event of contamination, the product can be purified by a simple batchwise recrystallization from aqueous isopropanol.
The 2-deutero-3-fluoro-D~alanine benzenesulfonate is converted to 2-deutero-3-fluoro~D-alanine by dissolving the salt in water and adsorbing the amino 4* acid on a sulfonic acid (H cycle) resin. The column is washed with water and then eluted with dilute aqueous ammonia solution. The eluate is concentrated to a small volume and the 2-deutero-3-fluoro-D-alanine crystallized by addition of isopropanol.
Example 2
In a manner analogous to that described in Example 1, 7 liters of n-propanol is charged to ) an eight liter kinetic resolution system, equipped with a dissolver, an L-column, a D-column and appropriate temperature controllers and pumps. To the dissolver are added 1200 grams of 2-deutero-3-fluoro-DL-alanine benzenesulfonate, and the system is saturated at 27°C ' for one hour. The D- and L-columns are adjusted to 25°C., and 100 grams of appropriate seed of 100-120 mesh (U.S. Standard) is- added to each column. The column temperatures are adjusted to 22°C, while the dissolver is maintained at 27°C. A flow rate of 300-600 ml./minute is maintained through each column for an eight hour period.
The flow rate is such as to maintain the maximum fluidized bed height throughout the run. After eight hours, the contents of the D-columns are filtered, the crystalline material is washed with two 400 ml. portions of n-propanol and four 400 ml. portions of n-hexane, and air-dried to give
400 grams of 2-deutero-3-fluoro-D-alanine
61698 benzenesulfonate of 100% optical purity. The crystalline 2-deutero-3-fli oro-L-alanine benzenesulfonate is recovered from the L-column in a similar manner.
grams of 2-deutcro-3-fluoro-D-alaninc benzenesulfonate is dissolved with stirring in 30 ml. of 50% aqueous lsopropanol at room temperature. The clear colorless solution is coo I cd with stirring to about 0MC.,and 3.H grams of triethyLamine is added dropwise to this solution; crystallization occurs fi flowing addition of the first drops of triethylamine. The crystalline slurry is stirred at 0°C. for a period of half an hour and filtered. The recovered crystalline material is washed with 50 ml. of cold 90% aqueous isopropanol, 50 ml. isopropanol, then with licxane, and air-dried at room temperature to give about 3-9 grains of 2-deutero-3-fluoro-D-alanine.
Claims (12)
1. · The process for resolving a DL-mixture of a 2-deutero3-fluoro-DL-alanine salt, which comprises preparing a saturated Cj_ g alkanoLie solution of said DL-mixture in a 2. - deutero-3-l’l uoro-D-al an ine benzene sul foliate.
2. A process as claimed in claimed in claim 1 which comprises preparing a saturated Cj g alkanol solution of a DL-mixture of a 2-deutero-3-fluoro-j)L-alanine salt in a solution zone; transforming the said solution into a super15 saturated solution of said DL-mixture; contacting said supersaturated solution with corresponding J>isomer crystals, thereby crystallizing said I^-ispmer from said solution; separating the mother liquor and contacting it with correspond ing D-isomer crystals, thereby crystallizing the corresponding 20 2-deutero-3-fluoro-D-alanine salt, and recovering said 2deutero-3-fluoro- J/—alanine salt.
3. · A process as claimed in claim 1 which comprises preparing a saturated Cj_ g alkanol solution of a DL-mixture of a 2-deutero-3-fluoro-DL-alanine salt in a solution zone; 25 transforming the said solution into a supersaturated solution of said DL-mixture; contacting said supersaturated solution with corresponding D-lsomer crystals, thereby crystallizing said D-isomer from said solution; separating the mother liquor and contacting it with additional DL-mixture of the 2-deutero30 3-fluoro-DJL-alanino salt, whereby the D-isomer present in the .DL-mixture is selectively dissolved leaving corresponding L-isomer undissolved in substantially pure form. - 0 41498
4. - A process as claimed in Claim 1, in which tile 2deuhero—3-11 uoro—DL—al ani ne sail- is 2—d<;utero- ΓI uoro-DL— alanine benzene sit 1 I’onate, an
5. - A process as claimed in Claim 2, in which the 2deutero-3-fluoro-DL.-alanlne salt is 3-fluoro-DL-alanlne benzene sulfonate, and the β-isomer recovered is 2-deutero3- f luoro-I)-alanine benzene sulfonate. h.
6. A process as claimed in CLaim 4, in which the alkanol is ethanol. 5 solution zone; transforming the said solution into a supersaturated solution of the DL-mixture; contacting the supersaturated solution with crystals of one of the corresponding individual isomers, thereby crystallizing the said Isomer from the said solution; and recovering the other individual
7. A process as claimed in Claim 4, in which the alkanol is propanol..
8. A process as claimed in Claim 6, in which the mother liquor I'rom the 2-dcutero-3-i'l uoro-D-alanine benzene sulfonate crystallization is returned to the dissolver, and the resolution is operated as a continuous process.
9. A process as claimed in Claim 7, in which the. mother liquor from the 2-deutero-3-fluoro-D-alaninc benzene sulfonate crystallization is returned to the dissolver, and the resoi ution is operated as a continuous process.
10. A process as claimed in Claim 3, in which the 2deutero-3-fluoro-DL-alanine salt is 2-deutero-3-fluoro-DLalanine benzene sulfonate, and the D-isomer recovered is 2-deutero-3-fluoro-D-alanine benzene sulfonate. 10 isomer from the resulting mother liquor.
11. A process as claimed in CLaim 1, substantially as hereinbefore described in Example I or in Example 2.
12. A ID or £ salt of 2-dciil.ero-3-f 1uoroalanine, when prepared by a process as claimed in any one of the preceding c 1 a ims.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US49335274A | 1974-07-31 | 1974-07-31 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE41498L IE41498L (en) | 1976-01-31 |
| IE41498B1 true IE41498B1 (en) | 1980-01-16 |
Family
ID=23959889
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE1592/75A IE41498B1 (en) | 1974-07-31 | 1975-07-17 | Resolution of 2-deutero-3-fluroalanine |
Country Status (24)
| Country | Link |
|---|---|
| JP (1) | JPS5139626A (en) |
| AR (1) | AR207648A1 (en) |
| AU (1) | AU497991B2 (en) |
| BE (1) | BE831760A (en) |
| CA (1) | CA1054158A (en) |
| CH (1) | CH598194A5 (en) |
| CS (1) | CS191271B2 (en) |
| DD (1) | DD119209A5 (en) |
| DE (1) | DE2534031A1 (en) |
| DK (1) | DK345875A (en) |
| ES (1) | ES439857A1 (en) |
| FI (1) | FI752130A (en) |
| FR (1) | FR2280366A1 (en) |
| GB (1) | GB1472396A (en) |
| HU (1) | HU170472B (en) |
| IE (1) | IE41498B1 (en) |
| LU (1) | LU73100A1 (en) |
| NL (1) | NL7508925A (en) |
| NO (1) | NO752551L (en) |
| PL (1) | PL103968B1 (en) |
| SE (1) | SE7508553L (en) |
| SU (1) | SU568362A3 (en) |
| YU (1) | YU190675A (en) |
| ZA (1) | ZA754918B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4028405A (en) * | 1974-10-15 | 1977-06-07 | Merck & Co., Inc. | Fluorinated amino acids |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL7300576A (en) * | 1972-02-03 | 1973-08-07 |
-
1975
- 1975-01-01 AR AR259830A patent/AR207648A1/en active
- 1975-07-17 NO NO752751A patent/NO752551L/no unknown
- 1975-07-17 IE IE1592/75A patent/IE41498B1/en unknown
- 1975-07-21 CA CA231,941A patent/CA1054158A/en not_active Expired
- 1975-07-23 AU AU83316/75A patent/AU497991B2/en not_active Expired
- 1975-07-24 CH CH968275A patent/CH598194A5/xx not_active IP Right Cessation
- 1975-07-24 FI FI752130A patent/FI752130A/fi not_active Application Discontinuation
- 1975-07-25 YU YU01906/75A patent/YU190675A/en unknown
- 1975-07-25 BE BE158335A patent/BE831760A/en not_active IP Right Cessation
- 1975-07-25 NL NL7508925A patent/NL7508925A/en not_active Application Discontinuation
- 1975-07-28 SE SE7508553A patent/SE7508553L/en unknown
- 1975-07-28 GB GB3148875A patent/GB1472396A/en not_active Expired
- 1975-07-29 DD DD187544A patent/DD119209A5/xx unknown
- 1975-07-29 FR FR7523617A patent/FR2280366A1/en active Granted
- 1975-07-30 CS CS755338A patent/CS191271B2/en unknown
- 1975-07-30 ZA ZA754918A patent/ZA754918B/en unknown
- 1975-07-30 SU SU7502163062A patent/SU568362A3/en active
- 1975-07-30 PL PL1975182389A patent/PL103968B1/en unknown
- 1975-07-30 ES ES439857A patent/ES439857A1/en not_active Expired
- 1975-07-30 DE DE19752534031 patent/DE2534031A1/en active Pending
- 1975-07-30 DK DK345875A patent/DK345875A/en unknown
- 1975-07-30 LU LU73100A patent/LU73100A1/xx unknown
- 1975-07-31 HU HUME1881A patent/HU170472B/hu unknown
- 1975-07-31 JP JP50092656A patent/JPS5139626A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| AU8331675A (en) | 1977-01-27 |
| NL7508925A (en) | 1976-02-03 |
| ZA754918B (en) | 1977-03-30 |
| GB1472396A (en) | 1977-05-04 |
| FI752130A (en) | 1976-02-01 |
| CA1054158A (en) | 1979-05-08 |
| NO752551L (en) | 1976-02-03 |
| AU497991B2 (en) | 1979-02-01 |
| ES439857A1 (en) | 1977-06-16 |
| DD119209A5 (en) | 1976-04-12 |
| AR207648A1 (en) | 1976-10-22 |
| HU170472B (en) | 1977-06-28 |
| BE831760A (en) | 1976-01-26 |
| DK345875A (en) | 1976-02-01 |
| FR2280366B1 (en) | 1982-07-30 |
| SU568362A3 (en) | 1977-08-05 |
| PL103968B1 (en) | 1979-07-31 |
| YU190675A (en) | 1984-02-29 |
| DE2534031A1 (en) | 1976-02-12 |
| LU73100A1 (en) | 1976-05-31 |
| JPS5139626A (en) | 1976-04-02 |
| CH598194A5 (en) | 1978-04-28 |
| FR2280366A1 (en) | 1976-02-27 |
| CS191271B2 (en) | 1979-06-29 |
| SE7508553L (en) | 1976-02-02 |
| IE41498L (en) | 1976-01-31 |
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