IE53279B1 - Process for preparing carnitine chloride - Google Patents
Process for preparing carnitine chlorideInfo
- Publication number
- IE53279B1 IE53279B1 IE1524/82A IE152482A IE53279B1 IE 53279 B1 IE53279 B1 IE 53279B1 IE 1524/82 A IE1524/82 A IE 1524/82A IE 152482 A IE152482 A IE 152482A IE 53279 B1 IE53279 B1 IE 53279B1
- Authority
- IE
- Ireland
- Prior art keywords
- carnitine
- chloride
- hours
- reaction
- tbe
- Prior art date
Links
- PHIQHXFUZVPYII-UHFFFAOYSA-N carnitine Chemical compound C[N+](C)(C)CC(O)CC([O-])=O PHIQHXFUZVPYII-UHFFFAOYSA-N 0.000 title claims abstract 3
- 229960000678 carnitine chloride Drugs 0.000 title claims 2
- 238000004519 manufacturing process Methods 0.000 title 1
- 229960004203 carnitine Drugs 0.000 claims abstract description 25
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims abstract description 10
- PHIQHXFUZVPYII-ZCFIWIBFSA-O (R)-carnitinium Chemical compound C[N+](C)(C)C[C@H](O)CC(O)=O PHIQHXFUZVPYII-ZCFIWIBFSA-O 0.000 claims abstract 5
- 239000012320 chlorinating reagent Substances 0.000 claims description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 8
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 4
- HKYGSMOFSFOEIP-UHFFFAOYSA-N dichloro(dichloromethoxy)methane Chemical compound ClC(Cl)OC(Cl)Cl HKYGSMOFSFOEIP-UHFFFAOYSA-N 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 7
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 239000006227 byproduct Substances 0.000 abstract description 4
- 239000003795 chemical substances by application Substances 0.000 abstract description 2
- 230000002140 halogenating effect Effects 0.000 abstract 1
- PHIQHXFUZVPYII-ZCFIWIBFSA-N (R)-carnitine Chemical class C[N+](C)(C)C[C@H](O)CC([O-])=O PHIQHXFUZVPYII-ZCFIWIBFSA-N 0.000 description 23
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- GUYHPGUANSLONG-SNAWJCMRSA-N (E)-4-(trimethylammonio)but-2-enoate Chemical compound C[N+](C)(C)C\C=C\C([O-])=O GUYHPGUANSLONG-SNAWJCMRSA-N 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- WHBMMWSBFZVSSR-UHFFFAOYSA-N 3-hydroxybutyric acid Chemical compound CC(O)CC(O)=O WHBMMWSBFZVSSR-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- JXXCENBLGFBQJM-UHFFFAOYSA-N (3-carboxy-2-hydroxypropyl)-trimethylazanium;chloride Chemical compound [Cl-].C[N+](C)(C)CC(O)CC(O)=O JXXCENBLGFBQJM-UHFFFAOYSA-N 0.000 description 1
- GSFNQBFZFXUTBN-UHFFFAOYSA-N 2-chlorothiophene Chemical compound ClC1=CC=CS1 GSFNQBFZFXUTBN-UHFFFAOYSA-N 0.000 description 1
- 244000025254 Cannabis sativa Species 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 241000534944 Thia Species 0.000 description 1
- JXXCENBLGFBQJM-FYZOBXCZSA-N [(2r)-3-carboxy-2-hydroxypropyl]-trimethylazanium;chloride Chemical compound [Cl-].C[N+](C)(C)C[C@H](O)CC(O)=O JXXCENBLGFBQJM-FYZOBXCZSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001277 beta hydroxy acids Chemical class 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- -1 esters end amides Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
-
- 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
- C07C229/22—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 oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C1/00—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon
-
- 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
-
- 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
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/363—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
-
- 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
- C07C59/01—Saturated compounds having only one carboxyl group and containing hydroxy or O-metal groups
- C07C59/115—Saturated compounds having only one carboxyl group and containing hydroxy or O-metal groups containing halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
D-L carnitine is converted into D,L- carnitine acid chloride by treating it, without previously protecting the hydroxyl group, with a halogenating agent at room temperature for a reaction period comprised between 1.5 hours and 12 hours. If the foregoing reaction conditions are not strictly complied with, a sharp decrease in the yield and the formation of by-products, primarily crotonylbetaine, will take place.
Description
D.L-carnitine chloride is aa all- round intermediate for the preparation of several carnitine derivatives, e.g. esters end amides, whose therapeutical properties are known.
O [-CHg-COO , contains in addition to a carboxyl group a hydroxyl group which, as known, is sensitive to acidic reaction environments.
It is in fact known, e.g. as disclosed in Bull. Soc. Chim.
Fr. (i960), 1196, that jS-hydroxy adds and -esters thereof easily eliminite a water molecule in an acid environment, thus forming unsaturated compounds. In Biochim. Biophys. Acta 137, 98-106 (1967) and 152, 559 (1968), carnitine dehydration is disclosed to take plaee in acidic environment under heating. In J. Biol.
Chem. 237/12. 3268 (1962) the formation of crotonoylbetaine as by-product is disclosed to take place by heating carnitine in an acidic environment.
Since a carboxylic acid is converted into acid chloride in acidic conditions, eannitine chlorination could not be expected to take place without previously protecting the hydroxyl group, with a view to avoiding the degradation of the starting material and the formation of undesired by-produets.
The foregoing is wholly confined froa what can be deduced fro· the prior art. The preparation of acid chlorides of hydroxysubstituted acids after the hydroxyl group has been previously protected, is disclosed in J. Org. Chen. 43/20. 3972 (1978). More specifically, the chlorination of β-hydroxybutyric acid (which is a β-hydroxy acid as is carnitine) after previous protection of the hydroxyl group with an acetyl group is disclosed in J.As. Chen. Soc. ££, 4106 (1973).
Surprisingly it has now been found that it is possible 1Ω to convert o.t-caraitine into the acid chloride of D.L-carnitine obtaining excellent yields without tha tarnation of unacceptable Mount» of by-products fro· aa industrial standpoint (particularly crotonoyl-betaine), this is done by chlorinating D.L-camitine without previous protection of the hydroxyl group (e.g. by converting the hydroxyl group into an acetyl group as taught in the prior art), provided that sone critical operative conditions are conplied with.
In fact it has been found that the aolar ratio carnitine/ chlorinating agent, the reaction tanperature and the reaction tiae are critical paraaeters affecting the conversion of 0,1c ami tine into the corresponding acid chloride and that the values of the foregoing paraaeters Bust fall within well53279 defined ranges.
Accordingly, the present invention provides a process for producing tbs add chloride of carnitine comprising chlorinating carnitine with a chlorinating agent which is thienyl chloride, dlchloromthyletber, or oxalychloride at about rocs temperature for a reaction tine of froa 1.5 to 12 hours, and the aolar ratio of carnitine to chlorinating agent being 1:1 to 1:3.
Phosphorus penteehlorlde could also be used as a chlorinating agent. However, thia chlorinating agent is sot preferred due to the remarkably higher reaction tines (1-3 days) in coaparisen with those previously indicated.
The aolar ratio earnitlne/ehlorlnatiag agent is Is the range of 1:1 to 1:3. With a view to obtaining high yields in the conversion of carnitine into the add chloride, it is essential that the foregoing teaperature and reaction tines be strictly complied with since eves minor variations bring about the fozaation of by-products. For instance, when oxalyl chloride is used as the chlorinating agent, a reaction tiae of 15 hours brings about the almost complete degradation of carnitine into erotoaoylbetaine.
The tolloviag aoa-linitiag examples 1 and 2 illustrate the process of the present invention. txasple 1 tchlorinating spent: thionyl chloride) 2.25 cc (0.03 «oles) of SOC12 were added to 1.98 grass 5 (0.01 moles) of D,L-carnitine hydrochloride. After 1 hour their solubilization was complete and after 1·* hours reaction see considered completed. The excess of SOC12 was distilled off and the residue consisting of carnitine acid chloride was washed with anhydrous ethyl ether. For the purpose of identification, the acid ehlo10 ride was converted into «ethyl ester: the reaction mixture was cooled to 0*C and 10 cc of anhydrous «ethanol were added dropwise; the resulting «ixture was then concentrated under vacuum at 35-40*0, thus obtaining a gelatinous raw product which,dried under vacua·,solidified remaining, however, very hygroscopic.
T.L.C. chloroform 35/ «ethanol 35/ BjO 5 I BH4OH 5 ma spectre OjO Solvent 4.82 (1H, «, -CH-); 3.83 (3B, s, -OCB3); 3.55 (28, d>S-CH2-); 3.30 (9H. s Ij); 2.73 (2H. d, -CHaC0-) elementary analysis Calculated found C 45,39 43.99 a 8.57 1.54 > 6,62 '6.09 Cl 16.75 16.92 example 2 (chlorinating «gene: dichloroaethyl ether) Tbe procedures of the preceding example were followed, except that io lieu of thionyl chloride dichloromethyl ether 10 (1.78 cc; 0.02 moles) was used. Tbe reaction mixture was left to stand overnight at room temperature. Tbe excess of dichloromethyl ether was distilled off and tbe residue was washed with anhydrous ethyl ether. Tbe residue turned out to consist of carnitine acid chloride.
CH HKS CD K b 3.33 (9H.S.CK CH 3-36-3.60 ( 4H.a,>i-CH2-, -CH2COCI]; 4.40-4.90 (IH.a, -CH-) OH After exchange with 020 the chemical shifts resuned the same values as those of the NM2 spectrum of carnitine. The raw S3279 add eUoride was subseguently converted into aethyl eater, 4a previously described. The «ethyl eater ot carnitine showed the ebeaico-physical characteristics corresponding to the previously isolated produet.
Tbe following exaaples A and B aia at illustrating that tbe foregoing operative conditions oust be absolutely eoaplied with in order to obtain the acid chloride of carnitine. txaaple A (tbe proper reaction teaperature is not eoaplied with) A mixture of carnitine and chionyl chloride (aolar ratio 1 : 1) was kept under stirring at 30’C. Saaples of tbe reaction nixture were drawn after 0.5 hour, 1 hour and 1.5 hours fro·' tbe beginning of tbe reaction. Tbe senples were checked by TLC (ehlorofom 55/ CH3OH 35/HjO 5/ BH4OH 5) after dilution with aethenol in order to convert tbe acid eUoride. if any, into •ethyl ester.
After 0.5 hour the presence of carnitine and aethyl ester of carnitine (Sf 0.4 and 0.8 respectively) was noticed.
After 1 hour erotonoylbetaine, carnitine and carnitine 20 aethyl ester (Bf 0.2-0.4-0.8 respectively, began to fora.
After 1.5 hours the presence of erotonoylbetaine along with other degradation products which could noe be identified, was 53379 noticed.
Sample » (the proper reaction tine is not complied with) Thienyl, chloride (2.3 ce; 0.03 moles) was added to carnitine hydrochloride (1.98 grams; o.Oi moles) and the resulting reaction mixture was kept under stirring at room temperature for 24 hours. The excess of thionyl chloride was distilled off and the raw residue was washed with anhydrous ethyl ether, thus obtaining a solid product having melting point 217-218*C.
TLC chloroform 55/ methanol 35/ H20 5/ MH4OH 5/ 0.2 IO UCK o2o ό 7.2-6.2 (2H. m, -CH-CK-); 4.2 (2H, d, >t-CHjr): As TLC and SMB spectrum show, in these reaction conditions the acid chloride of carnitine does not fora. Conversely a dehydration takes plaee with the formation of crotonoylbetaine
Claims (3)
1. CLAIMS:1. A proems for producing ths acid chloride of carnitine comprising chlorinating carnitine with a chlorinating agent which ie thionyl chloride, 5 dichloromethylether, or oxalylchloride at about roost teaperature for a reaction time of from 1.5 to 12 hours, and the aolar ratio of carnitine to chlorinating agent being 1:1 to 1:3.
2. A proems for producing the acid chloride of 10 carnitine substantially as hereinbefore described in Zxaspla 1 or Example 2.
3. Carnitine chloride whenever produced by a proems as claimed in Claim 1 or Claim 2.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT48817/81A IT1171360B (en) | 1981-07-03 | 1981-07-03 | PROCEDURE FOR THE PREPARATION OF CARNITINE ACID CHLORIDE |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE821524L IE821524L (en) | 1983-01-03 |
| IE53279B1 true IE53279B1 (en) | 1988-09-28 |
Family
ID=11268676
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE1524/82A IE53279B1 (en) | 1981-07-03 | 1982-06-25 | Process for preparing carnitine chloride |
Country Status (18)
| Country | Link |
|---|---|
| JP (1) | JPS5815943A (en) |
| KR (1) | KR860001886B1 (en) |
| AT (1) | AT390057B (en) |
| BE (1) | BE893713A (en) |
| CA (1) | CA1186332A (en) |
| CH (1) | CH648546A5 (en) |
| DE (1) | DE3224666A1 (en) |
| DK (1) | DK154425C (en) |
| ES (1) | ES513658A0 (en) |
| FR (1) | FR2510559B1 (en) |
| GB (1) | GB2101133B (en) |
| GR (1) | GR76546B (en) |
| IE (1) | IE53279B1 (en) |
| IL (1) | IL66251A0 (en) |
| IT (1) | IT1171360B (en) |
| LU (1) | LU84244A1 (en) |
| NL (1) | NL189666C (en) |
| SE (1) | SE448724B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1190358B (en) * | 1985-05-24 | 1988-02-16 | Sclavo Spa | PROCEDURE FOR THE PREPARATION OF L-CARNITINA |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3940439A (en) * | 1973-11-14 | 1976-02-24 | G. D. Searle & Co. | Acid chloride synthesis |
| IT1116037B (en) * | 1979-04-23 | 1986-02-10 | Sigma Tau Ind Farmaceuti | ACIL CARNITINE ESTERS AND AMIDS THEIR PREPARATION PROCEDURES AND THERAPEUTIC USE |
| DE2943433A1 (en) * | 1979-10-26 | 1981-05-07 | Bayer Ag, 5090 Leverkusen | METHOD FOR PRODUCING CARBONIC ACID HALOGENIDES |
-
1981
- 1981-07-03 IT IT48817/81A patent/IT1171360B/en active
-
1982
- 1982-06-24 CH CH3884/82A patent/CH648546A5/en not_active IP Right Cessation
- 1982-06-25 IE IE1524/82A patent/IE53279B1/en not_active IP Right Cessation
- 1982-06-29 GB GB08218824A patent/GB2101133B/en not_active Expired
- 1982-06-30 LU LU84244A patent/LU84244A1/en unknown
- 1982-06-30 DK DK295482A patent/DK154425C/en not_active IP Right Cessation
- 1982-06-30 CA CA000406463A patent/CA1186332A/en not_active Expired
- 1982-06-30 BE BE0/208502A patent/BE893713A/en not_active IP Right Cessation
- 1982-07-01 GR GR68615A patent/GR76546B/el unknown
- 1982-07-01 DE DE19823224666 patent/DE3224666A1/en active Granted
- 1982-07-01 KR KR8202945A patent/KR860001886B1/en active
- 1982-07-02 AT AT0257382A patent/AT390057B/en not_active IP Right Cessation
- 1982-07-02 ES ES513658A patent/ES513658A0/en active Granted
- 1982-07-02 JP JP57116084A patent/JPS5815943A/en active Granted
- 1982-07-02 SE SE8204117A patent/SE448724B/en not_active IP Right Cessation
- 1982-07-02 FR FR8211685A patent/FR2510559B1/en not_active Expired
- 1982-07-02 NL NLAANVRAGE8202677,A patent/NL189666C/en not_active IP Right Cessation
- 1982-07-07 IL IL66251A patent/IL66251A0/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| KR840000475A (en) | 1984-02-22 |
| DE3224666C2 (en) | 1991-01-24 |
| IE821524L (en) | 1983-01-03 |
| JPH0244300B2 (en) | 1990-10-03 |
| GR76546B (en) | 1984-08-10 |
| BE893713A (en) | 1982-10-18 |
| DK295482A (en) | 1983-01-04 |
| SE8204117D0 (en) | 1982-07-02 |
| DE3224666A1 (en) | 1983-01-20 |
| IT1171360B (en) | 1987-06-10 |
| NL189666C (en) | 1993-06-16 |
| AT390057B (en) | 1990-03-12 |
| JPS5815943A (en) | 1983-01-29 |
| IL66251A0 (en) | 1982-11-30 |
| DK154425C (en) | 1989-04-10 |
| SE448724B (en) | 1987-03-16 |
| IT8148817A0 (en) | 1981-07-03 |
| DK154425B (en) | 1988-11-14 |
| CH648546A5 (en) | 1985-03-29 |
| FR2510559A1 (en) | 1983-02-04 |
| SE8204117L (en) | 1983-01-04 |
| NL189666B (en) | 1993-01-18 |
| FR2510559B1 (en) | 1986-05-09 |
| ES8304064A1 (en) | 1983-03-01 |
| GB2101133A (en) | 1983-01-12 |
| GB2101133B (en) | 1985-08-14 |
| ES513658A0 (en) | 1983-03-01 |
| LU84244A1 (en) | 1983-01-20 |
| CA1186332A (en) | 1985-04-30 |
| ATA257382A (en) | 1989-08-15 |
| KR860001886B1 (en) | 1986-10-24 |
| NL8202677A (en) | 1983-02-01 |
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| MM4A | Patent lapsed |