CA1054153A - PROCESS FOR THE PRODUCTION OF .alpha.(-2-(P-CHLOROPHENOXY)-ISOBUTYRYL)-.beta.-NICOTINOYL GLYCOL ESTER - Google Patents
PROCESS FOR THE PRODUCTION OF .alpha.(-2-(P-CHLOROPHENOXY)-ISOBUTYRYL)-.beta.-NICOTINOYL GLYCOL ESTERInfo
- Publication number
- CA1054153A CA1054153A CA234,142A CA234142A CA1054153A CA 1054153 A CA1054153 A CA 1054153A CA 234142 A CA234142 A CA 234142A CA 1054153 A CA1054153 A CA 1054153A
- Authority
- CA
- Canada
- Prior art keywords
- isobutyryl
- chlorophenoxy
- beta
- nicotinoyl
- glycol ester
- Prior art date
- Legal status (The legal status 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 status listed.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
PROCESS FOR THE PRODUCTION OF
?-[-2-(P-CHLOROPHENOXY)-ISOBUTYRYL]-.beta.-NICOTINOYL GLYCOL ESTER
Abstract of the Disclosure A process for the production of ?-[2-(p-chloro-phenoxy)-isobutyryl]- .beta.-nicotinoyl glycol ester. ?-[2-(p-Chlorophenoxy)-isobutyryl]- .beta.-ethyl-chloride ester is reacted with an alkali metal salt of nicotinie acid. The process is not moisture-sensitive and does not produce corrosive by-products, which are disadvantages of the best-known prior art method.
-i-
?-[-2-(P-CHLOROPHENOXY)-ISOBUTYRYL]-.beta.-NICOTINOYL GLYCOL ESTER
Abstract of the Disclosure A process for the production of ?-[2-(p-chloro-phenoxy)-isobutyryl]- .beta.-nicotinoyl glycol ester. ?-[2-(p-Chlorophenoxy)-isobutyryl]- .beta.-ethyl-chloride ester is reacted with an alkali metal salt of nicotinie acid. The process is not moisture-sensitive and does not produce corrosive by-products, which are disadvantages of the best-known prior art method.
-i-
Description
---``` lOS4153 The present invention relates to a process for the production of 5~-[2-(p-chlorophenoxy)-isobutyryl]-~ -nicotinoyl glycol ester.
~ -[2-(p-chlorophenoxy-isobutyryl]-~ -nicotinoyl glycol ester is a known chemical compound which melts at 47C. As a component of pharmaceutical preparations, ~-[2-(p-chlorophenoxy)-isobutyryl]-~ -nicotinoyl glycol ester has a liquid-lowering effect in the case of hyperlipoidemia and in the case of increased triglyceride and cholesterol values. Clinical tests have shown that with an intake of 300 mg of ~-[2-(p-chlorophenoxy)-isobutyryl]-~ -nicotinoyl glycol ester per patient per day, there is significant decrease in the content of cholesterol, triglyceride, phosphatides and free fatty acids in the blood of the patients.
A process for the production of ~ -[2-(p-chloro-phenoxy)-isobutyryl]-~ -nicotinoyl glycol ester is already known. According to German Patent No. 941 217, 2-(p-chloro-phenoxy)-isobutyric acid is reacted with an ethylene glycol excess in the presence of catalytic quantities of phosphoric acid and p-toluolsulphonic acid to give a semi-ester. This semi-ester is reacted with an excess of nicotinic acid chloride in tetrahydrofuran under cooling with ice. After re-crystallization from acetic acid, a 70% yield of ~-[2-(p-chlorophenoxy)-isobutyryl]- ~-nicotinoyl glycol ester hydrochloride having a melting point of 100C is obtained.
Although this known process leads to useful yields of the desired compound, it does have certain dis-advantages. The nicotinic acid chloride reacted with the semi-ester is a compound sensitive to hydrolysis. For this reason the reaction must be carried out in moisture-free conditions. Moreover, during the reaction free hydro-chloric acid is produced, which demands corrosion-resistant ~54153 apparatus.
The present invention seeks to provide an improved process for the production of ~-[2-~p-chlorophenoxy-isobutyryl]-~-nicotinoyl glycol ester, which substantially precludes the above-mentioned disadvantages and leads to an improved yield of the desired product.
According to the present invention there is provided a process for the production of ~ -[2-~p-chloro-phenoxy)-isobutyryl]- ~-nicotinoyl glycol ester in which ~ -[2-(p-chlorophenoxy)-isobutyryl]- ~-ethyl chloride ester is reacted with an alkali metal salt of nicotinic acid.
Under the reaction conditions which are provided in accordance with the invention, the desired ester is produced in yields Of 90 to 95%-To the expert it must be considered amazing that practically no quaternisation of the pyridine nitrogen occurs during the reaction of the higher alkyl chloride.with the nicotinic acid salt which is a pyridine derivative.
It is known from the Handbook of Synthetic Medicines (SYNTHETISCHE ARZNEIMITTEL), edited by Dr. W. Knoblock, Akademie-Verlag, Berlin 1961, page 531, that during the reaction of pyridine with cetyl chloride or other higher alkyl chloride, it is N-cetylpyridium-chloride which is chiefly obtained. Therefore, it is surprising that practically no alkylation of the pyridine nitrogen occurs ;
during the reaction provided in accordance with the inven-tion but that the desired ~ -[2-(p-chlorophenoxy)-isobutyryl)-~ -nicotinoyl glycol ester is obtained in yields of 90 to 95~.
In the process according to the invention the sodium salt of nicotinic acid is preferably used although other alkali metal salts, such as lithium and potassium nicotinates are also suitable.
The reaction is preferably carried out in a polar solvent having quite a high boiling point; solvents which can be used for this purpose are tetra-hydrofuran, dimethyl-5 formamide and dimethylsulphoxide. Dimethylformamide isespecially preferred because the best yields of ~ -[2-(p-chlorophenoxy)-isobutyryl]-~ -nicotinoyl glycol ester are-obtained. The process according to the invention is carried out at quite a high temperature. Temperatures of 120 to 180C are suitable. At these temperatures, approximately 20 to 200 minutes reaction duration is needed for a virtually complete reaction. However, even shorter times lead to ; a satisfactory reaction when the reactiontemperatures are higher.
The process of the invention for the production of ~ -[2-(p-chlorophenoxy)-isobutyryl]-~ -nicotinoyl glycol ester leads to particularly good yields when ~ -[2-(p-chloro-phenoxy)-isobutyryl]-~ -ethyl chloride ester is reacted with sodium nicotinate for 30 to 120 minutes in boiling dimethylformamide. At the same time approximately 5% of dimethylformamide is advantageously removed by distillation from the boiling dimethylformamide, so as to rid the reaction mixture of volatile impurities that have formed. When the reaction has ended, the reaction mixture is cooled to room temperature. The sodium chloride that has formed is filtered off and washed several times with small quantities of dimethyl-formamide. The washing dimethylformamide is combined with the reaction solution and the dimethylformamide is then completely removed by distillation at a moderately high temperature in vacuum. The raw ~ -[2-(p-clorophenoxy)-isobutyryl]-~ -nicotinoyl glycol ester which then remains, and which is virtually free of dimethylformamide, is absorbed in isopropanol and stirred in boiling isopropanol for about 40 to 120 minutes together with a bleaching agent.
The bleaching agent is subsequently filtered from the hot solution. An example of a suitable bleaching agent is Tonsil 70 CC (Trade ~ark). The warm filtered solution containing the desired product is then mixed in a ratio of about 1:1 with cold isopropanol and the crystallization of the desired ester commences. After about 6 to 10 hours at 6 to 8C the desired product has largely crystallized out and the crystalline pulp is spun off, comminuted and dried. A 70 to 75% yield of ~ -[2-(p-chlorophenoxy)-isobut-yryl]-~ -nicotinoyl glycol ester is obtained. It is a white to pale yellow product. During re-processing of the mother liquor, a further approximately 20% of ester is isolated so that using the process of the invention a total yield of about 90 to 95% is achieved.
The reactants, solvents and adjuvants used in the process according to the invention are, on the whole, easily accessible starting materials and are commercially obtainable.
If ~ -[2-(p-chlorophenoxy)-isobutyryl]-~ - ethyl chloride ester should not be available in the required quantity and/or purity, then this ester may, for example, be obtained quite easily from ethyl chloride and p-chlorophenoxy-isobutyric acid. For example, 4 moles of ethyl chloride may be heated to about 100C with 1 mole of p-chlorophenoxy-butyric acid in the presence of catalytic quantities of boron trifluoride (approx. 5%, referred to the acid), and caused to react at -this temperature within 50 to 60 minutes. The excess ethyl - -chloride is then removed by distillation, the residue is absorbed into chloroform and washed several times with 10%
NaHCO3 solution. Fractional distillation is then carried out.
- .
; . , ~054~53 It is possible for the d - [2-(p-chlorophenoxy)-isobutyryl]--ethyl chloride ester to be distilled in water jet vacuum without decomposing. Boiling point 181C/13 torr.
The invention will now be further described with reference to the following example.
Example:
, 8,310 kg of ~ -[2-(p-chlorophenoxy)-isobutyryl]--ethyl chloride ester, 4,350 kg of sodium nicotinate and 60,000 litres of dimethylformamide are placed in a reaction flask provided with stirring means and a column.
They are reacted while being stirred and heated to 150 to 155C, for 60 minutes. During the course of the reaction 3 litres of dimethylformamide are removed under normal pressure by way of the distillation column. When the reaction has ended, the deposit is cooled to room temperature and the sodium chloride that has separated out is removed by filtra-tion. Subsequent washing of the filter cake is effected with approx. 8 litres of dimethylformamide.
The filtrate is sub~ected to vacuum distillation at 15 to 20 torr, approximately 60 litres of dimethylformamide being removed during this process. The distillation residue is stirred under reflux with 5 litres of isopropanol and 0.5 kg of active carbon for a period of 60 minutes, and is then filtered in a pressure filter. The filter cake is sub-sequently washed with approximately 2 litres of isopropanol.
Finally, the filtrate is mixed with 3 litres of cold isopropanol and crystallized at 10C.
After standing overnight, the reaction product is centrifuged and is dried in a vacuum drying cabinet at 30C. In the next batch the mother lye is used instead of the isopropanol.
,~ ' ' lOS4153 Approximately 10 kg of ~ -[2-(p-chlorophenoxy)-isobutyryl]-~ -nicotinoyl glycol ester having a melting point of 46 to 48 is obtained (91% of theory).
The product has the following analysis: -C: calculated: 59.40%, found: 59.22%
H: " 4.95%, " 4.98~
Cl: " 9.80% " 9.59%
N: " 3.85% " 3.88%
- The ~ -[2-(p-chlorophenoxy)-isobutyryl]-~ -nicotinoyl glycol ester produced in accordance with the invention is a pale yellow, crystalline powder, which can be used as the active agent in pharmaceutical preparations. Both -in human beings and in animals, oral administration, e.g. in the form of tablets, lozenges, soft gelatin capsules and hard gelatin capsules leads to a significant reduction in the content of cholesterol, triglyceride phosphatides and free fatty acids in the blood. ~-[2-(p-chlorophenoxy)-isobutyryl]-~ -nicotinoyl glycol ester can also be worked into tablets, lozenges and capsules that release the active agent after a time-lag. A suitable medicine to be used orally may for example consist of gelatin capsules each of which contains 300 mg of ~ -[2-(p-chlorophenoxy)-isobutyryl]- ;
~-nicotinoyl glycol ester in 245 mg of wax mixture.
, , ' '
~ -[2-(p-chlorophenoxy-isobutyryl]-~ -nicotinoyl glycol ester is a known chemical compound which melts at 47C. As a component of pharmaceutical preparations, ~-[2-(p-chlorophenoxy)-isobutyryl]-~ -nicotinoyl glycol ester has a liquid-lowering effect in the case of hyperlipoidemia and in the case of increased triglyceride and cholesterol values. Clinical tests have shown that with an intake of 300 mg of ~-[2-(p-chlorophenoxy)-isobutyryl]-~ -nicotinoyl glycol ester per patient per day, there is significant decrease in the content of cholesterol, triglyceride, phosphatides and free fatty acids in the blood of the patients.
A process for the production of ~ -[2-(p-chloro-phenoxy)-isobutyryl]-~ -nicotinoyl glycol ester is already known. According to German Patent No. 941 217, 2-(p-chloro-phenoxy)-isobutyric acid is reacted with an ethylene glycol excess in the presence of catalytic quantities of phosphoric acid and p-toluolsulphonic acid to give a semi-ester. This semi-ester is reacted with an excess of nicotinic acid chloride in tetrahydrofuran under cooling with ice. After re-crystallization from acetic acid, a 70% yield of ~-[2-(p-chlorophenoxy)-isobutyryl]- ~-nicotinoyl glycol ester hydrochloride having a melting point of 100C is obtained.
Although this known process leads to useful yields of the desired compound, it does have certain dis-advantages. The nicotinic acid chloride reacted with the semi-ester is a compound sensitive to hydrolysis. For this reason the reaction must be carried out in moisture-free conditions. Moreover, during the reaction free hydro-chloric acid is produced, which demands corrosion-resistant ~54153 apparatus.
The present invention seeks to provide an improved process for the production of ~-[2-~p-chlorophenoxy-isobutyryl]-~-nicotinoyl glycol ester, which substantially precludes the above-mentioned disadvantages and leads to an improved yield of the desired product.
According to the present invention there is provided a process for the production of ~ -[2-~p-chloro-phenoxy)-isobutyryl]- ~-nicotinoyl glycol ester in which ~ -[2-(p-chlorophenoxy)-isobutyryl]- ~-ethyl chloride ester is reacted with an alkali metal salt of nicotinic acid.
Under the reaction conditions which are provided in accordance with the invention, the desired ester is produced in yields Of 90 to 95%-To the expert it must be considered amazing that practically no quaternisation of the pyridine nitrogen occurs during the reaction of the higher alkyl chloride.with the nicotinic acid salt which is a pyridine derivative.
It is known from the Handbook of Synthetic Medicines (SYNTHETISCHE ARZNEIMITTEL), edited by Dr. W. Knoblock, Akademie-Verlag, Berlin 1961, page 531, that during the reaction of pyridine with cetyl chloride or other higher alkyl chloride, it is N-cetylpyridium-chloride which is chiefly obtained. Therefore, it is surprising that practically no alkylation of the pyridine nitrogen occurs ;
during the reaction provided in accordance with the inven-tion but that the desired ~ -[2-(p-chlorophenoxy)-isobutyryl)-~ -nicotinoyl glycol ester is obtained in yields of 90 to 95~.
In the process according to the invention the sodium salt of nicotinic acid is preferably used although other alkali metal salts, such as lithium and potassium nicotinates are also suitable.
The reaction is preferably carried out in a polar solvent having quite a high boiling point; solvents which can be used for this purpose are tetra-hydrofuran, dimethyl-5 formamide and dimethylsulphoxide. Dimethylformamide isespecially preferred because the best yields of ~ -[2-(p-chlorophenoxy)-isobutyryl]-~ -nicotinoyl glycol ester are-obtained. The process according to the invention is carried out at quite a high temperature. Temperatures of 120 to 180C are suitable. At these temperatures, approximately 20 to 200 minutes reaction duration is needed for a virtually complete reaction. However, even shorter times lead to ; a satisfactory reaction when the reactiontemperatures are higher.
The process of the invention for the production of ~ -[2-(p-chlorophenoxy)-isobutyryl]-~ -nicotinoyl glycol ester leads to particularly good yields when ~ -[2-(p-chloro-phenoxy)-isobutyryl]-~ -ethyl chloride ester is reacted with sodium nicotinate for 30 to 120 minutes in boiling dimethylformamide. At the same time approximately 5% of dimethylformamide is advantageously removed by distillation from the boiling dimethylformamide, so as to rid the reaction mixture of volatile impurities that have formed. When the reaction has ended, the reaction mixture is cooled to room temperature. The sodium chloride that has formed is filtered off and washed several times with small quantities of dimethyl-formamide. The washing dimethylformamide is combined with the reaction solution and the dimethylformamide is then completely removed by distillation at a moderately high temperature in vacuum. The raw ~ -[2-(p-clorophenoxy)-isobutyryl]-~ -nicotinoyl glycol ester which then remains, and which is virtually free of dimethylformamide, is absorbed in isopropanol and stirred in boiling isopropanol for about 40 to 120 minutes together with a bleaching agent.
The bleaching agent is subsequently filtered from the hot solution. An example of a suitable bleaching agent is Tonsil 70 CC (Trade ~ark). The warm filtered solution containing the desired product is then mixed in a ratio of about 1:1 with cold isopropanol and the crystallization of the desired ester commences. After about 6 to 10 hours at 6 to 8C the desired product has largely crystallized out and the crystalline pulp is spun off, comminuted and dried. A 70 to 75% yield of ~ -[2-(p-chlorophenoxy)-isobut-yryl]-~ -nicotinoyl glycol ester is obtained. It is a white to pale yellow product. During re-processing of the mother liquor, a further approximately 20% of ester is isolated so that using the process of the invention a total yield of about 90 to 95% is achieved.
The reactants, solvents and adjuvants used in the process according to the invention are, on the whole, easily accessible starting materials and are commercially obtainable.
If ~ -[2-(p-chlorophenoxy)-isobutyryl]-~ - ethyl chloride ester should not be available in the required quantity and/or purity, then this ester may, for example, be obtained quite easily from ethyl chloride and p-chlorophenoxy-isobutyric acid. For example, 4 moles of ethyl chloride may be heated to about 100C with 1 mole of p-chlorophenoxy-butyric acid in the presence of catalytic quantities of boron trifluoride (approx. 5%, referred to the acid), and caused to react at -this temperature within 50 to 60 minutes. The excess ethyl - -chloride is then removed by distillation, the residue is absorbed into chloroform and washed several times with 10%
NaHCO3 solution. Fractional distillation is then carried out.
- .
; . , ~054~53 It is possible for the d - [2-(p-chlorophenoxy)-isobutyryl]--ethyl chloride ester to be distilled in water jet vacuum without decomposing. Boiling point 181C/13 torr.
The invention will now be further described with reference to the following example.
Example:
, 8,310 kg of ~ -[2-(p-chlorophenoxy)-isobutyryl]--ethyl chloride ester, 4,350 kg of sodium nicotinate and 60,000 litres of dimethylformamide are placed in a reaction flask provided with stirring means and a column.
They are reacted while being stirred and heated to 150 to 155C, for 60 minutes. During the course of the reaction 3 litres of dimethylformamide are removed under normal pressure by way of the distillation column. When the reaction has ended, the deposit is cooled to room temperature and the sodium chloride that has separated out is removed by filtra-tion. Subsequent washing of the filter cake is effected with approx. 8 litres of dimethylformamide.
The filtrate is sub~ected to vacuum distillation at 15 to 20 torr, approximately 60 litres of dimethylformamide being removed during this process. The distillation residue is stirred under reflux with 5 litres of isopropanol and 0.5 kg of active carbon for a period of 60 minutes, and is then filtered in a pressure filter. The filter cake is sub-sequently washed with approximately 2 litres of isopropanol.
Finally, the filtrate is mixed with 3 litres of cold isopropanol and crystallized at 10C.
After standing overnight, the reaction product is centrifuged and is dried in a vacuum drying cabinet at 30C. In the next batch the mother lye is used instead of the isopropanol.
,~ ' ' lOS4153 Approximately 10 kg of ~ -[2-(p-chlorophenoxy)-isobutyryl]-~ -nicotinoyl glycol ester having a melting point of 46 to 48 is obtained (91% of theory).
The product has the following analysis: -C: calculated: 59.40%, found: 59.22%
H: " 4.95%, " 4.98~
Cl: " 9.80% " 9.59%
N: " 3.85% " 3.88%
- The ~ -[2-(p-chlorophenoxy)-isobutyryl]-~ -nicotinoyl glycol ester produced in accordance with the invention is a pale yellow, crystalline powder, which can be used as the active agent in pharmaceutical preparations. Both -in human beings and in animals, oral administration, e.g. in the form of tablets, lozenges, soft gelatin capsules and hard gelatin capsules leads to a significant reduction in the content of cholesterol, triglyceride phosphatides and free fatty acids in the blood. ~-[2-(p-chlorophenoxy)-isobutyryl]-~ -nicotinoyl glycol ester can also be worked into tablets, lozenges and capsules that release the active agent after a time-lag. A suitable medicine to be used orally may for example consist of gelatin capsules each of which contains 300 mg of ~ -[2-(p-chlorophenoxy)-isobutyryl]- ;
~-nicotinoyl glycol ester in 245 mg of wax mixture.
, , ' '
Claims (7)
1. A process for the production of .alpha.-[2-(p-chlorophenoxy)-isobutyryl]- .beta.-nicotinoyl glycol ester which comprises reacting .alpha.-[2-(p-chlorophenoxy)-isobutyryl]-.beta. -ethyl chloride ester with an alkali metal salt of nicotinic acid at a temperature in the range 120° to 180°C.
2. A process as claimed in claim 1 in which .alpha. -[2-(p-chlorophenoxy)-isobutyryl-.beta. -ethyl chloride ester is reacted with sodium nicotinate.
3. A process as claimed in claim 1 which is carried out in a polar solvent having a high boiling point.
4. A process as claimed in claim 3 in which the solvent is dimethylformamide.
5. A process as claimed in claim 1 in which the reaction is carried out for 20 to 200 minutes.
6. A process as claimed in claim 5 in which .alpha.-[2-(p-chlorophenoxy)-isobutyryl]- .beta. -ethyl chloride ester is reacted with sodium nicotinate for 30 to 120 minutes in boiling dimethylformamide.
7. Process as claimed in claim 6 in which at the end of the reaction the dimethylformamide is largely sepa-rated out by distillation and the residue is crystallized from isopropanol.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB3877874A GB1442474A (en) | 1974-09-05 | 1974-09-05 | Process for the production of beta-2-p-chlorophenoxy-isobutyryloxy -ethyl nicotinate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1054153A true CA1054153A (en) | 1979-05-08 |
Family
ID=10405641
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA234,142A Expired CA1054153A (en) | 1974-09-05 | 1975-08-25 | PROCESS FOR THE PRODUCTION OF .alpha.(-2-(P-CHLOROPHENOXY)-ISOBUTYRYL)-.beta.-NICOTINOYL GLYCOL ESTER |
Country Status (17)
| Country | Link |
|---|---|
| JP (1) | JPS597702B2 (en) |
| AR (1) | AR205658A1 (en) |
| AT (1) | AT344173B (en) |
| BE (1) | BE832618R (en) |
| CA (1) | CA1054153A (en) |
| CH (1) | CH584198A5 (en) |
| DE (1) | DE2531254A1 (en) |
| DK (1) | DK145929C (en) |
| ES (1) | ES440711A1 (en) |
| FI (1) | FI60392C (en) |
| FR (1) | FR2283892A2 (en) |
| GB (1) | GB1442474A (en) |
| HU (1) | HU169891B (en) |
| NL (1) | NL7510526A (en) |
| NO (1) | NO752762L (en) |
| PL (1) | PL97697B1 (en) |
| YU (1) | YU37132B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4375545A (en) * | 1981-06-22 | 1983-03-01 | Westwood Pharmaceuticals, Inc. | Process for the synthesis of the nicotinyl ester of 6-aminonicotinic acid |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2304405A1 (en) * | 1972-03-08 | 1973-09-13 | Hurka Wilhelm | 4-chlorophenoxy-isobutyric acid esters - with antiarteriosclerotic activity |
-
1974
- 1974-09-05 GB GB3877874A patent/GB1442474A/en not_active Expired
-
1975
- 1975-01-01 AR AR260267A patent/AR205658A1/en active
- 1975-07-12 DE DE19752531254 patent/DE2531254A1/en not_active Withdrawn
- 1975-07-18 FI FI752079A patent/FI60392C/en not_active IP Right Cessation
- 1975-07-28 YU YU1923/75A patent/YU37132B/en unknown
- 1975-07-30 AT AT591475A patent/AT344173B/en not_active IP Right Cessation
- 1975-08-06 NO NO752762A patent/NO752762L/no unknown
- 1975-08-21 BE BE159356A patent/BE832618R/en active
- 1975-08-25 CA CA234,142A patent/CA1054153A/en not_active Expired
- 1975-08-29 DK DK390875A patent/DK145929C/en not_active IP Right Cessation
- 1975-08-30 JP JP50105573A patent/JPS597702B2/en not_active Expired
- 1975-09-04 HU HUME1893A patent/HU169891B/hu not_active IP Right Cessation
- 1975-09-04 ES ES440711A patent/ES440711A1/en not_active Expired
- 1975-09-05 NL NL7510526A patent/NL7510526A/en unknown
- 1975-09-05 FR FR7527367A patent/FR2283892A2/en active Granted
- 1975-09-05 PL PL1975183136A patent/PL97697B1/en unknown
- 1975-09-05 CH CH1151575A patent/CH584198A5/xx not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| FI60392B (en) | 1981-09-30 |
| YU192375A (en) | 1983-04-27 |
| FR2283892B2 (en) | 1980-08-08 |
| FR2283892A2 (en) | 1976-04-02 |
| JPS5168572A (en) | 1976-06-14 |
| BE832618R (en) | 1975-12-16 |
| AR205658A1 (en) | 1976-05-21 |
| FI60392C (en) | 1982-01-11 |
| AT344173B (en) | 1978-07-10 |
| DK390875A (en) | 1976-03-06 |
| CH584198A5 (en) | 1977-01-31 |
| NO752762L (en) | 1976-03-08 |
| NL7510526A (en) | 1976-03-09 |
| DK145929C (en) | 1983-09-26 |
| DK145929B (en) | 1983-04-18 |
| FI752079A (en) | 1976-03-06 |
| PL97697B1 (en) | 1978-03-30 |
| GB1442474A (en) | 1976-07-14 |
| ES440711A1 (en) | 1977-03-16 |
| JPS597702B2 (en) | 1984-02-20 |
| HU169891B (en) | 1977-02-28 |
| ATA591475A (en) | 1977-11-15 |
| YU37132B (en) | 1984-08-31 |
| DE2531254A1 (en) | 1976-03-25 |
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