GB2030131A - A process for producing 2-[4-(2- thienylcarbonyl)phenyl] propionic acid - Google Patents
A process for producing 2-[4-(2- thienylcarbonyl)phenyl] propionic acid Download PDFInfo
- Publication number
- GB2030131A GB2030131A GB7906726A GB7906726A GB2030131A GB 2030131 A GB2030131 A GB 2030131A GB 7906726 A GB7906726 A GB 7906726A GB 7906726 A GB7906726 A GB 7906726A GB 2030131 A GB2030131 A GB 2030131A
- Authority
- GB
- United Kingdom
- Prior art keywords
- acetal
- thienylcarbonyl
- phenyl
- formula
- solution
- 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.)
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
- C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
Abstract
A process for producing 2-[4-(2- thienylcarbonyl)phenyl] propionic acid comprises reacting a 2-substitued thiophene derivative with a Grignard reagent of 2-(4- bromophenyl)propionaldehyde acetal and thereafter oxidizing the resultant product to form 2-[4-(2- thienylcarbonyl)phenyl] propionaldehyde acetal which is hydrolyzed to form the corresponding aldehyde which latter is then oxidised to form 2-[4-(2- thienylcarbonyl)phenyl] propionic acid.
Description
SPECIFICATION
A process for producing 2-[4-(2-thienylcarbonyl)phenyl] propionic acid
This invention relates to a novel process for producing 2-[4-(2-thienylcarbonyl)phenyl]propionic acid.
2-[4-(2.thienylcarbonyl)phenyljpropionic acid is represented by the following formula (l)
and is a useful compound as a drug possessing an excellent antiinflammatory effect (Japanese Disclosure
Number 93346/1974).
Many processes for producing the compound of the formula (I) are described in Japenese patent, disclosure number 93346/1974.
The present invention comprises the following process;
wherein R represents a cyano or aldehyde group, and R1 and R2 represent a lower alkyl group or may jointly form an ethylene or propylene group.
That is, the present invention provides a process for producing 2-[4-(2-thienylcarbonyl)phenyl]propionic acid of the formula (I) which comprises reacting 2-substituted thiophene derivatives of the formula (II) with
Grignard agents of 2-(4-bromophenyl) propionaldehyde acetal of the formula (III) to produce the compounds of the formula (IV);;
wherein Y1 represents a hydrogen atom, Y2 represents a hydroxy group, or Y1 andY2 jointly form an oxygen atom, and R1 and R2 are the same as defined above, and oxidizing the resulting compounds where Y1 is a hydrogen atom and Y2 is a hydroxy group in the formula (IV) to produce 2-[4-(2-thienylcarbonyl)phenyl]- propionaldehyde acetal of the formula (V), and hydrolyzing the resulting acetal to produce 2-[4-(2thienylcarbonyl)phenyl]propionaldehyde of the formula (VII), and oxidizing the resulting aldehyde.
The starting materials of the formula (III) in the present invention include methyl acetal, ethyl acetal, propyl acetal, ethylene acetal and propylene acetal, which can, for instance, be produced by reacting 2-(4 bromophenyl)propionaldehyde with orthoalkyl carbonate, ethylene glycol or 1,3-propandiol in the presence of p-toluenesulfonic acid.
The present invention is carried as follows:
The compounds of the formulae (II) and (III) are reacted in a suitable solvent, among which is preferably used tetrahydrofuran(THF). The compound of the formula (III) may be prepared in an additional reaction system. However, in fact, 2-(4-bromophenyl)propionaldehyde acetal is reacted with metallic magnesium to produce the compound of the formula (III), then to the reaction mixture is added the compound of the formula (II). The reaction is preferably conducted at a temperature ranging from room temperature to
refluxing condition.
The product of the formula (IV) obtained by the above process is the compound of the formula (V) when the thiophene derivative of the formula (li) is a cyano-substituted compound, and is the compound of the formula (VI) when the thiophene derivative of the formula (II) is an aldehyde-substituted compound. The compound of the formula (VI) is further subjected to oxidation reaction to produce the compound of the formula (V).
The oxidation of the compound of the formula (VI) can be conducted in a suitable solvent such as dioxane
and acetone by the methods applicable for the oxidation process from secondary alcohols to the corresponding ketones, for instance, with sodium bichromate, chromium trioxide in the presence of sulfuric
acid, with hydrogen peroxide, or with aluminium t-butoxide. Of these methods is preferably used chromium
oxide method, by which the reaction proceeds under mild conditions.
The thus obtained compound of the formula (V) is hydrolized by the usual methods, for instance, with the
use of mineral acids, such as, hydrochloric acid and sulfuric acid.
Then, the compound of the formula (VII) is oxidized with a suitable oxidizing agent, such as sodium
bichromate, chromium oxide potassium permanganate in the presence of sulfuric acid, hydrogen peroxide,
and air to obtain the desired compound of the formula (I).
The present invention is illustrated below in further detail with reference to Examples, but the invention is
not limited to the Examples.
Example 1
In a 200 ml three-necked flask fitted with a condenser, a dropping funnel and a stirrer is placed 1.0 g of
metallic magnesium and nitrogen gas is passing through. To this is added 26 ml of dried THF, tetrahydrofuran and 2-3 drops of ethylbromide are added with well-stirring at room temperature and is
heated gradually to 30-40"C. To this solution is added dropwise the solution of 7.5 g of 2-(4-bromophenyl)
propionaldehyde ethylene acetal in 75 ml of dried THF. The solution is heated under reflux for another one
hour. Then, 3.0 g of 2-cyanothiophene in 50 ml of THF is added dropwise under reflux. The reaction solution
is refluxed for one hour and is continued to be stirred for 20 hours at room temperature.The reaction mixture
is poured in 170 ml of diluted acetic acid and is extracted with 500 ml of ether. The ether layer is washed with
50 ml of water and dried over anhydrous sodium sulfate. The ether is removed by distillation under reduced
pressure to obtain 7.25 g of 2-[4-(2-thienylcarbonyl)phenyl]propionaldehyde ethylene acetal.
Example 2 2-[4-(2-thienylcarbonyl)phenyl]propionaldehyde ethylene acetal obtained in Example 1 is dissolved in 30 ml of acetone. This solution is added slowly, with stirring, to 5.5 ml of 10% hydrochloric acid at room temperature. After a homogenious solution is completed, the solution is heated under reflux on a steam bath for 12 hours. After the reaction is completed, the solution is cooled to room temperature, the acetone is
removed by distillation under reduced pressure and the residue is removed by distillation under reduced
pressure and the residue is extracted three times with 25 ml of chloroform. The chloroform layer is washed with 10 ml of diluted aqueous solution of sodium hydroxide, and is dried over anhydrous sodium sulfate.
Chloroform is evaporated under reduced pressure to obtain 5.75 g of 2-[4-(2-thienylcarbonyl) phenyl]pro
pionaldehyde as yellow oil.
Example 3
5.75 g of 2-[4-(2-thienylcarbonyl)phenyl]propionaldehyde obtained in Example 2, is dissolved in 45 ml of acetone, and to this Jones reagent is added dropwise, while cooling at 5-10"C until the orange color does not disappear. After isopropanol is added to stop the reaction, the reaction mixture is filtered under reduced
pressure, the filtered is concentrated under reduced pressure. The residue is extracted three times with 45 ml
of chloroform and the chloroform layer is extracted twice with 27 ml of 2N-sodium hydroxide solution. The water layer is acidified with hydrochloric acid and extracted three times with 45 ml of chloroform. After the chloroform layer is dired over anhydrous sodium sulfate, and the chloroform is removed by distillation
under reduced pressure to obtain pale yellow oily product. It is crystallized from n-hexane and then is
recrystallized from acetonitrile to obtain 5.4 g of 2-[4-(2-thienylcarbonyl)phenyl]propionic acid as white fine crystals. (the yield based on 2-cyanothiophene is 75.4%)
Example 4
In a 500 ml three-necked flask fitted with a condenser, a dropping funnel, and a stirrer is placed 2.0 g of
metallic magnesium, and nitrogen gas is passing through. To this are added 30 ml of dired THF, and 3-6 drops of ethylbromide at room temperature, while the solution is being stirred. The solution is gradually heated to 30-40"C. To this solution is added dropwise 15 g of 2-(4-bromophenyl)propionaldehyde ethylene acetal in 150 ml of dried THF. After the addition, the solution is heated under reflux for another one hour. The solution of 6.0 g of 2-cyanothiophene in 50 ml of THF is added dropwise under reflux.The solution is heated under reflux for one hour and is continued to be stirred for 20 hours at room temperature. The reaction solution is poured into 340 ml of diluted acetic acid and is extracted with 1000 ml of ether. After the ether layer is washed with 50 ml of water and dried over an hydros sodium sulfate, the ether is removed by distillation under reduced pressure. The residue is dissolved in 50 ml of acetone, and 10 ml of 10% sulfuric acid is gradually added thereto and the solution is heated under reflux for 12 hours. After cooling, 50 ml of dioxane is added, and Jones reagent is added dropwise keeping the temperature below 5"C until the orange color does not disappear. After isopropanol is added to stop the reaction, the reaction mixture is filtered with kieselguhr and the filtrate is concentrated under reduced pressure.
The residue is extracted three times with 80 ml of chloroform, and the chloroform layer is extracted twice with 50 ml of 2N-sodium hydroxide aqueous solution. The water layer is separated and is acidified with hydrochloric acid, and extracted three times with 80 ml of chloroform. The chloroform layer is dried over anhydrous sodium sulfate and then the chloroform is removed by distillation under reduced pressure. The obtained oily product is crystallized by adding n-hexane and the crystals are recrystallized from acetonitrile to obtain 10.95 g of 2-[4-(2-thienylcarbonyl)phenyl]propionic acid as white fine crystals. (the yield based on 2-cyanothiophene is 76.5%)
Example 5
In a 100 ml three-necked flask fitted with a condenser and a dropping funnel is placed 830 mg of metallic magnesium, and nitrogen gas is passing through.To this is added 10 ml of dried THF, and 2-3 drops of ethyl bromide are added, with well-stirring, at room temperature, and heated gradually to 30-400C. When 7.9 g of 2-(4-bromophenyl)propionaldehyde ethylene acetal in 30 ml of dried THF is added to the solution, the reaction is initiated with foaming. The dropping is continued with keeping moderate reflux. After dropping, the solution is heated under reflux for one hourto complete the reaction. After the solution is allowed to come to room temperature, then cooled to 5-1 00C in an ice bath, the solution of 3.36 g of 2-thiophenealdehyde in 20 ml of THF is added dropwise slowly. After the addition is completed, the solution is heated gradually to room temperature and stirred for one day.After the reaction is completed, the reaction mixture is poured into diluted hydrochloric acid (50 g of ice and 50 ml of 10% hydrochloric acid) with stirring well. The reaction mixture is then extracted three times with 100 ml of chloroform. After the extract is di red over with anhydrous sodium sulfate, the solvent is removed by distillation to obtain 9.3 g of oil 2-[4-(2-thienylhydroxymethyl)phenyl]propionaldehyde ethylene acetal.
Example 6
9.3 of 2-[4-(2-thienylhydroxymethyl)phenyl)] propionaldehyde ethylene acetal obtained in Example 5 is dissolved in 80 ml of acetone and cooled to 5"C in an ice bath. To this solution Jones reagent is slowly added dropwise. With the start of dropping the reaction proceeds accompanying the generation of considerable amount of heat. The dropping is continued, while the reaction temperature is maintained at 5-1 00C, until the orange colour does not disappear. After the completion of the reaction, isopropanol is added to stop the reaction. The reaction mixture is filtered with cerite and the filtrate is concentrated under reduced pressure (the concentration is carried out at about 30"C). The residue is extracted three times with 50 ml of chloroform.
The chloroform layer is washed with diluted sodium carbonate aqueous solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give 8.7 g of yellow or brown colored oil.
This oil is purified by means if silicagel columnchlomatography (eluted with methylene chloride) to obtain 7.9 g of 2-[4-(2-thienylcarbonyl)phenyl]propionaldehyde ethylene acetal.
Example 7 2-[4-(2-thienylcarbonyl)phenyl]propionaldehyde ethylene acetal obtained in Example 6 is dissolved in 30 ml of acetone, and 6 ml of 10% hydrochloric acid is added at room temperature, with stirring, to make a homogenious solution. The solution is heated under moderate refluxfor 12 hours, on a water bath, and the reaction mixture is allowed to come to room temperature and the acetone is removed by distillation under reduced pressure at 30"C, and the residue is extracted three times with 30 ml of chloroform. The chloroform layer is washed with diluted sodium hydroxide aqueous solution and dried over anhydrous sodium sulfate.
The chloroform is removed by distillation under reduced pressure to obtain 6.5 g of yellow oily 2-[4-(2-thienylcarbonyl)phenyl]propionaldehyde.
Example 8
6.5 g of 2-[4-(2-thienylcarbonyl)phenyl]propionaldehyde obtained in Example 7 is dissolved in 50 ml of acetone, cooled to 50C in an ice bath, and then Jones reagent is added slowly. The dropwise addition is continued, while the reaction temperature is maintained at 5-1 0 C, until the orange color does not disappear.
After the completion of the reaction, isopropanol is added to stop the reaction. The reaction mixture is filtered at reduced pressure with cerite, and the filtrate is concentrated under reduced pressure. The residue is extracted three times with 50 ml of chloroform and then the chloroform layer is extracted twice with 30 ml of 2N-sodium hydroxide aqueous solution. The aqueous layer is acidified with hydrochloric acid and is extracted three times with 50 ml of chloroform. The orange layer is dried over an hydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure to give a pale yellow oil.This oil is crystallized from n-hexane, and recrystallized from acetonitrile to give 5.4 g of white 2-[4-(2thienylcarbonyl)phenyl]propionic acid. (the yield based on 2-thiophenealdehyde is 69.3%)
Example 9
In a 100 ml three-necked flask fitted with a condenser and a dropping funnel is placed 830 mg of metallic magnesium, and nitrogen gas is passing through. To this is added 10 ml of dried tetrahydrofuran, and 2-3 drops of ethyl bromide are added, with well-stirring, at room temperature, and then the mixture is heated gradually. When 7.9 g of 2-(4-bromophenyl) propionaldehyde ethylene acetal in 30 ml of dried THF is added to the solution is initiated with foaming. After the start of the reaction, the dropping is continued with keeping moderate reflux. After dropping, the solution is heated under reflux for one hour to complete the reaction.The solution is allowed to come to room temperature, and cooled to 5-10"C in an ice bath and then the solution of 3.36 g of 2-thiophenealdehyde in 20 ml of THF is added slowly, dropwise. After the dropping, the solution is heated gradually to room temperature and is stirred for one day. After the completion of the reaction, the reaction mixture is poured into diluted hydrochloric acid (50 g of ice and 50 ml of 10% hydrochloric acid), while stirring well. The reaction mixture is extracted three times with 100 ml of chloroform. The extract is dried over anhydrous sodium sulfate. The oily product obtained by evaporating the solvent, is dissolved in 80 ml of dioxane, and Jones reagent is added thereto dropwise at 5"C in an ice bath.The dropping is continued, while the reaction temperature is maintained at 5-1 0 C, until the orange color disappear. Then, 10 ml of isopropanol is added and continued to react for another ten minutes, and 10 ml of 10% sulfuric acid is added, the acidified solution is stirred for 12 hours at 80-90"C. After cooling, 40 ml of dioxane is added to the reaction solution and cooled to 5"C in an ice bath, and then Jones reagent is added dropwise until the orange color does not disappear.
After the completion of the reaction, isopropanol is added to stop the reaction. The reaction mixture is filtered by using kieselguhr and the filtrate is concentrated under reduced pressure. The residue is extracted three times with 50 ml of chloroform and the chloroform layer is washed twice with 30 ml of 2sodium hydroxide aqueous solution. The chloroform layer is dried over 5 g of anhydrous sodium sulfate and the chloroform is removed by distillation under reduced pressure to give a pale yellow oily product. It is crystallized from n-hexane and then is recrystallized from acetonitrile to obtain 5.5 g of 2-[4-(2 thienylcarbonyl)phenyl]propionic acid, as white powder. (the yield based on 2-thiophenealdehyde is 71.7%).
Claims (5)
1. A process for producing 2-[4-(2-thienylcarbonyl)phenyl]propionic acid which comprises reacting 2-substituted thiophene derivatives represented by the general formula (ill);
wherein R represents a cyano or aldehyde group, with Grignard agents of 2-(4bromophenyl)propionaldehyde acetal represented by the general formula (III);
wherein R1 and R2 represent a lower alkyl group or may jointly form an ethylene or propylene group to produce the compounds represented by the general formula (IV);;
wherein Y1 represents a hydrogen atom, Y2 represents a hydroxy group, or Y1 and Y2 jointly form an oxygen atom, and R1 and R2 are the same as defined above, and oxidizing the resulting compounds when Y1 is a hydrogen atom and Y2 is a hydroxy group in the formula (IV) to produce 2-[4-(2 thienylcarbonyl)phenyl]propionaldehyde acetal represented by the general formula (V);
wherein R1 and R2 are the same as defined above, and hydrolyzing the resulting acetal and oxidizing the resulting aldehyde.
2. A process as claimed in Claim 1 wherein the Grignard reagents of formula (III) are based on methyl acetal, ethyl acetal, propyl acetal, ethylene acetal or propylene acetal.
3. A process as claimed in Claim 1 or Claim 2 wherein the compounds of formula (II) and (III) are reacted together in the presence of a solvent.
4. A process as claimed in Claim 1 and substantially as described in any one of the specific examples hereinbefore set forth.
5. 2-[4-(2-thienylcarbonyl)phenyljpropionic acid whenever produced by the process claimed in any preceding claim or by an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP11199178A JPS5538340A (en) | 1978-09-12 | 1978-09-12 | Preparation of 2- 4-(2-thienylcarbonyl)phenyl propionic acid |
| JP11199078A JPS5538339A (en) | 1978-09-12 | 1978-09-12 | Preparation of 2- 4-(2-thienylcarbonyl)phenyl propionic acid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2030131A true GB2030131A (en) | 1980-04-02 |
| GB2030131B GB2030131B (en) | 1982-12-22 |
Family
ID=26451257
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB7906726A Expired GB2030131B (en) | 1978-09-12 | 1979-02-26 | Process for producing 2-(4-(2-thienyl-carbonyl) phenyl) propionic acid |
Country Status (3)
| Country | Link |
|---|---|
| DE (1) | DE2912052C2 (en) |
| FR (1) | FR2436146A1 (en) |
| GB (1) | GB2030131B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2545085A1 (en) * | 1983-04-28 | 1984-11-02 | Roussel Uclaf | NOVEL PROCESS FOR THE PREPARATION OF DERIVATIVES OF A-HYDROXY 2-THIOPHENE ACETIC ACID |
| EP0181568A2 (en) * | 1984-10-30 | 1986-05-21 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Anti-inflammatory/anti-allergic compounds |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1007643A (en) * | 1972-10-24 | 1977-03-29 | Janssen Pharmaceutica Naamloze Vennootschap | Aroyl-substituted phenylacetic acid derivatives |
| FR2345148A1 (en) * | 1976-03-24 | 1977-10-21 | Lipha | NEW SUBSTITUTE PROPIONIC ACID, PREPARATION AND APPLICATION |
-
1979
- 1979-02-26 GB GB7906726A patent/GB2030131B/en not_active Expired
- 1979-03-22 FR FR7907298A patent/FR2436146A1/en active Granted
- 1979-03-27 DE DE19792912052 patent/DE2912052C2/en not_active Expired
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2545085A1 (en) * | 1983-04-28 | 1984-11-02 | Roussel Uclaf | NOVEL PROCESS FOR THE PREPARATION OF DERIVATIVES OF A-HYDROXY 2-THIOPHENE ACETIC ACID |
| EP0181568A2 (en) * | 1984-10-30 | 1986-05-21 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Anti-inflammatory/anti-allergic compounds |
| EP0181568A3 (en) * | 1984-10-30 | 1989-04-26 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Anti-inflammatory/anti-allergic compounds |
Also Published As
| Publication number | Publication date |
|---|---|
| DE2912052A1 (en) | 1980-03-20 |
| FR2436146B1 (en) | 1983-01-14 |
| DE2912052C2 (en) | 1982-07-15 |
| FR2436146A1 (en) | 1980-04-11 |
| GB2030131B (en) | 1982-12-22 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |