ITMI20001661A1 - PROCESS FOR THE PREPARATION OF 1-METHYL-5- (4-METHYLBENZOIL) -PIRROL -2-ACETYLAMINOACETIC ACID - Google Patents
PROCESS FOR THE PREPARATION OF 1-METHYL-5- (4-METHYLBENZOIL) -PIRROL -2-ACETYLAMINOACETIC ACID Download PDFInfo
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- ITMI20001661A1 ITMI20001661A1 IT2000MI001661A ITMI20001661A ITMI20001661A1 IT MI20001661 A1 ITMI20001661 A1 IT MI20001661A1 IT 2000MI001661 A IT2000MI001661 A IT 2000MI001661A IT MI20001661 A ITMI20001661 A IT MI20001661A IT MI20001661 A1 ITMI20001661 A1 IT MI20001661A1
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- IT
- Italy
- Prior art keywords
- methyl
- pirrol
- methyl ester
- tolmetin
- preparation
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 14
- 238000002360 preparation method Methods 0.000 title claims description 8
- -1 4-methylbenzoyl Chemical group 0.000 claims description 14
- SIXINSDWVSIFEY-UHFFFAOYSA-N methyl 2-[1-methyl-5-(4-methylbenzoyl)pyrrol-2-yl]acetate Chemical compound CN1C(CC(=O)OC)=CC=C1C(=O)C1=CC=C(C)C=C1 SIXINSDWVSIFEY-UHFFFAOYSA-N 0.000 claims description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 11
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical group [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 10
- 150000004703 alkoxides Chemical class 0.000 claims description 9
- 230000009435 amidation Effects 0.000 claims description 5
- 238000007112 amidation reaction Methods 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 150000004702 methyl esters Chemical class 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 238000003786 synthesis reaction Methods 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- CWJNMKKMGIAGDK-UHFFFAOYSA-N amtolmetin guacil Chemical compound COC1=CC=CC=C1OC(=O)CNC(=O)CC(N1C)=CC=C1C(=O)C1=CC=C(C)C=C1 CWJNMKKMGIAGDK-UHFFFAOYSA-N 0.000 claims description 2
- 229950003227 amtolmetin guacil Drugs 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 8
- 230000004913 activation Effects 0.000 description 4
- UPSPUYADGBWSHF-UHFFFAOYSA-N tolmetin Chemical compound C1=CC(C)=CC=C1C(=O)C1=CC=C(CC(O)=O)N1C UPSPUYADGBWSHF-UHFFFAOYSA-N 0.000 description 4
- 229960001017 tolmetin Drugs 0.000 description 4
- 239000000203 mixture Substances 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 1
- FIPWRIJSWJWJAI-UHFFFAOYSA-N Butyl carbitol 6-propylpiperonyl ether Chemical compound C1=C(CCC)C(COCCOCCOCCCC)=CC2=C1OCO2 FIPWRIJSWJWJAI-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000002826 coolant Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229960005235 piperonyl butoxide Drugs 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
"Processo per la preparazione dell’acido l-metil-5-(4-metilbenzoil)-pirrol-2-acetil amminoacetico " "Process for the preparation of l-methyl-5- (4-methylbenzoyl) -pirrol-2-acetyl aminoacetic acid"
Descrizione Description
La presente invenzione riguarda un processo migliorato per la preparazione dell’acido l-metil-5-(4-metilbenzoil)-pirrol-2-acetilamminoacetico di formula The present invention relates to an improved process for the preparation of 1-methyl-5- (4-methylbenzoyl) -pirrol-2-acetylaminoacetic acid of formula
e dei suoi sali, e più in particolare, riguarda un processo per la preparazione del composto di formula (I) per ammidazione diretta del metil estere dell’acido 1-metil-5-(4-metilbenzoil)-pirrol-2-acetico con glieina. and its salts, and more particularly, it relates to a process for the preparation of the compound of formula (I) by direct amidation of the 1-methyl-5- (4-methylbenzoyl) -pirrol-2-acetic acid methyl ester with glieina.
L’acido l-metil-5-(4-metilbenzoil)-pirrol-2-acetammidoacetico è un intermedio noto per la sintesi dell’amtolmetin guacile, un farmaco antiinfiammatorio (The Merck Index, ΧΠ ed., n° 637, pag. 101). 1-methyl-5- (4-methylbenzoyl) -pirrol-2-acetamidoacetic acid is an intermediate known for the synthesis of amtolmetin guacil, an anti-inflammatory drug (The Merck Index, ΧΠ ed., N ° 637, p. 101).
In GB 2155417 (Sigma-Tau Industrie Farmaceutiche Riunite S.p.A. - Medosan Industrie Biochimiche Riunite S.p.A.) ed in WO 99/33797 viene descritta la sintesi dell’acido l-metil-5-(4-metilbenzoil)-pirrol-2-acetilamminoacetico a partire dal metil estere dell’acido l-metil-5-(4-metilbenzoil)-pirrol-2-acetico (d’ora in avanti indicato come tolmetin metil estere) per idrolisi, attivazione del tolmetin così ottenuto e reazione con glieina secondo lo schema illustrato qui di seguito. GB 2155417 (Sigma-Tau Industrie Farmaceutiche Riunite S.p.A. - Medosan Industrie Biochimiche Riunite S.p.A.) and WO 99/33797 describes the synthesis of l-methyl-5- (4-methylbenzoyl) -pirrol-2-acetylaminoacetic acid starting from from the methyl ester of l-methyl-5- (4-methylbenzoyl) -pirrol-2-acetic acid (hereinafter referred to as tolmetin methyl ester) by hydrolysis, activation of the tolmetin thus obtained and reaction with gliein according to the scheme illustrated below.
Schema Scheme
(II) (II)
(ΙΠ) (ΙΠ)
(IV) (IV)
(I) (THE)
in cui X è un gruppo attivante. where X is an activating group.
In particolare il tolmetin metil estere (II) viene idrolizzato con soda per ottenere il tolmetin (ΠΙ) come sale sodico. Quest’ultimo viene attivato al corrispondente intermedio (IV) per la successiva reazione con glieina. L’attivazione viene effettuata con l,l’-carbonil-diimidazolo in GB 2115417 e con isobutilcloroformiato in WO 99/33797. In particular, tolmetin methyl ester (II) is hydrolyzed with soda to obtain tolmetin (ΠΙ) as the sodium salt. The latter is activated at the corresponding intermediate (IV) for the subsequent reaction with gliein. Activation is carried out with l, carbonyl-diimidazole in GB 2115417 and with isobutyl chloroformate in WO 99/33797.
Abbiamo ora trovato che è possibile preparare l’acido l-metil-5-(4-metilbenzoil)-pirrol-2-acetilamminoacetico per reazione diretta del tolmetin metil estere con glieina evitando così sia ridrolisi del tolmetin metil estere sia l’attivazione del tolmetin. We have now found that it is possible to prepare 1-methyl-5- (4-methylbenzoyl) -pirrol-2-acetylaminoacetic acid by direct reaction of tolmetin methyl ester with gliein thus avoiding both redrolysis of tolmetin methyl ester and activation of tolmetin .
Costituisce pertanto oggetto della presente invenzione un processo per la preparazione dell’acido l-metil-5-(4-metilbenzoil)-pirrol-2-acetilamminoacetico o dei suoi sali per ammidazione diretta del metil estere dell’acido l-metil-5-(4-metilbenzoil)-pirrol-2-acetico con glieina. Therefore, the object of the present invention is a process for the preparation of 1-methyl-5- (4-methylbenzoyl) -pirrol-2-acetylaminoacetic acid or its salts by direct amidation of the methyl ester of 1-methyl-5- acid (4-methylbenzoyl) -pirrol-2-acetic with gliein.
L’ammidazione diretta viene effettuata facendo reagire una miscela di tolmetin metil estere in un adatto solvente con glieina in presenza di un alcossido alcalino. Preferibilmente viene utilizzato toluene come solvente. Direct amidation is carried out by reacting a mixture of tolmetin methyl ester in a suitable solvent with glyein in the presence of an alkaline alkoxide. Preferably, toluene is used as a solvent.
L’alcossido alcalino preferito è metossido di sodio, ma risultati analoghi si ottengono utilizzando altri alcossidi alcalini quali, ad esempio, t.butossido di sodio. The preferred alkaline alkoxide is sodium methoxide, but similar results are obtained by using other alkaline alkoxides such as, for example, sodium t.butoxide.
Il metossido di sodio viene utilizzato in soluzione metanolica. Sodium methoxide is used in methanolic solution.
La glieina e l’alcossido alcalino vengono utilizzati in eccesso rispetto al tolmetin metil estere. The glyein and the alkaline alkoxide are used in excess of the tolmetin methyl ester.
Preferibilmente vengono utilizzati da 1,2 a 2,0 equivalenti di glieina e da 1,3 a 2,0 equivalenti di alcossido alcalino per equivalente di tolmetin metil estere. Preferably, 1.2 to 2.0 equivalents of glyein and 1.3 to 2.0 equivalents of alkaline alkoxide per equivalent of tolmetin methyl ester are used.
La reazione viene effettuata preferibilmente alla temperatura di riflusso. The reaction is preferably carried out at the reflux temperature.
Una forma pratica preferita di attuazione del processo oggetto della presente invenzione è la seguente. A preferred practical embodiment of the process object of the present invention is the following.
Alla miscela di tolmetin metil estere in toluene si aggiungono nell'ordine 1,2 equivalenti di glieina e 1,9 equivalenti di sodio metossido al 30% in metanolo. Si porta la temperatura interna a 70°C e si lascia la miscela di reazione sotto agitazione a questa temperatura per due ore. Quando la reazione è finita, si caricano acqua e metanolo e si porta la temperatura a 64-65°C. Si lascia sotto agitazione per un'ora, poi si raffredda a 0°C in 5 ore e dopo 2 ore a 0°C si isola il solido per filtrazione. 1.2 equivalents of glyein and 1.9 equivalents of 30% sodium methoxide in methanol are added to the mixture of tolmetin methyl ester in toluene. The internal temperature is brought to 70 ° C and the reaction mixture is left under stirring at this temperature for two hours. When the reaction is over, water and methanol are loaded and the temperature is brought to 64-65 ° C. It is left under stirring for one hour, then it is cooled to 0 ° C in 5 hours and after 2 hours at 0 ° C the solid is isolated by filtration.
In questo modo si ottiene un prodotto con una purezza cromatografica del 99,9% (HPLC) e un titolo potenzio metri co del 100%. In this way, a product with a chromatographic purity of 99.9% (HPLC) and a potential titre of 100% is obtained.
La resa molare su isolato è pari alI'82-84% con una resa in soluzione del 90%. The molar yield on isolate is 82-84% with a solution yield of 90%.
E’ evidente come il processo migliorato oggetto della presente invenzione sia vantaggioso rispetto ai processi descritti in letteratura. It is evident how the improved process object of the present invention is advantageous with respect to the processes described in the literature.
Infatti, la possibilità di effettuare direttamente la reazione con glieina a partire dal tolmetin metil estere consente di evitare alcuni passaggi della sintesi, in particolare l’idrolisi del tolmetin metil estere e l’attivazione del tolmetin. In fact, the possibility of directly carrying out the reaction with gliein starting from the tolmetin methyl ester allows to avoid some steps of the synthesis, in particular the hydrolysis of the tolmetin methyl ester and the activation of the tolmetin.
Allo scopo di meglio illustrare la presente invenzione viene ora fornito il seguente esempio. In order to better illustrate the present invention, the following example is now provided.
Esempio 1 Example 1
Preparazione del sale sodico dell’acido l-metil-5-f4-metilbenzoi1Vpirrol-2-acetilamminoacetico Preparation of the sodium salt of l-methyl-5-f4-methylbenzoi1Vpirrol-2-acetylaminoacetic acid
In un reattore da 1,2 1, munito di agitatore meccanico, termometro, refrigerante e anidrificato, sono stati caricati a temperatura ambiente e in atmosfera inerte, toluene (450 mi) e tolmetin metil estere (100,0 g; 0,369 moli). Toluene (450 ml) and tolmetin methyl ester (100.0 g; 0.369 moles) were charged at room temperature and in an inert atmosphere into a 1.2 1 reactor, equipped with mechanical stirrer, thermometer, coolant and anhydrified.
Alla sospensione sono stati aggiunti a 30-32°C glieina (32,0 g; 0,427 moli) e successivamente sodio metossido al 29% (130,0 g; 0,698 moli). Glyine (32.0 g; 0.427 moles) and subsequently sodium methoxide at 29% (130.0 g; 0.698 moles) were added to the suspension at 30-32 ° C.
L’aggiunta è stata esotermica: la temperatura interna è salita da 30°C a 35-36°C. The addition was exothermic: the internal temperature rose from 30 ° C to 35-36 ° C.
La sospensione sotto vigorosa agitazione è stata scaldata fino a 70°C. Dopo 2 ore è stato prelevato un campione per il controllo di fine reazione. Terminata la reazione sono stati caricati acqua demineralizzata (85,0 mi) e metanolo (260,0 mi). The suspension was heated up to 70 ° C under vigorous stirring. After 2 hours a sample was taken for the control of the end of the reaction. At the end of the reaction, demineralized water (85.0 ml) and methanol (260.0 ml) were added.
La miscela (circa 1000 mi) è stata portata alla temperatura di riflusso (64-65°C interni) per un'ora circa, dopodiché è stata raffreddata a 0°C in 5 ore. Dopo 2 ore a 0°C è stato filtrato il solido fuori fase, che è stato lavato con metanolo (3x50 mi) pre-raffreddato a 0°C ottenendo il sale sodico dell’acido l-metil-5-(4-metilbenzoil)-pirrol-2-acetilamminoacetico (102,5 g). The mixture (about 1000 ml) was brought to the reflux temperature (internal 64-65 ° C) for about one hour, after which it was cooled to 0 ° C in 5 hours. After 2 hours at 0 ° C the out-of-phase solid was filtered and washed with methanol (3x50 ml) pre-cooled at 0 ° C to obtain the sodium salt of 1-methyl-5- (4-methylbenzoyl) acid -pirrol-2-acetylaminoacetic (102.5 g).
Titolo potenziometrico: 100,2% Potentiometric title: 100.2%
Purezza HPLC: 99,93% HPLC purity: 99.93%
Resa molare: 82,7%. Molar yield: 82.7%.
Claims (6)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT2000MI001661A IT1318634B1 (en) | 2000-07-21 | 2000-07-21 | PROCESS FOR THE PREPARATION OF 1-METHYL-5- (4-METHYLBENZOIL) -PIRROL-2-ACETYLAMINOACETIC ACID. |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT2000MI001661A IT1318634B1 (en) | 2000-07-21 | 2000-07-21 | PROCESS FOR THE PREPARATION OF 1-METHYL-5- (4-METHYLBENZOIL) -PIRROL-2-ACETYLAMINOACETIC ACID. |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| ITMI20001661A0 ITMI20001661A0 (en) | 2000-07-21 |
| ITMI20001661A1 true ITMI20001661A1 (en) | 2002-01-21 |
| IT1318634B1 IT1318634B1 (en) | 2003-08-27 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IT2000MI001661A IT1318634B1 (en) | 2000-07-21 | 2000-07-21 | PROCESS FOR THE PREPARATION OF 1-METHYL-5- (4-METHYLBENZOIL) -PIRROL-2-ACETYLAMINOACETIC ACID. |
Country Status (1)
| Country | Link |
|---|---|
| IT (1) | IT1318634B1 (en) |
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- 2000-07-21 IT IT2000MI001661A patent/IT1318634B1/en active
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| Publication number | Publication date |
|---|---|
| ITMI20001661A0 (en) | 2000-07-21 |
| IT1318634B1 (en) | 2003-08-27 |
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