ITMI952670A1 - PROCESS FOR THE PREPARATION OF OXATOMIDE - Google Patents
PROCESS FOR THE PREPARATION OF OXATOMIDE Download PDFInfo
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- ITMI952670A1 ITMI952670A1 IT95MI002670A ITMI952670A ITMI952670A1 IT MI952670 A1 ITMI952670 A1 IT MI952670A1 IT 95MI002670 A IT95MI002670 A IT 95MI002670A IT MI952670 A ITMI952670 A IT MI952670A IT MI952670 A1 ITMI952670 A1 IT MI952670A1
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- oxatomide
- alkali
- formula
- alkaline
- piperazine
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- BAINIUMDFURPJM-UHFFFAOYSA-N oxatomide Chemical compound O=C1NC2=CC=CC=C2N1CCCN(CC1)CCN1C(C=1C=CC=CC=1)C1=CC=CC=C1 BAINIUMDFURPJM-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 229960002698 oxatomide Drugs 0.000 title claims abstract description 18
- 238000000034 method Methods 0.000 title claims abstract description 12
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 8
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 6
- NWVNXDKZIQLBNM-UHFFFAOYSA-N diphenylmethylpiperazine Chemical compound C1CNCCN1C(C=1C=CC=CC=1)C1=CC=CC=C1 NWVNXDKZIQLBNM-UHFFFAOYSA-N 0.000 claims description 6
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 5
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 5
- 150000004649 carbonic acid derivatives Chemical class 0.000 claims description 5
- 229910021529 ammonia Inorganic materials 0.000 claims description 4
- 238000009835 boiling Methods 0.000 claims description 4
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- AYAOABSVDIFXFA-UHFFFAOYSA-N 2-oxo-3h-benzimidazole-1-carboxylic acid Chemical compound C1=CC=C2NC(=O)N(C(=O)O)C2=C1 AYAOABSVDIFXFA-UHFFFAOYSA-N 0.000 claims description 3
- QHEPVOLZUQXADW-UHFFFAOYSA-N 3-(2-chloropropyl)-1h-benzimidazol-2-one Chemical compound C1=CC=C2NC(=O)N(CC(Cl)C)C2=C1 QHEPVOLZUQXADW-UHFFFAOYSA-N 0.000 claims description 3
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 3
- 239000012458 free base Substances 0.000 claims description 3
- 150000004679 hydroxides Chemical class 0.000 claims description 3
- -1 phenyl ester Chemical class 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- HYOAGWAIGJXNQH-UHFFFAOYSA-N 1-bromo-1-chloropropane Chemical compound CCC(Cl)Br HYOAGWAIGJXNQH-UHFFFAOYSA-N 0.000 claims description 2
- 238000009833 condensation Methods 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims description 2
- 150000004678 hydrides Chemical class 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 239000003849 aromatic solvent Substances 0.000 claims 1
- 239000000043 antiallergic agent Substances 0.000 abstract 1
- 208000006673 asthma Diseases 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 239000000543 intermediate Substances 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- MFESCIUQSIBMSM-UHFFFAOYSA-N I-BCP Chemical compound ClCCCBr MFESCIUQSIBMSM-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 230000001088 anti-asthma Effects 0.000 description 1
- 239000000924 antiasthmatic agent Substances 0.000 description 1
- MYONAGGJKCJOBT-UHFFFAOYSA-N benzimidazol-2-one Chemical compound C1=CC=CC2=NC(=O)N=C21 MYONAGGJKCJOBT-UHFFFAOYSA-N 0.000 description 1
- 150000008641 benzimidazolones Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
La presente invenzione si riferisce ad un metodo per la preparazione di oxatomide (1-[3-[4-(difenilmetil)-1-piperazinil]propil]-1, 3diidro-2H-benzimidazolo-2-one), noto farmaco antiallergico e antiasmatico.The present invention relates to a method for the preparation of oxatomide (1- [3- [4- (diphenylmethyl) -1-piperazinyl] propyl] -1, 3dihydro-2H-benzimidazole-2-one), known antiallergic drug and asthma.
Description
Descrizione dell'invenzione industriale avente per titolo: "PROCESSO PER LA PREPARAZIONE DI OXATOMIDE" Description of the industrial invention entitled: "PROCESS FOR THE PREPARATION OF OXATOMIDE"
La presente invenzione si riferisce ad un metodo per la preparazione di oxatomide. The present invention relates to a method for the preparation of oxatomide.
L'oxatomide (1-[3-[4-(difenilmetil)-1-piperazinil ]propil]-1,3-diidro-2H-benzimidazolo-2-one ) è un noto farmaco antiallergico e antiasmatico . Oxatomide (1- [3- [4- (diphenylmethyl) -1-piperazinyl] propyl] -1,3-dihydro-2H-benzimidazole-2-one) is a well-known anti-allergic and anti-asthma drug.
Molti brevetti descrivono la sua preparazione a partire da prodotti di base che sono normalmente intermedi ottenuti dal benzimidazolone; questi conposti non sono spesso facilmente disponibili sul mercato oppure sono molto costosi; la loro sintesi richiede nella maggior parte dei casi una grande quantità di lavoro, talvolta con una resa estremamente bassa. Many patents describe its preparation starting from basic products which are normally intermediates obtained from benzimidazolone; these compounds are often not readily available on the market or are very expensive; their synthesis requires in most cases a large amount of work, sometimes with an extremely low yield.
Il processo secondo la presente invenzione utilizza invece materiali di partenza poco costosi e facilmente disponibili e permette di ottenere l'oxatomide in buona resa. La materia prima principale è 1H-benzimidazolo che, nel primo stadio, fornisce direttamente un derivato asimmetrico di benzimidazolone. Il gruppo protettivo dell'azoto permette di ottenere solo derivati monoalchilici nel secondo stadio ed è infine rimosso per mezzo di una semplice idrolisi alcalina. The process according to the present invention, on the other hand, uses inexpensive and easily available starting materials and allows to obtain the oxatomide in good yield. The main raw material is 1H-benzimidazole which, in the first stage, directly provides an asymmetric derivative of benzimidazolone. The nitrogen protective group allows to obtain only monoalkyl derivatives in the second stage and is finally removed by means of a simple alkaline hydrolysis.
Il processo per la preparazione di oxatomide secondo l'invenzione, schematizzato nel seguente schema, comprende: The process for the preparation of oxatomide according to the invention, schematized in the following scheme, includes:
a) la reazione di lH-benzimidazolo con fenilcloroformato in presenza di alcali a dare 1'intermedio di formula I (estere fenilico dell'acido 2-oxo-2,3-diidro-benzimidazol-l-carbossilico); a) the reaction of 1H-benzimidazole with phenylchloroformate in the presence of alkali to give the intermediate of formula I (phenyl ester of 2-oxo-2,3-dihydro-benzimidazol-1-carboxylic acid);
b) condensazione dell'intermedio di formula I con bromo-cloro-propano a dare l'intermedio di formula II (l-(2-cloropropil)-l,3-diidrobenzimidazol-2-one); b) condensation of the intermediate of formula I with bromo-chloro-propane to give the intermediate of formula II (1- (2-chloropropyl) -1, 3-dihydrobenzimidazol-2-one);
c) reazione fra l'intermedio di formula II e l-(difenilmetil)-piperazina; c) reaction between the intermediate of formula II and 1- (diphenylmethyl) -piperazine;
d) purificazione dell'oxatomide grezza ottenuta attraverso il sale cloridrato e ottenimento della base libera per mezzo di alcali. d) purification of the crude oxatomide obtained through the hydrochloride salt and obtaining the free base by means of alkali.
Lo stadio a) è effettuato facendo reagire 1H-benzimidazolo con fenilcloroformiato in presenza di alcali e di un opportuno solvente organico ad una temperatura fra -10 e 100°C. Esempi di elicali opportuni sono carbonati o bicarbonati alcalini o alcalino-terrosi, ammoniaca o animine organiche quali trietilammina, piperazina, piridina; solventi adatti sono chetoni, idrocarburi aromatici o alifatici, idrocarburi alogenati, ammidi, diossano, acqua o miscele di essi. Step a) is carried out by reacting 1H-benzimidazole with phenylchloroformate in the presence of alkali and a suitable organic solvent at a temperature between -10 and 100 ° C. Examples of suitable helicals are alkaline or alkaline-earth carbonates or bicarbonates, ammonia or organic animins such as triethylamine, piperazine, pyridine; suitable solvents are ketones, aromatic or aliphatic hydrocarbons, halogenated hydrocarbons, amides, dioxane, water or mixtures thereof.
Nello stadio b), l'intermedio di formula I è fatto reagire con 1-bromo-3-cloro-propano nell'intervallo di temperatura da 40 a 120°C in presenza di alcali, quali carbonati o bicarbonati alcalini o alcalinoterrosi, idruri o idrossidi alcalini o alcalino-terrosi, trietilammina; i solventi inpiegati sono idrocarburi aromatici altobollenti, dimetil o diacetilformammide . In step b), the intermediate of formula I is reacted with 1-bromo-3-chloro-propane in the temperature range from 40 to 120 ° C in the presence of alkalis, such as alkaline or alkaline earth carbonates or bicarbonates, hydrides or alkaline or alkaline earth hydroxides, triethylamine; the solvents used are high boiling aromatic hydrocarbons, dimethyl or diacetylformamide.
Lo stadio c) è effettuato facendo reagire l'intermedio di formula II ottenuto nello stadio b) con l-(difenilmetil) -piperazina ad ima temperatura da 80 a 120°C in presenza di una base in un solvente opportuno . Esempi di basi sono carbonati o bicarbonati alcalini o alcalino-terrosi, ammoniaca o animine organiche quali trietilammina, piridina o la stessa l1{difenilmetil)-piperazina; come solventi si impiegano preferibilmente idrocarburi aromatici altobollenti, dimetil o diacetilformammide. Si ottiene l'oxatomide grezza di formula III. Lo stadio d) è la purificazione attraverso il sale cloridrato in un solvente opportuno. L'oxatomide finale di formula IV è ottenuta come base libera impiegando una base allo scopo di neutralizzare l'acido cloridrico. Esempi di opportuni solventi sono idrocarburi aromatici, chetoni, alcoli, miscele di acqua con chetoni o alcoli. Esempi di alcali sono carbonati o bicarbonati alcalini o alcalino-terrosi, idrossidi alcalini o alcalino-terrosi, ammine organiche quali trietilammina, piridina, piperazina o ammoniaca. Step c) is carried out by reacting the intermediate of formula II obtained in step b) with 1- (diphenylmethyl) -piperazine at a temperature from 80 to 120 ° C in the presence of a base in a suitable solvent. Examples of bases are alkaline or alkaline-earth carbonates or bicarbonates, ammonia or organic animines such as triethylamine, pyridine or the same 1 (diphenylmethyl) -piperazine; high-boiling aromatic hydrocarbons, dimethyl or diacetylformamide, are preferably used as solvents. The crude oxatomide of formula III is obtained. Step d) is the purification through the hydrochloride salt in a suitable solvent. The final oxatomide of formula IV is obtained as a free base using a base for the purpose of neutralizing hydrochloric acid. Examples of suitable solvents are aromatic hydrocarbons, ketones, alcohols, mixtures of water with ketones or alcohols. Examples of alkalis are alkaline or alkaline earth carbonates or bicarbonates, alkaline or alkaline earth hydroxides, organic amines such as triethylamine, pyridine, piperazine or ammonia.
Il processo dell'invenzione è particolarmente semplice e può essere convenientemente utilizzato su scala industriale presentando il vantaggio di utilizzare come materiali di partenza materie prime poco costose e facilmente disponibili. I seguenti esempi illustrano ulteriormente l'invenzione. The process of the invention is particularly simple and can be conveniently used on an industrial scale, having the advantage of using inexpensive and readily available raw materials as starting materials. The following examples further illustrate the invention.
ESEMPIO 1 EXAMPLE 1
Estere fenilico dell'acido 2- oxo-2,3-diidro-benzimidazol-1-carbossilico (I) 2-oxo-2,3-dihydro-benzimidazol-1-carboxylic acid (I) phenyl ester
Si sciolse benzimidazolo (14,5 g) in una miscela di acetone e acqua (400 g). Si aggiunse carbonato di sodio (40 g) e si aggiunse goccia a goccia fenilcloroformiato facendo salire la temperatura a 30-40 “C; la miscela di reazione fu riscaldata lentamente alla temperatura di 60eC, mantenuta a questa temperatura per 15 minuti e raffreddata alla temperatura ambiente. Si aggiunse acqua (120 g) durante il raffreddamento allo scopo di diluire la massa. I cristalli precipitati furono filtrati, lavati con 100 g di una miscela di acetone:acqua 40:60. Dopo essiccazione sotto vuoto (15 mmHg) a 50°C, si ottennero 25 g dell'intermedio primo con resa dell'80%. Benzimidazole (14.5 g) was dissolved in a mixture of acetone and water (400 g). Sodium carbonate (40 g) was added and phenylchloroformate was added drop by drop, causing the temperature to rise to 30-40 ° C; the reaction mixture was slowly heated to a temperature of 60 ° C, maintained at this temperature for 15 minutes and cooled to room temperature. Water (120 g) was added during cooling in order to dilute the mass. The precipitated crystals were filtered, washed with 100 g of a 40:60 acetone: water mixture. After drying under vacuum (15 mmHg) at 50 ° C, 25 g of the first intermediate were obtained with a yield of 80%.
1-(2-cloropropil )-1,3-diidro-benzimidazol-2-one 1- (2-chloropropyl) -1,3-dihydro-benzimidazol-2-one
L'intermedio I (50 g) fu fatto reagire in 250 g di N, Ndimetilformammide con idrossido di sodio e l-bromo-3-cloro-propano per 6 ore alla temperatura di 50°C. Si aggiunse una soluzione di idrossido di potassio (26 g) in acqua (250 g) e la massa di reazione, dopo agitazione di 2 ore alla temperatura ambiente, fu versata in 2,5 1 di acqua contenente cloruro di sodio (200 g). Intermediate I (50 g) was reacted in 250 g of N, Ndimethylformamide with sodium hydroxide and 1-bromo-3-chloro-propane for 6 hours at a temperature of 50 ° C. A solution of potassium hydroxide (26 g) in water (250 g) was added and the reaction mass, after stirring for 2 hours at room temperature, was poured into 2.5 1 of water containing sodium chloride (200 g) .
Il prodotto cristallino precipitato fu filtrato, lavato con acqua (50 g) ed essiccato sotto vuoto (15 mmHg) alla temperatura di 50 "C. 28 g del composto III sono stati ottenuti con resa del 67%. La struttura fu confermata con l'analisi NMR. The precipitated crystalline product was filtered, washed with water (50 g) and dried under vacuum (15 mmHg) at a temperature of 50 "C. 28 g of compound III were obtained with a yield of 67%. The structure was confirmed with NMR analysis.
ESEMPIO 3 EXAMPLE 3
Oxatomide grezza Raw oxatomide
L'intermedio II (27 g), N, N-dimetilformammide (110 ml), carbonato di sodio (40,7 g) e l-(difenilmetil)-piperazina (32,3 g) furono fatti reagire per 6 ore alla temperatura di 100-105’C. Intermediate II (27 g), N, N-dimethylformamide (110 ml), sodium carbonate (40.7 g) and 1- (diphenylmethyl) -piperazine (32.3 g) were reacted for 6 hours at temperature of 100-105'C.
La massa di reazione fu versata in una miscela di etanolo (310 ml) e acqua (750 ml). Dopo 2 ore sotto agitazione, il prodotto cristallino fu filtrato, lavato con una miscela di etanolo (20 ml) ed acqua (48 ml) e quindi solo con acqua (380 ml); dopo essiccazione alla temperatura di 50“C sotto vuoto (15 mmHg), si ottenne 1'oxatomide grezza (37 g) con resa del 68%. The reaction mass was poured into a mixture of ethanol (310 ml) and water (750 ml). After 2 hours under stirring, the crystalline product was filtered, washed with a mixture of ethanol (20 ml) and water (48 ml) and then only with water (380 ml); after drying at a temperature of 50 ° C under vacuum (15 mmHg), the crude oxatomide (37 g) was obtained with a yield of 68%.
ESEMPIO 4 EXAMPLE 4
Oxatomide Oxatomide
L'oxatomide grezza (35 g) fu sciolta in toluene (300 ml) e lavata 3 volte con acqua (3 x 100 ml). La fase organica fu allontanata cautamente sottovuoto (15 mmHg) e l'olio rimanente fu sciolto in etanolo (100 ml); dopo gorgogliamento di cloruro di idrogeno (20 g) si filtrò l'oxatomide cloridrato. Il prodotto cristallino umido fu sospeso in etanolo (50 ml) e si aggiunse idrossido di potassio (20 g) sotto agitazione fino a pH alcalino. The crude oxatomide (35 g) was dissolved in toluene (300 ml) and washed 3 times with water (3 x 100 ml). The organic phase was removed carefully under vacuum (15 mmHg) and the remaining oil was dissolved in ethanol (100 ml); after bubbling of hydrogen chloride (20 g) the hydrochloride oxatomide was filtered. The wet crystalline product was suspended in ethanol (50 ml) and potassium hydroxide (20 g) was added under stirring up to an alkaline pH.
Si aggiunse goccia a goccia acqua (2,5 1) sotto buona agitazione. Si filtrò il prodotto cristallino precipitato che fu lavato con acqua (50 ml) ed essiccato sotto vuoto (15 mmHg) alla temperatura di 50°C. Si ottennero 28 g di oxatomide con resa del 70%. La struttura fu confermata con lo spettro di massa. Water (2.5 1) was added drop by drop with good stirring. The precipitated crystalline product was filtered and washed with water (50 ml) and dried under vacuum (15 mmHg) at a temperature of 50 ° C. 28 g of oxatomide were obtained with a yield of 70%. The structure was confirmed with the mass spectrum.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT95MI002670A IT1277104B1 (en) | 1995-12-19 | 1995-12-19 | PROCESS FOR THE PREPARATION OF OXATOMIDE |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT95MI002670A IT1277104B1 (en) | 1995-12-19 | 1995-12-19 | PROCESS FOR THE PREPARATION OF OXATOMIDE |
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| Publication Number | Publication Date |
|---|---|
| ITMI952670A0 ITMI952670A0 (en) | 1995-12-19 |
| ITMI952670A1 true ITMI952670A1 (en) | 1997-06-19 |
| IT1277104B1 IT1277104B1 (en) | 1997-11-04 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IT95MI002670A IT1277104B1 (en) | 1995-12-19 | 1995-12-19 | PROCESS FOR THE PREPARATION OF OXATOMIDE |
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| Country | Link |
|---|---|
| IT (1) | IT1277104B1 (en) |
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1995
- 1995-12-19 IT IT95MI002670A patent/IT1277104B1/en active IP Right Grant
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| Publication number | Publication date |
|---|---|
| IT1277104B1 (en) | 1997-11-04 |
| ITMI952670A0 (en) | 1995-12-19 |
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