LU87538A1 - PROCESS FOR THE PREPARATION OF LEVO-DROPROPIZINE AND DEXTRO-DROPROPIZINE - Google Patents
PROCESS FOR THE PREPARATION OF LEVO-DROPROPIZINE AND DEXTRO-DROPROPIZINE Download PDFInfo
- Publication number
- LU87538A1 LU87538A1 LU87538A LU87538A LU87538A1 LU 87538 A1 LU87538 A1 LU 87538A1 LU 87538 A LU87538 A LU 87538A LU 87538 A LU87538 A LU 87538A LU 87538 A1 LU87538 A1 LU 87538A1
- Authority
- LU
- Luxembourg
- Prior art keywords
- dropropizine
- levo
- dextro
- preparation
- glycidol
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 17
- PTVWPYVOOKLBCG-ZDUSSCGKSA-N levodropropizine Chemical compound C1CN(C[C@H](O)CO)CCN1C1=CC=CC=C1 PTVWPYVOOKLBCG-ZDUSSCGKSA-N 0.000 title claims description 8
- 229960002265 levodropropizine Drugs 0.000 title claims description 7
- 238000002360 preparation method Methods 0.000 title claims description 6
- PTVWPYVOOKLBCG-CYBMUJFWSA-N (2r)-3-(4-phenylpiperazin-1-yl)propane-1,2-diol Chemical compound C1CN(C[C@@H](O)CO)CCN1C1=CC=CC=C1 PTVWPYVOOKLBCG-CYBMUJFWSA-N 0.000 title claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- CTKINSOISVBQLD-VKHMYHEASA-N (S)-Glycidol Chemical compound OC[C@H]1CO1 CTKINSOISVBQLD-VKHMYHEASA-N 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 229960004722 dropropizine Drugs 0.000 claims description 8
- YZTJYBJCZXZGCT-UHFFFAOYSA-N phenylpiperazine Chemical compound C1CNCCN1C1=CC=CC=C1 YZTJYBJCZXZGCT-UHFFFAOYSA-N 0.000 claims description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- CTKINSOISVBQLD-GSVOUGTGSA-N (R)-Glycidol Chemical compound OC[C@@H]1CO1 CTKINSOISVBQLD-GSVOUGTGSA-N 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 238000009835 boiling Methods 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims 2
- 229960004592 isopropanol Drugs 0.000 claims 1
- PTVWPYVOOKLBCG-UHFFFAOYSA-N 3-(4-phenyl-1-piperazinyl)propane-1,2-diol Chemical compound C1CN(CC(O)CO)CCN1C1=CC=CC=C1 PTVWPYVOOKLBCG-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 3
- DFQNMODTAFTGHS-UHFFFAOYSA-N 2,3-dihydroxypropyl 4-methylbenzenesulfonate Chemical compound CC1=CC=C(S(=O)(=O)OCC(O)CO)C=C1 DFQNMODTAFTGHS-UHFFFAOYSA-N 0.000 description 2
- -1 4-phenylpiperazin-l-yl Chemical group 0.000 description 2
- CTKINSOISVBQLD-UHFFFAOYSA-N Glycidol Chemical compound OCC1CO1 CTKINSOISVBQLD-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 239000004146 Propane-1,2-diol Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229960004063 propylene glycol Drugs 0.000 description 2
- 235000013772 propylene glycol Nutrition 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- LHUBFUMPYZCAER-UHFFFAOYSA-N CCCN(CCNC)c1ccccc1 Chemical compound CCCN(CCNC)c1ccccc1 LHUBFUMPYZCAER-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003434 antitussive agent Substances 0.000 description 1
- 229940124584 antitussives Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- AELLFKPPLQHPRV-UHFFFAOYSA-N n-propan-2-yl-7-propan-2-yliminocyclohepta-1,3,5-trien-1-amine Chemical compound CC(C)NC1=CC=CC=CC1=NC(C)C AELLFKPPLQHPRV-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
La présente invention concerne un nouveau procédé de préparation de la lévo-dropropizine [S( — ) — 3—(4-phénylpipérazin-l-yl)propane-1,2-diol] et de la dextro-dropropizine [R(+)-3-(4-phénylpipéra-zin-l-yl)propane-1,2-diol] répondant respectivement aux formules suivantes:The present invention relates to a new process for the preparation of levo-dropropizine [S (-) - 3— (4-phenylpiperazin-l-yl) propane-1,2-diol] and dextro-dropropizine [R (+) -3- (4-phenylpipera-zin-1-yl) propane-1,2-diol] corresponding respectively to the following formulas:
(I) lévo-dropropizine(I) levo-dropropizine
( II) d extro-dropropizine r Les composés des formules (I) et (II) de même que leur mélange racémique sont connus et sont utiles comme agents antitussifs.(II) of extro-dropropizine r The compounds of formulas (I) and (II) as well as their racemic mixture are known and are useful as antitussive agents.
Suivant la demande de brevet européen ne 147.847, les composés des formules (I) et (II) peuvent être obtenus à partir de la dropropizine racémique par des procédés classiques de dédoublement optique ou bien peuvent être synthétisés au départ du (+)-l,2-isopropylidène-sn-glycérol qui est transformé en le tosylate correspondant qui est ensuite soumis à la décétalisation pour donner le 1-tosylate de (-)-glycérol, lequel est condensé avec la 1-phényl-pipérazine pour donner la forme lévo (I). La forme dextro (II), pour sa part, est obtenue à partir du 1-tosylate de (+ )-glycérol.According to European patent application no 147,847, the compounds of formulas (I) and (II) can be obtained from racemic dropropizine by conventional optical splitting processes or else can be synthesized from (+) - 1, 2-isopropylidene-sn-glycerol which is converted into the corresponding tosylate which is then subjected to decetalization to give the (-) - glycerol 1-tosylate, which is condensed with 1-phenyl-piperazine to give the levo form ( I). The dextro (II) form, for its part, is obtained from (+) -glycerol 1-tosylate.
Les rendements relativement faibles et la complexité des différents stades de la réaction font cependant que le procédé décrit ci-dessus n'est ni fort avantageux ni très économique et ne se prête donc guère à une application à l'échelle industrielle.The relatively low yields and the complexity of the various stages of the reaction, however, mean that the process described above is neither very advantageous nor very economical and therefore hardly suitable for application on an industrial scale.
Un autre procédé de préparation de la dro-propizine racémique est connu d'après le brevet anglais 938.646 et consiste à faire réagir la 1-phé-nylpipérazine avec le glycidol racémique. Toutefois, ce procédé donne la dropropizine racémique avec de mauvais rendements.Another process for the preparation of racemic dro-propizine is known from English Patent 938,646 and consists in reacting 1-phe-nylpiperazine with the racemic glycidol. However, this process gives the racemic dropropizine with poor yields.
La présente invention a dès lors pour but de procurer un procédé permettant d'obtenir de façon directe et plus simple les énantiomères distincts de la dropropizine des formules (I) et (II) par réaction sélective de la 1-phénylpipérazine avec le (R) -glycidol [(R)-2,3-époxy-l-propanol] ou avec le (S) -glycidol [(S)-2,3-époxy-l-propanol] conformément aux réactions suivantes:The object of the present invention is therefore to provide a process making it possible to obtain, directly and more simply, the distinct enantiomers of dropropizine of formulas (I) and (II) by selective reaction of 1-phenylpiperazine with (R) -glycidol [(R) -2,3-epoxy-l-propanol] or with (S) -glycidol [(S) -2,3-epoxy-l-propanol] in accordance with the following reactions:
(I) 1-phény]- (R)-glycidol pipérazine(I) 1-pheny] - (R) -glycidol piperazine
(S)-glycidol ( II) 1-phényl- pipérazine(S) -glycidol (II) 1-phenyl- piperazine
Les réactions sont habituellement exécutées en présence d'un solvant, comme l'eau, un alcool, le toluène ou leurs mélanges. Comme exemples d'alcools utilisés comme solvants, on peut citer l'éthanol, le méthanol ou, de préférence, 1'isopropanol.The reactions are usually carried out in the presence of a solvent, such as water, an alcohol, toluene or their mixtures. As examples of alcohols used as solvents, mention may be made of ethanol, methanol or, preferably, isopropanol.
Du point de vue pratique, les réactions sont exécutées de préférence en un stade par mélange des solutions des composés de départ l'une avec l'autre à la température d'ébullition du solvant choisi. Lorsque la réaction est achevée, le produit obtenu par refroidissement après filtration est cristallisé dans l'eau avec de très bons rendements ( 84 - ,87%). L'application du procédé et des conditions de réaction conformes à l'invention permet aussi.d'obtenir la forme racémique de la dropropizine avec de meilleurs rendements que ceux atteints dans le procédé suivant le brevet anglais précité.From a practical point of view, the reactions are preferably carried out in one stage by mixing the solutions of the starting compounds with one another at the boiling temperature of the chosen solvent. When the reaction is complete, the product obtained by cooling after filtration is crystallized from water with very good yields (84 -, 87%). The application of the process and reaction conditions in accordance with the invention also makes it possible to obtain the racemic form of dropropizine with better yields than those achieved in the process according to the abovementioned English patent.
Le nouveau procédé qui fait l'objet de la présente invention offre donc sur les procédés connus les avantages d'être exécuté sans difficulté, d'être spécifique et sélectif et de donner de meilleurs rendements.The new process which is the subject of the present invention therefore offers the known processes the advantages of being carried out without difficulty, of being specific and selective and of giving better yields.
Un autre aspect favorable du nouveau procédé est la cristallisation de la lévo-dropropizine et de la dextro-dropropizine dans l'eau qui donne des produits ayant un très bon degré de pureté, ce qui constitue un autre avantage du fait que ces composés sont utilisés dans le domaine pharmaceutique.Another favorable aspect of the new process is the crystallization of levo-dropropizine and dextro-dropropizine in water which gives products having a very good degree of purity, which is another advantage of the fact that these compounds are used in the pharmaceutical field.
La présente invention est illustrée plus en détail ci-après avec référence à des exemples non limitatifs.The present invention is illustrated in more detail below with reference to nonlimiting examples.
EXEMPLE. 1EXAMPLE. 1
Préparation de la lévo-dropropizine Ç S( — ) — 3—(4-Phénylpipérazin-l-yl)propane-1,2-diol]Preparation of levo-dropropizine Ç S (-) - 3— (4-Phenylpiperazin-l-yl) propane-1,2-diol]
On ajoute une solution de 81,1 g (0,5 mole) de 1-phénylpipérazine dans 100 ml.d1isopropanol à une solution de 37 g (0,5 mole) de (R)-glycidol dans 150 ml d1isopropanol en maintenant la température au-dessous de 30°C. Au terme de 1'addition, on chauffe la solution au reflux pendant 1 heure, puis on refroidit le mélange à 0°C et on le laisse reposer jusqu'au lendemain. On filtre le produit et on le cristallise dans 300 ml d'eau pour obtenir 102,1 g (86,4%) de S(-)-3-(4-phénylpipérazin-l-yl)propane—1,2-diol ayant un P.F. de 104-105° C, [a ]^5 = -11° (c = 3%, EtOH).A solution of 81.1 g (0.5 mole) of 1-phenylpiperazine in 100 ml of isopropanol is added to a solution of 37 g (0.5 mole) of (R) -glycidol in 150 ml of isopropanol while maintaining the temperature. below 30 ° C. At the end of the addition, the solution is heated to reflux for 1 hour, then the mixture is cooled to 0 ° C. and left to stand overnight. The product is filtered and crystallized from 300 ml of water to obtain 102.1 g (86.4%) of S (-) - 3- (4-phenylpiperazin-1-yl) propane-1,2-diol having a mp of 104-105 ° C, [a] ^ 5 = -11 ° (c = 3%, EtOH).
Analyse C13H20N2°2 ΛAnalysis C13H20N2 ° 2 Λ
Calculé Trouvé Z_ACalculated Found Z_A
C 66,07% C 66,04% - 0,03 H 8,53% H 8,58% + 0,05 N ^ 11,85% N 12,01% + 0,16 O 13,54% O 13,37% - 0,17C 66.07% C 66.04% - 0.03 H 8.53% H 8.58% + 0.05 N ^ 11.85% N 12.01% + 0.16 O 13.54% O 13 .37% - 0.17
En appliquant le même mode opératoire que dans l'exemple 1, mais au moyen de (S)-glycidol au lieu de (R)-glycidol, on obtient 101,4 g (85,9%) de dextro-dropropizine ayant un P.F. de 104-105°C et [ a]^5 = +11° (c = 3%, EtOH).By applying the same procedure as in Example 1, but using (S) -glycidol instead of (R) -glycidol, 101.4 g (85.9%) of dextro-dropropizine having a PF are obtained. 104-105 ° C and [a] ^ 5 = + 11 ° (c = 3%, EtOH).
EXEMPLE 2EXAMPLE 2
Préparation de la dropropizine racémique [(+)-3-(4-Phényl-pipérazin-l-yl)propane-1,2-diol]Preparation of racemic dropropizine [(+) - 3- (4-Phenyl-piperazin-1-yl) propane-1,2-diol]
On dissout 74 g (1 mole) de 2,3-époxy-l-propanol dans 300 ml d'isopropanol. On ajoute à cette solution une solution de 162,2 g (1 mole) de 1-phényl- pipérazine dans 200 ml d1isopropanol en laissant la température s'élever librement et en poursuivant le chauffage au reflux pendant 1 heure. On refroidit la solution de réaction ensuite à 0°C et on la laisse reposer jusqu'au lendemain. On recueille par filtration les cristaux blancs du produit obtenu et on les recristallise dans 600 ml d'eau. On obtient 200,4 g .(84,8%) du produit ayant un P.F. de 103-105°C.74 g (1 mole) of 2,3-epoxy-1-propanol are dissolved in 300 ml of isopropanol. To this solution is added a solution of 162.2 g (1 mol) of 1-phenylpiperazine in 200 ml of isopropanol, allowing the temperature to rise freely and continuing the heating at reflux for 1 hour. The reaction solution is then cooled to 0 ° C and allowed to stand overnight. The white crystals of the product obtained are collected by filtration and are recrystallized from 600 ml of water. 200.4 g (84.8%) of the product having a mp of 103-105 ° C. are obtained.
Analyse Cn,H„nN,0o 13 20 2 2 aAnalysis Cn, H „nN, 0o 13 20 2 2 a
Calculé Trouvé / \ C 66,07% C 66,02% - 0,05 H 8,53% H 8,62% + 0,09 N 11,85% N 11,98% + 0,13 O 13,54% O 13,38% - 0,16Calculated Found / \ C 66.07% C 66.02% - 0.05 H 8.53% H 8.62% + 0.09 N 11.85% N 11.98% + 0.13 O 13.54 % O 13.38% - 0.16
Claims (4)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT8821611A IT1226570B (en) | 1988-08-01 | 1988-08-01 | LEVO- AND RIGHT-DROPROPIZINE PREPARATION PROCEDURE |
| IT2161188 | 1988-08-01 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| LU87538A1 true LU87538A1 (en) | 1991-02-18 |
Family
ID=11184306
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| LU87538A LU87538A1 (en) | 1988-08-01 | 1989-06-14 | PROCESS FOR THE PREPARATION OF LEVO-DROPROPIZINE AND DEXTRO-DROPROPIZINE |
Country Status (5)
| Country | Link |
|---|---|
| ES (1) | ES2014187A6 (en) |
| FR (1) | FR2634765B1 (en) |
| IT (1) | IT1226570B (en) |
| LU (1) | LU87538A1 (en) |
| NL (1) | NL8901701A (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1231158B (en) * | 1989-07-20 | 1991-11-19 | Dompe Farmaceutici Spa | PROCEDURE FOR THE OPTICAL RESOLUTION OF DRUG. |
| IT1254452B (en) * | 1992-02-14 | 1995-09-25 | Dompe Farmaceutici Spa | N-OXIDES AND N, N'-DIOXIDES OF 3- (PIPERAZIN-1-IL) -PROPAN-1,2-DIOLS |
| IT1254993B (en) * | 1992-06-24 | 1995-10-11 | PROCEDURE FOR THE PREPARATION OF THE ENANTIOMERS OF DROPROPIZINE | |
| IT1318650B1 (en) | 2000-07-28 | 2003-08-27 | Dompe Spa | 1,3-DIOSSOLANS WITH ANTI-TOXIC ACTIVITY. |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB938646A (en) * | 1961-03-16 | 1963-10-02 | Henri Morren | New piperazine derivatives |
| IT1203721B (en) * | 1983-12-29 | 1989-02-23 | Dompe Farmaceutici Spa | OPTICALLY ACTIVE COMPOUNDS WITH ANTITOSSE AND CENTRAL SEDATIVE ACTIVITIES, PROCEDURE FOR PREPARATION AND COMPOSITIONS CONTAINING THEM |
| NL8801622A (en) * | 1988-06-25 | 1990-01-16 | Stamicarbon | PREPARATION OF ENANTIOMERS OF DROPROPIZINE. |
-
1988
- 1988-08-01 IT IT8821611A patent/IT1226570B/en active
-
1989
- 1989-05-18 FR FR8906484A patent/FR2634765B1/en not_active Expired - Lifetime
- 1989-06-14 LU LU87538A patent/LU87538A1/en unknown
- 1989-07-04 NL NL8901701A patent/NL8901701A/en not_active Application Discontinuation
- 1989-07-31 ES ES8902707A patent/ES2014187A6/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| IT8821611A0 (en) | 1988-08-01 |
| IT1226570B (en) | 1991-01-24 |
| FR2634765A1 (en) | 1990-02-02 |
| ES2014187A6 (en) | 1990-06-16 |
| FR2634765B1 (en) | 1994-05-27 |
| NL8901701A (en) | 1990-03-01 |
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| DT | Application date | ||
| TA | Annual fee |