CN102807562A - Method for preparing rupatadine and salt thereof - Google Patents
Method for preparing rupatadine and salt thereof Download PDFInfo
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- CN102807562A CN102807562A CN2012102702137A CN201210270213A CN102807562A CN 102807562 A CN102807562 A CN 102807562A CN 2012102702137 A CN2012102702137 A CN 2012102702137A CN 201210270213 A CN201210270213 A CN 201210270213A CN 102807562 A CN102807562 A CN 102807562A
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Abstract
The invention relates to the technical field of medicine, in particular to a method for preparing rupatadine and salt thereof, and particularly discloses a method for preparing the rupatadine. The method includes steps of subjecting phosphorus oxychloride and (4-(8-chlorine-5H-benzo-(5, 6) suberyl (1, 2-b) pyridine-11 (6H)-alkenyl) piperidine-1-alkyl) (5-methylpyridine-3-alkyl) ketone shown as the structural formula I to reaction, reducing (4-(8-chlorine-5H-benzo-(5, 6) suberyl (1, 2-b) pyridine-11 (6H)-alkenyl) piperidine-1-alkyl) (5-methylpyridine-3-alkyl) ketone shown as the structural formula I in alcohol solvent by zinc powder, and obtaining rupatadine. The invention further discloses a method for preparing rupatadine salt. The method for preparing rupatadine salt includes dissolving the obtained rupatadine in ethyl acetate, and then subjecting the ethyl acetate in acid dissolved in absolute ethyl alcohol to reaction to obtain the rupatadine salt. The methods are convenient to operate and low in cost of reagent used.
Description
Technical field
The present invention relates to medical technical field, the preparation method of particularly a kind of Rupatadine and salt thereof.
Background technology
Rupatadine and salt thereof have the dual function of antihistamine and antagonism platelet activation factor (PAF), and this medicine is applied to treatment of allergic rhinitis and spring fever in the listing in Europe in 2003, has vast market prospect.The Rupatadine chemical structural formula is following:
(formula II)
The preparation method of Rupatadine mainly contains two kinds, and the first is with decarboxylation loratadine and 3, and the 5-lutidine is a raw material, and earlier with 3, the 5-lutidine generates 3-methyl-5-bromo methyl cycloheptapyridine, then with decarboxylation loratadine prepared in reaction Rupatadine through bromo.Synthetic route is following:
It two is to be raw material with the decarboxylation loratadine, generates acid amides with the condensation reaction of 5-methylnicotinic acid, through reduction reaction, is amine with reduction of amide then, makes Rupatadine.Synthetic route is following:
In above-mentioned two kinds of methods, method one yield is low, and reaction is difficult to control, and is difficult to make purer product.
The crucial synthesis step of method two is the reduction of acid amides, and in disclosed bibliographical information, the method for preparing the Rupatadine reducing amide has following several kinds:
In patent ES2087818, reported that acid amides uses POCl earlier
3Handle, use NaBH then
4Reduce as reductive agent.But this method operational condition is harsh, POCl
3Corrodibility is strong, and particularly still-process is higher to equipment requirements.
In U.S. Pat 5407941, introduced in tetrahydrofuran solution,, have relatively high expectations as reductive agent reductive method with lithium aluminum hydride, and the reagent lithium aluminum hydride has been relatively more expensive but lithium aluminum hydride reduces same operational condition as reductive agent.
In the method that one Chinese patent application 200510070952.1 is introduced, prepare Rupatadine with two hydrogen sodium aluminates (Red-Al) for the raw material reducing amide, this method exists long reaction time, the expensive defective of the two hydrogen sodium aluminates of reagent.
In the method that one Chinese patent application 200810005209.1 is introduced, use trifluoroacetic acid and sodium borohydride reduction acid amides to prepare Rupatadine, this method is used trifluoroacetic acid and Peng Qinghuana, and reagent consumption is big, and reagent is relatively more expensive, and production cost is higher.
Summary of the invention
The object of the present invention is to provide the preparation method of a kind of Rupatadine and salt thereof, said method has solved the high problem of prior art production cost, and this method is simple to operate.
In first aspect of the present invention, a kind of preparation method of Rupatadine is provided, described method may further comprise the steps:
(1), structure is reacted suc as formula (4-(8-chloro-5H-benzo [5,6] suberyl [1,2-b] pyridine-11 (6H)-thiazolinyl) piperidines-1-alkyl) (5-picoline-3-alkyl) ketone and the POCl3 one shown in the I;
(formula I)
(2), after the reaction of said step (1) finishes, excessive POCl3 reduction vaporization is removed;
(3), the reactant of said step (2) is dissolved in the absolute alcohol, add zinc powder, the reflux reduction reaction makes Rupatadine;
Reaction formula of the present invention is:
In second aspect of the present invention; A kind of preparation method of Rupatadine salt is provided; Described method may further comprise the steps: described preparation method makes Rupatadine by first aspect present invention; The Rupatadine that makes is dissolved in the ETHYLE ACETATE, and then be dissolved in acid in the absolute ethyl alcohol and react and make Rupatadine salt.
Wherein, in the said step (1), said POCl3 and said (4-(8-chloro-5H-benzo [5; 6] suberyl [1; 2-b] pyridine-11 (6H)-thiazolinyl) piperidines-1-alkyl) mol ratio of (5-picoline-3-alkyl) ketone is 1:1～10:1, preferably, said POCl3 and said (4-(8-chloro-5H-benzo [5; 6] piperidines-1-alkyl suberyl [1,2-b] pyridine-11 (6H)-thiazolinyl)) mol ratio of (5-picoline-3-alkyl) ketone is 1.2:1～5:1.
Wherein, in the said step (1), temperature of reaction is 25 ℃～60 ℃, and the reaction times is 1～10 hour; Preferably, said temperature of reaction is 40 ℃～50 ℃, and the reaction times is 2～5 hours, after reaction finishes, removes excessive POCl3 with the method evaporation of conventional reduction vaporization.
Wherein, In the said step (3); The weight ratio of said absolute alcohol and said (4-(8-chloro-5H-benzo [5,6] suberyl [1,2-b] pyridine-11 (6H)-thiazolinyl) piperidines-1-alkyl) (5-picoline-3-alkyl) ketone is 5:1～30:1; Said zinc powder and said (4-(8-chloro-5H-benzo [5; 6] piperidines-1-alkyl suberyl [1,2-b] pyridine-11 (6H)-thiazolinyl)) mol ratio of (5-picoline-3-alkyl) ketone is 1:1～5:1, and said reduction reaction temperature is 40 ℃ of boiling points to alcohol; Preferably; The weight ratio of said absolute alcohol and said (4-(8-chloro-5H-benzo [5,6] suberyl [1,2-b] pyridine-11 (6H)-thiazolinyl) piperidines-1-alkyl) (5-picoline-3-alkyl) ketone is 8:1～20:1; Said zinc powder and said (4-(8-chloro-5H-benzo [5; 6] piperidines-1-alkyl suberyl [1,2-b] pyridine-11 (6H)-thiazolinyl)) mol ratio of (5-picoline-3-alkyl) ketone is 1.5:1～3:1, and said reduction reaction temperature is the boiling point of alcohol.The time of reduction reaction transforms to finish through structural formula I (4-(8-chloro-5H-benzo [5,6] suberyl [1,2-b] pyridine-11 (6H)-thiazolinyl) piperidines-1-alkyl) (5-picoline-3-alkyl) ketone in the thin-layer chromatographic analysis reaction solution and controls.Reaction removes by filter insoluble solid after accomplishing, and reduction vaporization is removed alcoholic solvent, obtains Rupatadine.
Wherein, in the said step (3), said absolute alcohol is meant anhydrous methanol, absolute ethyl alcohol, anhydrous propyl alcohol or anhydrous isopropyl alcohol.
In the method for second aspect present invention, described acid is selected from a kind of in fumaric acid, the hydrogenchloride.
Beneficial effect of the present invention is: first aspect of the present invention; With POCl3 and structure suc as formula (4-(8-chloro-5H-benzo [5 shown in the I; 6] suberyl [1; 2-b] pyridine-11 (6H)-thiazolinyl) piperidines-1-alkyl) (5-picoline-3-alkyl) ketone reacts, then in alcoholic solvent with zinc powder to structure suc as formula (4-(8-chloro-5H-benzo [5,6] suberyl [1 shown in the I; 2-b] pyridine-11 (6H)-thiazolinyl) piperidines-1-alkyl) (5-picoline-3-alkyl) ketone carries out reduction reaction, obtains Rupatadine; Second aspect of the present invention is dissolved in the Rupatadine that makes in the ETHYLE ACETATE, and then be dissolved in acid in the absolute ethyl alcohol and react and make Rupatadine salt; Above-mentioned method is easy and simple to handle, use reagent is cheap, cost is low.
Embodiment
Through embodiment the present invention is done further elaboration below:
Embodiment one:
(4-(8-chloro-5H-benzo [5,6] suberyl [1,2-b] pyridine-11 (6H)-thiazolinyl) piperidines-1-alkyl) (5-picoline-3-alkyl) ketone that in the 250ml single necked round bottom flask, adds 8.60g (0.02 mole); Add 3.07g (0.02 mole) POCl3 again, 50 ℃ of heating in water bath 2 hours, reduction vaporization 1 hour under-0.09MPa then; Obtain the compound of finishing dealing with, in the compound that this is finished dealing with, add anhydrous methanol 86.9ml, stirring and dissolving through POCl3; Add zinc powder 1.31g (0.02 mole); 40 ℃ of reflux are to (4-(8-chloro-5H-benzo [5,6] suberyl [1; 2-b] pyridine-11 (6H)-thiazolinyl) piperidines-1-alkyl) (5-picoline-3-alkyl) ketone carries out thin-layer chromatographic analysis; Treat to stop heating after the conversion of (4-(8-chloro-5H-benzo [5,6] suberyl [1,2-b] pyridine-11 (6H)-thiazolinyl) piperidines-1-alkyl) (5-picoline-3-alkyl) ketone finishes.
With above-mentioned reacted material filtering, filtrating is evaporated to absence of liq and flows out under-0.09MPa, 50 ℃, add 80ml ETHYLE ACETATE, stirs; Be heated to 60 ℃ of dissolvings, slowly cool to room temperature then, continue to stir 10 hours; Filter, filter cake obtains off-white color crystalline powder 6.54g 40 ℃ of drying under reduced pressure 5 hours; HPLC purity 99.3%, fusing point 128.0-130.5 ℃, yield 78.6%.
Embodiment two:
(4-(8-chloro-5H-benzo [5,6] suberyl [1,2-b] pyridine-11 (6H)-thiazolinyl) piperidines-1-alkyl) (5-picoline-3-alkyl) ketone that in the 250ml single necked round bottom flask, adds 8.60g (0.02 mole); Add 3.68g (0.024 mole) POCl3 again, 40 ℃ of heating in water bath 5 hours, reduction vaporization 1 hour under-0.09MPa then; Obtain the compound of finishing dealing with, in the compound that this is finished dealing with, add absolute ethyl alcohol 217.3ml, stirring and dissolving through POCl3; Add zinc powder 1.97g (0.03 mole), be heated to absolute ethyl alcohol, reflux; To (4-(8-chloro-5H-benzo [5; 6] piperidines-1-alkyl suberyl [1,2-b] pyridine-11 (6H)-thiazolinyl)) (5-picoline-3-alkyl) ketone carries out thin-layer chromatographic analysis, treats (4-(8-chloro-5H-benzo [5; 6] piperidines-1-alkyl suberyl [1,2-b] pyridine-11 (6H)-thiazolinyl)) (5-picoline-3-alkyl) ketone stops heating after transforming and finishing.
With above-mentioned reacted material filtering, filtrating is evaporated to absence of liq and flows out under-0.09MPa, 50 ℃, add 80ml ETHYLE ACETATE, stirs; Be heated to 60 ℃ of dissolvings, slowly cool to room temperature then, continue to stir 10 hours; Filter, filter cake obtains off-white color crystalline powder 6.62g 40 ℃ of drying under reduced pressure 5 hours; HPLC purity 99.5%, fusing point 125.0-128.5 ℃, yield 79.6%.
Embodiment three:
(4-(8-chloro-5H-benzo [5,6] suberyl [1,2-b] pyridine-11 (6H)-thiazolinyl) piperidines-1-alkyl) (5-picoline-3-alkyl) ketone that in the 250ml single necked round bottom flask, adds 8.60g (0.02 mole); Add 15.3g (0.1 mole) POCl3 again, 60 ℃ of heating in water bath 1 hour, reduction vaporization 1 hour under-0.09MPa then; Obtain the compound of finishing dealing with, in the compound that this is finished dealing with, add anhydrous propyl alcohol 54.8ml, stirring and dissolving through POCl3; Add zinc powder 3.93g (0.06 mole); 50 ℃ of reflux are to (4-(8-chloro-5H-benzo [5,6] suberyl [1; 2-b] pyridine-11 (6H)-thiazolinyl) piperidines-1-alkyl) (5-picoline-3-alkyl) ketone carries out thin-layer chromatographic analysis; Treat to stop heating after the conversion of (4-(8-chloro-5H-benzo [5,6] suberyl [1,2-b] pyridine-11 (6H)-thiazolinyl) piperidines-1-alkyl) (5-picoline-3-alkyl) ketone finishes.
With above-mentioned reacted material filtering, filtrating is evaporated to absence of liq and flows out under-0.09MPa, 50 ℃, add 90ml ETHYLE ACETATE, stirs; Be heated to 60 ℃ of dissolvings, slowly cool to room temperature then, continue to stir 10 hours; Filter, filter cake obtains off-white color crystalline powder 6.48g 40 ℃ of drying under reduced pressure 5 hours; HPLC purity 99.2%, fusing point 129.0-131.5 ℃, yield 77.9%.
Embodiment four:
(4-(8-chloro-5H-benzo [5,6] suberyl [1,2-b] pyridine-11 (6H)-thiazolinyl) piperidines-1-alkyl) (5-picoline-3-alkyl) ketone that in the 250ml single necked round bottom flask, adds 4.30g (0.01 mole); Add 15.3g (0.1 mole) POCl3 again, 25 ℃ of heating in water bath 10 hours, reduction vaporization 0.8 hour under-0.09MPa then; Obtain the compound of finishing dealing with, in the compound that this is finished dealing with, add anhydrous isopropyl alcohol 164.3ml, stirring and dissolving through POCl3; Add zinc powder 3.25g (0.05 mole), be heated to the boiling point of anhydrous isopropyl alcohol, reflux; To (4-(8-chloro-5H-benzo [5; 6] piperidines-1-alkyl suberyl [1,2-b] pyridine-11 (6H)-thiazolinyl)) (5-picoline-3-alkyl) ketone carries out thin-layer chromatographic analysis, treats (4-(8-chloro-5H-benzo [5; 6] piperidines-1-alkyl suberyl [1,2-b] pyridine-11 (6H)-thiazolinyl)) (5-picoline-3-alkyl) ketone stops heating after transforming and finishing.
With above-mentioned reacted material filtering, filtrating is evaporated to absence of liq and flows out under-0.09MPa, 50 ℃, add 50ml ETHYLE ACETATE, stirs; Be heated to 60 ℃ of dissolvings, slowly cool to room temperature then, continue to stir 8 hours; Filter, filter cake obtains off-white color crystalline powder 3.33g 40 ℃ of drying under reduced pressure 5 hours; HPLC purity 99.4%, fusing point 127.0-128.5 ℃, yield 80.0%.
Embodiment 6
With the material filtering of embodiment 2, filtrating is evaporated to absence of liq and flows out under-0.09MPa, 50 ℃, add 40ml ETHYLE ACETATE, stirs; Be heated to 60 ℃ of dissolvings, adding is dissolved in 2.32g (0.02 mole) fumaric acid in the 40ml absolute ethyl alcohol then, slowly cools to room temperature, continues to stir 5 hours; Filter, filter cake obtains Rupatadine fumarate 9.08g at 40 ℃ of following drying under reduced pressure; HPLC purity 99.4%, fusing point 195.0-197.8 ℃, yield 85.3%.Rupatadine also can with other acid-respons, generate corresponding salt, as making the Rupatadine tri hydrochloride with hcl reaction.
The above embodiment; It is preferred embodiments of the present invention; Be not to limit practical range of the present invention,, all should be included in the patent claim of the present invention so all equivalences of doing according to the described structure of claim of the present invention, characteristic and principle change or modify.
Claims (10)
1. the preparation method of a Rupatadine, it is characterized in that: described method may further comprise the steps:
(1), structure is reacted suc as formula (4-(8-chloro-5H-benzo [5,6] suberyl [1,2-b] pyridine-11 (6H)-thiazolinyl) piperidines-1-alkyl) (5-picoline-3-alkyl) ketone and the POCl3 one shown in the I;
(formula I) (formula II)
(2), after the reaction of said step (1) finishes, excessive POCl3 reduction vaporization is removed;
(3), the reactant of said step (2) is dissolved in the absolute alcohol, add zinc powder, the reflux reduction reaction makes structure suc as formula the Rupatadine shown in the II.
2. the preparation method of a Rupatadine salt; It is characterized in that: described preparation method makes Rupatadine by claim 1; Described Rupatadine is dissolved in the ETHYLE ACETATE, and then be dissolved in acid in the absolute ethyl alcohol and react and make Rupatadine salt.
3. the preparation method described in claim 1 or 2; It is characterized in that: said POCl3 and said (4-(8-chloro-5H-benzo [5; 6] piperidines-1-alkyl suberyl [1,2-b] pyridine-11 (6H)-thiazolinyl)) mol ratio of (5-picoline-3-alkyl) ketone is 1:1～10:1.
4. the preparation method described in claim 1 or 2, it is characterized in that: in the said step (1), temperature of reaction is 25 ℃～60 ℃, and the reaction times is 1～10 hour.
5. the preparation method described in claim 1 or 2; It is characterized in that: in the said step (3); The weight ratio of said absolute alcohol and said (4-(8-chloro-5H-benzo [5,6] suberyl [1,2-b] pyridine-11 (6H)-thiazolinyl) piperidines-1-alkyl) (5-picoline-3-alkyl) ketone is 5:1～30:1; Said zinc powder and said (4-(8-chloro-5H-benzo [5; 6] piperidines-1-alkyl suberyl [1,2-b] pyridine-11 (6H)-thiazolinyl)) mol ratio of (5-picoline-3-alkyl) ketone is 1:1～5:1, and said reduction reaction temperature is 40 ℃ of boiling points to absolute alcohol.
6. the preparation method described in claim 1 or 2, it is characterized in that: in the said step (3), said absolute alcohol is meant anhydrous methanol, absolute ethyl alcohol, anhydrous propyl alcohol or anhydrous isopropyl alcohol.
7. the preparation method described in claim 3; It is characterized in that: said POCl3 and said (4-(8-chloro-5H-benzo [5; 6] piperidines-1-alkyl suberyl [1,2-b] pyridine-11 (6H)-thiazolinyl)) mol ratio of (5-picoline-3-alkyl) ketone is 1.2:1～5:1.
8. the preparation method described in claim 4, it is characterized in that: said temperature of reaction is 40 ℃～50 ℃, and the said reaction times is 2～5 hours.
9. the preparation method described in claim 5; It is characterized in that: said absolute alcohol and said (4-(8-chloro-5H-benzo [5; 6] suberyl [1; 2-b] pyridine-11 (6H)-thiazolinyl) piperidines-1-alkyl) weight ratio of (5-picoline-3-alkyl) ketone is 8:1～20:1, said zinc powder and said (4-(8-chloro-5H-benzo [5,6] suberyl [1; 2-b] pyridine-11 (6H)-thiazolinyl) piperidines-1-alkyl) mol ratio of (5-picoline-3-alkyl) ketone is 1.5:1～3:1, said reduction reaction temperature is the boiling point of absolute alcohol.
10. preparation method as claimed in claim 2 is characterized in that: described acid is selected from a kind of in fumaric acid, the hydrogenchloride.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105130956A (en) * | 2015-07-23 | 2015-12-09 | 上海新亚药业有限公司 | Preparation method of rupatadine fumarate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2087818A1 (en) * | 1993-11-24 | 1996-07-16 | Uriach & Cia Sa J | 8-chloro-11-[1-[(5-methyl-3-pyridyl)-methyl]-4- piperidylidene]-6,11-dihydro-5H-benzo-[5,6]-cycloheptal-[1,2- b]-pyridine fumarate |
| CN101531654A (en) * | 2009-04-13 | 2009-09-16 | 浙江赐富医药有限公司 | Preparation method for Rupatadine |
-
2012
- 2012-07-31 CN CN2012102702137A patent/CN102807562A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2087818A1 (en) * | 1993-11-24 | 1996-07-16 | Uriach & Cia Sa J | 8-chloro-11-[1-[(5-methyl-3-pyridyl)-methyl]-4- piperidylidene]-6,11-dihydro-5H-benzo-[5,6]-cycloheptal-[1,2- b]-pyridine fumarate |
| CN101531654A (en) * | 2009-04-13 | 2009-09-16 | 浙江赐富医药有限公司 | Preparation method for Rupatadine |
Non-Patent Citations (2)
| Title |
|---|
| 唐国正等: "N,N-二异丙基-3-(2-甲氧基-5-甲基苯基)-苯丙酰胺的还原", 《华东理工大学学报》 * |
| 陈建华等: "富马酸卢帕他定的合成", 《中国医药工业杂志》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105130956A (en) * | 2015-07-23 | 2015-12-09 | 上海新亚药业有限公司 | Preparation method of rupatadine fumarate |
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Application publication date: 20121205 |