CA1100135A - Method for the preparation of apovincamine from vincamine and epivincamine - Google Patents
Method for the preparation of apovincamine from vincamine and epivincamineInfo
- Publication number
- CA1100135A CA1100135A CA308,873A CA308873A CA1100135A CA 1100135 A CA1100135 A CA 1100135A CA 308873 A CA308873 A CA 308873A CA 1100135 A CA1100135 A CA 1100135A
- Authority
- CA
- Canada
- Prior art keywords
- vincamine
- apovincamine
- epivincamine
- preparation
- starting
- 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.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D461/00—Heterocyclic compounds containing indolo [3,2,1-d,e] pyrido [3,2,1,j] [1,5]-naphthyridine ring systems, e.g. vincamine
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Saccharide Compounds (AREA)
Abstract
ABSTRACT
A method is disclosed for the preparation of apovinca-mine, a substance being used in the pharmaceutical field as the active ingredient of drugs having cerebral vaso-dilating activity.
The method of the invention permits the apovincamine to be directly obtained from vincamine or epivincamine by reaction with a Lewis acid.
A method is disclosed for the preparation of apovinca-mine, a substance being used in the pharmaceutical field as the active ingredient of drugs having cerebral vaso-dilating activity.
The method of the invention permits the apovincamine to be directly obtained from vincamine or epivincamine by reaction with a Lewis acid.
Description
L3~
"A METHOD FOR THE PREPAR~TION OF APOVINCAMINE FRO~I VINCAMINE AND
E~I VANCAMINE"
The present invention relates to the preparation of the apovincamine, having the formula (I), starting from vincamine (formula IIa) and from the isomer t11ereof, epivincamine (formula IIb).
f~
1~ ~ rI 7 C1~30~C
~i~'`~ rIT 7 ~ ~J
IIa : R = _OH; R' = _COGCH3 (vincamine) IIb : R = -COOCEI3; R' = _OH (epivincamine) ~povincamine is an indole alkaloid, naturally present in the Tabernaemontano rlgida and in tlle Vinca erectaj which was firstly described by J Trojane~ et al., Tetrahedron Letters, 1961, 702.
The apovincamine and the derivatives thereof, as pre-pared by a partial synthesis methods, const.itute a class of substances of high interest from the point of view of the use in therapy as cerebral vasodilating agents. In the French A~plication No~ 2023918 of Gedeon Richter, the apovincamine is obtained through the treatm~nt of vincamine with concentrated 3Q H2SOg in C~i2C12.
In this case the action of the chlorinated solvent, together with the hi.ghly acidic medium, yive place to coloured 3~
solutions and promote the forming of by-products.
The same drawbacks occur when the rnethod disclosed in the French patent No. 2191894 of Synthelabo is u~ed, which provides the treatment of vincamine with concentrated formic acid at the boiling point and for extended time intervals.
Furthermore, like the two methods above referred to, J. Mokry (Chem. Zvesti, 16,140(1962)),describes a method for the conversion of vincamine into apovincamine by strong mineral acids and thereafter, (Tetrah Lett., 27,1917(1963)), discloses a method according to which a methanol solution of vincamine is reacted with gaseous HC1.
In the French patent Application No. 2,178,027 of Sandoz, a method of total syntllesis of vincamine is described and in the several Belgian patents Nos. 761628 and 763730, as well as in the German Patent No. 2,201,795, in the name of Omnium Chimique, methods are dislosed for the partial synthesis of vincamine starting from tabersonine.
In the latter case the apovincamine is considered a~
an undesired by-product and is moreover isolated with very low yields~
- In the French patent No. 2,211,004 in the name of Synthelabo, a method is described for the preparation of vincamine and stereoisomers thereof. According to the step 2 of this method, the apovincamine is obtained from apovincaldeyde through the oxidation with MnO2 of the corresponding cyanohydrin with a yield of 80~, whereas in the step 5 the apovincarnine is prepared from epivincamine by treatment with boiling concentrated for-mic acid, the yield being 80~
According to J. Trojanek, Tetrah. Letters, 20~ 702 (196i), apovincamine can be prepared by heating vincamine to 220C as well as by treating vincamine with boiling acetic anhydride.
. .
3~
Lastly in the Hungarian patent No. 151,295 in the name of Gedeon Richter, ~here are reported, amongst others, two exam~les for the preparation of the apovincamine by dehydration of vincamine, the first one witil POC13 (yield 42~) and the second with acetic anhydride in the presence of p-toluensulfonic acid (yield 30%).
Tlle method of the present invention provides a relevant tecnnical advance over the prior art, it permitting the conversion of vincamine and of epivincamine under operating conditions wlllc.l are extremely advantageous and selective as regards re-actants, solvents and temperatures, ana permitting the a~ovincamine to be obtained with very high yields and with h~gh purity degree.
In fact, it has been found that, by treating a solution of vincamine or epivincamine in an anhydrous organic solvent, such as methanol and benzene, with Lewis acids, preferably selected among SnC14, PBr3, sF3, at a temperature of between 20C and 80C, for a time varying betwePn 30 minutes and 4 hours, the molar ratio between vincamine or epivincamine and tne Lewis acid being of between 1:1 and 1:1,5, apovincamine is ob-tained with optimum yields and high purity.
Some examples are hereinafter reported to illustratethe method of the present invention, these examples of course having no lim~tating meaning of the invention.
Example 1 ~ ~ .
5 g of ~incamine are suspended in 500 mls of anhydrous ~enzene and heated under stirring to 60-70C until a clear solution is o~tained~ 5 mls of a 45% solution of ~oron tri-fluoride etherate are added and the heating under stirring is continued until the reaction is completed (about 1 hour).
The end of the reaction i5 indicated by the dis--appearance, as rnonitored by thin layer chromatography (TLC)~ of tlle spot pertainin~ to the vincamine and by the appearance of a ~ ~ 3 -35;
spot having higher Rf. (Adsorbant, Silicagel G F254-eluant:
CHC13/~IeOII=95/5)~
The reaction mixture is cooled, added with 100 mls of 10% NH40H; stirred for 10 minutes and then diluted with H20.
Tlle phases are separated and the organic phase is exhausted by several extractions wlth benzene; the com~ined benzene solutions are washed with water until neutral and dried over anhydrous Na2S04. After filtration and concentration under reduced pressure, the raw apovincamine is recrystallized from MeOH, the yield being 4.4 g (about 92%).
Fxample 2 ; The example 1 is repeated, except t'nat epivincamine is substituted for the vincamine. In this case the apovincamine is obtained with a yield of 78%.
Example 3 1 g of vincamine is solved in 300 mls of hot methanol under stirring. There are added 0.4 mls of PBr3 and the reaction is monitored by TLC. At the end of the reaction, the steps of the example 1 are repeated.
Example 4 The example 3 is repeated, except that epivincamine is substituted for the vincamine. The yield of the conversion to apovincamine is 65%.
Example 5 1 g of vincamine is solved in 300 mls of anhydrous hot benzene. 0.4 mls of PBr3 are added under stirring and the reaction mixture is kept under slight reflux until the reaction is completed. After kreatment of the reaction mixture according to the steps of the example 1, 0.85g of pure apovincamine are obtained (yield 90~3.
- Example 6 The same reaction of the example 5 i~ repeated with epivincamine, the yield of conversion to apovincamine being a~out 85%.
Example 7 1 g of vincamine is solved under stirring in 300 mls of hot anhydrous benzene. 0.5 g of SnC14 are added and the mixture is maintained under boiling until -the disappearance of the spot corresponding to the vincamine is assessed by ~rLc.
After treatment of the reaction mixture according to the example 1 and recrystallizat-ion of the raw product, 0.7~ g of pure apov,ncamine are obtained.
Example 8 The same reaction of Example 7 is repeated with epivincamine and there isobtained apovincamine with a yield of about 80
"A METHOD FOR THE PREPAR~TION OF APOVINCAMINE FRO~I VINCAMINE AND
E~I VANCAMINE"
The present invention relates to the preparation of the apovincamine, having the formula (I), starting from vincamine (formula IIa) and from the isomer t11ereof, epivincamine (formula IIb).
f~
1~ ~ rI 7 C1~30~C
~i~'`~ rIT 7 ~ ~J
IIa : R = _OH; R' = _COGCH3 (vincamine) IIb : R = -COOCEI3; R' = _OH (epivincamine) ~povincamine is an indole alkaloid, naturally present in the Tabernaemontano rlgida and in tlle Vinca erectaj which was firstly described by J Trojane~ et al., Tetrahedron Letters, 1961, 702.
The apovincamine and the derivatives thereof, as pre-pared by a partial synthesis methods, const.itute a class of substances of high interest from the point of view of the use in therapy as cerebral vasodilating agents. In the French A~plication No~ 2023918 of Gedeon Richter, the apovincamine is obtained through the treatm~nt of vincamine with concentrated 3Q H2SOg in C~i2C12.
In this case the action of the chlorinated solvent, together with the hi.ghly acidic medium, yive place to coloured 3~
solutions and promote the forming of by-products.
The same drawbacks occur when the rnethod disclosed in the French patent No. 2191894 of Synthelabo is u~ed, which provides the treatment of vincamine with concentrated formic acid at the boiling point and for extended time intervals.
Furthermore, like the two methods above referred to, J. Mokry (Chem. Zvesti, 16,140(1962)),describes a method for the conversion of vincamine into apovincamine by strong mineral acids and thereafter, (Tetrah Lett., 27,1917(1963)), discloses a method according to which a methanol solution of vincamine is reacted with gaseous HC1.
In the French patent Application No. 2,178,027 of Sandoz, a method of total syntllesis of vincamine is described and in the several Belgian patents Nos. 761628 and 763730, as well as in the German Patent No. 2,201,795, in the name of Omnium Chimique, methods are dislosed for the partial synthesis of vincamine starting from tabersonine.
In the latter case the apovincamine is considered a~
an undesired by-product and is moreover isolated with very low yields~
- In the French patent No. 2,211,004 in the name of Synthelabo, a method is described for the preparation of vincamine and stereoisomers thereof. According to the step 2 of this method, the apovincamine is obtained from apovincaldeyde through the oxidation with MnO2 of the corresponding cyanohydrin with a yield of 80~, whereas in the step 5 the apovincarnine is prepared from epivincamine by treatment with boiling concentrated for-mic acid, the yield being 80~
According to J. Trojanek, Tetrah. Letters, 20~ 702 (196i), apovincamine can be prepared by heating vincamine to 220C as well as by treating vincamine with boiling acetic anhydride.
. .
3~
Lastly in the Hungarian patent No. 151,295 in the name of Gedeon Richter, ~here are reported, amongst others, two exam~les for the preparation of the apovincamine by dehydration of vincamine, the first one witil POC13 (yield 42~) and the second with acetic anhydride in the presence of p-toluensulfonic acid (yield 30%).
Tlle method of the present invention provides a relevant tecnnical advance over the prior art, it permitting the conversion of vincamine and of epivincamine under operating conditions wlllc.l are extremely advantageous and selective as regards re-actants, solvents and temperatures, ana permitting the a~ovincamine to be obtained with very high yields and with h~gh purity degree.
In fact, it has been found that, by treating a solution of vincamine or epivincamine in an anhydrous organic solvent, such as methanol and benzene, with Lewis acids, preferably selected among SnC14, PBr3, sF3, at a temperature of between 20C and 80C, for a time varying betwePn 30 minutes and 4 hours, the molar ratio between vincamine or epivincamine and tne Lewis acid being of between 1:1 and 1:1,5, apovincamine is ob-tained with optimum yields and high purity.
Some examples are hereinafter reported to illustratethe method of the present invention, these examples of course having no lim~tating meaning of the invention.
Example 1 ~ ~ .
5 g of ~incamine are suspended in 500 mls of anhydrous ~enzene and heated under stirring to 60-70C until a clear solution is o~tained~ 5 mls of a 45% solution of ~oron tri-fluoride etherate are added and the heating under stirring is continued until the reaction is completed (about 1 hour).
The end of the reaction i5 indicated by the dis--appearance, as rnonitored by thin layer chromatography (TLC)~ of tlle spot pertainin~ to the vincamine and by the appearance of a ~ ~ 3 -35;
spot having higher Rf. (Adsorbant, Silicagel G F254-eluant:
CHC13/~IeOII=95/5)~
The reaction mixture is cooled, added with 100 mls of 10% NH40H; stirred for 10 minutes and then diluted with H20.
Tlle phases are separated and the organic phase is exhausted by several extractions wlth benzene; the com~ined benzene solutions are washed with water until neutral and dried over anhydrous Na2S04. After filtration and concentration under reduced pressure, the raw apovincamine is recrystallized from MeOH, the yield being 4.4 g (about 92%).
Fxample 2 ; The example 1 is repeated, except t'nat epivincamine is substituted for the vincamine. In this case the apovincamine is obtained with a yield of 78%.
Example 3 1 g of vincamine is solved in 300 mls of hot methanol under stirring. There are added 0.4 mls of PBr3 and the reaction is monitored by TLC. At the end of the reaction, the steps of the example 1 are repeated.
Example 4 The example 3 is repeated, except that epivincamine is substituted for the vincamine. The yield of the conversion to apovincamine is 65%.
Example 5 1 g of vincamine is solved in 300 mls of anhydrous hot benzene. 0.4 mls of PBr3 are added under stirring and the reaction mixture is kept under slight reflux until the reaction is completed. After kreatment of the reaction mixture according to the steps of the example 1, 0.85g of pure apovincamine are obtained (yield 90~3.
- Example 6 The same reaction of the example 5 i~ repeated with epivincamine, the yield of conversion to apovincamine being a~out 85%.
Example 7 1 g of vincamine is solved under stirring in 300 mls of hot anhydrous benzene. 0.5 g of SnC14 are added and the mixture is maintained under boiling until -the disappearance of the spot corresponding to the vincamine is assessed by ~rLc.
After treatment of the reaction mixture according to the example 1 and recrystallizat-ion of the raw product, 0.7~ g of pure apov,ncamine are obtained.
Example 8 The same reaction of Example 7 is repeated with epivincamine and there isobtained apovincamine with a yield of about 80
Claims (4)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A method for the preparation of apovincamine starting from vincamine from the isomer thereof, epivincamine, characterized in that the starting alkaloid is reacted, as a solution in an organic anhydrous solvent at the boiling temperature of the same solvent, in the presence of Lewis acids, the ratio between the starting alkaloid and the Lewis acid being of between 1 : 1 and 1:1.5 by mole.
2. A method according to claim 1, characterized in that anhydrous methanol and benzene are used as the solvent.
3. A method according to claim 1, characterized in that the reaction temperature is of between 65°C and 80°C.
4. A method according to claim 1, characterized in that the Lewis acids are selected among tin tetrachloride, phosphrus tribromide and boron trifluoride etherate.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH009824/77 | 1977-08-10 | ||
| CH982477A CH625242A5 (en) | 1977-08-10 | 1977-08-10 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1100135A true CA1100135A (en) | 1981-04-28 |
Family
ID=4356032
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA308,873A Expired CA1100135A (en) | 1977-08-10 | 1978-08-08 | Method for the preparation of apovincamine from vincamine and epivincamine |
Country Status (19)
| Country | Link |
|---|---|
| JP (1) | JPS5452100A (en) |
| AR (1) | AR216684A1 (en) |
| AT (1) | AT365590B (en) |
| AU (1) | AU3874378A (en) |
| BE (1) | BE869537A (en) |
| CA (1) | CA1100135A (en) |
| CH (1) | CH625242A5 (en) |
| DE (1) | DE2833967A1 (en) |
| DK (1) | DK351478A (en) |
| ES (1) | ES472469A1 (en) |
| FI (1) | FI782447A (en) |
| FR (1) | FR2400023A1 (en) |
| GB (1) | GB2003860B (en) |
| HU (1) | HU176218B (en) |
| IT (1) | IT1200363B (en) |
| NL (1) | NL7808302A (en) |
| OA (1) | OA06023A (en) |
| SE (1) | SE7808521L (en) |
| ZA (1) | ZA784536B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU532001B2 (en) * | 1978-11-20 | 1983-09-15 | Sumitomo Chemical Company, Limited | Polycyclic indole derivatives |
| FR2468605A1 (en) * | 1979-10-30 | 1981-05-08 | Richter Gedeon Vegyeszet | Prepn. of apovincaminic acid ester(s) - by azeotropic dehydration of vincamic or epi-vincaminic acid ester(s); useful at hypotensives and vasodilators |
| DE2944036C2 (en) * | 1979-10-31 | 1986-11-06 | Richter Gedeon Vegyészeti Gyár R.T., Budapest | Process for the preparation of apovincaminic acid esters |
-
1977
- 1977-08-10 CH CH982477A patent/CH625242A5/it not_active IP Right Cessation
-
1978
- 1978-08-02 IT IT26420/78A patent/IT1200363B/en active
- 1978-08-03 DE DE19782833967 patent/DE2833967A1/en not_active Withdrawn
- 1978-08-04 BE BE189715A patent/BE869537A/en unknown
- 1978-08-07 AT AT0571278A patent/AT365590B/en not_active IP Right Cessation
- 1978-08-08 AU AU38743/78A patent/AU3874378A/en active Pending
- 1978-08-08 NL NL787808302A patent/NL7808302A/en not_active Application Discontinuation
- 1978-08-08 CA CA308,873A patent/CA1100135A/en not_active Expired
- 1978-08-09 SE SE7808521A patent/SE7808521L/en unknown
- 1978-08-09 GB GB7832887A patent/GB2003860B/en not_active Expired
- 1978-08-09 HU HU78CO355A patent/HU176218B/en unknown
- 1978-08-09 DK DK351478A patent/DK351478A/en not_active Application Discontinuation
- 1978-08-09 FR FR7823463A patent/FR2400023A1/en active Granted
- 1978-08-10 OA OA56577A patent/OA06023A/en unknown
- 1978-08-10 ZA ZA00784536A patent/ZA784536B/en unknown
- 1978-08-10 AR AR273263A patent/AR216684A1/en active
- 1978-08-10 JP JP9676978A patent/JPS5452100A/en active Pending
- 1978-08-10 ES ES472469A patent/ES472469A1/en not_active Expired
- 1978-08-10 FI FI782447A patent/FI782447A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| FR2400023A1 (en) | 1979-03-09 |
| NL7808302A (en) | 1979-02-13 |
| OA06023A (en) | 1981-06-30 |
| HU176218B (en) | 1981-01-28 |
| GB2003860A (en) | 1979-03-21 |
| IT1200363B (en) | 1989-01-18 |
| FR2400023B1 (en) | 1982-07-30 |
| AU3874378A (en) | 1980-02-14 |
| IT7826420A0 (en) | 1978-08-02 |
| JPS5452100A (en) | 1979-04-24 |
| ES472469A1 (en) | 1979-03-16 |
| AR216684A1 (en) | 1980-01-15 |
| BE869537A (en) | 1978-12-01 |
| FI782447A (en) | 1979-02-11 |
| SE7808521L (en) | 1979-02-11 |
| GB2003860B (en) | 1982-03-03 |
| ATA571278A (en) | 1981-06-15 |
| ZA784536B (en) | 1979-08-29 |
| DE2833967A1 (en) | 1979-03-01 |
| AT365590B (en) | 1982-01-25 |
| DK351478A (en) | 1979-02-11 |
| CH625242A5 (en) | 1981-09-15 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |