CN1045295C - Process for the preparation of 14,15-dihydro-14-hydroxy-(3,16)-eburnamenine-14-carboxylic acid - Google Patents
Process for the preparation of 14,15-dihydro-14-hydroxy-(3,16)-eburnamenine-14-carboxylic acid Download PDFInfo
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- CN1045295C CN1045295C CN95104860A CN95104860A CN1045295C CN 1045295 C CN1045295 C CN 1045295C CN 95104860 A CN95104860 A CN 95104860A CN 95104860 A CN95104860 A CN 95104860A CN 1045295 C CN1045295 C CN 1045295C
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- eburnamenine
- dihydro
- hydroxy
- beta
- carboxylic acid
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Abstract
Process for the preparation of 14,15-dihydro-14[beta] hydroxy-(3[alpha], 16[alpha] )-eburnamenine-14-carboxylic acid Comprises reacting 14,15-dihydro-14[beta]-hydroxy- (3[alpha], 16[alpha])-eburnamenine-14-methanol II with nickel peroxide in basic aqueous or methanolic medium at the boiling point of the solvent to produce 14,15-dihydro- 14[beta]-hydroxy-3[alpha],16[alpha])-eburnamenine-14- carboxylic acid I. Compound I has applications on account of its vasodilatory and cerebral oxygenating properties. It is also a useful intermediate in the synthesis of another important cerebral oxygenator, vinpocetin.
Description
The present invention relates to 14,15-dihydro-14 beta-hydroxy-(3 α, 16 α) preparation method of eburnamenine-14-carboxylic acid, this compound is very important product, this product especially have by its deutero-ester as in the Vincaminic acid ethyl ester (ethyl vincaminate) of the characteristic of vasodilator and brain oxygenation agent (cerebral oxy-genators) and Apovincaminic Acid Ethyl Ester (ethyl apovincaminate) semi-synthetic as intermediate.
14,15-dihydro-14 beta-hydroxy-(3 α, 16 α) eburnamenine-14-carboxylic acid (1) is known synthetic alkaloid intermediate (Drug Res.26,10a (1976) by its deutero-ester; PAT.BE 777.601; Pat.FR 2.191.890; Pat.ES 538.989; Pat.DE 3.236.144.).The advantage of the method that proposes is to be used as that other alkaloidal chemical conversion product of ivory alkane (eburnane) series obtains 14,15-dihydro-14 beta-hydroxy-(3 α, 16 α) eburnamenine-14-methyl alcohol (II) is as the initiator of synthetic compound (I), and make-(I) that dawn obtains can be converted to its known ester, just can obtain having vasodilator and the active compound of brain oxygenation agent.It is said that this method economy, productive rate are good and simple and easy to do.
The purpose of the inventive method is with good yield and simple and easy to do method preparation formula (I) 14,15-dihydro-14 beta-hydroxy-(3 α, 16 α) eburnamenine-14-carboxylic acid:
Formula (I) acid is really by the very important intermediate product in its deutero-ester semi-synthetic.The characteristics of these esters are its pharmacological property as vasodilator and brain oxygenation agent.For example, the serial chemical conversion of the ester that can produce a series of known activity that carries out of available formula (I) acid is as follows:
The method that this specification sheets is described comprises the derivative 14 with the eburnamenine skeleton, 15-dihydro-14 beta-hydroxy-(3 α, 16 α) eburnamenine-14-methyl alcohol (II) (being commonly referred to vincamine alcohol (vincaminol)) carries out catalytic oxidation with gentle condition and simple device with nickel peroxide, changes into acid (I) with good yield:
Compound (II) derives from the product (Pat.ES537,355) of some conversion process of ivory alkane really.
This method comprises that the not too known method for oxidation of employing for example uses the method (10C of nickel peroxide oxidizing alcohol, 27,597 (1962)), make 14,15-dihydro-14 beta-hydroxy-(3 α, 16 α) eburnamenine-14-methyl alcohol (II) reacted about 6 hours in the boiling point of water or methyl alcohol with the nickel peroxide of preparation recently under vigorous stirring in alkaline medium, form with its sodium salt obtains formula (I) 14,15-dihydro-14 beta-hydroxy-(3 α, 16 α) eburnamenine-14-carboxylic acid, by with inorganic aqueous acid precipitation, obtain free form.The yield of this method is greater than 70%.
Can understand the inventive method better by following non-restrictive example.The preparation of embodiment 1 nickel peroxide
The chlorine bleach liquor of preparation 300ml 6% to wherein adding 42g sodium hydroxide, adds at leisure by the 130g hydration nickel sulfate then and is dissolved in the solution that forms in the 300ml water.The mixture that forms was stirred 30 minutes in 20 ℃, obtain the nickel peroxide precipitation of black, it is filtered, wash to remove residual chlorine remnants with massive laundering.The solid that obtains is used the calcium chloride drying in vacuum drying oven.Embodiment 2 formulas (I) 14, the preparation of 15-dihydro-14 beta-hydroxy-(3 α, 16 α) eburnamenine-14-carboxylic acid
With 50g 14,15-dihydro-14 beta-hydroxy-(3 α, 16 α) eburnamenine-14-methyl alcohol is suspended in the 100ml 1M sodium hydroxide solution.With this solution vigorous stirring and at leisure to wherein adding the 150g nickel peroxide that makes recently according to embodiment 1 under room temperature.In case all superoxide are added, the boiling point of this solution in water were kept 6 hours.Then it is put and be chilled to room temperature, and filter with the thin pad of diatomite (celite prelayer).The solid that obtains is washed with water, be negative until the Mayer of mother liquor reaction.With filtrate with sulphuric acid soln (10%, W: V) be acidified to pH=6.5, be settled out 14,15-dihydro-14 beta-hydroxy-(3 α, 16 α) eburnamenine-14-carboxylic acid.With the product drying, obtain the 35g product (yield: 70%), its physico-chemical property and 14, the conforming to of 15-dihydro-14 beta-hydroxy-(3 α, 16 α) eburnamenine-14-carboxylic acid.Embodiment 3 formulas (I) 14, the preparation of 15-dihydro-14 beta-hydroxy-(3 α, 16 α) eburnamenine-14-carboxylic acid
With 50g 14,15-dihydro-14 beta-hydroxy-(3 α, 16 α) eburnamenine-14-methyl alcohol is suspended in the methanol solution of 100ml 2.5g sodium hydroxide.With this suspension vigorous stirring and at leisure to wherein adding the 150g nickel peroxide that makes recently according to embodiment 1 under room temperature.In case all superoxide are added, the boiling point of this solution in methyl alcohol were kept 6 hours.Then it is put and be chilled to room temperature, and filter with the thin pad of diatomite.The solid that obtains is washed with water, be negative until the Mayer of mother liquor reaction.Filtrate is hydrolyzed with 100ml water, and the usefulness sulphuric acid soln (10%, W: V) be acidified to pH=6.5, be settled out 14,15-dihydro-14 beta-hydroxy-(3 α, 16 α) eburnamenine-14-carboxylic acid.With the product drying, obtain the 40g product (yield: 80%), its physico-chemical property and 14, the conforming to of 15-dihydro-14 beta-hydroxy-(3 α, 16 α) eburnamenine-14-carboxylic acid.
Claims (3)
1. preparation formula (I) 14,15-dihydro-14 beta-hydroxy-(3 α, 16 α) eburnamenine-14-carboxylic acid
Method, it is characterized in that this method comprises: with 14,15-dihydro-14 beta-hydroxy-(3 α, 16 α) eburnamenine-14-methyl alcohol reacted about 6 hours with the nickel peroxide of preparation recently under as the boiling temperature of the water of solvent or methyl alcohol and vigorous stirring in the water-based of alkalescence or methyl alcohol medium, every weight part 14,15-dihydro-14 beta-hydroxy-(3 α, 16 α) eburnamenine-14-methyl alcohol uses 3 weight part nickel peroxide; Leach remaining nickel peroxide then, and under the condition of about 6.5pH, make 14,15-dihydro-14 beta-hydroxy-(3 α, 16 α) eburnamenine-14-carboxylic acid precipitation with mineral acid.
2. according to the method for claim 1, it is characterized in that described mineral acid is a sulphuric acid soln.
3. according to the method for claim 1, it is characterized in that alkaline medium is the methyl alcohol medium.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ES9401517 | 1994-07-12 | ||
| ES9401517A ES2105937B1 (en) | 1994-07-12 | 1994-07-12 | PROCEDURE FOR THE PREPARATION OF ACID 14,15-DIHIDRO-14B-HIDROXI- (3 *, 16 *) - EBURNAMENINA-14-CARBOXILICO. |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1118348A CN1118348A (en) | 1996-03-13 |
| CN1045295C true CN1045295C (en) | 1999-09-29 |
Family
ID=8286871
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN95104860A Expired - Fee Related CN1045295C (en) | 1994-07-12 | 1995-05-16 | Process for the preparation of 14,15-dihydro-14-hydroxy-(3,16)-eburnamenine-14-carboxylic acid |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN1045295C (en) |
| ES (1) | ES2105937B1 (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2001320A6 (en) * | 1986-11-12 | 1988-05-01 | Covex Sa | Prepn. of eburnamenine-14-carboxylic acid - by allylic oxidn of eburnamenine-14-methanol catalysed by nickel peroxide, useful e.g. as vasodilator |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2191890A1 (en) * | 1972-07-13 | 1974-02-08 | Synthelabo | Ethyl vincaminate and its salts - cerebral oxygenator and vasoregulator, prepd from vincaminic acid and diazoethane |
| ES537355A0 (en) * | 1984-11-02 | 1985-08-16 | Covex Sa | PROCEDURE FOR THE PREPARATION OF COMPOUNDS 14, 15-DIHIDRO-14 -14 -HIDROXI-14 -14 -METANOL-EBURNAMENINA |
-
1994
- 1994-07-12 ES ES9401517A patent/ES2105937B1/en not_active Expired - Lifetime
-
1995
- 1995-05-16 CN CN95104860A patent/CN1045295C/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2001320A6 (en) * | 1986-11-12 | 1988-05-01 | Covex Sa | Prepn. of eburnamenine-14-carboxylic acid - by allylic oxidn of eburnamenine-14-methanol catalysed by nickel peroxide, useful e.g. as vasodilator |
Also Published As
| Publication number | Publication date |
|---|---|
| ES2105937A1 (en) | 1997-10-16 |
| ES2105937B1 (en) | 1998-07-01 |
| CN1118348A (en) | 1996-03-13 |
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