CN1275944C - Process for preparing (s)-6,7-dimethoxy-1,2,3,4-tetrahydro isoquinoline-3-carboxylic acid - Google Patents
Process for preparing (s)-6,7-dimethoxy-1,2,3,4-tetrahydro isoquinoline-3-carboxylic acid Download PDFInfo
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- CN1275944C CN1275944C CN 200410017836 CN200410017836A CN1275944C CN 1275944 C CN1275944 C CN 1275944C CN 200410017836 CN200410017836 CN 200410017836 CN 200410017836 A CN200410017836 A CN 200410017836A CN 1275944 C CN1275944 C CN 1275944C
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Abstract
The present invention discloses a method for preparing (S)-6, 7-dimethoxy-1, 2, 3, 4-tetrahydro isoquinolyl-3-carboxyl acid. In the method, racemic 6, 7-dimethoxy-1, 2, 3, 4-tetrahydro isoquinolyl-3-carboxyl acid or a derivant thereof is used as raw materials, and (1R)-10-camphorsulfonic acid, or (1S)-10-camphorsulfonic acid, or (S)-mandelic acid or (R)-mandelic acid is used as a resolution agent. According to the difference in the dissolvability in a solvent between (S)-6, 7-dimethoxy-1, 2, 3, 4-tetrahydro isoquinolyl-3-carboxyl acid or the derivant thereof and a (R) configuration optical antimer thereof, and salt formed by the resolution agent, pure salt of the (S)-6, 7-dimethoxy-1, 2, 3, 4-tetrahydro isoquinolyl-3-carboxyl acid, the derivant thereof and the resolution agent can be obtained. The present invention has low requirements to equipment and reaction conditions and is suitable for large-scale production. The method only uses common raw materials and reagents, and the obtained product has low cost.
Description
Technical field
The present invention relates to (S)-6,7-dimethoxy-1,2,3, the preparation method of 4-tetrahydroisoquinoline-3-carboxylic acid and derivative thereof relates to optically pure (S)-6 specifically, 7-dimethoxy-1,2,3, the preparation method of 4-tetrahydroisoquinoline-3-carboxylic acid.
Background technology
(S)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid are a kind of important medicine intermediates, and this compounds is an alpha-non-natural amino acid 1,2,3, and the derivative of 4-tetrahydroisoquinoline-3-carboxylic acid is widely used in the synthetic of pharmaceutical prod and intermediate.As US 4,344, described in 949, (S)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid can obtain the angiotensin-convertion enzyme inhibitor SPM-925 through reactions such as esterification, condensation and hydrogenations, and the latter is a novel antihypertensive medicament, in the listing of a plurality of countries.
(S)-6 of being addressed, 7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid has following structure:
Wherein: a kind of in R=H, methyl, ethyl, benzyl, the tertiary butyl or the phenyl.
(US 4 for bibliographical information; 912; 221 and J.Med.Chem.1977; 99:6262) (S)-6; 7-dimethoxy-1; 2,3, the preparation method of 4-tetrahydroisoquinoline-3-carboxylic acid is first directional catalyzing hydrogenation α-benzamido-3; 4-dimethoxy-cinnamic acid methyl esters obtains (S) N-benzoyl-3; 4-dimethoxy phenylalanine methyl ester is sloughed protecting group again in hydrochloric acid, obtain optically pure (S)-6 by the Pictet-Spengler ring-closure reaction then; 7-dimethoxy-1; 2,3,4-tetrahydroisoquinoline-3-carboxylic acid hydrochloride.Because deprotection base and Pictet-Spengler ring-closure reaction all can produce racemization to established unsymmetrical carbon, optical purity is lower, and the ee value of final product is 94%.
Summary of the invention
The technical issues that need to address of the present invention are to disclose a kind of optically pure (S)-6,7-dimethoxy-1,2,3, and the preparation method of 4-tetrahydroisoquinoline-3-carboxylic acid is to overcome the lower defective of ee value of the final product that prior art exists.
Technical conceive of the present invention is such:
The present invention is with racemize 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid or derivatives thereof is a raw material, with (1R)-10-camphorsulfonic acid, (1S)-the 10-camphorsulfonic acid, (S)-a kind of in amygdalic acid or (R)-amygdalic acid etc. is resolving agent, utilizes (S)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid or derivatives thereof and its (R) configuration optical antipode and above-mentioned resolving agent the difference of salifiable solubleness in solvent, both are separated, obtain pure (S)-6,7-dimethoxy-1,2,3, the salt of 4-tetrahydroisoquinoline-3-carboxylic acid and derivative and resolving agent.
Method of the present invention comprises the steps:
(1) acid is added contain (±) 6,7-dimethoxy-1,2,3, the alkaline substance solution of 4-tetrahydroisoquinoline-3-carboxylic acid or derivatives thereof makes pH=4～6.5 of solution, obtains the white crystalline solid;
Said acid comprises a kind of or its mixture in hydrochloric acid, sulfuric acid or the acetate, and preferably adopting mass percent concentration is 1%～100% the aqueous solution;
Said alkaline matter comprises a kind of or its mixture in sodium hydroxide, potassium hydroxide or the calcium hydroxide;
Said racemize 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid or derivatives thereof can be with reference to Indian Journal of Chemistry 1975,13 (March): the method described in 220, with veratryl aldehyde and urobenzoic acid is that raw material is prepared, and its general structure is:
Wherein: a kind of in R=H, methyl, ethyl, benzyl, the tertiary butyl or the phenyl.
(2) the white crystalline solid that will be suspended in the step (1) in the organic solution under the room temperature reacts with the resolving agent that is dissolved in the organic solvent, collects the solid precipitate;
Said organic solvent comprises a kind of in methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol or the trimethyl carbinol;
Wherein: (±) 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid and derivative thereof are 1: 0.5～1: 1.5 with the ratio of the amount of substance of resolving agent.
Said resolving agent comprises a kind of in (1R)-10-camphorsulfonic acid, (1S)-10-camphorsulfonic acid, (S)-amygdalic acid or (R)-amygdalic acid etc.;
The general structure of said (1R)-10-camphorsulfonic acid is:
The general structure of said (1S)-10-camphorsulfonic acid is:
(3) under temperature is-20 ℃～100 ℃ condition, alkaline matter is splashed into the organic solvent of the reaction product that contains in steps (2), collect the white solid precipitate, be target product: (S)-6,7-dimethoxy-1,2,3, the acid of 4-tetrahydroisoquinoline.
Said organic solvent comprises C
1～C
4Unit alcohol, a kind of or its mixture in particular methanol, ethanol, propyl alcohol, Virahol, butanols or the trimethyl carbinol;
Said alkaline matter comprises triethylamine, N, a kind of in the carbonate of accelerine, diisopropylethylamine, N-methylmorpholine, ammoniacal liquor, yellow soda ash, sodium bicarbonate, sodium hydroxide, potassium hydroxide, calcium hydroxide and other alkali metal and alkaline-earth metal, supercarbonate or the oxyhydroxide.
The present invention prepares optically pure (S)-6 with Split Method, 7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.This method requires relatively lowly to equipment and reaction conditions, is fit to large-scale production.Because the used method of the present invention only relates to starting material commonly used and reagent, the cost of products obtained therefrom is relatively low.
Embodiment
Embodiment 1
Racemize 6,7-dimethoxy-1,2,3, the preparation of 4-tetrahydroisoquinoline acid
In sodium hydroxide 25g and solution that water 1000ml is become, add 1,2,3,4-tetrahydrochysene-6,7-dimethoxy-3-isoquinoline acid hydrochloride 56.2g, stirring and dissolving.Splash into 2mol/L hydrochloric acid in solution, the adularescent solid is separated out, and continues to drip 2mol/L hydrochloric acid to pH=6.0, filters, and gets the white crystalline solid.Dry (±)-6 that get, the 7-dimethoxy--1,2,3,4-tetrahydroisoquinoline acid 64.9g.
Embodiment 2
(S)-6,7-dimethoxy-1,2,3, the preparation of 4-tetrahydroisoquinoline acid (1R)-10-camsilate
At room temperature with 1,2,3,4-tetrahydrochysene-6,7-dimethoxy-3-isoquinoline acid 11.8g (0.05mol) is suspended among the ethanol 70ml, stirs, and (1R)-10-camphorsulfonic acid 11.6g (0.05mol) is poured into ethanol solution that 30ml becomes, and solid is molten clearly.Continue under the room temperature and stir, the adularescent solid is separated out, 30 minutes after-filtration, dry white crystalline solid 11.0g.With refining (S)-6 of Virahol, 7-dimethoxy-1,2,3,4-tetrahydroisoquinoline acid (1R)-10-camsilate
(c=1, methyl alcohol).
Embodiment 3
(S)-6,7-dimethoxy-1,2,3, the preparation of 4-tetrahydroisoquinoline acid
With (S)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline acid (1R)-10-camsilate 17.8g (0.038mol) is dissolved among the methyl alcohol 270ml, stirs, drip triethylamine 3.87g (0.038mol) down at 100 ℃, the adularescent solid is separated out, and continues to stir 30 minutes, filter, solid dry (S)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline acid 8.4g
(c=1,1mol/L HCl).
Embodiment 4
(R)-6,7-dimethoxy-1,2,3, the preparation of 4-tetrahydroisoquinoline acid
Adopt and embodiment 1,2 processing condition identical, but substitute (1R)-10-camphorsulfonic acid, get (S)-6 with (1S)-10-camphorsulfonic acid with 3,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline acid 7.2g,
(c=1,1mol/L HCl).
Embodiment 5
Adopt and embodiment 1,2 processing condition identical with 3, but substitute (1R)-10-camphorsulfonic acid with 7.6 gram (S)-amygdalic acids, with 40ml Virahol instead of ethanol salify, and to drip mass concentration down at 0 ℃ be 25% ammoniacal liquor 10 grams, get (S)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline acid 7.2g
(c=1,1mol/L HCl).
Claims (8)
1. (S)-6,7-dimethoxy-1,2,3, the preparation method of 4-tetrahydroisoquinoline-3-carboxylic acid is characterized in that, comprises the steps:
(1) acid is added contain (±) 6,7-dimethoxy-1,2,3, the alkaline substance solution of 4-tetrahydroisoquinoline-3-carboxylic acid or derivatives thereof makes pH=4～6.5 of solution, obtains the white crystalline solid;
(2) the white crystalline solid that will be suspended in the step (1) in the organic solution reacts with the resolving agent that is dissolved in the organic solvent, collects the solid precipitate;
Said resolving agent comprises a kind of in (1R)-10-camphorsulfonic acid, (1S)-10-camphorsulfonic acid, (S)-amygdalic acid or (R)-amygdalic acid etc.;
(3) under temperature is-20 ℃～100 ℃ condition, alkaline matter is splashed into the organic solvent of the reaction product that contains in steps (2), collect the white solid precipitate, be target product: (S)-6,7-dimethoxy-1,2,3, the acid of 4-tetrahydroisoquinoline.
2. method according to claim 1 is characterized in that, the said acid of step (1) comprises a kind of or its mixture in hydrochloric acid, sulfuric acid or the acetate, and said alkaline matter comprises a kind of or its mixture in sodium hydroxide, potassium hydroxide or the calcium hydroxide.
3. method according to claim 2 is characterized in that, said acid employing mass percent concentration is 1%～100% the aqueous solution.
4. method according to claim 1 is characterized in that, the said organic solvent of step (2) comprises a kind of in methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol or the trimethyl carbinol.
5. method according to claim 1 is characterized in that, (±) 6, and 7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid and derivative thereof are 1: 0.5～1: 1.5 with the ratio of the amount of substance of resolving agent.
6. method according to claim 1 is characterized in that, the said organic solvent of step (3) is selected from a kind of or its mixture in the unit alcohol of C1～C4.
7. method according to claim 6 is characterized in that unit alcohol is selected from methyl alcohol, ethanol, propyl alcohol, Virahol, butanols or the trimethyl carbinol.
8. according to each described method of claim 1～6, it is characterized in that, the said alkaline matter of step (3) comprises triethylamine, N, a kind of in the carbonate of accelerine, diisopropylethylamine, N-methylmorpholine, ammoniacal liquor, yellow soda ash, sodium bicarbonate, sodium hydroxide, potassium hydroxide, calcium hydroxide and other alkali metal and alkaline-earth metal, supercarbonate or the oxyhydroxide.
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| CN 200410017836 CN1275944C (en) | 2004-04-22 | 2004-04-22 | Process for preparing (s)-6,7-dimethoxy-1,2,3,4-tetrahydro isoquinoline-3-carboxylic acid |
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| CN 200410017836 CN1275944C (en) | 2004-04-22 | 2004-04-22 | Process for preparing (s)-6,7-dimethoxy-1,2,3,4-tetrahydro isoquinoline-3-carboxylic acid |
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| CN1275944C true CN1275944C (en) | 2006-09-20 |
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