JPH032145B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to L-erythro-3-(3,4-dihydroxyphenyl)-N-methylserine (referred to as L-erythro-adrenergic acid), which has extremely high pharmaceutical value. L-erythro-adrenergic acid, which is a compound of the present invention, can be obtained as follows. DL−
Optical resolution was performed by forming a salt of erythro-3-(3,4-dibenzyloxyphenyl) N-p-methoxybenzyloxycarbonylserine with an optically active amine, and the obtained
3-(3,4-dibenzyloxyphenyl)-N-
L-erythro-3-(3,4
L-erythro-3-(3,4-dibenzyloxyphenyl)- L-erythro-adrenergic acid can be obtained by converting it into N-methylserine and further removing the benzyl group. The present invention will be explained in more detail below. DL-erythro-3- which is the starting material of the present invention
(3,4-dibenzyloxyphenyl)-N-p-
Methoxybenzyloxycarbonylserine is a known compound DL-erythro-3-(3,4-
dibenzyloxyphenyl)serine can be obtained by N-p-methoxybenzyloxycarbonylation using a conventional method. Optical splitting is DL−
forming a salt of erythro-3-(3,4-dibenzyloxyphenyl)-N-p-methoxybenzyloxycarbonylserine and an optically active amine;
This is carried out by utilizing the difference in solubility between the D-form and L-form salts produced, and the optically active amine is optically active 2-amino-1,1-diphenyl-1-
Propanol, optically active threo-1-(p-nitrophenyl)-2-amino-propanediol, and the like are used. When using S-2-amino-1,1-diphenyl-1-propanol as an optical resolution agent, the following method can be used, for example. DL
-erythro-3-(3,4-dibenzyloxyphenyl)-N-p-methoxybenzyloxycarbonylserine in an equimolar amount of S-2-amino-
A homogeneous solution was prepared by adding 1,1-diphenyl-1-propanol, and by standing at an appropriate temperature, L-erythro-3-(3,4-
S-2-amino-1,1-diphenyl-1-propanol salt of N-p-methoxybenzyloxycarbonylserine (dibenzyloxyphenyl) precipitates out. The resulting salt is made optically pure by recrystallization from methanol. L-erythro-3-(3,4-dibenzyloxyphenyl)
-N-p-methoxydibenzyloxycarbonylserine can be obtained by making the resulting salt acidic with mineral acid water such as hydrochloric acid water, sulfuric acid water, phosphoric acid water, etc., and then extracting with an organic solvent. As the solvent for the separation step, a neutral solvent excluding solvents that prevent the formation of salts, such as acidic solvents such as formic acid and acetic acid, or basic solvents such as various amines, is selected because it is easy to operate and is inexpensive. Therefore, acetone, methyl ethyl ketone, methanol, ethanol, isopropanol, and water-containing solvents thereof, as well as ethyl acetate, toluene, acetonitrile, dichloroethane, or a mixed solvent thereof are desirable. The thus obtained L-erythro-3-(3,4-dibenzyloxyphenyl)-N-p-methoxybenzyloxycarbonylserine can be prepared using hydrochloric acid, sulfuric acid,
The amino protecting group is removed in good yield with a mineral acid such as hydrobromic acid or an organic acid such as trifluoroacetic acid in a lower alkanol solvent such as methanol or propanol at a temperature around room temperature, and L-erythro-3-( 3,4-dibenzyloxyphenyl)
Mineral or organic acid salts of serine are obtained. L-erythro-3-(3,4-dibenzyloxyphenyl)serine was prepared by adding potassium carbonate followed by dimethyl sulfate in anhydrous acetone.
-Erythro-3-(3,4-dibenzyloxyphenyl)-N-methylserine methyl ester is obtained and saponified in an alkaline aqueous solution (preferably 0.5-2.0N aqueous alkaline solution) without isolation. By this, L-erythro-3-(3,4-dibenzyloxyphenyl)-N-methylserine can be obtained in high yield. L-erythro-3-(3,4-dibenzyloxyphenyl)serine, which is the raw material for this reaction, can be used as it is, but surprisingly, the yield increases dramatically when a mineral salt is used. N-methylation can be carried out with a yield of 90%. Anhydrous potassium carbonate can be used in an amount of 2 to 10 equivalents, preferably 5 equivalents, and dimethyl sulfate can be used in an amount of 2 to 10 equivalents, preferably 4 equivalents. The reaction temperature used is between 0 and 50°C, but is preferably around room temperature. The obtained L-erythro-3-(3,4-dibenzyloxyphenyl)-N-methylserine is treated by a conventional method at normal pressure or in the presence of a noble metal catalyst such as palladium-carbon or platinum-carbon. Hydrogenolyzed under pressure. Preferred examples of the reaction solvent include lower alcohol solvents such as methanol and ethanol, and mixed solvents of these with water. Hydrogenolysis is usually carried out at a temperature around room temperature, but it can be carried out at any temperature between 0 and 80°C. Furthermore, it is desirable to add 1.0 to 2.0 equivalents of acid to the reaction solution for the purpose of promoting hydrogenolysis or increasing the solubility of the reaction product. A suitable example of the acid to be added is hydrochloric acid. After hydrogenolysis, the catalyst is removed by filtration,
When the solvent is concentrated or an acid is added,
Crystallized L-erythro-adrenergic acid is obtained by neutralizing the added acid. The physical properties of L-erythro-adrenergic acid thus obtained are as follows. Melting point: 164-167℃ [α] ²⁴゜_D : +60゜ (C1.0, 1N hydrochloric acid) Elemental analysis: As C ₁₀ H ₁₃ NO ₅ Calculated value: C52.86, H5.77, N6.16% Actual value : C52.87, H5.80, N5.94% L-erythro-adrenergic acid obtained by the above method is an amphoteric substance and can form a salt with an acid and a base. Salts thus produced are also included in the present invention. Examples of such acids include pharmaceutically acceptable inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, as well as trifluoroacetic acid, citric acid,
Pharmaceutically acceptable organic acids include ascorbic acid and maleic acid. Examples of such bases include pharmaceutically acceptable bases such as sodium hydroxide, potassium hydroxide, dicyclohexylamine, and the like. L-erythro-adrenergic acid, a compound of the present invention, has a hypotensive effect and is useful as a therapeutic agent for hypertension. The antihypertensive effect of the compound of the present invention is as follows. Hypertensive rats (weight 300-350 g, male) 1 group 3
400 mg of adrenergic acid suspended in 0.5% CMC was orally administered to the rats, and the drop in blood pressure was measured 6 hours later.
The results are shown in Table 1.

[Table] From Table 1, it is clear that L-erythro-adrenergic acid exhibits a blood pressure lowering effect on hypertensive rats and is useful as a therapeutic agent for hypertension. Hereinafter, examples of optical resolution of raw material compounds used in the production of the compounds of the present invention will be referred to as reference examples, and examples of production of the compounds of the present invention will be listed as examples, but the present invention is not limited thereto. Note that a corresponding production example of D-erythro-adrenergic acid is also shown as a reference example. Reference Example 1 82 g of DL-erythro-3-(3,4-dibenzyloxyphenyl)-N-p-methoxybenzyloxycarbonylserine was heated and dissolved in 1500 ml of methanol, and S-2-amino- 1,1
33.4 g (1.0 equivalent) of -diphenyl-1-propanol was dissolved. After this mixture was left at room temperature for 2 days, the precipitated crystals were filtered off and washed with methanol. The obtained crude crystals were recrystallized twice with methanol to obtain L-erythro-3-(3,4
-dibenzyloxyphenyl)-N-p-methoxybenzyloxycarbonylserine S-2-amino-1,1-diphenyl-1-propanol salt
44.0g was obtained. The analytical values of the obtained compound were as follows. Melting point: 84.0 - 86.0℃ [α] ²⁶゜_D : -19゜ (C1.0, tetrahydrofuran) Elemental analysis: C ₄₄ H ₄₈ N ₂ O ₉ Calculated values: C 71.92, H 6.16, N 3.57% Actual values: C71.66, H6.18, N3.58% The mother liquor from which the precipitated crystals were filtered off was concentrated to dryness, and the residue was dissolved in 400 ml of ethyl acetate and washed twice with 200 ml of 3N hydrochloric acid. The ethyl acetate layer was washed with 50 ml of water, dried over anhydrous sodium sulfate, and concentrated to dryness. The obtained solid was recrystallized from ethanol to obtain 27.7 g of D-erythro-3-(3,4-dibenzyloxyphenyl)-Np-methoxybenzyloxycarbonylserine. The physical properties of the obtained compound were as follows. Melting point: 123・0~125.0℃ [α] ²⁹゜_D : -36.5゜ (C0.91, chloroform:methanol = 10:1) Elemental analysis: As C ₃₂ H ₃₁ NO ₈ Calculated value: C68.93, H5. 60, N2.51% Actual value: C68.59, H5.56, N2.39% L-erythro-3-(3,4-dibenzyloxyphenyl)-N-p-methoxybenzyloxycarbonylserine S 44.0 g of -2-amino-1,1-diphenyl-1-propanol salt was dissolved in 400 ml of ethyl acetate and 200 ml of 3N hydrochloric acid, extracted, and the ethyl acetate layer was further extracted with 200 ml of 3N hydrochloric acid,
Then, it was washed with 50 ml of water. Washing solution with ethyl acetate
The extract was extracted with 100 ml, and the ethyl acetate layers were combined, dried over anhydrous sodium sulfate, and concentrated to dryness. The obtained solid was recrystallized from ethanol to obtain L-erythro-3-(3,4-dibenzyloxyphenyl).
29.0 g of -N-p-methoxybenzyloxycarbonylserine was obtained. The physical properties of the obtained compound were as follows. Melting point: 127.5-129.0℃ [α] ²⁹゜_D : +40゜ (C0.91, chloroform:methanol = 10:1) Elemental analysis: C ₃₂ H ₃₁ NO ₈ Calculated value: C68.93, H5.60, N2. 51% Actual value: C68.66, H5.55, N2.39% Example 1 To 15.7 g of L-erythro-3-(3,4-dibenzyloxyphenyl)-N-p-methoxybenzyloxycarbonylserine Methanol 480ml, 3N
160 ml of hydrochloric acid was added and dissolved by heating at 60°C, and then allowed to cool at room temperature for about 45 minutes. After distilling off methanol at 30°C or lower under reduced pressure, the precipitated crystals were collected by filtration and dried over phosphorus pentoxide to obtain L-erythro-3-(3,4-dibenzyloxyphenyl)serine hydrochloride. 11.2g was obtained. (Yield 91%). 60 ml of acetone dried over anhydrous potassium carbonate and 12.6 g of anhydrous potassium carbonate were added to 7.81 g of L-erythro-3-(3,4-dibenzyloxyphenyl)serine hydrochloride, and after stirring at room temperature for about 10 minutes. ,
6.9 ml of dimethyl sulfate was added and stirred overnight. After removing the anhydrous potassium carbonate by filtration and thoroughly washing it with acetone, 60 ml of 1N hydrochloric acid was added to the acetone filtrate at 15°C, and the mixture was stirred for 1.5 hours. This reaction solution was concentrated under reduced pressure at 30°C to remove acetone, and 62ml of ethanol and
After adding 31 ml of 4N sodium hydroxide and stirring at room temperature for about 30 minutes, the pH was adjusted to 5-6 with 3N hydrochloric acid and left overnight under ice cooling. The resulting precipitate was collected by filtration and 1N
Add and dissolve 25 ml of hydrochloric acid and 250 ml of ethanol, adjust the pH to 5-6 with 4N sodium hydroxide under ice-cooling, and leave it under ice-cooling overnight.The resulting crystals were filtered and dried under reduced pressure over phosphorus pentoxide overnight. Then, L-erythro-3-
7.51 g of (3,4-dibenzyloxyphenyl)-N-methylserine was obtained. Melting point: 162-165℃ [α] ²⁵゜_D : +45゜ (C1.0, 1N hydrochloric acid: ethanol =
1:3) Elemental analysis: C ₂₄ H ₂₅ NO ₅ Calculated values: C69.21, H6.29, N3.36% Actual values: C68.97, H6.04, N2.99% L-erythro-3- (3,4-dibenzyloxyphenyl)-N-methylserine (4.53 g), 9.3 ml of ethanol solution containing 10% concentrated hydrochloric acid and 36 ml of ethanol
and add 10% palladium-carbon 450 to the suspension.
mg was added thereto, and the mixture was stirred under a hydrogen stream at normal pressure. After the reaction was completed, the reaction solution was filtered, and the filtrate was neutralized with a 40% diethylamine-containing ethanol solution under ice cooling.
After standing at -15°C for 3 hours, filtration was performed to obtain 2.10 g of L-erythro-adrenergic acid. The obtained 2.10 g of L-erythro-adrenergic acid was recrystallized from 21 ml of water containing 4.2 mg of L-ascorbic acid to obtain 1.46 g of purified L-erythro-adrenergic acid. (Yield 58%). The physical properties of the obtained compound are as follows. Melting point: 164-167℃ [α] ²⁴゜_D : +60゜ (C1.0, 1N hydrochloric acid) Elemental analysis: As C ₁₀ H ₁₃ NO ₅ Calculated value: C52.86, H5.77, N6.16% Actual value : C52.87, H5.80, N5.94% Reference example 2 D-erythro-3-(3,4-dibenzyloxyphenyl)-N-p-methoxybenzyloxycarbonylserine 9.54g, methanol 290ml, 3N
Add 95ml of hydrochloric acid, heat to dissolve at 60°C, and then dissolve at room temperature for approx.
It was left to cool for 30 minutes. After distilling methanol off under reduced pressure at 30°C or lower, the precipitated crystals were collected by filtration and dried under reduced pressure to form D.
7.29 g of -erythro-3-(3,4-dibenzyloxyphenyl)serine hydrochloride was obtained. 53 ml of acetone dried over anhydrous potassium carbonate and 11.0 g of anhydrous potassium carbonate were added to 6.85 g of D-erythro-3-(3,4-dibenzyloxyphenyl)serine hydrochloride, and after stirring at room temperature for about 10 minutes,
6.0 ml of dimethyl sulfate was added and stirred overnight. Filter the reaction solution, wash the filtrate with acetone, and add to the filtrate washing liquid.
53 ml of 1N hydrochloric acid was added at 15°C, and the mixture was stirred for 1.5 hours. Acetone was distilled off from this solution under reduced pressure at 30°C or below, 55 ml of ethanol and 27.5 ml of 4N sodium hydroxide were added, and the mixture was stirred at room temperature for 30 minutes.
The mixture was neutralized with hydrochloric acid and left for 2 hours under ice cooling.
Collect the resulting precipitate by filtration, and add 40 ml of 1N hydrochloric acid to this precipitate.
The mixture was dissolved by adding 350 ml of ethanol, and neutralized with 4N sodium hydroxide under ice cooling to a pH of 5 to 6, and crystals were precipitated. Further, it was left at 0°C for 2 hours, and the precipitated crystals were collected by filtration and dried under reduced pressure.
3-(3,4-dibenzyloxyphenyl)-N-
5.81 g of methylserine was obtained. (Yield 89.6%). The physical properties of the obtained compound were as follows. Melting point: 167-168℃ [α] ²³⁸゜_D : -41゜ (C1.0, 1N hydrochloric acid: ethanol = 1:3) Elemental analysis: As C ₂₄ H ₂₅ NO ₅ Calculated value: C69.21, H6.29 , N3.36% Actual value: C69.11, H6.12, N3.01% D-erythro-3-(3,4-dibenzyloxyphenyl)-N-methylserine 5.5g and ethanol containing 10% concentrated hydrochloric acid Add 11.2 ml of solution and 45 ml of ethanol, and add 550 mg of 10% palladium-carbon to the suspension.
was added and stirred overnight under a hydrogen stream at normal pressure. The reaction solution was filtered, and the filtrate was neutralized with a 40% diethylamine-containing ethanol solution under ice cooling. After leaving it at -15℃ for 3 hours, it was filtered, washed with a small amount of ethanol, and D-erythro-adrenergic acid 2.44
I got g. The obtained D-erythro-adrenergic acid was recrystallized from 25 ml of water containing 5.0 mg of L-ascorbic acid to obtain 1.82 g of purified D-erythro-adrenergic acid. (Yield 59.3%). The physical properties of the obtained compound were as follows. Melting point: 164-167℃ [α] ^24.8゜_D : -56゜ (C1.0, 1N hydrochloric acid) Elemental analysis: As C ₁₀ H ₁₃ NO ₅ Calculated values: C52.86, H5.77, N6.16% Actual measurement Value: C52.86, H5.76, N6.06%

Claims (1)

[Claims] 1 L-erythro-3-(3,4-dihydroxyphenyl)-N-methylserine, its pharmaceutically acceptable salts, and hydrates thereof.