JPH078853B2 - Method for producing dopamine derivative - Google Patents

Description

TECHNICAL FIELD The present invention relates to a method for producing a dopamine derivative using a crystalline salt of a phenethylamine derivative.

[Conventional technology]

N- (N-acetylmethionyl) -O, O'-bis (ethoxycarbonyl) dopamine (hereinafter referred to as dopamine derivative) is a useful pharmaceutical compound having an excellent effect of increasing renal blood flow, and the compound has been conventionally used. As a production method of, for example, N-acetylmethionine as its reactive derivative,
There is known a method of reacting this with a p-tosylate salt of 3,4-bis (ethoxycarbonyloxy) phenethylamine (JP-A-55-7242).

[Problems to be Solved by the Invention]

However, in the known method described above, the solvent used in the activation step of N-acetylmethionine and the subsequent condensation step must be changed, so that the final target product, N of the dopamine derivative, can be obtained.
-There were problems such as a low yield from acetylmethionine.

[Means for Solving the Problems]

As a result of various studies, the present inventors have found that 3,4-bis (ethoxycarbonyloxy) phenethylamine forms an oxalate hemihydrate having good crystallinity, and the crystallinity If you use oxalate hemihydrate,
They have found that the dopamine derivative as the final target product can be obtained with a simple operation and in good yield, and have completed the present invention.

That is, the present invention relates to a method for producing a dopamine derivative using 3,4-bis (ethoxycarbonyloxy) phenethylamine oxalate hemihydrate.

According to the invention, the formula The dopamine derivative represented by is 3,4-bis (ethoxycarbonyloxy) phenethylamine / oxalate / 1 /
It can be produced by reacting a dihydrate with a reactive derivative of N-acetylmethionine.

The reaction of 3,4-bis (ethoxycarbonyloxy) phenethylamine oxalate hemihydrate with a reactive derivative of N-acetylmethionine should be carried out in a suitable solvent in the presence of a base. You can

Examples of the reactive derivative of N-acetylmethionine include, for example, N-hydroxysuccinimide, N-hydroxyphthalimide, active ester such as ester with 1-hydroxybenzotriazole or p-nitrophenol, or isobutyl chlorocarbonate, chlorocarbonic acid. A mixed acid anhydride prepared from ethyl or the like can be used.

In this condensation reaction, as a solvent, for example, tetrahydrofuran, methylene chloride, chloroform,
Further, as the base, for example, N-methylmorpholine,
Triethylamine or the like can be used as appropriate. This reaction suitably proceeds under cooling, for example, at -20 ° C to -10 ° C.

When a reactive derivative of N-acetylmethionine is prepared, for example, by activating N-acetylmethionine, the activation step and the condensation reaction may be continuously performed in the same solvent system (for example, tetrahydrofuran). it can.

In the above method, the compound [II] and the reactive derivative of N-acetylmethionine have two kinds of optically active substances, and the present invention includes any optically active substance and a mixture thereof. However, the compound [II]
When is used as a medicine, a compound having L-coordination is particularly preferable.

In addition, 3,4-bis (ethoxycarbonyloxy) phenethylamine oxalate hemihydrate has the general formula (In the formula, Z represents a protecting group for an amino group that can be removed with an acid.) The compound can be obtained by treating the compound with oxalic acid hydrate and collecting the precipitated crystals.

In the above reaction, examples of the amino-protecting group (Z) which can be removed with an acid include 1-methyl-3-oxo-1
-Butenyl group, (2-ethoxycarbonyl-1-methyl) vinyl group and the like.

The treatment of compound [I] with oxalic acid hydrate can be suitably carried out by heating with stirring in a suitable solvent. Examples of the solvent include tetrahydrofuran,
Ethyl acetate, chloroform and the like can be used as appropriate. This treatment is preferably carried out, for example, at 50 ° C to 60 ° C.

By the above treatment, the protecting group (Z) of the amino group is removed, and the product is precipitated as an oxalate hemihydrate by cooling the reaction solution. Therefore, by collecting this, The target 3,4-bis (ethoxycarbonyloxy) phenethylamine oxalate hemihydrate can be obtained.

The starting compound [I] of the present invention is prepared, for example, by introducing a protecting group into the amino group of dopamine by a conventional method, and then subjecting the product and ethyl chlorocarbonate to a condensation reaction in the presence of a deoxidizing agent. Can be manufactured.

〔Example〕

Example 1 (1) N- (1-methyl-3-oxo-1-butenyl)
To a mixture of 47.1 g of -3,4-dihydroxyphenethylamine and 250 ml of chloroform, 44.5 g of triethylamine was added dropwise at 15 to 20 ° C, and then ethyl chlorocarbonate 46.
Add 4 g dropwise. After stirring the mixed solution for 80 minutes, the reaction solution is washed and dried, and the solvent is distilled off under reduced pressure. The obtained oily substance [N
-(1-Methyl-3-oxo-1-butenyl) -3,4-
Bis (ethoxycarbonyloxy) phenethylamine]
Is dissolved in 205 ml of tetrahydrofuran, 50.4 g of oxalic acid dihydrate is added, and the mixture is stirred at 50 ° C for 30 minutes. The reaction solution is cooled, and the precipitated crystals are collected by filtration and dried to obtain 67.6 g of 3,4-bis (ethoxycarbonyloxy) phenethylamine • oxalate • hemihydrate as crystals. Yield 85.3
% Mp 102-104 ℃ Water content (Karl Fischer method) Measured value: 2.31% Theoretical value: 2.27% Elemental analysis (as C ₁₄ H ₁₉ NO ₆・ C ₂ H ₂ O ₄・ 1 / 2H ₂ O) Measured value: C , 48.41%; H, 5.36%; N, 3.35% Theoretical value: C, 48.48%; H, 5.59%; N, 3.53% ¹ H-NMR (DMSO-d ₆ ) δ: 1.28 (6H, t, J = 7.1Hz), 2.88-2.
96 (2H, m), 3.03-3.10 (2H, m), 4.25 (4H, q, J = 7.1H
z), 7.24 (1H, dd, J = 2.0 and 8.4Hz), 7.33 (1H, d, J =
2.0Hz), 7.36 (1H, d, J = 8.4Hz), 5.5-8.3 (5H, Br) The above product was subjected to powder X-ray diffraction using CuKα ₁ (λ = 1.5450Å) radiation, and exhibited the d-value and the line intensity (I) shown in Table 1. The line intensity (I) was visually measured, and st = strong, m = medium, and w = weak.

(2) N-acetyl-L-methionine 20.0 g, N-hydroxysuccinimide 12.0 g and tetrahydrofuran 300 ml
21.6 g of dicyclohexylcarbodiimide is added to the mixture of at -10 to -15 ° C, and the mixture is stirred at the same temperature for 20 hours. To the reaction solution, 37.7 g of 3,4-bis (ethoxycarbonyloxy) phenethylamine oxalate hemihydrate was added, and N-
After dropping 19.2 g of methylmorpholine, 2 at -10 to -15 ℃
Stir for 0 hours. The reaction solution is filtered, ethyl acetate is added to the filtrate, and after washing and drying, the solvent is distilled off. The residue is dissolved in ethyl acetate, the insoluble material is filtered off, and the solvent is evaporated. Isopropyl alcohol-n-hexane was added to the oily residue,
The precipitated crystals were collected by filtration and recrystallized from ethanol-water to give N- (N-acetyl-L-methionyl) -3,4-
Bis (ethoxycarbonyloxy) phenethylamine 3
I get 6.2g. Yield 81.0% mp 106 ℃ Specific rotation ▲ [α] ²⁰ _D ▼ -16.2 ° (c = 5, ethanol) Reference example Dissolve 94.8 g of dopamine hydrochloride in 470 ml of water and add 6 g of activated carbon and 0.4 g of sodium hydroxide to decolorize the activated carbon. Remove it. 55.1 g of acetylacetone was added to the filtrate and the temperature was adjusted to 50-55 ° C. Then, aqueous sodium hydroxide solution (sodium hydroxide 2
0.6 g dissolved in 95 ml of water). After cooling the reaction solution to 15 ° C, the precipitated crystals were collected by filtration, washed and dried to give N-
114.9 g of (1-methyl-3-oxo-1-butenyl) -3,4-dihydroxyphenethylamine are obtained. Yield 97.7% mp118-120 ° C [Effect of the invention] 3,4-bis (ethoxycarbonyloxy) phenethylamine oxalate having good crystallinity and being easily obtained as high-purity crystals・ 1/2
Dopamine derivative according to the present invention using a hydrate [II]
The production method of is characterized in that the target product can be produced in high purity, as compared with the above-mentioned conventional method which uses 3,4-bis (ethoxycarbonyloxy) phenethylamine hydrochloride or p-tosylate as a raw material compound. Have.

Further, the method for producing the dopamine derivative [II] of the present invention comprises the preparation of a reactive derivative of N-acetylmethionine, which is one of the starting compounds, and the subsequent preparation of 3,4-bis (ethoxycarbonyloxy) phenethylamine oxalate. Since the condensation reaction with hemihydrate can be continuously carried out in the same solvent, the operability is remarkably improved as compared with the conventional method described above, and N-acetylmethionine is also used. It is possible to prevent the loss of the reactive derivative by isolation and purification, and to significantly increase the yield of the final target dopamine derivative [II] from N-acetylmethionine.

[Brief description of drawings]

FIG. 1 is an IR spectrum of the compound obtained in Example 1.

 ─────────────────────────────────────────────────── ─── Continuation of front page (72) Inventor Shigeru Nishimoto 1-16-B-110, Ayu Gaien, Minoh City, Osaka Prefecture (56) References JP-A-47-9565 (JP, A)

Claims (1)

[Claims] 1. 1,4-Bis (ethoxycarbonyloxy)
Formula characterized by reacting phenethylamine oxalate hemihydrate with a reactive derivative of N-acetylmethionine A method for producing a dopamine derivative represented by: