JPS58170775A - Preparation of optically active (s)-(-)-2-acetyl-7-(2- hydroxy-3-isopropylaminopropoxy)benzofuran hydrochloride - Google Patents

Abstract

PURPOSE:To introduce the asymmetric charbon atom of (D)-mannitol into the titled compound useful as a beta-adrenergic neuronal blocking agent, in high efficiency, by the redox dehydrative condensation of a phenolic hydroxyl group with an alcoholic hydroxyl group under specific condition. CONSTITUTION:The compound of formula IV is prepared by the redox dehydrative condensation of 2-acetyl-7-hydroxybenzofuran of formula II with (S)- (-)-2-phenyl-3-isopropyl-5-hydroxymethyloxazolidine of formula III in an inert organic solvent in the presence of triphenylphosphine of formula V and dialkyl azodicarboxylate of formula VI (R is preferably 1-4C alkyl). It is not necessary to separate and purify the produced compound. The product is treated with hydrochloric acid to obtain the titled optically active compound of formula I which is extremely useful for the prevention of cardiopathy, hypertension, etc. and remedy for glaucoma, easily, in high optical purity and high yield.

Description

Detailed Description of the Invention Hydroxy-3-isobrobylaminopp-boxy)benzofuran hydrochloride (hereinafter referred to as (S)-(-)ippe7p
The (S)-benolol hydrochloride obtained by the present invention is used as a β-adrenergic nerve blocker (hereinafter referred to as β-blocker). It is an extremely useful compound for the prevention and treatment of heart diseases (arrhythmia, angina, etc.) and hypertension, as well as for the treatment of glaucoma.

Many of the β-blockers have a unique skeleton represented by the formula (A): H, and therefore optical isomers centering on an asymmetric carbon atom (the carbon atom marked with an asterisk) exist. Many conventionally known β-beta'Q
In the -y car, the optically active form having the (S) -configuration (hereinafter referred to as the S form) is its enantiomer (hereinafter referred to as the R form).
) and racemic K, which are said to have high pharmacological activity (e.g. LMed-C)lea, , ILl.
llB (1968) #Reference). (S)-(-)-Befunolol hydrochloride is no exception; for example, in a study that investigated the antagonistic effect of isoproterenol on the enhancement of cardiac contraction in dogs, it was found that the activity was approximately 40 times higher than that of the S-form F11. is recognized. Therefore, there is a need for the development of a method for selectively synthesizing optically active (S)-(-)-befunolol hydrochloride in a simple and high-yield manner.

As a typical method for obtaining 5-blockers, a method has been widely studied that uses optically active (D)-mannitol as a raw material and incorporates its asymmetric carbon into the target compound. . The characteristics Fi (
D) Various optically active reaction reagents derived from mannitol (e.g. optically active substances such as epichlorohydrin, mesityloxymethyloxirane, 3-tosyloxy-1,2-propanediol acetonide) are phenolicized under basic conditions. It can be reacted with a compound (nucleophilic substitution reaction). However, when this more nucleophilic substitution reaction is applied to the production of (S)-(-)-befunolol hydrochloride, the yield of the desired reaction product is lower, perhaps because relatively strong basic conditions are adopted. It's hard to be seen.

- The present inventors have determined that the asymmetric carbon of (D)-mannitol is (
As a new method for efficiently introducing S)-(-)-befunolol hydrochloride, I came up with the idea of using a redox dehydration condensation reaction between a phenolic hydroxyl group and an alcoholic hydroxyl group. It was discovered that the target product having optical purity could be obtained easily and in high yield, and the present invention was completed.

That is, the present invention provides 2-a7tyl-7-hydroxybenzo7rane represented by formula (1): % formula % and (B)-H-2-phenyl-3-isopropyl represented by formula (1): The formula (
I): Concerning a method for producing an optically active (3)-(he)-2-acetyl-7-(2-hydroxy-6-p-pylaminopropoxy)benzofuran salt represented by:

The redox dehydration condensation reaction method employed in the me method of the present invention has been employed as a method for introducing a side chain (a moiety having a skeleton represented by the above formula (A)) in the field of conventional β-blocker production. The reaction proceeds in a manner that involves a nucleophilic substitution reaction and a Fi-membered reaction. That is, this is an extremely mild method for introducing side chains, in which the 11 reaction proceeds while the reaction system is kept under neutral conditions throughout.

The formula (1) used as a starting material for the production method of the present invention
) is a compound represented by orthovanillin.
Compound H (D) represented by the above formula (1)
- Found in a relatively short process from mannitol. In the dehydration condensation reaction of these starting materials, 0□7 to 1.5 equivalents of the compound represented by the formula (Shu) are used per equivalent of the compound represented by the formula (I [), but only in this range. ,
It is not limited. Also, triphenylphosphine (compound represented by formula (■):) and dialkyl, ruazodicarboxylic acid ester (-4 formula (Vl): RO, CN: NC) used as reaction reagents
O, R(Vl) (in the formula, R is preferably a compound represented by 1 to 4 carbon atoms), each of which is used is usually 1 to 1.0% per equivalent of the compound represented by formula (II). It is preferable to use it between 5 meals. This dehydration condensation reaction is usually carried out in an inert gas atmosphere (nitrogen gas, argon gas, etc.) in a dry inert organic solvent (eg, tetrahydro7rane, chloroform, benzene, etc.). Although the order of charging is not particularly limited, it is preferable to dissolve the compound represented by formula (1), the compound represented by formula (1), and triphenylphosphine in that order in an organic solvent, and then add the dialkyl azodicarboxylic acid with stirring. A suitable method is to gradually add the ester dropwise. The reaction temperature is usually -20 to 80
'C, preferably θ~200C, and after dropping the dialkyl azodicarboxylic acid ester, 1~1~1 at the same temperature.
, the reaction can be completed by stirring for 5 hours. Through this dehydration condensation reaction, a compound represented by formula (W) is produced as an intermediate.

Although the compound represented by the formula (mV) can be isolated and purified, this is not particularly necessary in the production method of the present invention, and the residue obtained from the dehydration condensation reaction is treated with hydrochloric acid according to the 11m method. By doing so, the hydrolysis of the oxazolidine ring and the conversion to the hydrochloride proceed simultaneously, resulting in the desired (S)-(-)- represented by formula (I).
Befunolol vanilate is obtained.

The production method of the present invention can be expressed as follows using a reaction equation.

(Reaction formula) %Formula% () (1) According to the W production method of the present invention, the target compound represented by formula (I) has a reaction rate of about 65 to 80% based on the compound represented by formula (1).
It can be obtained with a high yield of %.

Next, the manufacturing method of the present invention will be explained in more detail with reference to Example # and Examples, but the present invention is not limited to these Examples.

Reference Example 1 (Production of ($)-(-)-2-y ale-3-isopropyl-5- and droxymethyloxazolidine) LjM@Weimst from (n) v > 2)-
The method of Ock et al. (J, Org-chew, 41.
25 g of (S)-3-inpurpylamino-1,2-propanediol prepared II with reference to 3121 (1976) wA) at room temperature and under a nitrogen atmosphere.
Stirred for 4 hours.

After the reaction, magnesium sulfate was added to PAL, and the solution was concentrated under reduced pressure.The resulting concentrated residue was subjected to vacuum distillation, and the boiling point 141°C/l mmHgO fraction was collected to obtain the desired (S)-( -) -34 g of -2-phenyl-3-isopropyl-5-hydroxymethyloxazolidine were obtained as a colorless oil (yield: 85%).

When this product was analyzed by gas chromatography, it was found to contain about 5≦benzaldehyde.

Optical rotation: [α)” -13,5° (c = i, o doctor M@
OH) Mass spectrum: m/e 221 (M”), 220.190.16
2.143.100.72 Example 1 (Preparation of (S)-(-)-befunolol hydrochloride (1)
(S)-(-)-2-y1 di-3-isopropyl-5-hydroxymethyloxazolidine 22 g (approximately 0.01 mol), 2-acetyl-7-hydro-I-xybenzo7ran, which was found in Reference Example 1. 21g (approx. 0.012 mol)
Oyohitriphenylphosphine 31.5 g (approx.
012 mol) in 300 ml of dry tetrahydrofuran
Then, 21 g (about 0.012 mol) of diethyl azodicarboxylic acid ester was added dropwise under a nitrogen gas atmosphere while maintaining the temperature of the reaction solution at 0 to 20 QC.

After the dropwise addition was completed, the mixture was further stirred at 10 to 20°C for 3 hours to complete the reaction. Next, the reaction solution was concentrated under reduced pressure, and 3 ooml of ether was added to the resulting residue, which was cooled on ice. The deposited precipitate was removed by filtration, and Solution F was concentrated under reduced pressure.

(III) Pour the residual liquid found in (1) into methanol 200a.
1,115mj of concentrated clay was added thereto, and the mixture was stirred at room temperature for 10 hours. Thereafter, methanol was distilled off under reduced pressure, and the remaining 1 liter and 250 ml of IK water were added. Wash this aqueous solution with chloroform.
), and then evaporated to dryness under reduced pressure, and 100 ml of isopropyl alcohol was added, heated to dissolve, and allowed to cool to precipitate the desired (S)-(-)-befunolol hydrochloride. This product was further purified by recrystallization from isopropyl alcohol.

Yield: 29.3 liters (yield: 74.4%) Melting point: 152-1530C Elemental analysis value: "1llH1l"4.HO2 (molecular weight: 3
27.45) Theoretical value (%): C58,43116,67N 4.
14 Actual value (%): C58,62H6,76N 4
．． 274 Optical rotation: (α), -14.9° (C: 1.00,
MeOH) Infrared absorption spectrum (nujitol): 3375.3100-2900.28
00-2400.1680 cm-1 nuclear magnetic resonance spectrum (solvent = D.

0, internal standard: TMS): δ1.55 (6H,d), 2.52
(3B.

a), 3.50 (2H, d), 3.65 (IH, m
), 4.25 (2H,d), 4°45 (IHXm)
, 6.9-7.3 (3H.

Peng), 7.45 (I H, B) ppm Mass spectrum: m) I'* 291 (M +), 2
76, 247.176.16L 102.73 Example 2 (Production of (S)-(-)-befunolol hydrochloride) 24.3 g of diimpropylazodicarboxylic acid ester (approx. 0
The experiment was carried out in the same manner as in Example 1 except that 12 mol) was used, and the target compound was obtained.

Yield: 27.4 g (yield: 69.5 g) The physicochemical data of the product corresponded to that of the product obtained in Example 1.

Claims (1)

[Claims] 12-acetyl-7-hydroxybenzo7lane and (S)
-(-)-2-y-double-3-isopropyl-5-hydroxymethyloxazolidine in an inert organic solvent;
redox dehydration condensation in the presence of triphenylphosphine and dialkylazosica carboxylic acid ester;
Optically active (S) is then treated with hydrochloric acid.
)-(-)-2-acetyl-7-(2-hydroxy-3
-Production method of benzofuran hydrochloride (isopropylaminopropoxy).