KR890001809B1 - Process for preparing 2,3-cis 1,2,3,4-tetrahydro-5-(2-hydroxy-3-tert-butylamino)propoxy-2,3-napththalenediol - Google Patents

Abstract

Title cpd. (I) was treated by epichlorohydrine with piperidine as a catalyst, and the powder state of the product obtained was reacted with tert-buthylamine to produce amino alcohol (III). 2,3-cis- 1,2,3,4-tetrahydro-5-[(2-hydroxy-3-tert-buthylamino)propoxy -2,3- naphthalenediol was prepared by hydrolysis of amino alcohol (III). The title cpd. is useful for treating heart attack and high blood pressure.

Description

Method for preparing 2,3-cis-1,2,3,4-tetrahydro-5-[(2-hydroxy-3-tert-butylamino) -propoxy] -2,3-naphthalenediol

The present invention relates to nadolol, a nonselective beta-adrenergic receptor blocker useful for the treatment of angina and hypertension, namely 2,3-cis-1,2,3,4-tetrahydro-5-[(2-hydroxy- 3-tert-butylamino) propoxy] -2,3-naphthalenediol. Nadolol and methods for its preparation are described in US Pat. No. 3,935,267 to Hawk et al. In particular, in Example 34, 5,8-dihydro-1-naphthol was reacted to give cis-5,6,7,8-tetrahydro-1,6,7-naphthalenetriol, which was then epiolated. Treatment with chlorohydrin yields 2,3-cis-1,2,3,4-tetrahydro-5- [2,3- (epoxy) propoxy] -2,3-taphthalenediol, which intermediate is A method for producing the desired product, i.e. nadolol, by reaction with tert-butylamine is described.

East German Patent No. 129,322 to Hawk et al. Discloses cis-5,6,7,8-tetrahydro-1,6,7-naphthalenetriol reacted with acetal or ketal to the following general formula,

To obtain a compound represented by the above reaction, and reacting the compound with epichlorohydrin in the presence of an organic solvent,

The epoxide is obtained, and this epoxide is treated with tert-butylamine in the presence of methanol to give the following general formula,

The method of obtaining a compound shown by following, and then hydrolyzing this compound to manufacture a nadolol is described.

The present invention is an improvement of the method for producing nadolol described in the East German patent.

According to this invention, the following general formula (I),

The cyclic derivative represented by the following method is a required method of the lower equivalent of epichlorohydrin, the following general formula (III),

It is converted to amino alcohol represented by.

In addition, the reaction between the cyclic intermediate of Formula (I) and epichlorohydrin proceeds without an organic solvent, and when reacted with tert-butylamine in water without extracting the resultant crude mixture, The desired aminoalcohol intermediate of formula (III) can be obtained. Next, nadolol is obtained by hydrolyzing the amino alcohol of the general formula (III) by a known method.

Therefore, the method of the present invention has an economical advantage compared to the conventional method because it requires a smaller amount of epichlorohydrin, requires no organic solvent, and further reduces the number of extraction and manipulation.

According to an improved process of the invention, the cyclic derivatives of formula (I) react with up to 6 equivalents of epichlorohydrin in the absence of an organic solvent. In this method, a catalytic amount of piperidine is used. By this reaction, a mixture of a compound of the following general formula (IIa) and a compound of the general formula (IIb) is produced.

Subsequently, without extracting this mixture, water is used as a solvent and reacted with 5 equivalents of tert-butylamine to obtain an amino alcohol of the general formula (III). Hydrolysis of this amino alcohol produces nadolol.

로 표시되는 케톤, 또는 아세탈, 케탈 또는 이들의 엔올 에테르 유도체와 반응시킴으로써 얻어진다. 이 반응은 카르보닐(또는 카르보닐 유도체) 반응물 중의 트리올 현탁액 또는 용액을 산 촉매, 예를들면, 과염소산, p-톨루엔술폰산, 염산 등으로 처리 후 중화시키고, 이어서 생성된 시클릭 아세탈 또는 케탈 유도체 [일반식 (I)]를 회수함으로써 진행시키는 것이 좋다. 사용한 카르보닐(또는 카르보닐 유도체) 반응물이 고체일 경우에는 유기 용매도 역시 사용된다. 이 반응은 약20°-120℃, 바람직하게는 20°-50℃에서 수행되며, 약 0.5-24시간이 소요된다.As described in East German Patent No. 192,322 to Hawk et al., Cyclic derivatives of general formula (I) are cis-5,6,7,8-tetrahydro-1,6,7-naphthalenetriol as aldehyde or general expression,

It is obtained by reacting with a ketone or acetal, ketal or an enol ether derivative thereof. This reaction neutralizes the triol suspension or solution in the carbonyl (or carbonyl derivative) reactant after treatment with an acid catalyst such as perchloric acid, p-toluenesulfonic acid, hydrochloric acid, and the like, followed by the resulting cyclic acetal or ketal derivatives. It is good to advance by recovering [General Formula (I)]. If the carbonyl (or carbonyl derivative) reactant used is a solid, an organic solvent is also used. This reaction is carried out at about 20 ° -120 ° C., preferably 20 ° -50 ° C., and takes about 0.5-24 hours.

Wherein R ₁ is hydrogen, lower alkyl, halo lower alkyl, carboxy lower alkyl (or ester thereof), monocyclic cycloalkyl, monocarbocyclic aryl, monocarbocyclic aryl lower alkyl, monocyclic hetero A cyclic or monocyclic heterocyclic lower alkyl group, R ₂ is lower alkyl, halo lower alkyl, carboxy lower alkyl (or ester thereof), monocyclic cycloalkyl, monocarbocyclic aryl, monocyclic aryl lower Alkyl, monocyclic heterocyclic or monocyclic heterocyclic lower alkyl groups.

"Lower alkyl group" is a straight or branched chain hydrocarbon group having up to 7 carbon atoms, such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, t-butyl group, etc., provided that R ₁ and Only one of R ₂ can be a branched chain hydrocarbon group.

"Halo" means fluorine, chlorine, bromine and iodine, of which chlorine and bromine are preferred.

It is preferable that both R ₁ and R ₂ are methyl groups.

The present invention will be described in more detail with reference to the following examples.

EXAMPLE

2,3-cis-1,2,3,4-tetrahydro-5-[(2-hydroxy-3-tert-butylamino) propoxy] -2,3-naphthalenediol

a) 5- (2,3-epoxypropoxy) -3a, 4,9,9a-tetrahydro-2,2-dimethyl-2H-naphtho [2,3-d] -1,3-dioxol and 5- (3-chloro-2-hydroxypropoxy) -3a, 4,9,9a-tetrahydro-2,2-dimethyl-2H-naphtho [2,3-d] -1,3-diosol Mixture of

5-hydroxy-3a, 9a-cis-3a, 4,9,9a-tetrahydro-2,2-dimethyl-2H-naphtho [2,3-d] -1,3-diosol 121.15 g (0.55) Mole) was treated with 13 drops of piperidine (about 0.005) in 259 ml (3.3 moles) of epichlorohydrin. This suspension was quickly heated to reflux (116 ° C.) and the resulting brown solution was maintained at this reflux for 4 hours. The volatile components were removed by rotary evaporation, and about 160 ml of the remaining residue was azeotrope mixed twice with 200 ml of water under reduced pressure to obtain about 200 ml of viscous residue. This residue is taken from 5- (2,3-epoxypropoxy) -3a, 4,9,9a-tetrahydro-2,2-dimethyl-2H-naphtho [2,3-d] -1,3-di Oxol and 5- (3-chloro-2-hydroxypropoxy) -3a-4,9,9a-tetrahydro-2,2-dimethyl-2H-naphtho [2,3-d] -1,3- It was confirmed that it consisted of a mixture of dioxol.

b) 5-[(2-hydroxy-3-tert-butylamino) propoxy] -3a, 4,9,9a-tetrahydro-2,2-dimethyl-2H-naphtho [2,3-d] Dioxol

The residue obtained in step a) was dissolved in 289 ml (2.75 moles) of tert-butylamine and 85 ml of water was added to this solution. The resulting pale brown homogeneous solution was refluxed for 2 hours (72 ° C.) and then cooled slightly. Water was removed under reduced pressure to yield a viscous residue, 5-[(2-hydroxy-3-tert-butylamino) propoxy] -3a, 4,9,9a-tetrahydro-2,2-dimethyl-2H-naph Approximately 350 ml of earth [2,3-d] -1,3-dioxol were obtained.

c) 2,3-cis-1,2,3,4-tetrahydro-5-[(2-hydroxy-3-tert-butylamino) propoxy] -2,3-naphthalenediol

The residue obtained in step b) was dissolved in 500 ml of methylene chloride and 100 ml of water, and the aqueous layer was washed with the addition of methyl chloride. The combined organic extracts were added followed by 800 ml of water followed by 85 ml of concentrated HCI. To the mixture was further added concentrated HCI to adjust the pH to 0.7-0.9. The mixture was stirred at 30 ° -35 ° C. for 2.5 hours and then cooled. The aqueous layer was washed with 150 ml of methylene chloride, to which further methylene chloride was added, followed by 100 ml of 10N sodium hydroxide. The aqueous layer was extracted twice with methylene chloride, and the organic extracts were collected and warmed at 30 ° -35 ° C. This suspension was filtered and the filtrate was concentrated under reduced pressure to give about 260 ml of viscous residue. The residue was poured into 1600 ml of acetone and cooled at 0 ° -5 ° C. for 4 hours, after which the product was filtered and washed with 270 ml of cold acetone. The precipitate was dried at 50 ° C. to give 2,3-cis-1,2,3,4-tetrahydro-5-[(2-hydroxy-3-tert-butylamino) propoxy] -2,3-naphthalenediol 133.28 g was obtained.

Claims (6)

(a) treating the cyclic derivative of formula (I) with epichlorohydrin in the presence of a catalytic amount of piperidine, (b) tert-butyl as a crude reaction product obtained in step (a) 2,3-cis-1 comprising a step of obtaining an amino alcohol of the following general formula (III) by treating with an amine, and then (c) hydrolyzing the amino alcohol product of the step (b). Method for preparing 2,3,4-tetrahydro-5-[(2-hydroxy-3-tert-butylamino) propoxy] -2,3-naphthalenediol

In each formula, R ₁ is hydrogen, lower alkyl, halo lower alkyl, carboxy lower alkyl, monocyclic cycloalkyl, monocarbocyclic aryl, monocarbocyclic aryl lower alkyl, monocyclic heterocyclic or mono Cyclic heterocyclic lower alkyl group, R ₂ is lower alkyl, halo alkyl, carboxy lower alkyl, monocyclic cycloalkyl, monocarbocyclic aryl, mono carbocyclic aryl lower alkyl, monocyclic heterocyclic or mono Cyclic heterocyclic lower alkyl. The method of claim 1, wherein R ₁ and R ₂ are both methyl groups. The process according to claim 1, wherein in step (a) no more than 6 equivalents of epichlorohydrin are used and the reaction is carried out in the absence of an organic solvent, in step (b), 5 equivalents of tert-butylamine are used and the reaction is carried out in the absence of an organic solvent. How to proceed under. (a) treating the cyclic derivative of formula (II) with epichlorohydrin in the presence of a catalytic amount of piperidine and (b) the crude reaction product obtained in step (a) is treated with tert-butylamine A process for producing the amino alcohol of the general formula (III)

In each formula, R ₁ is hydrogen, lower alkyl, halo lower alkyl, carboxy lower alkyl, monocyclic cycloalkyl, monocarbocyclic aryl, monocarbocyclic aryl lower alkyl, monocyclic heterocyclic or mono Cyclic heterocyclic lower alkyl group, R ₂ is lower alkyl, halo alkyl, carboxy lower alkyl, monocyclic cycloalkyl, monocarbocyclic aryl, mono carbocyclic aryl lower alkyl, monocyclic heterocyclic or mono Cyclic heterocyclic lower alkyl group. The method of claim 4, wherein R ₁ and R ₂ are both methyl groups. The process according to claim 4, wherein in step (a) no more than 6 equivalents of epichlorohydrin are used and the reaction is carried out in the absence of an organic solvent, in step (b), 5 equivalents of tert-butylamine are used and the reaction is carried out in the absence of an organic solvent. How to proceed under