KR840001077B1 - Process for n4-carbamoylpiperazino propanal derivatives - Google Patents

Abstract

Title compds. (I, R=substituted aromatic group) were prepd. by reaction of arylglycidyl ethers and N-carbamoyl piperazine in nonreactive solvent. Thus, 5.7g 2,3-dimethyl-4-aminophenol in 50 ml pyridine was reacted with 9.6g methanesulfonyl- chloride and the resulting 2,3-dimethyl-4-methane sulfonaminophenol stirred with 6.0g CaCO and 25g epibromohydrine for 4 hr, followed by reaction with 2.0g N-carbamoyl piperazine in 100 ml MeOH for 6 hr to give 4.8g I(R=II).

Description

N4-카르바모일 피페라지노 프로판올 유도체의 제조방법Method for preparing N4-carbamoyl piperazino propanol derivative

본 발명은 N⁴위(位)에 카르바모일기를 갖는 신규인 피페라지노프로판올 유도체의 제법에 관한 것이다.The present invention relates to a method for producing a novel piperazinopropanol derivative having a carbamoyl group on the N ⁴ position.

본 발명자들은 오래전부터 N4-카르바모일피페라진의 각종의 신규유도체에 관해서 널리 연구를 속행중이었은나, 하기의[I]식 (R은 각종의 방향족기를 표시함)으로서 표시되는 N⁴-카르바모일피페라지노프로판올 유도체는 일반적으로 아드레날린 β-차단작용이 있다는 것을 발견하고, 새로운 타입의 β-차단제를 발명하기에 이르렀다.The present inventors have been extensively researching various new derivatives of N4-carbamoylpiperazine for a long time. However, N ⁴ -represented by the following formula (I) represents a variety of aromatic groups. Carbamoylpiperazinopropanol derivatives have generally been found to have adrenergic β-blocking action and have led to the invention of new types of β-blockers.

아드레날린의 β-작용이, 페녹시프로판올아민형의 약제에 의해서 길항(拮抗)되는일은 잘 알려진 사실이지만 기존의 페녹시프로판올아민형 β-차단제는 예의없이 다음의 일반식(Ⅱ)(R은 각종의 방향족기를 표시함)으로서 표시되는It is well known that the β-action of adrenergic is antagonized by a phenoxypropanolamine-type drug, but the conventional phenoxypropanolamine-type β-blocker is unexpectedly formulated in the following general formula (II) Represented by an aromatic group)

제2급 아민형구조를 가지고 있으며, R'은 이소프로필기, 제3급부틸기, 치환 β-페네틸기가 일반적이다. 아민부분이 제3급 아민으로된것은 매우 낮은 활성으로 되어있다. 본 발명에 의한 β 차단제는 그 아민부분으로서 피페라진골격을 가지고 있으며, 따라서 제3급아민구조이며, 더우기 피페라진의 N⁴위에 카르바모일기를 갖고 다고하는 과거에 알려지고 있는 β 차단제와는 전혀다른 특이한 구조적 특징을 가지고 있다. 카르바모일기는 β 차단작용 발현(發現)에 필수적인것으로서, N⁴위가 무치환의 유도체에는 활성이없다. 또 N⁴위가 카르바모일기 이외의 아실기, 설포닐기로서 치환된 것이거나, 혹은 카르바모일기의 질소상에 알킬치환기를 갖는것 등은 매우 낮은 활성이다.It has a secondary amine type structure, and R 'is isopropyl group, tertiary butyl group, and substituted (beta) -phenethyl group in general. The amine portion of the tertiary amine has very low activity. The β-blocker according to the present invention has a piperazine skeleton as its amine moiety, and thus has a tertiary amine structure, and moreover, the β-blocker is known to have a carbamoyl group on the N ⁴ of piperazine. It has other unusual structural features. Carbamoyl groups are essential for the expression of β-blocking action, and the N ⁴ position is inactive for unsubstituted derivatives. In addition, N ⁴ is substituted with an acyl group or sulfonyl group other than a carbamoyl group, or having an alkyl substituent on the nitrogen of the carbamoyl group has very low activity.

그런데 [Ⅱ]식으로서 표시된 기존의 β 차단제에 있어서, 그 구조상의 기본적특징은 모노알킬아미노프로판올 부분으로, 그것에 결합하는 방향환화합물 R의 구조는 매우 많은종류이며 다양하다. 문헌상, 각종의 치환기 예를들면 포화 또는 불포화의 알킬기, 알콕시기, 아실기, 할로겐기, 시아노기, 니트로기 각종의 치환아미노기, 아실아미노기, 수산기, 각종의 치환알킬기등을 치환기로서 갖는 방향환화합물은 활성이 강하다는 사실이 보고되고있다. 또, 각종의 축합환 화합물, 복소환화합물, 및 복소축합화합물 예를들면 인돌, 카르보스티릴, 이소카르보스티릴, 쿠마린 테트라론, 인다논, 히드로나프탈렌류, 인덴, 벤조티아졸, 벤조이미다졸, 벤조푸란, 프탈리드, 티아졸, 벤조티오펜, 티오쿠마론, 티아디아졸 등도 강한 활성을 갖는다는 사실이 문헌상 명백하다. [Ⅰ]식으로서 표시되는 본 발명 화합물의 경우도, 그 특징적 기본구조인 N4-카르바모일 피페라지노 프로판올부분에 결합하는 R로서는, 기존의 β 차단제[Ⅱ]에 있어서의 R가 모두같이 매우 다양한 방향족기가 채용될 수 있다. 사실상[Ⅱ] 식으로서 표시되는 종래형의 β 차단제에 있어서 채용되고 있는 R이 모두 본 발명에 있어서의 R로서 채용될 수 있다. 예를들면 아래에 나타낸 화합물이 그 예이다.By the way, in the existing β-blocker represented by the formula [II], the basic characteristic of the structure is a monoalkylaminopropanol moiety, and the structure of the aromatic ring compound R bonded thereto is very many and varied. In the literature, aromatic ring compounds having various substituents such as saturated or unsaturated alkyl groups, alkoxy groups, acyl groups, halogen groups, cyano groups, nitro groups, various substituted amino groups, acylamino groups, hydroxyl groups, various substituted alkyl groups, etc. Has been reported to have strong activity. In addition, various condensed cyclic compounds, heterocyclic compounds, and heterocondensed compounds such as indole, carbostyryl, isocarbostyryl, coumarin tetralone, indanone, hydronaphthalenes, indene, benzothiazole, and benzimidazole It is clear from the literature that benzofuran, phthalide, thiazole, benzothiophene, thiocoumarone, thiadiazole and the like also have strong activity. Also in the case of the compound of the present invention represented by the formula [I], as R bound to the N4-carbamoyl piperazino propanol moiety which is the characteristic basic structure, all of R in the existing β-blocker [II] are very similar. Various aromatic groups can be employed. In fact, all of the R employed in the conventional β-blocking agent represented by the formula [II] can be employed as R in the present invention. For example, the compounds shown below are examples.

본 발명에 의한 화합물은 어느 것이든 비대칭탄소를 가지고 있으며, 광학활성체로서 라세미형태가 존재할 수 있다.The compound according to the present invention has any asymmetric carbon, and racemic forms may exist as the optically active agent.

라세미체는 광학분할법으로서 그 자체공지의 방법, 예를들면 비대칭을 갖는 다른 화합물과의 부가물 염등을 경유하는 방법에 의해서 광학활성체로 분할할 수 있다. 이들의 광학활성체도 라세미체와 같이, 본 발명에 포함되는 것은 물론이다.The racemate can be divided into the optically active substance by a method known per se as an optical splitting method, for example, via an addition salt with another compound having an asymmetry. It goes without saying that these optically active substances are also included in the present invention like racemates.

본 발명에 의한 화합물은 모두가 염기성물질로서, 산과염을 형성한다. 일반적으로 의약품으로서 허용할수 있는 각종의산, 예를들면 염산, 황산, 질산, 취화수소산, 구연산, 주석산, 능금산, 말론산, 말레인산, 푸말산, 메탄설폰산, 톨루엔설폰산, 니코틴산, 안식향산등이 본 발명에 의한 화합물과의 조염(造鹽)으로 사용할 수 있다.The compounds according to the present invention are all basic substances and form acid persalts. In general, various types of acids that can be accepted as pharmaceuticals, such as hydrochloric acid, sulfuric acid, nitric acid, hydrochloric acid, citric acid, tartaric acid, nitric acid, malonic acid, maleic acid, fumaric acid, methanesulfonic acid, toluenesulfonic acid, nicotinic acid, benzoic acid, etc. It can be used for salt formation with the compound which concerns on this invention.

본 발명에 의한 화합물은 교감신경말초의 β 수용체(受容體)에 길항하므로서 신경전달을 저해하고, 임상적으로 사람에 대하여 1일 5-200mg의 경구투여량으로서, 고혈압, 협심증, 부정맥으로 대표되는 각종의 순환기게질환 및 지질(脂質) 대사이상등의 질환에 사용할 수 있다.The compound according to the present invention inhibits neurotransmission by antagonizing β receptors in the peripheral sympathetic nerve, and clinically is oral dosage of 5-200 mg per day to humans, which is represented by hypertension, angina, and arrhythmia. It can be used for diseases such as various circulatory disorders and abnormal lipid metabolism.

본 발명에 포함되는 혼합물은 일반적으로 낮은 독성이며, 더우기 심장의 자발(自發)운동, 그중에서도 심박수(心膊數)만을 특이적으로 억제하고, 심근(心筋) 수축력에의 영향이적다. 이는 본 발명 화합물로 대표되는 N₄-카르바모일피페라지노프로판올형 β 차단제에 공통적으로 보여지는 제일 특징적인 약리작용으로서, 다른 기의 β 차단제예를들면 프로프라노롤 등과 비교했을 경우와의 커다란 상위점이다.The mixtures included in the present invention are generally of low toxicity, furthermore specifically inhibiting only the spontaneous movement of the heart, inter alia, heart rate, and less influence on myocardial contractility. This is the most characteristic pharmacological action commonly seen in the N ₄ -carbamoylpiperazinopropanol type β blocker represented by the compound of the present invention, which is large in comparison with other group β blockers such as propranolol. It is the difference.

제1표에 본 발명에 포함되는 화합물의 대표적예에관해서 랫트 적출심방(摘出心房)의 자발운동 억제효과를 프로프라노롤(propranolol)과 비교하여 나타내며, 활성은 10^-5g/ml의 농도에 있어서의 억제활성을 구하고, 3점법에 의하여 프로프라노롤의 활성을 1.0으로 했을경우의 비활성(比活性)으로서 표시함, 이 데이터에서,Representative examples of the compounds included in the present invention in Table 1 show the effect of inhibiting spontaneous locomotor activity of rat isolated atrial in comparison with propranolol, and the activity was observed at a concentration of 10 ^-5 g / ml. The inhibitory activity in the sample was determined and expressed as inactive when the activity of propranolol was 1.0 by the three-point method.

본 발명 화합물은 기존약제에 필적하는 활성을 갖는다는 것이 명백하다.It is clear that the compound of the present invention has an activity comparable to existing pharmaceuticals.

[표 1]TABLE 1

본 발명에 포함되는 화합물은 모두가 신규물질이며, 아래에 설명하는 방법에 의하여 합성할 수 있다. 가장 일반적인 합성법은 각종의 아릴글리시딜에테르류를 비반응성 용매 예컨데 알코올 용매중에서 N-카르바모일피페라진과 반응시켜는 방법으로서, 이는 매우 간단하게 실시할 수 있다. 이 경우의 수율은 일반적으로 70-90%로서 양호하다. 또, 아릴글리 시딜에테르류를 먼저 과잉의 피페라진과 반응시켜 1-아릴옥시-3-피페라지노-2-프로판올로하고, 이어서 이를 예를들면 니트로 뇨소 또는 시안산염을 사용하여 N-카르바모일화하여 목적물을 합성하는 방법도 유리하다.All of the compounds included in the present invention are novel substances and can be synthesized by the method described below. The most common synthesis method is a method in which various arylglycidyl ethers are reacted with N-carbamoylpiperazine in a non-reactive solvent such as an alcohol solvent, which is very simple. The yield in this case is generally good as 70-90%. Further, arylglycidyl ethers are first reacted with excess piperazine to 1-aryloxy-3-piperazino-2-propanol, followed by N-carba using, for example, nitro urine or cyanate. The method of synthesizing a target object by bundling is also advantageous.

이하 본 발명에 포함되는 화합물의 구체예를들고, 그들의 합성법의 실시예를 나타냄.Hereinafter, the specific example of a compound contained in this invention is given, and the Example of the synthesis method is shown.

[표 2]TABLE 2

[실시예 1]Example 1

-화합물(I)의 합성Synthesis of Compound (I)

2,3-디메틸-4-아미노페놀[Compt. Rend.259, 4719(1964)], 5.7g을 피리딘 50ml에 용해하고, 메탄설포닐클로라이드 9.6g을 냉각해가면서 적하(滴下)하고, 3시간 교반후 하룻밤실온으로서 방치한 다음, 반응액을 어름위에 부어서, 석출된 결정을 여취(濾取)하고, 초산에틸로부터 재결정한다.2,3-dimethyl-4-aminophenol [Compt. Rend. 259 , 4719 (1964)], 5.7 g were dissolved in 50 ml of pyridine, and 9.6 g of methanesulfonyl chloride was added dropwise while cooling. After stirring for 3 hours, the mixture was left at room temperature overnight. The precipitated crystals are filtered off and recrystallized from ethyl acetate.

융 점 : 148-150°, 수량(收量) 6.5g.Melting point: 148-150 °, yield 6.5g.

위에서 얻어진 2,3-디메틸-4-메탄설폰아미노페놀 4.0g을 메틸에틸케톤 100ml 중 무수탄산칼륨 6.0g및 에피브롬히드린 25g과 4시간 가열교반 환류하고, 반응종료후 불용물(不溶物)을 여거하여 용매를 감압하 증류하여 제거하고, 잔류물을 실리카겔컬럼크로마토 그라피로서 정제(精製)한다. (용매 : 벤젠-초산에틸 2 : 1) 무색유상(油狀)의 반응성적체(成績體) 4.1g을 얻는다. 여기서 얻어진 에폭시화합물 4.0g 및 N-카르바모일피페라진 2.0g을 메탄올 100ml 중 6시간 가열 환류한다. 반응 종료후 반응액을 감압하 농축건고(乾固)하고, 잔류물을 실리카겔 컬럼크로마토그라피(Cnlumn Chromato-graph)로서 정제한다. (용매 : 클로로포름-메탄올 8 : 1-3 : 1 혼 액)에테르로서 재결정(再結晶)한다.4.0 g of 2,3-dimethyl-4-methanesulfonaminophenol obtained above was heated and refluxed under stirring with 6.0 g of anhydrous potassium carbonate and 25 g of epibrohydrin in 100 ml of methyl ethyl ketone for 4 hours. The solvent is distilled off under reduced pressure, and the residue is purified by silica gel column chromatography. (Solvent: Benzene-ethyl acetate 2: 1) Obtained 4.1 g of a colorless oily reactive substance. 4.0 g of the epoxy compound obtained and 2.0 g of N-carbamoylpiperazine were heated to reflux for 6 hours in 100 ml of methanol. After the completion of the reaction, the reaction solution was concentrated to dryness under reduced pressure, and the residue was purified as silica gel column chromatography (Cnlumn Chromato-graph). (Solvent: Chloroform-Methanol 8: 1: 1: 1 mixture) Recrystallized from ether.

융 점 : 113-115℃, 수량 4.8gMelting Point: 113-115 ℃, Quantity 4.8g

[실시예 2]Example 2

화합물(2)의 합성Synthesis of Compound (2)

C-브로모티오크로만-4-온옥심과 소듐메톡사이드로서 만든 옥심소듐염을 톨루엔중 에피클로로히드린과 가열환류하여만든 3-(6-브로모티오크로만-4-일리덴옥시미드)-1, 2-에폭시표로판[Europ. J. Med. Chem13, 374(1978)] 2.0g과 N-카르바모일피페라진 0.9g을 에탄올 40ml 중 6시간 가열환류한다. 반응 종료후 감압하 증류건고하고, 잔류물을 실리카겔 컬럼크로마토그라피로서 정제한다. (용매 : 클로로포름 -메탄올 5 : 1 혼액). 무색결정 2.6g을 얻는다.3- (6-bromothiochroman-4-ylideneoxymid)-made by heating and refluxing an oxime sodium salt made of C-bromothiochroman-4-one oxime and sodium methoxide with epichlorohydrin in toluene 1, 2-epoxy fluorophore [Europ. J. Med. Chem 13 , 374 (1978)] 2.0 g and 0.9 g of N-carbamoylpiperazine are heated to reflux for 6 hours in 40 ml of ethanol. After completion of the reaction, the mixture was distilled to dryness under reduced pressure, and the residue was purified by silica gel column chromatography. (Solvent: chloroform-methanol 5: 1 mixture). 2.6 g of colorless crystals are obtained.

융 점 : 101-103℃, 염산염 : 에탄올로서 재결정. 융점 : 186-188℃.Melting point: 101-103 ° C, hydrochloride: Recrystallized as ethanol. Melting point: 186-188 ° C.

6-플루오로티오크로만-3-온옥심로서 출발하고, 위와 같은 방법에 의하여 화합물(17)을 얻는다.Starting as 6-fluorothiochroman-3-one oxime, compound (17) is obtained by the above method.

염산염 : 에탄올로서 재결정한다. 융 점 : 185-187℃Hydrochloride: Recrystallized from ethanol. Melting Point: 185-187 ℃

[실시예 3]Example 3

5-하이드록시-α-테트라론과 에피클로로히드린으로서만든 α-테트라론-5-일 글리시딜에테르[J. Pharm. Sci,60, 1589(1971)] 3.13g과 N-카르바모일피페라진 1.95g을 메탄올 40ml 중 6시간 가열 환류한다. 반응 종료후 반응액을 감압하증류건조하고, 잔류하는 결정을 에탄올에테르혼액으로 재결정한다.Α-tetraron-5-yl glycidyl ether made from 5-hydroxy-α-tetraron and epichlorohydrin [J. Pharm. Sci, 60 , 1589 (1971)] 3.13 g and 1.95 g N-carbamoylpiperazine are heated to reflux for 6 hours in 40 ml of methanol. After completion of the reaction, the reaction solution was evaporated to dryness under reduced pressure, and the remaining crystals were recrystallized from ethanol ether mixture.

융 점 : 178-179℃, 수량 3.9g, 염산염 : 에탄올로서 재결정한다. 융 점 : 149-153℃.Melting point: 178-179 ° C, yield 3.9g, hydrochloride: Recrystallized from ethanol. Melting point: 149-153 ° C.

[실시예 4]Example 4

화합물(10)의 합성Synthesis of Compound (10)

3,4-디하드로쿠마린과 무수염화 알루미늄을 200℃로서 반응시켜 얻어지는 4-하이드록시인다논을 수산화나트륨의 수용액중 에피클로로히드린과 반응시켜 4-(2,3-에폭시프로폭시)-1-인다논을 얻는다(특공소 48-817호 공보). 여기서 얻어진 인다논 글리시딜에테르 6.15g과 N-카르바모일피페라진 3.87g을 메탄올 90ml 중 3.5시간 가열환류한다. 반응 종료후 반응액을 감압하 건고하고 잔류한 결정을 에탄올-n-헥산혼액으로서 재결정한다.4- (hydroxydinon) obtained by reacting 3,4-dihydrocoumarin and anhydrous aluminum chloride at 200 ° C. with epichlorohydrin in an aqueous solution of sodium hydroxide to react 4- (2,3-epoxypropoxy)- Obtain 1-Indannon (Publication No. 48-817). 6.15 g of indanone glycidyl ether and 3.87 g of N-carbamoylpiperazine obtained here were heated to reflux for 3.5 hours in 90 ml of methanol. After the reaction was completed, the reaction solution was dried under reduced pressure, and the remaining crystals were recrystallized as an ethanol-n-hexane mixture.

융 점 : 161-163℃, 수량 6.98g 염산염 에탄올로서 재결정한다. 융 점 : 143-150℃.Melting point: 161-163 ° C, water content 6.98 g Recrystallized from ethanol hydrochloride. Melting point: 143-150 ° C.

[실시예 5]Example 5

화합물(8)의 합성Synthesis of Compound (8)

4-하이드록시인다논으로부터 1,4-인단디올, 4-아세톡시-1-인다놀, 4-아세톡시-1-인덴을 거쳐서 얻어지는 4-하이드록-1-인덴올 수산화나트륨의 수용액중 에피클로로히드린과 반응시켜 4-(2,3-에폭시프로폭시)인덴을 얻는다. 약학잡지,92, 1358(1972) 여기서 얻어진 인덴글리시딜 에테르 1.89g과 N-카르바모일피페라진 1.24g을 메탄올 50ml 중 4시간 가열환류한다. 반응종료후 메탄올을 유거하고, 잔류하는 결정을 에탄올-초산에틸혼액으로서 재결정한다.Epi in aqueous solution of 4-hydroxy-1-indenol sodium hydroxide obtained from 4-hydroxyindanon via 1,4-indanediol, 4-acetoxy-1-indanol, 4-acetoxy-1-indene Reaction with chlorohydrin affords 4- (2,3-epoxypropoxy) indene. Pharmaceutical Journal, 92 , 1358 (1972) 1.89 g of indenglycidyl ether and 1.24 g of N-carbamoylpiperazine obtained here are heated and refluxed in 50 ml of methanol for 4 hours. Methanol is distilled off after completion | finish of reaction, and the remaining crystal | crystallization is recrystallized as ethanol-ethyl acetate mixture.

융 점 : 127-129℃. 수량 1.84g. 염산염 : 에탄올로서 재결정한다. 융 점 : 185-190℃.Melting point: 127-129 ° C. Quantity 1.84 g. Hydrochloride: Recrystallized from ethanol. Melting point: 185-190 ° C.

[실시예 6]Example 6

화합물(9)의 합성Synthesis of Compound (9)

5-하이드록시-α-테트라졸로서 만든 7,8-디히히드로 α-나프톨과 에피클로로히드린을 수산화나트륨의 수용액중에 반응시켜 1-(2,3-에폭시프로폭시)-7,8-디히드로나프탈렌을 얻는다. [J.Med,21, 913(1978)] 여기서 얻어지는 에폭시화합물 1.49g을 N-카르바모일피페라진 0.97g과 메탄올 40ml 중 5시간 가열환류한다. 반응 종료후 감압하 메탄올을 증류하여 제거하고, 잔류하는 결정을 에탄올로서 재결정한다.7,8-dihydroα-naphthol and epichlorohydrin made as 5-hydroxy-α-tetrazole in 1- (2,3-epoxypropoxy) -7,8-di by reaction in an aqueous solution of sodium hydroxide Obtain hydronaphthalene. [J. Med, 21 , 913 (1978)] 1.49 g of the epoxy compound obtained here was heated to reflux for 5 hours in 0.97 g of N-carbamoylpiperazine and 40 ml of methanol. After completion of the reaction, methanol was distilled off under reduced pressure, and the remaining crystals were recrystallized as ethanol.

융 점 : 163-164℃, 수량 1.94g. 염산염 : 에탄올로서 재결정한다. 융 점 : 201-203℃.Melting point: 163-164 ° C., yield 1.94 g. Hydrochloride: Recrystallized from ethanol. Melting point: 201-203 ° C.

[실시예 7]Example 7

화합물(4)의 합성Synthesis of Compound (4)

1,5-디히드록시나프탈렌을 에탄올중 같은물의 소듐에톡사이드와 반응시켜 모노나트륨염으로 하고, 계속해서 에피클로로히드린과 반응시켜 얻어지는 1-(2,3-에폭시프로폭시)-5-하이드록시나프탈렌 2.73g을 메탄올 70ml 중 N-카르바모일피페라진 1.63g과 5시간 가열 환류한다. 반응종료후, 메탄올을 감압하 증류하여 제거하고, 잔류물을 실리카겔컬럼크로마토그라피로서 정제한다.1- (2,3-epoxypropoxy) -5- obtained by reacting 1,5-dihydroxynaphthalene with sodium ethoxide of the same water in ethanol to monosodium salt, followed by reaction with epichlorohydrin 2.73 g of hydroxynaphthalene is heated to reflux with 1.63 g of N-carbamoylpiperazine in 70 ml of methanol for 5 hours. After completion of the reaction, methanol is distilled off under reduced pressure, and the residue is purified as silica gel column chromatography.

융 점 : 93-94℃, 수량 3.2g. 염산염 : 에탄올로서 재결정한다. 융점 149-151℃.Melting Point: 93-94 ℃, Quantity 3.2g. Hydrochloride: Recrystallized from ethanol. Melting point 149-151 ° C.

[실시예 8]Example 8

화합물(6)의 합성Synthesis of Compound (6)

5,6,7,8-테트라하이드로-1-나프톨을 메탄올중 소듐메톡 사이드와 반응시켜 나트륨염으로하고, 계속해서 에피클로로 히드린과반응시켜 1-(2,3-에폭시프로폭시) -5,6,7,8-테트라히드로나프탈렌을 얻는다. (특개소 52-53842호)여기서 얻어진 에폭시화합물 10g 및 N-카르바모일피페라진 7g을 메탄올 140ml중 2.5시간 가열 환류한다. 반응종료후 메탄올을 감압하 증류하여 제거하고, 잔류하는 결정을 에탄올 n-헥산혼액으로서 재결정한다.5,6,7,8-tetrahydro-1-naphthol is reacted with sodium methoxide in methanol to make sodium salt, followed by epichlorohydrin to give 1- (2,3-epoxypropoxy) -5 Obtain 6,7,8-tetrahydronaphthalene. 10 g of the epoxy compound obtained here and 7 g of N-carbamoylpiperazine are heated and refluxed in 140 ml of methanol for 2.5 hours. After completion of the reaction, methanol is distilled off under reduced pressure, and the remaining crystals are recrystallized as ethanol n-hexane mixture.

융 점 : 134-136℃. 수량 10.74g, 염산염 : 에탄올로서 재결정한다. 융 점 : 189-193℃.Melting point: 134-136 ° C. Yield 10.74 g, hydrochloride: Recrystallized from ethanol. Melting point: 189-193 ° C.

[실시예 9]Example 9

화합물(5)의 합성Synthesis of Compound (5)

이소바닐린으로서 4공정을 거쳐서 합성되는 5-메틸-8-하이드록시쿠마린을 메틸에틸케톤중, 탄산칼륨 존재하에 에피브롬히드린과 반응시켜 5-메틸-8-(2, 3-에폭시프로폭시) 쿠마린을 얻는다. [Chem. Pharm. Bull 20,905(1972)]. 여기서 얻어진 에폭시화합물 3.0g을 N-카르바모일피페라질 1.75g과 메탄올 50ml 중 7시간 가열 환류한다. 반응 종료후 메탄올을 감압하 증류하여 제거하고, 잔류물을 실리카겔컬럼크 로마토그라피로서 정제. (융매 : 클로로포름-메탄올 8:1-3:1) 에테르로서 재결정한다.5-Methyl-8-hydroxycoumarin synthesized in four steps as isovanillin is reacted with epibromhydrin in the presence of potassium carbonate in methyl ethyl ketone to 5-methyl-8- (2,3-epoxypropoxy) Get coumarin Chem. Pharm. Bull 20,905 (1972). 3.0 g of the epoxy compound obtained here was heated to reflux for 7 hours in 1.75 g of N-carbamoylpiperazil and 50 ml of methanol. After completion of the reaction, methanol was distilled off under reduced pressure, and the residue was purified by silica gel column romanography. (Solvent: chloroform-methanol 8: 1-3: 1) Recrystallized as ether.

융 점 : 171-173℃. 수량 3.2g.Melting point: 171-173 ° C. Quantity 3.2g.

[실시예 10]Example 10

7-하이드록시쿠마린을 메틸에틸케톤중 무수탄산칼륨 존재하에 에피브롬히드린과 반응시켜 얻어지는 7-(2,3-에폭시프로폭시) 쿠마린 5.0g 및 N-카르바모일피페라진 3.1g을 메탄올 10ml 중 7시간 가열환류한다. 반응종료후 메탄올을 감압하 증류하여 제거하고, 잔류하는 결정을 초산에틸로서 세척한다.5.0 g of 7- (2,3-epoxypropoxy) coumarin and 3.1 g of N-carbamoylpiperazine obtained by reacting 7-hydroxycoumarin with epibromhydrin in the presence of anhydrous potassium carbonate in methyl ethyl ketone in 10 ml of methanol Heat reflux for 7 hours. After completion of the reaction, methanol is distilled off under reduced pressure, and the remaining crystals are washed with ethyl acetate.

수량 7.9g, 염산염 : 에탄올-DMF 혼액으로 재결정한다. 융 점 : 198-200℃.Yield 7.9 g, hydrochloride: Recrystallize from ethanol-DMF mixture. Melting point: 198-200 ° C.

[실시예 11]Example 11

화합물(12)의 합성,Synthesis of compound (12),

4-하이드록시인돌과 에피클로로히드린으로서 얻어지는 4-(2,3-에폭시프로폭시)인돌 1.92g(네델란드 특허 6,601,040호) 및 N-카르바모일피페라진 1.38g을 메탄올 60ml 중 6시간가열환류한다. 반응종료후 메탄올을 감압하여 증류하여 제거하고, 잔류하는 결정을 메탄올로서 재결정한다.1.92 g of 4- (2,3-epoxypropoxy) indole obtained as 4-hydroxyindole and epichlorohydrin (Dutch Patent 6,601,040) and 1.38 g of N-carbamoylpiperazine were heated for 6 hours in 60 ml of methanol. do. After completion of the reaction, methanol is distilled off under reduced pressure, and the remaining crystals are recrystallized as methanol.

융 점 : 193-195℃. 수량 2.6g, 염산염 : 에탄올로서 재결정한다. 융 점 : 184-187℃.Melting point: 193-195 ° C. Yield 2.6 g, hydrochloride: Recrystallized from ethanol. Melting point: 184-187 ° C.

[실시예 12]Example 12

화합물(13)의 합성Synthesis of Compound (13)

시클로헥산-1,3-디온과 아크릴로니트릴로서 3공정을 거쳐서얻어지는 5-하이드록시-3,4-디히드로-2-퀴놀리논과 에피클로로 히드린으로서 얻어지는 5-(2,3-에폭시프로폭시)-3,4-디히드로-2-퀴놀리논[J. Med.Chem17, 5291(974)] 0.4g 및 N-카르바모일피페라진 0.27g을 메탄올 20ml 중 3시간 가염환류한다. 반응종료후 메탄올을감압하 증류하여 제거하고, 잔류물을 실리카겔 컬럼크로마토그라피로서 정제한다.5- (2,3-epoxypro) obtained as 5-hydroxy-3,4-dihydro-2-quinolinone and epichlorohydrin obtained through three steps as cyclohexane-1,3-dione and acrylonitrile. Foxy) -3,4-dihydro-2-quinolinone [J. Med. Chem 17 , 5291 (974)] 0.4 g and 0.27 g of N-carbamoylpiperazine are salt refluxed for 3 hours in 20 ml of methanol. After completion of the reaction, methanol is distilled off under reduced pressure and the residue is purified as silica gel column chromatography.

(용 매 : 클로로포름-메탄올 8 : 1 혼액). 에탄올-N-헥산혼액으로서 재결정. 융 점 : 200-203℃.(Solvent: chloroform-methanol 8: 1 mixture). Recrystallized as ethanol-N-hexane mixture. Melting point: 200-203 ° C.

수량 0.50g.Quantity 0.50g.

[실시예 13]Example 13

화합물(14)의 합성Synthesis of Compound (14)

m-하이드록시아닐린과 β-클로로프로피오닐클로리드로서 2공정으로 얻어지는 7-하이드록시-3,4-디히드로-2-퀴놀리논을 에피클로로히드린과 반응시켜 7-(2,3-에폭시프로폭시)-3,4-디히드로-2-퀴놀리논을 얻는다. [J. Med. Chem.17, 529(1974)] 여기서 얻어진 에폭시 화합물 1.0g을 N-카르바모일피페라진 0.6g과 메탄올 30ml 중 2.5시간 가열환류한다. 반응 종료 후 메탄올을 감압하증류하여 제거하고, 잔류물을 실리카겔컬럼크로마토그라피로서 정제(용매 : 클로로포름-메탄올 8 : 1 혼액). 에탄올-n-헥산혼액으로 재결정한다.7-hydroxy-3,4-dihydro-2-quinolinone obtained in two steps as m-hydroxyaniline and β-chloropropionyl chloride was reacted with epichlorohydrin to give 7- (2,3- Epoxypropoxy) -3,4-dihydro-2-quinolinone is obtained. [J. Med. Chem. 17 , 529 (1974)] 1.0 g of the epoxy compound obtained here was heated to reflux for 2.5 hours in 0.6 g of N-carbamoylpiperazine and 30 ml of methanol. After completion of the reaction, methanol was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (solvent: chloroform-methanol 8: 1 mixture). Recrystallize from ethanol-n-hexane mixture.

융 점 : 85-90℃. 수량 0.93g. 염산염 : 에탄올로서 재결정한다. 융 점 : 154-157℃.Melting point: 85-90 ° C. Quantity 0.93 g. Hydrochloride: Recrystallized from ethanol. Melting point: 154-157 ° C.

[실시예 14]Example 14

화합물(15)의 합성Synthesis of Compound (15)

메타크레졸로서 6공정을 거쳐서 얻어지는 2-(2,3-에폭시프로폭시) -4- 메틸-6-니트로아닐린 1.83g(특개소 54-112866호 공보) 및 N-카르바모일피레라진 1.11g을 메탄올 20ml 중 6시간 가열환류한다. 반응 종료후 메탄올을 감압하 증류하여 제거하고, 잔류물을 실리카겔컬럼크로마토그라피로서 정제(용매 : 클로로포름-메탄올 4 : 1 혼액). 적등색(赤橙色) 유리상물질 2.1g을 얻는다. 매스스펙트럼 : M+m/e=353, 베이스피이크 m/e=99,1.83 g of 2- (2,3-epoxypropoxy) -4-methyl-6-nitroaniline (JP-A 54-112866) and 1.11 g of N-carbamoylpyrazine obtained through six steps as methacresol Heat reflux for 6 hours in 20 ml of methanol. After completion of the reaction, methanol was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (solvent: chloroform-methanol 4: 1 mixture). Obtain 2.1 g of red-orange glassy matter. Mass Spectrum: M + m / e = 353, Base Peak m / e = 99,

여기서 얻어진 반응성적체 1.80g을 메탄올 50ml에 용해하고, 라네이니켈촉매 약 1ml을 가하여 상온상압으로 접촉환원시킨다. 수소가스의 흡수가 정지한다음 촉매를 증류하여 제거하고, 여액을 감압하 농축건고 한다. 잔류물을 에탄올 30ml에 용해하고, 크산토겐산칼륨 0.82g을 가하고, 6시간 가열환류한다. 반응 종료후 에탄올을 감압하증류 하여제거하고, 잔류물을 실리카겔 컬럼크로마토그라피로서 정제,1.80 g of the reactive substance obtained here is dissolved in 50 ml of methanol, and about 1 ml of a raney nickel catalyst is added to carry out contact reduction at room temperature and normal pressure. After absorption of hydrogen gas stops, the catalyst is distilled off and the filtrate is concentrated to dryness under reduced pressure. The residue is dissolved in 30 ml of ethanol, 0.82 g of potassium xanthogenate is added and heated to reflux for 6 hours. After completion of the reaction, ethanol was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography,

(용매 : 클로로포름-메탄올 4 : 1 혼액). 에탄올로서재결정. 융 점 : 226-229℃. 수량 1.2g.(Solvent: chloroform-methanol 4: 1 mixture). Recrystallize as ethanol. Melting point: 226-229 ° C. Quantity 1.2g.

[실시예 15]Example 15

화합물(16)의 합성Synthesis of Compound (16)

3-아세틸-4-하이드록시벤질시아니드[약학잡지,78, 647(1957)] 7.5g을 농염산 30ml 중 50℃로서 2시간 가온하고 어름위에 부어서 냉각, 석출하는 결정을 여취. 초산에틸로서 재결정.7.5 g of 3-acetyl-4-hydroxybenzyl cyanide (Pharmaceutical magazine, 78 , 647 (1957)) was heated at 50 ° C. in 30 ml of concentrated hydrochloric acid for 2 hours, poured over ice, and cooled and precipitated. Recrystallized as ethyl acetate.

융 점 : 162-163℃. 수량 5.4g,Melting point: 162-163 ° C. Quantity 5.4 g,

위해서 얻어진 3-아세틸-4-하이드록시페닐아세트아미드 1.0g을 금속나트륨 0.12g을 용해한 메탄올 10ml 중에서 용해하고, 에피클로로히드린 10ml을 가하여 6시간 가열 교반환류한다. 반응 종료후 반응액을 감압하고 견고하고, 잔류물을 초산에틸로서 추출. 초산에틸층을 수세, 건조후감압하에 증류하여 제거하고, 잔류한 결정을 초산에틸로서 재결정한다.1.0 g of 3-acetyl-4-hydroxyphenylacetamide thus obtained is dissolved in 10 ml of methanol in which 0.12 g of metallic sodium is dissolved, and 10 ml of epichlorohydrin is added thereto, followed by heating and refluxing for 6 hours. After the reaction was completed, the reaction solution was dried under a reduced pressure, and the residue was extracted as ethyl acetate. The ethyl acetate layer was washed with water, dried under reduced pressure, distilled off, and the remaining crystals were recrystallized as ethyl acetate.

융 점 : 85-87℃. 수량 0.75g.Melting point: 85-87 ° C. Quantity 0.75 g.

여기서 얻어진 3- 아세틸-4-(2,3-에폭시프로폭시) 페닐아세트아미드 0.62g을 N-카르바모일피페라진 0.34g과 메탄올 10ml 중 8시간 가열환류하고, 반응종료후 메탄올을 감압하증류하여 제거하여 잔류하는 반응성적체를 실리카겔컬럼크로마토그라피로서. (정체 : 용매클로로포름-메탄올 3 : 1). 무색유상의 (16) 물질 0.80g을 얻는다.0.62 g of 3-acetyl-4- (2,3-epoxypropoxy) phenylacetamide obtained here was heated to reflux for 8 hours in 0.34 g of N-carbamoylpiperazine and 10 ml of methanol, and methanol was distilled under reduced pressure after the reaction was completed. Reactive material remaining after removal by silica gel column chromatography. (Identification: solvent chloroform-methanol 3: 1). 0.80 g of colorless (16) material is obtained.

염산염 : 에탄올로서 재결정한다. 융 점 : 143-145℃.Hydrochloride: Recrystallized from ethanol. Melting point: 143-145 ° C.

[실시예 16]Example 16

화합물(7)의 합성Synthesis of Compound (7)

3-메틸-4-메톡시벤즈알데히드와 니트로메탄올 빙초산중 초산암모늄 존재하에 3시간 가열환류하여 만든 3-메틸-4-메톡시-β-니트로스티렌을 아연아말감과 염산으로서 에탄올중, 환원하고, 3-메틸-4-메톡시-β-페네틸아민을 얻는다. 여기서 얻어진 페네릴아민을 농취화수소산중 3시간 가열환류하고, 반응종료후 반응액을 감압하 증발건조하면 3-메틸-4-하이드록시-β-페네틸아민취화수소산염이 잔류한다. 여기서 얻어진 취화수소산염을 수산화나트륨용액에 용해하고, 클로로탄산메틸을 가하여 실온으로 1시간심하게 교반한다. 반응 종료후 반응액에 염화암모늄을 가하여 암모니아알칼리성으로 하고 반응성적체를 초산에틸로서 추출한다. 무색유상의 N-카르보메톡시 -3-메틸-4-하이드록시페네틸아민을 얻는다. NMR스펙트럼(중클로로포름중) : 2.20ppm, 3H싱글리트 2.5-2.8ppm, 2H 트리플리트 : 3.2-3.45ppm, 2H트리플리트 : 3.62ppm, 3H싱글리트 : 6.7-6.9ppm, 3H멀티플리트. 금속나트륨 0.94g을 메탄올 30ml에 용해하고, 위에서 얻어진 반응성적체 8.85g을 가하고, 다시 에피클로로히드린 30ml을 가하여 6시간 가열환류한다. 반응 종료후 반응 액을 감압하증발건고 하고, 잔류물을 초산 에틸로서 추출한다. 추출물을 실리카겔 컬럼크로마토그라피로서 정제(용매 : 벤젠-초산에틸 2 : 1 혼액).3-methyl-4-methoxy-β-nitrostyrene made by heating under reflux for 3 hours in the presence of ammonium acetate in 3-methyl-4-methoxybenzaldehyde and nitromethanol glacial acetic acid was reduced in ethanol as zinc amalgam and hydrochloric acid, -Methyl-4-methoxy-β-phenethylamine is obtained. The fenerylamine obtained here is heated to reflux for 3 hours in concentrated hydrochloric acid, and after completion of the reaction, the reaction solution is evaporated to dryness under reduced pressure to leave 3-methyl-4-hydroxy-β-phenethylamine emulsified hydrochloride. The brittle hydrochloride obtained here is dissolved in a sodium hydroxide solution, methyl chlorocarbonate is added, and the mixture is stirred vigorously at room temperature for 1 hour. After completion of the reaction, ammonium chloride was added to the reaction solution to make ammonia alkaline, and the reactive body was extracted as ethyl acetate. A colorless oily N-carbomethoxy-3-methyl-4-hydroxyphenethylamine is obtained. NMR spectrum (in medium chloroform): 2.20 ppm, 3H singlet 2.5-2.8 ppm, 2H triplet: 3.2-3.45 ppm, 2H triplet: 3.62 ppm, 3H singlet: 6.7-6.9 ppm, 3H multiply. 0.94 g of sodium metal is dissolved in 30 ml of methanol, 8.85 g of the reactive substance obtained above is added, and 30 ml of epichlorohydrin is further added thereto, followed by heating under reflux for 6 hours. After completion of the reaction, the reaction solution was evaporated to dryness under reduced pressure, and the residue was extracted as ethyl acetate. The extract was purified by silica gel column chromatography (solvent: benzene-ethyl acetate 2: 1 mixture).

융 점 : 56-57℃. 수량 8.3g.Melting point: 56-57 ° C. Quantity 8.3g.

여기서 얻어진 N-카르보메톡시-3-메틸-4-(2,3-에폭시프로폭시)-β-페네틸아민 4.0g과 N-카르바모일피페라진 2.0g을 메탄올 50ml 중 6시간 가열환류한다. 반응 종료후 메탄올을 감압하증류하여 제거하고, 잔류물을 실리카겔컬럼크로마토 그라피로서 저에(용매 : 클로로포름-메탄올 4 : 1 혼액). 무색유상의 반응성적체 5.8g을 얻었다.4.0 g of N-carbomethoxy-3-methyl-4- (2,3-epoxypropoxy) -β-phenethylamine and 2.0 g of N-carbamoylpiperazine obtained here are heated and refluxed in 50 ml of methanol for 6 hours. . Methanol was distilled off under reduced pressure after completion | finish of reaction, and the residue was made into silica gel column chromatography (solvent: chloroform-methanol 4: 1 mixture). 5.8 g of a colorless oily reactive substance were obtained.

염산염 : 에탄올로서 재결정한다. 융점 : 174-176℃.Hydrochloride: Recrystallized from ethanol. Melting point: 174-176 ° C.

[실시예 17]Example 17

화합물(18),(25)의 합성Synthesis of Compounds (18) and (25)

티라민(tyramine) 염산염 6.gg을 10% 수산화나트륨 수용액 50ml에 용해하고, 교반하클로로탄산이소부틸 7.0g을 적하한다. 30분간 실온에서 교반을 계속 한다음 반응액을 염산산성으로하여 에케르추출한다. 추출물을 이소프로판올 30ml에 용해하고, 10% 수산화나트륨수용액 30ml을 가하여 실온에서 30분간 교반한다. 반용액을 물 200ml로서 희석하고, 에테르로서 세척한후염산으로 산성화시키고 에테르추출한다. 무색유상의 반응성적체 8.8g을 얻는다. 여기서 얻어진 반응성적체 8.6g을 DMF 100ml에 용해하고, 아릴브로마이드 6.6g 및 무수탄산칼륨 7.0g을 가하여 70-80℃로서 3시간 교반, 물 400ml로서 반용액을 희석하고, 에테르로 추출, 담황색결정 6.4g을 얻는다.6.gg of tyramine hydrochloride is dissolved in 50 ml of 10% aqueous sodium hydroxide solution, and 7.0 g of isobutyl chlorocarbonate is added dropwise while stirring. Stirring was continued at room temperature for 30 minutes, and then the reaction solution was extracted with acid hydrochloric acid. The extract is dissolved in 30 ml of isopropanol, 30 ml of 10% aqueous sodium hydroxide solution is added and stirred at room temperature for 30 minutes. The semi-solution is diluted with 200 ml of water, washed with ether, acidified with hydrochloric acid and extracted with ether. 8.8 g of a colorless oily reactive substance is obtained. Dissolve 8.6 g of the reactive product obtained in 100 ml of DMF, add 6.6 g of aryl bromide and 7.0 g of anhydrous potassium carbonate, stir at 70-80 ° C. for 3 hours, dilute semi-solution with 400 ml of water, extract with ether, and pale yellow crystals 6.4. get g

융 점 : 57-59℃.Melting point: 57-59 ° C.

(N-카르보이소부톡시 C-아릴티라민). 여기서 얻어진 반응성적체 6.0g을 N-디메틸아닐린 25ml 중 6시간 가열환류한다. 냉각후 반용액을 에테르로서 희석하고, 5% 염산으로 세척후 2% 수산화나트륨 수용액으로 추출한다. 알칼리추출액은 즉시 염산으로 산성화시키고 에테르로 추출하면 N-카르보이소부톡시-3-아릴티라민 4.3g이 얻어진다.(N-carboisobutoxy C-aryltyramine). 6.0 g of the reactive product obtained here was heated to reflux for 6 hours in 25 ml of N-dimethylaniline. After cooling, the semi-solution is diluted with ether, washed with 5% hydrochloric acid and extracted with 2% aqueous sodium hydroxide solution. The alkaline extract was immediately acidified with hydrochloric acid and extracted with ether to give 4.3 g of N-carboisobutoxy-3-aryltyramine.

융 점 : 70-71℃.Melting point: 70-71 ° C.

위에서 얻어진 화합물 4.0g을 DMF 30ml에 용해하고, 에피브롬히드린 10ml, 무수탄산칼륨 5.0g을 가하여 70-80℃로서 3시간 교반한다. 반용액을 물 200ml로서 희석하고, 에테르로 추출하면 부색유상의 반응성적체 5.0g이 얻어진다. 이를 메탄올 500ml에 용해하고, N-카르바모일피페라진 2.5g을 가하여 2시간 가열환류한다. 반용액을 감압하증발건고하고, 잔류물을 실리카켈컬럼크로마토그라피로 서정(제용 : 매클로로포름-메탄올 10 : 1혼액). 얻어지는 반응성적체(화합물(25))를 염산염으로하여 이소프로판올로서 재결정한다.4.0 g of the compound obtained above was dissolved in 30 ml of DMF, 10 ml of epibrohydrin and 5.0 g of anhydrous potassium carbonate were added, followed by stirring at 70-80 ° C. for 3 hours. The semi-solution is diluted with 200 ml of water and extracted with ether to give 5.0 g of a colorant reactive substance. This was dissolved in 500 ml of methanol, and 2.5 g of N-carbamoylpiperazine was added and heated to reflux for 2 hours. The semi-solution was evaporated to dryness under reduced pressure, and the residue was subjected to silica gel column chromatography to prepare (for example: chloroform-methanol 10: 1 mixture). The resulting reactive product (Compound (25)) is hydrochloride and recrystallized as isopropanol.

융 점 : 175-178℃, 수량 3.88g.Melting point: 175-178 ° C., yield 3.88 g.

클로로탄산이소부틸 대신에 클로로탄산에틸을 사용하고, 위와같이 반응시키면 화합물(18)이 얻어진다.Ethyl chloro carbonate was used instead of isobutyl chloro carbonate, and the reaction was carried out as described above to obtain compound (18).

염산염 : 에탄올로서 재결한다.Hydrochloride: Recrystallized as ethanol.

융 점 : 165-167℃.Melting point: 165-167 ° C.

[실시예 18]Example 18

화합물(19),(31)의 합성Synthesis of Compounds (19), (31)

p-하이드록시페닐초산 5.0g을 DMF 30ml에 용해하고, 아릴브로마이드 100ml및 무수탄산칼륨 10g을 가하여 70-80℃로서 6시간 교반한다. 반용액을 물 300ml로서 희석하여 에테르로 추출하고, 얻어지는 추출물을 그대로 메탄올 100ml에 용해고고, 15% 탄산칼륨수용액 30ml을 가하여 1시간 가열환류한다. 반응액을 감압하 농축하고, 물 100ml을 가하여 에테르로서 세척후 염산성으로하여 에테르추출한다. p-아릴옥시페닐초산 5.0g을 얻는다.5.0 g of p-hydroxyphenylacetic acid is dissolved in 30 ml of DMF, and 100 ml of aryl bromide and 10 g of anhydrous potassium carbonate are added, followed by stirring at 70-80 ° C. for 6 hours. The semi-solution is diluted with 300 ml of water, extracted with ether, the resulting extract is dissolved in 100 ml of methanol as it is, and 30 ml of 15% aqueous potassium carbonate solution is added and heated to reflux for 1 hour. The reaction solution is concentrated under reduced pressure, and 100 ml of water is added thereto, washed with ether, followed by hydrochloric acid, and ether extraction. 5.0 g of p-aryloxyphenyl acetates are obtained.

융 점 : 61-62℃.Melting point: 61-62 ° C.

이를 벤젠 500ml에 용해하고, SOCl2 4ml을 가하여 1시간 가열환류한다. 반용액을 감압하 증발건고하고 잔류물을 벤젠 50ml에 용해, 빙냉교반하 n-부틸아민 10ml을 적하하고, 실온으로 2시간 교반한다. 반용액을 1% 염산으로 세척후 증발하여 제거하면 N-n-부틸-p-아릴옥시페닐 아세트아미드 5.87g을 얻는다.This is dissolved in 500 ml of benzene, and 4 ml of SOCl2 is added and heated to reflux for 1 hour. The semi-solution was evaporated to dryness under reduced pressure, the residue was dissolved in 50 ml of benzene, 10 ml of n-butylamine was added dropwise under ice-cooling stirring, and stirred at room temperature for 2 hours. The semi-solution is washed with 1% hydrochloric acid and evaporated to remove 5.87 g of N-n-butyl-p-aryloxyphenyl acetamide.

융 점 : 87-89℃Melting Point: 87-89 ℃

이를 N,N-디메틸아닐린 20ml 중에 용해하고, 6시간 가열환류한다. 반응액을 냉각후 에테르 100ml로서 희석하고, 5% 염산으로 세척후 2% 수산화나트륨으로 추출하고, 알칼리추출액을 즉시 염산산성으로하여 에테르추출한다. N-n-부틸-3-아릴-4-하이드록시페닐아세트아미드 4.8g을 얻는다.It is dissolved in 20 ml of N, N-dimethylaniline and heated to reflux for 6 hours. The reaction solution is cooled, diluted with 100 ml of ether, washed with 5% hydrochloric acid, extracted with 2% sodium hydroxide, and the alkaline extract is immediately extracted with hydrochloric acid. 4.8 g of N-n-butyl-3-aryl-4-hydroxyphenylacetamide is obtained.

융 점 : 48-50℃.Melting point: 48-50 ° C.

여기서 얻어진성적체 4.8g을 DMF 30ml에 용해하고, 에피브롬히드린 15ml, 무수탄산칼륨 10g을 가하여 75-80℃로서 2시간 교반한다.4.8 g of the obtained substance is dissolved in 30 ml of DMF, 15 ml of epibrohydrin and 10 g of anhydrous potassium carbonate are added, followed by stirring at 75-80 ° C for 2 hours.

물 100ml로서 희석하여, 에르르 추출하고, 얻어지는 추축물을 실리카겔컬럼 크로마토그라피로 정제(용매 : 클로로포름-초산에틸 8 : 1 혼액). 여기서 얻어지는 유상의 페닐글리시딜에테르 4.3g을 메탄올 50ml에 용해하고, N-카르바모일피페라진 2.0g을 가하여 2시간 가열 환류하나다. 반응요액을 감압하 증발건고하고, 잔류물을 실리카겔 컬럼 크로마토그라피로 정제(용매 : 클로로포름-메탄올 10 : 1 혼액) 화합물(31)을 업는다. 염산염 : 이소프로판올로서 재결정한다.Dilution with 100 ml of water, er extraction, and the resulting extract were purified by silica gel column chromatography (solvent: chloroform-ethyl acetate 8: 1 mixture). 4.3 g of the oily phenylglycidyl ether obtained here is dissolved in 50 ml of methanol, and 2.0 g of N-carbamoylpiperazine is added thereto, followed by heating to reflux for 2 hours. The reaction solution was evaporated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (solvent: chloroform-methanol 10: 1 mixture) to give compound (31). Hydrochloride: Recrystallized as isopropanol.

융 점 :162-164℃. 수 량 : 5.18g.Melting point: 162-164 ° C. Quantity: 5.18g.

n-부틸아민 대신에 디에틸아민을 사용하고, 상기한 바와 같이 반응시키면 화합물(19)가 얻어진다.Compound (19) is obtained when diethylamine is used instead of n-butylamine and reacted as described above.

염산염 : 이소프로판올로서 재결정한다.Hydrochloride: Recrystallized as isopropanol.

융 점 : 126-128℃. 수 량 : 4.80g.Melting point: 126-128 ° C. Quantity: 4.80g.

[실시예 19]Example 19

화합물(20),(26)의 합성Synthesis of Compound (20), (26)

0-이소프로필아니솔 55g, 포르말린 35g 및 염화아연 9g의 혼합물에 빙냉교반하 4시간 염산가스를 통하게 한다. 반응물을 빙수중에 가하고, 에테르로 추출, 조제(助劑)의 3-이소프로필-4-메톡시벤질클로라이드 70g을 얻는다. 시안화칼륨 26g을 아세트니트릴 400ml 중에 가하고, 18-클라운-6 100mg을 가하여 가열교반환류하여, 위에서 얻어진 벤질클로라이드를 적하한다. 적하후 10시간 가열교반환류한다. 반응액을 감압하 농축하고, 잔여물에 물을 가한후 에테르로 추출한다. 얻어지는 추출물을 감압증류에 붙여 정제한다. 3-이소프로필-4-메톡시벤질시아니다.A mixture of 55 g of 0-isopropylanisole, 35 g of formalin and 9 g of zinc chloride is passed through hydrochloric acid gas under ice-cooling stirring for 4 hours. The reaction is added to ice water and extracted with ether to give 70 g of crude 3-isopropyl-4-methoxybenzylchloride. 26 g of potassium cyanide was added to 400 ml of acetonitrile, and 100 mg of 18-Clear-6 was added thereto, followed by heating and refluxing to add dropwise benzyl chloride. After dropping, the mixture was heated and refluxed for 10 hours. The reaction solution is concentrated under reduced pressure, water is added to the residue, followed by extraction with ether. The resulting extract is subjected to reduced pressure distillation and purified. 3-isopropyl-4-methoxybenzylcia.

비 점 : 120-125℃/1mmHg. 수 량 : 40g.Boiling Point: 120-125 ° C / 1mmHg. Quantity: 40g.

리틈알미늄하이드라이드 2.4g을 무수에테르 100ml에 현탁하고, 실온교반하, 무수염화알루미늄 8.2g의 무수에테르 50ml을 가하고, 5분간 교반한다. 위에서 얻어진 벤질시아나이드 10.6g을 무수에테르 20ml에 용해하여, 상기한 반응액중에 적하하고, 4다시 1시간 교반한다. 이후 통상적인 방법에 따라 처리하고, 염기성물질을 에테르로 추출한다. 무색유상의 3-이소프로필-4-메톡시-β-페네틸아민 8.6g을 얻는다.2.4 g of rilim aluminum hydride is suspended in 100 ml of anhydrous ether, 50 ml of anhydrous ether of 8.2 g of anhydrous aluminum chloride is added under room temperature stirring, and it stirs for 5 minutes. 10.6 g of the benzyl cyanide obtained above is dissolved in 20 ml of anhydrous ether, it is dripped in the said reaction liquid, and it stirs for 4 hours for 1 hour. It is then treated according to conventional methods and the basics are extracted with ether. 8.6 g of colorless oily 3-isopropyl-4-methoxy-β-phenethylamine are obtained.

여기서 얻어진 페네틸아민 3.8g을 아세톤 50ml에 용해하여, 무수탄산칼륨 8.29g 을 가하고, 가열교반환류하에 클로로탄산 이소부틸 3.0g을 적하한후, 2시간 교반환류한다. 반응물을 여과하여 불용물을 제거하고, 여액을 감압하 중발 건고하면 담황색유상의 N-카르보이소부톡시체 5.9g을 얻는다. 에틸디르캅탄 5ml에 빙냉하 무수염화알루미늄 13g을 가하고, 앞에서 얻어진 N-카르보이소부톡시체 4.7g을 염화메틸렌 5ml에 용해하여 가한후 실온으로서 5시간 교반한다. 반용액을 어름위에 부어서 에테르 추출하고, N-카르보이소부톡시체 -3-이소프로필-4-하이드록시-β-페네틸아민 3.67g 을 얻는다.3.8 g of phenethylamine obtained here are dissolved in 50 ml of acetone, 8.29 g of anhydrous potassium carbonate is added, and 3.0 g of isobutyl chlorocarbonate is added dropwise under heating and stirring under reflux, followed by stirring under reflux for 2 hours. The reaction was filtered to remove insolubles, and the filtrate was dried under reduced pressure to obtain 5.9 g of a pale yellow oily N-carboisobutoxy compound. 13 g of anhydrous aluminum chloride was added to 5 ml of ethyl dircaptan under ice-cooling, 4.7 g of the N-carboisobutoxy compound obtained above was dissolved in 5 ml of methylene chloride, and then stirred for 5 hours at room temperature. The semi-solution is poured onto ice and extracted with ether to give 3.67 g of N-carboisobutoxy body-3-isopropyl-4-hydroxy-β-phenethylamine.

융 점 : 87℃.Melting point: 87 ° C.

위에서 얻어진 성적체 4.19g을 DMF 100ml에 용해하고, 무수탄산칼륨 4.16g 및 에피브롬히드린 4.11g을 가하고, 80℃로서 5시간 교반한다. 반용액을 물 400ml로서 희석하고, 초산에틸로 추출한다. 추출물을 실리카겔 컬럼 크로마토그라피로 정제(용매 : 벤젠-초산에틸 4 : 1 혼액)하고, 유상의 반응성적체 4.16g을 얻는다. 이를 3.88g, 메탄올 100ml에 용해하고, 카르바모일피페라진 1.64g을 가하여 5시간 가열 환류한다. 반용액을 감압하 건고하고, 잔류물을 실리카겔 컬럼 크로마토그라피로 정제(용매 : 클로로포름-메탄올 5 : 1 혼액). 화합물(20)을 얻는다.4.19 g of the above-obtained transcript was dissolved in 100 ml of DMF, 4.16 g of anhydrous potassium carbonate and 4.11 g of epibrohydrin were added and stirred at 80 ° C for 5 hours. The semi-solution is diluted with 400 ml of water and extracted with ethyl acetate. The extract was purified by silica gel column chromatography (solvent: benzene-ethyl acetate 4: 1 mixture) to obtain 4.16 g of an oily reactive substance. 3.88 g of this was dissolved in 100 ml of methanol, and 1.64 g of carbamoylpiperazine was added and heated to reflux for 5 hours. The semi-solution was dried under reduced pressure, and the residue was purified by silica gel column chromatography (solvent: chloroform-methanol 5: 1 mixture). Compound (20) is obtained.

염산염 : 에탄올로서 재결정, 융 점 : 156-158℃. 수 량 : 4.2g.Hydrochloride: recrystallized as ethanol, melting point: 156-158 ° C. Quantity: 4.2g.

클로로탄산이소부틸 대신에 클로로탄산에틸을 사용하고, 위화 같이 반응시키면 화합물(26)이 얻어진다.Ethyl chloro carbonate was used in place of isobutyl chloro carbonate, and the reaction was carried out in a countercurrent manner to obtain compound (26).

염산염 : 에탄올로서 재결정, 융 점 : 153-154℃.Hydrochloride: recrystallized as ethanol, melting point: 153-154 占 폚.

[실시예 20]Example 20

화합물(32),(33)의 합성Synthesis of Compounds (32) and (33)

실시예 19에서 얻어진 3-이소프로필-4-메톡시벤질시아니드 10g을 농염산 25ml에 용해하여 하룻밤 실온으로 방치한후, 물 70ml을 가하고, 80℃로서 6시간 가온한다. 반용액을 에테르로 추출하고, 추출액을 2% 수산화나트륨으로서 추출한다. 알칼리추출액을 염산산성으로 하고 에테르로 추출하여 3-이소프로필-4-메톡시페닐 초산 8.2g을 얻는다.10 g of 3-isopropyl-4-methoxybenzyl cyanide obtained in Example 19 was dissolved in 25 ml of concentrated hydrochloric acid, and allowed to stand at room temperature overnight. Then, 70 ml of water was added and heated at 80 ° C for 6 hours. The semi-solution is extracted with ether and the extract is extracted as 2% sodium hydroxide. The alkali extract is made hydrochloric acid and extracted with ether to give 8.2 g of 3-isopropyl-4-methoxyphenyl acetate.

융 점 : 94-96℃.Melting point: 94-96 ° C.

위에서 얻어진 페닐초산 4.0g을 SOCl2 5ml와 2시간 가열환류한다. 감압하 반응물을 증발건고하고, 잔류물을 클로로포름 15ml에 용해한후, 디에틸아민 2.8g의 클로로포름 30ml의 용액중에 빙냉 교반하여 적하한다. 2시간 실온으로 방치후 반용액을 수세하여 증류하여 제거하면 유상의 N,N-디에틸-3-이소프로필-4-메톡시페닐아세트아미드 4.8g을 얻는다. 여기서 얻어진 반응성적체 4.7g을 실시예 19와 같은 방법으로 에틸메르캅탄/AlCl₃법으로서 탈메틸화반응에 붙이고, N,N-디에틸-3-이소프로필-4-하이드록시페닐아세트아미드 2.6g을 얻는다.4.0 g of the phenyl acetate obtained above was heated to reflux with 5 ml of SOCl2 for 2 hours. The reaction was evaporated to dryness under reduced pressure, and the residue was dissolved in 15 ml of chloroform, and then added dropwise by ice-cooling stirring in a solution of 30 ml of chloroform of 2.8 g of diethylamine. After standing at room temperature for 2 hours, the semi-solution was washed with water and distilled off to obtain 4.8 g of oily N, N-diethyl-3-isopropyl-4-methoxyphenylacetamide. 4.7 g of the reactive substance obtained herein was added to a demethylation reaction by the method of ethyl mercaptan / AlCl _{3 in the} same manner as in Example 19, and 2.6 g of N, N-diethyl-3-isopropyl-4-hydroxyphenylacetamide was added. Get

융 점 : 112-113℃.Melting point: 112-113 ° C.

여기서 얻어진 하이드록시페닐아세트아미드 2.44g, 무수탄산칼륨 0.73g 및 에피브롬히드린 3.5g을 DMF 30ml 중 80℃로서 3시간 가열 교반한다. 반용액을 물 200ml로서 희석하고, 에테르로 추출한다. 얻어지는 추풀물을 토대로 메탄올 30ml에 용해하고, 카르바모일피페라진 2.5g을 가하고, 6시간 가열 환류한다. 반응액을 감압하 건고하고, 잔류물을 실리카켈 컬럼 크로마토그라피로 정제)용매 : 클로로포름-메탄올 7 : 1 혼액). 화합물(32) 1.4g을 얻는다.2.44 g of hydroxyphenylacetamide obtained here, 0.73 g of anhydrous potassium carbonate and 3.5 g of epibrohydrin are heated and stirred at 80 ° C. in 30 ml of DMF for 3 hours. The semi-solution is diluted with 200 ml of water and extracted with ether. It dissolves in 30 ml of methanol based on the obtained chute, 2.5 g of carbamoyl piperazine is added, and it heats and refluxs for 6 hours. The reaction mixture was dried under reduced pressure, and the residue was purified by silica gel column chromatography). Solvent: Chloroform-methanol 7: 1 mixture). 1.4 g of compound (32) is obtained.

염산염 : 에탄올로서 재결정, 융 점 : 107-110℃, 수 량 : 0.95g.Hydrochloride: recrystallized as ethanol, melting point: 107-110 ° C., yield: 0.95 g.

디에틸아민 대신에 디부틸아민을 사용하고, 위와 꼭같이 반응시키면 화합물 (33)이 얻어진다.When dibutylamine is used instead of diethylamine, and reacted as above, compound (33) is obtained.

염산염 : 에탄올로서 재경정한다. 융 점 : 102-105℃.Hydrochloride: Recalibrate as ethanol. Melting point: 102-105 ° C.

[실시예 21]Example 21

화합물(22),(27)의 합성Synthesis of Compounds (22) and (27)

C-t-부틸아니솔을 시시예 19와 같이 반응시키고, 3-t-부틸-4-메톡시벤질시아니드를 얻는다.C-t-butylanisole is reacted as in Example 19 to obtain 3-t-butyl-4-methoxybenzylcyanide.

비 점 : 140-145℃/0.9mmHg.Boiling Point: 140-145 ° C / 0.9mmHg.

이를 실시예 19와 같이 AlH₃로서 환원하고, 얻어지는 페네틸아민을 앞서와 같이 클로로탄산이소부틸과 반응시켜 N-카르보이소부톡시체로 하고, 계속해서 같은 조작에 의하여 탈메틸화하여 N-카르보이소부톡시-3-t-부틸-4-하이드록시-β-페네틸아민을 얻는다.This was reduced as AlH ₃ as in Example 19, and the resulting phenethylamine was reacted with isobutyl chlorocarbonate to form N-carboisobutoxy, as described above, followed by demethylation by the same operation. Sobutoxy-3-t-butyl-4-hydroxy-β-phenethylamine is obtained.

융 점 : 77℃.Melting point: 77 ° C.

상기와 같이 에피브롬히드린, 계속해서 카르바모일피페라진과 반응시키고, 화합물927)을 얻는다.Epibrohydrin and then carbamoylpiperazine are reacted as above to give compound 927).

융 점 : 167℃.Melting point: 167 ° C.

클로로탄산이소부틸 대신에 클로로탄산에틸을 사용하고, 앞서와 같이 반응시키면 화합물(22)을 얻는다.Ethyl chloro carbonate is used instead of isobutyl chloro carbonate, and the reaction is carried out as described above to obtain compound (22).

융 점 : 156℃.Melting point: 156 ° C.

[실시예 22]Example 22

화합물(34),(35)의 합성Synthesis of Compounds (34), (35)

실시예 21에서 얻어진 3-t-부틸-4-메톡시벤질시아니드를 실시예 20과 같이하여 가수분해하고, 3-t-부틸-4-메톡시페닐 초산을 얻는다.3-t-butyl-4-methoxybenzyl cyanide obtained in Example 21 was hydrolyzed in the same manner as in Example 20 to obtain 3-t-butyl-4-methoxyphenyl acetic acid.

융 점 : 93-94℃.Melting point: 93-94 ° C.

이후 실시예 20과 같이 반응시켜 N,N-디에틸-3-t-부틸-4-하이드록시페닐아세트아미드를 얻는다.Thereafter, the reaction was carried out as in Example 20 to obtain N, N-diethyl-3-t-butyl-4-hydroxyphenylacetamide.

융 점 : 124-126℃.Melting point: 124-126 ° C.

이를 앞서와 같이 에피브롬히드린, 계속해서 카르바모일피페라진과 반응시키고, 화합물(34)을 얻는다.This is reacted with epibrohydrin, followed by carbamoylpiperazine as before, to obtain compound (34).

융 점 : 138-140℃.Melting point: 138-140 ° C.

디에틸아민 대신에 디부틸아민을 사용하여 위화 같이 반응시키면 화합물(35)가 얻어진다.Compound (35) is obtained by reacting like diluting with dibutylamine instead of diethylamine.

융 점 : 108-110℃.Melting point: 108-110 ° C.

[실시예 23]Example 23

화합물(21),(36)의 합성Synthesis of Compound (21), (36)

C-메틸티몰을 실시예 19와 같이하여 반응하고, 2-메틸-4-메톡시-5-이소프로필벤질시아니드를 얻는다.C-methyl thymol is reacted in the same manner as in Example 19 to obtain 2-methyl-4-methoxy-5-isopropylbenzylcyanide.

비 점 : 127-130℃ 0.9mmHg.Boiling Point: 127-130 ° C. 0.9 mmHg.

이를 실시예 20과 같이 하여 가수분해하고, 2-메틸-4-메톡시-5-이소프로필페닐초산을 얻는다.This was hydrolyzed in the same manner as in Example 20 to obtain 2-methyl-4-methoxy-5-isopropylphenylacetic acid.

융 점 : 107-109℃.Melting point: 107-109 ° C.

이를 실시예 20과 같이하여 반응시키고, N-N-디메틸-2-메틸-4-하이드록시-5-이소프로필페닐 아세트아미드를 얻는다.This was reacted as in Example 20 to obtain N-N-dimethyl-2-methyl-4-hydroxy-5-isopropylphenyl acetamide.

융 점 : 138-139℃.Melting point: 138-139 ° C.

이후 앞서와 같이 에피브롬히드린, 계속하여 카르바모일피페라진과 반응하고, 화합물(36)을 얻는다.Thereafter, as before, epibromhydrin is subsequently reacted with carbamoylpiperazine to obtain compound (36).

융 점 : 138-141℃.Melting point: 138-141 ° C.

디에틸아민 대신에 디부틸아민을 사용하여 앞서와 같이 반응시키면 화합물(21)이 얻어진다.Compound (21) is obtained by reacting as before using dibutylamine instead of diethylamine.

융 점 : 95-97℃.Melting point: 95-97 ° C.

[실시예 24]Example 24

화합물(29),(30)의 합성Synthesis of Compounds (29), (30)

실시예 23에서 얻어진 2-메틸-4-메톡시-5-이소프로필벤질시아니드를 실시예 19와 같이 AlH₃로서 환원하고, 계속해서 클로로산에틸과 반응시켜 우레탄으로 한 후 앞서와 같이 탈메틸화 한다. 얻어지는 N-마르보에톡시-2-메틸-4-하이드록시-5-이소프로필-β-페네릴아민을 에피브롬히드린, 계속해서 카르바모일피페라진과 반응시켜 화합물(29)을 얻는다. 염산염 : 이소프로판올로서 재결정.The 2-methyl-4-methoxy-5-isopropylbenzyl cyanide obtained in Example 23 was reduced with AlH ₃ as in Example 19, and then reacted with ethyl chloroate to form a urethane, followed by demethylation. do. Compound (29) is obtained by reacting the obtained N-marboethoxy-2-methyl-4-hydroxy-5-isopropyl-β-phenylamine with epibromhydrin and then carbamoylpiperazine. Hydrochloride: Recrystallized as isopropanol.

융 점 : 135-138℃.Melting point: 135-138 ° C.

클로로탄산에틸 대신에 클로로탄산이소부틸을 사용하고, 위와 같이 반응시키면 화합물(30)이 얻어진다.Isobutyl chlorocarbonate is used instead of ethyl chlorocarbonate, and the reaction is carried out as described above to obtain compound (30).

융 점 : 92-94℃.Melting point: 92-94 ° C.

[실시예 25]Example 25

화합물(23)의 합성Synthesis of Compound (23)

C-시클로헥실아니솔을 실시예 19와 같이 반응시켜 3-시클로헥실-4-메톡시벤질시아니드를 얻는다.C-cyclohexylanisole is reacted as in Example 19 to obtain 3-cyclohexyl-4-methoxybenzyl cyanide.

실리카겔 컬럼 크로마토그라피로 정제(용매 : 벤젠). 이를 실시예 20과 같이 하여 가수분해하고, 3-시클로헥실-4-메톡시페닐초산을 얻는다.Purification by silica gel column chromatography (solvent: benzene). This was hydrolyzed in the same manner as in Example 20 to obtain 3-cyclohexyl-4-methoxyphenylacetic acid.

융 점 : 112-114℃.Melting point: 112-114 ° C.

이후 n-부틸아민을 사용하여 실시예 20과 같이 반응시키고, 계속해서 탈메틸화하여 N-부틸-3-시클로헥실-4-하이드록시페닐 아세트아미드를 얻는다.Thereafter, the reaction was carried out as in Example 20 using n-butylamine, followed by demethylation to obtain N-butyl-3-cyclohexyl-4-hydroxyphenyl acetamide.

융 점 : 118-120℃.Melting point: 118-120 ° C.

계속해서 에피브롬히드린, 카르바모일피페라진과 반응하여 화합물(25)를 얻는다.Subsequently, compound (25) is obtained by reaction with epibromhydrin and carbamoylpiperazine.

융 점 : 148-149℃.Melting point: 148-149 ° C.

[실시예 26]Example 26

화합물(28)의 합성Synthesis of Compound (28)

실시예 25에서 얻어진 3-시클로헥실-4-메톡시벤질아미드를 실시예 19와 같이 환원하고, 얻어진 페네틸아민을 클로로탄산에틸과 반응시켜 우레탄으로 하고, 계속해서 탈메틸화하여 N-카르보에톡시-3-시클로헥실-4-하이드록시-β-페네틸아민을 얻는다.The 3-cyclohexyl-4-methoxybenzylamide obtained in Example 25 was reduced in the same manner as in Example 19, and the resulting phenethylamine was reacted with ethyl chlorocarbonate to give a urethane, followed by demethylation to N-carbo Obtain oxy-3-cyclohexyl-4-hydroxy-β-phenethylamine.

융 점 : 97-98℃.Melting point: 97-98 ° C.

계속해서 앞서와 같이 에피브롬히드린, 카르바모일피페라진과 반응하고, 화합물(28)을 얻는다.Then, it reacts with epibrohydrin and carbamoyl piperazine as before, and compound (28) is obtained.

염산염 : 융 점 : 101-103℃.Hydrochloride: melting point: 101-103 ° C.

[실시예 27]Example 27

화합물(24),(37)의 합성Synthesis of Compounds (24), (37)

2-이소프로필-4-니트로페놀 18.1 g을 메틸에틸케톤 300ml에 용해하고, 무수탄산칼륨 22g 및 에피브롬히드린 68g을 가하여 3시간 가열교반환류한다. 반응액을 여과하여 불용물을 제거하고, 여액을 감압하 농축하고, 에테르로 추출. 2-이소프로필-4-니트로페닐글리시딜에테르 20.1g을 얻는다.18.1 g of 2-isopropyl-4-nitrophenol are dissolved in 300 ml of methyl ethyl ketone, and 22 g of anhydrous potassium carbonate and 68 g of epibrohydrin are added and the mixture is heated and refluxed for 3 hours. The reaction solution was filtered to remove insolubles, the filtrate was concentrated under reduced pressure and extracted with ether. 20.1 g of 2-isopropyl-4-nitrophenylglycidyl ether are obtained.

융 점 : 60-62℃.Melting point: 60-62 ° C.

위에서 얻어진 글리시딜에테르 7.0g 및 카르바모일피페라진 4.7g을 메탄올 50ml중 5시간 가열환류한다.7.0 g of glycidyl ether and 4.7 g of carbamoylpiperazine obtained above are heated and refluxed in 50 ml of methanol for 5 hours.

반응액을 감압하 중발견고하고, 잔류물을 실리카겔 컬럼 크로마토그라피로 정제(용매 : 클로로포름-메탄올 9 : 1 혼액). 수량 : 10.2g.The reaction solution was solidly extracted under reduced pressure, and the residue was purified by silica gel column chromatography (solvent: chloroform-methanol 9: 1 mixture). Quantity: 10.2g.

여기서 얻어진 반응성적체 3.3g을 에탄온 20ml 에 용해하고, 라네이니켈촉매 약 1ml을 가하여 상온상압으로 용해환원시킨다. 수소의 흡수가 정지된후 촉매를 여별하고, 여액을 감압하 증발건고한 다음, 잔류물을 실리카켈크로마토그라피로 정제(용매 : 클로로포름-메탄올 4 : 1 혼액). 수량 2.1g.3.3 g of the reactive substance obtained here was dissolved in 20 ml of ethanone, and about 1 ml of a raney nickel catalyst was added thereto, followed by dissolution and reduction at normal temperature and pressure. After the absorption of hydrogen has stopped, the catalyst is filtered off, the filtrate is evaporated to dryness under reduced pressure, and the residue is purified by silica gel chromatography (solvent: chloroform-methanol 4: 1 mixture). Quantity 2.1g.

매스 스펙트럼 : M⁺(m/e)=336.Mass spectrum: M ⁺ (m / e) = 336.

여기서 얻어진 아미노 화합물 1.13g을 피리딘 6ml에 용해하고, 빙냉교반하에 n-부탄설포닐클로라이드 0.52g을 적하, 2시간 빙냉하에서 교반하고, 반응액을 어름물 100ml로서 희석한 다음, 초산에틸로서 추출한다. 여기서 얻어지는 추출물을 실리카겔 컬럼 크로마토그라피(용매 : 클로로포름-메탄올 4 : 1 혼액)로서 정제. 화합물(37) 0.85g을 얻는다. 염산염 : 에탄올로서 재결정.1.13 g of the amino compound obtained herein was dissolved in 6 ml of pyridine, 0.52 g of n-butanesulfonyl chloride was added dropwise under ice-cooling stirring, stirred for 2 hours under ice-cooling, the reaction solution was diluted with 100 ml of acetic acid, and extracted as ethyl acetate. . The extract obtained here was purified as silica gel column chromatography (solvent: chloroform-methanol 4: 1 mixture). 0.85 g of compound (37) is obtained. Hydrochloride: Recrystallized as ethanol.

융 점 : 111-113℃.Melting point: 111-113 ° C.

n-부탄설포닐클로라이드 대신에 프로판설포닐클로라이드를 사용하고, 위와같이 반응시키면 화합물(24)가 얻어진다. 염산염 : 이소프로판올로서 재결정한다.Propanesulfonylchloride is used instead of n-butanesulfonylchloride, and the reaction as above gives compound (24). Hydrochloride: Recrystallized as isopropanol.

융 점 : 117-119℃.Melting point: 117-119 ° C.

Claims (1)

아릴글리시딜 에테르류를 비반응성 용매중에서 N-카르바모일피페라진과 반응시키는 것을 특징으로 하는 다음의 일반식(I)으로 표시되는 N⁴-카르바모일 피페라지노 프로판올 유도체의 제조방법.A method for producing an N ⁴ -carbamoyl piperazino propanol derivative represented by the following general formula (I), wherein arylglycidyl ethers are reacted with N-carbamoylpiperazine in a non-reactive solvent.

를 나타내고 여기서 n은 1 또는 2를 표시하고 X는 할로겐을 나타내고 R₁은 탄소수 6 이하의 불포화 결합을 가지고 있어도 좋은 시클로알킬기, 또는 아실기를 표시하며 R₂는 H 또는 메틸기를 표시한다. Z는

를 표시한다. 여기서 R₃는 탄소수 4 이하의 저급알킬기를 나타내고 R₄, R₅는 같거나 또는 다르며 H 또는 탄소수 4 이하의 저급알킬기를 표시한다.And n represents 1 or 2, X represents halogen, R ₁ represents a cycloalkyl group or an acyl group which may have an unsaturated bond having 6 or less carbon atoms, and R ₂ represents H or a methyl group. Z is

Is displayed. Wherein R ₃ represents a lower alkyl group having 4 or less carbon atoms and R ₄ , R ₅ represents the same or different and represents H or a lower alkyl group having 4 or less carbon atoms.