KR850001916B1 - Process for the preparation of amino-phenyl-ethanolamines - Google Patents

Process for the preparation of amino-phenyl-ethanolamines Download PDF

Info

Publication number
KR850001916B1
KR850001916B1 KR7501095A KR750001095A KR850001916B1 KR 850001916 B1 KR850001916 B1 KR 850001916B1 KR 7501095 A KR7501095 A KR 7501095A KR 750001095 A KR750001095 A KR 750001095A KR 850001916 B1 KR850001916 B1 KR 850001916B1
Authority
KR
South Korea
Prior art keywords
ethanol
phenyl
amino
tert
hydrochloride
Prior art date
Application number
KR7501095A
Other languages
Korean (ko)
Other versions
KR830000207A (en
Inventor
엥겔하르트 균터
켁크 요하네스
크류거 케르트
놀 크라우스-라인홀트
피이퍼 헬무트
Original Assignee
에른스트 제에거 프리츠 조메르
독크톨 카르르 로오마에 지엠베하
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from DE2261914A external-priority patent/DE2261914C3/en
Priority claimed from DE19732345442 external-priority patent/DE2345442C2/en
Priority claimed from DE19732351281 external-priority patent/DE2351281C3/en
Priority claimed from DE2354961A external-priority patent/DE2354961C2/en
Priority claimed from KR7302145A external-priority patent/KR790000255B1/en
Application filed by 에른스트 제에거 프리츠 조메르, 독크톨 카르르 로오마에 지엠베하 filed Critical 에른스트 제에거 프리츠 조메르
Publication of KR830000207A publication Critical patent/KR830000207A/en
Application granted granted Critical
Publication of KR850001916B1 publication Critical patent/KR850001916B1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
    • C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
    • C07C215/30—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings containing hydroxy groups and carbon atoms of six-membered aromatic rings bound to the same carbon atom of the carbon skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/58—Radicals substituted by nitrogen atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

Amino-phenyl-ethanolamines I [ R1 = H,F,Cl,Br,I,Cyano; R2 = F, alkyl containing 1-5 carbons, hydroxyalkyl, cyano, carboxyl, carbamoyl; R3, R4 = H, alkyl containing 1-6 carbons, alkenyl, alkynyl; R5 = H, alkyl were prepd.. Thus, 1-(4-acethylamino-3trifluoromethyl-phenyl)-2-t- butylamino-ethanol-hydrochloride was refluxed 3hrs in a mixt. of ethanol and a sodium hydroxide soln. The ppt. was filtered, and dissolved in 1N hydrochloric acid, and then recrystd. to give 1-(4- amino-3-trifluoromethyl-phenyl)-2-tbutyl amino-ethanol. The compds. I have β2-suspective activity and β1, β2-paralysis activity.

Description

아미노-페닐-에탄올 아민의 제조방법Method for preparing amino-phenyl-ethanol amine

본 발명은 일반구조식(Ⅰ)의 신규 아미노-페닐-에탄올아민 화합물과 무기산 혹은 유기산과 반응해서 생기는 생리학적으로 조화되는 산부가염의 제조방법에 관한 것이다.The present invention relates to a method for producing a physiologically compatible acid addition salt produced by reacting a novel amino-phenyl-ethanolamine compound of general formula (I) with an inorganic acid or an organic acid.

Figure kpo00001
Figure kpo00001

상기 일반식(Ⅰ)에서In the general formula (I)

R1은 수소, 불소, 염소, 브롬, 요드원자나, 시아노기를 표시한다.R 1 represents hydrogen, fluorine, chlorine, bromine, an iodine atom or a cyano group.

R2는 불소원자, 사슬 혹은 가지달린 1-5개의 탄소원자를 가진 알킬기, 히드록시알킬, 아미노알킬, 디알킬아미노알킬, 트리플로로메틸, 알코옥시, 니트로, 시아노, 칼복시, 카르브알코옥시나 카르바모일기를 표시한다.R 2 is a fluorine atom, an alkyl group having 1 to 5 carbon atoms or a chain or branched chain, hydroxyalkyl, aminoalkyl, dialkylaminoalkyl, trilomethyl, alcooxy, nitro, cyano, carboxyl, carbalco An oxy or carbamoyl group is represented.

R3나 R4는 같거나 상이하며 수소원자, 사슬 혹은 가지달린 1-6개의 탄소원자를 가진 알킬원자, 히드록시알킬, 시클로알킬, 시클로알킬알킬, 알케닐, 알키닐 혹은 선택적으로 치환된 아랄킬을 표시하며,R 3 or R 4 are the same or different and represent a hydrogen atom, a chain or branched alkyl atom of 1-6 carbon atoms, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl or optionally substituted aralkyl ,

R5는 수소원자나 사슬 혹은 가지달린 알킬기를 표시한다.R 5 represents a hydrogen atom, a chain or a branched alkyl group.

상기 일반식(Ⅰ)의 화합물은 가치있는 제약학적 성질을 가지며, 특히 β2-수용체(감각기관)에 대한 의사성(擬似性)활성 그리고/혹은 β1-수용체에 대한 보호활성을 가지고 있으며, 그외에 진통, 자궁경련성, 각근(脚筋)에 대한 진경(鎭痙)활성을 가지고 있으며 그곳에 그들의 치환에 의해서 하나 혹은 다른 활성이 더 우세해진다. d(+)-화합물은 특히 β1-수용체(감각기관)에 대해 선택적인 활성을 가지고 있으며 1(-)-화합물은 β2-수용체에 대해 선택적인 활성을 가지고 있다.Compounds of general formula (I) have valuable pharmaceutical properties, in particular have pseudo-active activity against β 2 -receptors (sensory organs) and / or protective activity against β 1 -receptors, In addition, it has analgesic activity against analgesic, spasmodic and angular muscles, and one or the other activity is predominant by their substitution there. d (+)-compounds have selective activity specifically for β 1 -receptors (sensory organs) and 1 (-)-compounds have selective activity for β 2 -receptors.

위 신규 화합물은 다음 과정에 의해 제조될 수 있다. 일반식(Ⅱ)의 화합물로부터 하나 혹은 그 이상의 보호기를 제거한다.The novel compounds can be prepared by the following procedure. Remove one or more protecting groups from the compound of formula (II).

Figure kpo00002
Figure kpo00002

위식에서,In the common sense,

R1, R2, R3는 상기한 바와 같고,R 1 , R 2 , R 3 are as described above,

X는 수산기 보호기나 수소원자를 표시하며X represents a hydroxyl protecting group or a hydrogen atom

Y1은 아미노기 보호기나 수소원자를 표시하며Y 1 represents an amino group protecting group or a hydrogen atom

Y2는 아미노기에 대한 보호기를 표시하거나 위 R4에 대한 것과 같은 의미를 가지나, 적어도 기 X1, Y1, 그리고/혹은 Y2중의 하나가 위에서 언급한 보호기의 하나를 표시해야 한다.Y 2 represents a protecting group for an amino group or has the same meaning as for R 4 above, but at least one of the groups X 1 , Y 1 , and / or Y 2 should represent one of the protecting groups mentioned above.

Y1그리고/혹은 Y2에 대해 특히 아실기의 의미, 예컨대 아세틸, 벤조일, 파라-톨루엔슬포닐기 혹은 벤질기의 뜻이 고려될 수 있고 X에 대해서는 아실기의 의미, 예컨대 아세틸, 벤조일, 파라-톨루엔 슬포닐기나 트리메틸실릴, 벤질, 테트라하이드로피라닐-(2)-기의 의미가 고려될 수 있다.The meaning of the acyl group, in particular for Y 1 and / or Y 2 , such as acetyl, benzoyl, para-toluenesulfonyl group or benzyl group may be considered and for X the meaning of acyl group such as acetyl, benzoyl, para- The meaning of the toluene sulfonyl group, trimethylsilyl, benzyl, tetrahydropyranyl- (2) -group can be considered.

만약 Y1, 그리고/혹은 Y2가 예컨대 아실기를 표시한다면 이 기의 제거는 예컨대 에탄올성 염산이나 수산화나트륨 용액으로 하용한 용매의 끊는점까지의 온도를 올리면서 가수분해에 의해 효과적으로 이루어진다. 만약 일반식(Ⅱ)에서 R2가 시아노기를 표시한다면 이기는 동시에 카르바밀이나 카복실기로 비누화되며 만약 R2가 카보알코옥시나 카르바밀기를 표시한다면 이 기들은 동시에 카복실기를 비누화한다.If Y 1 , and / or Y 2 represents, for example, an acyl group, removal of this group is effectively effected by hydrolysis, for example, by raising the temperature to the breaking point of the solvent dissolved in ethanol hydrochloric acid or sodium hydroxide solution. If R 2 in the formula (II) represents a cyano group, it is saponified at the same time as a carbamyl or carboxyl group. If R 2 represents a carboalcooxy or carbamyl group, these groups at the same time saponify a carboxyl group.

만약 X1, Y1그리고/혹은 Y2가 예컨대 R2가 니트로기를 표시하지 않는 일반식(Ⅱ)의 화합물에서 벤질기를 표시하지 아니한다면 이 기의 제거는, 석탄위에서 팔라듐이나 황산바륨위에서 수소화산화팔라듐이나 백금 레니-니켈과 같은 촉매의 존재하에서 수소로써 수소화촉매에 의해 효과적으로 수행되며 메탄올, 메탄올/염산 혹은 에탄올같은 용매존재하에서, 실온이나 약간 높여진 온도에서, 대기압이나 약간 더 높여진 압력에서 진행된다. 기 R3그리고/혹은 R4의 정의에서 언급한 알키닐이나 알케닐기는 동시에 반응동안 대응하여 알킬기로 전환된다.If X 1 , Y 1 and / or Y 2 do not represent a benzyl group in a compound of formula (II) where, for example, R 2 does not represent a nitro group, the removal of this group is hydrocracked on palladium or barium sulfate on coal. Effectively carried out by hydrogenation catalysts as hydrogen in the presence of a catalyst such as palladium or platinum lenny-nickel and proceeds at ambient or slightly elevated temperatures, at atmospheric or slightly elevated pressures, in the presence of solvents such as methanol, methanol / hydrochloric acid or ethanol. do. The alkynyl or alkenyl groups mentioned in the definition of groups R 3 and / or R 4 are simultaneously converted to alkyl groups during the reaction.

만약 X가 예컨대 아실기, 트리메틸실릴이나 테트라하이드로피라닐-(2)-기를 표시한다면 이 기들의 제거는 바람직하게 산의 존재하에서 사용한 용매의 끓는 온도에서 수소촉매에 의해 이루어진다.If X represents, for example, an acyl group, trimethylsilyl or tetrahydropyranyl- (2)-group, the removal of these groups is preferably done by hydrogen catalyst at the boiling temperature of the solvent used in the presence of an acid.

얻어진 일반식(Ⅰ)의 화합물들은, 원한다면, 부수적으로 라세메이트 분리나 일반식(Ⅲ)의 부분 대차체 혼합물의 분리에 의해서 그들의 광학활성 대차체를 분리하며 만약 R6가 아실기를 표시하고 R4가 선택적으로 치환된 벤질기를 표시한다면기 R7, R6와 R4는 부분적으로 제거된다.The compounds of general formula (I) obtained, if desired, separate their optically active vehicle by separation of racemate separation or partial vehicle mixture of general formula (III), if R 6 represents an acyl group and R 4 If R represents an optionally substituted benzyl group, groups R 7 , R 6 and R 4 are partially removed.

Figure kpo00003
Figure kpo00003

위 식에서From the stomach

R1, R2, R3와 R4는 상기한 바와 같다.R 1 , R 2 , R 3 and R 4 are as described above.

R6는 수소원자나 아실기를 표시하고R 6 represents a hydrogen atom or an acyl group

R7은 치랄 아실기를 표시한다.R 7 represents a chiral acyl group.

치랄 아실기 R7으로서, 예컨대 N-벤질-옥시카보닐-L-알라닐-기같이 질소원자에 보호된 광학활성 a-아미노-아실기나 예컨대(-)-메틸옥시카보닐-기같은 광학활성 터페닐-옥시카보닐-기가 특별히 고찰될 수 있다.As the chiral acyl group R 7 , an optically active a-amino-acyl group or a (-)-methyloxycarbonyl-group protected optically, such as N-benzyl-oxycarbonyl-L-alanyl-group Terphenyl-oxycarbonyl-groups can be particularly contemplated.

위 일반식(Ⅲ)의 부분대차체 혼합물의 순수한 부분대차체화합물로의 분리는 적당히 분별결정 그리고/혹은 불활성 전달체에서 칼럼 크로마토 그래피에 의한다.Separation of the subcarrier mixture of general formula (III) into the pure subcarrier compound is by column chromatography in fractionated crystals and / or inert carriers as appropriate.

기 R6와 R7의 부수적인 제거는 적당히 물이나, 메탄같은 적당한 알콜의 존재하에서 각각의 가용매 분해에 해당하는 가수분해에 의해 효과적으로 이루어지며 선택적으로 산이나 염기의 존재하에서 온도 0-100℃에서 이루어진다.Incidental removal of the groups R 6 and R 7 is effectively effected by hydrolysis corresponding to the respective solubilizations in the presence of a suitable alcohol such as water or methane, optionally in the presence of acids or bases at temperatures of 0-100 ° C. Is done in

기 R7의 제거는 역시 에텔, 테트라히드로푸란이나 디옥산같은 적당한 용매속에서 수소화알루미늄리튬 같은 착금속 수소화물에 의해 효과적으로 이루어지며 적당히 온도 -20∼20℃에서 만약 일반식(Ⅲ) 화합물에서 R2가 시아노기를 표시한다면, 이 기는 동시에 환원될 것이며, 치환기 R6와 R7의 성질에 따라서 이들의 제거는 여러단계 혹은 한단계로서 효과적으로 이루어진다.The removal of the groups R 7 is also effected effectively by complex metal hydrides such as lithium aluminum hydride in suitable solvents such as ether, tetrahydrofuran or dioxane and at moderate temperatures -20 to 20 ° C. If two displays a cyano group, this group will be reduced at the same time, removing properties thereof, depending on the substituents R 6 and R 7 are made effective as the number of steps or one step.

만약 R4가 선택적으로 치환된 벤질기를 표시한다면 이 기의 제거는 R2가 니트로기를 표시하지 않는 화합물속에서 석탄위나 황산바륨위의 팔라듐같은 적합한 촉매의 존재하에서 메탄올, 에탄올같은 알콜이나 식초산같은 적합한 용매속에서 가수소분해에 의해, 선택적으로 염산같은 광산의 부가에 의해 선택적으로 높여진 수소압력하에서 바람직하게 20-25℃의 온도에서 이루어진다.If R 4 represents an optionally substituted benzyl group, the removal of this group is carried out in the presence of a suitable catalyst such as palladium on coal or barium sulfate in compounds where R 2 does not represent nitro groups, such as alcohols such as methanol, ethanol or vinegar By hydrogenolysis in a suitable solvent, optionally at a temperature of 20-25 ° C. under elevated hydrogen pressure, optionally by addition of a mineral acid such as hydrochloric acid.

만약 R2가 일반식(Ⅲ)에서 시아노기를 표시한다면 이 기들은 동시에 환원된다. 기 R4의 제거는 기 R6와 R7이 제거되기 전이나 후에 효과적으로 이루어진다.If R 2 represents a cyano group in formula (III), these groups are reduced simultaneously. Removal of groups R 4 takes place effectively before or after groups R 6 and R 7 are removed.

상기 일반식(Ⅰ) 화합물의 d, 1-형태의 라세메이트 제거는 D(-)-주석산, L(+)-주석산, 디벤조일-D-주석산, 디벤조일-L-주석산, (+)-장뇌-10-슬폰산, L(-)-능금산, L(+)-만델산, d-α-브로모캄퍼-π-슬폰산 혹은 1-키닌산과 같은 광학활성산을 사용하여 그들의 부분 대차체염의 혼합물을 분별 결정함에 의해 바람직하게 수행된다. 그러나, 라세메이트 제거는 예컨대 아세틸셀루로즈같은 광학활성 전달체를 사용하여 칼럼-크로마토그래피에 의해 효과적으로 이루어진다.The racemic removal of d, 1-form of the compound of general formula (I) is D (-)-tartrate, L (+)-tartrate, dibenzoyl-D-tartrate, dibenzoyl-L-tartrate, (+)- Their partial counterparts using optically active acids such as camphor-10-sulfonic acid, L (-)-nungumic acid, L (+)-mandelic acid, d-α-bromocamphor-π-sulfonic acid or 1-kininic acid It is preferably carried out by fractional determination of a mixture of salts. However, racemate removal is effectively accomplished by column-chromatography, for example using an optically active carrier such as acetylcellulose.

만약 R2가 시아노기를 표시하는 일반식(Ⅰ) 화합물이 얻어졌다면, 이 화합물은 대응하는 카르바모일 화합물 그리고/혹은 카르바모일이나 카브알코옥시화합물로 전환될 수 있고 이 화합물은 가수분해에 의해서 대응하는 일반식(Ⅰ)의 카르브알코옥시 화합물로 전환될 수 있고 그리고/혹은 R3나 R4가 수소원자를 표시하는 일반식(Ⅰ) 화합물이 얻어진다면 이 화합물은 일반식(Ⅳ)의 알데히드로 대응하는 옥사졸리딘으로 전환될 수 있을 것이다.If a compound of the general formula (I) in which R 2 represents a cyano group is obtained, this compound may be converted into the corresponding carbamoyl compound and / or carbamoyl or carbalcooxy compound, which compound If a compound of formula (I) is obtained which can be converted into the corresponding carbalcooxy compound of formula (I) and / or R 3 or R 4 represents a hydrogen atom, the compound is of formula (IV) The aldehyde of may be converted to the corresponding oxazolidine.

R5-CHO (Ⅳ)R 5 -CHO (Ⅳ)

위 식에서,In the above formula,

R5는 상기한 바와 같다.R 5 is as described above.

일반식(Ⅳ)의 알데히드와의 반응은 적당히 예컨대 무수황산 구리(Ⅱ)의 존재하에서와 같이 탈수조건에서 에탄올, 벤젠, 톨루엔 혹은 디옥산과 같은 용매속에서, 예컨대 온도 20-100℃의 온도에서 사용한 용매의 끓는 온도에서 반응이 수행되나 반응은 역시 용매없이도 수행될 수 있다. 반응은 벤젠이나 톨루엔같은 용매의 존재하에서 물분리 깔때기를 도입하는 장치를 사용하면 특히 바람직스러운 일이다.The reaction with aldehydes of general formula (IV) is suitably carried out in a solvent such as ethanol, benzene, toluene or dioxane under dehydration conditions, for example in the presence of anhydrous copper (II) sulfate, for example at a temperature of 20-100 ° C. The reaction is carried out at the boiling temperature of the solvent used but the reaction can also be carried out without solvent. The reaction is particularly preferred using a device that introduces a water separation funnel in the presence of a solvent such as benzene or toluene.

얻어진 일반식(Ⅰ)의 화합물은 원한다면 대응하는 무기 혹은 유기산의 1, 2, 3배의 동량의 물을 사용하여 생리학적으로 조화되는 산부가염으로 전환될 수 있다. 산으로서는 예컨대 염산, 브롬산, 황산, 인산, 젖산, 귤산, 주석산, 말레인산이나 푸마린산이 적당하다고 밝혀졌다.The compound of general formula (I) obtained can be converted to physiologically compatible acid addition salts using the same amount of water in one, two or three times the corresponding inorganic or organic acid, if desired. As the acid, hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, lactic acid, manic acid, tartaric acid, maleic acid and fumaric acid have been found to be suitable.

시작물질로서 사용된 화합물들은 참고문헌으로부터 알려진 방법에 의해 얻어진다. 시작물질로서 사용된 일반식(Ⅱ)의 화합물은 예컨대 대응하는 2-할로겐-아세토페논을 대응하는 아민과 반응시킨 다음 얻어진 케톤을 예컨대 수소화붕소나트륨으로 환원하거나 또는 대응하는 화합물을 할로겐화하거나 대응하는 4-니트로-페닐화합물을 촉매환원시킴으로써 얻어진다. 시작화합물은 모든 경우에 있어서 정제될 필요가 없고 그들은 역시 조잡한 생성물로서 사용될 수 있다.Compounds used as starting materials are obtained by methods known from the references. Compounds of the general formula (II) used as starting materials are reacted, for example, with the corresponding 2-halogen-acetophenones with the corresponding amines and then the resulting ketones are reduced with, for example, sodium borohydride, or the corresponding compounds are halogenated or It is obtained by catalytic reduction of a nitro-phenyl compound. Starting compounds do not need to be purified in all cases and they can also be used as crude products.

위에서 언급한 바와 같이 일반식(Ⅰ)의 화합물은 가치있는 약리적인 성질을 가지고 있으며, 특히 β2-수용기(감각기관)에 대한 의사(擬似)활성을 가지며 그리고/혹은 β1-수용기에 대한 마비활성을 가지며 그들의 치환에 의해 하나 혹은 다른 활성이 더 우세해진다.As mentioned above, the compounds of general formula (I) have valuable pharmacological properties, in particular have pseudo activity on β 2 -receptors (sensory organs) and / or paralysis on β 1 -receptors. Have activity and one or the other activity predominates by their substitution.

d(+)-화합물은 특히 β1-수용기에 대해 선택적인 활성을 나타내고 1(-)-화합물은 β2-수용기에 대해 우선된 활성을 가지고 있다.d (+)-compounds exhibit selective activity, in particular for β 1 -receptors and 1 (−)-compounds have preferential activity for β 2 -receptors.

다음 물질들은 β-수용기에 대한 그들의 활성에 관해 시험되었다.The following materials were tested for their activity on β-receptors.

A=1-(3-아미노-3-브로모-5-플로로-페닐)-2-3급-부틸아미노-에탄올-하이드로클로라이드,A = 1- (3-amino-3-bromo-5-fluoro-phenyl) -2-tert-butylamino-ethanol-hydrochloride,

B=5-(4-아미노-3-브로모-3-플로로-페닐)-3-3급-부틸-옥사졸리딘-디하이드로클로라이드,B = 5- (4-Amino-3-bromo-3-fluoro-phenyl) -3-tert-butyl-oxazolidine-dihydrochloride,

C=1-(4-아미노-3-클로로-5-플로로-페닐)-2-시클로프로필아미노-에탄올-하이드로클로라이드,C = 1- (4-amino-3-chloro-5-fluoro-phenyl) -2-cyclopropylamino-ethanol-hydrochloride,

D=1-(4-아미노-3-클로로-5-플로로-페닐)-2-3급-부틸아미노-에탄올-하이드로클로라이드,D = 1- (4-amino-3-chloro-5-fluoro-phenyl) -2-tert-butylamino-ethanol-hydrochloride,

E=1-(4-아미노-3-클로로-페닐)-2-3급-부틸아미노-에탄올-하이드로클로라이드,E = 1- (4-amino-3-chloro-phenyl) -2-tert-butylamino-ethanol-hydrochloride,

F=1-(4-아미노-3-트리플로로메틸-페닐)-2-3급-펜틸아미노-에탄올-하이드로클로라이드,F = 1- (4-Amino-3-trifluoromethyl-phenyl) -2-tert-pentylamino-ethanol-hydrochloride,

G=1-(4-아미노-3-클로로-5-트리플로로메틸-페닐)-2-3급-부틸아미노-에탄올-하이드로클로라이드,G = 1- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol-hydrochloride,

H=1-(4-아미노-3-클로로-5-트리플로로메틸-페닐)-2-시클로부틸아미노-에탄올-하이드로클로라이드,H = 1- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2-cyclobutylamino-ethanol-hydrochloride,

I=1-(4-아미노-3-클로로-5-시아노-페닐)-2-3급-부틸아미노-에탄올,I = 1- (4-amino-3-chloro-5-cyano-phenyl) -2-tert-butylamino-ethanol,

J=1-(4-아미노-3-브로모-5-시아노-페닐)-2-3급-부틸아미노-에탄올-하이드로클로라이드,J = 1- (4-amino-3-bromo-5-cyano-phenyl) -2-tert-butylamino-ethanol-hydrochloride,

K=1-(4-아미노-3-브로모-5-플로로-페닐)-2-시클로부틸아미노-에탄올-하이드로클로라이드,K = 1- (4-amino-3-bromo-5-fluoro-phenyl) -2-cyclobutylamino-ethanol-hydrochloride,

L=1-(4-아미노-3-클로로-5-요도-페닐)-2-시클로프로필아미노-에탄올-하이드로클로라이드,L = 1- (4-amino-3-chloro-5-urido-phenyl) -2-cyclopropylamino-ethanol-hydrochloride,

M=1-(4-아미노-3-플로로-5-시아노-페닐)-2-이소프로필아미노-에탄올-하이드로클로라이드,M = 1- (4-amino-3-fluoro-5-cyano-phenyl) -2-isopropylamino-ethanol-hydrochloride,

N=1-(4-아미노-3-플로로-5-시아노-페닐)-2-3급-부틸아미노-에탄올-하이드로클로라이드,N = 1- (4-amino-3-fluoro-5-cyano-phenyl) -2-tert-butylamino-ethanol-hydrochloride,

O=1-(4-아미노-3-시아노-페닐)-2-시클로부틸아미노-에탄올-하이드로브로마이드,O = 1- (4-amino-3-cyano-phenyl) -2-cyclobutylamino-ethanol-hydrobromide,

P=1-(4-아미노-3-시아노-페닐)-2-3급-펜틸아미노-에탄올,P = 1- (4-amino-3-cyano-phenyl) -2-tert-pentylamino-ethanol,

Q=1-(4-아미노-3-클로로-5-시아노-페닐)-2-프로필아미노-에탄올-하이드로클로라이드,Q = 1- (4-amino-3-chloro-5-cyano-phenyl) -2-propylamino-ethanol-hydrochloride,

R=1-(4-아미노-3-클로로-5-시아노-페닐)-2-3급-부틸아미노-에탄올-하이드로클로라이드,R = 1- (4-amino-3-chloro-5-cyano-phenyl) -2-tert-butylamino-ethanol-hydrochloride,

S=1-(4-아미노-3-클로로-5-시아노-페닐)-2-(하이드록시-3급-부틸-아미노)-에탄올-하이드로클로라이드,S = 1- (4-Amino-3-chloro-5-cyano-phenyl) -2- (hydroxy-tert-butyl-amino) -ethanol-hydrochloride,

T=1-(4-아미노-3-클로로-5-시아노-페닐)-2-3급-펜틸아미노-에탄올-하이드로클로라이드,T = 1- (4-amino-3-chloro-5-cyano-phenyl) -2-tert-pentylamino-ethanol-hydrochloride,

U=1-(4-아미노-3-클로로-5-시아노-페닐)-2-시클로펜틸아미노-에탄올-하이드로클로라이드,U = 1- (4-amino-3-chloro-5-cyano-phenyl) -2-cyclopentylamino-ethanol-hydrochloride,

V=1-(4-아미노-3-클로로-5-시아노-페닐)-2-[1-(3, 4-메틸렌디옥시-페닐)-2-프로필아미노]-에탄올-하이드로클로라이드,V = 1- (4-amino-3-chloro-5-cyano-phenyl) -2- [1- (3, 4-methylenedioxy-phenyl) -2-propylamino] -ethanol-hydrochloride,

W=1-(4-아미노-3-브로모-5-시아노-페닐)-2-시클로부틸아미노-에탄올-하이드로클로라이드,W = 1- (4-Amino-3-bromo-5-cyano-phenyl) -2-cyclobutylamino-ethanol-hydrochloride,

X=1-(4-아미노-3,5-디시아노-페닐)-2-3급-부틸아미노-에탄올-하이드로클로라이드,X = 1- (4-amino-3,5-dicyano-phenyl) -2-tert-butylamino-ethanol-hydrochloride,

Y=1-(4-아미노-3-브로모-5-니트로-페닐)-2-3급-부틸아미노-에탄올과Y = 1- (4-amino-3-bromo-5-nitro-phenyl) -2-tert-butylamino-ethanol

Z=1-(4-아미노-3-클로로-5-니트로-페닐)-2-3급-부틸아미노-에탄올.Z = 1- (4-amino-3-chloro-5-nitro-phenyl) -2-tert-butylamino-ethanol.

β1-마비활성은 황산 N-이소프로필-노라드레날린 1.0γ/kg의 표준투여량에 의해 유발된 마취된 고양이의 빈맥(頻脈)에 대한 길항작용으로서 테스트된다.β 1 -Paralytic activity is tested as an antagonism against tachycardia in anesthetized cats caused by a standard dose of 1.0γ / kg sulfate N-isopropyl-noradrenaline.

황산 N-이소프로필-노라드레날린에 의해 유발된 당해의 화합물의 여러가지의 투여량에 의해 얻어진 심박도수(心搏度數)의 증가에 있어서 평균감소%로부터 ED50이 도표 외삽법에 의해 결정된다(표 Ⅱ와 Ⅲ를 참조).ED 50 is determined by graph extrapolation from the average reduction in the increase in heart rate obtained by various doses of the compound of interest induced by N-isopropyl-norradrenaline sulfate. (See Tables II and III).

β2-의사(擬似)활성은 본 발명 화합물의 투여에 참고하여, Konzett-Rossler방법에 의해 마취된 기니돼지에서 체중 kg당 20γ의 아세틸콜린을 정맥주사에 의해 유발된 기관지 경련에 대한 길항작용으로 테스트된다. 본 발명 화합물의 여러가지 투여에 의해 생긴 기관지 경련의 평균감소%로부터 ED50이 도표 외삽법에 의해 결정된다(표 Ⅰ 참조).β 2 -Physical activity was determined by antagonism of bronchospasm induced by intravenous injection of 20γ of acetylcholine per kg body weight in guinea pigs anesthetized by the Konzett-Rossler method with reference to the administration of the compound of the present invention. Is tested. ED 50 is determined by chart extrapolation from the average percent reduction in bronchial spasms resulting from various administrations of the compounds of the present invention (see Table I).

β2-마비활성은 마취시킨 기니돼지를 사용하여 아세틸콜린의 체중 kg당 20γ의 표준투약에 의해 야기된 기관지 경련이 유발되는 Konzett-Rossler의 시험방법에 의해 황산 N-이소프로필-노라드레드날린을 체중 1kg당 5γ의 투약에 의해 관찰되는 기관지 활성에 대한 길항작용으로 테스트된다(표 Ⅲ 참조).β 2 -Paralytic activity was determined using Konzett-Rossler's test method in which bronchial spasms caused by standard administration of 20γ / kg of acetylcholine using anesthetized guinea pigs were treated with N-isopropyl-norradrenaline sulfate. Tested with antagonism of bronchial activity observed by dose of 5γ per kg of body weight (see Table III).

물질의 급성독성은 쥐 10마리군에 대해서 조사 결정한다.Acute toxicity of the substance is determined and investigated in 10 rat groups.

동물의 50%가 죽은 후 14일만에 정맥에 투여된 투약량 LD50은 Litchfield와 Wilcoxon의 방법에 의해 계산된다(표 Ⅱ와 Ⅲ 참조).The dose LD 50 administered intravenously 14 days after 50% of the animals died is calculated by the method of Litchfield and Wilcoxon (see Tables II and III).

[표 Ⅰ]TABLE I

Figure kpo00004
Figure kpo00004

n1= 동물의 수/투약n 1 = number / dosage of animals

n2=ED50을 계산하기 위해 참작된 투여회수number of doses taken into account to calculate n 2 = ED 50

[표 Ⅱ]TABLE II

Figure kpo00005
Figure kpo00005

Figure kpo00006
Figure kpo00006

n1=동물의 수/투약 n2=투여회수n 1 = number of animals / dose n 2 = frequency of administration

[표 Ⅲ]TABLE III

Figure kpo00007
Figure kpo00007

n1=동물의 수 n2=동물의 수당 시험한 투여회수n 1 = number of animals n 2 = number of doses tested

일반식(Ⅰ)의 신규화합물은 선택적으로 다른 활성물질과 조합하여 통상의 제약학적인 조성을 가진 화합물을 합성할 수 있다. 단 한개의 투여량은 1-100γ이나 바람직하게 50-50γ이다. 다음 실시예는 본 발명을 설명해 준다.The novel compounds of formula (I) may optionally be combined with other active substances to synthesize compounds having conventional pharmaceutical compositions. Only one dose is 1-100γ but preferably 50-50γ. The following examples illustrate the invention.

[실시예 1]Example 1

1-(4-아미노-3-트리플로로메틸-페닐)-2-3급-부틸아미노-에탄올1- (4-Amino-3-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol

0.05g의 1-(4-아세틸아미노-3-트리플로로메틸-페닐)-2-3급-부틸아미노-에탄올-하이드로클로라이드를 50ml의 에탄올과 50ml의 4N수산화나트륨 용액의 혼합물에서 3시간동안 환류시킨다. 에탄올은 진공에서 제거되고 침전된 결정은 흡인 여과되어진다.0.05 g of 1- (4-acetylamino-3-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol-hydrochloride in a mixture of 50 ml of ethanol and 50 ml of 4N sodium hydroxide solution for 3 hours Reflux. Ethanol is removed in vacuo and the precipitated crystals are suction filtered.

융점 : 145-147℃(에탄올/물로부터)Melting Point: 145-147 ° C (from Ethanol / Water)

모노하이드로클로라이드로 전환시키기 위해 생성물을 이론양의 1N염산에 녹인다. 혼합물을 진공에서 증발시켜 말리고 고체찌꺼기는 이소프로판올/에틸로부터 재결정한다. 하이드로클로라이드의 융점 : 172-174℃(분해)The product is dissolved in theoretical 1N hydrochloric acid to convert to monohydrochloride. The mixture is dried by evaporation in vacuo and the solid residue is recrystallized from isopropanol / ethyl. Melting point of hydrochloride: 172-174 ° C. (decomposition)

[실시예 2]Example 2

1-(4-아미노-3-트리플로로메틸-페닐)-2-(N-벤질-N-3급부틸)-아미노-에탄올1- (4-Amino-3-trifluoromethyl-phenyl) -2- (N-benzyl-N-tertbutyl) -amino-ethanol

0.5g의 1-(4-아세틸아미노-3-트리플로로메틸-페닐)-2-(N-벤질-N-3급부틸)-아미노-에탄올(융점 98-100℃)을 10ml의 에탄올과 10ml의 4N수산화나트륨 용액의 혼합물에서 1½시간동안 환류시킨다. 에탄올은 진공에서 증류되어 없어지고, 수용액층은 초산에틸로 추출한다. 유기추출물은 물로 씻고 말리고 진공에서 증발시킨다. 기름같은 찌꺼기는 얇은층의 크로마토그래피적으로 순수하다.0.5 g of 1- (4-acetylamino-3-trifluoromethyl-phenyl) -2- (N-benzyl-N-tertbutyl) -amino-ethanol (melting point 98-100 ° C.) was mixed with 10 ml of ethanol. It is refluxed for 1½ hours in a mixture of 10 ml of 4N sodium hydroxide solution. Ethanol is distilled off in vacuo, and the aqueous layer is extracted with ethyl acetate. The organic extract is washed with water, dried and evaporated in vacuo. Oily debris is thin, chromatographically pure.

(실리카겔 : 클로로포름 : 메탄올=19 : 1, Rf값 : 0.5)(Silica gel: chloroform: methanol = 19: 1, R f value: 0.5)

[실시예 3]Example 3

1-(4-아미노-3-카복시-페닐)-2-3급-부틸아미노-에탄올1- (4-Amino-3-carboxy-phenyl) -2-tert-butylamino-ethanol

0.3g의 1-(4-아세틸아미노-3-카복시-페닐)-2-3급-부틸아미노-에탄올을 6ml의 에탄올에 녹이고 4ml의 진한 염산을 첨가한다. 혼합물을 40분동안 70℃까지 가열하고 진공에서 증발시켜 말리고, 생성물을 칼럼크로마토그래피에 의해 정제한다.0.3 g of 1- (4-acetylamino-3-carboxy-phenyl) -2-tert-butylamino-ethanol is dissolved in 6 ml of ethanol and 4 ml of concentrated hydrochloric acid is added. The mixture is heated to 70 ° C. for 40 minutes, evaporated to dryness in vacuo, and the product is purified by column chromatography.

(실리카겔 : 용출제로서 클로로포름 : 메탄올=3 : 2)(Silica gel: Chloroform: Methanol = 3: 2 as eluent)

얻어진 1-(4-아미노-3-카복시-페닐)-2-3급-부틸아미노-에탄올의 구조는 NMR스펙트럼(CD3OD)에 의해 확실시된다. 14ppm의 단 한개의[9개 프로톤, C(CH3)3], 3.3ppm의 다중(2개 프로톤, CH2), 4.5ppm의 다중(1프로톤, CH) 6.8-7.8ppm의 다중(3방향성 프로톤)The structure of the obtained 1- (4-amino-3-carboxy-phenyl) -2-tert-butylamino-ethanol is confirmed by NMR spectrum (CD 3 OD). Only one [9 protons, C (CH 3 ) 3 ] 14 ppm, 3.3 ppm multiple (2 protons, CH 2 ), 4.5 ppm multiple (1 proton, CH) 6.8-7.8 ppm multiple (3-directional) Protons)

[실시예 4]Example 4

1-(4-아미노-3-트리플로로메틸-페닐)-2-3급부틸아미노-에탄올1- (4-Amino-3-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol

0.45g의 1-(4-아미노-3-트리플로로메틸-페닐)-2-(N-벤질-N-3급부틸)-아미노-에탄올을 수소화 용기에서 10ml의 메탄올과 1.4ml의 1N염산에 녹이고 1몰의 수소가 흡입될 때까지 50mg의 팔라듐/목탄-촉매(10%)의 존재하에서 수소화시킨다. 촉매는 여과에 의해 제거되고, 용액을 진공에서 증발시키고 찌꺼기는 초산에틸과 2N암모니아 사이에 분산시킨다. 유기층은 물로 씻고 말리고 다시 진공에서 증발시킨다. 찌꺼기는 에탄올/물로부터 결정화한다.0.45 g of 1- (4-amino-3-trifluoromethyl-phenyl) -2- (N-benzyl-N-tertbutyl) -amino-ethanol in a hydrogenation vessel with 10 ml of methanol and 1.4 ml of 1N hydrochloric acid Is dissolved in the presence of 50 mg of palladium / charcoal-catalyst (10%) until 1 mole of hydrogen is inhaled. The catalyst is removed by filtration, the solution is evaporated in vacuo and the residue is dispersed between ethyl acetate and 2N ammonia. The organic layer is washed with water, dried and evaporated again in vacuo. The residue is crystallized from ethanol / water.

융점 : 145-147℃Melting Point: 145-147 ℃

[실시예 5]Example 5

1-(4-아미노-3-클로로-5-트리플로로메틸-페닐)-2-3급-부틸아미노-에탄올-하이드로클로라이드1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol-hydrochloride

0.76g의 1-(4-아미노-3-클로로-5-트리플로로메틸-페닐)-2-N-벤질-N-3급부틸)-아미노-에탄올을 수소화 용기에서 20ml의 메탄올과 1.9ml의 1N염산에 녹이고 1몰의 수소가 흡수될 때까지 80mg의 팔라듐/목탄-촉매(10%)의 존재하에서 수소화시킨다. 촉매가 여과에 의해 제거된 후, 여과물을 진공에서 증발시켜 말린다. 기름같은 찌꺼기는 칼럼크로마토그래피에 의해 정제된다. (실리카 : 용출제로서 클로로포름 : 메탄올 : 진한 암모니아=80 : 20 : 1) 2물질을 포함하는 유분은 합해지고 용매는 진공에서 제거된다. 원하는 화합물의 남은 결정염기는 이소프로판올속에서 1.07N염산의 계산된 양으로 하이드로클로라이드로 전환되고 초산에틸/에텔로부터 재결정된다.0.76 g of 1- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2-N-benzyl-N-tertbutyl) -amino-ethanol in a hydrogenation vessel with 20 ml of methanol and 1.9 ml Is dissolved in 1N hydrochloric acid and hydrogenated in the presence of 80 mg of palladium / charcoal-catalyst (10%) until 1 mole of hydrogen is absorbed. After the catalyst is removed by filtration, the filtrate is evaporated to dryness in vacuo. Oily residue is purified by column chromatography. (Silica: Chloroform: Methanol: Concentrated Ammonia = 80: 20: 1) The oil containing two substances is combined and the solvent is removed in vacuo. The remaining crystal base of the desired compound is converted to hydrochloride in a calculated amount of 1.07 N hydrochloric acid in isopropanol and recrystallized from ethyl acetate / ether.

융점 : 205-207℃(분해)Melting Point: 205-207 ° C (Decomposition)

[실시예 6]Example 6

1-(4-아미노-3-클로로-5-메틸-페닐)-2-3급-부틸아미노-에탄올-디하이드로클로라이드1- (4-Amino-3-chloro-5-methyl-phenyl) -2-tert-butylamino-ethanol-dihydrochloride

0.7g의 1-(4-아미노-3-클로로-5-메틸-페닐)-2-(N-벤질-N-3급부틸)-아미노-에탄올-하이드로클로라이드를 50ml의 메탄올과 0.92ml의 2N염산에 녹이고 50mg의 목탄위에 팔라듐(10%)의 존재하에서 수소화한다. 수소화는 41ml의 수소가 흡수된 후에 중단된다. 촉매는 여과되어 없어지고 여과물은 진공에서 증발되어 말린다. 찌꺼기는 에탄올에 녹이고 에텔의 첨가에 의해 디하이드로클로라이드로서 침전된다.0.7 g of 1- (4-amino-3-chloro-5-methyl-phenyl) -2- (N-benzyl-N-tertbutyl) -amino-ethanol-hydrochloride in 50 ml of methanol and 0.92 ml of 2N It is dissolved in hydrochloric acid and hydrogenated in the presence of palladium (10%) on 50 mg of charcoal. Hydrogenation is stopped after 41 ml of hydrogen has been absorbed. The catalyst is filtered off and the filtrate is evaporated to dryness in vacuo. The residue is dissolved in ethanol and precipitated as dihydrochloride by the addition of ether.

융점 : >95℃(분해)Melting Point:> 95 ℃ (Decomposition)

[실시예 7]Example 7

1-(4-아미노-3-메톡시-페닐)-2-3급-부틸아미노-에탄올1- (4-Amino-3-methoxy-phenyl) -2-tert-butylamino-ethanol

0.5g의 1-(4-아미노-3-메톡시-페닐)-2-(N-벤질-3급부틸)-아미노-에탄올을 150ml의 메탄올에 녹이고 에탄올성 염산으로 pH 6으로 산성화한다. 1g의 목탄위에 팔라듐(10%)을 이 용액에 가하고 혼합물을 실온, 대기압에서 수소의 이론양만큼 흡수될 때까지 교반기에서 수소화한다. 촉매가 흡인여과된후 혼합물을 더 적은 부피로 조린다. 침전된 결정도 흡인여과하고 에탄올로 재결정한다. 원하는 물질이 얻어진 디하이드로클로라이드의 무색결정은 174-176℃(분해)에서 녹는다.0.5 g of 1- (4-amino-3-methoxy-phenyl) -2- (N-benzyl tert-butyl) -amino-ethanol is dissolved in 150 ml of methanol and acidified to pH 6 with ethanolic hydrochloric acid. Palladium (10%) is added to 1 g of charcoal and the mixture is hydrogenated in a stirrer until the theoretical amount of hydrogen is absorbed at room temperature, atmospheric pressure. The mixture is quenched to a lower volume after the catalyst has been suction filtered. The precipitated crystals are also suction filtered and recrystallized from ethanol. Colorless crystals of the dihydrochloride from which the desired material is obtained dissolve at 174-176 ° C. (decomposition).

[실시예 8]Example 8

1-(4-아미노-3-플루오로-페닐)-2-시클로프로필아미노-에탄올1- (4-amino-3-fluoro-phenyl) -2-cyclopropylamino-ethanol

하이드로클로라이드의 융점 : 157-158℃(분해) 실시예 1과 같이 1-(4-아세틸아미노-3-플루오로-페닐)-2-시클로프로필아미노-에탄올과 수산화나트륨 용액으로부터 제조된다.Melting point of hydrochloride: 157-158 ° C. (decomposition) Prepared from 1- (4-acetylamino-3-fluoro-phenyl) -2-cyclopropylamino-ethanol and sodium hydroxide solution as in Example 1.

[실시예 9]Example 9

1-(4-아미노-3-플루오로-페닐)-2-3급-부틸아미노-에탄올1- (4-Amino-3-fluoro-phenyl) -2-tert-butylamino-ethanol

하이드로클로라이드의 융점 : 196-197℃(분해)Melting point of hydrochloride: 196-197 ° C (decomposition)

실시예 7과 같이 1-(4-아미노-3-플루오로-페닐)-2-(N-벤질-N-3급부틸)-아미노-에탄올-하이드로클로라이드와 촉매와 활성수소로부터 과정 C에 의해 제조된다.Process C from 1- (4-amino-3-fluoro-phenyl) -2- (N-benzyl-N-tertbutyl) -amino-ethanol-hydrochloride and catalyst and active hydrogen as in Example 7 Are manufactured.

[실시예 10]Example 10

2-에틸아미노-1-(4-아미노-3-플루오로-페닐)-에탄올2-ethylamino-1- (4-amino-3-fluoro-phenyl) -ethanol

하이드로클로라이드의 융점 : 187-188℃(분해)Melting point of hydrochloride: 187-188 ° C (decomposition)

실시예 1과 같이 1-(4-아세틸아미노-3-플루오로-페닐)-2-에틸아미노-에탄올과 수산화나트륨용액으로부터 제조된다.Prepared from 1- (4-acetylamino-3-fluoro-phenyl) -2-ethylamino-ethanol and sodium hydroxide solution as in Example 1.

[실시예 11]Example 11

1-(4-아미노-3-플루오로-페닐)-2-이소프로필아미노-에탄올1- (4-amino-3-fluoro-phenyl) -2-isopropylamino-ethanol

하이드로클로라이드의 융점 : 156-158℃(분해)Melting Point of Hydrochloride: 156-158 ° C (Decomposition)

실시예 1과 같이 1-(4-아세틸아미노-3-플루오로-페닐)-2-이소프로필아미노-에탄올과 수산화나트륨 용액으로부터 제조된다.Prepared from 1- (4-acetylamino-3-fluoro-phenyl) -2-isopropylamino-ethanol and sodium hydroxide solution as in Example 1.

[실시예 12]Example 12

1-(4-아미노-3-플루오로-페닐)-2-3급 펜틸아미노-에탄올1- (4-amino-3-fluoro-phenyl) -2-tert-pentylamino-ethanol

하이드로클로라이드의 융점 : 153-155℃(분해)Melting point of hydrochloride: 153-155 ° C. (decomposition)

실시예 1과 같이 1-(4-아세틸아미노-3-플루오로-페닐)-2-3급펜틸아미노-에탄올과 수소화나트륨 용액으로부터 제조된다.Prepared from 1- (4-acetylamino-3-fluoro-phenyl) -2-tert-pentylamino-ethanol and sodium hydride solution as in Example 1.

[실시예 13]Example 13

1-(4-아미노-3-플루오로-페닐)-2-디메틸아미노-에탄올1- (4-amino-3-fluoro-phenyl) -2-dimethylamino-ethanol

실시예 1과 같이 1-(4-아세틸아미노-3-플루오로-페닐)-2-디메틸아미노-에탄올과 수산화나트륨 용액으로부터 제조된다. 기름이며 IR과 UV스펙트럼에 의해 구조의 증명 IR(CH2Cl2) : 3500cm-1에서 유리 OH기 3370과 3450cm-1에서 NH2가 3200-3500cm-1에서 화합된 OH기 2780과 2830cm-1에서 N(CH3)2기, 1635cm-1에서 방향성 C=C, UV(에탄올) 288nm(E=0.13)과 238nm(E=0.6)에서 최대.Prepared from 1- (4-acetylamino-3-fluoro-phenyl) -2-dimethylamino-ethanol and sodium hydroxide solution as in Example 1. Oil and proof of structure by IR and UV spectrum IR (CH 2 Cl 2): free OH group with an OH group 2780 and 2830cm unity at the NH 2 3200-3500cm -1 at 3370 and 3450cm -1 -1 at 3500cm -1 In N (CH 3 ) 2 groups, aromatic C = C at 1635 cm −1 , UV (ethanol) at 288 nm (E = 0.13) and at 238 nm (E = 0.6).

[실시예 14]Example 14

1-(4-아미노-3-플루오로-페닐)-2-디메틸아미노-에탄올1- (4-amino-3-fluoro-phenyl) -2-dimethylamino-ethanol

하이드로클로라이드의 융점 : 122-125℃(분해)Melting point of hydrochloride: 122-125 ° C (decomposition)

실시예 1과 같이 1-(4-아세틸아미노-3-플루오로-페닐)-2-디메틸아미노-에탄올과 수산화나트륨 용액으로부터 제조된다.Prepared from 1- (4-acetylamino-3-fluoro-phenyl) -2-dimethylamino-ethanol and sodium hydroxide solution as in Example 1.

[실시예 15]Example 15

1-(4-아미노-3-디메틸아미노메틸-페닐)-2-3급부틸아미노-에탄올1- (4-amino-3-dimethylaminomethyl-phenyl) -2-tert-butylamino-ethanol

융점 : 55-59℃Melting Point: 55-59 ℃

실시예 1과같이 1-(4-아세틸-아미노-3-디메틸아미노메틸-페닐)-2-3급부틸아미노-에탄올과 에탄올성 수산화나트륨 용액의 비누화에 의해 제조된다.Prepared by saponification of 1- (4-acetyl-amino-3-dimethylaminomethyl-phenyl) -2-tert-butylamino-ethanol and ethanolic sodium hydroxide solution as in Example 1.

[실시예 16]Example 16

1-(4-아미노-3-디메틸아미노메틸-페닐)-2-디메틸아미노-에탄올1- (4-amino-3-dimethylaminomethyl-phenyl) -2-dimethylamino-ethanol

실시예 1과 같이 1-(4-아세틸아미노-3-디메틸아미노에틸-페닐)-2-디메틸아미노-에탄올과 에탄올성 수산화나트륨 용액과의 비누화에 의해 제조된다.Prepared by saponification of 1- (4-acetylamino-3-dimethylaminoethyl-phenyl) -2-dimethylamino-ethanol with ethanol sodium hydroxide solution as in Example 1.

NMR스펙트럼(CDCl3)에 의한 구조의 증명 2.2ppm의 단 한개의 [6프로톤-N(CH3)2], 2.35ppm의 단 한개의[6프로톤-N(CH3)2], 1.6-2ppm의 다중[2프로톤, CH2], 3.42ppm의 단 한개의[2프로톤, CH2], 4.4-4.8ppm의 다중(1프로톤, CH), 6.6-7.18ppm의 다중[3방향성 프로톤].Proof of structure by NMR spectrum (CDCl 3 ) Only one [6 proton-N (CH 3 ) 2 ] of 2.2 ppm, only one [6 proton-N (CH 3 ) 2 ] of 2.35 ppm, 1.6-2 ppm Multiple [2 protons, CH 2 ], only one [2 protons, CH 2 ] of 3.42 ppm, multiples (1 proton, CH) of 4.4-4.8 ppm, multiple [3-way protons] of 6.6-7.18 ppm.

[실시예 17]Example 17

1-(4-아미노-3-하이드록시메틸-페닐)-2-3급 부틸아미노-에탄올1- (4-amino-3-hydroxymethyl-phenyl) -2-tert-butylamino-ethanol

융점 : 123-128℃Melting Point: 123-128 ℃

실시예 1과 같이 1-(4-아미노-3-히드록시메틸-페닐)-2-(N-벤질-N-3급 부틸)-아미노-에탄올과 팔라듐-목탄의 존재하에서 수소와의 반응으로부터 제조된다.From reaction of hydrogen in the presence of 1- (4-amino-3-hydroxymethyl-phenyl) -2- (N-benzyl-N-tert-butyl) -amino-ethanol with palladium-charcoal as in Example 1 Are manufactured.

[실시예 18]Example 18

1-(4-아미노-3-클로로-5-히드록시메틸-페닐)-2-3급 부틸아미노-에탄올1- (4-amino-3-chloro-5-hydroxymethyl-phenyl) -2-tert-butylamino-ethanol

실시예 4와 같이 1-(4-아미노-3-클로로-5-히드록시메틸-페닐)-2-(N-벤질-N-3급부틸)-아미노-에탄올과 팔라듐-목탄의 존재하에서 수소와의 반응으로부터 제조된다.Hydrogen in the presence of 1- (4-amino-3-chloro-5-hydroxymethyl-phenyl) -2- (N-benzyl-N-tertbutyl) -amino-ethanol and palladium-charcoal as in Example 4 It is prepared from the reaction with.

NMR스펙트럼에 의한 구조의 증명(CDCl3) : 1.1ppm의 단 한개의[9프로톤, C(CH3)3], 2.0-3.6ppm의 다중[2프로톤, CH2], 4.6ppm의 단 한개의(2프로톤, CH2), 4.2-4.6ppm의 다중(1프로톤, CH), 6.9ppm의 2중과 7.2ppm의 2중(2방향성 프로톤).Proof of structure by NMR spectrum (CDCl 3 ): 1.1 ppm single [9 protons, C (CH 3 ) 3 ], 2.0-3.6 ppm multiple [2 protons, CH 2 ], 4.6 ppm single (2 protons, CH 2 ), 4.2-4.6 ppm multiple (1 proton, CH), 6.9 ppm double and 7.2 ppm double (bidirectional protons).

[실시예 19]Example 19

1-(4-아미노-3-클로로-5-트리플루오로메틸-페닐)-2-3급-부틸아미노-에탄올1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol

하이드로클로라이드의 융점 : 205-207℃(분해)Melting Point of Hydrochloride: 205-207 ° C (Decomposition)

실시예 2와 같이 2-3급 부틸아미노-1-[3-클로로-4-(p-클로로-벤조일아미노)-5-트리플루오로메틸-페닐]-에탄올과 수산화나트륨 용액으로부터 제조된다.Prepared from 2-3 butylamino-1- [3-chloro-4- (p-chloro-benzoylamino) -5-trifluoromethyl-phenyl] -ethanol and sodium hydroxide solution as in Example 2.

[실시예 20]Example 20

1-(4-아미노-3-플루오로-페닐)-2-3급 부틸아미노-에탄올1- (4-amino-3-fluoro-phenyl) -2-tert-butylamino-ethanol

하이드로클로라이드의 융점 : 196-197℃(분해)Melting point of hydrochloride: 196-197 ° C (decomposition)

실시예 1과 같이 1-(4-벤조일아미노-3-플루오로-페닐)-2-3급 부틸아미노-에탄올과 수산화나트륨 용액으로부터 제조한다.Prepared from 1- (4-benzoylamino-3-fluoro-phenyl) -2-tert-butylamino-ethanol and sodium hydroxide solution as in Example 1.

[실시예 21]Example 21

1-(4-아미노-3-클로로-5-플루오로-페닐)-2-3급 부틸아미노-에탄올1- (4-amino-3-chloro-5-fluoro-phenyl) -2-tert-butylamino-ethanol

하이드로클로라이드의 융점 : 206-208℃(분해)Melting Point of Hydrochloride: 206-208 ° C (Decomposition)

실시예 1과 같이 2-3급 부틸아미노-1-(3-클로로-5-플루오로-4-프로피오닐아미노-페닐)-에탄올과 수산화나트륨 용액으로부터 제조한다.Prepared from 2-3 butylamino-1- (3-chloro-5-fluoro-4-propionylamino-phenyl) -ethanol and sodium hydroxide solution as in Example 1.

[실시예 22]Example 22

1-(4-아미노-3-디에틸아미노메틸-페닐)-2-3급-부틸아미노-에탄올1- (4-Amino-3-diethylaminomethyl-phenyl) -2-tert-butylamino-ethanol

6.0g과 1-(4-아세틸아미노-3-디에틸아미노메틸-페닐)-2-3급 부틸아미노-에탄올을 35시간동안 50ml의 에탄올과 50ml의 4N수산화나트륨 용액으로 혼합물속에서 환류시킨다. 에탄올은 증류하여 제거하고 혼합물은 물로 희석하고 2번 클로로포름으로 추출한다. 유기층은 황산나트륨으로 건조되고 증발된다. 칼럼크로마토그래피적 정제(실리카겔, 메탄올)후에 1-(4-아미노-3-디에틸아미노메틸-페닐)-2-3급 부틸아미노-에탄올은 석유에테르로 결정화한다.6.0 g and 1- (4-acetylamino-3-diethylaminomethyl-phenyl) -2-tert-butylamino-ethanol are refluxed in a mixture with 50 ml of ethanol and 50 ml of 4N sodium hydroxide solution for 35 hours. Ethanol is distilled off and the mixture is diluted with water and extracted with chloroform twice. The organic layer is dried over sodium sulfate and evaporated. After column chromatographic purification (silica gel, methanol), 1- (4-amino-3-diethylaminomethyl-phenyl) -2-tert-butylamino-ethanol is crystallized with petroleum ether.

융점 : 86-90℃Melting Point: 86-90 ℃

[실시예 23]Example 23

1-(4-아미노-3-클로로-5-플루오로-페닐)-2-이소프로필아미노-에탄올1- (4-amino-3-chloro-5-fluoro-phenyl) -2-isopropylamino-ethanol

하이드로클로라이드의 융점 : 152-154℃(분해)Melting point of hydrochloride: 152-154 ° C. (decomposition)

실시예 1과 같이 1-(4-아세틸아미노-3-클로로-5-플루오로-페닐)-2-이소프로필아미노-에탄올-하이드로클로라이드로부터 실시예 4와 같이 1-(4-아미노-3-클로로-5-플루오로-페닐)-2-(N-벤질-N-이소프로필)-아미노-에탄올로부터 제조한다.From 1- (4-acetylamino-3-chloro-5-fluoro-phenyl) -2-isopropylamino-ethanol-hydrochloride as in Example 1 1- (4-amino-3- as in Example 4 Prepared from chloro-5-fluoro-phenyl) -2- (N-benzyl-N-isopropyl) -amino-ethanol.

다음 화합물들은 이 과정과 같이 제조되었다.The following compounds were prepared as in this procedure.

1-(4-아미노-3-클로로-5-플루오로-페닐)-2-시클로프로필아미노-에탄올-하이드로클로라이드1- (4-Amino-3-chloro-5-fluoro-phenyl) -2-cyclopropylamino-ethanol-hydrochloride

융점 : 175-177℃(분해).Melting point: 175-177 ° C. (decomposition).

1-(4-아미노-3-클로로-5-플루오로-페닐)-2-3급펜틸아미노-에탄올-하이드로클로라이드1- (4-Amino-3-chloro-5-fluoro-phenyl) -2-tert-pentylamino-ethanol-hydrochloride

융점 : 187-188℃(분해).Melting point: 187-188 ° C. (decomposition).

1-(4-아미노-3-브로모-5-플루오로-페닐)-2-이소프로필아미노-에탄올-하이드로클로라이드1- (4-Amino-3-bromo-5-fluoro-phenyl) -2-isopropylamino-ethanol-hydrochloride

융점 : 171-173℃(분해).Melting point: 171-173 ° C. (decomposition).

1-(4-아미노-3-브로모-5-플루오로-페닐)-2-3급 부틸아미노-에탄올-하이드로클로라이드1- (4-Amino-3-bromo-5-fluoro-phenyl) -2-tert-butylamino-ethanol-hydrochloride

융점 : 207-208℃(분해).Melting point: 207-208 ° C. (decomposition).

1-(4-아미노-3-브로모-5-플루오로-페닐)-2-시클로부틸아미노-에탄올-하이드로클로라이드1- (4-Amino-3-bromo-5-fluoro-phenyl) -2-cyclobutylamino-ethanol-hydrochloride

융점 : 164-166℃(분해).Melting point: 164-166 ° C. (decomposition).

1-(4-아미노-3-플루오로-5-요도-페닐)-2-시클로프로필아미노-에탄올-하이드로클로라이드1- (4-Amino-3-fluoro-5-urido-phenyl) -2-cyclopropylamino-ethanol-hydrochloride

융점 : 199-201℃(분해).Melting point: 199-201 ° C. (decomposition).

1-(4-아미노-3-트리플루오로메틸-페닐)-2-3급 펜틸아미노-에탄올-하이드로클로라이드1- (4-Amino-3-trifluoromethyl-phenyl) -2-tert-pentylamino-ethanol-hydrochloride

융점 : 174-175℃(분해).Melting point: 174-175 ° C. (decomposition).

1-(4-아미노-3-클로로-5-트리플루오로메틸-페닐)-2-이소프로필아미노-에탄올1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-isopropylamino-ethanol

융점 : 104-106℃(분해).Melting point: 104-106 ° C. (decomposition).

1-(4-아미노-3-클로로-5-트리플루오로메틸-페닐)-2-3급부틸아미노-에탄올-하이드로클로라이드1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol-hydrochloride

융점 : 205-207℃(분해).Melting point: 205-207 ° C. (decomposition).

1-(4-아미노-3-클로로-5-트리플루오로메틸-페닐)-2-시클로부틸아미노-에탄올-하이드로클로라이드1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-cyclobutylamino-ethanol-hydrochloride

융점 : 177-178℃(분해).Melting point: 177-178 ° C. (decomposition).

1-(4-아미노-3-클로로-5-트리플루오로메틸-페닐)-2-3급펜틸아미노-에탄올-하이드로클로라이드1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-pentylamino-ethanol-hydrochloride

융점 : 176-178℃(분해).Melting point: 176-178 ° C. (decomposition).

1-(4-아미노-3-브로모-5-트리플루오로메틸-페닐)-2-이소프로필아미노-에탄올-하이드로클로라이드1- (4-Amino-3-bromo-5-trifluoromethyl-phenyl) -2-isopropylamino-ethanol-hydrochloride

융점 : 177-179℃(분해).]Melting Point: 177-179 ° C (Decomposition).]

[실시예 24]Example 24

1-(4-아미노-3-클로로-5-니트로-페닐)-2-3급 부틸아미노-에탄올1- (4-amino-3-chloro-5-nitro-phenyl) -2-tert-butylamino-ethanol

융점 : 148-149℃Melting Point: 148-149 ℃

실시예 1과 같이 1-(4-아세틸아미노-3-클로로-5-니트로-페닐)-2-3급 부틸아미노-에탄올-하이드로클로라이드로부터 제조한다.Prepared from 1- (4-acetylamino-3-chloro-5-nitro-phenyl) -2-tert butylamino-ethanol-hydrochloride as in Example 1.

다음 화합물들은 이 과정에 의해 제조되었다.The following compounds were prepared by this procedure.

1-(4-아미노-3-브로모-5-니트로-페닐)-2-3급 부틸아미노-에탄올1- (4-amino-3-bromo-5-nitro-phenyl) -2-tert-butylamino-ethanol

융점 : 151-152℃Melting Point: 151-152 ℃

1-(4-아미노-3-클로로-5-시아노-페닐)-2-디메틸아미노-에탄올1- (4-amino-3-chloro-5-cyano-phenyl) -2-dimethylamino-ethanol

0.5g의 1-아세톡시-1-(4-아미노-3-클로로-5-시아노-페닐)-2-디메틸아미노-에탄(융점 : 120-124℃)을 20℃에서 1시간동안 메탄올성 수산화나트륨에서 교반한다. 물을 첨가하고 메탄올을 진공에서 여과제거하고 남은 수용액층을 클로로포름으로 추출하고 클로로포름층을 황산나트륨위에서 말리고 진공에서 증발건조시키고 찌꺼기를 이소프로판올에 녹이고 이소프로판올성 염산의 첨가에 의해 1-(4-아미노-3-클로로-5-시아노-페닐)-2-디메틸아미노-에탄올의 하이드로클로라이드가 결정화된다.0.5 g of 1-acetoxy-1- (4-amino-3-chloro-5-cyano-phenyl) -2-dimethylamino-ethane (melting point: 120-124 ° C.) was methanoly at 20 ° C. for 1 hour. Stir in sodium hydroxide. Water was added, methanol was filtered off in vacuo, the remaining aqueous layer was extracted with chloroform, the chloroform layer was dried over sodium sulfate, evaporated to dryness in vacuo, the residue was dissolved in isopropanol and 1- (4-amino-3) added by isopropanol hydrochloric acid. Hydrochloride of -chloro-5-cyano-phenyl) -2-dimethylamino-ethanol is crystallized.

융점 : 187-189℃Melting Point: 187-189 ℃

[실시예 26]Example 26

1-(4-아미노-3-시아노-5-플루오로-페닐)-2-디메틸아미노-에탄올1- (4-amino-3-cyano-5-fluoro-phenyl) -2-dimethylamino-ethanol

7g의 1-아세톡시-1-(4-아미노-3-시아노-5-플루오로-페닐)-2-디메틸아미노-에탄올 100ml의 메탄올에 녹인다. 5ml의 10N수용성 수산화나트륨 용액을 첨가하고 용액을 실온에서 1시간동안 방치한다. 부수적으로 반응혼합물을 포화염화나트륨 용액으로희석하고 클로로포름으로 남김없이 추출한다. 클로로포름 용액을 포화염화나트륨 용액으로 씻고 황산나트륨위에서 말리고 진공에서 증발건조시킨다. 무색기름이 얻어진다. NMR스펙트럼에 의한 구조증명(CD3OD)2.2-2.65ppm의 다중[8프로톤 :Dissolve in 7 g of 1-acetoxy-1- (4-amino-3-cyano-5-fluoro-phenyl) -2-dimethylamino-ethanol in 100 ml of methanol. 5 ml of 10N aqueous sodium hydroxide solution is added and the solution is left at room temperature for 1 hour. Incidentally, the reaction mixture is diluted with saturated sodium chloride solution and extracted with chloroform. The chloroform solution is washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness in vacuo. Colorless oil is obtained. Structural proof by NMR spectrum (CD 3 OD) 2.2-2.65 ppm of multiple [8 protons:

Figure kpo00008
Figure kpo00008

[실시예 27]Example 27

1-(4-아미노-3-클로로-5-시아노-페닐)-2-3급 부틸아미노-에탄올1- (4-amino-3-chloro-5-cyano-phenyl) -2-tert-butylamino-ethanol

0.5g의 N-아세틸-N-[2-아세톡시-2-(4-아미노-3-클로로-5-시아노-페닐)-에틸]-3급 부틸아민(융점 : 160-162℃)을 메탄올성 수산화나트륨 용액으로 20℃에서 1/2시간동안 교반한다. 물을 첨가하고 메탄올을 진공에서 여과해 버리고 남은 수용액측을 황산나트륨위에서 말리고 반응생성물을 진공에서 증발건조시키고 찌꺼기를 에탄올로 결정화한다. 1-(4-아미노-3-클로로-5-시아노-페닐)-2-3급 부틸아미노-에탄올을 얻는다.0.5 g of N-acetyl-N- [2-acetoxy-2- (4-amino-3-chloro-5-cyano-phenyl) -ethyl] tert-butylamine (melting point: 160-162 ° C.) Stir at methanol at 20 ° C. for 1/2 hour. Water is added, methanol is filtered off in vacuo, the remaining aqueous solution is dried over sodium sulfate, the reaction product is evaporated to dryness in vacuo and the residue is crystallized from ethanol. Obtain 1- (4-amino-3-chloro-5-cyano-phenyl) -2-tert butylamino-ethanol.

융점 : 131-135℃Melting Point: 131-135 ℃

하이드로클로라이드의 융점 : 204-207℃Melting Point of Hydrochloride: 204-207 ° C

다음 화합물들은 실시예 25-27과 같이 제조되었다.The following compounds were prepared as in Examples 25-27.

1-(4-아미노-3-플루오로-페닐)-2-3급 부틸아미노-에탄올-하이드로클로라이드1- (4-amino-3-fluoro-phenyl) -2-tert-butylamino-ethanol-hydrochloride

융점 : 196-197℃(분해).Melting point: 196-197 ° C. (decomposition).

1-(4-아미노-3-클로로-5-플루오로-페닐)-2-이소프로필아미노-에탄올-하이드로클로라이드1- (4-Amino-3-chloro-5-fluoro-phenyl) -2-isopropylamino-ethanol-hydrochloride

융점 : 152-154℃(분해).Melting point: 152-154 ° C. (decomposition).

1-(4-아미노-3-클로로-5-플루오로-페닐)-2-시클로프로필아미노-에탄올-하이드로클로라이드1- (4-Amino-3-chloro-5-fluoro-phenyl) -2-cyclopropylamino-ethanol-hydrochloride

융점 : 175-177℃(분해).Melting point: 175-177 ° C. (decomposition).

1-(4-아미노-3-클로로-5-플루오로-페닐)-2-3급 부틸아미노-에탄올-하이드로클로라이드1- (4-Amino-3-chloro-5-fluoro-phenyl) -2-tert-butylamino-ethanol-hydrochloride

융점 : 206-208℃(분해).Melting point: 206-208 ° C. (decomposition).

1-(4-아미노-3-클로로-5-플루오로-페닐)-2-3급 펜틸아미노-에탄올-하이드로클로라이드1- (4-amino-3-chloro-5-fluoro-phenyl) -2-tert-pentylamino-ethanol-hydrochloride

융점 : 187-188℃(분해).Melting point: 187-188 ° C. (decomposition).

1-(4-아미노-3-브로모-5-플루오로-페닐)-2-이소프로필아미노-에탄올-하이드로클로라이드1- (4-Amino-3-bromo-5-fluoro-phenyl) -2-isopropylamino-ethanol-hydrochloride

융점 : 171-173℃(분해).Melting point: 171-173 ° C. (decomposition).

1-(4-아미노-3-브로모-5-플루오로-페닐)-2-3급 부틸아미노-에탄올-하이드로클로라이드1- (4-Amino-3-bromo-5-fluoro-phenyl) -2-tert-butylamino-ethanol-hydrochloride

융점 : 207-208℃(분해).Melting point: 207-208 ° C. (decomposition).

1-(4-아미노-3-브로모-5-플루오로-페닐)-2-시클로부틸아미노-에탄올-하이드로클로라이드1- (4-Amino-3-bromo-5-fluoro-phenyl) -2-cyclobutylamino-ethanol-hydrochloride

융점 : 164-166℃(분해).Melting point: 164-166 ° C. (decomposition).

1-(4-아미노-3-플루오로-5-요도-페닐)-2-시클로프로필아미노-에탄올-하이드로클로라이드1- (4-Amino-3-fluoro-5-urido-phenyl) -2-cyclopropylamino-ethanol-hydrochloride

융점 : 199-201℃(분해).Melting point: 199-201 ° C. (decomposition).

1-(4-아미노-3-시아노-5-플루오로-페닐)-2-이소프로필아미노-에탄올-하이드로클로라이드1- (4-Amino-3-cyano-5-fluoro-phenyl) -2-isopropylamino-ethanol-hydrochloride

융점 : 182-184℃(분해).Melting point: 182-184 ° C. (decomposition).

1-(4-아미노-3-시아노-5-플루오로-페닐)-2-3급 부틸아미노-에탄올-하이드로클로라이드1- (4-Amino-3-cyano-5-fluoro-phenyl) -2-tert-butylamino-ethanol-hydrochloride

융점 : 242-243℃(분해).Melting point: 242-243 ° C. (decomposition).

1-(4-아미노-3-시아노-페닐)-2-시클로부틸아미노-에탄올-하이드로브로마이드1- (4-Amino-3-cyano-phenyl) -2-cyclobutylamino-ethanol-hydrobromide

융점 : >193℃(분해).Melting point:> 193 ° C. (decomposition).

1-(4-아미노-3-시아노-페닐)-2-3급 펜틸아미노-에탄올1- (4-amino-3-cyano-phenyl) -2-tert-pentylamino-ethanol

융점 : 143℃.Melting point: 143 ° C.

1-(4-아미노-3-클로로-5-시아노-페닐)-2-프로필아미노-에탄올-하이드로클로라이드1- (4-Amino-3-chloro-5-cyano-phenyl) -2-propylamino-ethanol-hydrochloride

융점 : 187-189℃Melting Point: 187-189 ℃

1-(4-아미노-3-클로로-5-시아노-페닐)-2-2급 부틸아미노-에탄올-디하이드로클로라이드1- (4-Amino-3-chloro-5-cyano-phenyl) -2-secondary butylamino-ethanol-dihydrochloride

융점 : 190-191℃Melting Point: 190-191 ℃

1-(4-아미노-3-클로로-5-시아노-페닐)-2-(하이드록시-3급 부틸아미노)-에탄올-하이드로클로라이드1- (4-Amino-3-chloro-5-cyano-phenyl) -2- (hydroxy-tertiary butylamino) -ethanol-hydrochloride

융점 : 228-230℃(분해).Melting point: 228-230 ° C. (decomposition).

1-(4-아미노-3-클로로-5-시아노-페닐)-2-3급 펜틸아미노-에탄올-하이드로클로라이드1- (4-Amino-3-chloro-5-cyano-phenyl) -2-tert-pentylamino-ethanol-hydrochloride

융점 : 218-220℃(분해).Melting point: 218-220 ° C. (decomposition).

1-(4-아미노-3-클로로-5-시아노-페닐)-2-시클로펜틸아미노-에탄올-하이드로클로라이드1- (4-Amino-3-chloro-5-cyano-phenyl) -2-cyclopentylamino-ethanol-hydrochloride

융점 : 138-144℃.Melting point: 138-144 ° C.

1-(4-아미노-3-클로로-5-시아노-페닐)-2-[1-(3, 4-메틸렌디옥시-페닐)-2-프로필아미노]-에탄올-하이드로클로라이드1- (4-Amino-3-chloro-5-cyano-phenyl) -2- [1- (3, 4-methylenedioxy-phenyl) -2-propylamino] -ethanol-hydrochloride

융점 : 189-192℃.Melting point: 189-192 ° C.

1-(4-아미노-3-브로모-5-시아노-페닐)-2-이소프로필아미노-에탄올-하이드로클로라이드1- (4-Amino-3-bromo-5-cyano-phenyl) -2-isopropylamino-ethanol-hydrochloride

융점 : 186-189℃.Melting point: 186-189 ° C.

1-(4-아미노-3-브로모-5-시아노-페닐)-2-3급 부틸아미노-에탄올-하이드로클로라이드1- (4-Amino-3-bromo-5-cyano-phenyl) -2-tert-butylamino-ethanol-hydrochloride

융점 : 213-215℃.Melting point: 213-215 ° C.

1-(4-아미노-3-브로모-5-시아노-페닐)-2-시클로부틸아미노-에탄올-하이드로클로라이드1- (4-Amino-3-bromo-5-cyano-phenyl) -2-cyclobutylamino-ethanol-hydrochloride

융점 : 215-216℃(분해).Melting point: 215-216 ° C. (decomposition).

1-(4-아미노-3, 5-디시아노-페닐)-2-3급 부틸아미노-에탄올 하이드로클로라이드1- (4-amino-3, 5-dicyano-phenyl) -2-tert-butylamino-ethanol hydrochloride

융점 : 251-253℃(분해).Melting point: 251-253 ° C. (decomposition).

1-(4-아미노-3-트리플루오로메틸-페닐)-2-3급 부틸아미노-에탄올-하이드로클로라이드1- (4-Amino-3-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol-hydrochloride

융점 : 172-174℃(분해).Melting point: 172-174 ° C. (decomposition).

1-(4-아미노-3-트리플루오로메틸-페닐)-2-3급 펜틸아미노-에탄올-하이드로브로마이드1- (4-Amino-3-trifluoromethyl-phenyl) -2-tert-pentylamino-ethanol-hydrobromide

융점 : 174-175℃(분해).Melting point: 174-175 ° C. (decomposition).

1-(4-아미노-3-클로로-5-트리플루오로메틸-페닐)-2-이소프로필아미노-에탄올1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-isopropylamino-ethanol

융점 : 104-106℃(분해).Melting point: 104-106 ° C. (decomposition).

1-(4-아미노-3-클로로-5-트리플루오로메틸-페닐)-2-3급 부틸아미노-에탄올-하이드로클로라이드1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol-hydrochloride

융점 : 205-207℃(분해).Melting point: 205-207 ° C. (decomposition).

1-(4-아미노-3-클로로-5-트리플루오로메틸-페닐)-2-시클로부틸아미노-에탄올-하이드로클로라이드1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-cyclobutylamino-ethanol-hydrochloride

융점 : 177-178℃(분해).Melting point: 177-178 ° C. (decomposition).

1-(4-아미노-3-클로로-5-트리플루오로메틸-페닐)-2-3급 펜틸아미노-에탄올-하이드로클로라이드1- (4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-pentylamino-ethanol-hydrochloride

융점 : 176-178℃(분해).Melting point: 176-178 ° C. (decomposition).

1-(4-아미노-3-브로모-5-트리플루오로메틸-페닐)-2-이소프로필아미노-에탄올-하이드로클로라이드1- (4-Amino-3-bromo-5-trifluoromethyl-phenyl) -2-isopropylamino-ethanol-hydrochloride

융점 : 177-179℃(분해).Melting point: 177-179 ° C. (decomposition).

1-(4-아미노-3-클로로-5-니트로-페닐)-2-3급 부틸아미노-에탄올1- (4-amino-3-chloro-5-nitro-phenyl) -2-tert-butylamino-ethanol

융점 : 148-149℃(분해).Melting point: 148-149 ° C. (decomposition).

1-(4-아미노-3-브로모-5-니트로-페닐)-2-3급 부틸아미노-에탄올1- (4-amino-3-bromo-5-nitro-phenyl) -2-tert-butylamino-ethanol

융점 : 151-152℃Melting Point: 151-152 ℃

[실시예 28]Example 28

1-1-(4-아미노-3-플루오로-페닐)-2-3급부틸아미노-에탄올과 d-1-(4-아미노-3-플루오로-페닐)-2-3급 부틸아미노-에탄올1-1- (4-amino-3-fluoro-phenyl) -2-tert-butylamino-ethanol and d-1- (4-amino-3-fluoro-phenyl) -2-tert-butylamino- ethanol

a) 1-1-(4-아세틸아미노-3-플루오로-페닐)-2-(N-벤질-N-3급 부틸)-아미노-0-(N-카르보벤조옥시-L-알라닐)-에탄올과 d-1-(4-아세틸아미노-3-플루오로-페닐)-2-(N-벤질-N-3급부틸)-아미노-0-(N-카르보벤조옥시-알라닐)-에탄올a) 1-1- (4-acetylamino-3-fluoro-phenyl) -2- (N-benzyl-N-tert-butyl) -amino-0- (N-carbobenzooxy-L-alanyl ) -Ethanol and d-1- (4-acetylamino-3-fluoro-phenyl) -2- (N-benzyl-N-tertbutyl) -amino-0- (N-carbobenzooxy-alanyl )-ethanol

300ml의 무수 테트라히드로푸란속에 녹인 15g의 N-카르보벤조옥시-L-알라닌의 용액에 14.5g의 N, N'-카르보닐-디이미다졸을 가하고 실온에서 3시간동안 교반한다. 부수적으로 200ml의 무수 테트라하이드로푸란에 녹인 10g의 d, 1-1-(4-아세틸아미노-3-플루오로-페닐)-2-(N-벤질-N-3급부틸)-아미노-에탄올의 용액과 작은 조각의 나트륨을 가하고 혼합물을 실온에서 12일동안 교반하고 진공에서 증발건조시킨다. 찌꺼기를 클로로포름과 물사이에 분산시킨다. 클로로포름층은 황산나트륨위에서 말리고 진공에서 증발건조시킨다. 혼합물에서 얻어진 2개의 부분대차체 에스테르는 얇은층 크로마토그래피(실리카겔 G, Merck : 클로로포름 : 아세톤=10 :1)에서 서로 다른 Rf값을 나타낸다. 상기 증발찌꺼기는 광학대차체 에스테르를 분리함이 없이 실리카겔 크로마토그래피 칼럼(500g의 실리카겔 : 용출액 : 클로로포름 : 아세톤=10 : 1)에서 정제된다.To a solution of 15 g of N-carbenzobenzooxy-L-alanine dissolved in 300 ml of anhydrous tetrahydrofuran, 14.5 g of N, N'-carbonyl-diimidazole is added and stirred at room temperature for 3 hours. Incidentally, 10 g of d, 1-1- (4-acetylamino-3-fluoro-phenyl) -2- (N-benzyl-N-tertbutyl) -amino-ethanol dissolved in 200 ml of anhydrous tetrahydrofuran The solution and a small piece of sodium are added and the mixture is stirred for 12 days at room temperature and evaporated to dryness in vacuo. The debris is dispersed between chloroform and water. The chloroform layer is dried over sodium sulfate and evaporated to dryness in vacuo. The two subcarrier esters obtained in the mixture show different R f values in thin layer chromatography (silica gel G, Merck: chloroform: acetone = 10: 1). The evaporation residue is purified on a silica gel chromatography column (500 g of silica gel: eluent: chloroform: acetone = 10: 1) without separating the optical collimator ester.

2물질을 포함하는 유분은 진공에서 증발건조되고 에테르로 재결정한다. 1-1-(4-아세틸아미노-3-플루오로-페닐)-2-(N-벤질-N-3급 부틸)-아미노-0-(N-카르보벤조옥시-L-알라닐)-에탄올이 무색결정으로 얻어진다.The fraction containing the two substances is evaporated to dryness in vacuo and recrystallized from ether. 1-1- (4-acetylamino-3-fluoro-phenyl) -2- (N-benzyl-N-tert-butyl) -amino-0- (N-carbobenzooxy-L-alanyl)- Ethanol is obtained as colorless crystals.

[α]

Figure kpo00009
=-101°(C=2.0 : 메탄올 ; Rf값 =0.27 얻어진 모액은 진공에서 증발건조시킨다. 더 큰 Rf값(Rf=0.33)을 가진 광학대차체 에스테르는 크로마토그래피칼럼(100g의 실리카겔 : 유출액 : 클로로포름 : 아세톤=20 : 1)에서 분리된다. d-1-(4-아세틸아미노-3-플루오로-페닐)-2-(N-벤질-N-3급부틸-아미노-0-(N-카르보벤조옥시-L-알라닐-에탄올이 무색기름으로 얻어진다.[α]
Figure kpo00009
= -101 ° (C = 2.0: Methanol; R f value = 0.27 The resulting mother liquor is evaporated to dryness in vacuo. The optical collimator ester with a larger R f value (R f = 0.33) is obtained by chromatography column (100 g of silica gel). : Distillate: chloroform: acetone = 20: 1) d-1- (4-acetylamino-3-fluoro-phenyl) -2- (N-benzyl-N-tert-butyl-amino-0- (N-carbobenzooxy-L-alanyl-ethanol is obtained as colorless oil.

[α]

Figure kpo00010
=-65°(C=2.0 : 메탄올) : Rf값=0.33[α]
Figure kpo00010
= -65 ° (C = 2.0: methanol): R f value = 0.33

b) 1-1-(4-아미노-3-플루오로-페닐)-2-3급부틸아미노-에탄올b) 1-1- (4-amino-3-fluoro-phenyl) -2-tert-butylamino-ethanol

2g의 1-1-(4-아세틸아미노-3-플루오로-페닐)-2-(N-벤질-N-3급-부틸)-아미노-0-(N-카르보벤조옥시-L-알라닐)-에탄올을 60ml의 에탄올에 녹인다. 20ml의 5N수산화나트륨용액을 첨가하고 4시간동안 환류시킨다. 냉각한 후 용액을 클로로포름과 물사이에 분산시키고 수용액층은 클로로포름으로 4번 추출한다. 합해진 클로로포름용액은 황산나트륨위에서 말리고 진공에서 증발건조시킨다. 1-1-(4-아미노-3-플루오로-페닐)-2-(N-벤질-N-3급부틸)-아미노-에탄올을 함유하는 찌꺼기를 50ml의 메탄올에 녹이고 에테르성 염산으로 pH 6으로 산성화하고 0.2g의 목탄위의 팔라듐을 첨가하고 반응생성물을 실온에서 5기압의 압력에서 모든 수소가 흡수될 때가지 Parr장치에서 수소화한다. 촉매가 흡인여과된 후 반응생성물을 진공에서 증발건조시키고 1-1-(4-아미노-3-플루오로-페닐)-2-3급부틸아미노-에탄올-하이드로클로라이드를 포함하는 고체찌꺼기를 에테르를 첨가하여 이소프로판올로부터 결정화한다.2 g of 1-1- (4-acetylamino-3-fluoro-phenyl) -2- (N-benzyl-N-tert-butyl) -amino-0- (N-carbobenzooxy-L-ala Nil) -ethanol is dissolved in 60 ml of ethanol. 20 ml of 5N sodium hydroxide solution is added and refluxed for 4 hours. After cooling, the solution is dispersed between chloroform and water, and the aqueous layer is extracted four times with chloroform. The combined chloroform solution is dried over sodium sulfate and evaporated to dryness in vacuo. The residue containing 1-1- (4-amino-3-fluoro-phenyl) -2- (N-benzyl-N-tertbutyl) -amino-ethanol is dissolved in 50 ml of methanol and pH 6 with etheric hydrochloric acid. Acidify and add 0.2 g of palladium on charcoal and the reaction product is hydrogenated in a Parr apparatus until all hydrogen is absorbed at a pressure of 5 atmospheres at room temperature. After the catalyst was suction filtered, the reaction product was evaporated to dryness in vacuo and the solid residue comprising 1-1- (4-amino-3-fluoro-phenyl) -2-tert-butylamino-ethanol-hydrochloride was removed with ether. Crystallize from isopropanol by addition.

융점 : 199-200℃(분해)Melting Point: 199-200 ℃ (Decomposition)

[α]

Figure kpo00011
=-123.3°(C=1.0 : 메탄올)[α]
Figure kpo00011
= -123.3 ° (C = 1.0: methanol)

c) d-1-(4-아미노-3-플루오로-페닐)-2-3급부틸아미노-에탄올c) d-1- (4-amino-3-fluoro-phenyl) -2-tert-butylamino-ethanol

상기 얻어진 기름같은 d-1-(4-아세틸아미노-3-플루오로-페닐)-2-(N-벤질-N-3급부틸)-아미노-0-(N-카르보벤조옥시-L-알라닐)-에탄올을 30ml의 에탄올에 녹인다. 10ml의 5N수산화나트륨용액을 첨가하고 용액을 4시간동안 환류시킨다. 식힌후에 반응용액을 클로로포름과 물사이에 분산시키고 수용액층은 클로로포름으로 4번 추출한다. 합해진 클로로포름용액을 황산나트륨위에서 건조시키고 진공에서 증발건조시킨다. d-1-(4-아미노-3-플루오로-페닐)-2-(N-벤질-N-3급부틸)-아미노-에탄올로 구성된 찌꺼기를 25ml의 메탄올에 녹이고 에테르성 염산으로 pH 6으로 산성화하고 0.1g의 목탄위의 팔라듐(10%)를 첨가하고 반응생성물을 실온에서 5기압의 압력에서 모든 수소가 흡수될 때까지 Parr장치에서 수소화시킨다. 촉매가 흡인여과된 후 혼합물을 진공에서 증발건조시키고 d-1-(4-아미노-3-플루오로-페닐)-2-3급부틸아미노-에탄올-하이드로클로라이드로 구성된 고체찌꺼기를 에테르 부가에 의해 이소프로판올로 결정화한다.D-1- (4-acetylamino-3-fluoro-phenyl) -2- (N-benzyl-N-tertbutyl) -amino-0- (N-carbobenzooxy-L- Alanyl) -ethanol is dissolved in 30 ml of ethanol. 10 ml of 5N sodium hydroxide solution is added and the solution is refluxed for 4 hours. After cooling, the reaction solution is dispersed between chloroform and water, and the aqueous layer is extracted four times with chloroform. The combined chloroform solution is dried over sodium sulfate and evaporated to dryness in vacuo. The residue consisting of d-1- (4-amino-3-fluoro-phenyl) -2- (N-benzyl-N-tertbutyl) -amino-ethanol is dissolved in 25 ml of methanol and brought to pH 6 with etheric hydrochloric acid. Acidify and add 0.1 g of palladium (10%) over charcoal and hydrogenate the reaction product in a Parr apparatus until all hydrogen is absorbed at a pressure of 5 atmospheres at room temperature. After the catalyst was suction filtered, the mixture was evaporated to dryness in vacuo and the solid residue consisting of d-1- (4-amino-3-fluoro-phenyl) -2-tert-butylamino-ethanol-hydrochloride was added by ether addition. Crystallize with isopropanol.

융점 : 198-200℃(분해).Melting point: 198-200 ° C. (decomposition).

[α]=

Figure kpo00012
=+124.4°(C=1.142 : 메탄올)[α] =
Figure kpo00012
= + 124.4 ° (C = 1.142: methanol)

[실시예 29]Example 29

d-1-(4-아미노-3-클로로-5-트리플루오로메틸-페닐)-2-3급부틸아미노-에탄올과 1-1-(4-아미노-3-클로로-5-트리플루오로메틸-페닐)-2-3급 부틸아미노-에탄올d-1- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol and 1-1- (4-amino-3-chloro-5-trifluoro Methyl-phenyl) -2-tert-butylamino-ethanol

a) d,1-1-(4-아미노-3-클로로-5-트리플루오로메틸-페닐)-2-3급부틸아미노-0-[(-)-메토옥시-카르보닐]-에탄올a) d, 1-1- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-0-[(-)-methooxy-carbonyl] -ethanol

56.6ml의 톨루엔에 녹이고 0.5몰의 클로로-포름산-(-)-멘틸에스테르의 용액을 20℃에서 계속 교반하면서 50ml의 피리딘에 녹인 8.8g의 d,1-1-(4-아미노-3-클로로-5-트리플루오로메틸페닐)-2-3급부틸아미노-에탄올의 용액에 떨어뜨린다. 2시간후에 용액은 진공에서 증발건조시킨다. 기름같은 찌꺼기는 물로, 가루로 만들고 부수적으로 수용액을 딴그릇에 옮긴 후 에테르에 녹인다. 에테르성용액은 계속적으로 물로 씻고 2N암모니아(층사이에서 얻어진 침전물을 녹인다)로 씻고 다시 물로 씻는다. 에테르성 용액은 황산마그네슘과 건조시키고 4N이소프로판성 염산 pH 6으로 조절한다.8.8 g of d, 1-1- (4-amino-3-chloro) dissolved in 56.6 ml of toluene and dissolved in 50 ml of pyridine while the solution of 0.5 mol of chloro-formic acid-(-)-mentylester was kept stirring at 20 ° C. Drop into a solution of -5-trifluoromethylphenyl) -2-tert-butylamino-ethanol. After 2 hours the solution is evaporated to dryness in vacuo. Oily residues are made of water, powdered and incidentally transferred to another bowl with an aqueous solution and then dissolved in ether. The ethereal solution is continuously washed with water, washed with 2N ammonia (dissolves the precipitate obtained between the layers) and again with water. The ethereal solution is dried with magnesium sulfate and adjusted to pH 6 with 4N isopropane hydrochloric acid.

상기한 광학대차체 화합물의 하이드로클로라이드의 혼합물이 결정으로 석출된다. 반응생성물은 흡인여과되고 에테르로 씻는다. 초산부틸 : 시클로헥산=9 :1이고 실리카겔 G. Merck위의 얇은층의 크로마토그램에서 결정은 대략 Rf값이 0.45와 0.55인 같은 농도의 2점을 나타낸다.A mixture of the hydrochlorides of the optically-balanced compound described above precipitates as crystals. The reaction product is suction filtered and washed with ether. In a thin layer chromatogram on butyl acetate: cyclohexane = 9: 1 and on silica gel G. Merck, the crystals show approximately two points of the same concentration with R f values of 0.45 and 0.55.

b) d-와 1-1-(4-아미노-3-클로로-5-트리플루오로메틸-페닐)-2-3급부틸아미노-0-[(-)-멘토옥시-카르보닐]-에탄올b) d- and 1-1- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-0-[(-)-mentooxy-carbonyl] -ethanol

3.0g의 상기 얻어진 d-와 1-1-(4-아미노-3-클로로-5-트리플루오로메틸-페닐)-2-3급 부틸아미노-0-[(-)-멘토옥시-카르보닐]-에탄올의 하이드로클로라이드의 혼합물을 소량의 물에 서스팬드시키고 에테르로 층을 만들게 하고 5.0ml의 2N암모니아를 첨가하고 혼합물을 모든 것이 녹을 때까지 흔든다. 에테르층은 분리되고 물로 씻고 황산마그네슘위에서 말리고 실리카겔칼럼(직경 6.5cm, 길이 107cm, 무게 2.2kg)위에서 초산부틸과 시클로헥산(19 : 1)(유동속도 120ml/hr)의 혼합물로 Rf값 0.55의 순수한 물질의 유분을 합해지고 용매는 진공에서 제거한다. 얻어진 d-1-(4-아미노-3-클로로-5-트리플루오로-메틸-페닐)-2-3급 부틸아미노-0-[(-)-멘토옥시-카르보닐]-에탄올을 석유에테르(비점 : 40-60℃)로 결정화한다.3.0 g of the obtained d- and 1-1- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-0-[(-)-mentooxy-carbonyl ] Sparate a mixture of hydrochloride of ethanol in a small amount of water, layer with ether, add 5.0 ml of 2N ammonia and shake the mixture until everything is dissolved. The ether layer is separated and washed with water, dried over magnesium sulfate, silica gel column (diameter 6.5cm, length 107cm, weight 2.2kg) on the butyl acetate and cyclohexane (19: 1) mixture with R f value of 0.55 (flow rate 120ml / hr) The fractions of pure substances are combined and the solvent is removed in vacuo. The obtained d-1- (4-amino-3-chloro-5-trifluoro-methyl-phenyl) -2-tert-butylamino-0-[(-)-mentooxy-carbonyl] -ethanol was obtained by petroleum ether. Crystallize at (boiling point: 40-60 ° C).

융점 : 95.5-96.5℃Melting Point: 95.5-96.5 ℃

[α]

Figure kpo00013
=+74.1°(C=1.0 : 클로로포름)[α]
Figure kpo00013
= + 74.1 ° (C = 1.0: Chloroform)

광학대차체 화합물의 혼합물을 포함하고 더 크로마토그래피적으로 분리하기 위해 첨가될 수 있는 유분은 제거된다. Rf값 0.45의 거의 순수한 물질을 포함하는 유분은 부수적으로 합해져서 진공에서 증발시킨다. 찌꺼기는 한번 석유에테르로부터 재결정하고 크로마토그래피적으로 순수한 1-1-(4-아미노-3-클로로-5-트리플루오로메틸-페닐)-2-3급 부틸아미노-0-[(-)-멘토옥시-카르보닐]-에탄올을 얻는다.The fraction comprising the mixture of the optobalance compound and which can be added for further chromatographic separation is removed. Fractions containing nearly pure materials with an R f value of 0.45 are incidentally combined and evaporated in vacuo. The residue is once recrystallized from petroleum ether and chromatically pure 1-1- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-0-[(-)- Mentooxy-carbonyl] -ethanol.

융점 : 102-104℃Melting Point: 102-104 ℃

[α]

Figure kpo00014
=-273.5°(C=1.0 : 클로로포름)[α]
Figure kpo00014
= -273.5 ° (C = 1.0: Chloroform)

c) d-1-(4-아미노-3-클로로-5-트리플루오로메틸-페닐)-2-3급 부틸아미노-에탄올c) d-1- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol

1.6g의 d-1-(4-아미노-3-클로로-5-트리플루오로메틸-페닐)-2-3급부틸아미노-0-[(-)-멘토옥시-카르보닐]-에탄올을 16ml의 메탄올에 녹이고 약 20℃에서 65시간동안 방치한다. 혼합물을 진공에서 증발시키고 찌꺼기는 칼럼크로마토그래피(실리카겔 : 클로로포름 : 메탄올 : 진한암모니아=90 : 10 : 1)에 의해 정제된다. 유분은 원하는 물질과 합해지고 진공에서 증발시킨다. 찌꺼기는 초산에틸에 녹이고 이소프로판올에 녹인 4N염산의 이론치를 첨가하고 거기서 상기 언급한 화합물의 하이드로클로라이드가 결정화한다.16 ml of 1.6 g of d-1- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-0-[(-)-mentooxy-carbonyl] -ethanol Dissolved in methanol and left at about 20 ° C. for 65 hours. The mixture is evaporated in vacuo and the residue is purified by column chromatography (silica gel: chloroform: methanol: concentrated ammonia = 90: 10: 1). The oil is combined with the desired material and evaporated in vacuo. The residue is dissolved in ethyl acetate and the theoretical value of 4N hydrochloric acid dissolved in isopropanol is crystallized from the hydrochloride of the above-mentioned compounds.

융점 : >194℃ 천천히 분해Melting point:> 194 ℃ Slow decomposition

[α]

Figure kpo00015
=+154.9°(C=1.0 : 메탄올)[α]
Figure kpo00015
= + 154.9 ° (C = 1.0: methanol)

d) 1-1-(4-아미노-3-클로로-5-트리플루오로메틸-페닐)-2-3급 부틸아미노-에탄올d) 1-1- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-ethanol

1.58g의 1-1-(4-아미노-3-클로로-5-트리플루오로메틸-페닐)-2-3급부틸아미노-0-[(-)-멘토옥시-카르보닐]-에탄올을 메탄올로 가용매 분해하여 에난티오머 화합물을 실시예와 같이 크로마토그래피적 정제에 의해 제조한다.1.58 g of 1-1- (4-amino-3-chloro-5-trifluoromethyl-phenyl) -2-tert-butylamino-0-[(-)-mentooxy-carbonyl] -ethanol Solvent decomposition was carried out to prepare an enantiomer compound by chromatographic purification as in Example.

하이드로클로라이드의 융점 : >194℃ 천천히 분해Melting point of hydrochloride: Slow decomposition> 194 ℃

[α]

Figure kpo00016
=-154.8°(C=1.0 : 메탄올)[α]
Figure kpo00016
= -154.8 ° (C = 1.0: methanol)

Claims (1)

일반식(Ⅱ)의 화합물을 가수분해나 수소화시켜 일반식(Ⅰ)의 아미노-페닐-에탄올 아민류를 제조하는 방법.A method for producing amino-phenyl-ethanol amines of general formula (I) by hydrolyzing or hydrogenating a compound of general formula (II).
Figure kpo00017
Figure kpo00017
 상기식에서 R1은 수소, 불소, 염소, 브롬이나 요드원자 또는 시아노기를 표시하고 R2는 불소원자, 1-5개의 탄소원자를 가진 직쇄 혹은 측쇄알킬기, 히드록시알킬, 아미노알킬, 디알킬아미노알킬, 트리플루오로메틸, 알코옥시, 니트로, 시아노, 카르복시, 카르브알코옥시 또는 카르바모일기를 표시하고, R3와 R4는 같거나 서로 다른 수소원자, 1-6개의 탄소원자를 가진 직쇄 혹은 측쇄알킬기, 히드록시알킬, 시클로알킬, 시클로알킬알킬, 알케닐, 알키닐 또는 선택적으로 치환된 아랄킬기를 표시하고, X는 아세틸, N-카르보벤조옥시-L-알라닐, (-)-멘톡시-카르보닐기 또는 수소원자를 표시하고, Y1은 아세틸, 프로피오닐, 벤조일, p-클로로-벤조일기 또는 수소원자를 표시하고, Y2는 1-6개의 탄소원자를 가진 직쇄 혹은 측쇄 알킬기, 히드록시알킬, 시클로알킬, 선택적으로 치환된 아랄킬, 벤질기 또는 수소원자를 표시하는데, 단, X, Y1또는 Y2의 기중 적어도 하나는 수소원자가 아니다.Wherein R 1 represents hydrogen, fluorine, chlorine, bromine or iodine atom or cyano group and R 2 represents fluorine atom, straight or branched chain alkyl group having 1-5 carbon atoms, hydroxyalkyl, aminoalkyl, dialkylaminoalkyl , Trifluoromethyl, alkoxy, nitro, cyano, carboxy, carbalcooxy or carbamoyl group, R 3 and R 4 are the same or different hydrogen atoms, straight chain having 1-6 carbon atoms or Branched alkyl groups, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl or optionally substituted aralkyl groups, X represents acetyl, N-carbobenzooxy-L-alanyl, (-)- Menthoxy-carbonyl group or hydrogen atom, Y 1 represents acetyl, propionyl, benzoyl, p-chloro-benzoyl group or hydrogen atom, Y 2 is a straight or branched chain alkyl group having 1-6 carbon atoms, Oxyalkyl, cycloalkyl, Optionally substituted aralkyl, benzyl or hydrogen atoms, provided that at least one of the groups X, Y 1 or Y 2 is not a hydrogen atom.
KR7501095A 1972-12-08 1975-05-19 Process for the preparation of amino-phenyl-ethanolamines KR850001916B1 (en)

Applications Claiming Priority (13)

Application Number Priority Date Filing Date Title
US2261914.3 1972-12-08
DE2261914.3 1972-12-18
DE2261914A DE2261914C3 (en) 1972-12-18 1972-12-18 Amino-phenyl-ethanolamines and their acid addition salts, processes for their production and pharmaceuticals
DE19732345442 DE2345442C2 (en) 1973-09-08 1973-09-08 d- and l-phenylethanolamines and their salts, manufacturing processes and drugs based on them
DE2345442.4 1973-09-08
US2345442.4 1973-09-08
DE2351281.4 1973-10-12
US2351281.4 1973-10-12
DE19732351281 DE2351281C3 (en) 1973-10-12 1973-10-12 Aminophenylethanolamine derivatives, their production and use
DE2354961.3 1973-11-02
US2354961.3 1973-11-02
DE2354961A DE2354961C2 (en) 1973-11-02 1973-11-02 Process for the preparation of aminophenylethanolamines
KR7302145A KR790000255B1 (en) 1973-11-02 1973-12-14 Process of manufacturing amino-penyl-ethanolamines

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
KR7302145A Division KR790000255B1 (en) 1972-12-08 1973-12-14 Process of manufacturing amino-penyl-ethanolamines

Publications (2)

Publication Number Publication Date
KR830000207A KR830000207A (en) 1983-03-30
KR850001916B1 true KR850001916B1 (en) 1985-12-31

Family

ID=27431596

Family Applications (1)

Application Number Title Priority Date Filing Date
KR7501095A KR850001916B1 (en) 1972-12-08 1975-05-19 Process for the preparation of amino-phenyl-ethanolamines

Country Status (20)

Country Link
JP (1) JPS5811852B2 (en)
KR (1) KR850001916B1 (en)
BG (1) BG21209A3 (en)
CA (1) CA1027955A (en)
CH (2) CH614188A5 (en)
DD (1) DD111574A5 (en)
DK (1) DK150502C (en)
FI (1) FI62052C (en)
FR (1) FR2210414B1 (en)
GB (1) GB1445740A (en)
HK (1) HK6680A (en)
HU (1) HU168701B (en)
IE (1) IE39065B1 (en)
IL (1) IL43837A (en)
MY (1) MY8800145A (en)
NL (1) NL176168C (en)
NO (1) NO137782C (en)
PL (1) PL97194B1 (en)
RO (1) RO63025A (en)
SE (1) SE409700B (en)

Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2430486A1 (en) * 1978-07-07 1980-02-01 Oreal Disinfectant deodorant stick for hanging in WC - is in cage within sealed cartridge which is removed by tearing strip defined by rupture lines
NL8105170A (en) * 1980-12-10 1982-07-01 Thomae Gmbh Dr K NEW PHENYL ALKYLAMINS, METHOD FOR THE PREPARATION THEREOF AND THE USE THEREOF AS MEDICINES.
FR2515177A1 (en) * 1981-10-28 1983-04-29 Lafon Labor 1-Amino:phenyl 2-isopropyl or tert.butyl-amino 1-ethanol derivs. - used as antidepressants, sedatives, vasodilators and hypotensives, without hyper:reactivity and excitation side effects
US4943591A (en) * 1984-10-17 1990-07-24 Glaxo Group Limited Dichloroaniline derivatives
GB8426191D0 (en) * 1984-10-17 1984-11-21 Glaxo Holdings Ltd Chemical compounds
EP0224001B1 (en) * 1985-10-17 1991-03-20 American Cyanamid Company Anthranilonitrile derivatives and related compounds as useful agents for promoting growth, improving feed efficiency, and for increasing the lean meat to fat ratio of warm-blooded animals
US4863959A (en) * 1985-10-17 1989-09-05 American Cyanamid Company Anthranilonitrile derivatives as useful agents for promoting growth, improving feed efficiency, and for increasing the lean meat to fat ratio of warm-blooded animals
GB8603475D0 (en) * 1986-02-12 1986-03-19 Glaxo Group Ltd Chemical compounds
JPS63290852A (en) * 1987-02-10 1988-11-28 グラクソ、グループ、リミテッド Compound
GB8703007D0 (en) * 1987-02-10 1987-03-18 Glaxo Group Ltd Chemical compounds
ES2861266T3 (en) * 2003-08-29 2021-10-06 Mitsui Chemicals Agro Inc Intermediate products for the preparation of agricultural / horticultural insecticides and method of using them
GB0604822D0 (en) * 2006-03-09 2006-04-19 Arakis Ltd The treatment of inflammatory disorders and pain
CN100497296C (en) * 2006-07-07 2009-06-10 沈阳药科大学 Novel optical activity phenylethanolamine compounds and preparation method thereof
GB201714736D0 (en) 2017-09-13 2017-10-25 Atrogi Ab New compounds and uses
GB201714734D0 (en) * 2017-09-13 2017-10-25 Atrogi Ab New compounds and uses

Also Published As

Publication number Publication date
NO137782B (en) 1978-01-16
DK150502C (en) 1987-10-26
NO137782C (en) 1978-04-26
BG21209A3 (en) 1976-03-20
NL176168B (en) 1984-10-01
RO63025A (en) 1978-12-15
AU6369373A (en) 1975-06-19
JPS4994640A (en) 1974-09-09
GB1445740A (en) 1976-08-11
CA1027955A (en) 1978-03-14
FR2210414B1 (en) 1977-01-28
IE39065L (en) 1974-06-18
DD111574A5 (en) 1975-02-20
FR2210414A1 (en) 1974-07-12
MY8800145A (en) 1988-12-31
KR830000207A (en) 1983-03-30
CH605622A5 (en) 1978-10-13
SE409700B (en) 1979-09-03
IL43837A (en) 1977-02-28
FI62052C (en) 1982-11-10
HK6680A (en) 1980-03-07
IE39065B1 (en) 1978-08-02
IL43837A0 (en) 1974-03-14
JPS5811852B2 (en) 1983-03-04
NL176168C (en) 1985-03-01
NL7316139A (en) 1974-06-20
DK150502B (en) 1987-03-16
HU168701B (en) 1976-06-28
CH614188A5 (en) 1979-11-15
PL97194B1 (en) 1978-02-28
FI62052B (en) 1982-07-30

Similar Documents

Publication Publication Date Title
KR850001916B1 (en) Process for the preparation of amino-phenyl-ethanolamines
FR2696453A1 (en) Novel arylalkyl (thio) amides, process for their preparation, and pharmaceutical compositions containing them
JPS59507B2 (en) Method for producing novel heterocyclic compounds
US3804899A (en) 3-alkylamino-2-(3,4-dihydroxyphenyl)propanols and the salts thereof
FR2582309A1 (en) NOVEL DERIVATIVES OF MORPHINANE AND MORPHINE, THEIR PREPARATION, THEIR APPLICATION AS MEDICAMENTS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
US3592824A (en) 3-substituted amino-1,2,3,4-tetrahydrocarbazoles
US3267117A (en) Novel substituted indol-5-ols
US4503252A (en) Process for the preparation of serinol and of serinol derivatives, and products obtained therefrom
FI62528B (en) ETT NYTT FOERFARANDE FOER FRAMSTAELLNING AV 1- (3,5-DIHYDROXIPHENYL) -1-HYDROXY-2- (1-METHYL-2- (4-HYDROXYPHENYL) -ETHYL) -AMINOETHANE
US4442126A (en) 1,2,3,4-Tetrahydronaphthalene derivatives
CH630629A5 (en) MORPHINE DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR USE AS A MEDICINAL PRODUCT.
US3491097A (en) 3-(piperazinoalkyl)-pyrazoles
US3462451A (en) 2,3-bis(alkoxyphenyl)pyrroles
KR800000541B1 (en) Process for the preparation of amin-phen-ethanolamines
US3092660A (en) 1-acyl-2-alkyl-hydrazine derivatives
KR800000539B1 (en) Process for the preparation of amino-pheny-ethanolamines
EP0001585B1 (en) Piperazino-pyrrolobenzodiazepines, methods for their preparation and pharmaceutical compositions containing them
EP0062919B1 (en) Indole derivatives, process for their preparation and pharmaceutical compositions containing them
US6303791B1 (en) One pot synthesis of 2-oxazolidinone derivatives
US4011329A (en) Tetrahydropyrid-4-yl-chroman-5-ol derivatives in the treatment of hypertension
FR2702211A1 (en) New derivatives of 2-phenoxyethylamine, their preparation and their therapeutic application.
US4123545A (en) N-Propyl-3(β-hydroxyethyl)-3-(meta-hydroxyphenyl)-pyrrolidine
US2646445A (en) Resolution process and compounds produced therein
FR2555580A1 (en) NOVEL AZABICYCLIC COMPOUNDS, PROCESS FOR THEIR PREPARATION AND MEDICAMENTS CONTAINING THEM
US3422141A (en) 3,4-dihydroxyphenylalkanamides

Legal Events

Date Code Title Description
E701 Decision to grant or registration of patent right