KR790001382B1 - Process for preparing of containing heterocyclic compounds - Google Patents

Process for preparing of containing heterocyclic compounds Download PDF

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KR790001382B1
KR790001382B1 KR7902785A KR790002785A KR790001382B1 KR 790001382 B1 KR790001382 B1 KR 790001382B1 KR 7902785 A KR7902785 A KR 7902785A KR 790002785 A KR790002785 A KR 790002785A KR 790001382 B1 KR790001382 B1 KR 790001382B1
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group
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dithiane
compound
methyl
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라무즈 헨리
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진 자퀘스 오가이, 한스 스뤼크린
에프·호프만-라룻슈주식회사
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Abstract

Sulfur containing heterocyclic compds. (I; R is formula II; R1,R2,R3 = any combination of H, halogen, lower alkyl, phenyl, lower alkanoyl, or sulfamoyl etc. ; R4 = H, lower alkyl group ; R5,R6,R7 = H, halogen, lower alkyl, or lower alkoxy etc. X = sulfur, SO,SO2 ; Y = hydroxy group substituted C2-8 aliphatic group; Z = hydroxy group substituted C1-8 aliphatic group; m = 0,1; n = 2,3) and its acid added salts, useful for treating angina pectoris, were pred. by treating, e.g., compd. (III) with compd.(IV).

Description

황함유 복소환 화합물의 제조방법Method for preparing sulfur-containing heterocyclic compound

본 발명은 황을 함유하는 다음 구조식(I)화합물 및 이의 산 부가염의 제조방법에 관한 것이다.The present invention relates to a process for preparing the following compound of formula (I) containing sulfur and acid addition salts thereof.

Figure kpo00001
Figure kpo00001

상기 구조식에서In the above structural formula

R은 다음 구조식(a) 또는 (b)이고R is the following structural formula (a) or (b)

Figure kpo00002
Figure kpo00002

여기에서 R1, R2및 R3는 각각 수소 또는 할로겐, 저급알킬, 저급알콕시, 아릴－(저급알콕시), 아릴옥시, 페닐, 니트로, 아미노, 저급알킬르오, 트리플루오로메틸, 하이드록시, 시아노, 디(저급알킬)아미노, 저급알카노일아미노, 카복실, 저급알콕시카보닐, 저급알킬설포닐, 하이드록시메틸, 저급알카노일옥시, 아미도, 저급알카노일, 설파모일, 모노(저급알킬)설파모일, 디(저급알킬)설파모일, 아미노카보닐옥시, 모노(저급알킬)아미노카보닐옥시, 디(저급알킬)아미노카보닐옥시 또는 (저급알킬아미노)－(저급알킬) 그룹 또는 두 개의 인접한 R1, R2및 R3는 함께 메틸렌 디옥시, 에틸렌옥시 또는 부타디엔－1, 3－일렌－1, 4그룹을 나타내고Wherein R 1 , R 2 and R 3 are each hydrogen or halogen, lower alkyl, lower alkoxy, aryl- (low alkoxy), aryloxy, phenyl, nitro, amino, lower alkylthio, trifluoromethyl, hydroxy, Cyano, di (lower alkyl) amino, lower alkanoylamino, carboxyl, lower alkoxycarbonyl, lower alkylsulfonyl, hydroxymethyl, lower alkanoyloxy, amido, lower alkanoyl, sulfamoyl, mono (lower alkyl) Sulfamoyl, di (lower alkyl) sulfamoyl, aminocarbonyloxy, mono (lower alkyl) aminocarbonyloxy, di (lower alkyl) aminocarbonyloxy or (lower alkylamino)-(lower alkyl) groups or two Adjacent R 1 , R 2 and R 3 together represent methylene dioxy, ethyleneoxy or butadiene-1, 3-ylene-1, 4 groups

R4는 수소 또는 저급알킬그룹이고R 4 is hydrogen or a lower alkyl group

R5, R6및 R7은 각각 수소 또는 할로겐 또는 저급알킬, 저급알콕시, 하이드록시 또는 벤질옥시그룹 또는 두개의 인접한 R5, R6및 R7는 함께 메틸렌디옥시, 에틸렌옥시를 나타내고R 5 , R 6 and R 7 each represent hydrogen or halogen or lower alkyl, lower alkoxy, hydroxy or benzyloxy group or two adjacent R 5 , R 6 and R 7 together represent methylenedioxy, ethyleneoxy

X는 황이나 SO 또는 SO2이고X is sulfur or SO or SO 2

Y는 탄소수 2 내지 8중 2 내지 4가 쇄를 이룬, 직쇄 또는 측쇄의 임의로 하이드록시기로 치환된 지방족그룹이고Y is an aliphatic group substituted with a linear or branched, optionally hydroxy group having 2 to 4 carbon atoms of 2 to 8 carbon atoms.

Z는 탄소수 1 내지 8중 1내지 4가 쇄를 이룬 직쇄 또는 측쇄의 임의로 하이드록시기로 치환된 지방족그룹이고Z is an aliphatic group substituted with a linear or branched, optionally hydroxy group having 1 to 4 of 1 to 8 carbon atoms

m은 0 또는 1이며m is 0 or 1

n은 2 또는 3이다.n is 2 or 3.

본 명세서에서 "저급알킬"은 탄소수 1 내의 6의 직쇄 또는 측쇄의 알킬그룹이다(예 : 메틸, 에틸, n－프로필, 이소프로필, n－부틸, 이소부틸, 3급－부틸, 아밀, 헥실등). "저급알콕시"는 저급알킬 에테르그룹으로서 저급알킬은 전술한 바와 같다.As used herein, "lower alkyl" is a linear or branched alkyl group of 6 carbon atoms (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, amyl, hexyl, etc.). ). "Lower alkoxy" is a lower alkyl ether group wherein lower alkyl is as described above.

"할로겐"은 불소, 염소, 브롬, 요오드를 의미한다."Halogen" means fluorine, chlorine, bromine, iodine.

"저급알카노일"은 탄소수 6까지의 알카노일그룹을 의미한다(예 : 포밀, 아세틸, 프로피오닐, 부티릴 등)"Lower alkanoyl" means an alkanoyl group having up to 6 carbon atoms (e.g. formyl, acetyl, propionyl, butyryl, etc.)

"아릴"은 비치환 또는 치환된 페닐이며 치환체는 할로겐, 저급알킬, 저급알콕시, 니트로, 아미노이다."Aryl" is unsubstituted or substituted phenyl and the substituents are halogen, lower alkyl, lower alkoxy, nitro, amino.

다음에서 사용하는 "이탈원자" 또는 "그룹"의 예를 들면 할로겐, 특히 브롬 또는 염소, 트실옥시와 같은 아릴설포닐옥시, 메실옥시 또는 에폭시와 같은 알킬설포닐옥시 등이 있다.Examples of "leaving atoms" or "groups" used in the following include halogens, especially arylsulfonyloxy such as bromine or chlorine, tsyloxy, alkylsulfonyloxy such as mesyloxy or epoxy and the like.

구조식(1)의 바람직한 화합물은 다음 구조식(Ia)이다.Preferred compound of formula (1) is the following formula (Ia).

Figure kpo00003
Figure kpo00003

여기에서 R1, R7, m은 전술한 바와 같고,Where R 1 , R 7 , m are as described above,

R1 4는 메틸 또는 에틸이며,R 1 4 is methyl or ethyl,

X1은 황 또는 SO2이다.X 1 is sulfur or SO 2 .

구조식(Ia)의 화합물로서 바람직한 것은 R1, R2및 R3중 하나가 수소이며 나머지는 각각 저급알콕시, 특히 메톡시이거나 또는 함께 부타니엔－1, 3－일렌－1, 4그룹이고 R1, R2및 R3중 2개가 수소이면 나머지가 니트로그룹이며 R5, R6및 R7중 하나가 수소이면 나머지 2개는 각각 저급알콕시그룹 특히 메톡시인 경우이다. 특히 가장 바람작한 화합물은 N－(3, 4－디메톡시펜에틸)－2－(3, 4－디메톡시페닐)－N－메틸－m－디티안－2－프로필아민－1, 1, 3, 3－테르라옥사이드이다.Preferred as compounds of formula (Ia) are those in which one of R 1 , R 2 and R 3 is hydrogen and the other is lower alkoxy, in particular methoxy or together butaniene-1, 3-ylene-1, 4 group and R If two of 1 , R 2 and R 3 are hydrogen the remainder is nitro group and if one of R 5 , R 6 and R 7 is hydrogen the other two are lower alkoxy groups, in particular methoxy. In particular, the most preferred compound is N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N-methyl-m-dithiane-2-propylamine-1, 1, 3 And 3-terraoxide.

본 발명에 따른 화합물(구조식(I) 및 그의 산부가염)은 다음 구조식(Ⅳ)의 화합물을 다음 구조식(Ⅴ)의 화합물과 반응시키거나Compounds according to the present invention (formula (I) and acid addition salts thereof) react with a compound of formula (IV) with a compound of formula (V)

Figure kpo00004
Figure kpo00004

다음 구조식(Ⅵ)의 화합물을 다음 구조식(Ⅶ)의 화합물과 반응시키거나Reacting a compound of formula (VI) with a compound of formula

Figure kpo00005
Figure kpo00005

다음 구조식(Ⅷ)의 화합물을 다음 구조식(Ⅸ)의 화합물과 반응시키거나Reacting the compound of the following formula with the compound of the following formula

Figure kpo00006
Figure kpo00006

다음 구조식(Ⅹ)의 화합물을 다음 구조식(XI)의 화합물과 반응시키거나Reacting a compound of formula (VII) with a compound of formula (XI)

Figure kpo00007
Figure kpo00007

다음 구조식(XII)의 카보닐그룹 또는 다음 구조식(XIII)의 A그룹을 환원시키고 필요에 따라 X가 황원자인 구조식(I)화합물을 X가 SO 또는 SO2인 구조식(I)화합물로 산화시키거나, R4가 수소인 구조식(I)화합물을 N－(저급알킬화)하거나 저급알콕시그룹 또는 아릴－(저급알콕시)그룹을 하이드록시그룹으로 전환시키거나 니트로그룹을 아미노그룹으로 환원시키거나, 시아노그룹을 카복실그룹으로 검화시키거나 시아노그룹을 카복실그룹으로 검화하거나, 카복실그룹을 에스테르화 또는 아미드화 또는 환원하거나 하이드록실그룹을 에테르화 또는 에스테르확 또는 카바모일화하거나 아미노그룹을 모노(저급알킬화) 또는 디(저급알킬화)하거나 알킬렌그룹을 알킬설포닐그룹으로 산화시키거나 수득된 염기를 산부가염으로 전환시척시 제조한다.Reducing the carbonyl group of the following formula (XII) or the A group of the following formula (XIII) and oxidizing the compound of formula (I) wherein X is a sulfur atom to the compound of formula (I) wherein X is SO or SO 2 , or N- (lower alkylation) of a compound of formula (I) wherein R 4 is hydrogen, or a lower alkoxy group or an aryl- (lower alkoxy) group is converted to a hydroxy group or a nitro group is reduced to an amino group, Groups are carboxylated to carboxyl groups or cyano groups to carboxyl groups, esterified or amidated or reduced carboxyl groups, etherified or esterified or carbamoylated hydroxyl groups or mono (lower alkylated) amino groups. Or di (lower alkylation) or oxidation of an alkylene group to an alkylsulfonyl group or conversion of the obtained base to an acid addition salt.

Figure kpo00008
Figure kpo00008

상기 구조식에서In the above structural formula

R, R4－R8, X, Y, Z, m 및 n은 전술한 바와 같고,R, R 4 -R 8 , X, Y, Z, m and n are as described above,

Y1및 Z1은 각기 카보닐그룹을 함유하는 Y 또는 Z에 상응하는 그룹이고 A는 다음 구조식의 그룹이다.Y 1 and Z 1 are groups corresponding to Y or Z, each containing a carbonyl group, and A is a group of the following structural formula.

Figure kpo00009
Figure kpo00009

구조식(Ⅳ)의 화합물과 구조식(Ⅴ)의 화합물을 반응조건에서 불활성인 할로겐화 탄화수소(예 : 클로로포름, 메틸렌클로라이드등) 또는 에틸렌글리콜 디메틸에테르와 같은 극성용매중에서 반응시키고 0℃ 내지 환류온도, 특히 실온에서 탈수제(예 : 황산, 할로겐화 수소산, 인산등)존재하에 용이하게 수행한다.The compound of formula (IV) and the compound of formula (V) are reacted in a polar solvent such as halogenated hydrocarbons (e.g., chloroform, methylene chloride, etc.) or ethylene glycol dimethyl ether which are inert under the reaction conditions and are reacted at 0 to reflux temperature, especially room temperature. Is easily carried out in the presence of a dehydrating agent (eg sulfuric acid, hydrochloric acid, phosphoric acid, etc.).

출발물질인 구조식(Ⅴ)의 화합물은 기지의 방법으로 제조한다.Compounds of formula (V) as starting materials are prepared by known methods.

출발물질인 구조식(Ⅳ)의 화합물은 신규이며 본 발명에 속한다.The compounds of formula IV which are starting materials are novel and belong to the present invention.

구조식(Ⅳ)의 화합물은 다음 구조식(XIVa)의 화합물을 다음 구조식(Ⅶ)의 화합물과 반응시켜 제조한다.Compounds of formula (IV) are prepared by reacting a compound of formula (XIVa) with a compound of formula (VII).

Figure kpo00010
Figure kpo00010

상기 구조식에서In the above structural formula

R, R4－R7, Y, Z 및 m은 전술한 바와 같다.R, R 4 -R 7 , Y, Z and m are as described above.

반응은 3급아민(예 : N－에틸－N, N－디이소프로필아민)과 같은, 용매로서도 작용하는 산결합제 존재하에 수행하며 용매의 비점에 따라 높은 온도, 바람직하게는 130℃까지의 온도에－용이하게 수용된다.The reaction is carried out in the presence of an acid binder which also acts as a solvent, such as tertiary amines (e.g., N-ethyl-N, N-diisopropylamine) and, depending on the boiling point of the solvent, a high temperature, preferably up to 130 ° C. E-easily accepted.

구조식(XIVa)의 화합물은 일부는 기지의 것이고 일부는 신규의 것이다. 신규의 화합물도 기지의 화합물과 같은 방법으로 제조하며. 구조식(Ⅶ)의 화합물은 기지의 것이다.The compounds of formula (XIVa) are some known and some new. Novel compounds are also prepared in the same manner as known compounds. The compound of structural formula is known.

구조식(Ⅵ)의 화합물과 구조식(Ⅶ)화합물과의 반응은 반응조건에서 불활성인 에테르(디부틸에테르, 디옥산, 테트하이드로푸란) 또는 알칸올(메탄올, 프로판올), 방향족 탄화수소(벤젠, 톨루엔, 크실렌), 아세토니트릴, 디메틸포름아마이드, 디메틸설폭사이드등의 유기용매중에서 실온과 환류온도사이에서, 특히 환류온도에서 수행하며, 반응중에 산이 떨어져 나오는 경우에는 염기(예 : 트리메틸아민, N－에틸－N, N－디이소프로필아민, N, N－디메틸아닐린등의 3급아민) 존재하에 반응을 수행한다.The reaction between the compound of formula (VI) and the compound of formula (VII) is carried out by reaction of ether (dibutyl ether, dioxane, tetrahydrofuran) or alkanol (methanol, propanol), aromatic hydrocarbon (benzene, toluene, In organic solvents such as xylene), acetonitrile, dimethylformamide and dimethyl sulfoxide, it is carried out between room temperature and reflux temperature, especially at reflux temperature, and when the acid is released during the reaction, base (e.g. trimethylamine, N-ethyl- Reaction is carried out in the presence of N, N-diisopropylamine, tertiary amine such as N, N-dimethylaniline and the like.

출발물질인 구조식(Ⅶ)의 화합물은 기지이나 구조식(Ⅵ)의 화합물은 신규의 것으로 본 발명에 속한다.The compounds of formula (VII) as starting materials are known but the compounds of formula (VI) are novel and belong to the present invention.

구조식(Ⅵ)화합물은 구조식(XIV)의 화합물을 구조식(V)의 화합물과 반응시켜 제조된다.Compound (VI) is prepared by reacting a compound of formula (XIV) with a compound of formula (V).

Figure kpo00011
Figure kpo00011

상기 구조식에서In the above structural formula

R, R8, Y 및 n은 전술한 바와 같다.R, R 8 , Y and n are as described above.

필요한 경우, 얻어진 X가 황인 구조식(Ⅳ)의 화합물을 산화시켜 X가 SO 또는 SO2인 구조식(Ⅳ)의 화합물로 전환시킨다.If necessary, the obtained compound of formula (IV) wherein X is sulfur is oxidized to convert to compound of formula (IV) wherein X is SO or SO 2 .

구조식(XIV)의 화합물과 구조식(Ⅴ)의 화합물과의 반응은 반응조건하에서 불활성인, 특히 할로겐화 탄화수소(예 : 클로로포름, 메틸렌클로라이드등) 또는 에틸렌글리콜 디메틸에테르와 같은 용매중에서 0℃ 내지 환류온도, 특히 실온에서 수행하는 것이 바람직하다.The reaction of the compound of formula (XIV) with the compound of formula (V) is inert under the reaction conditions, in particular from 0 ° C. to reflux temperature in a solvent such as a halogenated hydrocarbon (eg chloroform, methylene chloride, etc.) or ethylene glycol dimethyl ether, It is particularly preferable to carry out at room temperature.

얻어진 X가 황인 구조식(Ⅵ)의 화합물을 X가 SO 또는 SO2인 화합물로 전환하는 것은 과아세트산, 과프탈산, m－염화과벤조산등의 과산으로 산화하여 수행한다. 과아세트산은 동일반응계내에서 빙초산과 과산화수소로 제조한다.The conversion of the compound of the formula (VI) in which X is sulfur to a compound in which X is SO or SO 2 is carried out by oxidation with peracids such as peracetic acid, perphthalic acid and m-perchloric acid. Peracetic acid is prepared with glacial acetic acid and hydrogen peroxide in situ.

구조식(Ⅷ)의 화합물과 구조식(XI)과의 반응은 반응건조하에서 불활성인 에테르(예 : 테트라하이드로푸란, 디옥산, 디에틸렌글리콜 디에틸에테르등) 또는 아세토니트릴, 디메틸포름아마이드 등의 용매존재하에 실온 내지 환류온도, 특히 실온에서 수행하는 것이 바람직하다. 그리고 부틸리튬 또는 그리나드화합물, 나트륨, 나트륨하이드라이드등의 강염기 존재하에 반응을 수행한다. 특히 X가 황일 경우에는 부틸리튬 또는 그리나드화합물과 같은 강염기를 사용하는 것이 바람직하다.The reaction between the compound of formula (VII) and formula (XI) is carried out under an ether inert reaction (eg, tetrahydrofuran, dioxane, diethylene glycol diethyl ether, etc.) or solvents such as acetonitrile and dimethylformamide. Preferably at room temperature to reflux, in particular at room temperature. And the reaction is carried out in the presence of a strong base such as butyllithium or Grignard compound, sodium, sodium hydride. In particular, when X is sulfur, it is preferable to use a strong base such as butyllithium or Grignard compound.

출발물질인 구조식(Ⅷ)의 화합물은 기지의 것이다. 그러나 구조식(Ⅸ)의 화합물은 신규의 것이며, 본 발명에 속한다. 구조식(Ⅸ)의 화합물은 다음 구조식(XV)의 화합물을 구조식(Ⅲ)의 화합물과 반응조건에서 불활성인 유기용매 존재하에 -80℃ 내지 환류온도, 특히 0°내지 50℃, 더욱 바람직하게는 실온에서 반응시켜 제조한다. 용매로서는 에테르류(예 : 디에틸에테르, 테트라하이드로푸란, 디옥산등) 또는 방향족 탄화수소(예 : 벤젠, 톨루엔, 크실렌등), 디메틸포름아마이드, 디메틸설폭사이드등이 있다.The starting compound is a known compound. However, the compound of formula (VIII) is novel and belongs to the present invention. The compound of formula (XV) is a compound of formula (XV) wherein the compound of formula (III) is reacted with the compound of formula (III) in the presence of an organic solvent which is inert under the reaction conditions. It is prepared by reacting at. Examples of the solvent include ethers (e.g. diethyl ether, tetrahydrofuran, dioxane, etc.) or aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), dimethylformamide, dimethyl sulfoxide and the like.

Figure kpo00012
Figure kpo00012

상기 구조식에서 X 및 n은 전술한 바와 같다.X and n in the above structural formula are as described above.

본 반응은 부틸리튬, 그리나드화합물, 나트륨, 나트륨하이드 등의 강염기존재하에 수행하며, 특히 X가 황일 경우에는 부틸리튬 또는 그리나드화합물과 같은 강염기를 사용한다.The reaction is carried out in the presence of strong bases such as butyllithium, Grignard compound, sodium, sodium hydride, and especially, when X is sulfur, a strong base such as butyllithium or Grignard compound is used.

구조식(XV)의 화합물은 기지의 것이다. 구조식(Ⅲ)의 화합물은 일부는 기지의 것이고 일부는 신규의 것이다. 구조식(Ⅲ)의 신규 화합물도 기지의 것과 동일한 방법으로 제조한다.The compound of formula (XV) is known. The compounds of formula III are some known and some novel. New compounds of the formula (III) are also prepared in the same manner as the known ones.

구조식(X)의 화합물과 구조식(XI)의 화합물과의 반응은 반응조건하에서 불활성인 에테르(예 : 디부틸에테르, 디옥산, 테트라하이드로푸란) 또는 알콜(예 : 에탄올, 프로판올), 방향족 탄화수소(예 : 벤젠, 톨루엔, 크실렌), 아세토니트릴, 디메틸포름아마이드, 디메틸설폭사이드등의 용매중에서 실온 내지 환류온도사이, 특히 실온에서 수행하며 반응중에 산이 떨어져 나오는 경우에는 염기(예 : 트리에틸아민, N－에틸－N, N－디이소프로필아민, N, N－디메틸아닐－등과 같은 3급아민) 존재하에 반응을 수행한다.The reaction of the compound of formula (X) with the compound of formula (XI) can be carried out under reaction conditions in ether (e.g. dibutyl ether, dioxane, tetrahydrofuran) or alcohol (e.g. ethanol, propanol), aromatic hydrocarbon ( Example: Benzene, toluene, xylene), acetonitrile, dimethylformamide, dimethylsulfoxide and other solvents, such as triethylamine, N The reaction is carried out in the presence of a tertiary amine such as -ethyl-N, N-diisopropylamine, N, N-dimethylaniyl- and the like.

출발물질인 구조식(XI)은 기지의 것이다. 그러나 출발물질인 구조식(X)은 일부는 기지의 것이고 일부는 신규의 것이며 본 발명에 속한다. 구조식(X)의 화합물은 구조식(Vla)의 화합물과 구조식(XVI)의 화합물을 반응시켜 제조한다.The starting material structural formula (XI) is known. However, the starting material Structural Formula (X) is partly known and partly novel and belongs to the present invention. Compounds of formula (X) are prepared by reacting a compound of formula (Vla) with a compound of formula (XVI).

Figure kpo00013
Figure kpo00013

상기 구조식에서In the above structural formula

R, R4, X, Y 및 n은 전술한 바와 같다. 반응을 수행하는데 있어서, 염산이 떨어져나오기 때문에 염기 존재하에 반응을 수행하거나 구조식(XVI)의 아민을 과량으로 사용하는 것이 편리하다. 더우기 구조식(Ⅵ)와 구조식(Ⅶ)의 화합물을 반응시킴에 있어서 전술한 바와 유사한 방법으로 반응을 수행할 수 있다.R, R 4 , X, Y and n are as described above. In carrying out the reaction, it is convenient to carry out the reaction in the presence of a base or to use an excess of the amine of the formula (XVI) because hydrochloric acid is released. Furthermore, in the reaction of the compound of formula (VI) with the compound of formula (VII), the reaction can be carried out in a similar manner as described above.

구조식(VIX)의 화합물은 기지의 것이다. 구조식(VIa)의 화합물은 일부는 신규의 것으로 구조식(Ⅵ)의 화합물을 제조하는 방법과 유사한 방법으로 제조한다.The compound of formula VIX is known. The compounds of formula VIa are some new and are prepared in a similar manner to the preparation of compounds of formula VI.

구조식(XII) 또는 (XIII) 중의 카보닐그룹 또는 A그룹의 환원은 기지의 방법으로 수행한다.Reduction of the carbonyl group or A group in the formula (XII) or (XIII) is carried out by a known method.

따라서 카보닐그룹이 직접 질소와 결합되어 있는 구조식(XII) 또는 (XIII)의 아민은 금속 하이드라이드(예 : 리튬알미늄하이드라이드 또는 디이소부틸알미늄하이드라이드) 또는 디보란등으로 처리하여 환원시킨다. 환원반응은 반응조건에서 불활성인 유기용매(예 : 디에틸에테르, 테트라하이드로푸란등의 에테르 또는 디글라임)중에서 0℃ 내지 환류 온도 사이에서 측히 실온에서 수행한다. 다른 카보닐그룹들도(질소와 직접 결합하지 않는 것 등)같은 방법으로 환원한다. 특히, 하이드록시메틸렌그룹으로 환원하여 다시 메틸렌그룹으로 환원하거나 또는 직접 메틸렌그룹으로 환원시키는 방법으로 반응을 수행한다.Therefore, the amine of formula (XII) or (XIII) in which the carbonyl group is directly bonded to nitrogen is reduced by treating with metal hydride (eg lithium aluminum hydride or diisobutyl aluminum hydride) or diborane. The reduction reaction is carried out at room temperature between 0 ° C. and reflux temperature in an organic solvent (eg ether or diglyme such as diethyl ether, tetrahydrofuran, etc.) which is inert under the reaction conditions. Other carbonyl groups (such as not directly binding to nitrogen) are reduced in the same way. In particular, the reaction is carried out by reducing to a hydroxymethylene group and reducing to a methylene group or directly to a methylene group.

하이드록시메틸렌그룹으로 환원하는 것은 알카리금속알미늄 하이드라이드 또는 알카리금속 보로하이드라이드와 같은 금속수소 착화합물로 처리하여 수행한다.Reduction into the hydroxymethylene group is carried out by treatment with a metal hydrogen complex such as alkali metal aluminum hydride or alkali metal borohydride.

알카리금속 알미늄 하이드라이드 또는 알카리금속 보로하이드라이드를 사용하여 실온 또는 실온 주변온도와 불활성 유기용매중에서 용이하게 환원시킬 수 있다. 그중에서도 알카리금속 알미늄하이드라이드를 사용하는 경우에 적합한 용매로는 디에틸에테르 및 테트라하이드로푸란과 같은 무수에테르류이다. 알카리금속 보로하이드라이드로 환원을 할 경우에는 탄소수 1 내지 4의 알칸올류(메탄올, 에탄올), 디옥산등을 사용한다. 알카리금속 알미늄하이드라이드로서는 리튬알미늄하이드라이드가 바람직하고 알카리금속 보로하이드라이드로서는 나트륨보로하이드라이드가 바람직하다.Alkali metal aluminum hydrides or alkali metal borohydrides can be used to readily reduce in room temperature or at room temperature and in an inert organic solvent. Among them, suitable solvents in the case of using alkali metal aluminum hydride are anhydrous ethers such as diethyl ether and tetrahydrofuran. When reducing with alkali metal borohydride, alkanols (methanol, ethanol) and dioxane having 1 to 4 carbon atoms are used. Lithium aluminum hydride is preferable as the alkali metal aluminum hydride, and sodium borohydride is preferable as the alkali metal borohydride.

하이드록시메틸렌그룹을 메틸렌기로 더욱 환원시키는 것은 금속 수소착화합물을 사용하여 상응하는 설폰산 에스테르 또느 할라이드로 전환시킴으로써 수행되며 이러한 환원은 전술한 카보닐그룹의 환원방법과 같은 방법으로 수행할 수 있다.Further reduction of the hydroxymethylene group to the methylene group is carried out by conversion of the hydroxymethylene group to the corresponding sulfonic acid ester or halide using a metal hydrogen complex, which can be carried out in the same manner as the reduction method of the carbonyl group described above.

카보닐그룹을 직접 메틸렌그룹으로 환원시키는 것은 울프－키쉬너(wolff－kishner)반응에 따라 케톤을 하이드라진과 반응시켜 하이드라존을 만들고 염기성 조건하에서 하이드라존을 분해시킨다.Reducing the carbonyl group directly to the methylene group reacts the ketone with hydrazine following the wolff-kishner reaction to form hydrazones and break down the hydrazones under basic conditions.

구조식(XII) 및 (XIII)은 신규의 것이고 본 발명에 속한다.Structural formulas (XII) and (XIII) are novel and belong to the present invention.

구조식(XII)의 아마이드는 구조식(XVII)의 산을 구조식(Ⅶ)의 아민과 반응시켜 제조함Amides of formula (XII) are prepared by reacting an acid of formula (XVII) with an amine of formula (XVII)

Figure kpo00014
Figure kpo00014

상기 구조식에서In the above structural formula

R, R4－R7, Y, X, Z, m 및 n은 전술한 바와 같다.R, R 4 -R 7 , Y, X, Z, m and n are as described above.

반응은 3급아민(예 : 트리에틸아민)과 할로카복실산 에스테르(예 : 클로로포름산 이소부틸에스테르)(혼합 무수물법) 존재하에 불활성 유기용매(예 : 테트라하이드로푸란)중에서 0°내지 30℃의 온도로 수행한다.The reaction is carried out at a temperature of 0 ° to 30 ° C. in an inert organic solvent (eg tetrahydrofuran) in the presence of tertiary amine (eg triethylamine) and halocarboxylic acid ester (eg chloroformic acid isobutyl ester) (mixed anhydride method). To perform.

구조식(XVI)의 산은 구조식(XVIII)의 화합물들을 출발물질로 하여 전술한 구조식(Ⅵ)의 화합물을 제조하는 방법과 유사한 방법으로 제조할 수 있다.The acid of formula (XVI) may be prepared by a similar method to the preparation of the compound of formula (VI) using the compounds of formula (XVIII) as starting materials.

Figure kpo00015
Figure kpo00015

상기 구조식에서In the above structural formula

R은 전술한 바와 같다. 구조식(XVIII)의 화합물은 기지의 것이다.R is as described above. The compound of formula XVIII is known.

구조식(XII)의 케톤은 상응하는 알코을 피리딘중에서 －20℃ 내지 실온, 특히 0℃의 온도로 크로뮴트리옥사이드/피리딘을 사용하여 산화시켜 제조한다.Ketones of formula (XII) are prepared by oxidizing the corresponding alcohols in pyridine with chromium trioxide / pyridine at temperatures from −20 ° C. to room temperature, in particular 0 ° C.

구조식(XIII)의 아마이드는 구조식(I)의 R4가 수소인 화합물을 3급아민(예 : 피리딘)중에서 0℃ 내지 30℃, 특히 실온에서 저급카복실산 할라이드로 아실화하여 제조한다.Amides of formula (XIII) are prepared by acylating a compound in which R 4 of formula (I) is hydrogen with a lower carboxylic acid halide in tertiary amines such as pyridine at 0 ° C. to 30 ° C., in particular at room temperature.

구조식(I)의 X가 황인 화합물을 X가 SO 또는 SO2인 화합물－전환시키는 것은 적합한 용매중에서 과아세트산, 과프탈산, m－염화과벤조산등의 과산으로 산화하여 수행하며, 과아세트산은 동일한반응계내에시 빙초산과 과산화수소로부터 제조한다.X is of formula (I) X is SO or SO 2 A compound of sulfur compounds and the conversion is carried out by oxidation with a peracid in a suitable solvent such as acetic acid, and phthalic acid, m- yeomhwagwa acid, and acetic acid in the same reaction system Is prepared from glacial acetic acid and hydrogen peroxide.

구조식(I)의 R4가 수소인 화합물은 저급알킬 할라이드를 사용하여 N－(저급알킬화)할 수 있다. 이반응에서 구조식(I)의 각 화합물은 저온에서 직접 알킬할라이드와 용이하게 반응한다.Compounds in which R 4 in formula (I) is hydrogen can be N- (lower alkylated) using lower alkyl halides. In this reaction, each compound of formula (I) readily reacts with the alkylhalide directly at low temperatures.

저급알콕시그룹 또는 아릴－(저급알콕시)그룹을 하이드록시그룹으로 전환시키는 것은 진한 할로겐화 수소산, 특히 계속하여 비등하는 브롬화 수소산으로 가열하여 수행한다.The conversion of the lower alkoxy group or the aryl- (lower alkoxy) group to the hydroxy group is carried out by heating with concentrated hydrochloric acid, in particular with subsequent boiling hydrobromic acid.

니트로그룹을 아미노그룹으로 환원하는 것은 화학적, 혹은 촉매적으로 기지의 방법으로 수행한다. : 예를들면, 귀금속촉매존재하에 주석/염산이나 수소로 환원한다. 수소첨가는 알칸올, 특히 에탄올중에서, 상압 실온에서 팔라듐/탄소 또는 산화백금존재하에서 바람직하게 수행된다.Reduction of nitro groups to amino groups is carried out chemically or catalytically by known methods. : For example, reduced to tin / hydrochloric acid or hydrogen in the presence of a noble metal catalyst. Hydrogenation is preferably carried out in alkanols, especially ethanol, in the presence of palladium / carbon or platinum oxide at atmospheric pressure.

시아노그룹의 검화는 산이나 염기를 사용하여 기지의 방법으로 수행한다.The saponification of cyanogroups is carried out by known methods using acids or bases.

카복실그룹의 에스테르화나 아마이드화는 적합한 알콜 또는 아민을 사용하여 수행한다.Esterification or amidation of carboxyl groups is carried out using suitable alcohols or amines.

아미노그룹은 산 할라이드로 처리하여 알킬화하고, 산무수물로 처리하여 아실화할 수 있다.Amino groups can be alkylated by treatment with acid halides and acylated by treatment with acid anhydrides.

하이드록시그룹은 적합한 할라이드로 처리하여 에테르화 하고, 적합한 산 할라이드 또는 산무수물로 처리하여 에스테르화 할 수 있다.Hydroxy groups can be etherified by treatment with a suitable halide and esterified by treatment with a suitable acid halide or acid anhydride.

카복실그룹의 환원은 불활성 유기용매중에서 디보란 또는 리튬알미늄 하이드라이드를 사용하여 수행할 수 있다.Reduction of the carboxyl group can be carried out using diborane or lithium aluminum hydride in an inert organic solvent.

알킬티오그룹의 산화는 과산화수소를 사용하여 수행할 수 있다.Oxidation of alkylthio groups can be carried out using hydrogen peroxide.

구조식(I)의 화합물은 할로겐화수소산(염산, 브롬화수소산등), 황산, 인산등의 무기산 또는 옥살산, 타타르산, 시트르산, 메탄설폰산등의 유기산으로 처리하여 산부가염으로 전환사킬 수 있다. 구조식(I)의 산부가염 화합물중에서 약제학적으로 무독한 산부가염이 바람직하다. 본 발명의 화합물을 제조하는 중에 구조식(I)의 화합물의 산부가염이 얻어질 경우 이 염은 유리염기로 전환시킬 수 있으며(알카리처리등), 우리염기는 필요에 따라 다른 산부가염으로 전환시킬 수도 있다.Compounds of formula (I) can be converted to acid addition salts by treatment with inorganic acids such as hydrochloric acid (hydrochloric acid, hydrobromic acid, etc.), sulfuric acid, phosphoric acid, or organic acids such as oxalic acid, tartaric acid, citric acid, methanesulfonic acid. Among the acid addition salt compounds of formula (I), pharmaceutically harmless acid addition salts are preferred. If acid addition salts of compounds of formula (I) are obtained during the preparation of the compounds of the present invention, these salts can be converted to free bases (alkaline treatment, etc.), and our bases can be converted to other acid addition salts as necessary. have.

부제탄소가 함유된 구조식(I)화합물은 라세믹체로 존재할 수 있으며 광학적 활성형으로 존재할 수도 있다. 본 발명에서는 라세믹체뿐만 아니라 광학적 활성형도 포함된다. 필요한 경우, 라세메이트는 광학적 활성산으로 상응하는 염을 분별결정화시켜서 광학적 대장체로 분리시킬 수 있다.Structural formula (I) compound containing the subtitle carbon may exist as a racemic body and may exist as an optically active form. In the present invention, not only racemic bodies but also optically active forms are included. If necessary, racemates can be separated into the optical colon by fractional crystallization of the corresponding salts with optically active acids.

구조식(I)의 화합물 및 그 산부가염은 관동맥 확장작용이 있으며 특히 협심증치료에도 사용된다.Compounds of formula (I) and acid addition salts thereof have coronary dilatation and are particularly used for the treatment of angina.

관동맥 확장작용은 다음과 같은 방법으로 측정할 수 있다.Coronary dilatation can be measured by the following methods.

체중 20 내지 30kg의 몬그렐(Mongrels)을 실험동물로 하여 펜토바비탈 30㎎/kg을 정맥주사하여 비취시키고 크로랄로즈－우레탄으로 마취를 지속시킨다. 동물을 대기로 인공호흡시키고, 흉곽을 절개하여 심장을 노출시키고, 혈류울(血流率)을 측정하기 위해 미리 맞추어논 전자혈류 계기를 좌측 관동맥의 회유지

Figure kpo00016
에 장치한다. 동맥혈압을 대퇴동맥에 있는 카테터(catheter)를 통하여 압력변환기로 측정한다. 또 좌심실의 표면에 심근수축력을 직접 측정하기 위한 눈금있는 신장성있는 측정 띠를 붕합한다. 심박수를 재기 위해 혈류속도계측을 하여 혈압의 맥파를 구한다. 생리적 식염수에 수용성 화합물을 녹여 정맥주사하고 프로필렌글리콜에 수불용성 화합물을 녹여서 정맥주사로, 또는 아라비아 고무에 현탁시켜 십이지장으로 투여한다. 본 화합물의 극대작용은 출발용량에 대한 백불율로 계산하고, 그라프로 나타낸다. 관혈류량을 측정할 때 작용의 지속성을 주의하여 관찰한다.Mongrels with a body weight of 20 to 30 kg (Mongrels) as an experimental animal, pentabarbital 30 mg / kg by intravenous jade and anesthesia is continued with Chloralose-urethane. Ventilate the left coronary artery with a pre-arranged electronic blood flow meter to artificially breathe the animal into the atmosphere, cut the rib cage to expose the heart, and measure blood flow.
Figure kpo00016
To the device. Arterial blood pressure is measured with a pressure transducer through a catheter in the femoral artery. They also incorporate a graduated, stretchable band of measurement on the surface of the left ventricle to directly measure myocardial contractility. In order to measure heart rate, blood pressure is measured to obtain pulse wave of blood pressure. Water-soluble compounds are dissolved in physiological saline and injected intravenously. Water-insoluble compounds are dissolved in propylene glycol and injected intravenously or suspended in Arabian gum and administered as duodenum. Maximal action of this compound is calculated as a white light rate relative to the starting dose and is shown in graphs. Observe the continuity of the action carefully when measuring the blood flow.

결과는 다음 표와 같으며 n은 시험한 동물의 수이다.The results are shown in the table below, where n is the number of animals tested.

[표][table]

Figure kpo00017
Figure kpo00017

구조식(I)의 화합물 및 그의 약제학적으로 무독한 산부가염은 복합가능한 약학적 담체와 혼합하여 의약품 제제 형태의 의약품으로 사용한다. 담체물질로는 유기 또는 무기의 불활성 담체로서 장내 또는 비경구투여에 적합한 것으로 예를 들면 물, 젤라틴, 아라비아고무, 유당, 전분, 마그네슘 스테아레이트, 탈크, 식물류, 폴리알킬렌글리콜류, 와세린등이 있다. 의약품 제제로는 고형제제(예 : 정제, 당의정, 캅셀제) 또는 액상제제(예 : 액제, 현탁제제, 유제)가 있다. 의약품 제제는 멸균 및/또는 방부제, 안정제, 흡습제, 유화제, 삼투압 및 완충액을 위한 염류등의 보조제를 함유할 수 있다.Compounds of formula (I) and pharmaceutically toxic acid addition salts thereof are used as pharmaceuticals in the form of pharmaceutical preparations in admixture with complex pharmaceutical carriers. Carrier materials are organic or inorganic inert carriers suitable for enteral or parenteral administration. For example, water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, plants, polyalkylene glycols, waserine, etc. There is this. Pharmaceutical preparations include solid preparations (eg tablets, dragees, capsules) or liquid preparations (eg liquids, suspensions, emulsions). Pharmaceutical formulations may contain adjuvants such as sterile and / or preservatives, stabilizers, hygroscopics, emulsifiers, osmotic pressure and salts for buffers.

경구투여의 경우 1일 용량은 약 10 내지 200mg이며, 정맥내 투여의 경우 약 1 내지 20mg이다.For oral administration the daily dose is about 10 to 200 mg and for intravenous administration is about 1 to 20 mg.

그러나 전술한 투여량은 한 예를 든 것이며 치료받아야 할 환자의 상태와 의사의 지시에 따라 달라질 수 있다.However, the dosages described above are examples and may vary depending on the condition of the patient to be treated and the doctor's instructions.

다음의 실시예는 본 발명을 설명한 것이다.The following examples illustrate the invention.

[실시예 1]Example 1

3, 4－디메톡시벤즈알데하이드 74.7g을 클로로포름 1,250㎖에 용해하고 1, 3－프로판디티올 50mg으로 처리하여 교반하면서 0℃로 냉각시킨다. 3불화 붕소 에테레이트 20ml를 가하고 그 혼합물을 냉장고 속에서 18시간동안 방치한다음 연속적으로 7% 수산화칼륨 500ml로 3회 세척후 10% 염화나트륨 수용액 500ml로 세척한다. 유기 추출액층을 합쳐서 황산나트륨으로 탈수하여 증발시킨다. 잔유물을 에테르로 2회 재결정하면 융점 99 내지 101℃의 2－(3, 4－디메톡시페닐)－m－디티안 102.6g이 얻어진다.74.7 g of 3,4-dimethoxybenzaldehyde is dissolved in 1,250 ml of chloroform, treated with 50 mg of 1,3-propanedithiol, and cooled to 0 ° C while stirring. 20 ml of boron trifluoride etherate is added and the mixture is left in the refrigerator for 18 hours, followed by three successive washes with 500 ml of 7% potassium hydroxide, followed by 500 ml of 10% aqueous sodium chloride solution. The combined organic extract layers are dehydrated with sodium sulfate and evaporated. Recrystallization of the residue twice with ether yields 102.6 g of 2- (3,4-dimethoxyphenyl) -m-dithiane having a melting point of 99 to 101 ° C.

다음의 디티안류는 유사한 방법으로 제조될 수 있다.The following dithiane can be prepared by a similar method.

2－(0－메톡시페닐)－m－디티안, 융점 126 내지 127℃(메틸렌클로라이드/이소프로필에테르)2- (0-methoxyphenyl) -m-dithiane, melting point 126-127 degreeC (methylene chloride / isopropyl ether)

2－페닐－m－디티안, 융점 72 내지 73℃(메틸렌클로라이드/이소프로필에테르)2-phenyl-m-dithiane, melting | fusing point 72-73 degreeC (methylene chloride / isopropyl ether)

2－(p－클로로페닐)－m－디티안, 융점 87 내지 88℃(메틸렌클로라이드/이소프로필에테르)2- (p-chlorophenyl) -m-dithiane, melting | fusing point 87-88 degreeC (methylene chloride / isopropyl ether)

2－(m－메톡시페닐)－m－디티안, 융점 : 62 내지 63℃(이소프로필에테르)2- (m-methoxyphenyl) -m-dithiane, melting | fusing point: 62-63 degreeC (isopropyl ether)

2－(3, 4, 5－트리메톡시페닐)－m－디티안, 융점 : 88 내지 89℃(메틸렌클로라이드/이소프로필에테르)2- (3,4,5-trimethoxyphenyl) -m-dithiane, melting | fusing point: 88-89 degreeC (methylene chloride / isopropyl ether)

2－(m－클로로페닐)－m－디티안, 융점 : 63 내지 64℃(사이클로헥산)2- (m-chlorophenyl) -m-dithiane, melting | fusing point: 63-64 degreeC (cyclohexane)

2－(3, 5－디메톡시페닐)－m－디티안, 융점 : 90 내지 91℃(사이클로헥산)2- (3,5-dimethoxyphenyl) -m-dithiane, melting | fusing point: 90-91 degreeC (cyclohexane)

p－(m－디티안－2－일)N, N－디메틸아닐린 융점 : 118 내지 119℃(사이클로헥산)p- (m-dithiane-2-yl) N, N-dimethylaniline melting | fusing point: 118-119 degreeC (cyclohexane)

2－(m－니트로페닐)－m－디티안, 융점 : 117 내지 118℃(사이클로헥산)2- (m-nitrophenyl) -m-dithiane, melting | fusing point: 117-118 degreeC (cyclohexane)

2－p－톨릴－m－디티안, 융점 : 89 내지 90℃(에테르/헥산)2-p-tolyl-m-dithiane, melting | fusing point: 89-90 degreeC (ether / hexane)

2－m－(브로모페닐)－m－디티안, 융점 : 78 내지 79℃(사이클로헥산)2-m- (bromophenyl) -m-dithiane, melting | fusing point: 78-79 degreeC (cyclohexane)

2－(2－나프틸)－m－디티안, 융점 : 110 내지 111℃(사이클로헥산)2- (2-naphthyl) -m-dithiane, melting | fusing point: 110-111 degreeC (cyclohexane)

2－(2, 4, 5－트리메톡시페닐)－m－디티안, 융점 : 156 내지 157℃(메틸렌클로라이드/메탄올)2- (2,4,5-trimethoxyphenyl) -m-dithiane, melting | fusing point: 156-157 degreeC (methylene chloride / methanol)

2－(p－플루오로페닐)－m－디티안, 융점 : 105 내지 106℃(사이클로헥산)2- (p-fluorophenyl) -m-dithiane, melting | fusing point: 105-106 degreeC (cyclohexane)

2－(4－바이페니릴)－m－디티안, 융점 : 148 내지 151℃(테트라하이드로푸란 /사이클로헥산)2- (4-biphenyl) -m-dithiane, melting point: 148 to 151 ° C (tetrahydrofuran / cyclohexane)

2－(

Figure kpo00018
,
Figure kpo00019
,
Figure kpo00020
－트리플루오로－p－톨릴)－m－디티안, 융점 : 103 내지 104℃(사이클로헥산)2-(
Figure kpo00018
,
Figure kpo00019
,
Figure kpo00020
-Trifluoro-p-tolyl) -m-dithiane, melting | fusing point: 103-104 degreeC (cyclohexane)

2－(1－나프틸)－m－디티안, 융점 : 147 내지 148℃(사이클로헥산)2- (1-naphthyl) -m-dithiane, melting | fusing point: 147-148 degreeC (cyclohexane)

2－(3－벤질옥시－4－메톡시페닐)－m－디티안, 융점 : 168 내지 170℃(사이클로헥산)2- (3-benzyloxy-4-methoxyphenyl) -m-dithiane, melting | fusing point: 168-170 degreeC (cyclohexane)

2－(4－벤질옥시－3－메톡시페닐)－m－디티안, 융점 : 118 내지 119℃(사이클로헥산)2- (4-benzyloxy-3-methoxyphenyl) -m-dithiane, melting | fusing point: 118-119 degreeC (cyclohexane)

2－(2－티에닐)－m－디티안, 융점 : 74 내지 75℃(사이클로헥산)2- (2-thienyl) -m-dithiane, melting | fusing point: 74-75 degreeC (cyclohexane)

2－(

Figure kpo00021
,
Figure kpo00022
,
Figure kpo00023
－트리플루오로－m－톨릴)－m－디티안, 융점 : 69 내지 71℃(헵탄)2-(
Figure kpo00021
,
Figure kpo00022
,
Figure kpo00023
-Trifluoro-m-tolyl) -m-dithiane, melting | fusing point: 69-71 degreeC (heptane)

2－(p－이소프로필렌)－m－디티안, 융점 : 58 내지 59℃(헥산)2- (p-isopropylene) -m-dithiane, melting point: 58-59 ° C. (hexane)

2－(3, 4－크실릴)－m－디티안, 융점 : 74 내지 75℃(석유 에테르)2- (3,4-xylyl) -m-dithiane, melting | fusing point: 74-75 degreeC (petroleum ether)

2－(3－부톡시－4－메톡시페닐)－m－디티안2- (3-butoxy-4-methoxyphenyl) -m-dithiane

2－(4－에톡시－3－메톡시페닐)－m－디티안, 융점 : 84 내지 86℃(이소프로필에테르)2- (4-ethoxy-3-methoxyphenyl) -m-dithiane, melting | fusing point: 84-86 degreeC (isopropyl ether)

6－(m－디티안－2－일)－1, 4－벤조디옥산, 융점 140 내지 142℃(메틸렌클로라이드/이소프로필에테르)6- (m-dithiane-2-yl) -1,4-benzodioxane, melting point 140-142 degreeC (methylene chloride / isopropyl ether)

2－(4－메톡시－m－톨릴)－m－디티안, 융점 : 75 내지 77℃(사이클로헥산)2- (4-methoxy-m-tolyl) -m-dithiane, melting | fusing point: 75-77 degreeC (cyclohexane)

[실시예 2]Example 2

실시예 1에서 제조한 2－(3, 4－디메톡시페닐)－m－디티안 60g을 빙초산 470ml에 용해하고 실온에서 30% 과산화수소액 235ml로 처리하고 액온을 약 40℃까지 올린다. 실온에서 하루밤 방치후 진공여과하여 결정성 침전을 얻고 약간의 빙초산으로 세척한다음 60℃에서 하루밤 진공 건조후 아세토니트릴으로 재결정하면 융점 243 내지 245℃의 2－(3, 4－디메톡시페닐)－m－디티안 57.1g이 얻어진다.60 g of 2- (3,4-dimethoxyphenyl) -m-dithiane prepared in Example 1 were dissolved in 470 ml of glacial acetic acid, treated with 235 ml of 30% hydrogen peroxide solution at room temperature, and the liquid temperature was raised to about 40 ° C. After standing overnight at room temperature, it was vacuum filtered to obtain crystalline precipitate, washed with a slight amount of glacial acetic acid, and then vacuum dried at 60 ° C. overnight, and then recrystallized with acetonitrile to give 2- (3,4-dimethoxyphenyl)-with a melting point of 243 to 245 ° C. 57.1 g of m-dithiane are obtained.

다음 디티안 테트라옥사드류는 유사한 방법으로 제조될 수 있다.The following dithiane tetraoxads can be prepared by a similar method.

2－(m－브로모페닐)－m－디티안－1, 1, 3, 4－테트라옥사이드 융점 : 230 내지 231℃(아세토니트릴)2- (m-bromophenyl) -m-dithiane-1, 1, 3, 4- tetraoxide melting | fusing point: 230-231 degreeC (acetonitrile)

2－(p－플루오로페닐)－m－디티안－1, 1, 3, 3－테트라옥사이드 융점 : 283 내지 284℃(아세토니트릴)2- (p-fluorophenyl) -m-dithiane-1, 1, 3, 3- tetraoxide melting | fusing point: 283-284 degreeC (acetonitrile)

2－(m－니트로페닐)－m－디티안－1, 1, 3, 3－테트라옥사이드 융점 : 256 내지 257℃(아세토니트릴)2- (m-nitrophenyl) -m-dithiane-1, 1, 3, 3- tetraoxide melting | fusing point: 256-257 degreeC (acetonitrile)

2－(3, 4, 5－트리메톡시페닐)－m－디티안－1, 1, 3, 3－테트라옥사이드 융점 : 310℃이상(아세토니트릴)2- (3,4,5-trimethoxyphenyl) -m-dithiane-1,1,3,3-tetraoxide melting point: 310 ° C or higher (acetonitrile)

2－(2－나프틸)m－디티안－1, 1, 3, 3－테트라옥사이드 융점 : 277 내지 278℃(아세토/니트릴톨릴)2- (2-naphthyl) m-dithiane-1, 1, 3, 3-tetraoxide melting | fusing point: 277-278 degreeC (aceto / nitrile tolyl)

2－p－톨릴－m－디티안－1, 1, 3, 3－테트라옥사이드 융점 : 284 내지 285℃(아세토니트릴);2-p-tolyl-m-dithiane-1, 1, 3, 3- tetraoxide melting | fusing point: 284-285 degreeC (acetonitrile);

2－(4－벤질옥시－3－메톡시페닐)－m－디티안－1, 1, 3, 3－테트라옥사이드 융점 : 220 내지 223℃(아세톤/아세토니트릴);2- (4-benzyloxy-3-methoxyphenyl) -m-dithiane-1, 1, 3, 3- tetraoxide melting | fusing point: 220-223 degreeC (acetone / acetonitrile);

2－(3, 4－디메톡시페닐)－1, 3－디티올란－1, 1, 3, 3－테트라옥사이드 융점 : 194 내지 196℃(아씨톤/아씨토니트릴);2- (3,4-dimethoxyphenyl) -1,3-dithiolane-1,1,3,3-tetraoxide melting point: 194 to 196 ° C (acetone / acetonitrile);

2－(3, 4－메틸렌디옥시페닐)－m－디티안－1, 1, 3, 3－테트라옥사이드 융점 : 300℃이상(아세톤/아세토니트릴);2- (3,4-methylenedioxyphenyl) -m-dithiane-1, 1, 3, 3- tetraoxide melting | fusing point: 300 degreeC or more (acetone / acetonitrile);

2－(2'－티에닐)－m－디티안－1, 1, 3, 3－테트라옥사이드 융점 : 300℃(아세톤/아세토니트릴);2- (2'-thienyl) -m-dithiane-1, 1, 3, 3- tetraoxide melting | fusing point: 300 degreeC (acetone / acetonitrile);

2－(3, 4－디클로로페닐)－m－디티안－1, 1, 3, 3－테트라옥사이드 융점 : 254 내지 255℃(빙초산/물);2- (3,4-dichlorophenyl) -m-dithiane-1, 1, 3, 3- tetraoxide melting | fusing point: 254-255 degreeC (glacial acetic acid / water);

2－(

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,
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,
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－트리플루오로－m－톨릴)－m－디티안－1, 1, 3, 3－테트라옥사이드 융점 : 239 내지 242℃(빙초산/물);2-(
Figure kpo00024
,
Figure kpo00025
,
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-Trifluoro-m-tolyl) -m-dithiane-1, 1, 3, 3-tetraoxide melting point: 239 to 242 ° C (glacial acetic acid / water);

2－(p－이소프로필페닐)－m－디티안－1, 1, 3, 3－테트라옥사이드 융점 : 204 내지 205℃(아세토니트릴/에탄올);2- (p-isopropylphenyl) -m-dithiane-1, 1, 3, 3- tetraoxide melting | fusing point: 204-205 degreeC (acetonitrile / ethanol);

2－(3, 4－크실릴)－m－디티안－1, 1, 3, 3－테트라옥사이드 융점 : 268 내지 269℃(아세토니트릴/메탄올);2- (3,4-xylyl) -m-dithiane-1, 1, 3, 3-tetraoxide melting point: 268 to 269 ° C (acetonitrile / methanol);

2－(3－부톡시－4－메톡시페닐)－m－디티안－1, 1, 3, 3－테트라옥사이드 융점 : 225°내지 227℃(빙초산/물);2- (3-butoxy-4-methoxyphenyl) -m-dithiane-1, 1, 3, 3-tetraoxide melting point: 225 ° to 227 ° C. (glacial acetic acid / water);

2－(4－에톡시－3－메톡시페닐)－m－디티안－1, 1, 3, 3－테트라옥사이드 융점 : 242 내지 244℃(아세톤/아세토니트릴);2- (4-ethoxy-3-methoxyphenyl) -m-dithiane-1, 1, 3, 3- tetraoxide melting | fusing point: 242-244 degreeC (acetone / acetonitrile);

m－(m－디티안－2'－일)－벤조니트릴－1', 1', 3', 3'－테트라옥사이드 융점 : 259 내지 260℃(빙초산/물);m- (m-dithiane-2'-yl) -benzonitrile-1 ', 1', 3 ', 3'- tetraoxide melting | fusing point: 259-260 degreeC (glacial acetic acid / water);

6－(m－디티안－2'－일)－1, 4－벤조디옥산－1', 1', 3', 3'－테트라옥사이드 융점 : 232℃(분해)(빙초산/물);6- (m-dithia-2'-yl) -1,4-benzodioxane-1 ', 1', 3 ', 3'-tetraoxide melting point: 232 DEG C (decomposition) (glacial acetic acid / water);

2－(4－메톡시－m－톨릴)－m－디티안－1', 1', 3', 3'－테트라옥사이드 융점 : 225°내지 227℃(빙초산/물);2- (4-methoxy-m-tolyl) -m-dithiane-1 ', 1', 3 ', 3'-tetraoxide melting point: 225 ° to 227 ° C (glacial acetic acid / water);

[실시예 3]Example 3

2－(3, 4－디메톡시페닐)－m－디티안(실시예 1에서 기술한 방법으로 제조)19.2g과 테트라하이드로푸란 200ml를 설폰화 플라스크내에서 아르곤가스를 통해 주면서 －60℃로 냉각시키고 헥산중의 부틸리튬 33ml로 처리한다음 －20℃에서 2시간동안 교반한다. 여기에 테트라하이드로푸란 200ml중의 N－(3－클로로프로필)－3, 4－디메톡시－N－메틸－펜에틸아민 18g을 －70℃에서 15분내에 적가시키고 강한 냉동기중에서 －20℃로 18시간동안 방치한 다음 실온으로 3시간동안 방치한 다음 용액을 물에 붓고 에테르로 3회 추출한다. 이 에테르 추출액을 1N 염산 250ml씩으로 3회 추출하여 산성 추출액을 3N 수산화나트륨으로 pH를 12 이상으로 만들고, 분리된 오일층을 에테르로 추출한다. 이 에테르층을 황산마그네슘으로 탈수후 증발시켜 얻은 오일(30g)을 에틸아세테이트에 용해하고 브롬화수소산 에테르용액으로 처리하여 침전을 분리하고 에탄올로 재결정하면 융점 170 내지 172℃의 N－(3, 4－디메톡시펜에틸)－2－(3, 4－디메톡시페닐)－N－메틸－m－디티안－2－프로필아민 하이드로브로마이드가 얻어진다.19.2 g of 2- (3,4-dimethoxyphenyl) -m-dithiane (prepared by the method described in Example 1) and 200 ml of tetrahydrofuran are cooled to -60 DEG C while passing through argon gas in a sulfonated flask. The mixture was treated with 33 ml of butyllithium in hexane and stirred at −20 ° C. for 2 hours. 18 g of N- (3-chloropropyl) -3 and 4-dimethoxy-N-methyl-phenethylamine in 200 ml of tetrahydrofuran were added dropwise at 15 minutes at -70 ° C and 18 hours at -20 ° C in a strong freezer. The mixture is allowed to stand for 3 hours, and then the solution is poured into water and extracted three times with ether. The ether extract was extracted three times with 250 ml of 1N hydrochloric acid, and the acidic extract was extracted with 3N sodium hydroxide to a pH of 12 or more, and the separated oil layer was extracted with ether. The ether layer was dehydrated with magnesium sulfate and evaporated. The oil (30 g) obtained was dissolved in ethyl acetate, treated with an aqueous hydrobromic acid ether solution to separate the precipitate, and recrystallized from ethanol to give N- (3, 4--) at a melting point of 170 to 172 ° C. Dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N-methyl-m-dithia- 2-propylamine hydrobromide is obtained.

원소분석 : C26H37NO4S2HBrElemental analysis: C 26 H 37 NO 4 S 2 HBr

계 산 치 : C 54.54, H 6.69, N 2.45, Br 13.95Calculated Value: C 54.54, H 6.69, N 2.45, Br 13.95

실 측 치 : C 54.54, H 6.74, N 2.31, Br 14.05Found: C 54.54, H 6.74, N 2.31, Br 14.05

출발물질인 N－(3－클로로프로필)－3, 4－디메톡시－N－메틸－페네틸아민은 다음과 같이 제조한다.The starting materials, N- (3-chloropropyl) -3,4-dimethoxy-N-methyl-phenethylamine, are prepared as follows.

N－메틸－호무베라트릴아민 292.5g을 디메틸포름아마이드 1,000ml에 용해하고 무수탄산칼륨 415g으로 처리한 후 이 혼합물을 5℃에서 교반하면서 디메틸포름 아마이드 500ml중의 1, 3－브로무클로로티로판 237g으로 처리하고 실온에서 4시간 더 교반한다음 6ℓ의 물에 부어 분리된 오일을 에테르 2ℓ씩으로 3회 추출하고 그 추출혼액을 황산마그네슘으로 탈수후 진공 증발시킨다. 잔유오일을 69℃ 및 70℃사이에서 0.005Torr로 수은 확산 펌프로 증류하면 비점 69 내지 70℃/0.005Torr의 N－(3－클로로프로필)－3, 4－디메톡시－N－메틸펜에틸아민 206.7g 얻어졌다.292.5 g of N-methyl-homveratrilamine was dissolved in 1,000 ml of dimethylformamide, treated with 415 g of anhydrous potassium carbonate, and the mixture was stirred at 5 ° C. with 1,3-bromchlorotyrophan in 500 ml of dimethylformamide. The mixture was treated with 237 g, stirred for 4 hours at room temperature, poured into 6 L of water, extracted three times with 2 L of ether, and the extract mixture was dehydrated with magnesium sulfate and evaporated in vacuo. The remaining oil is distilled with a mercury diffusion pump at 0.005 Torr between 69 ° C and 70 ° C for N- (3-chloropropyl) -3,4-dimethoxy-N-methylphenethylamine with a boiling point of 69 to 70 ° C / 0.005 Torr. 206.7 g was obtained.

다음의 화합물들은 본 실시예에서 기술된 바와 유사한 방법으로 제조할 수 있다.The following compounds can be prepared by methods similar to those described in this example.

N－(3, 4－디메톡시펜에틸)－2－(m－메톡시페닐)－N－메틸－m－디티안－2－프로필아민 하이드로클로라이드 융점 : 113 내지 115℃(아세톤)N- (3,4-dimethoxyphenethyl) -2- (m-methoxyphenyl) -N-methyl-m-dithiane-2-propylamine hydrochloride Melting point: 113-115 degreeC (acetone)

N－(3, 4－디메톡시펜에틸)－2－(3, 4, 5－트리메톡시페닐)－N－메틸－m－디티안－2－프로필아민 하이드로클로라이드 융점 : 147 내지 150℃(아세톤)N- (3,4-dimethoxyphenethyl) -2- (3,4,5-trimethoxyphenyl) -N-methyl-m-dithia- 2-propylamine hydrochloride Melting | fusing point: 147-150 degreeC ( Acetone)

N－(3, 4－디메톡시펜에틸)－2－(p－메톡시페닐)－N－메틸－m－디티안－2－프로필아민 하이드로클로라이드 융점 : 160 내지 161℃(아세톤)N- (3,4-dimethoxyphenethyl) -2- (p-methoxyphenyl) -N-methyl-m-dithiane-2-propylamine hydrochloride Melting point: 160-161 degreeC (acetone)

N－(3, 4－디메톡시펜에틸)－2－(0－메톡시페닐)－N－메틸－m－디티안－2－프로필아민 하이드로클로라이드 융점 : 151 내지 152℃(아세톤)N- (3,4-dimethoxyphenethyl) -2- (0-methoxyphenyl) -N-methyl-m-dithiane-2-propylamine hydrochloride Melting point: 151-152 degreeC (acetone)

2－(p－클로로페닐)－N－(3, 4－디메톡시펜에틸)－N－메틸－m－디티안－2－프로필아민 하이드로클로라이드 융점 : 137 내지 139℃(아세톤)2- (p-chlorophenyl) -N- (3,4-dimethoxyphenethyl) -N-methyl-m-dithiane-2-propylamine hydrochloride Melting point: 137-139 degreeC (acetone)

N－(3, 4－디메톡시펜에틸)－N－메틸－2－페닐－m－디티안－2－프로필아민 하이드로클로라이드 융점 : 170 내지 172℃(아세톤)N- (3,4-dimethoxyphenethyl) -N-methyl- 2-phenyl-m-dithia- 2-propylamine hydrochloride Melting point: 170-172 degreeC (acetone)

N－(3, 4－디메톡시펜에틸)－N－메틸－2－(3, 4－메틸렌디옥시페닐)－m－디티안－2－프로필아민 하이드로클로라이드 융점 : 139 내지 141℃(아세톤)N- (3,4-dimethoxyphenethyl) -N-methyl-2- (3,4-methylenedioxyphenyl) -m-dithian-2-propylamine hydrochloride Melting point: 139-141 degreeC (acetone)

N－(3, 4－디메톡시펜에틸)－N－메틸－2－(p－톨릴)－m－디티안－2－프로필아민 하이드로클로라이드 융점 : 139 내지 141℃(아세톤)N- (3,4-dimethoxyphenethyl) -N-methyl- 2- (p-tolyl) -m-dithian-2- propylamine hydrochloride Melting point: 139-141 degreeC (acetone)

2－(m－클로로페닐)－N－(3, 4－디메톡시－에틸)－N－메틸－m－디티안－2－티로필아민 하이드로클로라이드 융점 : 108 내지 110℃(아세톤)2- (m-chlorophenyl) -N- (3,4-dimethoxy-ethyl) -N-methyl-m-dithiane-2-tyrophylamine hydrochloride Melting point: 108 to 110 ° C (acetone)

N－(3, 4－디메톡시펜에틸)－2－(3, 5－디메톡시페닐)－N－메틸－m－디티안－2－프로필아민 옥살레이트(1 : 1) 융점 : 155 내지 156℃(아세톤)N- (3,4-dimethoxyphenethyl) -2- (3,5-dimethoxyphenyl) -N-methyl-m-dithiane-2-propylamine oxalate (1: 1) melting | fusing point: 155-156 ℃ (acetone)

N－(3, 4－디메톡시펜에틸)－2－(p－디메틸아미노페닐)－N－메틸－m－디티안－2－프로필아민 하이드로클로라이드 융점 : 183 내지 184℃(아세톤)N- (3,4-dimethoxyphenethyl) -2- (p-dimethylaminophenyl) -N-methyl-m-dithiane-2-propylamine hydrochloride Melting | fusing point: 183-184 degreeC (acetone)

N－(3, 4－디메톡시펜에틸)－N－메틸－2－(2－나프틸)－m－디티안－2－프로필아민 하이드로클로라이드 융점 : 195 내지 196℃(아세톤)N- (3,4-dimethoxyphenethyl) -N-methyl-2- (2-naphthyl) -m-dithiane-2-propylamine hydrochloride Melting point: 195-196 degreeC (acetone)

N－(3, 4－디메톡시펜에틸)－N－메틸－2－(2, 4, 5－트리메톡시페닐)－m－디티안－2－프로필아민 하이드로클로라이드 융점 : 156 내지 158℃(아세톤)N- (3,4-dimethoxyphenethyl) -N-methyl-2- (2,4,5-trimethoxyphenyl) -m-dithiane-2-propylamine hydrochloride Melting | fusing point: 156-158 degreeC ( Acetone)

N－(3, 4－디메톡시펜에틸)－2－(p－플루오로페닐)－N－메틸－디티안－2－프로필아민 하이드로클로라이드 융점 : 138 내지 139℃(아세톤)N- (3,4-dimethoxyphenethyl) -2- (p-fluorophenyl) -N-methyl-dithiane-2-propylamine hydrochloride Melting point: 138-139 degreeC (acetone)

2－(4－바이페닐릴)－N－(3, 4－디메톡시펜에틸)－N－메틸－m－디티안－2－프로필아민 옥살레이트(1 : 1) 융점 : 167 내지 169℃(아세톤)2- (4-biphenylyl) -N- (3,4-dimethoxyphenethyl) -N-methyl-m-dithiane-2-propylamine oxalate (1: 1) melting | fusing point: 167-169 degreeC ( Acetone)

N－(p－클로로펜에틸)－N－메틸－2－페닐－m－디티안－2－프로클아민 하이드로클로라이드 융점 : 145 내지 147℃(아세톤)N- (p-chlorophenethyl) -N-methyl- 2-phenyl-m-dithia- 2-procleamine hydrochloride melting | fusing point: 145-147 degreeC (acetone)

2－페닐－m－디티안 및 N－(3－클로로프로필)－4－클로로－N－메틸－펜에틸아민으로부터 제조.Prepared from 2-phenyl-m-dithiane and N- (3-chloropropyl) -4-chloro-N-methyl-phenethylamine.

N－메틸－N－펜에틸－2－페닐－m－디티안－2－프로필아민 하이드로클로라이드 융점 : 136 내지 137℃(아세톤)N-methyl-N-phenethyl-2-phenyl-m-dithiane-2-propylamine hydrochloride Melting | fusing point: 136-137 degreeC (acetone)

2－페닐－m－디티안 및 N－(3－클로로프로필)－N－메틸－펜에틸아민으로부터 제조(비점 78 내지 80℃/0.001Torr)Prepared from 2-phenyl-m-dithiane and N- (3-chloropropyl) -N-methyl-phenethylamine (boiling point 78 to 80 ° C./0.001 Torr)

N－(3, 4－디메톡시펜에틸)－N－메틸－2－페닐－m－디티안－2－에틸아민 하이드로클로라이드 융점 : 172 내지 174℃(아세톤)N- (3,4-dimethoxyphenethyl) -N-methyl- 2-phenyl-m-dithiane-2-ethylamine hydrochloride Melting | fusing point: 172-174 degreeC (acetone)

2－페닐－m－디티안 및 N－(2－클로로에틸)－3, 4－디메톡시－N－메틸－펜틸아민으로부터 제조.Manufacture from 2-phenyl-m-dithiane and N- (2-chloroethyl) -3,4-dimethoxy-N-methyl-pentylamine.

N－(3, 4－디메톡시펜에틸)－N－메틸－2－(2－티에닐)－m－디티안－2－프로필아민 하이드로클로라이드 융점 : 138 내지 140℃(아세톤)N- (3,4-dimethoxyphenethyl) -N-methyl-2- (2-thienyl) -m-dithiane-2-propylamine hydrochloride Melting | fusing point: 138-140 degreeC (acetone)

rac－N－(3, 4－디메톡시펜에틸)－2－(3, 4－디메톡시페닐)－N, β－디메틸－m－디티안－2－프로필아민 옥살레이트(1 : 1), 융점 : 138 내지 139℃(아세톤/에틸아세테이트)rac-N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N, (beta) -dimethyl-m-dithia- 2-propylamine oxalate (1: 1), Melting Point: 138-139 ° C. (Acetone / Ethyl Acetate)

2－(3, 4－디메톡시페닐)－m－디티안 및 N－(3－클로로－2－메틸프로필)－ 3, 4－디메톡시－N－메틸－펜에틸아민으로 부터 제조.2- (3,4-dimethoxyphenyl) -m-dithiane and N- (3-chloro-2-methylpropyl) -3 manufactured from 3,4-dimethoxy-N-methyl-phenethylamine.

2－(3, 4－디메톡알페닐)－N－[4－(3, 4－디메톡시페닐)－부틸]－N－메틸－ m－디티안－2－프로필아민.2- (3,4-dimethoxyalphenyl) -N- [4- (3,4-dimethoxyphenyl) -butyl] -N-methyl-m-dithiane-2-propylamine.

[실시예 4]Example 4

2－(3, 4－디메톡시페닐)－m－디티안－1, 1, 3, 3－테트라옥사이드(실시예 2에서와 같은 방법으로 제조)35.2g을 무수 디옥산 180ml에 현탁시키고 나트륨 2.53g으로 처리후 아르곤 가스하에서 20시간동안 가열하여 나트륨을 완전히 용해시킨 다음 실온에서 N－(3－클로로프로필)－3, 4－디메톡시－N－메틸－펜에틸아민(실시예 3에서와 같은 방법으로 제조)27.2g을 가하고 뿌연 용액을 실온에서 1시간동안 교반한 후 3시간동안 환류 비등시킨다. 이 혼합물을 얼음/물에 붓고 에틸아세테이트로 3회 추출하고 이 추출혼액을 1N 염산으로 3회 추출한다. 이 산성 추출액을 알카리성으로 하여 클로로포름으로 3회 추출한 후 물로 세척하고 황산마그네슘으로 탈수후 증발시킨다. 결정성 잔유물을 메탄올로 재결정하면 융점 143 내지 145℃의 결정이 얻어진다.35.2 g of 2- (3,4-dimethoxyphenyl) -m-dithiane-1,1,3,3-tetraoxide (produced in the same manner as in Example 2) were suspended in 180 ml of anhydrous dioxane and sodium 2.53 After treatment with g, the mixture was heated under argon gas for 20 hours to completely dissolve sodium, followed by N- (3-chloropropyl) -3,4-dimethoxy-N-methyl-phenethylamine (as in Example 3). 27.2 g are added and the cloudy solution is stirred at room temperature for 1 hour and then refluxed for 3 hours. The mixture is poured into ice / water and extracted three times with ethyl acetate and the extract mixture is extracted three times with 1N hydrochloric acid. The acidic extract was alkaline, extracted three times with chloroform, washed with water, dehydrated with magnesium sulfate and evaporated. Recrystallization of the crystalline residue with methanol yields crystals having a melting point of 143 to 145 캜.

하이드로클로라이드를 제조하기 위해서는 염기를 아세톤에 용해하고 빙욕상에서 디옥산중의 염산 20ml로 처리하고 생성된 결정성염을 진공 여과하여 아세토니트릴/아세톤(1 : 3)으로 재결정한다. 얻어진 N－(3, 4－디메톡시펜에틸)－2－(3, 4－디메톡시페닐)－N－메틸－m－디티안－2－프로필아민－1, 1, 3, 3－테트라옥사이트를 120℃의 고진공하에 하루밤동안 건조시키면 융점 167 내지 169℃의 물질 38.9이 얻어진다.To prepare hydrochloride, the base is dissolved in acetone, treated with 20 ml of hydrochloric acid in dioxane on an ice bath, and the resulting crystalline salt is vacuum filtered and recrystallized from acetonitrile / acetone (1: 3). N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N-methyl-m-dithiane-2-propylamine-1,1,3,3-tetraocta which were obtained Drying the site overnight under high vacuum at 120 ° C. yields material 38.9 with a melting point of 167-169 ° C.

원소분석 :Elemental Analysis:

계 산 치 : C 52.74, H 6.47, N 2.36, Cl 5.99, S 10.83Calculated Value: C 52.74, H 6.47, N 2.36, Cl 5.99, S 10.83

실 측 치 : C 52.74, H 6.58, N 2.16, Cl 6.19, S 10.53Found: C 52.74, H 6.58, N 2.16, Cl 6.19, S 10.53

다음－화합물들은 본 실시예에 기술된 바와 유사한 방법으로 제조할 수 있다.The following compounds can be prepared by methods analogous to those described in this example.

N－(3, 4－디메톡시펜에틸)－N－메틸－2－(2－나프틸)－m－디티안－2－프로필아민－1, 1, 3, 3－테트라옥사이드 옥살레이트(1 : 1) 융점 190℃ 내지 191℃(아세톤/메탄올)N- (3,4-dimethoxyphenethyl) -N-methyl-2- (2-naphthyl) -m-dithiane-2-propylamine-1,1,3,3- tetraoxide oxalate (1 1) Melting point 190 ° C to 191 ° C (acetone / methanol)

N－(3, 4－디메톡시펜에틸)－N－메틸－2－(3, 4, 5－트리메톡시페닐)－m－디티안－2－프로필아민－1, 1, 3, 3－테트라옥사이드 옥살레이트(1 : 1) 융점 146 내지 148℃(아세톤/에틸아세테이트)N- (3,4-dimethoxyphenethyl) -N-methyl-2- (3,4,5-trimethoxyphenyl) -m-dithiane-2-propylamine-1,1,3,3- Tetraoxide oxalate (1: 1) Melting point 146-148 degreeC (acetone / ethyl acetate)

2－(m－브로무페닐)－N－(3, 4－디메톡시펜에틸)－N－메틸－m－디티안－2－프로필아민－1, 1, 3, 3－테트라옥사이드 하이드로클로라이드, 융점 158℃ 내지 160℃(메탄올성 염산/에틸아세테이트)2- (m-bromuphenyl) -N- (3,4-dimethoxyphenethyl) -N-methyl-m-dithiane-2-propylamine-1,1,3,3- tetraoxide hydrochloride, Melting Point 158 ° C to 160 ° C (Methanol Hydrochloric Acid / Ethyl Acetate)

2－(m－니트로페닐)－N－(3, 4－디메톡시펜에틸)－N－메틸－m－디티안－2－프로필아민－1, 1, 3, 3－테트라옥사이드 하이드로클로라이드, 융점 212℃ 내지 214℃(아세톤)2- (m-nitrophenyl) -N- (3,4-dimethoxyphenethyl) -N-methyl-m-dithiane-2-propylamine-1,1,3,3- tetraoxide hydrochloride, melting point 212 ° C to 214 ° C (acetone)

N－(3, 4－디메톡시펜에틸)－2－(p－플루오로페닐)－N－메틸－m－디티안－2－프로필아민－1, 1, 3, 3－테트라옥사이드 하이드로클로라이드, 융점 234℃ 내지 236℃(메탄올)N- (3,4-dimethoxyphenethyl) -2- (p-fluorophenyl) -N-methyl-m-dithiane-2-propylamine-1,1,3,3- tetraoxide hydrochloride, Melting Point 234 ° C to 236 ° C (Methanol)

N－(3,4－디메톡시펜에틸)－N－메틸－2－페닐－m－디티안－2－프로필아민－1, 1, 3, 3－테트라옥사이드 하이드로클로하이드 융점 149℃(분해)(메탄올)N- (3,4-dimethoxyphenethyl) -N-methyl-2-phenyl-m-dithiane-2-propylamine-1,1,3,3-tetraoxide hydrochloride melting point 149 ° C (decomposition) (Methanol)

N－(3, 4－디메톡시펜에틸)－2－(3, 4－디메톡시펜에틸)－N－에틸－m－디티안－2－프로필아민－1, 1, 3, 3－테트라옥사이드 옥살레이트(1 : 1), 융점 177℃ 내지 179℃(메탄올/아세톤)N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenethyl) -N-ethyl-m-dithiane-2-propylamine-1,1,3,3- tetraoxide Oxalate (1: 1), melting point 177 ° C to 179 ° C (methanol / acetone)

[2－(3, 4－디메톡시페닐)－m－디티안－1, 1, 3, 3－테트라옥사이트 및 N－(3－클로로프로필)－3, 4－디메톡시－N－에틸－펜에틸아민으로부터 제조][2- (3,4-dimethoxyphenyl) -m-dithiane-1,1,3,3-tetraoxite and N- (3-chloropropyl) -3,4-dimethoxy-N-ethyl- From phenethylamine]

N－(3,4－디메톡시펜에틸)－2－(4－이소프로필페닐)－N－메틸－m－디티안－2－프로필아민－1, 1, 3, 3－테트라옥사이드 하이드로클로랄이드, 융점 : 225°내지 227℃(디옥산중의 염산/에틸아세테이트)N- (3,4-dimethoxyphenethyl) -2- (4-isopropylphenyl) -N-methyl-m-dithiane-2-propylamine-1,1,3,3- tetraoxide hydrochloral Id, melting point: 225 ° to 227 ° C (hydrochloric acid / ethyl acetate in dioxane)

N－(3, 4－디메톡시펜에틸)－2－(3－트리플루오로메틸페닐)－N－메틸－m－디티안－2－프로필아민－1, 1, 3, 3－테트라옥사이드 옥살레이트, 융점 : 128°내지 130℃(아세톤)N- (3,4-dimethoxyphenethyl) -2- (3-trifluoromethylphenyl) -N-methyl-m-dithiane-2-propylamine-1,1,3,3- tetraoxide oxalate , Melting Point: 128 ° to 130 ° C (acetone)

N－2－비스－(3,4－디메톡시페닐)－N－메틸－m－디티안－2－프로필아민－1, 1, 3, 3－테트라옥사이드N-2-bis- (3,4-dimethoxyphenyl) -N-methyl-m-dithiane-2-propylamine-1,1,3,3- tetraoxide

2－(3, 4－디메톡시페닐)－N－[4－(3, 4－디메톡시페닐)－부틸]－m－디티안－2－프로필아민－1, 1, 3, 3－테트라옥사이드2- (3,4-dimethoxyphenyl) -N- [4- (3,4-dimethoxyphenyl) -butyl] -m-dithiane-2-propylamine-1,1,3,3- tetraoxide

N－(3, 4－디메톡시펜에틸)－N－메틸－2－(3, 4－크실릴)－m－디티안－2－프로필아민－1, 1, 3, 3－테트라옥사이드 하이드로클로라이드 융점 : 176°내지 178℃(아세토니트릴)N- (3,4-dimethoxyphenethyl) -N-methyl-2- (3,4-xylyl) -m-dithiane-2-propylamine-1,1,3,3- tetraoxide hydrochloride Melting Point: 176 ° to 178 ° C (acetonitrile)

2－(3－부톡시－4－메톡시페닐)－N－(3, 4－디메톡시펜에틸)－N－메틸－m－디티안－2－프로필아민－1, 1, 3, 3－테트라옥사이드 융점 : 84°내지 85℃(메탄올 /이소프로필에테르)2- (3-butoxy-4-methoxyphenyl) -N- (3,4-dimethoxyphenethyl) -N-methyl-m-dithiane-2-propylamine-1, 1, 3, 3- Tetraoxide melting point: 84 ° to 85 ° C (methanol / isopropyl ether)

N－[3－2'－(3,4－디메톡시페닐)－m－디티안－2'－일－프로필]－N－메틸－1, 4－벤조디옥산－6－에틸아민－1', 1', 3', 3'－테트라옥사이드 하이드로클로라이드 융점 : 208 내지 210℃(아세토니트릴)N- [3-2 '-(3,4-dimethoxyphenyl) -m-dithiane-2'-yl-propyl] -N-methyl-1,4-benzodioxane 6-ethylamine-1' , 1 ', 3', 3'-tetraoxide hydrochloride Melting point: 208 to 210 ° C (acetonitrile)

N－4－(3, 4－디메톡시페닐)－부틸－2－(p－이소프로필페닐)－N－메틸－m－디티안－2－프로필아민－1, 1, 3, 3－테트라옥사이드 하이드로클로라이드, 융점 : 148 내지 150℃(에틸아세테이트/디옥산중의 염산)N-4- (3,4-dimethoxyphenyl) -butyl-2- (p-isopropylphenyl) -N-methyl-m-dithia- 2-propylamine-1, 1, 3, 3- tetraoxide Hydrochloride, melting point: 148-150 占 폚 (hydrochloric acid in ethyl acetate / dioxane)

rac－2－(3, 4－디메톡시페닐)－N－[3－(3, 4－디메톡시페닐)－1－메틸프로필]－N－메틸－m－디티안－2－프로필아민－1, 1, 3, 3－테트라옥사이드, 융점 : 115°내지 117℃rac-2- (3,4-dimethoxyphenyl) -N- [3- (3,4-dimethoxyphenyl) -1-methylpropyl] -N-methyl-m-dithiane-2-propylamine-1 , 1, 3, 3-tetraoxide, Melting point: 115 ° to 117 ° C

N－4－(3,4－디메톡시펜에틸)－2－(4－에톡시－3－메톡시페닐)－N－메틸－m－디티안－2－프로필아민－1, 1, 3, 3－테트라옥사이드 하이드로클로라이드, 융점 : 190°내지 192℃(아세토니트릴)N-4- (3,4-dimethoxyphenethyl) -2- (4-ethoxy-3-methoxyphenyl) -N-methyl-m-dithiane-2-propylamine-1, 1, 3, 3-tetraoxide hydrochloride, Melting point: 190 ° to 192 ° C. (acetonitrile)

m－{2'－[3－[(3,4－디메톡시펜에틸)－메틸아미노]－프로필]－m－디티안－2'－일}－벤조니트릴－1', 1', 3', 3'－테트라옥사이드 하이드로클로라이드, 융점 : 160℃(분해)m- {2 '-[3-[(3,4-dimethoxyphenethyl) -methylamino] -propyl] -m-dithiane-2'-yl} -benzonitrile-1', 1 ', 3' , 3'-tetraoxide hydrochloride, Melting point: 160 ° C (decomposition)

2－(1, 4－벤조디옥산－6－일)－N－(3, 4－디메톡시펜에틸)－N－메틸－m－디티안－2－프로클아민－1, 1, 3, 3－테트라옥사이드 하이드로클로라이드, 융점 : 201 내지 204℃2- (1,4-benzodioxane-6-yl) -N- (3,4-dimethoxyphenethyl) -N-methyl-m-dithiane-2-procleamine-1, 1, 3, 3-tetraoxide hydrochloride, Melting point: 201 to 204 캜

N－(3,4－디메톡시페닐)－2－(4－메톡시－m－톨릴)－N－메틸－m－디티안－2－프로필아민－1, 1, 3, 3－테트라옥사이드 하이드로클로라이드, 융점 : 146℃(분해)(아세톤)N- (3,4-dimethoxyphenyl) -2- (4-methoxy-m-tolyl) -N-methyl-m-dithiane-2-propylamine-1,1,3,3-tetraoxide hydro Chloride, Melting Point: 146 ° C (Decomposition) (Acetone)

m－{2'－[3－[4－(3, 4－디메톡시페닐)－부틸]－메틸아미노프로필]－m－디티안－2'－일}－벤조니트릴－1', 1', 3', 3'－테트라옥사이드 하이드로클로라이드, 융점 : 120°내지 122℃(물)m- {2 '-[3- [4- (3,4-dimethoxyphenyl) -butyl] -methylaminopropyl] -m-dithia-2'-yl}-benzonitrile-1', 1 ', 3 ', 3'-tetraoxide hydrochloride, Melting point: 120 ° to 122 ° C (water)

2－(3, 4－디메톡시페닐)－N－메틸－N－(p－메틸펜에틸)－m－디티안－2－프로필아민－1, 1, 3, 3－테트라옥사이드 하이드로클로라이드, 융점 : 169°내지 171℃(아세톤/에틸아세테이트).2- (3,4-dimethoxyphenyl) -N-methyl-N- (p-methylphenethyl) -m-dithiane-2-propylamine-1,1,3,3- tetraoxide hydrochloride, melting point : 169 ° to 171 ° C. (acetone / ethyl acetate).

[실시예 5]Example 5

2－(3, 4－메틸렌디옥시페닐)－m－디티안－1, 1, 3, 3－테트라옥사이드(실시예 2에서와 같은 방법으로 6.08g을 아르곤 가스하에서 디메틸포름아마이드 25ml와 교반하고 55% 나트륨 하이드라이드 현탁액 0.8g으로 처리한 후, 반응 혼합물을 실온에서 30분간, 40℃에서 1시간동안 방치한다. 실온으로 냉각후, N－(3－클로로프로필)－3,4－디메톡시－N－메틸－펜에틸아민(실시예 3에서와 같은 방법으로 제조) 4.8g을 가하고 100℃에서 16시간 동안 가열한다. 냉각시킨 후 얼음에 붓고 에틸아세테이트로 3회 추출한 다음 유기추출 혼합액을 물로 세척하고 황산마그네슘으로 탈수후 진공증발시킨다. 잔유오일을 아세톤에 용해하고 디옥산중의 6N－염산 5ml로 처리하여 얻어진 침전물을 진공여과하고 아세톤으로 재결정하면 융점 247 내지 248℃의 N－(3, 4－디메톡시－펜에틸)－N－메틸－2－(3, 4－메틸렌디옥시페닐)－m－디티안－2－프로필아민－1, 1, 3, 3－테트라옥사이드 하이드로 클로라이드 7.5g이 얻어진다.2- (3,4-methylenedioxyphenyl) -m-dithiane-1,1,3,3-tetraoxide (in the same manner as in Example 2, 6.08 g was stirred with 25 ml of dimethylformamide under argon gas, After treatment with 0.8 g of 55% sodium hydride suspension, the reaction mixture is left for 30 minutes at room temperature for 1 hour at 40 ° C. After cooling to room temperature, N- (3-chloropropyl) -3,4-dimethoxy 4.8 g of -N-methyl-phenethylamine (prepared in the same manner as in Example 3) were added and heated for 16 hours at 100 ° C. After cooling, poured into ice, extracted three times with ethyl acetate, and then the organic extract mixture was extracted with water. After washing, dehydration with magnesium sulfate and evaporation in vacuo The residue obtained by dissolving the residual oil in acetone and treating with 5 ml of 6N hydrochloric acid in dioxane is vacuum filtered and recrystallized with acetone to obtain N- (3, 4) -Dimethoxy-phenethyl)- 7.5 g of N-methyl-2- (3,4-methylenedioxyphenyl) -m-dithiane-2-propylamine-1,1,3,3- tetraoxide hydrochloride is obtained.

원소분석 :Elemental Analysis:

계 산 치 : C 52.12, H 5.95, N 2.43Calculated Value: C 52.12, H 5.95, N 2.43

실 측 치 : C 51.91, H 5.86, N 2.23Found: C 51.91, H 5.86, N 2.23

다음의 화합물들은 본 실시예에서 기술된 바와 유사한 방법으로 제조할 수 있다.The following compounds can be prepared by methods similar to those described in this example.

N－(3, 4－디메톡시에틸)－N－메틸－2－p－톨릴－m－디티안－2－프로필아민－1, 1, 3, 3－테트라옥사이드 하이드로클로라이드, 융점 : 203 내지 207℃(아세토니트릴/아세톤)N- (3,4-dimethoxyethyl) -N-methyl-2-p-tolyl-m-dithiane-2-propylamine-1,1,3,3- tetraoxide hydrochloride, melting | fusing point: 203-207 ℃ (acetonitrile / acetone)

2－(4－벤질옥시)－3－메톡시페닐－N－(3, 4－디메톡시펜에틸)－N－메틸－m－디티안－2－프로필아민－1, 1, 3, 3－테트라옥사이드 하이드로플로라이드, 융점 : 220°내지 221℃(에탄올)2- (4-benzyloxy) -3-methoxyphenyl-N- (3,4-dimethoxyphenethyl) -N-methyl-m-dithia- 2-propylamine-1, 1, 3, 3- Tetraoxide Hydrofluoride, Melting Point: 220 ° to 221 ° C (ethanol)

N－(3, 4－디메톡시펜에틸)－N－메틸－2－(2'－티에닐)－m－디티안－2－프로필아민－1, 1, 3, 3－테트라옥사이드 하이드로클로라이드, 융점 : 179°내지 182℃(아세톤)N- (3,4-dimethoxyphenethyl) -N-methyl-2- (2'-thienyl) -m-dithiane-2-propylamine-1,1,3,3- tetraoxide hydrochloride, Melting Point: 179 ° to 182 ° C (Acetone)

2－(3, 4－디클로로페닐)－N－(3, 4－디메톡시펜에틸)－N－메틸－m－디티안－2－프로필아민－1, 1, 3, 3－테트라옥사이드 하이드로클로라이드, 융점 : 175 내지 177℃(메탄올)2- (3,4-dichlorophenyl) -N- (3,4-dimethoxyphenethyl) -N-methyl-m-dithiane-2-propylamine-1,1,3,3- tetraoxide hydrochloride Melting point: 175 to 177 ° C (methanol)

N－(3,4－디메톡시펜에틸)－2－(3,4－디메톡시페닐)－N－메틸－m－디티안－2－에틸아민－1, 1, 3, 3－테트라옥사이드 옥살레이트(1 : 1), 융점 : 202°내지 204℃(아세톤)N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N-methyl-m-dithiane-2-ethylamine-1,1,3,3- tetraoxide oxal Rate (1: 1), melting point: 202 ° to 204 ° C. (acetone)

3', 4'－디메톡시－4－(메틸베라트릴아미노)부티로페논 하이드로 클로라이드를 클로로포름 50ml에 용해하고 1, 3－프로판디티올 3.25g으로 처리하고, 실온에서 염화수소 가스를 통해준다. 24시간후 혼합물을 물에 붓고 3N－수산화나트륨액으로 염기성으로 하고 에테르로 추출한다. 탈수하고 용매를 증발한후, 오일상의 잔유물을 아세톤에 용해시키고 동몰량의 무수 옥살산으로 처리하여 결정성 침전을 아세톤으로 재결정하면 융점 133 내지 136℃의 2－(3, 4－디메톡시페닐)－N－메틸－N－베르트릴－m－디티안－2－프로필아민 옥살레이트(1 : 1)가 얻어진다.Dissolve 3 ', 4'-dimethoxy-4- (methylveratrilamino) butyrophenone hydrochloride in 50 ml of chloroform, treat with 3.25 g of 1,3-propanedithiol and give through hydrogen chloride gas at room temperature. After 24 hours the mixture is poured into water, basified with 3N sodium hydroxide solution and extracted with ether. After dehydration and evaporation of the solvent, the oily residue is dissolved in acetone, treated with an equimolar amount of oxalic anhydride, and the crystalline precipitate is recrystallized from acetone to give 2- (3,4-dimethoxyphenyl)-at a melting point of 133-136 ° C. N-methyl-N-bertryl-m-dithiane-2-propylamine oxalate (1: 1) is obtained.

원소분석 :Elemental Analysis:

계 산 치 : C 57.12, H 6.57, N 2.47Calculated Value: C 57.12, H 6.57, N 2.47

실 측 치 : C 56.68, H 6.64, N 2.46Found: C 56.68, H 6.64, N 2.46

출발물질인 3', 4'－디메톡시－4－(메틸베라트릴아미노)부티로페논은 다음과 같이 제조한다.Starting materials 3 ', 4'-dimethoxy-4- (methylveratrilamino) butyrophenone are prepared as follows.

폴리인산 500g과 베라트롤 69g을 직접 1ℓ용 플라스크에 넣고, 여기에 4－클로로부티린산 61g을 한번에 가하고 온도를 서서히 올려 55℃로 한다. 1시간후에 전 혼합물을 얼음에 붓고 에테르/메틸렌클로라이드(3 : 1)로 추출하고 이 추출액을 물, 포화중탄산나트륨용액, 다시 물로 추출하여 황산마그네슘으로 탈수후 진공증류시킨다. 잔유의 결정성 덩어리를 에테르로 재결정하면 융점 91 내지 92℃의 3, 4－디메톡시－ℓ－클로로부티로페논 62.9g이 얻어진다.500 g of polyphosphoric acid and 69 g of veratrol are directly added to a 1 L flask, and 61 g of 4-chlorobutyric acid is added thereto at once, and the temperature is gradually raised to 55 ° C. After 1 hour, the whole mixture was poured into ice, extracted with ether / methylene chloride (3: 1), and the extract was extracted with water, saturated sodium bicarbonate solution and water again, dehydrated with magnesium sulfate, and then vacuum distilled. Recrystallization of the crystalline mass of the residual oil with ether yields 62.9 g of 3,4-dimethoxy-l-chlorobutyrophenone having a melting point of 91 to 92 占 폚.

3, 4－디메톡시－

Figure kpo00027
－클로로부티로페논 12g을 N－에틸－N, N－디이소프로필아민 40ml 및 N－메틸－호모베라트릴아민 9g과 12℃에서 6시간동안 교반하면서 처리한다음 진공에서 용매를 증발시키고 점조성 덩어리를 에테르와 수산화나트륨으로 처리한다. 유기추출물을 물로 세척후 1N－염산으로 추출하고 이를 알카리성으로 하여 에테르로 추출한다. 에테르추출물을 합하고 황산나트륨으로 탈수한 후 증발시키면 3', 4'－디메톡시－4－(메틸베라트릴아미노)－부티로페논이 얻어지며 박층 크로마토그라피로 정제하면 더 이상의 정제를 할 필요없이 사용될 수 있다.3, 4-dimethoxy-
Figure kpo00027
12 g of chlorobutyrophenone was treated with 9 g of N-ethyl-N, N-diisopropylamine and 9 g of N-methyl- homoveratrilamine for 6 hours at 12 DEG C, followed by evaporation of the solvent in vacuo and consistency. The mass is treated with ether and sodium hydroxide. The organic extract is washed with water and extracted with 1N hydrochloric acid, which is made alkaline and extracted with ether. The ether extracts are combined, dehydrated with sodium sulfate, and evaporated to give 3 ', 4'-dimethoxy-4- (methylveratrilamino) -butyrophenone, which can be used without further purification by thin layer chromatography. have.

다음의 화합물은 본 실시예와 동일한 방법으로 제조될 수 있다.The following compounds can be prepared in the same manner as in this example.

N－(3, 4－디메톡시펜에틸)－2－(3, 4－디메톡시페닐)－N－메틸－m－디티안－2－부틸아민 옥살레이트(1 : 1), 융점 : 134 내지 136℃(아세톤)N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N-methyl-m-dithiane-2-butylamine oxalate (1: 1), melting | fusing point: 134- 136 ° C (acetone)

1, 3－프로판디티올과 5－[(3, 4－디메톡시펜에틸)－메틸아미노]－3', 4'－디메톡시발레로페논(하이드로클로라이드의 융점 : 165 내지 166℃)을 출발물질로 하여 3, 4－디메톡시－δ－클로로발레로페논과 메틸호로－베라트릴아민으로부터 얻어진다.1,3-propanedithiol and 5-[(3,4-dimethoxyphenethyl) -methylamino] -3 ', 4'-dimethoxyvalerophenone (melting point of hydrochloride: 165 to 166 ° C) start As a substance, it is obtained from 3,4-dimethoxy-δ-chlorovalerophenone and methyl horo-veratrilamine.

N－(3, 4－디메톡시펜에틸)－2－(3, 4－디메톡시페닐)－N－메틸－m－디티안－2－펜틸아민 옥살레이트(1 : 1), 융점 : 109 내지 111℃(아세톤)N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N-methyl-m-dithiane-2-pentylamine oxalate (1: 1), melting | fusing point: 109- 111 ° C (acetone)

1, 3－프로판디티올과 6－[(3, 4－디메톡시펜에틸)－메틸아미노]－3', 4'－디메톡시헥사노페논(하이드로클로라이드의 융점 : 128 내지 129℃)을 출발물질로 하여 6－클로로－3', 4'－디메톡시헥사노페논과 메틸호로－베라트릴아민으로부터 얻어진다.Start with 1,3-propanedithiol and 6-[(3,4-dimethoxyphenethyl) -methylamino] -3 ', 4'-dimethoxyhexanophenone (melting point of hydrochloride: 128 to 129 ° C) As a substance, it is obtained from 6-chloro-3 ', 4'-dimethoxyhexanophenone and methyl horo-veratrilamine.

2－(3, 4－디메톡시페닐)－N－[3－(3, 4－디메톡시페닐)－프로필]－N－메틸－m－디티안－2－프로필아민 옥살레이트(1 : 1), 융점 : 116 내지 118℃(아세톤)2- (3,4-dimethoxyphenyl) -N- [3- (3,4-dimethoxyphenyl) -propyl] -N-methyl-m-dithia- 2-propylamine oxalate (1: 1) Melting point: 116 to 118 ° C (acetone)

1, 3－프로판디티올 및 3', 4'－디메톡시－4－[(3, 4－디메톡시페닐)－프로필－메틸아미노]－부티로페논을 출발물질로 하여 3, 4－디메톡시－

Figure kpo00028
－클로로부티로페닐과 3－(3, 4－디메톡시페닐)－N－메틸프로필아민으로부터 얻어진다.3,4-dimethoxy using 1,3-propanedithiol and 3 ', 4'-dimethoxy-4-[(3,4-dimethoxyphenyl) -propyl-methylamino] -butyrophenone as a starting material －
Figure kpo00028
It is obtained from -chlorobutyrophenyl and 3- (3,4-dimethoxyphenyl) -N-methylpropylamine.

2－(3, 4－ 디메톡시페닐)－N－메틸－N－메틸－N－(

Figure kpo00029
－메틸펜에틸)－m－디티안－2－프로필아민 옥살레이트(1 : 1), 융점 : 131 내지 132℃(아세톤/에틸아세테이트)2- (3,4-dimethoxyphenyl) -N-methyl-N-methyl-N- (
Figure kpo00029
-Methylphenethyl) -m-dithiane-2-propylamine oxalate (1: 1), melting | fusing point: 131-132 degreeC (acetone / ethyl acetate)

1, 3－프로판디티올 및 4－[(3, 4－디메톡시－

Figure kpo00030
－메틸펜에틸)－메틸아미 노]-3', 4'－디메톡시부티로페놀을 출발물질로 하여 3, 4－디메톡시－
Figure kpo00031
－클로로부티로페논 및 N, a－디메틸－β－페닐에틸아민(비점 : 130 내지 140℃/20mmHg)으로부터 얻어진다.1,3-propanedithiol and 4-[(3,4-dimethoxy-
Figure kpo00030
-Methylphenethyl) -methylamino] -3 ', 4'-dimethoxy-butyrophenol 3,4-dimethoxy-
Figure kpo00031
It is obtained from -chlorobutyrophenone and N, a-dimethyl- (beta) -phenylethylamine (boiling point: 130-140 degreeC / 20mmHg).

N－(3, 4－디메톡시펜에틸)－2－(3, 4－디메톡시페닐)－N－메틸－1, 3－디티올란－2－프로필아민 옥살레이트(1 : 1), 융점 : 150 내지 152℃(아세톤)N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N-methyl-1,3-dithiolane-2-propylamine oxalate (1: 1), melting | fusing point: 150 to 152 ° C (acetone)

4－[(3, 4｜디메톡시펜에틸)－메틸아미노]－3', 4'－디메톡시부티로페논 및 1, 2－에탄디티올을 출발물질로 한다.4-[(3,4- | dimethoxyphenethyl) -methylamino] -3 ', 4'- dimethoxybutyrophenone, and 1, 2- ethanedithiol are used as starting materials.

[실시예 7]Example 7

2－(3－클로로프로필)－2－(3, 4－디메톡시페닐)－m－디티안－1, 1, 3, 3－테트라옥사이드 10.4g을 N－메틸－호모베라트릴아민 5.11g과 N－에틸－N, N－디이소프로필아민 30ml, 디메틸포름 아마이드 70ml로 처리하고 120℃에서 6시간동안 가열한다. 증발시킨 후 잔유물을 실시예 5에서와 유사한 방법으로 조작하여 융점 : 167 내지 169℃의 N－(3, 4－디메톡시펜에틸)－2－(3, 4－디메톡시페닐)－N－메틸－m－디티안－2－프로필아민－1, 1, 3, 3－테트라옥사이드 하이드로클로라이드를 얻는다. 다음의 화합물은 본 실시예에서와 유사한 방법으로 제조될 수 있다.10.4 g of 2- (3-chloropropyl) -2- (3,4-dimethoxyphenyl) -m-dithiane-1,1,3,3-tetraoxide is mixed with 5.11 g of N-methyl-homobetrarylamine Treat with 30 ml of N-ethyl-N, N-diisopropylamine, 70 ml of dimethylformamide and heat at 120 ° C. for 6 hours. After evaporation, the residue was operated in a similar manner as in Example 5 to give N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N-methyl at a melting point of 167 to 169 ° C. -M-dithiane-2-propylamine-1, 1, 3, 3- tetraoxide hydrochloride is obtained. The following compounds can be prepared in a similar manner as in this example.

N－(3,4－디메톡시펜에틸)－N－메틸－2－페닐－m－디티안－2－프로필아민－1, 1, 3, 3－테트라옥사이드 하이드로클로라이드, 융점 : 149℃(분해)(메탄올)N- (3,4-dimethoxyphenethyl) -N-methyl-2-phenyl-m-dithiane-2-propylamine-1,1,3,3- tetraoxide hydrochloride, melting | fusing point: 149 degreeC (decomposition) ) (Methanol)

N－(p－클로로펜에틸)－N－메틸－2－페닐－m－디티안－2－프로필아민－1, 1, 3, 3－테트라옥사이드 하이드로클로라이드, 융점 : 246 내지 249℃(분해)(메탄올/메틸렌클로라이드)N- (p-chlorophenethyl) -N-methyl- 2-phenyl-m-dithia- 2-propylamine-1, 1, 3, 3- tetraoxide hydrochloride, melting | fusing point: 246-249 degreeC (decomposition) (Methanol / methylene chloride)

N－메틸－N－펜에틸－2－페닐－m－디티안－2－프로필아민－1, 1, 3, 3－테트라옥사이드 하이드로클로라이드, 융점 : 165 내지 167℃(아세톤)N-methyl-N-phenethyl-2-phenyl-m-dithiane-2-propylamine-1, 1, 3, 3- tetraoxide hydrochloride, melting | fusing point: 165-167 degreeC (acetone)

2－(3,4－디메톡시페닐)－N－메틸－N－베라트릴－m－디티안－2－프로필아민－1, 1, 3, 3－테트라옥사이드, 융점 : 137 내지 139℃(아세톤/에탄올)2- (3,4-dimethoxyphenyl) -N-methyl-N-veratril-m-dithiane-2-propylamine-1, 1, 3, 3- tetraoxide, melting | fusing point: 137-139 degreeC (acetone /ethanol)

N－(3, 4－디메톡시펜에틸)－2－(3, 4－디메톡시페닐)－N－디티안－2－프로필아민－1, 1, 3, 3－테트라옥사이드 하이드로클로라이드, 융점 : 130°내지 132℃(아세톤)N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N-dithiane-2-propylamine-1,1,3,3- tetraoxide hydrochloride, melting point: 130 ° to 132 ° C (acetone)

본 실시예에서 출발물질로 사용되는 2－(3－클로로프로필)－2－(3, 4－디메톡시페놀)－m－디티안－1, 1, 3, 3－테트라옥사이드는 다음과 같이 제조할 수 있다.2- (3-chloropropyl) -2- (3,4-dimethoxyphenol) -m-dithiane-1,1,3,3-tetraoxide used as starting materials in this Example was prepared as follows. can do.

3, 4－디메톡시－

Figure kpo00032
－클로로부티로페논(실시예 6에서와 같은 방법으로 제조) 10.9g을 클로로포름 120ml에 용해하고 1, 3－프로판디티올 5ml와 삼불화붕소 에테레이트 1ml로 실온에서 처리한다. 실온에서 1시간 방치후, 클로로포름 용액을 물로 3회, 1N 수산화나트륨으로 3회, 다시 물로 3회 세척하고 유기층을 황산마그네슘으로 탈수후 진공증발시킨다. 오일상의 잔유물을 0 내지 5°에서 즉시 클로로포름에 용해하고 고체 m-염화과벤조산 45.7g으로 5℃가 넘지 않는 온도에서 처리한다음 그 혼합물을 즉시 냉장고 속에서 64시간동안 방치하고 유기층을 1N－수산화나트륨으로 3회, 물로 3회 세척하여 황산마그네슘으로 탈수시키고 진공증발시킨다. 그 잔유물을 염화메틸렌/이소프로필에테르로 재결정하면, 융점 : 183 내지 184℃의 2－(3－클로로프로필)－2－(3, 4－디메톡시페닐)－m－디티안－1, 1, 3, 3－테트라옥사이드가 얻어진다.3, 4-dimethoxy-
Figure kpo00032
10.9 g of chlorobutyrophenone (prepared in the same manner as in Example 6) is dissolved in 120 ml of chloroform and treated with 5 ml of 1,3-propanedithiol and 1 ml of boron trifluoride etherate at room temperature. After standing at room temperature for 1 hour, the chloroform solution was washed three times with water, three times with 1N sodium hydroxide and three times with water again, and the organic layer was dehydrated with magnesium sulfate and then evaporated in vacuo. The oily residue is immediately dissolved in chloroform at 0 to 5 °, treated with 45.7 g of solid m-perchloric acid at a temperature not exceeding 5 ° C, and the mixture is immediately left in a refrigerator for 64 hours and the organic layer is dissolved in 1N sodium hydroxide. 3 times with water, 3 times with water, dehydrated with magnesium sulfate and evaporated in vacuo. When the residue was recrystallized from methylene chloride / isopropyl ether, melting point: 2-83- (3-chloropropyl) -2- (3,4-dimethoxyphenyl) -m-dithiane-1, 1, of 183 to 184 占 폚. 3, 3-tetraoxide is obtained.

또한 본 실시예에서 출발물질로 사용되는 2－(3－클로로프로필)－2－페닐－m－디티안－1, 1, 3, 3－테트라옥사이드는 다음과 같이 제조할 수 있다.In addition, 2- (3-chloropropyl) -2-phenyl-m-dithiane-1, 1, 3, 3-tetraoxide used as starting materials in this embodiment can be prepared as follows.

2－페닐－m－디티안 19.63g을 테트라하이드로푸란 300ml에 용해하고 헥산중의 부틸리튬용액 43.5ml를 아르곤가스를 통해주면서 －70℃에서 적가시키고, 그 혼합물을 －20℃에서 총 1.5시간동안 교반시킨다. 얻어진 붉은 용액을 －70℃에서 무수 테트라하이드로푸란 250ml중에 1, 3－브로모클로로프로판 15.74g을 녹인 용액에 가하고 -20℃에서 1시간 방치후 실온에서 1시간 방치한다. 진공에서 용매를 증발시키고 오일상의 잔유물을 에테르에 용해한 후 1N－수산화나트륨 및 물로 세척하고 황산마그네슘으로 탈수한 후 진공증발시킨다. 얻어진 2－(3－클로로프로필)－2－페닐－m－디티안을 0 내지 5℃에서 클로로포름중의 m－염화과벤조산으로 과산화하고 에틸아세테이트로 재결정화하면 융점 182℃의 2－(3－클로로프로필)－2－페닐－m－디티안－1, 1, 3, 3－테트라옥사이드가 얻어진다.19.63 g of 2-phenyl-m-dithiane was dissolved in 300 ml of tetrahydrofuran, 43.5 ml of butyllithium solution in hexane was added dropwise at -70 DEG C while argon gas was added, and the mixture was added at -20 DEG C for 1.5 hours. Stir. The obtained red solution was added to a solution obtained by dissolving 15.74 g of 1,3-bromochloropropane in 250 ml of anhydrous tetrahydrofuran at −70 ° C., and left at −20 ° C. for 1 hour, followed by 1 hour at room temperature. The solvent is evaporated in vacuo, the oily residue is dissolved in ether, washed with 1N-sodium hydroxide and water, dehydrated with magnesium sulfate and then evaporated in vacuo. When the obtained 2- (3-chloropropyl) -2-phenyl-dithiane is peroxidized with m-chloride perbenzoic acid in chloroform at 0-5 degreeC and recrystallized by ethyl acetate, 2- (3-chloropropyl) of melting | fusing point 182 degreeC ) -2-phenyl-m-dithiane-1,1,3,3- tetraoxide is obtained.

[실시예 8]Example 8

2－(3,4－디메톡시페닐)－2－(2, 3－에톡시프로필)－m－디티안－1, 1, 3, 3－테트라옥사이드 3.76g을 아르곤 가스하에서 에탄올 50ml, 클로로포름 30ml, N－메틸－호모베라트릴아민 1.95g과 18시간동안 환류시키고, 용매를 증발시킨 후 잔유물을 실리카겔상에서 클로로푸름 에탄올(98 : 2)로 크로마토그라피하여 얻어진 오일상의 물질을 아세톤에 용해하고, 동몰량의 무수 옥살산으로 처리한다. 침전물을 여과하여 메탄올/아세톤으로 재결정하면 융점 162 내지 164℃의 라세믹

Figure kpo00033
－[(3, 4－디메톡시펜에틸)－메틸아미노]－메틸－2－(3, 4－디메톡시페닐)－m－디티안－2－에탄올－1, 1, 3, 3－테트라옥사이드 옥살레이트(1 : 1)(아세톤 1몰로 결정화)가 얻어진다.3.76 g of 2- (3,4-dimethoxyphenyl) -2- (2,3-ethoxypropyl) -m-dithiane-1,1,3,3-tetraoxide was dissolved in argon gas with 50 ml of ethanol and 30 ml of chloroform. The mixture was refluxed with 1.95 g of N-methyl-homoberatrylamine for 18 hours, the solvent was evaporated, and the residue was chromatographed with chloro blue ethanol (98: 2) on silica gel to dissolve the oily substance in acetone. Treat with molar amount of oxalic anhydride. The precipitate was filtered off and recrystallized from methanol / acetone to give a racemic temperature of 162 to 164 ° C.
Figure kpo00033
-[(3,4-dimethoxyphenethyl) -methylamino] -methyl-2- (3,4-dimethoxyphenyl) -m-dithiane-2-ethanol-1,1,3,3- tetraoxide Oxalate (1: 1) (crystallized with 1 mole of acetone) is obtained.

원소분석 :Elemental Analysis:

계 산 치 : C 51.73, H 6.30, N 1.95Calculated Value: C 51.73, H 6.30, N 1.95

실 측 치 : C 51.68, H 6.53, N 2.00Found: C 51.68, H 6.53, N 2.00

출발물질로서 사용되는 2－(3, 4－디메톡시페닐)－2－(2, 3－에톡시프로필)－m－디티안－1, 1, 3, 3－테트라옥사이드는 다음과 같이 제조한다.2- (3,4-dimethoxyphenyl) -2- (2,3-ethoxypropyl) -m-dithiane-1,1,3,3-tetraoxide used as starting material is prepared as follows. .

2－(3, 4－디메톡시페닐)－m－디티안－1, 1, 3, 3－테트라옥사이드(실시예 2에서와 같은 방법으로 제조)9.6g을 디메틸포름 아마이드 35ml에 용해하고 아르곤 가스하에서 교반하면서 실온에서 나트륨 하이드라이드 1.2g으로 처리하고, 그 현탁액을 40℃로 30분간 교반후 냉각하여 에피클로로히드린 2.8g으로 처리한 다음 이 혼합물을 16시간동안 100℃로 가열한 후 실온으로 냉각하고 그 현탁액을 물에 붓고 오일상의 물질을 클로로포름으로 추출한다. 용매를 증발시킨 후 잔유물을 실리카겔상에서 클로로포름/에탄올(98 : 2)로 크로마토그라피하여 염화메틸렌/에탄올로 재결정하면 융점 175 내지 176℃의 2－(3, 4－디메톡시페닐)－2－(2, 3－에톡시프로필)－m－디티안－1, 1, 3, 3－테트라옥사이드가 얻어진다.Dissolve 9.6 g of 2- (3,4-dimethoxyphenyl) -m-dithiane-1, 1, 3, 3-tetraoxide (produced in the same manner as in Example 2) in 35 ml of dimethylformamide and argon gas. Treated with 1.2 g of sodium hydride at room temperature with stirring under stirring, the suspension was stirred at 40 ° C. for 30 minutes, cooled, treated with 2.8 g of epichlorohydrin, and the mixture was heated to 100 ° C. for 16 hours and then returned to room temperature. After cooling, the suspension is poured into water and the oily material is extracted with chloroform. After evaporating the solvent, the residue was chromatographed on silica gel with chloroform / ethanol (98: 2) and recrystallized from methylene chloride / ethanol to give 2- (3,4-dimethoxyphenyl) -2- (2) having a melting point of 175 to 176 ° C. , 3-ethoxypropyl) -m-dithiane-1, 1, 3, 3- tetraoxide is obtained.

[실시예 9]Example 9

2－(3－클로로프로필)－2－(3, 4－디메톡시페닐)－m－디티안－1, 3－디옥사이드 3.65g 및 N－메틸－호모베라트릴아민 7.8g 디메틸설폭사이드 20ml를 아르곤 가스하에서 16시간동안 50℃로 가열한다음 용액을 물 200ml에 붓고 강알카리성으로 한다. 고량의 N－메틸－호모베라트릴아민을 에테르로 추출한다. 이 알카리성 용액을 염화메틸렌으로 추출하고 이 추출액을 황산마그네슘으로 탈수시킨다. 용매를 증발시킨 후 잔유물을 아세톤으로 취하여 디옥산중의 염산(＞pH2)으로 처리한다.2.65 g of 2- (3-chloropropyl) -2- (3,4-dimethoxyphenyl) -m-dithiane-1,3-dioxide and 7.8 g of N-methyl- homoveratrilamine 7.8 g dimethyl sulfoxide 20 ml Heat to 50 ° C. under gas for 16 hours, then pour the solution into 200 ml of water and make it strongly alkaline. A large amount of N-methyl- homoveratrilamine is extracted with ether. The alkaline solution is extracted with methylene chloride and the extract is dehydrated with magnesium sulfate. After evaporation of the solvent, the residue is taken up with acetone and treated with hydrochloric acid (> pH 2) in dioxane.

아세톤/아세토니트릴로 재결정하면 융점 148 내지 149℃의 N－(3, 4－디메톡시펜에틸)－2－(3, 4－디메톡시페닐)－N－메틸－m－디티안－2－프로필아민－1, 3－디옥사이드 하이드로클로라이드(부분입체성 혼합물)를 얻는다.Recrystallization with acetone / acetonitrile N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N-methyl-m-dithiane-2-propyl at a melting point of 148 to 149 ° C Amine-1, 3-dioxide hydrochloride (diastereomeric mixture) is obtained.

출발물질로 사용되는 2－(3－클로로프로필)－2－(3, 4－디메톡시페닐)－m－디티안－1, 3－디옥사이드는 다음과 같이 제조할 수 있다 :2- (3-chloropropyl) -2- (3,4-dimethoxyphenyl) -m-dithiane-1,3-dioxide used as starting material can be prepared as follows:

2－(3, 4－디메톡시페닐)－m－디티안(실시예 1에서와 같은 방법으로 제조)76.9g을 무수테트란라하이드로푸란 900ml에 용해하고 －70℃로 냉각하여 －60℃가 넘지 않는 온도에서 부틸리튬액 128ml로 처리한 후 이 혼합물을 －20℃로 2시간 방치하여 침전을 형성시킨다. 혼합물을 다시 －70℃로 냉각하여 무수 테트라하으드로푸란 750ml중의 1, 3－브로모 클로로프로판 47.3g을 가하고 －20℃에서 1시간, 실온에서 1시간 방치한다, 그후 테트라하이드로푸란을 증발시키고 잔유물을 에테르로 추출한다. 용매를 증발시키면 2－(3－클로로프로필)－2－(3, 4－디메톡시페닐)－m－디티안이 얻어진다.76.9 g of 2- (3,4-dimethoxyphenyl) -m-dithiane (manufactured in the same manner as in Example 1) was dissolved in 900 ml of anhydrous tetratranslahydrofuran, cooled to -70 deg. After treatment with 128 ml of butyllithium liquid at a temperature not exceeding, the mixture was left at -20 DEG C for 2 hours to form a precipitate. The mixture is again cooled to -70 DEG C, 47.3 g of 1,3-bromo chloropropane in 750 ml of anhydrous tetrahydrofuran is added, and is left at -20 DEG C for 1 hour at room temperature for 1 hour, after which the tetrahydrofuran is evaporated and the residue is left over. Is extracted with ether. When the solvent is evaporated, 2- (3-chloropropyl) -2- (3,4-dimethoxyphenyl) -m-dithiane is obtained.

2－(3－클로로프로필)－2－(3, 4－디메톡시페닐)－m－디티안 55.25g을 빙초산 500ml에 용해하고 5℃에서 교반하면서 빙초산 300ml중의 30% 과산화수소 34g 용액을 2시간내에 가하고, 실온에서 60시간동안 방치후 40℃에서 진공하에 농축한다. 얻어진 오일을 실리카겔 1.51kg상에서 클로로포름/에탄올로 처음에는 98 : 2, 나중에는 95 : 5로 크로마토 그라피하여 아세토니트릴로 재결정하면 융점 163 내지 164℃의 2－(3－클로로프로필)－2－(3, 4－디메톡시페닐)－m－디티안－1, 3－디옥사이드(부분입체성 혼합물)가 얻어진다.55.25 g of 2- (3-chloropropyl) -2- (3,4-dimethoxyphenyl) -m-dithiane are dissolved in 500 ml of glacial acetic acid and stirred at 5 ° C. with a solution of 34 g of 30% hydrogen peroxide in 300 ml of glacial acetic acid within 2 hours. It is added, left at room temperature for 60 hours, and then concentrated in vacuo at 40 ° C. The resulting oil was chromatographed first with 98: 2 and later with 95: 5 on chloroform / ethanol over 1.51 kg of silica gel and recrystallized with acetonitrile to give 2- (3-chloropropyl) -2- (3) having a melting point of 163 to 164 ° C. , 4-dimethoxyphenyl) -m-dithiane-1 and 3-dioxide (diasteremic mixture) are obtained.

[실시예 10]Example 10

실시예 8과 유사한 방법으로, 2－(3, 4－디메톡시페닐)－2－(2, 3－에톡시프로필)－m－디티안 및 N－메틸－호모베라트릴아민을 출발물질로 하여 라세믹

Figure kpo00034
－[(3, 4－디메톡시펜에틸)－메틸아미노]－메틸－2－(3, 4－디메톡시페닐)－m－디티안－2－에탄올을 제조할 수 있다.In a similar manner as in Example 8, starting with 2- (3,4-dimethoxyphenyl) -2- (2,3-ethoxypropyl) -m-dithiane and N-methyl-homoveratrirylamine as starting materials Racemic
Figure kpo00034
-[(3,4-dimethoxyphenethyl) -methylamino] -methyl-2- (3,4-dimethoxyphenyl) -m-dithiane-2-ethanol can be manufactured.

본 화합물의 하이드로브로마이드의 융점은 97 내지 99℃이고 아세토니트릴/에틸아세테이트로 결정화한다.The hydrobromide of this compound has a melting point of 97-99 ° C. and crystallizes with acetonitrile / ethylacetate.

출발물질로 사용되는 2－(3, 4－디메톡시페닐)－2－(2, 3－에톡시프로필)－m－디티안은 2-(3, 4-디메톡시페닐)-m-디티안(실시예 1에서와 같은 방법으로 제조)을 출발물질로 하여 1, 3－브로모클로로프로판 대신 에피클로로히드린을 사용하여 실시예 9와 유사한 방법으로 제조할 수 있다.2- (3,4-dimethoxyphenyl) -2- (2,3-ethoxypropyl) -m-dithiane used as starting material is 2- (3,4-dimethoxyphenyl) -m-dithiane ( It can be prepared in a similar manner to Example 9 using epichlorohydrin instead of 1,3-bromochloropropane as a starting material).

[실시예 11]Example 11

테트라하이드로푸란 60ml중의 리튬알미늄 하이드라이드 3.4g을 환류 가열하고 테트라하이드로푸란 80ml중의 N－(3, 4－디메틸펜에틸)－2－(3, 4－디메톡시페닐)－m－디티안－2－프로피온 아마이드 14.7g을 적가시킨다. 얻어진 현탁액을 3시간 더 환류 가열하고 0℃로 냉각시켜 포화 황산나트륨 50ml로 주의하여 처리하고 진공여과하여 물로 희석하고 에테르로 희석한다. 에테르추출액을 1N 수산화나트륨, 물로 세척하고 황산마그네슘으로 탈수후 증발시킨다. 오일상의 잔유물을 실리카겔상에 클로로포름/에탄올(95 : 5)로 크로마토그라피하고, 얻어진 염기를 아세톤에 용해시킨 후 동몰량의 무수 옥살산으로 처리한다. 형성된 침전물을 메탄올/아세톤으로 재결정하면 융점 : 186 내지 188℃의 N－(3, 4－디메톡시펜에틸)－2－(3, 4－디메톡시페닐)－m－디티안－2－프로필아민 옥살레이트(1 : 1)가 얻어진다.3.4 g of lithium aluminum hydride in 60 ml of tetrahydrofuran was heated to reflux, and N- (3,4-dimethylphenethyl) -2- (3,4-dimethoxyphenyl) -m-dithiane-2 in 80 ml of tetrahydrofuran. -14.7 g of propionamide is added dropwise. The resulting suspension is further heated to reflux for 3 hours, cooled to 0 ° C., carefully treated with 50 ml of saturated sodium sulfate, vacuum filtered, diluted with water and diluted with ether. The ether extract is washed with 1N sodium hydroxide and water, dehydrated with magnesium sulfate and evaporated. The oily residue is chromatographed on silica gel with chloroform / ethanol (95: 5), and the resulting base is dissolved in acetone and treated with an equimolar amount of anhydrous oxalic acid. When the precipitate formed was recrystallized from methanol / acetone, the melting point was N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -m-dithiane-2-propylamine at 186 to 188 ° C. Oxalate (1: 1) is obtained.

원소분석 :Elemental Analysis:

계 산 치 : C 57.12, H 6.57, N 2.67Calculated Value: C 57.12, H 6.57, N 2.67

실 측 치 : C 56.97, H 6.73, N 2.39Found: C 56.97, H 6.73, N 2.39

출발물질로 사용되는 N－(3, 4－디메톡시펜에틸)－2－(3, 4－디메톡시페닐)－m－디티안－2－프로피온아마이드는 다음과 같이 제조한다.N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -m-dithiane-2-propionamide used as a starting material is prepared as follows.

3－베라트로일프로피온산 50g을 클로로포름 400ml중에 녹인 용액 및 1, 3－프로판디티올 22.7g을 교반하면서 염화수소가스를 통해 포화시킨다. 실온에서 3시간후 용액이 50ml가 될 때까지 증발시키고 에테르로 희석한다. 이 용액을 5% 중탄산나트륨으로 3회 추출하고, 이 추출합액을 진한 염산으로 산성으로 하여 에테르/메틸렌클로라이드(1 : 3)로 추출하여 건조 증발시키고 잔유물을 에탄올로 재결정하면 융점 134 내지 135℃의 2－(3, 4－디메톡시페닐)－m－디티안－2－프로피온산이 얻어진다.A solution of 50 g of 3-veratroylpropionic acid dissolved in 400 ml of chloroform and 22.7 g of 1,3-propanedithiol are saturated with hydrogen chloride gas with stirring. After 3 hours at room temperature the solution is evaporated to 50 ml and diluted with ether. The solution was extracted three times with 5% sodium bicarbonate, the extract was acidified with concentrated hydrochloric acid, extracted with ether / methylene chloride (1: 3), evaporated to dryness, and the residue was recrystallized from ethanol to have a melting point of 134 to 135 ° C. 2- (3,4-dimethoxyphenyl) -m-dithiane-2-propionic acid is obtained.

2－(3, 4－디메톡시페닐)－m－디티안－2－프로피온산 13.2g 및 트리에틸아민 4g, 테트라하이드로푸란 180ml를 0℃로 냉각하고, 테트라하이드로푸란 80ml중의 클로로포름산 이소부틸 에스테르 5.44g을 10분 이내에 적가시킨다. 이 혼합물을 실온으로 올려 3시간동안 방치하고 테트라하이드로 푸란 40ml중의 호모베라트릴아민 7.25g으로 처리하여 생긴 현탁액을 3℃에서 48시간동안 방치후 증발시키고, 물로 처리후 에테르/메틸렌클로라이드(3 : 1)로 추출한다. 이 에테르추출액을 물로 세척하고 중탄산나트륨용액 1N 타타르산, 다시 물로 세척한다. 유기용매층을 황산마그네슘으로 탈수후 증발시키고 메틸렌클로라이드/에테르로 0℃에서 재결정하면 융점 135 내지 136℃ N－(3, 4－디메톡시펜에틸)－2－(3, 4－디메톡시페닐)－m－디티안－2－프로피온아마이드가 얻어진다.13.2 g of 2- (3,4-dimethoxyphenyl) -m-dithiane-2-propionic acid, 4 g of triethylamine, and 180 ml of tetrahydrofuran are cooled to 0 ° C., and 5.44 chloroformic isobutyl ester in 80 ml of tetrahydrofuran. g is added dropwise within 10 minutes. The mixture was allowed to stand at room temperature for 3 hours and treated with 7.25 g of homoveratrilamine in 40 ml of tetrahydrofuran. The resulting suspension was left at 3 ° C. for 48 hours, then evaporated, treated with water, and then ether / methylene chloride (3: 1). Extract with). This ether extract is washed with water, sodium bicarbonate solution 1N tartaric acid, and then washed with water. The organic solvent layer was dehydrated with magnesium sulfate, evaporated, and recrystallized with methylene chloride / ether at 0 ° C. to a melting point of 135 to 136 ° C. N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -M-dithiane-2-propionamide is obtained.

N－(3, 4－디메톡시펜에틸)－2－(3, 4－디메톡시페닐)－N－메틸－m－디티안－2－프로필아민 브롬화수소산염을 전술한 방법과 동일하게 제조할 수 있으며 융점은 170 내지 172℃(에탄올)이다.N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N-methyl-m-dithiane-2-propylamine hydrobromide can be produced in the same manner as described above. Melting point is 170-172 ° C. (ethanol).

[실시예 12]Example 12

2－{[3－[2"－(3, 4－디메톡시페닐)－m－디티안－2"－일－프로피]－메틸아미노}－3', 4'－디메톡시아세톡시페논－1", 1", 3", 3"－테트라옥사이드 0.5g을 에탄올 15ml와 테트라하이드로푸란 30ml에 용해하고 나트륨 보로하이드라이드 50mg으로 처리한다. 16시간동안 교반후 1N 염산 15ml 및 1N－수산화나트륨 12ml로 처리하고 테트라하이드로푸란을 증발시킨 후 그 잔유물을 메틸렌클로라이드로 추출한다. 이 유기추출액을 수세하고 황산마그네슘으로 탈수후 메탄올로 재결정하면 융점 : 132 내지 133℃의

Figure kpo00035
－1－{[3－[2'－(3, 4－디메톡시페닐)－m－디티안－2'－일]－프로필－메틸아미노}－메틸－베라트릴알콜－1', 1', 3', 3'－테트라옥사이드 0.3g이 얻어진다.2-{[3- [2 "-(3,4-dimethoxyphenyl) -m-dithiane-2" -yl-propy-methylamino} -3 ', 4'-dimethoxyacetoxyphenone-1 0.5 g of ", 1", 3 ", 3" -tetraoxide is dissolved in 15 ml of ethanol and 30 ml of tetrahydrofuran and treated with 50 mg of sodium borohydride. After stirring for 16 hours, the mixture was treated with 15 ml of 1N hydrochloric acid and 12 ml of 1N-sodium hydroxide, the tetrahydrofuran was evaporated, and the residue was extracted with methylene chloride. The organic extract was washed with water, dehydrated with magnesium sulfate and recrystallized with methanol, and the melting point was 132 to 133 ° C.
Figure kpo00035
-1-{[3- [2 '-(3,4-dimethoxyphenyl) -m-dithia-2'-yl] -propyl-methylamino} -methyl- veratril alcohol-1', 1 ', 0.3 g of 3 'and 3'- tetraoxides are obtained.

출발물질인 2－{[3－[2"－(3, 4－디메톡시페닐)－m－디티안－2"－일]－프로필]－메틸아미노}－3', 4'－디메톡시아세토페논－1", 1", 3", 3"－테트라옥사이드는 2－(3－클로로프로필)－2－(3, 4－디메톡시페닐)－m－디티안－1, 1, 3, 3－테트라옥사이드를 ω－메틸아미노－3, 4－디메톡시아세토페논과 반응시켜 제조하여, 융점은 140℃(분해)(아세톤)이다.Starting material 2-{[3- [2 "-(3,4-dimethoxyphenyl) -m-dithiane-2" -yl] -propyl] -methylamino} -3 ', 4'-dimethoxyaceto Phenone-1 ", 1", 3 ", 3"-tetraoxide is 2- (3-chloropropyl) -2- (3, 4- dimethoxyphenyl) -m-dithiane-1, 1, 3, 3 It is produced by reacting —tetraoxide with ω-methylamino-3 and 4-dimethoxyacetophenone, and the melting point is 140 ° C. (decomposition) (acetone).

[실시예 13]Example 13

ω－(3, 4－디메톡시펜에틸)－2－(3, 4－디메톡시페닐)－N－메틸－m－디티안－2－펜틸아민(실시예 6에서와 같은 방법으로 제조) 10g을 빙초산 50ml에 용해하고 실온에서 30%과산화수소 20ml로 처리한다음 3시간후 35℃로 3시간동안 가열하고 다시 40℃로 18시간동안 가열한다. 용액을 물에 붓고 수산화나트륨으로 알카리성으로 하여 메틸렌클로라이드로 추출한다. 용매를 제거한 후 잔유물을 실리카겔상에서 클로로포름과 암모니아로 포화시킨 메탄올(97 : 3)로 크로마토그라피하여 얻은 생성물을 아세톤에 용해하고 동몰량의 옥실산으로 처리하여 생기는 침전을 아세톤/메탄올로 재결정하면 융점 189 내지 191℃의 N－(3, 4－디메톡시펜에틸)－2－(3, 4－디메톡시페닐)－N－메틸－m－디티안－2－펜틸아민－1, 1, 3, 3－테트라옥사이드 옥살레이트(1 : 1)가 얻어진다.10 g of ω- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N-methyl-m-dithiane-2-pentylamine (prepared in the same manner as in Example 6) Is dissolved in 50 ml of glacial acetic acid, treated with 20 ml of 30% hydrogen peroxide at room temperature, then heated to 35 ° C. for 3 hours after 3 hours, and then to 40 ° C. for 18 hours. The solution is poured into water, made alkaline with sodium hydroxide and extracted with methylene chloride. After removing the solvent, the residue was chromatographed on silica gel with methanol (97: 3) saturated with chloroform and ammonia. The product obtained was dissolved in acetone and treated with an equimolar amount of oxylic acid to recrystallize acetone / methanol. To 191 ° C N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N-methyl-m-dithiane-2-pentylamine-1, 1, 3, 3 -Tetraoxide oxalate (1: 1) is obtained.

원소분석 :Elemental Analysis:

계 산 치 : C 53.48, H 6.43, N 2.08Calculated Value: C 53.48, H 6.43, N 2.08

실 측 치 : C 53.37, H 6.50, N 1.87Found: C 53.37, H 6.50, N 1.87

다음의 화합물은 전술한 바와 동일한 방법으로 제조될 수 있다.The following compounds can be prepared in the same manner as described above.

N－(3, 4－디메톡시펜에틸)－2－(3, 4－디메톡시페닐)－N－메틸－m－디티안－2－부틸아민－1, 1, 3, 3－테트라옥사이드 옥살레이트, 융점 161 내지 163℃(아세톤/메탄올), (염기 : 123 내지 126℃, 에탄올)N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N-methyl-m-dithiane-2-butylamine-1,1,3,3- tetraoxide oxal Rate, melting point 161 to 163 ° C (acetone / methanol), (base: 123 to 126 ° C, ethanol)

N－(3, 4－디메톡시펜에틸)－2－(3, 4－디메톡시페닐)－N－메틸－m－디티안－2－부틸아민(실시예 6과 같은 방법으로 제조)을 출발물질로 사용.N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N-methyl-m-dithiane-2-butylamine (produced in the same manner as in Example 6) starts Used as a substance.

2－(3,4－디메톡시페닐)－N－3－(3, 4－디메톡시페닐)－프로필－N－메틸－m－디티안－2－프로필아민－1, 1, 3, 3－테트라옥사이드 하이드로브마이드, 융점 : 138 내지 140℃(아세토니트릴/에틸아세테이트)2- (3,4-dimethoxyphenyl) -N-3- (3,4-dimethoxyphenyl) -propyl-N-methyl-m-dithiane-2-propylamine-1, 1, 3, 3- Tetraoxide hydrobromide, Melting point: 138-140 ° C. (acetonitrile / ethyl acetate)

2－(3,4－디메톡시페닐)－N－3－(3, 4－디메톡시페닐)－프로필－N－메틸－m－디티안－2－프로필아민(실시예 6과 같은 방법으로 제조)을 출발물질로 사용.2- (3,4-dimethoxyphenyl) -N-3- (3,4-dimethoxyphenyl) -propyl-N-methyl-m-dithia-2-propylamine (produced in the same manner as in Example 6 ) As starting material.

라세믹 N－(3, 4－디메톡시펜에틸)－2－(3, 4－디메톡시페닐)－N, β－디메틸－m－디티안－2－프로필아민-1, 1, 3, 3-테트라옥사이드 하이드로클로라이드, 융점 : 183 내지 185℃(아세톤/에틸아세테이트)Racemic N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N, β-dimethyl-m-dithiane-2-propylamine-1, 1, 3, 3 Tetraoxide hydrochloride, Melting point: 183 to 185 ° C (acetone / ethyl acetate)

라세믹 N－(3, 4－디메톡시펜에틸)－2－(3, 4－디메톡시페닐)－N, β－디메틸(실시예 3과 같은 방법으로 제조)을 출발물질로 사용.Racemic N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N and β-dimethyl (prepared in the same manner as in Example 3) were used as starting materials.

2－(3, 4－디메톡시페닐)－N－메틸－N－(

Figure kpo00036
－메틸펜에틸)－m－디티안－2－프로필아민－1, 1, 3, 3－테트라옥사이드 하이드로클로라이드, 융점 : 185 내지 187℃(아세톤/에틸아세테이트)2- (3,4-dimethoxyphenyl) -N-methyl-N- (
Figure kpo00036
-Methylphenethyl) -m-dithiane-2-propylamine-1,1,3,3-tetraoxide hydrochloride, melting | fusing point: 185-187 degreeC (acetone / ethyl acetate)

2－(3, 4－디메톡시페닐)－N－메틸－N－(

Figure kpo00037
－메틸펜에틸)－m－디티안－2－프로필아민(실시예 6과 같은 방법으로 제조)을 출발물질로 사용.2- (3,4-dimethoxyphenyl) -N-methyl-N- (
Figure kpo00037
-Methylphenethyl) -m-dithia- 2-propylamine (made by the same method as Example 6) was used as a starting material.

[실시예 14]Example 14

2－(4－벤질옥시－3－메톡시페닐)－N－(3,4－디메톡시페닐에틸)－N－메틸－m－디티안－2－프로필아민－1, 1, 3, 3－테트라옥사이드(실시예 5와 같은 방법으로 제조)11.2g을 48% 브롬화수소산 100ml와 증기욕상에서 2분간 가열후 에테르로 추출한 후 진공증발하고 공비증류를 에탄올/벤젠으로 3회한다. 잔유물을 아세톤으로 결정화하고 이 결정성 덩어리를 메탄올/아세토니트릴로 3회 재결정하면 융점 192℃(분해)의 4－{2'－[3－[3,4－디메톡시펜에틸)－메틸아미노]－프로필]－m－디티안－2'－일}－2－메톡시페놀－1', 1', 3', 3'－테트라옥사이드 하이드로브로마이드가 얻어진다.2- (4-benzyloxy-3-methoxyphenyl) -N- (3,4-dimethoxyphenylethyl) -N-methyl-m-dithia- 2-propylamine-1, 1, 3, 3- 11.2 g of tetraoxide (prepared in the same manner as in Example 5) was heated with 100 ml of 48% hydrobromic acid in a steam bath for 2 minutes, extracted with ether, evaporated in vacuo, and azeotropic distillation was performed three times with ethanol / benzene. The residue was crystallized with acetone and the crystallized mass was recrystallized three times with methanol / acetonitrile to give 4- {2 '-[3- [3,4-dimethoxyphenethyl) -methylamino] with a melting point of 192 ° C (decomposition). -Propyl] -m-dithiane-2'-yl} -2-methoxyphenol-1 ', 1', 3 ', 3'- tetraoxide hydrobromide is obtained.

원소분석 :Elemental Analysis:

계 산 치 : C 48.23, H 5.83, N 2.25Calculated Value: C 48.23, H 5.83, N 2.25

실 측 치 : C 48.12, H 5.93, N 2.07Found: C 48.12, H 5.93, N 2.07

같은 방법으로 2－(3－벤질옥시－3－메톡시페닐)－N－(3,4－디메톡시펜에틸)－N－메틸－m－디티안－2－프로필아민－1, 1, 3, 3－테트라옥사이드를 출발물질로 하여 융점 201℃(분해)(아세토니트릴)의 5－{2'－[3－[(3, 4－디메톡시펜에틸)－메틸아미노]－프로필]－m－디티안－2'－일}－2－메톡시페닐－1', 1', 3', 3'－테트라옥사이드 하이드로브로마이드를 수득한다.In the same manner, 2- (3-benzyloxy-3-methoxyphenyl) -N- (3,4-dimethoxyphenethyl) -N-methyl-m-dithiane-2-propylamine-1, 1, 3 5- {2 '-[3-[(3,4-dimethoxyphenethyl) -methylamino] -propyl] of melting point 201 ° C (decomposition) (acetonitrile) using 3-tetraoxide as starting material -Dithia-2'-yl} -2-methoxyphenyl-1 ', 1', 3 ', 3'- tetraoxide hydrobromide is obtained.

[실시예 15]Example 15

5－{2'－[3－[(3,4－디메톡시펜에틸)－메틸아미노프로필]－m－디티안－2'－일}－2－메톡시페닐－1', 1', 3', 3'－테트라옥사이드 2g을 무수 피리딘에 용해하고 과량의 무수 아세트산으로 처리하여 16시간동안 실온에서 방치후, 용매를 증발시키고, 잔유물을 실리카겔상에서, 크로마토그라피하면 5－{2'－[3－(3, 4－디메톡시펜에틸)－메틸아미노프로필]－m－디티안－2'－일}－2－메톡시페닐아세테이트－1', 1', 3', 3'－테트라옥사이드가 점조성 오일로서 얻어진다.5- {2 '-[3-((3,4-dimethoxyphenethyl) -methylaminopropyl] -m-dithiane-2'-yl} -2-methoxyphenyl-1', 1 ', 3 2 g of ', 3'-tetraoxide was dissolved in anhydrous pyridine, treated with excess acetic anhydride, left at room temperature for 16 hours, the solvent was evaporated, and the residue was chromatographed on silica gel. -(3,4-dimethoxyphenethyl) -methylaminopropyl] -m-dithiane-2'-yl} -2-methoxyphenyl acetate-1 ', 1', 3 ', 3'- tetraoxide Obtained as a viscous oil.

원소분석 :Elemental Analysis:

계 산 치 : C 55.67, H 6.39, N 2.40Calculated Value: C 55.67, H 6.39, N 2.40

실 측 치 : C 55.22, H 6.41, N 2.23Found: C 55.22, H 6.41, N 2.23

2－(3, 4－디메톡시페닐)－N－메틸－m－디티안－2－프로필아민－1, 1, 3, 3－테트라옥사이드 0.3g을 3, 4－디메톡시－β－펜에틸클로라이드 0.16g 및 N, N－디이소프로필－N－에틸아민 5ml, 디메틸포름아마이드 1.5ml로 처리하고 이 혼합물을 130℃로 16시간동안 가열한다음 이 용액을 수층과 에틸 아세테이트층으로 분리하고 잔유물을 실리카겔상에서 크로마토 그라피하면 융점 144℃(메탄올)의 N－(3, 4－디메톡시펜에틸)－2－(3,4－디메톡시페닐)－N－메틸－m－디티안－2－프로필아민－1, 1, 3, 3－테트라옥사이드가 얻어진다.0.3 g of 2- (3,4-dimethoxyphenyl) -N-methyl-m-dithiane-2-propylamine-1,1,3,3-tetraoxide was substituted with 3,4-dimethoxy- beta-phenethyl 0.16 g of chloride, 5 ml of N, N-diisopropyl-N-ethylamine, 1.5 ml of dimethylformamide and the mixture were heated to 130 ° C. for 16 hours, and the solution was separated into an aqueous layer and an ethyl acetate layer, and the residue Was chromatographed on silica gel to give N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N-methyl-m-dithiane-2-propyl at a melting point of 144 ° C. Amine-1, 1, 3, 3- tetraoxide is obtained.

출발물질로 사용되는 2－(3, 4－디메톡시펜에틸)－N－메틸－m－디티안－2－프로필아민－1, 1, 3, 3－테트라옥사이드는 다음과 같이 제조한다.2- (3,4-dimethoxyphenethyl) -N-methyl-m-dithiane-2-propylamine-1,1,3,3-tetraoxide used as starting material is prepared as follows.

2－(3－클로로프로필)－2－(3, 4－디메톡시페닐)－m－디티안－1, 1, 3, 3－테트라옥사이드 3.95g을 디메틸 포름아마이드 50ml에 용해하고 0℃로 냉각한 후 메틸아민 15g으로 처리하여 이 혼합물을 가압하 40℃에서 18시간동안 가열한 다음 용액을 농축하고 생성된 결정성 잔유물을 소량의 메탄올로 재결정화하면 융점 164℃의 목적한 출발물질이 얻어진다.3.95 g of 2- (3-chloropropyl) -2- (3,4-dimethoxyphenyl) -m-dithiane-1,1,3,3-tetraoxide are dissolved in 50 ml of dimethyl formamide and cooled to 0 ° C. The mixture was then treated with 15 g of methylamine and the mixture was heated under pressure at 40 ° C. for 18 hours, then the solution was concentrated and the resulting crystalline residue was recrystallized from a small amount of methanol to give the desired starting material with melting point of 164 ° C. .

[실시예 17]Example 17

N－(3, 4－디메톡시펜에틸)－2－(3, 4－디메톡시페닐)－m－디티안)－2－프로필아민을 무수피리딘 20ml에 용해하고 무수 아세트산 200ml로 처리한 다음 8시간후 그 혼합물을 농축시키고, 잔유물을 에테르와 5% 탄산나트륨액으로 처리하여 에테르용매를 증발시켜 얻어지는 오일 1.2g을 무수테트라히드로푸란 20ml에 용해한 후 이 용액을 20ml의 무수테트라하이드로푸란 20ml중에 리튬알미늄 하이드라이드 0.4g을 현탁시킨 액에 서서히 적가시키고 진한 황산나트륨수용액으로 서서히 처리한 다음 흡인 여과한다. 용매를 증발시킨 후, 잔유물을 에테르와 물층으로 나누어 유기용매층을 조작하여 오일상의 잔유물을 아세톤/에틸아세테이트중에서 옥살산으로 처리하면 융점 126 내지 127℃의 N－(3, 4－디메톡시펜에틸)－2－(3, 4－디메톡시페닐) －N－에틸－m－디티안－2－프로필아민－1, 1, 3, 3－테트라옥사이드 옥살레이트가 얻어진다.N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -m-dithiane) -2-propylamine was dissolved in 20 ml of anhydrous pyridine and treated with 200 ml of acetic anhydride, and 8 After time, the mixture was concentrated, and the residue was treated with ether and 5% sodium carbonate solution to dissolve 1.2 g of an oil obtained by evaporating the ether solvent in 20 ml of anhydrous tetrahydrofuran, and then the solution was dissolved in 20 ml of 20 ml of anhydrous tetrahydrofuran. 0.4 g of hydride is slowly added dropwise to the suspended solution, and then treated slowly with concentrated aqueous sodium sulfate solution, followed by suction filtration. After evaporating the solvent, the residue was divided into ether and water layers, and the organic solvent layer was operated to treat the oily residue with oxalic acid in acetone / ethyl acetate. N- (3,4-dimethoxyphenethyl) having a melting point of 126 to 127 ° C. 2- (3,4-dimethoxyphenyl) -N-ethyl-m-dithiane-2-propylamine-1,1,3,3- tetraoxide oxalate is obtained.

[실시예 18]Example 18

호모베라트린산 1g을 무수테트라하이드로푸란 15ml에 용해하고 트리에틸아민 0.15g으로 처리한다. 그후 클로로포름산 이소부틸 에스테르 0.72을 0 내지 5℃에서 서서히 적가시키고 5 내지 10℃에서 1시간동안 교반한다. 여기에 테트라하이드로푸란 5ml중의 2－(3, 4－디메톡시페닐)－N－메틸－m－디티안－2－프로필아민[실시예 15와 같은 방법으로 2－(

Figure kpo00038
－클로로프로필)－2－(3, 4－디메톡시페닐)－m－디티안 및 메틸아민으로부터 제조] 1.63g액을 적가시켜 실온에서 하루밤동안 방치한다. 용매를 증발시킨 후, 잔유물을 1M 염산과 에테르로 분리시키고 유기층을 5% 탄산나트륨과 물로 세척한 후 황산 마그네슘으로 탈수시키고 용매를 증발시켜 얻은 오일상의 잔유물(1.5g)을 테트라하이드로푸란 15ml에 용해하고 리튬알미늄 하이드라이드 0.15g의 현탁액에 아르곤 가스하에서 환류시키면서 적가시킨다, 혼합물을 두시간동안 비등시킨 후 서서히 진한 황산나트륨수용액으로 처리후 메틸렌클로라이드 10ml로 처리한다음 흡인 여과하여 농축하고 잔유물을 실리카겔상에서 크로마토그라피하면 점조성 오일인 N－(3, 4－디메톡시펜에틸)－2－(3, 4－디메톡시페닐)－N－메틸－m－디티안－2－프로필아민이 얻어진다.1 g of homoveratriic acid is dissolved in 15 ml of anhydrous tetrahydrofuran and treated with 0.15 g of triethylamine. Then chloroformic acid isobutyl ester 0.72 is slowly added dropwise at 0-5 占 폚 and stirred at 5-10 占 폚 for 1 hour. 2- (3,4-dimethoxyphenyl) -N-methyl-m-dithian-2-propylamine in 5 ml of tetrahydrofuran [2-(
Figure kpo00038
-Chloropropyl) -2- (3,4-dimethoxyphenyl) -m-dithiane and prepared from methylamine] 1.63 g of the solution is added dropwise and allowed to stand at room temperature overnight. After evaporation of the solvent, the residue was separated with 1M hydrochloric acid and ether, the organic layer was washed with 5% sodium carbonate and water, dehydrated with magnesium sulfate, the solvent was evaporated and the oily residue (1.5 g) was dissolved in 15 ml of tetrahydrofuran. To a suspension of 0.15 g of lithium aluminum hydride was added dropwise while refluxing under argon gas. The mixture was boiled for 2 hours, then treated with a saturated sodium sulfate aqueous solution, treated with 10 ml of methylene chloride, concentrated by suction filtration, and the residue was chromatographed on silica gel. N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N-methyl-m-dithiane-2-propylamine which is a viscous oil is obtained.

[실시예 19]Example 19

통상의 방법으로 다음과 같은 조성을 가진 캅셀제를 제조한다.The capsule which has a composition as follows is manufactured by a conventional method.

N－(3,4－디메톡시펜에틸)－2－(3, 4－디메톡시페닐)－N－메틸－m－디티안－2－프로필아민 25mg25 mg of N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N-methyl-m-dithiane-2-propylamine

만니톨 115mgMannitol 115mg

옥수수 전분 40mgCorn Starch 40mg

탈크 18mgTalc 18mg

마그네슘 스테아레이트 2mgMagnesium Stearate 2mg

200mg200 mg

[실시예 20]Example 20

통상의 방법으로 다음과 같은 조성을 가진 정제를 제조한다.In a conventional manner, a tablet having the following composition is prepared.

N－(3,4－디메톡시펜에틸)－2－(3,4－디메톡시페닐)－N－메틸－m－디티안－2－프로필아민－1, 1, 3, 3－테트라옥사이드 25mg25 mg of N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N-methyl-m-dithiane-2-propylamine-1,1,3,3- tetraoxide

유 당 90mgLactose 90mg

옥수수 전분 75mgCorn Starch 75mg

마그네슘 스테아레이트 1mgMagnesium Stearate 1mg

탈 크 9mgTalc 9mg

200mg200 mg

Claims (1)

다음 구조식(Ⅳ)의 화합물을 다음 구조식(Ⅴ)의 화합물과 반응시키거나,Reacting a compound of formula (IV) with a compound of formula (V), or 다음 구조식(Ⅵ)의 화합물을 다음 구조식(Ⅶ)의 화합물과 반응시키거나,Reacting a compound of formula (VI) with a compound of formula 다음 구조식(Ⅷ)의 화합물을 다음 구조식(XI)의 화합물과 반응시키거나,Reacting a compound of formula (VII) with a compound of formula (XI), or 다음 구조식(XII)의 카보닐그룹 또는 다음 구조식(Ⅷ)의 A그룹을 환원시키고 필요에 따라 X가 황원자인 구조식(Ⅰ)화합물을 X가 SO 또는 SO2인 구조식(Ⅰ)화합물로 산화시키거나, R4가 수소인 구조식(Ⅰ)화합물을 N－(저급알킬화)하거나 저급알콕시그룹 또는 아릴－(저급알콕시)그룹을 하이드록시그룹으로 전환시키거나 니트로그룹을 아미노그룹으로 환원시키거나, 시아노그룹을 카복실그룹으로 검화시키거나, 카복실그룹을 에스테르화 또는 아미드화 또는 환원하거나 하이드록시그룹을 에테르화 또는 에스테르화 또는 카바모일화하거나 아미노그룹을 모노(저급알킬화) 또는 디(저급알킬화)하거나 알킬티오그룹을 알킬설포닐그룹으로 산화시켜 다음 구조식(Ⅰ) 화합물 및 이의 산부가 염을 제조하는 방법.Reduce the carbonyl group of the following formula (XII) or the A group of the following formula (VII) and, if necessary, oxidize the compound of formula (I) wherein X is a sulfur atom to a compound of formula (I) wherein X is SO or SO 2 , or N- (lower alkylation) of a compound of formula (I) wherein R 4 is hydrogen, or a lower alkoxy group or an aryl- (lower alkoxy) group is converted to a hydroxy group or a nitro group is reduced to an amino group, Saponifying the group to a carboxyl group, esterifying or amidating or reducing the carboxyl group, etherifying or esterifying or carbamoylating the hydroxy group, or mono (lower alkylating) or di (lower alkylating) or alkyl groups of the amino groups Oxidizing a thio group to an alkylsulfonyl group to prepare the following compound of formula (I) and an acid addition salt thereof.
Figure kpo00039
Figure kpo00039
Figure kpo00040
Figure kpo00040
 상기 구조식에서In the above structural formula R은 구조식(a) 또는 (b)이고R is of formula (a) or (b)
Figure kpo00041
Figure kpo00041
 여기에서 R1, R2및 R3는 각각 수소 또는 할로겐, 저급알킬, 저급알콕시, 아릴－(저급알콕시), 아릴옥시, 페닐, 니트로, 아미노, 저급알킬티오, 트리플루오로메틸, 하이드록시, 시아노, 디(저급알킬)아미노, 저급알카노일아미노, 카복실, 저급알콕시카보닐, 저급알킬설포닐, 하이드록시메틸, 저급알카노일옥시, 아미도, 저급알카노일, 설파모일, 모노(저급알킬)설파모일, 디(저급알킬)설파모일, 아미노카보닐옥시, 모노(저급알킬)아미노카보닐옥시, 디(저급알킬)아미노카보닐옥시 또는 (저급알킬아미노)－(저급알킬)그룹 또는 두개의 인접한 R1, R2및 R3는 함께 메틸렌디옥시, 또는 부타디엔－1, 3－일렌－1, 4그룹을 나타내고Wherein R 1 , R 2 and R 3 are each hydrogen or halogen, lower alkyl, lower alkoxy, aryl- (lower alkoxy), aryloxy, phenyl, nitro, amino, lower alkylthio, trifluoromethyl, hydroxy, Cyano, di (lower alkyl) amino, lower alkanoylamino, carboxyl, lower alkoxycarbonyl, lower alkylsulfonyl, hydroxymethyl, lower alkanoyloxy, amido, lower alkanoyl, sulfamoyl, mono (lower alkyl) Sulfamoyl, di (lower alkyl) sulfamoyl, aminocarbonyloxy, mono (lower alkyl) aminocarbonyloxy, di (lower alkyl) aminocarbonyloxy or (lower alkylamino)-(lower alkyl) groups or two Adjacent R 1 , R 2 and R 3 together represent methylenedioxy or butadiene-1,3-ylene-1,4 group R4는 수소 또는 저급알킬그룹이고R 4 is hydrogen or a lower alkyl group R5, R6및 R7은 각각 수소 또는 할로겐 또는 저급알킬, 저급알콕시, 하이드록시 또는 벤질옥시그룹 또는 두개의 인접한 R5, R6및 R7는 함께 메틸렌디옥시, 에틸렌디옥시를 나타내고R 5 , R 6 and R 7 each represent hydrogen or halogen or lower alkyl, lower alkoxy, hydroxy or benzyloxy group or two adjacent R 5 , R 6 and R 7 together represent methylenedioxy, ethylenedioxy X는 황이나 SO 또는 SO2이고X is sulfur or SO or SO 2 Y는 탄소수 2 내지 8중 2 내지 4가 쇄를 이룬, 직쇄 또는 측쇄의 임의로 하이드록시기로 치환된 지방족그룹이고Y is an aliphatic group substituted with a linear or branched, optionally hydroxy group having 2 to 4 carbon atoms of 2 to 8 carbon atoms. Z는 탄소수 1 내지 8중 1 내지 4가 쇄를 이룬 직쇄 또는 측쇄의 임의로 하이드록시기로 치환된 지방족그룹이고Z is an aliphatic group substituted with a linear or branched optionally hydroxy group having 1 to 4 carbon atoms of 1 to 8 carbon atoms m은 0 또는 1이며m is 0 or 1 n은 2 또는 3이고n is 2 or 3 Y1및 Z1은 각기 카보닐그룹을 함유하는 Y 또는 Z에 상응하는 그룹이고Y 1 and Z 1 are groups corresponding to Y or Z, each containing a carbonyl group R8은 이탈원자 또는 그룹이고R 8 is a leaving atom or group A는 다음 구조식의 그룹이다.A is a group of the following structural formulas.
Figure kpo00042
Figure kpo00042
KR7902785A 1979-08-16 1979-08-16 Process for preparing of containing heterocyclic compounds KR790001382B1 (en)

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