KR900006444B1 - Process for the preparation of 2-amino-3,5-dibromobenzyl amine derivative - Google Patents

Process for the preparation of 2-amino-3,5-dibromobenzyl amine derivative Download PDF

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KR900006444B1
KR900006444B1 KR1019870011775A KR870011775A KR900006444B1 KR 900006444 B1 KR900006444 B1 KR 900006444B1 KR 1019870011775 A KR1019870011775 A KR 1019870011775A KR 870011775 A KR870011775 A KR 870011775A KR 900006444 B1 KR900006444 B1 KR 900006444B1
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동화약품공업 주식회사
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/68—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings and hydroxy groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/70—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings and hydroxy groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton

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Abstract

2-Amino-3,5-dibromobenzylamine deriv. of formula (I) is prepd. by reacting a cpd. of formula (II) with a cpd. of formula (III), and then removing syllyl gp. of the obtained cpd. in the presence of water or alcohol. In the formulas, X is halogen or sulfonate (e.g. Cl, Br, OMs or OTs). (I) is useful as expectorants and bronchial asthma treating agents.

Description

2-아미노-3,5-디브로모벤질아민 유도체의 제조방법.Process for the preparation of 2-amino-3,5-dibromobenzylamine derivatives.

본 발명은 기관지 천식 치료 및 진해거담제로 유용한 다음 구조식(I)의 화합물 2-아미노The present invention provides compounds 2-amino of the following structural formula (I) useful as a treatment for bronchial asthma and antitussive expectorants

-3,5-디브로모-N-(트란스-4-히드록시시클로헥실)벤질아민 또는 그의 염산염의 제조방법에 관한 것이다.A method for producing -3,5-dibromo-N- (trans-4-hydroxycyclohexyl) benzylamine or a hydrochloride thereof.

Figure kpo00001
Figure kpo00001

상기 구조식(I)의 공지의 제조방법을 예로 들면 독일공개특허 2218647, 2223193호, 스페인특허 534063호등에 그 제조방법이 기술되어 있다.For example, the production method is described in German Patent Publication No. 2218647, 2223193, Spanish Patent No. 534063 and the like.

상기 구조식(I)의 공지의 제조방법을 살펴보면, 첫째 2-아이노-3,5-디브로모벤즈알데히드와 트란스-4-아미노시클로헥산올을 포름산과 반응시켜 환원적 아민화(Reductive amination) 반응으로 구조식(I)을 제조하거나 2-아미노-3,5-디브로모벤즈알데히드와 트란스-4-아미노시클로헥산올을 반응시켜 얻어진 구조식(II)의 이민을 수소화붕소나트륨(NaBH4)으로 환원하여 구조식(I)을 제조하는 방법, 둘째, O-톨루이딘의 아미노그룹을 디아세틸화하고 N-브로모석신이미드로 브롬화하여 5-브롬화된 벤질브로마이드를 제조한 다음 트란스-4-아미노시클로헥산올과 반응시켜 구조식(Ⅲ)의 화합물을 얻고 탈아세틸화를 거쳐 3-위치에 다시 브롬화 반응을 시켜 구조식(I)을 제조하는 방법등이 있다.Looking at the known production method of the structural formula (I), first, the reductive amination reaction by reacting 2-ino-3,5-dibromobenzaldehyde and trans-4-aminocyclohexanol with formic acid To prepare Structural Formula (I) or by reacting 2-amino-3,5-dibromobenzaldehyde with trans-4-aminocyclohexanol, the imine of Structural Formula (II) was reduced to sodium borohydride (NaBH 4 ). Method of preparing Structural Formula (I), second, diacetylated O-toluidine amino group and brominated with N-bromosuccinimide to prepare 5-brominated benzylbromide, followed by trans-4-aminocyclohexanol And a compound of Structural Formula (III), followed by deacetylation and bromination at 3-position to prepare Structural Formula (I).

제조방법(I)Manufacturing Method (I)

Figure kpo00002
Figure kpo00002

제조방법(II)Manufacturing Method (II)

Figure kpo00003
Figure kpo00003

그러나, 이들 방법중 첫째 방법은 2-아미노-3,5-디브로모벤즈알데히드를 제조하기 위해서는 여러단계를 거쳐야 하는 어려움이 있으므로 그 제조방법이 용이하지 않으며 환원적 아민화 반응시는 고온(l50℃-250℃)를 필요로 하며 수율이 낮은 단점이 있다. 둘째 방법은 반응공정이 길어 수율이 낮고 트란스-4-아미노시클로헥산올을 사용함으로써 N- 또는 O-알킬화 반응이 동시에 일어날 수 있으므로 수율 및 정제분리에 어려움이 있다. 따라서 본 발명은 새로운 제조경로를 택하여 종래의 방법에 의한 상기 결점을 보완 개선하여 높은 수율과 순도로 쉽게 공업화할 수 있는 제조방법을 제공한다.However, the first of these methods is difficult to prepare the 2-amino-3,5-dibromobenzaldehyde in order to produce a multi-step to prepare the process is not easy and high temperature (l50 ℃ during the reductive amination reaction -250 ℃) and has a disadvantage of low yield. The second method is difficult in the yield and purification separation because the reaction process is long, the yield is low and the N- or O-alkylation reaction can occur simultaneously by using trans-4-aminocyclohexanol. Therefore, the present invention provides a manufacturing method that can be easily industrialized with high yield and purity by taking advantage of the new manufacturing route to complement and improve the above-mentioned drawbacks of the conventional method.

본 발명은 2-아미노벤조산으로부터 브롬화 반응을 하여 제조된 구조식(IV)의 화합물을 구조식(V)인 알킬클로로포름에이트와 반응시켜 구조식(VI)의 혼합무수물을 제조한 후 한 반응용기내에서 수소화붕소나트륨으로 환원하여 구조식(Ⅶ)의 알코올을 쉽게 제조하고 통상의 방법에 따라 구조식(Ⅷ)의 할라이드 또는 설포네이트로 제조하여 이 화합물을 트란스-4-아미노시클로헥산을 또는 그의 염산염인 구조식(IX)으로부터 제조되어진 알코올이 실릴화합물로 보호된 구조식(X)와 반응시켜 구조식(ⅩⅠ)화합물을 제조하고 알코올이나 물로서 쉽게 보호화시킴으로서 목적화합물인 구조식(I)을 높은 수율과 순도로 용이하게 제조할 수 있는 방법이다.The present invention is prepared by reacting a compound of formula (IV) prepared by bromination from 2-aminobenzoic acid with alkylchloroformate of formula (V) to prepare a mixed anhydride of formula (VI), followed by boron hydride in one reaction vessel. Reduced to sodium, it is easy to prepare an alcohol of formula (VII) and prepared according to a conventional method with a halide or sulfonate of formula (VII), and the compound is trans-4-aminocyclohexane or a hydrochloride thereof. The alcohol prepared from reacts with the structural formula (X) protected by the silyl compound to prepare the structural formula (XI) and easily protects it with alcohol or water to easily prepare the structural formula (I) as a high yield and purity. That's how it can be.

본 발명을 간단히 도약하면 다음과 같다.Briefly, the present invention is as follows.

Figure kpo00004
Figure kpo00004

(상기 식중 R1은 메틸, 에틸등의 알킬그룹이나 또는 벤질그룹을 나타내며 X는 C1, Br, OMs, OTs과 같은 할로겐 또는 설포네이트를 나타냄).(Wherein R 1 represents an alkyl group such as methyl, ethyl or benzyl group and X represents a halogen or sulfonate such as C 1 , Br, OMs, OTs).

본 발명을 즘더 상세히 설명하면 상기 구조식(IV)의 화합물은 공지의 방법에 따라 쉽게 제조할 수 있다(독일공개특허 2911266호).When the present invention is described in more detail, the compound of formula IV can be easily prepared according to a known method (Germany Patent Publication No. 2911266).

구조식(Ⅳ)로부터 본 발명의 새로운 경로인 구조식(VI)을 제조하기 위하여 구조식(Ⅳ)와 알킬클로로포름에이트의 반응몰비는 1:1.0-1.5당량을 사용하는 것이 바람직하며 용매는 디옥산, 테트라히드로푸란과 디클로로메탄, 디클로로에탄 같은 할로겐화 탄화수소등이 적합하고 염기로서는 트리에틸아민, 디에틸아민 등이 사용될 수 있다. 반응 온도는 -10℃-+10℃ 범위내에서 3시간내에 반응은 거의 완결된다. 또한 구조식(Ⅶ)의 화합물을 얻기 위하여 구조식(VI)과 수소화붕소나트륨의 반응 몰비는 1:1.0-5.0당량을 사용하는것이 바람직하며 용매로는 디옥산, 테트라히드로푸란 및 디클로로메탄, 디클로로에탄 같은 할로겐화 탄화수소와 메탄올, 에탄올과의 혼합용매가 바람직하다. 반응 온도는 0℃-40℃ 범위내에서 4시간내에 반응이 완결되어 구조식(Ⅶ)의 알코올을 쉽게 제조할 수 있다.In order to prepare a new route of the present invention (VI) from the formula (IV), the reaction molar ratio of the formula (IV) and the alkylchloroformate is preferably 1: 1.0-1.5 equivalents, and the solvent is dioxane, tetrahydro. Halogenated hydrocarbons such as furan, dichloromethane, dichloroethane and the like are suitable, and triethylamine, diethylamine and the like may be used as the base. The reaction is almost complete within 3 hours in the reaction temperature range of -10 ° C to + 10 ° C. In addition, in order to obtain a compound of the formula (VI), the reaction molar ratio of the formula (VI) and sodium borohydride is preferably 1: 1.0-5.0 equivalents, and as a solvent, dioxane, tetrahydrofuran, dichloromethane, dichloroethane, and the like. Preferred are mixed solvents of halogenated hydrocarbons with methanol and ethanol. The reaction temperature is completed within 4 hours within the range of 0 ° C.-40 ° C. to easily prepare an alcohol of the structural formula.

구조식(Ⅸ)로부터 실리화시켜 얻은 본 발명의 특징적인 새로운 구조식(X)을 얻기 위해서는 트리메틸클로로실란, 헥사메틸디실라잔 등과 같은 실릴화 시약을 여분으로 사용하는 것이 바람직하다. 이때 용매로는 디클로로메탄, 디클로로에탄과 같은 할로겐화 탄화수소류 및 아세토니트릴, N,N'-디메틸포름아미드, N,N'-디메틸아세트아미드 등과 같은 어프로틱(aprotic) 용매가 좋다.In order to obtain the characteristic novel structural formula (X) of the present invention obtained by silicifying from the structural formula (IV), it is preferable to use an extra silylation reagent such as trimethylchlorosilane, hexamethyldisilazane and the like. The solvent may be halogenated hydrocarbons such as dichloromethane, dichloroethane, and aprotic solvents such as acetonitrile, N, N'-dimethylformamide, N, N'-dimethylacetamide, and the like.

용매에 따라 환류 온도 내지 130℃ 온도 범위내에서 15시간내에 반응은 거의 완결되며 트리메틸클로로실란과 같은 할로겐실릴화 시약을 사용할 때는 염기로서 1당량의 트리에틸아민, 디에틸아민, 탄산나트륨, 탄산칼륨 등이 사용될 수 있다.Depending on the solvent, the reaction is almost completed within 15 hours in the temperature range from reflux to 130 ° C. When using a halogensilylating reagent such as trimethylchlorosilane, one equivalent of triethylamine, diethylamine, sodium carbonate, potassium carbonate, etc. This can be used.

그리고 본 발명의 목적화합물인 구조식(I)을 제조하기 위하여 구조식(Ⅶ)으로부터 통상의 방법에 따라 제조된 구조식(Ⅷ)의 화합물을 구조식(X)의 화합물과 반응시킬때 용매로서는 아세토니트릴, N,N'-디메틸포름아미드, N,N'-디메틸아세트아미드, 디메틸설폭시드 등 어프로틱 용매를 사용할 수 있으며 용매에 따라 환류 온도 내지 130℃ 온도 범위내에서 10시간내에 반응은 거의 완결되며 생성된 구조식(ⅩⅠ)의 화합물은 알코올 또는 물로 쉽게 탈실릴화되어 목적화합물(I)을 높은 수율과 순도로 쉽게 제조할 수 있다. 이때 트리에틸아민, 디에틸아민 등과 같은 유기염기나 탄산칼륨, 탄산나트륨 등과 같은 무기염기를 사용할 수 있으며 구조식(X)가 염산염인 경우는 2당량의 염기를 사용하고 염산염이 아닌 경우는 1당량의 염기를 사용하는 것이 바람직하다.In addition, acetonitrile, N may be used as a solvent when the compound of formula (VII) prepared according to a conventional method from formula (VII) to react with the compound of formula (X) to prepare formula (I) which is the target compound of the present invention. Aprotic solvents such as, N'-dimethylformamide, N, N'-dimethylacetamide, and dimethyl sulfoxide may be used. The reaction is almost complete within 10 hours at reflux to 130 ° C depending on the solvent. The compound of formula (XI) can be easily desilylated with alcohol or water to easily prepare the desired compound (I) in high yield and purity. At this time, an organic base such as triethylamine or diethylamine, or an inorganic base such as potassium carbonate or sodium carbonate may be used. When the structural formula (X) is a hydrochloride salt, 2 equivalents of base is used. Preference is given to using.

다음의 실시예는 본 발명을 이해하고 실시할 수 있도록 하기 위한 것이지 본 발명을 제한하는 것은 아니다.The following examples are intended to enable the understanding and implementation of the present invention, but not to limit the present invention.

NMR은 80MHZ(Bruker)를 사용하였으며 화학적 이동은 ppm으로 나타내었다.NMR used 80MHZ (Bruker) and the chemical shift was expressed in ppm.

[실시예 1]Example 1

2-아미노-3,5-디브로모벤질 알코올(Ⅶ)2-amino-3,5-dibromobenzyl alcohol

테트라히드로푸란 300㎖에 2-아미노-3,5-디브로모벤조산 58.7그람과 트리에틸아민 20.1그람을 넣고 0℃로 냉각한다. 여기에 에틸클로로포름에이트 21.6그람을 30분간 적가하고 0℃에서 30분간 교반한다. 수소화붕소나트륨을 한번에 가한 후 메탄올 120ml를 1시간 동안 적가한다. 0℃에서 1시간 교반한 다음 6N-염산수용액 300m1를 천천히 가한다. 반응물에 디클로로메탄 300ml를 가하여 추출하고 10% 수산화탄산나트륨용액으로 세척한다. 디클로로메탄층을 물로 세척하고 무수황산나트륨으로 건조한 후 여과하여 감압농축하면 목적화합물 47.5그람(수율 85%)을 얻는다(융점:165℃-167℃).To 300 ml of tetrahydrofuran were added 58.7 grams of 2-amino-3,5-dibromobenzoic acid and 20.1 grams of triethylamine, followed by cooling to 0 ° C. 21.6 grams of ethylchloroformate was added dropwise thereto for 30 minutes and stirred at 0 ° C for 30 minutes. Sodium borohydride is added at once and 120 ml of methanol is added dropwise for 1 hour. After stirring for 1 hour at 0 ° C, 300m1 of 6N hydrochloric acid solution is slowly added. 300 ml of dichloromethane was added to the reaction, followed by washing with 10% sodium hydroxide solution. The dichloromethane layer was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 47.5 grams (yield 85%) of the title compound (melting point: 165 ° C.-167 ° C.).

[실시예 2]Example 2

2-아미노-3,5-디브로모벤질클로리드(Ⅷ)2-amino-3,5-dibromobenzyl chloride

테트라히드로푸란 300㎖에 2-아미노-3,5-디브로모벤질알코올 28.1그람과 티오닐클로리드 18그람을 넣고 3시간 동안 환류시킨다. 용매와 여분의 티오닐클로리드를 감압농축하여 제거하고, 시럽상태의 잔유물이 정량적으로 얻어진다. 이것을 아세토니트릴로 재결정하면 목적화합물 26.4그람(수율 88%)을 얻는다.28.1 grams of 2-amino-3,5-dibromobenzyl alcohol and 18 grams of thionyl chloride were added to 300 ml of tetrahydrofuran and refluxed for 3 hours. The solvent and excess thionyl chloride are removed by concentration under reduced pressure, and a syrup residue is obtained quantitatively. When this is recrystallized with acetonitrile, 26.4 grams (yield 88%) of the title compound are obtained.

[실시예 3]Example 3

트란스-4-아미노-(O-트리메틸실릴)시클로헥산올염산염(X)Trans-4-amino- (O-trimethylsilyl) cyclohexanol hydrochloride (X)

디클로로에탄 150m1에 트란스-4-아미노시클로헥산을 염산염 7.6그람, 헥사메틸디실라잔 32.3그람과 황산암모늄을 촉매량 넣고 질소하에서 15시간 환류한다.To 150 m 1 of dichloroethane, trans-4-aminocyclohexane is added, 7.6 grams of hydrochloride, 32.3 grams of hexamethyldisilazane, and ammonium sulfate are added and refluxed under nitrogen for 15 hours.

용매와 여분의 헥사메틸디실라잔을 감압농축하여 제거하면 목적화합물이 정량적으로 얻어진다.Concentration of the solvent and excess hexamethyldisilazane under reduced pressure removes the desired compound quantitatively.

Figure kpo00005
Figure kpo00005

Figure kpo00006
Figure kpo00006

용매:DMSO-d6.Solvent: DMSO-d 6 .

내부표준물질:디클로로메탄(5.27ppm).Internal standard: dichloromethane (5.27 ppm).

[실시예 4]Example 4

2-아미노-3,5-디브로모-N-(트란스-4-히드록시시클로헥실) 벤질아민(I) 염산염2-amino-3,5-dibromo-N- (trans-4-hydroxycyclohexyl) benzylamine (I) hydrochloride

실시예 3에서 얻은 농축 잔유물에 N,N'-디에틸포를아미드 125ml을 가하고 2-아미노-3,5-디브로모벤질클로리드 11.5그람과 트리에틸아민 7.80그람을 가하여 질소하에서 100℃에서 10시간 교반시킨다. TLC로 반응이 거의 완결되었음을 확인한 후 실온으로 냉각한다. 이 반응액에 디클로로메탄 200m1와 물 100m1를 가하여 10분간 교반 후 유기층을 취하여 물로 세척하고 0℃로 냉각한다.125 ml of N, N'-diethyl foramide was added to the concentrated residue obtained in Example 3, 11.5 grams of 2-amino-3,5-dibromobenzyl chloride and 7.80 grams of triethylamine were added thereto at 100 캜 under nitrogen. Stir for 10 hours. TLC confirms that the reaction is almost complete and then cools to room temperature. Dichloromethane 200m1 and 100m1 of water were added to the reaction solution, the mixture was stirred for 10 minutes, the organic layer was taken out, washed with water and cooled to 0 ° C.

이 용액에 이소프로필 알코올의 포화염산용액 1당량을 적가하고 1시간 동안 0℃-10℃에서 교반한다. 생성된 침전물을 여과하여 건조하면 목적화합물 13.1그람(수율 82%)을 얻는다.1 equivalent of saturated hydrochloric acid solution of isopropyl alcohol is added dropwise to this solution and stirred at 0 ° C-10 ° C for 1 hour. The resulting precipitate was filtered and dried to yield 13.1 grams (yield 82%) of the title compound.

융점:232℃ -235℃.Melting point: 232 ° C -235 ° C.

TLC:실리카겔 GF254/헥산 : 초산에틸 : 프로필알코올 : 암모니아수=(70:20:10:0.2) Rf=0.3.TLC: silica gel GF254 / hexane: ethyl acetate: propyl alcohol: ammonia water = (70: 20: 10: 0.2) Rf = 0.3.

Claims (1)

구조식(IV)과 구조식(V)을 염기의 존재하에서 반응시켜 구조식(VI)의 혼합무수물을 제Reacting formula (IV) and formula (V) in the presence of a base to remove the mixed anhydride of formula (VI) 조하고 수소화붕소나트륨을 환원제로하여 구조식(Ⅶ)의 알코올을 제조하고 통상의 방법에 따라 구조식(Ⅷ)을 제조한 다음 구조식(X)와 반응시켜 구조식(ⅩⅠ)의 화합물을 제조한 후 물 또는 알코올로 쉽게 탈실릴화 반응을 시켜 목적화합물(I)을 제조하는 방법.To prepare an alcohol of formula (VII) by using sodium borohydride as a reducing agent, to prepare a formula (VII) according to a conventional method and then react with the formula (X) to prepare a compound of formula (XI) and then water or A process for preparing the target compound (I) by easily desilylation with alcohol.
Figure kpo00007
Figure kpo00007
Figure kpo00008
Figure kpo00008
 (상기 식중 R1은 메틸, 에틸그룹 등의 알킬그룹 또는 벤질그룹을 나타내며 X는 C1, Br, OMs, OTs과 같은 할로겐 또는 설포네이트를 나타냄).(Wherein R 1 represents an alkyl group such as methyl, ethyl group or benzyl group and X represents halogen or sulfonate such as C1, Br, OMs, OTs).
KR1019870011775A 1987-10-23 1987-10-23 Process for the preparation of 2-amino-3,5-dibromobenzyl amine derivative KR900006444B1 (en)

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