KR0177901B1 - The new process for preparation of melatonin - Google Patents

The new process for preparation of melatonin Download PDF

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KR0177901B1
KR0177901B1 KR1019960005730A KR19960005730A KR0177901B1 KR 0177901 B1 KR0177901 B1 KR 0177901B1 KR 1019960005730 A KR1019960005730 A KR 1019960005730A KR 19960005730 A KR19960005730 A KR 19960005730A KR 0177901 B1 KR0177901 B1 KR 0177901B1
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melatonin
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KR970065517A (en
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장혜경
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성재갑
주식회사엘지화학
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
    • C07C243/10—Hydrazines
    • C07C243/22—Hydrazines having nitrogen atoms of hydrazine groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/11—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound oxygen atoms bound to the same saturated acyclic carbon skeleton
    • C07C255/13—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound oxygen atoms bound to the same saturated acyclic carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms

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Abstract

본 발명은 인돌아민계 호르몬인 하기 구조식 (I)의 멜라토닌의 신규한 제조방법 및 그를 유효성분으로 함유하는 불면증 치료, 골다공증 예방 및 암 치료용 약제학적으로 허용되는 조성물에 관한 것이다.The present invention relates to a novel method for preparing melatonin of the following structural formula (I), an indoleamine-based hormone, and a pharmaceutically acceptable composition for treating insomnia, preventing osteoporosis, and treating cancer, containing the same as an active ingredient.

Description

멜라토닌의 신규한 제조방법Novel Method of Making Melatonin

본 발명은 멜라토닌의 신규한 제조방법에 관한 것이다.The present invention relates to a novel method for preparing melatonin.

더욱 구체적으로, 본 발명은 인돌아민계 호르몬인 하기 구조식 (I) 의 멜라토닌의 신규한 제조방법 및 그를 유효성분으로 함유하는 불면증 치료, 골다공증예방 및 암 치료용 약제학적으로 허용되는 조성물에 관한 것이다.)More specifically, the present invention relates to a novel method for producing melatonin of the following structural formula (I), an indoleamine-based hormone, and a pharmaceutically acceptable composition for treating insomnia, osteoporosis prevention and cancer treatment, containing the same as an active ingredient. )

멜라토닌은 송과선에서 분비되는 호르몬으로 화학적 명칭은 N-아세틸-5-메톡시트립타민이다. 이 물질은 시상하부를 제어하며 갑상선, 가슴샘, 췌장과 부신 등에 영향을 미친다. 지난 20 여년 동안의 연구 결과 밝혀진 멜라토닌의 효능으로는 항 산화제, 면역 시스템 강화와 불면증 치료가 있으며, 골다공증 예방과 암치료에 보조 의약으로도 사용될 수 있다. 기타 다른 여러가지 작용들로는 노화방지, 임신방지와 같은 것들이 보고되어 있다. 멜라토닌은 현재까지 부작용이 없다고 보고되어 있다(Newsweek, 1995/8/14).Melatonin is a hormone secreted by the pineal gland and its chemical name is N-acetyl-5-methoxytrytamine. This substance controls the hypothalamus and affects the thyroid, thymus, pancreas and adrenal glands. The benefits of melatonin found over the past two decades include antioxidants, immune system strengthening and insomnia treatment, as well as adjuvant medications for osteoporosis prevention and cancer treatment. Many other actions have been reported, such as anti-aging and anti-pregnancy. Melatonin has been reported to have no side effects to date (Newsweek, 1995/8/14).

현재까지 알려진 제법 특허로는 유일하게 1989 년에 유럽 특허(EP 1989 0 330625 A2)가 보고되어 있으며 반응공정은 다음과 같다(반응도식 I).The only known manufacturing patent to date is the European Patent (EP 1989 0 330625 A2) reported in 1989 and the reaction process is as follows (Scheme I).

본 발명은 하기 구조식 (I)의 화합물을 제조하는 신규한 방법에 관한 것이다.The present invention relates to a novel process for preparing a compound of formula (I).

본 발명에 따르면, 상기 구조식 (I) 의 목적 화합물은 하기 구조식 (IV)의 화합물을 동시에 환원반응과 아세틸화 반응시킴을 특징으로 하는 방법에 의해 제조할 수 있다.According to the present invention, the target compound of formula (I) can be prepared by a method characterized by simultaneously reducing and acetylating the compound of formula (IV).

본 발명에서는 상업적으로 구입 가능한 하기 구조식 (III) 의 4-메톡시페닐하이드라진 하이드로클로라이드와 하기 구조식 (III)의 3-시아노프로피온알데히드 디에틸아세탈을 축합, 폐환반응시켜 하기 구조식 (IV) 의 멜라토닌의 모핵을 합성하는 방법과 하기 구조식 (IV) 를 수소부가 반응, 또는 나트륨 보로하이드라이드로 환원시키고 아세틸화시켜 멜라토닌으로 변환시키는 방법(반응도식 II)을 기술하고 있고, 이 방법은 기존의 5 단계의 공정을 2 단계로 줄이고 더 높은 수율로 얻는 큰 잇점을 가지고 있다.In the present invention, commercially available 4-methoxyphenylhydrazine hydrochloride of the following structural formula (III) and 3-cyanopropionaldehyde diethylacetal of the following structural formula (III) are condensed and cyclized to react melatonin of the following structural formula (IV) And a method of synthesizing the mother nucleus of the following formula (IV) and hydrogenation reaction or reduction of sodium borohydride and acetylation to melatonin (Scheme II). This has the great advantage of reducing the process to two stages and achieving higher yields.

본 발명의 방법에 따르면, 반응을 용매의 존재하에서 나트륨 보로하이드라이드, 코발터스 클로라이드와 무수초산을 동시에 사용하거나,용매의 존재하에서 촉매하 수소첨가 반응과 무수초산을 이용한 아세틸화 반응을 동시에 수행하여 상기 구조식 (I) 의 목적 화합물을 수득한다.According to the method of the present invention, the reaction is carried out simultaneously using sodium borohydride, cobalt chloride and acetic anhydride in the presence of a solvent, or simultaneously performing a hydrogenation reaction under a catalyst and an acetylation reaction using acetic anhydride in the presence of a solvent. To obtain the target compound of the above formula (I).

본 반응이 완결된 후에 생성물은 통상적인 후처리 방법, 예를 들면 크로마토그래피, 재결정화 등의 방법에 의해 분리 및 정제할 수 있다.After the completion of the reaction, the product can be separated and purified by conventional workup methods such as chromatography, recrystallization and the like.

상기 반응도식 II 에서 본 발명의 구조식 (I) 의 화합물을 제조하는데 중간체로 사용된 하기 구조식 (IV) 의 5-메톡시 3-인돌릴아세토니트릴은 4-메톡시페닐하이드라진 염산염과 3-시아노프로피온알데히드 디에틸아세탈을 반응시켜 제조할 수 있다.5-methoxy 3-indolylacetonitrile of the following formula (IV) used as an intermediate to prepare a compound of formula (I) of the present invention in Scheme II is 4-methoxyphenylhydrazine hydrochloride and 3-cyano It can be prepared by reacting propionaldehyde diethylacetal.

상기 언급한 바와 같이 본 발명에 따르는 상기 구조식 (I) 의 화합물은 항산화제, 면역 시스템 강화와 불면증 치료, 골다공증 예방 및 암 치료에 유용하다.As mentioned above, the compounds of formula (I) according to the present invention are useful for antioxidants, immune system strengthening and insomnia treatment, osteoporosis prevention and cancer treatment.

따라서, 본 발명은 구조식 (I) 의 화합물을 유효성분으로 함유하는 불면증 치료, 골다공증 에방 및 암 치료용 조성물을 제공하는 것을 또다른 목적으로 한다.Therefore, another object of the present invention is to provide a composition for treating insomnia, osteoporosis prevention and cancer, which contains the compound of formula (I) as an active ingredient.

본 발명은 다음 제조예와 실시예에 의해 더욱 구체적으로 설명되나, 본 발명이 이들에 의해 어떤 식으로든 제한되는 것은 아니다.The invention is further illustrated by the following Preparation Examples and Examples, but the invention is not limited in any way by these.

[제조예 1 : 5-메톡시 3-인돌릴아세토니트릴 (IV)의 합성]Preparation Example 1 Synthesis of 5-methoxy 3-indolylacetonitrile (IV)

[방법 1][Method 1]

175 ㎎(1.0 밀리몰)의 4-메톡시페닐하이드라진 하이드로클로라이드를 4㎖ 의 초산-물-에탄올 혼합 용액(25 : 25 : 40)에 용해시킨 후 159 ㎎(1.0 밀리올)의 3-시아노프로피온알데히드 디에틸아세탈을 0.4 ㎖ 에탄올에 용해시킨 용액을 80℃에서 가해준 후 1 시간 가열한다. 반응 후 에탄올을 제거한 후 남은 잔류물에 얼음물을 가해준 후 에테르로 3 회 추출해 준다. 에테르 추출물을 포화 탄산수소화나트륨(NaHCO3)과 염화 나트륨(NaCl)으로 세척한 후 무수 마그네슘 술포네이트로 물을 제거하고 농축시켜 170 mg(91 %) 의 5-메톡시-3-인돌릴아세토니트릴이 얻어졌다.175 mg (1.0 mmol) of 4-methoxyphenylhydrazine hydrochloride was dissolved in 4 mL of acetic acid-water-ethanol mixed solution (25:25:40) and then 159 mg (1.0 mmol) of 3-cyanopropion A solution in which aldehyde diethylacetal was dissolved in 0.4 ml ethanol was added at 80 ° C. and then heated for 1 hour. After the reaction, ethanol was removed and ice water was added to the remaining residue, followed by extraction three times with ether. The ether extracts were washed with saturated sodium bicarbonate (NaHCO 3 ) and sodium chloride (NaCl), then dried with anhydrous magnesium sulfonate and concentrated to 170 mg (91%) of 5-methoxy-3-indolylacetonitrile. Was obtained.

[방법 2][Method 2]

175 ㎎(1.0 밀리몰)의 4-메톡시페닐하이드라진 하이드로클로라이드와 159㎎(1.0 밀리몰)의 3-시아노프로피온알데히드 디에틸아세탈을 초산에 용해시킨 후 80℃ 에서 1 시간 가열한다. 반응 후 흔합물을 얼음물에 가해준 후 에테르로 3 회 추출해 준다. 에테르 추출물을 포화 탄산수소화 나트륨과 염화 나트륨으로 세척한 후 무수 마그네슘 술포네이트로 물을 제거하여 농축시킨다. 140 mg(75 %)의 수율로 5-메톡시-3-인돌릴아세토니트릴이 얻어졌다.175 mg (1.0 mmol) of 4-methoxyphenylhydrazine hydrochloride and 159 mg (1.0 mmol) of 3-cyanopropionaldehyde diethylacetal are dissolved in acetic acid and then heated at 80 ° C. for 1 hour. After the reaction, the mixture is added to ice water and extracted three times with ether. The ether extract is washed with saturated sodium bicarbonate and sodium chloride, and then concentrated by removing water with anhydrous magnesium sulfonate. 5-methoxy-3-indolylacetonitrile was obtained in a yield of 140 mg (75%).

[방법 3][Method 3]

138㎎(1.0 밀리몰)의 4-메톡시페닐하이드라진과 159 mg(1.0 밀리몰)의 3-시아노프로피온알데히드 디에틸아세탈을 무수 초산에 용해시킨 후 151 mg (1.0 밀리몰, 0.14 ㎖)의 트리플루오라이드-에테르를 가해준 후 90℃ 에서 1 시간 가열한다. 반응후 혼합물을 얼음물에 가해준후 에테르로 3회 추출해 준다. 에테르 추출물을 포화 탄산수소화 나트륨과 염화 나트륨으로 세척한 후 무수 마그네슘 술포네이트로 물을 제거한 후 농축시킨다. 150 ㎎(80 %)의 수율로 5-메톡시-3-인돌릴아세토니트릴이 얻어졌다.138 mg (1.0 mmol) of 4-methoxyphenylhydrazine and 159 mg (1.0 mmol) of 3-cyanopropionaldehyde diethylacetal in acetic anhydride followed by 151 mg (1.0 mmol, 0.14 mL) of trifluoride -Add ether and heat at 90 ℃ for 1 hour. After the reaction, the mixture is added to ice water and extracted three times with ether. The ether extract is washed with saturated sodium bicarbonate and sodium chloride, then water is removed with anhydrous magnesium sulfonate and concentrated. 5-methoxy-3-indolylacetonitrile was obtained in a yield of 150 mg (80%).

[실시예 1 : N-아세틸-5-메톡시트립타민(멜라토닌)의 합성]Example 1 Synthesis of N-Acetyl-5-methoxytrytamine (melatonin)

제조예의 방법 1 에서 얻어진 150 ㎎(1.00 밀리몰)의 5-메톡시-3-인돌릴아세토니트릴, 380 mg(1.60 밀리몰)의 코발터스 클로라이드 6 수화물과 0.74㎖(8.1밀리몰)의 아세트산 무수물을 10 ㎖의 메탄올에 용해시킨 후 상온에서 300 ㎎(80 밀리몰)의 나트륨 보로하이드라이드를 조금씩 가해준다. 상온에서 1 시간 동안 교반한후, 1 N HCl 를 가해준 다음 메탄올을 날려 보낸다. 남아있는 잔류물에 얼음물을 가해준 후 에테르로 3 회 추출해 준다. 에테르 추출물을 포화 탄산수소화 나트륨과 염화 나트륨으로 세척한 후 무수 마그네슘 술포네이트로 물을 제거하여 농축시킨다. 컬럼 크로마토그래피(클로로포름:메탄올 99 : 1 -1 96 : 4)를 이용하여 분리, 84 % 의 수율로 N-아세틸-5-메록시트립타민이 얻어졌다. 목탄과 아세톤으로 탈색시킨 후, 아세톤과 물을 사용하여 재결정한다(수율 73 %).150 mg (1.00 mmol) of 5-methoxy-3-indolylacetonitrile, 380 mg (1.60 mmol) of cobalt chloride hexahydrate and 0.74 mL (8.1 mmol) of acetic anhydride obtained in Method 1 of Preparation Example 10 were obtained. After dissolving in ml of methanol, 300 mg (80 mmol) of sodium borohydride is added little by little at room temperature. After stirring for 1 hour at room temperature, 1 N HCl is added and then methanol is blown off. Add ice water to the remaining residues and extract three times with ether. The ether extract is washed with saturated sodium bicarbonate and sodium chloride, and then concentrated by removing water with anhydrous magnesium sulfonate. Separation was carried out by column chromatography (chloroform: methanol 99: 1 -1 96: 4) to obtain N-acetyl-5-methoxytrytamine in a yield of 84%. After decolorizing with charcoal and acetone, recrystallization with acetone and water (yield 73%).

[실시예 2 : N-아세틸-5-메톡시트립타민의 합성]Example 2 Synthesis of N-acetyl-5-methoxytrytamine

제조예의 방법 1 로 얻어진 186 me(1.00 밀리몰)의 5-메톡시-3-인돌릴아세토니트릴을 3 ㎖의 초산에 용해시킨 후 1.02 g(10 밀리몰, 0.92 ㎖)의 아세트산 무수물, 5 ㎎ 의 레이니 니켈(Ra-Ni) 혹은 Pt/C, Rh/Al2O3를 가해준 후 2 기압에서 10 기압하에서 수소부가 반응시킨다. 반응 후 셀라이트를 통과, 얼음물에 가해 준 후 에테르로 3 회 추출해 준다. 에테르 추출물을 포화 탄산수소화 나트륨과 염화 나트륨으로 세척한 후 무수 마그네슘 술포네이트로 물을 제거하여 농축시킨다. 85-95% 의 수율로 N-아세틸-5-메톡시트립타민이 얻어졌다.1.02 g (10 mmol, 0.92 mL) of acetic anhydride, 5 mg of Raney after dissolving 186 me (1.00 mmol) of 5-methoxy-3-indolylacetonitrile obtained in Method 1 of Preparation Example in 3 mL of acetic acid Nickel (Ra-Ni) or Pt / C, Rh / Al 2 O 3 is added and then hydrogenated reacts at 2 at 10 atm. After the reaction, the mixture was passed through celite, added to ice water, and extracted three times with ether. The ether extract is washed with saturated sodium bicarbonate and sodium chloride, and then concentrated by removing water with anhydrous magnesium sulfonate. N-acetyl-5-methoxytryptamine was obtained with a yield of 85-95%.

Claims (4)

하기 구조식 (IV) 의 화합물을 동시에 환원 반응과 아세틸화 반응시킴을 특징으로 하여, 하기 구조식 (I) 의 멜라토닌 화합물을 제조하는 방법.A method for producing a melatonin compound of formula (I), characterized in that the compound of formula (IV) is subjected to a reduction reaction and an acetylation reaction simultaneously. 제1항에 있어서, 용매의 존재하에서 나트륨 보로하이드라이드, 코발터스 클로라이드와 무수초산을 동시에 사용하여 반응시킴을 특징으로 하는 방법.A process according to claim 1, characterized in that the reaction is carried out simultaneously using sodium borohydride, cobalt chloride and acetic anhydride in the presence of a solvent. 제1항에 있어서, 용매의 존재하에서 동시에 촉매하 수소부가 반응과 무수초산을 이용한 아세틸화 반응시킴을 특징으로 하는 방법.The method according to claim 1, wherein the hydrogenation under the catalyst and the acetylation reaction using acetic anhydride are simultaneously carried out in the presence of a solvent. 제1항에 있어서, 구조식 (IV) 의 화합물이 4-메톡시페닐하이드라진 염산염과 3-시아노프로피온알데히드 디에틸아세탈을 반응시킴으로써 제조된 화합물임을 특징으로 하는 방법.A process according to claim 1, wherein the compound of formula (IV) is a compound prepared by reacting 4-methoxyphenylhydrazine hydrochloride with 3-cyanopropionaldehyde diethylacetal.
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