KR860000845B1 - Process for preparing chromore-2-carboxylic acid and salts thereof - Google Patents
Process for preparing chromore-2-carboxylic acid and salts thereof Download PDFInfo
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- KR860000845B1 KR860000845B1 KR1019830000202A KR830000202A KR860000845B1 KR 860000845 B1 KR860000845 B1 KR 860000845B1 KR 1019830000202 A KR1019830000202 A KR 1019830000202A KR 830000202 A KR830000202 A KR 830000202A KR 860000845 B1 KR860000845 B1 KR 860000845B1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
Abstract
Description
본 발명은 다음의 구조식(I)로 표시되는 크로몬-2-카르복실산이나 크로몬-2-카르복실산치환물 및 그의 유도체를 제조하는 방법에 관한 것으로서,The present invention relates to a method for producing chromone-2-carboxylic acid, chromone-2-carboxylic acid substituent and derivatives thereof represented by the following structural formula (I),
상기 식중 R은 수소나 염소, 메톡시기, 메틸기 또는 하이드록시기를 나타내며, M+는 칼슘이나 마그네슘 같은 양이온, B+는 디에틸아민이나 모르포린 같은 유기염기나 아르기닌이나 리신 같은 염기성아미노산 중에서 선택된 염기성 양이온을 나타낸다.Wherein R represents hydrogen or chlorine, methoxy, methyl or hydroxy group, M + is a cation such as calcium or magnesium, B + is a basic cation selected from organic bases such as diethylamine or morpholine or basic amino acids such as arginine or lysine Indicates.
상기와 같은 구조식(I)로 표시되는 화합물의 유도체에는 칼슘이나 마그네슘 같은 무기염기, 디에틸아민이나 모르포린 같은 유기염기 또는 아르기닌이나 리신같은 염기성아미노산 및 약리학적으로 허용가능한 염기를 첨가시켜서 되어진 염류가 포함된다.Derivatives of the compounds represented by the above formula (I) include salts obtained by adding inorganic bases such as calcium or magnesium, organic bases such as diethylamine or morpholine, basic amino acids such as arginine or lysine, and pharmacologically acceptable bases. Included.
일반적으로 크로몬-2-카르복실산과 특히 그의 디에틸아민염은 정맥질환과 모세혈관질환에 사용되는 혈관보호약제로서 유용한 것으로 알려져 있는바, 종래에 상기 구조식(I)의 화합물을 출발물질로서 0-하이드록시아세토페논과 에틸옥살레이트를 사용하여 제조하였는데, 이와같은 종래의 방법에 따라 제조할 경우 초기 반응물질인 0-하이드록시아세토페논이 최종 생성물이 제조된 후에도 그 최종생성물과 함께 남아 있게 되므로 순수한 최종 생성물을 얻기 위해서는 여러번 재결정화시켜야만 하는 공정상의 번거로움이 있었을뿐만 아니라 출발물질인 0-하이드록시아세토페논은 가격이 비싸 제조원가가 매우 높은 단점이 있었다.In general, chromone-2-carboxylic acid and especially diethylamine salt thereof are known to be useful as vascular protective agents used for venous diseases and capillary diseases. Conventionally, the compounds of formula (I) are used as starting materials. It was prepared using hydroxyacetophenone and ethyl oxalate, but when prepared according to this conventional method, since the initial reactant 0-hydroxyacetophenone remains with the final product even after the final product is prepared. In addition to the process hassles that need to be recrystallized several times to obtain a pure final product, the starting material 0-hydroxyacetophenone has a disadvantage that the manufacturing cost is very expensive.
따라서, 본 발명은 상기와 같은 종래의 문제점을 해결하기 위해 출발물질로서 저렴하고 공업상 제일의 원료라고 할 수 있는 살리실산메틸에스테르와 글리옥실산에틸에스테르를 사용하므로써 매우 저렴한 가격으로 종래에 비하여 간편한 공정에 의해 높은 수득율의 고순도 크로몬-2-카르복실산과 그 염을 제조하는 방법을 제공하는데 그 목적이 있다.Therefore, the present invention is a simple process compared to the conventional at a very low price by using a salicylic acid methyl ester and glyoxylic acid ethyl ester which is inexpensive and the industry's first raw material as a starting material to solve the above conventional problems It is an object of the present invention to provide a method for producing high purity chromone-2-carboxylic acid and its salt having high yield.
이하 본 발명의 제조방법을 상세히 설명하면 다음과 같다.Hereinafter, the manufacturing method of the present invention will be described in detail.
본 발명은 살리실산메틸에스테르와 메틸설피닐메틸나트륨을 반응시켜서 다음 구조식(II)로 표시도는 2'-하이드록시-2-메틸설피닐아세토페논을 얻은 다음, 이것을 글리옥실산에틸에스테르와 축합반응시켜서 다음 구조식(III)으로 표시되는 2-에톡시카르보닐-3-메틸설피닐크로마논 유도체를 형성시키고, 이를 묽은 황산매체중에서 가열하여 가수분해시킨후 메틸설펜산 1분자를 제거시켜서 높은 수득율로 고순도의 상기 구조식(I)의 크로몬-2-카르복실산과 그 염을 제조하는 방법인 것이다. 이때 살리실산메틸에스테르 대신에 살리실산메틸에스테르 치환물을 출발물질로 사용하게 되면 이에 상응하는 크로몬-2-카르복실산 치환물 유도체도 제조할 수 있게 된다.The present invention reacts methyl salicylate with methylsulfinylmethylsodium to obtain 2'-hydroxy-2-methylsulfinylacetophenone represented by the following structural formula (II), and then condensation reaction with ethyloxyglyoxylic acid. To form a 2-ethoxycarbonyl-3-methylsulfinylchromanone derivative represented by the following structural formula (III), which is heated in a dilute sulfuric acid medium to hydrolyze and remove one molecule of methylsulfenoic acid at high yield. It is a method of producing the high purity chromone-2-carboxylic acid and its salt of the said structural formula (I). In this case, when the salicylic acid methyl ester substituent is used as a starting material instead of the methyl salicylate, it is also possible to prepare a corresponding chromone-2-carboxylic acid derivative derivative.
이와 같은 본 발명을 반응식으로 나타내보면 다음과 같다.The present invention as described above is represented as follows.
이와 같은 본 발명을 실시예에 의거 더욱 상세히 설명하면 다음과 같다.Referring to the present invention in more detail based on the embodiment as follows.
[실시예 1]Example 1
2'-하이드록시-2-메틸설피닐아세토페논의 제조Preparation of 2'-hydroxy-2-methylsulfinylacetophenone
본 반응은 질소기류의 순환장치가 구비된 반응기에서 시행하였다.The reaction was carried out in a reactor equipped with a nitrogen gas circulation system.
미네랄오일중에 용해시켜서 된 0.3몰(12.7g)의 60% 수소화나트륨 현탁액을 100ml의 디메틸설폭사이드와 300ml의 벤젠혼합물속에서 완전히 용해될때까지 약 90℃의 온도로 가열시키면서 교반시킨다.0.3 mol (12.7 g) of 60% sodium hydride suspension dissolved in mineral oil is stirred while heating to a temperature of about 90 ° C. until completely dissolved in 100 ml of dimethyl sulfoxide and 300 ml of benzene mixture.
상기 용액을 완전히 용해시킨후 여기에 0.1몰(15.2g)의 살리실산에틸에스테르를 가한 다음 가열하지 않는 상태에서 1시간동안 반응시킨다.After completely dissolving the solution, 0.1 mol (15.2 g) of salicylic acid ethyl ester was added thereto, followed by reaction for 1 hour without heating.
상기 용액을 냉각시킨 다음 여기에 1000ml의 에틸에테르를 가하고 에테르로 세척하여 걸쭉한 덩어리를 얻은후 30ml의 아세트산을 가하여 15분동안 다시 반응시키고 150ml의 증류수를 첨가하여 침전시킨다.After cooling the solution, 1000 ml of ethyl ether was added thereto, washed with ether to obtain a thick mass, and 30 ml of acetic acid was added thereto to react again for 15 minutes, and 150 ml of distilled water was added to precipitate.
이와 같이 하여 형성된 침전물은 여과시키고 물로 세척한 다음 무수에탄올로 재결정화시켜서 얻어낸 화합물의 물성을 살펴보면 다음과 같다.The precipitate thus formed is filtered, washed with water and then recrystallized with anhydrous ethanol.
융점:150℃Melting Point: 150 ℃
수득률:65%Yield: 65%
적외선스펙틀머으로 그 구조를 확인한다.Check the structure with an infrared spectrometer.
[실시예 2]Example 2
2-에톡시카르보닐-3-메틸설피닐 크로마논의 제조Preparation of 2-ethoxycarbonyl-3-methylsulfinyl chromanone
40℃ 온도의 증탕기가 장치된 반응기에 100ml의 메탄올에 용해시킨 10g(0.05몰)의 2'-하이드록시-2-메틸설피닐아세토페논 용액과 200ml의 증류수에 용해시킨 30g의 탄산칼륨(K2CO3) 용액을 혼합시켜서된 미지근한 혼합용액을 넣고 10.2g(0.1몰)의 글리옥실산에틸에스테르를 교반시키면서 첨가시킨다. 상기 용액을 40℃의 온도에서 1시간동안 교반시킨후 1/2로 희석시킨 염산으로 pH1이 될때까지 산성화시키고, 이를 냉각장치에서 하룻밤동안 냉각시키면 적색의 걸쭉한 생성물이 얻어지게 되는데 이 생성물은 증류수로 세척한다.10 g (0.05 mol) of 2'-hydroxy-2-methylsulfinylacetophenone solution dissolved in 100 ml of methanol and a 30 g potassium carbonate (K 2) dissolved in 200 ml of distilled water in a reactor equipped with a steam bath at 40 ° C. The lukewarm mixed solution obtained by mixing the CO 3 ) solution was added, and 10.2 g (0.1 mol) of glyoxylic acid ethyl ester was added with stirring. The solution was stirred for 1 hour at a temperature of 40 ° C. and acidified with dilute hydrochloric acid until pH1 and cooled overnight in a chiller to give a thick red product which was then distilled into water. Wash.
이와 같이 하여 얻어낸 생성물은 그 자체로써 실용화될 수 있다.The product obtained in this way can be put into practical use by itself.
[실시예 3]Example 3
크로몬-2-카르복실산의 제조Preparation of Chromone-2-carboxylic Acid
상기 실시예 2에 의해 얻어진 적색의 걸쭉한 상태의 2-에톡시카르보닐-3-메틸설피닐크로마논에다 50% 황산을 가하고 50~60℃ 온도의 중탕기안에서 1시간동안 가열시킨다.50% sulfuric acid is added to the red, thick 2-ethoxycarbonyl-3-methylsulfinylchromenone obtained in Example 2 and heated in a hot water bath at a temperature of 50 to 60 ° C for 1 hour.
상기 용액을 냉각시킨 다음 얼음물을 부으면 크로몬-2-카르복실산이 침전된다.After cooling the solution, poured ice water to precipitate chromone-2-carboxylic acid.
상기 화합물의 물성을 살펴보면 다음과 같다.Looking at the physical properties of the compound is as follows.
융점:255~260℃Melting Point: 255 ~ 260 ℃
수득률:80%Yield: 80%
원소분석Elemental analysis
이론치:C 63.16% H 3.16%Theoretic value: C 63.16% H 3.16%
실험치:C 63.63% H 3.28%Experimental value: C 63.63% H 3.28%
[실시예 4]Example 4
크로몬-2-카르복실산의 디에틸아민염의 제조Preparation of diethylamine salt of chromone-2-carboxylic acid
무수에탄올중에서 11.4g(0.06몰)의 크로몬-2-카르복실산과 4.4g의 디에틸아민을 1시간동안 환류하에 가열시킨 다음 냉각시키면 염이 침전된다. 이것을 무수알코올과 아세톤의 혼합물중에서 재결정시키면 수용성 백색분말이 얻어지게 된다.In anhydrous ethanol, 11.4 g (0.06 mole) of chromone-2-carboxylic acid and 4.4 g of diethylamine are heated under reflux for 1 hour and then cooled to precipitate salts. This is recrystallized in a mixture of anhydrous alcohol and acetone to obtain a water-soluble white powder.
융점:139℃Melting Point: 139 ℃
수득률:90%Yield: 90%
[실시예 5]Example 5
크로몬-2-카르복실산의 리신염의 제조Preparation of Lysine Salt of Chromon-2-carboxylic Acid
100ml의 에탄올중에서 9.5g(0.05몰)의 크로몬산을 60℃의 온도까지 가열하고 거기에다 10ml의 증류에 용해된 14.6g의 50% 리신을 첨가시켜 완전히 용해시킨다. 그 다음으로 여기에다 100ml의 아세톤을 가하고, -5℃의 온도에서 하룻밤동안 냉각시킨후, 여과건조시키면 담황색분말의 크로몬-2-카르복실산의 리신염 14.8g이 얻어진다.In 100 ml of ethanol, 9.5 g (0.05 mole) of chromonic acid is heated to a temperature of 60 ° C. and dissolved in it by adding 14.6 g of 50% lysine dissolved in 10 ml of distillation. Next, 100 ml of acetone was added thereto, cooled overnight at a temperature of −5 ° C., and then filtered and dried to obtain 14.8 g of a lysine salt of chromone-2-carboxylic acid as pale yellow powder.
수득률:88%Yield: 88%
[실시예 6]Example 6
크로몬-2-카르복실산의 마그네슘염의 제조Preparation of Magnesium Salt of Chromon-2-carboxylic Acid
100ml의 증류수와 10ml의 95% 에탄올의 혼합물에다 19g(0.1몰)의 크로몬-2-카르복실산을 용해시켜서 된 현탁액내에 50ml의 증류수에 5g의 수산화탄산마그네슘을 용해시켜서 된 용액을 첨가시킨다.A solution obtained by dissolving 5 g of magnesium hydroxide in 50 ml of distilled water is added to a suspension of 19 g (0.1 mole) of chromone-2-carboxylic acid in a mixture of 100 ml of distilled water and 10 ml of 95% ethanol.
이 용액을 하룻밤동안 냉각시킨후 45℃의 온도조건하에 진공상태에서 농축시켜서 이때 얻어지는 생성물을 무수에탄올로 재결정시키고 메틸에틸케톤으로 세척한다.The solution was cooled overnight and then concentrated in vacuo under a temperature condition of 45 DEG C. The resulting product was recrystallized from anhydrous ethanol and washed with methyl ethyl ketone.
이때 수득률은 90%이고 이 생성물을 다시 2몰의 H2O로 결정화시킨다.The yield is then 90% and the product is crystallized again with 2 moles of H 2 O.
본 발명은 상술한 실시예에 한정되는 것이 아니라 다른 변형예로도 실시 가능하다.The present invention is not limited to the above-described embodiment but can be implemented in other modifications.
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