KR940009792B1 - Process for preparing benzoxazine carboxylic acid derivatives - Google Patents
Process for preparing benzoxazine carboxylic acid derivatives Download PDFInfo
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- KR940009792B1 KR940009792B1 KR1019910020043A KR910020043A KR940009792B1 KR 940009792 B1 KR940009792 B1 KR 940009792B1 KR 1019910020043 A KR1019910020043 A KR 1019910020043A KR 910020043 A KR910020043 A KR 910020043A KR 940009792 B1 KR940009792 B1 KR 940009792B1
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Abstract
Description
본 발명은 다음 구조식(Ⅰ)로 표시되는 베즈옥사진 카르복실산 유도체의 제조방법에 관한 것이다.The present invention relates to a method for producing a benzoxazine carboxylic acid derivative represented by the following structural formula (I).
상기 구조식에서 X는 할로겐 원자를 표시하며, Z는 단일치환된 아미노기, 이 치환된 아미노기 또는 헤테로 원자를 함유할 수 있는 환상 치환 아미노기를 표시하고, R은 수소 혹은 탄소수 1-6개의 알킬기를 의미한다.In the structural formula, X represents a halogen atom, Z represents a monosubstituted amino group, a cyclic substituted amino group which may contain a substituted amino group or a hetero atom, and R means hydrogen or an alkyl group having 1-6 carbon atoms. .
상기 구조식(Ⅰ) 화합물중에서 특히 X가 불소이고, Z가 4-메틸피페라지닐기이며, R이 메틸기인 화합물은 그램 양성균 및 그램 음성균에 대하여 탁월한 항균 활성을 갖는 퀴놀론계 항생제인 오플록사신(ofloxacin)으로 널리 알려져 있다.Among the compounds of the above formula (I), in particular, X is fluorine, Z is 4-methylpiperazinyl group, and R is methyl group, which is oxloxacin, a quinolone antibiotic having excellent antibacterial activity against gram positive and gram negative bacteria. ofloxacin).
종래의 알려진 상기 구조식(Ⅰ) 화합물의 제조방법을 보면, 일본특허공고 소58-72589호 및 한국특허공고 제84-2141호에 다음과 같은 제법이 소개되어 있다.As a known method for preparing the compound of formula (I), the following production method is introduced in Japanese Patent Publication No. 58-72589 and Korean Patent Publication No. 84-2141.
상기 반응식에서 X, R , Z는 상술한 바와 같다.X, R, Z in the above scheme is as described above.
그러나, 이러한 종래의 방법에서는 마지막 공정에서 4-메틸피페라진을 도입할때 100 내지 130℃의 고온에서 반응시켜야 하고, 디메틸설폭사이드나 디메틸포름아미드와 같은 극성, 고비점의 용매를 사용해야 하며 반응에도 장시간이 소요될 뿐 아니라 마지막 공정의 수율도 43%에 불과한등 개선의 여지가 많이 남아 있었다.However, in this conventional method, when introducing 4-methylpiperazine in the last step, the reaction must be performed at a high temperature of 100 to 130 ° C, and a polar, high boiling solvent such as dimethyl sulfoxide or dimethylformamide should be used. Not only did it take a long time, but the yield of the last process was only 43%.
따라서 본 발명자들은 종래기술의 이러한 문제점을 개선하기 위하여 꾸준히 연구해 오던중, 8번 위치에 4-메틸피페라진이 미리 도입되어 있는 신규한 반응 중간체를 사용하면 종래 방법에 비해 보다 간편한 공정으로 고수율의 목적물을 제조할 수 있다는 사실을 알고 본 발명에 이르게 되었다.Therefore, the present inventors have been steadily studying to improve these problems of the prior art, using a new reaction intermediate that is pre-introduced with 4-methylpiperazine in position 8, the higher yield in a simpler process than the conventional method The present invention has been realized by knowing that the object of the present invention can be prepared.
본 발명의 목적은, 상기 구조식(Ⅰ)에 벤즈옥사진 카르복실산 유도체를 제조함에 있어서 보다 간편한 공정으로 고수율의 목적물을 얻을 수 있는 새로운 방법을 제공하는 것이다.An object of the present invention is to provide a novel method for obtaining a high yield of the target product in a simpler step in the preparation of benzoxazine carboxylic acid derivatives in the above formula (I).
이하, 본 발명을 상세히 설명하면 다음과 같다.Hereinafter, the present invention will be described in detail.
본 발명은 다음 구조식(Ⅰ)의 벤즈옥사진 카르복실산 유도체를 제조함에 있어서, 다음 구조식(Ⅱ)의 화합물을 에톡시메틸렌말론산 디에틸과 반응시켜 구조식(Ⅲ)의 화합물을 얻고, 여기에다 다중인산이나 그의 에스테르, 디페닐에테르, 또는 디페닐에테르와 바이페닐의 혼합용액중 어느 하나를 첨가, 가열하여 구조식(Ⅳ)의 화합물을 제조한 다음, 이를 가수분해시킴을 특징으로 하는 다음 구조식(Ⅰ)의 벤즈옥사진 카르복실산 유도체의 제조방법이다.The present invention provides a compound of formula (III) by reacting a compound of formula (II) with diethyl ethoxymethylenemalonic acid in preparing a benzoxazine carboxylic acid derivative of formula (I): The compound of formula (IV) is prepared by adding and heating phosphoric acid or its ester, diphenyl ether, or a mixed solution of diphenyl ether and biphenyl, and then hydrolyzing it. Benzoxazine carboxylic acid derivative of
상기 구조식에서, X, Z, R은 상술한 바와 같다.In the above structural formula, X, Z, R are as described above.
구조식(Ⅲ)의 화합물은 구조식(Ⅱ)의 화합물을 에톡시말론산 디에틸과 반응시키되 초산과 벤젠의 혼합용액중에서 환류반응시키거나, 초산, 염산등의 산 조건하에서, 또는 무용매중에서 20 내지 130℃의 온도로 1 내지 12시간동안 교반 반응시켜서 제조할 수 있다. 이때 상기 구조식(Ⅲ)의 화합물은 정량적인 수율로 결정화되는데 이를 분리하여도 좋고, 분리하지 않고 직접 다음 반응을 진행하여도 좋다.The compound of formula (III) may be reacted with diethyl ethoxymalonic acid with reflux in a mixed solution of acetic acid and benzene, under acidic conditions such as acetic acid, hydrochloric acid, or in a solvent-free solution. It can be prepared by stirring and stirring at a temperature of 130 ° C. for 1 to 12 hours. In this case, the compound of formula (III) is crystallized in quantitative yield, and may be separated, or may proceed directly to the next reaction without separation.
다음으로, 구조식(Ⅲ)의 화합물에 다중인산 혹은 그의 에스테르, 디페닐에테르, 또는 디페닐에테르와 바이페닐의 혼합용액을 가하고 130℃ 내지 250℃의 온도로 구조식(Ⅳ)의 화합물을 얻고, 계속해서 구조식(Ⅳ)의 화합물을 가수분해하면 본 발명의 목적화합물인 구조식(Ⅰ)의 화합물을 얻는다.Next, polyphosphoric acid or its ester, diphenyl ether, or a mixed solution of diphenyl ether and biphenyl is added to the compound of formula (III) to obtain a compound of formula (IV) at a temperature of 130 ° C to 250 ° C, and then By hydrolyzing the compound of formula (IV), the compound of formula (I), which is the target compound of the present invention, is obtained.
한편, 본 발명에서 출발물질로 사용된 구조식(Ⅱ)의 화합물은 신규물질로서 다음과 같은 방법으로 제조할 수 있다.On the other hand, the compound of formula (II) used as a starting material in the present invention can be prepared by the following method as a novel material.
상기 반응식에서 X, Z, R은 상술한 바와 같다.X, Z, R in the scheme is as described above.
이하, 실시예를 들어 본 발명을 설명하면 다음과 같다.Hereinafter, the present invention will be described with reference to Examples.
[제조예 1][Production Example 1]
7-플루오로-8-(4-메틸피페라지닐)-2, 3-디히디로-3-메틸-4H-벤즈옥사진의 제조Preparation of 7-fluoro-8- (4-methylpiperazinyl) -2,3-dihydrodi-3-methyl-4H-benzoxazine
2, 3-디플루오로-6-니트로페놀(105g, 60mmole)과 4-메틸피페라진(8.6g, 85mmole)을 반응시켜 얻은 2-(4-메틸피페라지닐)-3-플루오로-6-니트로페놀 염산염(18, 7g)을 클로로포름(100ml)에 용해시켜 pH 9.0으로 조정하고, 클로로포름층을 분리한다. 추출물을 건조시켜 진공 농축하고, 이를 아세톤에 넣고 모노클로아세톤(2.7g)과 요오드화칼륨(0.31g)을 가하고 환류시켰다. 반응 완결후에, 불용물질을 제거하고, 잔사를 클로로포름에 용해시켜 포화식염수로 세척하고 건조시킨 후 재결정하여 2-아세토닐옥시-3-(4-메틸피페라지닐)-4-플루오로니트로벤젠(3.5g)을 얻었다.2- (4-methylpiperazinyl) -3-fluoro-6 obtained by reacting 2,3-difluoro-6-nitrophenol (105g, 60mmole) with 4-methylpiperazine (8.6g, 85mmole) -Nitrophenol hydrochloride (18, 7 g) is dissolved in chloroform (100 ml), adjusted to pH 9.0, and the chloroform layer is separated. The extract was dried and concentrated in vacuo, which was added to acetone and added to monocloacetone (2.7 g) and potassium iodide (0.31 g) to reflux. After completion of the reaction, the insolubles were removed, the residue was dissolved in chloroform, washed with saturated brine, dried and recrystallized to give 2-acetonyloxy-3- (4-methylpiperazinyl) -4-fluoronitrobenzene ( 3.5 g) was obtained.
상기 생성물을 에틸알콜(150ml)에 용해한 후 활성화된 라니 니켈(2ml)을 넣고 상압하, 25℃에서 2시간 동안 접촉환원 반응시키고, 촉매를 여과에 의해 제거하고 에틸알콜로 3회 세척하였다. 용매를 증발시킨 후 클로로포름에 용해하고 활성탄으로 처리하여 갈색 오일 형태의 7-플루오로-8-(4-메틸피페라지닐)-2, 3-디히디로-3-메틸-4H-벤즈옥사진(2.91g)을 얻었다.After dissolving the product in ethyl alcohol (150ml), activated Raney Nickel (2ml) was added thereto, and under reduced pressure, catalytic reduction was carried out at 25 ° C for 2 hours. The catalyst was removed by filtration and washed three times with ethyl alcohol. The solvent was evaporated and then dissolved in chloroform and treated with activated charcoal to give 7-fluoro-8- (4-methylpiperazinyl) -2, 3-dihydrodi-3-methyl-4H-benzoxazine in brown oil form. (2.91 g) was obtained.
[실시예 1]Example 1
제조예 1에서 수득한 7-플루오로-8-(4-메틸피페라지닐)-2, 3-디히디로7-fluoro-8- (4-methylpiperazinyl) -2,3-dihydro obtained from Preparation Example 1
-3-메틸-4H-벤즈옥사진(4.0g, 15.08mmole)을 디에틸에폭시메틸렌 말로네이트(3.94g, 15.08mmole)에 넣고 교반하면서 135℃로 가열하여 1시간동안 반응시킨 후 다중인산에틸(14g)을 넣고 가열하여 145℃의 온도에서 1시간동안 교반후 냉수를 가했다. 완전히 냉각한 후 클로로포름으로 추출한 추출물을 포화식염수로 세척, 건조하고 농축하였다. 이 잔사를 에탄올과 재결정하여 9-플루오로-3-메틸-10-(4-메틸-1-피페라지닐)-7-옥소-2, 3-디히드로-7H-피라도[1, 2, 3-de][1, 4]벤즈옥사진-6-카르복실산 에틸(4.4g, 수율 75%)을 얻었다.-3-Methyl-4H-benzoxazine (4.0g, 15.08mmole) was added to diethylepoxymethylene malonate (3.94g, 15.08mmole), heated to 135 ° C with stirring and reacted for 1 hour, followed by ethyl polyphosphate ( 14 g) was added thereto, and the mixture was heated, stirred for 1 hour at a temperature of 145 ° C, and cold water was added thereto. After cooling completely, the extract extracted with chloroform was washed with saturated brine, dried and concentrated. The residue was recrystallized from ethanol to give 9-fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-2, 3-dihydro-7H-pyrado [1, 2, 3-de] [1,4] benzoxazine-6-ethyl carboxylic acid (4.4 g, yield 75%) was obtained.
1HNMR : (TFA) δ1.2~1.7(m, 6H), 2.4(s, 3H), 2.62(m, 4H), 3.2(m, 4H), 3.7~4.4(m, 5H), 8.4(d, 1H), 9.3(s, 1H) 1 HNMR: (TFA) δ 1.2 to 1.7 (m, 6H), 2.4 (s, 3H), 2.62 (m, 4H), 3.2 (m, 4H), 3.7 to 4.4 (m, 5H), 8.4 (d , 1H), 9.3 (s, 1H)
IR(cm-1) : 3004, 2981, 1735, 1720, 1625IR (cm -1 ): 3004, 2981, 1735, 1720, 1625
[실시예 2]Example 2
제조예 1에서 수득한 7-플루오로-8-(4-메틸피페라지닐)-2, 3-디히디로-3-메틸-4H-벤즈옥사진(4.0g, 15.08mmole)을 디에틸에톡시메틸렌 말로네이트(3.9g, 15.08 mmole)에 넣고 교반하면서 130℃로 가열하여 1시간동안 반응시킨 후 진공에서 농축하였다. 잔사에 디페닐에테르와 바이페닐의 혼합물(1 : 4) 50ml를 가하여 1시간동안 환류시켰다. 반응 완결후, 혼합물을 냉각시킨후 실시예(Ⅰ)와 동일한 방법으로 처리하여 9-플루오로-3-메틸-10-[4-메틸-1-피페라지닐]-7-옥소-2, 3-디히드로-7H-피라도[1, 2, 3-de][1, 4]벤즈옥사진-6-카르복실산에틸(4.4g, 수율 75.0%)를 얻었다.7-Fluoro-8- (4-methylpiperazinyl) -2 and 3-dihydrodimethyl-3-H-benzoxazine (4.0 g, 15.08 mmoles) obtained in Preparation Example 1 were added to diethyl. It was added to methoxymethylene malonate (3.9 g, 15.08 mmole), heated to 130 ° C. under stirring, and reacted for 1 hour, followed by concentration in vacuo. 50 ml of a mixture of diphenyl ether and biphenyl (1: 4) was added to the residue, and the mixture was refluxed for 1 hour. After completion of the reaction, the mixture was cooled and treated in the same manner as in Example (I) to give 9-fluoro-3-methyl-10- [4-methyl-1-piperazinyl] -7-oxo-2, 3 -Dihydro-7H-pyrado [1,2,3-de] [1,4] benzoxazine-6-ethyl carboxylate (4.4 g, yield 75.0%) was obtained.
[실시예 3]Example 3
제조예 1에서 수득한 7-플루오로-8-(4-메틸피페라지닐)-2, 3-디히디로-3-메틸-4H-벤즈옥사진(4.0g, 15.08mmole)을 디에틸에톡시메틸렌 말로네이트(3.94g, 15.08 mm ole)에 넣고 교반하면서 130℃로 가열하여 1시간동안 반응시킨 후 진공에서 농축하였다. 잔사에 디페닐 에테르를 가하여 250℃에서 1시간동안 잘 교반하였다. 반응이 완결된 후, 혼합물을 냉각시키고 실시예 1과 동일한 방법으로 처리하여 9-플루오로-3-메틸-10-[4-메틸-1-피페라지닐]-7-옥소-2, 3-디히드로-7H-피라도[1, 2, 3-de][1, 4]벤즈옥사진-6-카르복실산 에틸(4.29g, 수율 73.0%)를 얻었다.7-Fluoro-8- (4-methylpiperazinyl) -2 and 3-dihydrodimethyl-3-H-benzoxazine (4.0 g, 15.08 mmoles) obtained in Preparation Example 1 were added to diethyl. It was added to methoxymethylene malonate (3.94 g, 15.08 mm ole), heated to 130 ° C. under stirring, and reacted for 1 hour, followed by concentration in vacuo. Diphenyl ether was added to the residue, and the mixture was stirred well at 250 ° C for 1 hour. After the reaction was completed, the mixture was cooled and treated in the same manner as in Example 1 to give 9-fluoro-3-methyl-10- [4-methyl-1-piperazinyl] -7-oxo-2, 3- Dihydro-7H-pyrado [1,2,3-de] [1,4] benzoxazine-6-ethyl carboxylic acid (4.29 g, yield 73.0%) was obtained.
[실시예 4]Example 4
제조예 1에서 수득한 7-플루오로-8-(4-메틸피페라지닐)-2, 3-디히드로-3-메틸-4H-벤즈옥사진(4.0g, 15.08mmole)을 초산과 벤젠의 혼합물에 넣고 잘 교반한 후 디에틸에톡시메틸렌 말로네이트(3.94g, 15.08mmole)를 넣고 2시간동안 환류시켰다. 진공하에서 농축하고 잔사를 클로로로름 250ml로 추출한 후 포화 소금물로 3번 세척하고 잘 건조시킨다음 여과하여 농축하였다. 디페닐에테르와 바이페닐의 혼합물 50ml를 가하여 1시간 동안 환류시켰다. 반응이 완결된 후, 혼합물을 냉각시키고 실시예 1과 동일한 방법으로 처리하여 9-플루오로-3-메틸-10-4-메틸-1-피페라지닐-7-옥소-2, 3-디히드로-7H-피라도[1, 2, 3-de][1, 4]벤즈옥사진-6-카르복실산 에틸(3.93g, 수율 67% )을 얻었다.7-Fluoro-8- (4-methylpiperazinyl) -2 and 3-dihydro-3-methyl-4H-benzoxazine (4.0 g, 15.08 mmol) obtained in Preparation Example 1 were prepared using acetic acid and benzene. After the mixture was stirred well, diethylethoxymethylene malonate (3.94 g, 15.08 mmol) was added thereto, and the mixture was refluxed for 2 hours. Concentrated in vacuo and the residue was extracted with 250 ml of chlorolol, washed three times with saturated brine, dried well and then filtered and concentrated. 50 ml of a mixture of diphenyl ether and biphenyl were added and refluxed for 1 hour. After the reaction was completed, the mixture was cooled and treated in the same manner as in Example 1 to give 9-fluoro-3-methyl-10-4-methyl-1-piperazinyl-7-oxo-2, 3-dihydro -7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-ethyl carboxylic acid (3.93 g, yield 67%) was obtained.
[실시예 5]Example 5
실시예 1 내지 4에서 얻은 9-플루오로-3-메틸-10-4-메틸-1-피페라지닐-7-옥소-2, 3-디히드로-7H-피라도[1, 2, 3-de][1, 4]벤즈옥사진-6-카르복실에틸(3.0g, 7.7mmole)을 진한 염산과 초산의 혼합물(500ml)에 가한 후 그 혼합물을 100∼110℃의 온도에서 3시간동안 교반하고 혼합물을 진공에서 농축하고 물을 첨가한 후 클로로포름(150ml)으로 추출하고 건조, 농축하였다. 그 잔사를 에탄올로 재결정하여 9-플루오로-3-메틸-10-(4-메틸-1-피페라지닐)-7-옥소-2, 3-디히드로-7H-피라도[1, 2, 3-de][1, 4]벤즈옥사진-6-카르복실산(2.783g, 수율 100%)를 무색 침상 결정으로 얻었다. 융점 250∼258-(분해)9-Fluoro-3-methyl-10-4-methyl-1-piperazinyl-7-oxo-2, 3-dihydro-7H-pyrido obtained in Examples 1 to 4 [1, 2, 3- de] [1,4] benzoxazine-6-carboxyethyl (3.0 g, 7.7 mmole) was added to a mixture of concentrated hydrochloric acid and acetic acid (500 ml), and the mixture was stirred at a temperature of 100 to 110 ° C. for 3 hours. The mixture was concentrated in vacuo, water was added, extracted with chloroform (150 ml), dried and concentrated. The residue was recrystallized from ethanol to give 9-fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-2, 3-dihydro-7H-pyrado [1, 2, 3-de] [1,4] benzoxazine-6-carboxylic acid (2.783 g, yield 100%) was obtained as colorless needles. Melting Point 250-258- (Decomposition)
1H NMR : (TFA) δ1.3(d, 3H), 2.35(s, 3H), 2.6(m, 4H), 3.1(m, 4H), 3.5~4.4(m, 3H), 8.3(d, 1H), 9.7(s, 1H) 1 H NMR: (TFA) δ 1.3 (d, 3H), 2.35 (s, 3H), 2.6 (m, 4H), 3.1 (m, 4H), 3.5 to 4.4 (m, 3H), 8.3 (d, 1H), 9.7 (s, 1H)
IR(cm-1) : 3540, 2999, 2985, 1718, 1702, 1630IR (cm -1 ): 3540, 2999, 2985, 1718, 1702, 1630
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