KR0148125B1 - Processes for the preparation of 1,4-dihydropyridine - Google Patents

Processes for the preparation of 1,4-dihydropyridine

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KR0148125B1
KR0148125B1 KR1019900010929A KR900010929A KR0148125B1 KR 0148125 B1 KR0148125 B1 KR 0148125B1 KR 1019900010929 A KR1019900010929 A KR 1019900010929A KR 900010929 A KR900010929 A KR 900010929A KR 0148125 B1 KR0148125 B1 KR 0148125B1
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dihydropyridine
general formula
formula
dicarboxylic acid
compound
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KR1019900010929A
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KR920002542A (en
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서정진
홍유화
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연만희
주식회사유한양행
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

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  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

본 발명은 일반식(I)로 표시되는 신규의 1,4-디하이드로피리딘-3,5-디카르복실산모노에스테르 유도체 및 그의 제조방법에 관한 것이다.The present invention relates to a novel 1,4-dihydropyridine-3,5-dicarboxylic acid monoester derivative represented by general formula (I) and a method for producing the same.

Figure kpo00001
Figure kpo00001

상기 일반식(I)중 R1및 R2는 서로 같거나 다른 수소, 할로겐, 또는 니트로이며 ; R3는 2-시아노에틸 또는 메틸티오메틸이다.R 1 and R 2 in formula (I) are the same or different hydrogen, halogen, or nitro; R 3 is 2-cyanoethyl or methylthiomethyl.

Description

1,4-디하이드로피리딘 카복실산 유도체 및 그의 제조방법1,4-dihydropyridine carboxylic acid derivative and preparation method thereof

본 발명은 일반식(I)로 표시되는 신규화합물 즉, 1,4-디하이드로피리딘-3,5-디카르복실산모노에스테르 유도체 및 그의 제조방법에 관한 것이다.The present invention relates to a novel compound represented by general formula (I), that is, 1,4-dihydropyridine-3,5-dicarboxylic acid monoester derivative and a method for producing the same.

Figure kpo00002
Figure kpo00002

상기 일반식(I)중 R1 및 R2는 서로 같거나 다른 수소, 할로겐, 또는 니트로이며 ; R3는 2-시아노에틸 또는 메틸티오메틸이다.R1 and R2 in the general formula (I) are the same or different hydrogen, halogen, or nitro; R 3 is 2-cyanoethyl or methylthiomethyl.

1,4-디하이드로피리딘-3,5-디카르복실산모노에스테르 유도체는 순환기계 의약품으로 유용한 디에스테르류 합성의 중요한 중간체로서 다음과 같은 제조방법이 있다.The 1,4-dihydropyridine-3,5-dicarboxylic acid monoester derivative is an important intermediate of the synthesis of diesters useful as circulatory medicines and has the following preparation method.

1. 대칭성디에스테르류의 알칼리 가수분해방법1. Alkali hydrolysis of symmetric diesters

[J.Heterocycl. chem., 12, 363(1975)]J. Heterocycl. chem., 12, 363 (1975)]

2. 1위의 질소원소를 보호한 대칭성에스테르류를 이용하는 방법2. Method using symmetric esters protecting nitrogen

[chem. Pharm. Bull., 27, 2809(1980)]chem. Pharm. Bull., 27, 2809 (1980)]

3. 시아노에틸에스테르류를 이용한 선택적 알칼리 가수분해 방법3. Selective Alkaline Hydrolysis Method Using Cyanoethyl Esters

[일본공개공보 55-64570(1980)][JP-A 55-64570 (1980)]

4. 트리메틸실릴 요오다이드를 이용한 선택적 가수분해 방법4. Selective Hydrolysis Method Using Trimethylsilyl Iodide

[일본공개공보 61-161263(1986)][JP-A 61-161263 (1986)]

5. 톨루엔 용매중에서 브롬산의 초산용액(HBr/HAc)를 사용하는 산 가수분해방법5. Acid hydrolysis method using acetic acid solution of bromic acid (HBr / HAc) in toluene solvent

[일본공개 특허공보 61-40,262(1986)][Japanese Patent Laid-Open No. 61-40,262 (1986)]

이들의 제조방법은 수율이 극히 낮거나 반응조작이 복잡하거나 까다로우며 또한 브롬산의 초산용액(HBr/HAc)과 같은 유독한 물질을 사용해야 하는 등 많은 문제를 갖고 있으며 또한 1,4-디하이드로피리딘-3,5-디카르복실산의 복잡하고 비대칭적인 에스테르류를 합성하기 위해서는 완화한 조건에서 정교한 선택성과 높은 수율로 1,4-디하이드로피리딘-3,5-디카르복실산모노에스테르 유도체를 제조할 수 있는 방법이 필요하였다.Their production method has many problems, such as extremely low yield, complicated or difficult reaction operation, and the use of toxic substances such as acetic acid solution of bromic acid (HBr / HAc). In order to synthesize complex and asymmetric esters of pyridine-3,5-dicarboxylic acid, the 1,4-dihydropyridine-3,5-dicarboxylic acid monoester derivative is obtained with high selectivity and fine selectivity under mild conditions. There was a need for a method to prepare.

본 발명자들은 1,4-디하이드로피리딘-3,5-디카르복실산모노에스테르 유도체의 완화한 조건에서 정교한 선택성 및 높은 수율로 합성할 것을 목적으로 연구한 결과 특징 1,4-디하이드로피리딘의 알칼리 가수분해 반응을 이용하여 상기 목적을 달성하였다.The present inventors have studied for the purpose of synthesizing with high selectivity and fine selectivity under mild conditions of 1,4-dihydropyridine-3,5-dicarboxylic acid monoester derivatives. The above object was achieved by using an alkali hydrolysis reaction.

본 발명은 일반식 (II)로 표시되는 화합물과 요오도메탄을 반응시켜 일반식 (III)으로 표시되는 화합물을 만들고 이것을 알칼리 조건에서 가수분해하는 것을 특징으로 하는 R3가 2-시아노에틸로 치환된 화합물 (일반식 (Ia)) 즉 1,4-디하이드로피리딘-3,5-디카르복실산모노에스테르 유도체 및 그의 제조방법에 관한 것이다.The present invention provides a compound represented by formula (III) by reacting iodomethane with a compound represented by formula (II), wherein R3 is substituted with 2-cyanoethyl, which is hydrolyzed under alkaline conditions. To a 1,4-dihydropyridine-3,5-dicarboxylic acid monoester derivative and a method for producing the same.

Figure kpo00003
Figure kpo00003

Figure kpo00004
Figure kpo00004

Figure kpo00005
Figure kpo00005

상기 일반식 (Ia), (II), (III)중 R1및 R2는 일반식(I)의 정의와 동일하다.R <1> and R <2> in the said general formula (Ia), (II), (III) is the same as that of the general formula (I).

일반식 (II)로 표시되는 화합물은 일반적으로 알려진 한쯔디하이드로피리딘합성법에 (Hantsch Dihydropyridine Synthesis)따라 용이하게 제조할 수 있다.The compound represented by the general formula (II) can be easily prepared according to the generally known Hanzdihydropyridine Synthesis method (Hantsch Dihydropyridine Synthesis).

일반식 (III)으로 표시되는 화합물은 일반식 (II)로 표시되는 화합물과 요오드메탄을 반응시켜 제조되며 이때에 요오도메탄은 반응물 및 용제로 사용된다. 반응온도는 실온 또는 요오도메탄의 비점에서 수행될 수 있으며 반응시간은 6∼24기간이 소요된다. 이 때에 일반식 (III)으로 표시되는 화합물은 거의 정량적으로 얻은 수 있다.The compound represented by the general formula (III) is prepared by reacting the compound represented by the general formula (II) with iodine methane, where iodomethane is used as a reactant and a solvent. The reaction temperature can be carried out at room temperature or at the boiling point of iodomethane and the reaction time takes 6 to 24 hours. At this time, the compound represented by general formula (III) can be obtained almost quantitatively.

R3가 2-시아노에틸로 치환된 일반식(Ia)로 표시되는 본 발명의 화합물은 일반식 (III)로 표시되는 화합물을 물과 저급알콜 예를들면 메탄올, 에탄올, 이소프로필알콜등의 혼합용제를 사용하여 알칼리금속의 수산화물의 묽은 수용액을 점적하여 가수분해하여 제조할 수 있다. 이 때에 종말점의 pH는 10~12이며 구체적으로는 pH 11±0.5가 적당하다. 적정속도는 1시간이내에 수행되며 구체적으로는 30분이 가장 적당하며 이 때의 온도는 0℃~20℃에서 수행되나 대부분 10℃이하에서 실시할 수 있고 대부분의 반응이 정량적으로 일어나며 묽은 산으로 산석하여 높은 수율로 목적물을 얻을 수 있다. 본 발명의 제조방법은 종래의 방법에 비해 매우 정교한 가수분해 방법이다. 즉 가수분해가 잘 일어나는 2-시아노에틸기가 존재함에도 불구하고 선택적으로 메틸요오드염쪽의 에스테르에서 가수분해가 일어나 높은 수율로 상기 일반식(I)로 표시되는 화합물을 얻을 수 있다.The compound of the present invention represented by the general formula (Ia) in which R 3 is substituted with 2-cyanoethyl may be substituted with water and lower alcohols such as methanol, ethanol, and isopropyl alcohol. A dilute aqueous solution of an alkali metal hydroxide may be added dropwise and hydrolyzed using a mixed solvent. At this time, the pH of the end point is 10-12, specifically, pH 11 ± 0.5 is suitable. The titration rate is carried out within 1 hour, specifically 30 minutes is most suitable at this time, the temperature is carried out at 0 ℃ ~ 20 ℃, but most can be carried out below 10 ℃, most reactions occur quantitatively, The desired product can be obtained in high yield. The production method of the present invention is a very sophisticated hydrolysis method compared to the conventional method. In other words, despite the presence of 2-cyanoethyl group which is well hydrolyzed, the compound represented by the above general formula (I) can be obtained in a high yield by selectively hydrolyzing at the ester of the methyl iodide salt side.

R3가 메틸티오메틸로 치환된 화합물 (일반식 (Ib))은 상기의 제조방법으로 제조한 일반식 (Ia)로 표시되는 화합물로부터 공지의 방법에 따라 일반식 (IV)의 화합물을 만들고 이것을 공지의 방법에 따라 가수분해하여 제조할 수 있다.A compound in which R 3 is substituted with methylthiomethyl (formula (Ib)) is a compound of formula (IV) prepared according to a known method from a compound represented by formula (Ia) prepared by the above-described preparation method and It can be manufactured by hydrolysis according to a known method.

Figure kpo00006
Figure kpo00006

Figure kpo00007
Figure kpo00007

상기 일반식 (Ib) 또는 (IV)에서 R1및 R2는 상기의 정의와 동일하다.R 1 and R 2 in the general formula (Ib) or (IV) are the same as defined above.

일반식 (IV)로 표시되는 화합물은 (Ia)로 표시되는 화합물을 트리에틸아민, 탄산수나트륨, 탄산나트륨, 탄산칼륨, 탄산수소칼륨 등과 같은 산수용체를 사용하여 아세토니트릴중에서 클로로메틸설파이드와 반응시켜 합성할 수 있으며, 일반식 (IV)의 화합물은 다시 물 및 에탄올 혼합용제에서 금속알칼리의 수산화물의 묽은 수용액중에서 가수분해시켜 일반식 (Ib)의 화합물로 제조할 수 있다. 이때에 반응시간은 6∼24시간이며, 반응온도는 0℃~40℃에서 수행되나 대부분 실온에서 실시하며 5℃이하의 저온에서 묽은 염산으로 산석하여 높은 수율로 목적물을 얻을 수 있다.The compound represented by formula (IV) is synthesized by reacting the compound represented by formula (Ia) with chloromethyl sulfide in acetonitrile using an acid acceptor such as triethylamine, sodium carbonate, sodium carbonate, potassium carbonate, potassium hydrogen carbonate and the like. The compound of the general formula (IV) may be prepared in the form of the compound of the general formula (Ib) by hydrolysis in a dilute aqueous solution of hydroxide of metal alkali in water and ethanol mixed solvent. At this time, the reaction time is 6 to 24 hours, the reaction temperature is carried out at 0 ℃ ~ 40 ℃, but is carried out mostly at room temperature and can be obtained in high yield by diluting with dilute hydrochloric acid at low temperature below 5 ℃.

[실시예 1]Example 1

2,6-디메틸-4-(3‘-니트로페닐)-1,4-디하이드로피리딘-3,5-디카르복실산3-(2’-시아노에틸) 에스테르 5-(2‘메틸티오에틸)에스테르2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3- (2'-cyanoethyl) ester 5- (2'methylthio Ethyl) ester

3-니트로벤즈알데히드 (5.63g, 0.037mole), 2-메틸티오에틸 아세토아세테이트(7.05g, 0.04mole) 및 피페리딘 0.5ml를 무수벤젠 150ml에 혼합하고 3시간동안 환류한다. 반응액을 감압농축하고 여기에 2‘-시아노에틸 3-아미노크로토네이트 (5.7g, 0.037mole) 및 이소프로필알콜 150ml를 가하여 혼합한 후 12시간동안 환류한다. 감압농축하여 생성된 적색유상 물질을 실리카겔 크로마토그라피를 사용하여 (용출제에틸아세테이트 : n-헥산 =1:1 (v/v)) 정제한다.3-nitrobenzaldehyde (5.63 g, 0.037 mole), 2-methylthioethyl acetoacetate (7.05 g, 0.04 mole) and 0.5 ml of piperidine are mixed in 150 ml of anhydrous benzene and refluxed for 3 hours. The reaction solution was concentrated under reduced pressure, 2'-cyanoethyl 3-aminocrotonate (5.7 g, 0.037 mole) and 150 ml of isopropyl alcohol were added thereto, mixed and refluxed for 12 hours. The red oily substance produced by concentration under reduced pressure is purified using silica gel chromatography (eluent ethyl acetate: n-hexane = 1: 1 (v / v)).

수율 : 7g(42.5%)Yield: 7 g (42.5%)

융점 : 148~150℃Melting Point: 148 ~ 150 ℃

Figure kpo00008
Figure kpo00008

[실시예 2]Example 2

2,6-디메틸-4-(3‘-니트로페닐)-1,4-디하이드로피리딘-3,5-디카르복실산3-(2’-시아노에틸) 에스테르 5-(2‘메틸티오)에틸에스테르 메틸요오다이드염2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3- (2'-cyanoethyl) ester 5- (2'methylthio Ethyl ester methyl iodide salt

2,6-디메틸-4-(3‘-니트로페닐)-1,4-디하이드로피리딘-3,5-디카르복실산 3-(2’-시아노에틸) 에스테르 5-(2‘메틸티오에틸)에스테르 (11.14g, 0.025mole)을 메틸요오다이드 50ml에 현탁시키고 16시간동안 교반한다. 용매를 감압농축하여 제거하고 잔류물에 에테르 (150ml)를 가하여 교반한다. 생성된 황색결정을 여과하여 분리하고 건조한다.2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3- (2'-cyanoethyl) ester 5- (2'methylthio Ethyl) ester (11.14 g, 0.025 mole) is suspended in 50 ml of methyl iodide and stirred for 16 hours. The solvent is removed by concentration under reduced pressure, and ether (150 ml) is added to the residue, followed by stirring. The resulting yellow crystals are separated by filtration and dried.

수율 : 13.64g(92%)Yield: 13.64 g (92%)

융점 : 140~142℃Melting Point: 140 ~ 142 ℃

Figure kpo00009
Figure kpo00009

Figure kpo00010
Figure kpo00010

[실시예 3]Example 3

2,6-디메틸-4-(3‘-니트로페닐)-1,4-디하이드로피리딘-3,5-디카르복실산 3-(2’-시아노에틸) 에스테르2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3- (2'-cyanoethyl) ester

2,6-디메틸-4-(3‘-니트로페닐)-1,4-디하이드로피리딘-3,5-디카르복실산 3-(2’-시아노에틸) 에스테르 5-(2‘메틸티오)에틸에스테르 메틸요오다이드염(11.75g, 0.02mole)을 에탄올 100ml 및 물 100ml의 혼액에 현탁한다. 여기에 2-수산화나트륨용액을 서서히 가하여 pH를 11~12로 조정하면 맑은 황색용액이 된다. 1시간동안 교반한 후 d-염산을 가하여 pH 1~2로 하면 황색 침전이 생성된다. 여과하고 오산화인 데시케이터에서 진공건조하에 황색결정을 얻는다.2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3- (2'-cyanoethyl) ester 5- (2'methylthio ) Ethyl ester methyl iodide salt (11.75 g, 0.02 mole) is suspended in a mixture of 100 ml of ethanol and 100 ml of water. The pH is adjusted to 11 ~ 12 by slowly adding 2-sodium hydroxide solution to give a clear yellow solution. After stirring for 1 hour, when d-hydrochloric acid is added to pH 1-2, yellow precipitates are formed. Filtration and yellow crystals are obtained under vacuum drying in a phosphorus pentoxide.

수율 : 7.43g (92%)Yield: 7.43 g (92%)

융점 : 178~181℃Melting Point: 178 ~ 181 ℃

Figure kpo00011
Figure kpo00011

Figure kpo00012
Figure kpo00012

[실시예 4]Example 4

2,6-디메틸-4-(3‘-니트로페닐)-1,4-디하이드로피리딘-3,5-디카르복실산 3-메틸티오메틸에스테르 5-(2‘-시아노에틸) 에스테르2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-methylthiomethylester 5- (2'-cyanoethyl) ester

2,6-디메틸-4-(3‘-니트로페닐)-1,4-디하이드로피리딘-3,5-디카르복실산 3-(2‘-시아노에틸) 에스테르 (6.68g, 0.018mole)을 아세토니트릴 (100ml)에 현탁시키고 빙수욕상에서 0℃로 냉각한다. 여기에 트리에틸아민 (5ml, 2eq)를 가하고 30분간 교반하면 맑게 용해된다. 여기에 클로로메틸메틸설파이드 (2.3㎖, 1.5eq.)가하고 실온으로 하여 72시간동안 교반한다. 반응혼합물을 감압농축하여 용매를 제거하고 에틸아세테이트 (100ml)를 가한후 물 및 포화식염수로 세척한다. 유기층을 분리하여 무수황산마그네슘으로 건조한 후 농축하여 생성된 황색고체를 에탄올로 재결정한다.2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3- (2'-cyanoethyl) ester (6.68 g, 0.018 mole) Is suspended in acetonitrile (100 ml) and cooled to 0 ° C. on an ice water bath. Triethylamine (5ml, 2eq) was added thereto and stirred for 30 minutes to dissolve clearly. Chloromethylmethylsulfide (2.3 ml, 1.5 eq.) Was added thereto, and the mixture was stirred at room temperature for 72 hours. The reaction mixture is concentrated under reduced pressure to remove the solvent, ethyl acetate (100 ml) is added, and the mixture is washed with water and brine. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated to recrystallize the resulting yellow solid with ethanol.

수율 : 7.2g (88.1%)Yield: 7.2 g (88.1%)

융점 : 147~149℃Melting Point: 147 ~ 149 ℃

Figure kpo00013
Figure kpo00013

[실시예 5]Example 5

2,6-디메틸-4-(3‘-니트로페닐)-1,4-디하이드로피리딘-3,5-디카르복실산 3-메틸티오메틸에스테르2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-methylthiomethylester

2,6-디메틸-4-(3‘-니트로페닐)-1,4-디하이드로피리딘-3,5-디카르복실산 3-메틸티오메틸에스테르 5-(2‘-시아노에틸) 에스테르 (4.31g, 0.01mole)을 물 50ml 및 에탄올 50ml에 현탁시킨 후 2N-수산화나트륨(6ml)를 가하고 실온에서 4시간동안 교반하면 맑은 황색용액이 된다. 여기에 3N-염산을 가하여 pH 1~2로 하여 생성된 황색침전을 여과분리하여 건조한다.2,6-dimethyl-4- (3'-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-methylthiomethylester 5- (2'-cyanoethyl) ester ( 4.31 g, 0.01 mole) is suspended in 50 ml of water and 50 ml of ethanol, and then 2N-sodium hydroxide (6 ml) is added and stirred at room temperature for 4 hours to give a clear yellow solution. 3N hydrochloric acid was added thereto to pH 1-2, and the yellow precipitate produced by filtration was dried by filtration.

수율 : 3.14g (83%)Yield: 3.14 g (83%)

융점 : 184~186℃Melting Point: 184 ~ 186 ℃

Figure kpo00014
Figure kpo00014

Claims (3)

하기 일반식(I)로 표시되는 1,4-디하이드로피리딘-3,5-디카르복실산모노에스테르 유도체.1,4-dihydropyridine-3,5-dicarboxylic acid monoester derivative represented by the following general formula (I).
Figure kpo00015
Figure kpo00015
 상기에서 R1및 R2는 서로 같거나 다른 수소, 할로겐, 또는 니트로이며, R3는 2-시아노에틸 또는 메틸티오메틸이다.Wherein R 1 and R 2 are the same or different hydrogen, halogen, or nitro and R 3 is 2-cyanoethyl or methylthiomethyl. 일반식 (II)의 화합물과 요오드메탄을 반응시켜 일반식 (III)의 화합물을 제조한 후, 이를 알칼리 조건에서 가수분해하는 것을 특징으로 하는 일반식 (Ia)로 표시되는 1,4-디하이드로피리딘-3,5-디카르복실산모노에스테르 유도체의 제조방법.1,4-dihydro represented by general formula (Ia) characterized by reacting a compound of general formula (II) with iodine methane to produce a compound of general formula (III), and then hydrolyzing it under alkaline conditions. Process for the preparation of pyridine-3,5-dicarboxylic acid monoester derivatives.
Figure kpo00016
Figure kpo00016
Figure kpo00017
Figure kpo00017
 상기에서 R1및 R2는 서로 같거나 다른 수소, 할로겐, 또는 니트로이다.Wherein R 1 and R 2 are the same or different hydrogen, halogen, or nitro. 일반식 (Ia)의 화합물로부터 일반식 (IV)의 화합물을 제조한 후, 이를 가수분해하는 것을 특징으로 하는 일반식 (Ib)로 표시되는 1,4-디하이드로피리딘-3,5-디카르복실산모노에스테르 유도체의 제조방법.1,4-dihydropyridine-3,5-dicar represented by formula (Ib) characterized by preparing a compound of formula (IV) from a compound of formula (Ia) and then hydrolyzing it Method for producing acid monoester derivative.
Figure kpo00018
Figure kpo00018
 상기에서 R1및 R2는 서로 같거나 다른 수소, 할로겐, 또는 니트로이다.Wherein R 1 and R 2 are the same or different hydrogen, halogen, or nitro.
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