KR950001277B1 - Process for the preparation of oxybenzene derivatives - Google Patents

Process for the preparation of oxybenzene derivatives Download PDF

Info

Publication number
KR950001277B1
KR950001277B1 KR1019910024648A KR910024648A KR950001277B1 KR 950001277 B1 KR950001277 B1 KR 950001277B1 KR 1019910024648 A KR1019910024648 A KR 1019910024648A KR 910024648 A KR910024648 A KR 910024648A KR 950001277 B1 KR950001277 B1 KR 950001277B1
Authority
KR
South Korea
Prior art keywords
formula
cpd
compound
solvent
basic
Prior art date
Application number
KR1019910024648A
Other languages
Korean (ko)
Other versions
KR930012679A (en
Inventor
김찬우
박상후
Original Assignee
주식회사 코오롱
하기주
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 주식회사 코오롱, 하기주 filed Critical 주식회사 코오롱
Priority to KR1019910024648A priority Critical patent/KR950001277B1/en
Publication of KR930012679A publication Critical patent/KR930012679A/en
Application granted granted Critical
Publication of KR950001277B1 publication Critical patent/KR950001277B1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
    • C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
    • C07C201/16—Separation; Purification; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/39—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by esterified hydroxy groups
    • C07C205/42—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by esterified hydroxy groups having nitro groups or esterified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C205/43—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by esterified hydroxy groups having nitro groups or esterified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

2,3-Dihalo-6-nitro substd. oxybenzene cpd. of formula (I) to be useful as an intermediate for preparation of quinoline based antibiotics, is prepd. by: reacting the cpd. of formula (II) with propagyl alcohol in the presence of the basic cpd. in an organic solvent to prepare the cpd. of formula (III) as the intermediate; and then preparing the oxybenzene deriv. (I). In the process, the org. solvent is one or more mixt. of benzene, toluene, halomethane or tetrahydrofuran; the basic cpd. is alkali metal fluoride, alkali (earth) metal hydride, alkali metal carbonate or basic org. solvent cpd.. In the formulas, X1,X2,X3 are halogen.

Description

옥시벤젠 유도체의 제조방법Method for preparing oxybenzene derivative

본 발명은 퀴놀린계 항생물질인 오플록사신 합성의 중간단계 물질로서 유용한 다음 일반식(I)로 표시되는, 2,3-디할로-6-니트로-치환옥시벤젠화합물을 제조하는 제조방법에 관한 것이다.The present invention relates to a preparation method for preparing a 2,3-dihalo-6-nitro-substitutedoxybenzene compound represented by the following general formula (I), which is useful as an intermediate step of synthesizing the ofloxacin, a quinoline antibiotic will be.

상기식에서 X1, X2는 플루오르 또는 염소 등의 할로겐 원소를 의미하며, 바람직하게는 플루오르를 의미한다.In the above formula, X 1 , X 2 means a halogen element such as fluorine or chlorine, and preferably means fluorine.

본 발명은 공지의 방법과는 전혀 다른 루트로 목적화합물을 제조하는 방법을 제공하는 것이다. 오플록사신의 제조방법으로서 기존에 알려진 방법은 다음의 공정도와 같다.The present invention provides a method for producing the target compound in a route completely different from the known methods. The conventionally known method for producing oploxacin is as follows.

상기시에서 X1, X2, X3은 할로겐 원소이다.In the above case, X 1 , X 2 , X 3 are halogen elements.

2,3,4-트리할로 니트로벤젠을 전구물질로하여 X플루오로기를 히드록시기로 치환한 후에 할로겐화 아세톤과 치환반응에 의하여 일반식(I)의 화합물을 얻고 환원-고리화 반응에 의하여 7,8-디할로-3,4-디하이드로-2H-(1,4)벤즈옥사진을 얻는다.2,3,4-trihalo nitrobenzene was used as a precursor to replace the X fluoro group with a hydroxy group, followed by substitution reaction with acetone halide to obtain a compound of formula (I), and by reduction-ring reaction 7, Obtain 8-dihalo-3,4-dihydro-2H- (1,4) benzoxazine.

그러나 이 방법은 히드록시기의 도입에서 부반응의 진행이 일어나며 분리 및 정제에 어려움이 있는 단점이 있다.However, this method has a disadvantage in that side reactions occur in the introduction of a hydroxyl group and are difficult to separate and purify.

본 발명은 상기 7,8-디할로-3,4-디하이드로-2H-(1,4)벤즈옥사진을 제조하기 위한 중간단계의 물질인 일반식(I)의 화합물의 합성에 그 목적이 있다.The present invention aims at the synthesis of the compound of formula (I), which is an intermediate material for preparing the 7,8-dihalo-3,4-dihydro-2H- (1,4) benzoxazine. have.

본 발명의 제조반응식은 다음과 같다.The reaction scheme of the present invention is as follows.

상기식에서 X1, X2는 서로 같거나 다르며, 각각 불소 또는 염소와 같은 할로겐 원자를 나타낸다.Wherein X 1 and X 2 are the same as or different from each other, and each represent a halogen atom such as fluorine or chlorine.

일반식(II)의 화합물과 프로파길 알콜을 염기의 존재하에서 반응시킴으로써 상기 일반식(III)의 화합물을 얻는다.The compound of formula (III) is obtained by reacting a compound of formula (II) with propargyl alcohol in the presence of a base.

염기성 화합물에는 무기염으로서 불화칼륨, 불화나트륨등과 같은 알카리금속의 불화물, 소디움 하이드라이드, 칼슘하이드라이드 등과 같은 금속 하이드라이드, 및 탄산칼륨, 탄산 소다 등과 같은 알카리금속의 탄산염 등을 예로 들 수 있다.Examples of the basic compound include inorganic fluorides of alkali metals such as potassium fluoride and sodium fluoride, metal hydrides such as sodium hydride and calcium hydride, and alkali metal carbonates such as potassium carbonate and soda carbonate. .

염기성 유기용매인 아세토니트릴, 피리딘, 디메틸포름아미드, 트리에틸아민등도무기염기와 같이 사용될 수 있다.Basic organic solvents such as acetonitrile, pyridine, dimethylformamide, triethylamine and the like can also be used with inorganic bases.

구조식(II)의 화합물과 프로파길 알콜의 사용몰비는 사용하는 염기의 종류에 따라 다를 수 있으나, 1:1.02-1:4의 범위가 적당하다.The molar ratio of the compound of formula (II) and propargyl alcohol may vary depending on the type of base used, but the range of 1: 1.02-1: 4 is appropriate.

반응용매로는 이 반응조건에 안정한 용매를 사용하는 것이 바람직하며, 예를들면, 벤젠, 톨루엔, 할로메탄, 에테르등과 같은 용매를 단독 또는 상기 언급한 염기성 용매와의 혼합용매를 사용할 수도 있다.It is preferable to use a solvent that is stable under these reaction conditions as the reaction solvent. For example, a solvent such as benzene, toluene, halomethane, ether or the like may be used alone or as a mixed solvent with the above-mentioned basic solvent.

반응조건으로서 비극성 유기용매인 벤젠, 톨루엔이나 테트라하이드로퓨란등의 에테르를 용매로하여 금속 하이드라이드 또는 불화칼륨을 염기로 사용하는 것이 바람직하다.As reaction conditions, it is preferable to use a metal hydride or potassium fluoride as a base using ethers such as benzene, toluene and tetrahydrofuran, which are nonpolar organic solvents, as a solvent.

반응온도는 -20도 내지 160도의 온도 사이에서 수행되며, 반응시간은 2-48시간내에 완결된다.The reaction temperature is carried out between -20 degrees and 160 degrees, and the reaction time is completed within 2-48 hours.

일반식(III)의 화합물을 초산 제2수은의 촉매 존재하에 초산과 반응시키고 황산등의 산으로 처리하여 일반식(IV)의 화합물을 얻을 수 있다.The compound of formula (III) can be reacted with acetic acid in the presence of a catalyst of the second mercury acetate and treated with an acid such as sulfuric acid to obtain a compound of formula (IV).

반응온도는 80-120도에서 수행되며, 반응시간은 2-8시간이다.The reaction temperature is carried out at 80-120 degrees, the reaction time is 2-8 hours.

본 발명의 장점은 비교적 값이 저렴한 프로파길 알콜을 합성원료로 사용함으로서 제조원가를 절감시킬 수 있으며, 높은 수율로 목적화합물로의 전환이 가능한데 있다.The advantage of the present invention is that by using a relatively inexpensive propargyl alcohol as a synthetic raw material can reduce the manufacturing cost, it is possible to convert to the target compound in a high yield.

본 발명에서 사용한 분리, 정제의 방법은 통상의 조작법인 추출, 실리카겔 컬럼 크로마토그라피 등의 방법을 사용하였다.Separation and purification methods used in the present invention used a method such as extraction, silica gel column chromatography, which is a common operation.

[실시예 1]Example 1

2,3-디플루오로-6-니트로[(프로-2-피닐)옥시]벤젠(화합물 III에서 X1, X2가 불소인 화합물)의, 합성; 얼음조에 냉각시킨 20㎖의 무수 톨루엔에 810㎎의 소디움 하이드라이드(60％ 미네랄 오일)을 넣고 교반시키면서 10㎖의 무수 톨루엔에 용해시킨 1.04g의 프로파길 알콜을 점적시킨다.Synthesis of 2,3-difluoro-6-nitro [(prop-2-pinyl) oxy] benzene (compound wherein X 1 , X 2 in fluorine III is fluorine); 810 mg of sodium hydride (60% mineral oil) was added to 20 ml of anhydrous toluene cooled in an ice bath, and 1.04 g of propargyl alcohol dissolved in 10 ml of anhydrous toluene was added while stirring.

20분동안 이 반응계를 교반시킨후에 10㎖의 무수톨루엔에 용해시킨 3.00g의 2,3,4-트리플루오로 니트로벤젠을 침적시키고 상온에서 12시간 교반시킨다.After stirring the reaction system for 20 minutes, 3.00 g of 2,3,4-trifluoro nitrobenzene dissolved in 10 ml of anhydrous toluene was deposited and stirred at room temperature for 12 hours.

반응혼합물에 얼음물과 클로로포름을 더하여 반응생성물을 추출해 낸후에 유기층을 취하여 무수 황산 마그네슘으로 탈수시키고 용매를 감압증류하여 제거한다.After the reaction mixture is extracted by adding ice water and chloroform to the reaction mixture, the organic layer is taken, dehydrated with anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure.

생성물을 칼럼 크로마토그라피로 정제하여 4.28g의 황색을 띤 점조성 액체를 얻었다.The product was purified by column chromatography to give 4.28 g of a yellowish viscous liquid.

1H-NMR(CDCl3) : 2.57(1H,s,C≡CH), 4.62(2H,d,-o-CH2-C≡C), 6.73-7.05(1H,ben-zene,m), 7.81-8.11(1H, benzene,m) 1 H-NMR (CDCl 3 ): 2.57 (1H, s, C≡CH), 4.62 (2H, d, -o-CH 2 -C≡C), 6.73-7.05 (1H, ben-zene, m), 7.81-8.11 (1H, benzene, m)

[실시예 2]Example 2

2,3-디플루오로-6-니트로[(프로-2-피닐)옥시]벤젠(화합물 III에서 X1, X2가 불소인 화합물)의 합성 : 불화칼륨 394㎎, 프로파길 알콜 410㎎, 및 2,3,4-트리플루오로 니트로벤젠 1.00g을 테트라하이드로퓨란 5㎖에 더하고 80-90도로 가열한다.Synthesis of 2,3-difluoro-6-nitro [(prop-2-pinyl) oxy] benzene (Compound where X 1 and X 2 are fluorine in Compound III): Potassium fluoride 394 mg, propargyl alcohol 410 mg, And 1.00 g of 2,3,4-trifluoro nitrobenzene are added to 5 ml of tetrahydrofuran and heated to 80-90 degrees.

5시간 가열한후에 감압증류로 반응용매를 제거하고 물과 에틸 아세테이트를 더하여 유기층을 취한다.After heating for 5 hours, the reaction solvent was removed by distillation under reduced pressure, and water and ethyl acetate were added to form an organic layer.

유기층을 증류수로 씻어준후에 무수 황산 마그네슘으로 탈수한후 용매를 감압증류로 제거한후에 칼럼 정제하여 1.21g의 생성물을 얻었다.The organic layer was washed with distilled water, dehydrated with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the column was purified to obtain 1.21 g of product.

[실시예 3]Example 3

2,3-디플루오로-6-니트로[(2-옥소프로필)옥시]벤젠(화합물 I에서 X1, X2가 불소인 화합물)의 합성 : 실시예 1에서 얻어진 생성물 3.5g을 빙초산 50㎖와 메틸알콜 100㎖에 녹이고 5㎖의 황산, 1.5g의 초산 제2수은을 더한 후에 90-100도에서 6시간동안 가열한다.Synthesis of 2,3-difluoro-6-nitro [(2-oxopropyl) oxy] benzene (Compound where X 1 and X 2 are fluorine in Compound I): 3.5 g of the product obtained in Example 1 was dissolved in 50 ml of glacial acetic acid. Dissolve in 100 ml of methyl alcohol, add 5 ml of sulfuric acid and 1.5 g of mercury acetate, and heat at 90-100 degrees for 6 hours.

반응혼합물에 증류수와 디클로로메탄을 더하여 생성물을 추출한다.Distilled water and dichloromethane are added to the reaction mixture to extract the product.

유기층을 취하여 수용액층의 산도가 중성이 될 때까지 증류수로 씻어준다.Take the organic layer and wash with distilled water until the acidity of the aqueous layer becomes neutral.

무수 황산마그네슘으로 탈수시킨 후에 용매를 감압증류로 제거하고 컬럼정제하여 1.21g의 생성물을 얻었다.After dehydration with anhydrous magnesium sulfate, the solvent was removed by distillation under reduced pressure and column purified to obtain 1.21 g of product.

Claims (3)

유기용매중에서 일반식(II)의 화합물과 프로파길 알콜을 염기성 화합물의 존재하에 일반식(III)의 중간체를 거쳐서 일반식(I)의 화합물을 제조함을 특징으로하는 일반식(I)의 옥시벤젠 유도체를 제조하는 방법.Oxygen of formula (I), characterized in that the compound of formula (II) and propargyl alcohol are prepared in an organic solvent through the intermediate of formula (III) in the presence of a basic compound. Process for preparing benzene derivatives. 식중 X1, X2및 X3는 할로겐 원자이다.Wherein X 1 , X 2 and X 3 are halogen atoms. 제1항에서 유기용매는 벤젠, 톨루엔, 할로메탄, 테트라하이드로퓨란을 단독 또는 2종이상의 용매를 혼합하여 사용함을 특징으로 하는 일반식(I)의 옥시벤젠 유도체를 제조하는 방법.The organic solvent according to claim 1, wherein benzene, toluene, halomethane, tetrahydrofuran is used alone or in combination of two or more solvents. 제1항에서 염기성 화합물은 알카리금속의 불화물, 알카리금속 또는 알카리토류금속의 하이드라이드, 알칼리금속의 탄산염 또는 염기성 유기용매 화합물을 사용함을 특징으로 하는 일반식(I)의 옥시벤젠 유도체를 제조하는 방법.The method of claim 1, wherein the basic compound is a fluoride of an alkali metal, a hydride of an alkali metal or an alkali earth metal, a carbonate of an alkali metal, or a basic organic solvent compound. .
KR1019910024648A 1991-12-27 1991-12-27 Process for the preparation of oxybenzene derivatives KR950001277B1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
KR1019910024648A KR950001277B1 (en) 1991-12-27 1991-12-27 Process for the preparation of oxybenzene derivatives

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
KR1019910024648A KR950001277B1 (en) 1991-12-27 1991-12-27 Process for the preparation of oxybenzene derivatives

Publications (2)

Publication Number Publication Date
KR930012679A KR930012679A (en) 1993-07-21
KR950001277B1 true KR950001277B1 (en) 1995-02-15

Family

ID=19326252

Family Applications (1)

Application Number Title Priority Date Filing Date
KR1019910024648A KR950001277B1 (en) 1991-12-27 1991-12-27 Process for the preparation of oxybenzene derivatives

Country Status (1)

Country Link
KR (1) KR950001277B1 (en)

Also Published As

Publication number Publication date
KR930012679A (en) 1993-07-21

Similar Documents

Publication Publication Date Title
EP1390359B1 (en) Synthesis of cannabinoids
US4425273A (en) Process for production of chenodeoxycholic acid
JP2014201545A (en) METHOD OF MANUFACTURING 2-HYDROXYMETHYL-2,3-DIHYDRO-THIENO[3,4-b][1,4]DIOXIN-5,7-DICARBOXYLIC ACID DIALKYL ESTER
JP4667691B2 (en) Process for the preparation of nitroxyalkyl esters of naproxen
US4658055A (en) Method for manufacture of 7-(2,5-dioxocyclopentyl)heptanoic acid derivative
JP4303792B2 (en) Method for producing quinolone derivative
KR950001277B1 (en) Process for the preparation of oxybenzene derivatives
SU1356957A3 (en) Method of producing acetate 7(e)-9(z)-dodecadienol
JPH02188589A (en) Production of tri-lower alkanoyloxyboron
US4225524A (en) Steroid derivatives and process for preparing the same
US4179452A (en) 3α,6α-Dihydroxy-5β-cholestan-24-one derivatives and process for preparing the same
WO2004007418A1 (en) A process for the preparation of 2-acetoxymethyl-4 halo-but-1-yl acetates
EP0131232B1 (en) Stereoselective process for the preparation of anthracycline derivatives
DK161705B (en) PROCEDURE FOR PREPARING A 13-HYDROXY-5-KETOMIL BEMYCINE DERIVATIVE
CN116120238B (en) Preparation method of imidazole derivative
JPS61152673A (en) Production of dibenzo(b,e)oxepine derivative
FR2935975A1 (en) PROCESS FOR PREPARING 1,6: 2,3-DIANHYDRO-B-D-MANNOPYRANOSE
JPS6231700B2 (en)
RU2277083C1 (en) Method for preparing 5,8-dihydroxy-2,6,7-trimethoxy-3-ethyl-1,4-naphthoquinone
JP2522926B2 (en) Method for producing 2'-deoxy-5-trifluoromethyluridine derivative
JP2984848B2 (en) Process for producing N-alkylpyrazole derivatives
JP2805114B2 (en) α, β-unsaturated ketoester derivatives
KR940006531B1 (en) Process for preparation of pyridine derivatives
JP2571059B2 (en) Method for producing 1,3,4-tri-O-acyl-2-deoxy-β-D-erythro-pentapyranose
US5196608A (en) Use of an allylchloride for preparing an aldehyde

Legal Events

Date Code Title Description
A201 Request for examination
G160 Decision to publish patent application
E701 Decision to grant or registration of patent right
GRNT Written decision to grant
LAPS Lapse due to unpaid annual fee