KR810000431B1 - Process for preparing substituted 2-(2-hydroxyethyl)-tetrahydro-1,4-oxazines - Google Patents
Process for preparing substituted 2-(2-hydroxyethyl)-tetrahydro-1,4-oxazines Download PDFInfo
- Publication number
- KR810000431B1 KR810000431B1 KR770000470A KR770000470A KR810000431B1 KR 810000431 B1 KR810000431 B1 KR 810000431B1 KR 770000470 A KR770000470 A KR 770000470A KR 770000470 A KR770000470 A KR 770000470A KR 810000431 B1 KR810000431 B1 KR 810000431B1
- Authority
- KR
- South Korea
- Prior art keywords
- compound
- tetrahydro
- formula
- oxazine
- reacted
- Prior art date
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
Description
[발명의 명칭][Name of invention]
치환된 2-(2-하이드록시에틸)-테트라하이드로-1, 4-옥사진의 제조방법Method for preparing substituted 2- (2-hydroxyethyl) -tetrahydro-1,4-oxazine
[발명의 상세한 발명]Detailed invention of the invention
본 발명은 다음 일반식의 치환된 2-(2-하이드록시에틸)-테트라하이드로-1, 4-옥사진 및 4급염의 제조방법에 관한 것이다.The present invention relates to a process for the preparation of substituted 2- (2-hydroxyethyl) -tetrahydro-1, 4-oxazine and quaternary salts of the general formula:
상기식에서 Ar 및 Ar1은 같거나 다르며 각각 방향족 잔기를 나타내며 할로겐원자로 치환될 수도 있다.Ar and Ar 1 in the formula are the same or different and each represent an aromatic moiety and may be substituted with a halogen atom.
R 및 R1은 같거나 다르며 탄소수 1 내지 4의 저급알킬기를 나타내며,는 Cl-, Br-, I-또는 CH3SO4 -를 나타낸다.R and R 1 are the same or different and represent a lower alkyl group having 1 to 4 carbon atoms, Is Cl -, Br -, I - or CH 3 SO 4 - represents a.
상기 신규 화합물은 다음 구조식의 2-시아노 메틸테트라 하이드로-1, 4-옥사진을 (1)의 에탄올중에서 HCl과 반응시키고 수득된 생성물을 가수분해하고, 무수 암모니아로 처리하여 상응하는 에스테르를 수득하고, (2) 수득된 에스테르를 하나 이상의 일반식 Ar-MgX' 또는 Ar1-MgX'(여기에서 X'는 할로겐원자이다)의 유기마그네슘 화합물과 반응시켜 3급아민을 제조한다.The novel compound was reacted with HCl in ethanol of (1) with 2-cyano methyltetra hydro-1,4-oxazine of the following structure and hydrolyzed the obtained product and treated with anhydrous ammonia to give the corresponding ester. And (2) the obtained ester is reacted with an organomagnesium compound of at least one of the general formulas Ar-MgX 'or Ar 1 -MgX', wherein X 'is a halogen atom, to prepare a tertiary amine.
3급 아민은 일반식 R1X(여기에서 R1은 탄소수 1 내지 4의 저급알킬기이며, X는 X는 Cl-, Br-, I-또는 CH3SO4 -이다)와 반응시켜서 4급 염을 제조한다.The tertiary amine is reacted with the general formula R 1 X (wherein R 1 is a lower alkyl group having 1 to 4 carbon atoms and X is Cl − , Br − , I − or CH 3 SO 4 − ) to form a quaternary salt. To prepare.
이들 유도체는 경련성 증후군의 치료에 유용하다.These derivatives are useful for the treatment of convulsive syndrome.
많은 종류의 아미노알콜 유도체가 진경작용을 가진것이 알려졌다(Erhart/Ruschig Arzneimittel II P 75-97). 이들 진경작용은 항코린작용 또는 무스큐로트로픽 작용(musculotropic action)과 관계가 있다.It is known that many kinds of aminoalcohol derivatives have a hardening effect (Erhart / Ruschig Arzneimittel II P 75-97). These mycelial actions are associated with anticholinergic or musculotropic actions.
본 발명의 2-(2-하이드록시에틸)-테트라하이드로-1, 4-옥사진의 4급 염은 현저한 항코린 작용과 무스큐로트로픽 작용을 가지고 있다. 다음 일반식과 같은 구조를 가진다.The quaternary salts of 2- (2-hydroxyethyl) -tetrahydro-1 and 4-oxazine of the present invention have remarkable anticholinergic and muscurotropic effects. It has the same structure as the following general formula.
상기식에서 Ar 및 Ar1은 같거나 다르며, 페닐과 같은 방향족 잔기를 나타내며, 이들은 할로겐원자로 치환될 수도 있다.Ar and Ar 1 in the formula are the same or different, and represent an aromatic moiety such as phenyl, which may be substituted with a halogen atom.
R과 R1은 같거나 다르며 탄소수 1 내지 4의 저급알킬기이며, X는 Cl-, Br-, I-또는 CH3SO4 -등의 음이온을 나타낸다.R and R 1 are the same or different and are a lower alkyl group having 1 to 4, X is Cl -, Br -, I - or CH 3 SO 4 - represents an anion such as.
본 발명의 화합물은 2-시아노 메틸테트라하이드로-1, 4-옥사진을 출발물질로 하여 합성하며, 이 화합물의 제법은 본 발명자들에 의하여 1974년 5월 10일자 출원한 불란서 특허원 제 74 16 331에 기술되어 있다. 이 출발물질은 다음과 같은 구조를 가진다.The compound of the present invention is synthesized using 2-cyano methyltetrahydro-1,4-oxazine as starting materials, and the preparation of this compound is based on the French patent application filed on May 10, 1974 by the present inventors. 16 331. This starting material has the following structure.
상기식에서 R은 상술한 바와 같다.In which R is as described above.
이런 류의 유도체는 에탄올중에서 HCl의 작용에 의하여 쉽게 전환된다. 다음에 이 화합물을 가수분해시키고, 무수 암모니아로 처리하여 상응하는 에스테르를 제조한다.Derivatives of this class are readily converted by the action of HCl in ethanol. This compound is then hydrolyzed and treated with anhydrous ammonia to produce the corresponding ester.
다음에 이 에스테르를 Ar-MgX1또는 Ar1-MgX1등의 유기 마그네슘 화합물 1종 이상과 에틸 에테르와 같은 용매중에서 반응시킨다. 여기에서 Ar(또는 Ar1)은 상술한 바와 같으며, X'는 할로겐원자이다.This ester is then reacted with one or more organic magnesium compounds such as Ar-MgX 1 or Ar 1 -MgX 1 in a solvent such as ethyl ether. Wherein Ar (or Ar 1 ) is as described above, and X 'is a halogen atom.
상기에서 수득된 화합물은 합성시 중간체로 이용할 수 있다. 예를 들면, 이 화합물은 R1-X의 반응물질과 반응시켜서 상응하는 4급 암모늄염을 제조할 수가 있으며, 이 화합물의 약리학적 특성은 경련치료제로 사용할 수가 있다.The compound obtained above can be used as an intermediate in synthesis. For example, the compound can be reacted with a reactant of R 1 -X to produce the corresponding quaternary ammonium salt, and the pharmacological properties of the compound can be used as an anticonvulsant.
본 발명의 합성 반응은 다음과 같이 표시할 수 있다.The synthetic reaction of the present invention can be expressed as follows.
다음에 실시예로서 본 발명을 더욱 상세히 설명한다.Next, the present invention will be described in more detail by way of examples.
그러나 이 실시예가 본 발명의 범위를 제한하는 것은 아니다.However, this embodiment does not limit the scope of the present invention.
[실시예 1]Example 1
1단계 : 다음 구조의 2-카브에톡시-메틸-4-메틸테트라하이드로-1, 4-옥사진의 제조Step 1: Preparation of 2-carbethoxy-methyl-4-methyltetrahydro-1,4-oxazine having the following structure
무수에탄올 1000ml에 2-시이오메틸-테트라하이드로-1,4-옥사진 70g을 융해시키고 이 용액을 -10℃에서 무수 HCl가스로 포화시킨다.70 g of 2-thiomethyl-tetrahydro-1,4-oxazine is dissolved in 1000 ml of anhydrous ethanol and the solution is saturated with anhydrous HCl gas at -10 占 폚.
다음에 물 20ml를 가하고 1시간 환류시킨다.Then 20 ml of water was added and refluxed for 1 hour.
용매를 제거한 후에 수득된 잔류물을 무수클로로포름 400ml에 취하고, 용액을 무수 암모니아 기부로 치러한다.The residue obtained after removal of the solvent is taken up in 400 ml of anhydrous chloroform and the solution is subjected to anhydrous ammonia base.
침전된 염화암모늄을 여고하여 제거한 후, 용매를 증류한 후 잔사를 정제하여 상기 에트테르52g을 얻는다. BP12-108℃, NB=1,4480동상의 조건하에서, 무수에틸에스테르에 페닐마그네슘 브로마이드를 용해시킨 용액을 제조(마그네슘조각 7.2g, 브로모벤젠 47.1g(0.3몰)및 무수 에테르 100ml로부터 반하여 가하고, 집차로 약하게 교반하며, 용매를 환류시킨다. 완전히 다 가한 후 3시간 더 환류시킨다.The precipitated ammonium chloride was filtered off and then the solvent was distilled off and the residue was purified to give 52 g of the ether. Under the conditions of BP12-108 DEG C and NB = 1,4480 copper phase, a solution in which phenylmagnesium bromide was dissolved in anhydrous ethyl ester was prepared. After stirring gently, reflux the solvent and reflux for another 3 hours.
이것은 보통 조건하에서 염화암모늄의 포화용액으로 기수분해시킨다. 유기츠응 경사시키고, 이것을 4N 염산수용액으로 추출한다. 물층을 에테르트 세척한 후, 탄산나트륨으로 알카리성으로 한다. 무수 에테르로 재결정시켜서 화합물 1을 105g수득한다. 융점=110℃It is hydrolyzed to a saturated solution of ammonium chloride under normal conditions. The organic solvent was decanted and extracted with 4N aqueous hydrochloric acid solution. The ethereal layer is washed with ether and then made alkaline with sodium carbonate. 105 g of compound 1 was obtained by recrystallization with anhydrous ether. Melting point = 110 ° C
이 화합물의 염산부가염은 무수 에탄올중에서 염기 용액을 무수 HCl가스로 처리하여 수득하며, 융점 212℃이고 다음의 분석특성을 가진다.The hydrochloric acid addition salt of this compound is obtained by treating a base solution in anhydrous ethanol with anhydrous HCl gas, and has a melting point of 212 占 폚 and has the following analytical properties.
화합물 1을 순수 아세톤 50ml에 용해시킨 메틸브로마이드 5g으로 처리한다. 수 시간후에 생성물이 결정으로 석출한다. 액을 버리고, 무수 에탄올중에서 재결정시키서 생성물 5g을 얻는다.Compound 1 is treated with 5 g of methyl bromide dissolved in 50 ml of pure acetone. After several hours the product precipitates out as crystals. Discard the liquid and recrystallize in anhydrous ethanol to give 5 g of product.
융점 =233℃ 분자량 : 392.35Melting point = 233 ° C Molecular weight: 392.35
[실시예 3]Example 3
실시예 1에 기술된 것과 같은 조건하에서 실시예 1에서 기술한 대로 제조한 2-카브에톡시-메틸-4-n-부틸-테트라하이드로-1, 4-옥사진 22.9g(0.1몰)을 출발물질로 하여, 무수에탄올 대신에 무수 n-부탄올을 사용하여 반응시켜서 화합물 3을 16g을 수득한다.Starting 22.9 g (0.1 mol) of 2-carbethoxy-methyl-4-n-butyl-tetrahydro-1, 4-oxazine prepared as described in Example 1 under the same conditions as described in Example 1 As a substance, 16 g of compound 3 was obtained by reacting with anhydrous n-butanol instead of anhydrous ethanol.
[실시예 4]Example 4
무수 아세톤 50ml에 화합물 3을 2g용해시킨 용액을 메틸브로마이트 2g으로 처라한다. 수득된 결정은 무수에탄올로 재결정시켜서, 화합물 4을 2.5g을 얻는다.A solution of 2 g of Compound 3 dissolved in 50 ml of anhydrous acetone is treated with 2 g of methyl bromite. The obtained crystals were recrystallized from anhydrous ethanol to obtain 2.5 g of compound 4.
융점 = 244℃ 분자량 : 433.42Melting Point = 244 ° C Molecular Weight: 433.42
[실시예 5]Example 5
아세톤 50ml에 화합물 3을 5g을 용해시킨 용액을 새로 증류한 메틸설페이트 2g으로 처리하고 12시간후에 용매를 제거하여 수득된 잔류물을 아세트산 에틸로 처리하여, 화합물 5을 4.5g 얻는다.A solution of 5 g of Compound 3 dissolved in 50 ml of acetone was treated with 2 g of freshly distilled methyl sulfate, and the solvent was removed after 12 hours. The resulting residue was treated with ethyl acetate to obtain 4.5 g of Compound 5.
융점 = 165℃ 분자량 : 449.62Melting Point = 165 ° C Molecular Weight: 449.62
[실시예 6]Example 6
실시예 1에 기술된 것과 유사한 조건하에서, 마그네슘 7.2g, 4-플루오로브로모벤젠 52.5g(0.3몰), 무수 에테르 100ml 및 2-카브에톡시-메틸-4-메틸테트라하이드-1, 4-옥사진 18.7g으로부터 화합물 6을 16.7g 수득한다.Under similar conditions as described in Example 1, 7.2 g of magnesium, 52.5 g of 4-fluorobromobenzene (0.3 mol), 100 ml of anhydrous ether and 2-carethoxy-methyl-4-methyltetrahydro-1, 4- 16.7 g of compound 6 is obtained from 18.7 g of oxazine.
염산부가염의 융점 = 128℃(조해성) 염산부가염의 분석 : (분자량 : 369.85)Melting point of hydrochloric acid addition salt = 128 ° C. (degradability) Analysis of hydrochloric acid addition salt: (molecular weight: 369.85)
[실시예 7]Example 7
순수한 아세톤 60ml에 화합물 6을 5g 용해시킨 용액을 메틸브로마이드 4.5g으로 처리하고, 무수 이소프로판올에서 재결정시켜서 생성물 4.8g을 수득한다.A solution of 5 g of Compound 6 in 60 ml of pure acetone was treated with 4.5 g of methyl bromide and recrystallized from anhydrous isopropanol to give 4.8 g of the product.
융점=134℃(조해성) 분석(분자량 : 428.33)Melting point = 134 ° C (degradability) analysis (molecular weight: 428.33)
[약리학적 실험]Pharmacological experiment
본 발명 화합물의 약리학적 특성은 아세틸코린, 히스타민 및 이온으로 유도된 평활근의 경련치에 대하여 진경작용의 강도를 측정함으로써 측정한다. 이 실험은 시험관중에서, 생리학적 인디케이터로, 첫번째 애고니스트(agonist)로 쥐의 공장(Jejvnum)을 사용하고 다른 두 애고니스트로 몰모트의 회장(ileum)을 사용하여 마그누스(Magnus)의 방법(pflug. Arch, Ges physiolo 1904, 102, 349 및 1904, 103, 515 및 525)으로 행한다.The pharmacological properties of the compounds of the present invention are determined by measuring the intensity of mycelial action against the spasm of smooth muscle induced by acetylcholine, histamine and ions. This experiment was carried out in vitro using Magnus' method (pflug. P. 5) using the jejunum of the rat as the first agonist and the ileum of the two other agonists. Arch, Ges physiolo 1904, 102, 349 and 1904, 103, 515 and 525).
적출장기는 항온 산소타이로드 용액에서 30℃로 살아있도록 유지하고 그 수축을 기록한다.The extractor is kept alive at 30 ° C. in a constant temperature oxygen tie rod solution and the shrinkage recorded.
본 발명의 화합물은 서로 다른 형의 리시터(receiptor)(Van. Rossum J. M-Arch. Int 1963, 143, 299-330)에 대한 친화력 척도(pA2및 pD2)를 용량의 함수로서 감응커브 곡선으로부터 계산할 수 있다.Compounds of the invention respond to affinity measures (pA 2 and pD 2 ) for different types of receivers (Van. Rossum J. M-Arch. Int 1963, 143, 299-330) as a function of dose. The curve can be calculated from the curve.
본 발명의 화합물과 대조물질로서 통상의 두 화합물을 사용하여 얻어진 결과를 다음의 표(I)에 기록하였다.The results obtained using two conventional compounds as the compound of the present invention and the control material are recorded in the following table (I).
[표 1]TABLE 1
아린스들(Ariens etal)이 개발한 분자 약리학 원리(Medicinal chem Molecular pharmacology 1, 119-286)에 의하면 이 결과는 화합물 그와 티에모니움 사이에는 그 작용기전이 대단히 유사하며 강도도 유사함을 보여주고 있으며, 화합물 7은 동시에 티에모니움과는 상경적 작용기전을, 그리고 파파베린과는 비상경적 작용을 보여주고 있다.According to the principles of pharmacological pharmacology developed by Arins etal (Medicinal chem Molecular pharmacology 1, 119-286), the results show that the mechanism of action is very similar and the strength is similar between the compound and thiernium. Compound 7 is also shown to have an autologous mechanism of action with thiernium and an emergency action with papaverine.
이러한 2원적 작용은 기타의 진경제에는 알려지지 않은 것이다. 따라서 이러한 약리학적 결과는 이들 화합물을 혈관, 소화관 또는 기관지등 모든 평활근의 경련 증후군의 치료에 치료제로 사용할 수 있음을 보여주고 있다.This dual action is unknown to other antispasmodics. Therefore, these pharmacological results show that these compounds can be used as a therapeutic agent for the treatment of all the smooth muscle spasm syndromes such as blood vessels, digestive tracts or bronchus.
이 화합물은 활성화합물을 10 내지 500mg을 함유하는 일일용량이로 투여 경로에 통상의 약학적 제제형태로 하여 투여할 수 있다. 이들 활성화합물은 통상의 약학적 부형제나 담체와 조합하여 사용할 수도 있다.This compound may be administered in the form of a conventional pharmaceutical formulation in the route of administration at a daily dose containing 10 to 500 mg of the active compound. These active compounds can also be used in combination with conventional pharmaceutical excipients or carriers.
Claims (1)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR770000470A KR810000431B1 (en) | 1977-02-26 | 1977-02-26 | Process for preparing substituted 2-(2-hydroxyethyl)-tetrahydro-1,4-oxazines |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR770000470A KR810000431B1 (en) | 1977-02-26 | 1977-02-26 | Process for preparing substituted 2-(2-hydroxyethyl)-tetrahydro-1,4-oxazines |
Publications (1)
Publication Number | Publication Date |
---|---|
KR810000431B1 true KR810000431B1 (en) | 1981-05-01 |
Family
ID=19203939
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
KR770000470A KR810000431B1 (en) | 1977-02-26 | 1977-02-26 | Process for preparing substituted 2-(2-hydroxyethyl)-tetrahydro-1,4-oxazines |
Country Status (1)
Country | Link |
---|---|
KR (1) | KR810000431B1 (en) |
-
1977
- 1977-02-26 KR KR770000470A patent/KR810000431B1/en active
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AT396685B (en) | METHOD FOR PRODUCING NEW 1,4-DISUBSTITUTED PIPERAZINE DERIVATIVES | |
NO152079B (en) | DENTAL FILLING MATERIALS BASED ON ORGANIC ARTICLES IN PASTOE'S FORM | |
JPS6049192B2 (en) | New substituted benzamides, their production methods, and psychotropic drugs containing them as active ingredients | |
DK148688B (en) | METHOD OF ANALOGUE FOR THE PREPARATION OF BASIC SUBSTITUTED 7-ALKYLTEOPHYLLINE DERIVATIVES OR SALTS THEREOF WITH PHARMACEUTICAL ACCEPTABLE ACIDS | |
EA022266B1 (en) | Method for the manufacturing of naltrexone | |
CS204008B2 (en) | Process for preparing new derivatives of 0-/3-amino-2-hydroxypropyl/-amidoxime | |
US3557127A (en) | Substituted cyclohexenes,derivatives thereof and processes for obtaining same | |
JPH089580B2 (en) | Amino alcohol, its production method and its use | |
US20100216838A1 (en) | Fexofenadine base polymorphic forms | |
KR810000431B1 (en) | Process for preparing substituted 2-(2-hydroxyethyl)-tetrahydro-1,4-oxazines | |
US2619484A (en) | Y-dihydro - sh-dibenz | |
US4474783A (en) | Cyclopropylmethyl piperazines, the process for preparing the same and their use in therapeutics | |
EP0005091B1 (en) | Monosubstituted piperazines, processes for their preparation and pharmaceutical compositions containing them | |
JPS6136754B2 (en) | ||
US4307091A (en) | Process for treatment of allergic conditions with benzoxazinediones | |
US4062956A (en) | Substituted 2-(2-hydroxyethyl)tetrahydro-1,4 oxazines and quaternary salts thereof useful for treating spasmodic syndromes | |
WO1985002186A1 (en) | Ether of n-propanolamine derivative | |
US4843085A (en) | Pyridine derivatives, process for production thereof and pharmaceutical compositions useful as anti-arhytmics | |
JPH0124793B2 (en) | ||
JPS62108863A (en) | 2-pyridylacetic derivative, its preparation and medicine containing the same | |
IE58497B1 (en) | New process for the preparation of derivatives of 4h-1, 2,4-triazole, the new triazoles so obtained, their use as medicaments and the pharmaceutical compositions containing them | |
HU180716B (en) | Process for preparing substituted amino-alkyl-guanidines | |
US4318909A (en) | Benzoxazocines | |
CA1077040A (en) | Pharmaceutically active decahydroquinoline derivatives | |
US3700663A (en) | Dibenzothiazepine ethers |