KR830002349B1 - Method for preparing 4- (5) -hydroxymethyl 5 (4) -lower alkylimidazoles - Google Patents
Method for preparing 4- (5) -hydroxymethyl 5 (4) -lower alkylimidazoles Download PDFInfo
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- KR830002349B1 KR830002349B1 KR1019790002950A KR790002950A KR830002349B1 KR 830002349 B1 KR830002349 B1 KR 830002349B1 KR 1019790002950 A KR1019790002950 A KR 1019790002950A KR 790002950 A KR790002950 A KR 790002950A KR 830002349 B1 KR830002349 B1 KR 830002349B1
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- 238000000034 method Methods 0.000 title claims description 15
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 22
- 150000001875 compounds Chemical class 0.000 claims description 17
- 238000006243 chemical reaction Methods 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 150000003512 tertiary amines Chemical class 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 239000002585 base Substances 0.000 description 11
- XLSZMDLNRCVEIJ-UHFFFAOYSA-N 4-methylimidazole Chemical compound CC1=CNC=N1 XLSZMDLNRCVEIJ-UHFFFAOYSA-N 0.000 description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- 150000003839 salts Chemical class 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 229930040373 Paraformaldehyde Natural products 0.000 description 7
- 229920002866 paraformaldehyde Polymers 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 239000013078 crystal Substances 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000004448 titration Methods 0.000 description 3
- 229940086542 triethylamine Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000020477 pH reduction Effects 0.000 description 2
- 239000012429 reaction media Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- -1 alkyl imidazole Chemical compound 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- CCGSUNCLSOWKJO-UHFFFAOYSA-N cimetidine Chemical compound N#CNC(=N/C)\NCCSCC1=NC=N[C]1C CCGSUNCLSOWKJO-UHFFFAOYSA-N 0.000 description 1
- 229960001380 cimetidine Drugs 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000008098 formaldehyde solution Substances 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 150000003138 primary alcohols Chemical class 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000001577 simple distillation Methods 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Steroid Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
내용 없음.No content.
Description
본 발명은 다음 일반식(Ⅰ) 또는 (Ⅰ')의 4(5)-하이드록시메틸 5(4)-저급알킬이미다졸 및 이의 산부가염의 제조방법에 관한 것이다.The present invention relates to a process for preparing 4 (5) -hydroxymethyl 5 (4) -lower alkylimidazoles of the following general formula (I) or (I ') and acid addition salts thereof.
상기 식에서, R은 저급알킬 그룹을 나타낸다.Wherein R represents a lower alkyl group.
상술한 바와 같이 본 발명의 화합물은 서로 평형상태에 있는 일반식(Ⅰ) 및 (Ⅰ')의 두 형태로 존재하는데, 일반식(Ⅰ)의 형태는 4-하이드록시-메틸-5-저급알킬 이미다졸에 상응하며 일반식(Ⅰ')의 형태는 5-하이드록시-메틸 4-저급알킬 이미다졸에 상응한다.As described above, the compounds of the present invention exist in two forms of general formula (I) and (I ') in equilibrium with each other, wherein the form of general formula (I) is 4-hydroxy-methyl-5-lower alkyl. Corresponds to imidazole and the form of formula (I ′) corresponds to 5-hydroxy-methyl 4-lower alkyl imidazole.
본 발명의 화합물은 의약품의 합성 부문에 있어 중간체로서 지대한 관심을 갖는 물질이다. 특히 4(5)-하이드록시메틸 (5)4-메틸이미다졸은 이미 잘 알려진 위궤양 치료제인 시메티딘의 합성에 있어서의 중간체이다.The compounds of the present invention are substances of great interest as intermediates in the synthesis section of pharmaceuticals. In particular, 4 (5) -hydroxymethyl (5) 4-methylimidazole is an intermediate in the synthesis of cimetidine, a well known therapeutic agent for gastric ulcers.
본 발명에 관한 화합물을 제조하는 최근의 한 방법으로는 다음 일반식(Ⅱ)의 에스테르를 다음 일반식(Ⅰ) 또는 (Ⅰ')의 1급 알코올로 환원시키는 방법이 있다.One recent method for preparing the compounds of the present invention is the method of reducing the ester of the following general formula (II) to the primary alcohol of the following general formula (I) or (I ′).
상기 식에서, R 및 R1은 모두 저급 알킬그룹을 나타낸다.Wherein R and R 1 both represent a lower alkyl group.
이러한 방법은 국영특허 제1,341,376호 그리고 벨기에 왕국 특허 제832,660 및 제844,830호에 기술되어 있다. 그렇지만 이러한 방법을 실시함에 있어서는 다음과 같은 2가지의 주요 결점이 있다. 첫째는, 사용하는 환원제(AlLiH4)의 가격이 높기 때문에 또는 사용하는 장치가 복잡하기 때문에(전해환원 및 액체 암모니아 내에서 나트륨으로 환원시킬 경우) 이에 따라 고가의 환원 시스템을 사용하게 되며, 둘째는 일반식(Ⅰ),(Ⅰ')의 화합물 및 이의 염산염이 물에서의 용해도가 높기 때문에 금 속염을 다량 함유한 분리시키기가 까닳운 조생성물이 형성된다.Such a method is described in National Patent Nos. 1,341,376 and Belgian Kingdom patents 832,660 and 844,830. However, there are two main drawbacks to implementing this method: Firstly, due to the high cost of the reducing agent (AlLiH 4 ) used or the complexity of the equipment used (reduction with sodium in electrolytic reduction and liquid ammonia), an expensive reduction system is used. Due to the high solubility of the compounds of the general formulas (I) and (I ′) and their hydrochlorides in water, a crude product which is difficult to separate contains large amounts of metal salts.
또한 수용액 중에서 다음 일반식(Ⅳ)의 화합물을 포름알데히드와 반응시켜 R이 CH3인 일반식(Ⅰ),(Ⅰ')와 화합물을 합성시키는 방법이 여러 저자들에 의해 기술되어 있다.In addition, several authors have described a method for synthesizing a compound of general formulas (I) and (I ') in which R is CH 3 by reacting a compound of the following general formula (IV) with formaldehyde in an aqueous solution.
〔참조 : Windaus "Berichte 42,758-862(1909)", Ewins " J. Chem. Soc. 99, 2052-2055(1911)" 및 Von Erlenmeyer "Helv. Chim. Acta, 31, 32-40(1938)"〕 :[Reference: Windaus "Berichte 42,758-862 (1909)", Ewins "J. Chem. Soc. 99, 2052-2055 (1911)" and Von Erlenmeyer "Helv. Chim. Acta, 31, 32-40 (1938)" 】:
그런데 여기서는 가장 좋은 경우(피크레이트의 형태로) 수율이 약 43%를 초과하지 않으며, 반응은 가압하에 120℃의 온도에서 이론치의 100%보다 더 많은 포름알데히드를 사용하여 수행한 다음 피크레이트 형태의 생성물을 침전시켜 중질의 중간체를 정제한 후, 염기 또는 염산염으로 전환시키는데, 이러한 방법으로는 단지 수 g의 일반식 (Ⅰ),(Ⅰ')의 화합물이 얻어질 뿐이며 목적하는 바의 화합물을 다량 얻기에는 어려움이 뒤따른다.In this case, however, in the best case (in the form of crate), the yield does not exceed about 43%, and the reaction is carried out under pressure at a temperature of 120 ° C. with more than 100% of the theoretical formaldehyde and then The product is precipitated to purify the heavy intermediate and then converted to base or hydrochloride, which yields only a few grams of the compounds of the general formulas (I) and (I ') and a large amount of the desired compound. Difficult to obtain.
본 발명의 목적은 상기의 결점을 보완하여 양질의 일반식 (Ⅰ),(Ⅰ')의 화합물 및 이의 산부가염을 쉽게 다량 제조하는 방법을 제공하는데 있다. 특히 본 발명은 강염기의 존재하에 반응을 진행시킴을 특징으로 하여, 다음 일반식 (Ⅴ)의 화합물과 포름알데히드를 반응시켜 일반식 (Ⅰ),(Ⅰ') 및 이의 산부가염을 제조하는 방법에 관한 것이다.It is an object of the present invention to provide a method for easily preparing a large amount of a compound of general formulas (I) and (I ′) and acid addition salts thereof, by compensating the above drawbacks. In particular, the present invention is characterized in that the reaction proceeds in the presence of a strong base, the reaction of the compound of formula (V) and formaldehyde to formula (I), (I ') and a method for preparing acid addition salts thereof It is about.
상기식에서 R은 저급알킬 그룹이다.R is a lower alkyl group.
본 발명의 방법에 있어서 강염기는 촉매 역할을 하여 온화한 조건(예 : 공지의 방법에서 보다 상당히 낮은 주위 온도 및 압력) 하에서도 반응이 잘 일어나게 한다. 반응 온도는 30 내지 95℃, 바람직하게는 50 내지 80℃이다. 또한 본 발명의 방법은 순수한 반응매질을 제공하는 잇점을 지니고 있어 산부가염이 물에 불용성인 염의 형태(피크레이트)로서 일반식 (Ⅰ),(Ⅰ')의 중간체 결정이 형성됨을 방지시키는 적당한 결정 용매내에서 결정화될 수 있게 된다.In the process of the present invention, the strong base acts as a catalyst to allow the reaction to occur well under mild conditions (e.g. significantly lower ambient temperature and pressure than in known processes). Reaction temperature is 30-95 degreeC, Preferably it is 50-80 degreeC. In addition, the process of the present invention has the advantage of providing a pure reaction medium, so that acid addition salts are suitable crystals to prevent the formation of intermediate crystals of formulas (I) and (I ') as salts of the insoluble salts in water (picrate). It can be crystallized in a solvent.
이러한 결정 용매로는 에탄올 또는 이소프로판올과 같은 알코올과 아세톤의 혼합물로 형성된 것이 바람직하다.Such crystalline solvent is preferably formed of a mixture of acetone with an alcohol such as ethanol or isopropanol.
또한 본 발명의 방법을 사용함으로써 일반적으로 염의수율을 60% 이상으로 할 수 있다.In addition, by using the method of the present invention, the yield of salt can generally be 60% or more.
본 발명의 방법에 있어서 반응은 용매가 없이 또는 물, 탄소수 1 내지 5인 알코올, 바람직하게 분자량이 적은 3급 아민 중에서 선택한 용매의 존재하에 진행한다. 그런데 용매가 알코올일 경우 에탄올 또는 이소프로판올을 사용함이 바람직한데, 이는 이들이 결정 용매 요소들 중의 하나를 이미 형성하기 때문이다. 결정이 형성될 때는 단지 아세톤만을 가한다.In the process of the invention the reaction proceeds without solvent or in the presence of a solvent selected from water, an alcohol having 1 to 5 carbon atoms, preferably a tertiary amine having a low molecular weight. However, it is preferred to use ethanol or isopropanol when the solvent is an alcohol, since they already form one of the crystalline solvent elements. When a crystal is formed, only acetone is added.
본 발명의 방법에 있어서 사용하는 강염기는 수산화 나트륨 또는 수산화 칼륨과 같은 무기 염기, 또는 3급 아민, 4급 암모늄 염기 및 알칼리금속 알코올 레이트와 같은 유기 염기를 사용할 수 있다.The strong base used in the method of this invention can use inorganic bases, such as sodium hydroxide or potassium hydroxide, or organic bases, such as a tertiary amine, a quaternary ammonium base, and an alkali metal alcoholate.
저분량의 3급 아민(예 : 트리에틸아민)과 같은 휘발성 강염기를 사용함이 바람직한데, 이러한 유형의 염기를 사용하게 되면 반응후에 이들을 단순 증류시켜 쉽게 제거할 수 있기 때문이다.It is preferable to use volatile strong bases, such as low levels of tertiary amines (eg triethylamine), since these types of bases can be easily removed by simple distillation after the reaction.
본 발명에 있어서 한 가지 특이한 것으로는 포름알데히드원으로서 파라포름알데히드를 사용하는 것이다. 사실상 포름알데히드의 공업적원은 일반적으로 40% 포름알데히드 수용액 또는 고체 파라포름알데히드이다. 파라포름알데히드를 사용함으로써 반응매체내에 물을 도입시킬 필요성이 없기 때문에 수득된 화합물을 분리 시키기 위해 물을 증발시킬 필요성이 없게 된다. 부산물의 형성을 최소로 하기 위해서는 일반식 (Ⅴ)의 화합물과 함께 반응에 사용된 포름알데히드의 양을 가능한 한 화학 양론적양에 가깝게One particular thing in the present invention is the use of paraformaldehyde as the formaldehyde source. In fact, the industrial source of formaldehyde is generally 40% aqueous formaldehyde solution or solid paraformaldehyde. The use of paraformaldehyde eliminates the need to introduce water into the reaction medium, eliminating the need to evaporate water to separate the obtained compound. In order to minimize the formation of by-products, the amount of formaldehyde used in the reaction with the compound of formula (V) should be as close to the stoichiometric amount as possible.
사용할 강염기의 양은 선택된 염기의 강도 및 반응 온도에 따르지만, 화합 양론적 양보다 다소 적은 편이 바람직하며 통상의 기술을 가진 사람은 염기의 성질과 반응 온도 등을 고려하여 최적의 결과를 얻을 수 있는 염기의 양을 쉽게 결정할 수 있다. 그러므로 수산화칼륨의 경우에 있어서, 사용할 양은 일반식 (Ⅴ)의 화합물 1몰당 약 0.01 내지 약 1몰이며, 반응 온도는 수산화칼륨의 양이 일반식 (Ⅴ)의 화합물 1몰당 0.01몰일 때 약 95℃로 함이 바람직하고 수산화칼륨의 양이 증가하여 일반식 (Ⅴ)의 화합물 1몰당 1몰일 때는 약 30℃에 도달할 때까지 내린다.The amount of strong base to be used depends on the strength of the selected base and the reaction temperature, but it is preferable that the amount is less than the stoichiometric amount, and those of ordinary skill in the art can consider the nature of the base and the reaction temperature to obtain an optimal result. The amount can be easily determined. Therefore, in the case of potassium hydroxide, the amount to be used is about 0.01 to about 1 mole per mole of the compound of formula (V), and the reaction temperature is about 95 ° C. when the amount of potassium hydroxide is 0.01 mole per mole of the compound of formula (V). When the amount of potassium hydroxide is increased to 1 mole per 1 mole of the compound of formula (V), it is lowered until it reaches about 30 ° C.
본 발명을 더욱 자세히 설명하기 위하여 다음의 네 실시예가 있는데, 모두 4(5)-하이드록시메틸 5(4)-메틸 이미다졸 하이드로클로라이드를 형성시키며 사용한 염기 및 또는 사용한 용매의 종류는 다르다.To further illustrate the invention, there are four examples, all of which form 4 (5) -hydroxymethyl 5 (4) -methyl imidazole hydrochloride and differ in the type of base and / or solvent used.
[실시예 1]Example 1
반응기에 4(5)-메틸이미다졸(2605g)과 물(4725ml) 및 파라포름알데히드(1182g)을 넣고, 트리에틸아민(788g)을 가한 다음 약 60 내지 65℃의 온도에서 6시간 동안 교반한다.4 (5) -methylimidazole (2605g), water (4725ml) and paraformaldehyde (1182g) were added to the reactor, triethylamine (788g) was added, followed by stirring at a temperature of about 60 to 65 ° C for 6 hours. do.
물과 트리에틸 아민을 감압 증발시키고 이소프로판올과 아세톤과의 혼합물을 가한 다음 가스상 염산으로써 산성화시킨다. 그리고는 수득한 침전물을 여과시킨다. 예기한 화합물 3165g(수율 67.1%)을 분리시켰으며 산적정에 의해 측정한 그의 적정 농도(titer)는 97.9%이었다.Water and triethyl amine are evaporated under reduced pressure, a mixture of isopropanol and acetone is added and acidified with gaseous hydrochloric acid. The precipitate obtained is then filtered. 3165 g (yield 67.1%) of the expected compound was isolated and its titer determined by acid titration was 97.9%.
[실시예 2]Example 2
반응기에 4(5)-메틸이미다졸(30g), 물(285ml) 파라포름알데히드(13.5g) 및 수산화칼륨(13.5g)을 넣고, 온도를 1시간 동안 50℃로 유지시킨 다음 염산 수용액으로써 산성화시킨다. 물을 증발시킨 다음 잔사를 이 소프로판올에 취하고 따뜻한 상태에서 금속염을 여과한다. 여과액을 냉각시키고 침전물을 여과한 후 건조시켜 예기한 염산염 28g(수율 51.5%)을 수득하였는데, 산걱정에 의해 측정한 그의 적정농도는 97.7%이었다.4 (5) -methylimidazole (30 g), water (285 ml) paraformaldehyde (13.5 g) and potassium hydroxide (13.5 g) were added to the reactor, and the temperature was maintained at 50 ° C. for 1 hour, followed by aqueous hydrochloric acid solution. Acidify. After evaporation of water the residue is taken up in isopropanol and the metal salt is filtered off in warm condition. The filtrate was cooled and the precipitate was filtered and dried to give 28 g (yield 51.5%) of the expected hydrochloride. The titer was 97.7% as measured by acid soaking.
[실시예 3]Example 3
반응기에 4(5)-메틸 이미다졸(30g), 물(120ml) 및 파라포름알데히드(13.7g)을 넣고, 여기에 30% 수산화나트륨 용액(32g)을 가한 다음 온도를 1시간 동안 50℃로 유지시킨다. 염산수용액으로 산성화시킨 다음, 물을 증발시키고, 잔사를 무수에탄올에 취한 후 금속염을 차거울 때 여과한다. 침전물이 수득될 때까지 에탄올을 농축시키고 여과한 후 건조시킨다. 예기한 염산염 34.5g(수율 63.5%)을 분리시켰는데 산적정에 의해 측정한 그의 적정 농도 97.4%이었다.4 (5) -methyl imidazole (30 g), water (120 ml) and paraformaldehyde (13.7 g) were added to the reactor, 30% sodium hydroxide solution (32 g) was added thereto, and the temperature was increased to 50 ° C. for 1 hour. Keep it. After acidification with aqueous hydrochloric acid solution, the water is evaporated and the residue is taken up in anhydrous ethanol and then filtered when the metal salt is cold. The ethanol is concentrated, filtered and dried until a precipitate is obtained. 34.5 g (yield 63.5%) of expected hydrochloride was isolated and its proper concentration measured by acid titration was 97.4%.
[실시예 4]Example 4
반응기에 4(5)-메틸 이미다졸(266.5g), 이소프로판올(266.5ml), 파라포름알데히드(97.5g) 및 수산화칼륨(3g)을 넣고 환류하에 5시간 동안 가열한 다음 냉각시키고, 가스상 염산으로 산성화시킨 후, 아세톤을 가하고 침전물을 여과하여 건조시킨다. 예기한 염산염 263g(수율 54.4%)을 수득하였는데 산적정에 의해 측정한 그의 적정 농도는 93.5%이었다.4 (5) -methyl imidazole (266.5 g), isopropanol (266.5 ml), paraformaldehyde (97.5 g) and potassium hydroxide (3 g) were added to the reactor, heated at reflux for 5 hours, and then cooled, and cooled with gaseous hydrochloric acid. After acidification, acetone is added and the precipitate is filtered off and dried. 263 g (yield 54.4%) of expected hydrochloride was obtained, and its proper concentration measured by acid titration was 93.5%.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1019790002950A KR830002349B1 (en) | 1979-08-29 | 1979-08-29 | Method for preparing 4- (5) -hydroxymethyl 5 (4) -lower alkylimidazoles |
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| Application Number | Priority Date | Filing Date | Title |
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| KR1019790002950A KR830002349B1 (en) | 1979-08-29 | 1979-08-29 | Method for preparing 4- (5) -hydroxymethyl 5 (4) -lower alkylimidazoles |
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