JPS6075465A - Preparation of 5(4)-hydroxymethylimidazole salt - Google Patents
Preparation of 5(4)-hydroxymethylimidazole saltInfo
- Publication number
- JPS6075465A JPS6075465A JP58180826A JP18082683A JPS6075465A JP S6075465 A JPS6075465 A JP S6075465A JP 58180826 A JP58180826 A JP 58180826A JP 18082683 A JP18082683 A JP 18082683A JP S6075465 A JPS6075465 A JP S6075465A
- Authority
- JP
- Japan
- Prior art keywords
- acid
- formaldehyde
- reaction
- hydroxymethylimidazole
- imidazole
- Prior art date
- Legal status (The legal status 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 status listed.)
- Pending
Links
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims abstract description 45
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims abstract description 38
- -1 imidazole compound Chemical class 0.000 claims abstract description 21
- 150000007522 mineralic acids Chemical class 0.000 claims abstract description 10
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 6
- 239000007864 aqueous solution Substances 0.000 claims abstract description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 3
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 238000000034 method Methods 0.000 abstract description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract description 19
- XLSZMDLNRCVEIJ-UHFFFAOYSA-N 4-methylimidazole Chemical compound CC1=CNC=N1 XLSZMDLNRCVEIJ-UHFFFAOYSA-N 0.000 abstract description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 abstract description 8
- 150000001875 compounds Chemical class 0.000 abstract description 6
- 239000002994 raw material Substances 0.000 abstract description 5
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 abstract description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 abstract description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 abstract description 2
- 239000003795 chemical substances by application Substances 0.000 abstract description 2
- 239000003822 epoxy resin Substances 0.000 abstract description 2
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 abstract description 2
- 229920000647 polyepoxide Polymers 0.000 abstract description 2
- 230000003449 preventive effect Effects 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- 230000002070 germicidal effect Effects 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 27
- 238000010438 heat treatment Methods 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 239000012299 nitrogen atmosphere Substances 0.000 description 5
- 229920002866 paraformaldehyde Polymers 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 229930040373 Paraformaldehyde Natural products 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 150000002460 imidazoles Chemical class 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- ZOMATQMEHRJKLO-UHFFFAOYSA-N 1h-imidazol-2-ylmethanol Chemical class OCC1=NC=CN1 ZOMATQMEHRJKLO-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- UBHDUFNPQJWPRQ-UHFFFAOYSA-N (5-methyl-1h-imidazol-3-ium-4-yl)methanol;chloride Chemical compound Cl.CC=1NC=NC=1CO UBHDUFNPQJWPRQ-UHFFFAOYSA-N 0.000 description 2
- RUEBPOOTFCZRBC-UHFFFAOYSA-N (5-methyl-2-phenyl-1h-imidazol-4-yl)methanol Chemical compound OCC1=C(C)NC(C=2C=CC=CC=2)=N1 RUEBPOOTFCZRBC-UHFFFAOYSA-N 0.000 description 2
- OPFNZHIUHJBGEW-UHFFFAOYSA-N 1-hydroxyimidazole Chemical compound ON1C=CN=C1 OPFNZHIUHJBGEW-UHFFFAOYSA-N 0.000 description 2
- LLPKQRMDOFYSGZ-UHFFFAOYSA-N 2,5-dimethyl-1h-imidazole Chemical compound CC1=CN=C(C)N1 LLPKQRMDOFYSGZ-UHFFFAOYSA-N 0.000 description 2
- TYOXIFXYEIILLY-UHFFFAOYSA-N 5-methyl-2-phenyl-1h-imidazole Chemical compound N1C(C)=CN=C1C1=CC=CC=C1 TYOXIFXYEIILLY-UHFFFAOYSA-N 0.000 description 2
- ULKLGIFJWFIQFF-UHFFFAOYSA-N 5K8XI641G3 Chemical compound CCC1=NC=C(C)N1 ULKLGIFJWFIQFF-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 235000011121 sodium hydroxide Nutrition 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- UAYQUZUNIRPAAV-UHFFFAOYSA-N (2,5-dimethyl-1h-imidazol-4-yl)methanol;hydrochloride Chemical compound Cl.CC1=NC(C)=C(CO)N1 UAYQUZUNIRPAAV-UHFFFAOYSA-N 0.000 description 1
- RNQFVXRSWLGWJU-UHFFFAOYSA-N (2-ethyl-5-methyl-1h-imidazol-4-yl)methanol;hydrochloride Chemical compound Cl.CCC1=NC(C)=C(CO)N1 RNQFVXRSWLGWJU-UHFFFAOYSA-N 0.000 description 1
- QIVUCLWGARAQIO-OLIXTKCUSA-N (3s)-n-[(3s,5s,6r)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl]-2-oxospiro[1h-pyrrolo[2,3-b]pyridine-3,6'-5,7-dihydrocyclopenta[b]pyridine]-3'-carboxamide Chemical compound C1([C@H]2[C@H](N(C(=O)[C@@H](NC(=O)C=3C=C4C[C@]5(CC4=NC=3)C3=CC=CN=C3NC5=O)C2)CC(F)(F)F)C)=C(F)C=CC(F)=C1F QIVUCLWGARAQIO-OLIXTKCUSA-N 0.000 description 1
- AXJZCJSXNZZMDU-UHFFFAOYSA-N (5-methyl-1h-imidazol-4-yl)methanol Chemical compound CC=1N=CNC=1CO AXJZCJSXNZZMDU-UHFFFAOYSA-N 0.000 description 1
- DKXKUKRKMTWVOY-UHFFFAOYSA-N (5-methyl-1h-imidazol-4-yl)methanol;sulfuric acid Chemical compound OS(O)(=O)=O.CC=1NC=NC=1CO DKXKUKRKMTWVOY-UHFFFAOYSA-N 0.000 description 1
- BGJSXRVXTHVRSN-UHFFFAOYSA-N 1,3,5-trioxane Chemical compound C1OCOCO1 BGJSXRVXTHVRSN-UHFFFAOYSA-N 0.000 description 1
- NKWCGTOZTHZDHB-UHFFFAOYSA-N 1h-imidazol-1-ium-4-carboxylate Chemical compound OC(=O)C1=CNC=N1 NKWCGTOZTHZDHB-UHFFFAOYSA-N 0.000 description 1
- VEOGZFDBTMWPDV-UHFFFAOYSA-N 2,4-dimethyl-1h-imidazol-1-ium;chloride Chemical compound Cl.CC1=CNC(C)=N1 VEOGZFDBTMWPDV-UHFFFAOYSA-N 0.000 description 1
- LXBGSDVWAMZHDD-UHFFFAOYSA-N 2-methyl-1h-imidazole Chemical compound CC1=NC=CN1 LXBGSDVWAMZHDD-UHFFFAOYSA-N 0.000 description 1
- RYKANBBWRLXVDN-UHFFFAOYSA-N 5-methyl-1h-imidazole;hydrochloride Chemical compound Cl.CC1=CNC=N1 RYKANBBWRLXVDN-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N alpha-ketodiacetal Natural products O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- AQIXAKUUQRKLND-UHFFFAOYSA-N cimetidine Chemical compound N#C/N=C(/NC)NCCSCC=1N=CNC=1C AQIXAKUUQRKLND-UHFFFAOYSA-N 0.000 description 1
- 229960001380 cimetidine Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000007859 condensation product Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000002845 discoloration Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229940015043 glyoxal Drugs 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 238000007031 hydroxymethylation reaction Methods 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 125000004372 methylthioethyl group Chemical group [H]C([H])([H])SC([H])([H])C([H])([H])* 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- AYOOGWWGECJQPI-NSHDSACASA-N n-[(1s)-1-(5-fluoropyrimidin-2-yl)ethyl]-3-(3-propan-2-yloxy-1h-pyrazol-5-yl)imidazo[4,5-b]pyridin-5-amine Chemical compound N1C(OC(C)C)=CC(N2C3=NC(N[C@@H](C)C=4N=CC(F)=CN=4)=CC=C3N=C2)=N1 AYOOGWWGECJQPI-NSHDSACASA-N 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- XULSCZPZVQIMFM-IPZQJPLYSA-N odevixibat Chemical compound C12=CC(SC)=C(OCC(=O)N[C@@H](C(=O)N[C@@H](CC)C(O)=O)C=3C=CC(O)=CC=3)C=C2S(=O)(=O)NC(CCCC)(CCCC)CN1C1=CC=CC=C1 XULSCZPZVQIMFM-IPZQJPLYSA-N 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 238000006276 transfer reaction Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Abstract
Description
【発明の詳細な説明】
本発明は、イミダゾール化合物のヒドロキシメチル化に
関するものである。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the hydroxymethylation of imidazole compounds.
ヒドロキシメチルイミダゾール化合物は、医薬中間原料
、エポキシ樹脂硬化剤、殺菌剤、防錆剤等として極めて
有用な化合物である。Hydroxymethylimidazole compounds are extremely useful compounds as pharmaceutical intermediate raw materials, epoxy resin curing agents, bactericidal agents, rust preventives, and the like.
例えば、４−メチル−５−ヒドロキシメチルイミダゾー
ルはシメチジンの名で知られるＮ−シアン−Ｎ’−メチ
ル−Ｎ″−［２−（４−メチル−５−イミダゾイル）−
メチルチオ−エチル〕−グアニジンの製造のための中間
体として重要になっているように、極めて有用な化合物
である。For example, 4-methyl-5-hydroxymethylimidazole is N-cyan-N'-methyl-N''-[2-(4-methyl-5-imidazoyl)-, also known as cimetidine.
It is a very useful compound, as it has become important as an intermediate for the production of methylthio-ethyl]-guanidine.
ヒドロキシメチルイミダゾール化合物の製造方法として
は次の方法が知られている。The following method is known as a method for producing a hydroxymethylimidazole compound.
すなわち、（１）アルカリ性媒質中で、イミダゾール化
合物とホルムアルデヒドまたはその重合体を反応させる
方法（特開昭５４−１３２５７０ ）、（２）イミダゾ
ール化合物をパラホルムアルデヒドまたはトリオキサン
と直接に、あるいは芳香族炭化水素系溶媒中で反応させ
て、１−ヒドロキシメチルイミダゾール化合物を合成し
た後、塩酸中で加熱、転移させる方法（特開昭５４−Ｌ
６３５７６）、（６）イミダゾール−５−カルボン酸ま
たはそのエステルを還元する方法、（Ｊ、 Ｍｅｄ、
Ｃｈｅｍ、 １９（力 ９２６〜８（１９７６）、 Ｇ
ｅｒ、 ｏｆｆｅｎ ２６ろ７６７０． Ｇｅｒ、 ｏ
ｆｆｅｎ２５３８６２１）等である。Namely, (1) a method of reacting an imidazole compound with formaldehyde or its polymer in an alkaline medium (Japanese Patent Application Laid-Open No. 132570/1983), (2) a method of reacting an imidazole compound with paraformaldehyde or trioxane directly, or a method of reacting an imidazole compound with formaldehyde or a polymer thereof, or a method of reacting an imidazole compound with formaldehyde or a polymer thereof in an alkaline medium; A method of synthesizing a 1-hydroxymethylimidazole compound by reacting it in a system solvent, and then heating and transferring it in hydrochloric acid (Japanese Patent Laid-Open No. 54-L
63576), (6) Method for reducing imidazole-5-carboxylic acid or its ester, (J, Med,
Chem, 19 (Power 926-8 (1976), G
er, offen 26ro7670. Ger, o
ffen2538621) etc.
これらの公知方法は、方法（１）が、イミダゾールとホ
ルムアルデヒドの反応によるヒドロキシメチルイミダゾ
ールの製造法として、古（からよく知られている方法の
改良法である。この方法では収率な大巾に向上させるこ
とが可能であるが、この反応条件では、５０℃で既に変
色した生成物が出来、更に高温（９０〜１２０℃）では
、強く変色する副反応が起り、生成物の著しい着色、収
率低下を起すことが記載されている。したがって、５０
℃以下の低温で反応させる必要があり、このため８０％
以」二の収量を得るためには、最適条件下でも６５〜７
５時間か〜るとの記述にみられる様に、極めて長時間の
反応となり、工業化に際しては装置が大型化し、コスト
高になる欠点がある。These known methods are improvements on the method (1), which has been well known since ancient times as a method for producing hydroxymethylimidazole by the reaction of imidazole and formaldehyde. However, under these reaction conditions, a product is already discolored at 50°C, and at even higher temperatures (90 to 120°C), a side reaction that causes strong discoloration occurs, resulting in significant coloration of the product and loss of yield. It has been described that the rate decreases.Therefore, 50
It is necessary to carry out the reaction at a low temperature below ℃, so 80%
In order to obtain a yield of 65 to 7 even under optimal conditions,
As can be seen in the description that it takes about 5 hours, the reaction takes an extremely long time, and in industrialization, the disadvantage is that the equipment becomes large and the cost increases.
また、方法（２）は新規な方法であるが、反応工程が■
イミダゾールから１−ヒドロキシイミダゾールの合成、
および■１−ヒドロキシイミダゾールの転移反応の二工
程であり、反応時間が長（、溶媒回収が必要であり操作
が煩雑である。また、反応■が直接反応の場合には、反
応時間の短縮は可能であるが工業化の際には、反応制御
が困難である。In addition, method (2) is a new method, but the reaction step is
Synthesis of 1-hydroxyimidazole from imidazole,
and (1) transfer reaction of 1-hydroxyimidazole, which requires a long reaction time (requires solvent recovery and is complicated to operate. In addition, if reaction (2) is a direct reaction, the reaction time cannot be shortened. Although it is possible, it is difficult to control the reaction during industrialization.
さらに、方法（３）では、水素化リチウムアルミニウム
、液体アンモニア中でアルカリ金属を用いての還元、あ
るいは電解還元等の極めて煩雑かつ高価な手段が必要で
あり、コスト高になる。Furthermore, method (3) requires extremely complicated and expensive means such as lithium aluminum hydride, reduction using an alkali metal in liquid ammonia, or electrolytic reduction, resulting in high costs.
以上のように、従来公知の方法は、工業的製造法として
は、いづれも欠点があり、満足出来る方法ではなかった
。As mentioned above, all of the conventionally known methods have drawbacks and are not satisfactory as industrial manufacturing methods.
本発明者らは、従来法の上記のような欠点を解消した５
（４）−ヒドロキシメチルイミダゾールの製造について
鋭意検討を行った結果、驚くべきことに、イミダゾール
化合物とホルムアルデヒドとの反応を無機酸水溶液中で
行わせることによって、直接にしかも高収率でイミダゾ
ールの５位へのヒドロキシメチル基の導入が出来ること
を見出し、本発明を完成するに到った。The present inventors have solved the above-mentioned drawbacks of the conventional method.
As a result of extensive research into the production of (4)-hydroxymethylimidazole, it was surprisingly discovered that by carrying out the reaction between an imidazole compound and formaldehyde in an aqueous inorganic acid solution, imidazole can be produced directly and in high yield. It was discovered that a hydroxymethyl group can be introduced into this position, and the present invention was completed.
すなわち、本発明は一般式（１）
（式中、Ｒ］は水素原子または炭素数１〜′５のアルキ
ル基、Ｒ２は水素原子炭素数１〜３のアルキル基または
フェニル基を示す）で表わされるイミダゾール化合物と
ホルムアルデヒドまたはホルムアルデヒドのオリゴマー
とを無機酸水溶液中で反応させることを特徴とする一般
式（Ｉｌｌ
２
（式中、Ｒ，、Ｒ２は一般式（１１の場°合と同じ意味
を示し、ＨＡは無機酸を示す）で表わされる５（４）−
ヒドロキシメチルイミダゾール塩類の製造方法である。That is, the present invention provides a compound represented by the general formula (1) (wherein R is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, and R2 is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms or a phenyl group). The general formula (Ill 2 (wherein R, and R2 have the same meaning as in the case of general formula (11) , HA indicates an inorganic acid)
This is a method for producing hydroxymethylimidazole salts.
５一
本発明の方法は、無機酸水溶液中でイミダゾール化合物
とホルムアルデヒドまたはその重合体とを加熱下に反応
させるところに特徴がある。51 The method of the present invention is characterized in that an imidazole compound and formaldehyde or a polymer thereof are reacted under heating in an aqueous inorganic acid solution.
本発明の方法で用いられる無機酸としては、塩酸、臭化
水素酸、硫酸、リン酸等であり、価格、後処理の容易さ
、製品の需要等から塩酸が特に好ましい。酸の使用量は
イミダゾール化合物に対し２〜１０倍当量、好ましくは
′５〜６倍当量であり、酸の濃度は１５〜６０％、好ま
しくは２５〜５０％である。酸の使用量と酸の濃度が、
それぞれ２倍当量未満、１５％未満の場合は、反応が遅
く好ましくない。一方、それぞれ１０倍当量６０％を越
えても、更に効果の向上は少な（、通常、上記の範囲で
使用すれば十分である。Inorganic acids used in the method of the present invention include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc., and hydrochloric acid is particularly preferred from the viewpoint of price, ease of post-treatment, product demand, etc. The amount of acid used is 2 to 10 equivalents, preferably 5 to 6 times the equivalent of the imidazole compound, and the concentration of the acid is 15 to 60%, preferably 25 to 50%. The amount of acid used and the concentration of acid are
If the amount is less than 2 times equivalent or less than 15%, the reaction will be slow and undesirable. On the other hand, even if the 10-fold equivalent exceeds 60%, the effect will not be further improved (although it is usually sufficient to use them within the above ranges).
本発明の方法で用いられるイミダゾール化合物は前記一
般式（Ｉ）で表わされるもので、例えば、イミダゾール
、２−メチルイミダゾール、４−メチルイミダゾール、
２，４−ジメチルイミダゾール、２−フェニル−４−メ
チルイミダゾール、２−プロピル−４−エチルイミタソ
ール、２−エチルー４−メチルイミダゾール等が挙げら
れフリーの状態でまたはあらかじめ無機酸で中和した塩
の形で使用される。これらのイミダゾール化合物はグリ
オキザール化合物、アンモニアおよびアルデヒド化合物
を反応させる通常よく知られた方法で得られる。The imidazole compound used in the method of the present invention is represented by the general formula (I), and includes, for example, imidazole, 2-methylimidazole, 4-methylimidazole,
Examples include 2,4-dimethylimidazole, 2-phenyl-4-methylimidazole, 2-propyl-4-ethylimitasol, 2-ethyl-4-methylimidazole, etc., in the free state or in advance neutralized with an inorganic acid. Used in salt form. These imidazole compounds are usually obtained by a well-known method of reacting a glyoxal compound, ammonia and an aldehyde compound.
本発明方法で用いられるホルムアルデヒドはホルムアル
デヒドを２０〜５０％含有する水溶液、あるいはバラホ
ルムアルデヒドまたは１．３．５− ）リオキサンの様
なオリゴマーの形で用いられる。The formaldehyde used in the process of the invention is used in the form of an aqueous solution containing 20 to 50% formaldehyde, or in the form of oligomers such as paraformaldehyde or 1.3.5-)lioxane.
イミダゾール化合物とホルムアルデヒドの反応モル比は
、１：０．８〜１．２、好ましくは１：０．９５〜１．
０５である。モル比１：０．８未満では、反応率が不充
分であり、モル比１：１．２を越えると副反応が起り易
くなるので好ましくない。ホルムアルデヒドのオリゴマ
ーを用いる場合は、モノマー相当量として使用する。The reaction molar ratio of the imidazole compound and formaldehyde is 1:0.8 to 1.2, preferably 1:0.95 to 1.
It is 05. When the molar ratio is less than 1:0.8, the reaction rate is insufficient, and when the molar ratio exceeds 1:1.2, side reactions tend to occur, which is not preferable. When formaldehyde oligomers are used, they are used in an amount equivalent to the monomer.
反応は、５０〜１５０℃の温度で行われ、好ましくは８
０〜１２０℃で行われる。５０℃未満では、反応が遅く
、１５０℃を越えると生成物の着色が著しくなるので好
ましくない。The reaction is carried out at a temperature of 50 to 150 °C, preferably 8
It is carried out at 0-120°C. If the temperature is less than 50°C, the reaction will be slow, and if it exceeds 150°C, the product will become significantly colored, which is not preferred.
反応時間は酸の種類、量、濃度または温度等によって異
るが、５〜３０時間、好ましくは１０〜２５時間である
。また、反応は常圧、加圧いづれでも実施出来る。反応
の進行は薄層クロマトグラフィー、高速液体クロマトグ
ラフィー、その他の方法で追跡される。The reaction time varies depending on the type, amount, concentration, temperature, etc. of the acid, but is 5 to 30 hours, preferably 10 to 25 hours. Further, the reaction can be carried out either at normal pressure or under increased pressure. Progress of the reaction is monitored by thin layer chromatography, high performance liquid chromatography, or other methods.
本発明の方法で生成する５（４）−ヒドロキシメチルイ
ミダゾール類は反応に用いた無機酸の塩として得られる
。生成物の取出しは過剰の酸を中和するか、または留去
するかして除いた後、減圧下に脱水濃縮を行い、エタノ
ール等の低級アルコールで再結晶することによって行わ
れる。この際、収率なよくするためには、極力水分を除
くことが望ましい。The 5(4)-hydroxymethylimidazole produced by the method of the present invention is obtained as a salt of the inorganic acid used in the reaction. The product is recovered by removing excess acid by neutralizing or distilling it off, followed by dehydration and concentration under reduced pressure, and recrystallization from a lower alcohol such as ethanol. At this time, in order to improve the yield, it is desirable to remove water as much as possible.
フリーの状態で取り出す必要のある場合には、反応終了
後過剰の酸を残留したまま、または留去した後、生成し
たイミダゾール誘導体をフリーとするのに必要な苛性ソ
ーダ等のアルカリ水溶液を加え、減圧下に濃縮乾固する
。この残１よりアルコール類、たとえばイソプロピルア
ルコール等テ熱時抽出し、無機塩を濾過により除く。If it is necessary to take it out in a free state, after the completion of the reaction, leave the excess acid remaining, or after distilling it off, add the alkaline aqueous solution such as caustic soda necessary to free the generated imidazole derivative, and then reduce the pressure. Concentrate to dryness. From this residue 1, an alcohol, such as isopropyl alcohol, is extracted while hot, and the inorganic salts are removed by filtration.
この抽出液を冷却してフリーのイミダゾール誘導体を結
晶として得ることができる。By cooling this extract, a free imidazole derivative can be obtained as crystals.
本発明の方法は、イミダゾールの１位または２位での置
換化合物またはイミダゾール環の−ＣＨ２−基、−ＣＨ
２−０−ＣＨ２−基を介しての高縮合生成物等を含まず
、選択的に５位へのヒドロキシメチル基の導入を可能に
した優れた方法であり、工業的にかつ極めて安価に５（
４）−ヒドロキシメチルイミダゾール塩類を製造する方
法を提供するものである。The method of the present invention involves substituting compounds at the 1- or 2-position of imidazole or the -CH2- group of the imidazole ring, -CH
This is an excellent method that does not involve high condensation products via the 2-0-CH2- group, and enables the selective introduction of a hydroxymethyl group into the 5-position, and is industrially and extremely inexpensive. (
4) A method for producing -hydroxymethylimidazole salts is provided.
以下、実施例により本発明の詳細な説明する。Hereinafter, the present invention will be explained in detail with reference to Examples.
実施例−１
攪拌装置、温度計、還流冷却器、滴下ロートおよび窒素
吹込み口を備えた２０〇−容五ツロ丸底フラスコに、３
５％−塩酸１３０ ｆ （１，２５モル）を入れた。氷
水で冷却し、窒素雰囲気で攪拌しながら、滴下ロートか
ら４−メチルイミダゾール２０．！Ｍ（０，２５モル）
を滴下した。冷却を止め、９２％−パラ９−
ホルムアルデヒド８．２１ （０，２５モル）を加工、
油浴で加温し、パラホルムアルデヒドを溶解した。更に
加温を続は窒素雰囲気下で還流下に１０時間反応を行っ
た。Example-1 In a 200-capacity round-bottomed flask equipped with a stirrer, a thermometer, a reflux condenser, a dropping funnel, and a nitrogen inlet, 3
130 f (1.25 mol) of 5% hydrochloric acid were charged. While cooling with ice water and stirring under a nitrogen atmosphere, add 20% of 4-methylimidazole from the dropping funnel. ! M (0.25 mol)
was dripped. Stop cooling, process 8.21 (0.25 mol) of 92%-para-9-formaldehyde,
The paraformaldehyde was dissolved by heating in an oil bath. After further heating, the reaction was carried out under reflux under a nitrogen atmosphere for 10 hours.
減圧下に過剰の塩酸を留去した後、エタノールを用いて
再結晶し微黄色の結晶２６．１ Ｆを得た。融点は２３
５〜２３８℃であり、４−メチル−５−ヒドロキシメチ
ルイミダゾール−塩酸塩として収率７ｏ、３％であった
。元素分析結果は次の通りであった。After distilling off excess hydrochloric acid under reduced pressure, recrystallization was performed using ethanol to obtain pale yellow crystals 26.1F. Melting point is 23
The temperature was 5 to 238°C, and the yield was 7o and 3% as 4-methyl-5-hydroxymethylimidazole hydrochloride. The elemental analysis results were as follows.
理論値 Ｃ：４０．４２％、Ｈ：６．１１％、Ｎ：１８
．８５％。Theoretical value C: 40.42%, H: 6.11%, N: 18
．． 85%.
Ｃ１： ２３．８６％
実測値 Ｃ： ４ ［１，３７％、Ｈ：６．３２％、Ｎ
：１Ｂ、７６％。C1: 23.86% Actual value C: 4 [1,37%, H: 6.32%, N
:1B, 76%.
Ｃ４：２３．８１％
なお、再結晶母液を濃縮乾固することによって、４−メ
チルイミダゾール塩酸塩と微量の不純物を含む４−メチ
ル−５−ヒドロキシメチルイミダゾール・塩酸塩１０．
Ｅｌを回収した。このものは反応原料として再使用可能
であった。C4: 23.81% By concentrating and drying the recrystallized mother liquor, 10% of 4-methyl-5-hydroxymethylimidazole hydrochloride containing 4-methylimidazole hydrochloride and trace amounts of impurities was obtained.
El was collected. This material could be reused as a reaction raw material.
実施例２
実施例−１と同様の装置を用い、５０％−硫酸９８１０
−
？（０，５モル）を入れた。氷水で冷却し、窒素雰囲気
下、攪拌しながら滴下ロートより４−メチルイミダゾー
ル２０．５Ｆ（０，２５モル）を加えた。冷却を止め、
４５％−ホルムアルデヒド水溶液１６．Ｂ（０，２４モ
ル）を入れ、油浴で加温し溶解した。Example 2 Using the same equipment as in Example-1, 50% sulfuric acid 9810
−? (0.5 mol) was added. The mixture was cooled with ice water, and 4-methylimidazole 20.5F (0.25 mol) was added from the dropping funnel while stirring under a nitrogen atmosphere. stop cooling,
45% formaldehyde aqueous solution 16. B (0.24 mol) was added and dissolved by heating in an oil bath.
更に加温を続け、微量の窒素を流しながら還流下で２０
０時間反応行った。Further heating was continued for 20 minutes under reflux while flowing a small amount of nitrogen.
The reaction was carried out for 0 hours.
反応後、冷却しながら過剰の硫酸を３０％−水酸化ナト
リウム水溶液で中和した。減圧下に濃縮乾固し、２−プ
ロパツールを加え加熱した後無機塩を減圧沖過して除い
た。ｐ液を冷却し、４−メチル−５−ヒドロキシメチル
イミダゾール硫酸塩の結晶２７．１ ｆｌ （収率６７
．２％）を得た。融点は２６０〜２３６℃（分解）であ
った。After the reaction, excess sulfuric acid was neutralized with a 30% aqueous sodium hydroxide solution while cooling. The mixture was concentrated to dryness under reduced pressure, 2-propanol was added and heated, and the inorganic salts were removed by filtration under reduced pressure. The p liquid was cooled and 27.1 fl of crystals of 4-methyl-5-hydroxymethylimidazole sulfate (yield 67
．． 2%). The melting point was 260-236°C (decomposition).
涙液を濃縮乾固し、原料と微量の不純物を含む粗製の４
−メチル−５−ヒドロキシメチルイミダゾール硫酸塩１
２８１を回収した。The lachrymal fluid is concentrated and dried to produce crude 4, which contains raw materials and trace impurities.
-Methyl-5-hydroxymethylimidazole sulfate 1
281 were recovered.
実施例−６
実施例−１と同様の装置を用い、４５％−臭化水素酸１
６２Ｍ（０，９モル）を入れた。冷却し、窒素を微量流
しながら、２−フェニル−４−メチルイミダゾール４７
．５ｆ（０，！、Ｄモル）を加えた。冷却を止め、９５
％−パラホルムアルデヒド９．８９（０，３１モル）を
入れ、油浴で加温して溶解した。Example-6 Using the same equipment as in Example-1, 45% hydrobromic acid 1
62M (0.9 mol) was added. With cooling and a small stream of nitrogen, add 2-phenyl-4-methylimidazole 47
．． 5f (0,!, D moles) was added. Stop cooling, 95
%-paraformaldehyde (0.31 mol) was added and dissolved by heating in an oil bath.
更に油浴で加温を続け、１２０°Ｃで２００時間反応行
った。Further heating was continued in an oil bath, and the reaction was carried out at 120°C for 200 hours.
反応後、減圧下に過剰の臭化水素酸を留去した後、冷却
しつ＼６０％−水酸化す） ＩＪウム水溶液でｐｌ−Ｉ
−９にした。得られた溶液を濃縮乾固１．．２−プロパ
ツールを加え、加熱溶解した後、無機塩を炉別して除い
た。ろ液を冷却し、２−フェニル−４−メチル−５−ヒ
ドロキシメチルイミダゾールの白色結晶６６．６ｆ（収
率６４．８％）を得た。融点は１９７〜２０１℃（分解
）であった。After the reaction, excess hydrobromic acid was distilled off under reduced pressure, and then cooled and 60% hydroxide was added to pl-I with an aqueous IJ solution.
I set it to -9. The obtained solution was concentrated to dryness 1. ．． 2-Propertool was added and dissolved by heating, and then the inorganic salt was removed by furnace. The filtrate was cooled to obtain 66.6f of white crystals of 2-phenyl-4-methyl-5-hydroxymethylimidazole (yield: 64.8%). The melting point was 197-201°C (decomposed).
涙液を濃縮乾固して原料および少量の副生物を含有−す
る粗Ｗの２−フェニル−４−メチル−５−ヒドロキシメ
チルイミダゾール１８６７を回収した。The lachrymal fluid was concentrated to dryness to recover crude W 2-phenyl-4-methyl-5-hydroxymethylimidazole 1867 containing raw materials and a small amount of by-products.
実施例−４
実施例−１と同様の装置を用い、２５％−塩酸２６３ｆ
（１，８モル）を入れた。氷水で冷却し、窒素雰囲気下
、攪拌しなから２−エチル−４−メチルイミダゾール３
３９（０，３０モル）を加えた。トリオキザン’ｌ（０
，３モル）を入れ、油浴で加温し、９０〜１００°Ｃで
２５時間反応を行った。Example-4 Using the same apparatus as Example-1, 25%-hydrochloric acid 263f
(1.8 mol) was added. Cool with ice water, stir under nitrogen atmosphere, and add 2-ethyl-4-methylimidazole 3.
39 (0.30 mol) was added. Triokizan'l (0
, 3 mol), heated in an oil bath, and reacted at 90 to 100°C for 25 hours.
反応後、減圧下に過剰の塩酸ケ除去し、濃縮乾固した後
エタノールで再結晶を行った。２−エチル−４−メチル
−５−ヒドロキシメチルイミダゾール塩酸塩５Ｂ、４ｆ
（収率７２．５％）が得られた。融点は１２６５〜１２
５．０℃であった。After the reaction, excess hydrochloric acid was removed under reduced pressure, concentrated to dryness, and then recrystallized from ethanol. 2-ethyl-4-methyl-5-hydroxymethylimidazole hydrochloride 5B, 4f
(yield 72.5%) was obtained. Melting point is 1265-12
The temperature was 5.0°C.
実施例−５
実施例−１と同様の装置を用い５５％−塩酸９４，０ｆ
（０，９モル）を入れた。窒素雰囲気下、攪拌しながら
９５％−バラホルムアルデヒド９．５Ｆ（０，５モル）
とあらかじめ調製した２、４−ジメチルイミダゾール塩
酸塩３９．Ｅｌ（０，３モル）を加え、油浴で加温し、
還流下に１５時間反応を行った。Example-5 55% hydrochloric acid 94.0f using the same equipment as Example-1
(0.9 mol) was added. 95% paraformaldehyde 9.5F (0.5 mol) with stirring under nitrogen atmosphere
and 2,4-dimethylimidazole hydrochloride prepared in advance with 39. Add El (0.3 mol) and warm in an oil bath.
The reaction was carried out under reflux for 15 hours.
反応後、実施例−１と同様に後処理を行い、融点２３５
〜２６６℃の２，４−ジメチル−５−ヒドロキシメチル
イミダゾール塩酸塩３８．１を得た。収率７８．２％で
あった。After the reaction, post-treatment was performed in the same manner as in Example-1, and the melting point was 235.
38.1 of 2,4-dimethyl-5-hydroxymethylimidazole hydrochloride at ~266°C was obtained. The yield was 78.2%.
１３−13-
Claims (1)
基、Ｒ２は水素原子、炭素数１〜３のアルキル基または
フェニル基を示′ｆ）で素わされるイミダゾール化合物
とホルムアルデヒドまたはホルムアルデヒドのオリゴマ
ーとを無機酸水溶液中で反応させることを特徴とする一
般式（ＩＩ）２ （式中、Ｒ１，Ｒ２は一般式（ＩＩ）の場合と同じ意味
を示し、ＨＡは無機酸を示す）で表わされる５ （４１
−ヒドロキシメチルイミー、ダゾール塩類の製造方法。[Scope of Claims] 1) General formula (I) 2 (wherein R1 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and R2 represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or a phenyl group) 'f) The imidazole compound and formaldehyde or an oligomer of formaldehyde are reacted in an inorganic acid aqueous solution. 5 (41
- Method for producing hydroxymethylimy and dazole salts.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP58180826A JPS6075465A (en) | 1983-09-30 | 1983-09-30 | Preparation of 5(4)-hydroxymethylimidazole salt |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP58180826A JPS6075465A (en) | 1983-09-30 | 1983-09-30 | Preparation of 5(4)-hydroxymethylimidazole salt |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS6075465A true JPS6075465A (en) | 1985-04-27 |
Family
ID=16090028
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP58180826A Pending JPS6075465A (en) | 1983-09-30 | 1983-09-30 | Preparation of 5(4)-hydroxymethylimidazole salt |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS6075465A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS61197095A (en) * | 1985-02-27 | 1986-09-01 | Mitsubishi Plastics Ind Ltd | Microbe carrier |
| JPS62195016A (en) * | 1986-02-21 | 1987-08-27 | Mitsubishi Petrochem Co Ltd | One-pack type epoxy resin composition |
-
1983
- 1983-09-30 JP JP58180826A patent/JPS6075465A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS61197095A (en) * | 1985-02-27 | 1986-09-01 | Mitsubishi Plastics Ind Ltd | Microbe carrier |
| JPS62195016A (en) * | 1986-02-21 | 1987-08-27 | Mitsubishi Petrochem Co Ltd | One-pack type epoxy resin composition |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US6177575B1 (en) | Process for manufacture of imidazoles | |
| JPS5938228B2 (en) | Imidazole and 2-alkylimidazoles and their production method | |
| JPS6075465A (en) | Preparation of 5(4)-hydroxymethylimidazole salt | |
| US4394511A (en) | Imidazole 4(5)-dithiocarboxylic acids or salts | |
| JP3364895B2 (en) | Production of folic acid | |
| US3201406A (en) | Pyridylcoumarins | |
| JPH01272570A (en) | Production of 4-methyl-5-((2-aminoethyl)-thiomethyl)-imidazole | |
| US4189592A (en) | Preparation of 4-methyl-5-[(2-aminoethyl)-thiomethyl]-imidazole dihydrochloride | |
| US3450709A (en) | Process for the preparation of ring-substituted 2-aminoimidazoles | |
| JP2851162B2 (en) | Improved production method of low chloride ion 1,2,4-triazol-5-one | |
| JPS6317837B2 (en) | ||
| EP0713865B1 (en) | 2-Aminobenzenesulphonic acid and 2-aminobenzenesulphonyl chloride derivatives, their preparation and their use as synthetic intermediates | |
| JPS6136270A (en) | Manufacture of 2_alkyl_4,5_dihydroxymethylimidazole | |
| CA1134839A (en) | Preparation of 5-hydroxymethylimidazoles | |
| JP2626710B2 (en) | Method for synthesizing 4-amino-1,2,4- (4H) triazole derivative | |
| JPH01197478A (en) | Production of n-(2-chlorobenzyl)-2-(2-thienyl) ethylamine | |
| AU680989B2 (en) | Method of preparing 6-aryloxymethyl-1-hydroxy-4-methyl-2-pyridones | |
| JPS6136753B2 (en) | ||
| KR940005014B1 (en) | Process for producting pyrrolidine derivatives | |
| JPS6160673A (en) | Preparation of guanidinothiazole derivative | |
| Ali et al. | Reactions with 2-Acylbenzimidazole Preparation of 2-Cinnamoylbenzimidazoles, their Reactions towards Grignard Reagents and Thiourea | |
| SU271410A1 (en) | METHOD OF OBTAINING 1-AMIDIN-3- (SUBSTITUTED PHENYL) -CARBAMIDE | |
| JPS60337B2 (en) | Method for producing α-amino acids | |
| CN111205226A (en) | Synthesis method of 1-methyl-4-iodopyrazole | |
| SU259888A1 (en) | METHOD OF OBTAINING 9- [2- (PYRIDIL-4) ETIHL] 3,6-DIMETHYL--1,2,3,4-TETRAG IDRO-u-CARBOL IKA |