JPH01242571A - Production of imidazole derivative - Google Patents
Production of imidazole derivativeInfo
- Publication number
- JPH01242571A JPH01242571A JP63065731A JP6573188A JPH01242571A JP H01242571 A JPH01242571 A JP H01242571A JP 63065731 A JP63065731 A JP 63065731A JP 6573188 A JP6573188 A JP 6573188A JP H01242571 A JPH01242571 A JP H01242571A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- general formula
- group
- compound
- acid
- 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
- 238000004519 manufacturing process Methods 0.000 title claims description 9
- 150000002460 imidazoles Chemical class 0.000 title description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 22
- 239000002253 acid Substances 0.000 claims abstract description 16
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 8
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 8
- 150000002367 halogens Chemical class 0.000 claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 4
- 125000003282 alkyl amino group Chemical group 0.000 claims abstract description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 4
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
- 125000004434 sulfur atom Chemical group 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims 5
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims 1
- QDYTUZCWBJRHKK-UHFFFAOYSA-N imidazole-4-methanol Chemical class OCC1=CNC=N1 QDYTUZCWBJRHKK-UHFFFAOYSA-N 0.000 abstract description 8
- 239000002994 raw material Substances 0.000 abstract description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 abstract description 4
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 3
- 229910052760 oxygen Inorganic materials 0.000 abstract description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 abstract 2
- 230000002490 cerebral effect Effects 0.000 abstract 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 229940079865 intestinal antiinfectives imidazole derivative Drugs 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- -1 methoxyl group Chemical group 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 2
- FYGHSUNMUKGBRK-UHFFFAOYSA-N 1,2,3-trimethylbenzene Chemical compound CC1=CC=CC(C)=C1C FYGHSUNMUKGBRK-UHFFFAOYSA-N 0.000 description 2
- VQKFNUFAXTZWDK-UHFFFAOYSA-N 2-Methylfuran Chemical compound CC1=CC=CO1 VQKFNUFAXTZWDK-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- AFBPFSWMIHJQDM-UHFFFAOYSA-N N-methylaniline Chemical compound CNC1=CC=CC=C1 AFBPFSWMIHJQDM-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- 230000003925 brain function Effects 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- UOHMMEJUHBCKEE-UHFFFAOYSA-N prehnitene Chemical compound CC1=CC=C(C)C(C)=C1C UOHMMEJUHBCKEE-UHFFFAOYSA-N 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- GGRBEFVMJHQWFG-UHFFFAOYSA-N (2-phenyl-1h-imidazol-5-yl)methanol Chemical compound OCC1=CNC(C=2C=CC=CC=2)=N1 GGRBEFVMJHQWFG-UHFFFAOYSA-N 0.000 description 1
- NVLHGZIXTRYOKT-UHFFFAOYSA-N 1-chloro-2,3-dimethylbenzene Chemical compound CC1=CC=CC(Cl)=C1C NVLHGZIXTRYOKT-UHFFFAOYSA-N 0.000 description 1
- IBSQPLPBRSHTTG-UHFFFAOYSA-N 1-chloro-2-methylbenzene Chemical compound CC1=CC=CC=C1Cl IBSQPLPBRSHTTG-UHFFFAOYSA-N 0.000 description 1
- BLMBNEVGYRXFNA-UHFFFAOYSA-N 1-methoxy-2,3-dimethylbenzene Chemical compound COC1=CC=CC(C)=C1C BLMBNEVGYRXFNA-UHFFFAOYSA-N 0.000 description 1
- ZMPAPJBFYQSNFM-UHFFFAOYSA-N 1-sulfanylimidazole Chemical class SN1C=CN=C1 ZMPAPJBFYQSNFM-UHFFFAOYSA-N 0.000 description 1
- FEORNCWZOSTSRO-UHFFFAOYSA-N 1h-imidazol-2-ylmethanol;hydrochloride Chemical compound Cl.OCC1=NC=CN1 FEORNCWZOSTSRO-UHFFFAOYSA-N 0.000 description 1
- XRUGBBIQLIVCSI-UHFFFAOYSA-N 2,3,4-trimethylphenol Chemical compound CC1=CC=C(O)C(C)=C1C XRUGBBIQLIVCSI-UHFFFAOYSA-N 0.000 description 1
- FJSKXQVRKZTKSI-UHFFFAOYSA-N 2,3-dimethylfuran Chemical compound CC=1C=COC=1C FJSKXQVRKZTKSI-UHFFFAOYSA-N 0.000 description 1
- QWBBPBRQALCEIZ-UHFFFAOYSA-N 2,3-dimethylphenol Chemical compound CC1=CC=CC(O)=C1C QWBBPBRQALCEIZ-UHFFFAOYSA-N 0.000 description 1
- BZYUMXXOAYSFOW-UHFFFAOYSA-N 2,3-dimethylthiophene Chemical compound CC=1C=CSC=1C BZYUMXXOAYSFOW-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- WZFUQSJFWNHZHM-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)N1CC2=C(CC1)NN=N2 WZFUQSJFWNHZHM-UHFFFAOYSA-N 0.000 description 1
- YSMYHWBQQONPRD-UHFFFAOYSA-N 2-chlorofuran Chemical compound ClC1=CC=CO1 YSMYHWBQQONPRD-UHFFFAOYSA-N 0.000 description 1
- GSFNQBFZFXUTBN-UHFFFAOYSA-N 2-chlorothiophene Chemical compound ClC1=CC=CS1 GSFNQBFZFXUTBN-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
- DTFKRVXLBCAIOZ-UHFFFAOYSA-N 2-methylanisole Chemical compound COC1=CC=CC=C1C DTFKRVXLBCAIOZ-UHFFFAOYSA-N 0.000 description 1
- QTWJRLJHJPIABL-UHFFFAOYSA-N 2-methylphenol;3-methylphenol;4-methylphenol Chemical compound CC1=CC=C(O)C=C1.CC1=CC=CC(O)=C1.CC1=CC=CC=C1O QTWJRLJHJPIABL-UHFFFAOYSA-N 0.000 description 1
- XQQBUAPQHNYYRS-UHFFFAOYSA-N 2-methylthiophene Chemical compound CC1=CC=CS1 XQQBUAPQHNYYRS-UHFFFAOYSA-N 0.000 description 1
- 239000004129 EU approved improving agent Substances 0.000 description 1
- QENGPZGAWFQWCZ-UHFFFAOYSA-N Methylthiophene Natural products CC=1C=CSC=1 QENGPZGAWFQWCZ-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical class CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 230000000767 anti-ulcer Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 150000001555 benzenes Chemical class 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 125000006309 butyl amino group Chemical group 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- XLSZMDLNRCVEIJ-UHFFFAOYSA-N methylimidazole Natural products CC1=CNC=N1 XLSZMDLNRCVEIJ-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 125000006308 propyl amino group Chemical group 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 150000008054 sulfonate salts Chemical class 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
（産業上の利用分野）
本発明は、イミダゾール誘導体の製造方法に関するもの
であり、より詳細には、４−ヒドロキシメチルイミダゾ
ール誘導体を原料とし、酸の存在下に一段階で、医薬と
して有用なイミダゾール誘導体を高収率で製造する方法
に関するものである。Detailed Description of the Invention (Industrial Field of Application) The present invention relates to a method for producing an imidazole derivative, and more specifically, a method for producing an imidazole derivative using a 4-hydroxymethylimidazole derivative as a raw material, and a method for producing an imidazole derivative in one step in the presence of an acid. The present invention relates to a method for producing imidazole derivatives useful as pharmaceuticals in high yield.
（従来の技術及びその問題点）
特開昭５６−３２４６３号公報には、本発明のによって
えられるものと同じイミダゾール誘導体が、抗高血圧活
性、抗血栓活性、利尿活性、抗菌活性および抗潰瘍活性
を示す医薬として有用であることが記載されており、こ
のイミダゾール誘導体は下記の反応によって製造される
ものであることが開示されている。(Prior art and its problems) JP-A-56-32463 discloses that the same imidazole derivatives obtained by the present invention have antihypertensive activity, antithrombotic activity, diuretic activity, antibacterial activity and antiulcer activity. It is disclosed that this imidazole derivative is useful as a medicine exhibiting the following reaction.
しかしながら、ここに開示されたイミダゾール誘導体の
製造方法はいずれも反応段数が長く、総数率も低く、効
率的な方法とはいえない。However, all of the methods for producing imidazole derivatives disclosed herein require a long number of reaction stages and a low total number ratio, and cannot be said to be efficient methods.
本発明は、該イミダゾール誘導体の効率的な製造方法に
ついて追求した結果到達したものである。The present invention was achieved as a result of pursuing an efficient method for producing the imidazole derivative.
本発明の目的は、原料である４−ヒドロキシメチルイミ
ダゾール誘導体から一段階の反応で、しかも高収率で、
医薬として有用なイミダゾール誘導体を製造する方法を
提供することにある。The purpose of the present invention is to perform a one-step reaction from a 4-hydroxymethylimidazole derivative as a raw material, and in a high yield.
An object of the present invention is to provide a method for producing imidazole derivatives useful as pharmaceuticals.
（問題点を解決するための手段）
本発明によれば、
１）一般式［ＩＩ
（式中、Ｒ１は水素原子またはフェニル基）で表わされ
る化合物またはその酸付加塩と、１ｉ）一般式［ＩＩ
］
（式中、Ｒ２乃至Ｒ８は、同一かまたは異なって、水素
原子、低級アルキル基、水酸基、低級アルコキシ基、低
級アルキルアミノ基、ハロゲンであり、それぞれが結合
して環を形成していてもよい）、または、ｉｉｉ ）一
般式［ＩＩＩ ］
（式中、Ｒ６、Ｒ７は同一かまたは異なって、水素原子
、低級アルキル基、ハロゲン、Ｘは酸素原子またはイオ
ウ原子）
で表わされる化合物を、酸の存在下に反応させることに
よって、−段階で、しかも高収率で、一般式［ｒＶ］
（式中、Ｒ１乃至Ｒ５は式［ＩＩ、［＋１コに同じ）、
または、
一般式［Ｖ］
（式中、Ｒ１、Ｒ６、Ｒ７およびＸは式［ＩＩ、［Ｉ！
］に同じ）
によって表わされるイミダゾール誘導体を製造すること
が可能になる。(Means for Solving the Problems) According to the present invention, 1) a compound represented by the general formula [II (wherein R1 is a hydrogen atom or a phenyl group) or an acid addition salt thereof; II
] (In the formula, R2 to R8 are the same or different and are a hydrogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group, a lower alkylamino group, or a halogen, and even if they are combined to form a ring, or iii) a compound represented by the general formula [III] (wherein R6 and R7 are the same or different, a hydrogen atom, a lower alkyl group, a halogen, and X is an oxygen atom or a sulfur atom), By reacting in the presence of the general formula [rV] (wherein R1 to R5 are the same as the formula [II, [+1]), in a -step and in high yield,
Or, General formula [V] (wherein R1, R6, R7 and X are formula [II, [I!
) It becomes possible to produce an imidazole derivative represented by
（作 用）
本発明は、一般式［１３の化合物またはその酸付加塩と
、一般式［ＩＩ ］または［ＩＩＩ ］の化合物を、酸
、とくに有機スルホン酸の存在下で反応させることによ
り、−段階で、しかも高収率で目的とするイミダゾール
誘導体を製造することができるという知見に基づくもの
である。(Function) The present invention provides the following method: - This is based on the knowledge that the desired imidazole derivative can be produced in a high yield in a single step.
（好適態様の説明）
一般式［ＩＩ
■
で表わされる４−ヒドロキシメチルイミダゾール誘導体
において、Ｒ１は水素原子またはフェニル基であり、該
化合物はフリーの形で用いてもよく、また、塩酸塩、硝
酸塩、硫酸塩、リン酸塩なとの鉱酸の塩、酢酸塩、プロ
ピオン酸塩などの有機酸の塩、メタンスルホン酸、ｐ−
トルエンスルホン酸などの有機スルホン酸塩の形で用い
ることもできる。(Description of preferred embodiments) In the 4-hydroxymethylimidazole derivative represented by the general formula [II (2), R1 is a hydrogen atom or a phenyl group, and the compound may be used in a free form, and may also be used as a hydrochloride, a nitrate, etc. , salts of mineral acids such as sulfates and phosphates, salts of organic acids such as acetates and propionates, methanesulfonic acid, p-
It can also be used in the form of organic sulfonate salts such as toluenesulfonic acid.
一般式［ｒ、ｌで表わされる化合物として具体的には、
４−ヒドロキシメチルイミダゾール、４−ヒドロキシメ
チル−２−フェニルイミダゾール等を例示することがで
きる。Specifically, as a compound represented by the general formula [r, l,
Examples include 4-hydroxymethylimidazole and 4-hydroxymethyl-2-phenylimidazole.
一般式［ｎ ］
で表わされるベンゼン誘導体において、Ｒ２乃至Ｒ５は
、同一かまたは異なって、メチル基、エチル基、プロピ
ル基、イソプロピル基、ブチル基、イソブチル基、ｔ−
ブチル基などの低級アルキル基、メトキシル基、エトキ
シル基、プロポキシル基、インプロポキシル基、ブトキ
シル基などの低級アルコキシル基、メチルアミノ基、エ
チルアミノ基、プロピルアミノ基、イソプロとルアミノ
基、ブチルアミノ基などの低級アルキルアミノ基、水素
原子、水酸基、もしくは、塩素原子、臭素原子、フッ素
原子などのハロゲンであり、それぞれが結合して環を形
成していてもよい。In the benzene derivative represented by the general formula [n], R2 to R5 are the same or different and are a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a t-
Lower alkyl groups such as butyl group, methoxyl group, ethoxyl group, propoxyl group, impropoxyl group, lower alkoxyl group such as butoxyl group, methylamino group, ethylamino group, propylamino group, isopro-ruamino group, butylamino group A lower alkylamino group such as a hydrogen atom, a hydroxyl group, or a halogen such as a chlorine atom, a bromine atom, or a fluorine atom, each of which may be bonded to form a ring.
この化合物は、一般式［ＩＩの化合物に対して、等モル
量乃至溶媒量（１０００倍モル量）の範囲で反応せしめ
るが、とくに１乃至２０倍モルの量で反応させることが
好ましい。This compound is reacted in an equimolar amount to a solvent amount (1000 times the molar amount) with respect to the compound of general formula [II, but it is particularly preferable to react in an amount of 1 to 20 times the molar amount.
一般式［ＩＩ ］で表わされる化合物として具体的には
、ベンゼン、トルエン、キシレン、トリメチルベンゼン
、テトラメチルベンゼン、フェノール、メチルフェノー
ル、ジメチルフェノール、トリメチルフェノール、アニ
リン、Ｎ−メチルアニリン、Ｎ、Ｎ−ジメチルアニリン
、メチル−Ｎ。Specifically, the compounds represented by the general formula [II] include benzene, toluene, xylene, trimethylbenzene, tetramethylbenzene, phenol, methylphenol, dimethylphenol, trimethylphenol, aniline, N-methylaniline, N,N- Dimethylaniline, methyl-N.
Ｎ−ジメチルアニリン、アニソール、クロロベンゼン、
ナフタレン、テトラヒドロキノリン、キノリン、メチル
アニソール、ジメチル−アニソール、メチル−クロロベ
ンゼン、ジメチルクロロベンゼン等を例示することがで
きる。N-dimethylaniline, anisole, chlorobenzene,
Examples include naphthalene, tetrahydroquinoline, quinoline, methylanisole, dimethylanisole, methylchlorobenzene, and dimethylchlorobenzene.
一般式［ＩＩＩ ］
で表わされるイミダゾール誘導体において、Ｒ６゜Ｒ７
は同一かまたは異なって、水素原子、メチル基、エチル
基、プロピル基、イソプロピル基、ブチル基、イソブチ
ル基、ｔ−ブチル基などの低級アルキル基、もしくは、
塩素原子、臭素原子、フッ素原子などのハロゲンを示し
、Ｘは酸素原子、またはイオウ原子である。In the imidazole derivative represented by the general formula [III], R6゜R7
are the same or different and are a hydrogen atom, a lower alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a t-butyl group, or
It represents a halogen such as a chlorine atom, a bromine atom, or a fluorine atom, and X is an oxygen atom or a sulfur atom.
このイミダゾール誘導体は、一般式［Ｉ］で表わされる
４−ヒドロキシメチルイミダゾール誘導体に対して、等
モル乃至溶媒量（１０００倍モル量）の範囲で反応せし
められるが、とくに１乃至２０倍モル量の範囲で反応さ
せることが好ましい。This imidazole derivative is reacted with the 4-hydroxymethylimidazole derivative represented by the general formula [I] in an equimolar to a solvent amount (1000 times the molar amount), but especially in a 1 to 20 times molar amount. It is preferable to react within a range.
、一般式［ＩＩＩ ］で表わされる化合物として具体的
には、チオフェン、フラン、メチルチオフェン、メチル
フラン、ジメチルチオフェン、ジメチルフラン、クロロ
チオフェン、クロロフラン等を例示することができる。, specific examples of the compound represented by the general formula [III] include thiophene, furan, methylthiophene, methylfuran, dimethylthiophene, dimethylfuran, chlorothiophene, and chlorofuran.
本発明においては、前記一般式［Ｉ］で表わされる化合
物と、［１１］、または［Ｉｌｌ ］で表わされる化合
物を酸の存在下で反応させることが特徴のひとつである
。酸としては、メタンスルホン酸、ベンゼンスルホン酸
、Ｐ−）−ルエンスルホン酸などの有機スルホン酸が用
いられ、とくに、Ｐ−トルエンスルホン酸が好ましく用
いられる。One of the features of the present invention is that the compound represented by the general formula [I] is reacted with the compound represented by [11] or [Ill] in the presence of an acid. As the acid, organic sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, and P-)-luenesulfonic acid are used, and P-toluenesulfonic acid is particularly preferably used.
反応に際して、前記酸の量は、一般式［Ｉ］の化合物の
モル数によって変化し、［Ｉ］の化合物がフリーの場合
は、１乃至２０倍モル、好ましくは、１乃至６倍モルで
あり、［Ｉ］の化合物が酸付加塩の場合は、０．０１乃
至２０倍モル、好ましくは０．１乃至５倍モルの量で使
用される。In the reaction, the amount of the acid varies depending on the number of moles of the compound of general formula [I], and when the compound [I] is free, it is 1 to 20 times the mole, preferably 1 to 6 times the mole. When the compound [I] is an acid addition salt, it is used in an amount of 0.01 to 20 times the mole, preferably 0.1 to 5 times the mole.
また、反応は、０乃至３００℃、好ましくは５０乃至２
５０℃の温度で常圧または加圧下に、０．１乃至２０時
間、好ましくは１乃至１２時間行われる。Further, the reaction is carried out at 0 to 300°C, preferably at 50 to 200°C.
It is carried out at a temperature of 50° C. under normal pressure or increased pressure for 0.1 to 20 hours, preferably 1 to 12 hours.
生成した反応混合物は、に２Ｃ０３水などのアルカリ溶
液を加えた後、後述の実施例で例示されるような通常の
後処理方法により、一般式［ｒＶ］または［Ｖ］で表わ
される最終生成物とするものであるが、更に、必要なら
ば、クロマトグラフや再結晶などの手段により精製する
こともできる。After adding an alkaline solution such as 2C03 water to the generated reaction mixture, a final product represented by the general formula [rV] or [V] is obtained by a usual post-treatment method as exemplified in the Examples below. However, if necessary, it can be further purified by means such as chromatography or recrystallization.
本発明によって得られるチオイミダゾール誘導体および
その酸付加塩は、単独、あるいは混合物の形で、優れた
抗脳虚血作用および抗低圧酸素作用を示し、脳機能改善
剤として有用である。該化合物は、それ自体を単独で投
与してもよいが、必要に応じて種々の剤型として、経口
的または非経口的に投与することができる。The thioimidazole derivatives and acid addition salts thereof obtained by the present invention, alone or in the form of a mixture, exhibit excellent anti-cerebral ischemic activity and anti-hypobaric oxygen activity, and are useful as brain function improving agents. The compound itself may be administered alone, but it can also be administered orally or parenterally in various dosage forms as necessary.
（発明の効果）
本発明によれば、一般式［Ｉ］で示される４−ヒドロキ
シメチルイミダゾール誘導体を原料として、試薬として
酸を用いることにより、−段階で、しかも高収率で、脳
機能改善剤として有用な、一般式［ｒＶ］または［Ｖ］
で表わされるイミダゾール誘導体を製造することができ
、この方法は、特開昭５６−３２４６３号に開示された
ような二段階法あるいは三段階法のものに比較してきわ
めて効率的な方法であるとともに、試薬として酸を用い
るだけでよいために経済的にもすぐれているという効果
がある。(Effects of the Invention) According to the present invention, by using a 4-hydroxymethylimidazole derivative represented by the general formula [I] as a raw material and an acid as a reagent, brain function can be improved in -steps and in high yield. General formula [rV] or [V] useful as an agent
The imidazole derivative represented by This method is also economically advantageous because it only requires the use of an acid as a reagent.
（実施例） 以下に実施例によって、本発明を具体的に説明する。(Example) The present invention will be specifically explained below using Examples.
実施例
４−ヒドロキシメチルイミダゾール塩酸塩１ｇを水５ｍ
ｇに溶かした溶液に２．４．６−ドリメチルベンゼン３
０ｍ１とｐ−トルエンスルホン酸１永和物４．７５ｇを
加え、１７０℃で７時間反応させる。反応混合物を冷却
し、これに炭化カリウムの飽和水溶液１０ｍ１！、を加
える。ついで、有機層を水洗後２Ｎ−塩酸１００ｍｆｆ
１で抽出する。水層をトルエン１００ｍ２で洗浄後、炭
酸カリウムでｐＨ８にして、クロロホルム１５０ｍ、５
で抽出し、得られたクロロホルム層を乾燥後濃縮する事
により、４− （２，４，６−ドリメチルフエニル）メ
チルイミダゾールを無色結晶として１．３４ｇ （収率
７６％）得た。これを化合物Ｎｏ １とする。Example 4 - 1 g of hydroxymethylimidazole hydrochloride in 5 m of water
2.4.6-Drimethylbenzene 3 in a solution dissolved in g
0ml and 4.75g of p-toluenesulfonic acid monohydrate were added and reacted at 170°C for 7 hours. The reaction mixture is cooled and added with 10 ml of a saturated aqueous solution of potassium carbide! , add. Then, after washing the organic layer with water, 100 mff of 2N hydrochloric acid was added.
Extract with 1. After washing the aqueous layer with 100 m2 of toluene, the pH was adjusted to 8 with potassium carbonate, and 150 m2 of chloroform was added.
The resulting chloroform layer was dried and concentrated to obtain 1.34 g (yield: 76%) of 4-(2,4,6-drimethylphenyl)methylimidazole as colorless crystals. This is designated as compound No. 1.
以下、同様にして化合物Ｎｏ ２乃至１２に示した置換
基の異なるイミダゾール誘導体を製造し、その収率とと
もに表に示した。Hereinafter, imidazole derivatives having different substituents as shown in Compounds Nos. 2 to 12 were produced in the same manner and are shown in the table together with their yields.
Claims (3)
れる化合物またはその酸付加塩と、ｉｉ）一般式［II］ ▲数式、化学式、表等があります▼［II］ （式中、Ｒ＾２乃至Ｒ＾５は、同一かまたは異なって、
水素原子、低級アルキル基、水酸基、低級アルコキシ基
、低級アルキルアミノ基、ハロゲンであり、それぞれが
結合して環を形成していてもよい）、または、 ｉｉｉ）一般式［III］ ▲数式、化学式、表等があります▼［III］ （式中、Ｒ＾６、Ｒ＾７は同一かまたは異なって、水素
原子、低級アルキル基、ハロゲン、Ｘは酸素原子または
イオウ原子） で表わされる化合物を、酸の存在下に反応させることを
特徴とする、 一般式［IV］ ▲数式、化学式、表等があります▼［IV］ （式中、Ｒ＾１乃至Ｒ＾５は式［ I ］、［II］に同じ
）、または、 一般式［Ｖ］ ▲数式、化学式、表等があります▼［Ｖ］ （式中、Ｒ＾１、Ｒ＾５、Ｒ＾７およびＸは式［ I ］
、［II］に同じ） によって表わされるイミダゾール誘導体の製造方法。(1)i) General formula [I] ▲Mathematical formula, chemical formula, table, etc.▼[I] (In the formula, R^1 is a hydrogen atom or a phenyl group) A compound or its acid addition salt, and ii) General formula [II] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [II] (In the formula, R^2 to R^5 are the same or different,
hydrogen atom, lower alkyl group, hydroxyl group, lower alkoxy group, lower alkylamino group, halogen, each of which may be bonded to form a ring), or iii) General formula [III] ▲ Numerical formula, chemical formula , tables, etc. ▼ [III] (In the formula, R^6 and R^7 are the same or different, a hydrogen atom, a lower alkyl group, a halogen, and X is an oxygen atom or a sulfur atom). General formula [IV] ▲There are mathematical formulas, chemical formulas, tables, etc.▼[IV] (In the formula, R^1 to R^5 are the formula [I], [II] ), or general formula [V] ▲Mathematical formula, chemical formula, table, etc.▼[V] (In the formula, R^1, R^5, R^7 and X are the formula [I]
, same as [II]).
の製造方法。(2) The manufacturing method according to claim (1), wherein the acid is an organic sulfonic acid.
に対する、一般式［II］または一般式［III］で表わさ
れる化合物が等モル量乃至１０００倍モル量で行われる
請求項（１）または（２）記載の製造方法。(3) Claim (1) wherein the reaction is carried out in an equimolar amount to 1000 times the molar amount of the compound represented by general formula [II] or general formula [III] to the compound represented by general formula [I]. Or the manufacturing method described in (2).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63065731A JPH01242571A (en) | 1988-03-22 | 1988-03-22 | Production of imidazole derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63065731A JPH01242571A (en) | 1988-03-22 | 1988-03-22 | Production of imidazole derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH01242571A true JPH01242571A (en) | 1989-09-27 |
Family
ID=13295456
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63065731A Pending JPH01242571A (en) | 1988-03-22 | 1988-03-22 | Production of imidazole derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH01242571A (en) |
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5068237A (en) * | 1990-05-21 | 1991-11-26 | Warner-Lambert Company | Substituted furans and derivatives thereof acting at muscarinic receptors |
| US5151526A (en) * | 1990-10-11 | 1992-09-29 | The United States Of America As Represented By The Secretary Of The Army | 4-[1-(1-naphthalenyl)ethyl]-1H-imidazole, method of making and use as an anesthetic |
| WO1995014007A1 (en) * | 1993-11-15 | 1995-05-26 | Schering Corporation | Phenyl-alkyl imidazoles as h3-receptor antagonists |
| US5750720A (en) * | 1996-03-28 | 1998-05-12 | Ortho Pharmaceutical Corporation | 4- (thien-3-yl)methyl!-imidazole analgesics |
| WO1999028300A1 (en) * | 1997-12-04 | 1999-06-10 | Allergan Sales, Inc. | Substituted imidazole derivatives having agonist-like activity at alpha 2b or 2b/2c adrenergic receptors |
| US6127396A (en) * | 1998-12-18 | 2000-10-03 | Adir Et Compagnie | Imidazoline compounds |
| WO2001000586A1 (en) * | 1999-06-10 | 2001-01-04 | Allergan Sales, Inc. | Compounds as selective agonists at alpha 2b or 2b/2c adrenergic receptors |
| US6329369B1 (en) | 1997-12-04 | 2001-12-11 | Allergan Sales, Inc. | Methods of treating pain and other conditions |
| US6426356B1 (en) | 1998-11-18 | 2002-07-30 | Ortho-Mcneil Pharmaceutical, Inc. | Imidazoethyl thiophenes |
| US6465486B1 (en) | 1999-03-12 | 2002-10-15 | Ortho-Mcneil Pharmaceutical, Inc. | Pyridyl/quinolinyl imidazoles |
| KR100385095B1 (en) * | 1997-07-15 | 2003-08-19 | 주식회사 엘지생명과학 | 2- or 3-membered ring aromatic compound having farnesyl transferase inhibiting activity |
| US6841684B2 (en) | 1997-12-04 | 2005-01-11 | Allergan, Inc. | Imidiazoles having reduced side effects |
| AU2002254265B2 (en) * | 1997-12-04 | 2008-05-15 | Allergan, Inc. | Imidiazole derivatives and their use as agonists selective at alpha 2B or 2B/2C adrenergic receptors |
| WO2008086131A1 (en) * | 2007-01-12 | 2008-07-17 | Allergan, Inc. | Naphthylmethylimidizoles as therapeutic agents |
-
1988
- 1988-03-22 JP JP63065731A patent/JPH01242571A/en active Pending
Cited By (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5068237A (en) * | 1990-05-21 | 1991-11-26 | Warner-Lambert Company | Substituted furans and derivatives thereof acting at muscarinic receptors |
| US5151526A (en) * | 1990-10-11 | 1992-09-29 | The United States Of America As Represented By The Secretary Of The Army | 4-[1-(1-naphthalenyl)ethyl]-1H-imidazole, method of making and use as an anesthetic |
| WO1995014007A1 (en) * | 1993-11-15 | 1995-05-26 | Schering Corporation | Phenyl-alkyl imidazoles as h3-receptor antagonists |
| US5750720A (en) * | 1996-03-28 | 1998-05-12 | Ortho Pharmaceutical Corporation | 4- (thien-3-yl)methyl!-imidazole analgesics |
| AU721867B2 (en) * | 1996-03-28 | 2000-07-13 | Johnson & Johnson Research Pty. Limited | 4-{(thien-3-yl)methyl} imidazole derivatives having alpha2-adrenoceptor agonistic activity |
| KR100385095B1 (en) * | 1997-07-15 | 2003-08-19 | 주식회사 엘지생명과학 | 2- or 3-membered ring aromatic compound having farnesyl transferase inhibiting activity |
| WO1999028300A1 (en) * | 1997-12-04 | 1999-06-10 | Allergan Sales, Inc. | Substituted imidazole derivatives having agonist-like activity at alpha 2b or 2b/2c adrenergic receptors |
| JP2001524542A (en) * | 1997-12-04 | 2001-12-04 | アラーガン・セイルズ・インコーポレイテッド | Substituted imidazole derivatives showing agonist-like activity at α2B or 2B / 2C adrenergic receptor |
| US6329369B1 (en) | 1997-12-04 | 2001-12-11 | Allergan Sales, Inc. | Methods of treating pain and other conditions |
| EP1413576A3 (en) * | 1997-12-04 | 2004-09-01 | Allergan, Inc. | Substituted imidazole derivatives having agonist-like activity at alpha 2B or 2B/2C adrenergic receptors |
| US6841684B2 (en) | 1997-12-04 | 2005-01-11 | Allergan, Inc. | Imidiazoles having reduced side effects |
| AU2002254265B2 (en) * | 1997-12-04 | 2008-05-15 | Allergan, Inc. | Imidiazole derivatives and their use as agonists selective at alpha 2B or 2B/2C adrenergic receptors |
| JP2010209111A (en) * | 1997-12-04 | 2010-09-24 | Allergan Inc | SUBSTITUTED IMIDAZOLE DERIVATIVE HAVING AGONIST-LIKE ACTIVITY AT alpha2B OR 2B/2C ADRENERGIC RECEPTOR |
| JP2014012724A (en) * | 1997-12-04 | 2014-01-23 | Allergan Inc | SUBSTITUTED IMIDAZOLE DERIVATIVE HAVING AGONIST-LIKE ACTIVITY AT α2B OR 2B/2C ADRENERGIC RECEPTOR |
| US6426356B1 (en) | 1998-11-18 | 2002-07-30 | Ortho-Mcneil Pharmaceutical, Inc. | Imidazoethyl thiophenes |
| US6127396A (en) * | 1998-12-18 | 2000-10-03 | Adir Et Compagnie | Imidazoline compounds |
| US6465486B1 (en) | 1999-03-12 | 2002-10-15 | Ortho-Mcneil Pharmaceutical, Inc. | Pyridyl/quinolinyl imidazoles |
| WO2001000586A1 (en) * | 1999-06-10 | 2001-01-04 | Allergan Sales, Inc. | Compounds as selective agonists at alpha 2b or 2b/2c adrenergic receptors |
| WO2008086131A1 (en) * | 2007-01-12 | 2008-07-17 | Allergan, Inc. | Naphthylmethylimidizoles as therapeutic agents |
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