JP4260241B2 - Method for producing imidazole derivatives - Google Patents
Method for producing imidazole derivatives Download PDFInfo
- Publication number
- JP4260241B2 JP4260241B2 JP11043398A JP11043398A JP4260241B2 JP 4260241 B2 JP4260241 B2 JP 4260241B2 JP 11043398 A JP11043398 A JP 11043398A JP 11043398 A JP11043398 A JP 11043398A JP 4260241 B2 JP4260241 B2 JP 4260241B2
- Authority
- JP
- Japan
- Prior art keywords
- tetrahydrofuran
- solution
- ethoxycarbonyl
- propyl
- formula
- 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.)
- Expired - Lifetime
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 13
- 150000002460 imidazoles Chemical class 0.000 title description 2
- 229940079865 intestinal antiinfectives imidazole derivative Drugs 0.000 title 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 118
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 58
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 36
- 239000007818 Grignard reagent Substances 0.000 claims description 25
- 150000004795 grignard reagents Chemical class 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 19
- ZQPMIDPIXSMOAD-UHFFFAOYSA-N diethyl 2-propyl-1h-imidazole-4,5-dicarboxylate Chemical compound CCCC1=NC(C(=O)OCC)=C(C(=O)OCC)N1 ZQPMIDPIXSMOAD-UHFFFAOYSA-N 0.000 claims description 19
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 claims description 15
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- 239000008096 xylene Substances 0.000 claims description 4
- 239000000243 solution Substances 0.000 description 50
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 21
- 239000003849 aromatic solvent Substances 0.000 description 21
- 239000011777 magnesium Substances 0.000 description 21
- 229910052749 magnesium Inorganic materials 0.000 description 21
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 12
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- 239000007788 liquid Substances 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 235000019270 ammonium chloride Nutrition 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000007789 gas Substances 0.000 description 5
- 229940050176 methyl chloride Drugs 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- PQAMFDRRWURCFQ-UHFFFAOYSA-N 2-ethyl-1h-imidazole Chemical compound CCC1=NC=CN1 PQAMFDRRWURCFQ-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 0 CCOC(C1C2(C(C)(C)O)N=C(CC*C)NC1C2)=O Chemical compound CCOC(C1C2(C(C)(C)O)N=C(CC*C)NC1C2)=O 0.000 description 3
- NQKKUSLBNWTXQI-UHFFFAOYSA-N diethyl 1h-imidazole-4,5-dicarboxylate Chemical class CCOC(=O)C=1N=CNC=1C(=O)OCC NQKKUSLBNWTXQI-UHFFFAOYSA-N 0.000 description 3
- -1 ethyl 2-n-propylimidazole-4,5-dicarboxylate Chemical compound 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 3
- FTWATMWYBQVYGG-UHFFFAOYSA-N (2-ethyl-1h-imidazol-5-yl)methanol Chemical class CCC1=NC=C(CO)N1 FTWATMWYBQVYGG-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- APQIUTYORBAGEZ-UHFFFAOYSA-N 1,1-dibromoethane Chemical compound CC(Br)Br APQIUTYORBAGEZ-UHFFFAOYSA-N 0.000 description 1
- DTGZORBDGLEVNY-UHFFFAOYSA-N 2-propyloxolane Chemical compound CCCC1CCCO1 DTGZORBDGLEVNY-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 102000005862 Angiotensin II Human genes 0.000 description 1
- 101800000733 Angiotensin-2 Proteins 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical group CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 229950006323 angiotensin ii Drugs 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229940102396 methyl bromide Drugs 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
Description
【０００１】
【発明の属する技術分野】
本発明は、医薬品中間体として有用なイミダゾール誘導体の製造法に関する。更に詳しくは、ビス（エトキシカルボニル）イミダゾール誘導体からグリニヤール反応により、優れたアンジオテンシンII拮抗作用及び血圧降下作用等を有する、ビフェニルメチルイミダゾール誘導体の中間体として有用な、ヒドロキシメチルエチルイミダゾール誘導体を製造する分野に利用することが出来る。
【０００２】
【従来の技術】
従来、式（１）
【０００３】
【化３】
で示される、ビス（エトキシカルボニル）イミダゾール誘導体、即ち２−ｎ−プロピル−４，５−ビス（エトキシカルボニル）イミダゾール〔或いは「２−ｎ−プロピルイミダゾール−４，５−ジカルボン酸エチル」ともいう〕から、式（２）
【０００５】
【化４】
で示される、ヒドロキシメチルエチルイミダゾール誘導体、即ち２−ｎ−プロピル−４−エトキシカルボニル−５−（１−ヒドロキシ−１−メチル）エチル−イミダゾール〔或いは４−（１−ヒドロキシ−１−メチルエチル）−２−ｎ−プロピルイミダゾール−５−カルボン酸エチル」ともいう〕を製造する方法としては、式（１）
【０００７】
【化５】
で示される２−ｎ−プロピル−４，５−ビス（エトキシカルボニル）イミダゾールをメチルマグネシウムブロミドのテトラヒドロフラン溶液と反応させる方法（特公平７−１２１９１８号）がある。
【０００９】
【発明が解決しようとする課題】
しかしながら、この従来技術では転換率が悪く、分離精製に手間がかかるため純度及び収率が余り満足すべきものではなく、工業的製法としては有利な方法とはいえなかった。
【００１０】
【課題を解決するための手段】
本発明者等は、かかる観点から、目的化合物である前記式（２）のメチルヒドロキシエチルイミダゾール誘導体を、高純度、高収率で製造できる工業的製造法を鋭意研究した結果、
テトラヒドロフラン或いはテトラヒドロフラン及び芳香族系溶媒の存在下、式（１）
【００１１】
【化６】
で示される、２−ｎ−プロピル−４，５−ビス（エトキシカルボニル）イミダゾールと、メチルマグネシウムクロリドのテトラヒドロフラン或いはテトラヒドロフラン及び芳香族系溶媒溶液であるグリニヤール試薬溶液とを反応させた後、加水分解することにより、式（２）
【００１３】
【化７】
で示される、２−ｎ−プロピル−４−エトキシカルボニル−５−（１−ヒドロキシ−１−メチル）エチル−イミダゾールを製造する方法を見出し本発明を完成した。
【００１５】
本発明の特徴は、従来技術中のメチルマグネシウムブロミドを、本発明では、メチルマグネシウムクロリドに代え、更に溶媒としてテトラヒドロフランばかりではなく、テトラヒドロフランと芳香族系溶媒との混合溶媒も使用出来るようにした点である。グリニヤール試薬のメチルマグネシウムブロミドを、メチルマグネシウムクロリドに代えることは僅かな相違のように思われるが、この変更により、従来技術の問題点、即ち転換率が悪く、分離精製に手間がかかるため、純度及び収率が低い等の問題点を、予想しなかったほど格段に改善出来ることを見出し本発明を完成するに至った。
【００１６】
本発明で使用される芳香族系溶媒としては、例えば、ベンゼン、トルエン、キシレン等が挙げられるが、最も好ましい例としては、反応性、取り扱い易さの面等からトルエンが挙げられる。
【００１７】
テトラヒドロフランと芳香族系溶媒は、テトラヒドロフラン単独で或いはテトラヒドロフラン及び芳香族系溶媒を併用することが出来、併用する場合の割合は特に限定されないが、通常、テトラヒドロフランを芳香族系溶媒よりも等量（容量）以上使用する方がよく、さらに好ましくは、テトラヒドロフラン：芳香族系溶媒の割合（容量）が２：１〜４：１である。
【００１８】
メチルマグネシウムクロリドの、テトラヒドロフラン或いはテトラヒドロフラン及び芳香族系溶媒溶液からなるグリニヤール試薬溶液の調製法は、従来公知の方法で行うことが出来、例えば、容器中に、テトラヒドロフラン或いはテトラヒドロフラン及び芳香族系溶媒とマグネシウムを入れ、マグネシウムの表面を活性化するために有効な、少量のヨウ素、ヨウ化メチル或いはジブロムエタン等を添加し、マグネシウムを活性化させる。
【００１９】
次いでテトラヒドロフラン或いはテトラヒドロフラン及び芳香族系溶媒を添加、希釈し、液温を２０〜５０℃、好ましくは３０〜４０℃に維持し、そこへ塩化メチルをマグネシウムに対して１．０倍当量以上吹き込むと、マグネシウムは消失し、メチルマグネシウムクロリドのグリニヤール試薬溶液が得られる。
【００２０】
本発明の方法を更に詳細に説明すると、先に調製したメチルマグネシウムクロリドの、テトラヒドロフラン或いはテトラヒドロフラン及び芳香族系溶媒溶液であるグリニヤール試薬溶液に、前記式（１）で示される２−ｎ−プロピル−４，５−ビス（エトキシカルボニル）イミダゾールのテトラヒドロフラン或いはテトラヒドロフラン及び芳香族系溶媒溶液を添加し、液温５〜３０℃、好ましくは１０〜２０℃で反応させる。その際のグリニヤール試薬の量は、式（１）の２−ｎ−プロピル−４，５−ビス（エトキシカルボニル）イミダゾールに対して３．０倍当量以上、好ましくは３．５〜５．０倍当量であればよい。又、テトラヒドロフラン或いはテトラヒドロフラン及び芳香族系溶媒の総量は、式（１）で示される２−ｎ−プロピル−４，５−ビス（エトキシカルボニル）イミダゾールに対して、８〜１１倍重量であればよい。また、加水分解する方法としては、水又はｐＨ７以上のアルカリ性水溶液、例えば塩化アンモニウム水溶液又は水酸化アンモニウム水溶液等のアンモニウム水溶液を用いることが出来るが、アンモニウム水溶液のような弱アルカリ性水溶液の方が好ましい。
【００２１】
【発明の実施の形態】
本発明の実施に当たっては、以下の実施態様を挙げることが出来る。
【００２２】
（１）テトラヒドロフラン及び芳香族系溶媒の存在下、式（１）
【００２３】
【化８】
で示される、２−ｎ−プロピル−４，５−ビス（エトキシカルボニル）イミダゾールと、メチルマグネシウムクロリドのテトラヒドロフラン及び芳香族系溶媒溶液であるグリニヤール試薬溶液とを反応させた後、加水分解することを特徴とする、式（２）
【００２５】
【化９】
で示される、２−ｎ−プロピル−４−エトキシカルボニル−５−（１−ヒドロキシ−１−メチル）エチル−イミダゾールの製造法。
【００２７】
（２）テトラヒドロフラン及び芳香族系溶媒の存在下、式（１）
【００２８】
【化１０】
で示される、２−ｎ−プロピル−４，５−ビス（エトキシカルボニル）イミダゾールと、メチルマグネシウムクロリドのテトラヒドロフラン溶液であるグリニヤール試薬溶液とを反応させた後、加水分解することを特徴とする、式（２）
【００３０】
【化１１】
で示される、２−ｎ−プロピル−４−エトキシカルボニル−５−（１−ヒドロキシ−１−メチル）エチル−イミダゾールの製造法。
【００３２】
（３）テトラヒドロフランの存在下、式（１）
【００３３】
【化１２】
で示される、２−ｎ−プロピル−４，５−ビス（エトキシカルボニル）イミダゾールと、メチルマグネシウムクロリドのテトラヒドロフラン及び芳香族系溶媒溶液であるグリニヤール試薬溶液とを反応させた後、加水分解することを特徴とする、式（２）
【００３５】
【化１３】
で示される、２−ｎ−プロピル−４−エトキシカルボニル−５−（１−ヒドロキシ−１−メチル）エチル−イミダゾールの製造法。
【００３７】
（４）テトラヒドロフランの存在下、式（１）
【００３８】
【化１４】
で示される、２−ｎ−プロピル−４，５−ビス（エトキシカルボニル）イミダゾールと、メチルマグネシウムクロリドのテトラヒドロフラン溶液であるグリニヤール試薬溶液とを反応させた後、加水分解することを特徴とする、式（２）
【００４０】
【化１５】
で示される、２−ｎ−プロピル−４−エトキシカルボニル−５−（１−ヒドロキシ−１−メチル）エチル−イミダゾールの製造法。
【００４２】
（５）テトラヒドロフラン：芳香族系溶媒が２：１〜４：１の存在下、式（１）
【００４３】
【化１６】
で示される、２−ｎ−プロピル−４，５−ビス（エトキシカルボニル）イミダゾールと、メチルマグネシウムクロリドのテトラヒドロフラン：芳香族系溶媒が２：１〜４：１の溶液であるグリニヤール試薬溶液とを反応させた後、加水分解することを特徴とする、式（２）
【００４５】
【化１７】
で示される、２−ｎ−プロピル−４−エトキシカルボニル−５−（１−ヒドロキシ−１−メチル）エチル−イミダゾールの製造法。
【００４７】
（６）テトラヒドロフラン：芳香族系溶媒が２：１〜４：１の存在下、式（１）
【００４８】
【化１８】
で示される、２−ｎ−プロピル−４，５−ビス（エトキシカルボニル）イミダゾールと、メチルマグネシウムクロリドのテトラヒドロフラン溶液であるグリニヤール試薬溶液とを反応させた後、加水分解することを特徴とする、式（２）
【００５０】
【化１９】
で示される、２−ｎ−プロピル−４−エトキシカルボニル−５−（１−ヒドロキシ−１−メチル）エチル−イミダゾールの製造法。
【００５２】
（７）テトラヒドロフランの存在下、式（１）
【００５３】
【化２０】
で示される、２−ｎ−プロピル−４，５−ビス（エトキシカルボニル）イミダゾールと、メチルマグネシウムクロリドの、テトラヒドロフラン：芳香族系溶媒が２：１〜４：１であるグリニヤール試薬溶液とを反応させた後、加水分解することを特徴とする、式（２）
【００５５】
【化２１】
で示される、２−ｎ−プロピル−４−エトキシカルボニル−５−（１−ヒドロキシ−１−メチル）エチル−イミダゾールの製造法。
【００５７】
これらの実態態様の中、好ましい実態態様としては、（１）〜（３）及び（５）〜（７）を挙げる事が出来、もっとも好ましくは（１）及び（５）を挙げることが出来る。
【００５８】
【実施例】
以下、実施例によって本発明を具体的に説明するが、本発明はこれらによって限定されるものではない。
【００５９】
［実施例１］
窒素置換した４ツ口フラスコにマグネシウム３０．２ｇ、テトラヒドロフラン４５．３ｇを仕込み、更にヨウ化メチル０．２ｇを加え、５０℃までゆっくり加熱し反応をスタートさせ、マグネシウムを活性化させる。次にテトラヒドロフラン２７６．７ｇとトルエン１３７．６ｇを添加し希釈する。液温を４０℃に保ちながら塩化メチルガスを１２５ｍｌ／分の速度で合計３０Ｌを吹き込み、グリニヤール試薬溶液を調製する。このときマグネシウムはほとんど消失する。２−ｎ−プロピル−４，５−ビス（エトキシカルボニル）イミダゾール６９．９ｇをテトラヒドロフラン１２２．４ｇとトルエン５２．４ｇに溶解した液を、予め調製したグリニヤール試薬溶液に、１５〜２０℃で添加し１５分間反応させる。得られた反応液を２０％塩化アンモニウム水溶液１，０６８ｇに添加し加水分解する。有機層を水洗し、濃縮、再結晶し、濾過、洗浄、乾燥することにより、目的化合物の２−ｎ−プロピル−４−エトキシカルボニル−５−（１−ヒドロキシ−１−メチル）エチル−イミダゾール６３ｇ（純度９７．５％，収率９３．０％）を得た。
【００６０】
［実施例２］
窒素置換した４ツ口フラスコにマグネシウム３０．２ｇ、テトラヒドロフラン４５．３ｇを仕込み、更にヨウ化メチル０．２ｇを加え、５０℃までゆっくり加熱し反応をスタートさせ、マグネシウムを活性化させる。次にテトラヒドロフラン２７６．７ｇとトルエン１３７．６ｇを添加し希釈する。液温を４０℃に保ちながら塩化メチルガスを１２５ｍｌ／分の速度で合計３０Ｌを吹き込み、グリニヤール試薬溶液を調製する。このときマグネシウムはほとんど消失する。２−ｎ−プロピル−４，５−ビス（エトキシカルボニル）イミダゾール６９．９ｇをテトラヒドロフラン１７４．８ｇに溶解した液を、予め調製したグリニヤール試薬溶液に、１５〜２０℃で添加し１５分間反応させる。得られた反応液を２０％塩化アンモニウム水溶液１，０６８ｇに添加し、加水分解する。トルエン５００ｍｌで抽出した有機層を水洗、濃縮、再結晶し、濾過、洗浄、乾燥することにより、目的化合物の２−ｎ−プロピル−４−エトキシカルボニル−５−（１−ヒドロキシ−１−メチル）エチル−イミダゾール６２ｇ（純度９８．０％，収率９２．０％）を得た。
【００６１】
［実施例３］
窒素置換した４ツ口フラスコにマグネシウム３０．２ｇ、テトラヒドロフラン４５．３ｇを仕込み、更にヨウ化メチル０．２ｇを加え、５０℃までゆっくり加熱し反応をスタートさせ、マグネシウムを活性化させる。次にテトラヒドロフラン４１４．３ｇを添加し希釈する。液温を４０℃に保ちながら塩化メチルガスを１２５ｍｌ／分の速度で合計３０Ｌを吹き込み、グリニヤール試薬溶液を調製する。このときマグネシウムはほとんど消失する。２−ｎ−プロピル−４，５−ビス（エトキシカルボニル）イミダゾール６９．９ｇをテトラヒドロフラン１２２．４ｇとトルエン５２．４ｇに溶解した液を、予め調製したグリニヤール試薬溶液に、１５〜２０℃で添加し１５分間反応させる。得られた反応液を２０％塩化アンモニウム水溶液１，０６８ｇに添加し、加水分解する。有機層を水洗、濃縮、再結晶し、濾過、洗浄、乾燥することにより、目的化合物の２−ｎ−プロピル−４−エトキシカルボニル−５−（１−ヒドロキシ−１−メチル）エチル−イミダゾール６１ｇ（純度９８．５％，収率９１．０％）を得た。
【００６２】
［実施例４］
窒素置換した４ツ口フラスコにマグネシウム３０．２ｇ、テトラヒドロフラン４５．３ｇを仕込み、更にヨウ化メチル０．２ｇを加え、５０℃までゆっくり加熱し反応をスタートさせ、マグネシウムを活性化させる。次にテトラヒドロフラン４１４．３ｇを添加し希釈する。液温を４０℃に保ちながら塩化メチルガスを１２５ｍｌ／分の速度で合計３０Ｌを吹き込みグリニヤール試薬溶液を調製する。このときマグネシウムはほとんど消失する。２−ｎ−プロピル−４，５−ビス（エトキシカルボニル）イミダゾール６９．９ｇをテトラヒドロフラン１７４．８ｇに溶解した液を予め調製したグリニヤール試薬溶液に１５〜２０℃で添加し１５分間反応させる。得られた反応液を２０％塩化アンモニウム水溶液１，０６８ｇに添加し加水分解する。トルエン５００ｍｌで抽出した有機層を水洗、濃縮、再結晶し、濾過、洗浄、乾燥することにより、目的化合物の２−ｎ−プロピル−４−エトキシカルボニル−５−（１−ヒドロキシ−１−メチル）エチル−イミダゾール５６ｇ（純度９５．０％，収率８０．０％）を得た。
【００６３】
［比較例１］ （メチルマグネシウムブロミドのＴＨＦ溶液を使用する従来法）窒素置換した４ツ口フラスコにマグネシウム３０．２ｇ、テトラヒドロフラン４５．３ｇを仕込み、更にヨウ化メチル０．２ｇを加え、５０℃までゆっくり加熱し反応をスタートさせ、マグネシウムを活性化させる。
【００６４】
次にテトラヒドロフラン４１４．３ｇを添加し希釈する。液温を４０℃に保ちながら臭化メチルガスを１２５ｍｌ／分の速度で合計３０Ｌを吹き込み、グリニヤール試薬を調製する。このときマグネシウムはほとんど消失する。２−ｎ−プロピル−４，５−ビス（エトキシカルボニル）イミダゾール６９．９ｇをテトラヒドロフラン１７４．８ｇに溶解した液を、予め調製したグリニヤール試薬に１５〜２０℃で添加し、１５分間反応させる。得られた反応液を２０％塩化アンモニウム水溶液１０６８ｇに添加し加水分解する。トルエン５００ｍｌで抽出した有機層を、水洗、濃縮、再結晶し、濾過、洗浄、乾燥することにより、目的化合物の２−ｎ−プロピル−４−エトキシカルボニル−５−（１−ヒドロキシ−１−メチル）エチル−イミダゾール４４ｇ（純度７５．０％，収率５０．０％）を得た。この結果、転換率が悪く、分離精製に手間どり、純度及び収率が低くなった。
【００６５】
【発明の効果】
本発明の製造方法によれば、転換率がよく、分離精製に手間どることなく、目的化合物を高純度、高収率で工業的に得る事が出来る。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a method for producing an imidazole derivative useful as a pharmaceutical intermediate. More specifically, a field for producing hydroxymethylethylimidazole derivatives useful as intermediates of biphenylmethylimidazole derivatives having excellent angiotensin II antagonistic action and blood pressure lowering action, etc., from bis (ethoxycarbonyl) imidazole derivatives by Grignard reaction. Can be used.
[0002]
[Prior art]
Conventionally, formula (1)
[0003]
[Chemical 3]
A bis (ethoxycarbonyl) imidazole derivative, that is, 2-n-propyl-4,5-bis (ethoxycarbonyl) imidazole [also referred to as “ethyl 2-n-propylimidazole-4,5-dicarboxylate”] From equation (2)
[0005]
[Formula 4]
A hydroxymethylethylimidazole derivative represented by: 2-n-propyl-4-ethoxycarbonyl-5- (1-hydroxy-1-methyl) ethyl-imidazole [or 4- (1-hydroxy-1-methylethyl) As a method for producing “-2-n-propylimidazole-5-carboxylate”, formula (1)
[0007]
[Chemical formula 5]
There is a method in which 2-n-propyl-4,5-bis (ethoxycarbonyl) imidazole represented by the formula (1) is reacted with a tetrahydrofuran solution of methylmagnesium bromide (Japanese Patent Publication No. 7-121918).
[0009]
[Problems to be solved by the invention]
However, this conventional technique has a low conversion rate and takes a lot of time for separation and purification, so the purity and yield are not very satisfactory, and it cannot be said that it is an advantageous method as an industrial production method.
[0010]
[Means for Solving the Problems]
From the above viewpoints, the present inventors have intensively studied an industrial production method capable of producing the target compound methylhydroxyethylimidazole derivative of the formula (2) with high purity and high yield,
In the presence of tetrahydrofuran or tetrahydrofuran and an aromatic solvent, the formula (1)
[0011]
[Chemical 6]
It is hydrolyzed after reacting 2-n-propyl-4,5-bis (ethoxycarbonyl) imidazole represented by the following formula with methylmagnesium chloride in tetrahydrofuran or tetrahydrofuran and a Grignard reagent solution as an aromatic solvent solution. By formula (2)
[0013]
[Chemical 7]
The present invention was completed by finding a process for producing 2-n-propyl-4-ethoxycarbonyl-5- (1-hydroxy-1-methyl) ethyl-imidazole represented by the following formula.
[0015]
The feature of the present invention is that methylmagnesium bromide in the prior art is replaced with methylmagnesium chloride in the present invention, and not only tetrahydrofuran but also a mixed solvent of tetrahydrofuran and an aromatic solvent can be used as a solvent. It is. Replacing the Grignard reagent methylmagnesium bromide with methylmagnesium chloride seems to be a slight difference, but this change causes problems with the prior art, i.e. poor conversion and laborious separation and purification. In addition, the inventors have found that problems such as low yield can be improved as much as unexpected, and have completed the present invention.
[0016]
Examples of the aromatic solvent used in the present invention include benzene, toluene, xylene and the like. Most preferred examples include toluene from the viewpoint of reactivity and ease of handling.
[0017]
Tetrahydrofuran and an aromatic solvent can be used alone or in combination with tetrahydrofuran and an aromatic solvent, and the ratio of the combined use is not particularly limited. The ratio (volume) of tetrahydrofuran: aromatic solvent is preferably 2: 1 to 4: 1.
[0018]
A preparation method of a Grignard reagent solution comprising methylmagnesium chloride in tetrahydrofuran or tetrahydrofuran and an aromatic solvent solution can be carried out by a conventionally known method. For example, tetrahydrofuran or tetrahydrofuran and an aromatic solvent and magnesium in a container. And a small amount of iodine, methyl iodide, dibromoethane or the like effective for activating the surface of magnesium is added to activate magnesium.
[0019]
Next, tetrahydrofuran or tetrahydrofuran and an aromatic solvent are added and diluted. When the liquid temperature is maintained at 20 to 50 ° C., preferably 30 to 40 ° C., methyl chloride is blown into the magnesium at 1.0 times or more equivalent to magnesium. The magnesium disappears and a Grignard reagent solution of methylmagnesium chloride is obtained.
[0020]
The method of the present invention will be described in more detail. To the Grignard reagent solution, which is the previously prepared methylmagnesium chloride, tetrahydrofuran or tetrahydrofuran and an aromatic solvent solution, 2-n-propyl- Tetrahydrofuran or tetrahydrofuran and an aromatic solvent solution of 4,5-bis (ethoxycarbonyl) imidazole are added, and the reaction is performed at a liquid temperature of 5 to 30 ° C, preferably 10 to 20 ° C. The amount of the Grignard reagent in that case is 3.0 times equivalent or more, preferably 3.5 to 5.0 times the 2-n-propyl-4,5-bis (ethoxycarbonyl) imidazole of the formula (1). The equivalent is sufficient. The total amount of tetrahydrofuran or tetrahydrofuran and the aromatic solvent may be 8 to 11 times the weight of 2-n-propyl-4,5-bis (ethoxycarbonyl) imidazole represented by the formula (1). . As a method for hydrolysis, water or an alkaline aqueous solution having a pH of 7 or higher, for example, an aqueous ammonium solution such as an aqueous ammonium chloride solution or an aqueous ammonium hydroxide solution can be used, but a weak alkaline aqueous solution such as an aqueous ammonium solution is preferred.
[0021]
DETAILED DESCRIPTION OF THE INVENTION
In carrying out the present invention, the following embodiments can be mentioned.
[0022]
(1) In the presence of tetrahydrofuran and an aromatic solvent, the formula (1)
[0023]
[Chemical 8]
2-n-propyl-4,5-bis (ethoxycarbonyl) imidazole represented by the following formula: Reaction of methylmagnesium chloride with tetrahydrofuran and Grignard reagent solution which is an aromatic solvent solution, followed by hydrolysis. Characteristic formula (2)
[0025]
[Chemical 9]
A method for producing 2-n-propyl-4-ethoxycarbonyl-5- (1-hydroxy-1-methyl) ethyl-imidazole represented by the formula:
[0027]
(2) Formula (1) in the presence of tetrahydrofuran and an aromatic solvent.
[0028]
[Chemical Formula 10]
Wherein 2-n-propyl-4,5-bis (ethoxycarbonyl) imidazole is reacted with a Grignard reagent solution, which is a tetrahydrofuran solution of methylmagnesium chloride, and then hydrolyzed. (2)
[0030]
Embedded image
A method for producing 2-n-propyl-4-ethoxycarbonyl-5- (1-hydroxy-1-methyl) ethyl-imidazole represented by the formula:
[0032]
(3) Formula (1) in the presence of tetrahydrofuran
[0033]
Embedded image
2-n-propyl-4,5-bis (ethoxycarbonyl) imidazole represented by the following formula: Reaction of methylmagnesium chloride with tetrahydrofuran and Grignard reagent solution which is an aromatic solvent solution, followed by hydrolysis. Characteristic formula (2)
[0035]
Embedded image
A method for producing 2-n-propyl-4-ethoxycarbonyl-5- (1-hydroxy-1-methyl) ethyl-imidazole represented by the formula:
[0037]
(4) Formula (1) in the presence of tetrahydrofuran
[0038]
Embedded image
Wherein 2-n-propyl-4,5-bis (ethoxycarbonyl) imidazole is reacted with a Grignard reagent solution, which is a tetrahydrofuran solution of methylmagnesium chloride, and then hydrolyzed. (2)
[0040]
Embedded image
A method for producing 2-n-propyl-4-ethoxycarbonyl-5- (1-hydroxy-1-methyl) ethyl-imidazole represented by the formula:
[0042]
(5) Tetrahydrofuran: aromatic solvent in the presence of 2: 1 to 4: 1, formula (1)
[0043]
Embedded image
2-n-propyl-4,5-bis (ethoxycarbonyl) imidazole and a Grignard reagent solution in which methylmagnesium chloride in tetrahydrofuran: aromatic solvent is a 2: 1 to 4: 1 solution. And then hydrolyzing, the formula (2)
[0045]
Embedded image
A method for producing 2-n-propyl-4-ethoxycarbonyl-5- (1-hydroxy-1-methyl) ethyl-imidazole represented by the formula:
[0047]
(6) Tetrahydrofuran: aromatic solvent in the presence of 2: 1 to 4: 1, formula (1)
[0048]
Embedded image
Wherein 2-n-propyl-4,5-bis (ethoxycarbonyl) imidazole is reacted with a Grignard reagent solution, which is a tetrahydrofuran solution of methylmagnesium chloride, and then hydrolyzed. (2)
[0050]
Embedded image
A method for producing 2-n-propyl-4-ethoxycarbonyl-5- (1-hydroxy-1-methyl) ethyl-imidazole represented by the formula:
[0052]
(7) Formula (1) in the presence of tetrahydrofuran
[0053]
Embedded image
2-n-propyl-4,5-bis (ethoxycarbonyl) imidazole represented by the following formula: Reaction of methylmagnesium chloride with a Grignard reagent solution having a tetrahydrofuran: aromatic solvent ratio of 2: 1 to 4: 1. And then hydrolyzing, formula (2)
[0055]
Embedded image
A method for producing 2-n-propyl-4-ethoxycarbonyl-5- (1-hydroxy-1-methyl) ethyl-imidazole represented by the formula:
[0057]
Among these actual aspects, preferred actual aspects include (1) to (3) and (5) to (7), and most preferably (1) and (5).
[0058]
【Example】
EXAMPLES Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited thereto.
[0059]
[Example 1]
A 4-necked flask purged with nitrogen is charged with 30.2 g of magnesium and 45.3 g of tetrahydrofuran. Further, 0.2 g of methyl iodide is added, and the reaction is started by slowly heating to 50 ° C. to activate magnesium. Next, 276.7 g of tetrahydrofuran and 137.6 g of toluene are added and diluted. While maintaining the liquid temperature at 40 ° C., 30 mL of methyl chloride gas was blown at a rate of 125 ml / min to prepare a Grignard reagent solution. At this time, magnesium is almost lost. A solution prepared by dissolving 69.9 g of 2-n-propyl-4,5-bis (ethoxycarbonyl) imidazole in 122.4 g of tetrahydrofuran and 52.4 g of toluene was added to a previously prepared Grignard reagent solution at 15 to 20 ° C. Allow to react for 15 minutes. The obtained reaction solution is added to 1,068 g of 20% aqueous ammonium chloride solution and hydrolyzed. The organic layer was washed with water, concentrated, recrystallized, filtered, washed and dried to give 63 g of the target compound 2-n-propyl-4-ethoxycarbonyl-5- (1-hydroxy-1-methyl) ethyl-imidazole. (Purity 97.5%, yield 93.0%) was obtained.
[0060]
[Example 2]
A 4-necked flask purged with nitrogen is charged with 30.2 g of magnesium and 45.3 g of tetrahydrofuran. Further, 0.2 g of methyl iodide is added, and the reaction is started by slowly heating to 50 ° C. to activate magnesium. Next, 276.7 g of tetrahydrofuran and 137.6 g of toluene are added and diluted. While maintaining the liquid temperature at 40 ° C., 30 mL of methyl chloride gas was blown at a rate of 125 ml / min to prepare a Grignard reagent solution. At this time, magnesium is almost lost. A solution prepared by dissolving 69.9 g of 2-n-propyl-4,5-bis (ethoxycarbonyl) imidazole in 174.8 g of tetrahydrofuran is added to a previously prepared Grignard reagent solution at 15 to 20 ° C. and allowed to react for 15 minutes. The obtained reaction solution is added to 1,068 g of 20% aqueous ammonium chloride solution and hydrolyzed. The organic layer extracted with 500 ml of toluene is washed with water, concentrated, recrystallized, filtered, washed and dried to give the target compound 2-n-propyl-4-ethoxycarbonyl-5- (1-hydroxy-1-methyl). 62 g of ethyl-imidazole (purity 98.0%, yield 92.0%) was obtained.
[0061]
[Example 3]
A 4-necked flask purged with nitrogen is charged with 30.2 g of magnesium and 45.3 g of tetrahydrofuran. Further, 0.2 g of methyl iodide is added, and the reaction is started by slowly heating to 50 ° C. to activate magnesium. Next, 414.3 g of tetrahydrofuran is added and diluted. While maintaining the liquid temperature at 40 ° C., 30 mL of methyl chloride gas was blown at a rate of 125 ml / min to prepare a Grignard reagent solution. At this time, magnesium is almost lost. A solution prepared by dissolving 69.9 g of 2-n-propyl-4,5-bis (ethoxycarbonyl) imidazole in 122.4 g of tetrahydrofuran and 52.4 g of toluene was added to a previously prepared Grignard reagent solution at 15 to 20 ° C. Allow to react for 15 minutes. The obtained reaction solution is added to 1,068 g of 20% aqueous ammonium chloride solution and hydrolyzed. The organic layer was washed with water, concentrated, recrystallized, filtered, washed and dried to give 61 g of the target compound 2-n-propyl-4-ethoxycarbonyl-5- (1-hydroxy-1-methyl) ethyl-imidazole ( Purity 98.5%, yield 91.0%).
[0062]
[Example 4]
A 4-necked flask purged with nitrogen is charged with 30.2 g of magnesium and 45.3 g of tetrahydrofuran. Further, 0.2 g of methyl iodide is added, and the reaction is started by slowly heating to 50 ° C. to activate magnesium. Next, 414.3 g of tetrahydrofuran is added and diluted. A total of 30 L of methyl chloride gas was blown at a rate of 125 ml / min while maintaining the liquid temperature at 40 ° C. to prepare a Grignard reagent solution. At this time, magnesium is almost lost. A solution prepared by dissolving 69.9 g of 2-n-propyl-4,5-bis (ethoxycarbonyl) imidazole in 174.8 g of tetrahydrofuran is added to a previously prepared Grignard reagent solution at 15 to 20 ° C. and reacted for 15 minutes. The obtained reaction solution is added to 1,068 g of 20% aqueous ammonium chloride solution and hydrolyzed. The organic layer extracted with 500 ml of toluene is washed with water, concentrated, recrystallized, filtered, washed and dried to give the target compound 2-n-propyl-4-ethoxycarbonyl-5- (1-hydroxy-1-methyl). 56 g of ethyl-imidazole (purity 95.0%, yield 80.0%) was obtained.
[0063]
[Comparative Example 1] (Conventional method using a solution of methylmagnesium bromide in THF) A nitrogen-substituted four-necked flask was charged with 30.2 g of magnesium and 45.3 g of tetrahydrofuran, and further 0.2 g of methyl iodide was added, Until the reaction is started and magnesium is activated.
[0064]
Next, 414.3 g of tetrahydrofuran is added and diluted. While maintaining the liquid temperature at 40 ° C., a total of 30 L of methyl bromide gas was blown at a rate of 125 ml / min to prepare a Grignard reagent. At this time, magnesium is almost lost. A solution prepared by dissolving 69.9 g of 2-n-propyl-4,5-bis (ethoxycarbonyl) imidazole in 174.8 g of tetrahydrofuran is added to a previously prepared Grignard reagent at 15 to 20 ° C. and allowed to react for 15 minutes. The obtained reaction solution is added to 1068 g of 20% aqueous ammonium chloride solution and hydrolyzed. The organic layer extracted with 500 ml of toluene is washed with water, concentrated, recrystallized, filtered, washed and dried to give the target compound 2-n-propyl-4-ethoxycarbonyl-5- (1-hydroxy-1-methyl). ) 44 g of ethyl-imidazole (purity 75.0%, yield 50.0%) was obtained. As a result, the conversion rate was poor, the separation and purification was troublesome, and the purity and yield were low.
[0065]
【The invention's effect】
According to the production method of the present invention, the conversion rate is good, and the target compound can be industrially obtained in high purity and high yield without troublesome separation and purification.
Claims (2)
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| JP11043398A JP4260241B2 (en) | 1998-04-21 | 1998-04-21 | Method for producing imidazole derivatives |
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| CN1976926A (en) | 2004-09-02 | 2007-06-06 | 特瓦制药工业有限公司 | Preparation of olmesartan medoxomil |
| KR20090108739A (en) | 2005-01-03 | 2009-10-16 | 테바 파마슈티컬 인더스트리즈 리미티드 | Olmesartan medoxomil with reduced levels of impurities |
| US20120116125A1 (en) * | 2009-06-29 | 2012-05-10 | Merz Pharma Gmbh & Co. Kgaa | Method of preparing neramexane |
| CA2765741A1 (en) * | 2009-06-29 | 2011-01-06 | Merz Pharma Gmbh & Co. Kgaa | Method of preparing 1-hydroxy-1,3,3,5,5-pentamethylcyclohexane |
| CN104356069B (en) * | 2014-11-18 | 2016-09-14 | 黄冈鲁班药业有限公司 | The preparation method and application of olmesartan medoxomil intermediate 4-(1-hydroxyl-1-Methylethyl)-2-propyl imidazole-5-carboxylic acid, ethyl ester |
-
1998
- 1998-04-21 JP JP11043398A patent/JP4260241B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPH11302260A (en) | 1999-11-02 |
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