JP3778521B2 - Method for producing cyclopropenone acetal derivative - Google Patents
Method for producing cyclopropenone acetal derivative Download PDFInfo
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- JP3778521B2 JP3778521B2 JP30112194A JP30112194A JP3778521B2 JP 3778521 B2 JP3778521 B2 JP 3778521B2 JP 30112194 A JP30112194 A JP 30112194A JP 30112194 A JP30112194 A JP 30112194A JP 3778521 B2 JP3778521 B2 JP 3778521B2
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- acetal derivative
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- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 title claims description 29
- -1 cyclopropenone acetal Chemical class 0.000 title claims description 27
- 238000004519 manufacturing process Methods 0.000 title claims description 19
- 125000004432 carbon atom Chemical group C* 0.000 claims description 30
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- 125000002947 alkylene group Chemical group 0.000 claims description 6
- 239000000010 aprotic solvent Substances 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 239000012752 auxiliary agent Substances 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 125000006630 butoxycarbonylamino group Chemical group 0.000 claims 1
- 239000012039 electrophile Substances 0.000 claims 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 150000001241 acetals Chemical class 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinon Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 102000005927 Cysteine Proteases Human genes 0.000 description 2
- 108010005843 Cysteine Proteases Proteins 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- ACRHGJOTQKKPAV-UHFFFAOYSA-N O=C1C(OC(C)(C)C)C1C1=CC=CC=C1 Chemical compound O=C1C(OC(C)(C)C)C1C1=CC=CC=C1 ACRHGJOTQKKPAV-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- GGRQLKPIJPFWEZ-UHFFFAOYSA-N cycloprop-2-en-1-one Chemical group O=C1C=C1 GGRQLKPIJPFWEZ-UHFFFAOYSA-N 0.000 description 2
- 239000002274 desiccant Substances 0.000 description 2
- 125000006575 electron-withdrawing group Chemical group 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- UTLPHZBACNJQKZ-UHFFFAOYSA-N 1,3-dibromo-1-phenylpropan-2-one Chemical compound BrCC(=O)C(Br)C1=CC=CC=C1 UTLPHZBACNJQKZ-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- VUMFQBHWWMEFPT-UHFFFAOYSA-N CC1(COC2(C(C2OC)C3=CC=CC=C3)OC1)C Chemical compound CC1(COC2(C(C2OC)C3=CC=CC=C3)OC1)C VUMFQBHWWMEFPT-UHFFFAOYSA-N 0.000 description 1
- BZJIWGWWODVJCG-UHFFFAOYSA-N CC1(COC2(CC2OC(C)(C)C)OC1)C Chemical compound CC1(COC2(CC2OC(C)(C)C)OC1)C BZJIWGWWODVJCG-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- VYLVYHXQOHJDJL-UHFFFAOYSA-K cerium trichloride Chemical compound Cl[Ce](Cl)Cl VYLVYHXQOHJDJL-UHFFFAOYSA-K 0.000 description 1
- 239000002852 cysteine proteinase inhibitor Substances 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000002510 isobutoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])O* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000005921 isopentoxy group Chemical group 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Substances CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N p-toluenesulfonic acid Substances CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 150000003014 phosphoric acid esters Chemical class 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 description 1
- 125000002130 sulfonic acid ester group Chemical group 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- BLQCLKFHTMOFAP-XJDOXCRVSA-N tert-butyl n-[(2s)-1-(6,6-dimethyl-1-phenyl-4,8-dioxaspiro[2.5]oct-1-en-2-yl)-1-hydroxy-3-methylbutan-2-yl]carbamate Chemical compound O1CC(C)(C)COC11C(C(O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)=C1C1=CC=CC=C1 BLQCLKFHTMOFAP-XJDOXCRVSA-N 0.000 description 1
- YMNBXYLOSIKZGL-MRVPVSSYSA-N tert-butyl n-[(2s)-3-methyl-1-oxobutan-2-yl]carbamate Chemical compound CC(C)[C@@H](C=O)NC(=O)OC(C)(C)C YMNBXYLOSIKZGL-MRVPVSSYSA-N 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
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- Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
Description
【０００１】
【産業上の利用分野】
本発明はシクロプロペノンアセタール誘導体の新しい製造法に関し、詳細にはシステインプロテアーゼ阻害剤の製造中間体として有用なシクロプロペノンアセタール誘導体の新しい製造法に関する。
【０００２】
【従来の技術および発明が解決しようとする課題】
シクロプロペノン骨格を有するある種の化合物は、システインプロテアーゼに対する阻害活性が強いことが知られており、この化合物の製造中間体のとして、シクロプロペノンアセタール誘導体が示されている（Journal of American Chemical Society, 115巻、1174ページ、1993年)。このシクロプロペノンアセタール誘導体は、１、３−ジクロロ−１−フェニル−２−プロパノンアセタールを液体アンモニア中でナトリウムアミドと反応させて製造できることは知られている（Tetrahedron Letters, 32巻、1339ページ、1991年）。
【０００３】
しかし、この方法では、液体アンモニアを用いなければならないために操作が煩雑であり、また廃棄物の処理にも多大な労力を要する。
【０００４】
【課題を解決するための手段】
そこで本発明者らは、簡便なシクロプロペノンアセタール誘導体の製造法について研究を進めた結果、本発明に到達した。
すなわち、本発明の要旨は、
下記一般式（Ｉ）
【０００５】
【化８】
（上記一般式中、Ｒ1は水素原子、炭素数1〜10のアルキル基、または置換基を有していてもよい炭素数６〜12のアリール基を表わし、Ｒ2は炭素数1〜５のアルキル基を表し、Ａは炭素数１〜３のアルキル基を有していてもよい炭素数２〜４のアルキレン基を表わす）で示されるシクロプロパノンアセタール誘導体を非プロトン性溶媒に溶解し、高極性の助剤の存在下、強塩基を加えることを特徴とする、下記一般式（II）
【０００７】
【化９】
（上記一般式中、Ｒ1およびＡは一般式（Ｉ）で定義した通りである）で示されるシクロプロペノンアセタール誘導体を製造する方法。
下記一般式（Ｉ）
【０００９】
【化１０】
（上記一般式中、Ｒ1は水素原子、炭素数1〜10のアルキル基、または置換基を有していてもよい炭素数６〜12のアリール基を表わし、Ｒ2は炭素数1〜５のアルキル基を表し、Ａは炭素数１〜３のアルキル基を有していてもよい炭素数２〜４のアルキレン基を表わす）で示されるシクロプロパノンアセタール誘導体を非プロトン性溶媒に溶解し、高極性の助剤の存在下、強塩基を加え、さらに下記一般式（III）または（IV）
【００１１】
【化１１】
Ｒ3−Ｘ （III）
【００１２】
【化１２】
（上記一般式中、Ｒ3は有機分子から水素原子を一つ除いた基を表わし、Ｘは電子吸引基を表し、Ｒ4およびＲ5はそれぞれ独立して水素原子または有機分子から水素原子を一つ除いた基を表わす）で示される求電子試薬を加えることを特徴とする、下記一般式（Ｖ）または（VI）
【００１４】
【化１３】
【化１４】
（上記一般式中、Ｒ1及びＡは一般式（Ｉ）で定義した通りであり、Ｒ3、Ｒ4およびＲ5は一般式（III）および（IV）で定義した通りである）で示されるシクロプロペノンアセタール誘導体を製造する方法に存する。
以下、本発明について詳細に説明する。
上記一般式（Ｉ）において、Ｒ1で定義される炭素数１〜10のアルキル基としては、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、sec-ブチル基、tert-ブチル基、ペンチル基、イソペンチル基、ネオペンチル基、tert-ペンチル基、ヘキシル基、イソヘキシル基、ヘプチル基、オクチル基、ノニル基、デシル基等が挙げられる。炭素数６〜12のアリール基としては、フェニル基、ナフチル基等があげられ、かかるアリール基は、フッ素原子、塩素原子、臭素原子等のハロゲン原子；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、sec-ブチル基、tert-ブチル基、ペンチル基、イソペンチル基、ネオペンチル基、tert-ペンチル基等の炭素数１〜５のアルキル基；トリフルオロメチル基；メトキシ基、エトシキ基、プロポキシ基、イソプロポシキ基、ブトキシ基、イソブトシキ基、tert-ブトキシ基、ペンチルオキシ基、イソペンチルオキシ基等の炭素数１〜５のアルコキシ基等で置換されていてもよい。
【００１７】
Ｒ2で定義される炭素数１〜５のアルキル基としては、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、sec-ブチル基、tert-ブチル基、ペンチル基、イソペンチル基、ネオペンチル基、tert-ペンチル基等があげられる。
Ａで定義される炭素数２〜４のアルキレン基としては、エチレン基、プロピレン基、ブチレン基等が挙げられ、かかるアルキレン基は、メチル基、エチル基、プロピル基等の炭素数１〜３のアルキル基を１〜４個有していてもよい。
【００１８】
Ｒ3、Ｒ4およびＲ5で定義される有機分子から水素原子を一つ除いた基は、特にその構造を限定されることはなく、本発明の製造法に大きな影響を与えるような官能基が結合していない限り、任意の構造をとることができる。
Ｘで定義される電子吸引基としては、ハロゲン原子、スルホン酸エステル基等が挙げられる。該ハロゲン原子としては、沃素原子、臭素原子、塩素原子等が挙げられ、該スルホン酸エステル基としては、メタンスルホン酸エステル基、ｐ−トルエンスルホン酸エステル基、トリフルオロメタンスルホン酸エステル基等が挙げられる。
【００１９】
本発明の製造法で用いられる原料あるいは本発明の製造法により製造された化合物中に存在する不斉炭素の立体化学については、それぞれ独立して（Ｒ）体、（Ｓ）体、あるいは（RS）体をとることができる。
上記本発明の製造法の原料である一般式（Ｉ）で示されるシクロプロパノンアセタール誘導体の具体的な例としては、下記表−１に示す化合物が挙げられる。
【００２０】
【表１】
【表２】
【表３】
【表４】
次に本発明の製造法について説明する。本発明の製造法の原料となる上記一般式（Ｉ）で示されるシクロプロパノンアセタール誘導体は、例えば１、３−ジブロモ−２−アルカノンアセタール誘導体をテトラヒドロフラン、ジメチルホルムアミド、ジメチルスルホキシド等の非プロトン性の溶媒に溶解し、アルコールの存在下、カリウム ｔｅｒｔ−ブトキシド等のアルコキシドを加えて反応させることにより得られる。
【００２５】
かくして得られた上記一般式（Ｉ）で示されるシクロプロパノンアセタール誘導体をテトラヒドロフラン、ジエチルエーテル、ヘキサン、トルエン等の非プロトン性溶媒に溶かし、上記一般式（Ｉ）で示されるシクロプロパノンアセタール誘導体に対して１〜５モル当量のN, N, N', N'-テトラメチルエチレンジアミン（TMEDA）、ジメチルイミダゾリジノン、ジメチルホルムアミド、ヘキサメチルホスホリック トリアミド等の高極性の助剤の存在下、上記一般式（Ｉ）で示されるシクロプロパノンアセタール誘導体に対して２モル当量のメチルリチウム、ｎ−ブチルリチウム、フェニルリチウム等の強塩基を加えて反応させた後、水またはアルコール等で反応を停止させれば、上記一般式（II）で示されるシクロプロペノンアセタール誘導体を得ることができる。この反応において、溶媒の量は特に制限されることなく、また反応温度については通常−１００〜０℃の温度で行なうが、特に−８０〜−４０℃で反応を行なうと良好な結果が得られることが多い。
【００２６】
また、上記一般式（Ｉ）で示されるシクロプロパノンアセタール誘導体をテトラヒドロフラン、ジエチルエーテル、ヘキサン、トルエン等の非プロトン性溶媒に溶かし、上記一般式（Ｉ）で示されるシクロプロパノンアセタール誘導体に対して１〜５モル当量のN, N, N', N'-テトラメチルエチレンジアミン（TMEDA）、ジメチルイミダゾリジノン、ジメチルホルムアミド、ヘキサメチルホスホリックトリアミド等の高極性の助剤の存在下、上記一般式（Ｉ）で示されるシクロプロパノンアセタール誘導体に対して２モル当量のメチルリチウム、ｎ−ブチルリチウム、フェニルリチウム等の強塩基を加えて反応させた後、そのままの温度でさらに上記一般式（III）あるいは（IV）で示されるケトンまたはアルデヒド、あるいはハロゲン化物またはスルホン酸エステル等の求電子試薬を加えることで、上記一般式（Ｖ）あるいは（VI）で示されるシクロプロペノンアセタール誘導体が得られる。特にこの製造法の場合、熱的に不安定なシクロプロペノンアセタール誘導体（II）を単離することなくそのまま次の反応を行なうことができるので、大量製造時には非常に有用である。
【００２７】
【実施例】
以下、参考例および実施例によりさらに詳しく説明するが、本発明はその要旨を越えない限り、これらの参考例および実施例に何ら制限を受けるものではない。
参考例１
２−ｔｅｒｔ−ブトキシ−３−フェニルシクロプロパノン ２、２−ジメチル−１、３−プロパンジイルアセタール（表−１の化合物番号４６）の製造
カリウム ｔｅｒｔ−ブトキシド１０．３ｇをテトラヒドロフラン３０ｍｌに溶かして０℃に冷却し、１、３−ジブロモ−１−フェニル−２−プロパノン１２．３ｇをテトラヒドロフラン４０ｍｌに溶かしてゆっくりと加える。室温で一晩撹拌してから溶媒を約半分減圧留去し、水４０ｍｌを加える。ヘキサンで抽出し、抽出液を飽和食塩水で洗浄してから硫酸ナトリウムで乾燥する。乾燥剤を濾過してから濃縮し、イソプロピルアルコール及び水の混合溶媒で再結晶すると、目的物８．３５ｇが得られる。
収率：88 ％
融点：75 -76 ℃
IR (KBr, cm-1)：2984, 2961, 2868, 1603, 1495, 1474, 1458, 1393, 1366, 1192, 1165, 1123, 1082, 1065, 1049, 897, 883, 696, 630．
NMR (CDCl3, d)： 0.72 (s, 3H), 1.20 (s, 3H), 1.27 (s, 9H), 2.25 (d, J = 4.9 Hz, 1H), 3.04 (d, J = 10.8 Hz, 1H), 3.32 (dd, J = 10.8 Hz, 2.1Hz, 1H), 3.62 (d, J = 10.7 Hz, 1H), 3.66 (d, J = 4.9 Hz, 1H), 3.72 (dd, J = 10.7 Hz, 2.1 Hz, 1H), 7.10 - 7.25 (m, 3H), 7.25 - 7.35 (m, 2H).
参考例１と同様の方法により、以下参考例２および参考例３の化合物を製造した。以下、その物性値を記す。
【００２８】
参考例２
２−ｔｅｒｔ−ブトキシシクロプロパノン ２、２−ジメチル−１、３−プロパンジイルアセタール（表−１の化合物番号９）の製造
IR (neat, cm-1)：2959，2907，2870，1474，1393，1366，1294，1100，1196，1157，1074，1040，966，905．
NMR (CDCl3, d)：0.88 (dd, J = 6.7 Hz, 4.7 Hz, 1H), 0.90 (s, 3H), 1.11 (dd, J = 8.0 Hz, 6.7 Hz, 1H), 1.13 (s, 3H), 1.29 (s, 9H), 3.38 (dd, J = 8.0 Hz, 4.7 Hz, 1H), 3.43 (d, J = 13.0 Hz, 1H), 3.52 (d, J = 13.0 Hz, 1H), 3.57 (d, J = 10.6 Hz, 1H), 3.68 (d, J = 10.6 Hz, 1H).
【００２９】
参考例３
２−メトキシ−３−フェニルシクロプロパノン ２、２−ジメチル−１、３−プロパンジイルアセタール（表−１の化合物番号３４） の製造
融点：46 -47 ℃
IR (KBr, cm-1)：2965, 2865, 2820, 1601, 1503, 1472, 1273, 1217, 1128, 1069, 978, 963, 910, 889, 792, 765, 694, 634, 498.
NMR (CDCl3, d)：0.86 (s, 3H), 1.12 (s, 3H), 2.38 (d, J = 4.5 Hz, 1H), 3.16 (d, J = 10.8 Hz, 1H), 3.38 (dd, J = 10.8 Hz, 1.3 Hz, 1H), 3.49 (s, 3H), 3.65 (d, J = 10.6 Hz, 1H), 3.67 (d, J = 4.5 Hz, 1H), 3.74 (dd, J = 10.6 Hz, 1.3 Hz, 1H), 7.15 - 7.25 (m, 3H), 7.25 - 7.35 (m, 2H).
【００３０】
実施例１
２ーフェニルシクロプロペノン ２、２−ジメチル−１、３−プロパンジイルアセタールの製造
参考例１で得られた２−ｔｅｒｔ−ブトキシ−３−フェニルシクロプロパノン ２、２−ジメチル−１、３−プロパンジイルアセタール１．０ｇ及びN, N, N', N'−テトラメチルエチレンジアミン１．０ｍｌをテトラヒドロフラン１０ｍｌに溶かして−６０℃に冷却し、１．６１ｍｏｌ／ｌのｎ−ブチルリチウムのヘキサン溶液４．３ｍｌをゆっくりと加える。−６０℃で２時間撹拌した後、ＴＨＦと水を４：１の割合で混合した溶液を３ｍｌ加えて反応を止め、室温まで温度を上げて硫酸ナトリウム３ｇを加える。乾燥剤を濾過して酢酸エチルで洗い、濾液を濃縮してから５％酢酸エチル含有ヘキサンを展開溶媒としたシリカゲルカラムクロマトグラフィーで精製すると、目的物５７９ｍｇが得られる。
収率：78％
融点：48〜53℃
IR (CCl4, cm-1)：3100, 2250, 1960, 1900, 1810, 1720, 1470, 1260.
NMR (CDCl3, d)：1.08 (s, 3H), 1.15 (s, 3H), 3.75 (s, 4H), 7.35 - 7.47 (m, 3H), 7.60 - 7.67 (m, 2H), 7.69 (s, 1H).
【００３１】
実施例２
２−フェニルシクロプロペノン ２、２−ジメチル−１、３−プロパンジイルアセタールの製造
参考例３で得られた２−メトキシ−３−フェニルシクロプロパノン ２、２−ジメチル−１、３−プロパンジイルアセタール３１６ｍｇを用いて実施例１と同様の操作を行ない、目的物２２０ｍｇを得た。
収率：80％
【００３２】
実施例３
２−（（２Ｓ）−２−ｔｅｒｔ−ブトキシカルボニルアミノ−１−ヒドロキシ−３−メチルブチル）−３−フェニルシクロプロペノン ２、２−ジメチル−１、３−プロパンジイルアセタールの製造
参考例１で得られた２−ｔｅｒｔ−ブトキシ−３−フェニルシクロプロパノン ２、２−ジメチル−１、３−プロパンジイルアセタール９９６ｍｇおよびN, N, N', N'-テトラメチルエチレンジアミン０．９７ｍｌをテトラヒドロフラン１０ｍｌに溶かして−６０℃に冷却し、１．６３ｍｏｌ／ｌのｎ−ブチルリチウムのヘキサン溶液３．９８ｍｌを加える。−６０℃で１．５時間反応させた後、無水塩化セリウムをテトラヒドロフラン２０ｍｌに懸濁させて加え、さらに１時間撹拌する。次に（２Ｓ）−２−ｔｅｒｔ−ブトキシカルボニルアミノ−３−メチルブタナ−ル（Ｌ−Ｂｏｃ−バリナール）２９３ｍｇをテトラヒドロフラン５ｍｌに溶かして加え、−６０℃で３．５時間反応させた後、テトラヒドロフランと水を４：１で混合した溶液を３ｍｌ加えてから、室温まで温度をあげる。反応液をセライトで濾過し、酢酸エチルで洗う。濾液を濃縮し、２０％酢酸エチル含有ヘキサンを展開溶媒としたシリカゲルカラムクロマトグラフィーで精製すると、目的物４８４ｍｇが得られる。
収率：79％
IR (KBr, cm-1)：3430, 2960, 1855, 1800, 1710, 1690
NMR (CD3OD, d)：0.95 - 1.60 (m, 12H), 1.38 (s, 3H), 1.42 (s, 6H), 1.95 - 2.15 (m, 1H), 3.60 - 3.75 (m, 1H), 3.75 - 3.95 (m, 4H), 5.00 - 5.10 (m, 1H), 6.03 (d, J = 10 Hz, 0.33H), 6.23 (d, J = 10 Hz, 0.67H), 7.40 - 7.65 (m, 3H), 7.70 - 7.90 (m, 2H).
【００３３】
【発明の効果】
本発明のシクロプロペノンアセタール誘導体の製造法は、システインプロテア−ゼ阻害活性を有するシクロプロペノン誘導体の製造中間体の簡便な製造法として用いることができる。[0001]
[Industrial application fields]
The present invention relates to a new process for producing cyclopropenone acetal derivatives, and more particularly to a new process for producing cyclopropenone acetal derivatives useful as intermediates for the production of cysteine protease inhibitors.
[0002]
[Background Art and Problems to be Solved by the Invention]
Certain compounds having a cyclopropenone skeleton are known to have strong inhibitory activity against cysteine proteases, and cyclopropenone acetal derivatives have been shown as intermediates for the production of these compounds (Journal of American Chemical Society, 115, 1174, 1993). It is known that this cyclopropenone acetal derivative can be produced by reacting 1,3-dichloro-1-phenyl-2-propanone acetal with sodium amide in liquid ammonia (Tetrahedron Letters, Vol. 32, page 1339). 1991).
[0003]
However, in this method, since liquid ammonia must be used, the operation is complicated, and a great deal of labor is required for disposal of waste.
[0004]
[Means for Solving the Problems]
Therefore, the present inventors have reached the present invention as a result of research on a simple method for producing a cyclopropenone acetal derivative.
That is, the gist of the present invention is as follows.
The following general formula (I)
[0005]
[Chemical 8]
(In the above general formula, R 1 represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, or an aryl group having 6 to 12 carbon atoms which may have a substituent, and R 2 represents 1 to 5 carbon atoms. And A represents an alkylene group having 2 to 4 carbon atoms which may have an alkyl group having 1 to 3 carbon atoms), dissolved in an aprotic solvent. The following general formula (II), characterized in that a strong base is added in the presence of a highly polar auxiliary agent
[0007]
[Chemical 9]
(Wherein R 1 and A are as defined in formula (I)), a process for producing a cyclopropenone acetal derivative represented by the general formula (I).
The following general formula (I)
[0009]
[Chemical Formula 10]
(In the above general formula, R 1 represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, or an aryl group having 6 to 12 carbon atoms which may have a substituent, and R 2 represents 1 to 5 carbon atoms. And A represents an alkylene group having 2 to 4 carbon atoms which may have an alkyl group having 1 to 3 carbon atoms), dissolved in an aprotic solvent. In the presence of a highly polar auxiliary, a strong base is added, and the following general formula (III) or (IV)
[0011]
Embedded image
R 3 -X (III)
[0012]
Embedded image
(In the above general formula, R 3 represents a group obtained by removing one hydrogen atom from an organic molecule, X represents an electron-withdrawing group, and R 4 and R 5 each independently represents a hydrogen atom or a hydrogen atom from an organic molecule. An electrophilic reagent represented by the following general formula (V) or (VI):
[0014]
Embedded image
Embedded image
(In the above general formula, R 1 and A are as defined in the general formula (I), and R 3 , R 4 and R 5 are as defined in the general formulas (III) and (IV)). The present invention relates to a method for producing a cyclopropenone acetal derivative.
Hereinafter, the present invention will be described in detail.
In the general formula (I), examples of the alkyl group having 1 to 10 carbon atoms defined by R 1 include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert- Examples thereof include a butyl group, a pentyl group, an isopentyl group, a neopentyl group, a tert-pentyl group, a hexyl group, an isohexyl group, a heptyl group, an octyl group, a nonyl group, and a decyl group. Examples of the aryl group having 6 to 12 carbon atoms include a phenyl group and a naphthyl group. The aryl group includes a halogen atom such as a fluorine atom, a chlorine atom or a bromine atom; a methyl group, an ethyl group, a propyl group or an isopropyl group. Alkyl group having 1 to 5 carbon atoms such as butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group; trifluoromethyl group; methoxy group, ethoxy group An alkoxy group having 1 to 5 carbon atoms such as a group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a tert-butoxy group, a pentyloxy group, and an isopentyloxy group.
[0017]
Examples of the alkyl group having 1 to 5 carbon atoms defined by R 2 include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, and isopentyl group. , Neopentyl group, tert-pentyl group and the like.
Examples of the alkylene group having 2 to 4 carbon atoms defined by A include an ethylene group, a propylene group, and a butylene group. The alkylene group has 1 to 3 carbon atoms such as a methyl group, an ethyl group, and a propyl group. You may have 1-4 alkyl groups.
[0018]
The group obtained by removing one hydrogen atom from the organic molecule defined by R 3 , R 4 and R 5 is not particularly limited in its structure, and is a functional group that greatly affects the production method of the present invention. As long as is not bound, any structure can be adopted.
Examples of the electron withdrawing group defined by X include a halogen atom and a sulfonate group. Examples of the halogen atom include an iodine atom, a bromine atom, and a chlorine atom. Examples of the sulfonic acid ester group include a methanesulfonic acid ester group, a p-toluenesulfonic acid ester group, and a trifluoromethanesulfonic acid ester group. It is done.
[0019]
The stereochemistry of the asymmetric carbon present in the raw material used in the production method of the present invention or the compound produced by the production method of the present invention is independently (R) isomer, (S) isomer, or (RS ) Can take the body.
Specific examples of the cyclopropanone acetal derivative represented by the general formula (I), which is a raw material for the production method of the present invention, include compounds shown in Table 1 below.
[0020]
[Table 1]
[Table 2]
[Table 3]
[Table 4]
Next, the manufacturing method of this invention is demonstrated. The cyclopropanone acetal derivative represented by the above general formula (I), which is a raw material for the production method of the present invention, is a non-proton such as 1,3-dibromo-2-alkanone acetal derivative such as tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, etc. It can be obtained by dissolving in an organic solvent and reacting by adding an alkoxide such as potassium tert-butoxide in the presence of alcohol.
[0025]
The cyclopropanone acetal derivative represented by the above general formula (I) thus obtained is dissolved in an aprotic solvent such as tetrahydrofuran, diethyl ether, hexane or toluene, and the cyclopropanone acetal derivative represented by the above general formula (I) is obtained. 1 to 5 molar equivalents of N, N, N ′, N′-tetramethylethylenediamine (TMEDA), dimethylimidazolidinone, dimethylformamide, hexamethylphosphoric triamide, etc. The cyclopropanone acetal derivative represented by the above general formula (I) is reacted by adding a strong molar base such as methyllithium, n-butyllithium, phenyllithium, etc., with water or alcohol. If stopped, the cyclopropenone acetal derivative represented by the above general formula (II) is obtained. Door can be. In this reaction, the amount of the solvent is not particularly limited, and the reaction temperature is usually from −100 to 0 ° C. Especially when the reaction is carried out at −80 to −40 ° C., good results are obtained. There are many cases.
[0026]
Further, the cyclopropanone acetal derivative represented by the above general formula (I) is dissolved in an aprotic solvent such as tetrahydrofuran, diethyl ether, hexane, toluene, etc., and the cyclopropanone acetal derivative represented by the above general formula (I) is dissolved. 1 to 5 molar equivalents of N, N, N ′, N′-tetramethylethylenediamine (TMEDA), dimethylimidazolidinone, dimethylformamide, hexamethylphosphoric triamide, etc. After reacting the cyclopropanone acetal derivative represented by the general formula (I) with a 2 molar equivalent of a strong base such as methyl lithium, n-butyl lithium or phenyl lithium, the above general formula is further maintained at the same temperature. (III) or (IV) ketone or aldehyde, halide or sulfur By adding an electrophilic reagent such as phosphate esters, cyclopropenoid non acetal derivative represented by the general formula (V) or (VI) is obtained. In particular, in the case of this production method, the following reaction can be carried out as it is without isolating the thermally unstable cyclopropenone acetal derivative (II), which is very useful during mass production.
[0027]
【Example】
Hereinafter, the present invention will be described in more detail with reference examples and examples. However, the present invention is not limited to these reference examples and examples without departing from the gist thereof.
Reference example 1
2-tert-Butoxy-3-phenylcyclopropanone Preparation of 2,2-dimethyl-1,3-propanediylacetal (Compound No. 46 in Table 1) Potassium tert-butoxide 10.3 g in tetrahydrofuran 30 ml Cool to ° C and dissolve 12.3 g of 1,3-dibromo-1-phenyl-2-propanone in 40 ml of tetrahydrofuran and add slowly. After stirring overnight at room temperature, the solvent is distilled off under reduced pressure about half and 40 ml of water is added. Extract with hexane, wash the extract with saturated brine, and dry over sodium sulfate. The desiccant is filtered, concentrated, and recrystallized with a mixed solvent of isopropyl alcohol and water to obtain 8.35 g of the desired product.
Yield: 88%
Melting point: 75 -76 ℃
IR (KBr, cm-1): 2984, 2961, 2868, 1603, 1495, 1474, 1458, 1393, 1366, 1192, 1165, 1123, 1082, 1065, 1049, 897, 883, 696, 630.
NMR (CDCl3, d): 0.72 (s, 3H), 1.20 (s, 3H), 1.27 (s, 9H), 2.25 (d, J = 4.9 Hz, 1H), 3.04 (d, J = 10.8 Hz, 1H ), 3.32 (dd, J = 10.8 Hz, 2.1 Hz, 1H), 3.62 (d, J = 10.7 Hz, 1H), 3.66 (d, J = 4.9 Hz, 1H), 3.72 (dd, J = 10.7 Hz, 2.1 Hz, 1H), 7.10-7.25 (m, 3H), 7.25-7.35 (m, 2H).
In the same manner as in Reference Example 1, the compounds of Reference Example 2 and Reference Example 3 were produced. The physical property values are described below.
[0028]
Reference example 2
Preparation of 2-tert-butoxycyclopropanone 2,2-dimethyl-1,3-propanediyl acetal (Compound No. 9 in Table 1)
IR (neat, cm-1): 2959, 2907, 2870, 1474, 1393, 1366, 1294, 1100, 1196, 1157, 1074, 1040, 966, 905.
NMR (CDCl3, d): 0.88 (dd, J = 6.7 Hz, 4.7 Hz, 1H), 0.90 (s, 3H), 1.11 (dd, J = 8.0 Hz, 6.7 Hz, 1H), 1.13 (s, 3H) , 1.29 (s, 9H), 3.38 (dd, J = 8.0 Hz, 4.7 Hz, 1H), 3.43 (d, J = 13.0 Hz, 1H), 3.52 (d, J = 13.0 Hz, 1H), 3.57 (d , J = 10.6 Hz, 1H), 3.68 (d, J = 10.6 Hz, 1H).
[0029]
Reference example 3
Production point of 2-methoxy-3-phenylcyclopropanone 2,2-dimethyl-1,3-propanediyl acetal (Compound No. 34 in Table 1): 46 -47 ° C
IR (KBr, cm-1): 2965, 2865, 2820, 1601, 1503, 1472, 1273, 1217, 1128, 1069, 978, 963, 910, 889, 792, 765, 694, 634, 498.
NMR (CDCl3, d): 0.86 (s, 3H), 1.12 (s, 3H), 2.38 (d, J = 4.5 Hz, 1H), 3.16 (d, J = 10.8 Hz, 1H), 3.38 (dd, J = 10.8 Hz, 1.3 Hz, 1H), 3.49 (s, 3H), 3.65 (d, J = 10.6 Hz, 1H), 3.67 (d, J = 4.5 Hz, 1H), 3.74 (dd, J = 10.6 Hz, 1.3 Hz, 1H), 7.15-7.25 (m, 3H), 7.25-7.35 (m, 2H).
[0030]
Example 1
Production of 2-phenylcyclopropenone 2,2-dimethyl-1,3-propanediyl acetal 2-tert-butoxy-3-phenylcyclopropanone 2,2-dimethyl-1,3-propane obtained in Reference Example 1 1.0 g of propanediyl acetal and 1.0 ml of N, N, N ′, N′-tetramethylethylenediamine were dissolved in 10 ml of tetrahydrofuran, cooled to −60 ° C., and 1.61 mol / l of hexane solution of n-butyllithium 4 Slowly add 3 ml. After stirring at −60 ° C. for 2 hours, 3 ml of a solution in which THF and water are mixed at a ratio of 4: 1 is added to stop the reaction, the temperature is raised to room temperature, and 3 g of sodium sulfate is added. The desiccant is filtered and washed with ethyl acetate, and the filtrate is concentrated and purified by silica gel column chromatography using 5% ethyl acetate-containing hexane as a developing solvent to obtain 579 mg of the desired product.
Yield: 78%
Melting point: 48-53 ° C
IR (CCl4, cm-1): 3100, 2250, 1960, 1900, 1810, 1720, 1470, 1260.
NMR (CDCl3, d): 1.08 (s, 3H), 1.15 (s, 3H), 3.75 (s, 4H), 7.35-7.47 (m, 3H), 7.60-7.67 (m, 2H), 7.69 (s, 1H).
[0031]
Example 2
Production of 2-phenylcyclopropenone 2,2-dimethyl-1,3-propanediyl acetal 2-methoxy-3-phenylcyclopropanone 2,2-dimethyl-1,3-propanediyl obtained in Reference Example 3 The same operation as in Example 1 was performed using 316 mg of acetal to obtain 220 mg of the target product.
Yield: 80%
[0032]
Example 3
Preparation of 2-((2S) -2-tert-butoxycarbonylamino-1-hydroxy-3-methylbutyl) -3-phenylcyclopropenone 2,2-dimethyl-1,3-propanediyl acetal obtained in Reference Example 1 2-tert-butoxy-3-phenylcyclopropanone 996 mg of 2,2-dimethyl-1,3-propanediyl acetal and 0.97 ml of N, N, N ′, N′-tetramethylethylenediamine were dissolved in 10 ml of tetrahydrofuran. The solution is cooled to −60 ° C. and 3.98 ml of a hexane solution of 1.63 mol / l n-butyllithium is added. After reacting at −60 ° C. for 1.5 hours, anhydrous cerium chloride is suspended in 20 ml of tetrahydrofuran and added, and the mixture is further stirred for 1 hour. Next, 293 mg of (2S) -2-tert-butoxycarbonylamino-3-methylbutanal (L-Boc-valinal) was dissolved in 5 ml of tetrahydrofuran and added, and reacted at −60 ° C. for 3.5 hours. Add 3 ml of a 4: 1 mixture of water and then raise the temperature to room temperature. The reaction is filtered through celite and washed with ethyl acetate. The filtrate is concentrated and purified by silica gel column chromatography using hexane containing 20% ethyl acetate as a developing solvent to obtain 484 mg of the desired product.
Yield: 79%
IR (KBr, cm-1): 3430, 2960, 1855, 1800, 1710, 1690
NMR (CD3OD, d): 0.95-1.60 (m, 12H), 1.38 (s, 3H), 1.42 (s, 6H), 1.95-2.15 (m, 1H), 3.60-3.75 (m, 1H), 3.75- 3.95 (m, 4H), 5.00-5.10 (m, 1H), 6.03 (d, J = 10 Hz, 0.33H), 6.23 (d, J = 10 Hz, 0.67H), 7.40-7.65 (m, 3H) , 7.70-7.90 (m, 2H).
[0033]
【The invention's effect】
The method for producing a cyclopropenone acetal derivative of the present invention can be used as a simple method for producing an intermediate for producing a cyclopropenone derivative having cysteine protease inhibitory activity.
Claims (2)
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| JP30112194A JP3778521B2 (en) | 1994-12-05 | 1994-12-05 | Method for producing cyclopropenone acetal derivative |
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| Application Number | Priority Date | Filing Date | Title |
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| JP30112194A JP3778521B2 (en) | 1994-12-05 | 1994-12-05 | Method for producing cyclopropenone acetal derivative |
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| JP3778521B2 true JP3778521B2 (en) | 2006-05-24 |
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