JP3598421B2 - Method for producing 2-substituted-1,3-propanediol - Google Patents
Method for producing 2-substituted-1,3-propanediol Download PDFInfo
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- JP3598421B2 JP3598421B2 JP23667895A JP23667895A JP3598421B2 JP 3598421 B2 JP3598421 B2 JP 3598421B2 JP 23667895 A JP23667895 A JP 23667895A JP 23667895 A JP23667895 A JP 23667895A JP 3598421 B2 JP3598421 B2 JP 3598421B2
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- propanediol
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- aldehyde
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- -1 2-substituted-1,3-propanediol Chemical class 0.000 title description 23
- 238000004519 manufacturing process Methods 0.000 title description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 14
- 239000003054 catalyst Substances 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 238000006722 reduction reaction Methods 0.000 claims description 4
- 238000009835 boiling Methods 0.000 claims description 3
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 description 14
- 238000000034 method Methods 0.000 description 11
- 150000001299 aldehydes Chemical group 0.000 description 10
- 239000007864 aqueous solution Substances 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- YGCZTXZTJXYWCO-UHFFFAOYSA-N 3-phenylpropanal Chemical compound O=CCCC1=CC=CC=C1 YGCZTXZTJXYWCO-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- LODRGECCKZZTEQ-UHFFFAOYSA-N 2-benzylpropane-1,3-diol Chemical compound OCC(CO)CC1=CC=CC=C1 LODRGECCKZZTEQ-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- 239000012280 lithium aluminium hydride Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 2
- ADMCJTXMFWBEBC-UHFFFAOYSA-N 2-benzyl-3-hydroxypropanal Chemical compound OCC(C=O)CC1=CC=CC=C1 ADMCJTXMFWBEBC-UHFFFAOYSA-N 0.000 description 2
- YGHRJJRRZDOVPD-UHFFFAOYSA-N 3-methylbutanal Chemical group CC(C)CC=O YGHRJJRRZDOVPD-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 239000007868 Raney catalyst Substances 0.000 description 2
- 229910000564 Raney nickel Inorganic materials 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000007031 hydroxymethylation reaction Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000013076 target substance Substances 0.000 description 2
- DNIAPMSPPWPWGF-VKHMYHEASA-N (+)-propylene glycol Chemical compound C[C@H](O)CO DNIAPMSPPWPWGF-VKHMYHEASA-N 0.000 description 1
- DAXJNUBSBFUTRP-RTQNCGMRSA-N (8r,9s,10r,13s,14s)-6-(hydroxymethyl)-10,13-dimethyl-7,8,9,11,12,14,15,16-octahydro-6h-cyclopenta[a]phenanthrene-3,17-dione Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(CO)C2=C1 DAXJNUBSBFUTRP-RTQNCGMRSA-N 0.000 description 1
- YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-propanediol Substances OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- BUUODSZYUAZDIF-UHFFFAOYSA-N 2-(4-benzyl-1-ethyl-4,9-dihydro-3h-pyrano[3,4-b]indol-1-yl)acetic acid Chemical compound N1C2=CC=CC=C2C2=C1C(CC)(CC(O)=O)OCC2CC1=CC=CC=C1 BUUODSZYUAZDIF-UHFFFAOYSA-N 0.000 description 1
- ZKNCHFIFMHZVCK-UHFFFAOYSA-N 2-benzyl-2-methylpropanedioic acid Chemical compound OC(=O)C(C(O)=O)(C)CC1=CC=CC=C1 ZKNCHFIFMHZVCK-UHFFFAOYSA-N 0.000 description 1
- SXKIULBEVVXDIH-UHFFFAOYSA-N 4-hydroxy-2-(hydroxymethyl)-3-phenylbutanal Chemical compound OCC(C=O)C(CO)C1=CC=CC=C1 SXKIULBEVVXDIH-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 239000005456 alcohol based solvent Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 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
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000005843 halogen group Chemical group 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
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229910052759 nickel Inorganic materials 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
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920000166 polytrimethylene carbonate Polymers 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
【０００１】
【発明の属する技術分野】
本発明は、２−置換−１，３−プロパンジオールの製造方法に関する。本発明により製造される２−置換−１，３−プロパンジオールは、各種医薬、農薬の合成中間体として、例えば抗炎症剤、鎮痛剤として効果が期待されている（１Ｓ，４Ｒ）−シス−１−エチル−１，３，４，９−テトラヒドロ−４−（フェニルメチル）ピラノ［３，４−ｂ］インドール−１−酢酸の合成中間体として有用である。
【０００２】
【従来の技術】
２−置換−１，３−プロパンジオールの合成法としては、例えば、マロン酸ジエチルをナトリウムエトキシドの存在下にベンジルクロリドでアルキル化したのち、水素化リチウムアルミニウムで還元することにより２−ベンジル−１，３−プロパンジオールを得る方法が知られている［マクロモレキュラズ（Ｍａｃｒｏｍｏｌｅｃｕｌｅｓ）、２０巻、１４１６〜１４１９頁（１９８７年）参照］。また、アルデヒドのα位にヒドロキシメチル基を導入する方法としては、イソバレルアルデヒドを、炭酸カリウム水溶液を用いてジエチルエーテルとホルマリン水溶液の二相系で反応させ、目的物であるヒドロキシメチル体を得る方法が知られている［ザ ジャーナル オブ アメリカン ケミカル ソサエティー（Ｔｈｅ Ｊｏｕｒｎａｌ ｏｆ Ａｍｅｒｉｃａｎ Ｃｈｅｍｉｃａｌ
Ｓｏｃｉｅｔｙ）、７０巻、１６９４〜１６９９頁（１９４８年）参照］。
【０００３】
【発明が解決しようとする課題】
上記の２−ベンジル−１，３−プロパンジオールの製造方法は、原料であるマロン酸ジエチルおよび還元剤である水素化リチウムアルミニウムが高価であること、さらに水素化リチウムアルミニウムは工業的に取り扱いが困難であることから、工業的に有利な製造方法とは言い難い。また、上記のアルデヒドのα位にヒドロキシメチル基を導入する方法は、反応溶媒にジエチルエーテルを使用しており、該溶媒の引火性、揮発性、過酸化物の蓄積性等の理由から、工業的に有利な製造方法とは言い難い。一方、ヒドロキシメチル化反応溶媒として一般的なアルコール系の溶媒は、後述の比較例からも明らかなように、反応速度が非常に速く、反応調節が困難なため、目的物であるモノヒドロキシメチル体がジヒドロキシメチル体および脱水体に変換し、収率が低下するという欠点を有している。
しかして、本発明の目的は、工業的に取り扱いの困難な溶剤を用いることなく、２−置換−１，３−プロパンジオールを選択的に製造し得る方法を提供することにある。
【０００４】
【課題を解決するための手段】
本発明よれば、上記の目的は、一般式（Ｉ）
【０００５】
【化３】
（式中、Ｒは置換基を有していてもよいアルキル基、アリール基またはアラルキル基を表す。）
で示されるアルデヒド（以下、これをアルデヒド（Ｉ）と略記することがある）を、沸点が５０℃より高いエーテル系溶媒中、塩基性触媒の存在下にホルマリン水溶液と反応させてα位をモノヒドロキシメチル化し、次いで還元反応に付すことを特徴とする一般式（ＩＩ）
【０００７】
【化４】
（式中、Ｒは前記定義のとおりである。）
で示される２−置換−１，３−プロパンジオール（以下、これを２−置換−１，３−プロパンジオール（ＩＩ）と略記することがある）の製造方法を提供することにより達成される。
【０００９】
【発明の実施の形態】
前記一般式（Ｉ）および（ＩＩ）においてＲが表すアルキル基は、直鎖状または分岐鎖状のいずれでもよく、炭素数１〜１０のアルキル基が好ましい。かかるアルキル基としては、例えば、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、イソアミル基、イソバレル基、ヘキシル基、オクチル基、デシル基等が挙げられる。Ｒが表すアリール基としては、例えばフェニル基、ナフチル基等が挙げられ、アラルキル基としてはベンジル基等が挙げられる。これらのアルキル基、アリール基およびアラルキル基は置換基を有していてもよく、置換基としては塩素原子、臭素原子等のハロゲン原子が挙げられる。また、アリール基およびアラルキル基のアリール基部分の置換基としては、メチル基、エチル基、プロピル基等の炭素数１〜６の低級アルキル基が挙げられる。
【００１０】
本発明において使用される沸点が５０℃より高いエーテル系溶媒としては、例えば、テトラヒドロフラン、テトラヒドロピラン、ジオキサン、１，１−ジメトキシエタン、１，２−ジメトキシエタン、ジイソプロピルエーテル等が挙げられる。中でもテトラヒドロフランが好ましい。
【００１１】
本発明において使用される塩基性触媒としては、例えば炭酸カリウム、炭酸ナトリウム等のアルカリ金属炭酸塩；水酸化ナトリウム、水酸化カリウム、水酸化リチウム等のアルカリ金属水酸化物等が挙げられるが、特に炭酸カリウム、炭酸ナトリウム等が好ましい。塩基性触媒の使用量は、アルデヒド（Ｉ）１モルに対して０．０５〜２０モルの範囲が好ましく、１〜２モルの範囲がより好ましい。かかる塩基性触媒は通常水溶液として使用するが、水溶液中の塩基性触媒の濃度は５〜２０ｗ／ｖ％の範囲であることが好ましい。
【００１２】
反応に用いられるホルマリン水溶液の濃度は特に限定されず、例えば、市販品の２０〜４５％水溶液を用いることができる。その使用量は、反応速度、経済性、副生成物の分離等の観点から、アルデヒド（Ｉ）１モルに対して１〜１００モルの範囲が好ましく、２〜２０モルの範囲がより好ましい。
【００１３】
反応温度は、０〜５０℃の範囲であることが好ましく、０〜５℃の範囲であることがより好ましい。
【００１４】
上記の方法により製造されるアルデヒドのヒドロキシメチル体の反応混合物からの単離精製は、通常の有機化合物の単離精製において用いられる方法と同様にして行われる。例えば、反応混合物を水にあけ、酢酸エチル、イソプロピルエーテル等の有機溶媒で抽出する。抽出液を水で洗浄中和し、次いで飽和食塩水で洗浄したのち、乾燥、濃縮して粗生成物が得られる。この粗生成物は、通常の分離方法に従って精製することも可能であるが、粗生成物をそのまま次の還元反応に用いることも可能である。
【００１５】
還元は、一般的な接触水素添加方法で行うことができる。かかる反応に使用される触媒としては、ニッケル、コバルト、ロジウム、パラジウム、プラチナ等の適当な金属触媒が挙げられる。好ましくはラネーニッケル等であるが、モリブデン変性のラネーニッケルを使用することがより好ましい。この反応は溶媒中で行うのが好ましく、溶媒としては、例えばエタノール、メタノール等のアルコール系溶媒等が使用される。水添温度は、２０〜１５０℃の範囲であることが好ましく、９０〜１１０℃の範囲であることがより好ましい。反応水素圧は、通常、５〜１００ｋｇ／ｃｍ２ の範囲であることが好ましく、１０〜３０ｋｇ／ｃｍ２ の範囲であることがより好ましい。
【００１６】
このようにして得られた２−置換−１，３−プロパンジオール（ＩＩ）の反応混合物からの単離・精製は、上記の方法により製造される水添生成物から触媒を濾別したのち、濾液を減圧下に濃縮することによって粗生成物を得、該生成物を必要に応じて蒸留、再結晶またはクロマトグラフィー等により精製することによって行われる。
【００１７】
【実施例】
以下、本発明を実施例によりさらに具体的に説明するが、本発明はこれらの実施例により限定されるものではない。
【００１８】
比較例１
３−フェニルプロピオンアルデヒド１ｇをメタノール１０ｍｌに溶解し、得られた溶液に、２０℃で３７％ホルマリン水溶液３．０ｍｌ、１０％炭酸カリウム水溶液１０．４ｍｌを順次加え、３０分間撹拌した。得られた２−ヒドロキシメチル−３−フェニルプロピオンアルデヒド（目的物）、並びに副生成物であるジヒドロキシメチル体（２，３−ジヒドロキシメチル−３−フェニルプロピオンアルデヒド）および脱水体（Ｃ６ Ｈ５ −ＣＨ２ −Ｃ（＝ＣＨ２ ）−ＣＨＯ）のＨＰＬＣでの収率はそれぞれ５．９％、４５．２％、３１．８％であった。
【００１９】
実施例１
２−ヒドロキシメチル−３−フェニルプロピオンアルデヒドの合成
実施例１−ａ
３−フェニルプロピオンアルデヒド１ｇをテトラヒドロフラン１０ｍｌに溶解し、得られた溶液に２０℃で３７％ホルマリン水溶液３．０ｍｌ、１０％炭酸カリウム水溶液１０．４ｍｌを順次加え、３時間撹拌した。得られた２−ヒドロキシメチル−３−フェニルプロピオンアルデヒド、ジヒドロキシメチル体（２，３−ジヒドロキシメチル−３−フェニルプロピオンアルデヒド）および脱水体（Ｃ6 Ｈ5 −ＣＨ2 −Ｃ（＝ＣＨ2 ）−ＣＨＯ）のＨＰＬＣでの収率はそれぞれ４５．６％、１６．３％、２７．６％であった。
【００２０】
実施例１−ｂ
反応温度を１℃、反応時間を１５時間にした以外は実施例１−ａと同様の条件で反応を行った。得られた２−ヒドロキシメチル−３−フェニルプロピオンアルデヒド、ジヒドロキシメチル体（２，３−ジヒドロキシメチル−３−フェニルプロピオンアルデヒド）および脱水体（Ｃ6 Ｈ5 −ＣＨ2 −Ｃ（＝ＣＨ2 ）−ＣＨＯ）のＨＰＬＣでの収率はそれぞれ５６．０％、６．７％、１２．９％であった。
【００２１】
実施例１−ｃ
３−フェニルプロピオンアルデヒド１０ｇをテトラヒドロフラン１００ｍｌに溶解したのち、１℃に冷却した。この溶液に、３７％ホルマリン水溶液を加え、次いで、１４％炭酸カリウム水溶液７３．５ｍｌを滴下し、１℃のまま５時間撹拌した。反応終了液を水にあけ、酢酸エチルで抽出した。抽出液を水で洗浄中和し、次いで飽和食塩水で洗浄し、無水硫酸ナトリウムを用いて乾燥させたのち、減圧下に濃縮し、粗ヒドロキシメチル体１４．４ｇを得た。
【００２２】
実施例２
２−ベンジル−１，３−プロパンジオールの合成
実施例１−ｃで得られた粗ヒドロキシメチル体１４．４ｇにエタノール１４４ｍｌを加えたのち、モリブデン変性ラネーニッケル１．４４ｇを添加し、１００℃、水素圧２０気圧、１１時間反応させた。反応終了後、反応液を濾過し、ラネーニッケルを除去したのち、濾液を濃縮、真空蒸発した。これにトルエンを加え再結晶することによって２−ベンジル−１，３−プロパンジオール５．６ｇを得た。
【００２３】
【発明の効果】
本発明によって、２−置換−１，３−プロパンジオールを工業的に有利に製造することができる。[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a method for producing 2-substituted-1,3-propanediol. The 2-substituted-1,3-propanediol produced by the present invention is expected to be effective as an intermediate for synthesis of various medicines and agricultural chemicals, for example, as an anti-inflammatory agent and an analgesic (1S, 4R) -cis-. It is useful as a synthetic intermediate for 1-ethyl-1,3,4,9-tetrahydro-4- (phenylmethyl) pyrano [3,4-b] indole-1-acetic acid.
[0002]
[Prior art]
As a method for synthesizing 2-substituted-1,3-propanediol, for example, alkyl malonate is alkylated with benzyl chloride in the presence of sodium ethoxide, and then reduced with lithium aluminum hydride to give 2-benzyl-methyl-malonate. A method for obtaining 1,3-propanediol is known [see Macromolecules, Vol. 20, pp. 1416 to 1419 (1987)]. Further, as a method for introducing a hydroxymethyl group at the α-position of the aldehyde, isovaleraldehyde is reacted in a two-phase system of diethyl ether and a formalin aqueous solution using an aqueous potassium carbonate solution to obtain a hydroxymethyl derivative as an objective product. Methods are known [The Journal of American Chemical Society]
Society), 70, 1694-1699 (1948)].
[0003]
[Problems to be solved by the invention]
In the above-mentioned method for producing 2-benzyl-1,3-propanediol, diethyl malonate as a raw material and lithium aluminum hydride as a reducing agent are expensive, and lithium aluminum hydride is industrially difficult to handle. Therefore, it is hard to say that the production method is industrially advantageous. Further, the above-mentioned method of introducing a hydroxymethyl group at the α-position of an aldehyde uses diethyl ether as a reaction solvent, and the method is industrial because of the flammability, volatility, and accumulation of peroxide of the solvent. It is difficult to say that this is a production method that is economically advantageous. On the other hand, a general alcohol-based solvent as a hydroxymethylation reaction solvent has a very high reaction rate and is difficult to control the reaction, as is apparent from a comparative example described later, and therefore, the monohydroxymethyl compound which is the target substance is used. Has the drawback that it is converted into a dihydroxymethyl form and a dehydrated form, and the yield is reduced.
Thus, an object of the present invention is to provide a method capable of selectively producing 2-substituted-1,3-propanediol without using a solvent that is industrially difficult to handle.
[0004]
[Means for Solving the Problems]
According to the present invention, the above objects have the general formula (I)
[0005]
Embedded image
(In the formula, R represents an alkyl group, an aryl group or an aralkyl group which may have a substituent.)
(Hereinafter sometimes abbreviated as aldehyde (I)) is reacted with an aqueous formalin solution in an ether-based solvent having a boiling point higher than 50 ° C. in the presence of a basic catalyst to convert the α-position into a mono-form. General formula (II) characterized in that hydroxymethylation and subsequent reduction reaction
[0007]
Embedded image
(Wherein, R is as defined above.)
This is achieved by providing a method for producing 2-substituted-1,3-propanediol represented by the following formula (hereinafter sometimes abbreviated as 2-substituted-1,3-propanediol (II)).
[0009]
BEST MODE FOR CARRYING OUT THE INVENTION
The alkyl group represented by R in the general formulas (I) and (II) may be linear or branched, and is preferably an alkyl group having 1 to 10 carbon atoms. Examples of such an alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, an isoamyl group, an isovaler group, a hexyl group, an octyl group, and a decyl group. Examples of the aryl group represented by R include a phenyl group and a naphthyl group, and examples of the aralkyl group include a benzyl group. These alkyl group, aryl group and aralkyl group may have a substituent, and examples of the substituent include a halogen atom such as a chlorine atom and a bromine atom. Examples of the substituent of the aryl group portion of the aryl group and the aralkyl group include a lower alkyl group having 1 to 6 carbon atoms such as a methyl group, an ethyl group, and a propyl group.
[0010]
Examples of the ether solvent having a boiling point higher than 50 ° C. used in the present invention include tetrahydrofuran, tetrahydropyran, dioxane, 1,1-dimethoxyethane, 1,2-dimethoxyethane, diisopropyl ether and the like. Among them, tetrahydrofuran is preferred.
[0011]
Examples of the basic catalyst used in the present invention include alkali metal carbonates such as potassium carbonate and sodium carbonate; and alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide. Potassium carbonate, sodium carbonate and the like are preferred. The amount of the basic catalyst used is preferably in the range of 0.05 to 20 mol, more preferably in the range of 1 to 2 mol, per 1 mol of the aldehyde (I). Such a basic catalyst is usually used as an aqueous solution, and the concentration of the basic catalyst in the aqueous solution is preferably in the range of 5 to 20 w / v%.
[0012]
The concentration of the formalin aqueous solution used for the reaction is not particularly limited, and for example, a commercially available 20 to 45% aqueous solution can be used. From the viewpoints of reaction rate, economy, separation of by-products, and the like, the amount is preferably 1 to 100 mol, more preferably 2 to 20 mol, per 1 mol of the aldehyde (I).
[0013]
The reaction temperature is preferably in the range of 0 to 50 ° C, more preferably in the range of 0 to 5 ° C.
[0014]
Isolation and purification of the hydroxymethyl form of the aldehyde produced by the above-mentioned method from the reaction mixture are carried out in the same manner as in a method generally used in the isolation and purification of organic compounds. For example, the reaction mixture is poured into water and extracted with an organic solvent such as ethyl acetate or isopropyl ether. The extract is washed and neutralized with water, then washed with saturated saline, dried and concentrated to obtain a crude product. This crude product can be purified according to a usual separation method, but the crude product can be used as it is in the next reduction reaction.
[0015]
The reduction can be performed by a general catalytic hydrogenation method. Suitable catalysts for use in such reactions include nickel, cobalt, rhodium, palladium, platinum and the like. Preferably, Raney nickel or the like is used, but it is more preferable to use molybdenum-modified Raney nickel. This reaction is preferably performed in a solvent. As the solvent, for example, an alcoholic solvent such as ethanol and methanol is used. The hydrogenation temperature is preferably in the range of 20 to 150C, more preferably in the range of 90 to 110C. The reaction hydrogen pressure is generally preferably in the range of 5 to 100 kg / cm 2, and more preferably in the range of 10 to 30 kg / cm 2.
[0016]
Isolation and purification of the thus-obtained 2-substituted-1,3-propanediol (II) from the reaction mixture is carried out by filtering off the catalyst from the hydrogenated product produced by the above-mentioned method, The reaction is carried out by concentrating the filtrate under reduced pressure to obtain a crude product, and purifying the product by distillation, recrystallization, chromatography or the like, if necessary.
[0017]
【Example】
Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples.
[0018]
Comparative Example 1
1 g of 3-phenylpropionaldehyde was dissolved in 10 ml of methanol, and 3.0 ml of a 37% aqueous solution of formalin and 10.4 ml of a 10% aqueous solution of potassium carbonate were sequentially added to the obtained solution at 20 ° C., followed by stirring for 30 minutes. The obtained 2-hydroxymethyl-3-phenylpropionaldehyde (target substance), and dihydroxymethyl derivative (2,3-dihydroxymethyl-3-phenylpropionaldehyde) and dehydrated product (C 6 H 5 −) as by-products The yields of CH 2 —C (＝ CH 2 ) —CHO) by HPLC were 5.9%, 45.2%, and 31.8%, respectively.
[0019]
Example 1
Synthesis of 2-hydroxymethyl-3-phenylpropionaldehyde Example 1- a
1 g of 3-phenylpropionaldehyde was dissolved in 10 ml of tetrahydrofuran, and 3.0 ml of a 37% aqueous solution of formalin and 10.4 ml of a 10% aqueous solution of potassium carbonate were sequentially added to the obtained solution at 20 ° C., followed by stirring for 3 hours. The resulting 2-hydroxymethyl-3-phenylpropionic aldehyde, dihydroxy methyl derivatives (2,3-dihydroxy-3-phenylpropionic aldehyde) and dried body (C 6 H 5 -CH 2 -C (= CH 2) - The yield of CHO) by HPLC was 45.6%, 16.3%, and 27.6%, respectively.
[0020]
Example 1- b
The reaction was carried out under the same conditions as in Example 1- a except that the reaction temperature was 1 ° C. and the reaction time was 15 hours. The resulting 2-hydroxymethyl-3-phenylpropionic aldehyde, dihydroxy methyl derivatives (2,3-dihydroxy-3-phenylpropionic aldehyde) and dried body (C 6 H 5 -CH 2 -C (= CH 2) - The yield of CHO) by HPLC was 56.0%, 6.7%, and 12.9%, respectively.
[0021]
Example 1- c
After dissolving 10 g of 3-phenylpropionaldehyde in 100 ml of tetrahydrofuran, the mixture was cooled to 1 ° C. To this solution, a 37% aqueous formalin solution was added, and then 73.5 ml of a 14% aqueous potassium carbonate solution was added dropwise, followed by stirring at 1 ° C. for 5 hours. The reaction-terminated liquid was poured into water and extracted with ethyl acetate. The extract was washed with water and neutralized, then washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 14.4 g of a crude hydroxymethyl compound.
[0022]
Example 2
Synthesis of 2-benzyl-1,3-propanediol To 14.4 g of the crude hydroxymethyl compound obtained in Example 1- c , 144 ml of ethanol was added, and 1.44 g of molybdenum-modified Raney nickel was added. The reaction was carried out at a pressure of 20 atm for 11 hours. After completion of the reaction, the reaction solution was filtered to remove Raney nickel, and then the filtrate was concentrated and evaporated in vacuo. Toluene was added thereto and recrystallized to obtain 5.6 g of 2-benzyl-1,3-propanediol.
[0023]
【The invention's effect】
According to the present invention, 2-substituted-1,3-propanediol can be industrially advantageously produced.
Claims (1)
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