JP3693473B2 - Method for producing polyanhydride and polyanhydride copolymer - Google Patents
Method for producing polyanhydride and polyanhydride copolymer Download PDFInfo
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- JP3693473B2 JP3693473B2 JP24717997A JP24717997A JP3693473B2 JP 3693473 B2 JP3693473 B2 JP 3693473B2 JP 24717997 A JP24717997 A JP 24717997A JP 24717997 A JP24717997 A JP 24717997A JP 3693473 B2 JP3693473 B2 JP 3693473B2
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- polyanhydride
- dicarboxylic acid
- phosgene
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- dda
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- 238000004519 manufacturing process Methods 0.000 title claims description 11
- 229920002732 Polyanhydride Polymers 0.000 title description 24
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 21
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical group [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical group ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 18
- 150000008064 anhydrides Chemical class 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 13
- 239000012320 chlorinating reagent Substances 0.000 claims description 10
- 229920001577 copolymer Polymers 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 7
- 150000007529 inorganic bases Chemical class 0.000 claims description 7
- 125000002947 alkylene group Chemical group 0.000 claims description 6
- 150000007530 organic bases Chemical class 0.000 claims description 6
- 125000001931 aliphatic group Chemical group 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 125000002723 alicyclic group Chemical group 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 36
- TVIDDXQYHWJXFK-UHFFFAOYSA-N dodecanedioic acid Chemical compound OC(=O)CCCCCCCCCCC(O)=O TVIDDXQYHWJXFK-UHFFFAOYSA-N 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 13
- 230000015572 biosynthetic process Effects 0.000 description 11
- 150000003839 salts Chemical class 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 238000001914 filtration Methods 0.000 description 8
- 230000032683 aging Effects 0.000 description 7
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- 238000006116 polymerization reaction Methods 0.000 description 5
- -1 salt compound Chemical class 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 229910017053 inorganic salt Inorganic materials 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 230000018044 dehydration Effects 0.000 description 3
- 238000006297 dehydration reaction Methods 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- KKEYFWRCBNTPAC-UHFFFAOYSA-N Terephthalic acid Chemical compound OC(=O)C1=CC=C(C(O)=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-N 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 238000010528 free radical solution polymerization reaction Methods 0.000 description 2
- CBFCDTFDPHXCNY-UHFFFAOYSA-N icosane Chemical compound CCCCCCCCCCCCCCCCCCCC CBFCDTFDPHXCNY-UHFFFAOYSA-N 0.000 description 2
- JJOJFIHJIRWASH-UHFFFAOYSA-N icosanedioic acid Chemical compound OC(=O)CCCCCCCCCCCCCCCCCCC(O)=O JJOJFIHJIRWASH-UHFFFAOYSA-N 0.000 description 2
- QQVIHTHCMHWDBS-UHFFFAOYSA-N isophthalic acid Chemical compound OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 description 2
- BDJRBEYXGGNYIS-UHFFFAOYSA-N nonanedioic acid Chemical compound OC(=O)CCCCCCCC(O)=O BDJRBEYXGGNYIS-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 235000011181 potassium carbonates Nutrition 0.000 description 2
- CXMXRPHRNRROMY-UHFFFAOYSA-N sebacic acid Chemical compound OC(=O)CCCCCCCCC(O)=O CXMXRPHRNRROMY-UHFFFAOYSA-N 0.000 description 2
- TYFQFVWCELRYAO-UHFFFAOYSA-N suberic acid Chemical compound OC(=O)CCCCCCC(O)=O TYFQFVWCELRYAO-UHFFFAOYSA-N 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000001361 adipic acid Substances 0.000 description 1
- 235000011037 adipic acid Nutrition 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- KYQRDNYMKKJUTH-UHFFFAOYSA-N bicyclo[2.2.1]heptane-3,4-dicarboxylic acid Chemical compound C1CC2(C(O)=O)C(C(=O)O)CC1C2 KYQRDNYMKKJUTH-UHFFFAOYSA-N 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000003431 cross linking reagent Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 150000001991 dicarboxylic acids Chemical class 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003759 ester based solvent Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 238000006068 polycondensation reaction Methods 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 229920002717 polyvinylpyridine Polymers 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
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Description
【０００１】
【発明の属する技術分野】
本発明はポリ酸無水物及びポリ酸無水物共重合体の製造方法に関する。
ポリ酸無水物及びポリ酸無水物共重合体は、生体医学の分野特にドラッグデリバリーの分野において有用な化合物である。この場合は、フィルム形成性、高い引っ張り強度等の物理的、機械的性質が要求されるために比較的高分子量のポリ酸無水物が必要とされる。また、オリゴマー化された直鎖脂肪族ジカルボン酸のポリ酸無水物は、粉体塗料の架橋剤として自動車塗装の分野等において使用されている。
【０００２】
【従来の技術】
ポリ酸無水物及びポリ酸無水物共重合体の一般的製造方法としては、無水酢酸を用いた溶融重縮合が知られている。しかしながらこの方法では高温での反応が余儀なくされるので、熱的に安定なモノマーしか用いることができなかった。
【０００３】
また、他の製造方法として溶液重合が挙げられる。この方法では、塩基の存在下、ジカルボン酸とジカルボン酸クロライドとの反応（Ｓｃｈｏｔｔｅｎ−Ｂａｕｍａｎｎ縮合）によりポリ酸無水物が製造されるが、塩基の存在下でジカルボン酸クロライドが一部加水分解を起こし、ポリ酸無水物が低分子量になる等の問題点があった。さらに、生成したポリ酸無水物に塩基の塩酸塩等の副生成物が混入し、これらを除去するために水洗を行う際に、ポリ酸無水物の加水分解が起こる等の問題点があった（Ｍａｃｒｏｍｏｌｅｃｕｌｅｓ，２０（４），７０５（１９８７））。また、直鎖脂肪族ジカルボン酸のジトリメチルシリルエステルと塩化チオニルとの反応（Ｍａｃｒｏｍｏｌ．Ｃｈｅｍ．，Ｒａｐｉｄ Ｃｏｍｍｕｎ．（１９９０），１１（６），２６１−２６６）またはジカルボン酸クロライドとの反応（Ｍａｃｒｏｍｏｌ．Ｃｈｅｍ．，Ｒａｐｉｄ Ｃｏｍｍｕｎ．（１９９０），１１（２），８３−８８）によりポリ酸無水物を製造する方法もあるが、工程が煩雑で工業的に有利な方法であるとは言えなかった。
【０００４】
さらに溶液重合法の改良法として、溶剤に不溶のポリアミンや炭酸カリウム等の存在下ジカルボン酸にホスゲン等の塩素化剤を反応させる製造法（ＵＳ４９１６２０４号明細書）が開示されているが、分子量を意図的にコントロールしてポリ酸無水物を製造する方法については知られていない。
【０００５】
【発明が解決しようとする課題】
本発明は上記した従来のポリ酸無水物及びポリ酸無水物共重合体の製造方法の問題点を解消するためになされたものである。本発明の目的は、広範囲にわたるジカルボン酸に適用でき、かつ、工業的に有利なポリ酸無水物の製造方法を提供することにある。
【０００６】
【課題を解決するための手段】
本発明者らは、ポリ酸無水物及びポリ酸無水物共重合体の製造方法について鋭意検討を行った結果、ジカルボン酸の造塩化合物と塩素化剤との反応により、容易にポリ酸無水物及びポリ酸無水物共重合体の製造ができることを見出した。さらに、ジカルボン酸の造塩化合物の造塩率を調製することにより、ポリ酸無水物及びポリ酸無水物共重合体の分子量をコントロールできることを見出し本発明を完成するに至った。
【０００７】
即ち本発明は、
１）．一般式（１）
【０００８】
【化２】
【０００９】
で表されるジカルボン酸と、該化合物のカルボキシル基に対して当量以下の無機塩基及び／または有機塩基を反応させることにより得られるジカルボン酸の造塩化合物に、塩素化剤を反応させることを特徴とするポリ酸無水物及びポリ酸無水物共重合体の製造方法、
２）．塩素化剤がホスゲンまたはホスゲンダイマーである前記１）の製造方法、
３）．無機塩基及び／または有機塩基が、水酸化カリウム及び／またはトリエチルアミンである前記１）または前記２）の製造方法である。
【００１０】
【発明の実施の形態】
本発明の一般式（１）において置換基Ｒは、直鎖脂肪族アルキレン基及び／または脂環式アルキレン基及び／または芳香環であり、即ち本発明で使用されるジカルボン酸としては、例えば、アジピン酸、スベリン酸、アゼライン酸、セバシン酸、ドデカン二酸（ＤＤＡ）、エイコサン二酸、１，３−シクロヘキサンカルボン酸、１，４−シクロヘキサンカルボン酸、ノルボルナンジカルボン酸、イソフタル酸、テレフタル酸、またはこれらの混合物等が挙げられるがこれらに限定されるものではない。
【００１１】
本発明で使用される無機塩基及び／または有機塩基としては、例えば、水酸化ナトリウム、炭酸ナトリウム、炭酸水素ナトリウム、水酸化カリウム、炭酸カリウム、炭酸水素カリウム、水酸化カルシウム、炭酸カルシウム、水酸化マグネシウム、炭酸マグネシウム等の無機塩基及び／またはトリエチルアミン、ピリジン、ポリビニルピリジン、テトラエチレンジアミン等の有機アミン、またはこれらの混合物等であり、特に好ましくは、水酸化カリウムまたはトリエチルアミンである。
【００１２】
本発明で使用されるジカルボン酸の造塩化合物は、ジカルボン酸と無機塩基及び／または有機塩基を溶媒中反応させることにより容易に製造できる。造塩マス中に水を含有する場合は、共沸剤等を使用し系外へ水を除去しておくと、重合中の加水分解等が抑制でき好ましい。
【００１３】
また、この際塩基の使用量は、原料であるジカルボン酸の２つのカルボキシル基に対して当量以下であれば良く、それ以上使用すると残存塩基により重合中の副反応が多くなる。更に、使用量を当量から少なくしていくとそれに比例して重合後の分子量が小さくなる。つまり、ジカルボン酸の造塩化合物の造塩率を調製することにより、ポリ酸無水物及びポリ酸無水物共重合体の分子量を意図的にコントロールすることができる。ここで言う造塩率とは、本発明におけるジカルボン酸の２つのカルボキシル基が無機塩または有機アミンによって理論的に造塩された場合を１００％とした時の、実際に造塩された割合を示す。
【００１４】
本発明で使用される塩素化剤としては、ホスゲン、ホスゲンダイマー、塩化チオニル、酸クロライド等が挙げられるが、好ましくは、ホスゲンまたはホスゲンダイマーである。ホスゲン及びホスゲンダイマーの使用量は、ホスゲンの場合、造塩されたジカルボン酸と同モル数つまりジカルボン酸の造塩化合物に造塩率を掛けたモル数あれば十分であり、ホスゲンダイマーの場合はホスゲンの１／２モル数あれば良い。それ以上用いても過剰の塩素化剤は反応に使用されることは無く、ポリ酸無水物の分子量に影響を与えない。使用量が少ない場合は、生成物の分子量が低下する上、残存する塩基が後処理工程において悪影響を与える。
【００１５】
塩素化剤の使用方法としては溶媒に溶解させて用いてもよく、また、直接反応混合物に装入しても良い。塩素化剤を添加する速度は発熱量をコントロールできる速度であれば良く、所定量を１時間以上かけて装入する。添加速度はポリ酸無水物の分子量には影響しない。
【００１６】
本発明の重合工程では、溶媒を用いるのが好ましい。使用される溶媒は、プロトン性極性溶媒以外であれば特に限定はされない。例えば、ベンゼン、トルエン、キシレン、ヘキサン、ヘプタン、シクロヘキサン等の炭化水素系溶媒、１，２−ジクロロエタン、クロロホルム、四塩化炭素等のハロゲン化炭化水素系溶媒、酢酸エチル、酢酸ブチル等のエステル系溶媒等が挙げられるが、これらに限定されるものではない。ただし、生成するポリ酸無水物及びポリ酸無水物共重合体と副生する無機塩の溶解度が著しく異なる溶媒、例えば、生成するポリ酸無水物が溶解しやすく、副生する無機塩が溶解しにくい溶媒を用いると反応後の取り出しが容易になり好ましい。
【００１７】
本発明の重合工程における反応温度は、反応基質、溶媒によって左右されるが一般的には室温〜１２０℃で選ばれる。例えば、トルエンの場合は好ましくは１０５〜１１０℃であり、この範囲内では、主反応速度が大きくジカルボン酸塩の転化率が高い。
【００１８】
反応の終点は、理論量の炭酸ガスが発生した時点である。
【００１９】
反応混合物からのポリ酸無水物の取り出し方法は、反応に用いる溶媒によって左右されるが、一般的には生成したポリ酸無水物を溶媒に溶解させた状態でろ過により無機塩及び／または有機アミンの塩酸塩を除去し、ろ液から晶析等によりポリ酸無水物を取り出すことができる。
【００２０】
【実施例】
以下、実施例により本発明を詳細に説明するが、本発明はこれらに限定されるものではない。尚、生成したポリ酸無水物の重量平均分子量（Ｍｗ）は、ＴＳＫｇｅｌ Ｇ２０００ＨXLおよびＴＳＫ ｇｅｌ Ｇ３０００ＨHR（東ソー（株）製）を用い、テトラヒドロフラン溶媒で測定した。Ｍｗ値はポリスチレン換算値である。
【００２１】
実施例１
ＤＤＡ５７．５８ｇ（０．２５ｍｏｌ）にトルエン４１７ｇを加え、続いて４９．８％ＫＯＨ水溶液５６．３３ｇ（０．５０ｍｏｌ）、水１５３ｇを加えて８５℃で２時間熟成し、造塩率１００％のＤＤＡ−２Ｋを合成した。その後、共沸脱水により系内の水分を除去した。続いてこれにホスゲン２４．７３ｇ（０．２５ｍｏｌ）のトルエン（６２．５ｇ）溶液を５０℃で１時間かけて滴下した。その後、１１０℃で３０分間熟成した。続いて、反応混合物を９０℃で熱濾過して生成したＫＣｌを除去した。濾液を４５℃に保ち、これにｎ−ヘキサン（８６ｇ）を滴下し、これを２〜３℃まで冷却してポリＤＤＡ無水物（ＰＤＤＡ）を晶析させた。ＰＤＤＡを濾過により取り出し、５０℃で１日間乾燥させて、ＰＤＤＡ４５．２ｇを得た。得られたＰＤＤＡの重量平均分子量は１７５００であった（図１参照）。
【００２２】
実施例２
ＤＤＡ５７．５８ｇ（０．２５ｍｏｌ）にトルエン４１７ｇを加え、続いて４９．８％ＫＯＨ水溶液４５．１ｇ（０．４０ｍｏｌ）、水１５３ｇを加えて８５℃で２時間熟成し、造塩率８０％のＤＤＡ−２Ｋを合成した。その後、共沸脱水により系内の水分を除去した。続いてこれにホスゲン１９．７８ｇ（０．２０ｍｏｌ）のトルエン（６２．５ｇ）溶液を５０℃で１時間かけて滴下した。その後、１１０℃で３０分間熟成した。続いて、反応混合物を９０℃で熱濾過して生成したＫＣｌを除去した。濾液を２〜３℃まで冷却してＰＤＤＡを晶析させた。ＰＤＤＡを濾過により取り出し、５０℃で１日間乾燥させて、ＰＤＤＡ４３．７ｇを得た。得られたＰＤＤＡの重量平均分子量は２８００であった（図１参照）。
【００２３】
実施例３
ＤＤＡ５７．５８ｇ（０．２５ｍｏｌ）にトルエン４１７ｇを加え、続いてトリエチルアミン（ＴＥＡ）５０．６０ｇ（０．５０ｍｏｌ）を加えて２５℃で１時間攪拌し、造塩率１００％のＤＤＡ−２ＴＥＡを合成した。続いてこれにホスゲン２４．７３ｇ（０．２５ｍｏｌ）のトルエン（６２．５ｇ）溶液を５０℃で１時間かけて滴下した。その後、１１０℃で３０分間熟成した。続いて、反応混合物を９０℃で熱濾過して生成したトリエチルアミン塩酸塩を除去した。濾液を２〜３℃まで冷却してＰＤＤＡを晶析させた。ＰＤＤＡを濾過により取り出し、５０℃で１日間乾燥させて、ＰＤＤＡ４４．１ｇを得た。得られたＰＤＤＡの重量平均分子量は１２５００であった。
【００２４】
実施例４
ＤＤＡ５７．５８ｇ（０．２５ｍｏｌ）にトルエン４１７ｇを加え、続いてトリエチルアミン４０．４８ｇ（０．４０ｍｏｌ）を加えて２５℃で１時間攪拌し、造塩率８０％のＤＤＡ−２ＴＥＡを合成した。続いてこれにホスゲン１９．７８ｇ（０．２０ｍｏｌ）のトルエン（６２．５ｇ）溶液を５０℃で１時間かけて滴下した。その後、１１０℃で３０分間熟成した。続いて、反応混合物を９０℃で熱濾過して生成したトリエチルアミン塩酸塩を除去した。濾液を２〜３℃まで冷却してＰＤＤＡを晶析させた。ＰＤＤＡを濾過により取り出し、５０℃で１日間乾燥させて、ＰＤＤＡ５０．４０ｇを得た。得られたＰＤＤＡの重量平均分子量は２７００であった。
【００２５】
実施例５
ＤＤＡ１０３．６４ｇ（０．４５ｍｏｌ）、エイコサンニ酸１０２．１５ｇ（０．３０ｍｏｌ）にトルエン１２５１ｇを加え、続いて４９．８％ＫＯＨ水溶液１６８．９９ｇ（１．５０ｍｏｌ）、水４５９ｇを加えて８５℃で２時間熟成し、造塩率１００％のＤＤＡ−２Ｋ、造塩率１００％のエイコサン二酸−２Ｋの混合物を合成した。その後、共沸脱水により系内の水分を除去した。続いてこれにホスゲン７４．１９ｇ（０．７５ｍｏｌ）のトルエン（１８７．５ｇ）溶液を５０℃で１時間かけて滴下した。その後、１１０℃で３０分間熟成した。続いて、反応混合物を９０℃で熱濾過して生成したＫＣｌを除去した。濾液を４５℃に保ち、これにｎ−ヘキサン２５８ｇを滴下し、これを２〜３℃まで冷却してＤＤＡ−エイコサン二酸共重合体を晶析させた。ＤＤＡ−エイコサン二酸共重合体を濾過により取り出し、５０℃で１日間乾燥させて、ＤＤＡ−エイコサン二酸共重合体１２７．２ｇを得た。得られたＤＤＡ−エイコサン二酸共重合体の重量平均分子量は９５００であった。
【００２６】
【発明の効果】
本発明により、比較的温和な条件で、かつ、分子量を自在にコントロールできる工業的に優位なポリ酸無水物及びポリ酸無水物共重合体の製造方法を提供できた。
【図面の簡単な説明】
【図１】ＤＤＡ−２Ｋの造塩率とＰＤＤＡの重量平均分子量の関係を示す。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a method for producing a polyacid anhydride and a polyacid anhydride copolymer.
Polyanhydrides and polyanhydride copolymers are useful compounds in the biomedical field, particularly in the field of drug delivery. In this case, since physical and mechanical properties such as film formability and high tensile strength are required, a relatively high molecular weight polyanhydride is required. In addition, oligomerized linear aliphatic dicarboxylic acid polyanhydrides are used in the field of automobile coating as a crosslinking agent for powder coatings.
[0002]
[Prior art]
As a general method for producing polyanhydrides and polyanhydride copolymers, melt polycondensation using acetic anhydride is known. However, this method necessitates a reaction at a high temperature, so that only thermally stable monomers can be used.
[0003]
Moreover, solution polymerization is mentioned as another manufacturing method. In this method, a polyanhydride is produced by the reaction of a dicarboxylic acid and a dicarboxylic acid chloride (Schottten-Baumann condensation) in the presence of a base, but the dicarboxylic acid chloride partially undergoes hydrolysis in the presence of a base. There were problems such as low molecular weight of the polyanhydride. Furthermore, by-products such as base hydrochloride were mixed in the generated polyacid anhydride, and there was a problem that hydrolysis of the polyacid anhydride occurred when washing with water to remove these. (Macromolecules, 20 (4), 705 (1987)). Also, a reaction between a ditrimethylsilyl ester of a linear aliphatic dicarboxylic acid and thionyl chloride (Macromol. Chem., Rapid Commun. (1990), 11 (6), 261-266) or a reaction with a dicarboxylic acid chloride (Macromol. Chem., Rapid Commun. (1990), 11 (2), 83-88), there is a method for producing a polyanhydride, but the process is complicated and cannot be said to be an industrially advantageous method.
[0004]
Furthermore, as a method for improving the solution polymerization method, a production method (US Pat. No. 4,916,204) is disclosed in which a chlorinating agent such as phosgene is reacted with a dicarboxylic acid in the presence of a polyamine or potassium carbonate insoluble in a solvent. There is no known method for producing polyanhydrides with intentional control.
[0005]
[Problems to be solved by the invention]
The present invention has been made to solve the above-described problems of the conventional methods for producing polyanhydrides and polyanhydride copolymers. An object of the present invention is to provide a process for producing polyanhydrides which can be applied to a wide range of dicarboxylic acids and is industrially advantageous.
[0006]
[Means for Solving the Problems]
As a result of intensive studies on the production methods of polyacid anhydrides and polyanhydride copolymers, the present inventors have found that polyanhydrides can be easily obtained by the reaction between a salt compound of dicarboxylic acid and a chlorinating agent. It was also found that a polyanhydride copolymer can be produced. Furthermore, it has been found that the molecular weight of the polyacid anhydride and the polyacid anhydride copolymer can be controlled by adjusting the salt formation rate of the salt compound of the dicarboxylic acid, and the present invention has been completed.
[0007]
That is, the present invention
1). General formula (1)
[0008]
[Chemical formula 2]
[0009]
A chlorinating agent is reacted with a salt-forming compound of dicarboxylic acid obtained by reacting the dicarboxylic acid represented by the following formula with an inorganic base and / or an organic base having an equivalent amount or less with respect to the carboxyl group of the compound. A process for producing a polyacid anhydride and a polyacid anhydride copolymer,
2). The production method of the above 1), wherein the chlorinating agent is phosgene or phosgene dimer,
3). In the production method of the above 1) or 2), the inorganic base and / or the organic base is potassium hydroxide and / or triethylamine.
[0010]
DETAILED DESCRIPTION OF THE INVENTION
In the general formula (1) of the present invention, the substituent R is a linear aliphatic alkylene group and / or an alicyclic alkylene group and / or an aromatic ring. That is, as the dicarboxylic acid used in the present invention, for example, Adipic acid, suberic acid, azelaic acid, sebacic acid, dodecanedioic acid (DDA), eicosanedioic acid, 1,3-cyclohexanecarboxylic acid, 1,4-cyclohexanecarboxylic acid, norbornane dicarboxylic acid, isophthalic acid, terephthalic acid, or Examples thereof include, but are not limited to, mixtures thereof.
[0011]
Examples of the inorganic base and / or organic base used in the present invention include sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium hydroxide, potassium carbonate, potassium hydrogen carbonate, calcium hydroxide, calcium carbonate, magnesium hydroxide. Inorganic bases such as magnesium carbonate and / or organic amines such as triethylamine, pyridine, polyvinylpyridine, tetraethylenediamine, or a mixture thereof, particularly preferably potassium hydroxide or triethylamine.
[0012]
The salt-forming compound of dicarboxylic acid used in the present invention can be easily produced by reacting dicarboxylic acid with an inorganic base and / or an organic base in a solvent. When water is contained in the salt-forming mass, it is preferable to use an azeotropic agent or the like to remove water from the system because hydrolysis during polymerization can be suppressed.
[0013]
Moreover, the usage-amount of a base should just be below an equivalent with respect to two carboxyl groups of the dicarboxylic acid which is a raw material at this time, and if it uses more than it, the side reaction during superposition | polymerization will increase with a residual base. Further, when the amount used is decreased from the equivalent amount, the molecular weight after polymerization is reduced in proportion to the amount used. That is, the molecular weight of the polyacid anhydride and the polyacid anhydride copolymer can be intentionally controlled by adjusting the salt formation rate of the salt compound of the dicarboxylic acid. The salt formation rate mentioned here is the ratio of actual salt formation when the two carboxyl groups of the dicarboxylic acid in the present invention are theoretically salted with an inorganic salt or an organic amine as 100%. Show.
[0014]
Examples of the chlorinating agent used in the present invention include phosgene, phosgene dimer, thionyl chloride, acid chloride and the like, and phosgene or phosgene dimer is preferable. In the case of phosgene, the amount of phosgene and phosgene dimer used should be the same as the number of moles of the salted dicarboxylic acid, that is, the number of moles obtained by multiplying the salt formation compound of the dicarboxylic acid by the salt formation rate. What is necessary is just 1/2 mol of phosgene. Even if it is used more than that, the excess chlorinating agent is not used in the reaction and does not affect the molecular weight of the polyanhydride. When the amount used is small, the molecular weight of the product decreases and the remaining base adversely affects the post-treatment process.
[0015]
As a method of using the chlorinating agent, it may be used after being dissolved in a solvent, or may be directly charged into the reaction mixture. The rate at which the chlorinating agent is added may be any rate that can control the calorific value, and a predetermined amount is charged over 1 hour or more. The addition rate does not affect the molecular weight of the polyanhydride.
[0016]
In the polymerization step of the present invention, it is preferable to use a solvent. The solvent used is not particularly limited as long as it is not a protic polar solvent. For example, hydrocarbon solvents such as benzene, toluene, xylene, hexane, heptane and cyclohexane, halogenated hydrocarbon solvents such as 1,2-dichloroethane, chloroform and carbon tetrachloride, and ester solvents such as ethyl acetate and butyl acetate However, it is not limited to these. However, the solubility of the resulting polyacid anhydride and polyanhydride copolymer and the inorganic salt produced as a by-product is significantly different, for example, the produced polyacid anhydride is easily dissolved, and the by-product inorganic salt is dissolved. It is preferable to use a difficult solvent because it can be easily taken out after the reaction.
[0017]
The reaction temperature in the polymerization step of the present invention depends on the reaction substrate and the solvent, but is generally selected from room temperature to 120 ° C. For example, in the case of toluene, the temperature is preferably 105 to 110 ° C. Within this range, the main reaction rate is large and the conversion rate of the dicarboxylate is high.
[0018]
The end point of the reaction is when a theoretical amount of carbon dioxide gas is generated.
[0019]
The method for removing the polyanhydride from the reaction mixture depends on the solvent used in the reaction, but in general, the resulting polyacid anhydride is dissolved in the solvent and filtered to filter the inorganic salt and / or organic amine. The polyacid anhydride can be removed from the filtrate by crystallization or the like.
[0020]
【Example】
EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, this invention is not limited to these. In addition, the weight average molecular weight (Mw) of the produced polyanhydride was measured with a tetrahydrofuran solvent using TSKgel G2000H XL and TSK gel G3000H HR (manufactured by Tosoh Corporation). The Mw value is a polystyrene equivalent value.
[0021]
Example 1
417 g of toluene was added to 57.58 g (0.25 mol) of DDA, followed by 56.33 g (0.50 mol) of 49.8% KOH aqueous solution and 153 g of water, followed by aging at 85 ° C. for 2 hours. DDA-2K was synthesized. Thereafter, water in the system was removed by azeotropic dehydration. Subsequently, a solution of 24.73 g (0.25 mol) of phosgene in toluene (62.5 g) was added dropwise thereto at 50 ° C. over 1 hour. Thereafter, aging was performed at 110 ° C. for 30 minutes. Subsequently, KCl produced by removing the reaction mixture by hot filtration at 90 ° C. was removed. The filtrate was kept at 45 ° C., n-hexane (86 g) was added dropwise thereto, and this was cooled to 2-3 ° C. to crystallize poly DDA anhydride (PDDA). PDDA was removed by filtration and dried at 50 ° C. for 1 day to obtain 45.2 g of PDDA. The obtained PDDA had a weight average molecular weight of 17,500 (see FIG. 1).
[0022]
Example 2
417 g of toluene was added to 57.58 g (0.25 mol) of DDA, followed by 45.1 g (0.40 mol) of 49.8% KOH aqueous solution and 153 g of water, followed by aging at 85 ° C. for 2 hours. DDA-2K was synthesized. Thereafter, water in the system was removed by azeotropic dehydration. Subsequently, a solution of 19.78 g (0.20 mol) of phosgene in toluene (62.5 g) was added dropwise at 50 ° C. over 1 hour. Thereafter, aging was performed at 110 ° C. for 30 minutes. Subsequently, KCl produced by removing the reaction mixture by hot filtration at 90 ° C. was removed. The filtrate was cooled to 2-3 ° C. to crystallize PDDA. PDDA was removed by filtration and dried at 50 ° C. for 1 day to obtain 43.7 g of PDDA. The obtained PDDA had a weight average molecular weight of 2800 (see FIG. 1).
[0023]
Example 3
Add 417 g of toluene to 57.58 g (0.25 mol) of DDA, then add 50.60 g (0.50 mol) of triethylamine (TEA) and stir at 25 ° C. for 1 hour to synthesize DDA-2TEA with a salt formation rate of 100%. did. Subsequently, a solution of 24.73 g (0.25 mol) of phosgene in toluene (62.5 g) was added dropwise thereto at 50 ° C. over 1 hour. Thereafter, aging was performed at 110 ° C. for 30 minutes. Subsequently, the reaction mixture was filtered hot at 90 ° C. to remove the generated triethylamine hydrochloride. The filtrate was cooled to 2-3 ° C. to crystallize PDDA. PDDA was removed by filtration and dried at 50 ° C. for 1 day to obtain 44.1 g of PDDA. The weight average molecular weight of the obtained PDDA was 12500.
[0024]
Example 4
417 g of toluene was added to 57.58 g (0.25 mol) of DDA, then 40.48 g (0.40 mol) of triethylamine was added, and the mixture was stirred at 25 ° C. for 1 hour to synthesize DDA-2TEA having a salt formation rate of 80%. Subsequently, a solution of 19.78 g (0.20 mol) of phosgene in toluene (62.5 g) was added dropwise at 50 ° C. over 1 hour. Thereafter, aging was performed at 110 ° C. for 30 minutes. Subsequently, the reaction mixture was filtered hot at 90 ° C. to remove the generated triethylamine hydrochloride. The filtrate was cooled to 2-3 ° C. to crystallize PDDA. PDDA was removed by filtration and dried at 50 ° C. for 1 day to obtain 50.40 g of PDDA. The obtained PDDA had a weight average molecular weight of 2,700.
[0025]
Example 5
1251 g of toluene was added to 103.64 g (0.45 mol) of DDA and 102.15 g (0.30 mol) of eicosannic acid, followed by addition of 168.999 g (1.50 mol) of 49.8% KOH aqueous solution and 459 g of water at 85 ° C. The mixture was aged for 2 hours to synthesize a mixture of DDA-2K having a salt formation rate of 100% and eicosane diacid-2K having a salt formation rate of 100%. Thereafter, water in the system was removed by azeotropic dehydration. Subsequently, a solution of 74.19 g (0.75 mol) of phosgene in toluene (187.5 g) was added dropwise at 50 ° C. over 1 hour. Thereafter, aging was performed at 110 ° C. for 30 minutes. Subsequently, KCl produced by removing the reaction mixture by hot filtration at 90 ° C. was removed. The filtrate was kept at 45 ° C., and 258 g of n-hexane was added dropwise thereto, and this was cooled to 2-3 ° C. to crystallize the DDA-eicosane diacid copolymer. The DDA-eicosane diacid copolymer was taken out by filtration and dried at 50 ° C. for 1 day to obtain 127.2 g of a DDA-eicosane diacid copolymer. The weight average molecular weight of the obtained DDA-eicosane diacid copolymer was 9,500.
[0026]
【The invention's effect】
INDUSTRIAL APPLICABILITY According to the present invention, an industrially superior method for producing a polyacid anhydride and a polyanhydride copolymer capable of freely controlling the molecular weight under relatively mild conditions can be provided.
[Brief description of the drawings]
FIG. 1 shows the relationship between the salt formation rate of DDA-2K and the weight average molecular weight of PDDA.
Claims (3)
で表されるジカルボン酸と、該化合物のカルボキシル基に対して当量以下の無機塩基及び／または有機塩基を反応させることにより得られるジカルボン酸の造塩化合物に、塩素化剤を反応させることを特徴とするポリ酸無水物及びポリ酸無水物共重合体の製造方法。General formula (1)
A chlorinating agent is reacted with a salt-forming compound of dicarboxylic acid obtained by reacting the dicarboxylic acid represented by the following formula with an inorganic base and / or an organic base having an equivalent amount or less with respect to the carboxyl group of the compound. And a method for producing a polyacid anhydride and a polyacid anhydride copolymer.
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