JP6227147B2 - カルボキシル基を含有するポリマー、その製造方法及び用途、担持型金属触媒及びペネム系抗生物質中間体の製造方法 - Google Patents
カルボキシル基を含有するポリマー、その製造方法及び用途、担持型金属触媒及びペネム系抗生物質中間体の製造方法 Download PDFInfo
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 104
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 90
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 72
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
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- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
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- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 3
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- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 3
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 claims description 3
- 238000010558 suspension polymerization method Methods 0.000 claims description 3
- 239000002609 medium Substances 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 93
- 239000000243 solution Substances 0.000 description 59
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 36
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- 239000000706 filtrate Substances 0.000 description 26
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
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Classifications
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Description
モノマーBは、式(II−1)乃至(II−8)の中の一つに示す構造を有し、
さらに、担持型金属触媒は、担持型ロジウム、パラジウム、白金、ルテニウム又はイリジウム触媒である。
本発明のカルボキシル基を含有するポリマー、その製造方法と用途、担持型触媒及びペネム系抗生物質中間体の製造方法を応用する。本発明に提供されるカルボキシル基を含有するポリマーは架橋型ポリマーで、ポリマーの鎖に大量のベンゼン環を有し、ポリマーの剛性及び硬さを向上させて、ポリマーの機械性能を有効に改善することができる。同時に、該ポリマーはカルボキシル基を主官能基とし、それを担体として、カルボキシル基と重金属とが配合反応し、製造された担持型金属触媒中の金属とポリマーとの間には一層良好な接続安定性を有する。上述した二つの方面の要素により、担持型金属触媒の安定性を改善し、触媒を繰り返して使用しても触媒の活性を失うことがない。さらに、重金属活性成分の流失を減少し、コストを低減できる。
モノマーBは式(II−1)乃至(II−8)の中の一つに示す構造を有し、
担持型金属触媒が、担持型ロジウム、パラジウム、白金、ルテニウム又はイリジウム触媒であることが好ましい。
実施例1乃至11において異なるカルボキシル基を含有するポリマーを製造した。
実施例1
モノマーの合成
化合物4:1H NMR(CDC13, 400MHz): δ 1.25−1.35(m, 12H), 1.59−1.69(m, 4H), 2.35(t, J=7.5Hz, 4H), 5.10(s, 4H), 5.26(d, J=10.9Hz, 2H), 5.76(d, J=17.6Hz, 2H), 6.72(dd, J=17.6, 10.9Hz, 2H), 7.31(d, J=8.1Hz, 4H), 7.40(d, J=8.1Hz, 4H)。
ポリマー6、FT−IR(KBr, cm−1):3416, 3083, 3060, 2920, 2851, 1636, 1601, 1130, 757, 696。1800cm−1付近に吸収ピークがなく、二重結合が完全に重合したことを説明する。
モノマーの合成
室温で、ドデカン二酸(2,20.6g, 89.5mmol)をテトラヒドロフラン(350mL)に溶解させて、複数回に分けてジカルボニルイミダゾール(29.0g, 179mmol)を添加し、継続して1時間攪拌してから、化合物8(12.5g, 1H NMR含有量:84.9mmol)を添加した。室温で4時間反応させ、濃縮して、粗製品を酢酸エチル(200mL)で溶解させた後、3Nの塩酸(50mL×2)と飽和食塩水(100mL)で洗浄し、無水硫酸ナトリウムで乾燥させる。ろ過して乾燥剤を除去し、濃縮し、粗製品をシリカゲルカラムクロマトグラフィーで純化して白色固体の化合物9(14.7g, 48% 収率)と化合物10(9.84g, 45%収率)を得た。
モノマーの合成
室温で、順に反応瓶に8−ブロモ−1−オクタノール(12, 11.0g, 52.6mmol)、ジヒドロピラン(22.1g, 263mmol)、パラトルエンスルホン酸ピリジニウム(528.7mg, 2.1mmol)のジクロロメタン(110mL)を添加し、室温で完全に反応するまで攪拌する。反応液を留分無しまで濃縮し、粗製品をシリカゲルカラムクロマトグラフィーで純化して黄色いオイル状化合物13(14.1g, 89%収率)を得た。
氷水浴で、4−ビニルベンジルアルコール(1, 4.0g, 29.8mmol)のDMF(2mL)溶液をNaH(60%含有量, 1.30g, 32.4mmol)のDMF(36mL)懸濁液に添加し、その後、氷水浴で15分攪拌する。化合物13(7.92g, 27.0mmol)をDMF(2mL)に溶解させて、反応液を添加し、その後、温度を室温まで上昇させて、継続して4時間攪拌し、その後、氷水浴で冷却し、飽和塩化アンモニウムで反応をクエンチする。EtOAc(3×40mL)で抽出し、有機相を合併し、飽和食塩水(40mL)で洗浄し、無水硫酸ナトリウムで乾燥させる。ろ過して乾燥剤を除去し、ろ過液を濃縮し、粗製品をシリカゲルカラムクロマトグラフィーで純化して大極性物質を除去して、無色のオイル状化合物14(8.0g, 85% 粗収率)を得た。
室温で、1.0gのポリマー18を量りとって、40mLのジクロロメタンに懸濁させ、30〜40分静置した後、攪拌しながら2.0gのベンジルアミン、220mgの4−ジメチルアミノピリジン、1.87gのトリエチルアミンを添加し、最後に、複数回に分けて3.56gのEDCIを添加し、攪拌して一夜放置した。体系をろ過し、順に、ジクロロメタン、テトラヒドロフラン、メチルアルコール、水、メチルアルコールで洗浄した。得られたポリマーを同一の条件で2回反応させ、最後に得たポリマーを40〜50℃で減圧乾燥して一夜放置した。
モノマーの合成
室温で、反応瓶に水素化ナトリウム(60%含有量、 7.15g, 178.7mmol)とDMF(80mL)を添加し、0℃まで冷却し、p−ビニルベンジルアルコール(1, 20g, 149.0mmol)のDMF(20mL)溶液を滴下し、滴下終了後、継続して30分攪拌し、その後、1,6−ジブロモヘキサン(36.3g, 149.0mmol)のDMF(20mL)溶液を滴下する。滴下終了後、反応温度を室温まで上昇させて継続して5時間攪拌する。飽和塩化アンモニウムを添加して反応をクエンチし、メチル基tert−ブチル基エーテルで抽出した。有機相を合併し、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥させる。ろ過して乾燥剤を除去し、減圧して留分無しまで濃縮し、粗製品をシリカゲルカラムクロマトグラフィーで純化して、化合物19(15.9g, 36%収率)と化合物20(3.91g, 15%収率)を得た。
室温で、反応瓶に化合物19(12g, 40.0mmol)とジメチルスルホキシド(36mL)を添加した後、炭酸カリウム(11.1g)の水(12mL)溶液を添加し、80℃まで加熱して20時間攪拌する。室温まで冷却し、水を添加して希釈し、その後、酢酸エチルで抽出した。有機相を合併し、飽和塩化アンモニウムで洗浄し、無水硫酸ナトリウムで乾燥した。ろ過して乾燥剤を除去し、減圧して留分無しまで濃縮し、粗製品をシリカゲルカラムクロマトグラフィーで純化して化合物21(7.1g, 75%収率)を得た。
室温で、1.0gのポリマー23を量りとって、40mLのジクロロメタンに懸濁させ、30〜40分静置し、その後、攪拌しながら2.0gのベンジルアミン、220mgの4−ジメチルアミノピリジン、1.87gのトリエチルアミンを添加し、最後に、複数回に分けて3.56gのEDCIを添加し、攪拌して一夜放置した。体系をろ過し、順にジクロロメタン、テトラヒドロフラン、メチルアルコール、水、メチルアルコールで洗浄した。得られたポリマーをさらに同一の条件で2回反応させ、最後に得られたポリマーを40〜50℃で減圧乾燥して一夜放置した。
モノマーの合成
室温で、反応瓶にマグネシウムくず(7.07g, 295mmol)及びジエチルエーテル(12mL)を添加し、その後、p−ビニルベンジルクロリド(7, 15g, 98.3mmol)を100mLのジエチルエーテルに溶解させ、まず約6%の溶液を添加して少し加熱して反応を開始させた後、反応体系を微沸騰を保持した状況下、その他の溶液を徐々に反応体系に滴下する。滴下終了後、38〜40℃で0.5時間攪拌し、その後室温まで冷却し、静置した。
室温で、反応瓶にマグネシウムくず(7.07g, 295mmol)及びジエチルエーテル(12mL)を添加し、その後、p−ビニルベンジルクロリド(7, 15g, 98.3mmol)を100mLのジエチルエーテルに溶解させ、まず約6%の溶液を添加して少し加熱して反応を開始させた後、反応体系を微沸騰を保持した状況下、徐々に反応体系に滴下する。滴下終了後、38〜40℃で0.5時間攪拌し、その後、室温まで冷却し、静置した。
元素分析を経て測定した値は、C:90.07%、H:8.259%で、得られたOの含有量は1.671%であるので、カルボキシル基の実際の含有量は約0.522mmol/gである。
室温で、反応瓶に化合物8(9.27g, 63mmol、前の工程による理論上の製造量で計算)の粗製品と、炭酸ナトリウム(14.6g, 138mmol)と、1,6−ジブロモヘキサン(5.12g, 21mmol)と、N,N−ジメチルアセトアミド(50mL)とを添加し、反応液を75℃まで加熱して16時間反応させる。水を添加して希釈し、酢酸エチルで抽出した。有機相を合併し、飽和食塩水で洗浄し、その後、無水硫酸ナトリウムで乾燥した。ろ過して乾燥剤を除去し、減圧して留分無しまで濃縮し、粗製品をシリカゲルカラムクロマトグラフィーで純化して、化合物31(3.88g, 49% 収率)を得た。
元素分析によって測定された値は、C:90.10%、H:7.930%、N:0.82%で、計算されたO含有量は1.150%であるので、カルボキシル基の実際の含有量は約0.359mmol/gである。
室温で、反応瓶に3,5−ジヒドロキシ安息香酸(50g, 324.4mmol)及びメチルアルコール(500mL)を添加し、その後、濃い硫酸(5g)を添加する。混合液を逆流するまで加熱し、10時間反応させる。反応液を室温まで冷却し、減圧して留分無しまで濃縮した。酢酸エチルを添加して溶解させ、その後、順に飽和炭酸水素ナトリウム溶液と飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥した。ろ過して乾燥剤を除去し、減圧して留分無しまで濃縮した。粗製品にジクロロメタン(750mL)及びp−トルエンスルホン酸一水和物(3.08g, 16mmol)を添加し、0℃まで冷却し、ジヒドロピラン(81.8g, 974mmol)を滴下し、滴下終了後、自然に室温まで回復させて反応させる。完全に反応した後、体系を10体積の飽和NaHCO3でクエンチし、有機相を分離し、5体積の飽和食塩水で洗浄し、その後、無水硫酸ナトリウムで乾燥した。ろ過して乾燥剤を除去し、減圧して留分無しまで濃縮して、化合物34の粗製品(98.2g, 〜90%収率)を得て、直接に次の工程の反応に利用した。
室温で、反応瓶に化合物37(6.0g, 23.4mmol)と、6−ブロモヘキサン酸メチル(10.76g, 51.5mmol)と、炭酸カリウム(7.12g, 51.5mmol)と、ヨウ化カリウム(777mg, 4.7mmol)と、アセトニトリル(120mL)とを添加し、反応液を逆流するまで加熱し、20時間反応させた。減圧ろ過して固体を除去し、ろ過液を減圧して留分無しまで濃縮し、粗製品をシリカゲルカラムクロマトグラフィーで純化して、化合物38(9.72g, 81%収率)を得た。
室温で、1.0gのポリマー40を量りとって、40mLのジクロロメタンに懸濁させ、30〜40分静置し、その後、攪拌しながら2.0gのベンジルアミンと、220mgの4−ジメチルアミノピリジンと、1.87gのトリエチルアミンとを添加し、最後に、複数回に分けて3.56gのEDCIを添加し、攪拌して一夜放置した。体系をろ過し、順にジクロロメタン、テトラヒドロフラン、メチルアルコール、水、メチルアルコールで洗浄した。得られたポリマーをさらに同一の条件で2回反応させ、最後に得られたポリマーを40〜50℃で減圧乾燥して一夜放置した。
モノマーの合成
室温で、反応瓶にp−水酸基スチレン(44, 5.0g, 41mmol)と、6−ブロモヘキサン酸メチル(10.76g, 51.5mmol)と、炭酸カリウム(7.12g, 51.5mmol)と、ヨウ化カリウム(690mg, 0.41mmol)と、アセトニトリル(75mL)とを添加し、反応液を逆流するまで加熱し20時間反応させた。減圧ろ過して固体を除去し、ろ過液を減圧して留分無しまで濃縮し、粗製品をシリカゲルカラムクロマトグラフィーで純化して、化合物45(8.96g, 88%収率)を得た。
化合物49は、文献(化学試薬、2006,28:1〜2)を参照して合成した。
共重合反応
室温で、1.0gのポリマー50を量りとって、40mLのジクロロメタンに懸濁させ、30〜40分静置し、その後、攪拌しながら2.0gのベンジルアミンと、220mgの4−ジメチルアミノピリジンと、1.87gのトリエチルアミンとを添加し、最後に、複数回に分けて3.56gのEDCIを添加し、攪拌して一夜放置した。体系をろ過し、順にジクロロメタン、テトラヒドロフラン、メチルアルコール、水、メチルアルコールで洗浄した。得られたポリマーをさらに同一の条件で2回反応させ、最後に得られたポリマーを40〜50℃で減圧乾燥して一夜放置した。
モノマーの合成
室温で、反応瓶に無水塩化アルミニウム(400g, 3mol)と、ジクロロメタン(1.5L)とを添加し、温度を0℃まで下げて、塩化アセチル(234.7g, 3mol)のジクロロメタン(500mL)溶液を滴下し、その後、βーブロモエチルベンゼン(500g, 2.72mmol)のジクロロメタン(500mL)溶液を滴下する。反応体系を0℃で継続して3時間攪拌し、氷水に入れてクエンチし、液体を分層し、有機相をジクロロメタンで抽出した。有機相を合併し、飽和食塩水で洗浄し、減圧して濃縮して、化合物51の粗製品(567g, 92%収率)を得て、直接に次の工程の反応に利用した。液相のパラ異性体及びオルト異性体の比例は8.2:1である。
室温で、反応瓶に化合物53(80g, 379mmol)と酢酸(240mL)を添加した後、無水酢酸ナトリウム(74.4g, 758mmol)を添加し、加熱して24時間逆流させた。室温まで下げて、体系を徐々に氷水浴で冷却した飽和炭酸水素ナトリウム溶液に滴下し、その後、酢酸エチルで抽出した。有機相を合併し、飽和食塩水で洗浄し、その後、留分無しまで濃縮して、化合物54の粗製品(72.4g)を得て、直接に次の工程の反応に利用した。
室温で、化合物55(20g, 135mmol)、アジピン酸(18.1g, 135mmol)、4−ジメチルアミノピリジン(1.65g, 13.5mmol)のテトラヒドロフラン(300mL)溶液に複数回に分けてジシクロヘキシルカルボジイミド(30.4g, 148mmol)を添加した。室温で継続して4時間攪拌し、ろ過して不溶物を除去した。ろ過液を濃縮し、残物を酢酸エチル(300mL)で溶解し、1N塩酸(100mL×2)で洗浄し、無水硫酸ナトリウムで乾燥した後、留分無しまで濃縮した。残物をシリカゲルカラムクロマトグラフィーで純化して、化合物56(14.9g, 40%収率)と化合物57(11.2g,41%収率)を得た。
共重合反応
ロジウム交換反応
ロジウム交換反応
ロジウム交換反応
ロジウム交換反応
カルベン挿入反応
カルベン挿入反応
カルベン挿入反応
回分反応によるロジウム触媒の回収と循環使用
担持ロジウム触媒の触媒作用による連続性流動相反応
担持ロジウム触媒の触媒作用による連続性流動相反応
共重合反応:共重合反応の操作方法及び工程条件は実施例1と同じであって、ただ、各モノマーの使用量が異なっていて、具体的なモノマー使用量は、スチレン(5, 24.7g, 237.4mmol)、モノマー(3, 62g, 178.8mmol)、モノマー(4, 82.7g, 178.8mmol)である。
共重合反応:共重合反応の操作方法及び工程条件は実施例1と同様であって、ただ、各モノマーの使用量が異なっていて、具体的なモノマーの使用量は、スチレン(5, 29.6g, 284.9mmol)、モノマー(3, 51.7g, 149mmol)、モノマー(4, 68.9g, 149mmol)である。
共重合反応:共重合反応の操作方法及び工程条件は実施例1と同様であって、ただ、各モノマーの使用量が異なっていて、具体的なモノマーの使用量は、スチレン(5, 61g, 587.6mmol)、モノマー(3, 1g, 3mmol)、モノマー(4, 1.4g, 3mmol)である。
共重合反応:共重合反応の操作方法及び工程条件は実施例1と同様であって、ただ、各モノマーの使用量が異なっていて、具体的なモノマーの使用量は、スチレン(5, 49.4g, 474.8mmol)、モノマー(3, 21g, 59.6mmol)、モノマー(4, 27.6g, 59.6mmol)である。
共重合反応:共重合反応の操作方法及び工程条件は実施例1と同様であって、ただ、各モノマーの使用量が異なっていて、具体的なモノマーの使用量は、スチレン(5, 55.6g, 534.2mmol)、モノマー(3, 16.5g, 47.7mmol)、モノマー(4, 5.5g, 12mmol)である。
共重合反応:共重合反応の操作方法及び工程条件は実施例1と同様であって、ただ、各モノマーの使用量が異なっていて、具体的なモノマーの使用量は、スチレン(5, 55.6g, 534.2mmol)、モノマー(3, 10.3g, 30mmol)、モノマー(4, 14g, 30mmol)である。
カルベン挿入反応のHPLC外部標準法による収率の測定方法は以下のようである:同一のクロマトグラフィー条件で、オクタン酸ロジウムを触媒とした反応処理を経て得られた有機相を標準品とし、各カルベン挿入反応処理を経て得られた有機相を測定対象品とし、標準品と測定対象品の面積比が両方の濃度比に等しいに従って、各カルベン挿入反応の外部標準法による収率を計算した。ロジウムの流失量の測定方法は以下のようである:伝統的なICP(誘導結合プラズマ発光分光分析装置)方法によって、ロジウムの含有量を測定して、ロジウムの流失量を計算した。測定結果は表3に示す。
Claims (19)
- 前記ポリマーは、モルパーセントで、
(1)80%〜99%の前記モノマーAと、
(2)0.5%〜10%の前記モノマーBと、
(3)0.5%〜10%の前記モノマーCとが重合してなることを特徴とする請求項1に記載のポリマー。 - 前記ポリマーは、モルパーセントで、
(1)90%〜99%の前記モノマーAと、
(2)0.5%〜8%の前記モノマーBと、
(3)0.5%〜5%の前記モノマーCとが重合してなることを特徴とする請求項2に記載のポリマー。 - 前記ポリマーは、モノマーAと、モノマーBと、モノマーCとから懸濁重合方法によって製造される請求項1乃至3の中のいずれかに記載のカルボキシル基を含有するポリマーの製造方法。
- 前記ポリマーは、前記モノマーAと、前記モノマーBと、前記モノマーCとから、水媒体で開始剤、安定剤、ポロゲンの存在下で、前記懸濁重合方法によって製造されることを特徴とする請求項4に記載の製造方法。
- 前記開始剤は、アゾビスイソブチロニトリル又は過酸化ベンゾイルであって、前記開始剤のモル量はモノマー総モル量の0.05〜10%であることを特徴とする請求項5に記載の製造方法。
- 前記安定剤は、水溶性ポリマーと無機塩からなる混合物であって、
前記水溶性ポリマーはポリビニルアルコール又はアラビアガムであって、前記無機塩は塩化ナトリウムであって、前記水溶性ポリマーの前記水媒体中の質量濃度は0.1〜10%で、前記無機塩の前記水媒体中の質量濃度は0.2〜20%であることを特徴とする請求項5に記載の製造方法。 - 前記ポロゲンは、メチルベンゼン、ジメチルベンゼン、クロロベンゼン、テトラヒドロフランの中の1種又は複数種で、前記ポロゲンの質量とモノマー総質量の比は0.1〜3:1であることを特徴とする請求項5に記載の製造方法。
- 請求項1乃至3の中のいずれかに記載のカルボキシル基を含有するポリマーを担持型金属触媒の担体とする用途。
- 前記担持型金属触媒は、担持型ロジウム、パラジウム、白金、ルテニウム又はイリジウム触媒であることを特徴とする請求項9に記載の用途。
- 請求項1乃至3の中のいずれかに記載のポリマーを担体とすることを特徴とする担持型金属触媒。
- 前記担持型金属触媒は、担持型ロジウム、パラジウム、白金、ルテニウム又はイリジウム触媒であることを特徴とする請求項11に記載の触媒。
- 前記反応は有機溶剤の中で行われ、前記有機溶剤はテトラヒドロフラン、メチルベンゼン、ジメチルベンゼン、クロロベンゼン又はジエチレングリコールジメチルエーテルから選ばれることを特徴とする請求項14に記載の製造方法。
- 前記反応は有機溶剤の中で行われ、前記有機溶剤は酢酸エチル、酢酸メチル、酢酸イソプロピル、1,4−ジオキサン、テトラヒドロフラン、メチル基tert−ブチル基エーテル、ジエチルエーテル、ジクロロメタン又は1,2−ジクロロエタンから選ばれることを特徴とする請求項16に記載の方法。
- 前記担持型ロジウム触媒と前記式(V)に示す化合物とのモル比は1:50〜2000であることを特徴とする請求項16又は17に記載の方法。
- 前記反応の温度は20〜50℃であることを特徴とする請求項18に記載の方法。
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