JP7402935B2 - ブリバラセタムの合成のための重要な中間体である(r)-4-プロピルピロリジン-2-オンの調製のための改良されたプロセス - Google Patents
ブリバラセタムの合成のための重要な中間体である(r)-4-プロピルピロリジン-2-オンの調製のための改良されたプロセス Download PDFInfo
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- JP7402935B2 JP7402935B2 JP2022114937A JP2022114937A JP7402935B2 JP 7402935 B2 JP7402935 B2 JP 7402935B2 JP 2022114937 A JP2022114937 A JP 2022114937A JP 2022114937 A JP2022114937 A JP 2022114937A JP 7402935 B2 JP7402935 B2 JP 7402935B2
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- oxoethyl
- propyl
- brivaracetam
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- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 1
- LOPBUDFWZJEGTJ-YHMJZVADSA-N methyl 2-[(4r)-2-oxo-4-propylpyrrolidin-1-yl]butanoate Chemical compound CCC[C@H]1CN(C(CC)C(=O)OC)C(=O)C1 LOPBUDFWZJEGTJ-YHMJZVADSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000003533 narcotic effect Effects 0.000 description 1
- LFNLGNPSGWYGGD-UHFFFAOYSA-N neptunium atom Chemical compound [Np] LFNLGNPSGWYGGD-UHFFFAOYSA-N 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- XULSCZPZVQIMFM-IPZQJPLYSA-N odevixibat Chemical compound C12=CC(SC)=C(OCC(=O)N[C@@H](C(=O)N[C@@H](CC)C(O)=O)C=3C=CC(O)=CC=3)C=C2S(=O)(=O)NC(CCCC)(CCCC)CN1C1=CC=CC=C1 XULSCZPZVQIMFM-IPZQJPLYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- GSWAOPJLTADLTN-UHFFFAOYSA-N oxidanimine Chemical compound [O-][NH3+] GSWAOPJLTADLTN-UHFFFAOYSA-N 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000000506 psychotropic effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 235000008164 pyridoxal Nutrition 0.000 description 1
- 239000011674 pyridoxal Substances 0.000 description 1
- 229960003581 pyridoxal Drugs 0.000 description 1
- ZMJGSOSNSPKHNH-UHFFFAOYSA-N pyridoxamine 5'-phosphate Chemical compound CC1=NC=C(COP(O)(O)=O)C(CN)=C1O ZMJGSOSNSPKHNH-UHFFFAOYSA-N 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- KMIOJWCYOHBUJS-HAKPAVFJSA-N vorolanib Chemical compound C1N(C(=O)N(C)C)CC[C@@H]1NC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C KMIOJWCYOHBUJS-HAKPAVFJSA-N 0.000 description 1
Classifications
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- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
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- C12N9/14—Hydrolases (3)
- C12N9/16—Hydrolases (3) acting on ester bonds (3.1)
- C12N9/18—Carboxylic ester hydrolases (3.1.1)
- C12N9/20—Triglyceride splitting, e.g. by means of lipase
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- C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
- C12P41/003—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions
- C12P41/005—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions by esterification of carboxylic acid groups in the enantiomers or the inverse reaction
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Description
(a)式(II)の3-プロピルペンタン二酸をエステル化して式(III)のジメチル3-プロピルペンタンジオエートを生成すること、
(b)NovozymeのPromea(登録商標)を使用して、式(III)の不斉非対称化技術及び立体選択的加水分解を用いて、式(IV)の(S)-3-(2-メトキシ-2-オキソエチル)ヘキサン酸を得ること、
(c)化合物(IV)をカルボン酸の活性化に供し、続いて1つのポットでアミド化して、式(V)のメチル(S)-3-(2-アミノ-2-オキソエチル)ヘキサノエートを得ること、及び
(d)化合物(V)を酸と反応させて、式(VI)の(S)-3-(2-アミノ-2-オキソエチル)ヘキサン酸を生成すること、
(e)化合物(VI)のホフマン転位とそれに続く環化によって(R)-4-プロピル-ピロリジン-2-オン(I)を得ること、及び
(f)式(I)の生成物をブリバラセタムに変換すること。
化学的純度は、以下の条件下でHPLCを使用して決定した:カラム:Inertsil ODS3V、250×4.6mm、5μm;移動相:アセトニトリル:緩衝液(0.1%オルトリン酸)(90:10v/v);流量:1.0mL/min;カラム温度:30℃;検出:210nm。
カラム:Chiral Pak IC、250×4.6mm、5μm。
化合物(IV)の方法A:
移動相:n-ヘキサン:エタノール:トリフルオロ酢酸(98:2:0.1mL);流速:0.5mL/min;カラム温度:25℃;検出:212nm。
化合物(V)及び(VI)の方法B:
移動相:n-ヘキサン:エタノール:トリフルオロ酢酸(80:20:0.1mL);流速:1.0mL/min;カラム温度:25℃、検出:220nm。
化合物(I)の方法C:
移動相:n-ヘキサン:エタノール:トリフルオロ酢酸(70:30:0.1mL);流速:1.0mL/min;カラム温度:27℃、検出:210nm。
硫酸(14.2g、0.14mol)を、15℃~20℃で300mLのメタノール中の3-プロピルペンタン二酸(100g、0.57mol)の溶液に添加した。反応混合物を温め、室温で約20時間撹拌して、反応を完了させた。溶媒を減圧下で蒸発させ、得られた残留物を50mLの水で希釈し、そしてジクロロメタン(100mL×3)で抽出した。ジクロロメタン溶液を10%重炭酸ナトリウム溶液、続いて水(100mL)で洗浄した。有機相を硫酸ナトリウムで乾燥させ、減圧下で蒸発させて、粗生成物を得、これを高真空蒸留によって精製した。純粋な生成物を蒸気温度80℃~90℃、0.5mmHgで収集して、94.8gの無色のジメチル3-プロピルペンタンジオエート(III)を得た(GCによる82%の収率と99.05%の純度)。
リン酸カリウム緩衝液(50mL、0.2M、pH7.2)の溶液に、10g(0.05mol)のジメチル3-プロピルペンタンジオエート(III)を加え、25(±5)℃で撹拌した。反応混合物に0.25g(2.5%w/w)のPromea[NovozymeのPromea(登録商標)はリパーゼ液体酵素(EC3.1.1.3;CAS No.9001-62-1)である。5000LU/g]を加え、10%水酸化アンモニウム溶液を使用して、pH statの助けを借りて、pHを7.2に24時間維持した。反応の完了はTLCによってモニターした。濃HClを使用して反応混合物をpH2.0に調整し、ジクロロメタン(50mL×2)で抽出した。有機層を水で洗浄し、硫酸ナトリウムで乾燥させた。有機層を減圧下で濃縮して、9.1gの(S)-3-(2-メトキシ-2-オキソエチル)ヘキサン酸(IV)を得た。HPLCによると97.8%の収率、85.22%のeeであり、GCによると99.56%の純度であった。
上記の例-2を、2.5%w/wではなく20%w/wの酵素負荷で繰り返した。反応は約4時間で完了した。GCによると96.7%の収率、85.8%のee、99.38%の純度であった。
上記の例-2を、2.5%w/wではなく10%w/wの酵素負荷で繰り返した。反応は約6時間で完了した。GCによると98.9%の収率、84.35%のee、99.68%の純度であった。
上記の例-2を、2.5%w/wではなく5%w/wの酵素負荷で繰り返した。反応は約18時間で完了した。GCによると96.7%の収率、83.82%のee、99.47%の純度であった。
上記の例-2を、2.5%w/wではなく1%w/wの酵素負荷で繰り返した。反応は約68時間で完了した。GCによると92.5%の収率、82.97%のee、99.41%の純度であった。
500mLのジクロロメタン中の50g(0.266mol)の(S)-3-(2-メトキシ-2-オキソエチル)ヘキサン酸(IV)及びN-メチルモルホリン(40.3g、0.398mol)の冷却溶液にクロロギ酸メチル(27.6g、0.292mol)を-15℃で滴下した。60分間撹拌した後、アンモニア水(220mL)を20分間滴下し、混合物をさらに60分間撹拌して反応を完了させた。反応混合物を室温まで冷却し、層を分離させた。水層をジクロロメタンで再抽出した。両方の有機層を合わせ、無水硫酸ナトリウムで乾燥させ、濃縮して、粗生成物を得た。これをヘキサン(100mL)中で25~30℃で10分間スラリー化し、デカントし、高真空を適用して、44.3gのメチル(S)-3-(2-アミノ-2-オキソエチル)ヘキサノエート(V)を半固体として得た。HPLCによると89%の収率、84.44%のee、GCによると97.66%の純度であった。
上記の例-7を、N-メチルモルホリンの代わりにトリエチルアミンを使用して繰り返した。93.5%の収率と83.25%のeeであった。
10gのメチル(S)-3-(2-アミノ-2-オキソエチル)ヘキサノエート(V)と100mLの1.8MのHCl水溶液(15mLの濃HClと85mLの水)の混合物を25(±5)℃で20時間撹拌した。反応混合物を5℃に冷却し、苛性ソーダライ溶液を使用してpHを1.0に調整し、30分間撹拌した。得られた固体を濾過し、乾燥させた。これを酢酸エチル(20mL)中で25(±5)℃で60分間スラリー化し、濾過して4.5gの(VI)固体を得た。HPLCによると48.6%の収率、99.95%のee、HPLCによると99.28%の純度であった。
上記の両方の濾液を混合し、50℃で減圧下で濃縮した。得られた粗生成物を水(30mL)及び濃HCl(30mL)混合物に溶解し、100℃に加熱し、そして15時間撹拌した。反応混合物を25(±3)℃に冷却し、ジクロロメタン(25mL×2)で抽出した。 有機層を無水硫酸ナトリウムで乾燥し、濃縮して、4.2gの3-プロピルペンタン二酸(II)を得た。GCによると純度99.19%であった。
上記の例-9を、1.8MのHCl水溶液(100mL)の代わりに、3.6MのHCl水溶液(50mL)で繰り返した。HPLCによると35%の収率、99.55%のee、HPLCによると97.97%の純度であった。
0~5℃で、撹拌した水(80mL)中の水酸化ナトリウム(4.62g、0.116mol)の溶液に、(S)-3-(2-アミノ-2-オキソエチル)ヘキサン酸(VI)(4.0gm、0.023mol)を添加した。反応混合物に、トリクロロイソシアヌル酸2.15g(0.009mol)を0~5℃で30分間、少しずつ加え、室温まで上昇させ、12~15時間続けた。反応混合物を100℃及び120℃に加熱し、45~48時間撹拌した。次にそれを25℃に冷却し、30mLのジクロロメタン(DCM)を加えて10分間撹拌した。DCM層を分離し、水層をDCMで再抽出した。両方の有機層を混合し、無水硫酸ナトリウムで乾燥させ、濃縮して、減圧下で溶媒を完全に除去し、液体として2.18gm(74.14%収率)の(R)-4-プロピル-ピロリジン-2-オン(I)を得た。GCによると99.96%のee、99.39%の純度であった。
0~5℃で、50mLのテトラヒドロフラン中の水素化ナトリウム(60%油性分散液、7.54g、0.3144mol)の混合物に、30mLのテトラヒドロフラン中(R)-4-プロピル-ピロリジン-2-オン(I)(10.0g、0.0786mol)の溶液を加えた。混合物に、20mLのテトラヒドロフラン中の2-ブロモブタン酸(15.75g、0.094mol)の溶液を加えた。反応混合物を温め、室温で10~12時間撹拌した。混合物を砕いた氷に注ぎ、過剰の水素化ナトリウムを分解した。テトラヒドロフランを減圧下で蒸留し、水性残留物を塩酸を使用して0~5℃でpH2.0に調整した。残留物を酢酸イソプロピル(25mL×3)で抽出した。有機層を濃縮して、(2RS)-2-[(4R)-4-プロピル-2-オキソピロリジン-1-イル]酪酸を無色の固体として得た(15.8g、94.2%)。
Claims (1)
- [化1]の構造を有する(2S)-2-[(4R)-2-オキソ-4-プロピル-ピロリジン-1-イル]ブタンアミドの調製方法であって、
を含む方法。
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