JP2009532386A - キラルアミドおよびキラルアミンの調製 - Google Patents
キラルアミドおよびキラルアミンの調製 Download PDFInfo
- Publication number
- JP2009532386A JP2009532386A JP2009503314A JP2009503314A JP2009532386A JP 2009532386 A JP2009532386 A JP 2009532386A JP 2009503314 A JP2009503314 A JP 2009503314A JP 2009503314 A JP2009503314 A JP 2009503314A JP 2009532386 A JP2009532386 A JP 2009532386A
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- JP
- Japan
- Prior art keywords
- substituted
- unsubstituted
- formula
- enamide
- oxime
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- 150000001412 amines Chemical class 0.000 title claims abstract description 43
- 238000002360 preparation method Methods 0.000 title description 8
- 238000000034 method Methods 0.000 claims abstract description 169
- 150000001875 compounds Chemical class 0.000 claims abstract description 91
- 125000005610 enamide group Chemical group 0.000 claims abstract description 87
- 150000002923 oximes Chemical class 0.000 claims abstract description 59
- 239000003054 catalyst Substances 0.000 claims abstract description 52
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 31
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 18
- -1 alkyl anhydride Chemical class 0.000 claims description 64
- 125000003118 aryl group Chemical group 0.000 claims description 57
- 239000000203 mixture Substances 0.000 claims description 57
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- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 50
- 125000000217 alkyl group Chemical group 0.000 claims description 43
- 125000001072 heteroaryl group Chemical group 0.000 claims description 42
- 229910052739 hydrogen Inorganic materials 0.000 claims description 34
- 239000001257 hydrogen Substances 0.000 claims description 30
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 25
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 25
- 125000002252 acyl group Chemical group 0.000 claims description 23
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 23
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- C07C231/14—Preparation of carboxylic acid amides by formation of carboxamide groups together with reactions not involving the carboxamide groups
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- C07C209/44—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers
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- C07C209/62—Preparation of compounds containing amino groups bound to a carbon skeleton by cleaving carbon-to-nitrogen, sulfur-to-nitrogen, or phosphorus-to-nitrogen bonds, e.g. hydrolysis of amides, N-dealkylation of amines or quaternary ammonium compounds
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C249/04—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes
- C07C249/08—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes by reaction of hydroxylamines with carbonyl compounds
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
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Abstract
Description
本明細書で用いる「COD」は、1,5−シクロオクタジエンを意味する。
置換基が、慣用的な化学式によって左から右に記されて特定される場合、それらは、構造を右から左に記すことで生ずる化学的に同一な置換基を等しく包含する。例えば、−CH2O−は、好ましくは−OCH2−も列挙することが意図される。
本発明は、オキシムを対応するエナミドに変換するための非金属仲介方法を提供する。エナミドは、高収率および高純度で形成され、それらはエナンチオマーが豊富なアミドを与えるプロセスである均一な不斉水素化の好適な基質となる。アミドを脱保護することによって、エナンチオマーが豊富なアミンを供給することができる。アミンのいずれのエナンチオマーも、この方法によって得ることができる。したがって、ケトンおよびアルデヒドは、エナンチオマーが豊富なキラルアミンに変換することができる。このプロセスは大規模生産に受け入れられる。
A.オキシムからエナミド
第1の態様では、本発明は、オキシムをエナミドに変換するための方法を提供する。この方法は、オキシムをエナミドに変換するのに適切な条件下で、オキシムをホスフィンおよびアシル供与体と接触させる工程を含む。例示的な条件は、本明細書に示されている。
本質的に任意の構造のアシル供与体が本発明において用いられる。例示的アシル供与体は、式
Z−C(O)−R5
(式中、Zは脱離基である)を有する。R5は、H、置換または非置換のアルキル、置換または非置換のヘテロアルキル、置換または非置換のアリール、置換または非置換のヘテロアリール、および置換または非置換のヘテロシクロアルキルから選択されるメンバーである。
R6−C(O)−O−
(式中、R6は、置換または非置換のアルキル、置換または非置換のヘテロアルキル、置換または非置換のアリール、置換または非置換のヘテロアリール、および置換または非置換のヘテロシクロアルキルから選択されるメンバーである)を有する。
ホスフィンなどの任意の構造のリン試薬は、本発明を行うのに用いられる。例えば、一般に、ホスフィンは、式
P(Q)3
(式中、各Qは、H、置換または非置換のアルキル、および置換または非置換のアリールから独立して選択される)を有する。
例示的な実施形態では、オキシムは、有機溶媒の存在下でリン試薬(例えば、ホスフィン)およびアシル供与体と接触する。当該溶媒は、プロトン性溶媒であっても、非プロトン性溶媒であってもよい。好ましい実施形態では、当該溶媒は非プロトン性溶媒である。さらなる好ましい実施形態では、非プロトン性溶媒は芳香族溶媒(例えば、トルエン、キシレン、およびその組合せ)である。
別の態様では、本発明は、エナミドをアミドに変換するための方法を提供する。当該方法は、エナミドの炭素−炭素二重結合を水素化するのに適切な条件下で、エナミドを水素化触媒および水素または水素移動試薬と接触させ、それによってエナミドをアミドに変換する工程を含む。
エナミドの炭素−炭素二重結合は、二級アルコールなどの水素供与体、特にイソプロパノールが用いられる水素移動、および分子の水素が用いられる水素化などのプロセスによって還元される。水素移動および水素化プロセスの両方は、還元剤、すなわち、それぞれアルコールまたは分子水素を活性化するために触媒または触媒系を必要とする。
エナミドのC−C二重結合の対応するC−C単結合への変換が水素化によってもたらされる場合、反応容器中の水素の圧力を調整することによって、反応収率および立体選択性を最適化することができる。本発明の方法は任意の有用な水素圧で行われ、当業者は所望の結果を最適化するための水素圧の調整方法を理解するであろう。
本発明の方法は、任意の一溶媒または任意の分類、例えば、プロトン性、非プロトン性、芳香族、もしくは脂肪族の溶媒を用いて行うことに限定されない。特定の反応に対する適切な溶媒の選択は、十分に当業者の能力の範囲内である。
本発明の方法によって形成されるアミドは多様な構造を有し、アルキル、ヘテロアルキル、アリール、およびヘテロアリールのサブ構造を含むことができる。例示的な実施形態では、アミドは、式
好ましい実施形態では、本方法によって生成される、所望のエナンチオマーのエナンチオマー過剰(ee)または所望のジアステレオマーのジアステレオマー過剰(de)は、約60%のee/deから約99%のee/de、好ましくは約70%のee/deから約99%のee/de、より好ましくは約80%のee/deから約99%のee/de、さらにより好ましくは約90%のee/deから約99%のee/deである。
別の態様では、本発明は、対応するエナミドから形成されたアミドをアミンに変換する方法を提供する。例示的な実施形態では、当該方法は、アミドを脱アシル化するのに適切な条件下でアミドを脱アシル化試薬と接触させ、それによってアミンを形成する工程を含む。
別の態様では、本発明は、
R6−C(O)−O−
を有する(式中、R6は、置換または非置換のアルキル、置換または非置換のヘテロアルキル、置換または非置換のアリール、置換または非置換のヘテロアリール、および置換または非置換のヘテロシクロアルキルから選択されるメンバーである。)、前述の段落のいずれかによる方法。
P(Q)3
を有する(式中、各Qは、H、置換または非置換のアルキルおよび置換または非置換のアリールから独立して選択されるメンバーである。)、前述の段落のいずれかによる方法。
1.1 オキシム2の合成
メタノール(168mL)中の(S)−テトラロン1(56.0g、0.192mol)、ヒドロキシルアミン塩酸塩(14.7g、0.212mol)、および酢酸ナトリウム(17.4g、0.212mol)の混合物から形成された懸濁液を、N2雰囲気下で1から5時間加熱還流した。反応の進行は、HPLCによってモニターした。反応が完了した後、反応混合物を真空で濃縮した。残渣を、トルエン(400mL)および水200mLで希釈した。有機層を分離し、追加の水200mLで洗浄した。この有機層を濃縮し、乾燥させることによって、粗製の固体オキシム2(58.9g、100%)、融点117〜120℃を生じた。
1H NMR(400MHz,CDCl3)δ(ppm)9.17(br,1H,OH)、7.98(m,1H)、7.36(d,1H,J=8.0Hz)、7.29(m,2H)、7.20(d,1H,J=2.4Hz)、6.91(m,2H)、4.11(dd,1H,J=7.2Hz,4.4Hz)、2.82(m,2H)、2.21(m,1H)、2.08(m,1H)。13C NMR(100MHz,CDCl3)δ 154.94、144.41、140.40、132.83、130.92、130.82、130.68、130.64、129.98、129.38、128.12、127.64、124.48、44.52、29.51、21.27。
トルエン(500mL)中の粗オキシム2(59g、0.193mol)の溶液を、N2で30分間パージした。Et3P(25g、0.212mol)を入れた。10分間攪拌した後、無水酢酸(21.6g、20mL、0.212mol)を加えた。反応混合物を、8から13時間還流した。反応の進行は、HPLCによってモニターした。反応混合物を室温に冷却した。メタノール(1.0mL)中の6NのNaOH(水溶液)(86mL、0.516mol)および1.0Mの(n−Bu)4NOHを加えた。加水分解は、約2から4時間で完了した。有機層を分離し、EtOAc(300mL)および2−BuOH(30mL)で希釈した。希釈した有機溶液を1%のHOAc(水溶液)溶液(300mL)およびDI水(3×300mL)で洗浄し、真空で約350mLのスラリーに濃縮した。このスラリーをヘプタン(100mL)および2−BuOH(4mL)で希釈し、加熱還流することによって透明な溶液を形成した。濁った溶液が形成するまで、ヘプタン(50から200mL)を徐々に加えた。懸濁液を室温まで徐々に冷却した。生成物をろ別し、30%のトルエンおよび70%のヘプタン(3×100mL)の溶液で洗浄し、真空オーブン中で乾燥させることによって、56.9gの白色固体(エナミド3、89%の収率)、融点167〜168℃を生じた。
1H NMR(400MHz,CDCl3)δ(ppm)7.35(d,1H,J=8.4Hz)、7.26(m,3H)、7.17(m,1H)、7.05(dd,1H,J=8.0,1.6Hz)、7.00(br,1H)、6.87(m,0.82H,82% NH 回転異性体)、6.80(br,0.18H,18% NH 回転異性体)、6.31(t,0.82H,J=4.8Hz,82% H 回転異性体)、5.91(br,0.18H,18% H 回転異性体)、4.12(br,0.18H,18% H 回転異性体)、4.03(t,0.82H,J=8.0Hz,82% H 回転異性体)、2.72(m,1H)、2.61(ddd,1H,J=16.8,8.0,4.8Hz)、2.17(s,2.46H,82% CH3 回転異性体)、1.95(s,0.54H,18% CH3 回転異性体)。100MHz 13C NMR(CDCl3)δ 169.3、143.8、137.7、132.3、131.8、131.4、130.5、130.3、130.2、128.8、128.1、127.8、127.2、123.8、122.5、121.2、117.5、42.6、30.3、24.1。
エナミド3(24g、72mmol)を脱気したイソプロパノール(200mL)中でスラリーにした。得られたスラリーを適切な反応器に移した。触媒溶液を加える前に、反応器の内容物を窒素でパージした。イソプロパノール(IPA)中の(R,R)−MeBPE(COD)RhBF4触媒(20.1mg、0.036mmol、0.05mol%)の(100mL)の溶液を、反応器に加えた。内容物を0℃に冷却し、窒素で3回パージした。次いで、反応器を水素でパージし、ゲージ圧90psiに加圧した。反応物を、0℃で7.5時間、攪拌しながら熟成し、変換を水素の取り込みによってモニターした。次いで、内容物を室温に加温し、水素を抜いた。窒素でパージした後、内容物を排出した。反応混合物を50℃に加熱し、Celiteのパッドを通してろ過した。透明な橙色溶液を約50%の容積(150mL)まで濃縮し、トルエン(5.9g、5wt%)で希釈した。懸濁液を65℃に加熱し、水(14.7mL)を液滴で加えることによって、濁った溶液を形成した。スラリーを−10℃に徐々に冷却し、30分間熟成した。固体をろ過し、冷IPA(2×45mL)で洗浄した。ケーキを真空下、45℃で一晩乾燥させることによって、20.0g(83%の収率)のトランスアセトアミド4(99%超のde)を得た。
1H NMR(CDCl3)400MHz δ 7.34(dd,2H,J=7.9,2.4Hz)、7.23(t,1H,J=7.5Hz)、7.15(m,2H)、6.85(dd,1H,J=8.2,2.0Hz)、6.82(d,1H,J=7.7Hz)、5.72(d,1H,J=8.4Hz)、5.31(dd,1H,J=13.2,8.1Hz)、4.10(dd,1H,J=7.0,5.9Hz)、2.17(m,2H)、2.06(s,3H)、1.87(m,1H)。1.72(m,1H);13C NMR(CDCl3)100MHz δ 169.7、146.9、138.8、137.7、132.6、130.8、130.6、130.5、130.3、128.4、128.3、127.9、127.4、47.9、44.9、30.5、28.4、23.8。
トランス−アセトアミド4(9.0g、26.9mmol)、n−プロパノール(45mL)および5Mの塩酸(45mL)の溶液を、約48時間(90〜93℃)還流した。この時間の間、反応温度が92℃を超えるまで留出物を定期的に採取することによって、反応温度を90℃以上に維持した。追加のn−プロパノールを定期的に加えることによって、溶液を、その当初の容積に維持した。加水分解が完了した後、溶液を0℃に徐々に冷却するとスラリーとなり、これを0℃で1時間熟成した。反応混合物をろ過し、ケーキを1:1のメタノール/水(20mL)で洗浄し、その後、t−ブチルメチルエーテル(20mL)で洗浄した。湿ったケーキを、真空下、45から50℃で乾燥させることによって、7.0gの当該アミン塩酸塩5(80%の収率)を得た。
1H NMR(DMSO−d6)δ 1.81〜1.93(m,2H)、2.12〜2.21(m,1H)、2.28〜2.36(m,1H)、4.28(t,1H,J=6.8)、4.59(br.s,1H)、6.84(d,1H,J=7.6)、7.05(dd,1H,J=8.4,1.6)、7.25(t,1H,J=7.6)、7.32(t,1H,J=7.6)、7.37(d,1H,J=1.6)、7.56(d,1H,J=8.4)、7.76(d,1H,J=7.2)、8.80(br.s,3H);13C NMR(DMSO−d6)147.4、138.9、133.6、131.0、130.5、130.4、130.1、129.0、128.9、128.4、128.2、126.8、47.9、43.1、27.8、25.2。
オキシム2をin situでアシル化して中間体2Aを得て、これに還元的アシル化を施すことによって、アシル化されたエナミド3およびジアシル化された類似体3Aの混合物を提供する。反応は、トルエンまたはo−キシレン中で還流して行った。次いで、3および3Aの混合物を相間移動触媒とともに(例えば、テトラブチルアンモニウムヒドロゲンスルフェート/ヒドロキシド)また該相間移動触媒なしで、水酸化ナトリウムまたは炭酸ナトリウムなどの塩基の水溶液で処理することによって、中間体3Aを所望のエナミド3に変換した。オキシム2をエナミド3に変換するための例示的な反応条件をスキーム3aおよび3bに示す。
スキーム4に示すように、キラル触媒、H2、および溶媒の存在下で、エナミド3に均一触媒不斉水素化を施した。この実施例において、触媒は、キラルホスフィン配位子である(1R,2S,4R,5S)−P,P−1,2−フェニレンビス{(2,5−エンド−ジメチル)−7−ホスファビシクロ[2.2.1]ヘプタン}(R,S,R,S−MePennPhos)との遷移金属ロジウム錯体から得た。水素化は、約0.12Mから約0.24Mの化合物3の基質濃度で行った。
スキーム5に示すように、キラル触媒、H2、および溶媒の存在下で、エナミド3に均一触媒不斉水素化を施した。この実施例において、触媒は、キラルホスフィン配位子である(R,R)−1,2−ビス(2,5−ジメチルホスホラノ)エタン(R,R−MeBPE)との遷移金属ロジウム錯体から得た。水素化は、基質3に対して、約0.12Mから約0.24Mの濃度範囲で行った。
イソプロパノール(595.0g)中の(S)−エンアセトアミドであるN−((S)−4−(3,4−ジクロロフェニル)−3,4−ジヒドロナフタレン−1−イル)アセトアミド(60.4g、0.18mol)のスラリーを、真空/窒素サイクルを用いて酸素でパージした。均一の触媒前駆体(「触媒」と称する)である、(R,R)−Norphos(COD)RH−BF4を、メタノール溶液(34.6mg、0.025mol%、0.53mL)として加えた。系を水素で数回パージした後、所望の反応圧力(約7バール)で、容器を水素で満たした。混合物を25℃で攪拌し、反応進行を水素の取り込みによってモニターした。反応が完了したと判断したら(水素の取り込みおよびHPLC)、圧力を解放し、系を窒素で繰り返しパージした。淡黄色スラリーをイソプロパノール(194.7g)で希釈し、加熱して溶解させ(65℃)、ポリッシュろ過した。混合物を加熱還流することによって、すべての固体を溶解させた。溶液を60〜65℃に徐々に冷却し、このときに生成物が結晶化した。抗溶媒である水(262g)を約60〜65℃で加え、次いで混合物を、2時間にわたって0℃に冷却し、熟成のためにその温度で保持した。薄い色の固体をろ過した後、冷イソプロパノールで洗浄した(2×61g)。オフホワイト固体を、減圧下、50〜55℃で乾燥させることにより、(1R,4S)−アセトアミドが99%のdeで提供された(56.6g、93%の収率)。
キラルな(4S)−テトラロン(100.0g、0.34mol)を、103℃で約2時間、トルエン(1.37L)中のヒドロキシルアミン塩酸塩(28.7g、0.41mol)および酢酸ナトリウム(33.8g、0.41mol)と反応させた。共沸蒸留によって反応混合物から水を除去した。反応を、25℃で、2Nの水酸化ナトリウム(167.0g)を用いてクエンチした。水相を分離し、有機相を水(400.0g)で1回洗浄した。トルエン(700.0g)を加え、オキシムを含有する得られた有機溶液を、減圧下で所望の反応物濃度まで、共沸蒸留によって乾燥させた。トリエチルホスフィン(89.0g、0.38mol、トルエン中50wt%)を加え、その後、無水酢酸(38.5g、0.38mol)を加えることによって、オキシムアセテート中間体を得た。残りのオキシムアセテートがHPLCでの判定で生成物の2%未満になるまで、反応混合物を還流して(112〜113℃)反応させた。反応混合物を20〜25℃に冷却し、微量のエニミド副生成物を、相間移動試薬である水酸化テトラブチルアンモニウム(5.0g)とともに6Nの水酸化ナトリウム(210g)を用いて、加水分解(エンアセトアミドに)した。二相の混合物を相分離させ、水相を廃棄した。有機相を0.5%の酢酸水溶液(67℃、600.0g)で洗浄した。水相を除去し、有機相を水(67℃、600.0g)で1回洗浄することによって無機塩を除去した。この有機相を濃縮し、温かい溶液をポリッシュろ過することによって、さらに無機塩を除去した。ヘプタン(150g)および2−ブタノール(7.0g)を加え、スラリーを100℃に加熱することによって、溶解を行った。この溶液を約85℃に冷却することによって、結晶化を開始した。追加のヘプタン(190g)を85℃でスラリーに加え、次いでこの混合物を0℃に冷却した。スラリーを0℃で15分間熟成し、次いでろ過し、ヘプタンおよびトルエンの混合物(125g)からなる溶液で3回洗浄した。生成物を35〜45℃で真空乾燥した。17.8g(89%の収率)の白色結晶固体である(S)−エンアセトアミドを回収した。
乾燥THF(212.7g、239.3mL)中の(1R,4S)−アセトアミドの溶液を、乾燥ピリジン(8.7g、8.9mL、110mmol)で処理した。得られた透明無色溶液を約0℃に冷却した。発熱ならびにCOおよびCO2の泡立ちに注意しながら、塩化オキサリル(12.9g、8.9mL、101.6mmol)を攪拌した溶液に液滴で加えた。活性化試薬の添加によって、スラリーが形成した。このスラリーを短期間(約15分)冷状態で攪拌した後、変換の評価のために試料採取した。反応が完了したら、乾燥プロピレングリコールを反応物に加え、その結果、微量に発熱した。反応物を25℃に加温し、その時間の間に、スラリーの色およびコンシステンシーが変化した。第2の試料のHPLC分析により完了が示された後、1−プロパノール(96.9g、120.5mL)を加えた。6NのHCl(128.0g、120.0mL)を加えた。混合物を加熱することによって溶解させ、得られた混合物をポリッシュろ過した。THFを常圧蒸留によって除去した。この混合物を濃縮した後、これを3℃に徐々に冷却した。得られた薄い色のスラリーをろ過することによって、オフホワイトのケーキを得た。このケーキを脱イオン水中の17wt%のn−PrOH(72.6g、全部で75mL)で最初洗浄し、次いで、冷mtBE(55.5g、75mL)で洗浄した。オフホワイトの湿ったケーキを、真空下、45〜50℃で乾燥させた。生成物を、優れた純度(HPLCによって、99%超の純度)のオフホワイトから白色の固体(24.8g、84.1%の収率)として回収した。
Claims (51)
- オキシムをエナミドに変換するための方法であって、
(a)前記オキシムを前記エナミドに変換するのに適切な条件下で、前記オキシムをホスフィンおよびアシル供与体と接触させる工程を含む方法。 - R4が置換または非置換のアリールである、請求項3に記載の方法。
- R4が置換または非置換のフェニルである、請求項4に記載の方法。
- R4が少なくとも1個のハロゲンで置換されたフェニルである、請求項5に記載の方法。
- X1およびX2がそれぞれクロロである、請求項7に記載の方法。
- Arが置換または非置換のフェニルである、請求項3に記載の方法。
- 前記アシル供与体が、式
Z−C(O)−R5
(式中、
Zは、脱離基であり、
R5は、H、置換または非置換のアルキル、置換または非置換のヘテロアルキル、置換または非置換のアリール、置換または非置換のヘテロアリール、および置換または非置換のヘテロシクロアルキルから選択されるメンバーである)を有する、請求項1に記載の方法。 - Zが、式
R6−C(O)−O−
(式中、
R6は、置換または非置換のアルキル、置換または非置換のヘテロアルキル、置換または非置換のアリール、置換または非置換のヘテロアリール、および置換または非置換のヘテロシクロアルキルから選択されるメンバーである)を有する、請求項11に記載の方法。 - R5およびR6の両方が、独立して選択される置換または非置換のC1〜C4部分である、請求項12に記載の方法。
- 前記ホスフィンが、式
P(Q)3
(式中、
各Qは、H、置換または非置換のアルキル、および置換または非置換のアリールから独立して選択されるメンバーである)を有する、請求項1に記載の方法。 - 各Qが、置換または非置換のC1〜C6アルキルから独立して選択されるメンバーである、請求項14に記載の方法。
- 前記接触させる工程が非プロトン性溶媒を含む溶液中である、請求項1に記載の方法。
- 前記非プロトン性溶媒が芳香族溶媒である、請求項16に記載の方法。
- 前記非プロトン性芳香族溶媒が、トルエン、キシレン、およびその組合せから選択される、請求項17に記載の方法。
- C−4がR、S、およびその混合から選択される配置を有する、請求項19に記載の方法。
- C−4がS配置である、請求項20に記載の方法。
- (b)前記エナミドの炭素−炭素二重結合を水素化するのに適切な条件下で、工程(a)において形成された前記エナミドを、水素化触媒および水素または水素移動試薬と接触させ、それによって前記エナミドをアミドに変換する工程をさらに含む、請求項1に記載の方法。
- 前記触媒がキラル触媒である、請求項22に記載の方法。
- 前記キラル触媒がキラルホスフィン配位子との遷移金属錯体である、請求項23に記載の方法。
- 前記アミドがラセミアミドまたはキラルアミドである、請求項22に記載の方法。
- C−1およびC−4が、RおよびSから独立して選択される配置を有する、請求項26に記載の方法。
- C−1がR配置であり、C−4がS配置である、請求項27に記載の方法。
- (c)前記アミドの−HNC(O)R5を脱アシル化するのに適切な条件下で、前記アミドを脱アシル化試薬と接触させ、それによってアミンを形成する工程をさらに含む、請求項22に記載の方法。
- (d)前記アミンを単離する工程をさらに含む、請求項29に記載の方法。
- 前記単離する工程が選択的結晶化を含む、請求項30に記載の方法。
- C−1およびC−4がRおよびSから独立して選択される配置を有する、請求項32に記載の方法。
- C−1がR配置であり、
C−4がS配置である、請求項33に記載の方法。 - C−4がS配置である、請求項35に記載の方法。
- 前記ホスフィンがトリアルキルホスフィンである、請求項34に記載の方法。
- 前記オキシム、前記アシル供与体、および前記ホスフィンが芳香族溶媒中に溶解される、請求項35に記載の方法。
- 前記アシル供与体がアルキル無水物である、請求項35に記載の方法。
- 前記キラル触媒が、キラルホスフィン配位子に錯体形成したロジウムを含む、請求項40に記載の方法。
- 前記脱アシル化試薬が酵素である、請求項42に記載の方法。
- 前記脱アシル化試薬が酸である、請求項42に記載の方法。
- Aが、Bに対して少なくとも90%のジアステレオマー過剰で前記混合物中に存在する、請求項45に記載の方法。
- Aが、Bに対して少なくとも98%のジアステレオマー過剰で前記混合物中に存在する、請求項46に記載の方法。
- xおよびyがRである、請求項45に記載の方法。
- xおよびyがSである、請求項45に記載の方法。
- xがSであり、yがRである、請求項45に記載の方法。
- 請求項45に記載の混合物および薬学的に許容できる担体を含む医薬製剤。
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