CN1230554C - 3(r)-与3(s)-羟基-1-甲基-4-(2,4,6-三甲氧基苯基)-1,2,3,6-四氢吡啶或其羧酸酯对映体的酶催分离方法 - Google Patents
3(r)-与3(s)-羟基-1-甲基-4-(2,4,6-三甲氧基苯基)-1,2,3,6-四氢吡啶或其羧酸酯对映体的酶催分离方法 Download PDFInfo
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Abstract
本发明涉及用于制备3(R)-与3(S)-羟基-1-甲基-4-(2,4,6-三甲氧基苯基)-1,2,3,6-四氢吡啶或其羧酸酯的光学纯化合物的方法,即用一种酶使对映体混合物进行立体选择性反应。
Description
本发明涉及光学纯的式(I)化合物的制备方法,该方法借助一种酶进行对映体混合物的立体分化反应。
3(S)-与3(R)-羟基-1-甲基-4-(2,4,6-三甲氧基苯基)-1,2,3,6-四氢吡啶(式(I)中R=H的化合物)或其酯衍生物(式(I)中R=COR1的化合物)是下列物质合成的重要单元或前体:专利申请HMR 98/L 001(“(-)顺式-3-羟基-1-甲基-4(R)-(2,4,6-三甲氧基苯基)哌啶的制备方法”)中描述的flavopiridol(HMR 1275或L 86 8275)、cyclin-依赖性蛋白激酶的第一种强效抑制剂(例如参见Sedlacek,Hans Harald;Czech,Joerg;Naik,Ramachandra;Kaur,Gurmeet;Worland,Peter;Losiewicz,Michael;Parker,Bernard;Carlson,Bradley;Smith,Adaline等“Flavopiridol(L868275;NSC 649890),用于肿瘤治疗的一种新的激酶抑制剂”《国际肿瘤学杂志》(Int.J.Oncol.)(1996),9(6),1143-1168或Czech,Joerg;Hoffmann,Dieter;Naik,Ramachandra;Sedlacek,Hans-Harald“黄酮L 86 8275的抗肿瘤活性”《国际肿瘤学杂志》(1995),6(1),31-36)。
式(I)化合物的外消旋物拆分或对映体分离是未知的。
现已发现,通过酶催酯裂解(水解或醇解)可以从对映体混合物得到式(I)化合物的光学纯形式。
本发明因此涉及式(I)化合物外消旋物的动态拆分方法,
其中
R是COR1,其中R1=(C1-C16)-烷基、(C2-C16)-烯基或(C3-C16)-炔基、CnH2n-环烷基,其中n=1-16,它们可以是支链或非支链的,并且可以被1-3个取代基取代,取代基选自F、Cl、Br、I、CF3、CN、NO2、羟基、甲氧基、乙氧基和COOR2,其中R2=(C1-C4)-烷基和(C2-C4)-烯基,它们可以是支链或非支链的并且可以被1-3个取代基取代,取代基选自F、Cl、Br、CF3,
该方法包括在均相或多相、含水、含水/有机或有机介质中,在一种酶的存在下,例如一种脂肪酶或酯酶,例如来自哺乳动物肝脏或胰腺或微生物来源,例如来自假丝酵母属(Candida)、假单胞菌属(Pseudomonas)和曲霉属,或者一种蛋白酶,例如来自芽胞杆菌属,在有或没有助溶剂和缓冲剂的存在下,将式(I)化合物的对映体混合物或外消旋混合物在10-80℃温度下进行立体选择性水解或醇解,其中反应混合物优选地含有2-50重量%的酯,
在反应已经发生后,分离未反应的酯(式(I)中R=COR1的化合物)和所生成的醇(式(I)中R=H的化合物),以及因此两种对映体。
根据本发明的方法是经济、简单和快速的。反应不需要任何等摩尔量的光学纯助剂、昂贵的试剂、不相称大量的溶剂和任何耗费的操作步骤。反应完成后,可以采取简单的措施进行产物或对映体的分离,例如萃取。
优选地,在式(I)化合物中,
R是COR1,其中R1=(C1-C12)-烷基、(C2-C12)-烯基或(C3-C12)-炔基、CnH2n-环烷基,其中n=1-12,它们可以是支链或非支链的,并且可以被1-3个取代基取代,取代基选自F、Cl、Br、CF3、CN、NO2、羟基、甲氧基、乙氧基和COOR2,其中R2=甲基、乙基和乙烯基,它们可以被1-3个取代基取代,取代基选自F、Cl、CF3。
特别优选地,在式(I)化合物中,
R是COR1,其中R1=(C1-C10)-烷基、(C2-C10)-烯基或(C3-C10)-炔基、CnH2n-环烷基,其中n=1-10,它们可以是支链或非支链的,并且可以被1-3个取代基取代,取代基选自F、Cl、Br、CF3、CN、NO2、甲氧基,和COOR2,其中R2=甲基、乙基和乙烯基,它们可以被1-3个取代基取代,取代基选自F、Cl、CF3。
非常特别优选地,在式(I)化合物中,
R是COR1,其中R1=(C1-C10)-烷基、(C2-C10)-烯基或(C3-C10)-炔基,它们可以是支链或非支链的,并且可以被1-3个取代基取代,取代基选自F、Cl、Br、CF3和甲氧基。
优选使用的操作是将式(I)的酯用一种脂肪酶、酯酶或蛋白酶在含水或含醇溶液中处理并搅拌,在式(I)中例如R=COR1,其中R1=C3H7或C8H17。有利的是对所述溶液进行缓冲处理,例如用磷酸盐或TRIS(=三(羟甲基)甲胺)缓冲液。加入量例如可以是0.01-1.0摩尔。适当的缓冲范围是pH 5-9。
还可以有利地加入助溶剂。适当的助溶剂例如有二甲氧基乙烷、丙酮、THF、二噁烷、己烷、叔丁基甲基醚和叔丁醇。助溶剂在溶液中的比例优选为10-80%。
所用的酶优选为脂肪酶和酯酶,例如来自牛胰腺的胆固醇酯酶(EC3.1.1.13)(Sigma Chemical Co.)、猪肝酯酶(PLE,Sigma Chemical Co.)、胰酶(Fluka和Sigma Chemical Co.)、来自牛的胰腺丙酮粉末(SigmaChemical Co.)、来自马的肝脏丙酮粉末(Sigma Chemical Co.)和来自猪胰腺的脂肪酶(PPL,Sigma Chemical Co.)、来自皱落假丝酵母的脂肪酶OF(Meito Sangyo)、来自黑曲霉的脂肪酶AP-6(Amano Pharmaceuticals)。
所述各种酶都可以使用其游离形式或固定化形式(《固定化的生物催化剂》W.Hartmeier,Springer Verlag Berlin,1988)。酶的量是自由选择的,这取决于反应速率或所需反应时间和酶的性质(例如游离或固定化),并且通过简单的预实验是易于测定的。
反应混合物优选地含有2-50重量%的酯,特别优选为5-20%。反应温度是10-80℃,优选为20-60℃,特别优选为20-40℃。
酯(式(I)中R=COR1的化合物)适宜按照已知的酯化方法(Haslam《四面体》1980,36,2409;Hoefle,Steglich,Vorbrueggen,《应用化学》(Angew.Chem.)1978,90,602)从醇(式(I)中R=H的化合物)进行制备,或者如专利申请HMR 98/L 001(“(-)顺式-3-羟基-1-甲基-4(R)-(2,4,6-三甲氧基苯基)哌啶的制备方法”)所述进行制备。
方法所得产物或剩余产物可以用一种简单的方式分离,例如萃取或色谱法。例如使反应溶液在水与正庚烷之间分配,浓缩有机相,得到剩余的酯。所得的醇然后可以从含水相中用乙酸乙酯萃取出来。酶可以通过冷冻干燥法回收。酶的分离(以及可能的话后面的再利用)可以通过固定化而加以促进。
通过适当地进行反应,总是可能得到至少一种光学纯的对映体。如果需要得到光学纯的酯,转化率应当超过(或等于)50%,如果需要得到光学纯的醇,转化率应当小于(或等于)50%。酶催水解或醇解的转化率是用HPLC(RP 18 LiChrosorb)测定的,光学纯度的测定是通过HPLC(Chiralpak AD)进行的。外消旋物拆分过程所产生的酯或剩余的酯可以通过已知的酯裂解方法(S.J.Salomon,E.G.Mata,O.A.Mascaretti,《四面体》1993,49,3691-3748)转化为对应的醇,而不会反转或外消旋化。相反,所得的醇可以通过已知的酯化方法(Haslam,《四面体》1980,36,2409)转化为对应的酯,而不会反转或外消旋化。
方法所得产物或剩余产物可以按照已知方法进行外消旋作用,并且在外消旋物拆分中再次利用,所述已知方法例如是金属催化的重排(L.E.Overman,《应用化学》1984,96,565-573和已经引用过的文献)。这样,产率可提高到50%以上。例如,式(I)中R=COR1的化合物可以直接进行外消旋作用,式(I)中R=H的化合物例如可以在转化为适当的衍生物之后进行外消旋作用,如L.E.Overman,《应用化学》1994,96,565-573所述。可以使用的金属催化剂例如有Hg(II)、Pd(O)或Pd(II)化合物或盐。
本发明将通过下列实施例进行详细阐述。
实施例:
所有分离后的产物或粗产物混合物用1H-NMR和质谱或HPLC鉴定。
产物的光学纯度用HPLC测定,例如Chiralpak AD 250×4.6(Daicel)。
实施例1:
向1ml磷酸钾缓冲液(0.1M,pH=7.0)/二甲氧基乙烷(5∶1)中加入10mg乙酸酯(式I中R=COR1、R1=CH3的化合物)。加入5mg胰酶。混合物在20-25℃下搅拌,直到转化率达到约40%(HPLC)时为止。然后过滤,浓缩至干,所得混合物用HPLC(Chiralpak AD 250×4.6,正己烷+EtOH5+1,流速1ml/分钟,25℃,220/240nm)测定:
剩余(R)-乙酸酯的ee:63%;(S)-醇的ee:85%。
实施例2:
向1ml磷酸钾缓冲液(0.1M,pH=7.0)/二甲氧基乙烷(5∶1)中加入10mg丁酸酯(式I中R=COR1、R1=(CH2)2CH3的化合物)。加入5mg PPL(来自猪胰腺的脂肪酶,Sigma Chemical Co.)。混合物在30℃下搅拌,直到转化率达到约48%(HPLC)时为止。然后过滤,浓缩至干,所得混合物用HPLC(Chiralpak AD 250×4.6,正己烷+EtOH 6+1,流速1ml/分钟,25℃,220/240nm)测定:
(R)-丁酸酯的ee:90%;(S)-醇的ee:97%。
实施例3:
向8ml二甲氧基乙烷与40ml磷酸钾缓冲液(0.1M,pH=7.0)中加入1.0g(2.86mmol)丁酸酯(式I中R=COR1、R1=(CH2)2CH3的化合物)。加入90mg胰酶。混合物在22-25℃下搅拌,直到转化率超过50%时为止。然后在真空中浓缩,与水混合,用约50ml正庚烷萃取六次。干燥(Na2SO4)后,在真空中浓缩。得到450mg(45%)(R)-丁酸酯;ee(HPLC):≥99%。剩余含水相用乙酸乙酯萃取后,干燥(Na2SO4),在真空中浓缩,得到190mg(23.8%)(S)-醇;ee(HPLC):97%。
实施例4:
向1ml磷酸钾缓冲液(0.1M,pH=7.0)/二甲氧基乙烷(5∶1)中加入10mg丁酸酯(式I中R=COR1、R1=(CH2)2CH3的化合物)。加入5mg PPL。混合物在30℃下搅拌,直到转化率达到约48%(HPLC)时为止。然后过滤,浓缩至干,所得混合物用HPLC(Chiralpak AD 250×4.6,正己烷+EtOH 6+1,流速1ml/分钟,25℃,220/240nm)测定:
(R)-丁酸酯的ee:90%;(S)-醇的ee:97%。
实施例5:
向1ml磷酸钾缓冲液(0.1M,pH=7.0)/二甲氧基乙烷(5∶1)中加入10mg丁酸酯(式I中R=COR1、R1=(CH2)2CH3的化合物)。加入5mg PLE(猪肝酯酶,Sigma Chemical Co.)。混合物在30℃下搅拌,直到转化率达到约47%(HPLC)时为止。然后过滤,浓缩至干,所得混合物用HPLC(Chiralpak AD 250×4.6,正己烷+EtOH 6+1,流速1ml/分钟,25℃,220/240nm)测定:
(R)-丁酸酯的ee:88%;(S)-醇的ee:97%。
实施例6:
向1ml磷酸钾缓冲液(0.1M,pH=7.0)/二甲氧基乙烷(5∶1)中加入10mg己酸酯(式I中R=COR1、R1=(CH2)4CH3的化合物)。加入5mg PLE。混合物在30℃下搅拌,直到转化率达到约40%(HPLC)时为止。然后过滤,浓缩至干,所得混合物用HPLC(Chiralpak AD 250×4.6,正己烷+EtOH 6+1,流速1ml/分钟,25℃,220/240nm)测定:
(R)-己酸酯的ee:66%;(S)-醇的ee:96%。
实施例7:
向1ml磷酸钾缓冲液(0.1M,pH=7.0)/二甲氧基乙烷(5∶1)中加入10mg己酸酯(式I中R=COR1、R1=(CH2)4CH3的化合物)。加入5mg来自牛胰腺的胆固醇酯酶。混合物在30℃下搅拌,直到转化率达到约50%(HPLC)时为止。然后过滤,浓缩至干,所得混合物用HPLC(ChiralpakAD 250×4.6,正己烷+EtOH 6+1,流速1ml/分钟,25℃,220/240nm)测定:
(R)-己酸酯的ee:≥99.8%;(S)-醇的ee:≥99.8%。
实施例8:
向1ml磷酸钾缓冲液(0.1M,pH=7.0)/二甲氧基乙烷(5∶1)中加入10mg癸酸酯(式I中R=COR1、R1=(CH2)8CH3的化合物)。加入5mg PPL。混合物在30℃下搅拌,直到转化率达到约10%(HPLC)时为止。然后过滤,浓缩至干,所得混合物用HPLC(Chiralpak AD 250×4.6,正己烷+EtOH 6+1,流速1ml/分钟,25℃,220/240nm)测定:
(R)-癸酸酯的ee:≥11%;(S)-醇的ee:95%。
实施例9:
向1ml磷酸钾缓冲液(0.1M,pH=7.0)/二甲氧基乙烷(5∶1)中加入10mg丁酸酯(式I中R=COR1、R1=(CH2)2CH3的化合物)。加入5mg马肝丙酮粉末。混合物在30℃下搅拌,直到转化率达到约46%(HPLC)时为止。然后过滤,浓缩至干,所得混合物用HPLC(Chiralpak AD 250×4.6,正己烷+EtOH 6+1,流速1ml/分钟,25℃,220/240nm)测定:
(R)-丁酸酯的ee:82%;(S)-醇的ee:96%。
Claims (4)
1、式(I)化合物外消旋物的动力学拆分方法,
其中
R是COR1,其中R1=(C1-C16)-烷基、(C2-C16)-烯基或(C3-C16)-炔基、CnH2n-环烷基,其中n=1-16,它们可以是支链或非支链的,并且可以被1-3个取代基取代,取代基选自F、Cl、Br、I、CF3、CN、NO2、羟基、甲氧基、乙氧基和COOR2,其中R2=(C1-C4)-烷基和(C2-C4)-烯基,它们可以是支链或非支链的并且可以被1-3个取代基取代,取代基选自F、Cl、Br、CF3,
该方法包括在均相或多相、含水、含水/有机或有机介质中,在脂肪酶、酯酶或蛋白酶的存在下,在有或没有助溶剂和缓冲剂的存在下,将式(I)化合物的对映体混合物或外消旋混合物在10-80℃温度下进行立体选择性水解或醇解,其中反应混合物含有2-50重量%的酯,
在反应已经发生后,分离未反应的式(I)中R=COR1的酯和所生成的式(I)中R=H的醇,以及因此两种对映体。
2、如权利要求1所要求保护的式(I)化合物外消旋物的动态拆分方法,
其中
R是COR1,其中R1=(C1-C12)-烷基、(C2-C12)-烯基或(C3-C12)-炔基、CnH2n-环烷基,其中n=1-12,它们可以是支链或非支链的,并且可以被1-3个取代基取代,取代基选自F、Cl、Br、CF3、CN、NO2、羟基、甲氧基、乙氧基和COOR2,其中R2=甲基、乙基和乙烯基,它们可以被1-3个取代基取代,取代基选自F、Cl、CF3。
3、如权利要求1或2所要求保护的式(I)化合物外消旋物的动态拆分方法,其中
R是COR1,其中R1=(C1-C10)-烷基、(C2-C10)-烯基或(C3-C10)-炔基、CnH2n-环烷基,其中n=1-10,它们可以是支链或非支链的,并且可以被1-3个取代基取代,取代基选自F、Cl、Br、CF3、CN、NO2、甲氧基和COOR2,其中R2=甲基、乙基和乙烯基,它们可以被1-3个取代基取代,取代基选自F、Cl、CF3。
4、如权利要求1或2所要求保护的式(I)化合物外消旋物的动态拆分方法,其中
R是COR1,其中R1=(C1-C10)-烷基、(C2-C10)-烯基或(C3-C10)-炔基,它们可以是支链或非支链的,并且可以被1-3个取代基取代,取代基选自F、Cl、Br、CF3和甲氧基。
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DE19809649.6 | 1998-03-06 | ||
DE19809649A DE19809649A1 (de) | 1998-03-06 | 1998-03-06 | Verfahren zur enzymatischen Enantiomeren-Trennung von 3(R)- und 3(S)-Hydroxy-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydro-pyridin bzw. der Carbonsäureester |
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CN1292034A CN1292034A (zh) | 2001-04-18 |
CN1230554C true CN1230554C (zh) | 2005-12-07 |
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US (1) | US6406912B1 (zh) |
EP (1) | EP1071807B1 (zh) |
JP (1) | JP4344089B2 (zh) |
KR (1) | KR100779864B1 (zh) |
CN (1) | CN1230554C (zh) |
AR (1) | AR018574A1 (zh) |
AT (1) | ATE474061T1 (zh) |
AU (1) | AU758106B2 (zh) |
BR (2) | BR9908557A (zh) |
CA (1) | CA2322842C (zh) |
CY (1) | CY1110919T1 (zh) |
CZ (1) | CZ301944B6 (zh) |
DE (2) | DE19809649A1 (zh) |
DK (1) | DK1071807T3 (zh) |
ES (1) | ES2348394T3 (zh) |
HK (1) | HK1035001A1 (zh) |
HU (1) | HU227994B1 (zh) |
ID (1) | ID27000A (zh) |
PL (1) | PL195006B1 (zh) |
PT (1) | PT1071807E (zh) |
RU (1) | RU2241040C2 (zh) |
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BR0010544A (pt) | 1999-05-13 | 2002-02-19 | Shell Int Research | Método para produzir hidrogênio e um produto hidroprocessado |
US7153675B2 (en) * | 2001-05-15 | 2006-12-26 | Speedel Pharma Ag | Process for the preparation of substituted carboxylic esters |
CN104278061A (zh) * | 2014-10-01 | 2015-01-14 | 青岛科技大学 | 一种生产氟苯基甲基丙酸甲酯的产朊酵母还原法 |
CN104232700A (zh) * | 2014-10-01 | 2014-12-24 | 青岛科技大学 | 一种生物法生产(2r,3s)羟基丙酸甲酯的方法 |
RU2717829C2 (ru) | 2015-04-20 | 2020-03-26 | Толеро Фармасьютикалз, Инк. | Прогнозирование ответа на альвоцидиб с помощью анализа профиля митохондрий |
TR201911032T4 (tr) | 2015-05-18 | 2019-08-21 | Tolero Pharmaceuticals Inc | Artırılmış biyoyararlanıma sahip alvocıdıb ön ilaçları. |
JP7083497B2 (ja) | 2015-08-03 | 2022-06-13 | スミトモ ファーマ オンコロジー, インコーポレイテッド | がんの処置のための併用療法 |
US11279694B2 (en) | 2016-11-18 | 2022-03-22 | Sumitomo Dainippon Pharma Oncology, Inc. | Alvocidib prodrugs and their use as protein kinase inhibitors |
CA3047557A1 (en) | 2016-12-19 | 2018-06-28 | Tolero Pharmaceuticals, Inc. | Profiling peptides and methods for sensitivity profiling |
WO2019055579A1 (en) | 2017-09-12 | 2019-03-21 | Tolero Pharmaceuticals, Inc. | TREATMENT REGIME FOR CANCERS THAT ARE INSENSITIVE TO BCL-2 INHIBITORS USING THE MCL-1 ALVOCIDIB INHIBITOR |
KR20210099066A (ko) | 2018-12-04 | 2021-08-11 | 스미토모 다이니폰 파마 온콜로지, 인크. | 암의 치료를 위한 작용제로서 사용하기 위한 cdk9 억제제 및 그의 다형체 |
US11793802B2 (en) | 2019-03-20 | 2023-10-24 | Sumitomo Pharma Oncology, Inc. | Treatment of acute myeloid leukemia (AML) with venetoclax failure |
CN110577974B (zh) * | 2019-09-10 | 2021-07-20 | 杭州澳赛诺生物科技有限公司 | 手性3-羟基-1,2,3,6-四氢吡啶的合成方法 |
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JP2691986B2 (ja) * | 1987-08-28 | 1997-12-17 | チッソ株式会社 | ピリジン骨格を有する光学活性化合物の製造法 |
DE3743824C2 (de) | 1987-12-23 | 1997-03-06 | Hoechst Ag | Verfahren zur enzymatischen Racematspaltung von racemischen Alkoholen mit/in Vinylestern durch Umesterung |
JPH0641075A (ja) * | 1990-09-01 | 1994-02-15 | Kazuo Achinami | 新規な1,4−ジヒドロピリジン化合物及びその製造方法 |
CA2064676A1 (en) * | 1991-04-02 | 1992-10-03 | Manfred Schneider | Immobilized biocatalyst, its preparation and use for ester synthesis in a column reactor |
JPH0690790A (ja) * | 1992-09-08 | 1994-04-05 | Mercian Corp | 光学活性1,4−ジヒドロピリジン−3,5−ジカルボン酸・モノエステル誘導体の製造方法 |
DE19802449A1 (de) * | 1998-01-23 | 1999-07-29 | Hoechst Marion Roussel De Gmbh | Verfahren zur Herstellung von (-)cis-3-Hydroxy-1-methyl-4-(2,4,6-trimethoxypyhenyl)-piperidin |
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