CN1946855A - 从外消旋酯中制备光学活性的酯衍生物及其酸的方法 - Google Patents
从外消旋酯中制备光学活性的酯衍生物及其酸的方法 Download PDFInfo
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Abstract
本发明涉及从外消旋的β-羟基丁酯衍生物中制备集中用作重要的手性中间体的光学活性的酯衍生物及其酸衍生物的方法。更详细地,本发明涉及在水相或包括水性溶剂的有机相中,使用脂肪酶或产生脂肪酶的微生物,通过外消旋的β-羟基丁酯衍生物的立体专一性水解制备光学活性的β-羟基丁酯衍生物及其酸衍生物的方法。与常规的方法相比,通过方案1中通式1所示的β-羟基丁酯衍生物的水解产生光学活性的酯衍生物及其酸衍生物的方法更容易且更经济,并且所述产物具有高光学纯度。反应后也易于从酸衍生物中分离酯衍生物。因此在工业规模上该方法是有用的方法。
Description
技术领域
本发明涉及制备光学活性的β-羟基丁酯衍生物及其酸衍生物的方法。更具体地,本发明涉及通过用脂肪酶或产生脂肪酶的微生物水解方案1中通式1所示的外消旋的β-羟基丁酯衍生物来制备光学活性的β-羟基丁酯衍生物及其酸衍生物的方法。
上述光学活性的β-羟基丁酯衍生物及其酸衍生物的方法可集中用作重要的手性中间体。此外,由本发明产生的β-羟基丁酯衍生物及其酸衍生物具有高光学纯度,并且因为所述产物易于分离和回收,所以此方法可用于实践过程。因此本发明可用于工业规模。
[方案1]
(R=CnH2n+1,(n=1~8))
(X=H、N3、CN、F、Cl、Br、I)
据报导,(R)-3-羟基丁酸乙酯是抗青光眼药物的中间体(Chirality inindustryП.Chichester,UK:Wiley,1997,245-262),以及(S)-3-羟基丁酸酯用于合成信息素(Tertahedron,45:3233-3298)和碳青霉烯类(Journalof the Chemical Society.Perkin Transaction,1999,1:2489-2494)。
以及(R)-4-氯-3-羟基丁酸乙酯用于合成L-肉毒碱(Journal of theAmerican Chemical Society,1983,105:5925-5926)、(R)-4-氨基-3-羟丁酸(GABOB)和(R)-羟基-2-吡咯烷酮。(S)-4-氯-3-羟基丁酸乙酯是产生羟甲基戊二酰辅酶A(HMG-CoA)还原酶抑制剂的有价值的合成子(Journalof Medicinal Chemistry,1990,33:2952-2956)。
背景技术
存在制备光学活性的β-羟基丁酯衍生物的多种方法。使用BINAP-配位Ru(II)络合物通过乙酰乙酸乙酯的不对称氢化合成(S)-3-羟基丁酸乙酯(Journal of the American Chemical Society,1987,109:5856-5858)。但是,该方法具有在反应过程中需要高压和高成本的金属催化剂的缺点。
另一方法是采用微生物还原3-氧-酯类。Jayasinghe等人(Tetrahedron Lettes,1993,34:3949-3950)在石油醚中使用冻干的酵母通过还原乙酰乙酸乙酯得到(S)-3-羟基丁酸乙酯(收率58%,94%e.e),以及Medson等人(Tetrahedron:Asymmetry,1997,8:1049-1054)在有机溶剂中使用酵母通过还原由乙酰乙酸乙酯得到(S)-3-羟基丁酸乙酯(收率69%,99%e.e)。Chin-Joe等人(Biotechnology and Bioengineering,2000,69:370-376)使用Baker′s酵母通过还原乙酰乙酸乙酯以85%的转化率得到(S)-3-羟基丁酸乙酯(99%e.e)。但是,这些方法具有收率低和反应后纯化问题的缺点。
另一方面,Sugai等人(Agricultural Biological Chemistry,1989,53:2009-2010)使用丁酸乙烯酯作为酰化剂和猪的胰脂肪酶作为催化剂,通过酯交换外消旋的3-羟基丁酸乙酯得到(S)-3-羟基丁酸乙酯(99.4%e.e)。Fishman 等人(Biotechnology Bio-engineering,2001,74:256-263)使用CALB(Candida antartica)脂肪酶和作为酰基供体的乙酸乙烯酯得到(S)-3-羟基丁酸乙酯(收率40%,99.4%e.e)。
在另一情况下,可通过微生物酸性醇解蓄积的聚-(R)-3-羟基丁酸酯制备(R)-3-羟基丁酸乙酯(Enzyme and Microbial Technology,2000,27:33-36)。
可通过4-氯乙酰乙酸乙酯的还原产生光学活性的4-氯-3-羟基丁酸乙酯。Matsuyama等人(Japan Tokkyo Koho,06-209782,Aug.2,1994)用乳酸克鲁维酵母(Kluyveromyces lactis)NRIC 1329获得了(S)-4-氯-3-羟基丁酸乙酯(收率97%,98%e.e)。Kataoka等人(Applied microbiologyand Biotechnology,1999,51:486-490)用重组体微生物得到(R)-4-氯-3-羟基丁酸乙酯(收率94%,92%e.e),该重组体微生物共表达来自赭色掷孢酵母(Sporobolomyces salmonicolor)的醇还原酶I基因和来自巨大芽孢杆菌(Bacillus megaterium)的葡萄糖脱氢酶基因。Yamamoto等人(Bioscience Biotechnology and Biochemistry,2002,66(2):481-483)用表达来自近平滑假丝酵母(Candida parapsilosis)的第二醇脱氢酶的重组体微生物产生(R)-4-氯-3-羟基丁酸乙酯(收率95.2%,99%e.e)。但是,这些方法具有反应时间长的缺点。
另一方面,Hoff等人(Tetrahedron;Asymmetry,1999,10:1401-1412)在有机相(苯)中用米黑根毛霉脂肪酶(Rhizomucor miehei lipase)(RML)通过酯交换5天,得到(S)-4-氯-3-羟基丁酸乙酯(收率24%,86%e.e)。
Suzuki等人(Enzyme Microbiology and Technology,1999,24:13-20)用产生脱氯酶的微生物产生(R)-4-氯-3-羟基丁酸乙酯(99.8%e.e)。
如先前所述,可通过酮酸酯的立体选择性还原或酶促的酯交换制备光学活性的β-羟基丁酯衍生物。但是,这些方法不是适合的,因为其具有包括低对映体过量、低收率或反应后难以分离产物和反应物的缺点。为了解决这些问题,水解β-羟基丁酯衍生物。Santaniello等人(Gazzetta Chemica Italiana,1989,119:581-584)用猪的肝酯酶通过水解4-氯-3-羟基丁酸乙酯得到(R)-4-氯-3-羟基丁酸乙酯及其(S)酸。但是,此方法具有低收率(23%)和低对映体过量(16%e.e)的缺点,并且不适于工业应用。
发明的公开
技术问题
开发了采用脂肪酶或产生脂肪酶的微生物通过立体专一性水解,从方案1中通式1所示的外消旋的β-羟基丁酯衍生物制备高光学纯度的β-羟基丁酯衍生物及其酸衍生物的方法。
本方法简单,并且与常规方法相比,可获得更高光学纯度的酯衍生物及其酸衍生物。
因此,本发明的目的是提供了使用酶或微生物由外消旋的β-羟基丁酯衍生物制备光学活性的酯及其酸的方法。
为了上述目的,本发明由如下方法组成:在水相或包括水性溶剂的有机相中,使用脂肪酶或产生脂肪酶的微生物作为生物催化剂,通过立体专一性水解由外消旋的β-羟基丁酯衍生物制备高光学活性的β-羟基丁酯衍生物及其酸。
技术解决方案
如下对本发明进行了更详细地解释。如上所述,本发明涉及在水相或包括水性溶剂的有机相中,使用脂肪酶或产生脂肪酶的微生物作为生物催化剂,通过立体专一性水解由外消旋的β-羟基丁酯衍生物制备高光学活性的β-羟基丁酯衍生物及其酸的方法。
在本发明中,3-羟基丁酸甲酯、3-羟基丁酸乙酯、3-羟基丁酸丁酯、3-叠氮基-3-羟基丁酸乙酯、4-氯-3-羟基丁酸乙酯、4-溴-3-羟基丁酸乙酯和4-氰基-3-羟基丁酸乙酯被用作外消旋的β-羟基丁酯,但是所述反应物并不限于它们。在方案1中的通式1中,X为H、CN、N3、F、Cl、Br或I以及R为CnH2n+1(n=1~8)。
商业可用的脂肪酶的非限制性例子包括来自Amano Inc.的PS脂肪酶、皱褶假丝酵母(Candida rugosa)脂肪酶和Novozyme 435,以及产生脂肪酶的微生物的非限制性例子包括皱褶假丝酵母和Rhodococcusbutanica。
反应后,通过溶剂萃取法或柱色谱法分别分离出光学活性的酯及其酸。
在本发明中,通过配备有HP-FFAP柱(Agilent,Inc.,30mm×0.53m)的气相色谱(Donam Instrument Inc.6200型)测定外消旋化合物。最初将炉温在70℃下保持5分钟,然后以10℃/min的速率升至220℃,并保持10分钟。使用氦气作为载气,速率为2ml/min,并且用FID检测器检测化合物。在本发明中所述组分的典型的保留时间如下所示:
外消旋的3-羟基丁酸甲酯-15.48分钟
外消旋的3-羟基丁酸乙酯-14.32分钟
外消旋的3-羟基丁酸丁酯-17.16分钟
外消旋的4-叠氮基-3-羟基丁酸乙酯-22.50分钟
外消旋的4-氯-3-羟基丁酸乙酯-20.31分钟
除了炉温以20℃/min的速率升高以外,采用与外消旋的3-羟基丁酸甲酯分析中所使用的相同的方法分析外消旋的4-溴-3-羟基丁酸乙酯和外消旋的4-氰基3-羟基丁酸乙酯。在此条件下,分别在11.7分钟和14.07分钟时检测到外消旋的4-溴-3-羟基丁酸乙酯和外消旋的4-氰基3-羟基丁酸乙酯。
使用己烷和异丙醇的混合物(90∶10)作为流动相,通过配备有手性柱OD-H(Daicel,0.46cm×25cm)的HPLC(Waters,Inc.,1525型)测定光学活性的3-羟基丁酸甲酯、3-羟基丁酸乙酯、3-羟基丁酸丁酯和4-叠氮基-3-羟基丁酸乙酯。吸光度为220nm以及流速为0.7ml/min。本发明所述组分的典型的保留时间如下所示:
(R)-3-羟基丁酸甲酯-10.28分钟
(S)-3-羟基丁酸甲酯-12.44分钟
(R)-3-羟基丁酸乙酯-12.77分钟
(S)-3-羟基丁酸乙酯-11.43分钟
(R)-3-羟基丁酸丁酯-9.4分钟
(S)-3-羟基丁酸丁酯-10.64分钟
(R)-4-叠氮基-3-羟基丁酸乙酯-8.7分钟
(S)-4-叠氮基-3-羟基丁酸乙酯-10.86分钟
通过配备有手性柱G-TA(Astec,30mm×0.32m)的气相色谱(DonamInstrument Inc.6200型)测定光学活性的4-氰基-3-羟基丁酸乙酯。最初将炉温在100℃下保持5分钟,然后以10℃/min的速率升至170℃,并保持20分钟。氦气用作载气,并将柱头压力保持在10psi,用FID检测器检测化合物。在此条件下,(R)-4-氰基-3-羟基丁酸乙酯和(S)-4-氰基-3-羟基丁酸乙酯分别为16.75分钟和16.53分钟。
使用己烷和异丙醇的混合物(95∶5)作为流动相,通过配备有手性柱OB-H(Daicel,0.45cm×25cm)的HPLC(Lab Alliance,201型)测定光学活性的4-氯-3-羟基丁酸乙酯。流速为0.7ml/min以及吸光度为215nm。在此条件下,(R)-4-氯-3-羟基丁酸乙酯和(S)-4-氯-3-羟基丁酸乙酯分别为14.42分钟和15.38分钟。
使用己烷和异丙醇的混合物(90∶10)作为流动相,通过配备有手性柱AD-H(Daicel,0.46cm×25cm)的HPLC(Lab Alliance,201型)测定光学活性的4-溴-3-羟基丁酸乙酯。流速为0.7ml/min以及吸光度为220nm。在此条件下,(R)-4-溴-3-羟基丁酸乙酯和(S)-4-溴-3-羟基丁酸乙酯分别为12.23分钟和11.24分钟。
并且通过FT-NMR(Burker,DRX300型或JEOL,AR400型)确认了外消旋化合物,结果如下:
4-叠氮基-3-羟基丁酸乙酯:
1H-NMR(CDCl3,300MHz)δ(ppm)=1.28(t,3H),2.53(m,2H),3.28(d,1H),3.34(m,2H),4.21(q,2H)
4-氯-3-羟基丁酸乙酯:
1H-NMR(CDCl3,400MHz)δ(ppm)=1.28(t,3H),2.62(d,2H),3.53(br,1H),3.60(d,2H),4.20(q,2H),4.33(m,1H)
4-溴-3-羟基丁酸乙酯:
1H-NMR(CDCl3,400MHz)δ(ppm)=1.28(t,3H),2.7(m,2H),3.48(dd,1H),3.51(dd,1H),4.17(q,2H),4.20(m,1H)
4-氰基-3-羟基丁酸乙酯:
1H-NMR(CDCl3,400MHz)δ(ppm)=1.26(t,3H),2.5~2.7(m,4H),4.18(q,2H),4.32(m,1H)
通过以下实施例可更好地理解本发明,所给出的实施例是为了示例性说明,不应理解为对本发明的限制。
实施例1
将外消旋的3-羟基丁酸乙酯(1%,v/v)加入含有5ml磷酸氢二钾缓冲液(pH 8.0,0.1M)和Novozyme 435(4%,w/v)的管形瓶中。在30℃下所述反应进行2小时。用乙酸乙酯萃取所述反应混合物并用上述方法进行分析。以55%的转化率从有机溶剂中得到(S)-3-羟基丁酸乙酯(97%e.e)。用盐酸酸化水溶液并用有机溶剂萃取。在酯化后,得到具有80.4%e.e光学纯度的(R)-3-羟基丁酸乙酯。
实施例2-3
用全细胞(20%(w/v))代替实施例1中所用的脂肪酶。通过在含有1%甘油三丁酸酯的培养基中进行培养来分离产生脂肪酶的微生物。分离出的株吸收甘油三丁酸酯并产生亮区。将该株生长在LB培养基或含有葡萄糖的GYP培养基,使用离心机收获微生物并将其用作生物催化剂。所述结果显示于表1中。
表1
实施例 | 微生物 | 反应时间(小时) | 转化率(%) | 酯的%e.e | 构型 |
2 | 皱褶假丝酵母KCCM 50521 | 62 | 69.6 | 99 | S |
3 | RhodococcusbutanicaATCC 21197 | 3.5 | 63.9 | 99 | S |
实施例4-5
将1%的3-羟基丁酸甲酯和5%的3-羟基丁酸丁酯用作反应物,代替实施例1中所用的3-羟基丁酸乙酯。用novozyme 435脂肪酶进行所述反应,所述结果显示于表2中。
表2
实施例 | 反应物 | 反应时间(小时) | 转化率(%) | 酯的%e.e | 构型 |
4 | 3-羟基丁酸甲酯 | 5 | 78.0 | 98.8 | S |
5 | 3-羟基丁酸丁酯 | 6 | 82.0 | 78.5 | S |
实施例6
使用4-叠氮基-3-羟基丁酸乙酯代替实施例1中所用的3-羟基丁酸乙酯。所述反应进行1小时,以83.5%的转化率得到(S)-4-叠氮基-3-羟基丁酸乙酯(80.2%e.e)。
实施例7-8
将4-氯-3-羟基丁酸乙酯用作反应物以及脂肪酶用作生物催化剂,代替实施例1中所用的3-羟基丁酸乙酯。所述结果显示于表3中。
表3
实施例 | 脂肪酶 | 反应时间(小时) | 转化率(%) | 酯的%e.e | 构型 |
7 | 洋葱假单胞菌(Pseudomonas cepatia)脂肪酶 | 22 | 71.0 | 99 | S |
8 | 皱褶假丝酵母脂肪酶 | 32 | 76.0 | 99 | R |
实施例9
将4-溴-3-羟基丁酸乙酯(1%,w/v)用作反应物以及novozyme 435脂肪酶用作生物催化剂,代替实施例1中所用的3-羟基丁酸乙酯。反应1小时40分钟后,以88.3%的转化率得到(R)-4-溴-3-羟基丁酸乙酯(99%e.e)。
实施例10
将4-氰基-3-羟基丁酸乙酯(1%,w/v)用作反应物以及novozyme435脂肪酶用作生物催化剂,代替实施例1中所用的3-羟基丁酸乙酯。反应3小时后,以57.3%的转化率得到(R)-4-氰基-3-羟基丁酸乙酯(99%e.e)。
实施例11-13
将4-氯-3-羟基丁酸用作反应物,代替实施例2中的3-羟基丁酸乙酯,并将表4中的微生物用作生物催化剂。所述结果显示于表4中
表4
实施例 | 微生物 | 反应时间(小时) | 转化(%) | 酯的%e.e | 构型 |
11 | 皱褶假丝酵母KCTC 7292 | 32 | 76.1 | 99 | S |
12 | 皱褶假丝酵母KCCM 50521 | 47 | 77.3 | 99 | S |
13 | Rhodococcusbutanica ATCC21197 | 8 | 76.1 | 99 | R |
工业实用性
根据实施例1-13,可以使用本发明的水解容易地产生光学活性的β-羟基丁酯衍生物。采用适当的脂肪酶或微生物,可产生高光学纯度的β-羟基丁酯衍生物。此外,反应后容易从其酸中分离出光学活性的酯。因此,在工业规模上该方法是有用的方法。
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CN102321690A (zh) * | 2011-07-27 | 2012-01-18 | 陆宏国 | 一种酯类手性胺化合物的制备方法 |
CN104313064A (zh) * | 2014-10-01 | 2015-01-28 | 青岛科技大学 | 一种细胞法生产手性溴苯基丙酸甲酯的方法 |
CN105452395A (zh) * | 2013-08-02 | 2016-03-30 | 伊士曼化工公司 | 包含烷基3-羟基丁酸酯的水性清洁组合物 |
CN105543191A (zh) * | 2016-02-24 | 2016-05-04 | 中国科学院南海海洋研究所 | 一种酯酶phe21及其编码基因和应用 |
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CN1948499B (zh) * | 2006-05-26 | 2010-12-08 | 江南大学 | 生物催化制备(r)-4,4,4-三氟-3-羟基丁酸乙酯的方法 |
KR100893763B1 (ko) | 2007-08-29 | 2009-04-20 | 한국화학연구원 | 광학활성 알킬 3-하이드록시부타노에이트 유도체의 제조방법 |
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US5108916A (en) | 1989-06-05 | 1992-04-28 | Rhone-Poulenc Rorer, S.A. | Process for stereoselectively hydrolyzing, transesterifying or esterifying with immobilized isozyme of lipase from candida rugosa |
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CN102321690A (zh) * | 2011-07-27 | 2012-01-18 | 陆宏国 | 一种酯类手性胺化合物的制备方法 |
CN102321690B (zh) * | 2011-07-27 | 2012-07-18 | 陆宏国 | 一种酯类手性胺化合物的制备方法 |
CN105452395A (zh) * | 2013-08-02 | 2016-03-30 | 伊士曼化工公司 | 包含烷基3-羟基丁酸酯的水性清洁组合物 |
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