CN1982301A - 2’,2’-二氟核苷及其中间体的制备方法 - Google Patents
2’,2’-二氟核苷及其中间体的制备方法 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings 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
- C07D307/32—Oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings 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
- C07D307/32—Oxygen atoms
- C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members 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
- C07D307/20—Oxygen atoms
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
本发明涉及2’-脱氧-2’,2’-二氟核苷及其中间体的改进制备方法,将(3RS)-2,2-二氟-3-羟基-3-(2,2-二烷基二氧杂环戊烷-4-基)丙酸烷基酯使用由乙酸或氯乙酸与水混合组成的混合液、或由乙酸或氯乙酸与水和有机溶剂混合组成的混合液,形成内酯后,在3-位和5-位引入取代苯甲酰基保护基,通过再结晶制备98%以上高纯度的赤型对映体。另外,以α∶β比例约为2∶3制备3’-位和5’-位由取代苯甲酰基保护的2’-脱氧-2’,2’-二氟核苷,并通过再结晶选择性地制备99%以上纯度的3’-位和5’-位由取代苯甲酰基保护的β-2’-脱氧-2’,2’-二氟核苷。
Description
技术领域
本发明涉及具有良好抗肿瘤活性的由下述化学式1表示的2’,2’-二氟核苷及其中间体的制备方法。
化学式1
背景技术
欧洲专利EP184365记载了由上述化学式1表示的2’-脱氧-2’,2’-二氟核苷具有用作肿瘤细胞的消除化合物的用途,该2’-脱氧-2’,2’-二氟核苷目前广泛用作非小细胞肺癌、胰腺癌、膀胱癌以及转移性乳腺癌的治疗剂。
上述2’-脱氧-2’,2’-二氟核苷的制备方法已公开US 4526988和US4808614中。其反应式如下述反应式1。
[反应式1]
上述反应式1中,R4和R5分别独立地表示C1-C3的烷基,P表示羟基保护基,L表示离去基团。
具有良好抗肿瘤活性的2’-脱氧-2’,2’-二氟核苷制备中,碳水化合物具有核糖的立体化学结构。通过上述现有的制备方法制得的中间体内酯化合物(III)为赤型(erthro)和苏型(threo)对映异构体的混合物。
(赤型) (苏型)
上述现有技术由于赤型对映体可提供天然核糖立体化学结构的碳水化合物,所以理想。
上述现有技术中,在第一反应步骤中制得的由化学式IV表示的化合物2,2-二氟-3-羟基-3-(2,2-二烷基二氧杂环戊烷-4-基)丙酸烷基酯为3-R-对映体和3-S-对映体以约3∶1的比例的混合物。
由于3-R-羟基对映体具有适当的立体化学结构,因而可得到所需的部分赤型的对映异构体(diasteromer)。上述现有技术中记载,利用柱色谱方法将3-R-对映体和3-S-对映体分离得到3-R-羟基对映体后,在酸性条件下进行水解,制备非保护的由化学式III表示的内酯化合物2-脱氧-2,2-二氟-D-赤-戊呋喃糖-1-苷的制备方法。但是,上述现有技术的制备方法由于需要柱色谱,所以成本高且工业实用性差。
另外,由上述化学式II表示的化合物可提供β-端基差向异构体(anomer)前体具有良好生物活性的2’-脱氧-2’,2’-二氟核苷。上述现有技术还记载作为保护基团的叔丁基甲硅烷基的用途。
上述现有技术中提到的保护基团可用于2’-脱氧-2’,2’-二氟核苷的合成,所以生成物中α-端基差向异构体和β-端基差向异构体的比例可以为约4∶1。上述现有技术的由上述化学式II表示的化合物制备方法的缺点是,上述生成物需要通过成本高且工业实用性差的柱色谱进行精制才能得到所需的β-端基差向异构体。而且,β-端基差向异构体的收率低。
韩国专利公告第1997-2659号记载了上述现有技术的改进方法。该制备方法不需要成本高且工业实用性差的柱色谱进行精制,即可得到所需的具有赤型及β-立体化学结构的2’-脱氧-2’,2’二氟核苷。该方法可由下述反应式2表示。
[反应式2]
但是,上述制备方法是利用强酸在78℃以上的高温回流8小时以上进行反应。因此,由于在严格条件下制备,通过上述制备方法生成的由上述化学式IX表示的化合物非常不稳定,制备的生成物的收率也非常低。另外,上述制备方法为了制备由化学式VIII表示的纯化合物,将赤型和苏型混合物进行再结晶后分离,但赤型纯度仍限定在95%。因此,根据上述现有制备方法非常难制得高纯度的2’-脱氧-2’,2’-二氟核苷。
另外,上述制备方法是将由化学式VII表示的化合物与适当的碱B-H反应,得到由化学式VI表示的化合物后,再次与碱反应,消除苯甲酰基保护基团,制得2’-脱氧-2’,2’-二氟核苷化合物。
但是,通过上述制备方法制得的2’-脱氧-2’,2’-二氟核苷化合物,其α-端基差向异构体:β-端基差向异构体比例限定在1∶1,所以含有50%以上的不必要的α-端基差向异构体。当由化学式VII表示的化合物与碱B-H反应时,需要使用高成本的三甲基硅烷基三氟乙酸酯试剂。
上述制备方法中,为了选择性地分离具有β立体化学结构的2’-脱氧-2’,2’-二氟核苷,制备α∶β=1∶1的端基差向异构体盐酸盐,将混合物用热水溶解,加入丙酮,除去固体沉淀,并重复上述操作,得到纯度约99%的β-2’-脱氧-2’,2’-二氟核苷盐酸盐。但是,上述精制方法中,为了提高纯度而需要反复进行再结晶,所以操作复杂,且再结晶时会降低收率,因此降低经济性。
另一方面,韩国专利公告第424990号提出了2’-脱氧-2’,2’-二氟核苷的分离及精制方法。
上述现有技术中,在碱和碳水化合物的糖基化反应中,使用α-端基差向异构体的碳水化合物或大量含有α-端基差向异构体的碳水化合物。韩国专利公告第302087号记载了α-端基差向异构体的碳水化合物的制备方法,该方法是首先在低温下制备α端基差向异构体和β-端基差向异构体混合的碳水化合物后,进行再结晶,分离α-端基差向异构体。但是,该精制收率为35.5~68%,较低,而且不能再现,所以工业上不实用。这样分离的大量含有α-端基差向异构体的碳水化合物与碱进行糖基化反应,可以制备大量含有β-端基差向异构体的混合物,但是反应后利用液相色谱方法分析结果,α∶β比例为约4∶6。因此,没有必要以68%以下的低收率分离α-端基差向异构体后进行糖基化反应。另外,反应溶剂使用沸点为154℃的有毒的苯甲醚,所以反应后处理非常繁琐。因此,最终产物2’-脱氧-2’,2’-二氟核苷残留有溶剂,这会影响纯度。
发明内容
本发明目的是提供由下述化学式1表示的2’-脱氧-2’,2’-二氟核苷的制备方法,该方法能够制得具有高纯度的天然核糖立体化学结构的中间体化合物。
另外,本发明目的是提供通过脱保护反应制得99.9%以上高纯度的由化学式1表示的2’-脱氧-2’,2’-二氟核苷的制备方法。
本发明提供通过引入作为新保护基团的取代苯甲酰基制得新中间体化合物的制备方法、以及通过N-糖基化反应制得99%以上纯度的β-端基差向异构体的精制方法。
本发明提供通过脱保护反应选择性地制得99.9%以上纯度的由化学式1表示的2’-脱氧-2’,2’-二氟核苷盐酸盐制备方法。
具体实施方式
下面详细说明本发明。
本发明制备方法用下述反应式3简要表示。
[反应式3]
上述反应式3中,R表示
或H,X表示F、Cl、Br、I或NO2,Y表示H、F、Cl、Br、I或NO2,X和Y优选为3-位或5-位取代的取代苯甲酰基。另外,L表示甲基磺酰基,P表示对甲苯基磺酰基,R4和R5分别独立地表示C1-C3的烷基。
本发明提供在由上述化学式4表示的化合物中,引入取代苯甲酰基作为新保护基团,制得由化学式6表示的新中间体化合物的合成方法。由化学式4表示的化合物利用不是强酸的弱酸或较强酸的温和水解剂进行反应,以温和条件制备由化学式6表示的上述内酯化合物。将强酸作为水解剂使用时,生成的由化学式5表示的化合物在强酸中不稳定,在反应中产生分解,因此降低收率。
本发明中用作水解剂的“弱酸或较强酸”是乙酸或氯乙酸。本发明中,将上述乙酸与水混合使用作为水解剂,或者将乙酸与有机溶剂和水适当混合使用作为水解剂。本发明中的乙酸是,将乙酸与水混合形成的10~95%的乙酸。有机溶剂可使用乙腈、二氧杂环己烷、四氢呋喃以及甲苯等中的至少一种。乙酸、有机溶剂和水按10~95∶0~70∶5~90重量比混合。
本发明中为了制备高纯度的2’-脱氧-2’,2’-二氟核苷,必须制备高纯度的具有天然核糖立体化学结构的由化学式6表示的中间体化合物。
因此,本发明中,引入如下定义的取代苯甲酰基保护基团,制得由下述化学式6’表示的化合物的赤型和苏型内酯的对映体混合物。特别是,在有机合成反应中,在3-位或5-位引入卤素或硝基等吸电子基团,醇中引入保护基团时,其反应性比苯甲酰基的反应性更强。因此,本发明中使用取代苯甲酰基时,容易制备由化学式6’表示的化合物。另外,引入取代苯甲酰基保护基团的由化学式6’表示的化合物的赤型和苏型内酯的对映体混合物,与引入苯甲酰基保护基团的以往化合物相比,在进行再结晶精制时,可选择性地制得更高纯度的由化学式6表示的化合物的赤型化合物。另外,作为再结晶溶剂可以使用乙酸乙酯、己烷或庚烷。本发明可制得约98.0%以上高纯度的具有如下定义的取代苯甲酰基保护基团的所需赤型化合物。
上述式6和式6’中,R表示
X表示F、Cl、Br、I或NO2,Y表示H、F、Cl、Br、I或NO2,X和Y优选为3-位或5-位取代的取代苯甲酰基。另外,L表示甲基磺酰基,P表示对甲苯基磺酰基。
如反应式3所示,由化学式6表示的化合物可通过已知方法(Synthesis1992,565)转换为由化学式8表示的化合物,优选的离去基团为甲基磺酰基。
另外,本发明可提供将由上述化学式9表示的已保护碳水化合物和硅烷基化的碱进行糖基化反应,在该反应中不需要使用高成本三甲基硅烷基三氟乙酸酯试剂的制备方法;使用α-端基差向异构体:β-端基差向异构体比例为1∶1的碳水化合物进行反应的制备方法;以及不使用高沸点的溶剂、特别是苯甲醚可进行反应的制备方法。
本发明为了提高糖基化反应中的碱的反应性,氧原子优选利用硅烷基保护基团进行烯醇化。根据本发明的合成方法,将碱与硅烷基化试剂进行硅烷基化反应后,不需要另外使用溶剂,在硅烷基化试剂中加入碳水化合物或除去硅烷基化试剂后加入碳水化合物,进行糖基化反应,使α-端基差向异构体和β-端基差向异构体的比例约为2∶3,提高选择性。作为硅烷基化试剂可使用六甲基硅氨烷(HMDS)或双三甲硅烷基乙酰胺(BSA)。反应温度为60~160℃,优选为120~140℃,反应时间约为4小时至72小时。
根据本发明的精制方法,将制备成α∶β约为2∶3的由化学式9’表示的2’-脱氧-2’,2’-二氟-3’,5’-双(取代苯甲酸酯基)胞嘧啶利用再结晶,精制得到β-端基差向异构体的纯度为99%以上的、由化学式9表示的化合物。此时,作为再结晶溶剂可使用甲醇、乙醇、异丙醇、乙酸乙酯、氯仿、二氯甲烷中的至少一种,优选乙酸乙酯。
上述式中,R表示
X表示F、Cl、Br、I或NO2,Y表示H、F、Cl、Br、I或NO2,X和Y优选为3-位或5-位取代的取代苯甲酰基。另外,L表示甲基磺酰基,P表示对甲苯基磺酰基。
因此,将高纯度的2’-脱氧-2’,2’-二氟-3’,5’-双(取代苯甲酸酯基)胞嘧啶,按已知方法利用氨等进行脱保护,制得β-2’-脱氧-2’,2’-二氟胞嘧啶,并将其在乙醇中加热溶解后,加入相同当量的浓盐酸,选择性地制得99.9%以上高纯度的β-2’-脱氧-2’,2’-二氟胞嘧啶盐酸盐。
下面根据实施例进一步详细说明本发明,下述实施例只是用于说明本发明,本发明的保护范围并不限定在这些。
实施例1
2-脱氧-2,2-二氟-1-氧代核糖的制备
(3R,S)-2,2-二氟-3-羟基-3-(2,2-二甲基二氧杂环戊烷-4-基)丙酸乙酯(30克,0.118摩尔)中加入乙腈(165毫升)、乙酸(67.6毫升)以及水(11.7毫升)溶解后,搅拌回流4小时。减压浓缩反应液后,加入甲苯(165毫升)进行减压浓缩。该浓缩物中加入乙腈(165毫升),并加入甲苯(300毫升),进行蒸馏并减压浓缩。该浓缩物中加入乙酸乙酯(200毫升)进行稀释后,加入活性炭(3克)搅拌10分钟。将混合液用无水硫酸钠处理后,用硅藻土过滤,得到的滤液进行减压浓缩,得到2-脱氧-2,2-二氟-1-氧代核糖(20克,100%)。
1H NMR(DMSO d6);δ=3.6~3.8(m,2H),4.2~4.3(m,1H),4.3~4.5(m,1H)
实施例2
2-脱氧-2,2-二氟-D-赤-3,5-双(3-氟苯甲酸酯基)戊呋喃糖-1-苷的制备
2-脱氧-2,2-二氟-1-氧代核糖(20克,0.119摩尔)中加入乙酸乙酯(200毫升)溶解后,加入4-二甲基胺基吡啶(29克),并加入吡啶(28克)后,加入3-氟苯甲酰氯(2.5克)。将反应液在60℃昼夜搅拌。反应结束后,利用稀盐酸水溶液以及饱和食盐水分别洗涤。将有机层利用无水硫酸钠干燥后,过滤、减压浓缩后,在该浓缩液中加入乙酸乙酯(23毫升)溶解后,加入己烷(68毫升),冷却至0℃。将生成的结晶过滤后,利用冷却的乙酸乙酯∶己烷=1∶3(体积比)混合液进行洗涤,干燥后,得到2-脱氧-2,2-二氟-D-赤-3,5-双(3-氟苯甲酸酯基)戊呋喃糖-1-苷(26.7克,46%)。
1H NMR(CDCl3);δ=4.69~4.73(dd,J=1.2Hz,2H),4.96(q,1H),5.72(m,1H),7.24~7.49(m,4H),7.66~8.86(m,4H)
实施例3
2-脱氧-2,2-二氟-3,5-双(3-氟苯甲酸酯基)-D-呋喃核糖的制备
2-脱氧-2,2-二氟-D-赤-3,5-双(3-氟苯甲酸酯基)戊呋喃糖-1-苷(24克,0.058摩尔)中加入四氢呋喃(240毫升)溶解后,加入氢化三叔丁氧基铝锂(22.2克,0.087摩尔)后,在室温下搅拌30分钟。确认反应结束后,将反应液利用乙酸乙酯(960毫升)稀释后,利用稀盐酸水溶液、饱和碳酸氢钠水溶液、水以及饱和食盐水分别洗涤。利用无水硫酸钠干燥后,过滤、减压浓缩,得到2-脱氧-2,2-二氟-3,5-双(3-氟苯甲酸基)-D-呋喃核糖(24克,100%)。
1H NMR(CDCl3);δ=4.4~4.75(m,3H),5.55(d,1H),5.4~5.7(m,1H),7.23~7.45(m,4H),7.70~7.89(m,4H)
实施例4
2-脱氧-2,2-二氟-D-呋喃核糖基-3,5-双(3-氟苯甲酸酯基)-1-甲基磺酸酯的制备
2-脱氧-2,2-二氟-3,5-双(3-氟苯甲酸酯基)-D-呋喃核糖(24克,0.057摩尔)利用二氯甲烷(240毫升)溶解后,加入三乙胺(9.8克,0.097摩尔)溶解后,冷却至5℃。加入甲基磺酰氯(7.8克,0.068摩尔),搅拌2小时。反应结束后,将反应液利用稀盐酸水溶液和水分别洗涤。利用无水硫酸钠干燥后,过滤、减压浓缩,得到2-脱氧-2,2-二氟-D-呋喃核糖基-3,5-双-(3-氟苯甲酸酯基)-1-甲基磺酸酯(28.5克,100%)。
1H NMR(CDCl3);δ=3.10(s,3H),4.67~4.72(m,2H),4.8(m,1H),5.5(dd,1H),6.1(d,1H),7.24~7.46(m,4H),7.70~7.85(m,4H)
实施例5
2’,2’-二氟-3’,5’-双(3-氟苯甲酸酯基)-2’-脱氧胞嘧啶的制备
胞嘧啶(63.2克,0.57摩尔)中加入1,1,1,3,3,3-六甲基硅氨烷(3 16毫升)和硫酸铵(7.5克,0.057摩尔)后,回流搅拌2小时。加入2-脱氧-2,2-二氟-D-呋喃核糖基-3,5-双(3-氟苯甲酸酯基)-1-甲基磺酸酯(28.5克,0.057摩尔)后,搅拌回流。反应结束后,加入异丙醇(63.2毫升),并加入稀HBr溶液后,在60℃搅拌约1小时。将混合物冷却并离心分离后,用水洗涤,并用异丙醇洗涤。将得到的结晶热风干燥后,溶解在甲醇(160毫升)中,加入30%氨水(2.7毫升)搅拌后,减压浓缩。该浓缩物中加入乙酸乙酯(500毫升)混浊后,用水洗涤。将有机层减压浓缩,用乙酸乙酯再结晶,得到99%以上为β异构体的2’,2’-二氟-3’,5’-双(3-氟苯甲酸基)-2’-脱氧胞嘧啶(10.4克,36%)。
1H NMR(CDCl3);δ=4.53(m,1H),4.71~4.75(m,2H),5.60(m,1H),5.71(d,1H),6.60(m,1H),7.24~7.87(m,8H)
实施例6
2’-脱氧-2’,2’-二氟胞嘧啶的制备
2’,2’-二氟-3’,5’-双(3-氟苯甲酸基)-2’-脱氧胞嘧啶(10.4克,0.02摩尔)中加入甲醇(104毫升)溶解后,加入30%氨水(20.8毫升),常温下搅拌3小时。确认反应结束后,将反应液减压浓缩,该浓缩物中加入水(104毫升)溶解。用乙酸乙酯(100毫升)洗涤两次后,将水层减压浓缩,得到2’-脱氧-2’,2’-二氟胞嘧啶(5.4克,100%)。
1H NMR(DMSO-d6);δ=3.60~3.64(dd,J=3.6Hz,1H),3.75~3.78(dd,1H),3.88(m,1H),4.16(m,1H),6.04(m,1H),6.24(d,1H),8.14(d,1H),8.89(s,1H),10.04(s,1H)
实施例7
2’-脱氧-2’,2’-二氟胞嘧啶盐酸盐的制备
2’-脱氧-2’,2’-二氟胞嘧啶(5.4克,0.02摩尔)中加入乙醇(54毫升),加入浓盐酸(1.82毫升)后,回流搅拌30分钟。冷却反应液后,过滤生成的晶体。将该晶体用冷却的乙醇洗涤后,热风干燥12小时,得到99.9%以上纯度的2’-脱氧-2’,2’-二氟胞嘧啶盐酸盐(5.5克,90%)。
1H NMR(DMSO-d6);δ=3.60~3.64(dd,J=3.6Hz,1H),3.75~3.78(dd,1H),3.88(m,1H),4.16(m,1H),6.04(m,1H),6.24(d,1H),8.14(d,1H),8.89(s,1H),10.04(s,1H)
本发明提供通过引入作为新保护基团的取代苯甲酰基制得新中间体化合物的制备方法、以及通过N-糖基化反应制得99%以上纯度的β-端基差向异构体的精制方法。
另外,根据本发明,通过脱保护反应,选择性地制得99.9%以上纯度的由化学式1表示的2’-脱氧-2’,2’-二氟核苷盐酸盐。
Claims (10)
2、如权利要求1所述的由化学式5表示的赤型和苏型内酯的对映体混合物的制备方法,其特征是,所述作为水解剂使用的乙酸或氯乙酸与水和有机溶剂的混合液是按10~95∶5~90∶0~70重量%混合的。
3、一种由下述化学式6表示的化合物的2-脱氧-2,2-二氟-3,5-双(取代苯甲酸酯基)-D-赤-戊呋喃糖-1-苷的选择性分离方法,其特征是,该方法包括将由下述化学式6’表示的化合物的赤型和苏型内酯的对映体混合物溶解于乙酸乙酯中后,加入己烷,将该溶液冷却至0至-5℃温度后,得到赤型对映体沉淀的步骤,从由下述化学式6’表示的化合物的赤型和苏型内酯的对映体混合物以98%以上纯度选择性地分离由化学式6表示的化合物的2-脱氧-2,2-二氟-3,5-双(取代苯甲酸酯基)-D-赤-戊呋喃糖-1-苷,
4、如权利要求3所述的方法,其中,该方法还包括在所述溶解于乙酸乙酯中的对映体混合物溶液中加入己烷或庚烷,得到己烷/乙酸乙酯或庚烷/乙酸乙酯溶剂的混合物。
5、一种由化学式9表示的2’-脱氧-2’,2’-二氟-3’,5’-双(取代苯甲酸酯基)胞嘧啶的精制方法,其中,首先将碱与硅烷基化试剂进行烯醇化后,在将硅烷基化试剂作为反应溶剂、或除去硅烷基化试剂后无溶剂条件下,将碱和由下述化学式8表示的已保护碳水化合物加热反应后,得到由化学式9’表示的化合物的α-端基差向异构体和β-端基差向异构体混合物,并将其进行再结晶,得到β-端基差向异构体的纯度为98%以上的、由化学式9表示的2’-脱氧-2’,2’-二氟-3’,5’-双(取代苯甲酸酯基)胞嘧啶,
6、如权利要求5所述的方法,其中,将六甲基硅氨烷或双三甲硅烷基乙酰胺作为反应溶剂使用。
7、如权利要求5所述的方法,其中,反应的温度为60~160℃。
8、如权利要求5所述的方法,其中,使用甲醇、乙醇、异丙醇、乙酸乙酯、氯仿和二氯甲烷中的至少一种作为再结晶溶剂。
10、一种通过权利要求5所述的方法分离的β-端基差向异构体的纯度为98%以上的、由下述化学式9表示的2’-脱氧-2’,2’-二氟-3’,5’-双(取代苯甲酸酯基)胞嘧啶化合物。
上述化学式9中,R表示
,X表示F、Cl、Br、I或NO2,Y表示H、F、Cl、Br、I或NO2。
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