CN1183110C - N-保护的氮杂环丁烷-2-羧酸(AzeOHs)的制备方法 - Google Patents
N-保护的氮杂环丁烷-2-羧酸(AzeOHs)的制备方法 Download PDFInfo
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- CN1183110C CN1183110C CNB998100579A CN99810057A CN1183110C CN 1183110 C CN1183110 C CN 1183110C CN B998100579 A CNB998100579 A CN B998100579A CN 99810057 A CN99810057 A CN 99810057A CN 1183110 C CN1183110 C CN 1183110C
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- IADUEWIQBXOCDZ-UHFFFAOYSA-N azetidine-2-carboxylic acid Chemical compound OC(=O)C1CCN1 IADUEWIQBXOCDZ-UHFFFAOYSA-N 0.000 claims abstract description 18
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- 125000003118 aryl group Chemical group 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
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- 150000001539 azetidines Chemical class 0.000 claims 1
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- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
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- OUCUOMVLTQBZCY-BYPYZUCNSA-N (2s)-1-azaniumylpyrrolidine-2-carboxylate Chemical compound NN1CCC[C@H]1C(O)=O OUCUOMVLTQBZCY-BYPYZUCNSA-N 0.000 description 1
- QJAUYWBVJFULHK-UHFFFAOYSA-N 1-benzyl-1-hydroxyguanidine Chemical class NC(=N)N(O)CC1=CC=CC=C1 QJAUYWBVJFULHK-UHFFFAOYSA-N 0.000 description 1
- LJCZNYWLQZZIOS-UHFFFAOYSA-N 2,2,2-trichlorethoxycarbonyl chloride Chemical compound ClC(=O)OCC(Cl)(Cl)Cl LJCZNYWLQZZIOS-UHFFFAOYSA-N 0.000 description 1
- ABSNGNUGFQIDDO-UHFFFAOYSA-N 2-benzylguanidine Chemical class NC(N)=NCC1=CC=CC=C1 ABSNGNUGFQIDDO-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
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- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 1
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- 229910052794 bromium Inorganic materials 0.000 description 1
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- 229910052731 fluorine Inorganic materials 0.000 description 1
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- 238000010438 heat treatment Methods 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
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- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Peptides Or Proteins (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Saccharide Compounds (AREA)
Abstract
提供N-被护氮杂环丁烷-2-羧酸的制备方法，所述方法包括如下步骤：(a)向含氮杂环丁烷-2-羧酸的有机酸加成盐的含水溶剂中加入碱；和(b)向生成的反应混合物中加入保护剂。
Description
本发明涉及制备保护的氮杂环丁烷-2-羧酸(AzeOHs)的新方法。
先有技术
已知L-氮杂环丁烷-2-羧酸(L-AzeOH)可用于尤其是高分子量多肽的合成及特别用作熟知的氨基酸脯氨酸的类似物。
在J.Heterocyclic Chem.(1969)6,993、日本专利申请号第14457/74、Bull.Chem.Soc.Jpn.(1973)46,699、Biochem.J.(1956)64,323及国际专利申请WO97/02241、WO97/41084、WO98/02568和WO98/02417中，描述了对映异构体纯的AzeOH及其衍生物的拆分。
肽合成中，在进行肽偶合反应前，往往希望对基于氨基酸的组分的氨基或羧酸基进行化学保护。如同所有的化学方法一样，若能以方便及在进行后续反应步骤之前将必需大量后处理减至最低的方式完成该方法，则该方法是有利的。
在进行偶合或保护反应前，氨基酸如AzeOH合成或拆分之后，技术人员往往会认为有必要分离所述化合物(如以对映异构体形式为主)。这是为了获得尽可能高的得率的最终偶合或保护的化合物。
令人惊喜地，我们已发现N-保护的的AzeOH及其衍生物可有效地并以高得率获得，而无需从某些反应混合物中分离所述的游离氨基酸(已形成于该混合物中)。
本发明介绍
根据本发明的第一方面，提供了制备N-保护的AzeOH的方法，该方法包括这些步骤：(a)通过向含有所述盐的含水溶剂中加入碱，从AzeOH的有机酸加成盐中置换出有机酸；之后(b)通过向生成的反应混合物中加入胺保护剂保护AzeOH，该方法在下文中称作“本发明的方法”。
介绍的AzeOHs的有机酸加成盐包括AzeOHs的酒石酸加成盐。国际专利申请WO 97/02241和WO 97/41084描述了用酒石酸拆分AzeOH及AzeOH-酒石酸盐的制备。
本发明的方法中，在进行置换步骤(a)之前，所述的含水溶剂包含(即包括)所述的有机酸加成盐。术语“含水溶剂”被本领域的技术人员理解为包括任何单相或多相的溶剂混合物，其中存在水，比如以大于50％，更优选大于75％，特别是大于90％及尤其是大于95％(以溶剂总体积的百分比表示)的量存在。我们优选所述的含水溶剂为单相的和/或基本由水组成的。“基本由水组成”包括所述溶剂为至少99％的纯(如去离子)水。
在进行上述置换步骤(a)(即：向盐的水溶液中加入碱)前，我们优选至少有95％的所述的有机酸加成盐溶于该含水溶剂。
AzeOHs的有机酸加成盐可以某种形式用于本发明的方法，在该形式中羧酸官能度被保护或优选未保护。适用的羧酸保护基包括C1-6烷基或苄基。
可用于本发明的方法的AzeOHs的有机酸加成盐也包括那些其中AzeOH的3-和/或4-位被一个或多个基团如C1-4烷基、C1-4烷氧基、卤素(F、Cl、Br或I)、芳基(如苯基)或芳基-C1-6-烷基(如苄基)所取代的酸加成盐。然而，我们优选采用未被取代的AzeOHs(如AzeOH)的盐。
D-AzeOH或L-AzeOH(优选地)或两种对映异构体的混合物(包括外消旋混合物)可用于本发明的方法。优选的有机酸加成盐为富含非对映体的AzeOH-酒石酸盐，特别是L-AzeOH-D-酒石酸盐。“富含非对映体形式的AzeOH-酒石酸盐”包括有大于40％的非对映体过量的AzeOH-酒石酸盐(如：L-AzeOH-D-酒石酸盐或D-AzeOH-L-酒石酸盐)。
用于置换步骤的含适的碱包括那些碱，它们能从AzeOH中置换出有机酸，而不会置换出所用的任何羧酸保护基，不会与AzeOH或有机酸进行化学反应，也不会引起AzeOH分子内的立体化学变化(如，造成有机酸置换后形成的富含对映体形式的AzeOH的外消旋化)。特别适用的碱包括无机碱，如碱金属(如Na或K)的氢氧化物、醇盐或碳酸盐；有机碱，如普通叔胺碱(如，三乙胺和二异丙基乙胺)或氨。特别优选的碱为氢氧化钾。碱可以固态或优选作为液态(如以溶液形式)加入。
当氢氧化钾用作碱时，置换步骤的适用反应温度在0-80℃范围，特别是15-70℃且更特别地为室温至60℃，但是技术人员会明白这尤其取决于所用的溶剂体系。
置换步骤(a)之后，所置换的有机酸(可以是所述酸的盐)优选在进行保护步骤(b)之前，采用本领域的技术人员所熟知的方法(虽然这种去除不是本发明的方法的必需部分)从反应混合物中去除。
比如，被置换的有机酸(或酸式盐)可以通过结晶除去，通过过饱和于生成的反应混合物(如，通过冷却至过饱和温度和/或通过蒸发溶剂)而进行结晶。最终的结晶温度可取决于溶液中有机酸/酸式盐的浓度和所用的溶剂体系。适用的温度一般在-20-10℃的范围，比如，-10至5℃，优选-5至3℃。可用或不用晶种进行结晶。
采用本领域的技术人员所熟知的方法，如倾析、过滤或离心，分离所置换的酸/酸式盐。
通过向含有来自置换步骤(无论所置换的酸是否除去)的AzeOH的水溶剂中加入合适的保护剂，进行保护步骤(b)。
优选向所述反应混合物中加入碱，以促进保护。碱可以在加入保护剂的同时、之后或优选之前加入。适用的碱包括无机碱，如碱金属(如Na或K)的氢氧化物、醇盐或碳酸盐；有机碱，如普通叔胺碱(如，三乙胺和二异丙基乙胺)或氨。
适用的保护剂包括那些能提供适于保护氨基官能度的保护基团的试剂，这些基团有苄氧基羰基(Cbz)、2-三甲基甲硅烷基乙脂基(Teoc)、4-甲氧基苯甲酰甲基羰基(Phenoc)基团、2，2，2-三氯-乙基羰基(Troc)、2，7-双-叔丁基-(10，10-二氧代-10，10，10-四氢呫吨基)甲基羰基(DBD-Tmoc)或特别是叔丁氧基羰基(Boc)。因此适用的保护剂包括二-叔丁基二碳酸酯。可适量加入保护剂，该量易为本领域的技术人员所确定或估计。例见Int.J.Peptide Protein Res.，21，227(1983)。
本领域的技术人员明白，将适量保护剂加入在适量合适溶剂中的反应混合物中。若所述的保护剂为二-叔丁基碳酸酯时，适用的溶剂包括丙酮、乙酸异丙脂、甲苯、乙腈、乙酸乙酯、乙酸丁脂、二氯甲烷、氯仿、苯和醚(如四氢呋喃)。优选的溶剂包括丙酮、乙酸异丙脂、乙酸乙酯、乙酸丁酯、二氯甲烷、乙腈、四氢呋喃及，尤其是甲苯，可非发明创造性地(non-inventively)确定这类溶剂适当的用量。
进行保护步骤的合适温度取决于诸如所用的保护剂、所用的溶剂体系及反应物的相对用量等因素，且可非发明创造性地确定。比如，当保护剂为二-叔丁基二碳酸脂时，合适的反应温度在室温(如20℃)至40℃范围。
采用本领域的技术人员熟知的技术方法包括下文描述的那些技术方法，可以分离及提纯(如需要)所述的N-护AzeOH。
经本发明的方法生成的N-保护的AzeOH可用于后续的肽偶合反应。生成的N-保护的AzeOH可去保护(在N-原子上和/或如存在羧酸盐保护基则在O-原子上)，使生成的化合物与含氨基的化合物和/或含羧基的化合物反应。如带一游离羧基的N-保护的AzeOH可与脒基苄胺、羟基脒基苄胺或在苯环上含取代基的类似苄胺(用标准方法(如氰基)可转化为脒基或羟基脒基的苄胺)反应。优选的这类苄胺包括在对-位被脒基、羟基脒基或可转变为脒基或羟基脒基的基团(如氰基)取代的苄胺，而且特别包括这样的对-位取代而在其它位置未被取代的苄胺。然后可除去生成的偶合化合物上的N-保护基，且根据本领域技术人员所熟知的方法，将生成的去保护化合物进行进一步的肽偶合反应。
本发明的方法具有惊人的优点：N-保护的AzeOHs可从相应的AzeOH获得，而无需分离未保护(在N-位上)氨基酸的额外工艺步骤。
而且，本发明的方法还有优点：与先有技术所介绍制备方法相比，可以以更高得率、更少时间、更方便且以更低成本的方式制备N-保护的AzeOHs。
通过下列实施例说明但不限制本发明。
实施例1
L-AzeOH水溶液的制备
将L-AzeOH-D-酒石酸盐(14.0克；56毫摩尔；用类似于国际专利申请WO 97/02441所介绍的方法制备)于室温下加入水(17毫升)中。所述的混合物加热到60℃再加入额外量的水(9毫升)以完全溶解L-AzeOH-D-酒石酸盐。用7分钟将KOH(10.8毫升；5.7摩尔)加入到生成的淡黄色溶液中。然后将反应混合物冷却至室温。该温度下放置过夜。再将反应混合物在冰上冷却7个小时，结晶出酒石酸氢钾并滤出。过滤出呈白色固体的酒石酸氢钾(9.5克；91％)和含释出的L-AzeOH的淡黄色水溶液。后者用于下一步而无需进一步鉴定。
实施例2
N-叔丁氧基羰基-AzeOH的制备
用15分钟，将KOH(3.8克；58毫摩尔)加入来自上述实施例1的含L-AzeOH(6.0克；56毫摩尔)的淡黄色水溶液中。将该溶液冷却至17℃，再用10分钟加入溶于甲苯(6毫升)的二-叔丁基二碳酸脂(14.9克；65毫摩尔)溶液。搅拌反应混合物直到达到＞95％转化率(HPLC)。用NaOH(50％水溶液)调节pH至12±0.5且分离两相。有机相用水(5毫升)萃取一秒钟。合并水相，并加入HCl(水溶液)直至pH达到1.8-2.5。用乙酸乙脂(17毫升)萃取含水相两次。蒸发有机相得到叔丁氧基羰基保护的AzeOH白色晶体(9.2克；自L-AzeOH-D-酒石酸脂的得率为85％)。Mp106.2℃1H NMR(200MHz；CDCl3)δ1.45(9H，S)，2.46(2H，d)，3.91(2H，t)，4.75(1H，t)，11.27(1H，S)
Claims (8)
1.N-保护的氮杂环丁烷-2-羧酸的制备方法，所述方法包括下列步骤：(a)向含氮杂环丁烷-2-羧酸的有机酸加成盐的含水溶剂中加入碱；和(b)向生成的反应混合物中加入保护剂；
其中所述氮杂环丁烷-2-羧酸为L-氮杂环丁烷-2-羧酸，其是未被取代的或在3位和/或4-位被一或一以上取代的，其中所述取代基为C1-4烷基、C1-4烷氧基、卤素、芳基或芳基-C1-6-烷基；并且其中的羧酸官能度被保护或未保护；
其中所述碱从氮杂环丁烷-2-羧酸中置换有机酸，但不置换所用的任何羧酸保护基，不与氮杂环丁烷-2-羧酸或有机酸反应，也不在氮杂环丁烷-2-羧酸分子中产生立体化学变化；
其中所述保护剂提供适于保护氨基官能度的保护基团。
2.权利要求1的方法，其特征在于所述有机酸为酒石酸。
3.权利要求2的方法，其特征在于所述酒石酸为D-酒石酸。
4.权利要求1的方法，其特征在于所述芳基为苯基。
5.权利要求1的方法，其特征在于所述芳基-C1-6-烷基为苄基。
6.权利要求1-5中任一顶的方法，其特征在于所述氮杂环丁烷-2-羧酸为羧酸官能度未保护的和/或在3位和/或4-位未被取代的氮杂环丁烷-2-羧酸。
7.权利要求1-5中任一项的方法，其特征在于所述盐为L-氮杂环丁烷-2-羧酸-D-酒石酸盐。
8.权利要求1-5中任一项的方法，其特征在于所述保护剂提供叔丁氧基羰基基团。
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| US7489026B2 (en) * | 2006-10-31 | 2009-02-10 | Freescale Semiconductor, Inc. | Methods and apparatus for a Quad Flat No-Lead (QFN) package |
| KR102349264B1 (ko) | 2019-04-12 | 2022-01-10 | 최병환 | 냉온수 기능과 향상된 살균 및 음이온발생 기능이 부여된 자화수기 |
| KR102349271B1 (ko) | 2019-04-12 | 2022-01-10 | 최병환 | 살균 및 음이온발생 성능이 향상된 육각 자화수기 공급구조 |
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| CA2140598C (en) | 1994-01-27 | 2010-03-09 | Masahiro Ohshima | Prolineamide derivatives |
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| IN187238B (zh) | 1995-06-30 | 2002-03-09 | Astra Ab | |
| SE9601600D0 (sv) | 1996-04-26 | 1996-04-26 | Astra Ab | Improved process |
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| ES2246092T3 (es) | 2006-02-01 |
| AU770530B2 (en) | 2004-02-26 |
| AU6014099A (en) | 2000-03-21 |
| NO20011031D0 (no) | 2001-02-28 |
| WO2000012473A8 (en) | 2000-11-16 |
| NZ509984A (en) | 2003-07-25 |
| DE69926642T2 (de) | 2006-06-08 |
| NO319783B1 (no) | 2005-09-12 |
| DE69926642D1 (de) | 2005-09-15 |
| KR100643824B1 (ko) | 2006-11-10 |
| KR20010073068A (ko) | 2001-07-31 |
| CY1106051T1 (el) | 2011-04-06 |
| JP2002523490A (ja) | 2002-07-30 |
| US20030149280A1 (en) | 2003-08-07 |
| EP1109782A1 (en) | 2001-06-27 |
| PT1109782E (pt) | 2005-11-30 |
| IL141284A0 (en) | 2002-03-10 |
| DK1109782T3 (da) | 2005-10-17 |
| SE9802939D0 (sv) | 1998-09-01 |
| SI1109782T1 (sl) | 2005-12-31 |
| BR9913249A (pt) | 2001-05-22 |
| NO20011031L (no) | 2001-05-02 |
| CA2339826A1 (en) | 2000-03-09 |
| ZA200101587B (en) | 2002-05-27 |
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| CN1314886A (zh) | 2001-09-26 |
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