CN102127155B - 促生长素抑制素肽的制备 - Google Patents
促生长素抑制素肽的制备 Download PDFInfo
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- CN102127155B CN102127155B CN2010105957529A CN201010595752A CN102127155B CN 102127155 B CN102127155 B CN 102127155B CN 2010105957529 A CN2010105957529 A CN 2010105957529A CN 201010595752 A CN201010595752 A CN 201010595752A CN 102127155 B CN102127155 B CN 102127155B
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- 238000002360 preparation method Methods 0.000 title description 6
- 102000005157 Somatostatin Human genes 0.000 title description 4
- 108010056088 Somatostatin Proteins 0.000 title description 4
- 238000000034 method Methods 0.000 claims abstract description 35
- NHXLMOGPVYXJNR-ATOGVRKGSA-N somatostatin Chemical class C([C@H]1C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N1)[C@@H](C)O)NC(=O)CNC(=O)[C@H](C)N)C(O)=O)=O)[C@H](O)C)C1=CC=CC=C1 NHXLMOGPVYXJNR-ATOGVRKGSA-N 0.000 claims abstract description 7
- 238000004519 manufacturing process Methods 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 29
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 24
- 150000001413 amino acids Chemical class 0.000 claims description 19
- -1 substituted-phenyl Chemical group 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 16
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 15
- 125000003368 amide group Chemical group 0.000 claims description 14
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 claims description 13
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 claims description 13
- 125000006239 protecting group Chemical group 0.000 claims description 11
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 230000000903 blocking effect Effects 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- BOTNYLSAWDQNEX-UHFFFAOYSA-N phenoxymethylbenzene Chemical compound C=1C=CC=CC=1COC1=CC=CC=C1 BOTNYLSAWDQNEX-UHFFFAOYSA-N 0.000 claims 2
- 239000003153 chemical reaction reagent Substances 0.000 claims 1
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- 239000000543 intermediate Substances 0.000 abstract 1
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
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- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 5
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- 229910052801 chlorine Inorganic materials 0.000 description 5
- 238000005984 hydrogenation reaction Methods 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- 206010013786 Dry skin Diseases 0.000 description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 238000005520 cutting process Methods 0.000 description 4
- 238000000151 deposition Methods 0.000 description 4
- NOAAMORLQWOAEL-UHFFFAOYSA-N ethoxy-n,n-di(propan-2-yl)phosphonamidous acid Chemical compound CCOP(O)N(C(C)C)C(C)C NOAAMORLQWOAEL-UHFFFAOYSA-N 0.000 description 4
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 4
- 229940011051 isopropyl acetate Drugs 0.000 description 4
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 4
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 238000010532 solid phase synthesis reaction Methods 0.000 description 4
- SWZCTMTWRHEBIN-QFIPXVFZSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-(4-hydroxyphenyl)propanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)C1=CC=C(O)C=C1 SWZCTMTWRHEBIN-QFIPXVFZSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 0 CC(C)(C([C@](CCCCN)NC(C)(C)C([C@@](Cc1c[n]c2ccccc12)NC(C(c1ccccc1)NC([C@](C[C@](C1)OC(N*)=O)N1C(C)(C)C([C@@](Cc1ccccc1)N1)=O)=O)=O)=O)=O)NC(C*)C1=O Chemical compound CC(C)(C([C@](CCCCN)NC(C)(C)C([C@@](Cc1c[n]c2ccccc12)NC(C(c1ccccc1)NC([C@](C[C@](C1)OC(N*)=O)N1C(C)(C)C([C@@](Cc1ccccc1)N1)=O)=O)=O)=O)=O)NC(C*)C1=O 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
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- 125000003277 amino group Chemical group 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
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- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 3
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- 239000001301 oxygen Substances 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
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- REHSJSKPWIOKIJ-LJAQVGFWSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-(4-phenylmethoxyphenyl)propanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)C(C=C1)=CC=C1OCC1=CC=CC=C1 REHSJSKPWIOKIJ-LJAQVGFWSA-N 0.000 description 2
- UMRUUWFGLGNQLI-QFIPXVFZSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-6-[(2-methylpropan-2-yl)oxycarbonylamino]hexanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(O)=O)C3=CC=CC=C3C2=C1 UMRUUWFGLGNQLI-QFIPXVFZSA-N 0.000 description 2
- OBTZDIRUQWFRFZ-UHFFFAOYSA-N 2-(5-methylfuran-2-yl)-n-(4-methylphenyl)quinoline-4-carboxamide Chemical compound O1C(C)=CC=C1C1=CC(C(=O)NC=2C=CC(C)=CC=2)=C(C=CC=C2)C2=N1 OBTZDIRUQWFRFZ-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- SORGEQQSQGNZFI-UHFFFAOYSA-N [azido(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(N=[N+]=[N-])OC1=CC=CC=C1 SORGEQQSQGNZFI-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-L aspartate group Chemical group N[C@@H](CC(=O)[O-])C(=O)[O-] CKLJMWTZIZZHCS-REOHCLBHSA-L 0.000 description 2
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- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 2
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- MVLULFFLSSSRIU-NXCFDTQHSA-N methyl (2s)-2-[[(2r)-2-[[(2s)-2-amino-2-phenylacetyl]amino]-3-(1h-indol-3-yl)propanoyl]amino]-6-[(2-methylpropan-2-yl)oxycarbonylamino]hexanoate Chemical compound C1([C@H](N)C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OC)=CC=CC=C1 MVLULFFLSSSRIU-NXCFDTQHSA-N 0.000 description 2
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- HNCIZPXIEYTVEQ-DSPMFFIESA-N methyl (2s)-2-[[(2r)-3-(1h-indol-3-yl)-2-[[(2s)-2-phenyl-2-(phenylmethoxycarbonylamino)acetyl]amino]propanoyl]amino]-6-[(2-methylpropan-2-yl)oxycarbonylamino]hexanoate Chemical compound N([C@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OC)C=1C=CC=CC=1)C(=O)OCC1=CC=CC=C1 HNCIZPXIEYTVEQ-DSPMFFIESA-N 0.000 description 2
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- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
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- 150000001412 amines Chemical class 0.000 description 1
- 150000003862 amino acid derivatives Chemical class 0.000 description 1
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- 238000004458 analytical method Methods 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 239000012964 benzotriazole Substances 0.000 description 1
- 150000003857 carboxamides Chemical class 0.000 description 1
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- 238000001816 cooling Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 125000004956 cyclohexylene group Chemical group 0.000 description 1
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
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- 150000002148 esters Chemical class 0.000 description 1
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- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 1
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- 229910052736 halogen Inorganic materials 0.000 description 1
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- MXHTZQSKTCCMFG-UHFFFAOYSA-N n,n-dibenzyl-1-phenylmethanamine Chemical compound C=1C=CC=CC=1CN(CC=1C=CC=CC=1)CC1=CC=CC=C1 MXHTZQSKTCCMFG-UHFFFAOYSA-N 0.000 description 1
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
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- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
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- 229920002223 polystyrene Polymers 0.000 description 1
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- 125000004076 pyridyl group Chemical group 0.000 description 1
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- 238000000926 separation method Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
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- 238000003786 synthesis reaction Methods 0.000 description 1
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- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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Abstract
提供制备环促生长素抑制素类似物的方法以及用于该方法中的线性中间体。
Description
本申请是申请日为2004年8月6日、发明名称为“促生长素抑制素肽的制备”的中国专利申请200480022794.6(PCT/EP2004/008850)的分案申请。
本发明涉及制备环促生长素抑制素类似物的方法以及该方法中使用的中间体。
本发明更具体地提供制备式I的环促生长素抑制素类似物或其盐的方法。
其中
R1为-C2-6亚烷基-NR3R4、-C2-6亚烷基-胍或-C2-6亚烷基-COOH,其中R3和R4各独立为H、C1-4烷基、ω-羟基-C2-4亚烷基或酰基,或R3和R4与它们所连接的氮原子形成可以含有其它杂原子的杂环基团,并且
R2为Z1-CH2-R5、-CH2-CO-O-CH2-R5
其中Z1为O或S,R5任选为取代苯基。
可以是任何酰基例如RaCO-,其中Ra为H、C1-4烷基、C2-4链烯基、C3-6环烷基或苯甲基。当NR3R4形成杂环基团时,这类基团可以是芳香或饱和的基团,并且可以含有一个氮原子或一个氮原子和另一个选自氮和氧的杂原子。杂环基团优选为例如吡啶基或吗啉代。C2-6亚烷基优选为-CH2-CH2-。当R5为取代苯基时,苯环可以在例如邻位和/或对位被卤素、甲基、乙基、甲氧基或乙氧基取代。R5优选为未取代苯基。
2和/或5位的氨基酸可以具有D或L构型。其中它们都具有L构型。
式I的化合物可以以例如游离或盐形式存在。盐包括与例如有机酸、聚合酸或无机酸(例如盐酸、醋酸、乳酸、天冬氨酸、苯甲酸、琥珀酸或双羟萘酸)的加酸盐,或例如当R1含有COOH基团时为碱金属盐。取决于将1个还是2个酸等价物加入游离碱形式的式I的化合物上,加酸盐可以以单价或二价盐存在。优选的盐为天冬氨酸二盐(或酯)或双羟萘酸单盐。
本发明的生产方法包括受保护形式的相应线性肽的环化步骤。现在惊奇地发现环化步骤尤其依赖于相应线性肽2个末端氨基酸的选择。在6种环化可能中,惊奇地发现在氨基酸3和4、或4和5、或6和1之间的环化提供令人显著关注的结果。尤其优选氨基酸4和5之间的环化。根据本发明在氨基酸3和4、或4和5、或6和1之间的环化引起产量的提高并伴随手性位点异构化的降低。另外,可以以较低的严紧性条件和反应物实施这些环化步骤:例如可以避免通过使用叠氮化合物环化。
在本发明第一个实施方案中,提供制备如上所示的式I化合物或其盐的方法,包括环化式II
或式III
或式IV
的线性促生长素抑制素类似物,
并且在需要的地方去除保护基团,
并回收由此获得的游离形式或盐形式的式I化合物,
其中R1和R2如上所定义,
R11和R12各独立为氨基保护基团,
由此当R1含有末端NH2时,该末端NH2也被氨基保护基团保护。
合适的氨基保护基团如例如《Protective Groups in OrganicSynthesis》,T.W.Greene等人,John Wiley & Sons Inc.,第二版,1991所述。这类氨基保护基团的实例例如用于肽合成的乙酰基或氨基基团,例如叔丁氧基羰基、苯氧羰基、芴基甲氧羰基、alloxycarbonyl、1-(4,4-二甲基-2,6-二氧环亚己基)乙基、1-(4,4-二甲基-2,6-二氧环亚己基)-3-甲基丁基、4-甲基三苯甲基。(W.C.Chan和P.D.White,《Fmoc solid Phase PeptideSynthesis》,Oxford University Press,2000)。
可以在用于原位羧基活化的基于铵或磷酸、膦(phonium)的衍生物存在下方便地实施环化,所述衍生物例如O-(苯并三唑-1-基)N,N,N′,N′-四甲基脲阳离子六氟磷酸、苯并三唑-1-基氧基三(吡咯烷)膦六氟磷酸、N-[(1H-苯并三唑-1)(二甲胺亚甲基)]-N-甲基甲铵四氟硼酸N氧化物、N-(二甲胺-1H-1,2,3-三唑[4,5-b]吡啶-1-基亚甲基)-N-甲基甲铵、7-氮杂苯并三唑-1-基氧基三(吡咯烷)膦六氟磷酸。可以优选在碱(例如有机胺,例如N-乙基二异丙胺、N-甲基吗啉、三乙胺或三苄胺)存在下及辅助性亲核试剂(例如1-羟苯并三唑、N-羟琥珀酰亚胺、3-羟基-3,4-二氢-1,2,3-苯并三唑-4-酮或1-羟基-7-氮杂苯并三唑)存在下实施该反应。
式II、III或IV化合物的环化产生受保护形式的式I的化合物,即存在于分子中的一个或多个或所有氨基受氨基保护基团保护的式I的化合物。这类化合物的实例例如环[(2S,4R)-4-(Boc-NH-CH2-CH2-NH-CO-O)-Pro-Phg-D-Trp(Boc)-Lys(Boc)-Tyr(Bzl)-Phe-]、环[(2S,4R)-4-(Boc-NH-CH2-CH2-NH-CO-O)-Pro-Phg-D-Trp-Lys(Boc)-Tyr(Bzl)-Phe-]和环[(2S,4R)-4-(Boc-NH-CH2-CH2-NH-CO-O)-Pro-DPhg-D-Trp-Lys(Boc)-Tyr(Bzl)-Phe-]。
可以根据本领域已知的方法去除氨基保护基团,例如,以例如三氟乙酸;3M HCl、EtOAc;Me3CCl、苯酚、CH2Cl2;10%H2SO4、二氧杂环己烷;溴代儿茶酚硼烷切割。
式II、III和IV的化合物或其盐是全新的并且组成本发明的一部分。可以通过酰胺键将两个肽单元连接到一起而制备这些化合物,所述两个肽单元中每个至少含有一个受保护或未保护形式的氨基酸,其中以获得如式II、III或IV所定义的所需氨基酸序列的方式形成酰胺键。
可以根据本领域已知的方法,例如以第一个氨基酸开始,在溶液中或通过固相合成实施合成。在固相合成中,任选地通过合适的接头(例如在温和条件下可切割以保证侧链保护完整的接头,例如基于任选的取代三苯甲游基的接头,例如4-(羟联苯甲基)苯甲酸,其中苯基之一可任选地被例如Cl取代)将第一个氨基酸附着于树脂(例如可通过商业途径获得的基于聚苯乙烯的树脂)上。无论在溶液中还是通过固相合成,可以以常规方式实现所需肽链的形成,例如使用末端氨基为Fmoc保护、侧链氨基不同氨基保护基团(例如Boc或CBO)保护的氨基酸。
通过固相合成实现合成时,根据本领域已知的方法从树脂取下形成的肽,例如用乙酸;三氟乙酸;乙酸-三氟乙醇-二氯甲烷;二氯甲烷中的六氟异丙醇。例如使用基于非氯化三苯甲基的接头时,从固相取下形成肽的优选方法是例如以甲醇/二氯甲烷优选于室温处理,或以酮(例如甲乙酮)优选于约50℃温度处理。
式II、III和IV的化合物的实例为例如
H-Lys(Boc)-D-Tyr(Bzl)-Phe-(2S,4R)-4-(Boc-NH-CH2-CH2-NH-CO-O)-Pro-Phg-D-Trp(Boc)-OH
H-Lys(Boc)-D-Tyr(Bzl)-Phe-(2S,4R)-4-(Boc-NH-CH2-CH2-NH-CO-O)-Pro-Phg-D-Trp-OH
H-(2S,4R)-4-(Boc-NH-CH2-CH2-NH-CO-O)-Pro-Phg-D-Trp(Boc)-Lys(Boc)-Tyr(Bzl)-Phe-OH
H-Tyr(Bzl)-Phe-(2S,4R)-4-(Boc-NH-CH2-CH2-NH-CO-O)-Pro-DPhg-DTrp(Boc)-Lys(Boc)-OH
H-Tyr(Bzl)-Phe-(2S,4R)-4-(Boc-NH-CH2-CH2-NH-CO-O)-Pro-Phg-DTrp-Lys(Boc)-OH
H-Tyr(Bzl)-Phe-(2S,4R)-4-(Boc-NH-CH2-CH2-NH-CO-O)-Pro-Phg-D-Trp(Boc)Lys(Boc)-OH
式II、III或IV的化合物可以以如上关于式I的化合物公开的盐形式存在。
式I的化合物是有用的促生长素抑制素激动剂,具有如WO 97/01579或WO 02/10192中所公开的有意义的药理学特性,所述WO 97/01579或WO 02/10192的内容在此引用作为参考。优选的化合物为环[{(4-NH2-C2H4-NH-CO-O)-Pro}-Phg-DTrp-Lys-Tyr(4-苯甲基)-Phe]或其盐。优选的盐为天冬氨酸盐(单或二天冬氨酸盐)或双羟萘酸盐。
使用本发明的方法时,可能获得式II、III或IV的相应线性肽的高于70%的环化得率。
下列实施例为本发明的说明。所有温度为℃。
使用下列缩写:
Bzl=苯甲基
DAEM=二乙胺
DICI=二异丙基碳二亚胺
DMF=N,N-二甲基甲酰胺
DPPA=二苯磷酰叠氮化物(diphenylphosphoryl azide)
EDIPA=N-乙基二异丙胺
HBTU=O-(苯并三唑-1-基)-N,N,N′,N′-四甲基脲阳离子六氟磷酸
HOBT=1-羟苯并三唑
IPA=异丙醇
Phg=苯基甘氨酸
RT=室温
TBME=叔丁基甲基醚
实施例1:
[H-Tyr(Bzl)-Phe-(2S,4R)-4-(Boc-NH-CH2-CH2-NH-CO-O)-Pro-Phg-D-Trp-Lys(Boc)-OH]
将10.4g(FMOC-Tyr(Bzl)-Phe-[(2S,4R)-4-(Boc-NH-CH2-CH2-NH-CO-O)]-Pro-Phg-D-Trp-Lys(BOC)-OH)溶解于100ml DMF中。于室温加入2.0ml二乙胺并于室温连续搅拌4小时。将该黄色透明溶液于40°蒸发。将150ml乙酸异丙酯加入残余物中。于室温结晶(seeding)并搅拌18小时,过滤并以20ml乙酸异丙酯清洗。于40°干燥。HPLC 87.5%b.a.(17.6分钟)。ESI-MS:1287.5(M+Na)+;1H-NMR(DMSO)(α,DMSO):1.14(2H,m)、1.33(2H,m)、1.37(18H,m)、1.53(1H,m)、1.64(1H,m)、2.06(1H,m)、2.22(1H,m)、2.78-3.15(12H,m)、3.38(1H,m)、3.79(2H,br)、4.12(1H,m)、4.55-4.75(3H,m)、5.06(2H,s)、5.15(1H,d)、5.54(1H,d)、6.75(1H,br)、6.83(1H,br)、6.89(2H,d)、6.94(1H,t)、6.99(1H,s)、7.43(2H,d)、7.10-7.50(arom.H)、7.59(1H,d)、8.14(1H,d)、8.45-8.55(2H,m)、8.60(1H,d)、10.71(1H,br)。
如下制备用作起始材料的化合物:
a)Z-D-Trp-Lys(BOC)-OMe
于室温向含有23.7g Z-D-Trp-OH的230ml THF溶液加入9.5gHOBt。形成透明无色溶液。然后于室温加入20.8g H-Lys(BOC)-OMe.HCl,继之为7.7ml N-甲基吗啉。将精制的悬浮液冷却至0°,并加入11.4ml二异丙基碳二亚胺。于0°搅拌1小时、然后于室温搅拌3小时。将120ml水中含有7.0g浓硫酸的溶液加入该悬浮液。以150ml乙酸乙酯萃取,分离各相,从而以100ml饱和盐水、100ml 25%盐水、5%碳酸氢钠溶液清洗有机相。然后将有机相在MgSO4上干燥并蒸发。在250ml乙酸异丙酯中吸收残余物并于室温搅拌2小时。过滤并于40°干燥产生40.9gZ-D-Trp-Lys(BOC)-OMe白色物质。HPLC条件:MN Nucleosil 100A/C18;5微米;250×4mm;A相:0.24%磷酸,B相乙腈;梯度:30分钟内从20至80%B;波长220nm;流速1.3ml/分钟;温度35°:纯度97.8%b.a.(24.2分钟)。
b)H-D-Trp-Lys(BOC)-OMe
将19.8(34.1mmol)g Z-D-Trp-Lys(BOC)-OMe溶解于220ml甲醇中,加入催化剂2.2g PdC 10%并于室温氢化。于室温1小时后结束氢化,滤除催化剂,并于30°蒸发滤液:白色固体。HPLC:98.1%b.a.(16.2分钟)。
c)Z-Phg-D-Trp-Lys(BOC)-OMe
将17.0g H-D-Trp-Lys(BOC)-OMe与80ml THF混合。于室温将9.2gZ-Phg-OH加入该灰色悬浮液。加入4.4g HOBt,以20ml THF漂洗。将该黄色混浊溶液冷却至0°,在10分钟内加入含有5.3ml DICI的15mlTHF溶液。于0°搅拌2小时,然后于室温搅拌2小时。然后加入57ml水中含有3.6硫酸的溶液,以70ml乙酸乙酯萃取,以水、饱和盐水、5%碳酸氢钠、25%盐水清洗,在MgSO4上干燥并蒸发。于40°将白色残余物在125ml乙酸异丙酯中搅拌2小时,过滤该悬浮液。于40°干燥残余物:淡黄色物质。HPLC:96.3%b.a.(25.3分钟)。
d)H-Phg-D-Trp-Lys(BOC)-OMe
将23.4g(23.8mmol)(Z-Phg-D-Trp-Lys(BOC)-OMe)溶解于260ml甲醇中,加入2.6g Pd/C 10%并于室温常压氢化。3小时后滤除催化剂,并于30°蒸发滤液:白色固体。HPLC:95.9%b.a.(17.6分钟)。
e)Z-[(2S,4R)-4-(Boc-NH-CH2-CH2-NH-CO-O)]-Pro-Phg-D-Trp-Lys(BOC)-OMe
将11.1g(2S,4R)-4-(2-叔丁氧羰基氨乙基氨甲酰氧)-吡咯烷-1-羧酸苯甲基酯-2-羧酸和19.0g H-Phg-D-Trp-Lys(BOC)-OMe于室温溶解于290mlTHF中。加入3.32g HOBt,将该混浊溶液冷却至0°。加入4.56ml DICI于90ml THF的溶液。于0°搅拌24小时。然后于室温加入22ml水中含有2.2g硫酸的溶液,将该淡乳白色溶液搅拌15分钟,然后滴加至500ml水中。将该白色悬浮液于50°蒸发直至不再有THF被蒸馏出。过滤该悬浮液并清洗残余物4次,每次80ml水,然后以250ml甲醇,然后总共以80ml甲醇2次。于50°干燥过夜。HPLC:91.0%b.a.(19.5分钟)。
f)H-[(2S,4R)-4-(Boc-NH-CH2-CH2-NH-CO-O)]-Pro-Phg-D-Trp-Lys(BOC)-OMe
将22.0g(12.7mmol)Z-[(2S,4R)-4-(Boc-NH-CH2-CH2-NH-CO-O)]-Pro-Phg-D-Trp-Lys(BOC)-OMe溶解于220ml DMF中,并加入4.4g Pd/C 10%。于室温氢化4小时。然后滤除催化剂,并将滤液加入600g冰和400ml水的混合物中。滤出沉淀产物并以水清洗。于30°干燥产生灰色固体。HPLC:97.0%b.a.(12.3分钟)。
g)Z-Phe-[(2S,4R)-4-(Boc-NH-CH2-CH2-NH-CO-O)]-Pro-Phg-D-Trp-Lys(BOC)-OMe
将5.1g Z-Phe-OH和16.5gH-[(2S,4R)-4-(Boc-NH-CH2-CH2-NH-CO-O)]-Pro-Phg-D-Trp-Lys(BOC)-OMe溶解于250ml THF中,加入2.29g HOBT并将该黑色溶液冷却至0°。将3.1ml DICI溶解于80ml THF中,并于0°加入反应混合物中。于0°搅拌24小时。将反应混合物加入200ml硫酸10%,滤出沉淀固体并以水清。过滤后将残余物与200ml甲醇混合,过滤掉悬浮液。于40°干燥。HPLC:97.2%b.a.(21.1分钟)。
h)(H-Phe-[(2S,4R)-4-(Boc-NH-CH2-CH2-NH-CO-O)]-Pro-Phg-D-Trp-Lys(BOC)-OMe)
将8.5g Z-Phe-[(2S,4R)-4-(Boc-NH-CH2-CH2-NH-CO-O)]-Pro-Phg-D-Trp-Lys(BOC)-OMe溶解于180ml DMF中,加入4.25g Pd/C 10%,并将该混合物于室温氢化6小时。然后滤除催化剂,于40°蒸发滤液。于室温将600ml叔丁基甲基醚滴加到残余物(30g)中,过滤悬浮液,并以300ml TBME清洗残余物。于40°干燥。HPLC 93.1%b.a.(16.6分钟)。
i)FMOC-Tyr(Bzl)-Phe-[(2S,4R)-4-(Boc-NH-CH2-CH2-NH-CO-O)]-Pro-Phg-D-Trp-Lys(BOC)-OMe
将6.5gH-Phe-[(2S,4R)-4-(Boc-NH-CH2-CH2-NH-CO-O)]-Pro-Phg-D-Trp-Lys(BOC)-OMe和3.1g FMOC-Tyr(Bzl)-OH和0.86g HOBT悬浮于180mlTHF中,并冷却至0°。加入5.5g LiBr及20ml THF。然后加入溶解于50ml THF中的1.18ml DICI,并于0°将此黑色悬浮液搅拌2小时。移开冷却浴并连续搅拌24小时。加入0.65g硫酸与6.5ml水的溶液,然后加入160ml水。于40°蒸发,过滤残余物,以水清洗直至最后的清洗水具有4.0的pH。在30ml甲醇中搅拌过滤沉积物,过滤悬浮液并以10ml甲醇清洗残余物。于35°干燥产生灰色物质。HPLC 95.4%b.a.(26.0分钟)。
10)FMOC-Tyr(Bzl)-Phe-[(2S,4R)-4-(Boc-NH-CH2-CH2-NH-CO-O)]-Pro-Phg-D-Trp-Lys(BOC)-OH
将13.0gFMOC-Tyr(Bzl)-Phe-[(2S,4R)-4-(Boc-NH-CH2-CH2-NH-CO-O)]-Pro-Phg-D-Trp-Lys(BOC)-OMe悬浮于250ml THF中。加入7.3g LiBr和75mlTHF。然后于室温在20分钟内缓慢加入8.7ml1摩尔NaOH。于室温连续搅拌3小时,然后在接下来的15小时内加入另外5ml 1摩尔NaOH。将最终反应溶液加入34ml水中含有1.7g硫酸的溶液中。将产生的2相混合物加入50ml乙酸乙酯中。进行相分离后,将有机相以盐水清洗3次然后蒸发。将25ml DIF加入残余物。将产生的透明DIF溶液加入260ml水中。过滤产生的悬浮液,以水清洗过滤沉积物三次并于40°干燥过夜。HPLC71.9%b.a.(28.6分钟)。
实施例2:
制备4-(氯二苯甲基)苯甲酰氨甲基聚苯乙烯树脂
在人工操作的配备烧结玻璃釉料的1L搅拌批反应器中于氮气下执行合成。将可通过商业途径获得的氨甲基聚苯乙烯树脂(30.4g,41.07mmol,以DMF预处理)于室温与含有4-(羟二苯甲基)苯甲酸(15.0g,49.28mmol,1.2当量、羟苯并三唑(HOBT)(7.54g,49.28mmol,1.2当量)及DICI(12.43g,98.57mmol,2.4当量)的DMF溶液(140ml)反应过夜。在减压下经过釉料过滤去除溶剂,将树脂依次以DMF清洗5次及以甲醇清洗5次。于40°真空干燥产生44.69g树脂。使用该树脂作为下面六肽合成的起始材料。
受保护线性肽的合成过程
通过在配备烧结玻璃釉料的1L搅拌批反应器中于氮气下的反复耦联反应,以C至N的方向人工组装连接树脂的线性六肽。使用4-(氯(二苯)甲基)苯甲酰氨甲基聚苯乙烯树脂作为起始材料并通过标准方案实施,该方案由Nα-去保护的反复循环(于DMF中20%v/v二乙胺(DAEM))、依次以DMF和IPK反复清洗并于室温耦联(DIPCI/HOBT,DIEPA andDMF)组成。在该耦联过程的微小改进中,特别注意通过于0°实施所述氨基酸的耦联将苯基甘氨酸的外消旋作用最小化。在从其树脂支持物切割完全组装的受保护线性肽之前,去除Nα-Fmoc保护。
按照WO02/101192中的公开内容合成Fmoc-(2S,4R)-4-(Boc-NH-CH2-CH2-NH-CO-O)-Pro-OH。其他所有氨基酸可通过商业途径获得。
合成H-Tyr(Bzl)-Phe-(2S,4R)-4-(Boc-NH-CH2-CH2-NH-CO-O)-Pro-Phg-D-Trp(Boc)Lys(Boc)-OH
a)合成Fmoc-Lys(Boc)-O-树脂
于室温在甲苯中将4-(氯(二苯)甲基)苯甲酰氨甲基聚苯乙烯树脂(20g,19.4mmol,以甲苯预处理)以乙酰氯(7.6g,97mmol)处理4小时。过滤后将该过程重复过夜,此后过滤树脂并以甲苯和二氯甲烷清洗。以Fmoc-Lys(Boc)-OH(18.2g,38.8mmol;2当量)和N-甲基吗啉(3.94g,38.8mmol,2当量)的混合物于室温实施4小时耦联。过滤后将树脂依次以DMF和IPA清洗3次并真空干燥得到0.566mmol/g容量(以Fmoc方法测定)的浅黄色Fmoc-Lys(Boc)-O-树脂26.5g。
(详细的Fmoc方法见:Meienhofer,J.;Waki.M;Heimer,E.P.;Lambros,T.J.;Makofske,R.C.Chang,C.D.Int.J.Pep.Prot.Res.1979,13,35)
b)树脂-O-Lys(Boc)-D-Trp(Boc)-Phg-(2S,4R)-4-4(Boc-NH-CH2-CH2-NH-CO-O)-Pro-Phe-Try(Bzl)-H
将Fmoc-Lys(Boc)-O-树脂(28.0g,19.96mmol)悬浮于DMF中,并于室温以DAEM的DMF溶液(20%)处理10分钟。过滤后重复该过程,然后依次以DMF和IPA清洗3次,随后以DMF清洗3次。在每个耦联步骤后重复该Nα-Fmoc-去保护和清洗过程。
以于室温搅拌30分钟的氨基酸、HOBT和DICI的混合物执行耦联,然后立即加至树脂。持续耦联直至完全,即直至通过阴性“Kaiser”Ninhydrin测试监测到残余氨基基团的完全消失。经过耦联后,将树脂以DMF清洗5次,然后准备Fmoc保护。
随后耦联下列氨基酸衍生物:
Fmoc-D-Tyr(Boc)-OH(16.81g,31.92mmol,2当量),DIF(100ml),HOBT(4.93g,32.24mmol,2.02当量),DIC(5.35g,42.45mmol,2.66当量)。
Fmoc-Phg-OH(11.92g,31.92mmol,2当量),THF(70ml),HOBT(4.93g,32.24mmol,2.02当量),DICI(5.35g,42.45mmol,2.66当量)。特别注意通过于0°执行所述氨基酸的耦联将苯基甘氨酸的外消旋作用最小化。
Fmoc-(2S,4R)4-(Boc-NH-CH2-CH2-NH-CO-O)-Pro-OH(17.26g,31.92mmol,2当量),DIF(100ml),HOBT(4.93g,32.24mmol,2.02当量),DICI(5.35g,42.45mmol,2.66当量)。
Fmoc-Phe-OH(12.36g,31.92mmol,2当量),DIF(100ml),HOBT(4.93g,32.24mmol,2.02当量),DICI(5.35g,42.45mmol,2.66当量)。
Fmoc-Tyr(Bzl)-OH(15.75g,31.92mmol,2当量),DIF(100ml),HOBT(4.93g,32.24mmol,2.02当量),DICI(5.35g,42.45mmol,2.66当量)。
在从其树脂支持物切割完全组装的受保护线性肽之前,通过以DAEM的DMF溶液(20%)于室温处理树脂10分钟去除Nα-Fmoc保护。过滤后重复该过程,并依次以DMF和IPA清洗3次,随后以DMF清洗3次。
(于40°真空干燥树脂产生浅黄色树脂)。
c)从其树脂支持物切割线性肽:H-Tyr(Bzl)-Phe-(2S,4R)-4-(Boc-NH-CH2-CH2-NH-CO-O)-Pro-Phg-D-Trp(Boc)Lys(Boc)-OH
Ca)使用AcOH/CH2Cl2/H2O 45/45/5的方法
将完全组装的受保护线性肽树脂-O-Lys(Boc)-D-Trp(Boc)-Phg-(2S,4R)-4-(Boc-NH-CH2-CH2-NH-CO-O)-Pro-Phe-Tyr(Bzl)-H(24.5g)悬浮于AcOH/CH2Cl2/H2O 45/45/5混合物(150ml)中,并于室温搅拌一小时,过滤并以CH2Cl2清洗。蒸发滤液至干燥,将残余物以TBME和庚烷的混合物(7/3,v/v)搅拌一小时,过滤并真空干燥。获得浅黄色固体;含量:93.5%HPLC;纯度91.6%(F)-HPLC和2.5%(F)-HPLC D-Phg-立体异构体。
将树脂(4-(氯(二苯)甲基)苯甲酰氨甲基聚苯乙烯树脂)以甲醇清洗3次并干燥,并且可以再生。
Cb)使用CH2Cl2和MeOH的方法
将完全组装的受保护线性肽树脂-O-Lys(Boc)-D-Trp(Boc)-Phg-(2S,4R)-4-(Boc-NH-CH2-CH2-NH-CO-O)-Pro-Phe-Tyr(Bzl)-H(6.2g)悬浮于CH2Cl2/MeOH混合物(1/1,v/v,115ml)中,并于室温搅拌3天,过滤并以CH2Cl2清洗。蒸发滤液至干燥,将残余物以TBME和庚烷的混合物(7/3,v/v,60ml)搅拌一小时,过滤并真空干燥。含量:93.5%HPLC;纯度92.6%(F)-HPLC和1.1%(F)-HPLCD-Phg-立体异构体。
将树脂(4-(氯(二苯)甲基)苯甲酰氨甲基聚苯乙烯树脂)以甲醇清洗3次并干燥,并且可以再生。
Cc)使用甲乙酮/MeOH的方法
将完全组装的受保护线性肽树脂-O-Lys(Boc)-D-Trp(Boc)-Phg-(2S,4R)-4-(Boc-NH-CH2-CH2-NH-CO-O)-Pro-Phe-Tyr(Bzl)-H(4.0g)悬浮于二乙基甲基酮混合物(1/1,v/v,24ml)中,并于50℃搅拌15小时,过滤并以MeOH清洗。蒸发滤液至干燥,将残余物以TBME和庚烷的混合物(7/3,v/v,60ml)搅拌一小时,过滤并真空干燥。含量:88.1%HPLC;纯度95.2%(F)-HPLC和1.8%(F)-HPLCD-Phg-立体异构体。
将树脂(4-(氯(二苯)甲基)苯甲酰氨甲基聚苯乙烯树脂)以甲醇清洗3次并干燥,并且可以再生。
纯化
为了分析,通过RP层析纯化线性肽。
特征描述
通过FAB-MS、LC-MS和NMR数据(以ppm DMSO,1.16、1.34、1.55、1.61(3H)、1.66、2.05、2.20、2.51、2.83(2H)、2.91、2.96、2.98、3.02、3.41、3.78、4.13、4.61、5.13、5.51、6.74、6.83、6.88(2H)、7.01(2H)、7.11(2H)、7.38、7.42(2H)、7.49、7.72、8.01、8.29、8.48、8.62、8.75)证实经RP层析纯化的分析样品的结构。通过氨基酸分析确定氨基酸构型:该混合物在酸性条件下经水解转化为衍生物,通过对映选择性气相色谱(enantioselective gas chromatography)/化学电离质谱指定每个单独的氨基酸的构型。
额外的结构证据是不同线性肽向充分描述特征的环肽的转化。
根据所述过程合成下列化合物。
H-Lys(Boc)-Tyr(Bzl)-Phe-(2S,4R)-4-(Boc-NH-CH2-CH2-NH-CO-O)-Pro-Phg-D-Trp(Boc)-OH;
H-Lys(Boc)-Tyr(Bzl)-Phe-(2S,4R)-4-(Boc-NH-CH2-CH2-NH-CO-O)-Pro-Phg-D-Trp-OH;
H-(2S,4R)-4-(Boc-NH-CH2-CH2-NH-CO-O)-Pro-Phg-D-Trp(Boc)-Lys(Boc)-Tyr(Bzl)-Phe-OH;
H-Phe-(2S,4R)-4-(Boc-NH-CH2-CH2-NH-CO-O)-Phg-D-Trp(Boc)-Lys(Boc)-Try(Bzl)-OH;
H-Tyr(Bzl)-Phe-(2S,4R)-4-(Boc-NH-CH2-CH2-NH-CO-O)-Pro-DPhg-DTrp(Boc)-Lys(Boc)-OH
实施例3:环化线性受保护肽以合成环[(2S,4R)-4-(Boc-NH-CH2-CH2-NH-CO-O)-Pro-Phg-D-Trp(Boc)-Lys(Boc)-Tyr(Bzl)-Phe-]
H-Phe-(2S,4R)-4-(Boc-NH-CH2-CH2-NH-CO-O)-Pro-Phg-D-Trp(Boc)-Lys(Boc)Tyr(Bzl)-OH的环化
叠氮化物方法
为了环化,将线性片段(2.5g,1.83mmol)溶解于DMF(391ml)中,冷却至-5°,以EDIPA(0.47g,3.66mmol,2当量)及DPPA(0.75g,2.75mmol,1.5当量)处理,并于该温度搅拌至完全(约20小时)。将水(391ml)逐滴加入反应混合物,过滤沉淀并以水清洗至没有叠氮化物可检测。获得4.9g水湿的白色固体(HPLC的Rf与参照一致),该固体用于去保护反应而不经过进一步纯化。通过HPLC与参照化合物直接比较描述该化合物的特征。
H-Tyr(Bzl)-Phe-(2S,4R)-4-(Boc-NH-CH2-CH2-NH-CO-O)-Pro-Phg-D-Trp(Boc)Lys(Boc)-OH的环化
a)HBTU方法a
为了环化,将线性片段(6.0g,3.5mmol)溶解于DMF(780ml)中,冷却至-5°,以EDIPA(1.13g,8.75mmol,2.5当量)、HOBT(1.18g,8.75mmol,2.5当量)、HBTU(3.3g,8.78mmol,2.5当量)处理,并于该温度搅拌至完全(约2小时)。将水(391ml)于室温逐滴加入反应混合物,过滤沉淀并以水和庚烷清洗并于真空干燥过夜。获得5.4g白色、黄色固体。通过HPLC与参照化合物直接比较描述该化合物的特征。含量55%w/wHPLC,纯度78(A%)-HPLC。
b)HBTU方法b
为了环化,将线性片段(6.0g,4.16mmol)溶解于DMF(60ml)中,于-5°滴加入DMF(135ml)中的HBOT(4.15g,10.4mmol,2.5当量)、HBTU(4.15g,10.4mmol,2.5当量)和EDIPA(1.41g,10.4mmol,2.5当量)混合物中,并于该温度搅拌至完全(约2小时)。将水(559ml)于室温逐滴加入反应混合物,过滤沉淀并以水和庚烷清洗并于真空干燥过夜。获得白色、黄色固体。通过HPLC与参照化合物直接比较描述该化合物的特征。含量77%(w/w)HPLC,纯度84(A%)-HPLC。
根据上述过程环化下列线性肽:
H-Lys(Boc)-Tyr(Bzl)-Phe-(2S,4R)-4-(Boc-NH-CH2-CH2-NH-CO-O)-Pro-Phg-D-Trp(Boc)-OH
H-Lys(Boc)-Tyr(Bzl)-Phe-(2S,4R)-4-(Boc-NH-CH2-CH2-NH-CO-O)-Pro-Phg-D-Trp-OH
H-(2S,4R)-4-(Boc-NH-CH2-CH2-NH-CO-O)-Pro-Phg-D-Trp(Boc)-Lys(Boc)-Tyr(Bzl)-Phe-OH
H-Phe-(2S,4R)-4-(Boc-NH-CH2-CH2-NH-CO-O)-Phg-D-Trp(Boc)-Lys(Boc)-Try(Bzl)-OH
H-Tyr(Bzl)-Phe-(2S,4R)-4-(Boc-NH-CH2-CH2-NH-CO-O)-Pro-DPhg-DTrp(Boc )-Lys(Boc)-OH
实施例4:合成环[(2S,4R)-4-(Boc-NH-CH2-CH2-NH-CO-O)-Pro-Phg-D-Trp-Lys-Tyr(Bzl)-Phe-]三氟乙酸盐
为了完全去保护,将残余物(1.5g,0.79mmol)于0°溶解于TFA/H2O 95:5(8.3ml)中,将该混合物低温搅拌30分钟。将低温反应混合物于室温滴加到TBME(29ml)与庚烷(13ml)的混合物中并搅拌2小时。过滤沉淀,以TBME/庚烷1∶1清洗并于真空干燥。获得浅褐色固体,含量53%(w/w)HPLC,纯度:79(A%)-HPLC。
Claims (5)
1.产生式I的化合物或其盐的方法
其中
R1为-C2-6亚烷基-NR3R4、-C2-6亚烷基-胍或-C2-6亚烷基-COOH,其中R3和R4各独立为H、C1-4烷基、ω-羟基-C2-4亚烷基或酰基,或R3和R4与它们所连接的氮原子形成可以含有其它杂原子的杂环基团,并且
R2为Z1-CH2-R5、-CH2-CO-O-CH2-R5
其中Z1为O或S,R5任选为取代苯基,
所述方法包括在碱存在下环化式II
的线性促生长素抑制素类似物,
并且在需要的地方去除保护基团,
并收获式I的化合物从而获得游离形式或盐形式,
其中R1和R2如上所定义,
R11和R12各独立为氨基保护基团,
由此当R1含有末端NH2时,该末端NH2也受氨基保护基团保护,
其中所用的环化试剂是HOBT和HBTU。
2.权利要求1的方法,包括环化式II的线性促生长素抑制素类似物
并且在需要的地方去除保护基团,
并回收由此获得的游离形式或盐形式的式I化合物,其中其中R1为-CH2-CH2-NR3R4,R2为4-苄氧基苯,
其中R1为-CH2-CH2-NR3R4,R2为4-苄氧基苯,R3、R4、R11和R12如权利要求1所定义,
由此当R1含有末端NH2时,该末端NH2也受氨基保护基团保护。
3.权利要求1或2的方法,其中式II的化合物选自:H-Tyr(Bzl)-Phe-(2S,4R)-4-(Boc-NH-CH2-CH2-NH-CO-O)-Pro-DPhg-DTrp(Boc)-Lys(Boc)-OH、H-Tyr(Bzl)-Phe-(2S,4R)-4-(Boc-NH-CH2-CH2-NH-CO-O)-Pro-Phg-DTrp-Lys(Boc)-OH和H-Tyr(Bzl)-Phe-(2S,4R)-4-(Boc-NH-CH2-CH2-NH-CO-O)-Pro-Phg-D-Trp(Boc)Lys(Boc)-OH。
4.权利要求1或2的方法,该方法还包括产生式II的化合物的步骤,其包括通过酰胺键将两个肽单元连接到一起,并回收由此获得的游离形式或盐形式的式II化合物,所述肽单元中每个至少含有一个受保护或未保护形式的氨基酸,其中以获得如式II所定义的所需氨基酸序列的方式形成酰胺键,并且在需要的地方去除至少一个保护基团。
5.权利要求1或2的方法,其中式I的化合物是环[{(4-NH2-C2H4-NH-CO-O)-Pro}-Phg-DTrp-Lys-Tyr(4-苯甲基)-Phe]。
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