CN101189242A - 去氧生物素基六亚甲基二胺-dota的合成 - Google Patents
去氧生物素基六亚甲基二胺-dota的合成 Download PDFInfo
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- 230000015572 biosynthetic process Effects 0.000 title abstract description 4
- 238000003786 synthesis reaction Methods 0.000 title abstract description 3
- 238000000034 method Methods 0.000 claims abstract description 20
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 18
- QWVNTBHBRBLRRJ-YDHLFZDLSA-N 5-[(3as,4s,6ar)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]-n-(6-aminohexyl)pentanamide Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)NCCCCCCN)SC[C@@H]21 QWVNTBHBRBLRRJ-YDHLFZDLSA-N 0.000 claims abstract description 8
- -1 benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate Chemical compound 0.000 claims abstract description 5
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 7
- 229910052698 phosphorus Inorganic materials 0.000 claims description 5
- 239000011574 phosphorus Substances 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- 230000002194 synthesizing effect Effects 0.000 claims description 3
- 239000000047 product Substances 0.000 description 11
- 239000000243 solution Substances 0.000 description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- WDLRUFUQRNWCPK-UHFFFAOYSA-N Tetraxetan Chemical compound OC(=O)CN1CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CC1 WDLRUFUQRNWCPK-UHFFFAOYSA-N 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 238000009833 condensation Methods 0.000 description 4
- 230000005494 condensation Effects 0.000 description 4
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 229930003756 Vitamin B7 Natural products 0.000 description 3
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- 238000009834 vaporization Methods 0.000 description 3
- 239000011735 vitamin B7 Substances 0.000 description 3
- 235000011912 vitamin B7 Nutrition 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- DAMKKDNKIVOVQK-HZPCBCDKSA-N 5-[(3as,4s,6ar)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]-n-(6-aminohexyl)pentanamide;hydrochloride Chemical compound Cl.N1C(=O)N[C@@H]2[C@H](CCCCC(=O)NCCCCCCN)SC[C@@H]21 DAMKKDNKIVOVQK-HZPCBCDKSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000004057 biotinyl group Chemical group [H]N1C(=O)N([H])[C@]2([H])[C@@]([H])(SC([H])([H])[C@]12[H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C(*)=O 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
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- 125000000524 functional group Chemical group 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- MEFBJEMVZONFCJ-UHFFFAOYSA-N molybdate Chemical compound [O-][Mo]([O-])(=O)=O MEFBJEMVZONFCJ-UHFFFAOYSA-N 0.000 description 1
- 238000006068 polycondensation reaction Methods 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
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Abstract
本文描述了合成去氧生物素基六亚甲基二胺－DOTA的方法。所述方法包含，在有作为缩合剂的六氟磷酸苯并三唑－1－基－氧基三吡咯烷基磷和作为碱的三乙胺存在下，使生物素基六亚甲基二胺与三叔丁基－DOTA反应。
Description
发明领域
本文公开的发明涉及改进的合成去氧生物素基六亚甲基二胺-DOTA的方法。
发明背景
在申请人名下的国际专利申请WO 02066075中，已经描述了化合物去氧生物素基六亚甲基二胺-DOTA。DOTA是1，4，7，10-四氮杂环十二烷四乙酸(1，4，7，10-四氮杂环十二烷四乙酸)。
为完整起见，本文公开去氧生物素基六亚甲基二胺-DOTA的结构式。
在同一专利申请WO 02066075中，也描述了合成该产物的方法，并在上述申请第15页上的实施例中予以报道。本文报道为ST2210的化合物与WO 02066075实施例中的化合物4相对应。更具体地，用制备型色谱获得中间产物生物素基六亚甲基二胺盐酸盐(ST2551或WO02066075实施例中的化合物3)，产率为55％，滴定度未限定。
如图1所示，通过缩合ST2551和DOTA，获得最终的去氧生物素基六亚甲基二胺-DOTA产物(ST2210或WO02066075实施例中的化合物4)。
图1
以此方式进行的反应产生低的合成产率(在DOTA中存在4个未保护的羧基官能团当量，参与形成多种副产物)和纯化的问题。实际上，为了得到最终产物，必需使用制备级HPLC，产率为20％。
发明描述
在放大研究中，为了提高该方法的产率和使纯化过程更容易，检查了替代合成方法：
与早前所述的方法相比，改进的合成方法具有下述优点：
1.在偶联步骤或缩合(在WO 02066075中描述为″步骤d″)中，三叔丁基-DOTA的应用避免了更多缩合产物的形成，这是由于游离羧基的部分反应性(甚至在控制的pH条件下工作时也发生)；
2.仍然在相同步骤中，改变了缩合剂和碱；使用六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷(PyBOP-六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷)作为缩合剂，三乙胺(TEA)作为碱，得到了提高的产率；
3.生物素基六亚甲基二胺(ST2251)用作游离碱，已经证实，二盐酸盐的应用会造成不希望的产物的量增加；更具体地，显著形成了与二聚体相对应的副产物，其中ST2551与2分子的三叔丁基-DOTA反应；
4.最后一步是在酸性含水溶液中水解3个叔丁基基团，例如使用与产物不同比例的3N-6N HCl，持续时间是1小时至12小时，产率是96％-98％；
5.从合成工艺中删除了2个相当费力的制备型色谱阶段；
6.获得产品的滴定度为94％-96％。
因此，本发明的目的是，合成去氧生物素基六亚甲基二胺-DOTA的方法，其包括，在有作为缩合剂的六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷和作为碱的三乙胺存在下，使生物素基六亚甲基二胺与三叔丁基-DOTA反应。
因此，本发明的方法包含，在缩合步骤之后的一个步骤，即在酸性pH水解。
缩合优选地在有机溶剂中进行。更优选地，该溶剂是二氯甲烷。
在分析过的方法中，开发的最好的合成方法是包含图2所示的阶段的方法。
另外，用实施例解释了本发明，这些实施例不以任意方式限制发明本身。
图2
实施例(化合物的编号参见图2)
方法
使用连接到二极管阵列检测器和具有电喷射的质谱仪上的分析型HPLC系统，监测进行的试验。开发的分析方法包含，使用ACE C-18分析柱(150×4.60mm，5μ)，流速为1.0mL/min，线性洗脱梯度为在20min内5-95％的B(A＝H2O+0.1％TFA；B＝AcCN+0.1％TFA)，或在20min内10-90％的B，或者10％B等度溶液保持6min，随后在20min内梯度10-90％的B。关于最终产物ST2210，使用在15％B等度溶液中工作的方法40min。通过检测器检查的波长范围是205-400nm。
通过TLC快速监测包含，使用OEt酸类型∶异丙醇∶NH3 30％或DCM∶异丙醇∶NH3 30％(4∶5∶1)的洗脱液混合物，借助于I2或磷钼试剂，揭示分选出的产物(紫外不可见)。
作为游离碱的生物素基六亚甲基二胺(ST2551)(2)的制备
将产物ST2551[(1)，纯度91％，400mg，1.0mmol)溶于水(20mL)中，将溶液置于分液漏斗中；加入NaOH 2M溶液(20mL)，将沉淀的产物用DCM(40mL)萃取3次。用无水Na2SO4脱水合并的有机相，在减压下蒸发。得到的产物(2)是白色固体(290mg，产率＝98％)。
1H-NMR(200MHz，CDCl3)δ(ppm)：1.25-2.05[m，16H，CH(CH2)4和NHCH2(CH2)4)]；2.50-3.30(m，9H，2xHCHS和CHS和3xCH2N)；4.32(m，1H，CHCHNH)；4.51(m，1H，CHCHNH)；5.77(s，1H，CONH)；6.05(s，1H，CONH).
ES-MS m/z：329.5[M+H]+。
去氧生物素基六亚甲基二胺-叔丁基-DOTA(4)的合成
在室温，搅拌三叔丁基-DOTA[(3)，524mg，0.915mmol，1当量]，PyBOP(714mg，1.37mmol，1.5当量)和三乙胺(166μL，1.19mmol，1.3当量)于DCM(5mL)中的溶液10分钟，逐滴加入ST2551-游离碱[(2)，300mg，0.915mmol，1当量)于DCM(5mL)中的溶液中，后一种溶液通过在40℃加热混合物5min得到。在室温反应3小时，根据上述方法，通过TLC和LC-MS监测反应的完全。
在反应结束时，在减压下蒸发溶剂，将残余物溶于DCM中，用NaOH1M洗涤2次。在Na2SO4上脱水有机相，并在真空下蒸发。将这样得到的残余物接受硅胶柱色谱(粗产物∶二氧化硅的重量比为1∶30)，使用5∶4的DCM混合物∶异丙醇作为洗脱液系统，向其中加入递增浓度的30％氨水(0.2-1)。给柱填充初始DCM混合物∶异丙醇∶NH3(5∶4∶0.2)，用NH3梯度继续该方法[洗脱液混合物通常在搅拌后变得均匀；只是在洗脱的最后阶段，NH3＝1，可能证实必需加入异丙醇来提高混溶性，在该情况下，使用体积比(4∶5∶1)(DCM∶异丙醇∶NH3)。得到浅黄色油状产物，其在真空下倾向于产生泡沫状固体[(4)，600mg，产率＝74％)。1H-NMR(300MHz，DMSO-d6，T＝50℃)δ(ppm)：1.16-1.70(m，43H，CH(CH2)4和NHCH2(CH2)4和9 x CH3)；2.40-3.32(m，34H，2 xHCHS和3 x CH2N，8 x DOTA-环CH2和CHS和4 x DOTA CH2CO和NH胺)；4.13(m，1H，CHCHNH)；4.29(m，1H，CHCHNH)；6.18(s，1H，NH生物素)；6.21(s，1H，NH生物素)；8.10(t，1H，NH酰胺)。
13C-NMR(75MHz，DMSO-d6)δ(ppm)：27.22；27.35；27.56；28.50；28.61；29.04；29.23；30.14；30.25；30.39；39.14；40.42；50.07；52.59；52.82；53.24；54.72；56.14；56.92；57.38；59.31；60.05；61.90；80.75；163.34；170.98；171.25.
ES-MS m/z：883.4[M+H]+.
去氧生物素基六亚甲基二胺-DOTA[ST2210，(5)]的合成
在室温，搅拌(4)(210mg，0.238mmol)于HCl 6N中的溶液[1mL，(4)的20％w/v溶液]1小时。然后，在减压下蒸发混合物，将残余物溶于H2O(约1∶50w/v)中，将溶液冷冻干燥。得到白色固体(205mg，96％)。1H-NMR(200 MHz，DMSO-d6)δ(ppm)：1.30-1.77[m，16H，CH(CH2)4和NHCH2(CH2)4]；2.59(d，1H，HCHS)；2.77-2.88(m，7H，HCHS和3 x CH2N)；2.98-3.70(m，25H，8 x DOTA-环CH2和CHS和4x DOTA CH2CO)；4.15(m，1H，CHCHNH)；4.31(m，1H，CHCHNH)；7.58(br s，2H，2 x生物素NH)；8.86(t，1H，NH酰胺)；9.19(br s，2H，NH2 +).
13C-NMR(75MHz，DMSO-d6)δ(ppm)：25.77；25.85；26.32；26.53；26.70；28.74；29.16；47.08；47.16；48.54；49.00；51.35；53.13；54.51；55.38；56.02；59.90；61.61；163.44；165.58；168.90；172.31.
ES-MS m/z：715.4[M+H]+.
Claims (4)
1.合成去氧生物素基六亚甲基二胺-DOTA的方法，其包含，在有作为缩合剂的六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷和作为碱的三乙胺存在下，使生物素基六亚甲基二胺与三叔丁基-DOTA反应。
2.根据权利要求1的方法，其中生物素基六亚甲基二胺与三叔丁基-DOTA在有机溶剂中反应。
3.根据权利要求2的方法，其中所述有机溶剂是二氯甲烷。
4.根据任一项前述权利要求的方法，其包含在酸性pH的含水环境中水解的后续步骤。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT000345A ITRM20050345A1 (it) | 2005-06-30 | 2005-06-30 | Sintesi di deossi-biotinil esametilen diammina-dota. |
| ITRM2005A000345 | 2005-06-30 | ||
| PCT/EP2006/062800 WO2007003478A1 (en) | 2005-06-30 | 2006-05-31 | Synthesis of deoxybiotinyl hexamethylenediamine-dota |
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| CN101189242A true CN101189242A (zh) | 2008-05-28 |
| CN101189242B CN101189242B (zh) | 2011-04-13 |
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| EP (1) | EP1899354B1 (zh) |
| JP (1) | JP5009285B2 (zh) |
| KR (1) | KR101268350B1 (zh) |
| CN (1) | CN101189242B (zh) |
| AT (1) | ATE427309T1 (zh) |
| AU (1) | AU2006265245B2 (zh) |
| BR (1) | BRPI0613494A2 (zh) |
| CA (1) | CA2607262C (zh) |
| DE (1) | DE602006006060D1 (zh) |
| DK (1) | DK1899354T3 (zh) |
| ES (1) | ES2325000T3 (zh) |
| HK (1) | HK1117830A1 (zh) |
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| IT (1) | ITRM20050345A1 (zh) |
| ME (1) | ME01702B (zh) |
| MX (1) | MX2007015364A (zh) |
| PL (1) | PL1899354T3 (zh) |
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| ITRM20010079A1 (it) | 2001-02-16 | 2002-08-16 | Sigma Tau Ind Farmaceuti | Amminoderivati della biotina e loro coniugati con chelanti macrociclici. |
| JP2006500407A (ja) * | 2002-09-20 | 2006-01-05 | ワイス・ホールディングズ・コーポレイション | チュブリン阻害剤の合成に有用な中間体の合成方法 |
| AU2004240924A1 (en) * | 2003-05-16 | 2004-12-02 | Wyeth Holdings Corporation | Process for synthesizing beta-lactamase inhibitor intermediates |
| US7145019B2 (en) * | 2003-10-16 | 2006-12-05 | Ambergen, Inc. | Photocleavable isotope-coded affinity tags |
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- 2006-05-31 AT AT06763428T patent/ATE427309T1/de active
- 2006-05-31 CN CN2006800197526A patent/CN101189242B/zh not_active Expired - Fee Related
- 2006-05-31 BR BRPI0613494-7A patent/BRPI0613494A2/pt not_active Application Discontinuation
- 2006-05-31 ME MEP-2009-250A patent/ME01702B/me unknown
- 2006-05-31 DE DE602006006060T patent/DE602006006060D1/de active Active
- 2006-05-31 EP EP06763428A patent/EP1899354B1/en active Active
- 2006-05-31 DK DK06763428T patent/DK1899354T3/da active
- 2006-05-31 MX MX2007015364A patent/MX2007015364A/es active IP Right Grant
- 2006-05-31 AU AU2006265245A patent/AU2006265245B2/en not_active Ceased
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Also Published As
| Publication number | Publication date |
|---|---|
| CA2607262A1 (en) | 2007-01-11 |
| JP5009285B2 (ja) | 2012-08-22 |
| ME01702B (me) | 2010-08-31 |
| JP2009500368A (ja) | 2009-01-08 |
| EP1899354B1 (en) | 2009-04-01 |
| DK1899354T3 (da) | 2009-06-15 |
| US20100184972A1 (en) | 2010-07-22 |
| ATE427309T1 (de) | 2009-04-15 |
| PL1899354T3 (pl) | 2009-09-30 |
| WO2007003478A1 (en) | 2007-01-11 |
| HK1117830A1 (en) | 2009-01-23 |
| CA2607262C (en) | 2013-10-22 |
| EP1899354A1 (en) | 2008-03-19 |
| CN101189242B (zh) | 2011-04-13 |
| DE602006006060D1 (de) | 2009-05-14 |
| MX2007015364A (es) | 2008-02-11 |
| BRPI0613494A2 (pt) | 2011-01-11 |
| ITRM20050345A1 (it) | 2007-01-01 |
| SI1899354T1 (sl) | 2009-08-31 |
| KR101268350B1 (ko) | 2013-05-28 |
| US7851621B2 (en) | 2010-12-14 |
| KR20080021021A (ko) | 2008-03-06 |
| AU2006265245B2 (en) | 2011-11-10 |
| AU2006265245A1 (en) | 2007-01-11 |
| HRP20090258T1 (en) | 2009-06-30 |
| ES2325000T3 (es) | 2009-08-21 |
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