CN102292318B - 制备活化酯的方法 - Google Patents
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- 238000000034 method Methods 0.000 title claims abstract description 30
- 150000002148 esters Chemical class 0.000 title abstract description 3
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000002904 solvent Substances 0.000 claims abstract description 10
- 125000003118 aryl group Chemical group 0.000 claims abstract description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 6
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims description 18
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical group CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 16
- 150000002576 ketones Chemical class 0.000 claims description 14
- 238000002360 preparation method Methods 0.000 claims description 13
- CGIHPACLZJDCBQ-UHFFFAOYSA-N acibenzolar Chemical compound SC(=O)C1=CC=CC2=C1SN=N2 CGIHPACLZJDCBQ-UHFFFAOYSA-N 0.000 claims description 12
- HOGDNTQCSIKEEV-UHFFFAOYSA-N n'-hydroxybutanediamide Chemical compound NC(=O)CCC(=O)NO HOGDNTQCSIKEEV-UHFFFAOYSA-N 0.000 claims description 8
- -1 succinimido esters Chemical class 0.000 claims description 8
- 238000000926 separation method Methods 0.000 claims description 6
- 125000001118 alkylidene group Chemical group 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 5
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims description 4
- 238000001556 precipitation Methods 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- ZPFKRQXYKULZKP-UHFFFAOYSA-N butylidene Chemical group [CH2+]CC[CH-] ZPFKRQXYKULZKP-UHFFFAOYSA-N 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- RFPMGSKVEAUNMZ-UHFFFAOYSA-N pentylidene Chemical group [CH2+]CCC[CH-] RFPMGSKVEAUNMZ-UHFFFAOYSA-N 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 239000011541 reaction mixture Substances 0.000 claims description 2
- OSFBJERFMQCEQY-UHFFFAOYSA-N propylidene Chemical group [CH]CC OSFBJERFMQCEQY-UHFFFAOYSA-N 0.000 claims 2
- 238000001816 cooling Methods 0.000 claims 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract description 3
- PFYXSUNOLOJMDX-UHFFFAOYSA-N bis(2,5-dioxopyrrolidin-1-yl) carbonate Chemical compound O=C1CCC(=O)N1OC(=O)ON1C(=O)CCC1=O PFYXSUNOLOJMDX-UHFFFAOYSA-N 0.000 abstract description 3
- 150000003839 salts Chemical class 0.000 abstract description 2
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 abstract 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 abstract 1
- 125000000592 heterocycloalkyl group Chemical group 0.000 abstract 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 10
- 229940043265 methyl isobutyl ketone Drugs 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 6
- 0 *C(C1CCCCC1)C1CCCCC1 Chemical compound *C(C1CCCCC1)C1CCCCC1 0.000 description 5
- WQOXQRCZOLPYPM-UHFFFAOYSA-N Dimethyl disulfide Natural products CSSC WQOXQRCZOLPYPM-UHFFFAOYSA-N 0.000 description 5
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 229940070710 valerate Drugs 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- OBNCKNCVKJNDBV-UHFFFAOYSA-N ethyl butyrate Chemical compound CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- PGNQJMCTZVDVGY-UHFFFAOYSA-N 3-nitropyrrolidine-2,5-dione Chemical group [O-][N+](=O)C1CC(=O)NC1=O PGNQJMCTZVDVGY-UHFFFAOYSA-N 0.000 description 1
- 235000018185 Betula X alpestris Nutrition 0.000 description 1
- 235000018212 Betula X uliginosa Nutrition 0.000 description 1
- QKHWKVBHJYQWBL-JHJMLUEUSA-N C(C1)CC=CC1[NH2][C@@H]1CC=CCC1 Chemical compound C(C1)CC=CC1[NH2][C@@H]1CC=CCC1 QKHWKVBHJYQWBL-JHJMLUEUSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 238000003287 bathing Methods 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 150000007942 carboxylates Chemical group 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- KZNICNPSHKQLFF-UHFFFAOYSA-N dihydromaleimide Natural products O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 1
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000037452 priming Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 229960001866 silicon dioxide Drugs 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 238000009834 vaporization Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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
- C07D207/36—Oxygen or sulfur atoms
- C07D207/40—2,5-Pyrrolidine-diones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/70—Sulfur atoms
- C07D213/71—Sulfur atoms to which a second hetero atom is attached
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyridine Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pyrrole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一种制备式(I)的活化酯的方法，其中R为(C1-C6)烷基、芳基、杂芳基、环烷基或杂环烷基，且Alk为(C1-C6)亚烷基，所述方法包括：将二环己基胺P1盐与碳酸二琥珀酰亚胺基酯(DSC)在溶剂中反应，其中N-羟基琥珀酰亚胺的二环己基胺盐P2沉淀。本发明还涉及式P1的产物。
Description
本发明涉及式(I)的活化酯(activated ester)的制备：
其中R为(C1-C6)烷基、芳基、杂芳基、环烷基或杂环烷基，且Alk为(C1-C6)亚烷基。所述活化酯可用于制备缀合物(conjugate)，即其中抗体与生物活性化合物(例如细胞毒性化合物)经共价键连接。缀合物化学的更详细内容请参考例如，Birch和Lennox，Monoclonal Antibodies：Principles and Applications，Chap.4，Wiley-Liss，New York，N.Y.(1995)。
现有技术
WO 2004/016801公开了包括硝基琥珀酰亚胺单元的活化酯。在图1至图6中公开的这些化合物的制备基于与本发明不同的反应。
J.Med.Chem.2006，49(14)，4392-4408公开了活化酯的制备，特别是方案6的N-琥珀酰亚胺基-[4-甲基-4-(甲基二硫基)]戊酸酯，其通过与本发明不同的反应制备。
Langmuir 2000，16(1)，81-86在方案1中公开了琥珀酰亚胺基-3-(2-吡啶基二硫基)丁酸酯(SPDB)的制备，其通过将相应的酸与N-羟基琥珀酰亚胺偶合。
US 6407263、US 5872261、US 5892057和US 5942628公开了活化酯及其制备方法。
Can.J.Chem.1982，60，976公开了N-羟基琥珀酰亚胺的二环己基胺盐(P2)的制备，其通过二环己基胺与N-羟基琥珀酰亚胺在丙酮中反应。该化合物的CAS号为82911-72-6。
Can.J.Chem.1986，64(11)，2097-2102；J.Chem.Soc.，Perkin Trans.11985，4，765-8；Bull.Soc.Chem.Jpn 1986，59(8)，2505-8；Coll.Czech.Chem.Comm.1985，50(12)，2925-2936公开了由二环己基胺盐制备琥珀酰亚胺酯，但不使用碳酸二琥珀酰亚胺基酯。
Tetrahedron Letters 1979，49，4745-4746公开了DSC及其在合成中的价值(见方案2)。
Biochem.J.1978，173，723-737公开了在N-羟基琥珀酰亚胺和二环己基碳二亚胺的存在下制备活化酯。
JACS 2003，125(30)，8994-8995为技术背景的一部分。
发明概述
本发明涉及制备式(I)的活化酯的方法：
其中R为直链或支链的(C1-C6)烷基、芳基、杂芳基、环烷基或杂环烷基，且Alk为直链或支链的(C1-C6)亚烷基，所述方法包括将二环己基胺盐P1与碳酸二琥珀酰亚胺基酯(disuccinimidyl carbonate，DSC)在溶剂中反应，
其中N-羟基琥珀酰亚胺的二环己基胺盐P2沉淀出来
本发明还涉及式P1的产物：
更具体地，下列产物：
发明详述
定义
·烷基：直链或支链的饱和脂肪族烃基，其通过从烷烃除去一个氢原子得到。可以具体提及以下基团：甲基、乙基、丙基、丁基、戊基、己基、2-甲基丁基、2-甲基戊基和1-甲基戊基；
·亚烷基：二价基团，其通过从烷烃除去两个氢原子得到。可以具体提及以下基团：亚甲基(-CH2-)、亚乙基(-CH2CH2-)、亚正丙基(-CH2CH2CH2-)和亚丁基(-CH2CH2CH2CH2-)；
·环烷基：在环状结构中包含3至10个碳原子的环状烷基。可以具体提及以下基团：环丙基、环戊基和环己基；
·芳基：含有6至10个碳原子的芳香基团。可以具体提及以下基团：苯基、萘基、茚基和芴基；
·杂芳基：5至10个环原子的香基团，其包括一个或多个选自O、S或N的杂原子作为形成环的原子；
·杂环烷基：如上定义的环烷基，其还包括一个或多个选自O、S或N的杂原子作为形成环的原子。
所述制备基于二环己基胺盐P1与碳酸二琥珀酰亚胺基酯(DSC)在溶剂中反应，其中N-羟基琥珀酰亚胺的二环己基胺盐P2沉淀(方案1)。
R为：
·(C1-C6)烷基：例如甲基、乙基、丙基、丁基或戊基，其任选为支链的；
·(C3-C7)环烷基：例如环丙基；
·芳基：例如苯基；
·杂芳基：例如2-吡啶基
·杂环烷基：例如哌啶基。
Alk为(C1-C6)亚烷基，例如亚丙基、亚丁基或亚戊基，其任选为支链的。更具体地为(CH2)n基团，其中n表示1至6的整数。
二环己基胺的作用在于促进反应，并使得N-羟基琥珀酰亚胺不溶，因此得以释出。该反应具有以下优势：
·容易实现：简单接触、不加热、缓慢且可控地放出CO2；
·由于化合物P1呈羧酸盐形式，因此不必加入另外的碱以活化反应；
·释出的化合物P2在所用溶剂中仅具有极低的溶解度，并且其沉淀。因此大部分的P2可容易地通过简单的机械分离(例如过滤)去除；
·该反应使得以良好产率和良好纯度容易地获得活化酯成为可能。
P2通过用二环己基胺中和相应的酸进行制备。DSC为市售产品。
溶剂有利地为酮，其比常用于该类型的反应的溶剂(二氯甲烷或二甲基甲酰胺)显示出较低毒理性问题。所述酮可(例如)为丙酮或甲基异丁基酮(MIBK)。优选MIBK，因为其为水-可混溶的(在20℃，为1.55％ w/w)，其允许水性清洗产物，因此促进除去残留的P2。其还使得通过共沸蒸馏除去残留水成为可能。最后，MIBK为活化酯的良溶剂，但不是化合物P2和P1以及DSC的良溶剂，其允许P1与DSC之间缓慢且可控地反应：因此所述反应物可在最初完全混合，而没有产生安全性问题(快速反应且不可控地释放CO2)。
该反应在环境温度(大约20℃)进行。P2可在一些溶剂中自发地沉淀。为了促进P2的沉淀，在P1和DSC反应之后，可以冷却反应混合物(例如至接近0℃的温度)。
该反应使得具体制备以下活化酯成为可能：N-琥珀酰亚胺基-3-(2-吡啶基二硫基)丙酸酯(SPDP)、N-琥珀酰亚胺基-3-(2-吡啶基二硫基)丁酸酯(SPDB)或N-琥珀酰亚胺基-[4-甲基-4-(甲基二硫基)]戊酸酯，它们分别由以下的相应的酸的盐制备：
实施例
实施例1：N-琥珀酰亚胺基-[4-甲基-4-(甲基二硫基)]戊酸酯的制备
反应如下：
将4-甲基-4-(甲基二硫基)戊酸的二环己基胺盐(23g)和DSC(18.2g，1.1eq.)在161ml的MIBK中的悬浮液在大约20℃搅拌5小时。然后将悬浮液冷却至大约0℃，再在该温度搅拌1小时，然后过滤。
将固体用2×23ml的MIBK洗涤。合并有机相，用2×58ml的6N HCl水溶液洗涤，然后用92ml去离子水洗涤。然后将有机相在真空下浓缩至干。将所得固体溶于230ml二氯甲烷(DCM)，并将所得溶液用46g二氧化硅处理并搅拌10分钟，然后滤除二氧化硅，并用2×69ml的DCM洗涤。将该操作重复第二次。然后将有机相浓缩至大约一半体积，然后在大约20℃，在大约30分钟加入391ml的正庚烷。将所得白色悬浮液在该温度搅拌大约1小时，经大约1小时冷却至大约-10℃，然后在该温度搅拌大约1小时。然后过滤固体，用2×23ml的正庚烷洗涤，冷却至大约-10℃，然后在真空下在40℃干燥15小时。分离得到4-N-羟基琥珀酰亚胺基-[4-甲基-4-(甲基二硫基)]戊酸酯，产率为70.6％。其通过HPLC测定的纯度为99.65％(除去溶剂)。
实施例2：制备N-琥珀酰亚胺基-3-(2-吡啶基二硫基)丁酸酯(SPDB)反应如下：
将二环己基胺盐(40g，1eq.)和DSC(28.7g，1.1eq.)悬浮于280ml的MIBK中。将混合物在20±3℃搅拌4小时。将悬浮液冷却至0±3℃，在该温度放置30分钟并过滤，将获得的固体用冰冷的MIBK(120ml)洗涤。将母液用水(3×176ml)洗涤，并在旋转蒸发仪(浴温50℃)上在减压下蒸发至干，直至达到MIBK的量≤2.5％。获得的粗品SPDB为黄色油状物的形式。
然后在35±2℃将SPDB(32.5g)溶于乙醇(455ml)。将获得的溶液冷却至18±2℃：纯的SPDB开始结晶。经10分钟加入90ml正庚烷，剧烈结晶。将混合物冷却至0±3℃并经20分钟加入820ml正庚烷。将混合物在0±3℃搅拌1小时。通过过滤分离纯的SPDB，用2×90ml冰冷的正庚烷洗涤，并在烘箱中干燥(30℃，50mbar)。产率：84.8％，HPLC纯度：98.7％。
Claims (25)
1.一种制备式(I)的活化酯的方法：
其中R为直链或支链的(C1-C6)烷基、芳基、杂芳基、环烷基或杂环烷基，且Alk为直链或支链的(C1-C6)亚烷基，
所述方法包括将二环己基胺盐P1与碳酸二琥珀酰亚胺基酯(DSC)在溶剂中反应，
其中N-羟基琥珀酰亚胺的二环己基胺盐P2沉淀出来
2.权利要求1的方法，其中R为甲基、乙基、直链或支链的丙基、直链或支链的丁基、或直链或支链的戊基，或为2-吡啶基。
3.权利要求1的方法，其中Alk为直链或支链的亚丙基、直链或支链的亚丁基、或直链或支链的亚戊基。
4.权利要求2的方法，其中Alk为直链或支链的亚丙基、直链或支链的亚丁基、或直链或支链的亚戊基。
5.权利要求1的方法，其中Alk为(CH2)n基团，n表示1至6的整数。
6.权利要求2的方法，其中Alk为(CH2)n基团，n表示1至6的整数。
7.权利要求1的方法，其中所述反应在酮中进行。
8.权利要求2的方法，其中所述反应在酮中进行。
9.权利要求3的方法，其中所述反应在酮中进行。
10.权利要求4的方法，其中所述反应在酮中进行。
11.权利要求5的方法，其中所述反应在酮中进行。
12.权利要求6的方法，其中所述反应在酮中进行。
13.权利要求7的方法，其中所述酮为MIBK。
14.权利要求8的方法，其中所述酮为MIBK。
15.权利要求9的方法，其中所述酮为MIBK。
16.权利要求10的方法，其中所述酮为MIBK。
17.权利要求11的方法，其中所述酮为MIBK。
18.权利要求12的方法，其中所述酮为MIBK。
19.权利要求1至18中任一项的方法，其中，在P1与DSC反应后，将反应混合物冷却，以促进P2的沉淀。
20.权利要求1至18中任一项的方法，其中P2通过机械分离去除。
21.权利要求19的方法，其中P2通过机械分离去除。
22.权利要求20的方法，其中所述机械分离为过滤。
23.权利要求21的方法，其中所述机械分离为过滤。
24.式P1的产物：
其中R和Alk如权利要求1至6中任一项所定义。
25.权利要求24的产物，其为下式：
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