CN116283682B - 一种同位素标记的氨磷汀代谢物的制备方法 - Google Patents
一种同位素标记的氨磷汀代谢物的制备方法 Download PDFInfo
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- JKOQGQFVAUAYPM-UHFFFAOYSA-N amifostine Chemical class NCCCNCCSP(O)(O)=O JKOQGQFVAUAYPM-UHFFFAOYSA-N 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title abstract description 20
- 150000001875 compounds Chemical class 0.000 claims abstract description 61
- 239000003513 alkali Substances 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 14
- 239000002253 acid Substances 0.000 claims abstract description 7
- 229940126062 Compound A Drugs 0.000 claims abstract description 6
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims abstract description 6
- -1 ester compound Chemical class 0.000 claims abstract description 6
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims abstract description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 26
- 238000006243 chemical reaction Methods 0.000 claims description 26
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- 239000003960 organic solvent Substances 0.000 claims description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 13
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- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 10
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- 230000035484 reaction time Effects 0.000 claims description 7
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- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 2
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
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- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 2
- 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 claims description 2
- 239000002585 base Substances 0.000 claims 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims 1
- 238000003756 stirring Methods 0.000 claims 1
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- 229960001097 amifostine Drugs 0.000 abstract description 7
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- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- 229940031098 ethanolamine Drugs 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
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- 102000002260 Alkaline Phosphatase Human genes 0.000 description 2
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 206010033128 Ovarian cancer Diseases 0.000 description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
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- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
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- 238000003786 synthesis reaction Methods 0.000 description 2
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- JXRGUPLJCCDGKG-UHFFFAOYSA-N 4-nitrobenzenesulfonyl chloride Chemical compound [O-][N+](=O)C1=CC=C(S(Cl)(=O)=O)C=C1 JXRGUPLJCCDGKG-UHFFFAOYSA-N 0.000 description 1
- ITZMJCSORYKOSI-AJNGGQMLSA-N APGPR Enterostatin Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(=O)N1[C@H](C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)CCC1 ITZMJCSORYKOSI-AJNGGQMLSA-N 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
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- 206010029155 Nephropathy toxic Diseases 0.000 description 1
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- 230000009286 beneficial effect Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
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- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- QIFQSGPBTMOXCE-UHFFFAOYSA-N n'-(2-dihydroxyphosphinothioyloxyethyl)propane-1,3-diamine Chemical compound NCCCNCCOP(O)(O)=S QIFQSGPBTMOXCE-UHFFFAOYSA-N 0.000 description 1
- 230000007694 nephrotoxicity Effects 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/02—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of thiols
- C07C319/06—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of thiols from sulfides, hydropolysulfides or polysulfides
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- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
- C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
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- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
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- G01—MEASURING; TESTING
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Abstract
本发明公开了一种稳定同位素标记的氨磷汀代谢物的制备方法，该方法以化合物A为起始原料，然后将其先做成活性酯化合物B，再与化合物C反应，通过取代反应得到中间体化合物D，然后再依次通过碱和酸脱保护，最终得到稳定同位素标记的氨磷汀代谢物。本发明整个路线设计合理，后处理简单、原料易得；制备得到的目标产物纯度可达99.0％以上，氘丰度99.0％以上，可用于药代动力学研究，为氨磷汀的代谢机理研究提供测试样品，具有重要的应用价值。
Description
技术领域
本发明涉及一种氨磷汀代谢物的制备方法，尤其涉及一种稳定同位素标记的氨磷汀代谢物的制备方法。
背景技术
氨磷汀(Amifostine)化学名称为2-(3-氨基丙胺基)-乙硫醇磷酸酯或3-氨基丙基胺乙基硫代磷酸，是1996年美国食品和药物管理局(Food and Drug Adminis-tration，FDA)批准上市的第一个广谱细胞保护剂。通常用于放疗时正常细胞保护剂及预防和减少多剂量顺铂对晚期卵巢癌或非小细胞肺癌化疗和用环磷酰胺对晚期卵巢癌化疗时，出现的累积性肾毒性、神经毒性和造血系统的损害。随着研究的深入，人们发现氨磷汀在组织中可被碱性磷酸酶(AlkalinePhosphatase，ALP或AKP)水解而生成活性代谢产物WR-1065[化学式为H2N-(CH2)3-NH-(CH2)2-SH]，其可选择性地摄入正常细胞，具有清除组织中自由基的作用。
稳定同位素标记的氨磷汀代谢物是氨磷汀代谢物WR-1065的标记形式，通过对标记氨磷汀代谢物的合成和研究，可以对氨磷汀进行相关的药理学、药动学等进行研究，可为氨磷汀的代谢机理研究提供供试样品，非标记氨磷汀代谢物WR-1065在文献(Journal ofOrganic Chemistry,1962,vol.27,p.4222-4226)中有报道合成方法，但是该方法反应选择性不好，反应产物比较杂，比较浪费原料并且提纯困难，收率很低，不适合稳定同位素标记的氨磷汀代谢物的合成，但是目前通过查阅文献尚未发现关于稳定同位素标记的氨磷汀代谢物文献报道合成方法。
发明内容
发明目的：本发明旨在提供一种目标产物纯度高的稳定同位素标记的氨磷汀代谢物的制备方法。
技术方案：本发明所述的稳定同位素标记的氨磷汀代谢物的制备方法，包括如下步骤：
(1)取化合物A，加入到有机溶剂中，然后加入碱和R1-Cl；反应得到化合物B，结构式如下：
(2)取化合物B，加入到有机溶剂中，然后加化合物C和碱；反应得到化合物D，结构式如下：
(3)取化合物D，加入到有机溶剂中，然后加入有机碱；反应得到化合物E，结构式如下：
(4)取化合物E，加入到有机溶剂中，然后加入酸；反应得到化合物F，结构式如下：
其中，X为取代基保护的氮，取代基选自芴甲氧羰基、邻苯二甲酰基或三氟乙酰基；Y为HCOO-、CH3COO-、Cl-或CF3COO-；R1选自甲磺酰基、对甲苯磺酰基或对硝基苯磺酰基，优选对甲苯磺酰氯；R2选自乙酰基、三苯甲基或叔丁基。
作为优选方案，以上所述步骤中，步骤(1)所述的有机溶剂为四氢呋喃，二氯甲烷，DMF和二氧六环等，优选二氯甲烷；所述的碱为三乙胺、N,N-二异丙基乙胺、碳酸钠、碳酸钾、氢氧化钠等，优选三乙胺；所述化合物A与R1-Cl的摩尔比为1:1～1:3，化合物A与碱的摩尔比为1:1～1:5；所述反应温度为0～60℃，所述反应时间为10～20小时。
作为优选方案，以上所述步骤中，步骤(2)所述的有机溶剂为乙腈、N,N-二甲基甲酰胺、二氧六环、丙酮等，优选N,N-二甲基甲酰胺；所述的碱为碳酸钠，碳酸钾，碳酸铯和氢氧化钠等，优选碳酸钠；所述化合物B与化合物C的摩尔比为1:1～1:3；化合物B与碱的摩尔比为1:1.5～1:3.5；所述反应温度为30～100℃，所述反应时间为10～20小时。
作为优选方案，以上所述步骤中，步骤(3)所述溶剂为甲醇、乙醇、二氧六环、四氢呋喃等，优选乙醇；所述的碱为甲胺、乙醇胺，水合肼、二甲胺等，优选乙醇胺，所述化合物D与碱的摩尔比为1:5～1:15，所述反应温度为25～90℃，所述反应时间为10～20小时。
作为优选方案，以上所述步骤中，步骤(4)所述的溶剂为二氯甲烷、二氯乙烷、四氢呋喃、二氧六环等，优选四氢呋喃；所述酸为甲酸、乙酸、盐酸、三氟乙酸等，优选盐酸；所述化合物E与酸的摩尔比为1:2～1:10，所述反应温度为0～60℃，所述反应时间为1～10小时。
有益效果：与现有技术相比，本发明具有如下显著优点：(1)所述制备方法制备得到的目标产物纯度可达99.0％以上，氘丰度99.0％以上，可用于药代动力学研究，为氨磷汀的代谢机理研究提供测试样品，具有重要的应用价值；(2)该制备方法的合成路线设计合理，后处理简单、原料易得，可操作性强。
附图说明
图1为实施例1化合物F的核磁氢谱图；
图2为实施例1化合物F的质谱图；
图3为实施例1化合物F的色谱图。
具体实施方式
下面结合实施例对本发明的技术方案作进一步说明。
实施例1
(1)化合物B-1的制备，取10.00g的A-1溶解在四氢呋喃中，冰浴下加入11.98g的三乙胺和6.51g的甲基磺酰氯，混合液在10℃反应15小时，薄层色谱显示反应完全，加水二氯甲烷萃取，有机相干燥浓缩，硅胶柱纯化得到11.10g的化合物B-1，收率81.05％。
(2)化合物D-1的制备，取11.00g的化合物B-1和14.58g的化合物C-1溶解在N,N-二甲基甲酰胺中，加12.09g的碳酸钠，在90℃反应15小时，薄层色谱显示反应完全，反应结束，加水萃取，硅胶柱纯化得到14.30g的化合物D-1，收率73.36％；MS:513.2[M+H]+。
(3)化合物E-1的制备，取12.00g的化合物D-1溶解在乙醇中，加入23.85g的乙醇胺，50度反应14小时，薄层色谱显示反应完全，浓缩至干，硅胶柱纯化得到8.20g的化合物E-1，收率76.84％，MS:383.2[M+H]+。
(4)化合物F的制备，取8.00g的化合物E-1溶解在四氢呋喃中，冰浴下加入24ml盐酸，20度反应5小时，薄层色谱显示反应完全，浓缩至干，粗产物重结晶纯化得到1.80g的化合物F，收率61.37％，MS:141.2[M+H]+，氘丰度99.20％，1HNMR(400MHz,CD3OD)δ3.22(t,2H),2.81(t 2H)。化合物F的核磁氢谱图、质谱图和色谱图见图1-3。
实施例2
(1)化合物B-2的制备，取10.00g的化合物A-2溶解在四氢呋喃中，冰浴下加入8.34g的三乙胺和7.54g的对甲苯磺酰氯，混合液在10℃反应15小时，薄层色谱显示反应完全，加水二氯甲烷萃取，有机相干燥浓缩，硅胶柱纯化得到12.90g的化合物B-2，收率85.53％。
(2)化合物D-2的制备，取12.00g的化合物B-2和4.19g的化合物C-2溶解在N,N-二甲基甲酰胺中，加8.34g的碳酸钠，在90℃反应12小时，薄层色谱显示反应完全，反应结束，加水萃取，硅胶柱纯化得到8.30g的化合物D-2，收率75.60％。
(3)化合物E-2的制备，取8.00g的化合物D-2溶解在乙醇中，加入14.95g的乙醇胺，50度反应14小时，薄层色谱显示反应完全，浓缩至干，硅胶柱纯化得到3.00g的化合物E-2，收率79.94％。
(4)化合物F的制备，取3.00g的化合物E-2溶解在四氢呋喃中，冰浴下加入12ml盐酸，20度反应5小时，薄层色谱显示反应完全，浓缩至干，粗产物重结晶提纯得到1.50g的化合物F，收率70.00％，MS:141.2[M+H]+，氘丰度99.10％。
实施例3
(1)化合物B-3的制备，取8.00g的化合物A-3溶解在四氢呋喃中，冰浴下加入11.42g的三乙胺和12.01g的对硝基苯磺酰氯，混合液在10℃反应15小时，薄层色谱显示反应完全，加水二氯甲烷萃取，有机相干燥浓缩，硅胶柱纯化得到12.10g的化合物B-3，收率73.96％。
(2)化合物D-3的制备，取12.00g的化合物B-3和4.74g的化合物C-3溶解在N,N-二甲基甲酰胺中，加10.53g的碳酸钠，在90℃反应12小时，薄层色谱显示反应完全，反应结束，加水萃取，硅胶柱纯化得到7.60g的化合物D-3，收率82.45％。
(3)化合物E-3的制备，取7.00g的化合物D-2溶解在乙醇中，加入21.51g的乙醇胺，50度反应14小时，薄层色谱显示反应完全，浓缩至干，硅胶柱纯化得到3.30g的化合物E-3，收率71.97％。
(4)化合物F的制备，取3.00g的化合物E-3溶解在四氢呋喃中，冰浴下加入12ml盐酸，20度反应5小时，薄层色谱显示反应完全，浓缩至干，粗产物重结晶提纯得到1.60g的化合物F，收率69.31％，MS:141.2[M+H]+，氘丰度99.10％。
Claims (9)
1.一种同位素标记的氨磷汀代谢物的制备方法，其特征在于，合成路线如下：
其中，X为取代基保护的氮，取代基选自芴甲氧羰基、邻苯二甲酰基或三氟乙酰基；Y为Cl-；R1选自甲磺酰基、对甲苯磺酰基或对硝基苯磺酰基；R2选自乙酰基、三苯甲基或叔丁基；
所述合成路线的反应过程如下：
（1）取化合物A，加入到有机溶剂中，然后加入碱和R1-Cl，反应得到化合物B；
（2）取化合物B，加入到有机溶剂中，然后加化合物C和碱，反应得到化合物D；
（3）取化合物D，加入到有机溶剂中，然后加有机碱，反应得到化合物E；
（4）取化合物E，加入到有机溶剂中，然后加入酸，反应得到化合物F，所述酸为盐酸。
2.根据权利要求1所述同位素标记的氨磷汀代谢物的制备方法，其特征在于，步骤（1）所述的有机溶剂为四氢呋喃、二氯甲烷、DMF或二氧六环；所述的碱为三乙胺、N,N-二异丙基乙胺、碳酸钠、碳酸钾或氢氧化钠。
3.根据权利要求1所述同位素标记的氨磷汀代谢物的制备方法，其特征在于，步骤（1）所述化合物A与R1-Cl的摩尔比为1:1~1:3，化合物A与碱的摩尔比为1:1~1:5；在0~60℃下搅拌反应10~20小时。
4.根据权利要求1所述同位素标记的氨磷汀代谢物的制备方法，其特征在于，步骤（2）所述的有机溶剂为乙腈、N,N-二甲基甲酰胺、二氧六环或丙酮；所述的碱为碳酸钠、碳酸钾、碳酸铯或氢氧化钠。
5.根据权利要求1所述同位素标记的氨磷汀代谢物的制备方法，其特征在于，步骤（2）所述化合物B与化合物C的摩尔比为1:1~1:3；化合物B与碱的摩尔比为1:1.5~1:3.5；反应温度为30~100℃，反应时间为10~20小时。
6.根据权利要求1所述同位素标记的氨磷汀代谢物的制备方法，其特征在于，步骤（3）所述有机溶剂为甲醇、乙醇、二氧六环或四氢呋喃，所述的有机碱为甲胺、乙醇胺、水合肼或二甲胺。
7.根据权利要求1所述同位素标记的氨磷汀代谢物的制备方法，其特征在于，步骤（3）所述化合物D与有机碱的摩尔比为1:5~1:15，所述反应温度为25~90℃，反应时间为10~20小时。
8.根据权利要求1所述同位素标记的氨磷汀代谢物的制备方法，其特征在于，步骤（4）所述有机溶剂为二氯甲烷、二氯乙烷、四氢呋喃或二氧六环。
9.根据权利要求1所述同位素标记的氨磷汀代谢物的制备方法，其特征在于，步骤（4）所述化合物E与酸的摩尔比为1:2~1:10，反应温度为0~60℃，反应时间为1~10小时。
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