CN103415503A - 1-氨基-3-羟基-环丁烷-1-甲酸衍生物的制备 - Google Patents
1-氨基-3-羟基-环丁烷-1-甲酸衍生物的制备 Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- OEQBVNDAVKXWBS-UHFFFAOYSA-N 1-amino-3-hydroxycyclobutane-1-carboxylic acid Chemical class OC(=O)C1(N)CC(O)C1 OEQBVNDAVKXWBS-UHFFFAOYSA-N 0.000 title 1
- 238000000034 method Methods 0.000 claims abstract description 41
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 52
- 150000001875 compounds Chemical class 0.000 claims description 33
- 229910052763 palladium Inorganic materials 0.000 claims description 25
- 230000000903 blocking effect Effects 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- 238000007327 hydrogenolysis reaction Methods 0.000 claims description 10
- -1 platinum metals Chemical class 0.000 claims description 10
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 9
- 239000012429 reaction media Substances 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 238000006555 catalytic reaction Methods 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
- 150000001412 amines Chemical class 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 229910052751 metal Inorganic materials 0.000 claims description 5
- 239000002184 metal Substances 0.000 claims description 5
- 229910052697 platinum Inorganic materials 0.000 claims description 5
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical group [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 2
- 150000001721 carbon Chemical group 0.000 claims description 2
- 229910052741 iridium Inorganic materials 0.000 claims description 2
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052762 osmium Inorganic materials 0.000 claims description 2
- SYQBFIAQOQZEGI-UHFFFAOYSA-N osmium atom Chemical compound [Os] SYQBFIAQOQZEGI-UHFFFAOYSA-N 0.000 claims description 2
- 229910052703 rhodium Inorganic materials 0.000 claims description 2
- 239000010948 rhodium Substances 0.000 claims description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 2
- 229910052707 ruthenium Inorganic materials 0.000 claims description 2
- 229940027541 fluciclovine f-18 Drugs 0.000 abstract description 9
- 239000002243 precursor Substances 0.000 abstract description 9
- NTEDWGYJNHZKQW-DGMDOPGDSA-N fluciclovine ((18)F) Chemical compound OC(=O)[C@]1(N)C[C@H]([18F])C1 NTEDWGYJNHZKQW-DGMDOPGDSA-N 0.000 abstract description 8
- 238000006243 chemical reaction Methods 0.000 abstract description 7
- 239000012217 radiopharmaceutical Substances 0.000 abstract description 6
- 229940121896 radiopharmaceutical Drugs 0.000 abstract description 6
- 230000002799 radiopharmaceutical effect Effects 0.000 abstract description 6
- 150000001413 amino acids Chemical class 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 150000003862 amino acid derivatives Chemical class 0.000 abstract description 2
- 238000002600 positron emission tomography Methods 0.000 abstract 2
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- 238000011503 in vivo imaging Methods 0.000 abstract 1
- 239000003054 catalyst Substances 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 238000005984 hydrogenation reaction Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- 238000006264 debenzylation reaction Methods 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 238000009206 nuclear medicine Methods 0.000 description 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 3
- 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000005903 acid hydrolysis reaction Methods 0.000 description 2
- NPPVRRHAPWWXME-UHFFFAOYSA-N cyclobutane formic acid Chemical compound C(=O)O.C1CCC1 NPPVRRHAPWWXME-UHFFFAOYSA-N 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 230000004153 glucose metabolism Effects 0.000 description 2
- 238000007689 inspection Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 2
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 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
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 125000001743 benzylic group Chemical group 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 238000002485 combustion reaction Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 201000010235 heart cancer Diseases 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 208000024348 heart neoplasm Diseases 0.000 description 1
- 239000002638 heterogeneous catalyst Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- AFDMODCXODAXLC-UHFFFAOYSA-N phenylmethanimine Chemical group N=CC1=CC=CC=C1 AFDMODCXODAXLC-UHFFFAOYSA-N 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000011895 specific detection Methods 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/46—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C229/48—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups and carboxyl groups bound to carbon atoms of the same non-condensed ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/0404—Lipids, e.g. triglycerides; Polycationic carriers
- A61K51/0406—Amines, polyamines, e.g. spermine, spermidine, amino acids, (bis)guanidines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
本发明涉及一种方法，其用于制备放射性药物前体，特别是受保护的氨基酸衍生物，其用作用于生产体外成像程序（例如正电子发射层析成像(PET)）所用的放射性标记的氨基酸的前体。特别是，本发明涉及一种用于制备[18F]-1-氨基-3-氟环丁烷甲酸([18F]FACBC)PET试剂的前体的方法，确保反应有效地完成。
Description
本发明涉及一种方法，其用于制备放射性药物前体，特别是受保护的氨基酸衍生物，其用作用于生产体内成像程序（例如正电子发射层析成像(PET)）所用的放射性标记的氨基酸的前体。特别地，本发明涉及一种用于制备[18F]-1-氨基-3-氟环丁烷甲酸([18F] FACBC) PET试剂的前体的方法。
以正电子发射层析成像(PET)为代表的核医学检查有效用于诊断多种疾病，包括心脏病和癌症。这些技术涉及向患者给予特定的放射性同位素标记的试剂(下文称为放射性药物)，接着检测由该试剂直接或间接发射的γ-射线。与其它检查技术相比，核医学检查的特性在于其对疾病具有不仅高特异性和灵敏度，而且具有提供关于损害的机能的信息的优点。例如，[18F]2-氟-2-脱氧-D-葡萄糖(“[18F]FDG”)，一种用于PET检查的放射性药物，倾向于在葡萄糖代谢增强的区域中浓缩，从而使得可特异性检测其中葡萄糖代谢增强的肿瘤。通过跟踪给予的放射性药物的分布进行核医学检查，并且由此得到的数据根据放射性药物的性质而变化。因此，已开发用于不同疾病的不同放射性药物，并且其中的一些投入临床使用。例如，已开发各种肿瘤诊断试剂、血流诊断试剂和受体定位试剂。
近年来，已设计一系列放射性卤素标记的氨基酸化合物作为新的放射性药物，包括[18F]-1-氨基-3-氟环丁烷甲酸([18F]FACBC)。认为[18F]FACBC有效用作高度增殖肿瘤的诊断试剂，因为其具有被氨基酸转运体特异性吸收的性质。寻求用于制备[18F]FACBC及其前体的改进方法。
EP1978015 (A1)提供用于小规模生产[18F] FACBC的方法。在该方法中的一种中间体为1-(N-(叔丁氧基羰基)氨基)-3-羟基-环丁烷-1-甲酸乙酯(以下流程1中的式IV)。在用于制备该中间体的EP1978015 (A1)的方法步骤中，使用中性pH的干燥的钯。流程1显示在EP1978015中概述的用于制备[18F] FACBC的多步合成。
流程1。
在以上流程1中，BnO表示苄基醚，Boc表示叔丁基氨基甲酸酯(叔丁氧基羰基)且OTf表示三氟甲磺酸酯。
在自动化合成器单元上进行的合成[18F]FACBC的最后步骤基于从式(V)前体以[18F]氟化物亲核置换三氟甲磺酸酯(triflate)基团。[18F]氟化物可连同kryptofix (K222)、碳酸钾、水和乙腈的溶液引入反应容器中。18F-标记的中间体化合物随后经历两个脱保护步骤，其中乙基和Boc保护基团分别通过碱性和酸性水解除去。
式(IV)的化合物：
命名为1-(N-(叔丁氧基羰基)氨基)-3-羟基-环丁烷-1-甲酸乙酯。该中间体通过1-(N-(叔丁氧基羰基)氨基)-3-苄氧基-环丁烷-1-甲酸乙酯(式III)的氢解制备，如流程1的步骤3所示。这样的氢解或脱苄基化可通过使用钯催化剂和氢气来进行。在小规模上，干燥的钯催化剂可接受使用，但是在较大规模上，由于钯在某些条件下自燃并且能因此点燃，所以从安全性角度，使用湿钯催化剂更好。然而，当以较大规模进行该氢解和用湿钯替换干钯时，经历（experience）了苄基的去除不完全，即使在若干天后。在较小规模并且使用干钯时，在2-4天后氢解反应完成。
因此，需要安全并且有效完成的制备式(IV)的化合物的方法。
现在意外地发现，使用特定的条件，使用湿钯可成功地进行所述方法。因此，本发明的方法避免与干钯相关的点燃的风险，并且氢解反应在可接受的时间段内完成。所发现的方案是为了降低包含待氢解的化合物的起始材料的pH和使用湿钯。
因此，在第一方面，本发明提供一种用于由式IIIa的化合物制备式IVa的化合物的方法：
(IIIa)
其中：
R表示具有1-5个碳原子的烷基；
Y表示胺的保护基团；
X表示醇的保护基团；
其中所述方法包括将包含式IIIa化合物的反应介质的pH调节至2.0-5.0，和使用选自铂族金属的湿催化剂进行X的氢解。
R部分为线性或支化烷基链，并且优选为选自甲基、乙基、1-丙基或异丙基的烷基，最优选为乙基。
术语“烷基”单独或组合地表示具有通式CnH2n+1的直链或支链烷基。这样的基团的实例包括甲基、乙基和异丙基。
本文术语“醇”是指包含基团-OH的取代基。
本文术语“胺”是指基团-NR'R''，其中R'和R''独立地为氢或烷基，并且优选两者均为氢。
术语“保护基团”是指抑制或压制不期望的化学反应的基团，但是其设计为具有足够的反应性，使其可在不改变分子的其余部分的足够温和的条件下从所讨论的官能团切断以得到期望的产物。保护基团为本领域技术人员熟知的，并且描述于‘Protective Groups in Organic Synthesis(有机合成中的保护基团)’，Theorodora W. Greene和Peter G. M. Wuts，(第4版，John Wiley & Sons，2007)。
用于本发明的优选氨基保护基团选自叔丁氧基羰基、烯丙基氧基羰基、邻苯二甲酰亚胺基和N-亚苄基胺取代基。Y部分因此为胺（例如氨基甲酸酯）的保护基团。
X部分为醇的保护基团，选择该保护基团使得保护基团形成其相关的醚，例如苄基(Bn)、苄基碳酸酯、甲氧基甲基(MOM)、2-甲氧基乙氧基甲基(MEM)、甲硫基甲基(MTM)、四氢吡喃基(THP)、苄氧基甲基(BOM)、对甲氧基苯基、对甲氧基苄基(MPM)、对甲氧基苄氧基甲基(PMBM)、三异丙基甲硅烷基(TIPS)、叔丁基二甲基甲硅烷基(TBDMS)、2-(三甲基甲硅烷基)乙氧基甲基(SEM)和(苯基二甲基甲硅烷基)甲氧基甲基(SMOM)。优选可通过氢化除去的基团，并且在一种优选的实施方案中，X为苄基。
在一个特别优选的实施方案中，根据流程1，R为乙基，Y为BOC，X为苄基，使得式IVa的化合物为式IV的化合物，并且式IIIa的化合物为式III的化合物。
用于本发明的方法的催化剂选自铂金属族，因此选自钌、铑、钯、锇、铱和铂。更优选，催化剂为钯。
用于本发明的方法的催化剂应为湿的，以避免任何点燃的风险。所用的催化剂优选为稠浆料形式，这样的浆料包括水。在一个实施方案中，湿催化剂包括30-70%重量%水，更优选40-60重量%水，最优选45-55重量%水。在一个特别优选的实施方案中，湿催化剂包括约50重量%水。此外，所用的催化剂优选为非均质催化剂，即其包括悬浮在反应介质中的金属的固体颗粒。在本发明中所用的催化剂(例如钯)优选在细微分散的碳上分布，称为碳载钯(Pd/C)。这些催化剂市售可得，金属载荷为1-30%，并且这些可用于本发明的方法。金属载荷(例如钯载荷)更优选为1-10%，最优选5-10%。用于所述方法的催化剂的量取决于选择的种催化剂和载荷百分比。例如，具有10%载荷的碳载钯催化剂，用于本发明的方法的催化剂的量为1-30重量%/化合物，更优选5-20重量%/化合物，最优选约10重量%/化合物。在本上下文中，“化合物”为起始材料，即式IIIa的化合物，例如式III的化合物。
本发明的方法的氢解反应使用氢源在催化下进行。优选的氢源为氢气。
当实施本发明的方法时，意外地发现，通过组合使用湿催化剂和调节pH，成功地驱使脱苄基化完成。通过加入酸，将包含式IIIa的化合物(例如式III的化合物)和溶剂的反应介质的pH调节至2.0-5.0。更优选，将pH调节至2.5-3.5，最优选调节至3.0。意外地发现，脱苄基化反应在这些条件下在可接受的短时间内完成，同时胺官能的保护基团(基团Y)不受影响。该保护基团随后通过酸性水解除去，关键是在本发明的方法的加氢脱除（dehydrogenolysis）步骤期间不被除去。用于所述方法的酸为无机酸或有机酸，优选选自盐酸、乙酸、甲酸和硫酸。最优选所述酸为乙酸。在本发明的方法中，式IIIa的化合物因此溶解于溶剂中，测量pH并且通过向反应介质中加入酸而调节pH至期望的水平。用于溶解式IIIa的化合物(例如式III的化合物)的溶剂为极性溶剂，为质子或非质子的，并且优选选自醇、酯、醚和氯化的溶剂。溶剂更优选为醇，最优选乙醇。溶剂的量应足以完全溶解式IIIa的化合物。式IIIa的化合物与溶剂之间的mol/ml比率例如为1:4-1:8。
本发明的方法可用于所有规模，并且当大规模制备时特别有用，例如当制备100 g或更多(例如300 g，或至500 g或更多)的式IVa的化合物时。在较小规模中，可使用干的铂族金属催化剂，但是当放大时，出于安全的原因，有利的是使用湿形式的这种催化剂。发现包括湿钯和将反应介质的pH调节至2.0-5.0的本发明的方法更安全、更有效，并且还更加成本高效，因为氢解反应在短时间内完成。未加入酸，反应不完全，而当实施本发明的方法时，在例如5天或更少，优选4天或更少，最优选3天或更少内，加氢脱除完成。
在另一方面，本发明提供制备根据式V的前体化合物18F-FACBC的方法：
所述方法包括根据第一方面的方法制备式IV的化合物的步骤。OTf表示三氟甲磺酸酯。式IVa中的Y则为Boc且R为乙基。
通过以下实施例来说明本发明。
实施例
实施例1:
将不同量的1-(N-(叔丁氧基羰基)氨基)-3-苄氧基-环丁烷-1-甲酸乙酯(式III的化合物)加入乙醇(18.4-20.0 ml/g)中。进行数个测试以优化脱苄基化反应，以制备1-(N-(叔丁氧基羰基)氨基)-3-羟基-环丁烷-1-甲酸乙酯(式IV的化合物)。将不同量的乙酸加入到包含式III的化合物和乙醇的反应介质中，以将pH调节至约3。不同量的碳载钯(10%载荷)用于加氢脱除，测试湿和干催化剂两者。反应通过TLC示踪。结果见表1中。
表1：
发现当使用湿形式的钯催化剂并且将pH调节至约3时，反应在仅2-4天内完成。没有pH调节，在中性pH下进行反应，并且使用湿钯，脱苄基化未完成，或者耗时长达10天才完成。
Claims (10)
1. 一种用于由式IIIa的化合物制备式IVa的化合物的方法：
(IIIa)
其中：
R表示具有1-5个碳原子的烷基；
Y表示胺的保护基团；和，
X表示醇的保护基团；
其中所述方法包括将包含式IIIa的化合物的反应介质的pH调节至2.0-5.0，和使用选自铂族金属的湿催化剂进行X的氢解。
2. 权利要求1的方法，其中R为乙基，Y为BOC，且X为苄基。
3. 权利要求1或权利要求2的方法，其中所述催化剂选自钌、铑、钯、锇、铱和铂。
4. 权利要求1-3中任一项的方法，其中所述催化剂为钯。
5. 权利要求1-4中任一项的方法，其中所述催化剂为钯载荷为1-10%的碳载钯。
6. 权利要求1-5中任一项的方法，其中所述反应介质还包含溶剂。
7. 权利要求6的方法，其中所述溶剂为乙醇。
8. 权利要求1-7中任一项的方法，其中通过向所述反应介质中加入酸进行pH的调节。
9. 权利要求8的方法，其中所述酸为乙酸。
10. 权利要求1-9中任一项的方法，其中将pH调节至2.5-3.5。
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