CN117800875B - 一种反式-(N-Boc-4-氨基环己基)乙酸的制备方法 - Google Patents
一种反式-(N-Boc-4-氨基环己基)乙酸的制备方法 Download PDFInfo
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- IHXBNSUFUFFBRL-UHFFFAOYSA-N 2-[4-[(2-methylpropan-2-yl)oxycarbonylamino]cyclohexyl]acetic acid Chemical compound CC(C)(C)OC(=O)NC1CCC(CC(O)=O)CC1 IHXBNSUFUFFBRL-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title abstract description 11
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims abstract description 21
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims abstract description 14
- LXCICYRNWIGDQA-UHFFFAOYSA-N 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-oxazole Chemical compound O1C(C)(C)C(C)(C)OB1C1=CON=C1 LXCICYRNWIGDQA-UHFFFAOYSA-N 0.000 claims abstract description 10
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims abstract description 10
- VLGPDTPSKUUHKR-UHFFFAOYSA-N tert-butyl n-(4-bromophenyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=C(Br)C=C1 VLGPDTPSKUUHKR-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000011698 potassium fluoride Substances 0.000 claims abstract description 7
- 235000003270 potassium fluoride Nutrition 0.000 claims abstract description 7
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims abstract description 6
- 238000005859 coupling reaction Methods 0.000 claims abstract description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 12
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 235000011056 potassium acetate Nutrition 0.000 claims description 6
- 101150003085 Pdcl gene Proteins 0.000 claims description 4
- 229910052763 palladium Inorganic materials 0.000 claims description 4
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical group C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- -1 N-Boc-4-isoxazoleboronic acid Chemical compound 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 230000008878 coupling Effects 0.000 claims description 2
- 238000010168 coupling process Methods 0.000 claims description 2
- 238000005984 hydrogenation reaction Methods 0.000 claims description 2
- 239000011261 inert gas Substances 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 239000002994 raw material Substances 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 2
- 230000007062 hydrolysis Effects 0.000 abstract description 3
- 238000007142 ring opening reaction Methods 0.000 abstract description 2
- 239000000758 substrate Substances 0.000 abstract description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 229910001220 stainless steel Inorganic materials 0.000 description 2
- 239000010935 stainless steel Substances 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- YBADLXQNJCMBKR-UHFFFAOYSA-N (4-nitrophenyl)acetic acid Chemical compound OC(=O)CC1=CC=C([N+]([O-])=O)C=C1 YBADLXQNJCMBKR-UHFFFAOYSA-N 0.000 description 1
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 1
- 206010026749 Mania Diseases 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 239000003693 atypical antipsychotic agent Substances 0.000 description 1
- 229940127236 atypical antipsychotics Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- KPWSJANDNDDRMB-QAQDUYKDSA-N cariprazine Chemical compound C1C[C@@H](NC(=O)N(C)C)CC[C@@H]1CCN1CCN(C=2C(=C(Cl)C=CC=2)Cl)CC1 KPWSJANDNDDRMB-QAQDUYKDSA-N 0.000 description 1
- 229960005123 cariprazine Drugs 0.000 description 1
- GPPJWWMREQHLQT-BHQIMSFRSA-N cariprazine hydrochloride Chemical compound Cl.C1C[C@@H](NC(=O)N(C)C)CC[C@@H]1CCN1CCN(C=2C(=C(Cl)C=CC=2)Cl)CC1 GPPJWWMREQHLQT-BHQIMSFRSA-N 0.000 description 1
- 230000006196 deacetylation Effects 0.000 description 1
- 238000003381 deacetylation reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- YMFBUTYXVRUNAR-UHFFFAOYSA-N n-(2-oxocyclohexyl)acetamide Chemical class CC(=O)NC1CCCCC1=O YMFBUTYXVRUNAR-UHFFFAOYSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 239000004031 partial agonist Substances 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940050365 vraylar Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
-
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
本发明提供一种反式‑(N‑Boc‑4‑氨基环己基)乙酸的制备方法，具体步骤包括：第一步、4‑异恶唑硼酸频哪醇酯与N‑Boc‑4‑溴苯胺发生偶联反应得到N‑Boc‑4‑异恶唑苯胺；第二步、钌/碳催化氢化下加成纯化后得到反式‑4‑(异恶唑‑4‑基)环己烷氨基甲酸叔丁酯；第三步、氟化钾和氢氧化钾开环水解得到反式‑(N‑Boc‑4‑氨基环己基)乙酸。本发明提供的制备方法与现有文献相比具有对映选择性高，总收率高，操作简单且底物适用性广。
Description
技术领域
本发明涉及反式-(N-Boc-4-氨基环己基)乙酸的制备方法，属于医药中间体技术领域。
背景技术
反式-(N-Boc-4-氨基环己基)乙酸是一中重要医药中间体，其为卡利拉(Cariprazine)关键中间体。卡利拉嗪(商品Vraylar)胶囊,卡利拉嗪为非典型抗精神病药物，属于多巴胺D2、D3受体部分激动剂，主要用于治疗成人精神分裂症及双相躁狂症。
现有文献反式-(N-Boc-4-氨基环己基)乙酸的制备主要有两种：
第一种(专利US5977110,1999,A和WO2019/16828,2019,A1)公开路线为：对硝基苯乙酸雷尼镍或钯碳催化氢化苯环加成和硝基还原，然后碱性条件下二碳酸二叔丁酯对氨基进行Boc保护制得。该方式得到的反式异构体相对少，收率低。
反应路线采用方程式表示如下：
第二种(同样专利WO2019/16828,2019,A1)提供另一种路线：对乙酰氨基环己酮与乙氧基-2-(二乙氧基磷酰基)乙酸酯亲核取代，然后Pd/C催化氢化加成双键，接着氢氧化钠水解酯、纯化，然后去乙酰基保护，最后Boc保护。该方法步骤多，操作复杂，收率低。
反应路线采用方程式表示如下：
为了弥补现有合成方法的不足，有必要对反式-(N-Boc-4-氨基环己基)乙酸的制备方法进行改进，开发出一种对映选择性高，总收率高，操作简单的合成路线。
发明内容
为了更好的解决上述问题，本发现提供了一种反式-(N-Boc-4-氨基环己基)乙酸的制备方法，具体步骤包括：4-异恶唑硼酸频哪醇酯与N-Boc-4-溴苯胺偶联反应得到N-Boc-4-异恶唑苯胺；钌/碳催化氢化下加成纯化后得到反式-4-(异恶唑-4-基)环己烷氨基甲酸叔丁酯；氟化钾和氢氧化钾开环水解得到反式-(N-Boc-4-氨基环己基)乙酸。本发明提供的制备方法与现有文献相比具有对映选择性高，总收率高，操作简单且底物适用性广。
为实现上述目的，本发明所述反式-(N-Boc-4-氨基环己基)乙酸的工艺，包括以下步骤：
第一步，偶联反应：4-异恶唑硼酸频哪醇酯、N-Boc-4-溴苯胺、钯催化剂和醋酸钾溶于有机溶剂中，惰性气体保护下，升温偶联得到N-Boc-4-异恶唑苯胺；
第二步，催化氢化：N-Boc-4-异恶唑苯胺、钌/碳和有机溶剂混合，加氢至1.0-1.5Mpa，升温催化氢化得到反/顺式-4-(异恶唑-4-基)环己烷氨基甲酸叔丁酯混合物，重结晶得到反式-4-(异恶唑-4-基)环己烷氨基甲酸叔丁酯；
第三步，水解反应：反式-4-(异恶唑-4-基)环己烷氨基甲酸叔丁酯、氟化钾和DMSO升温反应，随后降温加入氢氧化钾水溶液水解反应得到反式-(N-Boc-4-氨基环己基)乙酸。
反应路线表示如下：
进一步地，第一步所述催化剂选自PdCl2dppf、Pd(PPh3)4。
进一步地，第一步所述有机溶剂选自1,4-二氧六环或乙二醇二甲醚。
进一步地，第一步所述4-异恶唑硼酸频哪醇酯、N-Boc-4-溴苯胺、催化剂与醋酸钾摩尔比为1:1.05-1.08:0.008-0.010:3.5-4.0。
进一步地，第二步所述钌/碳选自5％钌/碳，加入量为原料重量的1-2％，所述有机溶剂选自乙醇/水＝70:30或异丙醇/水＝80:20。
进一步地，第二步所述3-硼酸吡啶-2-羧酸与氯化亚砜摩尔比为1:1.3-1.4。
进一步地，第三步所述反式-4-(异恶唑-4-基)环己烷氨基甲酸叔丁酯、氟化钾与氢氧化钾摩尔比为1:2.5-3.0:2.5:3.0。
发明有益效果
本发明反式-(N-Boc-4-氨基环己基)乙酸的制备方法相比于现有技术，第二步对映选择性高，反式比例高达90％，并且容易进行提纯，整体操作简单，总收率高。
附图说明
图1为实施例5中产物反式-(N-Boc-4-氨基环己基)乙酸的HNMR谱图(附图中11.63ppm出峰未标示)。
具体实施方式
下面详细描述本发明的实施例。下面描述的实施例是示例性的，仅用于解释本发明，而不能理解为对本发明的限制。为描述本发明，以下列出了实施例。但需要理解，本发明不限于这些实施例，只是提供实践本发明的方法。
实施例1
将97.5g(0.5mol)4-异恶唑硼酸频哪醇酯、142.9g(0.525mol)N-Boc-4-溴苯胺、3g(0.004mol)PdCl2(dppf)和176.7g(1.8mol)醋酸钾溶于900mL 1,4-二氧六环中，氮气保护下，升温至85-90℃反应4小时，取样4-异恶唑硼酸频哪醇酯反应完毕，趁热过滤，滤液减压浓缩至不无液体流出，加入600mL二氯甲烷和200mL石油醚热打浆得到116gN-Boc-4-异恶唑苯胺，收率89.1％，HPLC 98.9％。1HNMR(400MHz,CDCl3)δ:9.36(s,1H),8.68(d,1H),8.05(d,1H),7.78-7.74(m,2H),7.61-7.57(m,2H),1.39(s,9H)。
实施例2
将97.5g(0.5mol)4-异恶唑硼酸频哪醇酯、142.9g(0.525mol)N-Boc-4-溴苯胺、3.7g(0.005mol)PdCl2(dppf)和196.3g(2.0mol)醋酸钾溶于1000mL乙二醇二甲醚中，氮气体保护下，升温至85-90℃反应21小时，取样4-异恶唑硼酸频哪醇酯剩余1.3％，趁热过滤，滤液减压浓缩至不无液体流出，加入600mL二氯甲烷和200mL石油醚热打浆得到110g N-Boc-4-异恶唑苯胺，收率84.5％，HPLC 98.7％。
实施例3
将26g(0.1mol)N-Boc-4-异恶唑苯胺、0.52g 5％Ru/C溶于210mL和50mL水中，高压不锈钢反应釜氮气加压至0.2Mpa，并置换三次，氢气加压至1Mpa，并置换三次，升温至70-75℃，氢气保持压力1.0-1.5Mpa，反应24小时，取样反/顺式-4-(异恶唑-4-基)环己烷氨基甲酸叔丁酯比例为86％/12％，泄压、降温至室温，通过硅藻土过滤，滤饼用异丙醇淋洗，滤液减压浓缩至无液体流出，加入120mL MTBE升温溶解，然后降温至35℃，滴加60mL正庚烷，降温至5-10℃，过滤，滤饼用冷MTBE和正庚烷混合溶剂淋洗，烘干得到19.3g反式-4-(异恶唑-4-基)环己烷氨基甲酸叔丁酯，收率72.6％，HPLC 99.6％。1HNMR(400MHz,DMSO-d6)δ:8.19(d,1H),7.96(d,1H),7.61(s,1H),3.57-3.52(m,1H),2.68-2.63(m,1H),1.85-1.74(m,4H),1.60-1.49(m,4H),1.41(s,9H).
实施例4
将26g(0.1mol)N-Boc-4-异恶唑苯胺、0.3g 5％Ru/C溶于185mL和75mL水中，高压不锈钢反应釜氮气加压至0.2Mpa，并置换三次，氢气加压至1Mpa，并置换三次，升温至70-75℃，氢气保持压力1.0-1.5Mpa，反应16小时，取样反/顺式-4-(异恶唑-4-基)环己烷氨基甲酸叔丁酯比例为90％/10％，泄压、降温至室温，通过硅藻土过滤，滤饼用乙醇淋洗，滤液减压浓缩至无液体流出，加入120mL MTBE升温溶解，然后降温至35℃，滴加60mL正庚烷，降温至5-10℃，过滤，滤饼用冷MTBE和正庚烷混合溶剂淋洗，烘干得到20.7g反式-4-(异恶唑-4-基)环己烷氨基甲酸叔丁酯，收率77.8％，HPLC 99.6％。
实施例5
将26.6g(0.1mol)反式-4-(异恶唑-4-基)环己烷氨基甲酸叔丁酯、17.4g(0.3mol)氟化钾溶于100mL二甲基亚砜中，氮气体保护下，升温至110-115℃反应3小时，降温至室温，加入42.1g(0.3mol)40％氢氧化钾，升温至85-90℃反应11小时，加入100mL甲苯和60mL水，趁热分层，保留水相，水相降温至10-15℃，滴加1％硫酸溶液至pH＝3.5-4.0，然后升温至40℃搅拌2小时，降温至室温，过滤，滤饼去离子水和正庚烷淋洗得到23.5g反式-(N-Boc-4-氨基环己基)乙酸，收率91.3％，HPLC 99.8％。1HNMR(400MHz,CDCl3)δ:11.63(s,1H),4.41(m,1H),3.99(m,1H),2.23-2.27(m,2H),2.02(m,2H),1.83-1.86(m,2H),1.74-1.78(m,1H),1.46(s,9H),1.06-1.20(m,4H).
以上实施例描述了本发明的基本原理、主要特征及优点。本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明原理的范围下，本发明还会有各种变化和改进，这些变化和改进均落入本发明保护的范围内。
Claims (5)
1.一种反式-(N-Boc-4-氨基环己基)乙酸的制备方法，其特征在于，包括如下步骤：
第一步，偶联反应：4-异恶唑硼酸频哪醇酯、N-Boc-4-溴苯胺、钯催化剂和醋酸钾溶于有机溶剂中，惰性气体保护下，升温偶联得到N-Boc-4-异恶唑苯胺；所述钯催化剂选自PdCl2(dppf)或Pd(PPh3)4；
第二步，催化氢化：N-Boc-4-异恶唑苯胺、钌/碳和有机溶剂混合，加氢至1.0-1.5Mpa，升温催化氢化得到反/顺式-4-(异恶唑-4-基)环己烷氨基甲酸叔丁酯混合物，重结晶得到反式-4-(异恶唑-4-基)环己烷氨基甲酸叔丁酯；所述有机溶剂选自乙醇/水＝70:30或异丙醇/水＝80:20；
第三步，水解反应：反式-4-(异恶唑-4-基)环己烷氨基甲酸叔丁酯、氟化钾和DMSO升温反应，随后降温加入氢氧化钾水溶液水解反应，最后加入盐酸水溶液处理，得到反式-(N-Boc-4-氨基环己基)乙酸。
2.根据权利要求1所述反式-(N-Boc-4-氨基环己基)乙酸的制备方法，其特征在于：第一步中，所述有机溶剂选自1,4-二氧六环或乙二醇二甲醚。
3.根据权利要求1所述反式-(N-Boc-4-氨基环己基)乙酸的制备方法，其特征在于：第一步中，所述4-异恶唑硼酸频哪醇酯、N-Boc-4-溴苯胺、钯催化剂与醋酸钾摩尔比为1:1.05-1.08:0.008-0.010:3.5-4.0。
4.根据权利要求1所述反式-(N-Boc-4-氨基环己基)乙酸的制备方法，其特征在于：第二步中，所述钌/碳选自5％钌/碳，加入量为原料重量的1-2％。
5.根据权利要求1所述反式-(N-Boc-4-氨基环己基)乙酸的制备方法，其特征在于：第三步中，所述反式-4-(异恶唑-4-基)环己烷氨基甲酸叔丁酯、氟化钾与氢氧化钾摩尔比为1:2.5-3.0:2.5:3.0。
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