CN108456154A - 一种n-叔丁氧羰基烃基胍的制备方法 - Google Patents
一种n-叔丁氧羰基烃基胍的制备方法 Download PDFInfo
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- CN108456154A CN108456154A CN201810330093.2A CN201810330093A CN108456154A CN 108456154 A CN108456154 A CN 108456154A CN 201810330093 A CN201810330093 A CN 201810330093A CN 108456154 A CN108456154 A CN 108456154A
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- alkyl
- potassium
- sodium
- tertbutyloxycarbonyl
- tertbutyloxycarbonyls
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- -1 alkyl guanidine Chemical compound 0.000 title claims abstract description 37
- ZRALSGWEFCBTJO-UHFFFAOYSA-N anhydrous guanidine Natural products NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 title claims abstract description 22
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 title claims abstract description 17
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 25
- 239000002904 solvent Substances 0.000 claims abstract description 15
- 239000002994 raw material Substances 0.000 claims abstract description 14
- 239000003513 alkali Substances 0.000 claims abstract description 9
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 3
- 125000006239 protecting group Chemical group 0.000 claims abstract description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 6
- 239000011734 sodium Substances 0.000 claims description 6
- 229910052708 sodium Inorganic materials 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 235000019441 ethanol Nutrition 0.000 claims description 4
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- IWVLDMTUKDWODM-UHFFFAOYSA-N CC(C)C[K] Chemical compound CC(C)C[K] IWVLDMTUKDWODM-UHFFFAOYSA-N 0.000 claims description 2
- 239000004215 Carbon black (E152) Substances 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 125000003710 aryl alkyl group Polymers 0.000 claims description 2
- YKYMGFHOJJOSEB-UHFFFAOYSA-N butan-1-ol;potassium Chemical compound [K].CCCCO YKYMGFHOJJOSEB-UHFFFAOYSA-N 0.000 claims description 2
- BDFJWKALVSRGSR-UHFFFAOYSA-N butan-1-ol;sodium Chemical compound [Na].CCCCO BDFJWKALVSRGSR-UHFFFAOYSA-N 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
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 claims description 2
- 229930195733 hydrocarbon Natural products 0.000 claims description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N methyl tert-butyl ether Substances COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- WQKGAJDYBZOFSR-UHFFFAOYSA-N potassium;propan-2-olate Chemical compound [K+].CC(C)[O-] WQKGAJDYBZOFSR-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- LMHHRCOWPQNFTF-UHFFFAOYSA-N s-propan-2-yl azepane-1-carbothioate Chemical compound CC(C)SC(=O)N1CCCCCC1 LMHHRCOWPQNFTF-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims 3
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims 1
- VXJPCEOTZNHHOA-UHFFFAOYSA-N [K].OC Chemical compound [K].OC VXJPCEOTZNHHOA-UHFFFAOYSA-N 0.000 claims 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims 1
- KCIDZIIHRGYJAE-YGFYJFDDSA-L dipotassium;[(2r,3r,4s,5r,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] phosphate Chemical compound [K+].[K+].OC[C@H]1O[C@H](OP([O-])([O-])=O)[C@H](O)[C@@H](O)[C@H]1O KCIDZIIHRGYJAE-YGFYJFDDSA-L 0.000 claims 1
- 235000011007 phosphoric acid Nutrition 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 16
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 5
- 150000001875 compounds Chemical class 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 238000012805 post-processing Methods 0.000 abstract description 3
- 125000000217 alkyl group Chemical group 0.000 abstract 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 abstract 2
- 238000011017 operating method Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 15
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- 239000012043 crude product Substances 0.000 description 7
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 229960001866 silicon dioxide Drugs 0.000 description 6
- 238000001035 drying Methods 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 2
- 150000002357 guanidines Chemical class 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000013589 supplement Substances 0.000 description 2
- OZNAPDASJUBDQG-UHFFFAOYSA-N tert-butyl n-carbamimidoyl-n-propan-2-ylcarbamate Chemical class CC(C)N(C(N)=N)C(=O)OC(C)(C)C OZNAPDASJUBDQG-UHFFFAOYSA-N 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- UZEKTDVGUQCDBI-UHFFFAOYSA-N 2-propan-2-ylguanidine Chemical compound CC(C)NC(N)=N UZEKTDVGUQCDBI-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- SHLDRGRIHSAHQU-UHFFFAOYSA-N C(O)(O)=O.C(OC(C)(C)C)(OC(C)(C)C)=O Chemical compound C(O)(O)=O.C(OC(C)(C)C)(OC(C)(C)C)=O SHLDRGRIHSAHQU-UHFFFAOYSA-N 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- 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 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- RODAXCIRMWKKKU-UHFFFAOYSA-N [Cs].CC1=CC=CC=C1 Chemical compound [Cs].CC1=CC=CC=C1 RODAXCIRMWKKKU-UHFFFAOYSA-N 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 229940113088 dimethylacetamide Drugs 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- ODCCJTMPMUFERV-UHFFFAOYSA-N ditert-butyl carbonate Chemical group CC(C)(C)OC(=O)OC(C)(C)C ODCCJTMPMUFERV-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 229940083094 guanine derivative acting on arteriolar smooth muscle Drugs 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C277/08—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups of substituted guanidines
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了一种N‑叔丁氧羰基烃基胍的制备方法，该方法以易得的N,N’‑双叔丁氧羰基烃基胍为原料，在溶剂存在下,以碱为试剂进行选择性脱保护去掉一个保护基，得到N‑叔丁氧羰基烃基胍；本发明具有反应试剂廉价易得，反应条件温和，选择性高，操作工艺简单，后处理简便，所得产品纯度和收率高，适合大量制备等特点，本发明制得的N‑叔丁氧羰基烃基胍可作为关键有机合成中间体，用于多种功能化合物的合成。
Description
技术领域
本发明属于化学合成技术领域，具体涉及一种N-叔丁氧羰基烃基胍的制备方法，该类化合物可作为重要有机合成中间体，用于多种功能化合物的合成。
背景技术
烃基胍是一类非常重要的医药与精细化工中间体，其应用范围及其广泛。由于其独特的化学结构及理化性质，胍类化合物已被发现具有多种药理活性：抗病毒、抗细菌、抗炎、治疗疟疾、糖尿病等作用。胍类化合物的合成因而备受关注，已报道了大量不同胍的合成方法。
N-叔丁氧羰基烃基胍类化合物，作为关键有机合成中间体，具有重要的应用价值，通过它们可以合成出许多不同结构的胍类衍生物以作生物活性筛选。
文献J.Med.Chem. 2005, 48, 6472-6481 报导了以异丙基胍为原料，采用二碳酸二叔丁酯(Boc)2O为试剂，一步直接生成N-叔丁氧羰基异丙基胍。但是该反应需在－40℃进行，不利于大量制备；且该反应不具通用性，其它无空间位阻的烃基胍和(Boc)2O反应主要得到双Boc保护的副产物，即N,N’-双叔丁氧羰基烃基胍。
；
文献Tetrahedron Letters, 2007, 48, 2357-2359报道了一种 N-叔丁氧羰基烃基胍的合成方法，该方法以化合物A为原料，以(Boc)2O为试剂反应得到单Boc保护的化合物B，然后和胺反应制得N-叔丁氧羰基烃基胍。该方法的缺点是对于空间位阻较大的胺收率很低，甚至不反应；
。
发明内容
为克服现有技术的不足，本发明提供了一种反应原料廉价易得，反应条件温和，操作工艺简单，后处理简便，所得产品纯度和收率高，可进行大量制备N-叔丁氧羰基烃基胍的方法。
本发明N-叔丁氧羰基烃基胍的制备方法是以N，N’-双叔丁氧羰基烃基胍为原料，在溶剂存在下,用碱进行选择性脱保护，脱掉一个Boc保护基，得到N-叔丁氧羰基烃基胍，其中N，N’-双叔丁氧羰基烃基胍与碱的摩尔比为1:2.0~6.0，反应温度为0～150℃，反应时间为3～22小时；
；
其中：R选自氢、C1~C20烷基、C1~C20环烷基、单取代或多取代芳基、单取代或多取代芳基烃基；R’选自氢、C1~C20烷基、C1~C20环烷基、单取代或多取代芳基、单取代或多取代芳基烃基。
本发明中所述反应使用了溶剂和碱，所用溶剂为甲醇、乙醇、乙二醇、异丙醇、正丁醇、叔丁醇、乙醚、异丙醚、甲基特丁基醚、二氯甲烷、三氯甲烷、水、四氢呋喃、二氧六环、乙腈、甲苯、二甲苯、乙苯、二甲亚砜、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甘醇二甲醚、氮-甲基吡咯烷酮中一种或任意比两种；碱为氢氧化钠、氢氧化钾、甲醇钠、乙醇钠、正丙醇钠、异丙醇钠、正丁醇钠、异丁醇钠、叔丁醇钠、甲醇钾、乙醇钾、正丙醇钾、异丙醇钾、正丁醇钾、异丁醇钾、叔丁醇钾、磷酸钾、磷酸二氢钾、磷酸氢二钾、碳酸钠、碳酸钾、碳酸铯、碳酸氢钠、三乙胺、吡啶中一种或任意比两种。
本发明方法所用碱以乙醇钠为最优；反应温度优选20～80℃。
本发明所述的N-叔丁氧羰基烃基胍的制备方法，具有反应试剂廉价易得、反应条件温和，产品后处理和提纯方法操作简便，产率和纯度高，对环境污染小，易于大量制备等特点。
具体实施方式
下面通过实施例对本发明作进一步详细说明，但本发明保护范围不局限于所述内容。
实施例1：制备N-叔丁氧羰基-(4-甲氧基苄基)胍的方法，具体操作如下：
于干燥三颈瓶中加入N,N’-双叔丁氧羰基-(4-甲氧基苄基)胍（0.007mol），用300mL异丙醇溶解后，加入甲醇钠（0.021mol），逐渐升温至82℃，回流搅拌反应，TLC跟踪8h后，原料点消失，停止反应，旋干溶剂，剩余物用100mL乙酸乙酯溶解，分别用水和饱和食盐水洗三次，经无水硫酸钠干燥后旋干，粗产品经过硅胶柱层析（正己烷：乙酸乙酯 = 3:1洗脱）后，获得无色油状液体1.8g，收率：92%。1H NMR (300 MHz, CDCl3) δppm 7.11(br s, 1H, NH),6.80 (m, 2H, Ph), 6.77 (m, 2H, Ph), 4.83(m, 2H, CH2), 4.25 (s, 3H, CH3), 3.70(br s, 1H, NH), 1.95 (br s, 1H, NH), 1.29 (s, 9H, (CH3)3)。
实施例2：制备N-叔丁氧羰基异丙基胍的方法，具体操作如下：
于干燥三颈瓶中加入N,N’-双叔丁氧羰基异丙基胍（0.013mol），用100mL甲醇溶解后加入氢氧化钠（0.026mol），逐渐升温至65℃，回流搅拌反应，TLC跟踪约9h后，原料点消失，停止反应，旋干溶剂，剩余物用100mL乙酸乙酯溶解，分别用水和饱和食盐水洗三次，经无水硫酸钠干燥后旋干，得无色油状液体2.1g，HPLC纯度98%，收率：81%；1H NMR (600 MHz, CDCl3)δppm 8.59 (br s, 1H, NH), 4.77 (m, 1H, CH), 2.48 (br s, 1H, NH) , 1.94 (br s,1H, NH) , 1.56 (s, 9H, (CH3)3) , 1.19 (d, J =6.4 Hz, 6H, (CH3)2) 。
实施例3：制备N-叔丁氧羰基丙基胍的方法，具体操作如下：
于干燥三颈瓶中加入N,N’-双叔丁氧羰基丙基胍（0.009mol），用100mL四氢呋喃溶解后加入氢氧化钾（0.054mol），逐渐升温至66℃，回流搅拌反应，TLC跟踪约3h后，原料点消失，停止反应，旋干溶剂，剩余物用100mL乙酸乙酯溶解，分别用水和饱和食盐水洗三次，经无水硫酸钠干燥后旋干，粗产品经过硅胶柱柱层析（正己烷：乙酸乙酯 = 3:1）后，获得类黄色油状液体1.5g，收率：83%；1H NMR (300 MHz, CDCl3) δppm 7.19 (br s, 1H, NH) , 4.17 (m,2H, CH2) , 2.91 (br s, 1H, NH) , 2.01(br s, 1H, NH) , 1.94 (d, 2H, J = 24.1Hz, CH2) , 1.18 (s, 9H, (CH3)3) , 0.80 (d, 3H, J = 7.3Hz, CH3)。
实施例4：制备N-叔丁氧羰基苯乙基胍的方法，具体操作如下：
于干燥三颈瓶中加入N,N’-双叔丁氧羰基苯乙基胍（0.007mol），用50mL N,N-二甲基甲酰胺溶解后加入碳酸钾（0.023mol），逐渐升温至120℃，搅拌反应，TLC跟踪约22h后，原料点消失，停止反应，旋干溶剂，剩余物用100mL乙酸乙酯溶解，分别用水和饱和食盐水洗三次，经无水硫酸钠干燥后旋干，粗产品经过硅胶柱柱层析（正己烷：乙酸乙酯 = 3:1）后，获得类黄色油状液体1.8g，收率：89%；1H NMR (300 MHz, CDCl3) δppm 7.16 (br s, 1H, NH),6.83 – 6.77 (m, 5H, Ph), 4.25 (m, 2H, CH2), 3.70 (m, 2H, CH2), 3.45 (br s, 1H,NH), 1.29 (s, 9H, (CH3)3)。
实施例5：制备N-叔丁氧羰基-1-(仲丁基)胍的方法，具体操作如下：
于干燥三颈瓶中加入N,N’-双叔丁氧羰基-1-(仲丁基)胍（0.015mol），用150mL乙醇溶解后加入乙醇钠（0.03mol），升温至78℃回流反应，TLC跟踪约12h后，原料点消失，停止反应，旋干溶剂，剩余物用100mL乙酸乙酯溶解，分别用水和饱和食盐水洗三次，经无水硫酸钠干燥后旋干，粗产品经过硅胶柱柱层析（正己烷：乙酸乙酯 = 3:1）后，获得无色油状液体2g，收率: 64%；1H NMR (600 MHz, CDCl3) δppm 7.06 (br s, 1H, NH), 3.12 (d, 1H, J =5.2 Hz, CH), 2.57 (br s, 1H, NH), 2.06 (br s, 1H, NH), 1.59 (m, 2H, CH2),1.38 (s, 9H, (CH3)3), 1.25 (s, 3H, CH3), 0.94 (t, 3H, J = 7.4 Hz, CH3)。
实施例6：制备N-叔丁氧羰基丁基胍的方法，具体操作如下：
于干燥三颈瓶中加入N,N’-双叔丁氧羰基丁基胍（0.01mol），用100mL甲苯溶解后加入碳酸铯（0.031mol），逐渐升温升温至110℃，回流搅拌反应，TLC跟踪约12h后，原料点消失，停止反应，旋干溶剂，剩余物用100mL乙酸乙酯溶解，分别用水和饱和食盐水洗三次，经无水硫酸钠干燥后旋干，粗产品经过硅胶柱柱层析（正己烷：乙酸乙酯 = 3:1）后，获得无色油状液体1.6g，收率：72%；1H NMR (300 MHz, CDCl3) δppm 7.51(br s, 1H, NH), 2.73 (m, 2H,CH2), 2.42 (br s, 1H, NH), 1.98 (br s, 1H, NH), 1.60 (m, 2H, CH2), 1.39 (s,9H, (CH3)3), 1.19 (m, 2H, CH2), 0.82 (dt, 3H, J = 7.0 Hz, CH3) 。
实施例7：制备N-叔丁氧羰基苄基胍的方法，具体操作如下：
于干燥三颈瓶中加入N,N’-双叔丁氧羰基苄基胍（0.008mol），用100mL乙二醇溶解后加入氢氧化钾（0.025mol），逐渐升温至150℃，搅拌反应，TLC跟踪约9h原料点消失，停止反应，旋干溶剂，剩余物用100mL乙酸乙酯溶解，分别用水和饱和食盐水洗三次，经无水硫酸钠干燥后旋干，粗产品经过硅胶柱柱层析层析（正己烷：乙酸乙酯 = 3:1）后，获得无色油状液体1.7g，收率：82%；1H NMR (300 MHz, CDCl3) δppm 7.29(br s, 1H, NH), 5.72 (t, 5H, J =6.2 Hz, Ph), 3.98 (d, 2H, J = 6.2 Hz, CH2), 2.42 (br s, 1H, NH), 1.98 (br s,1H, NH), 1.39 (s, 9H, (CH3)3)。
实施例8：制备N-叔丁氧羰基-1-甲基苄基胍的方法，具体操作如下：
于干燥三颈瓶中加入N,N’-双叔丁氧羰基-1-甲基苄基胍（0.008mol），用100mL乙腈溶解后加入氢氧化钠（0.026mol），逐渐升温至82℃，回流搅拌反应，TLC跟踪约12h原料点消失，停止反应，旋干溶剂，剩余物用100mL乙酸乙酯溶解，分别用水和饱和食盐水洗三次，经无水硫酸钠干燥后旋干，粗产品经过硅胶柱柱层析（正己烷：乙酸乙酯 = 3:1）后，获得无色油状液体1.7g，收率：74%；1H NMR (300 MHz, CDCl3) δppm7.83(br s, 1H, NH), 7.52 (t,5H, J = 6.2 Hz, Ph), 4.71 (d, 1H, CH), 2.51 (br s, 1H, NH), 1.98 (br s, 1H,NH), 1.51(m,3H, CH3), 1.39 (s, 9H, (CH3)3)。
以上所述仅是本发明的优选或部分实施方式。应当指出，对于本技术领域的普通技术人员，在不脱离本发明的前提下，还可进行若干改进和补充，这些可能的改进和补充也应视为本发明的保护范围。
Claims (3)
1.一种N-叔丁氧羰基烃基胍的制备方法，其特征在于：以N，N’-双叔丁氧羰基烃基胍为原料，在溶剂存在下,用碱进行选择性脱保护，脱掉一个Boc保护基，得到N-叔丁氧羰基烃基胍，所述N，N’-双叔丁氧羰基烃基胍与碱的摩尔比为1:2.0~6.0，反应温度为0～150℃，反应时间为3～22小时；
；
其中：R选自氢、C1~C20烷基、C1~C20环烷基、单取代或多取代芳基、单取代或多取代芳基烃基；R’选自氢、C1~C20烷基、C1~C20环烷基、单取代或多取代芳基、单取代或多取代芳基烃基。
2.根据权利要求1所述的N-叔丁氧羰基烃基胍的制备方法，其特征在于：溶剂为甲醇、乙醇、乙二醇、异丙醇、正丁醇、叔丁醇、乙醚、异丙醚、甲基特丁基醚、二氯甲烷、三氯甲烷、水、四氢呋喃、二氧六环、乙腈、甲苯、二甲苯、乙苯、二甲亚砜、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甘醇二甲醚、氮-甲基吡咯烷酮中一种或任意比两种。
3.根据权利要求1所述的N-叔丁氧羰基烃基胍的制备方法，其特征在于：碱为氢氧化钠、氢氧化钾、甲醇钠、乙醇钠、正丙醇钠、异丙醇钠、正丁醇钠、异丁醇钠、叔丁醇钠、甲醇钾、乙醇钾、正丙醇钾、异丙醇钾、正丁醇钾、异丁醇钾、叔丁醇钾、磷酸钾、磷酸二氢钾、磷酸氢二钾、碳酸钠、碳酸钾、碳酸铯、碳酸氢钠、三乙胺、吡啶中一种或任意比两种。
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