CN116854605A - 一种合成l-别异亮氨酸的方法 - Google Patents
一种合成l-别异亮氨酸的方法 Download PDFInfo
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- AGPKZVBTJJNPAG-UHNVWZDZSA-N L-allo-Isoleucine Chemical compound CC[C@@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-UHNVWZDZSA-N 0.000 title claims abstract description 36
- 238000000034 method Methods 0.000 title claims abstract description 18
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 13
- -1 (3R) -2-bromo-3-methylpentanoic acid Chemical compound 0.000 claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- AGPKZVBTJJNPAG-CNZKWPKMSA-N (3r)-2-amino-3-methylpentanoic acid Chemical compound CC[C@@H](C)C(N)C(O)=O AGPKZVBTJJNPAG-CNZKWPKMSA-N 0.000 claims abstract description 6
- IGIDLTISMCAULB-RXMQYKEDSA-N (3r)-3-methylpentanoic acid Chemical compound CC[C@@H](C)CC(O)=O IGIDLTISMCAULB-RXMQYKEDSA-N 0.000 claims abstract description 6
- 238000005915 ammonolysis reaction Methods 0.000 claims abstract description 5
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 4
- 229940095064 tartrate Drugs 0.000 claims description 4
- YONLFQNRGZXBBF-ZIAGYGMSSA-N (2r,3r)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@@H](C(=O)O)[C@@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-ZIAGYGMSSA-N 0.000 claims description 3
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 2
- 229910021529 ammonia Inorganic materials 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 230000031709 bromination Effects 0.000 abstract description 4
- 238000005893 bromination reaction Methods 0.000 abstract description 4
- 238000005821 Claisen rearrangement reaction Methods 0.000 abstract description 3
- IGIDLTISMCAULB-UHFFFAOYSA-N anteisohexanoic acid Natural products CCC(C)CC(O)=O IGIDLTISMCAULB-UHFFFAOYSA-N 0.000 abstract description 3
- 230000008901 benefit Effects 0.000 abstract description 3
- 230000032050 esterification Effects 0.000 abstract description 3
- 238000005886 esterification reaction Methods 0.000 abstract description 3
- 238000011914 asymmetric synthesis Methods 0.000 abstract description 2
- 230000003287 optical effect Effects 0.000 abstract description 2
- 239000000047 product Substances 0.000 abstract description 2
- 239000012467 final product Substances 0.000 abstract 1
- 238000000746 purification Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- OVBFMEVBMNZIBR-UHFFFAOYSA-N 2-methylvaleric acid Chemical compound CCCC(C)C(O)=O OVBFMEVBMNZIBR-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000006203 ethylation Effects 0.000 description 2
- 238000006200 ethylation reaction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- WCJYTPVNMWIZCG-UHFFFAOYSA-N xylylcarb Chemical compound CNC(=O)OC1=CC=C(C)C(C)=C1 WCJYTPVNMWIZCG-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-M Aminoacetate Chemical compound NCC([O-])=O DHMQDGOQFOQNFH-UHFFFAOYSA-M 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 241000228212 Aspergillus Species 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- 102000001189 Cyclic Peptides Human genes 0.000 description 1
- 108010069514 Cyclic Peptides Proteins 0.000 description 1
- 108010008292 L-Amino Acid Oxidase Proteins 0.000 description 1
- 102000007070 L-amino-acid oxidase Human genes 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- 229930182844 L-isoleucine Natural products 0.000 description 1
- 101710150975 N-acyl-L-amino acid amidohydrolase Proteins 0.000 description 1
- 102000015636 Oligopeptides Human genes 0.000 description 1
- 108010038807 Oligopeptides Proteins 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- DPJYJNYYDJOJNO-NRPADANISA-N camphorsultam Chemical compound C1S(=O)(=O)N[C@H]2C[C@H]3C(C)(C)[C@@]12CC3 DPJYJNYYDJOJNO-NRPADANISA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- BLHLJVCOVBYQQS-UHFFFAOYSA-N ethyllithium Chemical compound [Li]CC BLHLJVCOVBYQQS-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000033444 hydroxylation Effects 0.000 description 1
- 238000005805 hydroxylation reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
Classifications
-
- 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
- C07C227/18—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 involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
- C07C227/20—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 involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters by hydrolysis of N-acylated amino-acids or derivatives thereof, e.g. hydrolysis of carbamates
-
- 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
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
- C07C227/06—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid
- C07C227/08—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid by reaction of ammonia or amines with acids containing functional groups
-
- 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
-
- 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
- C07C227/18—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 involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/363—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及一种合成L‑别异亮氨酸的方法。主要解决通过不对称Claisen重排反应，或利用手性辅基立体控制不对称合成等等获得光学纯L‑别异亮氨酸存在的条件苛刻，操作繁琐，不适合放大生产的技术问题。本发明合成通过五个步骤，（1）(R)‑3‑甲基戊酸的溴化；（2）(3R)‑2‑溴‑3‑甲基戊酸的氨解；（3）(3R)‑2‑氨基‑3‑甲基戊酸的酯化；（4）(3R)‑2‑氨基‑3‑甲基戊酸乙酯的拆分；（5）L‑别异亮氨酸乙酯水解后得最终产品L‑别异亮氨酸。通过五步反应得到光学纯的目标产物。本发明具有高选择性，高收率，低成本，操作及纯化简便、经济效益好，更适合放大生成的优点。
Description
技术领域
本发明涉及一种合成L-别异亮氨酸的方法。L-别异亮氨酸是一种用于合成多肽药物的原料，属于药物合成化工技术领域。
背景技术
L-别异亮氨酸是天然L-异亮氨酸的非对映体之一，β-碳原子构型相反。由于这一特点，它经常被多肽化学家用于SAR研究，将L-别异亮氨酸并入肽链可引起构象变化。在具有支链侧链的氨基酸中，L-别异亮氨酸在抗生素等生物活性寡肽和环肽中起着重要作用，其潜力已引起了广泛的关注。
合成（Synthesis, 1999, 9, 1671–1677, Mikio Bakke等）报道了一种合成L-别异亮氨酸的合成方法，该方法是以(E)-but-2-en-1-yl (2,2,2-trifluoroacetyl)glycinate为原料经过金属螯合不对称Claisen重排反应得到立体异构混合物，其中(2S,3R)-构型占约90%，然后经过Aspergillus L-aminoacylase酶解选择性水解(2S,3R)-和(2S, 3S)-构型的三氟乙酰基得到一对非对映异构体，其中(2S,3R)-构型占约96.4%，再通过Crotalus L-amino acid oxidase氧化除掉(2S,3S)-异构体得到更纯的(2S,3R)-构型异构体，最后经过氢化得到L-别异亮氨酸。由于这个反应复杂，收率很低，不适宜放大生产。
合成线路如下:
。
四面体快报（Tetrahedron Letters, 27 (7), 831-834, 1986, Oppolzer,Wolfgang等）报道了一种合成L-别异亮氨酸的合成方法，该方法是以巴豆酰氯原料，利用(-)-N,N-二环己基-(1S)-异冰片-10-磺酰胺为手性辅基，通过不对称乙基化和不对称溴代，然后与叠氮化钠反应得到手性叠氮，最后在钛酸四苄酯作用下脱掉手性辅基，并用钯催化氢化还原得到L-别异亮氨酸。连续两步低温反应，分别用到了乙基锂和LDA，并用到剧毒试剂氰化物和叠氮化钠。反应条件苛刻，不适宜放大生产。
合成线路如下:
。
合成通讯（Synthetic Communications, 2000, vol. 30, # 12, p. 2245 -2252 Belzecki, Czeslaw等）报道了一种合成L-别异亮氨酸的合成方法，该方法是以巴豆酰氯原料，利用左旋樟脑磺内酰胺为手性辅基，通过不对称乙基化，水解后得到(R)-3-甲基戊酸。再利用右旋樟脑磺内酰胺为手性辅基，通过不对称羟胺化，然后用锌粉还原，最后用氢氧化锂水解脱掉手性辅基后得到L-别异亮氨酸。反应复杂，条件苛刻，不适宜放大生产。
合成线路如下:
发明内容
本发明的目的是公开一种简洁，高效，条件温和适合放大生产的用于合成L-别异亮氨酸的方法。主要解决通过不对称Claisen重排反应，或利用手性辅基立体控制不对称合成等等获得光学纯L-别异亮氨酸存在的条件苛刻，操作繁琐，不适合放大生产的技术问题。
本发明的技术方案为：一种合成L-别异亮氨酸的方法，其特征是：包括以下步骤：
步骤1：(R)-3-甲基戊酸在催化剂三溴化磷存在下，加入液溴，经溴化得到(3R)-2-溴-3-甲基戊酸；
步骤2：将步骤1得到的(3R)-2-溴-3-甲基戊酸在氨的甲醇溶液中经过氨解，得到(3R)-2-氨基-3-甲基戊酸；
步骤3：将步骤2得到的(3R)-2-氨基-3-甲基戊酸酯化得到(3R)-2-氨基-3-甲基戊酸乙酯；
步骤4：将步骤3得到的(3R)-2-氨基-3-甲基戊酸乙酯用经过L-二苯甲酰基酒石酸在有机溶剂中，加热，化学拆分得到L-别异亮氨酸乙酯的L-二苯甲酰基酒石酸盐，经碳酸氢钠游离后得到L-别异亮氨酸乙酯；
步骤5：将步骤4得到的L-别异亮氨酸乙酯经盐酸水解后，得到L-别异亮氨酸。
反应式如下：
上述反应中，第四步所述的有机溶剂为四氢呋喃、丙酮或甲基叔丁基醚中的一种；
第四步拆分的加热反应温度为45℃~55℃，优选温度为50℃。
本发明的有益效果：本发明以(R)-3-甲基戊酸为原料经过溴化，氨解，酯化，随后化学拆分，制备得到高光学纯度的手性L-别异亮氨酸。此方法原料便宜易得，反应条件温和，方法简洁，高效，且质量产率较高，经济有效，适于放大生产。
具体实施方式
实施例1
第一步，2-甲基戊酸的溴化
向2 L三口烧瓶中加入(R)-3-甲基戊酸 (116.1 g, 1.0 mol)和液溴 (67 mL)。室温下加入三溴化磷 (1 mL)。加毕，升温到70℃。反应4小时后，冷却，反应混合物倒入冰水中，并用二氯甲烷萃取两次。合并有机相，无水硫酸钠干燥，过滤，滤液直接旋干，得到(3R)-2-溴-3-甲基戊酸 (152.1 g，产率78 %)。
第二步，(3R)-2-溴-3-甲基戊酸的氨解
向2 L三口烧瓶中加入(3R)-2-溴-3-甲基戊酸 (152.0 g， 0.78 mol)和甲醇(150 mL)，搅拌，加入5 M的氨的甲醇溶液 (600 mL, 3.0 mol)。加热到50℃反应12小时。直接旋干，加入500 mL的无水乙醇，加热至50℃搅拌1小时。抽滤，滤液直接旋干，得到(3R)-2-氨基-3-甲基戊酸 (92.2 g，产率90 %)。
第三步，(3R)-2-溴-3-甲基戊酸的酯化
向2 L三口烧瓶中加入(3R)-2-溴-3-甲基戊酸 (92.0, 0.70 mol) 和无水乙醇，置换氮气。冷却至0℃，滴加氯化亚砜 (85 g, 0.71 mol)。加毕，升温到78℃。反应6小时后，LC-MS分析显示没有原料。直接旋干，得到(3R)-2-氨基-3-甲基戊酸乙酯盐酸盐。将得到的(3R)-2-氨基-3-甲基戊酸乙酯盐酸用饱和碳酸氢钠溶液游离，pH = 8~9, 再用的乙酸乙酯萃取，饱和氯化钠溶液洗涤。有机相用无水硫酸钠干燥，旋干，得黄色油状物(3R)-2-氨基-3-甲基戊酸乙酯(110.6 g, 产率99 %)。
第四步，(3R)-2-氨基-3-甲基戊酸乙酯的化学拆分
向3 L三口烧瓶中加入(3R)-2-氨基-3-甲基戊酸乙酯 (110.5 g, 0.69 mol)和四氢呋喃 (1500 mL)，加热至50℃，加入L-二苯甲酰基酒石酸（173.0 g, 0.48 mol），温度50℃搅拌1小时。过滤收集析出的固体，并用四氢呋喃洗涤，干燥后得到 L-别异亮氨酸乙酯的L-二苯甲酰基酒石酸盐，将得到的L-别异亮氨酸乙酯的L-二苯甲酰基酒石酸盐用饱和碳酸氢钠溶液游离，pH = 8~9, 再用的乙酸乙酯萃取，饱和氯化钠溶液洗涤。有机相用无水硫酸钠干燥，旋干，得黄色油状物L-别异亮氨酸乙酯(32.9 g, 产率60 %)。
第五步，L-别异亮氨酸乙酯的水解
向250 mL三口烧瓶中加入L-别异亮氨酸乙酯 (32.9 g, 0.19 mol)，用乙醇溶解，在室温下加入4 M的氢氧化钠水溶液 (100 mL)，室温搅拌过夜。
次日，用3 N的盐酸调节pH = 6，过滤析出的固体，并用无水乙醇洗涤，干燥后得到产物37.1 g，产率93%。
1H NMR (D2O, 300 MHz): d 3.40 (d, J = 3.9 Hz, 1H), 1.83-1.79 (m, 1H),1.31-1.17 (m, 2H), 0.81 (t, J = 7.5 Hz, 3H), 0.75 (d, J = 6.9 Hz, 3H)。
实施例2，第四步有机溶剂为丙酮，反应温度为45℃，其余同实施例1。
实施例3，第四步有机溶剂为四氢呋喃，反应温度为55℃，其余同实施例1。
Claims (4)
1.一种合成L-别异亮氨酸的方法，其特征是：包括下步骤：
步骤1：(R)-3-甲基戊酸在催化剂三溴化磷存在下，加入液溴，经溴化得到(3R)-2-溴-3-甲基戊酸；
步骤2：将步骤1得到的(3R)-2-溴-3-甲基戊酸在氨的甲醇溶液中经过氨解，得到(3R)-2-氨基-3-甲基戊酸；
步骤3：将步骤2得到的(3R)-2-氨基-3-甲基戊酸酯化得到(3R)-2-氨基-3-甲基戊酸乙酯；
步骤4：将步骤3得到的(3R)-2-氨基-3-甲基戊酸乙酯用L-二苯甲酰基酒石酸在有机溶剂中，加热，化学拆分得到L-别异亮氨酸乙酯的L-二苯甲酰基酒石酸盐，经碳酸氢钠游离后得到L-别异亮氨酸乙酯；
步骤5：将步骤4得到的L-别异亮氨酸乙酯经盐酸水解后，得到L-别异亮氨酸；反应式如下：
。
2.根据权利要求1所述的一种合成L-别异亮氨酸的方法，其特征是：所述步骤4有机溶剂是四氢呋喃、丙酮或甲基叔丁基醚中的一种。
3.根据权利要求1所述的一种合成L-别异亮氨酸的方法，其特征是：所述步骤4，加热反应温度是45℃~55℃。
4.根据权利要求3所述的一种合成L-别异亮氨酸的方法，其特征是：所述加热反应温度为50℃。
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