CN117924139A - 一种Fmoc-Hyp(tBu)-OH的放大合成方法 - Google Patents
一种Fmoc-Hyp(tBu)-OH的放大合成方法 Download PDFInfo
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- WPBXBYOKQUEIDW-VFNWGFHPSA-N (2s,4r)-1-(9h-fluoren-9-ylmethoxycarbonyl)-4-[(2-methylpropan-2-yl)oxy]pyrrolidine-2-carboxylic acid Chemical compound C1[C@H](OC(C)(C)C)C[C@@H](C(O)=O)N1C(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 WPBXBYOKQUEIDW-VFNWGFHPSA-N 0.000 title claims abstract description 19
- 238000001308 synthesis method Methods 0.000 title abstract description 6
- -1 L-hydroxyproline ester Chemical class 0.000 claims abstract description 16
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000003513 alkali Substances 0.000 claims abstract description 9
- VQTUBCCKSQIDNK-UHFFFAOYSA-N Isobutene Chemical compound CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000002904 solvent Substances 0.000 claims abstract description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 7
- STSCVKRWJPWALQ-UHFFFAOYSA-N TRIFLUOROACETIC ACID ETHYL ESTER Chemical compound CCOC(=O)C(F)(F)F STSCVKRWJPWALQ-UHFFFAOYSA-N 0.000 claims abstract description 4
- 150000001413 amino acids Chemical class 0.000 claims abstract description 4
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims abstract description 3
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 3
- AQEFLFZSWDEAIP-UHFFFAOYSA-N di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 claims abstract description 3
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229960002591 hydroxyproline Drugs 0.000 claims abstract description 3
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims abstract 2
- 238000006243 chemical reaction Methods 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 230000002194 synthesizing effect Effects 0.000 claims description 10
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- ZORHSASAYVIBLY-UHNVWZDZSA-N methyl (2s,4r)-4-hydroxypyrrolidine-2-carboxylate Chemical group COC(=O)[C@@H]1C[C@@H](O)CN1 ZORHSASAYVIBLY-UHNVWZDZSA-N 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 3
- 229960004126 codeine Drugs 0.000 claims description 2
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 claims description 2
- JMHQESARJMGVCZ-RITPCOANSA-N ethyl (2s,4r)-4-hydroxypyrrolidine-2-carboxylate Chemical compound CCOC(=O)[C@@H]1C[C@@H](O)CN1 JMHQESARJMGVCZ-RITPCOANSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 3
- 229910001385 heavy metal Inorganic materials 0.000 abstract description 3
- 239000001257 hydrogen Substances 0.000 abstract description 3
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- KLGSHNXEUZOKHH-JBUOLDKXSA-N hydron;methyl (2s,4r)-4-hydroxypyrrolidine-2-carboxylate;chloride Chemical compound Cl.COC(=O)[C@@H]1C[C@@H](O)CN1 KLGSHNXEUZOKHH-JBUOLDKXSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- 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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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及一种Fmoc‑Hyp(tBu)‑OH的放大合成方法。主要解决现有合成方法引入重金属,第二用到氢气会给生产带来难度和安全风险的技术问题。本发明通过如下技术方案实现:(1)L‑羟脯氨酸酯在碱的作用下在溶剂中与三氟乙酸乙酯反应生成三氟乙酰基保护的羟脯氨酸酯;(2)三氟乙酰基保护的羟脯氨酸酯在浓硫酸催化下与异丁烯反应上叔丁醚;(3)叔丁醚化合物在碱的作用下水解成氨基酸,然后上Fmoc保护得到Fmoc‑Hyp(tBu)‑OH。
Description
技术领域
本发明涉及一种Fmoc-Hyp(tBu)-OH的放大合成方法。
背景技术
L-羟脯氨酸是一种天然氨基酸,在多肽药合成领域应用广泛。在固相合成多肽时为了避免副反应通常要羟基保护,叔丁基保护由于稳定性和易脱性通常成为首选。常规方法一般用Cbz保护L-羟脯氨酸酯。脱Cbz保护要用到Pd/C氢化。第一会引入重金属,第二用到氢气会给生产带来难度和安全风险。其合成反应式如下:
。
发明内容
本发明的目的在于绕开使用重金属和氢气的使用,提供一种更经济,更安全的Fmoc-Hyp(tBu)-OH的放大合成方法。
本发明的技术方案如下:一种Fmoc-Hyp(tBu)-OH的放大合成方法, 包括以下步骤:第一步,L-羟脯氨酸酯在碱的作用下在溶剂中与三氟乙酸乙酯反应生成三氟乙酰基保护的羟脯氨酸酯;第二步,氟乙酰基保护的羟脯氨酸酯在浓硫酸催化下与异丁烯反应上叔丁醚;第三步,叔丁醚化合物在碱的作用下水解成氨基酸,然后上Fmoc保护得Fmoc-Hyp(tBu)-OH。合成路线如下:
。
上述反应中,第一步,L-羟脯氨酸酯为L-羟脯氨酸甲酯或L-羟脯氨酸乙酯,优选L-羟脯氨酸甲酯,所用的碱为三乙胺、DIPEA或者N-甲基***林中的一种,优选三乙胺。所用的溶剂为MeOH、EtOH或者THF中的一种,优选MeOH。反应温度控制在室温,;第二步,所用的浓硫酸的量为整个反应体积2~6%(W/V),优选3%。; 反应的温度为10~15℃。第三步反应的碱为NaOH、KOH或LiOH中的一种,优选LiOH,。
本发明具有以下优点:原料便宜易得,步骤短,操作简单,反应收率高,易放大生产,一般的工厂和实验室都能合成。
具体实施方式
实施例
反应式如下:
第一步L-羟脯氨酸甲酯盐酸盐(70 kg)悬浮在MeOH(350 L)中,加入三乙胺(60kg)和三氟乙酸乙酯(90 kg),加完后室温搅拌24小时,浓缩掉大部分溶剂,加入二氯甲烷(1000 kg), 2N HCl (500 L)洗涤分液。有机相干燥,浓缩得化合物1 (73.5 kg, 78.8% 收率)。
第二步化合物1(73.5 kg)溶在二氯甲烷(900 kg),加入浓硫酸(24 kg),温度控制在10~15℃, 搅拌下通入异丁烯气体,大约通10小时,HPLC检测反应完毕。 加入饱和NaHCO3溶液(400 L), 搅拌半小时,分调水相。有机相浓缩得化合物2 (75.4 kg, 83.3%收率)。
第三步化合物2(75.4 kg)溶在水(600 kg)和甲醇(70 kg),分批加入LiOH.H2O(32.8 kg),温度控制在0~10℃, 搅拌反应5小时。 分批加入3NHCl调pH 到8左右,加入NaHCO3固体(40 kg), THF(400 L), FmocOSu(73.8kg)。反应搅拌12小时。3NHCl调pH到1~2,甲叔醚萃取,盐酸洗涤,饱和食盐水洗涤至中性。有机相干燥浓缩得Fmoc-Hyp(tBu)-OH(87.5 kg, 81.1%收率)。
Claims (9)
1.一种Fmoc-Hyp(tBu)-OH的放大合成方法,其特征在于:包括以下步骤:(1)L-羟脯氨酸酯在碱的作用下在溶剂中与三氟乙酸乙酯反应生成三氟乙酰基保护的羟脯氨酸酯;(2)三氟乙酰基保护的羟脯氨酸酯在浓硫酸催化下与异丁烯反应上叔丁醚;(3)叔丁醚化合物在碱的作用下水解成氨基酸,然后上Fmoc保护得到Fmoc-Hyp(tBu)-OH,反应式如下:
。
2.根据权利要求1所述的一种Fmoc-Hyp(tBu)-OH的放大合成方法,其特征在于:步骤(1)L-羟脯氨酸酯为L-羟脯氨酸甲酯或L-羟脯氨酸乙酯,所用的碱为三乙胺、DIPEA或者N-甲基***林中的一种,所用的溶剂为MeOH、EtOH或者THF中的一种。
3.根据权利要求2所述的一种Fmoc-Hyp(tBu)-OH的放大合成方法,其特征在于:步骤(1)L-羟脯氨酸酯为L-羟脯氨酸甲酯,所用的碱为三乙胺,所用的溶剂为MeOH。
4.根据权利要求1所述的一种Fmoc-Hyp(tBu)-OH的放大合成方法,其特征在于:步骤(1)反应的温度为室温。
5.根据权利要求1所述的一种Fmoc-Hyp(tBu)-OH的放大合成方法,其特征在于:步骤(2)反应所用的浓硫酸的量为整个反应体积2~6%。
6.根据权利要求5所述的一种Fmoc-Hyp(tBu)-OH的放大合成方法,其特征在于:步骤(2)反应所用的浓硫酸的量为整个反应体积3%。
7.根据权利要求1所述的一种Fmoc-Hyp(tBu)-OH的放大合成方法,其特征在于:步骤(2)反应的温度为10~15℃。
8.根据权利要求1所述的一种Fmoc-Hyp(tBu)-OH的放大合成方法,其特征在于:步骤(3)反应用的碱为NaOH、KOH或LiOH中的一种。
9.根据权利要求8所述的一种Fmoc-Hyp(tBu)-OH的放大合成方法,其特征在于:步骤(3)反应用的碱为LiOH。
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