CN117924139A - Amplifying synthesis method of Fmoc-Hyp (tBu) -OH - Google Patents
Amplifying synthesis method of Fmoc-Hyp (tBu) -OH Download PDFInfo
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- CN117924139A CN117924139A CN202410069077.8A CN202410069077A CN117924139A CN 117924139 A CN117924139 A CN 117924139A CN 202410069077 A CN202410069077 A CN 202410069077A CN 117924139 A CN117924139 A CN 117924139A
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- hyp
- tbu
- fmoc
- amplifying
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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
Abstract
The invention relates to an amplifying synthesis method of Fmoc-Hyp (tBu) -OH. Mainly solves the technical problems that the prior synthesis method introduces heavy metals and the second use of hydrogen brings difficulty and safety risk to production. The invention is realized by the following technical scheme: (1) Reacting L-hydroxyproline ester with ethyl trifluoroacetate in a solvent under the action of alkali to generate trifluoroacetyl-protected hydroxyproline ester; (2) Trifluoroacetyl protected hydroxyproline ester reacts with isobutene to form tert-butyl ether under the catalysis of concentrated sulfuric acid; (3) The tert-butyl ether compound is hydrolyzed into amino acid under the action of alkali, and Fmoc protection is carried out to obtain Fmoc-Hyp (tBu) -OH.
Description
Technical Field
The invention relates to an amplifying synthesis method of Fmoc-Hyp (tBu) -OH.
Background
L-hydroxyproline is a natural amino acid and is widely applied in the field of polypeptide drug synthesis. In solid phase synthesis of polypeptides, hydroxyl protection is often desired to avoid side reactions, tertiary butyl protection is often preferred for stability and ease of removal. Conventional methods generally use Cbz to protect the L-hydroxyproline ester. Pd/C hydrogenation is used for the removal of Cbz protection. The first one introduces heavy metals and the second use of hydrogen presents difficulties and safety risks to the production. The synthetic reaction formula is as follows:
。
Disclosure of Invention
The invention aims to provide a more economical and safer amplifying synthesis method of Fmoc-Hyp (tBu) -OH by bypassing the use of heavy metals and hydrogen.
The technical scheme of the invention is as follows: a method for amplifying and synthesizing Fmoc-Hyp (tBu) -OH comprises the following steps: the first step, L-hydroxyproline ester reacts with ethyl trifluoroacetate in a solvent under the action of alkali to generate trifluoroacetyl-protected hydroxyproline ester; secondly, reacting the fluoroacetyl-protected hydroxyproline ester with isobutene to obtain tert-butyl ether under the catalysis of concentrated sulfuric acid; and thirdly, hydrolyzing the tert-butyl ether compound into amino acid under the action of alkali, and then performing Fmoc protection to obtain Fmoc-Hyp (tBu) -OH. The synthetic route is as follows:
。
In the above reaction, in the first step, the L-hydroxyproline ester is L-hydroxyproline methyl ester or L-hydroxyproline ethyl ester, preferably L-hydroxyproline methyl ester, and the base used is one of triethylamine, DIPEA or N-methyl morphine, preferably triethylamine. The solvent used is one of MeOH, etOH or THF, preferably MeOH. The reaction temperature is controlled at room temperature; in the second step, the amount of concentrated sulfuric acid used is 2 to 6% (W/V), preferably 3%, of the total reaction volume. The reaction temperature is 10-15 ℃. The alkali of the third reaction is one of NaOH, KOH or LiOH, preferably LiOH.
The invention has the following advantages: the method has the advantages of cheap and easily obtained raw materials, short steps, simple operation, high reaction yield, easy mass production and synthesis in common factories and laboratories.
Detailed Description
Examples
The reaction formula is as follows:
in the first step L-hydroxyproline methyl ester hydrochloride (70 kg) was suspended in MeOH (350L), triethylamine (60 kg) and ethyl trifluoroacetate (90 kg) were added, and after addition, the mixture was stirred at room temperature for 24 hours, most of the solvent was concentrated, dichloromethane (1000 kg) was added, and the 2N HCl (500L) was washed to separate the liquid. The organic phase was dried and concentrated to give compound 1 (73.5 kg, 78.8% yield).
In the second step, the compound 1 (73.5 kg) is dissolved in dichloromethane (900 kg), concentrated sulfuric acid (24 kg) is added, the temperature is controlled to be 10-15 ℃, isobutene gas is introduced under stirring, the reaction is carried out for about 10 hours, and HPLC detection is carried out. Saturated NaHCO 3 solution (400L) was added and stirred for half an hour to separate the aqueous phase. The organic phase was concentrated to give compound 2 (75.4 kg, 83.3% yield).
And in the third step, the compound 2 (75.4 kg) is dissolved in water (600 kg) and methanol (70 kg), liOH.H 2 O (32.8 kg) is added in portions, the temperature is controlled to be 0-10 ℃, and stirring reaction is carried out for 5 hours. pH was adjusted to about 8 by addition of 3N HCl in portions, naHCO 3 solid (40 kg), THF (400L), fmocOSu (73.8 kg) was added. The reaction was stirred for 12 hours. 3NHCl is adjusted to pH 1-2, methyl tertiary ether is used for extraction, hydrochloric acid is used for washing, and saturated saline water is used for washing to neutrality. The organic phase was concentrated by drying to give Fmoc-Hyp (tBu) -OH (87.5 kg, 81.1% yield).
Claims (9)
1. A method for amplifying and synthesizing Fmoc-Hyp (tBu) -OH is characterized by comprising the following steps: the method comprises the following steps: (1) Reacting L-hydroxyproline ester with ethyl trifluoroacetate in a solvent under the action of alkali to generate trifluoroacetyl-protected hydroxyproline ester; (2) Trifluoroacetyl protected hydroxyproline ester reacts with isobutene to form tert-butyl ether under the catalysis of concentrated sulfuric acid; (3) The tert-butyl ether compound is hydrolyzed into amino acid under the action of alkali, fmoc protection is carried out to obtain Fmoc-Hyp (tBu) -OH, and the reaction formula is as follows:
。
2. The method for amplifying and synthesizing Fmoc-Hyp (tBu) -OH according to claim 1, wherein the method comprises the following steps: in the step (1), the L-hydroxyproline ester is L-hydroxyproline methyl ester or L-hydroxyproline ethyl ester, the base is one of triethylamine, DIPEA or N-methyl morphine, and the solvent is one of MeOH, etOH or THF.
3. The method for amplifying and synthesizing Fmoc-Hyp (tBu) -OH according to claim 2, wherein the method comprises the following steps: the L-hydroxyproline ester in the step (1) is L-hydroxyproline methyl ester, the base used is triethylamine, and the solvent used is MeOH.
4. The method for amplifying and synthesizing Fmoc-Hyp (tBu) -OH according to claim 1, wherein the method comprises the following steps: the temperature of the reaction in the step (1) is room temperature.
5. The method for amplifying and synthesizing Fmoc-Hyp (tBu) -OH according to claim 1, wherein the method comprises the following steps: the amount of the concentrated sulfuric acid used in the reaction in the step (2) is 2-6% of the whole reaction volume.
6. The method for amplifying and synthesizing Fmoc-Hyp (tBu) -OH according to claim 5, wherein the method comprises the following steps: the amount of concentrated sulfuric acid used in the reaction in step (2) was 3% of the entire reaction volume.
7. The method for amplifying and synthesizing Fmoc-Hyp (tBu) -OH according to claim 1, wherein the method comprises the following steps: the reaction temperature in the step (2) is 10-15 ℃.
8. The method for amplifying and synthesizing Fmoc-Hyp (tBu) -OH according to claim 1, wherein the method comprises the following steps: the alkali used in the reaction in the step (3) is one of NaOH, KOH or LiOH.
9. The method for amplifying and synthesizing Fmoc-Hyp (tBu) -OH according to claim 8, wherein the method comprises the following steps: the alkali used in the reaction in the step (3) is LiOH.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202410069077.8A CN117924139A (en) | 2024-01-17 | 2024-01-17 | Amplifying synthesis method of Fmoc-Hyp (tBu) -OH |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202410069077.8A CN117924139A (en) | 2024-01-17 | 2024-01-17 | Amplifying synthesis method of Fmoc-Hyp (tBu) -OH |
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| Publication Number | Publication Date |
|---|---|
| CN117924139A true CN117924139A (en) | 2024-04-26 |
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|---|---|---|---|
| CN202410069077.8A Pending CN117924139A (en) | 2024-01-17 | 2024-01-17 | Amplifying synthesis method of Fmoc-Hyp (tBu) -OH |
Country Status (1)
| Country | Link |
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| CN (1) | CN117924139A (en) |
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- 2024-01-17 CN CN202410069077.8A patent/CN117924139A/en active Pending
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