CN118324662A - Preparation method of [2- [2- (Fmoc-amino) ethoxy ] acetic acid - Google Patents
Preparation method of [2- [2- (Fmoc-amino) ethoxy ] acetic acid Download PDFInfo
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- CN118324662A CN118324662A CN202410292033.1A CN202410292033A CN118324662A CN 118324662 A CN118324662 A CN 118324662A CN 202410292033 A CN202410292033 A CN 202410292033A CN 118324662 A CN118324662 A CN 118324662A
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- Prior art keywords
- fmoc
- amino
- ethoxy
- acetic acid
- boc
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- LBVXPUINIMIGAU-UHFFFAOYSA-N 2-[2-(9h-fluoren-9-ylmethoxycarbonylamino)ethoxy]acetic acid Chemical compound C1=CC=C2C(COC(=O)NCCOCC(=O)O)C3=CC=CC=C3C2=C1 LBVXPUINIMIGAU-UHFFFAOYSA-N 0.000 title claims abstract description 42
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 29
- 239000000203 mixture Substances 0.000 claims abstract description 23
- GIAFURWZWWWBQT-UHFFFAOYSA-N 2-(2-aminoethoxy)ethanol Chemical compound NCCOCCO GIAFURWZWWWBQT-UHFFFAOYSA-N 0.000 claims abstract description 20
- 150000002466 imines Chemical class 0.000 claims abstract description 20
- 230000008569 process Effects 0.000 claims abstract description 18
- -1 fluorenylmethoxycarbonyl succinimide Chemical compound 0.000 claims abstract description 16
- 230000002378 acidificating effect Effects 0.000 claims abstract description 15
- KZNICNPSHKQLFF-UHFFFAOYSA-N dihydromaleimide Natural products O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 claims abstract description 14
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229960002317 succinimide Drugs 0.000 claims abstract description 12
- KDPAWGWELVVRCH-UHFFFAOYSA-N bromoacetic acid Chemical class OC(=O)CBr KDPAWGWELVVRCH-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000002156 mixing Methods 0.000 claims abstract description 10
- LQVMZVKOVPITOO-UHFFFAOYSA-N 9h-fluoren-1-ylmethyl carbonochloridate Chemical compound C1C2=CC=CC=C2C2=C1C(COC(=O)Cl)=CC=C2 LQVMZVKOVPITOO-UHFFFAOYSA-N 0.000 claims abstract description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 44
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 42
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- 238000006243 chemical reaction Methods 0.000 claims description 24
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 20
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- 239000003054 catalyst Substances 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- 238000010511 deprotection reaction Methods 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- 239000012043 crude product Substances 0.000 claims description 9
- 230000002829 reductive effect Effects 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- HXMVNCMPQGPRLN-UHFFFAOYSA-N 2-hydroxyputrescine Chemical group NCCC(O)CN HXMVNCMPQGPRLN-UHFFFAOYSA-N 0.000 claims description 6
- 230000001105 regulatory effect Effects 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 5
- IRXSLJNXXZKURP-UHFFFAOYSA-N fluorenylmethyloxycarbonyl chloride Chemical compound C1=CC=C2C(COC(=O)Cl)C3=CC=CC=C3C2=C1 IRXSLJNXXZKURP-UHFFFAOYSA-N 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 abstract description 10
- 230000008901 benefit Effects 0.000 abstract description 6
- 239000002994 raw material Substances 0.000 abstract description 5
- 238000007670 refining Methods 0.000 abstract description 3
- 238000007086 side reaction Methods 0.000 abstract description 3
- 239000000047 product Substances 0.000 description 16
- 239000000243 solution Substances 0.000 description 13
- 235000011121 sodium hydroxide Nutrition 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 7
- 239000007788 liquid Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
- 238000000967 suction filtration Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- 239000012467 final product Substances 0.000 description 4
- NIHNNTQXNPWCJQ-UHFFFAOYSA-N fluorene Chemical compound C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 208000030507 AIDS Diseases 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 150000002894 organic compounds Chemical class 0.000 description 3
- 229920001184 polypeptide Polymers 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- WMSUFWLPZLCIHP-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 9h-fluoren-9-ylmethyl carbonate Chemical compound C12=CC=CC=C2C2=CC=CC=C2C1COC(=O)ON1C(=O)CCC1=O WMSUFWLPZLCIHP-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical group O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical group CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 108091005804 Peptidases Proteins 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 101800001690 Transmembrane protein gp41 Proteins 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 150000002484 inorganic compounds Chemical class 0.000 description 2
- 229910010272 inorganic material Inorganic materials 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000000575 pesticide Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000003223 protective agent Substances 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 238000006467 substitution reaction Methods 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
- AWGBKZRMLNVLAF-UHFFFAOYSA-N 3,5-dibromo-n,2-dihydroxybenzamide Chemical compound ONC(=O)C1=CC(Br)=CC(Br)=C1O AWGBKZRMLNVLAF-UHFFFAOYSA-N 0.000 description 1
- 241000725303 Human immunodeficiency virus Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108010033276 Peptide Fragments Proteins 0.000 description 1
- 102000007079 Peptide Fragments Human genes 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 239000002262 Schiff base Substances 0.000 description 1
- 150000004753 Schiff bases Chemical class 0.000 description 1
- 241000713311 Simian immunodeficiency virus Species 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 239000005456 alcohol based solvent Substances 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 239000001569 carbon dioxide Chemical group 0.000 description 1
- 229910002092 carbon dioxide Chemical group 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000006243 carbonyl protecting group Chemical group 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- GESQDUURIFFZPE-UHFFFAOYSA-N cyclopenta-1,3-diene-1,2,3,4-tetrol Chemical compound OC1=C(C(=C(C1)O)O)O GESQDUURIFFZPE-UHFFFAOYSA-N 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000003009 desulfurizing effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012039 electrophile Substances 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000007130 inorganic reaction Methods 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- QGOKIEUFWNCGFO-UHFFFAOYSA-N propanoic acid;pyrrole-2,5-dione Chemical compound CCC(O)=O.O=C1NC(=O)C=C1 QGOKIEUFWNCGFO-UHFFFAOYSA-N 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- 235000019419 proteases Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 235000019633 pungent taste Nutrition 0.000 description 1
- 238000011403 purification operation Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 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
- C07C269/04—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 from amines with formation of carbamate 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
- 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
- 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
- C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
- C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
- C07C2603/18—Fluorenes; Hydrogenated fluorenes
-
- 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)
Abstract
The application discloses a preparation method of [2- [2- (Fmoc-amino) ethoxy ] acetic acid, which comprises the following steps: mixing diglycolamine and Boc 2 O to react to generate imine; reacting imine with bromoacetic acid or bromoacetic acid derivative, and deprotecting under acidic condition to obtain initial mixture; reacting the initial mixture with any one of Fmoc-osu (fluorenylmethoxycarbonyl succinimide) or Fmoc-c l (fluorenylmethoxycarbonyl chloride) under alkaline conditions to obtain a crude [2- [2- (Fmoc-amino) ethoxy ] acetic acid, and treating to obtain [2- [2- (Fmoc-amino) ethoxy ] acetic acid; the method adopts a cheap initial raw material, and prepares the [2- [2- (Fmoc-amino) ethoxy ] acetic acid with the content of more than 99 percent by simple operation, has high yield and lower production cost, avoids side reaction in the way of the route, simplifies the refining process, improves the yield and has higher production benefit.
Description
Technical Field
The invention relates to the field of polypeptide synthesis, in particular to a preparation method of [2- [2- (Fmoc-amino) ethoxy ] acetic acid.
Background
AIDS, acquired immunodeficiency syndrome, english abbreviation AIDS.
[2- (2- (Fmoc-amino) ethoxy ] acetic acid (Fmoc-AEEAC for short) is a key intermediate of a fourth generation anti-H IV drug, namely, ilabolt, wherein according to research data, gp41 variant peptide has the characteristics of inhibiting virus infection and resisting fusion, particularly has strong activity on human immunodeficiency virus (H IV) and simian immunodeficiency virus (S IV), has long acting time, can increase in vivo stability and reduce the sensibility of peptidase or protease degradation through coupling Fmoc-AEEA and maleimide propionic acid and connecting gp41 peptide fragments and modified analogues thereof, but the cost for preparing Fmoc-AEEAC by adopting the existing method is higher, and the production benefit is lower.
Disclosure of Invention
The application provides a preparation method of [2- [2- (Fmoc-amino) ethoxy ] acetic acid, which aims to solve the technical problems of higher cost and low effective benefit generated in the preparation of Fmoc-AEEAC in the prior art.
In order to achieve the above purpose, the technical scheme adopted by the application is as follows: a process for the preparation of [2- [2- (Fmoc-amino) ethoxy ] acetic acid comprising the steps of:
The method comprises the steps of obtaining diglycolamine and Boc 2 O, and mixing the diglycolamine and the Boc 2 O to react to generate imine; obtaining bromoacetic acid or bromoacetic acid derivatives, reacting imine with any one of bromoacetic acid or bromoacetic acid derivatives, and deprotecting under acidic condition to obtain an initial mixture; fmoc-osu (fluorenylmethoxycarbonyl succinimide) or Fmoc-c l (fluorenylmethoxycarbonyl succinimide) was obtained, and the initial mixture was reacted with either Fmoc-osu (fluorenylmethoxycarbonyl succinimide) or Fmoc-c l (fluorenylmethoxycarbonyl chloride) under basic conditions to give crude [2- [2- (Fmoc-amino) ethoxy ] acetic acid, which was treated to give [2- [2- (Fmoc-amino) ethoxy ] acetic acid.
As one of the optimized embodiments of the invention, the mixing proportion of the diglycolamine and the Boc 2 O is equal molar quantity.
As one of the preferred embodiments of the present invention, diglycolamine and Boc 2 O are mixed to react to produce an imine, specifically: and (3) obtaining tetrahydrofuran and a catalyst, mixing diglycolamine and Boc 2 O, reacting by taking tetrahydrofuran as a solvent to obtain Boc-diglycolamine, adding the catalyst based on Boc-diglycolamine, adjusting the pH value, cooling, and reacting to generate imine.
As one of the preferred embodiments of the present invention, the catalyst includes any one of sodium hydroxide and potassium hydroxide.
As one of the optimized embodiments of the invention, the pH value is adjusted and cooled, specifically: the pH value is regulated to be 10-14, and the temperature is controlled to be reduced to be 10-15 ℃.
As one of the preferred embodiments of the present invention, deprotection under acidic conditions gives an initial mixture, specifically: the reaction is carried out under acidic condition to obtain Boc-AEEA, and an initial mixture is obtained after deprotection, wherein the initial mixture is AEEA.
As one of the optimized embodiments of the invention, the solvent used for treating the [2- [2- (Fmoc-amino) ethoxy ] acetic acid crude product is any one of ethyl acetate, methanol, ethanol, acetonitrile, tetrahydrofuran, dichloromethane, chloroform and acetone.
Compared with the prior art, the invention has the beneficial effects that: the method adopts a cheap initial raw material, and prepares the [2- [2- (Fmoc-amino) ethoxy ] acetic acid with the content of more than 99 percent by simple operation, and has high yield and lower production cost; wherein, diglycolamine and Boc 2 O are mixed and reacted to generate imine; then obtaining bromoacetic acid or bromoacetic acid derivatives, reacting with imine, and carrying out deprotection under acidic condition, thereby being beneficial to improving the purity and yield of the product; fmoc-osu (fluorenylmethoxycarbonyl succinimide) or Fmoc-c l (fluorenylmethoxycarbonyl chloride) is then obtained to prepare the final product, thereby avoiding side reactions, simplifying the refining process, improving the yield and having higher production benefits.
Drawings
In order to more clearly illustrate the embodiments of the application or the technical solutions of the prior art, the drawings which are used in the description of the embodiments or the prior art will be briefly described, it being obvious that the drawings in the description below are only some embodiments of the application, and that other drawings can be obtained from these drawings without inventive faculty for a person skilled in the art.
FIG. 1 is a flow chart showing the steps of a process for producing [2- [2- (Fmoc-amino) ethoxy ] acetic acid according to the first embodiment of the present invention.
Detailed Description
For the purpose of making the objects, technical solutions and advantages of the embodiments of the present application more apparent, the technical solutions of the embodiments of the present application will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present application, and it is apparent that the described embodiments are some embodiments of the present application, but not all embodiments of the present application. The components of the embodiments of the present application generally described and illustrated in the figures herein may be arranged and designed in a wide variety of different configurations.
Thus, the following detailed description of the embodiments of the application, as presented in the figures, is not intended to limit the scope of the application, as claimed, but is merely representative of selected embodiments of the application. All other embodiments, which can be made by those skilled in the art based on the embodiments of the application without making any inventive effort, are intended to be within the scope of the application.
It should be noted that: like reference numerals and letters denote like items in the following figures, and thus once an item is defined in one figure, no further definition or explanation thereof is necessary in the following figures.
In the description of the present application, it should be noted that, if the terms "center", "upper", "lower", "left", "right", "vertical", "horizontal", "inner", "outer", etc. indicate an azimuth or a positional relationship based on that shown in the drawings, or an azimuth or a positional relationship in which a product of the application is conventionally put in use, it is merely for convenience of describing the present application and simplifying the description, and it is not indicated or implied that the referred device or element must have a specific azimuth, be constructed and operated in a specific azimuth, and thus should not be construed as limiting the present application. Furthermore, the terms "first," "second," and the like in the description of the present application, if any, are used for distinguishing between the descriptions and not necessarily for indicating or implying a relative importance.
Furthermore, the terms "horizontal," "vertical," and the like in the description of the present application, if any, do not denote a requirement that the component be absolutely horizontal or overhang, but rather may be slightly inclined. As "horizontal" merely means that its direction is more horizontal than "vertical", and does not mean that the structure must be perfectly horizontal, but may be slightly inclined.
In the description of the present application, it should also be noted that, unless explicitly stated and limited otherwise, the terms "disposed," "mounted," "connected," and "connected" should be construed broadly, and may be, for example, fixedly connected, detachably connected, or integrally connected; can be mechanically or electrically connected; can be directly connected or indirectly connected through an intermediate medium, and can be communication between two elements. The specific meaning of the above terms in the present application will be understood in specific cases by those of ordinary skill in the art.
Referring to fig. 1, a method for preparing [2- [2- (Fmoc-amino) ethoxy ] acetic acid according to a first embodiment of the present invention comprises the following steps:
Step S1: the method comprises the steps of obtaining diglycolamine and Boc 2 O, and mixing the diglycolamine and the Boc 2 O to react to generate imine;
Step S2: obtaining bromoacetic acid or bromoacetic acid derivatives, reacting imine with any one of bromoacetic acid or bromoacetic acid derivatives, and deprotecting under acidic condition to obtain an initial mixture;
Step S3: fmoc-osu (fluorenylmethoxycarbonyl succinyl) imine) or Fmoc-c l (fluorenylmethoxycarbonyl chloride), the initial mixture is reacted with either Fmoc-osu (fluorenylmethoxycarbonyl succinimide) or Fmoc-c l (fluorenylmethoxycarbonyl chloride) under alkaline conditions to obtain crude [2- [2- (Fmoc-amino) ethoxy ] acetic acid, which is treated to obtain [2- [2- (Fmoc-amino) ethoxy ] acetic acid.
Diglycolamine is mainly used as an acid gas absorbent, a surfactant and a wetting agent; also used as a raw material for polymers, which are particularly excellent in performance as desulfurizing agents; boc 2 O refers to BOC anhydride, is commonly used as an intermediate in medicine and organic synthesis, and is an important amino protective agent applied to the synthesis of medicine and agrochemical products; the method is used for introducing tert-butoxycarbonyl protecting groups in organic synthesis, has higher safety, no strong pungent taste and no toxic action on human body, and when the product is adopted to synthesize polypeptide, the condition of removing the protecting genes is mild, and the separation and purification of the products after reaction are easier than the use of other types of amino acid protecting agents.
Imines are a class of organic compounds formed by substitution of an oxygen atom on a carbonyl group (aldehyde carbonyl group or ketone carbonyl group) with nitrogen, and have the general formula R 2 c=nr ', wherein R and R' may be hydrocarbon groups or hydrogen, the nitrogen atom also carries a hydrogen atom or other organic residues, and imines, especially schiff bases, may be used as carbonyl protecting groups in synthesis.
Bromoacetic acid, also called 2-bromoacetic acid or bromoacetic acid, is an organic compound, and has wide application in the fields of chemical synthesis, medicine, pesticide and the like, and in the aspect of chemical synthesis, bromoacetic acid is an important intermediate, and various compounds are synthesized through various modes such as substitution reaction, esterification reaction, reduction reaction and the like.
It can be stated that Fmoc-osu (fluorenylmethoxycarbonyl succinimide) or Fmoc-c l (fluorenylmethoxycarbonyl chloride), the core is fluorenylmethoxycarbonyl (Fmoc), the group consisting of fluorene and methoxycarbonyl has unique chemical properties, wherein fluorene is an aromatic hydrocarbon with high stability; the methoxycarbonyl group endows the group with good electrophilicity, so that the methoxycarbonyl group can react with various compounds; in Fmoc-OSu, fluorenylmethoxycarbonyl is connected with succinimide to form a molecule with multiple functions, the succinimide is of a five-membered ring structure and can react with amino to form a stable amide bond, so that Fmoc-OSu becomes an effective amino protection reagent and is widely used for synthesizing polypeptides and proteins; fmoc-C l is a compound formed by connecting fluorenylmethoxycarbonyl with a chlorine atom, and Fmoc-C l becomes an active electrophile due to the high electronegativity of the chlorine atom, and can undergo nucleophilic substitution reaction with an amino-containing compound to form an amide bond.
[2- [2- (Fmoc-amino) ethoxy ] acetic acid, which molecule comprises an Fmoc (9-fluorenylmethoxycarbonyl) protecting group attached to the amino group, forming an Fmoc-amino moiety, which protecting group is commonly used in organic chemistry to protect the amino group from unwanted reactions; and the amino group is connected with the main chain through the ethoxy group, so that the flexibility and water solubility of the molecule are improved, and in addition, the tail end of the main chain is an acetic acid group, so that the molecule is provided with the characteristics of carboxylic acid, such as acidity and coordination capability with metal ions.
It can be understood that the [2- [2- (Fmoc-amino) ethoxy ] acetic acid with the content of more than 99 percent is prepared by adopting a cheap initial raw material through simple operation, the yield is high, and the production cost is lower; wherein, diglycolamine and Boc 2 O are mixed and reacted to generate imine; then obtaining bromoacetic acid or bromoacetic acid derivatives, reacting with imine, and carrying out deprotection under acidic condition, thereby being beneficial to improving the purity and yield of the product; fmoc-osu (fluorenylmethoxycarbonyl succinimide) or Fmoc-c l (fluorenylmethoxycarbonyl chloride) is then obtained to prepare the final product, thereby avoiding side reactions, simplifying the refining process, improving the yield and having higher production benefits.
Further, the mixing ratio of diglycolamine and Boc 2 O is equimolar, which is set to avoid the formation of double protection on nitrogen.
Further, the step S1 specifically includes:
And (3) obtaining tetrahydrofuran and a catalyst, mixing diglycolamine and Boc 2 O, reacting by taking tetrahydrofuran as a solvent to obtain Boc-diglycolamine, adding the catalyst based on Boc-diglycolamine, adjusting the pH value, cooling, and reacting to generate imine.
Further, the catalyst comprises any one of sodium hydroxide and potassium hydroxide.
Further, the pH value is regulated and the temperature is reduced, specifically: the pH value is regulated to be 10-14, and the temperature is controlled to be reduced to be 10-15 ℃.
By way of illustration, tetrahydrofuran, i.e., tetrahydroxycyclopentadiene, is a colorless transparent liquid, has good solubility, can dissolve organic compounds, and has high chemical stability; diglycolamine and Boc 2 O are mixed and dissolved in tetrahydrofuran, the temperature is controlled to be reduced, the violent molecular movement of the compound and the solvent can be avoided, and the instability of the dissolution process is reduced.
It can be stated that the catalyst comprises sodium hydroxide or potassium hydroxide, the catalyst can accelerate the rate of chemical reaction, reduce the reaction time, and ensure that the catalyst itself does not change in quality or property before and after the reaction.
Sodium hydroxide, commonly known as caustic soda, caustic soda or caustic soda, is an inorganic compound with strong alkalinity, usually exists in the form of white solid particles or liquid, is easily dissolved in water and releases a large amount of heat, has strong catalytic activity, and can effectively promote the progress of various organic and inorganic reactions; potassium hydroxide, also a strongly basic inorganic compound, is chemically similar to sodium hydroxide, usually in the form of a white solid or liquid, and is also readily soluble in water with concomitant release of heat, acting as a catalyst to promote smooth reaction.
Further, deprotection in step S2 under acidic conditions gives an initial mixture, specifically:
The reaction is carried out under the acidic condition to obtain Boc-AEEA, and an initial mixture is obtained after deprotection, wherein the initial mixture is AEEA.
The reaction environment under the acidic condition can promote the rupture and formation of certain chemical bonds to realize the conversion of compounds, boc-AEEA is a protected amino acid ethyl ester, wherein the Boc group is a common amino protecting group and can be removed under the acidic condition to expose amino groups, and AEEA is a product of removing the Boc protecting group from the Boc-AEEA, is an important organic intermediate, is widely applied to the fields of medicines, pesticides and the like, and can provide enough protons in the reaction under the acidic condition to promote the synthesis of the Boc-AEEA.
Deprotection refers to the process of removing the Boc group from the Boc-AEEA under certain conditions; illustratively, common deprotection methods include acidic hydrolysis, in which a dilute acid solution, such as dilute sulfuric acid or dilute hydrochloric acid, is typically used to hydrolyze the Boc group to isopropanol and carbon dioxide, which needs to be performed at appropriate temperature and pH conditions to ensure smooth reaction and stability of the product, and the like.
Further, the solvent used for treating the crude [2- [2- (Fmoc-amino) ethoxy ] acetic acid is any one of ethyl acetate, methanol, ethanol, acetonitrile, tetrahydrofuran, dichloromethane, chloroform and acetone.
It can be stated that after the deprotection reaction is completed, the initial mixture AEEA obtained is then mixed with Fmoc-osu or Fmoc-c l in an alkaline environment to obtain crude [2- [2- (Fmoc-amino) ethoxy ] acetic acid, which may contain some raw materials, byproducts and other impurities that are not completely reacted, and in order to obtain the target product with higher purity, subsequent separation and purification steps are required, and the target product is effectively separated from the mixture by using a solvent, so as to improve the purity of the product.
Illustratively, solvents act as mediators and transport materials in chemical reactions, and suitable solvents can increase reaction rates, increase product purity, and reduce the formation of byproducts; wherein, the ethyl acetate is an organic solvent, has good solubility and volatility, can effectively dissolve the [2- [2- (Fmoc-amino) ethoxy ] acetic acid crude product, and is convenient for subsequent separation and purification operation; methanol and ethanol are used as alcohol solvents, have stronger polarity, can form hydrogen bonds with polar groups in the [2- [2- (Fmoc-amino) ethoxy ] acetic acid crude product, and can improve the dissolution efficiency; acetonitrile and tetrahydrofuran are used as polar aprotic solvents, have good solubility and stability in chemical reaction, can effectively dissolve [2- [2- (Fmoc-amino) ethoxy ] acetic acid crude product, and have relatively low requirements on reaction conditions; the halogenated hydrocarbon solvents such as dichloromethane and chloroform have higher hydrophobicity, can dissolve some compounds with smaller polarity, can effectively extract target products, and improve the purity of the products; acetone has good solubility and reactivity, can interact with functional groups in the [2- [2- (Fmoc-amino) ethoxy ] acetic acid crude product, and promotes the reaction to be carried out so as to improve the production efficiency of the product.
Specifically, weighing 1.0 mol of diglycolamine 105.1g, dissolving in 1L of tetrahydrofuran solution, slowly adding 1 mol of Boc 2 O218.2g in the stirring process, heating to 40 ℃ after the addition is finished, and reacting for 2 hours, wherein TLC shows that the reaction is complete, thus obtaining a tetrahydrofuran solution of H2; 1.1 mol of bromoacetic acid 153g is dissolved in 0.1L of tetrahydrofuran solution for later use; then cooling the tetrahydrofuran solution of H2 to 10-15 ℃ and keeping, regulating the pH value to 10-14 by 30% liquid alkali and keeping, dropwise adding bromoacetic acid into the tetrahydrofuran solution, continuously adding for 1-2H, and stirring at room temperature overnight after the addition is finished; after the TLC reaction is finished, 3 mol/L hydrochloric acid solution is dripped until the pH value of the water phase is about 6-7, and the THF is recovered by concentration for reuse; after THF was recovered, ethyl acetate was added to the aqueous layer and extracted three times, the ethyl acetate layers were combined, backwashed twice with saturated brine, dried and evaporated to dryness to give crude product H3, 215g was obtained, and the yield was 82%.
215G of 0.81 mol H3 is dissolved in 100mL of ethyl acetate, 3.5 mol/L of hydrogen chloride/ethyl acetate solution (800 mL) is slowly added, a large amount of white solid is separated out, the reaction is about 1H, suction filtration can be carried out after TLC detection reaction is finished, an AEEA.HCl crude product is obtained, and a pure product is obtained after stirring, washing and suction filtration by new ethyl acetate, so that 113.6g of H4 is obtained, and the yield is 70.6%.
0.1 ML of H4 is dissolved in 80mL of tetrahydrofuran and 80mL of water, 0.14 mol of Na 2CO3 g is added, after stirring for 20 minutes under the indoor temperature environment, the mixture is cooled to 15 ℃, 0.096 mol of Fmoc-OSu32.5g is added in batches, after the addition is finished, the mixture is stirred at the indoor temperature overnight, the phase is separated in the next day, the aqueous phase is extracted once by ethyl acetate, the aqueous phase is acidified to the pH value of 3 by 1mol/L of hydrochloric acid, the extraction is carried out three times by ethyl acetate, the organic phases are combined, the mixture is washed twice by saturated salt water, the mixture is dried and evaporated to obtain 36.12 g of crude [2- [2- (Fmoc-amino) ethoxy ] acetic acid, 20g of crude product is dissolved by 30 mL of ethyl acetate under the heating condition, is naturally crystallized after cooling, 30 mL of petroleum ether is added, 34.6 g of solid is obtained by suction filtration, the yield is 93.5%, and the HPLC detection content is 99.35%.
The process for preparing [2- [2- (Fmoc-amino) ethoxy ] acetic acid provided in the second embodiment of the present invention is different from the process for preparing [2- [2- (Fmoc-amino) ethoxy ] acetic acid provided in the first embodiment in that:
1.1 mol of tert-butyl bromoacetate 215g is dissolved in 0.1L of tetrahydrofuran solution for standby, the rest conditions are unchanged, H3 is prepared, 195g is obtained, and the yield is 74.4%; dissolving 195g of 0.744 mol H3 in 100m l ethyl acetate, and reacting under the same conditions to obtain H4, wherein 102g is obtained with the yield of 69%; the suction filtration solid prepared by H4 is 33.1g, the yield is 89.5%, and the content detected by HPLC is 99.12%.
The process for producing [2- [2- (Fmoc-amino) ethoxy ] acetic acid provided in the third example of the present invention is different from the process for producing [2- [2- (Fmoc-amino) ethoxy ] acetic acid provided in the first example and the process for producing [2- [2- (Fmoc-amino) ethoxy ] acetic acid provided in the second example in that:
153g of 1.1 mol of ethyl bromoacetate is dissolved in 0.1L of tetrahydrofuran solution for standby, then the temperature of the prepared H2 is reduced to 10-15 ℃ and kept, the rest conditions are unchanged, H3 is prepared, 223g is obtained, and the yield is 85.1%; 0.85 mol of H3 223g is dissolved in 100ml of ethyl acetate, the rest conditions are unchanged, H4 is prepared through reaction, 120g is obtained, and the yield is 71.1%; the suction filtration solid prepared by H4 is 33.8g, the yield is 91.3%, and the content detected by HPLC is 99.57%.
It can be stated that the preparation method is optimized aiming at the prior art, liquid alkali is used for replacing sodium hydrogen, no hydrogen is generated in the reaction process, the reaction risk can be reduced, the industrial production is facilitated, impurities generated on the N surface of the final product Fmoc-AEEA are avoided by using the liquid alkali, the purification times of the process are reduced, and the purity of the final product is improved.
The above description is only of the preferred embodiments of the present application and is not intended to limit the present application, but various modifications and variations can be made to the present application by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application should be included in the protection scope of the present application.
Claims (7)
1. A preparation method of [2- [2- (Fmoc-amino) ethoxy ] acetic acid is characterized by comprising the following steps: the method comprises the following steps:
The method comprises the steps of obtaining diglycolamine and Boc 2 O, and mixing the diglycolamine and the Boc 2 O to react to generate imine;
obtaining bromoacetic acid or bromoacetic acid derivatives, reacting imine with any one of bromoacetic acid or bromoacetic acid derivatives, and deprotecting under acidic condition to obtain an initial mixture;
Fmoc-osu (fluorenylmethoxycarbonyl succinimide) or Fmoc-cl (fluorenylmethoxycarbonyl carbonyl chloride) was obtained, and the initial mixture was reacted with either Fmoc-osu (fluorenylmethoxycarbonyl succinimide) or Fmoc-cl (fluorenylmethoxycarbonyl chloride) under basic conditions to give crude [2- [2- (Fmoc-amino) ethoxy ] acetic acid, which was treated to give [2- [2- (Fmoc-amino) ethoxy ] acetic acid.
2. A process for the preparation of [2- [2- (Fmoc-amino) ethoxy ] acetic acid according to claim 1, wherein: the mixing proportion of the diglycolamine and the Boc 2 O is equal molar quantity.
3. A process for the preparation of [2- [2- (Fmoc-amino) ethoxy ] acetic acid according to claim 2, wherein: the diglycolamine and Boc 2 O are mixed and reacted to produce imine, specifically: and (3) obtaining tetrahydrofuran and a catalyst, mixing diglycolamine and Boc 2 O, reacting by taking tetrahydrofuran as a solvent to obtain Boc-diglycolamine, adding the catalyst based on Boc-diglycolamine, adjusting the pH value, cooling, and reacting to generate imine.
4. A process for the preparation of [2- [2- (Fmoc-amino) ethoxy ] acetic acid according to claim 3, wherein: the catalyst comprises any one of sodium hydroxide and potassium hydroxide.
5. A process for the preparation of [2- [2- (Fmoc-amino) ethoxy ] acetic acid according to claim 3, wherein: the pH value is regulated and cooled, and the method specifically comprises the following steps: the pH value is regulated to be 10-14, and the temperature is controlled to be reduced to be 10-15 ℃.
6. A process for the preparation of [2- [2- (Fmoc-amino) ethoxy ] acetic acid according to claim 1, wherein: deprotection under acidic conditions gives the initial mixture, specifically: the reaction is carried out under acidic condition to obtain Boc-AEEA, and an initial mixture is obtained after deprotection, wherein the initial mixture is AEEA.
7. A process for the preparation of [2- [2- (Fmoc-amino) ethoxy ] acetic acid according to claim 1, wherein: the solvent used for treating the [2- [2- (Fmoc-amino) ethoxy ] acetic acid crude product is any one of ethyl acetate, methanol, ethanol, acetonitrile, tetrahydrofuran, dichloromethane, chloroform and acetone.
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