CN112920086A - Preparation method of L-tyrosine derivative - Google Patents
Preparation method of L-tyrosine derivative Download PDFInfo
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- CN112920086A CN112920086A CN202110097072.2A CN202110097072A CN112920086A CN 112920086 A CN112920086 A CN 112920086A CN 202110097072 A CN202110097072 A CN 202110097072A CN 112920086 A CN112920086 A CN 112920086A
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- Prior art keywords
- formula
- tyrosine
- reaction
- solvent
- compound
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- 238000002360 preparation method Methods 0.000 title claims abstract description 34
- 125000003798 L-tyrosyl group Chemical class [H]N([H])[C@]([H])(C(=O)[*])C([H])([H])C1=C([H])C([H])=C(O[H])C([H])=C1[H] 0.000 title 1
- 229960004441 tyrosine Drugs 0.000 claims abstract description 43
- 238000006243 chemical reaction Methods 0.000 claims abstract description 40
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 claims abstract description 30
- 238000000034 method Methods 0.000 claims abstract description 19
- 150000008553 L-tyrosines Chemical class 0.000 claims abstract description 18
- 238000007112 amidation reaction Methods 0.000 claims abstract description 16
- 125000005519 fluorenylmethyloxycarbonyl group Chemical group 0.000 claims abstract description 11
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 10
- 239000002994 raw material Substances 0.000 claims abstract description 10
- 238000005886 esterification reaction Methods 0.000 claims abstract description 8
- 238000006266 etherification reaction Methods 0.000 claims abstract description 7
- 230000009435 amidation Effects 0.000 claims abstract description 4
- 230000007062 hydrolysis Effects 0.000 claims abstract description 4
- 230000032050 esterification Effects 0.000 claims abstract description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 44
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- 150000001875 compounds Chemical class 0.000 claims description 36
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 30
- 239000002904 solvent Substances 0.000 claims description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 20
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 20
- 238000001914 filtration Methods 0.000 claims description 20
- 238000001035 drying Methods 0.000 claims description 18
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 16
- 239000000243 solution Substances 0.000 claims description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical group CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 12
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 claims description 12
- 238000004537 pulping Methods 0.000 claims description 10
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 10
- 238000005406 washing Methods 0.000 claims description 10
- 239000007864 aqueous solution Substances 0.000 claims description 9
- 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 claims description 8
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 8
- 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
- 239000012043 crude product Substances 0.000 claims description 8
- -1 diester compounds Chemical class 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 7
- GPTXCAZYUMDUMN-UHFFFAOYSA-N tert-butyl n-(2-hydroxyethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCO GPTXCAZYUMDUMN-UHFFFAOYSA-N 0.000 claims description 7
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical group [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical group [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- 239000011259 mixed solution Substances 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- OTJZCIYGRUNXTP-UHFFFAOYSA-N but-3-yn-1-ol Chemical compound OCCC#C OTJZCIYGRUNXTP-UHFFFAOYSA-N 0.000 claims description 5
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 claims description 5
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 claims description 5
- QKSQWQOAUQFORH-UHFFFAOYSA-N tert-butyl n-[(2-methylpropan-2-yl)oxycarbonylimino]carbamate Chemical compound CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C QKSQWQOAUQFORH-UHFFFAOYSA-N 0.000 claims description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical group [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 150000008282 halocarbons Chemical class 0.000 claims description 4
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical group O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 3
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- YPBRKXFDMDCCEA-UHFFFAOYSA-N 3-cyclopropylprop-2-yn-1-ol Chemical compound OCC#CC1CC1 YPBRKXFDMDCCEA-UHFFFAOYSA-N 0.000 claims description 2
- IRJKSAIGIYODAN-ISLYRVAYSA-N benzyl (ne)-n-phenylmethoxycarbonyliminocarbamate Chemical compound C=1C=CC=CC=1COC(=O)/N=N/C(=O)OCC1=CC=CC=C1 IRJKSAIGIYODAN-ISLYRVAYSA-N 0.000 claims description 2
- NCBFTYFOPLPRBX-UHFFFAOYSA-N dimethyl azodicarboxylate Substances COC(=O)N=NC(=O)OC NCBFTYFOPLPRBX-UHFFFAOYSA-N 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims description 2
- NCBFTYFOPLPRBX-AATRIKPKSA-N methyl (ne)-n-methoxycarbonyliminocarbamate Chemical compound COC(=O)\N=N\C(=O)OC NCBFTYFOPLPRBX-AATRIKPKSA-N 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical group [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 5
- 239000007858 starting material Substances 0.000 claims 1
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000000926 separation method Methods 0.000 abstract description 3
- 238000005580 one pot reaction Methods 0.000 abstract 1
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 abstract 1
- NXGXFAKJUWEFEC-UHFFFAOYSA-N n-(8-hydroxy-2-phenyl-6-phenylmethoxy-4,4a,6,7,8,8a-hexahydropyrano[3,2-d][1,3]dioxin-7-yl)acetamide Chemical compound CC(=O)NC1C(O)C2OC(C=3C=CC=CC=3)OCC2OC1OCC1=CC=CC=C1 NXGXFAKJUWEFEC-UHFFFAOYSA-N 0.000 description 25
- VXYFARNRGZWHTJ-FVGYRXGTSA-N methyl (2s)-2-amino-3-(4-hydroxyphenyl)propanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CC1=CC=C(O)C=C1 VXYFARNRGZWHTJ-FVGYRXGTSA-N 0.000 description 18
- 238000004128 high performance liquid chromatography Methods 0.000 description 16
- 239000007787 solid Substances 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 238000003760 magnetic stirring Methods 0.000 description 10
- 229940024606 amino acid Drugs 0.000 description 9
- 235000001014 amino acid Nutrition 0.000 description 9
- 150000001413 amino acids Chemical class 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
- 238000012544 monitoring process Methods 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 239000005457 ice water Substances 0.000 description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 6
- 108090000765 processed proteins & peptides Proteins 0.000 description 6
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 208000012839 conversion disease Diseases 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 102000004196 processed proteins & peptides Human genes 0.000 description 4
- 125000003158 alcohol group Chemical group 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 229960005190 phenylalanine Drugs 0.000 description 3
- 229920001184 polypeptide Polymers 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 150000001350 alkyl halides Chemical class 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- QUPDWYMUPZLYJZ-UHFFFAOYSA-N ethyl Chemical compound C[CH2] QUPDWYMUPZLYJZ-UHFFFAOYSA-N 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- RUZLIIJDZBWWSA-INIZCTEOSA-N methyl 2-[[(1s)-1-(7-methyl-2-morpholin-4-yl-4-oxopyrido[1,2-a]pyrimidin-9-yl)ethyl]amino]benzoate Chemical group COC(=O)C1=CC=CC=C1N[C@@H](C)C1=CC(C)=CN2C(=O)C=C(N3CCOCC3)N=C12 RUZLIIJDZBWWSA-INIZCTEOSA-N 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 125000003367 polycyclic group Chemical group 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- VOLGAXAGEUPBDM-UHFFFAOYSA-N $l^{1}-oxidanylethane Chemical compound CC[O] VOLGAXAGEUPBDM-UHFFFAOYSA-N 0.000 description 1
- YKYIFUROKBDHCY-ONEGZZNKSA-N (e)-4-ethoxy-1,1,1-trifluorobut-3-en-2-one Chemical group CCO\C=C\C(=O)C(F)(F)F YKYIFUROKBDHCY-ONEGZZNKSA-N 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102100036672 Interleukin-23 receptor Human genes 0.000 description 1
- 101710195550 Interleukin-23 receptor Proteins 0.000 description 1
- 102000000536 PPAR gamma Human genes 0.000 description 1
- 108010016731 PPAR gamma Proteins 0.000 description 1
- 108010090804 Streptavidin Proteins 0.000 description 1
- 150000001294 alanine derivatives Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 150000002308 glutamine derivatives Chemical class 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 238000000520 microinjection Methods 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 150000002993 phenylalanine derivatives Chemical class 0.000 description 1
- 230000004481 post-translational protein modification Effects 0.000 description 1
- 230000008672 reprogramming Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 150000003667 tyrosine derivatives Chemical class 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
-
- 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
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of an L-tyrosine derivative, wherein the L-tyrosine derivative is O-alkyl-N- [ fluorenylmethyloxycarbonyl ] -L-tyrosine, the O-alkyl-N- [ fluorenylmethyloxycarbonyl ] -L-tyrosine is prepared by taking L-tyrosine as an initial raw material and sequentially carrying out esterification, amidation, etherification/hydrolysis and amidation, the total yield of a target product can reach 61.5%, and the ee value can reach more than 99%. The preparation method has the advantages of cheap and easily obtained raw materials, low cost and the like, for example, the separation of triphenyl phosphine oxide is avoided in the etherification reaction; the method has the advantages of simple process, short route, mild reaction conditions and the like, for example, the etherification and the hydrolysis adopt a one-pot method; the three wastes generated in the whole process are less, the product yield and purity are higher, and the method is suitable for industrial production.
Description
Technical Field
The invention belongs to the field of synthesis of medical intermediates, and particularly relates to a preparation method of an L-tyrosine derivative for synthesizing polypeptide and bioactive small molecules.
Background
In nature, only 20 natural amino acids synthesize diverse proteins for the life activities of organisms. However, with the development of chemical and biological research and application, natural amino acids have failed to meet the needs of protein engineering, enzyme engineering, directed evolution, and the like. Over the last decade, advances in the field of genetic code reprogramming have rapidly brought hundreds of unnatural amino acids into protein structure and manipulated with unprecedented precision at the monoatomic level. Thus, unnatural amino acids have great potential for development in the biotechnology, biocatalysis, and biomedical fields.
The synthesis of unnatural amino acids is mainly carried out by chemical synthesis, biosynthesis, microinjection, auxotrophy, posttranslational modification, and the like. The currently reported unnatural amino acids mainly include phenylalanine derivatives, tyrosine derivatives, glutamine derivatives, alanine derivatives, and the like, and the unnatural amino acids generally need protection groups to form protected amino acids for polypeptide synthesis. Among them, O-alkyl-L-tyrosine derivatives are present in a variety of polypeptides and drug molecules, such as PPAR-gamma inhibitor GW1929, polycyclic peptides, etc.
O-alkyl-N- [ fluorenylmethyloxycarbonyl ] -L-tyrosine is an important protected amino acid for synthesizing O-alkyl-L-tyrosine derivatives, wherein O2amY is not only applied to a novel peptide inhibitor of interleukin-23 receptor, but also O2 amY-mediated polycyclic peptide has strong binding affinity to streptavidin, and the structural formula is shown as (I):
at present, no literature is reported about the synthesis process of O-alkyl-N- [ fluorenylmethyloxycarbonyl ] -L-tyrosine. The key of the preparation method of the general O-alkyl-L-tyrosine derivative is the reaction of phenolic hydroxyl and alkyl halide, and the two main methods are as follows:
douglas D.Young et al reported the synthesis of O- (4-alkynylpropyl) -L-tyrosine. The method is mainly characterized in that N-tert-butyloxycarbonyl-L-tyrosine methyl ester and alkyl halide are subjected to nucleophilic substitution reaction to generate ether, and the reaction yield of the step is only 3.9%. The method has the defects of extremely low yield, unsuitability for industrial production and the like. (Bioconjugate chem.2015,26,1884-1889.)
Fang Hao et al reported the synthesis of O-benzyl-N-t-butyloxycarbonyl-L-tyrosine. The method has a short route, the yield is 46%, but the operation is complicated, heavy metal salt is used, and the separation cost is high. (bioorg. Med. chem.2017,25, 138-
Aiming at the problems of lower yield, fussy steps, poor safety, difficult separation and the like in the synthetic method. The invention develops a synthesis process of O-alkyl-N- [ fluorenylmethyloxycarbonyl ] -L-tyrosine, which has the advantages of easily obtained raw materials, simple process, economy and environmental protection.
Disclosure of Invention
The invention aims to provide a method for preparing O-alkyl-N- [ fluorenylmethyloxycarbonyl ] -L-tyrosine by taking L-tyrosine as an initial raw material, which has the characteristics of simple process, convenient operation, higher yield, lower cost and the like.
The preparation method of the L-tyrosine derivative is characterized in that the L-tyrosine derivative is O-alkyl-N- [ fluorenylmethyloxycarbonyl ] -L-tyrosine shown in a formula (I), and the L-tyrosine derivative is obtained by taking L-tyrosine shown in a formula (II) as an initial raw material and sequentially carrying out esterification, amidation, etherification/hydrolysis and amidation reactions, and is characterized by specifically comprising the following steps:
s1: the L-tyrosine shown in the formula (II) is used as an initial raw material and is obtained through esterification reaction, and the method specifically comprises the following steps: starting L-tyrosine shown in a formula (II) as a raw material, carrying out esterification reaction with methanol at a reflux temperature in the presence of a catalyst, cooling and concentrating to remove the methanol after the reaction is finished, and drying to obtain L-tyrosine ester hydrochloride shown in a formula (III);
s2: adding a compound shown as a formula (III) into a solvent A, carrying out amidation reaction with trifluoroacetic anhydride in the solvent A at a reflux temperature in the presence of alkali A, concentrating to remove the solvent A after the reaction is finished, washing with water, filtering, and drying to obtain a compound shown as a formula (IV);
s3: adding a compound shown in a formula (IV) into a solvent B, carrying out etherification reaction with alcohol ROH in the solvent B in the presence of triphenylphosphine and azodicarbonic diester compounds, and concentrating to obtain a crude compound shown in a formula (V) after the reaction is finished; directly adding the obtained crude product of the compound shown in the formula (V) into a mixed solvent of lower alcohol and water, adding alkali B for hydrolysis reaction, acidifying the reaction solution with acid until the pH value is 5-6 after the reaction is finished, filtering, pulping with a halogenated hydrocarbon solvent, filtering, and drying to obtain the compound shown in the formula (VI);
s4: adding a compound shown as a formula (VI) and a sodium carbonate aqueous solution into a solvent D, adding 9-fluorenylmethyl-N-succinimidyl carbonate to perform amidation reaction, concentrating to remove part of the solvent after the reaction is finished, acidifying with acid until the pH value is 6-7, extracting with ethyl acetate, washing with saturated saline solution, and concentrating to obtain a compound shown as a formula (I), namely O-alkyl-N- [ fluorenylmethoxycarbonyl ] -L-tyrosine;
in the formulas (I), (IV), (V) and (VI), a substituent R is C1-C9 alkyl or substituted alkyl, and the substituent of the substituted alkyl is C2-C4 alkynyl or N-tert-butyloxycarbonyl; for example, the substituent R may be selected from ethyl, isopropyl, (N-t-butoxycarbonyl) ethyl, 3-alkynyl-butyl, and the like;
the substituents R in the alcohol ROH are the same as R in formula (I);
in step S3, the halogenated hydrocarbon solvent is selected from dichloromethane.
The preparation method of the L-tyrosine derivative is characterized in that in the step S1, the catalyst is concentrated sulfuric acid, thionyl chloride or anhydrous hydrogen chloride, and is preferably thionyl chloride; the amount ratio of the catalyst to the amount of the substance of tyrosine represented by formula (II) is 1.5-2.5: 1, preferably 1.7-2.0: 1.
The preparation method of the L-tyrosine derivative is characterized in that in the step S2, the base A is pyridine, triethylamine or N, N-diisopropylethylamine, and pyridine is preferred; the solvent A is ethyl acetate, tetrahydrofuran, methyl acetate, chloroform, dichloromethane or 1, 2-dichloroethane, preferably tetrahydrofuran; the mass ratio of the base A to the compound represented by the formula (III) is 2.1 to 3.5:1, preferably 2.2 to 2.8: 1; the mass ratio of trifluoroacetic anhydride to the compound represented by formula (III) is 1.2 to 1.8:1, preferably 1.3 to 1.6: 1.
The preparation method of the L-tyrosine derivative is characterized in that in the step S3, the solvent B is ethyl acetate, tetrahydrofuran, methyl acetate, toluene, chloroform, dichloromethane or 1, 2-dichloroethane, preferably tetrahydrofuran; the azodicarboxylic acid diester compound is dimethyl azodicarboxylate, diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate or dibenzyl azodicarboxylate, preferably diethyl azodicarboxylate; the alcohol ROH is ethanol, tert-butyl alcohol, N-propanol, N- (tert-butoxycarbonyl) ethanolamine, 3-cyclopropyl-2-propyn-1-ol or 3-butyn-1-ol; the alkali B is sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide or potassium tert-butoxide, and potassium carbonate is preferred;
the mass ratio of triphenylphosphine to the compound of formula (IV) is 1.2-2.0: 1, preferably 1.3-1.6: 1; the mass ratio of the azodicarboxylic acid diester compound to the compound represented by the formula (IV) is 1.2-2.0: 1, preferably 1.3-1.6: 1; the mass ratio of the alcohol ROH to the compound represented by the formula (IV) is 1.2-1.8: 1, preferably 1.3-1.5: 1;
the lower alcohol is methanol or ethanol, and the mixed solvent of the lower alcohol and water is a methanol-water mixed solution with a volume ratio of 1-5: 1 or an ethanol-water mixed solution with a volume ratio of 1-4: 1, preferably a methanol-water mixed solution with a volume ratio of 1-3: 1; the ratio of the amount of the base B to the amount of the compound represented by the formula (V) is 2.5 to 5.0:1, preferably 3.0 to 4.0: 1.
The preparation method of the L-tyrosine derivative is characterized in that in the step S4, a solvent D is tetrahydrofuran, dioxane or acetone, and tetrahydrofuran is preferred; the mass ratio of sodium carbonate to the compound of formula (VI) is 1.1-2.5: 1, preferably 1.3-2.0: 1; the ratio of the amount of the 9-fluorenylmethyl-N-succinimidyl carbonate to the amount of the compound represented by the formula (VI) is 1.0 to 1.3:1, preferably 1.05 to 1.20: 1.
By adopting the technology, compared with the prior art, the invention has the beneficial effects that:
(1) the synthetic route is short, the process is simple, and the reaction conditions are mild;
(2) the raw materials are cheap, the cost is low, and the environment is friendly;
(3) the three wastes generated in the whole process are less, the product yield and purity are higher, and the method is suitable for industrial production.
Detailed Description
The present invention is further illustrated by the following examples, which should not be construed as limiting the scope of the invention.
Example 1:
taking ROH as N-tert-butyloxycarbonyl-ethanolamine as a specific example, O-alkyl-N- [ fluorenylmethoxycarbonyl ] -L-tyrosine is prepared according to the following synthetic route:
1. preparation of L-tyrosine methyl ester hydrochloride (III)
Adding L-tyrosine (1.81g, 10mmol) and 20mL of methanol into a 50mL three-neck flask with a magnetic stirring thermometer, slowly dropwise adding thionyl chloride (1.78g, 15mmol) in an ice bath at-10 ℃, ensuring the temperature of the reaction liquid to be below room temperature, after dropwise adding, heating to reflux for esterification reaction, and monitoring by TLC until the reaction is finished. After cooling, concentration to remove methanol and drying, 2.21g of white solid L-tyrosine methyl ester hydrochloride is obtained, the yield is 95.5 percent and the HPLC purity is 98.6 percent.
2. Preparation of N-trifluoroacetyl-L-tyrosine methyl ester (IV)
Adding L-tyrosine methyl ester hydrochloride (2.32g, 10mmol) and 25mL of tetrahydrofuran into a 50mL three-neck flask with a magnetic stirring thermometer, placing the reaction flask in an ice-water bath at 0-5 ℃, adding pyridine (1.18g, 21mmol), then dropwise adding trifluoroacetic anhydride (2.52g, 12mmol), ensuring that the temperature of the reaction solution is below room temperature, after dropwise adding, heating to reflux for amidation reaction, and monitoring by TLC until the reaction is finished. Cooling, concentrating to remove tetrahydrofuran, washing with water, filtering and drying to obtain white solid N-trifluoroacetyl-L-tyrosine methyl ester 2.69g with yield 92.2% and HPLC purity 99.4%,1H NMR(400MHz,DMSO-d6)δ9.90(d,J＝8.0Hz,1H),9.30(s,1H),7.04(d,J＝8.0Hz,2H),6.68(d,J＝7.2Hz,2H),4.56–4.49(m,1H),3.67(s,3H),3.08(dd,J＝13.6,4.4Hz,1H),2.91(m,1H).
3. preparation of O- [2- [ [ (tert-butoxy) carbonyl ] amino ] ethyl ] -L-tyrosine (VI-a)
Adding N-trifluoroacetyl-L-tyrosine methyl ester (2.91g, 10mmol) and tetrahydrofuran (30 mL) into a 100mL three-neck flask with a magnetic stirring thermometer, adding N-tert-butoxycarbonyl-ethanolamine (1.93g, 12mmol) and triphenylphosphine (3.15g, 12mmol), placing the reaction bottle in an ice-water bath at 0-5 ℃, dropwise adding di-tert-butyl azodicarboxylate (2.76g, 12mmol) to ensure that the temperature of the reaction solution is below room temperature, reacting at room temperature after dropwise adding, and monitoring by HPLC until the reaction conversion rate of N-trifluoroacetyl-L-tyrosine methyl ester is 96%. Concentrating to remove tetrahydrofuran to obtain (S) -3- (4- [2- [ [ tert-butoxycarbonyl group)]Amino group]Ethoxy radical]Phenyl) -2- (2,2, 2-trifluoroacetamido) propionic acid methyl ester crude product (V-a). To the crude product (V-a), 20mL of methanol was added, and 27.0g of an aqueous solution of potassium carbonate having a mass concentration of 25.6% was added to conduct hydrolysis reaction at room temperature, followed by TLC until the reaction was completed. Acidifying with 2N hydrochloric acid until the pH value is 5-6, separating out a white-like solid, filtering, pulping with dichloromethane, filtering, and drying to obtain a white solid O- [2- [ [ tert-butoxycarbonyl group]Amino group]Ethyl radical]2.64g of L-tyrosine, two-step yield 81.4% and HPLC purity 99.3%. LC-MS (ESI) m/z calcd for C16H25N2O5[M+H]+:325.18,found:325.06.
4. Preparation of O- [2- [ [ (tert-butyloxycarbonyl) amino ] ethyl ] -N- [ fluorenylmethoxycarbonyl ] -L-tyrosine (I-a)
A100 mL three-neck flask with a magnetic stirring thermometer is charged with O- [2- [ [ tert-butoxy carbonyl ] carbonyl]Amino group]Ethyl radical]L-tyrosine (3.24g, 10mmol), 21.2g of sodium carbonate aqueous solution with mass concentration of 5.5%, 20mL of tetrahydrofuran solution of 9-fluorenylmethyl-N-succinimidyl carbonate (3.37g, 10mmol) was added dropwise at room temperature, after the addition, amidation reaction was carried out at room temperature, and TLC was monitored until the reaction was completed. Concentrating to remove partial solvent, acidifying with 2N hydrochloric acid until the pH value is 6-7, extracting with ethyl acetate, washing with saturated saline solution, concentrating, pulping with petroleum ether, filtering, and drying to obtain white solid O-alkyl-N- [ fluorenylmethyloxycarbonyl ]]4.68g of L-tyrosine, yield 85.7%, HPLC purity 99.8%, ee value 99.8%.1H NMR(400MHz,DMSO-d6)δ12.75(s,1H),7.89(d,J＝7.6Hz,2H),7.72–7.64(m,3H),7.44–7.40(t,J＝7.6Hz,2H),7.35–7.28(m,2H),7.19(d,J＝8.0Hz,2H),7.00(t,J＝5.6Hz,1H),6.84(d,J＝8.4Hz,2H),4.24–3.90(m,4H),3.91(t,J＝6.0Hz,2H),3.29(q,J＝6.0Hz,2H),3.03(m,J＝14.0,4.4Hz,1H),2.82(m,1H),1.39(s,9H).
Example 2:
1. preparation of L-tyrosine methyl ester hydrochloride (III)
Adding L-tyrosine (1.81g, 10mmol) and 20mL of methanol into a 50mL three-neck flask with a magnetic stirring thermometer, slowly dropwise adding thionyl chloride (2.97g, 25mmol) in an ice bath at-10 ℃, ensuring the temperature of the reaction liquid to be below room temperature, after dropwise adding, heating to reflux for esterification reaction, and monitoring by TLC until the reaction is finished. Cooling, concentrating to remove methanol, and drying to obtain white solid L-tyrosine methyl ester hydrochloride 2.25g, yield 97.2%, and HPLC purity 99.3%.
2. Preparation of N-trifluoroacetyl-L-tyrosine methyl ester (IV)
Adding L-tyrosine methyl ester hydrochloride (2.32g, 10mmol) and 25mL of dichloromethane into a 50mL three-neck flask with a magnetic stirring thermometer, placing the reaction bottle in an ice-water bath at 0-5 ℃, adding pyridine (2.77g, 35mmol), dropwise adding trifluoroacetic anhydride (3.15g, 15mmol), ensuring the temperature of the reaction solution to be below room temperature, after dropwise adding, heating to reflux for amidation reaction, and monitoring by TLC until the reaction is finished. After cooling, concentration to remove dichloromethane, water washing, filtration and drying, 2.73g of white-like solid N-trifluoroacetyl-L-tyrosine methyl ester is obtained, the yield is 93.6 percent, and the HPLC purity is 99.2 percent.
3. Preparation of O- [2- [ [ (tert-butoxy) carbonyl ] amino ] ethyl ] -L-tyrosine (VI-a)
Adding N-trifluoroacetyl-L-tyrosine methyl ester (2.91g, 10mmol) and 30mL of toluene into a 100mL three-neck flask with a magnetic stirring thermometer, adding N-tert-butoxycarbonyl-ethanolamine (2.90g, 18mmol) and triphenylphosphine (5.24g, 20mmol), placing the reaction bottle in an ice-water bath at 0-5 ℃, dropwise adding diethyl azodicarboxylate (3.48g, 20mmol) to ensure that the temperature of the reaction solution is below room temperature, reacting at room temperature after dropwise adding, and monitoring by HPLC until the reaction conversion rate of N-trifluoroacetyl-L-tyrosine methyl ester is 97%. The toluene was removed by concentration to obtain a crude methyl (S) -3- (4- [2- [ [ tert-butoxycarbonyl ] amino ] ethoxy ] phenyl) -2- (2,2, 2-trifluoroacetamido) propionate product (V-a). To the crude product (V-a), 20mL of ethanol was added, and 21g of an aqueous solution of sodium hydroxide having a mass concentration of 4.7% was added to conduct hydrolysis reaction at room temperature, followed by TLC until the reaction was completed. Acidifying with 2N hydrochloric acid until the pH value is 5-6, separating out a white solid, filtering, pulping with dichloromethane, filtering, and drying to obtain 2.78g of white solid O- [2- [ [ tert-butoxycarbonyl ] amino ] ethyl ] -L-tyrosine, wherein the yield of the two steps is 85.8%, and the HPLC purity is 99.1%.
4. Preparation of O- [2- [ [ (tert-butyloxycarbonyl) amino ] ethyl ] -N- [ fluorenylmethoxycarbonyl ] -L-tyrosine (I-a)
O- [2- [ [ tert-butoxycarbonyl ] amino ] ethyl ] -L-tyrosine (3.24g, 10mmol) and 22.6g of an aqueous solution of sodium carbonate having a mass concentration of 11.7% were charged into a 100mL three-necked flask equipped with a magnetic stirrer and a thermometer, 20mL of a tetrahydrofuran solution of 9-fluorenylmethyl-N-succinimidyl carbonate (4.38g, 13mmol) was added dropwise at room temperature, and after completion of the addition, amidation reaction was carried out at room temperature, and TLC was monitored until the reaction was completed. Concentrating to remove part of solvent, acidifying with 2N hydrochloric acid until the pH value is 6-7, extracting with ethyl acetate, washing with saturated saline solution, concentrating, pulping with petroleum ether, filtering, and drying to obtain white solid O-alkyl-N- [ fluorenylmethyloxycarbonyl ] -L-tyrosine 4.51g, the yield is 82.6%, the HPLC purity is 99.5%, and the ee value is 99.6%.
Example 3:
example 1 was repeated with ROH as ethanol, but mainly N-tert-butoxycarbonyl-ethanolamine was replaced with an equimolar amount of ethanol during the preparation of compound (vi);
the synthetic route of example 3 is as follows:
1. preparation of L-tyrosine methyl ester hydrochloride (III)
Preparation of L-tyrosine methyl ester hydrochloride (III) in example 3 example 1 was repeated.
2. Preparation of N-trifluoroacetyl-L-tyrosine methyl ester (IV)
Example 3 preparation of methyl N-trifluoroacetyl-L-tyrosine (IV) example 1 is repeated.
3. Preparation of 4-ethoxy-L-phenylalanine (VI-b)
Adding N-trifluoroacetyl-L-tyrosine methyl ester (2.91g, 10mmol) and tetrahydrofuran (30 mL) into a 100mL three-neck flask with a magnetic stirring thermometer, adding ethanol (0.55g, 12mmol) and triphenylphosphine (3.15g, 12mmol), placing the reaction flask in an ice-water bath at 0-5 ℃, dropwise adding di-tert-butyl azodicarboxylate (2.76g, 12mmol) to ensure that the temperature of the reaction solution is below room temperature, reacting at room temperature after dropwise adding, and monitoring by HPLC until the reaction conversion rate of the N-trifluoroacetyl-L-tyrosine methyl ester is 98%. The tetrahydrofuran was removed by concentration to give a crude (S) -methyl 3- (4-ethoxy ] phenyl) -2- (2,2, 2-trifluoroacetamido) propionate (V-b). To the crude product (V-b), 20mL of methanol was added, 23.5g of an aqueous solution of potassium carbonate having a mass concentration of 14.7% was added, hydrolysis reaction was carried out at room temperature, and TLC was carried out until the reaction was completed. Acidifying with 2N hydrochloric acid until the pH value is 5-6, separating out a white solid, filtering, pulping with dichloromethane, filtering, and drying to obtain 1.78g of white solid 4-ethoxy-L-phenylalanine, wherein the yield of the two steps is 85.2%, and the HPLC purity is 99.5%.
4. Preparation of 4-ethoxy-N- [ fluorenylmethoxycarbonyl ] -L-phenylalanine (I-b)
A100 mL three-necked flask equipped with a magnetic stirrer and a thermometer was charged with 4-ethoxy-L-phenylalanine (2.09g, 10mmol) and 22.1g of a 9.6% aqueous sodium carbonate solution, 20mL of an acetone solution of 9-fluorenylmethyl-N-succinimidyl carbonate (3.71g, 11mmol) was added dropwise at room temperature, after completion of the addition, amidation reaction was carried out at room temperature, and TLC was carried out until the reaction was completed. Concentrating to remove part of solvent, acidifying with 2N hydrochloric acid until the pH value is 6-7, extracting with ethyl acetate, washing with saturated saline solution, concentrating, pulping with petroleum ether, filtering, and drying to obtain white solid O-alkyl-N- [ fluorenylmethyloxycarbonyl ] -L-tyrosine 3.74g, with the yield of 86.6%, the HPLC purity of 99.6% and the ee value of 99.7%.
Example 4:
example 1 was repeated with the experimental procedure of example 3 using ROH as 3-butyn-1-ol, except that in the preparation of compound (VI), N-tert-butoxycarbonyl-ethanolamine was replaced with an equimolar amount of 3-butyn-1-ol;
the synthetic route of example 4 is as follows:
1. preparation of L-tyrosine methyl ester hydrochloride (III)
Preparation of L-tyrosine methyl ester hydrochloride (III) in example 4 example 1 was repeated.
2. Preparation of N-trifluoroacetyl-L-tyrosine methyl ester (IV)
Example 4 preparation of methyl N-trifluoroacetyl-L-tyrosine (IV) example 1 is repeated.
3. Preparation of O- [ 3-butynyl ] -L-tyrosine (VI-c)
Adding N-trifluoroacetyl-L-tyrosine methyl ester (2.91g, 10mmol) and tetrahydrofuran (30 mL) into a 100mL three-neck flask with a magnetic stirring thermometer, adding 3-butyn-1-ol (0.84g, 12mmol) and triphenylphosphine (3.15g, 12mmol), placing the reaction bottle in an ice-water bath at 0-5 ℃, dropwise adding di-tert-butyl azodicarboxylate (2.76g, 12mmol) to ensure that the temperature of the reaction solution is below room temperature, reacting at room temperature after dropwise adding, and monitoring by HPLC until the reaction conversion rate of N-trifluoroacetyl-L-tyrosine methyl ester is 97%. The tetrahydrofuran was removed by concentration to obtain a crude product of (S) -methyl 3- (4- [ 3-butyn-1-oxy ] phenyl) -2- (2,2, 2-trifluoroacetamido) propionate (V-c). To the crude product (V-c), 20mL of methanol was added, 22g of an aqueous solution of 9.1% by mass sodium hydroxide was added, hydrolysis reaction was carried out at room temperature, and TLC was carried out until the reaction was completed. Acidifying with 2N hydrochloric acid until the pH value is 5-6, separating out a white solid, filtering, pulping with dichloromethane, filtering, and drying to obtain 1.96g of white solid O- [ 3-butyne ] -L-tyrosine, wherein the yield of the two steps is 84.1%, and the HPLC purity is 99.2%.
4. Preparation of O- [ 3-butyne ] -N- [ fluorenylmethoxycarbonyl ] -L-tyrosine (I-c)
O- [ 3-butyne ] -L-tyrosine (2.33g, 10mmol) and 22.1g of 9.6% sodium carbonate aqueous solution are added into a 100mL three-neck flask with a magnetic stirring thermometer, 20mL of 9-fluorenylmethyl-N-succinimidyl carbonate (3.71g, 11mmol) acetone solution is added dropwise at room temperature, after the addition, amidation reaction is carried out at room temperature, and TLC is monitored until the reaction is finished. Concentrating to remove part of solvent, acidifying with 2N hydrochloric acid until the pH value is 6-7, extracting with ethyl acetate, washing with saturated saline, concentrating, pulping with petroleum ether, filtering, and drying to obtain white solid O-alkyl-N- [ fluorenylmethoxycarbonyl ] -L-tyrosine 3.81g, wherein the yield is 83.7%, the HPLC purity is 99.5%, and the ee value is 99.7%.
The statements in this specification merely set forth a list of implementations of the inventive concept and the scope of the present invention should not be construed as limited to the particular forms set forth in the examples.
Claims (7)
1. A preparation method of L-tyrosine derivative is characterized in that the L-tyrosine derivative is O-alkyl-N- [ fluorenylmethyloxycarbonyl ] -L-tyrosine shown in formula (I), which is obtained by taking a compound shown in formula (III) as a raw material and sequentially carrying out amidation, etherification/hydrolysis and amidation reactions, and specifically comprises the following steps:
1) adding a compound shown as a formula (III) into a solvent A, carrying out amidation reaction with trifluoroacetic anhydride in the solvent A at a reflux temperature in the presence of alkali A, concentrating to remove the solvent A after the reaction is finished, washing with water, filtering, and drying to obtain a compound shown as a formula (IV);
2) adding a compound shown in a formula (IV) into a solvent B, carrying out etherification reaction with alcohol ROH in the solvent B in the presence of triphenylphosphine and azodicarbonic diester compounds, and concentrating to obtain a crude compound shown in a formula (V) after the reaction is finished; directly adding the obtained crude product of the compound shown in the formula (V) into a mixed solvent of lower alcohol and water, adding alkali B for hydrolysis reaction, acidifying the reaction solution with acid until the pH value is 5-6 after the reaction is finished, filtering, pulping with a halogenated hydrocarbon solvent, filtering, and drying to obtain the compound shown in the formula (VI);
3) adding a compound shown as a formula (VI) and a sodium carbonate aqueous solution into a solvent D, adding 9-fluorenylmethyl-N-succinimidyl carbonate to perform amidation reaction, concentrating to remove part of the solvent after the reaction is finished, acidifying with acid until the pH value is 6-7, extracting with ethyl acetate, washing with saturated saline solution, and concentrating to obtain a compound shown as a formula (I), namely O-alkyl-N- [ fluorenylmethoxycarbonyl ] -L-tyrosine;
in the formulas (I), (IV), (V) and (VI), a substituent R is C1-C9 alkyl or substituted alkyl, and the substituent of the substituted alkyl is C2-C4 alkynyl or N-tert-butyloxycarbonyl;
the substituents R in the alcohol ROH are the same as R in formula (I).
2. The process for preparing L-tyrosine derivative according to claim 1, wherein the compound of formula (III) is prepared by esterification of L-tyrosine of formula (II) as starting material, which comprises the following steps: starting L-tyrosine shown in a formula (II) as a raw material, carrying out esterification reaction with methanol at a reflux temperature in the presence of a catalyst, cooling and concentrating to remove the methanol after the reaction is finished, and drying to obtain L-tyrosine ester hydrochloride shown in a formula (III);
3. the process for preparing an L-tyrosine derivative according to claim 2, wherein the catalyst is concentrated sulfuric acid, thionyl chloride or anhydrous hydrogen chloride, preferably thionyl chloride; the amount ratio of the catalyst to the amount of the substance of tyrosine represented by formula (II) is 1.5-2.5: 1, preferably 1.7-2.0: 1.
4. The process for preparing an L-tyrosine derivative according to claim 1, wherein in step 1), the base a is pyridine, triethylamine or N, N-diisopropylethylamine, preferably pyridine; the solvent A is ethyl acetate, tetrahydrofuran, methyl acetate, chloroform, dichloromethane or 1, 2-dichloroethane, preferably tetrahydrofuran; the mass ratio of the base A to the compound represented by the formula (III) is 2.1 to 3.5:1, preferably 2.2 to 2.8: 1; the mass ratio of trifluoroacetic anhydride to the compound represented by formula (III) is 1.2 to 1.8:1, preferably 1.3 to 1.6: 1.
5. The process for preparing an L-tyrosine derivative according to claim 1, wherein in step 2), the solvent B is ethyl acetate, tetrahydrofuran, methyl acetate, toluene, chloroform, dichloromethane or 1, 2-dichloroethane, preferably tetrahydrofuran; the azodicarboxylic acid diester compound is dimethyl azodicarboxylate, diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate or dibenzyl azodicarboxylate, preferably diethyl azodicarboxylate; the alcohol ROH is ethanol, tert-butyl alcohol, N-propanol, N- (tert-butoxycarbonyl) ethanolamine, 3-cyclopropyl-2-propyn-1-ol or 3-butyn-1-ol; the alkali B is sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide or potassium tert-butoxide, and potassium carbonate is preferred;
the mass ratio of triphenylphosphine to the compound of formula (IV) is 1.2-2.0: 1, preferably 1.3-1.6: 1; the mass ratio of the azodicarboxylic acid diester compound to the compound represented by the formula (IV) is 1.2-2.0: 1, preferably 1.3-1.6: 1; the mass ratio of the alcohol ROH to the compound represented by the formula (IV) is 1.2-1.8: 1, preferably 1.3-1.5: 1;
the lower alcohol is methanol or ethanol, and the mixed solvent of the lower alcohol and water is a methanol-water mixed solution with a volume ratio of 1-5: 1 or an ethanol-water mixed solution with a volume ratio of 1-4: 1, preferably a methanol-water mixed solution with a volume ratio of 1-3: 1; the ratio of the amount of the base B to the amount of the compound represented by the formula (V) is 2.5 to 5.0:1, preferably 3.0 to 4.0: 1.
6. The process for preparing an L-tyrosine derivative according to claim 1, wherein in step 3), the solvent D is tetrahydrofuran, dioxane or acetone, preferably tetrahydrofuran; the mass ratio of sodium carbonate to the compound of formula (VI) is 1.1-2.5: 1, preferably 1.3-2.0: 1; the ratio of the amount of the 9-fluorenylmethyl-N-succinimidyl carbonate to the amount of the compound represented by the formula (VI) is 1.0 to 1.3:1, preferably 1.05 to 1.20: 1.
7. The process of claim 1, wherein in step 2), the halogenated hydrocarbon solvent is dichloromethane.
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