CN117886819A - Synthesis method of L-5-methyltetrahydrofolate and calcium salt thereof - Google Patents
Synthesis method of L-5-methyltetrahydrofolate and calcium salt thereof Download PDFInfo
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- CN117886819A CN117886819A CN202311851308.2A CN202311851308A CN117886819A CN 117886819 A CN117886819 A CN 117886819A CN 202311851308 A CN202311851308 A CN 202311851308A CN 117886819 A CN117886819 A CN 117886819A
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- methyltetrahydrofolate
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- ZNOVTXRBGFNYRX-STQMWFEESA-N (6S)-5-methyltetrahydrofolic acid Chemical compound C([C@@H]1N(C=2C(=O)N=C(N)NC=2NC1)C)NC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 ZNOVTXRBGFNYRX-STQMWFEESA-N 0.000 title claims abstract description 23
- 238000001308 synthesis method Methods 0.000 title claims abstract description 17
- 159000000007 calcium salts Chemical class 0.000 title claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 44
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 claims abstract description 38
- 238000000034 method Methods 0.000 claims abstract description 32
- 238000006722 reduction reaction Methods 0.000 claims abstract description 22
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 claims abstract description 21
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000003054 catalyst Substances 0.000 claims abstract description 20
- 235000019152 folic acid Nutrition 0.000 claims abstract description 20
- 239000011724 folic acid Substances 0.000 claims abstract description 20
- 229960000304 folic acid Drugs 0.000 claims abstract description 20
- 239000005460 tetrahydrofolate Substances 0.000 claims abstract description 17
- -1 4-methoxy-3, 5-xylyl Chemical group 0.000 claims abstract description 14
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 11
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims abstract description 11
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000003446 ligand Substances 0.000 claims abstract description 11
- FVZVCSNXTFCBQU-UHFFFAOYSA-N phosphanyl Chemical group [PH2] FVZVCSNXTFCBQU-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000006268 reductive amination reaction Methods 0.000 claims abstract description 10
- 230000009467 reduction Effects 0.000 claims abstract description 9
- MSTNYGQPCMXVAQ-RYUDHWBXSA-N (6S)-5,6,7,8-tetrahydrofolic acid Chemical compound C([C@H]1CNC=2N=C(NC(=O)C=2N1)N)NC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 MSTNYGQPCMXVAQ-RYUDHWBXSA-N 0.000 claims abstract description 8
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 8
- LEIDUYDLUJULKN-UHFFFAOYSA-L diiodoruthenium;1-methyl-4-propan-2-ylbenzene Chemical class I[Ru]I.CC(C)C1=CC=C(C)C=C1 LEIDUYDLUJULKN-UHFFFAOYSA-L 0.000 claims abstract description 8
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 20
- JMNIIIQOMSQWJN-ZEXVLMPOSA-L calcium;(2s)-2-[[4-[[(6s)-2-amino-5-methyl-4-oxo-1,6,7,8-tetrahydropteridin-6-yl]methylamino]benzoyl]amino]-5-hydroxy-5-oxopentanoate Chemical compound [Ca+2].C([C@@H]1N(C=2C(=O)NC(N)=NC=2NC1)C)NC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C(O)=O)C=C1.C([C@@H]1N(C=2C(=O)NC(N)=NC=2NC1)C)NC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C(O)=O)C=C1 JMNIIIQOMSQWJN-ZEXVLMPOSA-L 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- 239000011578 levomefolic acid Substances 0.000 claims description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 238000002425 crystallisation Methods 0.000 claims description 10
- 230000008025 crystallization Effects 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 239000012279 sodium borohydride Substances 0.000 claims description 10
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 10
- 230000002194 synthesizing effect Effects 0.000 claims description 10
- 230000001276 controlling effect Effects 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 239000002994 raw material Substances 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- JYZQJYHHWAITJQ-UHFFFAOYSA-N 1-methyl-4-propan-2-ylbenzene;ruthenium(2+) Chemical class [Ru+2].CC(C)C1=CC=C(C)C=C1 JYZQJYHHWAITJQ-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 238000004321 preservation Methods 0.000 claims description 4
- 230000001105 regulatory effect Effects 0.000 claims description 4
- 239000003381 stabilizer Substances 0.000 claims description 4
- 230000009471 action Effects 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 239000008098 formaldehyde solution Substances 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 238000009776 industrial production Methods 0.000 abstract description 7
- 239000013078 crystal Substances 0.000 abstract description 4
- 229940105150 5-methyltetrahydrofolic acid Drugs 0.000 abstract description 2
- 239000007858 starting material Substances 0.000 abstract description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 abstract 1
- 229910052791 calcium Inorganic materials 0.000 abstract 1
- 239000011575 calcium Substances 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 21
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 18
- 239000007787 solid Substances 0.000 description 18
- 238000005984 hydrogenation reaction Methods 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 239000000047 product Substances 0.000 description 10
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 9
- 229930003268 Vitamin C Natural products 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 9
- 238000010438 heat treatment Methods 0.000 description 9
- 239000008213 purified water Substances 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 235000019154 vitamin C Nutrition 0.000 description 9
- 239000011718 vitamin C Substances 0.000 description 9
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 6
- 239000012295 chemical reaction liquid Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000011259 mixed solution Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 238000006467 substitution reaction Methods 0.000 description 6
- 238000001291 vacuum drying Methods 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 238000005303 weighing Methods 0.000 description 5
- MSTNYGQPCMXVAQ-KIYNQFGBSA-N 5,6,7,8-tetrahydrofolic acid Chemical compound N1C=2C(=O)NC(N)=NC=2NCC1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 MSTNYGQPCMXVAQ-KIYNQFGBSA-N 0.000 description 4
- 239000012046 mixed solvent Substances 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 239000003638 chemical reducing agent Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000006184 cosolvent Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- AINBZKYUNWUTRE-UHFFFAOYSA-N ethanol;propan-2-ol Chemical compound CCO.CC(C)O AINBZKYUNWUTRE-UHFFFAOYSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- ZNOVTXRBGFNYRX-ABLWVSNPSA-N levomefolic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 ZNOVTXRBGFNYRX-ABLWVSNPSA-N 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 238000007789 sealing Methods 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- MOFFALDWBPYETF-UHFFFAOYSA-N [Ru+2].IC=1C(=C(C=CC1C)C(C)C)I Chemical class [Ru+2].IC=1C(=C(C=CC1C)C(C)C)I MOFFALDWBPYETF-UHFFFAOYSA-N 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 235000005934 calcium-L-methylfolate Nutrition 0.000 description 2
- 239000011681 calcium-L-methylfolate Substances 0.000 description 2
- VWBBRFHSPXRJQD-ZEDZUCNESA-L calcium-L-methylfolate Chemical compound [Ca+2].C1NC=2NC(N)=NC(=O)C=2N(C)C1CNC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 VWBBRFHSPXRJQD-ZEDZUCNESA-L 0.000 description 2
- JMNIIIQOMSQWJN-ACGFUFEJSA-L calcium;(4s)-4-[[4-[(2-amino-5-methyl-4-oxo-1,6,7,8-tetrahydropteridin-6-yl)methylamino]benzoyl]amino]-5-hydroxy-5-oxopentanoate Chemical compound [Ca+2].C1NC=2N=C(N)NC(=O)C=2N(C)C1CNC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C(O)=O)C=C1.C1NC=2N=C(N)NC(=O)C=2N(C)C1CNC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C(O)=O)C=C1 JMNIIIQOMSQWJN-ACGFUFEJSA-L 0.000 description 2
- VURFVHCLMJOLKN-UHFFFAOYSA-N diphosphane Chemical compound PP VURFVHCLMJOLKN-UHFFFAOYSA-N 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229960000485 methotrexate Drugs 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000003586 protic polar solvent Substances 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- 239000010948 rhodium Substances 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 230000000707 stereoselective effect Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- ZHKQAQKGVKBJPP-YUZLPWPTSA-N (2s)-2-[[4-[(2-amino-4-oxo-5,6,7,8-tetrahydro-1h-pteridin-6-yl)methyl-methylamino]benzoyl]amino]pentanedioic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2NC1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 ZHKQAQKGVKBJPP-YUZLPWPTSA-N 0.000 description 1
- BGJXXVMOQCHQBO-ZEDZUCNESA-N (2s)-2-[[4-[(2-amino-5-methyl-4-oxo-1,6,7,8-tetrahydropteridin-6-yl)methylamino]benzoyl]amino]pentanedioic acid;calcium Chemical compound [Ca].C1NC=2N=C(N)NC(=O)C=2N(C)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 BGJXXVMOQCHQBO-ZEDZUCNESA-N 0.000 description 1
- BOEUHAUGJSOEDZ-UHFFFAOYSA-N 2-amino-5,6,7,8-tetrahydro-1h-pteridin-4-one Chemical compound N1CCNC2=C1C(=O)N=C(N)N2 BOEUHAUGJSOEDZ-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 206010002065 Anaemia megaloblastic Diseases 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 208000000682 Megaloblastic Anemia Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000000729 antidote Substances 0.000 description 1
- 229940075522 antidotes Drugs 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 230000002457 bidirectional effect Effects 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000004052 folic acid antagonist Substances 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 235000007635 levomefolic acid Nutrition 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 231100001016 megaloblastic anemia Toxicity 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 201000010193 neural tube defect Diseases 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- 229960005055 sodium ascorbate Drugs 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical group [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- 208000035581 susceptibility to neural tube defects Diseases 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 208000002670 vitamin B12 deficiency Diseases 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The application specifically discloses a synthesis method of L-5-methyltetrahydrofolate and a calcium salt thereof, wherein folic acid is used as a starting material, and catalyst diiodide (p-cymene) ruthenium (II) dimer and chiral ligand (rp, rp) -1, 1-bis [ bis (4-methoxy-3, 5-xylyl) phosphino ] -2, 2-bis [ (R) -alpha- (dimethylamino) benzyl ] ferrocene are adopted to carry out asymmetric hydrogenation reduction, so that high stereoselectivity synthesis of 6S-tetrahydrofolate is realized. The 6S-tetrahydrofolic acid is subjected to reductive amination and salification in sequence, and the 6S-5-methyltetrahydrofolic acid calcium with high purity and stable crystal form can be obtained in high yield. The method has the advantages of simple and convenient reaction operation, short steps, high efficiency, low cost and high safety coefficient, and is suitable for industrial production.
Description
Technical Field
The application relates to the technical field of organic synthesis, in particular to a synthesis method of L-5-methyltetrahydrofolate and calcium salt thereof.
Background
L-5-methyltetrahydrofolate (also known as 6S-5-methyltetrahydrofolate), chemical name N- [4- [ [ (2-amino-1, 4,5,6,7, 8-hexahydro-4-oxo-5-methyl-6-pteridinyl) methyl ] amino ] benzoyl ] -L-glutamic acid, is the only drug in folic acid drugs that can permeate the blood brain barrier. The medicine has the following effects as a medicine: first, preventing and treating Alzheimer's disease; second, they are useful as antidotes for enhancing the compatibility of folic acid antagonists, particularly for enhancing the compatibility of methotrexate and methotrexate for the treatment of cancer; third, can be used to enhance the therapeutic effect of fluorinated pyrimidines; fourth, it can be used to reduce toxicity of dideoxytetrahydrofolate (dideazatetrahydrofolates) in chemotherapy; fifth, it can be used for treating autoimmune diseases such as psoriasis and rheumatoid arthritis. Sixth, administration of L-5-methyltetrahydrofolate also avoids the significant risk of vitamin B12 deficiency masking caused by folic acid alone. Meanwhile, the L-5-methyltetrahydrofolate calcium is also used for preventing fetal neural tube defects, arteriosclerosis, treating megaloblastic anemia and the like. At present, the L-5-methyltetrahydrofolate calcium is approved by the national Wei Jian Committee to be used as a new variety of food nutrition enhancers, has incomparable superiority of other folic acid medicines, and has very wide application and market prospect in the medical field.
At present, the synthesis method of L-5-methyltetrahydrofolate and calcium salt thereof has been reported. For example, chinese patent publication No. CN114957257a discloses a method for preparing calcium 5-methyltetrahydrofolate. In the synthetic line, folic acid is used as a raw material, sodium borohydride is used as a reducing agent, and a reduced product tetrahydrofolic acid is obtained; the tetrahydrofolic acid undergoes methylation reaction to obtain 5-methyltetrahydrofolic acid; and then the 5-methyltetrahydrofolate is subjected to acid dissolution refining treatment and then is mixed with calcium salt to generate the 5-methyltetrahydrofolate calcium.
The synthesis route still has the disadvantage of not being neglected: firstly, excessive sodium borohydride reducing agent is needed to be used, a large amount of hydrogen is generated in the post-treatment process, and potential safety hazards exist in industrial production; second, the product of the chemical reduction process is a mixture of two configurations (D/L) -tetrahydrofolate, and although the target configuration with purer optical purity can be obtained by chiral resolution, chiral resolution results in at least 50% of material being wasted and serious losses.
Disclosure of Invention
In order to solve the defects of the synthetic route of the L-5-methyltetrahydrofolate and the calcium salt thereof, the application provides a synthetic method of the L-5-methyltetrahydrofolate and the calcium salt thereof, so that the synthetic route of the L-5-methyltetrahydrofolate and the calcium salt thereof is short, simple and safe to operate, suitable for industrial production, high in yield and purity of the final product and stable in crystal form of the product.
In a first aspect, the application provides a synthesis method of L-5-methyltetrahydrofolate, which adopts the following technical scheme:
A synthesis method of L-5-methyltetrahydrofolate comprises the following steps:
Folic acid is used as a raw material, and is subjected to asymmetric hydrogenation reduction under the action of a catalyst diiodide (p-cymene) ruthenium (II) dimer and chiral ligand (rp, rp) -1, 1-bis [ bis (4-methoxy-3, 5-xylyl) phosphino ] -2, 2-bis [ (R) -alpha- (dimethylamino) benzyl ] ferrocene to generate 6S-tetrahydrofolic acid.
Furthermore, in the asymmetric hydrogenation reduction reaction, based on folic acid, the dosage of the catalyst diiodide (p-cymene) ruthenium (II) dimer is 0.2 to 0.4 per mill equivalent.
Furthermore, the dosage of the catalyst diiodide (p-cymene) ruthenium (II) dimer in the asymmetric hydrogenation reduction reaction is 0.2 per mill equivalent based on folic acid.
Further, the molar ratio of the catalyst diiodium (p-cymene) ruthenium (II) dimer to chiral ligand (rp, rp) -1, 1-bis [ bis (4-methoxy-3, 5-xylyl) phosphino ] -2, 2-bis [ (R) -alpha- (dimethylamino) benzyl ] ferrocene in the asymmetric hydrogenation reduction reaction is 1 (1.7-2.2).
Further, the molar ratio of the catalyst diiodide (p-cymene) ruthenium (II) dimer to the chiral ligand (rp, rp) -1, 1-bis [ bis (4-methoxy-3, 5-xylyl) phosphino ] -2, 2-bis [ (R) -alpha- (dimethylamino) benzyl ] ferrocene in the asymmetric hydrogenation reduction reaction is 1:2.
Further, the solvent used in the asymmetric hydrogenation reduction reaction is a mixed solvent system of an alcohol proton solvent and water (volume ratio is 1:1).
Still further, the alcoholic protic solvent satisfies at least one of the following characteristics: methanol, ethanol, isopropanol and t-butanol.
More preferably, the alcoholic protic solvent is methanol.
Further, an alkali cosolvent is added into the solvent.
Still further, the base co-solvent satisfies at least one of the following characteristics: sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, and sodium tert-butoxide.
More preferably, the base co-solvent is a 30wt% strength sodium hydroxide solution.
Further, the hydrogen pressure in the asymmetric hydrogenation reduction reaction is 0.05-0.4 MPa.
Further, the hydrogen pressure in the asymmetric hydrogenation reduction reaction is 0.1-0.2 MPa.
Further, the reaction temperature in the asymmetric hydrogenation reduction is 20-40 ℃.
Further, the asymmetric hydrogenation reduction reaction temperature is 40-45 ℃.
Further, the reaction time in the asymmetric hydrogenation reduction is 2.0-4.0 h.
Further, the reaction time in the asymmetric hydrogenation reduction was 3.0h.
In a second aspect, the application provides a method for synthesizing L-5-methyltetrahydrofolate calcium, which adopts the following technical scheme:
a synthesis method of L-5-methyltetrahydrofolate calcium comprises the following steps:
The 6S-tetrahydrofolic acid prepared by the synthesis method of the L-5-methyltetrahydrofolic acid is used as a raw material, and the L-5-methyltetrahydrofolic acid calcium is obtained through the steps of reductive amination and salification.
Further, the specific operation of the reductive amination step is as follows:
Adding formaldehyde solution into a 6S-tetrahydrofolate reaction system, controlling the reaction temperature to be 0-30 ℃, and carrying out heat preservation reaction for 0.5-2.0 h; adding sodium borohydride into a 6S-tetrahydrofolate reaction system, controlling the reaction temperature to be 60-80 ℃, carrying out heat preservation reaction for 1.0-3.0 h, adding a stabilizer, adjusting the pH value to be 4.0-4.5, and crystallizing to obtain 6S-5-methyltetrahydrofolate;
Wherein, the dosage of formaldehyde is 1.2 to 1.5 equivalents and the dosage of sodium borohydride is 2.0 to 4.0 equivalents based on 6S-tetrahydrofolate.
Further, the amount of formaldehyde used in the reductive amination step was 1.3 equivalents.
Still further, the amount of sodium borohydride used in the reductive amination step was 3.0 equivalents.
Further, the stabilizer is sodium ascorbate.
Further, the specific operation of the salifying step is as follows:
Adding soluble calcium salt into a 6S-5-methyltetrahydrofolate reaction system and adjusting the system to be dissolved, controlling the crystallization temperature to be 60-90 ℃, adding a poor solvent, and crystallizing to obtain the L-5-methyltetrahydrofolate calcium.
Further, the amount of calcium chloride used in the salification step was 4 equivalents.
Further, the poor solvent in the salifying step satisfies at least one of the following characteristics: methanol, ethanol, isopropanol, acetonitrile and tetrahydrofuran.
Further, the poor solvent in the salifying step is ethanol: isopropanol=4: 1.
The application has at least the following beneficial effects:
Firstly, the application provides a novel method for synthesizing 6S-tetrahydrofolate efficiently and conveniently, solves the problems of impurity introduction, material loss and low yield caused by subsequent resolution, and develops a novel method for obtaining high-purity and stable crystal form L-5-methyltetrahydrofolate calcium with high yield by a strategy of temperature control and bidirectional regulation of a crystallization mode in a crystallization process.
Secondly, the raw materials used in the preparation method are easy to obtain, and meanwhile, the method is mild in reaction condition, suitable for large-scale industrial production, high in safety and low in cost.
Thirdly, the disclosed experimental method is simple, the process is advanced, the three wastes generated in the production process are less, the environment-friendly pressure is low, the yield is high, the product purity is high, and the method is suitable for industrial production.
Drawings
FIG. 1 shows the XRD pattern of calcium L-5-methyltetrahydrofolate obtained in example 1 of the present application.
Detailed Description
Catalytic hydrogenation is a common method used early to reduce folic acid to tetrahydrofolate. However, the method uses noble metal as a catalyst, has high price, high reaction activation energy and harsh reaction conditions, and meanwhile, the product also needs chiral resolution, so that the application of the method is greatly limited.
In view of the above, the asymmetric reduction method has been developed in recent years as a new method for efficiently constructing chemical bonds such as saturated carbon-carbon bonds and carbon-nitrogen bonds. The chinese patent with publication No. CN113603691a discloses an asymmetric hydrogenation catalytic mode of folic acid, and this synthetic route uses folic acid as raw material, and reduces to generate (6S) -tetrahydrofolic acid under the action of Rh procatalyst and diphosphine ligand system, and the yield of (6S) -tetrahydrofolic acid is 90.0%. Also, this patent discloses a synthetic route for 6S-5-methyltetrahydrofolate, in which (6S) -5, 10-methyltetrahydrofolate is first cyclized under the catalysis of trifluoroacetic acid and then ring-opened to give 6S-5-methyltetrahydrofolate. The catalytic system of the patent has relatively poor stereoselectivity, the diastereoisomer excess value is more than 86 percent, and the chiral resolution is still needed to assist in purifying the target configuration. Meanwhile, the method has complex whole process and multiple steps, and is not beneficial to industrial production.
Chinese patent publication No. CN1781919a discloses a process for preparing optically pure tetrahydropterin and its derivatives, especially optically pure tetrahydrofolate and its derivatives, by stereospecific hydrogenation, in which various ruthenium, rhodium etc. metal complex catalysts and various chiral ligands are disclosed, and examples are given to demonstrate that different catalysts and chiral ligand combinations differ in final yields and purities of the products in asymmetric catalytic hydrogenation reactions. In addition, for the synthesis of the tetrahydrofolic acid with the target configuration, corresponding folic acid ester or folic acid ester salt is synthesized from folic acid, and then the tetrahydrofolic acid with the corresponding configuration is obtained by hydrolysis after asymmetric catalytic hydrogenation, so that the reaction steps are increased, and the risk of generating benzenesulfonate gene toxic impurities is increased.
Based on the above circumstances, the present inventors developed a novel synthesis method of L-5-methyltetrahydrofolate and its calcium salt, using folic acid as a starting material, and adopting catalyst diiodium (p-cymene) ruthenium (II) dimer and chiral ligand (rp, rp) -1, 1-bis [ bis (4-methoxy-3, 5-xylyl) phosphino ] -2, 2-bis [ (R) -alpha- (dimethylamino) benzyl ] ferrocene to perform asymmetric hydrogenation reduction, thereby realizing high stereoselective synthesis of 6S-tetrahydrofolate. In addition, the system has high catalytic efficiency and low cost, and avoids material waste caused by chiral resolution. The crystallization conditions are controlled from two dimensions of crystallization temperature and crystallization mode, and the obtained product has stable crystal form and high purity. In addition, in the synthesis method, the 6S-tetrahydrofolate is reduced into the 6S-5-methyltetrahydrofolate in one step, and cyclization and ring opening are not needed. Meanwhile, the high-purity L-5-methyltetrahydrofolate calcium can be obtained without refining the 6S-5-methyltetrahydrofolate in the synthesis method. The method has the advantages of simple and convenient reaction operation, short steps, high efficiency, low cost and high safety coefficient, and is suitable for industrial production.
In order to make the objects, technical solutions and advantages of the present application more apparent, the technical solutions of the present application will be further described below with reference to examples.
Examples
Example 1
The synthesis method of the L-5-methyltetrahydrofolate and the calcium salt thereof comprises the following steps:
Asymmetric catalytic hydrogenation: adding 2L of purified water and 1kg of folic acid into a 5L hydrogenation kettle, stirring, and adding 182g of 30% aqueous solution of sodium hydroxide into the reaction kettle to dissolve the system; sealing the kettle, replacing air in the reaction kettle with nitrogen for three times, continuously introducing nitrogen until the pressure in the kettle reaches 0.3MPa, maintaining the pressure, heating the feed liquid to 45 ℃, and stirring for 10min; weighing 0.96g of (rp, rp) -1, 1-bis [ bis (4-methoxy-3, 5-xylyl) phosphino ] -2, 2-bis [ (R) -alpha- (dimethylamino) benzyl ] ferrocene and 0.44g of diiodo (p-cymene) ruthenium (II) dimer, and dissolving the mixture with a proper amount of absolute ethyl alcohol to prepare a catalyst mixed solution; adding the prepared catalyst mixed solution into a hydrogenation kettle, carrying out nitrogen substitution for 3 times, and carrying out hydrogen substitution for 3 times; introducing hydrogen into the hydrogenation kettle, controlling the temperature in the kettle to be 45 ℃, maintaining the pressure to be 0.2MPa, and carrying out hydrogenation reaction for 3 hours until the reaction is complete; the reaction kettle is depressurized, the kettle is opened after 3 times of replacement by nitrogen, the reaction liquid is poured out, 4.0g of vitamin C is added, 2M hydrochloric acid is used for adjusting the pH value of the feed liquid to be 2.0-3.0, the mixture is centrifuged, and the solid is collected to be the 6S-tetrahydrofolate, and the next reaction is directly carried out without drying.
Reductive amination: adding 3L of purified water and the wet solid obtained in the first embodiment into a 5L three-port bottle, cooling to 10 ℃, dropwise adding 30% sodium hydroxide aqueous solution to dissolve the system, adding 1.3 equivalent of 37wt% formaldehyde aqueous solution, and after adding, keeping the temperature at 10 ℃ and stirring for reaction for 1h; slowly adding 3 equivalents of sodium borohydride into the system, heating to 60 ℃ after adding, and preserving heat for 2.0h; after the reaction is finished, 4.0g of vitamin C is added into the system, the pH=4.0-4.5 is regulated by using 2M hydrochloric acid, the temperature is kept for crystallization for 2 hours, the pressure is reduced, the suction filtration is carried out, the solid is collected, the vacuum drying is carried out, the yellowish green powdery solid is obtained, the weight is 890.0g, and the yield is: 85.50% (overall two-step yield).
1H NMR(DMSO-d6,300MHz)：δ2.040-2.055,m,1H;2.072-2.098,m,1H;2.320-2.350,m,2H;2.504-2.513,s,3H;2.787-2.825,m,1H;2.862-2.900,m,1H;2.936-2.948,m,1H;3.150-3.216,m,2H;4.333-4.377,m,1H;5.936,s,2H;6.067,s,1H;6.500,s,1H;7.656-7.673,d,2H;8.108-8.123,d,2H;9.965,s,1H;12.389,s,1H;13C NMR(DMSO-d6,100MHz)δ26.055,30.483,35.476,42.681,43.469,51.763,55.185,99.508,110.753,120.459,129.027,151.190,151.388,153.041,158.789,166.455,173.869,173.985;MS(m/z,M+H+)＝460.19.
Salt formation: adding 300.0g of dried 6S-5-methyltetrahydrofolate, 3L of purified water and 1.15g of vitamin C into a 10L three-mouth bottle, dropwise adding 30% sodium hydroxide solution at room temperature until the system is dissolved, dropwise adding 725mL of water solution of 362.3gCaCl 2 into the reaction liquid, heating to 60 ℃ after the addition, slowly dropwise adding 3L of ethanol-isopropanol (volume ratio=4:1) to obtain a mixed solvent, stirring and crystallizing for 2h after the addition, decompressing and filtering, collecting solid, and vacuum drying to obtain white powdery solid, namely the target product L-5-methyltetrahydrofolate calcium, and weighing 243.7g, wherein the yield: 75.0%.
1H NMR(D2O,300MHz)：δ2.027-2.057,m,1H;2.126-2.195,m,1H;2.273-2.342,m,2H;2.529,s,3H;2.941-2.982,m,1H;3.052-3.131,m,1H;3.222-3.251,m,1H;3.451-3.483,m,1H;4.303-4.330,m,1H;6.795-6.812,d,2H;7.685-7.703,d,2H;13C NMR(DMSO-d6,100MHz)δ28.607,34.377,35.742,42.648,43.417,55.025,55.916,102.469,112.897,121.588,129.090,152.015,153.731,159.259,169.908,170.708,179.350,182.449;MS(m/z,M-H-)＝458.18.
Referring to FIG. 1, the XRD pattern of calcium L-5-methyltetrahydrofolate can be seen to be in a stable crystalline form.
Example 2
The synthesis method of the L-5-methyltetrahydrofolate and the calcium salt thereof comprises the following steps:
asymmetric catalytic hydrogenation: adding 2L of purified water and 1kg of folic acid into a 5L hydrogenation kettle, stirring, and adding 182g of 30% aqueous solution of sodium hydroxide into the reaction kettle to dissolve the system; sealing the kettle, replacing air in the reaction kettle with nitrogen for three times, continuously introducing nitrogen until the pressure in the kettle reaches 0.2MPa, maintaining the pressure, heating the feed liquid to 40 ℃, and stirring for 5min; weighing 1.44g of (rp, rp) -1, 1-bis [ bis (4-methoxy-3, 5-xylyl) phosphino ] -2, 2-bis [ (R) -alpha- (dimethylamino) benzyl ] ferrocene and 0.4g of diiodide (p-cymene) ruthenium (II) dimer, and dissolving the mixture with a proper amount of absolute ethyl alcohol to prepare a catalyst mixed solution; adding the prepared catalyst mixed solution into a hydrogenation kettle, carrying out nitrogen substitution for 3 times, and carrying out hydrogen substitution for 3 times; introducing hydrogen into the hydrogenation kettle, controlling the temperature in the kettle to be 40 ℃, maintaining the pressure to be 0.2MPa, and carrying out hydrogenation reaction for 2.5 hours until the reaction is complete; the reaction kettle is depressurized, the kettle is opened after 3 times of replacement by nitrogen, the reaction liquid is poured out, 4.0g of vitamin C is added, 2M hydrochloric acid is used for adjusting the pH value of the feed liquid to be 2.0-3.0, the mixture is centrifuged, and the solid is collected to be the 6S-tetrahydrofolate, and the next reaction is directly carried out without drying.
Reductive amination: adding 3L of purified water and the wet solid obtained in the first embodiment into a 5L three-port bottle, cooling to 5 ℃, dropwise adding 30% sodium hydroxide aqueous solution to dissolve the system, adding 1.2 equivalent of 37% formaldehyde aqueous solution, and after adding, keeping the temperature at 5 ℃ and stirring for reaction for 1h; slowly adding 2 equivalents of sodium borohydride into the system, heating to 70 ℃ after adding, and preserving heat for reaction for 3.0h; after the reaction is finished, 4.0g of vitamin C is added into the system, the pH=4.0-4.5 is regulated by 2M hydrochloric acid, the temperature is kept for crystallization for 2 hours, the pressure is reduced, the suction filtration is carried out, the solid is collected, the vacuum drying is carried out, the yellowish green powdery solid is obtained, the weight is 873.2g, and the yield is: 83.89% (overall two-step yield).
Salt formation: adding 300.0g of dried 6S-5-methyltetrahydrofolate, 3L of purified water and 1.15g of vitamin C into a 10L three-mouth bottle, dropwise adding 30% sodium hydroxide solution at room temperature until the system is dissolved, dropwise adding 725mL of water solution of 362.3gCaCl 2 into the reaction liquid, heating to 75 ℃ after the addition, slowly dropwise adding 3L of ethanol-isopropanol (volume ratio=4:1) to obtain a mixed solvent, stirring and crystallizing for 2h after the addition, decompressing and filtering, collecting solid, and vacuum drying to obtain white powdery solid, namely the target product L-5-methyltetrahydrofolate calcium, weighing 221.4g, and obtaining the yield: 68.13%.
Example 3
The synthesis method of the L-5-methyltetrahydrofolate and the calcium salt thereof comprises the following steps:
Asymmetric catalytic hydrogenation: adding 2L of purified water and 1kg of folic acid into a 5L hydrogenation kettle, stirring, and adding 182g of 30% aqueous solution of sodium hydroxide into the reaction kettle to dissolve the system; sealing the kettle, replacing air in the reaction kettle with nitrogen for three times, continuously introducing nitrogen until the pressure in the kettle reaches 0.4MPa, maintaining the pressure, heating the feed liquid to 45 ℃, and stirring for 10min; 1.92g of (rp, rp) -1, 1-bis [ bis (4-methoxy-3, 5-xylyl) phosphino ] -2, 2-bis [ (R) -alpha- (dimethylamino) benzyl ] ferrocene and 0.52g of diiodo (p-cymene) ruthenium (II) dimer are weighed, and dissolved in a proper amount of absolute ethyl alcohol to prepare a catalyst mixed solution; adding the prepared catalyst mixed solution into a hydrogenation kettle, carrying out nitrogen substitution for 3 times, and carrying out hydrogen substitution for 3 times; introducing hydrogen into the hydrogenation kettle, controlling the temperature in the kettle to be 45 ℃, maintaining the pressure to be 0.2MPa, and carrying out hydrogenation reaction for 3 hours until the reaction is complete; the reaction kettle is depressurized, the kettle is opened after 3 times of replacement by nitrogen, the reaction liquid is poured out, 4.0g of vitamin C is added, 2M hydrochloric acid is used for adjusting the pH value of the feed liquid to be 2.0-3.0, the mixture is centrifuged, and the solid is collected to be the 6S-tetrahydrofolate, and the next reaction is directly carried out without drying.
Reductive amination: adding 3L of purified water and the wet solid obtained in the first embodiment into a 5L three-port bottle, cooling to 0 ℃, dropwise adding 30% sodium hydroxide aqueous solution to dissolve the system, adding 1.5 equivalent of 37% formaldehyde aqueous solution, and after adding, keeping the temperature at 0 ℃ and stirring for reaction for 3 hours; slowly adding 4 equivalents of sodium borohydride into the system, heating to 80 ℃ after adding, and preserving heat for reaction for 3.0h; after the reaction is finished, 4.0g of vitamin C is added into the system, the pH=4.0-4.5 is regulated by 2M hydrochloric acid, the temperature is kept for crystallization for 2 hours, the pressure is reduced, the suction filtration is carried out, the solid is collected, the vacuum drying is carried out, the yellowish green powdery solid is obtained, the weight is 894.7g, and the yield is: 85.95% (overall two-step yield).
Salt formation: adding 300.0g of dried 6S-5-methyltetrahydrofolate, 3L of purified water and 1.15g of vitamin C into a 10L three-mouth bottle, dropwise adding 30% sodium hydroxide solution at room temperature until the system is dissolved, dropwise adding 725mL of water solution of 362.3gCaCl 2 into the reaction liquid, heating to 80 ℃ after the addition, slowly dropwise adding 3L of ethanol-isopropanol (volume ratio=4:1) to obtain a mixed solvent, stirring and crystallizing for 2h after the addition, decompressing and filtering, collecting solid, and vacuum drying to obtain white powdery solid, namely the target product L-5-methyltetrahydrofolate calcium, weighing 237.5g, and obtaining the yield: 73.10%.
The technical features of the above-described embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above-described embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.
Moreover, the foregoing examples are illustrative of only a few embodiments of the invention, and are not intended to limit the scope of the invention in any way. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.
Claims (10)
1. The synthesis method of the L-5-methyltetrahydrofolate is characterized by comprising the following steps of: folic acid is used as a raw material, and is subjected to asymmetric hydrogenation reduction under the action of a catalyst diiodide (p-cymene) ruthenium (II) dimer and chiral ligand (rp, rp) -1, 1-bis [ bis (4-methoxy-3, 5-xylyl) phosphino ] -2, 2-bis [ (R) -alpha- (dimethylamino) benzyl ] ferrocene to generate 6S-tetrahydrofolic acid.
2. The method for synthesizing L-5-methyltetrahydrofolate according to claim 1, wherein: in the asymmetric hydrogenation reduction reaction, folic acid is used as a reference, and the dosage of the catalyst diiodide (p-cymene) ruthenium (II) dimer is 0.2-0.4 per mill equivalent.
3. The method for synthesizing L-5-methyltetrahydrofolate according to claim 1, wherein: the molar ratio of the catalyst diiodium (p-cymene) ruthenium (II) dimer to chiral ligand (rp, rp) -1, 1-bis [ bis (4-methoxy-3, 5-xylyl) phosphino ] -2, 2-bis [ (R) -alpha- (dimethylamino) benzyl ] ferrocene in the asymmetric hydrogenation reduction reaction is 1 (1.7-2.2).
4. A process for the synthesis of L-5-methyltetrahydrofolate according to claim 3, wherein: the molar ratio of the catalyst diiodium (p-cymene) ruthenium (II) dimer to the chiral ligand (rp, rp) -1, 1-bis [ bis (4-methoxy-3, 5-xylyl) phosphino ] -2, 2-bis [ (R) -alpha- (dimethylamino) benzyl ] ferrocene in the asymmetric hydrogenation reduction reaction is 1:2.
5. The method for synthesizing L-5-methyltetrahydrofolate according to claim 1, wherein: the reaction time in the asymmetric hydrogenation reduction is 2.0-4.0 h.
6. The method for synthesizing L-5-methyltetrahydrofolate according to claim 1, wherein: the hydrogen pressure in the asymmetric hydrogenation reduction reaction is 0.05-0.4 MPa.
7. A synthesis method of L-5-methyltetrahydrofolate calcium is characterized by comprising the following steps: the method comprises the following steps:
The method for synthesizing L-5-methyltetrahydrofolate according to any one of claims 1-6, wherein the L-5-methyltetrahydrofolate calcium is obtained by taking 6S-tetrahydrofolate as a raw material and performing reductive amination and salification steps.
8. The method for synthesizing the L-5-methyltetrahydrofolate calcium according to claim 7, wherein the method comprises the following steps: the specific operation of the reductive amination step is as follows:
Adding formaldehyde solution into a 6S-tetrahydrofolate reaction system, controlling the reaction temperature to be 0-30 ℃, and carrying out heat preservation reaction for 0.5-2.0 h; adding sodium borohydride into a 6S-tetrahydrofolate reaction system, controlling the reaction temperature to be 60-80 ℃, carrying out heat preservation reaction for 1.0-3.0 h, adding a stabilizer, adjusting the pH value to be 4.0-4.5, and crystallizing to obtain 6S-5-methyltetrahydrofolate;
Wherein, the dosage of formaldehyde is 1.2 to 1.5 equivalents and the dosage of sodium borohydride is 2.0 to 4.0 equivalents based on 6S-tetrahydrofolate.
9. The method for synthesizing the L-5-methyltetrahydrofolate calcium according to claim 7, wherein the method comprises the following steps: the specific operation of the salifying step is as follows:
adding a stabilizer into a 6S-5-methyltetrahydrofolate reaction system, regulating the system to dissolve, adding soluble calcium salt, controlling the crystallization temperature to be 60-90 ℃, adding a poor solvent, and crystallizing to obtain the L-5-methyltetrahydrofolate calcium.
10. The method for synthesizing the L-5-methyltetrahydrofolate calcium according to claim 7, wherein the method comprises the following steps: further, the poor solvent in the salifying step satisfies at least one of the following characteristics: methanol, ethanol, isopropanol, acetonitrile and tetrahydrofuran.
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