CN113666931B - Preparation method of high-purity calcium levofolinate - Google Patents
Preparation method of high-purity calcium levofolinate Download PDFInfo
- Publication number
- CN113666931B CN113666931B CN202111042834.5A CN202111042834A CN113666931B CN 113666931 B CN113666931 B CN 113666931B CN 202111042834 A CN202111042834 A CN 202111042834A CN 113666931 B CN113666931 B CN 113666931B
- Authority
- CN
- China
- Prior art keywords
- calcium
- solid
- levofolinate
- filtering
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 229960001921 calcium levofolinate Drugs 0.000 title claims abstract description 75
- KVUAALJSMIVURS-QNTKWALQSA-L calcium;(2s)-2-[[4-[[(6s)-2-amino-5-formyl-4-oxo-1,6,7,8-tetrahydropteridin-6-yl]methylamino]benzoyl]amino]pentanedioate Chemical compound [Ca+2].C([C@@H]1N(C=O)C=2C(=O)N=C(NC=2NC1)N)NC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 KVUAALJSMIVURS-QNTKWALQSA-L 0.000 title claims abstract description 75
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 239000007787 solid Substances 0.000 claims abstract description 128
- 239000000047 product Substances 0.000 claims abstract description 54
- KVUAALJSMIVURS-ZEDZUCNESA-L calcium folinate Chemical compound [Ca+2].C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 KVUAALJSMIVURS-ZEDZUCNESA-L 0.000 claims abstract description 48
- 235000008207 calcium folinate Nutrition 0.000 claims abstract description 47
- 239000011687 calcium folinate Substances 0.000 claims abstract description 47
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 47
- 238000001914 filtration Methods 0.000 claims abstract description 44
- 229940117803 phenethylamine Drugs 0.000 claims abstract description 23
- 239000000706 filtrate Substances 0.000 claims abstract description 22
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 21
- VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 claims abstract description 17
- 239000001639 calcium acetate Substances 0.000 claims abstract description 17
- 235000011092 calcium acetate Nutrition 0.000 claims abstract description 17
- 229960005147 calcium acetate Drugs 0.000 claims abstract description 17
- 238000001035 drying Methods 0.000 claims abstract description 14
- 238000003756 stirring Methods 0.000 claims abstract description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 48
- 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 description 21
- 235000011054 acetic acid Nutrition 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- 150000007524 organic acids Chemical class 0.000 claims description 14
- 238000002425 crystallisation Methods 0.000 claims description 13
- 230000008025 crystallization Effects 0.000 claims description 13
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 12
- 239000011575 calcium Substances 0.000 claims description 12
- 229910052791 calcium Inorganic materials 0.000 claims description 12
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 12
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 12
- 235000019152 folic acid Nutrition 0.000 claims description 11
- 239000011724 folic acid Substances 0.000 claims description 11
- 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 description 10
- 229960000304 folic acid Drugs 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 8
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 6
- CBOCVOKPQGJKKJ-UHFFFAOYSA-L Calcium formate Chemical compound [Ca+2].[O-]C=O.[O-]C=O CBOCVOKPQGJKKJ-UHFFFAOYSA-L 0.000 claims description 6
- BCZXFFBUYPCTSJ-UHFFFAOYSA-L Calcium propionate Chemical compound [Ca+2].CCC([O-])=O.CCC([O-])=O BCZXFFBUYPCTSJ-UHFFFAOYSA-L 0.000 claims description 6
- 239000004281 calcium formate Substances 0.000 claims description 6
- 235000019255 calcium formate Nutrition 0.000 claims description 6
- 229940044172 calcium formate Drugs 0.000 claims description 6
- 239000004330 calcium propionate Substances 0.000 claims description 6
- 235000010331 calcium propionate Nutrition 0.000 claims description 6
- 235000019253 formic acid Nutrition 0.000 claims description 6
- 235000019260 propionic acid Nutrition 0.000 claims description 6
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 6
- 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 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 4
- 230000001376 precipitating effect Effects 0.000 claims description 3
- 238000007670 refining Methods 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000008213 purified water Substances 0.000 claims description 2
- 239000012535 impurity Substances 0.000 abstract description 43
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 abstract description 16
- 239000003814 drug Substances 0.000 abstract description 6
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 abstract description 3
- 229910001424 calcium ion Inorganic materials 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 238000001228 spectrum Methods 0.000 description 44
- 230000000052 comparative effect Effects 0.000 description 27
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 24
- 238000005406 washing Methods 0.000 description 23
- 238000001816 cooling Methods 0.000 description 17
- 238000010438 heat treatment Methods 0.000 description 17
- 239000012043 crude product Substances 0.000 description 10
- 239000002994 raw material Substances 0.000 description 9
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 7
- 239000001110 calcium chloride Substances 0.000 description 7
- 229910001628 calcium chloride Inorganic materials 0.000 description 7
- 238000004090 dissolution Methods 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- VVIAGPKUTFNRDU-STQMWFEESA-N (6S)-5-formyltetrahydrofolic acid Chemical compound C([C@H]1CNC=2N=C(NC(=O)C=2N1C=O)N)NC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-STQMWFEESA-N 0.000 description 4
- HNXQXTQTPAJEJL-UHFFFAOYSA-N 2-aminopteridin-4-ol Chemical compound C1=CN=C2NC(N)=NC(=O)C2=N1 HNXQXTQTPAJEJL-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical compound CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000003638 chemical reducing agent Substances 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 229940075961 levoleucovorin calcium pentahydrate Drugs 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- GADGMZDHLQLZRI-VIFPVBQESA-N N-(4-aminobenzoyl)-L-glutamic acid Chemical compound NC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 GADGMZDHLQLZRI-VIFPVBQESA-N 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000011672 folinic acid Substances 0.000 description 2
- 229960001691 leucovorin Drugs 0.000 description 2
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 2
- -1 organic acid calcium salt Chemical class 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 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 description 1
- RWYRUDPAALLKPX-UHFFFAOYSA-N 2,2-difluoro-n-methylethanamine;hydrochloride Chemical compound Cl.CNCC(F)F RWYRUDPAALLKPX-UHFFFAOYSA-N 0.000 description 1
- VVIAGPKUTFNRDU-UHFFFAOYSA-N 6S-folinic acid Natural products C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-UHFFFAOYSA-N 0.000 description 1
- 206010002065 Anaemia megaloblastic Diseases 0.000 description 1
- 239000001749 Calcium fumarate Substances 0.000 description 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- MPJKWIXIYCLVCU-UHFFFAOYSA-N Folinic acid Natural products NC1=NC2=C(N(C=O)C(CNc3ccc(cc3)C(=O)NC(CCC(=O)O)CC(=O)O)CN2)C(=O)N1 MPJKWIXIYCLVCU-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 208000000682 Megaloblastic Anemia Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 108010022394 Threonine synthase Proteins 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 235000019296 calcium fumarate Nutrition 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 102000004419 dihydrofolate reductase Human genes 0.000 description 1
- OZRNSSUDZOLUSN-LBPRGKRZSA-N dihydrofolic acid Chemical compound N=1C=2C(=O)NC(N)=NC=2NCC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OZRNSSUDZOLUSN-LBPRGKRZSA-N 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 229940014144 folate Drugs 0.000 description 1
- 235000008191 folinic acid Nutrition 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 231100001016 megaloblastic anemia Toxicity 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000004289 sodium hydrogen sulphite Substances 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000005460 tetrahydrofolate Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D475/00—Heterocyclic compounds containing pteridine ring systems
- C07D475/02—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4
- C07D475/04—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the field of synthesis of chemical bulk drugs, and in particular relates to a preparation method of high-purity calcium levofolinate, which comprises the following steps: s-1, adding calcium folinate and a resolving agent into water, stirring to dissolve the calcium folinate and the resolving agent, and filtering to obtain filtrate; s-2, adding calcium acetate and a resolving agent into the filtrate, crystallizing and filtering to obtain primary resolved solid; s-3, dissolving, crystallizing, filtering and drying the primary resolution solid to obtain a crude calcium levofolinate product; s-4, purifying the crude calcium levofolinate to obtain a calcium levofolinate finished product; the resolving agent is R- (alpha) -phenethylamine. The invention introduces calcium ions in the form of calcium acetate, avoids introducing chloride ions, and has no chloride ion impurity in the finished product. In addition, R- (alpha) -phenethylamine is adopted as a resolving agent and calcium acetate is matched, so that the isomer of the finished product is less than 0.1 percent (less than 0.5 percent specified in pharmacopoeia).
Description
Technical Field
The invention belongs to the field of synthesis of chemical bulk drugs, and particularly relates to a preparation method of high-purity calcium levofolinate.
Background
Calcium levofolinate is a calcium salt of levofolinate, which is a pharmacologically active L-optical isomer of 5-leucovorin (i.e., folinate). Levofolinic acid does not need to be reduced by dihydrofolate reductase to participate in reactions that utilize folate as a source of one carbon unit, and levofolinic acid can pass through the cell membrane either actively or passively. The basic actions of levofolinic acid are the same as those of folic acid, but the effect is better than that of folic acid, because folic acid can be firstly changed into folinic acid in liver and bone marrow to act. The product, namely the calcium levofolinate, is an active form of the levofolinate, has the effect of stimulating the growth and maturation of leucocytes, and can improve megaloblastic anemia.
In addition, calcium levofolinate has also been used in practice in combination with methotrexate or fluorouracil to treat other types of malignancies, often as part of a multi-drug combination therapy regimen.
The calcium folinate is an active optical rotation body of the calcium folinate, and has the advantages of drug effect and safety. In the future, the product gradually replaces calcium folinate to become a new army in the domestic anti-tumor drug market. The market prospect of developing the calcium levofolinate product is very broad.
Regarding the preparation of calcium levofolinate, for example, a preparation method of high-yield calcium levofolinate is disclosed in patent No. CN103113372A, calcium levofolinate is prepared by a resolution process, a solution containing calcium levofolinate is added in the resolution process, and the calcium levofolinate in the calcium levofolinate solution accounts for more than 70% of the total calcium folinate, so that the method not only improves the resolution yield, but also recycles mother liquor generated by the resolution process, and has great significance in industrial production. However, at present, the purity of the levorotatory calcium folinate is difficult to meet the requirement, and the price is several times of that of the calcium folinate; the purity of the raw material medicine directly influences the safety of the medicine, and the price of the medicine is directly related to the production cost and the income, so that whether the medicine can be safely used in a large range is determined. And most of the preparation processes introduce chloride ions, so that the content of the chloride ions in the product cannot meet the standard.
Disclosure of Invention
The invention provides a preparation method of high-purity calcium levofolinate, which has no introduction of chloride ions and the optical purity of 99.95 percent.
The invention adopts the following technical scheme:
a preparation method of high-purity calcium levofolinate comprises the following steps:
s-1, adding calcium folinate and a resolving agent into water, stirring to dissolve the calcium folinate and the resolving agent, and filtering to obtain filtrate;
s-2, adding organic acid calcium and a resolving agent into the filtrate, crystallizing and filtering to obtain primary resolved solid;
s-3, filtering and drying the primary resolution solid to obtain a crude calcium levofolinate product;
s-4, refining the crude calcium levofolinate to obtain a finished product of calcium levofolinate.
The resolving agent is R- (alpha) -phenethylamine.
In the technical scheme, calcium ions are introduced in the form of organic acid calcium, so that the introduction of chloride ions is avoided, and no chloride ion impurity exists in the finished product. In addition, R- (alpha) -phenethylamine is adopted as a resolving agent and is matched with organic acid calcium, so that the isomer of the finished product is less than 0.1 percent (less than 0.5 percent specified in pharmacopoeia). The organic acid calcium salt can be calcium formate, calcium acetate, calcium propionate, etc.
The organic acid calcium is used for replacing calcium chloride, so that the introduction of chloride ions is avoided to cause the pollution of finished product chlorine, the resolution system is more stable, the impurities are reduced, and the optical purity of the obtained calcium levofolinate finished product can reach 99.95 percent by combining with the R- (alpha) -phenethylamine resolving agent.
Preferably, after the primary resolution solid is obtained, dropwise adding acid into the primary resolution solid, adding organic acid calcium and a resolving agent, crystallizing and filtering to obtain a secondary resolution solid; and filtering and drying the secondary resolution solid to obtain a crude calcium levofolinate product.
Preferably, in the step S-5, the purification method of the crude calcium levofolinate comprises the following steps:
s-11, adding the crude calcium levofolinate into purified water, and regulating the pH value by using acetic acid to obtain a dissolving solution;
s-12, filtering the solution, adding absolute ethyl alcohol into the filtrate, filtering, precipitating and drying to obtain a finished product of calcium levofolinate.
Preferably, the calcium folinate is prepared by NaHSO 3 Reducing folic acid to tetrahydrofolic acid, and preparing calcium folinate by using ethyl formate as formylating reagent.
The traditional sodium borohydride or catalytic hydrogenation reduction method is used for incomplete reduction, a large amount of dihydrofolic acid is generated, or the reactant is subjected to molecular fracture to generate byproducts, so that the yield is reduced, and the separation and purification are difficult. By NaHSO 3 As a reducing agent, TLC detection did not detect the presence of pterin, p-aminobenzoyl glutamic acid and other impurity spots generated by molecular cleavage. And compared with other reducing agents, naHSO is used 3 The reduced folic acid has the advantages of lower cost, simpler and more convenient operation, high yield and the like.
Preferably, the acid used in the step S-3 is low carbon chain fatty acid such as formic acid, acetic acid, propionic acid, etc., and replaces hydrochloric acid conventionally used, except that the pollution of finished chlorine caused by the introduction of chloride ions is avoided.
Preferably, in steps S-2 and S-3, the crystallization temperature is 0 to 20℃and the crystallization time is 5 to 10 hours, more preferably 5 to 6 hours.
By implementing the technical scheme, compared with the prior art, the invention has the following improvement points and advantages:
1. calcium ions are introduced in the form of organic acid calcium (calcium formate, calcium acetate, calcium propionate) and organic acid (formic acid, acetic acid, propionic acid and the like) is used for replacing hydrochloric acid to adjust the pH, so that the introduction of chloride ions is avoided, and no chloride ion impurity exists in the finished product.
2. R- (alpha) -phenethylamine is adopted as a resolving agent and is matched with organic acid calcium, so that the isomer of the finished product is less than 0.1 percent (less than 0.5 percent specified in pharmacopoeia).
3. The organic acid calcium is used for replacing calcium chloride, so that the introduction of chloride ions is avoided to cause the pollution of finished product chlorine, the resolution system is more stable, the impurities are reduced, and the optical purity of the obtained calcium levofolinate finished product can reach 99.95 percent by combining with the R- (alpha) -phenethylamine resolving agent.
4. By adopting organic acid calcium (especially calcium acetate) and R- (alpha) -phenethylamine, the invention surprisingly finds that the crystallization time is greatly shortened, and compared with about 20 hours in the prior art, the crystallization can be completed in about 5 hours.
5. By NaHSO 3 The folic acid is reduced to tetrahydrofolate, and the calcium folinate is prepared by taking ethyl formate as formylating reagent, so that the occurrence of pterin, p-aminobenzoyl glutamic acid and other impurity spots generated by molecular cleavage is not found. And compared with other reducing agents, naHSO is used 3 The reduced folic acid has the advantages of lower cost, simpler and more convenient operation, high yield and the like.
Drawings
FIG. 1 is an isomerism spectrum of the primary resolved solid obtained in example 1;
FIG. 2 is an impurity profile of the primary resolved solid obtained in example 1;
FIG. 3 is an isomerism spectrum of the secondary resolution solid obtained in example 1;
FIG. 4 is an impurity profile of the secondary resolution solid obtained in example 1;
FIG. 5 is an isomerism spectrum of crude calcium levofolinate obtained in example 1;
FIG. 6 is an impurity profile of crude calcium levofolinate obtained in example 1;
FIG. 7 is an isomerism spectrum of the calcium levofolinate finished product obtained in example 1;
FIG. 8 is an impurity profile of the calcium levofolinate finished product obtained in example 1;
FIG. 9 is an isomerism spectrum of the primary resolved solid obtained in comparative example 1;
FIG. 10 is an impurity profile of the primary resolved solid obtained in comparative example 1;
FIG. 11 is an isomerism spectrum of the secondary resolution solid obtained in comparative example 1;
FIG. 12 is an impurity profile of the secondarily resolved solid obtained in comparative example 1;
FIG. 13 is an isomerism spectrum of the crude calcium levofolinate product obtained in comparative example 1;
FIG. 14 is an impurity profile of the crude calcium levofolinate product obtained in comparative example 1;
FIG. 15 is an isomerism spectrum of the calcium levofolinate finished product obtained in comparative example 1;
FIG. 16 is an impurity profile of the calcium levofolinate finished product obtained in comparative example 1;
FIG. 17 is an isomerism spectrum of the primary resolved solid obtained in comparative example 2;
FIG. 18 is an impurity profile of the primary resolved solid obtained in comparative example 2;
FIG. 19 is an isomerism spectrum of the secondary resolution solid obtained in comparative example 2;
FIG. 20 is an impurity profile of the secondarily resolved solid obtained in comparative example 2;
FIG. 21 is an isomerism spectrum of crude calcium levofolinate obtained in comparative example 2;
FIG. 22 is an impurity profile of the crude calcium levofolinate product obtained in comparative example 2;
FIG. 23 is an isomerism spectrum of the calcium levofolinate finished product obtained in comparative example 2;
FIG. 24 is an impurity profile of the calcium levofolinate finished product obtained in comparative example 2;
FIG. 25 is an isomerism spectrum of the primary resolved solid obtained in comparative example 3;
FIG. 26 is an impurity profile of the primary resolved solid obtained in comparative example 3;
FIG. 27 is an isomerism spectrum of the secondary resolution solid obtained in comparative example 3;
FIG. 28 is an impurity profile of the secondarily resolved solid obtained in comparative example 3;
FIG. 29 is an isomerism spectrum of crude calcium levofolinate obtained in comparative example 3;
FIG. 30 is an impurity profile of crude calcium levofolinate obtained in comparative example 3;
FIG. 31 is an isomerism spectrum of the calcium levofolinate finished product obtained in comparative example 3;
FIG. 32 is an impurity profile of the calcium levofolinate finished product obtained in comparative example 3;
FIG. 33 is an isomerism spectrum of the calcium levofolinate finished product obtained in example 2;
FIG. 34 is an impurity profile of the finished calcium levofolinate product obtained in example 2;
FIG. 35 is an isomerism spectrum of the calcium levofolinate finished product obtained in example 3;
FIG. 36 is an impurity profile of the calcium levofolinate finished product obtained in example 3.
Detailed Description
The invention is further illustrated by the following specific examples.
It should be noted that the following embodiments are only for illustrating the technical solution of the present invention, and are not limiting; although the invention has been described in detail with reference to the following examples, it will be understood by those of ordinary skill in the art that: the technical scheme recorded in each embodiment can be modified or part of technical features in the technical scheme can be replaced equivalently; such modifications and substitutions do not depart from the spirit of the invention.
Example 1
Using calcium folinate as raw material to prepare Gao Chunzuo calcium folinate, as follows:
51.1g (0.1 mOl) of calcium folinate and 25g of sodium bromide are suspended in 400ml of water, the temperature is raised to 50 ℃ to dissolve the calcium folinate and the sodium bromide, the temperature of the dissolution liquid is reduced to 10 ℃ to crystallize for 6 hours, solids are separated out, the solids are filtered, the solids are washed by water, and the filtrates are combined.
Adding 10g of calcium acetate and 2g R- (alpha) -phenethylamine into the filtrate, cooling the solution to 10 ℃ for crystallization for 6 hours, separating out solid, filtering, washing the solid, and obtaining 59g of once resolved solid, wherein the yield = 90%, the once resolved isomerism spectrum is shown in figure 1, and the once resolved impurity spectrum is shown in figure 2.
Suspending the once resolved solid in 400ml water, heating to 50deg.C, adding acetic acid to dissolve, adding 10g calcium acetate and 2g R- (alpha) -phenethylamine into the solution, cooling to 10deg.C, crystallizing for 6h, separating out solid, filtering, washing the solid, and obtaining the twice resolved solid 51g ， Yield = 90%, the secondary resolution isomerism spectrum is shown in figure 3, and the secondary resolution impurity spectrum is shown in figure 4.
Suspending the total amount of the secondary resolution solid in 400ml of water, heating to 50 ℃, adding acetic acid to dissolve the solid, adding 10g of calcium acetate and 2g R- (alpha) -phenethylamine into the solution, cooling the solution to 10 ℃, crystallizing for 6 hours, separating out the solid, filtering, washing the solid with water, and obtaining the tertiary resolution solid, namely 44.5g of crude calcium levofolinate, wherein the yield=90%, the crude product isomerism map is shown in figure 5, and the crude product impurity map is shown in figure 6.
Suspending the crude calcium levofolinate in 400ml of water, heating to 50deg.C, adding acetic acid to dissolve, adding 1500ml of absolute ethanol into the solution for crystallization for 5h, separating out solid, filtering, washing with absolute ethanol, and drying to obtain 13.5g of calcium levofolinate product with yield=92%, chloride less than or equal to 0.05%, wherein the isomerism spectrum of the product is shown in figure 7, and the impurity spectrum of the product is shown in figure 8.
Comparative example 1:
using crude calcium folinate as raw material to prepare Gao Chunzuo calcium folinate, as follows:
51.1g (0.1 mOl) of crude calcium folinate and 25g of sodium bromide are suspended in 400ml of water, the temperature is raised to 50 ℃ to dissolve the crude calcium folinate and the sodium bromide, the temperature of the dissolution liquid is reduced to 15 ℃ to crystallize for 6 hours, solids are separated out, the solids are filtered, the solids are washed by water, and the filtrates are combined.
Adding 10g of calcium chloride and 2g R- (alpha) -phenethylamine into the filtrate, cooling the solution to 15 ℃ for crystallization for 6 hours, separating out solid, filtering, washing the solid, and obtaining 57g of once resolved solid, wherein the yield=88%, the once resolved isomerism spectrum is shown in figure 9, and the once resolved impurity spectrum is shown in figure 10.
Suspending the total amount of the first resolved solid in 400ml of water, heating to 50 ℃, adding acetic acid to dissolve the solid, adding 10g of calcium chloride and 2g R- (alpha) -phenethylamine into the solution, cooling the solution to 15 ℃ to crystallize for 6 hours, separating out the solid, filtering, washing the solid with water, and obtaining 49g of the second resolved solid, wherein the yield=87%, the second resolved isomerism spectrum is shown in figure 11, and the second resolved impurity spectrum is shown in figure 12.
Suspending the total amount of the secondary resolution solid in 400ml of water, heating to 50 ℃, adding acetic acid to dissolve the solid, adding 10g of calcium chloride and 2g R- (alpha) -phenethylamine into the solution, cooling the solution to 15 ℃ to crystallize for 6 hours, separating out the solid, filtering, washing the solid with water to obtain the tertiary resolution solid, namely 41g of crude calcium levofolinate, wherein the yield=90%, the crude product isomerism map is shown in figure 13, and the crude product impurity map is shown in figure 14.
Suspending the crude calcium levofolinate in 400ml of water, heating to 50deg.C, adding acetic acid to dissolve, adding 1500ml of absolute ethanol into the solution for crystallization for 5h, separating out solid, filtering, washing with absolute ethanol, and drying to obtain 12.5g of calcium levofolinate product with yield=92%, chloride not less than 0.5%, the isomerism spectrum of the product is shown in figure 15, and the impurity spectrum of the product is shown in figure 16.
The difference from example 1 is that calcium acetate is replaced by calcium chloride.
Comparative example 2:
using crude calcium folinate as raw material to prepare Gao Chunzuo calcium folinate, as follows:
51.1g (0.1 mOl) of crude calcium folinate and 25g of sodium bromide are suspended in 400ml of water, the temperature is raised to 50 ℃ to dissolve the crude calcium folinate and the sodium bromide, the temperature of the dissolution liquid is reduced to 15 ℃ to crystallize for 6 hours, solids are separated out, the solids are filtered, the solids are washed by water, and the filtrates are combined.
Adding 10g of calcium acetate and 2g S-methylbenzylamine into the filtrate, cooling the solution to 15 ℃ for crystallization for 6 hours, separating out solid, filtering, washing the solid, and obtaining 52.5g of once-resolved solid, wherein the yield=80%, the once-resolved isomerism spectrum is shown in figure 17, and the once-resolved impurity spectrum is shown in figure 18.
Suspending the total amount of the first resolved solid in 400ml of water, heating to 50 ℃, adding acetic acid to dissolve the first resolved solid, adding 10g of calcium acetate and 2g S-methylbenzylamine into the solution, cooling the solution to 15 ℃ to crystallize for 6 hours, separating out the solid, filtering, washing the solid with water to obtain 47g of the second resolved solid, wherein the yield=86%, the second resolved isomerism spectrum is shown in figure 19, and the second resolved impurity spectrum is shown in figure 20.
Suspending the total amount of the secondary resolution solid in 400ml of water, heating to 50 ℃, adding acetic acid to dissolve the solid, adding 10g of calcium acetate and 2g S-methylbenzylamine into the solution, cooling the solution to 15 ℃ to crystallize for 6 hours, separating out the solid, filtering, washing the solid with water to obtain the tertiary resolution solid, namely a crude calcium levofolinate product, 38g, wherein the yield=84%, the isomerism spectrum of the crude product is shown in figure 21, and the impurity spectrum of the crude product is shown in figure 22.
Suspending the crude calcium levofolinate in 400ml of water in total, heating to 50deg.C, adding acetic acid to dissolve, adding 1500ml of absolute ethanol into the solution to crystallize for 5h, separating out solid, filtering, washing with absolute ethanol, and drying to obtain 11.2g of calcium levofolinate, wherein the yield=90% is shown in figure 23, and the impurity profile is shown in figure 24.
The difference from example 1 is that the resolving agent R- (. Alpha. -phenethylamine is replaced by S-methylbenzylamine.
Comparative example 3:
using crude calcium folinate as raw material to prepare Gao Chunzuo calcium folinate, as follows:
51.1g (0.1 mOl) of crude calcium folinate and 25g of sodium bromide are suspended in 400ml of water, the temperature is raised to 50 ℃ to dissolve the crude calcium folinate and the sodium bromide, the temperature of the dissolution liquid is reduced to 15 ℃ to crystallize for 6 hours, solids are separated out, the solids are filtered, the solids are washed by water, and the filtrates are combined.
Adding 10g of calcium acetate and 2g S- (alpha) -phenethylamine into the filtrate, cooling the solution to 15 ℃ for crystallization for 6 hours, separating out solid, filtering, washing the solid, and obtaining 57.5g of once resolved solid, wherein the yield = 89%, the once resolved isomerism spectrum is shown in figure 25, and the once resolved impurity spectrum is shown in figure 26.
Suspending the primary resolution solid in 400ml of water, heating to 50 ℃, adding acetic acid to dissolve, adding 10g of calcium acetate and 2g S- (alpha) -phenethylamine into the solution, cooling the solution to 15 ℃ to crystallize for 6 hours, separating out the solid, filtering, washing the solid with water, and obtaining 47.8g of secondary resolution solid, wherein the yield = 88%, the secondary resolution isomer map is shown in figure 27, and the secondary resolution impurity map is shown in figure 28.
Suspending the total amount of the secondary resolution solid in 400ml of water, heating to 50 ℃, adding acetic acid to dissolve the solid, adding 10g of calcium acetate and 2g S- (alpha) -phenethylamine into the solution, cooling the solution to 15 ℃ to crystallize for 6 hours, separating out the solid, filtering, washing the solid with water to obtain the tertiary resolution solid-40.1 g of crude calcium levofolinate, wherein the yield=86%, the crude product isomerism map is shown in figure 29, and the crude product impurity map is shown in figure 30.
Suspending the crude calcium levofolinate in 400ml of water in total, heating to 50deg.C, adding acetic acid to dissolve, adding 1500ml of absolute ethanol into the solution to crystallize for 5h, separating out solid, filtering, washing with absolute ethanol, and drying to obtain 12.2g of calcium levofolinate product with yield=91%, wherein the isomerism spectrum of the product is shown in figure 31, and the impurity spectrum of the product is shown in figure 32.
The difference from example 1 is that the resolving agent R- (. Alpha. -phenethylamine is replaced by S- (. Alpha. -phenethylamine).
Example 2
Using calcium folinate as raw material to prepare Gao Chunzuo calcium folinate, as follows:
51.1g (0.1 mOl) of calcium folinate and 25g of sodium bromide are suspended in 400ml of water, the temperature is raised to (40-60) ℃ to dissolve the calcium folinate and the sodium bromide, the temperature of the dissolution liquid is reduced to (0-20) ℃ to crystallize (5-20) h, solids are separated out, the solids are filtered, the solids are washed by water, and the filtrates are combined.
8g of calcium formate and 2g R- (alpha) -phenethylamine are added into the filtrate, the solution is cooled to (0-20) DEG C for crystallization (5-20) h, solid is separated out, the solid is filtered and washed by water, 59.5g of once resolved solid can be obtained, and the yield=91%.
Suspending the total amount of the once-resolved solid in 400ml of waterHeating to (40-60) deg.C, adding formic acid to dissolve, adding 8g calcium formate and 2g R- (alpha) -phenethylamine into the solution, cooling to (0-20) deg.C, crystallizing for (5-20) h, separating out solid, filtering, washing the solid, and obtaining secondary resolution solid 50g ， Yield = 89%.
Suspending the total amount of the secondary resolution solid in 40 ml of water, heating to (40-60) ℃, adding formic acid to dissolve the solid, adding 8g of calcium formate and 2g R- (alpha) -phenethylamine into the solution, cooling the solution to (0-20) DEG C, crystallizing (5-20) h, separating out the solid, filtering, and washing the solid with water to obtain the tertiary resolution solid, namely 43.8g of calcium levofolinate crude product, wherein the yield is=89.2%.
Suspending the crude calcium levofolinate in 400ml of water in total, heating to (40-60) deg.C, adding formic acid to dissolve, adding 1500ml of absolute ethyl alcohol into the solution to crystallize (2-6) for h, separating out solid, filtering, washing with absolute ethyl alcohol, and drying to obtain 13.2g of calcium levofolinate product, wherein the yield=91.5% and chloride are less than or equal to 0.05%, the isomerism spectrum of the product is shown in figure 33, and the impurity spectrum of the product is shown in figure 34.
Example 3
Using calcium folinate as raw material to prepare Gao Chunzuo calcium folinate, as follows:
51.1g (0.1 mOl) of calcium folinate and 25g of sodium bromide are suspended in 400ml of water, the temperature is raised to (40-60) ℃ to dissolve the calcium folinate and the sodium bromide, the temperature of the dissolution liquid is reduced to (0-20) ℃ to crystallize (5-20) h, solids are separated out, the solids are filtered, the solids are washed by water, and the filtrates are combined.
Adding 12g of calcium propionate and 2g R- (alpha) -phenethylamine into the filtrate, cooling the solution to (0-20) DEG C, crystallizing (5-20) h, separating out solid, filtering, washing the solid with water to obtain 60g of once-resolved solid, wherein the yield is=90.5%.
Suspending the total amount of the once resolved solid in 400ml of water, heating to (40-60) ℃, adding propionic acid to dissolve, adding 12g of calcium propionate and 2g R- (alpha) -phenethylamine into the solution, cooling the solution to (0-20) DEG C, crystallizing (5-20) h, precipitating solid, filtering, washing the solid with water, and obtaining 51.5g of the twice resolved solid ， Yield = 90.3%.
Suspending the total amount of the secondary resolution solid in 400ml of water, heating to (40-60) ℃, adding propionic acid to dissolve, adding 12g of calcium propionate and 2g R- (alpha) -phenethylamine into the solution, cooling the solution to (0-20) DEG C, crystallizing (5-20) h, separating out the solid, filtering, and washing the solid with water to obtain the tertiary resolution solid, namely 44.8g of calcium levofolinate crude product, wherein the yield is=90.2%.
Suspending the crude calcium levofolinate in 400ml of water in total, heating to (40-60) deg.C, adding propionic acid to dissolve, adding 1500ml of absolute ethyl alcohol into the solution to crystallize (2-6) for h, separating out solid, filtering, washing with absolute ethyl alcohol, and drying to obtain 13.7g of calcium levofolinate product, wherein the yield=92.1% and chloride is less than or equal to 0.05%, the isomerism spectrum of the product is shown in figure 35, and the impurity spectrum of the product is shown in figure 36.
Example 4
Starting from the preparation of tetrahydrofolic acid to the preparation of Gao Chunzuo calcium fumarate, naHSO 3 Reducing folic acid to tetrahydrofolic acid, and preparing calcium folinate by using ethyl formate as formylating reagent. And preparing Gao Chunzuo calcium folinate by taking the obtained calcium folinate as a raw material.
10g of folic acid is suspended in 60ml of water, sodium hydroxide solution is added, stirring and dissolving are carried out, 15g of sodium bisulphite is added, decoloring and filtering are carried out for 1.5 hours at 70 ℃, vitamin C is added into filtrate, pH is regulated to 4.0, and filtering is carried out, thus obtaining solid A. Dissolving the solid A, adding 60ml of methyl formate, reacting for 20 hours, crystallizing, filtering and drying to obtain a solid B. Dissolving the solid B, reacting with calcium chloride, filtering, adding absolute ethyl alcohol into the filtrate, crystallizing, filtering, and drying to obtain crude calcium folinate.
Using the obtained calcium folinate as a raw material, gao Chunzuo calcium folinate was prepared as in example 3.
Claims (3)
1. The preparation method of the high-purity calcium levofolinate is characterized by comprising the following steps of:
s-1, adding calcium folinate and a resolving agent into water, stirring to dissolve the calcium folinate and the resolving agent, and filtering to obtain filtrate;
s-2, adding organic acid calcium and a resolving agent into the filtrate, crystallizing and filtering to obtain primary resolved solid;
s-3, dropwise adding acid into the primary resolution solid, adding organic acid calcium and a resolving agent, crystallizing and filtering to obtain a secondary resolution solid; filtering and drying the secondarily resolved solid to obtain a crude calcium levofolinate product;
s-4, refining the crude calcium levofolinate to obtain a finished product of calcium levofolinate;
the resolving agent is R- (alpha) -phenethylamine;
preparation of calcium folinate as described in step S-1: by NaHSO 3 Reducing folic acid to tetrahydrofolic acid, and preparing calcium folinate by taking ethyl formate as a formylating reagent;
the organic acid calcium in the step S-2 is calcium formate, calcium acetate or calcium propionate;
the acid in step S-3 is formic acid, acetic acid or propionic acid.
2. The method for preparing high-purity calcium levofolinate according to claim 1, wherein in the step S-4, the refining method of the crude calcium levofolinate comprises the following steps:
s-11, adding the crude calcium levofolinate into purified water, and adjusting the pH value by using an organic acid to obtain a solution;
s-12, filtering the solution, adding absolute ethyl alcohol into the filtrate, filtering, precipitating and drying to obtain a finished product of calcium levofolinate.
3. The process for preparing high-purity calcium levofolinate according to claim 1, wherein in step S-2, the crystallization temperature is 0 to 20 ℃ and the crystallization time is 5 to 10 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111042834.5A CN113666931B (en) | 2021-09-07 | 2021-09-07 | Preparation method of high-purity calcium levofolinate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111042834.5A CN113666931B (en) | 2021-09-07 | 2021-09-07 | Preparation method of high-purity calcium levofolinate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113666931A CN113666931A (en) | 2021-11-19 |
| CN113666931B true CN113666931B (en) | 2023-11-03 |
Family
ID=78548572
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111042834.5A Active CN113666931B (en) | 2021-09-07 | 2021-09-07 | Preparation method of high-purity calcium levofolinate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113666931B (en) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993017022A1 (en) * | 1992-02-20 | 1993-09-02 | Bracco S.P.A. | Process for separating stereoisomers of folinic acid |
| WO1995033749A1 (en) * | 1994-06-08 | 1995-12-14 | Bracco S.P.A. | A process for the preparation and separation of diastereomeric salts of folinic acid |
| CN1401647A (en) * | 2002-09-13 | 2003-03-12 | 中国科学院上海有机化学研究所 | High specific rotatory power levoleucovorin calcium and resolution method thereof |
| CN1456561A (en) * | 2003-04-01 | 2003-11-19 | 杭州华卫制药技术开发有限公司 | Preparations of leucovorin and its carbonates |
| CN101407518A (en) * | 2007-10-11 | 2009-04-15 | 南京莱尔生物化工有限公司 | Method for resolving and salifying (6R,S)-5-formyl-tetrahydrofolic acid |
| CN105367574A (en) * | 2015-10-27 | 2016-03-02 | 浙江大为药业有限公司 | Process for preparing high purity sinistral leucovorin calcium |
-
2021
- 2021-09-07 CN CN202111042834.5A patent/CN113666931B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993017022A1 (en) * | 1992-02-20 | 1993-09-02 | Bracco S.P.A. | Process for separating stereoisomers of folinic acid |
| WO1995033749A1 (en) * | 1994-06-08 | 1995-12-14 | Bracco S.P.A. | A process for the preparation and separation of diastereomeric salts of folinic acid |
| CN1401647A (en) * | 2002-09-13 | 2003-03-12 | 中国科学院上海有机化学研究所 | High specific rotatory power levoleucovorin calcium and resolution method thereof |
| CN1456561A (en) * | 2003-04-01 | 2003-11-19 | 杭州华卫制药技术开发有限公司 | Preparations of leucovorin and its carbonates |
| CN101407518A (en) * | 2007-10-11 | 2009-04-15 | 南京莱尔生物化工有限公司 | Method for resolving and salifying (6R,S)-5-formyl-tetrahydrofolic acid |
| CN105367574A (en) * | 2015-10-27 | 2016-03-02 | 浙江大为药业有限公司 | Process for preparing high purity sinistral leucovorin calcium |
Also Published As
| Publication number | Publication date |
|---|---|
| CN113666931A (en) | 2021-11-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0153696B1 (en) | Process for preparing 5,6,7,8-tetrahydro-6-(l-erythro-1',2'-dihydroxypropyl) pterin | |
| JPH0826022B2 (en) | Method for producing tetrahydrofolates | |
| CA2002430C (en) | Method for the resolution of folinic acid | |
| CN1030079C (en) | Process for preparation of (6S)-and (6R)-tetrahydrofolic acid | |
| CN107793418A (en) | Industrial production method of tofacitinib citrate | |
| US20230054325A1 (en) | Compositions comprising folic acid derivatives, their preparations and methods of use | |
| US9090925B2 (en) | Synthesis of (6S)-5,6,7,8-tetrahydrofolic acid | |
| US4649197A (en) | Sulfate of 5,6,7,8-tetrahydro-L-erythro-biopterin and process for preparing the same | |
| CN113666931B (en) | Preparation method of high-purity calcium levofolinate | |
| JPS60204786A (en) | Synthesis of (6r)-tetrahydrobiopterin and its relating substance | |
| CN110759933A (en) | Preparation method of cefdinir impurity G | |
| US8633202B2 (en) | Crystalline levofolinic acid and process for its preparation | |
| CA2814018C (en) | Preparation process of (6r)-tetrahydrobiopterin hydrochloride | |
| CN111777636B (en) | Preparation method of medicine for myocardial protection | |
| CN115611899B (en) | Preparation method of L-5-methyltetrahydrophthalic acid | |
| CN117865960A (en) | Method for synthesizing L-5-methyltetrahydrofolate calcium with enantioselectivity | |
| CN117186102A (en) | Preparation method of N2-methylamino-tetrahydrofolic acid | |
| CN116239464A (en) | Synthesis process of 3-hydroxybutyrate and 3-hydroxybutyrate | |
| CN114874216A (en) | Preparation method of L-5-methyltetrahydrofolic acid | |
| CN110540520A (en) | Method for purifying donepezil |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |