CN104045640B - A kind of method preparing high purity calcium levofolinate - Google Patents
A kind of method preparing high purity calcium levofolinate Download PDFInfo
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Abstract
The invention provides a kind of method preparing high purity calcium levofolinate; take folic acid as starting raw material; relate to the steps such as reduction, formylation, the fractionation of intermediate recrystallization, hydrolysis, recrystallizing and refining; by calcium levofolinate prepared by the present invention; color and luster becomes white to micro-yellow, and optical purity is not less than 98.5%, in Related substances separation; total impurities is not more than 1.0%, and single impurity is not more than 0.3%.The preparation method of high purity calcium levofolinate of the present invention is easy and simple to handle, process cycle is short, quality product is high, can be used for the suitability for industrialized production of drug manufacturing enterprise's related raw material medicine.
Description
Technical field
The invention belongs to the synthesis field of medicinal chemicals, be specifically related to a kind of method preparing high purity calcium levofolinate.
Background technology
Calcium levofolinate (L-CalciumLevofolinate), molecular formula is C
20h
21caN
7o
7, molecular weight 511.5, CASNo.:80433-71-2.Chemical name: (-)-N-[4-[[[(6S)-2-amino-5-formyl radical-Isosorbide-5-Nitrae, 5,6,7,8-six hydrogen-4-oxo-6-pteridyl] methyl] is amino] benzoyl]-Pidolidone calcium salt, its structural formula is as follows:
Calcium levofolinate is the calcium salt of l-leucovorin, and l-leucovorin is the L-optical isomer with pharmacological activity of 5-formyl tetrahydrofolic acid (i.e. folinic acid).L-leucovorin does not need can be participated in by Tetrahydrofolate dehydrogenase reduction the reaction that utilizes folate to originate as one carbon unit, and l-leucovorin can pass through cytolemma actively or passively.The basic role of l-leucovorin is identical with the basic role of folic acid, but effect is better than folic acid, just can work because folic acid first will become folinic acid in liver and marrow.And this product, i.e. calcium levofolinate, be the activity form of l-leucovorin, it also has the effect stimulating Leukocyte Growth maturation, can improve megaloblastic anemia.
Calcium levofolinate is mainly used in treating osteosarcoma symptom relevant to folic acid antagonist after High-dose Methotrexate Treatment, also can be used to treat the macrocytic that causes of folic acid deficiency, also can extend lifetime or the relief of symptoms of advanced colon cancer patient with Fluracil conbined usage.Calcium levofolinate treats the malignant tumour of other types with methotrexate or Fluracil conbined usage in practice, and a member usually as multiple medicines combined treatment uses.
In addition, calcium levofolinate also can be used for the medication for the treatment of psoriasis and rheumatoid arthritis and so on autoimmune disease, and for improving the resistance for some antiparasitic (such as trimethoprim-sulfamethoxazole) in chemotherapy.
First calcium levofolinate is succeeded in developing by U.S.'s Hui Shi drug company, first went on the market in Britain in 1994, now comprising the listing of several countries of Italy, Canada, Japan, South Africa, Finland, Iceland etc. 10, its preparation has tablet, aqueous injection and lyophilized injection, and by " European Pharmacopoeia " record, external clinical application fully confirms the safety and effectiveness of this medicine.This kind fails to obtain China's patent protection, does not also meet the condition of not applying for administrative protection, therefore can the raw material of legal this medicine of development and preparation at home.
Calcium levofolinate is the active optically active form of Calciumlevofolinate, has the comparative advantages of drug effect and security aspect.This product following becomes a Zhi Xin army on domestic antitumor drug market by progressively substituting Calciumlevofolinate.Exploitation calcium levofolinate produce market prospect is very wide.
Current published calcium levofolinate preparation technology is as follows:
1. asymmetric synthesis
Data source (1-3): [1] ReesL., etal.Asimpleandeffectivemethodforpreparationofthe6 (R)-and6 (S)-diastereoisomersof5-formyltetrahydrofolate (leucovorin) .JChemSocChemCommun1987, (6), 470; [2] YukihiroK., etal.Large-scalechemoenzymicsynthesisofcalcium (6S)-5-formyl-5,6,7,8-tetrahydrofolate [(–)-leucovorin] usingtheNADPHrecyclingmethod.J.Chem.Soc., PerkinTrans.1,1994, (11), 1427; [3] Pelletier, J.N.etal.Methenyltetrahydrofolatecyclohydrolasecatalyzes thesynthesisof (6S)-5-formyltetrahydrofolate.BioorgChem, 1996,24 (3): 220.
Asymmetric synthesis needs to utilize (1,5-cyclooctadiene) chlorine rhodium (I) dimer ([Rh (COD) Cl]
2) etc. chiral auxiliary reagent or the chirality enzyme such as Tetrahydrofolate dehydrogenase, 10-Tetrahydrofolic formylase be catalyzer, above-mentioned chiral auxiliary reagent or catalyzer do not have suitability for industrialized production at present at home, and grade product is expensive, taking cost into account this route is not suitable for preparation of industrialization.
2. DL Calciumlevofolinate splits recrystallization
Data source (4-5): [4] Muller, the Chinese this, the separation method .CN88102709.X of Rudoiph etc.-folinic acid; [5] the levoleucovorin calcium of-Gao specific optical rotation such as woods Guoqiang and method for splitting .2003, CN1401647A.
With DL Calciumlevofolinate for calcium levofolinate prepared by raw material, utilize Calciumlevofolinate enantiomorph different solubility and carry out crystallization fractionation in aqueous, not high from the efficiency of DL Chiral Separation left-handed mapping enantiomorph, according to published data, usually need to split the calcium levofolinate sample that just can obtain optical purity and be greater than 99% through three to four times.In addition, although repeatedly split the reduction being conducive to impurity level, increase fractionation number of times and product yield will be caused to reduce, according to calcium levofolinate solubleness (European Pharmacopoeia EP7.0), the rate of loss of each fractured operation calcium levofolinate is at least not less than 10%.Therefore, with DL Calciumlevofolinate for calcium levofolinate prepared by raw material, final quality product still depends on the quality of DL Calciumlevofolinate.
3. the synthesis of DL Calciumlevofolinate
Data source (6-10): [6] Temple.Jr., etal.PreparationandPurificationofL-(±)-5-Formyl-5,6,7,8-tetrahydrofolicAcid.Am.Chem.Soc., 1979,22 (6): 731; [7] Temple, Jr.etal.Preparationoftetrahydrofolicacidfromfolicacid.Un itedStatesPatent, 4148999,1979; [8] improvement of the .5-calcium leucovorin such as Huang Kai synthesis; Medicine industry, 1986,17 (10): 433; [9] Wang Biao waits synthesis and the purifying of 5-calcium leucovorin; Peking University's journal (medicine), 2006,38 (3): 436; [10] Pan Jicheng etc.; A preparation method .2012 for medicinal calcium folinate, CN102399223A.
The preparation of DL Calciumlevofolinate is starting raw material usually with folic acid, and folic acid carries out formylation reaction immediately and generates 5,10-CH2-THFA after being reduced to tetrahydrofolic acid (THFA), the latter in neutral conditions hydrolysis adds calcium precipitation and obtains Calciumlevofolinate.In above-mentioned open source information, two factors are had to cause the quality product in industrial production to be difficult to ensure.
First, at formylation step, due to formylation reagent large usage quantity, in order to enable hydroformylation product separate out, therefore published data all relates to the concentration process of formylation reaction liquid; Secondly, in open loop step, all use the strong base solutions such as NaOH to regulate open loop system pH.
Experiment shows in acid condition, and intermediate 5,10-CH2-THFA is to thermally labile, and its amido linkage is easily hydrolyzed.The formylation reagents such as formic acid due to boiling point high, the efficiency of underpressure distillation requires higher to the vacuum tightness of distillation plant and distillation temperature.In order at a lower temperature, (<60 DEG C) steams formylation reagent, need reach the vacuum tightness of 0.095Mpa ~ 0.1Mpa, and general industry working condition is difficult to realize, and improves the quality that Heating temperature must affect intermediate and finished product.
In open loop step; due to 5; 10-methylene tetrahydrofolate easily generates 10-formyl tetrahydrofolic acid (process of kinetic control, the document that sees reference [7]) in the basic conditions, according to open source information; regulate the pH value of open loop system with strong base solution under industrial scale; very easily cause local pH too high, generate 10 formylated by products, because such impurities exhibit is lower than calcium levofolinate; split process is usually separated out together along with precipitation principal product, is difficult to remove.
Summary of the invention
Object of the present invention is mainly to improve the formylation in existing Calciumlevofolinate synthesis technique and hydrolysis step.
On the one hand, the invention provides a kind of method preparing calcium levofolinate, said method comprising the steps of:
1) reduction of folates as raw material is obtained reduzate tetrahydrofolic acid (THFA), tetrahydrofolic acid (THFA) is added in formic acid, when with trifluoroacetic acid as catalyzer, carry out formylation, obtain formylation intermediate 5,10-CH2-THFA; In described 5,10-CH2-THFA, add the solution of haloid acid, obtain the halogen acid salt of formylation intermediate 5,10-CH2-THFA;
2) halogen acid salt of 5,10-CH2-THFA step 1) obtained redissolves in formic acid, then the solution adding the haloid acid identical with step 1) carries out recrystallization, thus obtains the halogen acid salt of purified 5,10-CH2-THFA;
3) by step 2) in obtain purified 5, the halogen acid salt of 10-methylene tetrahydrofolate is suspended in water and forms the aqueous solution, add basic solution so that the pH value of the described aqueous solution is adjusted to 5.5-7.5, then carry out heating hydrolysis open loop, in the solution after open loop, add anhydrous CaCl
2, and adjust ph is to 5.5-8.5, places, obtains calcium levofolinate solid;
4) recrystallization is carried out to the calcium levofolinate solid water that step 3) obtains, obtain target product calcium levofolinate.
Preferably, step 3) is also included in and adds basic solution with before the pH value of the described aqueous solution is adjusted to 5.5-7.5, adds alkali to make buffer system in the described aqueous solution.
Preferably, described in step 1) the volume of formic acid and described raw material folic acid to mass ratio with milliliter to gram counting 1.0-5.0:1.0, be preferably 2.0-4.0:1.0, be more preferably 3.0:1.0.
Preferably, in step 2) described in the volume of halogen acid salt of formic acid and described 5,10-CH2-THFA to mass ratio with milliliter to gram counting 2.0-5.0:1.0, be preferably 2.0-3.0:1.0, be more preferably 3.0:1.0.
Preferably, in step 1) and 2) described in haloid acid be selected from one in spirit of salt, Hydrogen bromide and hydroiodic acid HI, be preferably spirit of salt.
Preferably, the concentration of the solution of the haloid acid described in step 1) is 0.5mol/L-6mol/L, is preferably 2-3mol/L; Described in step 1), the volume of the solution of haloid acid is 0.25-2.5 times of the volume of described formic acid, is preferably 0.75-1.0 doubly.
Preferably, in step 2) in the concentration of solution of described haloid acid be 1.0mol/L-6.0mol/L, be preferably 2-3mol/L; In step 2) in the volume of solution of described haloid acid be the 0.25-2.5 of the volume of described formic acid doubly, be preferably 0.75-1.0 doubly.
Preferably, described alkali comprises that do not react with water, water miscible, that pKb scope is 2-8 non-volatile alkali.
Preferably, described basic solution comprises the aqueous solution of that do not react with water, water miscible, that pKb scope is 2-8 non-volatile alkali.
Preferably, described alkali is a kind of organic bases be selected from piperazine and derivative thereof, and described derivative is preferably alkylpiperazine, is more preferably N methyl piperazine or 2-methylpiperazine.
Preferably, described basic solution comprises the aqueous solution of a kind of organic bases be selected from piperazine and derivative thereof, and described derivative is preferably alkylpiperazine, is more preferably N methyl piperazine or 2-methylpiperazine; And/or be selected from the aqueous solution of a kind of mineral alkali in alkali-metal oxyhydroxide, the oxyhydroxide of alkaline-earth metal or quaternary ammonium hydroxide, be preferably the aqueous solution of alkali-metal oxyhydroxide, be more preferably the aqueous solution of sodium hydroxide or potassium hydroxide.
Preferably, the mol ratio of the halogen acid salt of the 5,10-CH2-THFA of described alkali and described purifying is 0.5-0.6:1.
On the other hand, the invention provides a kind of calcium levofolinate prepared by method of the present invention.
Preferably, the optical purity of described calcium levofolinate is greater than 98.5%.
Another aspect, the invention provides a kind of calcium levofolinate prepared according to method of the present invention for the preparation of the purposes in treatment autoimmune disease medicine.
Preferably, described autoimmune disease comprises psoriasis or rheumatoid arthritis.
The present invention preferred embodiment can be realized by following.
The schematic flow sheet of concrete technology is as follows:
(1) by the reduzate of raw material folic acid--tetrahydrofolic acid (THFA), when trifluoroacetic acid is as catalyzer, is added to formic acid and carries out in formylation, place 10-24 hour at the temperature of 10 DEG C-30 DEG C (room temperature) after, obtain 5,10-CH2-THFA; Add hydrochloric acid again, formylation intermediate-5,10-CH2-THFA is separated out with hydrochloride form;
(2) the hydrochloride formic acid of the 5,10-CH2-THFA of precipitation is redissolved, add recrystallization after hydrochloric acid, separate out 5,10-CH2-THFA hydrochloride highly finished product;
(3) by 5 after recrystallization, 10-methylene tetrahydrofolate hydrochloride is suspended in water, the aqueous solution adding middle highly basic such as piperazine makes buffer system, the aqueous solution adding middle highly basic such as piperazine or highly basic such as sodium hydroxide again tunes to open the pH value of ring reaction system to 5.5-7.5, carry out heating hydrolysis open loop, directly add the anhydrous CaCl with weight (w/w) such as intermediates to the solution after open loop
2, and adjust pH is to 5.5-8.5, place, the solid of precipitation is calcium levofolinate;
(4) by separate out calcium levofolinate with water recrystallization, obtain calcium levofolinate highly finished product.
Compared with prior art, advantage of the present invention is:
First aspect, in whole preparation method, add and utilize formic acid to 5, the halogen acid salt of 10-methylene tetrahydrofolate carries out the step of redissolution recrystallization, this step makes just to purify in the stage of the halogen acid salt obtaining 5,10-CH2-THFA in the process of the highly purified calcium levofolinate of preparation.Find through the present inventor, add this step and play the effect improving intermediate purity and decolouring, thus improve the optical purity of final product.Specifically, do not utilizing formic acid to 5, the halogen acid salt of 10-methylene tetrahydrofolate carries out redissolving in the prior art of recrystallization, the product finally obtained is the Calciumlevofolinate of DL, need to split the calcium levofolinate that just can obtain wishing through complicated purification, such purification split process not only complicated operation and also the calcium levofolinate purity that obtains not high yet.And the present invention adds and utilizes formic acid to 5 in the process of preparation high purity calcium levofolinate, the halogen acid salt of 10-methylene tetrahydrofolate carries out the step of redissolution recrystallization, directly obtain the enantiomorph of the halogen acid salt of the dextrorotation intermediate of certain optical purity, after this enantiomorph hydrolysis, be levofolinate.Higher with the ratio due to levo-enantiomer after this recrystallised sample open loop, foreign matter content is low, therefore after ring-opening reaction completes, directly can carry out the simple fractionation of levo-enantiomer in ring-opening reaction liquid, obtain the calcium levofolinate that purity is very high;
Second aspect, in whole preparation method, uses formic acid at twice, thus makes formic acid usage quantity in every step less, doing so avoids and uses the concentrated step of heating to remove formic acid; Add haloid acid to be preferably hydrochloric acid and to carry out crystallization operation simultaneously, do not carrying out under the prerequisite heating concentrated solvent, make 5,10-CH2-THFA be preferably hydrochloride form with halogen acid salt and separate out; Choice for use haloid acid in test, be because: nitric acid is oxidizing, even if dust technology, the tetrahydrochysene pterin parent nucleus of folinic acid can be oxidized; And sulfuric acid also has oxidisability when concentration height, even if use dilute sulphuric acid, the vitriol of 5,10-CH2-THFA is in open loop step, and sulfate radical can react to generate with the calcium ion added during open loop and precipitates, and affects quality product.Except use hydrochloric acid, other feasible haloid acid comprise Hydrogen bromide, hydroiodic acid HI;
The third aspect, in open loop step, in more weak with alkalescence, strong base solution replaces highly basic to be preferably the pH value of NaOH solution adjustment reaction system wholly or in part, utilize the buffering system that more weak organic bases and folinic acid derivative are formed, ensure that pH value can be stabilized in rational scope (6.5 ± 1.0).
Calcium levofolinate preparation method after the present invention improves, the effective control to quality product under industrial amplification scale can be realized, the corrosive reagents such as formic acid are distilled under avoiding high temperature, reduce the requirement of production unit, be convenient to amplifieroperation, simultaneously owing to decreasing splitting step, can the yield of larger raising finished product.
Embodiment
Below in conjunction with embodiment, the present invention is further described in detail, the embodiment provided only in order to demonstrate the present invention, instead of in order to limit the scope of the invention.
performance test:
In the examples below, 5, the quality of 10-methylene tetrahydrofolate is with specific optical rotation evaluation, testing conditions is: by 0.250g, 5,10-methylene tetrahydrofolate is dissolved in 25mL dimethyl sulfoxide (DMSO)-hydrochloric acid soln (concentration of hydrochloric acid 2mol/L, DMSO/HCl=3:1(volume ratio)), measure at 25 DEG C, and luminosity length of tube is 10cm.
The detection of related substance, such as folinic acid, adopt reversed-phased high performace liquid chromatographic to detect, testing conditions is:
Moving phase: methyl alcohol: water (every 780mL aqueous phase phosphoric acid disodium hydrogen 2.2g, 10% TBAH 8mL, utilizes phosphoric acid adjust pH to 7.5=22:78(volume ratio)); Chromatograph packing material: C
18reverse phase silica gel; Determined wavelength: 286nm; Flow velocity: 1mL/min;
HPLC areas of peak normalization method is adopted to evaluate the purity of folinic acid and the ratio of impurity.
The optical purity of calcium levofolinate detects and adopts high performance liquid chromatography, and testing conditions is:
Moving phase: Virahol: acetonitrile: water (every 890mL aqueous phase, containing 9.72g SODIUM PHOSPHATE, MONOBASIC, utilizes sodium hydroxide adjust pH to 5.0=100:10:890(volume ratio)); Chromatograph packing material: human serum albumin bonded silica gel; Determined wavelength: 286nm; Flow velocity: 1mL/min;
HPLC areas of peak normalization method is adopted to evaluate the optical purity of calcium levofolinate.
embodiment 1
1) take folic acid 300g, add the distilled water of 2.7L, stir; Regulate the pH value to 8.0 of reaction system with NaOH solution, pass into N
2protect, add the NaBH of 200g
4solid, and with salt acid for adjusting pH value to 3.0, separate out tetrahydrofolic acid (THFA) solid, filter; Added to by the solid leached in 300mL formic acid, after stirring and dissolving, the trifluoroacetic acid adding 6mL, as catalyzer, is placed 14 hours at the temperature of 10 DEG C-30 DEG C (room temperature); In this system, add the hydrochloric acid of 75mL, 6mol/L again, separate out formylation intermediate--the hydrochloride of 5,10-CH2-THFA;
2) will separate out 5, the hydrochloride 150g of 10-methylene tetrahydrofolate redissolves in the formic acid of 300mL, after stirring and dissolving, add the hydrochloric acid of 75mL, 6mol/L, place at the temperature of 10 DEG C-30 DEG C (room temperature), separate out the highly finished product of 5,10-CH2-THFA hydrochloride, detect specific optical rotation and be+24 °;
3) the highly finished product 100g of 5,10-CH2-THFA hydrochloride is added in 850mL water, then add 17.5g piperazine and make solution, get this solution 150mL, then add 1mol/LKOH solution, adjust pH to 5.5, at N
2the lower reflux of protection 3 hours, stops heating; Anhydrous CaCl is added in reaction solution
2100g, stirring and dissolving; The pH value to 8.0 of reaction solution is regulated with 2mol/LNaOH solution; Place at the temperature of 10 DEG C-30 DEG C (room temperature), separate out calcium levofolinate solid; After testing, optical purity is 90.5%, and related substance total amount is 2.0%, and maximum single contaminant is 0.6%;
4) the calcium levofolinate 70g that open loop is separated out is added in 700mL water, at N
270 DEG C are heated under protection; After dissolution of solid, add the anhydrous CaCl of 70g
2, stirring and dissolving; Adjust solution ph to 7.0 by NaOH solution, place at the temperature of 10 DEG C-30 DEG C (room temperature), separate out calcium levofolinate highly finished product solid; After testing, its optical purity is 99.0%, and related substance total amount is 1.0%, and maximum single contaminant is 0.3%.
embodiment 2
1) take folic acid 1.0kg, add the distilled water of 9.0L, stir; Regulate the pH value to 8.0 of reaction system with NaOH solution, pass into N
2protect, add 1.0kgNaBH
4solid, and with salt acid for adjusting pH value to 3.0, separate out tetrahydrofolic acid (THFA) solid, filter; Added to by the solid leached in 5L formic acid, after stirring and dissolving, the trifluoroacetic acid adding 200mL, as catalyzer, is placed 24 hours at the temperature of 10 DEG C-30 DEG C (room temperature); In this system, add the hydrochloric acid of 12.5L, 0.5mol/L again, separate out formylation intermediate--the hydrochloride of 5,10-CH2-THFA;
2) will separate out 5, the hydrochloride 300g of 10-methylene tetrahydrofolate redissolves in 1.5L formic acid, after stirring and dissolving, add the hydrochloric acid of 3.75L, 1mol/L, place at the temperature of 10 DEG C-30 DEG C (room temperature), separate out the highly finished product of 5,10-CH2-THFA hydrochloride, detect specific optical rotation and be+18 °;
3) the highly finished product 200g of 5,10-CH2-THFA hydrochloride is added in 2000mL water, then add 20.4gN-methylpiperazine and make solution, get this solution 200mL, then add 2mol/LNaOH solution, adjust ph to 7.5, at N
2the lower reflux of protection 4 hours; Stop heating, in reaction solution, add anhydrous CaCl
2200g, stirring and dissolving; The pH value to 8.5 of reaction solution is regulated with 2mol/LNaOH solution; Place at the temperature of 10 DEG C-30 DEG C (room temperature), separate out calcium levofolinate solid; After testing, optical purity is 92.5%, and related substance total amount is 1.8%, and maximum single contaminant is 0.7%;
4) the calcium levofolinate 150g that open loop is separated out is added in 700mL water, at N
270 DEG C are heated under protection; After dissolution of solid, add the anhydrous CaCl of 150g
2, stirring and dissolving; Adjust solution ph to 7.5 by NaOH solution, place at the temperature of 10 DEG C-30 DEG C (room temperature), separate out calcium levofolinate highly finished product solid; After testing, optical purity is 98.5%, and related substance total amount is 0.9%, and maximum single contaminant is 0.3%.
embodiment 3
1) take folic acid 2.5kg, add the distilled water of 25L, stir; Regulate the pH value to 7.5 of reaction system with NaOH solution, pass into N
2protect, add the NaBH of 2.5kg
4solid, and with salt acid for adjusting pH value to 3.0, separate out tetrahydrofolic acid (THFA) solid, filter; The solid leached is added in 10L formic acid, after stirring and dissolving, add the trifluoroacetic acid of 200mL as catalyzer; At the temperature of 10 DEG C-30 DEG C (room temperature), place the hydrochloric acid adding 7.5L2mol/L for 10 hours in backward formic acid, separate out formylation intermediate--the hydrochloride of 5,10-CH2-THFA;
2) will separate out 5, the hydrochloride 700g of 10-methylene tetrahydrofolate redissolves in 2.1L formic acid, after stirring and dissolving, add the hydrochloric acid of 2.1L, 2mol/L, place at the temperature of 10 DEG C-30 DEG C (room temperature), separate out the highly finished product of 5,10-CH2-THFA hydrochloride, detect specific optical rotation and be+26 °;
3) added in 4.0L water by the highly finished product 500g of 5,10-CH2-THFA hydrochloride, the 2-methylpiperazine adding 611g makes solution, gets this solution 1.0L, then adds 1mol/LNaOH solution, tune to open the pH value to 6.5 of member ring systems, at N
2the lower reflux of protection 4 hours; Stop heating, in reaction solution, add anhydrous CaCl
2500g, stirring and dissolving; The pH value to 7.5 of reaction solution is regulated with 2mol/LNaOH solution; Place at the temperature of 10 DEG C-30 DEG C (room temperature), separate out calcium levofolinate solid; After testing, optical purity is 95.0%, and related substance total amount is 1.7%, and maximum single contaminant is 0.6%;
4) the calcium levofolinate 300g that open loop is separated out is added in 3.0L water, at N
270 DEG C are heated under protection; After dissolution of solid, add the anhydrous CaCl of 300g
2, stirring and dissolving; Carry out regulator solution pH value to 7.0 by NaOH solution, place at the temperature of 10 DEG C-30 DEG C (room temperature), separate out calcium levofolinate highly finished product solid; After testing, optical purity is 99.3%, and related substance total amount is 0.8%, and maximum single contaminant is 0.2%.
embodiment 4
1) take folic acid 15kg, add the distilled water of 150L, stir; Regulate pH value of reaction system to 8.0 with NaOH solution, pass into N
2protect, add the NaBH of 15kg
4solid, and with hydrochloric acid adjust pH to 3.5, separate out tetrahydrofolic acid (THFA) solid, filter; The solid leached is added in 60L formic acid, after stirring and dissolving, add 1.25L trifluoroacetic acid as catalyzer; At the temperature of 10 DEG C-30 DEG C (room temperature), place the hydrochloric acid adding 30L, 3mol/L for 18 hours in backward formic acid, separate out the hydrochloride of formylation intermediate-5,10-CH2-THFA;
2) will separate out 5, the hydrochloride 7kg of 10-methylene tetrahydrofolate redissolves in 28L formic acid, after stirring and dissolving, add the hydrochloric acid of 21L, 3mol/L, place at the temperature of 10 DEG C-30 DEG C (room temperature), separate out the highly finished product of 5,10-CH2-THFA hydrochloride, detect specific optical rotation and be+30 °;
3) the highly finished product 5kg of 5,10-CH2-THFA hydrochloride is added in 40L water, then add 4.38kg piperazine and make solution, get this solution 10L, then add 1mol/LNaOH solution, tune to open the pH value to 6.5 of member ring systems, at N
2the lower reflux of protection 4 hours; Stop heating; Anhydrous CaCl is added in reaction solution
2500g, stirring and dissolving; The pH value to 5.5 of reaction solution is regulated with 2mol/LNaOH solution; Place at the temperature of 10 DEG C-30 DEG C (room temperature), separate out calcium levofolinate solid; Optical purity is 93.0% after testing, and related substance total amount is 2.5%, and maximum single contaminant is 0.9%;
4) the calcium levofolinate 3kg that open loop is separated out is added in 30L water, at N
275 DEG C are heated under protection; After dissolution of solid, add the anhydrous CaCl of 3kg
2, stirring and dissolving; Adjust solution ph to 6.0 by NaOH solution, place at the temperature of 10 DEG C-30 DEG C (room temperature), separate out calcium levofolinate highly finished product solid; After testing, optical purity is 99.1%, and related substance total amount is 1.0%, and maximum single contaminant is 0.3%.
Claims (27)
1. prepare a method for calcium levofolinate, it is characterized in that, said method comprising the steps of:
1) reduction of folates as raw material is obtained reduzate tetrahydrofolic acid (THFA), tetrahydrofolic acid (THFA) is added in formic acid, when with trifluoroacetic acid as catalyzer, carry out formylation, obtain formylation intermediate 5,10-CH2-THFA; In described 5,10-CH2-THFA, add the solution of haloid acid, obtain the halogen acid salt of formylation intermediate 5,10-CH2-THFA;
2) by step 1) obtain 5, the halogen acid salt of 10-methylene tetrahydrofolate redissolves in formic acid, adding and step 1 again) solution of identical haloid acid carries out recrystallization, thus obtains the halogen acid salt of purified 5,10-CH2-THFA;
3) by step 2) obtain purified 5, the halogen acid salt of 10-methylene tetrahydrofolate is suspended in water and forms the aqueous solution, add basic solution so that the pH value of the described aqueous solution is adjusted to 5.5-7.5, then carry out heating hydrolysis open loop, in the solution after open loop, add anhydrous CaCl
2, and adjust ph is to 5.5-8.5, places, obtains calcium levofolinate solid;
4) to step 3) the calcium levofolinate solid water that obtains carries out recrystallization, obtains target product calcium levofolinate.
2. method according to claim 1, is characterized in that, step 3) be also included in and add basic solution with before the pH value of the described aqueous solution is adjusted to 5.5-7.5, in the described aqueous solution, add alkali to make buffer system.
3. method according to claim 1, is characterized in that, in step 1) described in the volume of formic acid and described raw material folic acid to mass ratio with milliliter to gram counting 1.0-5.0:1.0.
4. method according to claim 3, is characterized in that, in step 1) described in the volume of formic acid and described raw material folic acid to mass ratio with milliliter to gram counting 2.0-4.0:1.0.
5. method according to claim 4, is characterized in that, in step 1) described in the volume of formic acid and described raw material folic acid to mass ratio with milliliter to gram counting 3.0:1.0.
6. method according to any one of claim 1 to 5, is characterized in that, in step 2) described in the volume of halogen acid salt of formic acid and described 5,10-CH2-THFA to mass ratio with milliliter to gram counting 2.0-5.0:1.0.
7. method according to claim 6, is characterized in that, in step 2) described in the volume of halogen acid salt of formic acid and described 5,10-CH2-THFA to mass ratio with milliliter to gram counting 2.0-3.0:1.0.
8. method according to claim 7, is characterized in that, in step 2) described in the volume of halogen acid salt of formic acid and described 5,10-CH2-THFA to mass ratio with milliliter to gram counting 3.0:1.0.
9. method according to any one of claim 1 to 5, is characterized in that, in step 1) and 2) described in haloid acid be selected from one in spirit of salt, Hydrogen bromide and hydroiodic acid HI.
10. method according to claim 9, is characterized in that, in step 1) and 2) described in haloid acid be spirit of salt.
11. methods according to any one of claim 1 to 5, is characterized in that, in step 1) described in the concentration of solution of haloid acid be 0.5mol/L-6mol/L; In step 1) described in the volume of solution of haloid acid be the 0.25-2.5 of the volume of described formic acid doubly.
12. methods according to claim 11, is characterized in that, in step 1) described in the concentration of solution of haloid acid be 2-3mol/L.
13. methods according to claim 11, is characterized in that, in step 1) described in the volume of solution of haloid acid be the 0.75-1.0 of the volume of described formic acid doubly.
14. methods according to any one of claim 1 to 5, is characterized in that, in step 2) described in the concentration of solution of haloid acid be 1.0mol/L-6.0mol/L; In step 2) described in the volume of solution of haloid acid be the 0.25-2.5 of the volume of described formic acid doubly.
15. methods according to claim 14, is characterized in that, in step 2) described in the concentration of solution of haloid acid be 2-3mol/L.
16. methods according to claim 14, is characterized in that, in step 2) described in the volume of solution of haloid acid be the 0.75-1.0 of the volume of described formic acid doubly.
17. methods according to any one of claim 2 to 5, it is characterized in that, described alkali comprises that do not react with water, water miscible, that pKb scope is 2-8 non-volatile alkali.
18. methods according to any one of claim 1 to 5, is characterized in that, described basic solution comprises the aqueous solution of that do not react with water, water miscible, that pKb scope is 2-8 non-volatile alkali.
19. methods according to any one of claim 2 to 5, it is characterized in that, described alkali is a kind of organic bases be selected from piperazine and derivative thereof.
20. methods according to claim 19, is characterized in that, described derivative is alkylpiperazine.
21. methods according to claim 20, is characterized in that, described alkylpiperazine is N methyl piperazine or 2-methylpiperazine.
22. methods according to any one of claim 1 to 5, it is characterized in that, described basic solution comprises the aqueous solution of a kind of organic bases be selected from piperazine and derivative thereof, and/or is selected from the aqueous solution of a kind of mineral alkali in alkali-metal oxyhydroxide, the oxyhydroxide of alkaline-earth metal or quaternary ammonium hydroxide.
23. methods according to claim 22, is characterized in that, described derivative is alkylpiperazine.
24. methods according to claim 23, is characterized in that, described alkylpiperazine is N methyl piperazine or 2-methylpiperazine.
25. methods according to claim 22, is characterized in that, described basic solution is the aqueous solution of alkali-metal oxyhydroxide.
26. methods according to claim 25, is characterized in that, described basic solution is the aqueous solution of sodium hydroxide or potassium hydroxide.
27. methods according to any one of claim 2 to 5, it is characterized in that, the mol ratio of the halogen acid salt of the 5,10-CH2-THFA of described alkali and described purifying is 0.5-0.6:1.
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| CN113387953B (en) * | 2021-06-16 | 2022-05-27 | 海南通用康力制药有限公司 | Synthesis method and application of calcium folinate |
| CN113603691B (en) * | 2021-08-12 | 2022-08-26 | 连云港冠昕医药科技有限公司 | Preparation process of L-5-methyl tetrahydrofolic acid calcium |
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| CN1063285A (en) * | 1991-01-16 | 1992-08-05 | 埃普罗瓦股份公司 | (6S)-and (6R) preparation method of tetrahydrofolic acid (THFA) |
| CN102399223A (en) * | 2011-10-21 | 2012-04-04 | 湖州展望药业有限公司 | Preparation method of medicinal calcium folinate |
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| CN1063285A (en) * | 1991-01-16 | 1992-08-05 | 埃普罗瓦股份公司 | (6S)-and (6R) preparation method of tetrahydrofolic acid (THFA) |
| CN102399223A (en) * | 2011-10-21 | 2012-04-04 | 湖州展望药业有限公司 | Preparation method of medicinal calcium folinate |
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