CN104045640A - Preparation method for high purity L-calcium levofolinate - Google Patents
Preparation method for high purity L-calcium levofolinate Download PDFInfo
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Abstract
The invention provides a preparation method for high purity L-calcium levofolinate. With folic acid as a starting raw material, the method relates to reduction, formylation, intermediate recrystallization splitting, hydrolysis ring opening, recrystallization refining and other steps. The L-calcium levofolinate prepared by the invention has a color ranging from white to light yellow, optical purity of not less than 98.5%, in related substance inspection, the total impurities are not greater than 1% and a single impurity is not greater than 0.3%. The preparation method for high purity L-calcium levofolinate provided by the invention has the advantages of simple operation, short process period and high product quality, and can be used for industrialized production of related bulk drugs by drug production enterprises.
Description
Technical field
The invention belongs to the synthetic field of medicinal chemicals, be specifically related to a kind of method of preparing high purity calcium levofolinate.
Background technology
Calcium levofolinate (L-Calcium Levofolinate), molecular formula is C
20h
21caN
7o
7, molecular weight 511.5, CAS No.: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] 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 (being folinic acid).L-leucovorin does not need can be participated in utilizing folate as the reaction in one carbon unit source by Tetrahydrofolate dehydrogenase reduction, 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, because folic acid will first become folinic acid in liver and marrow, just can work.And this product, calcium levofolinate, is the activity form of l-leucovorin, it also has the effect that stimulates 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 giant cells anaemia that folic acid deficiency causes, also can combine and make for extending advanced colon cancer patient's lifetime or relief of symptoms with Fluracil.Calcium levofolinate is combined and is made, for treating the malignant tumour of other types, usually as a member of multiple medicines combined treatment, to use with methotrexate or Fluracil in practice.
In addition, calcium levofolinate also can be used for treating the medication of psoriasis and rheumatoid arthritis and so on autoimmune disease, and in chemotherapy for improving for example, resistance for some antiparasitic (trimethoprim-sulfamethoxazole).
First calcium levofolinate is succeeded in developing by U.S.'s Hui Shi drug company, in 1994, first in Britain, go on the market, now comprising the listing of the 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 > >, recorded, external clinical application has fully confirmed the safety and effectiveness of this medicine.Therefore this kind fails to obtain China's patent protection, does not also meet the condition of not applying for administrative protection, raw material and the preparation of legal this medicine of development at home.
Calcium levofolinate is the active optically active form of Calciumlevofolinate, has the comparative advantages of drug effect and security aspect.Following this product becomes the Yi Zhixin 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] Rees L., et al.A simple and effective method for preparation of the6 (R)-and6 (S)-diastereoisomers of5-formyltetrahydrofolate (leucovorin) .J Chem Soc Chem Commun1987, (6), 470; [2] Yukihiro K., et al.Large-scale chemoenzymic synthesis of calcium (6S)-5-formyl-5,6,7,8-tetrahydrofolate[(–)-leucovorin] using the NADPH recycling method.J.Chem.Soc., Perkin Trans.1,1994, (11), 1427; [3] Pelletier, J.N.et al.Methenyltetrahydrofolate cyclohydrolase catalyzes the synthesis of (6S)-5-formyltetrahydrofolate.Bioorg Chem, 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 SILVER REAGENT valuable product, 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] levoleucovorin calcium and the method for splitting .2003 of woods Guoqiang etc.-Gao specific optical rotation, CN1401647A.
The DL Calciumlevofolinate of take is prepared calcium levofolinate as raw material, to utilize Calciumlevofolinate enantiomorph different solubility and carry out crystallization fractionation in the aqueous solution, not high from the efficiency of the left-handed mapping enantiomorph of DL Chiral Separation, according to published data, conventionally need to split and just can obtain the calcium levofolinate sample that optical purity is greater than 99% through three to four times.In addition, although repeatedly split the reduction that is conducive to impurity level, increase fractionation number of times and will cause product yield 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, the DL Calciumlevofolinate of take is prepared calcium levofolinate as raw material, and final quality product still depends on the quality of DL Calciumlevofolinate.
3. DL Calciumlevofolinate is synthetic
Data source (6-10): [6] Temple.Jr., et al.Preparation and Purification of L-(±)-5-Formyl-5,6,7,8-tetrahydrofolic Acid.Am.Chem.Soc., 1979,22 (6): 731; [7] Temple, Jr.et al.Preparation of tetrahydrofolic acid from folic acid.United States Patent, 4148999,1979; [8] the synthetic improvement of .5-calcium leucovorin such as Huang Kai; Medicine industry, 1986,17 (10): 433; [9] Wang Biao waits the synthetic and 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 be take folic acid conventionally as starting raw material, and folic acid carries out formylation reaction generation 5,10-CH2-THFA after being reduced to tetrahydrofolic acid (THFA) immediately, and the latter's hydrolysis under neutrallty condition adds calcium precipitation and obtains Calciumlevofolinate.In above-mentioned open source information, there are two factors to cause the quality product in industrial production to be difficult to guarantee.
First, in formylation step, due to formylation reagent large usage quantity, for formylation product can be separated 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.
Test and show under acidic conditions, intermediate 5,10-CH2-THFA is to thermally labile, and its amido linkage is easily hydrolyzed.The formylation reagents such as formic acid are because boiling point is high, and the efficiency of underpressure distillation is had relatively high expectations to the vacuum tightness of distillation plant and distillation temperature.For at a lower temperature, (<60 ℃) 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]) under alkaline condition, according to open source information; under industrial scale, with strong base solution, regulate the pH value of open loop system; very easily cause local pH too high, generate 10 formylated by products, because such impurity solubleness is lower than calcium levofolinate; split process is usually separated out together along with separating out principal product, is difficult to remove.
Summary of the invention
Object of the present invention is mainly to have improved formylation and the hydrolysis step in existing Calciumlevofolinate synthesis technique.
On the one hand, the invention provides a kind of method of preparing calcium levofolinate, said method comprising the steps of:
1) the folic acid reduction as raw material is obtained to reduzate tetrahydrofolic acid (THFA), tetrahydrofolic acid (THFA) is added in formic acid, in the situation that using trifluoroacetic acid as catalyzer, carry out formylation, obtain formylation intermediate 5,10-CH2-THFA; To the solution that adds haloid acid in described 5,10-CH2-THFA, obtain the halogen acid salt of formylation intermediate 5,10-CH2-THFA;
2) halogen acid salt of 5,10-CH2-THFA step 1) being obtained redissolves in formic acid, then adds the solution of the haloid acid identical with step 1) to carry out recrystallization, thereby 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 and in water, 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 regulate pH value to 5.5-8.5, and place, obtain calcium levofolinate solid;
4) calcium levofolinate solid water step 3) being obtained carries out recrystallization, obtains 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, in the described aqueous solution, adds alkali to make buffer system.
Preferably, at the volume of formic acid described in step 1) 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, 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, more preferably 3.0:1.0.
Preferably, in step 1) and 2) described in haloid acid be selected from a kind of in spirit of salt, Hydrogen bromide and hydroiodic acid HI, be preferably spirit of salt.
Preferably, in the concentration of the solution of the haloid acid described in step 1), be 0.5mol/L-6mol/L, be preferably 2-3mol/L; The 0.25-2.5 of the volume that is described formic acid at the volume of the solution of haloid acid described in step 1) doubly, 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 the described haloid acid volume that is described formic acid 0.25-2.5 doubly, be preferably 0.75-1.0 doubly.
Preferably, described alkali comprises the non-volatile alkali that do not react with water, water miscible, pKb scope is 2-8.
Preferably, described basic solution comprises the aqueous solution that do not react with water, water miscible, non-volatile alkali that pKb scope is 2-8.
Preferably, described alkali is a kind of organic bases being selected from piperazine and derivative thereof, and described derivative is preferably alkylpiperazine, more preferably N methyl piperazine or 2-methylpiperazine.
Preferably, described basic solution comprises the aqueous solution that is selected from a kind of organic bases in piperazine and derivative thereof, and described derivative is preferably alkylpiperazine, more preferably N methyl piperazine or 2-methylpiperazine; And/or be selected from the oxyhydroxide of alkali-metal oxyhydroxide, alkaline-earth metal or the aqueous solution of a kind of mineral alkali in quaternary ammonium hydroxide, be preferably the aqueous solution of alkali-metal oxyhydroxide, 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 of being 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 of preparing according to method of the present invention in the purposes for the preparation of in treatment autoimmune disease medicine.
Preferably, described autoimmune disease comprises psoriasis or rheumatoid arthritis.
The present invention can be by preferred embodiment realizing below.
The schematic flow sheet of concrete technology is as follows:
(1) by the reduzate of raw material folic acid--tetrahydrofolic acid (THFA), at trifluoroacetic acid, as catalyzer in the situation that, be added to formic acid and carry out in formylation, place after 10-24 hour the temperature (room temperature) of 10 ℃-30 ℃ are lower, obtain 5,10-CH2-THFA; Add again hydrochloric acid, formylation intermediate-5,10-CH2-THFA is separated out with hydrochloride form;
(2) hydrochloride of the 5,10-CH2-THFA of separating out is redissolved with formic acid, 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, add middle highly basic for example the aqueous solution of piperazine make buffer system, add again middle highly basic for example piperazine or the highly basic pH value that for example aqueous solution of sodium hydroxide tunes to open ring reaction system to 5.5-7.5, carry out heating hydrolysis open loop, to the solution after open loop, directly add the anhydrous CaCl with weight (w/w) such as intermediates
2, and adjust pH is to 5.5-8.5, places, the solid of separating out is calcium levofolinate;
(4) by the calcium levofolinate of separating out 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, added and utilized formic acid to 5, the step that the halogen acid salt of 10-methylene tetrahydrofolate redissolves recrystallization, this step makes in the stage that obtains the halogen acid salt of 5,10-CH2-THFA, just to purify in the process of the highly purified calcium levofolinate of preparation.Through the inventor, find, add this step to play the effect that improves intermediate purity and decolouring, thereby improved the optical purity of final product.Particularly, do not utilizing formic acid to 5, the halogen acid salt of 10-methylene tetrahydrofolate redissolves in the prior art of recrystallization, the product finally obtaining is the Calciumlevofolinate of DL, need to split and just can obtain the calcium levofolinate of 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 has added and utilizes formic acid to 5 in the process of preparation high purity calcium levofolinate, the step that the halogen acid salt of 10-methylene tetrahydrofolate redissolves recrystallization, the enantiomorph of halogen acid salt that directly obtains the dextrorotation intermediate of certain optical purity, is levofolinate after this enantiomorph hydrolysis.So that after this recrystallization sample open loop, the ratio due to levo-enantiomer is higher, foreign matter content is low, therefore, after ring-opening reaction completes, can directly in ring-opening reaction liquid, carry out the simple fractionation of levo-enantiomer, obtain the calcium levofolinate that purity is very high;
Second aspect, in whole preparation method, is used formic acid at twice, thereby makes in every step formic acid usage quantity less, has so just avoided using the concentrated step of heating to remove formic acid; Add haloid acid to be preferably hydrochloric acid simultaneously and carry out crystallization operation, do not heating under the prerequisite of 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 has oxidisability, even if rare nitric acid, the tetrahydrochysene pterin parent nucleus of folinic acid can be oxidized; And sulfuric acid also has oxidisability when concentration is high, even if use dilute sulphuric acid, the vitriol of 5,10-CH2-THFA is in open loop step, and the calcium ion that adds can be with open loop time of sulfate radical react to generate and precipitate, and affects quality product.Except using hydrochloric acid, other feasible haloid acid comprise Hydrogen bromide, hydroiodic acid HI;
The third aspect, in open loop step, with the weak middle strong base solution of alkalescence, replace wholly or in part highly basic to be preferably the pH value that NaOH solution regulates reaction system, the buffering system of utilizing weak organic bases and folinic acid derivative to form, guarantees that pH value can be stabilized in rational scope (6.5 ± 1.0).
Calcium levofolinate preparation method after the present invention improves, can realize the effective control to quality product under industrial amplification scale, avoid distilling the corrosive reagents such as formic acid under high temperature, reduced the requirement of production unit, be convenient to amplifieroperation, simultaneously owing to having reduced splitting step, yield that can larger raising finished product.
Embodiment
Below in conjunction with embodiment, the present invention is further described in detail, the embodiment providing is only in order to demonstrate the present invention, rather than in order to limit the scope of the invention.
performance test:
In following examples, 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)), at 25 ℃, measure, and luminosity length of tube is 10cm.
The detection of related substance, for example folinic acid, adopts reversed-phased high performace liquid chromatographic to detect, and testing conditions is:
Moving phase: methyl alcohol: water (every 780mL water 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; Detect wavelength: 286nm; Flow velocity: 1mL/min;
Adopt HPLC areas of peak normalization method 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 water, 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; Detect wavelength: 286nm; Flow velocity: 1mL/min;
Adopt HPLC areas of peak normalization method to evaluate the optical purity of calcium levofolinate.
embodiment 1
1) take folic acid 300g, add the distilled water of 2.7L, stir; The pH value to 8.0 that regulates reaction system with NaOH solution, passes 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; The solid leaching is added in 300mL formic acid, after stirring and dissolving, add the trifluoroacetic acid of 6mL as catalyzer, the lower placement of the temperature (room temperature) of 10 ℃-30 ℃ 14 hours; To the hydrochloric acid that adds 75mL, 6mol/L in this system, separate out formylation intermediate again--the hydrochloride of 5,10-CH2-THFA;
2) by separate out 5, the hydrochloride 150g of 10-methylene tetrahydrofolate redissolves in the formic acid of 300mL, after stirring and dissolving, the hydrochloric acid that adds 75mL, 6mol/L, in the lower placement of the temperature (room temperature) of 10 ℃-30 ℃, separate out the highly finished product of 5,10-CH2-THFA hydrochloride, detecting specific optical rotation is+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/L KOH solution, adjust pH to 5.5, at N
2the lower reflux of protection 3 hours, stops heating; In reaction solution, add anhydrous CaCl
2100g, stirring and dissolving; With 2mol/L NaOH solution, regulate the pH value to 8.0 of reaction solution; In the lower placement of the temperature (room temperature) of 10 ℃-30 ℃, 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) calcium levofolinate 70g open loop being separated out adds in 700mL water, at N
2under protection, be heated to 70 ℃; After dissolution of solid, add the anhydrous CaCl of 70g
2, stirring and dissolving; With NaOH solution, adjust pH to 7.0, in the lower placement of the temperature (room temperature) of 10 ℃-30 ℃, 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; The pH value to 8.0 that regulates reaction system with NaOH solution, passes into N
2protect, add 1.0kg NaBH
4solid, and with salt acid for adjusting pH value to 3.0, separate out tetrahydrofolic acid (THFA) solid, filter; The solid leaching is added in 5L formic acid, after stirring and dissolving, add the trifluoroacetic acid of 200mL as catalyzer, the lower placement of the temperature (room temperature) of 10 ℃-30 ℃ 24 hours; To the hydrochloric acid that adds 12.5L, 0.5mol/L in this system, separate out formylation intermediate again--the hydrochloride of 5,10-CH2-THFA;
2) by separate out 5, the hydrochloride 300g of 10-methylene tetrahydrofolate redissolves in 1.5L formic acid, after stirring and dissolving, the hydrochloric acid that adds 3.75L, 1mol/L, in the lower placement of the temperature (room temperature) of 10 ℃-30 ℃, separate out the highly finished product of 5,10-CH2-THFA hydrochloride, detecting specific optical rotation is+18 °;
3) the highly finished product 200g of 5,10-CH2-THFA hydrochloride is added in 2000mL water, then add 20.4g N methyl piperazine and make solution, get this solution 200mL, then add 2mol/L NaOH solution, regulate pH value to 7.5, at N
2the lower reflux of protection 4 hours; Stop heating, in reaction solution, add anhydrous CaCl
2200g, stirring and dissolving; With 2mol/L NaOH solution, regulate the pH value to 8.5 of reaction solution; In the lower placement of the temperature (room temperature) of 10 ℃-30 ℃, 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) calcium levofolinate 150g open loop being separated out adds in 700mL water, at N
2under protection, be heated to 70 ℃; After dissolution of solid, add the anhydrous CaCl of 150g
2, stirring and dissolving; With NaOH solution, adjust pH to 7.5, in the lower placement of the temperature (room temperature) of 10 ℃-30 ℃, 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; The pH value to 7.5 that regulates reaction system with NaOH solution, passes 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 leaching is added in 10L formic acid, after stirring and dissolving, add the trifluoroacetic acid of 200mL as catalyzer; At the lower hydrochloric acid that adds 7.5L2mol/L for 10 hours in backward formic acid of placing of the temperature (room temperature) of 10 ℃-30 ℃, separate out formylation intermediate--the hydrochloride of 5,10-CH2-THFA;
2) by separate out 5, the hydrochloride 700g of 10-methylene tetrahydrofolate redissolves in 2.1L formic acid, after stirring and dissolving, the hydrochloric acid that adds 2.1L, 2mol/L, in the lower placement of the temperature (room temperature) of 10 ℃-30 ℃, separate out the highly finished product of 5,10-CH2-THFA hydrochloride, detecting specific optical rotation is+26 °;
3) the highly finished product 500g of 5,10-CH2-THFA hydrochloride is added in 4.0L water, add the 2-methylpiperazine of 611g to make solution, get this solution 1.0L, then add 1mol/L NaOH 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; With 2mol/L NaOH solution, regulate the pH value to 7.5 of reaction solution; In the lower placement of the temperature (room temperature) of 10 ℃-30 ℃, 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) calcium levofolinate 300g open loop being separated out adds in 3.0L water, at N
2under protection, be heated to 70 ℃; After dissolution of solid, add the anhydrous CaCl of 300g
2, stirring and dissolving; With NaOH solution, carry out regulator solution pH value to 7.0, in the lower placement of the temperature (room temperature) of 10 ℃-30 ℃, 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; With NaOH solution, regulate pH value of reaction system to 8.0, 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 leaching is added in 60L formic acid, after stirring and dissolving, add 1.25L trifluoroacetic acid as catalyzer; At the lower hydrochloric acid that adds 30L, 3mol/L for 18 hours in backward formic acid of placing of the temperature (room temperature) of 10 ℃-30 ℃, separate out the hydrochloride of formylation intermediate-5,10-CH2-THFA;
2) by separate out 5, the hydrochloride 7kg of 10-methylene tetrahydrofolate redissolves in 28L formic acid, after stirring and dissolving, the hydrochloric acid that adds 21L, 3mol/L, in the lower placement of the temperature (room temperature) of 10 ℃-30 ℃, separate out the highly finished product of 5,10-CH2-THFA hydrochloride, detecting specific optical rotation is+30 °;
3) the highly finished product 5kg of 5,10-CH2-THFA hydrochloride is added in 40L water, then add 4.38kg piperazine to make solution, get this solution 10L, then add 1mol/L NaOH 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; With 2mol/L NaOH solution, regulate the pH value to 5.5 of reaction solution; In the lower placement of the temperature (room temperature) of 10 ℃-30 ℃, 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) calcium levofolinate 3kg open loop being separated out adds in 30L water, at N
2under protection, be heated to 75 ℃; After dissolution of solid, add the anhydrous CaCl of 3kg
2, stirring and dissolving; With NaOH solution, adjust pH to 6.0, in the lower placement of the temperature (room temperature) of 10 ℃-30 ℃, 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 (16)
1. a method of preparing calcium levofolinate, is characterized in that, said method comprising the steps of:
1) the folic acid reduction as raw material is obtained to reduzate tetrahydrofolic acid (THFA), tetrahydrofolic acid (THFA) is added in formic acid, in the situation that using trifluoroacetic acid as catalyzer, carry out formylation, obtain formylation intermediate 5,10-CH2-THFA; To the solution that adds haloid acid in described 5,10-CH2-THFA, obtain the halogen acid salt of formylation intermediate 5,10-CH2-THFA;
2) halogen acid salt of 5,10-CH2-THFA step 1) being obtained redissolves in formic acid, then adds the solution of the haloid acid identical with step 1) to carry out recrystallization, thereby 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 and in water, 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 regulate pH value to 5.5-8.5, and place, obtain calcium levofolinate solid;
4) calcium levofolinate solid water step 3) being obtained carries out recrystallization, obtains target product calcium levofolinate.
2. method according to claim 1, is characterized in that, 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, in the described aqueous solution, adds alkali to make buffer system.
3. method according to claim 1 and 2, is characterized in that, at the volume of formic acid described in step 1) 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, more preferably 3.0:1.0.
4. according to the method in any one of claims 1 to 3, it 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, be preferably 2.0-3.0:1.0, more preferably 3.0:1.0.
5. according to the method described in any one in claim 1 to 4, it is characterized in that, in step 1) and 2) described in haloid acid be selected from a kind of in spirit of salt, Hydrogen bromide and hydroiodic acid HI, be preferably spirit of salt.
6. according to the method described in any one in claim 1 to 5, it is characterized in that, is 0.5mol/L-6mol/L in the concentration of the solution of the haloid acid described in step 1), is preferably 2-3mol/L; The 0.25-2.5 of the volume that is described formic acid at the volume of the solution of the haloid acid described in step 1) doubly, is preferably 0.75-1.0 doubly.
7. according to the method described in any one in claim 1 to 6, it is characterized in that, in step 2) described in the concentration of solution of haloid acid be 1.0mol/L-6.0mol/L, be preferably 2-3mol/L; In step 2) described in the volume of solution of the haloid acid volume that is described formic acid 0.25-2.5 doubly, be preferably 0.75-1.0 doubly.
8. according to the method described in any one in claim 2 to 7, it is characterized in that the non-volatile alkali that described alkali comprises is that do not react with water, water miscible, pKb scope is 2-8.
9. according to the method described in any one in claim 1 to 8, it is characterized in that the aqueous solution that do not react with water, water miscible, non-volatile alkali that pKb scope is 2-8 that described basic solution comprises.
10. according to the method described in any one in claim 2 to 9, it is characterized in that, described alkali is a kind of organic bases being selected from piperazine and derivative thereof, and described derivative is preferably alkylpiperazine, more preferably N methyl piperazine or 2-methylpiperazine.
11. according to the method described in any one in claim 1 to 10, it is characterized in that, described basic solution comprises the aqueous solution that is selected from a kind of organic bases in piperazine and derivative thereof, and described derivative is preferably alkylpiperazine, more preferably N methyl piperazine or 2-methylpiperazine; And/or be selected from the oxyhydroxide of alkali-metal oxyhydroxide, alkaline-earth metal or the aqueous solution of a kind of mineral alkali in quaternary ammonium hydroxide, be preferably the aqueous solution of alkali-metal oxyhydroxide, more preferably the aqueous solution of sodium hydroxide or potassium hydroxide.
12. according to the method described in any one in claim 2 to 11, 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.
13. 1 kinds of calcium levofolinates of being prepared by the method described in any one in claim 1 to 12.
14. calcium levofolinates according to claim 13, is characterized in that, the optical purity of described calcium levofolinate is greater than 98.5%.
15. calcium levofolinates of preparing according to the method described in any one in claim 1 to 12 are in the purposes for the preparation of in treatment autoimmune disease medicine.
16. purposes according to claim 15, is characterized in that, described autoimmune disease comprises psoriasis or rheumatoid arthritis.
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Cited By (4)
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| CN105399747A (en) * | 2015-10-30 | 2016-03-16 | 天津药物研究院药业有限责任公司 | Preparation method of levo-5,10-methylenetetrahydrofolate |
| CN113387953A (en) * | 2021-06-16 | 2021-09-14 | 海南通用康力制药有限公司 | Synthesis method and application of calcium folinate |
| CN113603691A (en) * | 2021-08-12 | 2021-11-05 | 连云港冠昕医药科技有限公司 | Preparation process of L-5-methyl tetrahydrofolic acid calcium |
| CN114591330A (en) * | 2022-03-14 | 2022-06-07 | 河北冀衡药业股份有限公司 | Preparation method of calcium folinate |
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Cited By (5)
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| CN105399747A (en) * | 2015-10-30 | 2016-03-16 | 天津药物研究院药业有限责任公司 | Preparation method of levo-5,10-methylenetetrahydrofolate |
| CN113387953A (en) * | 2021-06-16 | 2021-09-14 | 海南通用康力制药有限公司 | Synthesis method and application of calcium folinate |
| CN113603691A (en) * | 2021-08-12 | 2021-11-05 | 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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| CN114591330B (en) * | 2022-03-14 | 2023-06-06 | 河北冀衡药业股份有限公司 | Preparation method of calcium folinate |
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