阅读说明：本技术 一种高纯左亚叶酸钙的制备方法 (Preparation method of high-purity calcium levofolinate ) 是由 俞旭峰 朱华 柴志善 于 2021-09-07 设计创作，主要内容包括：本发明属于化学原料药的合成领域,具体涉及一种高纯左亚叶酸钙的制备方法,包括如下步骤：S-1.亚叶酸钙、拆分剂加入到水中,搅拌使其溶解,过滤,得滤液；S-2.向所述滤液中加入乙酸钙和拆分剂,结晶、过滤,得一次拆分固体；S-3.将所述一次拆分固体经过溶解、结晶、过滤、干燥,得到左亚叶酸钙粗品；S-4.所述左亚叶酸钙粗品经经纯化得左亚叶酸钙成品；所述拆分剂为R-(α)-苯乙胺。本发明以乙酸钙的形式引入钙离子,避免了氯离子的引入,成品中无氯离子杂质。另外采用R-(α)-苯乙胺,作为拆分剂,配合乙酸钙,使得成品的异构体小于0.1%(药典规定小于0.5%)。(The invention belongs to the field of synthesis of chemical raw material medicines, and particularly 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 a filtrate; s-2, adding calcium acetate and a resolving agent into the filtrate, crystallizing and filtering to obtain a primary resolved solid; s-3, dissolving, crystallizing, filtering and drying the primary split solid to obtain a crude calcium levofolinate product; s-4, purifying the crude product of the calcium levofolinate to obtain a finished product of the calcium levofolinate; the resolving agent is R- (alpha) -phenylethylamine. The invention introduces calcium ions in the form of calcium acetate, avoids the introduction of chloride ions, and has no chloride ion impurities in the finished product. In addition, R- (alpha) -phenylethylamine is used as a resolving agent and is matched with calcium acetate, so that the isomer of a finished product is less than 0.1% (less than 0.5% specified in pharmacopoeia).)

1. The preparation method of high-purity calcium levofolinate is characterized by comprising 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 a filtrate;

s-2, adding organic acid calcium and a resolving agent into the filtrate, crystallizing and filtering to obtain a primary resolved solid;

s-3, filtering and drying the primary split solid to obtain a crude calcium levofolinate product;

s-4, refining the crude product of the calcium levofolinate to obtain a finished product of the calcium levofolinate;

the resolving agent is R- (alpha) -phenylethylamine.

2. The preparation method of high-purity calcium levofolinate as claimed in claim 1, wherein after the primary resolved solid is obtained, acid is added dropwise to the primary resolved solid, and then organic acid calcium and resolving agent are added, crystallized and filtered to obtain a secondary resolved solid; and filtering and drying the secondary split solid to obtain a crude calcium levofolinate product.

3. The method for preparing high-purity calcium levofolinate according to claim 1, wherein the purification method of crude calcium levofolinate in step S-5 comprises the following steps:

s-11, adding the crude calcium levofolinate into purified water, and adjusting the pH value with organic acid to obtain a dissolved solution;

s-12, filtering the dissolved solution, adding absolute ethyl alcohol into the filtrate, filtering, precipitating and drying to obtain the finished calcium levofolinate.

4. The method for preparing high-purity calcium levofolinate according to claim 1, which comprisesCharacterized in that the calcium folinate is prepared from NaHSO₃ Reducing folic acid to tetrahydrofolic acid, and preparing calcium folinate by using ethyl formate as a formylation reagent.

5. The method according to claim 2, wherein the acid used is acetic acid.

6. The method for preparing high-purity calcium levofolinate according to claim 1, wherein the crystallization temperature is 0 to 20 ℃ and the crystallization time is 5 to 10 hours in step S-2.

7. The method of claim 6, wherein the crystallization time in steps S-2 and S-3 is 5 to 6 hours.

Technical Field

The invention belongs to the field of synthesis of chemical raw material medicines, and particularly relates to a preparation method of high-purity calcium levofolinate.

Background

Calcium levofolinate is calcium salt of levofolinic acid, and levofolinic acid is L-optical isomer with pharmacological activity of 5-formyltetrahydrofolic acid (i.e. folinic acid). The levofolinic acid can participate in a reaction using folate as a source of one-carbon units without being reduced by dihydrofolate reductase, and the levofolinic acid can actively or passively pass through cell membranes. The basic action of levofolinic acid is the same as that of folic acid, but the effect is better than that of folic acid, which is changed into folinic acid in liver and bone marrow to play a role. The product, calcium levofolinate, is the active form of levofolinate, and also 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 combination with methotrexate or fluorouracil in practice to treat other types of malignancies, often as a member of a multi-drug combination regimen.

The levofolinic acid calcium is an active optical rotation body of the folinic acid calcium and has comparative advantages in the aspects of drug effect and safety. The product will gradually replace calcium folinate to become a new army in the domestic antitumor drug market in the future. Has wide market prospect in developing calcium levofolinate products.

Regarding the preparation of calcium levofolinate, for example, patent No. CN103113372A discloses a high-yield preparation method of calcium levofolinate, which prepares calcium levofolinate by a splitting process, wherein a solution containing calcium levofolinate is added during the splitting process, and calcium levofolinate in the calcium levofolinate solution accounts for more than 70% of the total amount of calcium folinate. However, at present, the purity of the levorotatory calcium folinate is difficult to meet the requirement, and the price of the levorotatory calcium folinate is several times 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 of the medicine, so that whether the medicine can be safely used in a large range or not is determined. And most of the preparation processes introduce chloride ions, so that the content of the chloride ions in the product can not meet the standard.

Disclosure of Invention

The invention provides a preparation method of high-purity calcium levofolinate, which is free from introducing chloride ions and has 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 a filtrate;

s-2, adding organic acid calcium and a resolving agent into the filtrate, crystallizing and filtering to obtain a primary resolved solid;

s-3, filtering and drying the primary split solid to obtain a crude calcium levofolinate product;

and S-4, refining the crude product of the calcium levofolinate to obtain a finished product of the calcium levofolinate.

The resolving agent is R- (alpha) -phenylethylamine.

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 the finished product is free of chloride ion impurities. In addition, R- (alpha) -phenylethylamine is used as a resolving agent and is matched with organic acid calcium, so that the isomer of a finished product is less than 0.1% (less than 0.5% specified in pharmacopoeia). The organic acid calcium salt can be calcium formate, calcium acetate, calcium propionate, etc.

The calcium chloride is replaced by the organic acid calcium, so that not only is the chlorine pollution of finished products caused by the introduction of chloride ions avoided, but also the splitting system is more stable, the impurities are reduced, and the optical purity of the obtained calcium levofolinate finished products can reach 99.95% by combining with an R- (alpha) -phenylethylamine splitting agent.

Preferably, after the primary resolved solid is obtained, dropwise adding acid into the primary resolved solid, then adding organic acid calcium and a resolving agent, crystallizing and filtering to obtain a secondary resolved solid; and filtering and drying the secondary split solid to obtain a crude calcium levofolinate product.

Preferably, in 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 adjusting the pH value with acetic acid to obtain a dissolved solution;

s-12, filtering the dissolved solution, adding absolute ethyl alcohol into the filtrate, filtering, precipitating and drying to obtain the finished calcium levofolinate.

Preferably, the calcium folinate is prepared from NaHSO₃ Reducing folic acid to tetrahydrofolic acid, and preparing calcium folinate by using ethyl formate as a formylation reagent.

With conventional boron hydrogenSodium hydride or catalytic hydrogenation reduction method, the reduction is incomplete, a large amount of dihydrofolic acid is generated, or the reactant is subjected to molecular breakage, a byproduct is generated, the yield is reduced, and the separation and purification are difficult. With NaHSO₃As a reducing agent, TLC was examined for the presence of no pterin, p-aminobenzoylglutamic acid and other impurity spots due to molecular cleavage. And with NaHSO in comparison with other reducing agents₃The reduced folic acid has the advantages of lower cost, simpler operation, high yield and the like.

Preferably, the acid used in step S-3 is a low-carbon fatty acid such as formic acid, acetic acid, propionic acid, etc., instead of the conventionally used hydrochloric acid, so as to avoid chlorine pollution of the finished product due to the introduction of chloride ions.

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.

Through 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 value, so that the introduction of chloride ions is avoided, and the finished product has no chloride ion impurities.

2. R- (alpha) -phenylethylamine is used as a resolving agent and is matched with organic acid calcium, so that the isomer of a finished product is less than 0.1% (less than 0.5% specified in pharmacopoeia).

3. The calcium chloride is replaced by the organic acid calcium, so that not only is the chlorine pollution of finished products caused by the introduction of chloride ions avoided, but also the splitting system is more stable, the impurities are reduced, and the optical purity of the obtained calcium levofolinate finished products can reach 99.95% by combining with an R- (alpha) -phenylethylamine splitting agent.

4. The adoption of organic acid calcium (especially calcium acetate) and R- (alpha) -phenylethylamine has been found to greatly shorten the crystallization time, and compared with 20 hours in the prior art, the invention can complete the crystallization within 5 hours.

5. With NaHSO₃ Reducing folic acid to tetrahydrofolic acid, preparing calcium folinate with ethyl formate as formylating agent, and preparing the productThe occurrence of pterin, p-aminobenzoylglutamic acid and other impurity spots generated by molecular cleavage was found. And with NaHSO in comparison with other reducing agents₃The reduced folic acid has the advantages of lower cost, simpler operation, high yield and the like.

Drawings

FIG. 1 is an isomeric diagram 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 isomeric diagram of the twice-resolved solid obtained in example 1;

FIG. 4 is an impurity profile of the twice-resolved solid obtained in example 1;

FIG. 5 is an isomeric diagram of the crude calcium levofolinate obtained in example 1;

FIG. 6 is an impurity profile of the crude calcium levofolinate obtained in example 1;

FIG. 7 is the isomeric diagram of the calcium levofolinate product obtained in example 1;

FIG. 8 is an impurity profile of the calcium levofolinate product obtained in example 1;

FIG. 9 is an isomeric diagram 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 isomerization diagram of the twice-resolved solid obtained in comparative example 1;

FIG. 12 is an impurity map of the twice-resolved solid obtained in comparative example 1;

FIG. 13 is an isomeric diagram of the crude calcium levofolinate obtained in comparative example 1;

FIG. 14 is an impurity profile of the crude calcium levofolinate obtained in comparative example 1;

FIG. 15 is an isomeric diagram of the calcium levofolinate product obtained in comparative example 1;

FIG. 16 is an impurity profile of the calcium levofolinate product obtained in comparative example 1;

FIG. 17 is an isomerization diagram 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 isomerization diagram of the twice-resolved solid obtained in comparative example 2;

FIG. 20 is an impurity map of the twice-resolved solid obtained in comparative example 2;

FIG. 21 is an isomeric diagram of the crude calcium levofolinate obtained in comparative example 2;

FIG. 22 is an impurity profile of the crude calcium levofolinate obtained in comparative example 2;

FIG. 23 is an isomeric diagram of the calcium levofolinate product obtained in comparative example 2;

FIG. 24 is an impurity profile of the calcium levofolinate product obtained in comparative example 2;

FIG. 25 is an isomerization diagram 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 isomerization diagram of the twice-resolved solid obtained in comparative example 3;

FIG. 28 is an impurity map of the twice-resolved solid obtained in comparative example 3;

FIG. 29 is an isomeric diagram of the crude calcium levofolinate obtained in comparative example 3;

FIG. 30 is an impurity profile of the crude calcium levofolinate obtained in comparative example 3;

FIG. 31 is an isomeric diagram of the calcium levofolinate product obtained in comparative example 3;

FIG. 32 is an impurity profile of the calcium levofolinate product obtained in comparative example 3;

FIG. 33 is an isomeric diagram of the calcium levofolinate product obtained in example 2;

FIG. 34 is an impurity profile of the calcium levofolinate product obtained in example 2;

FIG. 35 is an isomeric diagram of the calcium levofolinate product obtained in example 3;

FIG. 36 is an impurity profile of the calcium levofolinate 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 used to illustrate the technical solution of the present invention, and not to limit the same; although the present invention has been described in detail with reference to the following embodiments, those skilled in the art will understand that: the technical scheme described in each embodiment can still be modified, or equivalent replacement can be carried out on part of technical features; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.

Example 1

The high-purity levorotatory calcium folinate is prepared by taking calcium folinate as a raw material, and comprises the following steps:

suspending 51.1g (0.1 m o l) calcium folinate and 25g sodium bromide in 400ml water, heating to 50 ℃ to dissolve, cooling the dissolved solution to 10 ℃ to crystallize for 6h, separating out solid, filtering, washing the solid with water, and combining the filtrates.

Adding 10g of calcium acetate and 2g R- (alpha) -phenylethylamine into the filtrate, cooling the solution to 10 ℃, crystallizing for 6h, separating out a solid, filtering, and washing the solid with water to obtain 59g of a primary resolution solid, wherein the yield is =90%, the primary resolution isomeric pattern is shown in figure 1, and the primary resolution impurity pattern is shown in figure 2.

Suspending the total amount of the first resolved solid in 400ml water, heating to 50 deg.C, adding acetic acid to dissolve, adding 10g calcium acetate and 2g R- (alpha) -phenylethylamine into the dissolved solution, cooling to 10 deg.C, crystallizing for 6 hr, separating out solid, filtering, and washing with water to obtain 51g second resolved solid_，The yield is =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 split solid in 400ml of water, heating to 50 ℃, adding acetic acid to dissolve the secondary split solid, adding 10g of calcium acetate and 2g R- (alpha) -phenylethylamine into the dissolved solution, cooling the dissolved solution to 10 ℃, crystallizing for 6h, separating out the solid, filtering, and washing the solid with water to obtain 44.5g of tertiary split solid-calcium levofolinate crude product, wherein the yield is =90%, the crude product isomeric diagram is shown in figure 5, and the crude product impurity diagram is shown in figure 6.

Suspending the crude calcium levofolinate in 400ml of water, heating to 50 ℃, adding acetic acid to dissolve the crude calcium levofolinate, adding 1500ml of absolute ethyl alcohol into the dissolved solution to crystallize for 5 hours, separating out solids, filtering, washing with absolute ethyl alcohol, and drying to obtain 13.5g of a finished calcium levofolinate product, wherein the yield is =92%, the chloride is less than or equal to 0.05%, the isomeric pattern of the finished product is shown in figure 7, and the impurity pattern of the finished product is shown in figure 8.

Comparative example 1:

the high-purity levorotatory calcium folinate is prepared by taking a crude calcium folinate product as a raw material, and comprises the following steps:

suspending 51.1g (0.1 m o l) crude calcium folinate and 25g sodium bromide in 400ml water, heating to 50 ℃ to dissolve, cooling the dissolved solution to 15 ℃ to crystallize for 6h, separating out solid, filtering, washing the solid with water, and combining the filtrates.

Adding 10g of calcium chloride and 2g R- (alpha) -phenylethylamine into the filtrate, cooling the dissolved solution to 15 ℃, crystallizing for 6h, separating out a solid, filtering, and washing the solid with water to obtain 57g of a primary resolution solid, wherein the yield is =88%, the primary resolution isomeric pattern is shown in figure 9, and the primary resolution impurity pattern is shown in figure 10.

Suspending the total amount of the first-resolution solid in 400ml of water, heating to 50 ℃, adding acetic acid to dissolve the first-resolution solid, adding 10g of calcium chloride and 2g R- (alpha) -phenylethylamine into the dissolved solution, cooling the dissolved solution to 15 ℃, crystallizing for 6h, separating out the solid, filtering, and washing the solid with water to obtain 49g of second-resolution solid, wherein the yield is =87%, the second-resolution isomeric pattern is shown in figure 11, and the second-resolution impurity pattern is shown in figure 12.

Suspending the total amount of the secondary split solid in 400ml of water, heating to 50 ℃, adding acetic acid to dissolve the secondary split solid, adding 10g of calcium chloride and 2g R- (alpha) -phenylethylamine into the dissolved solution, cooling the dissolved solution to 15 ℃, crystallizing for 6h, separating out the solid, filtering, and washing the solid with water to obtain 41g of the tertiary split solid-calcium levofolinate crude product, wherein the yield is =90%, the crude product isomeric diagram is shown in figure 13, and the crude product impurity diagram is shown in figure 14.

Suspending the crude calcium levofolinate in 400ml of water, heating to 50 ℃, adding acetic acid to dissolve the crude calcium levofolinate, adding 1500ml of absolute ethyl alcohol into the dissolved solution to crystallize for 5 hours, separating out solids, filtering, washing with absolute ethyl alcohol, and drying to obtain 12.5g of a finished calcium levofolinate product, wherein the yield is =92%, the chloride is not less than 0.5%, the isomeric pattern of the finished product is shown in figure 15, and the impurity pattern of the finished product is shown in figure 16.

The difference from example 1 is that calcium acetate is replaced by calcium chloride.

Comparative example 2:

the high-purity levorotatory calcium folinate is prepared by taking a crude calcium folinate product as a raw material, and comprises the following steps:

suspending 51.1g (0.1 m o l) crude calcium folinate and 25g sodium bromide in 400ml water, heating to 50 ℃ to dissolve, cooling the dissolved solution to 15 ℃ to crystallize for 6h, separating out solid, filtering, washing the solid with water, and combining the filtrates.

Adding 10g of calcium acetate and 2g S-methylbenzylamine into the filtrate, cooling the solution to 15 ℃, crystallizing for 6h, separating out a solid, filtering, and washing the solid with water to obtain 52.5g of a primary resolved solid, wherein the yield is =80%, the primary resolved isomeric pattern is shown in figure 17, and the primary resolved impurity pattern is shown in figure 18.

Suspending the total amount of the first-resolution solid in 400ml of water, heating to 50 ℃, adding acetic acid to dissolve the first-resolution solid, adding 10g of calcium acetate and 2g S-methylbenzylamine into the dissolved solution, cooling the dissolved solution to 15 ℃, crystallizing for 6h, separating out the solid, filtering, and washing the solid with water to obtain 47g of second-resolution solid, wherein the yield is =86%, the second-resolution isomeric pattern is shown in figure 19, and the second-resolution impurity pattern is shown in figure 20.

Suspending the total amount of the secondary split solid in 400ml of water, heating to 50 ℃, adding acetic acid to dissolve the secondary split solid, adding 10g of calcium acetate and 2g S-methylbenzylamine into the dissolved solution, cooling the dissolved solution to 15 ℃, crystallizing for 6h, separating out a solid, filtering, and washing the solid with water to obtain a tertiary split solid, namely a crude calcium levofolinate product, 38g of the tertiary split solid, wherein the yield is =84%, the isomeric diagram of the crude product is shown in figure 21, and the impurity diagram of the crude product is shown in figure 22.

Suspending the crude calcium levofolinate in 400ml of water, heating to 50 ℃, adding acetic acid to dissolve, adding 1500ml of absolute ethyl alcohol into the dissolved solution to crystallize for 5h, separating out solids, filtering, washing with absolute ethyl alcohol, and drying to obtain 11.2g of the finished calcium levofolinate with yield =90%, wherein the isomeric diagram of the finished product is shown in figure 23, and the impurity diagram of the finished product is shown in figure 24.

The difference from example 1 is that the resolving agent R- (. alpha. -phenylethylamine is replaced by S-methylbenzylamine.

Comparative example 3:

the high-purity levorotatory calcium folinate is prepared by taking a crude calcium folinate product as a raw material, and comprises the following steps:

suspending 51.1g (0.1 m o l) crude calcium folinate and 25g sodium bromide in 400ml water, heating to 50 ℃ to dissolve, cooling the dissolved solution to 15 ℃ to crystallize for 6h, separating out solid, filtering, washing the solid with water, and combining the filtrates.

Adding 10g of calcium acetate and 2g S- (alpha) -phenylethylamine into the filtrate, cooling the solution to 15 ℃, crystallizing for 6h, separating out solid, filtering, and washing the solid with water to obtain 57.5g of primary resolved solid with yield =89%, wherein the primary resolved isomeric pattern is shown in figure 25, and the primary resolved impurity pattern is shown in figure 26.

Suspending the total amount of the first-resolution solid in 400ml of water, heating to 50 ℃, adding acetic acid to dissolve the first-resolution solid, adding 10g of calcium acetate and 2g S- (alpha) -phenylethylamine into the dissolved solution, cooling the dissolved solution to 15 ℃, crystallizing for 6h, separating out the solid, filtering, and washing the solid with water to obtain 47.8g of second-resolution solid, wherein the yield is =88%, the second-resolution isomeric pattern is shown in figure 27, and the second-resolution impurity pattern is shown in figure 28.

Suspending the whole amount of the secondary split solid in 400ml of water, heating to 50 ℃, adding acetic acid to dissolve the secondary split solid, adding 10g of calcium acetate and 2g S- (alpha) -phenylethylamine into the dissolved solution, cooling the dissolved solution to 15 ℃, crystallizing for 6h, separating out the solid, filtering, and washing the solid with water to obtain 40.1g of tertiary split solid-calcium levofolinate crude product, wherein the yield is =86%, the crude product isomeric diagram is shown in an attached figure 29, and the crude product impurity diagram is shown in an attached figure 30.

Suspending the crude calcium levofolinate in 400ml of water, heating to 50 ℃, adding acetic acid to dissolve, adding 1500ml of absolute ethyl alcohol into the dissolved solution to crystallize for 5h, separating out solids, filtering, washing with absolute ethyl alcohol, and drying to obtain 12.2g of the finished calcium levofolinate with yield =91%, wherein the isomeric diagram of the finished product is shown in figure 31, and the impurity diagram of the finished product is shown in figure 32.

The difference from example 1 is that the resolving agent R- (. alpha. -phenylethylamine is replaced by S- (. alpha. -phenylethylamine).

Example 2

The high-purity levorotatory calcium folinate is prepared by taking calcium folinate as a raw material, and comprises the following steps:

suspending 51.1g (0.1 m o l) calcium folinate and 25g sodium bromide in 400ml water, heating to 40-60 deg.C to dissolve, cooling to 0-20 deg.C to crystallize for 5-20 h, precipitating solid, filtering, washing the solid with water, and mixing filtrates.

Adding 8g of calcium formate and 2g R- (. alpha. -phenylethylamine) into the filtrate, cooling the dissolved solution to (0-20) ° C, crystallizing for (5-20) h, precipitating a solid, filtering, and washing the solid with water to obtain 59.5g of a first-time resolved solid, wherein the yield is = 91%.

Suspending the total amount of the first resolved solid in 400ml water, heating to 40-60 deg.C, adding formic acid to dissolve, adding 8g calcium formate and 2g R- (alpha) -phenylethylamine into the dissolved solution, cooling to 0-20 deg.C, crystallizing for 5-20 h, separating out solid, filtering, washing the solid with water to obtain 50g second resolved solid_，The yield = 89%.

Suspending the total amount of the secondary split solid in 400ml of water, heating to (40-60) DEG C, adding formic acid to dissolve the secondary split solid, adding 8g of calcium formate and 2g R- (alpha) -phenylethylamine into the dissolved solution, cooling the dissolved solution to (0-20) DEG C, crystallizing for (5-20) h, separating out the solid, filtering, and washing the solid with water to obtain the tertiary split solid, namely 43.8g of crude calcium levofolinate, wherein the yield is = 89.2%.

Suspending the crude calcium levofolinate in 400ml of water, heating to 40-60 deg.C, adding formic acid to dissolve, adding 1500ml of absolute ethanol into the dissolved solution, crystallizing for 2-6 h, separating out solid, filtering, washing with absolute ethanol, and drying to obtain 13.2g of calcium levofolinate, wherein the yield is =91.5%, the chloride is less than or equal to 0.05%, the isomeric pattern of the final product is shown in figure 33, and the impurity pattern of the final product is shown in figure 34.

Example 3

The high-purity levorotatory calcium folinate is prepared by taking calcium folinate as a raw material, and comprises the following steps:

suspending 51.1g (0.1 m o l) calcium folinate and 25g sodium bromide in 400ml water, heating to 40-60 deg.C to dissolve, cooling to 0-20 deg.C to crystallize for 5-20 h, precipitating solid, filtering, washing the solid with water, and mixing filtrates.

Adding 12g of calcium propionate and 2g R- (. alpha. -phenylethylamine) into the filtrate, cooling the solution to (0-20) DEG C, crystallizing for (5-20) h, precipitating a solid, filtering, and washing the solid with water to obtain 60g of a first-time resolved solid, wherein the yield is = 90.5%.

Suspending the total amount of the first resolved solid in 400ml water, heating to 40-60 deg.C, adding propionic acid to dissolve, adding 12g calcium propionate and 2g R- (alpha) -phenylethylamine into the dissolved solution, cooling to 0-20 deg.C, crystallizing for 5-20 h, separating out solid, filtering, and washing with water to obtain second resolved solid 51.5g_，Yield = 90.3%.

Suspending the total amount of the secondary split solid in 400ml of water, heating to (40-60) DEG C, adding propionic acid to dissolve the secondary split solid, adding 12g of calcium propionate and 2g R- (alpha) -phenylethylamine into the dissolved solution, cooling the dissolved solution to (0-20) DEG C, crystallizing for (5-20) h, separating out the solid, filtering, and washing the solid with water to obtain the tertiary split solid, namely 44.8g of crude calcium levofolinate, wherein the yield is = 90.2%.

Suspending the crude calcium levofolinate in 400ml of water, heating to 40-60 ℃, adding propionic acid to dissolve, adding 1500ml of absolute ethyl alcohol into the dissolved solution to crystallize for 2-6 h, separating out solids, filtering, washing with absolute ethyl alcohol, and drying to obtain 13.7g of the finished calcium levofolinate, wherein the yield is =92.1%, the chloride is less than or equal to 0.05%, the isomeric diagram of the finished product is shown in figure 35, and the impurity diagram of the finished product is shown in figure 36.

Example 4

From the preparation of tetrahydrofolic acid to the preparation of high-purity calcium levofolinate by NaHSO₃ Reducing folic acid to tetrahydrofolic acid, and preparing calcium folinate by using ethyl formate as a formylation reagent. And then the obtained calcium folinate is used as a raw material to prepare the high-purity L-calcium folinate.

Suspending 10g folic acid in 60ml water, adding sodium hydroxide solution, stirring to dissolve, adding 15g sodium bisulfite, standing at 70 deg.C for 1.5 hr, decolorizing, filtering, adding vitamin C into the filtrate, adjusting pH to 4.0, and filtering to obtain 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 a crude calcium folinate product.

The same procedure as in example 3 was repeated to produce high-purity calcium levofolinate from the obtained calcium folinate.