CN101143863B

CN101143863B - Resolution for 5-methyltetrahydrofolic acid and salifying method thereof

Info

Publication number: CN101143863B
Application number: CN2006100415414A
Authority: CN
Inventors: 陈新; 朱光旭; 陈伟
Original assignee: Laiyin Medicines Tech Co Ltd Nanjing
Current assignee: Laiyin Medicines Tech Co Ltd Nanjing
Priority date: 2006-09-13
Filing date: 2006-09-13
Publication date: 2010-08-11
Anticipated expiration: 2026-09-13
Also published as: WO2008031284A1; CN101143863A

Abstract

The invention brings forward a preparation method, which utilizes organic alkali Alpha-phenylethylamine to obtain (6S)-5-methyltetrahydrofolate by splitting racemate (6R, S)-5-methyltetrahydrofolate, and utilizes the hydroxide of alkaline earth, particularly calcium hydroxide, to generate (6S)-5-methyltetrahydrofolate calcium salt.

Description

The fractionation of 5-methyl tetrahydrofolate and salifying method thereof

Invention field

The present invention relates to organic chemistry filed, in particular to organic drug (6S)-5-methyl tetrahydrofolate from (6R, S)-fractionation and the salifiable method of 5-methyl tetrahydrofolate.

Background technology

(6S)-and the chemical name of 5-methyl tetrahydrofolate is N-(5-methyl)-6 (S)-5,6,7,8, and-tetrahydro pteroyl base-L-L-glutamic acid is called for short (6S)-5-MTHF, and structural formula is as follows:

(6S)-the 5-methyl tetrahydrofolate is the principal mode of tissue and blood folic acid.Participate in multiple important biochemical reaction in the body (as the biosynthesizing of purine and thymus pyrimidine etc.).Naturally occurring 5-MTHF only is the S type, and synthetic R type non-activity on biological chemistry excretes by kidney.(6S)-5-MTHF do not need can directly be utilized through loaded down with trivial details enzymatic metabolism step in human body.(Zhang Yue etc., meticulous and chemical, 13, (22), 13,2005).

More first, (6S)-5-MTHF has the vital role of two aspects as medicine: in the oncology treatment, unites with methotrexate (Methotrexate) and 5 FU 5 fluorouracil (5-Fluorouracil) and treats tumour; The anaemia that treatment is caused by folic acid.Nearest studies show that: (6S)-and 5-MTHF uniquely in the folic acid class medicine can see through hemato encephalic barrier, have the medicine of the effect of control Alzheimer (senile dementia).Synthetic (6S)-5-MTHF is main medicament active composition and foodstuff additive, and prevention fetal nerve defective tube is arranged, arteriosclerosis, effects such as treatment megaloblastic anemia.

Generally speaking, extract from human body or animal tissues and blood, separation and purifying (6S)-5-MTHF are difficult, and the cost costliness.And use synthetic method be by folic acid carry out hydrogenation and methylation reaction and prepare (6R, S) racemic modification (Federico.G etal, GB1572 138,1977; U.S 5,124, and 452,1978).Once the someone thought and split into corresponding enantiomorph 6R-acid or 6S-acid is impossible with chemical process.(Clinical?Science?andMolecular?Medicine?45，625-631，1973).

And Klaus.S etc. proposed with organic bases N-ethyl-2-aminomethylpentazaneand or its enantiomorph be resolving agent be feature from racemic modification (6R, S)-(U.S 5 for the method for 5-methyl tetrahydrofolate preparation (6S)-5-methyl tetrahydrofolate, 457,202,1992), for split (6R, S)-5-MTHF started precedent, but since N-ethyl-2-aminomethyl pyrroles especially the enantiomorph market value of (+) or (-) is more expensive, limited its application; What the document that has was used when generating calcium salt is that (U.S 5 for Fedrico G, etal for calcium chloride, 124,452,1992), final easy residual a large amount of chlorion and cause the chlorion limit examine that does not meet medicine or foodstuff additive in product (6S)-5-MTHF-Ca.

Summary of the invention

For fear of the existing (6R that splits, S)-defective and the weak point that exist in 5-MTHF and the salifiable technological process, the present invention proposes the organic bases α-Ben Yian that is easy to get with market and its enantiomorph and be resolving agent and be feature from racemic modification (6R, S)-the 5-methyl tetrahydrofolate splits the method for preparation (6S)-5-methyl tetrahydrofolate, and then with alkaline earth metal hydroxides or oxide compound, for example calcium hydroxide or magnesium hydroxide or zinc oxide are made (6S)-5-methyl tetrahydrofolate calcium salt or magnesium salts or zinc salt.

Defective and weak point at above-mentioned existing document (6S)-5-MTHF and its salt preparation method, we have found that can split (a 6R, S)-organic bases and the optical antipode thereof of 5-MTHF, and then find with the oxyhydroxide of alkaline-earth metal or the oxide compound method of calcium hydroxide or magnesium hydroxide or the salifiable preparation of zinc oxide (6S)-5-MTHF salt for example.

In view of (6S)-5-MTHF-Ca is difficult for crystalline deposit in water, the present invention further uses 95% ethanol, also can make it precipitated crystal with dehydrated alcohol, preferred 95% ethanol.

The present invention relates to the technological process of preparation (6S)-5-methyl tetrahydrofolate, split from racemic modification by the application organic bases and obtain product, wherein organic bases is the enantiomorph of α-Ben Yian or (+) or (-); α-Ben Yian is water-soluble, be heated to 20-80 ℃, stir down, repeatedly add on a small quantity (6R, S)-the 5-MTHF aqeous suspension, stir and progressively make it to dissolve complete salify, salt is cooled to 20 ℃, the salt crystallization that 6S-acid generates is filtered and separated; The salt suspension that 6S-acid is generated adds sodium hydroxide solution in water again, makes it into the sodium salt dissolving; Under 20-60 ℃, add calcium hydroxide again, repeatedly stirring adds on a small quantity, till dissolving; Add 95% ethanol then, make to produce precipitation, promptly be prepared into (6S)-5-methyl tetrahydrofolate calcium salt.

Above-mentioned already mentioned α-Ben Yian can be a racemic modification, also can be single optical isomer, and (-)-α-Ben Yian is first-selected.

Racemic modification (6R, S)-5-MTHF provides Calciumlevofolinate (Calcium Falinate) by the Su Rui of Suzhou City, Jiangsu Province medication chemistry company limited, through the neutralization reduction and prepare; α-Ben Yian and enantiomorph are to reach chemical industry company limited by Changzhou, Jiangsu Province Ke Run to provide.

The invention will be further described below by embodiment.It should be understood that the described preparation method of the embodiment of the invention is only used for illustrating the present invention, rather than limitation of the present invention, down preparation method's of the present invention simple modifications is all belonged to the scope of protection of present invention in advance in design of the present invention.Except as otherwise noted, the percentage ratio among the present invention is weight percentage.

Embodiment one,

In the 1000ml three-necked bottle, add 56.0g (0.4mol) (±)-α-Ben Yian and 300ml water, add again contain 107.1g (0.2mol) (6R, S)-the 300ml aqueous solution of 5-MTHF, stir, reacting by heating to 80 ℃ is cooled to 60 ℃, removes by filter sl. sol. 6R-hydrochlorate.Filtrate is added activated carbon decolorizing, filter, be cooled to 20 ℃, have crystallization to produce, vacuum filtration gets 6S-hydrochlorate crystallization 42.8g, yield 36.9%, [α] ²⁰ _D:+22.1 ° (C=1, ethanol).

Obtain to such an extent that the 6S-hydrochlorate is suspended in the 200ml water with above-mentioned, gradation adds 5.9g (0.08mol) calcium hydroxide powder, and stir on the limit, and the limit is heated to 40 ℃, to all dissolvings; Add 95% ethanol while cooling off, progressively adularescent or faint yellow precipitation produce, and filtration drying gets (6S)-5-MTHFCa5H ₂O 39.1g, primary crystallization yield 95.1%, [α] ²⁰ _D:+34.5 ° of (C=1, H ₂O) optical purity 〉=98.5%.

Embodiment two,

In the three-necked bottle of 1000ml, add 28.0g (0.2mol) (-)-α-Ben Yian and water 150ml, add again contain 107.1g (0.2mol) (6R, S)-the 300ml aqueous solution of 5-MTHF, be heated to 75 ℃, be cooled to 55 ℃, remove by filter undissolved 6R-hydrochlorate, mother liquor is added gac, filter, be cooled to 18-20 ℃, have crystallization to produce, vacuum filtration, get crystallization 6S-hydrochlorate 47.4g, yield 40.8%, [α] ²⁰ _D:+22.5 ° (C=1, ethanol).

The above-mentioned 6S-hydrochlorate that obtains is suspended in water, add 10% sodium hydroxide solution, making pH value is 8-9, makes temperature be no more than 30 ℃, gradation adds 7.4g (0.1mol) calcium hydroxide powder then, warm while stirring, temperature is no more than 40 ℃, should all dissolve, stir and add 95% ethanol down, adularescent precipitation or faint yellow precipitation produce, and filtration drying gets 46.4g (6S)-5-MTHFCa5H ₂O, primary crystallization yield 96.2%, [α] ²⁰ _D:+35.1 ° of (C=1, H ₂O) optical purity 〉=99.0%.

Embodiment three,

In the three-necked bottle of 1000ml, add 28.0g (0.2mol) (+)-α-Ben Yian and water 150ml, add again contain 107.1g (0.2mol) (6R, S)-the 300ml aqueous solution of 5-MTHF, operation is with embodiment one, get the 44.4g6S-hydrochlorate, yield 38.2%, [α] ²⁰ _D:+21.8 ° (C=1, ethanol).

The above-mentioned 6S-hydrochlorate that obtains is suspended in the 200ml water, join in the aqueous sodium carbonate, the pH value that makes solution is 7.5-8.5, and gradation adds 0.1mol calcium hydroxide powder then, warm while stirring, temperature is no more than 40 ℃, should all dissolve, and stirs down, add 95% ethanol, adularescent precipitation or faint yellow precipitation produce, and filtration drying gets 45.2g (6S)-5-MTHFCa5H ₂O, primary crystallization yield 96.1%, [α] ²⁰ _D:+34.5 ° of (C=1, H ₂O) optical purity 〉=99.0%.

Claims

One kind use the organic bases resolution of racemates (6R, S)-5-methyl tetrahydrofolate preparation (6S)-5-methyl tetrahydrofolate, again with the method for alkaline earth metal hydroxides or oxide compound salify preparation (6S)-5-methyl tetrahydrofolate calcium.Concrete preparation process is as follows:

Step 1: split from racemic modification and obtain product by using organic bases, wherein organic bases is the enantiomorph of α-Ben Yian or (+)-α-Ben Yian or (-)-α-Ben Yian.

Step 2: α-Ben Yian is water-soluble, be heated to 20-80 ℃, stir down, repeatedly add on a small quantity (6R, S)-5-methyl tetrahydrofolate aqeous suspension, stir and progressively make it to dissolve complete salify, salt is cooled to 20 ℃, the salt crystallization that 6S-acid generates is filtered and separated;

Step 3: the salt suspension that 6S-acid is generated adds sodium hydroxide solution in water again, makes it the salify dissolving; Under 20-60 ℃, add calcium hydroxide again, repeatedly stirring adds on a small quantity, till dissolving;

Step 4: add 95% ethanol then, make to produce precipitation, i.e. Zhi Bei (6S)-5-methyl tetrahydrofolate calcium salt.
2. according to claim 1, above-mentioned already mentioned α-Ben Yian can be a racemic modification, also can be single optical isomer.
3. according to claim 1, above-mentioned already mentioned α-Ben Yian, wherein (-)-α-Ben Yian are first-selected.