CN114437050B - Deprotection agent for halofuginone intermediate and application thereof - Google Patents
Deprotection agent for halofuginone intermediate and application thereof Download PDFInfo
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- CN114437050B CN114437050B CN202111629546.XA CN202111629546A CN114437050B CN 114437050 B CN114437050 B CN 114437050B CN 202111629546 A CN202111629546 A CN 202111629546A CN 114437050 B CN114437050 B CN 114437050B
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- halofuginone
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention provides a deprotection agent for a halofuginone intermediate and application thereof. The deprotection agent comprises a metal reducing agent and a mixed solvent, wherein the metal reducing agent comprises zinc powder and iron powder, and the mixed solvent comprises methanol, glacial acetic acid and water. The deprotection method of the halofuginone intermediate comprises the following steps: 1) Dissolving the halofuginone intermediate in a mixed solvent; 2) And adding a metal reducing agent, and carrying out reflux reaction. The deprotection agent provided by the invention can be selectively and efficiently removed under a highly specific condition, the rest part of the molecule is not influenced, and the product purity, the yield and the efficiency are high.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a deprotection agent for a halofuginone intermediate and application thereof.
Background
Halofuginone (Halofuginone, hal), the chemical name of which is 7-bromo-6-chloro-3- [3- (3-hydroxy-2-piperidinyl) -2-oxopropyl (propanoyl) ] -4 (3H) -quinazolinone hydrobromic acid, is a quinazolinone alkaloid, and is a derivative of halofugine, which is an extract of the traditional Chinese medicine Halofuginone. The chemical structure is shown as a formula III:
the commercial halofuginone is mainly in the form of halofuginone hydrobromide, the halofuginone hydrobromide is white or off-white crystalline powder, odorless, tasteless and good in stability, is mainly used for preventing and treating domesticated animals such as poultry and livestock against coccidiosis and malaria, can effectively control 6 chicken eimeria coccidiosis at the concentration of 3ppm in feed, can obviously control clinical symptoms of coccidiosis after administration, completely inhibit oocyst elimination, and therefore, the environment is not polluted any more, the possibility of reinfection is reduced, and the feed has the advantages of being broad-spectrum, efficient, irreversible, free of recurrence after drug withdrawal, free of cross drug resistance, low in toxicity, safe and the like. In recent years, halofuginone has also been found to be useful for preventing liver fibrosis, pulmonary fibrosis, scleroderma and other diseases, and malignant tumors such as bladder cancer, prostate cancer, skin cancer, breast cancer, lung cancer and the like, and has a broad market prospect.
As the synthesis process of the halofuginone is complex, the industrial production of the halofuginone cannot be realized in China, and the halofuginone is totally dependent on import, the current price is up to 13000 yuan/kg, and the halofuginone is limited to be widely applied in China. At present, the synthesis method of halofuginone comprises the steps of firstly synthesizing two intermediates, namely synthesizing a quinazolinone ring part, namely synthesizing 7-bromo-6-chloro-4 (3H) -quinazolinone, and synthesizing a piperidine ring part, then butting the two intermediates, and then carrying out N removal protection after butting, so that the final product halofuginone is obtained. Among them, a commonly used N protecting group is a 2,2-trichloroethoxycarbonyl protecting group (2, 2-trichloroethoxycarbonyl, troc), which protects an amino group by forming a urethane. In general, the conditions for the deprotection are carried out under zinc-acetic acid reduction conditions, and the reaction equation is as follows:
the mechanism of Troc deprotection is as follows: the metallic zinc transfers an electron to the carbon atom of the troc trichloromethyl to promote a chloride ion to leave, the formed dichloro methyl free radical continuously receives the electron transferred by the metallic zinc to form unstable carbanion, the carbanion immediately undergoes beta elimination to form 1, 1-dichloroethylene gas, the troc is completely decomposed due to obvious entropy increase and right reaction, and the reaction equation is as follows:
for example, in patent CN101987843a, in the deprotection reaction, zinc powder and acetic acid are used as reactants for the deprotection reaction, and a solvent is a mixed solvent of an inert solvent such as tetrahydrofuran, methanol, ethanol, acetic acid and distilled water, but this reaction has the following disadvantages:
1) In the deprotection process, the deprotection agent is very easy to remove bromine in the chlorobromoquinazolinone to generate larger impurities (structural formula IV), which reach more than 20%, so that side reactions are more, and the product is impure and not easy to purify;
2) The reaction does not continue to be converted into halofuginone, so that the yield of the deprotection reaction is greatly influenced, the yield is low, and the production cost is increased.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention provides a deprotection agent for a halofuginone intermediate and application thereof, and solves the problems of more side reactions, impure products and low yield existing in the prior art.
In one aspect of the invention, a deprotection agent for a halofuginone intermediate is provided, comprising a metal reducing agent comprising zinc powder and iron powder and a mixed solvent comprising methanol, glacial acetic acid and water.
Preferably, the mass ratio of the zinc powder to the iron powder is 5:1-1:5.
Preferably, the volume ratio of methanol, glacial acetic acid and water is 5-10:0.2-0.5:3-5.
Preferably, the dosage ratio of the metal reducing agent to the mixed solvent is 1:50-100 in g/mL.
Preferably, the halofuginone intermediate has a structural formula shown in formula I:
in another aspect of the present invention, there is provided a method for deprotection of a halofuginone intermediate comprising the steps of:
1) Dissolving the halofuginone intermediate in a mixed solvent;
2) Adding a metal reducing agent, and carrying out reflux reaction to obtain a product, wherein the structural formula of the product is shown as a formula II:
preferably, the mass ratio of the metal reducing agent to the halofuginone intermediate is 1:2-5.
Preferably, the reflux reaction is carried out for 3-5 hours at a temperature of 70-75 ℃ and a pH value of 2-3.
Preferably, step 3) is further included: and (3) extracting and purifying the product.
In yet another aspect of the invention, a deprotection agent for a halofuginone intermediate is used in the preparation of halofuginone.
The technical principle of the invention is as follows: the metal reducing agent supplies electrons during the reduction process, and combines with protons supplied from the proton supplying agent, thereby forming a reduction product. In the early test, the inventor tries to carry out deprotection reaction on various metal reducing agents, and unexpectedly discovers that the mixture of zinc and iron can carry out directional deprotection on N protecting groups in the halofuginone intermediate, and other easily reducible groups such as bromine, chlorine and the like are not influenced; less side reaction, high product purity, more than 97% of crude product purity, and no product refining step; the yield is high and exceeds 80 percent; high efficiency.
Compared with the prior art, the invention has the following beneficial effects:
1) Can selectively and efficiently remove N protecting groups under the highly specific condition without affecting the rest of molecules, and has high product purity, and the crude product purity reaches more than 97 percent.
2) The yield is high and exceeds 80%.
3) Short reaction time, mild reaction condition, high efficiency and high yield in a short time.
Detailed Description
The technical scheme of the invention is further described below by referring to examples.
EXAMPLE 1 deprotection of halofuginone intermediate
In a clean 100ml three-port bottle, 2.65g of halofuginone intermediate (expressed by SD-5 and shown in a structural formula I), 35ml of methanol, 17.5ml of purified water, 1.75ml of glacial acetic acid and 0.8g of zinc/iron powder (mass ratio of 1:1) are sequentially added at the temperature of T of 30 ℃, the pH value is adjusted to 2.0, the temperature is increased to 70 ℃, the reflux reaction is carried out for 5 hours, and the reaction is stopped. Filtering, concentrating the filtrate, transferring the concentrate into a separating funnel, adding 20ml of chloroform, taking a water layer, extracting the chloroform layer by using 1M hydrochloric acid (10 ml-20 ml) multiplied by 3, combining the water layer, adjusting the pH value by using 3M NaOH to=8, separating out white solid from the system, filtering, taking a filter cake, pulping by adding 30ml of chloroform under ultrasound, filtering, concentrating under reduced pressure to obtain oily matters, adding 5ml of ethyl acetate for crystallization, filtering, drying, and obtaining the product with the purity of 1.71g and the HPLC purity of 97.8 percent, and the yield of 92.1 percent.
EXAMPLE 2 deprotection of halofuginone intermediate
SD-5 g, methanol 30.49ml, purified water 18.30ml, glacial acetic acid 1.21ml and zinc/iron powder (5:1) 1.0g are sequentially added into a clean 100ml three-port bottle at the temperature of T of 30 ℃, the pH value is adjusted to 2.5, the temperature is raised to 75 ℃, the reflux reaction is carried out for 3 hours, stirring is continued for 45 minutes, and the reaction is stopped. Filtering, concentrating the filtrate, transferring the concentrate into a separating funnel, adding 20ml of chloroform, taking a water layer, extracting the chloroform layer by using 1M hydrochloric acid (10 ml-20 ml) multiplied by 3, combining the water layer, adjusting the pH value by using 3M NaOH to=8, separating out white solid from the system, filtering, taking a filter cake, pulping by adding 30ml of chloroform under ultrasound, filtering, concentrating under reduced pressure to obtain oily matters, adding 5ml of ethyl acetate for crystallization, filtering, drying, and obtaining the product with the purity of 1.60g and the HPLC purity of 97.5 percent, and the yield of 86.2 percent.
EXAMPLE 3 deprotection of halofuginone intermediate
SD-5 2g, methanol 64ml, purified water 32ml, glacial acetic acid 4ml and zinc/iron powder (1:5) 1.0g are sequentially added into a clean 100ml three-mouth bottle at the temperature of T of 25 ℃, the pH value is regulated to 3.0, the temperature is increased to 72 ℃, the reflux reaction is carried out for 4 hours, the stirring is continued for 45 minutes, and the reaction is stopped. Filtering, concentrating the filtrate, transferring the concentrate into a separating funnel, adding 20ml of chloroform, taking a water layer, extracting the chloroform layer by using 1M hydrochloric acid (10 ml-20 ml) multiplied by 3, combining the water layer, adjusting the pH value by using 3M NaOH to=8, separating out white solid from the system, filtering, taking a filter cake, pulping by adding 30ml of chloroform under ultrasound, filtering, concentrating under reduced pressure to obtain oily matter, adding 5ml of ethyl acetate for crystallization, filtering, drying, and obtaining a product with the purity of 1.66g and the HPLC purity of 97.1 percent, and the yield of 89.4 percent.
Comparative example 1
In a clean 100ml three-mouth bottle, SD-5.65 g, methanol 35ml, purified water 17.5ml, acetic acid 1.75ml and iron powder 0.8g are sequentially added at the temperature of T of 30 ℃, the pH value is regulated to 2.0, the temperature is raised to 70 ℃, the reflux reaction is carried out for 5 hours, and the reaction is not carried out.
Comparative example 2
In a clean 100ml three-necked flask, SD-5.65 g, methanol 35ml, purified water 17.5ml, acetic acid 1.75ml and zinc 0.8g are sequentially added at the temperature of T of 30 ℃, the pH value is adjusted to 2.0, the temperature is raised to 70 ℃, the reflux reaction is carried out for 5 hours, and the reaction is stopped. Filtering, concentrating the filtrate, transferring the concentrate into a separating funnel, adding 20ml of chloroform, taking a water layer, extracting the chloroform layer by using 1M hydrochloric acid (10 ml-20 ml) multiplied by 3, combining the water layer, adjusting the pH value by using 3M NaOH to=8, separating out white solid from the system, filtering, taking a filter cake, pulping by adding 30ml of chloroform under ultrasound, filtering, concentrating under reduced pressure to obtain oily matter, adding 5ml of ethyl acetate for crystallization, filtering, drying, and obtaining a product with the purity of 1.61g and 15.2 percent by HPLC.
From the above results, it can be seen that: the effect of adding iron powder alone, without deprotection reaction, is obviously inferior to that of examples 1-3, and therefore, it can be seen that iron powder and zinc powder as metal reducing agents have synergistic interaction, so as to promote the deprotection reaction of halofuginone intermediate together, and improve the yield and purity of the product.
Finally, it is noted that the above embodiments are only for illustrating the technical solution of the present invention and not for limiting the same, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications and equivalents may be made thereto without departing from the spirit and scope of the technical solution of the present invention, which is intended to be covered by the scope of the claims of the present invention.
Claims (4)
1. A method for deprotection of a halofuginone intermediate comprising the steps of:
1) Dissolving a halofuginone intermediate in a mixed solvent;
2) Adding a metal reducing agent, and carrying out reflux reaction to obtain a product, wherein the structural formula of the product is shown as a formula II:
wherein the metal reducing agent comprises zinc powder and iron powder, and the mixed solvent comprises methanol, glacial acetic acid and water; the mass ratio of the zinc powder to the iron powder is 5:1-1:5; the volume ratio of the methanol to the glacial acetic acid to the water is 5-10:0.2-0.5:3-5; the dosage ratio of the metal reducing agent to the mixed solvent is 1:50-100 in terms of g/mL; the structural formula of the halofuginone intermediate is shown in formula I:
2. The method for deprotection of halofuginone intermediate according to claim 1 wherein: the mass ratio of the metal reducing agent to the halofuginone intermediate is 1:2-5.
3. The method for deprotection of halofuginone intermediate according to claim 1 wherein: the reflux reaction time is 3-5h, the temperature is 70-75 ℃, and the pH value is 2-3.
4. The method for deprotection of halofuginone intermediate according to claim 1 wherein: further comprising step 3): and (3) extracting and purifying the product.
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