CN116514711A - New synthesis process of key intermediate of montelukast sodium - Google Patents

New synthesis process of key intermediate of montelukast sodium Download PDF

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Publication number
CN116514711A
CN116514711A CN202310480848.8A CN202310480848A CN116514711A CN 116514711 A CN116514711 A CN 116514711A CN 202310480848 A CN202310480848 A CN 202310480848A CN 116514711 A CN116514711 A CN 116514711A
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China
Prior art keywords
reaction
compound
montelukast sodium
key intermediate
synthesizing
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CN202310480848.8A
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Inventor
仲召亮
黄忠
张维冰
张连会
盛慧
王付全
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Jiangsu Alpha Pharmaceutical Co ltd
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Jiangsu Alpha Pharmaceutical Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/18—Halogen atoms or nitro radicals
    • 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

Abstract

The invention discloses a new synthesis process of a key intermediate of montelukast sodium, which is characterized in that 2- (methoxycarbonyl) phenylboronic acid and 3-chloropropionic acid are subjected to coupling reaction of a boric acid group and a halogenated group under the action of an alkali reagent and a catalyst to obtain a compound III; acylating the compound III obtained by the reaction with a chlorinating agent to obtain an acyl chloride product compound IV; a compound VII obtained by reacting the compound V with a compound VI; and (3) dissolving the reactant IV in an organic solvent, adding the reactant VII obtained in the third step into the solution, adding an organic base and a catalyst, and heating for reaction to obtain the target product montelukast sodium intermediate compound VIII. The beneficial effects of the invention are as follows: the invention improves the reaction stability, increases the reaction selectivity and reduces the production of byproducts through the coupling reaction of the boric acid group, the halogenated group and the acyl chloride.

Description

New synthesis process of key intermediate of montelukast sodium
Technical Field
The invention relates to the technical field related to synthesis of medical intermediates, in particular to a pharmaceutical intermediate.
Background
The chemical name of montelukast sodium (Montelukast Sodium) is: 1- (((1- (R) - (3- (2- (7-chloro-2-quinolinyl) -vinyl) phenyl) -3- (2- (1-hydroxy-1-methylethyl) phenyl) propyl) thio)) methyl) cyclopropylacetic acid sodium salt having the structural formula:
(E) -2- [3- [3- [2- (7-chloro-2-quinolinyl) vinyl ] phenyl ] -3-oxopropyl ] benzoic acid methyl ester the key intermediate in the currently reported process route for the synthesis of montelukast sodium, the chemical structure of which is shown below:
at present, the key intermediate has the following two main synthetic routes:
route one: merck company Montelukast synthesis process route
Route two: synthetic process route of Lunan pharmaceutical group company
The first route is that m-phthalaldehyde and 7-chloro-2-methylquinoline are used as initial raw materials, 3- [ (E) -2- (7-chloroquinoxalinyl) vinyl ] benzaldehyde is generated through condensation, then the 3- [ (E) -2- (7-chloroquinoxalinyl) vinyl ] benzaldehyde is reacted with Grignard reagent vinyl magnesium bromide, and finally the 3-chloroquine is reacted with o-bromobenzoate under the catalysis of palladium acetate to generate a compound shown in a formula (II), for example, J.org.Chem.58 (1993) 3731; WO 2008058118A1 uses this method; the method has the advantages of low yield, long route, troublesome post-treatment of the product and inapplicability to industrial production.
The second route takes isophthalaldehyde and 7-chloro-2-methylquinoline as initial raw materials, and nitrile compound B1 (3- [ (E) -2- (7-chloroquinolinyl) vinyl ] benzonitrile) is obtained by condensation with 3-cyanobenzaldehyde, the nitrile compound B1 reacts with the compound B2 in the form of a format reagent to obtain a key intermediate compound B3 ((E) -2- [3- [3- [2- (7-chloro-2-quinolinyl) vinyl ] phenyl ] -3-oxo-propyl ] methyl benzoate), and the compound B2 required by the route needs to be additionally configured, so that the steps for preparing the compound B2 are more, the overall process steps of the route are more, the production cycle is long, the cost is higher, the overall yield of the route is not high, and the route is not suitable for industrial production.
Disclosure of Invention
Aiming at the defects, the invention aims to provide a novel process for synthesizing a key intermediate of montelukast sodium, which improves the reaction stability, increases the reaction selectivity and reduces the generation of byproducts through the coupling reaction of a boric acid group, a halogenated group and acyl chloride. The technical scheme of the invention is as follows:
a novel synthesis process of a key intermediate of montelukast sodium comprises the following steps:
firstly, dissolving 2- (methoxycarbonyl) phenylboronic acid in an organic solvent, dropwise adding 3-chloropropionic acid, and carrying out a coupling reaction of a boric acid group and a halogenated group under the action of an alkali reagent and a catalyst to obtain a compound III;
step two, acylating the compound III obtained in the step one with a chlorinating agent to obtain an acyl chloride product compound IV;
thirdly, dissolving the compound V in an organic solvent, adding a compound VI, adding a dehydrating agent, heating for catalytic reaction, and separating a product after the reaction is finished to obtain a compound VII;
and fourthly, reacting, namely dissolving the reactant IV obtained in the second step in a solvent, adding the reactant VII obtained in the third step into the solution, adding organic base and a catalyst, heating for reaction, and separating the product after the reaction is finished to obtain the target product montelukast sodium intermediate compound VIII.
Further, the solvent used in the first step is tertiary butanol, the organic base is tertiary potassium butoxide, the catalyst is a complex of palladium acetate and tertiary butyl dimethyl phosphine, and the dosage molar ratio of the complex of palladium acetate to tertiary butyl dimethyl phosphine is 1:2.
Further, the amount of the catalyst used in the first reaction is 3 to 8%, preferably 5% of the molar amount of the boric acid-based compound, and the first reaction compound II: reaction compound i: the molar ratio of the alkali reagent is 1:1 to 1.2:2.5 to 3.5, preferably 1:1.1:3.
Furthermore, the chlorinating agent used in the second step is one of thionyl chloride, sulfonyl chloride, phosphorus oxychloride and phosphorus trichloride, and preferably thionyl chloride.
Further, the solvent used in the third step is one of acetic anhydride, propionic anhydride, trifluoroacetic anhydride or trichloromethanesulfonic anhydride.
Further, the reaction condition of the third step is that reflux reaction is carried out for 12-16 h at 140-180 ℃.
Further, the catalyst used in the fourth reaction step is palladium chloride, and the amount of the palladium chloride used in the catalyst is 1-3% mol, preferably 2% mol, of the reactant I.
Further, the molar ratio of the reactant IV to the reactant VII in the fourth reaction step is 1:1.
Furthermore, the solvent used in the fourth step is sodium dodecyl sulfate aqueous solution, and the alkali agent used in the fourth step is potassium carbonate.
Further, the concentration of the sodium dodecyl sulfate aqueous solution of the fourth step reaction solvent is 0.10-0.15M.
The beneficial effects of the invention are as follows: according to the invention, through the coupling reaction of the boric acid group and the halogenated hydrocarbon in the first step reaction and the fourth step reaction, the stability of the reaction of the boric acid group and the halogenated hydrocarbon is high, the reaction selectivity of the boric acid group is increased, and the generation of byproducts is reduced; the fourth step of reaction is easier to carry out by reacting boric acid groups with acyl chloridized reactants, and the production of benzene isomerism products is effectively avoided.
Drawings
Fig. 1 is a schematic diagram of the chemical structure of montelukast sodium;
FIG. 2 is a schematic illustration of the reaction process route of the present invention;
FIG. 3 is a schematic diagram of the chemical structure of the key intermediate of Montelukast sodium according to the present invention;
FIG. 4 is a schematic illustration of a process flow of route one;
FIG. 5 is a schematic diagram of a second process flow.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and completely with reference to the embodiments of the present invention and the accompanying drawings, and it is apparent that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
19.8g (0.11 mol) of 2- (methoxycarbonyl) phenylboronic acid is dissolved in 250ml of organic solvent tert-butyl alcohol, 0.3mol of alkali reagent potassium tert-butoxide is added, 0.005mol of palladium acetate and 0.01mol of ligand tert-butyldimethylphosphine mixed solution are added, stirring and mixing are carried out, 0.1mol of 3-chloropropionic acid is gradually dropwise added into the solution, the reaction is carried out for 6 to 8 hours at the temperature of 40 ℃, diluted hydrochloric acid is added after the reaction is finished to adjust the pH of the solution to be neutral, the solvent is evaporated, 80ml of toluene solvent is added, deionized water is added for washing for 2 to 3 times, the organic phase is separated, reduced pressure distillation is carried out, and the product is recrystallized by 40ml of benzene or toluene, thus 23.1g of compound III is obtained, and the yield is 93.9%, and the purity is 98.5%.
Example 2
24.6g (0.1 mol) of the compound III obtained in the first reaction step is dissolved in 80ml of chlorinating agent thionyl chloride, reflux reaction is carried out for 4-6 h at 75 ℃, the acyl chloride is obtained, the acyl chloride product is obtained, and decompression desolventizing is carried out, so that 21.6g of the compound IV is obtained, and the yield is 95.4%. Purity of 97.5%
Example 3
17.8g (0.1 mol) of compound V was dissolved in 200ml of acetic anhydride as an organic solvent, 15.0g (0.1 mol) of compound VI was added, the mixture was heated at 140℃for reflux reaction, after the reaction was completed, acetic anhydride was slowly quenched by adding water, 100ml of toluene was added for extraction, the organic matter was separated, the solvent was evaporated, and the product was recrystallized from 50ml of toluene to give 29.2g of compound VII in a yield of 94.1% and a purity of 97.2%.
Example 4
22.7g (0.1 mol) of the reactant IV obtained in the second step is dissolved in 200ml of 0.1-0.15M aqueous solution of sodium dodecyl sulfate, 0.1mol of the reactant VII obtained in the third step is added into the solution, 0.1mol of potassium carbonate is added, 0.002mol of palladium chloride catalyst is added, the temperature is raised to 60 ℃ for 6 hours, after the reaction is finished, dilute hydrochloric acid is added to neutralize the solution to be neutral, 100ml of toluene is added for extraction, organic matters are separated, saturated saline water and deionized water are added for 2-3 times, the solvent is evaporated, and the product is recrystallized by 50ml of acetone to obtain 43.1g of the target product montelukast sodium intermediate compound VIII, and the yield is 94.4% and the purity is 97.3%.
Example 5
The amount of 2- (methoxycarbonyl) phenylboronic acid in example 1 was adjusted to 0.1mol, and the remaining operations were unchanged, to give 23.0g of the product in 93.4% yield and 97.9% purity.
Example 6
The amount of 2- (methoxycarbonyl) phenylboronic acid in example 1 was adjusted to 0.12mol, and the remaining operations were unchanged, to give 23.5g of the product in 94.6% yield and 97.9% purity.
Example 7
The potassium tert-butoxide amount in example 1 was adjusted to 2.5eq, and the remaining operation was unchanged, to obtain 22.8g of a product, yield 92.6% and purity 96.9%.
Example 8
The potassium tert-butoxide content in example 1 was adjusted to 3.5eq, the remaining operation was unchanged, the yield was 23.0g, 93.4% and the purity was 97.1%.
Example 9
The chlorinating agent of example 2 was adjusted to sulfonyl chloride with the remainder of the procedure unchanged to give 21.2g of product in 93.6% yield and 97.3% purity.
Example 10
The solvent and catalyst of example 3 were adjusted to propionic anhydride, the temperature was adjusted to 170℃and the rest of the procedure was unchanged, yielding 23.9g of product with a yield of 93.1% and a purity of 96.9%.
Example 11
The catalyst amount in example 4 was adjusted to 0.001mol, the temperature was adjusted to 170℃and the rest of the operation was unchanged, to give 42.2g of the product in 92.4% yield and 97.5% purity.
Example 12
The catalyst amount in example 4 was adjusted to 0.003mol, the temperature was adjusted to 170℃and the rest of the operation was unchanged, to give 42.8g of the product in a yield of 93.7% and a purity of 97.3%.
Comparative document (CN 104496899B) example
Example 1-1
Compound (2 g,11.26 mmol) of formula (III) and compound (3.14 g,13.51 mmol) of formula (IV) were dissolved in acetic anhydride (20 mL), heated to 50 ℃, stirred overnight and concentrated, the concentrate was poured into ice water after cooling, stirred for 15 minutes, a large amount of a sulfogreen solid was precipitated, filtered, and the cake was washed successively with dilute aqueous sodium carbonate, water, ethyl acetate and petroleum ether (1:10) to give compound (3.5 g,80% yield) of formula (V).
Example 2-1
The compound of formula (VI) (5 g,18.1 mmol), sodium bicarbonate (3.8 g,45.3 mmol), tetrabutylammonium bromide (5.83 g,18.1 mmol) and anhydrous magnesium sulfate (4.5 g) were dissolved in DMF (70 mL), then palladium acetate (406 mg,1.81 mmol) and the compound of formula (VII) propenol (1.58 g,27.2 mmol) were added under nitrogen protection, the solution was heated to 50 ℃, stirred overnight, ethyl acetate (100 mL) was added, stirred for 20 minutes, insoluble material was removed by filtration, water (100 mL) was added, ethyl acetate was extracted 3 times, washed with saturated sodium chloride, concentrated, redissolved in ethyl acetate, activated carbon was decolorized, and concentrated to give the product (3.48 g,92.5% yield).
Examples 2 to 5
To the resulting solution, palladium acetate (51 mg,0.23 mmol) and pyrrolidine (4819 mg,6.9 mmol) were added under nitrogen protection, the solution was heated to 50 ℃ and stirred for 4 hours, water (50 mL) was added, and extracted 3 times with ethyl acetate, washed with saturated sodium chloride, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate=10:1), to the resulting solution was added palladium acetate (900 mg,0.23 mmol), tetrabutylammonium bromide (948 mg,4.6 mmol) and tetrabutylammonium bromide (741mg, 2.30 mmol), and concentrated to give the compound of formula (II) (786 mg,73% yield).
In summary, the total yield of the embodiment of the comparison document is about 55%, the comprehensive yield of the invention is higher than 70%, compared with the reaction stability of the prior art, the reaction selectivity is good, byproducts are few, the operation of the technical scheme of the invention is reverse and simple, the reaction products are easy to separate, the reaction steps are few, the yield is high, and the method is suitable for the requirements of industrial production.
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative embodiments, and that the present invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. Any reference sign in a claim should not be construed as limiting the claim concerned.
Furthermore, it should be understood that although the present disclosure describes embodiments, not every embodiment is provided with a separate embodiment, and that this description is provided for clarity only, and that the disclosure is not limited to the embodiments described in detail below, and that the embodiments described in the examples may be combined as appropriate to form other embodiments that will be apparent to those skilled in the art.

Claims (10)

1. The novel synthesis process of the key intermediate of the montelukast sodium is characterized by comprising the following steps of:
firstly, dissolving 2- (methoxycarbonyl) phenylboronic acid in an organic solvent, dropwise adding 3-chloropropionic acid, and carrying out a coupling reaction of a boric acid group and a halogenated group under the action of an alkali reagent and a catalyst to obtain a compound III;
step two, acylating the compound III obtained in the step one with a chlorinating agent to obtain an acyl chloride product compound IV;
thirdly, dissolving the compound V in an organic solvent, adding a compound VI, adding a dehydrating agent, heating for catalytic reaction, and separating a product after the reaction is finished to obtain a compound VII;
and fourthly, reacting, namely dissolving the reactant IV obtained in the second step in a solvent, adding the reactant VII obtained in the third step into the solution, adding organic base and a catalyst, heating for reaction, and separating the product after the reaction is finished to obtain the target product montelukast sodium intermediate compound VIII.
2. The novel process for synthesizing the key intermediate of montelukast sodium, as claimed in claim 1, is characterized in that: the solvent used in the first step is tertiary butanol, the organic base is tertiary potassium butoxide, the catalyst is a complex of palladium acetate and tertiary butyl dimethyl phosphine, and the dosage mole ratio of the complex of palladium acetate to tertiary butyl dimethyl phosphine is 1:2.
3. The novel process for synthesizing the key intermediate of montelukast sodium, as claimed in claim 1, is characterized in that: the dosage of the first-step reaction catalyst is 5% of the molar quantity of the boric acid group compound, and the first-step reaction compound II: reaction compound i: the molar ratio of the alkali reagent is 1:1 to 1.2:2.5 to 3.5 percent.
4. The novel process for synthesizing the key intermediate of montelukast sodium, as claimed in claim 1, is characterized in that: the chlorinating agent used in the second step is one of thionyl chloride, sulfonyl chloride, phosphorus oxychloride and phosphorus trichloride.
5. The novel process for synthesizing the key intermediate of montelukast sodium, as claimed in claim 1, is characterized in that: the reaction condition of the third step is that reflux reaction is carried out for 12-16 h at 140-180 ℃.
6. The novel process for synthesizing the key intermediate of montelukast sodium, as claimed in claim 1, is characterized in that: the fourth step reaction catalyst is palladium chloride, and the dosage is 1-3% mol of reactant IV.
7. The novel process for synthesizing the key intermediate of montelukast sodium, as claimed in claim 1, is characterized in that: the solvent and the catalyst used in the third step of reaction are one of acetic anhydride, propionic anhydride, trifluoroacetic anhydride or trichloromethane-sulfonic anhydride.
8. The novel process for synthesizing the key intermediate of montelukast sodium, as claimed in claim 1, is characterized in that: the molar ratio of the reactant IV to the reactant VII in the fourth reaction step is 1:1.
9. The novel process for synthesizing the key intermediate of montelukast sodium, as claimed in claim 1, is characterized in that: the solvent used in the fourth step is sodium dodecyl sulfate aqueous solution, and the alkali agent used in the fourth step is potassium carbonate.
10. The novel process for synthesizing the key intermediate of montelukast sodium, as claimed in claim 1, is characterized in that: the concentration of the sodium dodecyl sulfate aqueous solution of the fourth step reaction solvent is 0.10-0.15M.
CN202310480848.8A 2023-04-28 2023-04-28 New synthesis process of key intermediate of montelukast sodium Pending CN116514711A (en)

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