CN111848511A - Synthesis method of montelukast sodium intermediate - Google Patents
Synthesis method of montelukast sodium intermediate Download PDFInfo
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- CN111848511A CN111848511A CN201910331500.6A CN201910331500A CN111848511A CN 111848511 A CN111848511 A CN 111848511A CN 201910331500 A CN201910331500 A CN 201910331500A CN 111848511 A CN111848511 A CN 111848511A
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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
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Abstract
The invention provides a synthesis method of a montelukast sodium intermediate, which comprises the following steps: (1) carrying out Witting reaction on the compound (IV) and 3-bromobenzyl bromide to obtain a compound (II); (2) and (3) carrying out coupling reaction on the compound (II) and the compound (III) under the action of a palladium catalyst to obtain the compound (I). The synthesis method has the advantages of short steps, mild conditions and simple and convenient operation, is beneficial to reducing the process cost and realizing industrial production.
Description
1. Field of the invention
The invention belongs to the technical field of drug synthesis, and particularly relates to a synthesis method of a montelukast sodium intermediate.
2. Background of the invention
Montelukast Sodium (Montelukast Sodium) is an anti-asthma drug developed by the american merck company and is marketed under the approval of the U.S. Food and Drug Administration (FDA) on 20/2/1998 under the trade name of sunless (Singulair). The montelukast sodium as a selective leukotriene receptor antagonist can be selectively combined with leukotriene receptors in respiratory tracts, and is a high-efficiency, low-toxicity and safe antiasthmatic, anti-inflammatory and antiallergic drug.
The chemical name of montelukast sodium is: sodium 1- [ [ [ (1R) -1- [3- [ (1E) -2- (7-chloro-2-quinoline) ethenyl ] phenyl ] -3- [2- (1-hydroxy-1-methylethyl) phenyl ] propyl ] thio ] methyl ] cyclopropaneacetate, the chemical structural formula of which is shown below.
The compound of the formula (I) is an important intermediate for preparing montelukast sodium, wherein the name of the compound is ((E) -2- [3- [3- [2- (7-chloroquinolyl) ethenyl ] phenyl ] -3-oxopropyl ] benzoic acid methyl ester, and the chemical structural formula is shown as the following.
WO2008058118 discloses a method for preparing montelukast sodium intermediate from isophthalaldehyde and 7-chloro-2-methylquinoline as starting materials, which comprises the following steps:
the synthesis route is long (total 7 steps), the reaction conditions are harsh, the yield is low, so the cost is high, the production period is long, and the method is not suitable for industrial production. Therefore, it is urgently needed to develop a new process route which has simple reaction method and high yield and is suitable for industrial production.
3. Summary of the invention
The invention aims to solve the problems in the prior art and provides a novel synthesis method of a montelukast sodium intermediate. The synthesis method has the advantages of short steps, mild conditions and simple and convenient operation, is beneficial to reducing the process cost and realizing industrial production.
Specifically, the invention provides a method for synthesizing a montelukast sodium intermediate, which comprises the following steps:
(1) carrying out Wittig reaction on the compound (IV) and 3-bromobenzyl bromide to obtain a compound (II);
(2) and (3) carrying out coupling reaction on the compound (II) and the compound (III) under the action of a palladium catalyst to obtain the compound (I).
Wherein the content of the first and second substances,
in the step (1), the Wittig reaction comprises the following steps: 3-Bromobenzylbromide with P (R)3Reacting in an organic solvent to obtain a quaternary phosphonium salt intermediate, adding alkali to obtain a ylide intermediate, and reacting the ylide intermediate with the compound of the formula (IV) by a one-pot method to obtain a compound of a formula (II);
and R is phenyl or ethyl.
Preferably, R is phenyl.
Preferably, said 3-bromobenzyl bromide and P (R)3The reaction temperature in the organic solvent is 60-150 ℃, and preferably 80-120 ℃.
Preferably, said 3-bromobenzyl bromide and P (R)3The reaction time in the organic solvent is 2-12 h, preferably 2-6 h.
Preferably, the 3-bromobenzyl bromide, P (R)3The molar ratio of the compound to the compound of the formula (IV) is (1-1.5): (1-1.5): 1, preferably (1-1.1): (1-1.1): 1.
preferably, the organic solvent is one or more of methanol, ethanol, tetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide and toluene.
Preferably, the alkali is selected from one or more of NaOH, KOH, t-BuONa, t-BuOK, NaH, LiHMDS, NaHMDS, KHMDS and LDA.
In the step (2), the palladium catalyst is selected from one or more of palladium acetate, tetrakis (triphenylphosphine) palladium, tris (dibenzylideneacetone) dipalladium and 1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride.
Compared with the prior art, the invention has the beneficial effects that due to the adoption of the technical scheme:
(1) the invention provides a novel process route for preparing an intermediate of montelukast sodium, which is short;
(2) the reaction condition is mild, and the operation and production are easy;
(3) the obtained product has good purity, high quality and low cost, and is suitable for industrial production.
4. Detailed description of the preferred embodiments
The following detailed description of specific embodiments of the present invention is provided for illustrative purposes only and is not intended to limit the scope of the present invention.
Example 1: synthesis of Compounds of formula (II)
Dissolving 3-bromobenzyl bromide (97.8g, 391.4mmol) and triphenylphosphine (102.7g, 391.4mmol) in DMF (500mL), heating to 120 ℃, stirring for reaction for 2h, cooling to 0 ℃, stirring for 30min, adding sodium methoxide (42.3g, 782mmol), stirring for 30min, slowly adding the compound of formula (IV) (50g, 260.9mmol), gradually heating to room temperature, reacting for 1h, and detecting the completion of the raw material reaction by TLC. Pouring the reaction solution into 1L of 1mol/L diluted hydrochloric acid, adding 1L of ethyl acetate for extraction, washing an organic phase with saturated sodium bicarbonate solution and common salt water in sequence, collecting the organic phase, drying, decoloring, concentrating under reduced pressure, adding the concentrated solution into ice water, stirring for 30min, gradually separating out a solid, filtering, and leaching with sodium bicarbonate solution and methyl tert-butyl ether in sequence to obtain 73.8g of the compound shown in the formula (II), wherein the yield is 82%. MS 344[ M + H ]
Example 2: synthesis of Compounds of formula (II)
3-bromobenzyl bromide (65.2g, 260.9mmol) and triphenylphosphine (68.4g, 260.9mmol) were dissolved in THF (500mL), heated to 60 deg.C, stirred for 12h, cooled to 0 deg.C, stirred for 30min, potassium tert-butoxide (35.1g, 313.1mmol) was added, stirred for 30min, then the compound of formula (IV) (50g, 260.9mmol) was slowly added, gradually warmed to room temperature, reacted for 2h, and the starting material was detected by TLC to be completely reacted. Pouring the reaction solution into 1L of 1mol/L diluted hydrochloric acid, adding 1L of ethyl acetate for extraction, washing an organic phase with a saturated sodium bicarbonate solution and common salt water in sequence, collecting the organic phase, drying, decoloring, concentrating under reduced pressure, adding the concentrated solution into ice water, stirring for 30min, precipitating out a solid, filtering, and leaching with a sodium bicarbonate solution and methyl tert-butyl ether in sequence to obtain 67.4g of the compound of the formula (II), wherein the yield is 75%. MS 344[ M + H ]
Example 3: synthesis of Compounds of formula (II)
3-bromobenzyl bromide (71.7g, 287.0mmol) and triethylphosphorus (33.9g, 287.0mmol) were dissolved in toluene (500mL), heated to 100 ℃ and stirred for 6h, cooled to 0 ℃ and stirred for 30min, sodium hydride (17.2g, 430mmol) was added and stirred for 30min, then the compound of formula (IV) (50g, 260.9mmol) was slowly added, gradually warmed to room temperature and reacted for 2h, and the starting material was detected by TLC to be completely reacted. Pouring the reaction solution into 1L of 1mol/L diluted hydrochloric acid, adding 1L of ethyl acetate for extraction, washing an organic phase with a saturated sodium bicarbonate solution and common salt water in sequence, collecting the organic phase, drying, decoloring, concentrating under reduced pressure, adding the concentrated solution into ice water, stirring for 30min, precipitating out a solid, filtering, and leaching with a sodium bicarbonate solution and methyl tert-butyl ether in sequence to obtain 70.1g of the compound of the formula (II), wherein the yield is 78%. MS 344[ M + H ]
Example 4: synthesis of Compounds of formula (I)
Mixing the compound of formula (II) (5g, 14.5mmol), the compound of formula (III) (3.3g, 17.4mmol),
MS (1g) was added to DMF (50mL), palladium acetate (168mg, 0.75mmol), pyrrolidine (2.4g, 34.8mmol) and 2- (di-tert-butylphosphino) -1- (2-methoxyphenyl) -1H-pyrrole (238mg, 0.75mmol) were added under nitrogen, the solution was heated to 120 ℃ and stirred for 6 hours, TLC detected starting materialThe reaction was complete. Water (50mL) was added and extracted 3 times with ethyl acetate, washed with saturated sodium chloride, concentrated and the concentrate recrystallized to give 4.6g of the compound of formula (I) in 70% yield. MS:455[ M + H]
Example 5: synthesis of Compounds of formula (I)
Mixing the compound of formula (II) (5g, 14.5mmol), the compound of formula (III) (3.3g, 17.4mmol),
MS (1g) was added to DMA (50mL), tris (dibenzylideneacetone) dipalladium (394mg, 0.44mmol), pyrrolidine (2.4g, 34.8mmol) and 2- (di-tert-butylphosphino) -1- (2-methoxyphenyl) -1H-pyrrole (158mg, 0.5mmol) were added under nitrogen, the solution was heated to 140 deg.C and stirred for 4 hours, TLC detected complete reaction of starting material. Water (50mL) was added and extracted 3 times with ethyl acetate, washed with saturated sodium chloride, concentrated and the concentrate recrystallized to give 4.9g of the compound of formula (I) in 75% yield. MS:455[ M + H ]
The above description is only a preferred embodiment of the present invention, and is not intended to limit the present invention; those skilled in the art can make various changes, modifications and alterations without departing from the scope of the invention, and all equivalent changes, modifications and alterations to the disclosed technology are equivalent embodiments of the present invention; meanwhile, any changes, modifications, and evolutions of the equivalent changes of the above embodiments according to the actual techniques of the present invention are still within the protection scope of the technical solution of the present invention.
Claims (9)
1. A synthesis method of a montelukast sodium intermediate is characterized by comprising the following steps:
(1) carrying out Witting reaction on the compound (IV) and 3-bromobenzyl bromide to obtain a compound (II);
(2) and (3) carrying out coupling reaction on the compound (II) and the compound (III) under the action of a palladium catalyst to obtain the compound (I).
2. The synthesis method of montelukast sodium intermediate according to claim 1, characterized in that: in the step (1), the Wittig reaction comprises the following steps:
3-Bromobenzylbromide with P (R)3Reacting in an organic solvent to obtain a quaternary phosphonium salt intermediate, adding alkali to obtain a ylide intermediate, and reacting the ylide intermediate with the compound of the formula (IV) by a one-pot method to obtain a compound of a formula (II);
And R is phenyl or ethyl.
3. The synthesis method of montelukast sodium intermediate according to claim 2, characterized in that: r is phenyl.
4. The synthesis method of montelukast sodium intermediate according to claim 2, characterized in that: the 3-bromobenzyl bromide and P (R)3The reaction temperature in the organic solvent is 60-150 ℃.
5. The synthesis method of montelukast sodium intermediate according to claim 2, characterized in that: the 3-bromobenzyl bromide and P (R)3The reaction time in the organic solvent is 2-12 h.
6. The synthesis method of montelukast sodium intermediate according to claim 2, characterized in that: the 3-bromobenzyl bromide, P (R)3The molar ratio of the compound to the compound of the formula (IV) is (1-1.5): (1-1.5): 1.
7. the synthesis method of montelukast sodium intermediate according to claim 2, characterized in that: the organic solvent is one or more of methanol, ethanol, tetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide and toluene.
8. The synthesis method of montelukast sodium intermediate according to claim 2, characterized in that: the alkali is selected from one or more of NaOH, KOH, t-BuONa, t-BuOK, NaH, LiHMDS, NaHMDS, KHMDS and LDA.
9. The synthesis method of montelukast sodium intermediate according to claim 1, characterized in that: in the step (2), the palladium catalyst is selected from one or more of palladium acetate, tetrakis (triphenylphosphine) palladium, tris (dibenzylideneacetone) dipalladium and 1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN116375639A (en) * | 2023-04-19 | 2023-07-04 | 南京欧信医药技术有限公司 | Method for preparing montelukast sodium intermediate by micro-channel method |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN116375639A (en) * | 2023-04-19 | 2023-07-04 | 南京欧信医药技术有限公司 | Method for preparing montelukast sodium intermediate by micro-channel method |
| CN116375639B (en) * | 2023-04-19 | 2024-05-28 | 南京欧信医药技术有限公司 | Method for preparing montelukast sodium intermediate by micro-channel method |
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