CN114605282A - Preparation method of montelukast sodium side chain intermediate - Google Patents

Preparation method of montelukast sodium side chain intermediate Download PDF

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CN114605282A
CN114605282A CN202210282384.5A CN202210282384A CN114605282A CN 114605282 A CN114605282 A CN 114605282A CN 202210282384 A CN202210282384 A CN 202210282384A CN 114605282 A CN114605282 A CN 114605282A
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石利平
尹强
宋继国
李大伟
邱磊
仲召亮
张维冰
孙伟振
于娜娜
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Suqian Shengji Pharmaceutical Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/16—Preparation of carboxylic acid nitriles by reaction of cyanides with lactones or compounds containing hydroxy groups or etherified or esterified hydroxy groups
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
    • C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D327/00—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D327/10—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms two oxygen atoms and one sulfur atom, e.g. cyclic sulfates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
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Abstract

The invention relates to the field of medicines, in particular to the technical field of pharmacy, and more particularly relates to a preparation method of a montelukast sodium side chain intermediate, wherein 1-hydroxymethyl cyclopropyl acetonitrile can be prepared by taking 1, 1-cyclopropane dimethanol as a raw material only through two steps, so that the preparation process steps are greatly simplified, and the preparation method has important significance for industrial popularization. Meanwhile, in the synthetic route disclosed by the invention, the target product has high yield and high purity, does not need a complex post-treatment process, and is suitable for large-scale industrial production. Finally, the reaction conditions of the invention are simple and easy to realize, and the synthesis cost is low.

Description

Preparation method of montelukast sodium side chain intermediate
Technical Field
The invention relates to the field of medicines, in particular to the technical field of pharmacy, and more particularly relates to a preparation method of a montelukast sodium side chain intermediate.
Background
Montelukast sodium, an antiasthmatic, anti-inflammatory and antiallergic agent, is used for the prevention and long-term treatment of asthma, including the prevention of daytime and nighttime asthma symptoms, the treatment of aspirin-sensitive asthmatics and the prevention of exercise-induced bronchoconstriction. The chemical name is 1- [ [ [ (1R) -1- [3- [ (1E) -2- (7-chloro-2-quinoline) ethenyl ] phenyl ] -3- [2- (1-hydroxy-1-methylethyl) phenyl ] propyl ] thio ] methyl ] cyclopropane sodium acetate, the structural formula is as follows:
Figure BDA0003558280030000011
it can be seen from the structural formula that 1- (mercaptomethyl) cyclopropylacetic acid or its derivative of the side chain moiety is a key intermediate for the synthesis of montelukast sodium. At present, the synthesis of 1- (mercaptomethyl) cyclopropylacetic acid by 1-hydroxymethylcyclopropylacetonitrile is a mature technology, so that the synthesis of 1-hydroxymethylcyclopropylacetonitrile serving as a key intermediate has important influence on the preparation of 1- (mercaptomethyl) cyclopropylacetic acid and the industrial synthesis of montelukast sodium.
How to improve the synthesis yield of the 1-hydroxymethyl cyclopropyl acetonitrile and reduce the synthesis cost is a research hotspot of technicians in the field. For example, US7271268 reports a process for the preparation of 1-hydroxymethylcyclopropylacetonitrile: 1, 1-cyclopropyl dimethanol is used as a raw material, and is subjected to HBr/HOAc esterification and two-step conversion to prepare 1-hydroxymethyl cyclopropyl acetonitrile, wherein the specific route is as follows:
Figure BDA0003558280030000012
in the reaction, because the esterification reaction product is a mixture, the product needs to be further separated by a rectification mode, so that the complexity of the synthesis process is increased, a large amount of reaction raw material glycol is lost, and the synthesis cost is increased.
Disclosure of Invention
The technical problem to be solved by the invention is how to improve the yield of a target product, reduce the raw material loss caused by byproducts, simplify the synthesis process and reduce the cost loss caused by the separation of a mixture product in the process of preparing 1-hydroxymethyl cyclopropyl acetonitrile by taking 1, 1-cyclopropane dimethanol as a raw material.
In order to solve the technical problem, the invention discloses a preparation method of a montelukast sodium side chain intermediate, which takes 1, 1-cyclopropane dimethanol (compound 3) as a raw material to prepare 1-hydroxymethyl cyclopropyl acetonitrile (compound 1) by a two-step method, and the preparation route is as follows:
the first step is as follows:
Figure BDA0003558280030000021
the second step is that:
Figure BDA0003558280030000022
wherein R is SO2、CMe2Or CO.
More preferably, the feeding molar ratio of the compound 2 to the cyaniding agent is 1 (0.5-1.8), and the preferred ratio is 1: 1.2. The feeding molar ratio includes, but is not limited to, 1:0.5, 1:0.6, 1:0.8, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.5, 1:1.6, and 1: 1.8.
Further preferably, compound 2 is reacted with a cyanating reagent in the presence of ethanol and tetrabutylammonium bromide.
Further preferably, the reaction temperature of the compound 2 and the cyanating agent is 60 to 150 ℃, and preferably 90 ℃. Here, the reaction temperature includes, but is not limited to, 60 ℃, 65 ℃, 70 ℃, 75 ℃, 80 ℃, 85 ℃, 90 ℃, 95 ℃, 100 ℃, 105 ℃, 110 ℃, 115 ℃, 120 ℃, 125 ℃, 130 ℃, 135 ℃, 140 ℃, 145 ℃, 150 ℃.
Further preferably, the specific process flow of the second step reaction is as follows: adding the compound 2, a cyaniding reagent, ethanol and tetrabutylammonium bromide into a reaction bottle, slowly heating to 60-150 ℃, and reacting for 18-20 hours under the condition of heat preservation. After the reaction is finished, cooling to 50 ℃, dropwise adding toluene and water, and reacting for 1 hour at the temperature of 70 ℃. And (3) evaporating the solvent at the temperature of 70-75 ℃ under reduced pressure at 30-35 KPa, filtering out solids, and then carrying out high-pressure vacuum distillation at 270-275 Pa to collect the fraction at the temperature of 78-84 ℃ to obtain a light yellow oily substance, namely the product compound 1.
The invention further discloses a preparation method of three different compounds 2.
For convenience of explanation, when R is SO2When so, compound 2 a; when R is CMe2When so, is designated compound 2 b; when R is CO, compound 2c is named.
The chemical structural formulas of the compound 2a, the compound 2b and the compound 2c are as follows:
Figure BDA0003558280030000031
further, the invention also discloses that the compound 2a is prepared by reacting 1, 1-cyclopropane dimethanol (compound 3) with sulfonyl chloride, and the reaction route is as follows:
Figure BDA0003558280030000032
meanwhile, the invention further discloses a preparation process flow of the compound 2a as follows: adding toluene, 1-cyclopropane dimethanol and sodium methoxide into a reaction bottle, stirring and heating to a reflux state, cooling to room temperature after reflux reaction for about 15 hours, and adding dichloromethane to prepare a substance to be used; adding dichloromethane into a reaction kettle, keeping the internal temperature at-20 ℃ under the protection of nitrogen, adding sulfonyl chloride, dripping the prepared standby substance, keeping the temperature for reaction for more than 2 hours, adding water after the reaction is finished, layering the reaction liquid, decompressing and dissolving the organic phase to dryness, adding toluene and 15-crown-5, stirring for 1 hour at room temperature, filtering and drying to obtain the compound 2 a.
More preferably, the feeding molar ratio of the 1, 1-cyclopropane dimethanol to the sulfonyl chloride is 1: 0.6-1: 1.6, and is preferably 1: 1.1. It should be noted that the molar ratio of 1, 1-cyclopropane dimethanol to sulfonyl chloride as used herein includes, but is not limited to, 1:0.6, 1:0.8, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.5, and 1: 1.6.
The reaction temperature of-20 ℃ to 20 ℃ as used herein includes, but is not limited to, temperatures of-20 ℃, 15 ℃, 10 ℃, 5 ℃, 0 ℃, 5 ℃, 10 ℃, 15 ℃ and 20 ℃. With 0 c being the most preferred temperature.
Further, the invention also discloses that the compound 2b is prepared by the reaction of 1, 1-cyclopropane dimethanol (compound 3) and 2, 2-dimethoxy propane, and the reaction route is as follows:
Figure BDA0003558280030000041
meanwhile, the invention further discloses a preparation process flow of the compound 2b as follows: adding 2, 2-dimethoxypropane and p-toluenesulfonic acid monohydrate to a mixture of 1, 1-cyclopropane dimethanol in Thour F, and stirring at room temperature for 5-15 hours. The reaction was quenched by addition of TEA and distilled under vacuum to afford compound 2 b.
More preferably, the feeding molar ratio of the 1, 1-cyclopropane dimethanol to the 2, 2-dimethoxypropane is 1: 0.1-2.5, and preferably 1: 1.2. It is noted that the molar ratio of 1, 1-cyclopropanedimethanol to 2, 2-dimethoxypropane as used herein includes, but is not limited to, 1:0.1, 1:0.2, 1:0.5, 1:0.8, 1:1, 1:1.2, 1:1.5, 1:1.7, 1:2, 1:2.3, and 1: 2.5.
More preferably, the feeding molar ratio of the 1, 1-cyclopropane dimethanol to the p-toluenesulfonic acid monohydrate is 1: 0.01-1: 1, and preferably 1: 0.3. The molar ratios of 1, 1-cyclopropanedimethanol and p-toluenesulfonic acid monohydrate used herein include, but are not limited to, 1:0.1, 1:0.2, 1:0.3, 1:0.5, 1:0.7, 1:0.8, and 1: 9.
The stirring is carried out for 5 to 15 hours at room temperature, including but not limited to 5 hours, 7 hours, 10 hours, 12 hours and 15 hours; of these, 10 hours is preferable.
Meanwhile, the invention further discloses that the compound 2c is prepared by the reaction of 1, 1-cyclopropane dimethanol (compound 3) and dimethyl carbonate, and the reaction route is as follows:
Figure BDA0003558280030000051
meanwhile, the invention further discloses a preparation process flow of the compound 2c, which is as follows: 1, 1-cyclopropane dimethanol, dimethyl carbonate and THF are added into a reaction bottle and heated to reflux for reaction for 12 hours. After completion of the reaction, distillation was carried out at 30 ℃ under reduced pressure to obtain Compound 2 c.
More preferably, the feeding molar ratio of the 1, 1-cyclopropane dimethanol to the dimethyl carbonate is 1:0.1 to 2.5, preferably 1:1. The molar ratio of 1, 1-cyclopropane dimethanol to dimethyl carbonate is not limited to 1:0.1, 1:0.2, 1:0.5, 1:0.8, 1:1, 1:1.2, 1:1.5, 1:1.7, 1:2, 1:2.3, and 1: 2.5.
Further preferably, the heating reflux reaction is performed for 5 to 20 hours, including but not limited to 5 hours, 7 hours, 10 hours, 12 hours, 15 hours, 17 hours, 20 hours, and most preferably 12 hours.
The description of "about" in the present invention represents ± 2% on the basis of the designated numerical value.
According to the technical scheme disclosed by the invention, 1-hydroxymethyl cyclopropyl acetonitrile can be prepared by taking 1, 1-cyclopropane dimethanol as a raw material only through two steps, so that the preparation process steps are greatly simplified, and the method has important significance for industrial popularization. Meanwhile, in the synthetic route disclosed by the invention, the target product has high yield and high purity, does not need a complex post-treatment process, and is suitable for large-scale industrial production. Finally, the reaction conditions of the invention are simple and easy to realize, and the synthesis cost is low.
Detailed Description
In order that the invention may be better understood, we now provide further explanation of the invention with reference to specific examples.
Unless otherwise specified, all reagents used in the present invention are commercially available products. The room temperature of the invention is 20-30 ℃.
EXAMPLE group 1 preparation route with Compound 2a as intermediate product
Figure BDA0003558280030000061
Examples 1 to 1
The first step is as follows:
Figure BDA0003558280030000062
putting toluene (150ml), 1-cyclopropane dimethanol (1mol, 76g) and sodium methoxide (81g, 1.5mol) into a reaction bottle, stirring and heating to reflux, cooling to room temperature after 15h, and adding 150ml of dichloromethane to prepare sodium salt for later use;
dichloromethane (375ml) was added to the reaction vessel, the internal temperature was maintained at 0 ℃ under nitrogen protection, sulfuryl chloride (148g, 1.1mol) was added, the above sodium salt was added dropwise, and the reaction was allowed to proceed for 2 hours. After the reaction, water (150ml) was added, the reaction solution was partitioned, the organic phase was vacuum-desolventized to dryness, toluene (300ml) and 15-crown-5 (0.075g) were added, stirred at room temperature for 1 hour, filtered and dried to obtain Compound 2 a.
The second step is that:
Figure BDA0003558280030000063
a reaction flask was charged with Compound 2a (164.2g, 1mol), NaCN (58.8g, 1.2mol), ethanol (550mL), and 16g of tetrabutylammonium bromide, and the temperature was slowly raised to 90 ℃ and the reaction was maintained for 20 hours. After completion of the reaction, the reaction mixture was cooled to 50 ℃ and toluene (600mL) and water (54mL) were added dropwise, followed by reaction at 70 ℃ for 1 hour. And (3) evaporating the solvent at the temperature of 70-75 ℃ under reduced pressure at 30-35 KPa, filtering out solids, and then carrying out high-pressure vacuum distillation at 270-275 Pa to collect the fraction at the temperature of 78-84 ℃ to obtain a light yellow oily substance, namely the product compound 1.
The total yield of the two steps is 92.6 percent, and the purity of the target product is 99.5 percent.
Examples 1-2 to examples 1-11
In examples 1-2 to 1-11, part of the preparation conditions were changed to examine the changes in the product purity and the two-step total yield under different conditions, respectively.
Only the feed ratio or other conditions were changed, respectively, in the manner disclosed in example 1-1, as detailed in table 1.
Note: the white portion in the table represents that the conditions are the same as in example 1-1.
Table 1 different reaction conditions and results
Figure BDA0003558280030000071
Wherein n is3：n4Represents the feeding molar ratio of 1, 1-cyclopropane dimethanol (compound 3) to sulfonyl chloride; n is2a：nCyanidation reagentRepresents the molar ratio of compound 2a to the cyanating agent.
EXAMPLE group 2 preparation route with Compound 2b as intermediate product
Figure BDA0003558280030000072
Example 2-1
The first step is as follows:
Figure BDA0003558280030000073
2, 2-Dimethoxypropane (125g, 1.2mol), p-toluenesulfonic acid monohydrate (57g, 0.3mol) were added to a mixture of 1, 1-cyclopropanedimethanol (102g, 1mol) in THF (2L) and stirred at room temperature for 10 h. The reaction was quenched by addition of TEA and distilled under vacuum to afford compound 2 b.
The second step is that:
Figure BDA0003558280030000081
to a reaction flask were added compound 2b (142.2g, 1mol), sodium cyanide (58.8g, 1.2mol), ethanol (550mL), and 16g tetrabutylammonium bromide, and the reaction was incubated while slowly raising the temperature to 90 ℃ for 20 hours. After completion of the reaction, the reaction mixture was cooled to 50 ℃ and toluene (600mL) and water (54mL) were added dropwise, followed by reaction at 70 ℃ for 1 hour. The solvent was evaporated under reduced pressure, the solid was filtered off and the product compound 1 was evaporated under high vacuum.
The total yield of the two steps is 93.5 percent, and the purity of the target product is 99.5 percent.
Examples 2-2 to 2-13
In examples 2-2 to 2-13, part of the preparation conditions were changed to examine the changes in the product purity and the two-step total yield under different conditions, respectively.
Only the respective charge ratios or other conditions were changed in the manner disclosed in example 2-1, as detailed in Table 2.
Note: the white portion in the table represents that the conditions are the same as in example 2-1.
Table 2 different reaction conditions and results
Figure BDA0003558280030000082
Figure BDA0003558280030000091
Wherein n is3：n5Represents the feeding molar ratio of 1, 1-cyclopropane dimethanol (compound 3) to 2, 2-dimethoxypropane; n is2b：nCyanidation reagentRepresents the feeding molar ratio of the compound 2b and the cyaniding reagent; n is3：n6Represents the charged molar ratio of 1, 1-cyclopropanedimethanol (compound 3) to p-toluenesulfonic acid monohydrate.
EXAMPLE group 3 preparation route with Compound 2c as intermediate product
Figure BDA0003558280030000092
Example 3-1
The first step is as follows:
Figure BDA0003558280030000093
1, 1-cyclopropanedimethanol (92g, 1mol), dimethyl carbonate (90g, 1mol), 450ml THF were added to the reaction flask and refluxed at 80 ℃ for 12 hours. After the reaction was completed, the reaction mixture was distilled under reduced pressure at 30 ℃ using a rotary evaporator to obtain Compound 2 c.
The second step is that:
Figure BDA0003558280030000094
a reaction flask was charged with Compound 2c (128g, 1mol), NaCN (58.8g, 1.2mol), ethanol (550mL), and 16g tetrabutylammonium bromide, and the temperature was slowly raised to 90 ℃ and the reaction was maintained for 20 hours. After the reaction, the reaction mixture was cooled to 50 ℃ and toluene (600mL) and water (54mL) were added dropwise, followed by reaction at 70 ℃ for 1 hour. The solvent is distilled off under reduced pressure, the solid is filtered out, and the product compound 1 is distilled off under high vacuum, the total yield of the two steps is 92.8 percent, and the purity of the target product is 99.2 percent.
Example 3-2 to example 3-11
In examples 3-2 to 3-11, part of the preparation conditions were changed to examine the changes in the product purity and the two-step total yield under different conditions, respectively.
Only the feed ratio or other conditions were changed, respectively, in the manner disclosed in example 3-1, as specified in Table 3.
Note: the white portion in the table represents that the conditions are the same as in example 3-1.
Table 3 different reaction conditions and results
Figure BDA0003558280030000101
Wherein n is3：n7Represents the feeding molar ratio of 1, 1-cyclopropane dimethanol (compound 3) to dimethyl carbonate; n is2c：nCyanidation reagentRepresents the molar ratio of compound 2c to the cyanating agent charged.
What has been described above is a specific embodiment of the present invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principle of the present invention, and such improvements and modifications are also considered to be within the scope of the present invention.

Claims (8)

1. A preparation method of a montelukast sodium side chain intermediate is characterized in that: the method takes 1, 1-cyclopropane dimethanol (compound 3) as a raw material to prepare the 1-hydroxymethyl cyclopropyl acetonitrile (compound 1) by a two-step method, and the preparation route is as follows:
the first step is as follows:
Figure FDA0003558280020000011
the second step is that:
Figure FDA0003558280020000012
wherein R is SO2、CMe2Or CO.
2. The method for preparing a side chain intermediate of montelukast sodium according to claim 1, comprising: the feeding molar ratio of the compound 2 to the cyaniding agent is 1 (0.5-1.8), and the preferable ratio is 1: 1.2.
3. The method for preparing a montelukast sodium side chain intermediate according to claim 1, wherein: compound 2 is reacted with a cyanating reagent in the presence of ethanol and tetrabutylammonium bromide.
4. The method for preparing a montelukast sodium side chain intermediate according to claim 1, wherein: the reaction temperature of the compound 2 and the cyaniding reagent is 60-150 ℃, wherein the reaction temperature is preferably 90 ℃.
5. The method for preparing a montelukast sodium side chain intermediate according to claim 1, wherein: the specific process flow of the cyanidation reaction is as follows: adding a compound 2, a cyaniding reagent, ethanol and tetrabutylammonium bromide into a reaction bottle, slowly heating to 60-150 ℃, carrying out heat preservation reaction for 18-20 hours, cooling to 50 ℃ after the reaction is finished, dropwise adding toluene and water, and carrying out heat preservation reaction for 1 hour at 70 ℃; and (3) evaporating the solvent at the temperature of 70-80 ℃ under reduced pressure at 30-40 KPa, filtering out solids, and then carrying out high-pressure vacuum distillation at 270-280 Pa to collect the fraction at the temperature of 78-88 ℃ to obtain a light yellow oily substance, namely the product compound 1.
6. The method for preparing a montelukast sodium side chain intermediate according to claim 1, wherein: the compound 2a is prepared by reacting 1, 1-cyclopropane dimethanol (compound 3) with sulfonyl chloride, and the reaction route is as follows:
Figure FDA0003558280020000021
preferably, the preparation process flow of the compound 2a is as follows: adding toluene, 1-cyclopropane dimethanol and sodium methoxide into a reaction bottle, stirring and heating to a reflux state, cooling to room temperature after reflux reaction for about 15 hours, and adding dichloromethane to prepare a substance to be used; adding dichloromethane into a reaction kettle, keeping the internal temperature at-20 ℃ under the protection of nitrogen, adding sulfonyl chloride, dripping the prepared standby substance, keeping the temperature for reaction for more than 2 hours, adding water after the reaction is finished, carrying out pressure-less desolventizing on the organic phase until the organic phase is dry after the reaction liquid is layered, adding toluene and 15-crown-5, stirring for 1 hour at room temperature, filtering and drying to obtain a compound 2 a;
further preferably, the feeding molar ratio of the 1, 1-cyclopropane dimethanol to the sulfonyl chloride is 1: 0.6-1: 1.6, preferably 1: 1.1;
further preferably, the reaction temperature is 0 ℃ among-20 ℃ to 20 ℃.
7. The method for preparing a montelukast sodium side chain intermediate according to claim 1, wherein: the compound 2b is prepared by the reaction of 1, 1-cyclopropane dimethanol (compound 3) and 2, 2-dimethoxy propane, and the reaction route is as follows:
Figure FDA0003558280020000022
preferably, the preparation process of the compound 2b is as follows: adding 2, 2-dimethoxypropane and p-toluenesulfonic acid monohydrate into a mixture of 1, 1-cyclopropane dimethanol and THF, stirring at room temperature for 5-15 hours, adding TEA to quench the reaction, and distilling under a vacuum state to obtain a compound 2 b;
more preferably, the feeding molar ratio of the 1, 1-cyclopropane dimethanol to the 2, 2-dimethoxypropane is 1: 0.1-2.5, preferably 1: 1.2;
more preferably, the feeding molar ratio of the 1, 1-cyclopropane dimethanol to the p-toluenesulfonic acid monohydrate is 1: 0.01-1: 1, and preferably 1: 0.3;
more preferably, the stirring is carried out at room temperature for 5 to 15 hours, preferably 10 hours.
8. The method for preparing a montelukast sodium side chain intermediate according to claim 1, wherein: the compound 2c is prepared by reacting 1, 1-cyclopropane dimethanol (compound 3) with dimethyl carbonate, and the reaction route is as follows:
Figure FDA0003558280020000031
preferably, the preparation process of the compound 2c comprises the following steps: 1, 1-cyclopropane dimethanol, dimethyl carbonate and THF are added into a reaction bottle and heated to reflux for reaction for 12 hours. After the reaction is finished, carrying out reduced pressure distillation at 30 ℃ to obtain a compound 2 c;
more preferably, the feeding molar ratio of the 1, 1-cyclopropane dimethanol to the dimethyl carbonate is 1: 0.1-2.5, preferably 1: 1;
further preferably, the heating reflux reaction is carried out for 5 to 20 hours, and most preferably for 12 hours.
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