CN107365297A - A kind of Preparation Method And Their Intermediate of the benzyl propionate derivant of 2 methyl 2 ' - Google Patents
A kind of Preparation Method And Their Intermediate of the benzyl propionate derivant of 2 methyl 2 ' Download PDFInfo
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- CN107365297A CN107365297A CN201610916958.4A CN201610916958A CN107365297A CN 107365297 A CN107365297 A CN 107365297A CN 201610916958 A CN201610916958 A CN 201610916958A CN 107365297 A CN107365297 A CN 107365297A
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- 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
- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
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- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
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Abstract
The present invention relates to a kind of Preparation Method And Their Intermediate of the benzyl propionate derivant of 2 methyl 2 ', and this method is simple efficiently, side reaction is few, yield is high, cost is cheap, is adapted to industrialized production.
Description
Technical field
The present invention relates to medical field, more particularly to a kind of preparation method of 2- methyl -2 '-benzyl propionate derivant and its
New midbody compound.
Background technology
2- methyl -2 '-benzyl propionate derivant of following formula 1 is widely used in pharmaceutical field.
[formula 1]
Wherein, R2Hydrogen or-CH2CH2OR3；R3For side chain or the C of straight chain1-C10Alkyl.
The 2- benzyl propionate derivants of methyl -2 ' it is exclusive there is H1Anti-histamine activity, thus, without with other drugs acceptor
Effect, high selectivity can be also shown even if heavy dose, there is antihistamine property but without calm or Cardiovascular.Therefore,
2- methyl -2 '-benzyl propionate derivant can be used for anaphylactia patient, especially take the patient of other drugs simultaneously,
Such as those have the patient of cardiovascular disease.
CN 101952273A disclose a kind of preparation method of 2- methyl -2 '-benzyl propionate derivant of formula 1.But this
In the preparation process, elimination reaction inevitably occurs one method for key intermediate, and this make it that whole technical process is suitable
Cumbersome, reaction condition requirement is strict and bad control, substantial amounts of side reaction not only increase cost of material, while substantial amounts of secondary
Product also brings issues of purification, and therefore, this method is used for 2- methyl -2 '-benzyl propionate derivant of commercial scale formula 1
Yield be very low.
Therefore, it is necessary to improve the yield and purity of 2- methyl -2 '-benzyl propionate derivant of formula 1, and their system is made
Preparation Method is more suitable for industrialized production.
The content of the invention
The present invention provides the method and its intermediate that one kind prepares 2- methyl -2 '-benzyl propionate derivant.
On the one hand, the invention provides a kind of method for 2- methyl-the 2 '-benzyl propionate derivant for preparing following formula 1, including
The step of compound of following formula 2 is reacted with the compound of following formula 3：
[formula 2]
[formula 3]
[formula 1]
Wherein, R1For hydrogen, the C of side chain or straight chain1-C10Alkyl, or C3-C6Cycloalkyl；
R2It is hydrogen or-CH2CH2OR3；
R3For side chain or the C of straight chain1-C10Alkyl.
Optionally, the reaction is carried out in the presence of go back original reagent.
Optionally, the go back original reagent is acetic acid sodium borohydride, sodium cyanoborohydride, sodium borohydride, borine tetrahydrofuran.
Optionally, the R1For side chain or the C of straight chain1-C6Alkyl.
Optionally, the R3For side chain or the C of straight chain1-C6Alkyl.
Optionally, R1When not being hydrogen, the step of it further comprises ester hydrolysis in reaction product.
Optionally, R2For hydrogen when, its step of further reaction includes the compound reaction of reaction product and following formula 4：
[formula 4]
XCH2CH2OR3
Wherein, R3For side chain or the C of straight chain1-C10Alkyl；
X is leaving group.
Optionally, X is chlorine, bromine, iodine, tolysulfonyl epoxide, trifluoro-methanesulfonyl oxy or mesyloxy.
Optionally, 2- methyl -2 '-benzyl propionate derivant of formula 1 be 2- [4- (2- [4- [1- (2- ethoxy-ethyls) -
1H- benzimidazolyl-2 radicals-yl]-piperidin-1-yl)-ethyl]-phenyl] -2- rnethyl-propanoic acids.
On the other hand, the invention provides the compound of following formula 2：
[formula 2]
Wherein, R1For hydrogen, the C of side chain or straight chain1-C10Alkyl, or C3-C6Cycloalkyl.
Optionally, the R1For side chain or the C of straight chain1-C6Alkyl.
The beneficial effects of the invention are as follows：Preparation method of the present invention is simply efficient, and yield is high, and cost is cheap, purifying letter
It is single, particularly (work as R when the compound of formula 2 is carboxylic acid1For hydrogen when), carboxylic acid without protection, deprotection, can one-step synthesis 2- first
Base -2 '-benzyl propionate derivant, is easy to industrialized production.
Embodiment
At present, the method yield for 2- methyl -2 '-benzyl propionate derivant of formula 1 is very low, and purification difficult.
Therefore, it is necessary to improve the yield and purity of 2- methyl -2 '-benzyl propionate derivant of formula 1, and their system is made
Preparation Method is more suitable for industrialized production.
The present invention provides the method and its intermediate that one kind prepares 2- methyl -2 '-benzyl propionate derivant.
On the one hand, the invention provides a kind of method for 2- methyl-the 2 '-benzyl propionate derivant for preparing following formula 1, including
The step of compound of following formula 2 is reacted with the compound of following formula 3：
[formula 2]
[formula 3]
[formula 1]
Wherein, R1For hydrogen, the C of side chain or straight chain1-C10Alkyl, or C3-C6Cycloalkyl；R2It is hydrogen or-CH2CH2OR3；R3For
The C of side chain or straight chain1-C10Alkyl.
In the above-mentioned methods, the compound of the compound of formula 2 and formula 3 is reacted in the presence of go back original reagent.It is described
Go back original reagent does not have special restriction, as long as it is known to those skilled in the art, above-mentioned reaction can be realized.It is optional
, the go back original reagent is acetic acid sodium borohydride, sodium cyanoborohydride, sodium borohydride, borine tetrahydrofuran.Use these reduction
The compound of reagent formula 2 and the compound of formula 3 can preferably react the compound of production 1, and yield is high, simple efficient, into
This is cheap.
R1For hydrogen, the C of side chain or straight chain1-C10Alkyl, or C3-C6Cycloalkyl.Work as R1For hydrogen when, the compound and formula 3 of formula 2
Compound react to obtain 2- methyl -2 '-benzyl propionate derivant, carboxylic acid, can directly one-step synthesis 2- without protection, deprotection
Methyl -2 '-benzyl propionate derivant, it is easier to industrialized production；Work as R1For side chain or the C of straight chain1-C10Alkyl, or C3-C6Ring
During alkyl, after the compound reaction of the compound and formula 3 of formula 2, if it is desired, may further include in reaction product
Ester hydrolysis is into the step of acid, and ester hydrolysis condition does not have special restriction, as long as can realize.Optionally, the R1For
The C of side chain or straight chain1-C6Alkyl.Work as R1For side chain or the C of straight chain1-C6During alkyl, raw material is cheap and easy to get, and side reaction is few, production
Rate is high.R2It is hydrogen or-CH2CH2OR3, R3For side chain or the C of straight chain1-C10Alkyl, optionally, the R3For side chain or straight chain
C1-C6Alkyl.Work as R2For hydrogen when, if it is desired, reaction product further can react with the compound of following formula 4.
[formula 4]
XCH2CH2OR3。
R3For side chain or the C of straight chain1-C10Alkyl.Optionally, the R3For side chain or the C of straight chain1-C6Alkyl.X is to leave away
Group, there is no special limitation for X, as long as leaving group known to those skilled in the art, that above-mentioned reaction can be realized
Group, optionally, X are chlorine, bromine, iodine, tolysulfonyl epoxide, trifluoro-methanesulfonyl oxy or mesyloxy etc..
Optionally, 2- methyl -2 '-benzyl propionate derivant of formula 1 be 2- [4- (2- [4- [1- (2- ethoxy-ethyls) -
1H- benzimidazolyl-2 radicals-yl]-piperidin-1-yl)-ethyl]-phenyl] -2- rnethyl-propanoic acids.
On the other hand, the invention provides the compound of following formula 2：
[formula 2]
Wherein, R1For hydrogen, the C of side chain or straight chain1-C10Alkyl, or C3-C6Cycloalkyl, optionally, the R1For side chain or
The C of straight chain1-C6Alkyl.The compound of formula 2 is a new intermediate for being used to prepare 2- methyl -2 '-benzyl propionate derivant,
The method of 2- methyl-the 2 '-benzyl propionate derivant prepared using the compound of formula 2 is simply efficient, and yield is high, and cost is cheap,
It is easy to industrialized production.
It is prepared by the method that the compound of formula 2 can think feasible by any those skilled in the art, optionally, Ke Yitong
It is prepared by the compound for crossing following formula 5.
[formula 5]
Wherein, R1For hydrogen, the C of side chain or straight chain1-C10Alkyl, or C3-C6Cycloalkyl, optionally, the R1For side chain or
The C of straight chain1-C6Alkyl.
The compound of formula 5 can in the presence of oxidising agent formula 2 compound, it is special that the oxidising agent has no
Restriction, as long as can have the compound of the preparation of compounds of formula 2 of the formula of realization 5, the oxidising agent can be selected from Dess-
Martin oxidants, 2- iodosobenzoic acids (IBX), sulfur trioxide pyridine, Tempo oxidants, hydrogen peroxide or peroxide etc..
R1For hydrogen, the C of side chain or straight chain1-C10Alkyl, or C3-C6Cycloalkyl.
The compound of formula 5, R1For hydrogen, the C of side chain or straight chain1-C10Alkyl, or C3-C6Cycloalkyl, optionally, the R1For
The C of side chain or straight chain1-C6Alkyl.Work as R1When not being hydrogen, the compound of formula 5 can pass through R1Pass through ester for the compound of formula 5 of hydrogen
Change reaction to prepare.As long as the condition that the esterification can be realized, have no special restriction.Can in acid condition,
It can also carry out in the basic conditions.For acid condition, acid can be selected from sulfuric acid, thionyl chloride etc.；For alkalescence condition, alkali
Potassium carbonate, sodium carbonate, sodium acid carbonate, sodium hydroxide, dimethylamino naphthyridine etc. can be selected from.
Experiment reagent described in embodiment of the present invention is commercially available in addition to especially indicating.
In order to further illustrate the present invention, the present invention is described in detail by specific examples below.Wherein, under
Many details are elaborated in the description of face embodiment to facilitate a thorough understanding of the present invention, still the present invention can also use it
He is different from other manner described here to implement, therefore the present invention is not limited by following public specific embodiment.
Embodiment 1：The preparation of 2- methyl -2- (4- (2- ethoxys)-phenyl)-methyl propionate
In a reaction vessel, 2- methyl -2- (4- (2- ethoxys)-phenyl)-propionic acid (5.0g), methanol are added
(50mL) and the concentrated sulfuric acid (0.5mL), 80 DEG C are heated to, stirring reaction 20 hours, is cooled to room temperature, it is water-soluble that saturated sodium carbonate is added dropwise
Liquid, regulation pH are neutrality, are concentrated into no longer dropping liquid, add 30mL water and stir 1 hour, add the extraction of 10mL ethyl acetate three times,
Merge organic phase, with 10mL saturated common salt water washings, separate organic phase, with 2g anhydrous sodium sulfate dryings 2 hours, filtering, filtrate
It is concentrated under reduced pressure to give 2- methyl -2- (4- (2- ethoxys)-phenyl)-methyl propionate (5.3g, yield 100%).
1HNMR, 500MHZ, CDCl3, ppm：1.56 (s, 6H), 2.03 (t, 1H), 2.82 (t, 2H), 3.64 (s, 3H),
3.82 (t, 2H), 7.17 (d, 2H), 7.27 (d, 2H).MS(ESI)：[M+H]+=222.98
Embodiment 2：The preparation of 2- methyl -2- (4- (2- ethoxys)-phenyl)-methyl propionate
In a reaction vessel, 2- methyl -2- (4- (2- ethoxys)-phenyl)-propionic acid (2.5g), dimethyl methyl are added
Acid amides (12.5mL) and potassium carbonate (5g), are stirred at room temperature, and iodomethane (2.0g) is added dropwise, and reaction 4 hours is stirred at room temperature, adds 30mL
Water, stir 30 minutes, add the extraction of 5mL ethyl acetate three times, merge organic phase, with 10mL saturated common salts water washing three times, point
From organic phase, with 1g anhydrous sodium sulfate dryings 4 hours, filtering, filtrate decompression be concentrated to give 2- methyl -2- (4- (2- ethoxys) -
Phenyl)-methyl propionate (2.7g, yield 100%).
1HNMR, 500MHZ, CDCl3, ppm：1.56 (s, 6H), 2.03 (t, 1H), 2.82 (t, 2H), 3.64 (s, 3H),
3.82 (t, 2H), 7.17 (d, 2H), 7.27 (d, 2H).MS(ESI)：[M+H]+=222.98
Embodiment 3：The preparation of 2- methyl -2- (4- (2- ethoxys)-phenyl)-ethyl propionate
In a reaction vessel, 2- methyl -2- (4- (2- ethoxys)-phenyl)-propionic acid (2.5g), ethanol are added
(25mL) and the concentrated sulfuric acid (0.3mL), 80 DEG C are heated to, stirring reaction 22 hours, is cooled to room temperature, it is water-soluble that saturated sodium carbonate is added dropwise
Liquid, regulation pH are neutrality, are concentrated into no longer dropping liquid, add 10mL water and stir 1 hour, add the extraction of 5mL ethyl acetate three times, close
And organic phase, with 5mL saturated common salt water washings, organic phase is separated, with 1g anhydrous sodium sulfate dryings 3 hours, filtering, filtrate decompression
It is concentrated to give 2- methyl -2- (4- (2- ethoxys)-phenyl)-ethyl propionate (2.8g, yield 100%).
MS(ESI)：[M+H]+=237.03
Embodiment 4：The preparation of 2- methyl -2- (4- (2- ethoxys)-phenyl)-isopropyl propionate
In a reaction vessel, 2- methyl -2- (4- (2- ethoxys)-phenyl)-propionic acid (4g), dimethyl formyl are added
Amine (20mL) and potassium carbonate (8g), are stirred at room temperature, and Iso-Propyl iodide (3.9g) is added dropwise, and reaction 6 hours is stirred at room temperature, adds 80mL
Water, stir 30 minutes, add the extraction of 15mL ethyl acetate three times, merge organic phase, wash with saturated aqueous common salt 10mL secondary, divide
From organic phase, with 2g anhydrous sodium sulfate dryings 4 hours, filtering, filtrate decompression be concentrated to give 2- methyl -2- (4- (2- ethoxys) -
Phenyl)-isopropyl propionate (4.8g, yield 100%).
MS(ESI)：[M+H]+=251.10
Embodiment 5：The preparation of 2- methyl -2- (4- (2- ethoxys)-phenyl)-n-butyl propionate
In a reaction vessel, 2- methyl -2- (4- (2- ethoxys)-phenyl)-propionic acid (2.5g), n-butanol are added
(25mL) and the concentrated sulfuric acid (0.5mL), 90 DEG C are heated to, stirring reaction 24 hours, is cooled to room temperature, it is water-soluble that saturated sodium carbonate is added dropwise
Liquid, regulation pH are neutrality, are concentrated into no longer dropping liquid, add 10mL water, are stirred 1 hour, add the extraction of 5mL ethyl acetate three times,
Merge organic phase, with 5mL saturated common salt water washings, separate organic phase, with 1g anhydrous sodium sulfate dryings 3 hours, filtering, filtrate subtracted
Pressure is concentrated to give 2- methyl -2- (4- (2- ethoxys)-phenyl)-n-butyl propionate (3.1g, yield 98%).
MS(ESI)：[M+H]+=264.74
Embodiment 6：The preparation of 2- methyl -2- (4- (2- ethoxys)-phenyl)-cyclohexyl propionate
In a reaction vessel, 2- methyl -2- (4- (2- ethoxys)-phenyl)-propionic acid (2.5g), cyclohexanol are added
(25mL) and the concentrated sulfuric acid (1mL), 100 DEG C are heated to, stirring reaction 26 hours, is cooled to room temperature, it is water-soluble that saturated sodium carbonate is added dropwise
Liquid, regulation pH are neutrality, are concentrated into no longer dropping liquid, add 10mL water and stir 1 hour, add the extraction of 5mL ethyl acetate three times, close
And organic phase, with 5mL saturated common salt water washings, organic phase is separated, with 2g anhydrous sodium sulfate dryings 4 hours, filtering, filtrate decompression
It is concentrated to give 2- methyl -2- (4- (2- ethoxys)-phenyl)-cyclohexyl propionate (3.4g, yield 97%).
MS(ESI)：[M+H]+=291.01
Embodiment 7：The preparation of 2- methyl -2- (4- (2- oxoethyls)-phenyl) propionic acid
In a reaction vessel, 2- (4- (2- hydroxyethyls)-phenyl) -2 Methylpropionic acid (2.0g), Dess- are added
Martin oxidants (6.1g) and dichloromethane (60.0mL), reaction 5 hours is stirred at room temperature, filtering, filtrate is with the thio sulphur of 20mL
Acid sodium solution washs, and separates organic phase, then with 2g anhydrous sodium sulfate dryings, filtering, gained filtrate decompression be concentrated to give 2- methyl-
2- (4- (2- oxoethyls)-phenyl) propionic acid (2.0g, yield 100%).
1HNMR, 500MHZ, DMSO-d6, ppm：1.69 (s, 6H), 3.85 (d, 2H), 7.28 (d, 2H), 7.32 (d, 2H),
9.69 (t, 1H).MS(ESI)：[M+H]+=207.01
Embodiment 8：The preparation of 2- methyl -2- (4- (2- oxoethyls)-phenyl) propionic acid
In a reaction vessel, 2- (4- (2- hydroxyethyls) phenyl) -2 Methylpropionic acid (0.5g), IBX oxidations are added
Agent (1.0g) and ethyl acetate (20.0mL), are heated to 70 DEG C, stirring reaction 16 hours, filtering, and filtrate is with 10mL thiosulfuric acids
Sodium solution washs, and separates organic phase, then be concentrated to give 2- methyl -2- with 1g anhydrous sodium sulfate dryings, filtering, gained filtrate decompression
(4- (2- oxoethyls)-phenyl) propionic acid (0.5g, yield 100%).
1HNMR, 500MHZ, DMSO-d6, ppm：1.69 (s, 6H), 3.85 (d, 2H), 7.28 (d, 2H), 7.32 (d, 2H),
9.69 (t, 1H).MS(ESI)：[M+H]+=207.01
Embodiment 9：The preparation of 2- methyl -2- (4- (2- oxoethyls)-phenyl)-methyl propionate
In a reaction vessel, 2- methyl -2- (4- (2- ethoxys)-phenyl)-propionic acid first made from embodiment 1 is added
Ester (4.5g), Dess-Martin oxidants (12.2g) and dichloromethane (60mL), reaction 5 hours, filtering, filtrate is stirred at room temperature
Washed with 40mL hypo solutions, separate organic phase, with 4g anhydrous sodium sulfate dryings 3 hours.Filtering, filtrate decompression concentration
Obtain 2- methyl -2- (4- (2- oxoethyls)-phenyl)-methyl propionate (4.5g, yield 100%).
1HNMR, 500MHZ, DMSO-d6, ppm：1.50 (s, 6H), 3.58 (s, 3H), 3.73 (d, 2H), 7.23 (d, 2H),
7.30 (d, 2H), 9.68 (t, 1H).MS(ESI)：[M+H]+=220.98
Embodiment 10：The preparation of 2- methyl -2- (4- (2- oxoethyls)-phenyl)-methyl propionate
In a reaction vessel, 2- methyl -2- (4- (2- ethoxys)-phenyl)-propionic acid first made from embodiment 2 is added
Ester (2.2g), dichloromethane (20mL), it is cooled to 0 DEG C and stirs 30 minutes, add dimethyl sulfoxide 2mL, DIPEA
(DIPEA, 2.4mL), stirring reaction 30 minutes, sulfur trioxide pyridine is added, 0 DEG C is reacted 5 hours, adds 10mL sodium thiosulfate molten
Liquid stirs 1 hour, separates organic phase, with 10mL saturated common salt water washings, separates organic phase, small with 1g anhydrous sodium sulfate dryings 3
When.Filtering, filtrate decompression are concentrated to give 2- methyl -2- (4- (2- oxoethyls)-phenyl)-methyl propionate (2.1g, yield
95%).
1HNMR, 500MHZ, DMSO-d6, ppm：1.50 (s, 6H), 3.58 (s, 3H), 3.73 (d, 2H), 7.23 (d, 2H),
7.30 (d, 2H), 9.68 (t, 1H).MS(ESI)：[M+H]+=220.98
Embodiment 11：The preparation of 2- methyl -2- (4- (2- oxoethyls)-phenyl)-ethyl propionate
In a reaction vessel, 2- methyl -2- (4- (2- ethoxys)-phenyl)-propionic acid second made from embodiment 3 is added
Ester (2.3g), Dess-Martin oxidants (5.0g) and dichloromethane (25mL), reaction 3 hours, filtering, filtrate is stirred at room temperature
Washed with 10mL hypo solutions, separate organic phase, with 1.5g anhydrous sodium sulfate dryings 3 hours.Filtering, filtrate decompression are dense
Contracting obtains 2- methyl -2- (4- (2- oxoethyls)-phenyl)-ethyl propionate (2.3g, yield 100%).
1HNMR, 500MHZ, DMSO-d6, ppm：1.29 (t, 3H), 1.50 (s, 6H), 3.66 (m, 2H), 3.79 (d, 2H),
7.32 (d, 2H), 7.39 (d, 2H), 9.86 (t, 1H).MS(ESI)：[M+H]+=235.28
Embodiment 12：The preparation of 2- methyl -2- (4- (2- oxoethyls)-phenyl)-isopropyl propionate
In a reaction vessel, it is different to add 2- methyl -2- (4- (2- ethoxys)-phenyl)-propionic acid made from embodiment 4
Propyl ester (2.5g), Dess-Martin oxidants (7.0g) and dichloromethane (40mL), reaction 4 hours is stirred at room temperature, filters, filter
Liquid was washed with 10mL hypo solutions, separates organic phase, with 2g anhydrous sodium sulfate dryings 4 hours.Filtering, filtrate decompression are dense
Contracting obtains 2- methyl -2- (4- (2- oxoethyls)-phenyl)-isopropyl propionate (2.4g, yield 96%).
1HNMR, 500MHZ, DMSO-d6, ppm：1.21 (d, 6H), 1.53 (s, 6H), 3.59 (m, 1H), 3.94 (d, 2H),
7.31 (d, 2H), 7.42 (d, 2H), 9.82 (t, 1H).MS(ESI)：[M+H]+=249.34
Embodiment 13：The preparation of 2- methyl -2- (4- (2- oxoethyls)-phenyl)-n-butyl propionate
In a reaction vessel,-propionic acid is just by 2- methyl -2- (4- (2- ethoxys)-phenyl) made from addition embodiment 5
Butyl ester (2.6g), Dess-Martin oxidants (8.4g) and dichloromethane (50mL), reaction 5 hours is stirred at room temperature, filters, filter
Liquid was washed with 20mL hypo solutions, separates organic phase, with 1g anhydrous sodium sulfate dryings 3 hours.Filtering, filtrate decompression are dense
Contracting obtains 2- methyl -2- (4- (2- oxoethyls)-phenyl)-n-butyl propionate (2.6g, yield 100%).
1HNMR, 500MHZ, DMSO-d6, ppm：0.81 (m, 3H), 1.17 (m, 2H), 1.49 (m, 8H), 3.48 (m, 2H),
3.99 (m, 2H), 7.12 (d, 2H), 7.18 (d, 2H), 9.74 (t, 1H).MS(ESI)：[M+H]+=263.99
Embodiment 14：The preparation of 2- methyl -2- (4- (2- oxoethyls)-phenyl)-cyclohexyl propionate
In a reaction vessel, 2- methyl -2- (4- (2- ethoxys)-phenyl)-propionic acid ring made from embodiment 6 is added
Own ester (2.9g), Dess-Martin oxidants (8.4g) and dichloromethane (50mL), reaction 5 hours is stirred at room temperature, filters, filter
Liquid was washed with 10mL hypo solutions, separates organic phase, with 2g anhydrous sodium sulfate dryings 3 hours.Filtering, filtrate decompression are dense
Contracting obtains 2- methyl -2- (4- (2- oxoethyls)-phenyl)-cyclohexyl propionate (2.8g, yield 96%).
1HNMR, 500MHZ, DMSO-d6, ppm：1.04 (m, 2H), 1.23 (m, 6H), 1.52 (m, 8H), 3.48 (m, 1H),
3.84 (m, 2H), 7.17 (d, 2H), 7.22 (d, 2H), 9.70 (t, 1H).MS(ESI)：[M+H]+=288.98
Embodiment 15：2- (4- { 2- [4- (1- (2- ethoxyethyl groups) -1H- benzimidazolyl-2 radicals-yl)-piperidin-1-yl]-second
Base } phenyl) -2- methvl-propionic acid methyl estes preparation
In a reaction vessel, 2- methyl -2- (4- (2- oxoethyls)-phenyl)-propionic acid made from embodiment 9 is added
Methyl esters (1.1g), 1- (2- ethoxyethyl groups) -2- piperidin-4-yl -1H benzimidazoles (1.3g), tetrahydrofuran (20mL), room temperature
Reaction 4 hours, acetic acid sodium borohydride (2.1g) is added portionwise, stirring reaction 4 hours, filtering, filtrate decompression concentration, adds 30mL
Dichloromethane, 10mL saturated sodium bicarbonate solutions stir 30 minutes, separate organic phase, with 1g anhydrous sodium sulfate dryings 2 hours, mistake
Filter, filtrate decompression be concentrated to give 2- (4- 2- [4- (1- (2- ethoxyethyl groups) -1H- benzimidazolyl-2 radicals-yl)-piperidin-1-yl] -
Ethyl } phenyl) -2- methvl-propionic acid methyl estes (2.3g, yield 98%).
1HNMR, 500MHZ, DMSO-d6, ppm：1.00 (t, 3H), 1.49 (s, 6H), 1.85-1.90 (m, 4H), 2.09 (m,
2H), 2.54 (t, 2H), 2.74 (t, 2H), 3.04 (m, 3H), 3.34 (m, 2H), 3.58 (s, 3H), 3.65 (t, 2H), 4.39 (t,
2H), 7.15 (m, 2H), 7.20 (d, 2H), 7.26 (d, 2H), 7.51 (d, 1H), 7.55 (d, 1H).MS(ESI)：[M+H]+=
478.52
Embodiment 16：2- (4- { 2- [4- (1- (2- ethoxyethyl groups) -1H- benzimidazolyl-2 radicals-yl)-piperidin-1-yl]-second
Base } phenyl) -2- methvl-propionic acid methyl estes preparation
In a reaction vessel, 2- methyl -2- (4- (2- oxoethyls)-phenyl)-the third made from embodiment 10 is added
Sour methyl esters (1.1g), 1- (2- ethoxyethyl groups) -2- piperidin-4-yl -1H benzimidazoles (1.3g), tetrahydrofuran (20mL), room
Temperature reaction 4 hours, sodium cyanoborohydride (0.6g) is added portionwise, stirring reaction 6 hours, filtering, filtrate decompression concentration, adds
30mL dichloromethane, 10mL saturated sodium bicarbonate solutions stir 1 hour, separate organic phase, small with 1g anhydrous sodium sulfate dryings 2
When, filtering, filtrate is concentrated to give 2- (4- { 2- [4- (1- (2- ethoxyethyl groups) -1H- benzimidazolyl-2 radicals-yl)-piperidines -1-
Base]-ethyl } phenyl) -2- methvl-propionic acid methyl estes (2.2g, yield 93%).
1HNMR, 500MHZ, DMSO-d6, ppm：1.00 (t, 3H), 1.49 (s, 6H), 1.85-1.90 (m, 4H), 2.09 (m,
2H), 2.54 (t, 2H), 2.74 (t, 2H), 3.04 (m, 3H), 3.34 (m, 2H), 3.58 (s, 3H), 3.65 (t, 2H), 4.39 (t,
2H), 7.15 (m, 2H), 7.20 (d, 2H), 7.26 (d, 2H), 7.51 (d, 1H), 7.55 (d, 1H).MS(ESI)：[M+H]+=
478.52
Embodiment 17：2- (4- { 2- [4- (1H- benzimidazolyl-2 radicals-yl)-piperidin-1-yl]-ethyl } phenyl) -2- methyl -
The preparation of methyl propionate
In a reaction vessel, 2- methyl -2- (4- (2- oxoethyls)-phenyl)-propionic acid made from embodiment 9 is added
Methyl esters (1.1g), 2- (4- piperidines) -1H- benzimidazoles (1.0g), tetrahydrofuran (20mL), react at room temperature 2 hours, be added portionwise
Acetic acid sodium borohydride (3.6g), reaction 6 hours is added, filtering, filtrate concentration is dry, adds 20mL dichloromethane, 10mL saturated carbons
Sour hydrogen sodium solution stirs 1 hour, separates organic phase, and with 1g anhydrous sodium sulfate dryings 2 hours, filtering, filtrate was concentrated to give 2- (4-
{ 2- [4- (1H- benzimidazolyl-2 radicals-yl)-piperidin-1-yl]-ethyl } phenyl) -2- methvl-propionic acid methyl estes (1.9g, yield
95%).
MS(ESI)：[M+H]+=406.12
Embodiment 18：2- (4- { 2- [4- (1- (2- ethoxyethyl groups) -1H- benzimidazolyl-2 radicals-yl)-piperidin-1-yl]-second
Base } phenyl) -2- methvl-propionic acid methyl estes preparation
In a reaction vessel, 2- (4- { 2- [4- (1H- benzimidazolyl-2 radicals-yl)-piperazines made from embodiment 17 are added
Pyridine -1- bases]-ethyl } phenyl) -2- methvl-propionic acid methyl estes (1.6g), tetrahydrofuran (20mL), sodium hydrogen (0.8g), it is heated to 45
DEG C, tetrahydrofuran (5mL) solution of 2- ethyoxyls ethyl p-toluenesulfonate (1.5g) is added dropwise, drips off reaction 4 hours, is cooled to room
Temperature, it is concentrated under reduced pressure, adds 20mL dichloromethane, 10mL water stirs 30 minutes, separates organic phase, is washed with 10mL saturated common salts
Wash, separate organic phase, with 1g anhydrous sodium sulfate dryings 1 hour, filtering, filtrate decompression is concentrated to give 2- (4- { 2- [4- (1- (2-
Ethoxyethyl group) -1H- benzimidazolyl-2 radicals-yl)-piperidin-1-yl]-ethyl } phenyl) -2- methvl-propionic acid methyl estes (1.8g, yield
95%).
1HNMR, 500MHZ, DMSO-d6, ppm：1.00 (t, 3H), 1.49 (s, 6H), 1.85-1.90 (m, 4H), 2.09 (m,
2H), 2.54 (t, 2H), 2.74 (t, 2H), 3.04 (m, 3H), 3.34 (m, 2H), 3.58 (s, 3H), 3.65 (t, 2H), 4.39 (t,
2H), 7.15 (m, 2H), 7.20 (d, 2H), 7.26 (d, 2H), 7.51 (d, 1H), 7.55 (d, 1H).MS(ESI)：[M+H]+=
478.52
Embodiment 19：2- (4- { 2- [4- (1- (2- ethoxyethyl groups) -1H- benzimidazolyl-2 radicals-yl)-piperidin-1-yl]-second
Base } phenyl) -2- methvl-propionic acid ethvl esters preparation
In a reaction vessel, 2- methyl -2- (4- (2- oxoethyls)-phenyl)-the third made from embodiment 11 is added
Acetoacetic ester (1.2g), 1- (2- ethoxyethyl groups) -2- piperidin-4-yl -1H benzimidazoles (1.4g), tetrahydrofuran (20mL), room
Temperature reaction 4 hours, is added portionwise acetic acid sodium borohydride (2.1g), adds reaction 4 hours, filtering, filtrate decompression concentration, adds
20mL dichloromethane, 10mL saturated sodium bicarbonate solutions washing, separates organic phase, with 1g anhydrous sodium sulfate dryings 2 hours, mistake
Filter, filtrate are concentrated to give 2- (4- { 2- [4- (1- (2- ethoxyethyl groups) -1H- benzimidazolyl-2 radicals-yl)-piperidin-1-yl]-second
Base } phenyl) -2- methvl-propionic acid ethvl esters (2.4g, yield 100%).
MS(ESI)：[M+H]+=492.28
Embodiment 20：2- (4- { 2- [4- (1- (2- ethoxyethyl groups) -1H- benzimidazolyl-2 radicals-yl)-piperidin-1-yl]-second
Base } phenyl) -2- rnethyl-propanoic acids preparation
In a reaction vessel, 2- methyl -2- (4- (2- oxoethyls) phenyl) propionic acid made from embodiment 7 is added
(1.0g), 1- (2- ethoxyethyl groups) -2- piperidin-4-yl -1H benzimidazoles (1.3g), tetrahydrofuran (15mL), are stirred at room temperature
Reaction 5 hours, acetic acid sodium borohydride (4.2g) is added, reacted at room temperature 16 hours, filtering, filtrate decompression concentration, add 10mL
Dichloromethane and 5mL saturated sodium bicarbonate solutions stir 1 hour, separate organic phase, with 1g anhydrous sodium sulfate dryings 2 hours, mistake
Filter, gained filtrate decompression are concentrated to give 2- (4- { 2- [4- (1- (2- ethoxyethyl groups) -1H- benzimidazolyl-2 radicals-yl)-piperidines -1-
Base]-ethyl } phenyl) -2- rnethyl-propanoic acids (2.0g, yield 88%).
1HNMR, 500MHZ, DMSO-d6, ppm：1.00 (t, 3H), 1.46 (s, 6H), 1.88 (m, 4H), 2.13 (m, 2H),
2.57 (t, 2H), 2.75 (t, 2H), 3.08 (m, 3H), 3.34 (m, 2H), 3.65 (t, 2H), 4.39 (t, 2H), 7.15 (m, 2H),
7.21 (d, 2H), 7.26 (d, 2H), 7.53 (m, 2H).MS(ESI)：[M+H]+=464.45
Embodiment 21：2- (4- { 2- [4- (1- (2- ethoxyethyl groups) -1H- benzimidazolyl-2 radicals-yl)-piperidin-1-yl]-second
Base } phenyl) -2- rnethyl-propanoic acids preparation
In a reaction vessel, 2- (4- { 2- [4- (1- (2- ethoxyethyl groups) -1H- benzene made from embodiment 15 is added
And imidazoles -2- bases)-piperidin-1-yl]-ethyl phenyl) -2- methvl-propionic acid methyl estes (2.0g), sodium hydroxide 0.5g, water 1mL and
Ethanol 20mL, heating reflux reaction 7 hours, is cooled to room temperature, is concentrated under reduced pressure, and adds 20mL water, and pH is adjusted with dilute hydrochloric acid solution
For neutrality, stir one hour, filtering, obtain 2- (4- { 2- [4- (1- (2- ethoxyethyl groups) -1H- benzimidazolyl-2 radicals-yl)-piperazines
Pyridine -1- bases]-ethyl } phenyl) -2- rnethyl-propanoic acids (1.8g, yield 96%).
1HNMR, 500MHZ, DMSO-d6, ppm：1.00 (t, 3H), 1.46 (s, 6H), 1.88 (m, 4H), 2.13 (m, 2H),
2.57 (t, 2H), 2.75 (t, 2H), 3.08 (m, 3H), 3.34 (m, 2H), 3.65 (t, 2H), 4.39 (t, 2H), 7.15 (m, 2H),
7.21 (d, 2H), 7.26 (d, 2H), 7.53 (m, 2H).MS(ESI)：[M+H]+=464.45
Although above the present invention is described in detail with a general description of the specific embodiments,
On the basis of the present invention, some corrections can be made to it and improved, this will be apparent to those skilled in the art.Cause
This, the modification or improvement made without departing from theon the basis of the spirit of the present invention, belongs to the scope of protection of present invention.
Claims (12)
- A kind of 1. method for 2- methyl-the 2 '-benzyl propionate derivant for preparing following formula 1, it is characterised in that include the change of following formula 2 The step of compound of compound and following formula 3 is reacted：Wherein, R1For hydrogen, the C of side chain or straight chain1-C10Alkyl, or C3-C6Cycloalkyl；R2It is hydrogen or-CH2CH2OR3；R3For side chain or the C of straight chain1-C10Alkyl.
- 2. according to the method for claim 1, it is characterised in that the reaction is carried out in the presence of go back original reagent.
- 3. according to the method for claim 2, it is characterised in that the go back original reagent is acetic acid sodium borohydride, cyano group boron hydrogen Change sodium, sodium borohydride, borine tetrahydrofuran.
- 4. according to the method for claim 1, it is characterised in that the R1For side chain or the C of straight chain1-C6Alkyl.
- 5. according to the method for claim 1, it is characterised in that the R3For side chain or the C of straight chain1-C6Alkyl.
- 6. according to the method for claim 1, it is characterised in that R1When not being hydrogen, it further comprises ester water in reaction product The step of solution.
- 7. according to the method for claim 1, it is characterised in that R2For hydrogen when, its further reaction include reaction product and under The step of compound reaction of formula 4：[formula 4]XCH2CH2OR3Wherein, R3For side chain or the C of straight chain1-C10Alkyl；X is leaving group.
- 8. according to the method for claim 7, it is characterised in that X is chlorine, bromine, iodine, tolysulfonyl epoxide, fluoroform sulphur Acyloxy or mesyloxy.
- 9. according to the method for claim 7, it is characterised in that R3For side chain or the C of straight chain1-C6Alkyl.
- 10. according to the method for claim 1, it is characterised in that 2- methyl -2 '-benzyl propionate derivant of formula 1 is 2- [4- (2- [4- [1- (2- ethoxy-ethyls) -1H- benzimidazolyl-2 radicals-yl]-piperidin-1-yl)-ethyl]-phenyl] -2- methyl - Propionic acid.
- 11. the compound of following formula 2：Wherein, R1For hydrogen, the C of side chain or straight chain1-C10Alkyl, or C3-C6Cycloalkyl.
- 12. the compound according to claim 11, it is characterised in that the R1For side chain or the C of straight chain1-C6Alkyl.
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| CN110734375A (en) * | 2018-07-19 | 2020-01-31 | 上海天慈中商药业有限公司 | Preparation method of bilastine intermediates |
| CN110950837A (en) * | 2018-09-27 | 2020-04-03 | 上海天慈中商药业有限公司 | Preparation method of bilastine |
| CN111039922A (en) * | 2019-12-27 | 2020-04-21 | 山东罗欣药业集团恒欣药业有限公司 | Preparation process of bilastine |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107857702A (en) * | 2017-12-14 | 2018-03-30 | 重庆华邦制药有限公司 | A kind of preparation method of bilastine intermediate |
| CN110734375A (en) * | 2018-07-19 | 2020-01-31 | 上海天慈中商药业有限公司 | Preparation method of bilastine intermediates |
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| CN110950837A (en) * | 2018-09-27 | 2020-04-03 | 上海天慈中商药业有限公司 | Preparation method of bilastine |
| CN109694367A (en) * | 2019-03-06 | 2019-04-30 | 湖北省医药工业研究院有限公司 | A method of preparing bilastine |
| CN109694367B (en) * | 2019-03-06 | 2021-06-11 | 湖北省医药工业研究院有限公司 | Method for preparing bilastine |
| CN111039922A (en) * | 2019-12-27 | 2020-04-21 | 山东罗欣药业集团恒欣药业有限公司 | Preparation process of bilastine |
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