CN104326909A - Methods for preparation of alpha, alpha-dimethyl-4-(2-haloethyl) phenyl acetate and synthesis of bilastine - Google Patents
Methods for preparation of alpha, alpha-dimethyl-4-(2-haloethyl) phenyl acetate and synthesis of bilastine Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/62—Halogen-containing esters
- C07C69/65—Halogen-containing esters of unsaturated acids
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/317—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- 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
- C07C69/738—Esters of keto-carboxylic acids or aldehydo-carboxylic acids
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—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
Abstract
The invention discloses methods for preparation of alpha, alpha-dimethyl-4-(2-haloethyl) phenyl acetate and synthesis of bilastine. The invention first provides a method for preparation of the alpha, alpha-dimethyl-4-(2-haloethyl) phenyl acetate, and then provides a method for synthesis of the bilastine by use of the alpha, alpha-dimethyl-4-(2-haloethyl) phenyl acetate. The methods avoid the harsh reaction conditions in the existing technique, and raw materials and reagents are simple, cheap and easy to get, the raw materials and intermediates are stable in property; reaction conditions are mild, reaction time is short, after-treatment is simple, and the method is relative environmental friendly, simplifies the current synthesis route of the bilastine, reduces production cost, and meets the need of industrialization production.
Description
Technical field
The invention belongs to pharmaceutical synthesis field, relate to a kind of preparation method of bilastine, be specifically related to one and prepare α, the method for alpha-alpha-dimethyl-4-(2-haloethyl) phenylacetate, and the method for synthesis bilastine.
Background technology
Bilastine (Bilastine) is the oral non-sedating histamine H of 2nd generation
1receptor antagonist, is developed by FAES drugmaker of Spain, in the approval of 2010 Nian Huo European Union, is used for the treatment of rhinallergosis and chronic idiopathic urticaria.This product has needs dosage little, and safety range is large, the advantages such as the sedative effect that impermanence antihistamine drug is common and cardiac toxic.Formula 1 be shown in its chemical structural formula.
US5877187 reports the synthetic method of bilastine: with compound
12for raw material, through methylating, being hydrolyzed, carboxy protective, grignard reaction obtain intermediate
17.Its hydroxyl through Tosyl chloride esterification activation after, with another intermediate
5there is condensation, alkylation and deprotection reaction and obtain compound
1bilastine (see Fig. 1).
Because grignard reaction is poor to group compatibility, therefore need to use compared with Te Shu oxazole to protect carboxyl, and this step yield is very low.In addition, Grignard reaction conditions is harsher, requires high to anhydrous and oxygen-free, is not too applicable to large-scale production.
In general, complicated upper protecting group process makes route long, high cost; And the larger methylating reagent of the toxicity used also can cause comparatively major injury to producers, therefore, this route should not as the foundation of suitability for industrialized production.
(the Steven J.Collier et al.Alternative Synthesis of Bilastine such as Steven J.Collier, Synthetic Communications, 2011,41 (9): 1394-1402) above-mentioned route is improved: with compound
13for starting raw material, obtain intermediate through coupling, hydration
22.Again with compound
8for starting raw material, through upper protecting group, alkylation, deprotection reaction obtains intermediate
11.Finally, intermediate
22through methylsulfonyl chloride esterification activation after and intermediate
11bilastine (compound is obtained through condensation, hydrolysis reaction
1) (see Fig. 2).
For getting around the complicated carboxy protective of former patent route, use the compatible better palladium catalysed cross coupling reaction of group instead.But, no matter be Suzuki or Stille coupling, no matter the palladium catalyst of use is that homogeneous phase or load are all very expensive, and product purification difficulty is large, aftertreatment cost is high, and remaining palladium, phosphine and tin etc. all can cause severe contamination to environment, are not suitable for suitability for industrialized production.
Summary of the invention
In order to overcome the shortcoming of prior art with not enough, the object of the present invention is to provide a kind of α, the preparation method of alpha-alpha-dimethyl-4-(2-haloethyl) phenylacetate.Intermediate { α, alpha-alpha-dimethyl-4-(2-haloethyl) phenylacetate } stable in properties obtained by the method, may be used for preparing bilastine.
Another object of the present invention is to provide and utilize above-mentioned α, alpha-alpha-dimethyl-4-(2-haloethyl) phenylacetate prepares the method for bilastine.This method avoid reaction conditions harsh in prior art, and raw material is easy to get, simple to operate, cost is lower, environmental friendliness, is applicable to suitability for industrialized production.
Object of the present invention is achieved through the following technical solutions: a kind of α, and the preparation method of alpha-alpha-dimethyl-4-(2-haloethyl) phenylacetate, comprises the following steps:
(1) in solvent-free or solvent, α, there is friedel-crafts acylation in alpha-alpha-dimethyl-phenylacetate and halogen acetyl halide, obtain α under catalyst action, alpha-alpha-dimethyl-4-(2-halogen ethanoyl) phenylacetate;
(2) in a solvent, α, alpha-alpha-dimethyl-4-(2-halogen ethanoyl) phenylacetate issues raw reduction reaction at trifluoroacetic acid and triethyl silicane effect, obtains α, alpha-alpha-dimethyl-4-(2-haloethyl) phenylacetate;
Further, the solvent described in step (1) is any one in methylene dichloride, tetrahydrofuran (THF), DMF and tetracol phenixin; Be more preferably methylene dichloride;
α described in step (1), the structural formula of alpha-alpha-dimethyl-phenylacetate is shown below:
Wherein, R
1for the alkyl that carbon chain lengths is C1, C2;
Be more preferably α, alpha-alpha-dimethyl-methyl phenylacetate;
Halogen acetyl halide described in step (1) is preferably any one in bromoacetyl bromide, chloroacetyl chloride, bromoacetyl chloride and chloro-acetyl bromide; Be more preferably bromoacetyl bromide;
Catalyzer described in step (1) is preferably any one in aluminum chloride, boron trifluoride, iron trichloride and zinc chloride; Be more preferably aluminum chloride;
The condition optimization of the reaction described in step (1) is-10 DEG C ~ 0 DEG C reaction 1 ~ 20h; Be more preferably-5 DEG C ~ 0 DEG C reaction 3 ~ 10h;
α described in step (1), the mol ratio of alpha-alpha-dimethyl-phenylacetate, halogen acetyl halide and catalyzer is preferably 1:(1.2 ~ 2): (1.5 ~ 3); Be more preferably 1:(1.2 ~ 2): 2;
Solvent described in step (2) is preferably methylene dichloride;
What the reduction reaction described in step (2) adopted is trifluoroacetic acid/triethyl silicane method reduction, and condition optimization is 50 ~ 100 DEG C of reaction 20 ~ 40h; Be more preferably 60 DEG C of reaction 20h;
The mol ratio of the α described in step (2), alpha-alpha-dimethyl-4-(2-halogen ethanoyl) phenylacetate, trifluoroacetic acid and triethyl silicane is preferably at least 1:2:2; Trifluoroacetic acid and triethyl silicane mole be α respectively, alpha-alpha-dimethyl-4-(2-halogen ethanoyl) phenylacetate mole more than 2 times;
A kind of α, alpha-alpha-dimethyl-4-(2-haloethyl) phenylacetate, obtained by above-mentioned preparation method, its structural formula is shown below:
Wherein, X=Cl or Br, R
1for the alkyl that carbon chain lengths is C1, C2.
Utilize above-mentioned α, alpha-alpha-dimethyl-4-(2-haloethyl) phenylacetate prepares the method for bilastine, comprises the following steps:
(I) in a solvent, α, nucleophilic substitution reaction is there is in alpha-alpha-dimethyl-4-(2-haloethyl) phenylacetate and 2-(piperidin-4-yl)-1H-benzoglyoxaline under the catalysis of alkali, obtain 4-[2-[4-(1H benzimidazolyl-2 radicals base] piperidines-1 base) ethyl]-α, α dimethyl phenyl acetic acid ester;
(II) in a solvent, 4-[2-[4-(1H benzimidazolyl-2 radicals base] piperidines-1 base) ethyl] there is nucleophilic substitution reaction in-α, α dimethyl phenyl acetic acid ester and 2-haloethyl ether, obtain esterification bilastine under the catalysis of alkali;
(III) in a solvent, esterification bilastine issues raw hydrolysis reaction at catalyst action, obtains bilastine.
Further, the solvent described in step (I) is preferably any one in tetrahydrofuran (THF), acetonitrile, ethanol, DMF and acetone; Be more preferably tetrahydrofuran (THF);
Alkali described in step (I) is preferably any one in pyridine, DIPEA (DIPEA), triethylamine, sodium hydroxide, salt of wormwood and sodium carbonate;
The condition optimization of the reaction described in step (I) is 20 ~ 70 DEG C of reaction 7 ~ 24h; Be more preferably 60 DEG C of reaction 7h;
The mol ratio of 2-(the piperidin-4-yl)-1H-benzoglyoxaline described in step (I), α, alpha-alpha-dimethyl-4-(2-haloethyl) phenylacetate and alkali is preferably 1:1.2:(1.5 ~ 2);
Solvent described in step (II) is preferably any one in tetrahydrofuran (THF), acetonitrile, ethanol, DMF, acetone and aqueous sodium hydroxide solution; Be more preferably tetrahydrofuran (THF);
2-haloethyl ether described in step (II) is preferably 2-chloroethyl ether;
Alkali described in step (II) is preferably any one in sodium hydride, sodium hydroxide, sodium ethylate and sodium carbonate;
The condition optimization of the reaction described in step (II) is 20 ~ 80 DEG C of reaction 5 ~ 24h; Be more preferably 50 ~ 80 DEG C of reaction 16 ~ 24h; Most preferably be 60 DEG C of reaction 16h;
4-described in step (II) [2-[4-(1H benzimidazolyl-2 radicals base] piperidines-1 base) ethyl] mol ratio of-α, α dimethyl phenyl acetic acid ester, 2-haloethyl ether and alkali is preferably 1:(1.2 ~ 2): (2 ~ 3); Be more preferably 1:1.2:2;
Solvent described in step (III) is preferably at least one in methyl alcohol, ethanol, acetone, water, Virahol and tetrahydrofuran (THF); Be more preferably methanol-water;
Catalyzer described in step (III) is preferably any one in sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, Quilonum Retard and sulfuric acid; Be more preferably sodium hydroxide;
The condition optimization of the hydrolysis reaction described in step (III) is 50 ~ 100 DEG C of reaction 3 ~ 20h; Be more preferably 50 ~ 100 DEG C of reaction 5h; Most preferably be 100 DEG C of reaction 5h;
The mol ratio of the esterification bilastine described in step (III) and catalyzer is preferably 1:(2 ~ 3);
The present invention has following advantage and effect relative to prior art:
(1) the invention provides a kind of synthetic method of antihistamine drug bilastine, the great advantage of the method is embodied in key intermediate α, the synthesis of alpha-alpha-dimethyl-4-(2-haloethyl) phenylacetate.
The two (bis-Ya Benzyl benzylacetone of 1-methoxyl group-1-(trimethylsiloxy)-2-methyl-1-propylene and catalyzer in former patent US5877187 technique) palladium and tri-tert phosphorus etc. is not only expensive, and severe contamination can be caused to environment, and present invention, avoiding the use of these reagent, cheap and easy to get and eco-friendly.
(2) reaction needed involving raw material 1-methoxyl group-1-(trimethylsiloxy)-2-methyl-1-propylene and catalyzer tri-tert phosphorus, two (two sub-Benzyl benzylacetones) palladium etc. in former patent US5877187 technique operates under strict anhydrous and oxygen-free condition, severe reaction conditions; And in method provided by the present invention, feedstock property is stablized, simple to operate without the need to exacting terms.
(3) the present invention's raw material of being and reagent simple, cheap and easy to get; Reaction conditions is gentle, and the reaction times is short, and aftertreatment is simple, and environmental facies are to close friend.Simplify the synthetic route of existing bilastine, reduce production cost, meet the needs of industrialized production.
Accompanying drawing explanation
Fig. 1 is the synthetic route chart of bilastine in patent US5877187.
Fig. 2 is the synthetic route chart of bilastine in document " Alternative Synthesis of Bilastine, Synthetic Communications, 2011,41 (9): 1394-1402 ".
Fig. 3 is the synthetic route chart in spit of fland, Lars of the present invention.
Embodiment
Below in conjunction with embodiment and accompanying drawing, the present invention is described in further detail, but embodiments of the present invention are not limited thereto.
The present invention is to histamine H
1the existing synthetic route of receptor antagonist bilastine is improved, design have that cheaper starting materials is easy to get, step is few, productive rate is high, reacting phase is to the synthesis bilastine route (as shown in Figure 3) of the feature such as simple.
2-(piperidin-4-yl)-1H-benzoglyoxaline, 2-chloroethyl ether is all purchased from Town in Shanghai Nai Ji Chemical Co., Ltd..
The preparation of embodiment 1 α, alpha-alpha-dimethyl-4-(2-acetyl bromide) methyl phenylacetate (compound 3):
Aluminum chloride (44.8g is added in reaction flask, 336.8mmol), methylene dichloride 200mL, mol ratio is the α of 1:1.2, alpha-alpha-dimethyl-methyl phenylacetate (30.0g, drip wherein under 168.5mmol) stirring at-20 DEG C respectively with bromoacetyl bromide (40.8g, 202.0mmol), dropwise, be warming up to-5 DEG C, reaction 3h.After reaction terminates, diatomite filters, and filtrate is respectively with saturated sodium carbonate solution, saturated common salt water washing extremely clarification.Organic phase drying is concentrated, obtains 37.7g yellow oil, yield 75%.
1H-NMR(300MHz,CDCl
3)δ7.90-7.86(dd,2H),7.14-7.13(dd,2H),
3.59(s,3H),1.54(s,6H)。
The structural formula can being derived this product by above data is:
The preparation of embodiment 2 α, alpha-alpha-dimethyl-4-(2-acetyl bromide) methyl phenylacetate (compound 3):
Boron trifluoride diethyl etherate (4.8g is added in reaction flask, 33.7mmol), tetrahydrofuran (THF) 20mL, mol ratio is the α of 1:1.2, alpha-alpha-dimethyl-methyl phenylacetate (3.0g, drip wherein under 16.8mmol) stirring at-20 DEG C respectively with bromoacetyl bromide (4.1g, 20.2mmol), dropwise, be warming up to-5 DEG C, reaction 5h.After reaction terminates, add ice cube cancellation, filtrate is respectively with saturated sodium carbonate solution, saturated common salt water washing extremely clarification.Organic phase drying is concentrated, obtains 2.5g yellow oil, yield 50%.
1H-NMR(300MHz,CDCl
3)δ7.90-7.86(dd,2H),7.14-7.13(dd,2H),
3.59(s,3H),1.54(s,6H)。
The structural formula can being derived this product by above data is:
The preparation of embodiment 3 α, alpha-alpha-dimethyl-4-(2-acetyl bromide) Phenylacetic acid ethylester (compound 3):
Aluminum chloride (4.5g is added in reaction flask, 33.7mmol), methylene dichloride 20mL, mol ratio is the α of 1:2, alpha-alpha-dimethyl-Phenylacetic acid ethylester (3.2g, drip wherein under 16.8mmol) stirring at-20 DEG C respectively with bromoacetyl chloride (5.3g, 33.7mmol), dropwise, be warming up to 0 DEG C, reaction 10h.After reaction terminates, diatomite filters, and filtrate is respectively with saturated sodium carbonate solution, saturated common salt water washing extremely clarification.Organic phase drying is concentrated, obtains 3.7g yellow oil, yield 70%.
1H-NMR(300MHz,CDCl
3)δ7.90-7.86(dd,2H),7.14-7.13(dd,2H),4.40(s,2H),3.59(q,2H),1.54(s,6H),1.31(t,3H)。
The structural formula can being derived this product by above data is:
The preparation of embodiment 4 α, alpha-alpha-dimethyl-4-(2-bromotrifluoromethane) methyl phenylacetate (compound 4):
Respectively to adding 20mL methylene dichloride, α in reaction flask under ice bath cooling; alpha-alpha-dimethyl-4-(2-acetyl bromide) methyl phenylacetate (30.0g; 100.7mmol), trifluoroacetic acid (36mL; 201.4mmol), triethyl silicane (18mL, 201.4mmol).After stirring 0.5h under ice bath, be warming up to 60 DEG C of back flow reaction 20h.Reaction terminates, and drips the neutralization of unsaturated carbonate solution, adds extraction into ethyl acetate, organic phase concentrate drying, obtain the nearly colorless oil of 25.73g, yield 90%.
1H-NMR(300MHz,CDCl
3)δ7.33-7.31(dd,2H),7.21-7.19(dd,2H),3.67(s,3H),3.58-3.55(t,2H),3.17(t,2H),1.60(s,6H)。
The structural formula can being derived this product by above data is:
The preparation of embodiment 5 α, alpha-alpha-dimethyl-4-(2-bromotrifluoromethane) methyl phenylacetate (compound 4):
Respectively to adding 10mL methylene dichloride, α in reaction flask under ice bath cooling; alpha-alpha-dimethyl-4-(2-acetyl bromide) methyl phenylacetate (3.0g; 10.1mmol), trifluoroacetic acid (3.6mL; 20.1mmol), triethyl silicane (1.8mL, 20.1mmol).After stirring 0.5h under ice bath, be warming up to 50 DEG C of back flow reaction 40h.Reaction terminates, and drips the neutralization of unsaturated carbonate solution, adds extraction into ethyl acetate, organic phase concentrate drying, obtain the nearly colorless oil of 2.1g, yield 75%.
1H-NMR(300MHz,CDCl
3)δ7.33-7.31(dd,2H),7.21-7.19(dd,2H),3.67(s,3H),3.58-3.55(t,2H),3.17(t,2H),1.60(s,6H)。
The structural formula can being derived this product by above data is:
The preparation of embodiment 6 α, alpha-alpha-dimethyl-4-(2-bromotrifluoromethane) Phenylacetic acid ethylester (compound 4):
Respectively to adding 10mL methylene dichloride, α in reaction flask under ice bath cooling; alpha-alpha-dimethyl-4-(2-acetyl bromide) Phenylacetic acid ethylester (3.1g; 10.0mmol), trifluoroacetic acid (3.6mL; 20.1mmol), triethyl silicane (1.8mL, 20.1mmol).After stirring 0.5h under ice bath, be warming up to 100 DEG C of back flow reaction 20h.Reaction terminates, and drips the neutralization of unsaturated carbonate solution, adds extraction into ethyl acetate, organic phase concentrate drying, obtain the nearly colorless oil of 2.5g, yield 86%.
1H-NMR(300MHz,CDCl
3)δ7.33-7.31(dd,2H),7.21-7.19(dd,2H),3.67(q,2H),3.58-3.55(t,2H),3.17(t,2H),1.60(s,6H),1.21(t,3H)。
The structural formula can being derived this product by above data is:
Embodiment 7 4-[2-[4-(1H benzimidazolyl-2 radicals base] piperidines-1 base) ethyl] preparation of-alpha-alpha-dimethyl phenyl acetic acid methyl esters (compound 6):
Tetrahydrofuran (THF) (100mL), α is added in reaction flask, alpha-alpha-dimethyl-4-(2-bromotrifluoromethane) methyl phenylacetate (20.0g, 75.6mmol), 2-(piperidin-4-yl)-1H-benzoglyoxaline (12.7g, 63.2mmol), N, N-diisopropylethylamine (DIPEA) (10mL, 94.8mmol), 7h is reacted at 60 DEG C.After reaction terminates, add extraction into ethyl acetate, washing, organic phase concentrate drying, obtains 18.1g white solid, yield 71%.
1H-NMR(300MHz，CDCl
3)δ7.77-7.74(m,1H),7.34-7.19(m,7H),4.33-4.31(t,2H),3.74-3.71(t,2H),3.66(d,3H),3.41-3.39(q,2H),3.20-3.18(d,2H),3.03(m,1H),2.86-2.82(m,2H),2.69-2.66(m,2H),2.23-2.20(m,4H),1.99(bs,2H),1.58(s,6H),1.14-1.10(t,3H).
The structural formula can being derived this product by above data is:
Embodiment 8 4-[2-[4-(1H benzimidazolyl-2 radicals base] piperidines-1 base) ethyl] preparation of-α, α dimethylphenyl acetate (compound 6):
N is added in reaction flask, dinethylformamide (10mL), α, alpha-alpha-dimethyl-4-(2-bromotrifluoromethane) methyl phenylacetate (2.0g, 7.6mmol), 2-(piperidin-4-yl)-1H-benzoglyoxaline (1.3g, 6.3mmol), N, N-diisopropylethylamine (DIPEA) (1mL, 9.5mmol), reacts 24h at 20 DEG C.After reaction terminates, add ethyl acetate, salt solution repeatedly washs, organic phase concentrate drying, obtains 1.8g white solid, yield 70%.
1H-NMR(300MHz，CDCl
3)δ7.77-7.74(m,1H),7.34-7.19(m,7H),4.33-4.31(t,2H),3.74-3.71(t,2H),3.66(d,3H),3.41-3.39(q,2H),3.20-3.18(d,2H),3.03(m,1H),2.86-2.82(m,2H),2.69-2.66(m,2H),2.23-2.20(m,4H),1.99(bs,2H),1.58(s,6H),1.14-1.10(t,3H).
The structural formula can being derived this product by above data is:
Embodiment 9 4-[2-[4-(1H benzimidazolyl-2 radicals base] piperidines-1 base) ethyl] preparation of-α, α dimethylphenyl acetate (compound 6):
Acetone (10mL), α is added in reaction flask, alpha-alpha-dimethyl-4-(2-bromotrifluoromethane) methyl phenylacetate (2.0g, 7.6mmol), 2-(piperidin-4-yl)-1H-benzoglyoxaline (1.3g, 6.3mmol), salt of wormwood (1.8g, 12.6mmol), 24h is reacted at 70 DEG C.After reaction terminates, add extraction into ethyl acetate, washing, organic phase concentrate drying, obtains 1.3g white solid, yield 50%.
1H-NMR(300MHz，CDCl
3)δ7.77-7.74(m,1H),7.34-7.19(m,7H),4.33-4.31(t,2H),3.74-3.71(t,2H),3.66(d,3H),3.41-3.39(q,2H),3.20-3.18(d,2H),3.03(m,1H),2.86-2.82(m,2H),2.69-2.66(m,2H),2.23-2.20(m,4H),1.99(bs,2H),1.58(s,6H),1.14-1.10(t,3H).
The structural formula can being derived this product by above data is:
The preparation of embodiment 10 esterification bilastine (compound 7):
Tetrahydrofuran (THF) (100mL), 4-[2-[4-(1H benzimidazolyl-2 radicals base] piperidines-1 base is added in reaction flask) ethyl]-α, α dimethylphenyl acetate (20.0g, 49.6mmol), sodium ethylate (6.7g, 98.5mmol), under stirred at ambient temperature after 2h, add 2-chloroethyl ether (6.5g, 59.9mmol), be warming up to 60 DEG C of reaction 16h.After reaction terminates, add ice cube cancellation reaction, be extracted with ethyl acetate, organic phase concentrate drying, obtain 22.5g yellow oil, yield 95%.
1H-NMR(300MHz，CDCl
3)δ7.77-7.74(m,1H),7.34-7.19(m,7H),4.33-4.31(t,2H),3.74-3.71(t,2H),3.66(d,3H),3.41-3.39(q,2H),3.20-3.18(d,2H),3.03(m,1H),2.86-2.82(m,2H),2.69-2.66(m,2H),2.23-2.20(m,4H),1.99(bs,2H),1.58(s,6H),1.14-1.10(t,3H)。
The structural formula can being derived this product by above data is:
The preparation of embodiment 11 esterification bilastine (compound 7):
N is added in reaction flask, dinethylformamide (20mL), 4-[2-[4-(1H benzimidazolyl-2 radicals base] piperidines-1 base) ethyl]-α, α dimethylphenyl acetate (2.0g, 5.0mmol), sodium ethylate (0.7g, 10.0mmol), under stirred at ambient temperature after 2h, add 2-chloroethyl ether (0.6g, 6.0mmol), 50 DEG C of reaction 24h are warming up to.After reaction terminates, add ice cube cancellation reaction, be extracted with ethyl acetate, after saturated common salt water washing, organic phase concentrate drying, obtains 2.2g yellow oil, yield 91%.
1H-NMR(300MHz，CDCl
3)δ7.77-7.74(m,1H),7.34-7.19(m,7H),4.33-4.31(t,2H),3.74-3.71(t,2H),3.66(d,3H),3.41-3.39(q,2H),3.20-3.18(d,2H),3.03(m,1H),2.86-2.82(m,2H),2.69-2.66(m,2H),2.23-2.20(m,4H),1.99(bs,2H),1.58(s,6H),1.14-1.10(t,3H)。
The structural formula can being derived this product by above data is:
The preparation of embodiment 12 esterification bilastine (compound 7):
Acetone (20mL), 4-[2-[4-(1H benzimidazolyl-2 radicals base] piperidines-1 base is added in reaction flask) ethyl]-α, α dimethylphenyl acetate (2.0g, 5.0mmol), sodium hydroxide (0.4g, 10.0mmol), under stirred at ambient temperature after 2h, add 2-bromotrifluoromethane ether (0.9g, 6.0mmol), be warming up to 80 DEG C of reaction 24h.After reaction terminates, revolve desolventizing, add water, be extracted with ethyl acetate, organic phase concentrate drying, obtain 2.1g yellow oil, yield 87%.
1H-NMR(300MHz，CDCl
3)δ7.77-7.74(m,1H),7.34-7.19(m,7H),4.33-4.31(t,2H),3.74-3.71(t,2H),3.66(d,3H),3.41-3.39(q,2H),3.20-3.18(d,2H),3.03(m,1H),2.86-2.82(m,2H),2.69-2.66(m,2H),2.23-2.20(m,4H),1.99(bs,2H),1.58(s,6H),1.14-1.10(t,3H)。
The structural formula can being derived this product by above data is:
The preparation of embodiment 13 bilastine (compound 1):
Add sodium hydroxide saturated aqueous solution (14mL, 62.8mmol sodium hydroxide), methyl alcohol (15mL) in reaction flask, esterification bilastine (15g, 31.4mmol) prepared by embodiment 10,11 or 12, at 100 DEG C, react 5h.Reaction terminates, and adds extraction into ethyl acetate after acid neutralization, and organic phase is concentrated, dry, obtains 12.1g light yellow solid, yield 83%.
1H-NMR(300MHz，CD
3OD)δ7.65-7.17(m,8H),4.54-4.51(t,2H),3.79-3.76(t,2H),3.66-3.64(m,3H),3.60-3.58(d,2H),3.45-3.39(q,2H),3.19-3.04(m,4H),2.29-2.27(m,4H),1.55-1.50(d,6H),1.09-1.05(t,3H)。
The structural formula can being derived this product by above data is:
The preparation of embodiment 14 bilastine (compound 1):
Add the esterification bilastine (1.5g, 3.1mmol) of salt of wormwood saturated aqueous solution (1mL, 9.3mmol salt of wormwood), tetrahydrofuran (THF) (5mL), embodiment 10,11 or 12 preparation in reaction flask, at 50 DEG C, react 5h.Reaction terminates, and adds extraction into ethyl acetate after acid neutralization, and organic phase is concentrated, dry, obtains 0.9g light yellow solid, yield 65%.
1H-NMR(300MHz，CD
3OD)δ7.65-7.17(m,8H),4.54-4.51(t,2H),3.79-3.76(t,2H),3.66-3.64(m,3H),3.60-3.58(d,2H),3.45-3.39(q,2H),3.19-3.04(m,4H),2.29-2.27(m,4H),1.55-1.50(d,6H),1.09-1.05(t,3H)。
The structural formula can being derived this product by above data is:
Above-described embodiment is the present invention's preferably embodiment; but embodiments of the present invention are not restricted to the described embodiments; change, the modification done under other any does not deviate from spirit of the present invention and principle, substitute, combine, simplify; all should be the substitute mode of equivalence, be included within protection scope of the present invention.
Claims (10)
1. the preparation method of a α, alpha-alpha-dimethyl-4-(2-haloethyl) phenylacetate, is characterized in that comprising the following steps:
(1) in solvent-free or solvent, α, there is friedel-crafts acylation in alpha-alpha-dimethyl-phenylacetate and halogen acetyl halide, obtain α under catalyst action, alpha-alpha-dimethyl-4-(2-halogen ethanoyl) phenylacetate;
(2) in a solvent, α, alpha-alpha-dimethyl-4-(2-halogen ethanoyl) phenylacetate issues raw reduction reaction at trifluoroacetic acid and triethyl silicane effect, obtains α, alpha-alpha-dimethyl-4-(2-haloethyl) phenylacetate.
2. preparation method according to claim 1, is characterized in that:
α described in step (1), the mol ratio of alpha-alpha-dimethyl-phenylacetate, halogen acetyl halide and catalyzer is 1:(1.2 ~ 2): (1.5 ~ 3).
3. preparation method according to claim 1, is characterized in that:
Halogen acetyl halide described in step (1) is any one in bromoacetyl bromide, chloroacetyl chloride, bromoacetyl chloride and chloro-acetyl bromide;
Catalyzer described in step (1) is any one in aluminum chloride, boron trifluoride, iron trichloride and zinc chloride.
4. preparation method according to claim 1, is characterized in that:
The condition of the reaction described in step (1) is-10 DEG C ~ 0 DEG C reaction 1 ~ 20h;
The condition of the reduction reaction described in step (2) is 50 ~ 100 DEG C of reaction 20 ~ 40h.
5. preparation method according to claim 1, is characterized in that:
Solvent described in step (1) is any one in methylene dichloride, tetrahydrofuran (THF), DMF and tetracol phenixin;
α described in step (1), the structural formula of alpha-alpha-dimethyl-phenylacetate is shown below:
Wherein, R
1for the alkyl that carbon chain lengths is C1, C2;
Solvent described in step (2) is methylene dichloride.
6. utilize the α that the preparation method described in any one of claim 1 ~ 5 obtains, alpha-alpha-dimethyl-4-(2-haloethyl) phenylacetate prepares the method for bilastine, it is characterized in that comprising the following steps:
(I) in a solvent, α, nucleophilic substitution reaction is there is in alpha-alpha-dimethyl-4-(2-haloethyl) phenylacetate and 2-(piperidin-4-yl)-1H-benzoglyoxaline under the catalysis of alkali, obtain 4-[2-[4-(1H benzimidazolyl-2 radicals base] piperidines-1 base) ethyl]-α, α dimethyl phenyl acetic acid ester;
(II) in a solvent, 4-[2-[4-(1H benzimidazolyl-2 radicals base] piperidines-1 base) ethyl] there is nucleophilic substitution reaction in-α, α dimethyl phenyl acetic acid ester and 2-haloethyl ether, obtain esterification bilastine under the catalysis of alkali;
(III) in a solvent, esterification bilastine issues raw hydrolysis reaction at catalyst action, obtains bilastine.
7. method according to claim 6, is characterized in that:
The mol ratio of 2-(the piperidin-4-yl)-1H-benzoglyoxaline described in step (I), α, alpha-alpha-dimethyl-4-(2-haloethyl) phenylacetate and alkali is 1:1.2:(1.5 ~ 2).
8. method according to claim 6, is characterized in that:
4-described in step (II) [2-[4-(1H benzimidazolyl-2 radicals base] piperidines-1 base) ethyl] mol ratio of-α, α dimethyl phenyl acetic acid ester, 2-haloethyl ether and alkali is 1:(1.2 ~ 2): (2 ~ 3);
The mol ratio of the esterification bilastine described in step (III) and catalyzer is 1:(2 ~ 3).
9. method according to claim 6, is characterized in that:
The condition of the reaction described in step (I) is 20 ~ 70 DEG C of reaction 7 ~ 24h;
The condition of the reaction described in step (II) is 20 ~ 80 DEG C of reaction 5 ~ 24h;
The condition of the hydrolysis reaction described in step (III) is 50 ~ 100 DEG C of reaction 3 ~ 20h.
10. method according to claim 6, is characterized in that:
Solvent described in step (I) is any one in tetrahydrofuran (THF), acetonitrile, ethanol, DMF and acetone;
Alkali described in step (I) is any one in pyridine, DIPEA, triethylamine, sodium hydroxide, salt of wormwood and sodium carbonate;
Solvent described in step (II) is any one in tetrahydrofuran (THF), acetonitrile, ethanol, DMF, acetone and aqueous sodium hydroxide solution;
2-haloethyl ether described in step (II) is 2-chloroethyl ether;
Alkali described in step (II) is any one in sodium hydride, sodium hydroxide, sodium ethylate and sodium carbonate;
Solvent described in step (III) is at least one in methyl alcohol, ethanol, acetone, water, Virahol and tetrahydrofuran (THF);
Catalyzer described in step (III) is any one in sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, Quilonum Retard and sulfuric acid.
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| CN106336394A (en) * | 2015-07-13 | 2017-01-18 | 南京长澳医药科技有限公司 | Preparation method of bilastine oxide impurity |
| CN106349214A (en) * | 2015-07-13 | 2017-01-25 | 南京长澳医药科技有限公司 | Method for preparing bilastine impurity |
| CN106699728A (en) * | 2015-07-13 | 2017-05-24 | 南京长澳医药科技有限公司 | Bilastine intermediate impurity and preparation method thereof |
| EP3599235A1 (en) | 2018-07-24 | 2020-01-29 | Faes Farma, S.A. | Process and intermediates for the preparation of bilastine |
| CN110903278A (en) * | 2019-12-26 | 2020-03-24 | 山东罗欣药业集团恒欣药业有限公司 | Preparation method of bilastine |
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| CN106699728A (en) * | 2015-07-13 | 2017-05-24 | 南京长澳医药科技有限公司 | Bilastine intermediate impurity and preparation method thereof |
| CN106349214B (en) * | 2015-07-13 | 2020-11-03 | 南京长澳医药科技有限公司 | Preparation method of bilastine impurity |
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| CN112110893A (en) * | 2020-10-28 | 2020-12-22 | 山东齐环医药科技有限公司 | Preparation method of bilastine |
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