CN107857702A - A kind of preparation method of bilastine intermediate - Google Patents
A kind of preparation method of bilastine intermediate Download PDFInfo
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- CN107857702A CN107857702A CN201711335568.9A CN201711335568A CN107857702A CN 107857702 A CN107857702 A CN 107857702A CN 201711335568 A CN201711335568 A CN 201711335568A CN 107857702 A CN107857702 A CN 107857702A
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- Prior art keywords
- phenyl
- methvl
- propionic acid
- preparation
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- ACCMWZWAEFYUGZ-UHFFFAOYSA-N bilastine Chemical compound N=1C2=CC=CC=C2N(CCOCC)C=1C(CC1)CCN1CCC1=CC=C(C(C)(C)C(O)=O)C=C1 ACCMWZWAEFYUGZ-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 229960004314 bilastine Drugs 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 39
- BHIWKHZACMWKOJ-UHFFFAOYSA-N methyl isobutyrate Chemical compound COC(=O)C(C)C BHIWKHZACMWKOJ-UHFFFAOYSA-N 0.000 claims abstract description 37
- WDAXFOBOLVPGLV-UHFFFAOYSA-N isobutyric acid ethyl ester Natural products CCOC(=O)C(C)C WDAXFOBOLVPGLV-UHFFFAOYSA-N 0.000 claims abstract description 19
- HTMYMRSLEMVHNX-UHFFFAOYSA-N 1-bromo-2-phenylethanol Chemical compound OC(Br)CC1=CC=CC=C1 HTMYMRSLEMVHNX-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000003054 catalyst Substances 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 17
- 238000006467 substitution reaction Methods 0.000 claims abstract description 15
- -1 (4 ethoxy) phenyl Chemical group 0.000 claims abstract description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 45
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- 239000002585 base Substances 0.000 claims description 17
- OFYSAFPKXXTYLU-UHFFFAOYSA-N ethyl 2-methyl-2-phenylpropanoate Chemical class CCOC(=O)C(C)(C)C1=CC=CC=C1 OFYSAFPKXXTYLU-UHFFFAOYSA-N 0.000 claims description 16
- 239000000047 product Substances 0.000 claims description 14
- 239000012065 filter cake Substances 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical group C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- 229910052751 metal Inorganic materials 0.000 claims description 8
- 239000002184 metal Substances 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 7
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- 239000012044 organic layer Substances 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 5
- 229910052744 lithium Inorganic materials 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 150000007530 organic bases Chemical class 0.000 claims description 3
- 229910052763 palladium Inorganic materials 0.000 claims description 3
- 238000010189 synthetic method Methods 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 238000005859 coupling reaction Methods 0.000 claims description 2
- 239000013078 crystal Substances 0.000 claims description 2
- NEXSMEBSBIABKL-UHFFFAOYSA-N hexamethyldisilane Chemical compound C[Si](C)(C)[Si](C)(C)C NEXSMEBSBIABKL-UHFFFAOYSA-N 0.000 claims description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical group CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims 2
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 claims 2
- 150000003851 azoles Chemical class 0.000 claims 1
- NRUBUZBAZRTHHX-UHFFFAOYSA-N lithium;propan-2-ylazanide Chemical compound [Li+].CC(C)[NH-] NRUBUZBAZRTHHX-UHFFFAOYSA-N 0.000 claims 1
- PMOIAJVKYNVHQE-UHFFFAOYSA-N phosphanium;bromide Chemical compound [PH4+].[Br-] PMOIAJVKYNVHQE-UHFFFAOYSA-N 0.000 claims 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 13
- 230000015572 biosynthetic process Effects 0.000 abstract description 10
- 150000001875 compounds Chemical class 0.000 abstract description 10
- 238000003786 synthesis reaction Methods 0.000 abstract description 10
- 238000009776 industrial production Methods 0.000 abstract description 5
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- KQNPFQTWMSNSAP-UHFFFAOYSA-M isobutyrate Chemical compound CC(C)C([O-])=O KQNPFQTWMSNSAP-UHFFFAOYSA-M 0.000 abstract 2
- 239000012670 alkaline solution Substances 0.000 abstract 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
- 238000009413 insulation Methods 0.000 description 15
- 230000004224 protection Effects 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 9
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 7
- 239000011259 mixed solution Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- PMOSJSPFNDUAFY-UHFFFAOYSA-N 2-(4-bromophenyl)ethanol Chemical compound OCCC1=CC=C(Br)C=C1 PMOSJSPFNDUAFY-UHFFFAOYSA-N 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 3
- 239000007791 liquid phase Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- JGFBQFKZKSSODQ-UHFFFAOYSA-N Isothiocyanatocyclopropane Chemical compound S=C=NC1CC1 JGFBQFKZKSSODQ-UHFFFAOYSA-N 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000000739 antihistaminic agent Substances 0.000 description 2
- PWLNAUNEAKQYLH-UHFFFAOYSA-N butyric acid octyl ester Natural products CCCCCCCCOC(=O)CCC PWLNAUNEAKQYLH-UHFFFAOYSA-N 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 150000002460 imidazoles Chemical class 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- UUIQMZJEGPQKFD-UHFFFAOYSA-N n-butyric acid methyl ester Natural products CCCC(=O)OC UUIQMZJEGPQKFD-UHFFFAOYSA-N 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- BHHYHSUAOQUXJK-UHFFFAOYSA-L zinc fluoride Chemical compound F[Zn]F BHHYHSUAOQUXJK-UHFFFAOYSA-L 0.000 description 2
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- 229940124056 Histamine H1 receptor antagonist Drugs 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 206010041349 Somnolence Diseases 0.000 description 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 229940124623 antihistamine drug Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229940049706 benzodiazepine Drugs 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 208000023819 chronic asthma Diseases 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000006735 epoxidation reaction Methods 0.000 description 1
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001007 flame atomic emission spectroscopy Methods 0.000 description 1
- 125000006277 halobenzyl group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000000938 histamine H1 antagonist Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000000413 hydrolysate Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 description 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N o-dimethylbenzene Natural products CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 231100000004 severe toxicity Toxicity 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- WLBGIVZZFISEJL-UHFFFAOYSA-N tert-butyl 4-[1-(2-ethoxyethyl)benzimidazol-2-yl]piperidine-1-carboxylate Chemical compound N=1C2=CC=CC=C2N(CCOCC)C=1C1CCN(C(=O)OC(C)(C)C)CC1 WLBGIVZZFISEJL-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to field of pharmaceutical preparations, and in particular to a kind of preparation method of the methylpropanoate of bilastine intermediate 2 (4 ethoxy) phenyl 2.Above-mentioned intermediate to bromophenethyl alcohol and methyl isobutyrate by occurring substitution reaction generation.The reaction is carried out in alkaline solution, and has catalyst reaction, generates the methylpropanoate of 2 (4 ethoxy) phenyl 2.This method can be from raw material one-step synthesis target compound, and there is no the patent from the raw material one-step synthesis compound at present.Building-up process condition is controllable, is easy to industrial production, and obtained target compound purity is higher, has higher application value.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, and in particular to a kind of bilastine intermediate 2- (4- ethoxys) phenyl -2-
The preparation method of methvl-propionic acid ethvl ester.
Background technology
Bilastine (Bilastine), a kind of 2nd generation histamine H 1 receptor antagonist researched and developed for FAES companies of Spain,
Got the Green Light in European Union within 2010, be one of 15 recruit's entities of whole world approval then.As 2nd generation antihistamine drug,
Bilastine is mainly used in treating allergic rhinitis, nettle rash and chronic asthma, there is relatively low maincenter compared with 1st generation antihistamine
Nervous system sedation, and take the rear drowsiness Small side effects such as weak.
The Chinese chemical name of bilastine is：2- [4- (2- (4- (1- (2- ethoxyethyl groups)-benzimidazolyl-2 radicals-yl) piperazines
Pyridine -1- bases) ethyl) phenyl] -2 Methylpropionic acid, its structural formula is as follows：
Its molecular formula is C21H31N3O3, molecular weight 373.49.
At present, the synthetic method of bilastine is reported in patent WO2009102155A2, its synthetic route is as follows：
In this method, the synthesis of key intermediate 2- (4- ethoxys) phenyl -2- methvl-propionic acid ethvl esters is with to bromobenzene second
Alcohol and 1- methoxyl groups -1- (trimethylsiloxy) -2- methyl-1-propylenes are raw material, double (dibenzalacetone) in catalyst
It is condensed and is made in the presence of palladium, tri-butyl phosphine and zinc fluoride.
After the patent needs first to carry out the protection of hydroxyl, coupling synthesis, number of steps is longer, and reappearance is poor, can not
Reach patent and describe yield.And raw material 1- methoxyl groups -1 (trimethylsiloxy) -2- methyl-1-propylenes price is more high
It is expensive, it is not easy to buy, and it is not easy to maintain.
Used in patent CN102675101B and bromophenethyl alcohol is synthesized with carrying out reduction reaction again after chloracetyl chloride acylation
Patent product, this method use substantial amounts of alchlor, and environmental pollution is larger, while reduction reaction temperature is higher, is unfavorable for
Production.
Patent CN104276952B carries out reduction reaction epoxidation again after being acylated to bromophenethyl alcohol and chloracetyl chloride, is hydrogenated with
Open loop synthesizes patent product, and this method step is long, and yield is relatively low, is not suitable for large-scale industrial production.
Patent CN106565467A using TBS protections to halo benzyl carbinol, carbanion under effect it is anti-with acetone
After dimethyl benzene alcohol derivative should be synthesized, process is cyanalation, hydrolysis, and the hydrolysate of patents is formed after deprotection, should
Method and step is long, using the cyanide of severe toxicity in course of reaction, easily produces security incident, is not suitable for industrial production.
Therefore exploitation is a kind of easy to operate, and building-up process condition is controllable, can be from raw material one-step synthesis key intermediate 2-
The method of (4- ethoxys) phenyl -2- methvl-propionic acid ethvl esters.
The content of the invention
In view of this, an object of the present invention be to provide a kind of bilastine intermediate 2- (4- ethoxys) phenyl-
The preparation method of 2- methvl-propionic acid ethvl esters.
To achieve the above object, the technical scheme is that：Bilastine key intermediate 2- (4- ethoxys) phenyl-
2- methvl-propionic acid ethvl esters are by bromophenethyl alcohol and methyl isobutyrate occurring in the basic conditions substitution reaction generation, and reaction equation is such as
Under：
Wherein, the substitution reaction environment anhydrous and oxygen-free.
The preparation method of 2- (4- ethoxys) phenyl -2- methvl-propionic acid ethvl esters comprises the following steps：
1) alkali is added in a solvent, to bromophenethyl alcohol, methyl isobutyrate and catalyst, to bromophenethyl alcohol and methyl isobutyrate
Generation substitution reaction generates 2- (4- ethoxys) phenyl -2- methvl-propionic acid ethvl esters, obtains solution 1；
2) saturated ammonium chloride will be added in solution 1, filters to obtain filter cake 1；
3) filter cake 1 is washed with ethyl acetate, retains organic layer, adds salt acid for adjusting pH to obtain filter cake 2 after filtering to 2~3；
4) filter cake 2 is washed with ethyl acetate, retains organic layer, and it is 6~7 to be washed with water to pH, is spin-dried for solvent and obtains product
2- (4- ethoxys) phenyl -2- methvl-propionic acid ethvl esters.
As preferable scheme, the alkali described in step 1) is metal organic base.
More preferably dicyclohexyl amine base lithium, lithium diisopropylamine and hexamethyldisilane base amido lithium one kind or
It is a variety of.
More preferably dicyclohexyl amine base lithium, its generation that reacted after being added by dicyclohexyl amine and n-BuLi.
As preferable scheme, the catalyst described in step 1) is two (tri-butyl phosphine) bromide phosphine palladiums.
As preferable scheme, described in step 1) is 1 to the mol ratio of bromophenethyl alcohol and methyl isobutyrate:1~1.5.
As preferable scheme, the solvent described in step 1) is toluene, DMF, dimethyl sulfoxide (DMSO),
1.4- dioxane, the one or more of tetrahydrofuran.More preferably toluene.
As preferable scheme, step 3) and the process that 4) ethyl acetate washs are：Ethyl acetate washs 2 times, closes
And filtrate, liquid separation, aqueous layer with ethyl acetate extract 2 times, merge organic layer.
The second object of the present invention is to provide 2- (4- ethoxys) phenyl -2- prepared by a kind of method according to purpose one
Methvl-propionic acid ethvl ester, it can be from raw material one-step synthesis and simple to operate.
To achieve the above object, the technical scheme is that：The preparation method provided according to purpose one, in bilastine
Mesosome 2- (4- ethoxys) phenyl -2- methvl-propionic acid ethvl esters are by bromophenethyl alcohol and methyl isobutyrate occur in the basic conditions
Substitution reaction generates.
The third object of the present invention is to provide a kind of synthetic method of bilastine, and it is included by bromophenethyl alcohol and different
The process of substitution reaction generation 2- (4- ethoxys) phenyl -2- methvl-propionic acid ethvl esters occurs for methyl butyrate.
To achieve the above object, the technical scheme is that：
The synthesis of bilastine comprises the following steps：
1) alkali is added in a solvent, to bromophenethyl alcohol, methyl isobutyrate and catalyst, to bromophenethyl alcohol and methyl isobutyrate
Generation substitution reaction generates 2- (4- ethoxys) phenyl -2- methvl-propionic acid ethvl esters；
2) with methylsufonyl chloride substitution reaction generation 2- [4- occur for 2- (4- ethoxys) phenyl -2- methvl-propionic acid ethvl esters
(2- sulfonyloxy methyls epoxide-ethyl)-phenyl] -2- methvl-propionic acid ethvl esters；
3) it is condensed to obtain 2- (4- { 2- [4- (1H- benzos with 2- (4- piperidyls) -1H- benzimidazoles under sodium carbonate effect
Imidazoles -2- bases)-piperidin-1-yl]-ethyl }-phenyl) -2- methvl-propionic acid methyl estes；
4) substitution generation 2- [4- (2- { 4- [1- (2- ethoxyethyl groups) -1H- benzene occurs with ethoxyethyl group mesylate
And imidazoles -2- bases]-piperidin-1-yl-ethyl)-phenyl] -2- methvl-propionic acid ethvl esters；
5) product is walked on to hydrolyze with sodium hydroxide reaction, and adds butanol crystal acquisition
2- [4- (2- { 4- [1- (2- ethoxy-ethyls) -1H- benzimidazolyl-2 radicals-yl]-piperidin-1-yl }-ethyl)-benzene
Base] -2- rnethyl-propanoic acids, i.e. bilastine.
The beneficial effects of the present invention are：Bilastine intermediate 2- (4- ethoxys) phenyl -2- first provided by the invention
The preparation method of base-ethyl propionate is easy to operate, can be from raw material one-step synthesis patents, and there is no at present from raw material one
Step synthesizes the patent of the compound.Building-up process condition is controllable, reduces production cost, is easy to industrial production；Through purifying later
After step, the higher target compound of purity is can obtain, there is higher application value.
Brief description of the drawings
Fig. 1 is the high-efficient liquid phase chromatogram of the product of embodiment 4.
Fig. 2 is the mass-spectrogram of the product of embodiment 4.
Embodiment
It detailed description of a preferred embodiment of the present invention will be given below.The reality of unreceipted actual conditions in preferred embodiment
Proved recipe method, generally according to normal condition, illustrated embodiment is to preferably be illustrated to present disclosure, but is not
Present disclosure is only limitted to illustrated embodiment.So those skilled in the art according to foregoing invention content to embodiment party
Case carries out nonessential modifications and adaptations, still falls within protection scope of the present invention.
The charging order of embodiment 1
By following three experiments, the optimal charging order of the present invention is explored：
1. taking 100mL there-necked flasks, 4- bromophenethyl alcohol 2.0g, dicyclohexyl amine 2.25g are added, adds toluene 30mL, nitrogen is protected
0 DEG C is cooled under shield, n-BuLi (2.7M/L) 8.1mL is added dropwise, is added dropwise, -10-0 DEG C of insulation reaction 20min, is added dropwise different
Methyl butyrate 1.12g and toluene 10mL mixed solution, is added dropwise, insulation reaction 60min, adds catalyst 0.05g, slowly
50 DEG C are warming up to, reacts overnight
2. taking 100mL there-necked flasks 1., dicyclohexyl amine 2.25g is added, toluene 30mL is added, -15 is cooled under nitrogen protection
DEG C, n-BuLi (2.7M/L) 4.4mL is added dropwise, is added dropwise, 0-5 DEG C of insulation reaction；
Separately take 100mL there-necked flasks 2., add 4- bromophenethyl alcohol 2.0g, toluene 20mL, -10 DEG C are cooled under nitrogen protection,
N-BuLi (2.7M/L) 4.1mL is added dropwise, is added dropwise, -10-0 DEG C of insulation reactions；
To reaction system 1. middle dropwise addition methyl isobutyrate 1.12g and toluene 20mL mixed solution, it is added dropwise, insulation is anti-
30min is answered, merges reaction 1., 2. adds catalyst 0.05g, is to slowly warm up to 30 DEG C, reaction is overnight.
3. taking 100mL there-necked flasks, 4- bromophenethyl alcohol 5.0g, dicyclohexyl amine 6.07g are added, adds toluene 50mL, nitrogen is protected
- 10 DEG C are cooled under shield, n-BuLi (2.5M/L) 21mL is added dropwise, is added dropwise, -10-0 DEG C of insulation reaction 60min, addition is urged
Agent 0.05g, methyl isobutyrate 3.05g and toluene 20mL mixed solution is added dropwise, is added dropwise, insulation reaction 60min, slowly
50 DEG C are warming up to, reaction is overnight.
The reaction result of the different experiment of three charging order is shown in Table 1：
Reaction result corresponding to the charging order of table 1
Comparative experiments 1,2,3 is it can be seen that different charging sequence can all produce target product, but charging sequence is different, leads
Cause in course of reaction, the conversion ratio of raw material is different, and this main influence factor is the addition in material, can band in transfer process
Enter a small amount of water and air, cause partial catalyst to inactivate, in view of influence of the material transfer process for reaction, we select reality
Test the preferred operations order of 1 charging sequence as patent.
The metal base of embodiment 2
Take 100mL there-necked flasks 1., add dicyclohexyl amine 2.25g, add toluene 20mL, -10 DEG C are cooled under nitrogen protection,
N-BuLi (2.7M/L) 4.4mL is added dropwise, is added dropwise, -10-0 DEG C of insulation reaction 1h, methyl isobutyrate 1.12g and first is added dropwise
Benzene 5mL mixed solution, is added dropwise, insulation reaction 1h；
Separately take 100mL there-necked flasks 2., add metal base, toluene 20mL, be cooled to 5 DEG C under nitrogen protection, 4- bromobenzenes are added dropwise
Ethanol 2.0g and solvent 20mL mixed solution, is added dropwise, 5-10 DEG C of insulation reaction 1h；
Merge reaction 1., 2. add catalyst 0.05g, after being to slowly warm up to 30 DEG C of reaction 4h, be warming up to 50 DEG C and reacted
Night.
Reaction result corresponding to the metal base of table 2
| Metal base | Reaction result |
| 1.1eq n-BuLi | Target product HPLC contents are 74.30%, raw material peak 17.01% |
| 1.1eq sodium hydride | There is no target product, 23.34min has unknown impuritie |
| Nothing | There is no target product, 23.34min has unknown impuritie, |
It has selected different metal bases and carry out condition experiment, it is big to further demonstrate the selection section of n-BuLi equivalent
In 2.0eq.
The catalytic amount of embodiment 3
100mL there-necked flasks are taken, add 4- bromophenethyl alcohol 2.0g, dicyclohexyl amine 2.25g, add toluene 20mL, nitrogen protection
Under be cooled to 0 DEG C, n-BuLi (2.5M/L) 4.8mL is added dropwise, is added dropwise, -10-0 DEG C of insulation reaction 20min, isobutyl is added dropwise
Sour methyl esters 1.12g and toluene 6mL mixed solution, is added dropwise, insulation reaction 30min, adds catalyst, is to slowly warm up to 50
DEG C, reaction is overnight.
The amount of the catalyst of table 3 and corresponding reaction result
Different amounts of catalyst is have selected respectively carries out condition experiment, it is determined that when catalytic amount is 0.25%, reaction effect
Fruit is best, can excessively cause substantial amounts of cost to waste due to catalyst costly, and crossing can make reaction raw materials are remaining to add at least
Greatly.
The preparation of embodiment 4 bilastine intermediate 2- (4- ethoxys) phenyl -2- methvl-propionic acid ethvl esters
1. synthesis：
1. anhydrous and oxygen-free, 100g is added in bottle under nitrogen protection to bromophenethyl alcohol, 121.6g dicyclohexyl amines and 500ml first
Benzene；
2. being cooled to 0 DEG C, 453ml 2.5M butyl lithium reagents are slowly added dropwise, it is 0~5 DEG C to keep temperature of reaction system, drop
Finish and be cooled to -10 DEG C, insulation reaction 60min；
3. starting that the solution of methyl isobutyrate is added dropwise, 60.9g methyl isobutyrates are dissolved in 150ml toluene, drip and finish insulation reaction
60min；
4. N2 is replaced 1 time, catalyst two (tri-butyl phosphine) bromide phosphine palladium 250mg is added, nitrogen displacement 1 time, is warming up to
After 50 DEG C of insulation reaction 2h, liquid phase monitoring, to raw material methyl isobutyrate<10%.
2. purifying：
1. ice bath is cooled to 0~5 DEG C, the aqueous solution of 400ml saturated ammonium chlorides is added dropwise, is stirred overnight；
2. filter, filter cake 250ml*2 washing of ethyl acetate, merging filtrate, liquid separation, aqueous layer with ethyl acetate extraction
250ml*2 times, merge organic layer；
3. 1M aqueous hydrochloric acid solution (regulation pH to 2~3, stirring 60min is added dropwise.Filtering, filter cake ethyl acetate 150ml*
2 washing liquid separations, organic phase are washed with water to pH to 6~7, are spin-dried for solvent and obtain intermediate 2- (4- ethoxys) phenyl -2- first
Base-ethyl propionate, yellow liquid 105g.
Obtained intermediate is subjected to efficient liquid phase chromatographic analysis, collection of illustrative plates is as shown in Figure 1 at wavelength 220nm.In collection of illustrative plates
Occur seven peaks altogether, data are as shown in table 4.
The liquid chromatography results of table 4 are analyzed
According to the result of table 1, target compound purity is higher in obtained yellow liquid.
Product structure confirms that mass-spectrogram is shown in Fig. 2.
Wherein [M+H+]=223.3；[M+NH4+]=240.4；[M+Na+]=240.4；[M+H+-H2O]=205.3
From mass-spectrogram as can be seen that compound and target compound synthesized by patent are same compound.
Preparation method provided by the invention is easy to operate, can be from raw material one-step synthesis patents, and condition is controllable, subtracts
Lack the protection for active hydrogen and deprotection steps, production cost greatly reduces, be easy to industrial production；Locate later in warp
After managing step, the target compound of purity more than 95% is can obtain, product yield reaches more than 70%, and valency is applied with higher
Value.
Finally illustrate, the above embodiments are merely illustrative of the technical solutions of the present invention and it is unrestricted, although with reference to compared with
The present invention is described in detail good embodiment, it will be understood by those within the art that, can be to the skill of the present invention
Art scheme is modified or equivalent substitution, and without departing from the objective and scope of technical solution of the present invention, it all should cover at this
Among the right of invention.
Claims (10)
1. a kind of preparation method of bilastine intermediate 2- (4- ethoxys) phenyl -2- methvl-propionic acid ethvl esters, its feature exist
In the intermediate is generated by bromophenethyl alcohol and methyl isobutyrate occurring in the basic conditions coupling reaction, and reaction equation is as follows：
2. preparation method according to claim 1, it is characterised in that the substitution reaction is entered in anhydrous and oxygen-free environment
OK.
3. preparation method according to claim 1, it is characterised in that comprise the following steps：
1) alkali is added in a solvent, to bromophenethyl alcohol, methyl isobutyrate and catalyst, bromophenethyl alcohol and methyl isobutyrate are occurred
Substitution reaction generates 2- (4- ethoxys) phenyl -2- methvl-propionic acid ethvl esters, obtains solution 1；
2) saturated ammonium chloride will be added in solution 1, filters to obtain filter cake 1；
3) filter cake 1 is washed with ethyl acetate, retains organic layer, adds salt acid for adjusting pH to obtain filter cake 2 after filtering to 2~3；
4) filter cake 2 is washed with ethyl acetate, retains organic layer, and it is 6~7 to be washed with water to pH, is spin-dried for solvent and obtains product 2- (4-
Ethoxy) phenyl -2- methvl-propionic acid ethvl esters.
4. preparation method according to claim 3, it is characterised in that the alkali described in step 1) is metal organic base.
5. preparation method according to claim 4, it is characterised in that the metal organic base is dicyclohexyl amine base lithium, two
The one or more of isopropylamino lithium and hexamethyldisilane base amido lithium.
6. preparation method according to claim 3, it is characterised in that the catalyst described in step 1) is two (tri-terts
Phosphine) bromide phosphine palladium.
7. preparation method according to claim 3, it is characterised in that described in step 1) to bromophenethyl alcohol and isobutyric acid first
The mol ratio of ester is 1:1~1.5.
8. preparation method according to claim 3, it is characterised in that the solvent described in step 1) is selected from toluene, N, N- bis-
NMF, dimethyl sulfoxide (DMSO), 1.4- dioxane, the one or more of tetrahydrofuran.
9. 2- (4- ethoxys) phenyl -2- methvl-propionic acid ethvl esters prepared as the method described in claim 1.
10. a kind of synthetic method of bilastine, it is characterised in that comprise the following steps：
1) alkali is added in a solvent, to bromophenethyl alcohol, methyl isobutyrate and catalyst, bromophenethyl alcohol and methyl isobutyrate are occurred
Substitution reaction generates 2- (4- ethoxys) phenyl -2- methvl-propionic acid ethvl esters；
2) with methylsufonyl chloride substitution reaction generation 2- [4- (2- first occurs for 2- (4- ethoxys) phenyl -2- methvl-propionic acid ethvl esters
Base sulfonyloxy-ethyl)-phenyl] -2- methvl-propionic acid ethvl esters；
3) it is condensed to obtain 2- (4- { 2- [4- (1H- benzo miaows with 2- (4- piperidyls) -1H- benzimidazoles under sodium carbonate effect
Azoles -2- bases)-piperidin-1-yl]-ethyl }-phenyl) -2- methvl-propionic acid methyl estes；
4) substitution generation 2- [4- (2- { 4- [1- (2- ethoxyethyl groups) -1H- benzo miaows occur with ethoxyethyl group mesylate
Azoles -2- bases]-piperidin-1-yl }-ethyl)-phenyl] -2- methvl-propionic acid ethvl esters；
5) product is walked on to hydrolyze with sodium hydroxide reaction, and is added butanol crystal and obtained 2- [4- (2- { 4- [1- (2- second
Epoxide-ethyl) -1H- benzimidazolyl-2 radicals-yl]-piperidin-1-yl }-ethyl)-phenyl] -2- rnethyl-propanoic acids, i.e. bilastine.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110105204A (en) * | 2019-06-04 | 2019-08-09 | 荆楚理工学院 | A kind of 4- (the halogenated isobutyryl of 2-) benzyl carbinol derivative and preparation method thereof |
| CN110698343A (en) * | 2018-10-24 | 2020-01-17 | 荆门医药工业技术研究院 | Synthesis method of bilastine intermediate |
| 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 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101952273A (en) * | 2008-02-12 | 2011-01-19 | 柳韩洋行 | Process for preparation of 2-methyl-2'-phenylpropionic acid derivatives and novel intermediate compounds |
| CN107365297A (en) * | 2016-10-21 | 2017-11-21 | 罗欣生物科技（上海）有限公司 | A kind of Preparation Method And Their Intermediate of the benzyl propionate derivant of 2 methyl 2 ' |
-
2017
- 2017-12-14 CN CN201711335568.9A patent/CN107857702A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101952273A (en) * | 2008-02-12 | 2011-01-19 | 柳韩洋行 | Process for preparation of 2-methyl-2'-phenylpropionic acid derivatives and novel intermediate compounds |
| CN107365297A (en) * | 2016-10-21 | 2017-11-21 | 罗欣生物科技（上海）有限公司 | A kind of Preparation Method And Their Intermediate of the benzyl propionate derivant of 2 methyl 2 ' |
Non-Patent Citations (1)
| Title |
|---|
| TAKUO HAMA等: "α-Arylation of Esters Catalyzed by the Pd(I) Dimer {[P(t-Bu)3]PdBr}2", 《ORGANIC LETTERS 》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110698343A (en) * | 2018-10-24 | 2020-01-17 | 荆门医药工业技术研究院 | Synthesis method of bilastine intermediate |
| CN110698343B (en) * | 2018-10-24 | 2022-04-01 | 荆门医药工业技术研究院 | Synthesis method of bilastine intermediate |
| CN110105204A (en) * | 2019-06-04 | 2019-08-09 | 荆楚理工学院 | A kind of 4- (the halogenated isobutyryl of 2-) benzyl carbinol derivative and preparation method thereof |
| 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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