CN108129430A - A kind of synthetic method of Li Tasite intermediates - Google Patents
A kind of synthetic method of Li Tasite intermediates Download PDFInfo
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- CN108129430A CN108129430A CN201611080498.2A CN201611080498A CN108129430A CN 108129430 A CN108129430 A CN 108129430A CN 201611080498 A CN201611080498 A CN 201611080498A CN 108129430 A CN108129430 A CN 108129430A
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- reaction
- tasite
- bromobenzofurans
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- intermediate compound
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- 239000000543 intermediate Substances 0.000 title description 20
- 238000010189 synthetic method Methods 0.000 title description 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 48
- 150000001875 compounds Chemical class 0.000 claims abstract description 20
- 238000002360 preparation method Methods 0.000 claims abstract description 14
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims abstract description 12
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims abstract description 10
- 230000007062 hydrolysis Effects 0.000 claims abstract description 8
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 8
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000007858 starting material Substances 0.000 claims abstract description 8
- 229910052744 lithium Inorganic materials 0.000 claims abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 57
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- BBXQYOQXGGJUFK-UHFFFAOYSA-N 6-bromo-1-benzofuran Chemical class BrC1=CC=C2C=COC2=C1 BBXQYOQXGGJUFK-UHFFFAOYSA-N 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 3
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- 235000019270 ammonium chloride Nutrition 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 229940049706 benzodiazepine Drugs 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 235000019441 ethanol Nutrition 0.000 claims description 2
- -1 n-BuLi Furans Chemical class 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims 2
- 239000003513 alkali Substances 0.000 claims 1
- 235000021050 feed intake Nutrition 0.000 claims 1
- 150000002240 furans Chemical class 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 4
- 239000000047 product Substances 0.000 abstract description 3
- 239000006227 byproduct Substances 0.000 abstract description 2
- 239000012467 final product Substances 0.000 abstract description 2
- 238000005580 one pot reaction Methods 0.000 abstract description 2
- 238000000926 separation method Methods 0.000 abstract description 2
- RNEOFIVNTNLSEH-UHFFFAOYSA-N 2-bromo-1-benzofuran Chemical class C1=CC=C2OC(Br)=CC2=C1 RNEOFIVNTNLSEH-UHFFFAOYSA-N 0.000 abstract 1
- DDLYRGMLBFIGCN-UHFFFAOYSA-N C(=O)OC.O1C=CC2=C1C=CC=C2 Chemical class C(=O)OC.O1C=CC2=C1C=CC=C2 DDLYRGMLBFIGCN-UHFFFAOYSA-N 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 14
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical class OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 13
- 230000006837 decompression Effects 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 235000019253 formic acid Nutrition 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000005352 clarification Methods 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- 206010013774 Dry eye Diseases 0.000 description 2
- 238000003747 Grignard reaction Methods 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 125000003963 dichloro group Chemical group Cl* 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- JFOZKMSJYSPYLN-QHCPKHFHSA-N lifitegrast Chemical compound CS(=O)(=O)C1=CC=CC(C[C@H](NC(=O)C=2C(=C3CCN(CC3=CC=2Cl)C(=O)C=2C=C3OC=CC3=CC=2)Cl)C(O)=O)=C1 JFOZKMSJYSPYLN-QHCPKHFHSA-N 0.000 description 2
- 229960005381 lifitegrast Drugs 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- RVDHGRQELZPGCO-UHFFFAOYSA-N 1-benzofuran-6-carboxylic acid Chemical class OC(=O)C1=CC=C2C=COC2=C1 RVDHGRQELZPGCO-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- IAFNMXBIRZBSFU-UHFFFAOYSA-N 2,3-dihydro-1-benzofuran-6-ol Chemical class OC1=CC=C2CCOC2=C1 IAFNMXBIRZBSFU-UHFFFAOYSA-N 0.000 description 1
- 208000003556 Dry Eye Syndromes Diseases 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 241000208445 Sarcodes Species 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 238000003477 Sonogashira cross-coupling reaction Methods 0.000 description 1
- RMLHVYNAGVXKKC-UHFFFAOYSA-N [SH2]=N.C(F)(F)F Chemical compound [SH2]=N.C(F)(F)F RMLHVYNAGVXKKC-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 102000006495 integrins Human genes 0.000 description 1
- 108010044426 integrins Proteins 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229940054534 ophthalmic solution Drugs 0.000 description 1
- 239000002997 ophthalmic solution Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Furan Compounds (AREA)
Abstract
The present invention provides a kind of preparation methods of Li Tasite intermediate compound Is, using 6 bromobenzofurans as starting material, halogen lithium exchange reactions are carried out under the action of n-BuLi, 6 methyl formate benzofurans are then made with dimethyl carbonate, Li Tasite intermediate compound Is are obtained by hydrolysis.Raw material of the present invention is cheap and easy to get, and byproduct of reaction is few, high income, the step of final product purity is high, while step (1) and step (2) can carry out one pot reaction, simplify reaction, and reaction condition is mild, product did not needed to post separation, it is easy to accomplish industrialization.
Description
Technical field
The present invention relates to Li Tasite (lifitegrast), and in particular to the preparation method of Li Tasite intermediates belongs to
Field of pharmaceutical chemistry technology.
Background technology
Li Tasite (lifitegrast) ((S) -2- [two chloro- 1,2,3,4- tetra- of 2- (benzofuran -6- carbonyls) -5,7-
Hydrogen isoquinoline -6- formamidos] -3- (3- methanesulfonylphenYls) propionic acid) it is designed and developed by SARcode Bioscience
A kind of new small molecule integrin inhibitors are made into the topical ophthalmic solution of preservative free, for adult's dry eye disorders,
It is first medicine of eye chronic inflammation disease sign.2015 submitted New Drug Application to FDA, in 07 month 2016 11
FDA ratifies the medicine and lists and be used for eye dryness syndrome.
Li Tasite structural formulas are as follows：
Li Tasite structures are made of, important intermediate structure is as follows reverse synthesis analysis three parts important intermediate：
Intermediate compound I（Benzofuran -6- carboxylic acids）Synthesis be synthesize Li Tasite important difficult point, mainly have three at present
Route.Patent document US20030232853A discloses a kind of preparation method, former by starting of the iodo- 4-HBA methyl esters of 3-
Material, reacts, ring-closure reaction, hydrolysis is prepared by Sonogashira；Reaction route is as follows:
The disadvantages of this method is that the iodo- 4-HBA methyl esters of starting material 3- is more expensive, Sonogashira coupling reaction conditions
Harshness, first step product needs obtained by the reaction passed through column purification, and were unfavorable for industrialized production.
Patent document WO201418748A discloses a kind of method for preparing intermediate compound I, with 6- hydroxyl -2H- benzofurans -
3- ketone is starting material, carries out silicon substrate protection to phenolic hydroxyl group first, with sodium borohydride reduction carbonyl, after deprotection with fluoroform
Sulfimide introduces formic acid esters, then hydrolysis obtains intermediate compound I into ester under the action of palladium；Reaction route is as follows：
The disadvantages of this method is that reaction step is relatively long, and agents useful for same is more expensive, and severe reaction conditions are of high cost, are unfavorable for
Industrialized production.
Patent document WO2016100184 reports a kind of method for preparing intermediate compound I, is with 6- bromobenzofurans specifically
Starting material carries out grignard reaction first, generates grignard reagent, then passes to carbon dioxide and introduces carboxyl；Reaction route is as follows：
The disadvantages of this method is that, using 6- bromobenzofurans as starting material, grignard reaction is difficult to control, and reaction yield is low, document
Report yield only has 24%, is unfavorable for industrialized production.
Invention content
It is an object of the invention to be directed to the defects of existing synthetic technology, a kind of Li Tasite intermediate compound Is are provided
Preparation method, this method raw material are easy to get, concise in technology, and environmental protection and economy, is suitble to industrialized production at easy purification.
The object of the present invention is achieved like this, a kind of preparation method of Li Tasite intermediate compound Is, using following synthesis road
Line：
Using 6- bromobenzofurans as starting material, 6- lithium benzos are made in progress halogen-lithium exchange reactions under the action of n-BuLi
Furans, is then made 6- methyl formate benzofurans with dimethyl carbonate, and Li Tasite intermediate compound Is are obtained by hydrolysis.
Specifically, the preparation method of above-mentioned Li Tasite intermediate compound Is, using following steps：
(1) 6- bromobenzofurans are 1 according to molar ratio with n-BuLi:（1.1~1.5）It feeds intake, in -60 DEG C~-70 DEG C conditions
Under 6- lithium benzofurans, the wherein matter of 6- bromobenzofurans and solvent be made as 2~10h of solvent reaction using tetrahydrofuran or ether
Amount ratio is 1:（10~20）；
(2) after the completion for the treatment of step (1) reaction, dimethyl carbonate is added in, with identical solvent under the conditions of -60 DEG C~-70 DEG C
（Tetrahydrofuran or ether）6- methyl formate benzofurans are made in 2~10h of reaction；Saturated aqueous ammonium chloride is used after the completion of reaction
Reaction is quenched, the wherein molar ratio of 6- bromobenzofurans and dimethyl carbonate is 1:（1~1.3）, with 6- bromobenzofurans
Meter；
(3) step (3) adds in concentrated hydrochloric acid using dichloromethane, tetrahydrofuran, chloroform, DMSO, DMF, methanol or ethyl alcohol as solvent
(37%) or 20%~50% sodium hydrate aqueous solution hydrolysis methyl esters, prepare Li Tasite intermediate compound Is.
Above-mentioned steps（1）The molar ratio of 6- bromobenzofurans and n-BuLi preferably 1: 1.1；Reaction temperature preferably-
60~-65 DEG C；Preferably 3~5 hours reaction time；The preferred tetrahydrofuran of solvent.
Above-mentioned steps（2）The molar ratio of 6- bromobenzofurans and dimethyl carbonate preferably 1: 1.1；Reaction time is preferred
2~5 hours；Preferably -60~-65 DEG C of reaction temperature.
Above-mentioned steps（3）It is preferred that methanol or dichloromethane are solvent, the sodium hydroxide of addition a concentration of 30%~40% is water-soluble
Li Tasite intermediate compound Is are made in liquid, hydrolysis.
Concentrated hydrochloric acid of the present invention is the hydrochloric acid that mass concentration is 37%.
The present invention provides a kind of preparation method of Li Tasite intermediate compound Is, using 6- bromobenzofurans as starting material,
Halogen-lithium exchange reactions are carried out under the action of n-BuLi, 6- methyl formate benzofurans are then made with dimethyl carbonate,
Li Tasite intermediate compound Is are obtained by hydrolysis.Raw material of the present invention is cheap and easy to get, and byproduct of reaction is few, high income, final product purity
Height, while the step of step (1) and step (2) can carry out one pot reaction, simplify reaction, and reaction condition is mild, product
Post separation was not needed to, it is easy to accomplish industrialization.
Specific embodiment
In order to make the purpose of the present invention and technical solution clearer, the preferred embodiment of the present invention is carried out below detailed
Description.To illustrate that：Following embodiment is served only for that the present invention is further detailed, and it is not intended that this hair
The limitation of bright protection domain.Those skilled in the art's the above according to the present invention make some it is nonessential improvement and
Adjustment all belongs to the scope of protection of the present invention.The raw materials used in the present invention and reagent are commercial product.
Embodiment 1
1）The preparation of 6- methyl formate benzofurans：
By 5.28g（0.0268mol）6- bromobenzofurans are added in the three-necked bottle of 250mL, add in dry tetrahydrofuran 80ml,
It after stirring and dissolving, is put into refrigerator and is cooled to -65 DEG C, n-BuLi is added dropwise（2M）14.74mL keeps temperature during being added dropwise
- 60 DEG C are maintained hereinafter, 1h is added dropwise, after the reaction was continued 3 hours, at this point in the reaction, dimethyl carbonate 2.89g is added dropwise
（0.0321mol）, it is added dropwise within 1 hour, -65 DEG C of controlling reaction temperature, after reacting 4 hours, reaction is completed, under cryogenic
Saturated ammonium chloride solution is added dropwise, reaction is quenched, after decompression volatilizes solvent, add in 100mL water, the stirring of 100mL dichloromethane is remaining
Object, after layering, organic layer saturated common salt water washing 2 times, each 100mL, dichloromethane layer is dried with anhydrous magnesium sulfate
After filter, decompression volatilize dichloromethane, obtain 6- methyl formate benzofuran 4.3g, yield 91.2%, HPLC purity 97.2%, MS
[M++1,ESI+]:177。
2）The preparation of intermediate compound I benzofuran 6- formic acid：
By 6- methyl formate benzofurans 5.22g（0.0296mol）It is dissolved in 50mL methanol, 40% hydroxide is added in after dissolved clarification
Sodium solution 5ml is placed in and 2h is stirred at room temperature, and TLC monitorings are after the reaction was complete, and solvent, system are volatilized with the decompression of concentrated hydrochloric acid tune pH=2~3
After molten dichloromethane is molten, with saturated common salt water washing 2 times, each 100mL, after dichloromethane layer is dried with anhydrous magnesium sulfate, mistake
Filter, decompression volatilize dichloromethane, obtain benzofuran 6- formic acid 4.5g, yield 93.9%, HPLC purity 98%, MS [M--1,
ESI-]:161。
Embodiment 2
1）The preparation of 6- methyl formate benzofurans：
By 4.55g（0.0231mol）6- bromobenzofurans are added in the three-necked bottle of 250mL, add in dry tetrahydrofuran 80ml,
It after stirring and dissolving, is put into refrigerator and is cooled to -65 DEG C, n-BuLi is added dropwise（2M）15mL keeps temperature dimension during being added dropwise
It holds at -60 DEG C hereinafter, 1h is added dropwise, after the reaction was continued 3 hours, at this point in the reaction, dimethyl carbonate 2.28g is added dropwise
（0.0254mol）, it is added dropwise within 1 hour, -65 DEG C of controlling reaction temperature, after reacting 4 hours, reaction is completed, under cryogenic
Saturated ammonium chloride solution is added dropwise, reaction is quenched, after decompression volatilizes solvent, add in 100mL water, 100mL dichloromethane stirring and dissolvings remain
Excess, after layering, organic layer saturated common salt water washing 2 times, each 100mL, dichloromethane layer is done with anhydrous magnesium sulfate
It is filtered after dry, decompression volatilizes dichloromethane, obtains 6- methyl formate benzofuran 3.06g, yield 75%, HPLC purity 98.5%,
MS[M++1,ESI+]:177。
2）The preparation of intermediate compound I benzofuran 6- formic acid：
By 6- methyl formate benzofurans 15.3g（0.0869mol）It is dissolved in 100mL dichloromethane, concentrated hydrochloric acid is added in after dissolved clarification
（37%）20ml is placed in and 2h is stirred at room temperature, and TLC monitorings are after the reaction was complete, with saturated common salt water washing 2 times, each 100mL, dichloro
After methane layer is dried with anhydrous magnesium sulfate, filtering, decompression volatilizes dichloromethane, obtains benzofuran 6- formic acid 13.37g, yield
95%, HPLC purity 98%, MS [M--1,ESI-]:161。
Embodiment 3
1）The preparation of 6- methyl formate benzofurans：
By 8.28g（0.042mol）6- bromobenzofurans are added in the three-necked bottle of 250mL, add in dry tetrahydrofuran 100ml,
It after stirring and dissolving, is put into refrigerator and is cooled to -65 DEG C, n-BuLi is added dropwise（2M）23.1mL keeps temperature during being added dropwise
- 60 DEG C are maintained hereinafter, 1h is added dropwise, after the reaction was continued 3 hours, at this point in the reaction, dimethyl carbonate 4.9g is added dropwise
（0.054mol）, it is added dropwise within 1 hour, -65 DEG C of controlling reaction temperature, after reacting 4 hours, reaction is completed, under cryogenic
Saturated ammonium chloride solution is added dropwise, reaction is quenched, after decompression volatilizes solvent, add in 120mL water, the stirring of 120mL dichloromethane is remaining
Object, after layering, organic layer saturated common salt water washing 2 times, each 100mL, dichloromethane layer is dried with anhydrous magnesium sulfate
After filter, decompression volatilize dichloromethane, obtain 6- methyl formate benzofuran 6.5g, yield 88%, HPLC purity 98%, MS [M++
1,ESI+]:177。
2）The preparation of intermediate compound I benzofuran 6- formic acid：
By 6- methyl formate benzofurans 8.69g（0.049mol）It is dissolved in 100mL dichloromethane, concentrated hydrochloric acid is added in after dissolved clarification
（37%）10ml is placed in and 2h is stirred at room temperature, and TLC monitorings are after the reaction was complete, with saturated common salt water washing 2 times, each 100mL, dichloro
After methane layer is dried with anhydrous magnesium sulfate, filtering, decompression volatilizes dichloromethane, obtains benzofuran 6- formic acid 7.5g, yield
95%, HPLC purity 98%, MS [M--1,ESI-]:161；1HNMR(400MHz,CD3OD):δ 8.14 (s, 1H), 7.92 (m, 2H),
7.67 (d,J=8.5HZ, 1H), 6.92 (s, 1H).
Claims (5)
1. a kind of preparation method of Li Tasite intermediate compound Is, using following route：
Using 6- bromobenzofurans as starting material, 6- lithium benzos are made in progress halogen-lithium exchange reactions under the action of n-BuLi
Furans, is then made 6- methyl formate benzofurans with dimethyl carbonate, and Li Tasite intermediate compound Is are obtained by hydrolysis.
2. the method as described in claim 1, which is characterized in that using following steps：
(1) 6- bromobenzofurans are 1 according to molar ratio with n-BuLi: (1.1~1.5) feed intake, under cryogenic with tetrahydrochysene
6- lithium benzofurans, the wherein mass/volume of 6- bromobenzofurans and solvent (g/ml) is made for solvent reaction in furans or ether
Ratio is 1: (10~20)；
(2) after the completion for the treatment of step (1) reaction, dimethyl carbonate is added in, with identical solvent under the conditions of -60 DEG C~-70 DEG C
（Tetrahydrofuran or ether）6- methyl formate benzofurans are made in reaction；It is quenched instead with saturated aqueous ammonium chloride after the completion of reaction
Should, wherein the molar ratio of 6- bromobenzofurans and dimethyl carbonate is 1: (1~1.3), in terms of 6- bromobenzofurans；
(3) it using dichloromethane, tetrahydrofuran, chloroform, DMSO, DMF, methanol or ethyl alcohol as solvent, adds in acid or buck is retired
Ester is prepared into Li Tasite intermediate compound Is.
3. method as claimed in claim 1 or 2, it is characterised in that：Cryogenic conditions in the step (1) are reaction temperature
It is -60~-70 DEG C；Reaction time is 2~10h；Solvent is tetrahydrofuran or ether.
4. method as claimed in claim 2, it is characterised in that：The reaction time is 2~5h in the step (2).
5. method as claimed in claim 1 or 2, it is characterised in that：The concentrated hydrochloric acid that acid in the step (3) is 37%, alkali are
20%~50% sodium hydrate aqueous solution.
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| CN110305116A (en) * | 2019-08-13 | 2019-10-08 | 江苏恒盛药业有限公司 | A kind of Li Tasite and intermediate synthesis technology |
| CN112272665A (en) * | 2018-06-14 | 2021-01-26 | 欧伦股份公司 | Process for preparing sitagliptin |
| CN115872929A (en) * | 2022-12-27 | 2023-03-31 | 山东金城柯瑞化学有限公司 | Method for preparing Ritahast intermediate through continuous carboxylation reaction of aryl compounds |
| CN117466847A (en) * | 2022-07-22 | 2024-01-30 | 中国医药工业研究总院有限公司 | A kind of preparation method of Lelifest intermediate benzofuran-6-carboxylic acid |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112272665A (en) * | 2018-06-14 | 2021-01-26 | 欧伦股份公司 | Process for preparing sitagliptin |
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