CN104987320A - Preparation method of canagliflozin intermediates - Google Patents
Preparation method of canagliflozin intermediates Download PDFInfo
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- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
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Abstract
The invention relates to the technical field of preparation of medicine intermediates, and particularly discloses a preparation method of canagliflozin intermediates. High purity 2- ( 4- fluorophenyl)-5[(5- halogenating -2- methyl phenyl carbinol )]thiophene can be prepared, and the preparation method comprises the following steps of: adopting fluorine benzyl halide and 3- halogenating acrolein as raw materials, and under the existence of a sulfur reagent, obtaining 2-p-fluorophenyl thiophene; and enabling the 2-p-fluorophenyl thiophene and 5- halogenating -2- toluyl aldehyde to obtain a product of the 2- ( 4- fluorophenyl)-5[(5- halogenating -2- methyl phenyl carbinol )]thiophene under the condition of n-Butyllithium. Compared with the prior art, according to the method disclosed by the invention, the raw materials are easy to obtain, the yield is high, the reaction condition is easy to control, the product purity is high, the reaction is stable, and the commercialized production is easy.
Description
Technical field
The present invention relates to pharmaceutical intermediate synthesis technical field.
Background technology
Kan Gelie is clean, Ka Gelie is clean for another name, English name is Canagliflozin, be developed by Janssen Pharmaceutica under Johnson & Johnson's pharmacy effectively can control hypoglycemic medicament, Nikkei FDA (Food and Drug Adminstration) March 29 in 2013 (FDA), approval is used for the glycemic control of 2 type maturity-onset diabetes patients.The oral diabetes drug of Kan Gelie only for taking once day, belong to selectivity and receive glucose co-transporters body 2(sodium glucose co-transporter 2, SGLT2) kind new medicine of inhibitor, by blocking kidney to the excretion heavily absorbing and increase blood sugar in urine of blood sugar, reduce body blood sugar level.Its molecular formula is:
In the syntheti c route that current hypoglycemic agents Kan Gelie is clean, 2-(4-fluorophenyl)-5 [(5-halo-2-methylphenylmethyl)] thiophene (compound ii) is for the synthesis of the clean important intermediate of Kan Gelie.The existing preparation method of compound ii is first prepared 2-(4-fluorophenyl)-5 [(5-halo-2-methyl phenyl carbinol)] thiophene (chemical compounds I), then chemical compounds I is prepared into compound ii through reduction.
The method wherein preparing chemical compounds I has several as follows:
1) application number 20050233988A1 U.S. patents disclose a kind of synthetic route, by Suzuki coupling synthesis 2-aryl substituted thiophene, then with benzoyl halogen at AlCl
3carry out Friedel-Crafts reaction synthetic compound I under catalysis, then generate compound ii through boron trifluoride diethyl etherate and triethyl silicane reduction.Reaction formula is as follows:
The shortcoming of the method is:
1. Suzuki coupling needs to use expensive Pd or Ni agent catalyst, and reaction Raw autoimmunity syndrome is difficult to control, and is not suitable for suitability for industrialized production;
2. Friedel-Crafts reaction is difficult to react completely, and surplus stock is difficult to purifying, and products obtained therefrom purity is lower, and yield is on the low side.
2) document (Comptes Rendus des seances de 1 ' Academie des Sciences, C:1971,273 (2), 148-151) report the method for compound III and compounds Ⅳ generation ring-closure reaction, reaction formula is as follows:
Utilize this method to synthesize and prepare chemical compounds I:
The shortcoming of this method is:
1. raw materials used price, and be difficult to buy, be unfavorable for suitability for industrialized production;
2. reaction yield is on the low side, only has 50 ~ 55%.
3) CN102115468B discloses a kind of preparation method of 2,5-bis-substituted thiophene compound, and chemical compounds I preparation method is as follows:
This method shortcoming is:
1. raw materials usedly not easily to buy, and on the high side;
2. product purity is lower.
4) CN102115468B, CN101801371 all report the method preparing compound ii with chemical compounds I,
Reaction formula is as follows:
This method shortcoming is:
1. raw materials used triethyl silicane price is high, and yield only has 78%, high expensive;
2. boron trifluoride diethyl etherate and the irritant smell of triethyl silicane, very high to environmental requirement, is unfavorable for suitability for industrialized production.
Summary of the invention
The technical problem to be solved in the present invention is to provide the preparation method of the clean intermediate of a kind of Kan Gelie, high purity 2-(4-fluorophenyl)-5 [(5-halo-2-methyl phenyl carbinol)] thiophene can be prepared, the method reaction temperature and, operational condition is more conducive to control, the W-response cycle is short, and yield is high and stable, and cost is low, pollute low, be more conducive to suitability for industrialized production.
For solving the problems of the technologies described above, the technical solution used in the present invention is: the preparation method of the clean intermediate of a kind of Kan Gelie, comprises the following steps:
One, with to fluorine halogen benzyl and 3-halogen propenal for raw material, under sulphur reagent exists, occur to react as follows,
Obtain 2-to fluorophenyl thiophene;
Two, gained 2-is to fluorophenyl thiophene and 5-halo-2-tolyl aldehyde under n-Butyl Lithium catalysis, occurs to react as follows,
Obtain product 2-(4-fluorophenyl)-5-[(5-halo-2-methyl phenyl carbinol)] thiophene.
Further, step one, by sulphur reagent, fluorine halogen benzyl and 3-halogen propenal are dissolved in organic solvent respectively, temperature control 10 ~ 80 DEG C, adds fluorine halogen benzyl solution, stirring reaction in sulphur reagent solution, add 3-halogen acrolein solution again, coreaction 3 ~ 6h, after reacting completely, product obtains 2-to fluorophenyl thiophene through aftertreatment.
Further, step one aftertreatment is: product is cooled to 0 ~ 10 DEG C, adds water, and crystallization, filtration, obtain crude product, then obtains 2-to fluorophenyl thiophene through recrystallization;
Further; step 2; 2-is dissolved in aprotic solvent respectively to fluorophenyl thiophene and 5-halo-2-tolyl aldehyde; nitrogen protection borehole cooling, to-90 ~-50 DEG C, adds n-Butyl Lithium to 2-in fluorophenyl thiophene solution, stirring reaction; add 5-halo-2-tolyl aldehyde solution again; coreaction 1.5 ~ 3h, after reacting completely, product obtains 2-to fluorophenyl thiophene through aftertreatment.
Further, step 2 aftertreatment is: slowly rise again product to-20 ~-30 DEG C, add hydrochloric acid, termination reaction, continue to rise again to 20 ~ 30 DEG C, by product separatory, gained organic phase is after washing, concentrating under reduced pressure, add methyl tertiary butyl ether again, be warming up to 50 ~ 60 DEG C, after stirring for some time, then slow cooling to 0 ~ 5 DEG C, crystallization, filtration, gained solid obtains chemical compounds I after drying.
Further, described sulphur reagent is the one in potassium sulphide, lithium sulfide, aluminium sulfide, sodium sulphite, nine hydrated sodium sulfides.
Further, step one organic solvent is DMF, N-Methyl pyrrolidone, 1,3-dimethyl-imidazolinone, tetrahydrofuran (THF), toluene or methylene dichloride.
Further, described aprotic solvent is one or more in tetrahydrofuran (THF), 2-methyltetrahydrofuran, n-butyl ether, ether, toluene.
Further, in step one, 3-halogen propenal consumption is 1.0 ~ 2.0 molar equivalents to fluorine halogen benzyl, and sulphur reagent dosage is 1.0 ~ 3.0 molar equivalents to fluorine halogen benzyl.
Further, in step 2, n-Butyl Lithium consumption is 1.0 ~ 2.0 molar equivalents of 2-to fluorophenyl thiophene; 5-halo-2-tolyl aldehyde consumption is 1.0 ~ 1.5 molar equivalents of 2-to fluorophenyl thiophene.
The beneficial effect adopting technique scheme to produce is:
(1) the raw materials used easy buying of the inventive method, stable reaction, yield is high;
(2) the inventive method operational condition is easy to control, and products therefrom purity is high, stable yield, and the cycle is short, and cost is low, pollution-free, is suitable for suitability for industrialized production.
Embodiment
Embodiment 1: by Na
2s (57.8g, 741mmol) add in 2L four-hole bottle, N is added again to system, dinethylformamide 420ml, temperature control 65 ~ 75 DEG C drips fluorine bromobenzyl (140g, N 741mmol), dinethylformamide (140ml) solution, drip and finish, temperature control 65 ~ 75 DEG C of stirring reaction 1 ~ 2h, slowly drip 3-bromopropylene aldehyde (100g again, N 741mmol), dinethylformamide (140ml) solution, dropwise temperature control 70 ~ 80 DEG C and continue reaction 2 ~ 3h, 0 ~ 10 DEG C is cooled to after HPLC detection reaction is complete, by in water (140ml) instillation system, drip complete stirring and crystallizing 2h, system is filtered, methyl alcohol (420ml) recrystallization used again by solid, filter after being cooled to 0 ~ 5 DEG C of crystallization 2h, solid obtains fluorophenyl thiophene (122.8g after drying, HPLC:98.4%, yield 93%).
Embodiment 2: by Na
2s (58.9g, 755mmol) add in 2L four-hole bottle, N is added again to system, dinethylformamide 420ml, temperature control 65 ~ 75 DEG C drips fluorine bromobenzyl (140g, N 741mmol), dinethylformamide (140ml) solution, drip and finish, temperature control 65 ~ 75 DEG C of stirring reaction 1 ~ 2h, slowly drip 3-bromopropylene aldehyde (103g again, N 763mmol), dinethylformamide (140ml) solution, dropwise temperature control 70 ~ 80 DEG C and continue reaction 2 ~ 3h, 0 ~ 10 DEG C is cooled to after HPLC detection reaction is complete, by in water (140ml) instillation system, drip complete stirring and crystallizing 2h, system is filtered, methyl alcohol (420 ml) recrystallization used again by solid, filter after being cooled to 0 ~ 5 DEG C of crystallization 2h, solid obtains fluorophenyl thiophene (125.4g after drying, HPLC:98.9%, yield 95%).
Embodiment 3: by Na
2s (60.7g, 778mmol) add in 2L four-hole bottle, N is added again to system, dinethylformamide 420ml, temperature control 65 ~ 75 DEG C drips fluorine bromobenzyl (140g, N 741mmol), dinethylformamide (140ml) solution, drip and finish, temperature control 65 ~ 75 DEG C of stirring reaction 1 ~ 2h, slowly drip 3-bromopropylene aldehyde (110g again, N 815mmol), dinethylformamide (140ml) solution, dropwise temperature control 70 ~ 80 DEG C and continue reaction 2 ~ 3h, 0 ~ 10 DEG C is cooled to after HPLC detection reaction is complete, by in water (140ml) instillation system, drip complete stirring and crystallizing 2h, system is filtered, methyl alcohol (420 ml) recrystallization used again by solid, filter after being cooled to 0 ~ 5 DEG C of crystallization 2h, solid obtains fluorophenyl thiophene (125.4g after drying, HPLC:98.1%, yield 95%).
Embodiment 4: add tetrahydrofuran (THF) (336ml) in 1L four-hole bottle, add fluorophenyl thiophene (56g to system again, 314mmol), nitrogen protection borehole cooling is to-70 ~-60 DEG C, slowly drip n-Butyl Lithium (126ml to system, 2.5M, 314mmol), drip Bi Jixu temperature control-70 ~-60 DEG C of stirring reaction 0.5 ~ 1h, the bromo-2-tolyl aldehyde of 5-(62.5g is slowly dripped to system, tetrahydrofuran (THF) (56ml) solution 314mmol), drip complete temperature control-70 ~-60 DEG C reaction 1h, system is slowly risen again to-20 ~-30 DEG C, 2N hydrochloric acid (160ml) termination reaction is dripped to system, dripping Bi Jixu rises again to 20 ~ 30 DEG C, system separatory, organic phase uses saturated sodium bicarbonate solution (100ml) and saturated brine (100ml) washing again, organic phase concentrating under reduced pressure removing tetrahydrofuran (THF), add methyl tertiary butyl ether (168ml) again, be warming up to 50 ~ 60 DEG C and stir 1h, filter after DEG C crystallization 2h of slow cooling to 0 ~ 5 again, solid obtains 2-(4-fluorophenyl)-5 [(the bromo-2-methyl phenyl carbinol of 5-)] thiophene (107.9g) after drying, HPLC purity 99.3%, yield 91%
Embodiment 5: add tetrahydrofuran (THF) (336ml) in 1L four-hole bottle, add fluorophenyl thiophene (56g to system again, 314mmol), nitrogen protection borehole cooling is to-70 ~-60 DEG C, slowly drip n-Butyl Lithium (128ml to system, 2.5M, 320mmol), drip Bi Jixu temperature control-70 ~-60 DEG C of stirring reaction 0.5 ~ 1h, the bromo-2-tolyl aldehyde of 5-(64.4g is slowly dripped to system, tetrahydrofuran (THF) (56ml) solution 324mmol), drip complete temperature control-70 ~-60 DEG C reaction 1h, system is slowly risen again to-20 ~-30 DEG C, 2N hydrochloric acid (160ml) termination reaction is dripped to system, dripping Bi Jixu rises again to 20 ~ 30 DEG C, system separatory, organic phase uses saturated sodium bicarbonate solution (100ml) and saturated brine (100ml) washing again, organic phase concentrating under reduced pressure removing tetrahydrofuran (THF), add methyl tertiary butyl ether (168ml) again, be warming up to 50 ~ 60 DEG C and stir 1h, filter after DEG C crystallization 2h of slow cooling to 0 ~ 5 again, solid obtains 2-(4-fluorophenyl)-5 [(the bromo-2-methyl phenyl carbinol of 5-)] thiophene (111.5g) after drying, HPLC purity 99.6%, yield 94%
Embodiment 6 adds tetrahydrofuran (THF) (336ml) in 1L four-hole bottle, add fluorophenyl thiophene (56g to system again, 314mmol), nitrogen protection borehole cooling is to-70 ~-60 DEG C, slowly drip n-Butyl Lithium (132ml to system, 2.5M, 330mmol), drip Bi Jixu temperature control-70 ~-60 DEG C of stirring reaction 0.5 ~ 1h, the bromo-2-tolyl aldehyde of 5-(65.7g is slowly dripped to system, tetrahydrofuran (THF) (56ml) solution 330mmol), drip complete temperature control-70 ~-60 DEG C reaction 1h, system is slowly risen again to-20 ~-30 DEG C, 2N hydrochloric acid (165ml) termination reaction is dripped to system, dripping Bi Jixu rises again to 20 ~ 30 DEG C, system separatory, organic phase uses saturated sodium bicarbonate solution (100ml) and saturated brine (100ml) washing again, organic phase concentrating under reduced pressure removing tetrahydrofuran (THF), add methyl tertiary butyl ether (168ml) again, be warming up to 50 ~ 60 DEG C and stir 1h, filter after DEG C crystallization 2h of slow cooling to 0 ~ 5 again, solid obtains 2-(4-fluorophenyl)-5 [(the bromo-2-methyl phenyl carbinol of 5-)] thiophene (109.1g) after drying, HPLC purity 99.1%, yield 92%,
Embodiment 7 adds toluene (336ml) in 1L four-hole bottle, add fluorophenyl thiophene (28g to system again, 157mmol), nitrogen protection borehole cooling is to-70 ~-60 DEG C, slowly drip n-Butyl Lithium (64ml to system, 2.5M, 160mmol), drip Bi Jixu temperature control-70 ~-60 DEG C of stirring reaction 0.5 ~ 1h, the bromo-2-tolyl aldehyde of 5-(31.9g is slowly dripped to system, toluene (28ml) solution 160mmol), drip complete temperature control-70 ~-60 DEG C reaction 1h, system is slowly risen again to-20 ~-30 DEG C, 2N hydrochloric acid (80ml) termination reaction is dripped to system, dripping Bi Jixu rises again to 20 ~ 30 DEG C, system separatory, organic phase uses saturated sodium bicarbonate solution (50ml) and saturated brine (50ml) washing again, organic phase concentrating under reduced pressure removing toluene, add methyl tertiary butyl ether (84ml) again, be warming up to 50 ~ 60 DEG C and stir 1h, filter after DEG C crystallization 2h of slow cooling to 0 ~ 5 again, solid obtains 2-(4-fluorophenyl)-5 [(the bromo-2-methyl phenyl carbinol of 5-)] thiophene (55.7g) after drying, HPLC purity 98.6%, yield 94%,
Embodiment 8: add tetrahydrofuran (THF) (150ml) in 1L four-hole bottle, toluene (150ml), add fluorophenyl thiophene (30g to system again, 168mmol), nitrogen protection borehole cooling is to-70 ~-60 DEG C, slowly drip n-Butyl Lithium (69ml to system, 2.5M, 172mmol), drip Bi Jixu temperature control-70 ~-60 DEG C of stirring reaction 0.5 ~ 1h, the bromo-2-tolyl aldehyde of 5-(34.2g is slowly dripped to system, toluene (30ml) solution 172mmol), drip complete temperature control-70 ~-60 DEG C reaction 1h, system is slowly risen again to-20 ~-30 DEG C, 2N hydrochloric acid (86ml) termination reaction is dripped to system, dripping Bi Jixu rises again to 20 ~ 30 DEG C, system separatory, organic phase uses saturated sodium bicarbonate solution (50ml) and saturated brine (50ml) washing again, organic phase concentrating under reduced pressure removing toluene, add methyl tertiary butyl ether (90ml) again, be warming up to 50 ~ 60 DEG C and stir 1h, filter after DEG C crystallization 2h of slow cooling to 0 ~ 5 again, solid obtains 2-(4-fluorophenyl)-5 [(the bromo-2-methyl phenyl carbinol of 5-)] thiophene (60.3g) after drying, HPLC purity 99.2%, yield 95%,
Embodiment 9: add tetrahydrofuran (THF) (460ml) in 1L four-hole bottle, 2-(4-fluorophenyl)-5 [(the bromo-2-methyl phenyl carbinol of 5-)] thiophene (92g is added again in system, 244mmol), temperature control 20 ~ 30 DEG C, add aluminum chloride (35.8g to system in batches, 268mmol) finish, temperature control 20 ~ 30 DEG C adds sodium borohydride (10.1g to system in batches, 268mmol), finish and be slowly warming up to 45 ~ 55 DEG C afterwards, insulation reaction 6h, HPLC detection reaction is complete, system is cooled to 0 ~ 10 DEG C, system is instilled cancellation reaction in 1N hydrochloric acid (180ml), dropwising rises again 20 ~ 30 DEG C stirs 2h, by system separatory, organic phase saturated sodium bicarbonate solution (135ml) and saturated brine (135ml) washing, organic phase concentrating under reduced pressure removing tetrahydrofuran (THF), add methylene dichloride (92ml) again, be warming up to 30 ~ 40 DEG C complete molten after, temperature control 30 ~ 40 DEG C drips sherwood oil (276ml), drip to finish and filter after system slow cooling to-5 ~ 0 DEG C of crystallization 2h, solid obtains 2-(4-fluorophenyl)-5 [(the bromo-2-methylphenylmethyl of 5-)] thiophene (77.5g) after drying, HPLC purity 99.2%, yield 88%.
Embodiment 10: add tetrahydrofuran (THF) (460ml) in 1L four-hole bottle, 2-(4-fluorophenyl)-5 [(the bromo-2-methyl phenyl carbinol of 5-)] thiophene (92g is added again in system, 244mmol), temperature control 20 ~ 30 DEG C, add aluminum chloride (42.3g to system in batches, 317mmol) finish, temperature control 20 ~ 30 DEG C adds sodium borohydride (12.0g to system in batches, 317mmol), finish and be slowly warming up to 45 ~ 55 DEG C afterwards, insulation reaction 5h, HPLC detection reaction is complete, system is cooled to 0 ~ 10 DEG C, system is instilled cancellation reaction in 1N hydrochloric acid (180ml), dropwising rises again 20 ~ 30 DEG C stirs 2h, by system separatory, organic phase saturated sodium bicarbonate solution (135ml) and saturated brine (135ml) washing, organic phase concentrating under reduced pressure removing tetrahydrofuran (THF), add methylene dichloride (92ml) again, be warming up to 30 ~ 40 DEG C complete molten after, temperature control 30 ~ 40 DEG C drips sherwood oil (276ml), drip to finish and filter after system slow cooling to-5 ~ 0 DEG C of crystallization 2h, solid obtains 2-(4-fluorophenyl)-5 [(the bromo-2-methylphenylmethyl of 5-)] thiophene (83.7g) after drying, HPLC purity 99.6%, yield 95%.
Embodiment 11: add tetrahydrofuran (THF) (460ml) in 1L four-hole bottle, 2-(4-fluorophenyl)-5 [(the bromo-2-methyl phenyl carbinol of 5-)] thiophene (92g is added again in system, 244mmol), temperature control 20 ~ 30 DEG C, add aluminum chloride (48.8g to system in batches, 366mmol) finish, temperature control 20 ~ 30 DEG C adds sodium borohydride (113.8g to system in batches, 366mmol), finish and be slowly warming up to 45 ~ 55 DEG C afterwards, insulation reaction 4h, HPLC detection reaction is complete, system is cooled to 0 ~ 10 DEG C, system is instilled cancellation reaction in 1N hydrochloric acid (180ml), dropwising rises again 20 ~ 30 DEG C stirs 2h, by system separatory, organic phase saturated sodium bicarbonate solution (135ml) and saturated brine (135ml) washing, organic phase concentrating under reduced pressure removing tetrahydrofuran (THF), add methylene dichloride (92ml) again, be warming up to 30 ~ 40 DEG C complete molten after, temperature control 30 ~ 40 DEG C drips sherwood oil (276ml), drip to finish and filter after system slow cooling to-5 ~ 0 DEG C of crystallization 2h, solid obtains 2-(4-fluorophenyl)-5 [(the bromo-2-methylphenylmethyl of 5-)] thiophene (84.6g) after drying, HPLC purity 99.4%, yield 96%.
Embodiment 12: add 2-methyltetrahydrofuran (460ml) in 1L four-hole bottle, 2-(4-fluorophenyl)-5 [(the bromo-2-methyl phenyl carbinol of 5-)] thiophene (92g is added again in system, 244mmol), temperature control 20 ~ 30 DEG C, add aluminum chloride (42.3g to system in batches, 317mmol) finish, temperature control 20 ~ 30 DEG C adds sodium borohydride (12.0g to system in batches, 317mmol), finish and be slowly warming up to 45 ~ 55 DEG C afterwards, insulation reaction 3h, HPLC detection reaction is complete, system is cooled to 0 ~ 10 DEG C, system is instilled cancellation reaction in 1N hydrochloric acid (180ml), dropwising rises again 20 ~ 30 DEG C stirs 2h, by system separatory, organic phase saturated sodium bicarbonate solution (135ml) and saturated brine (135ml) washing, organic phase concentrating under reduced pressure removing tetrahydrofuran (THF), add methylene dichloride (92ml) again, be warming up to 30 ~ 40 DEG C complete molten after, temperature control 30 ~ 40 DEG C drips sherwood oil (276ml), drip to finish and filter after system slow cooling to-5 ~ 0 DEG C of crystallization 2h, solid obtains 2-(4-fluorophenyl)-5 [(the bromo-2-methylphenylmethyl of 5-)] thiophene (82.8g) after drying, HPLC purity 99.7%, yield 94%.
Embodiment 13: add tetrahydrofuran (THF) (460ml) in 1L four-hole bottle, 2-(4-fluorophenyl)-5 [(the bromo-2-methyl phenyl carbinol of 5-)] thiophene (92g is added again in system, 244mmol), temperature control 20 ~ 30 DEG C, add calcium chloride (35.2g to system in batches, 317mmol) finish, temperature control 20 ~ 30 DEG C adds sodium borohydride (12.0g to system in batches, 317mmol), finish and be slowly warming up to 45 ~ 55 DEG C afterwards, insulation reaction 6h, HPLC detection reaction is complete, system is cooled to 0 ~ 10 DEG C, system is instilled cancellation reaction in 1N hydrochloric acid (180ml), dropwising rises again 20 ~ 30 DEG C stirs 2h, by system separatory, organic phase saturated sodium bicarbonate solution (135ml) and saturated brine (135ml) washing, organic phase concentrating under reduced pressure removing tetrahydrofuran (THF), add methylene dichloride (92ml) again, be warming up to 30 ~ 40 DEG C complete molten after, temperature control 30 ~ 40 DEG C drips sherwood oil (276ml), drip to finish and filter after system slow cooling to-5 ~ 0 DEG C of crystallization 2h, solid obtains 2-(4-fluorophenyl)-5 [(the bromo-2-methylphenylmethyl of 5-)] thiophene (81.1g) after drying, HPLC purity 99.5%, yield 92%.
Embodiment 14: add tetrahydrofuran (THF) (460ml) in 1L four-hole bottle, 2-(4-fluorophenyl)-5 [(the bromo-2-methyl phenyl carbinol of 5-)] thiophene (92g is added again in system, 244mmol), temperature control 20 ~ 30 DEG C, add aluminum chloride (42.3g to system in batches, 317mmol) finish, temperature control 20 ~ 30 DEG C adds POTASSIUM BOROHYDRIDE (17.1g to system in batches, 317mmol), finish and be slowly warming up to 45 ~ 55 DEG C afterwards, insulation reaction 3h, HPLC detection reaction is complete, system is cooled to 0 ~ 10 DEG C, system is instilled cancellation reaction in 1N hydrochloric acid (180ml), dropwising rises again 20 ~ 30 DEG C stirs 2h, by system separatory, organic phase saturated sodium bicarbonate solution (135ml) and saturated brine (135ml) washing, organic phase concentrating under reduced pressure removing tetrahydrofuran (THF), add methylene dichloride (92ml) again, be warming up to 30 ~ 40 DEG C complete molten after, temperature control 30 ~ 40 DEG C drips sherwood oil (276ml), drip to finish and filter after system slow cooling to-5 ~ 0 DEG C of crystallization 2h, solid obtains 2-(4-fluorophenyl)-5 [(the bromo-2-methylphenylmethyl of 5-)] thiophene (83.7g) after drying, HPLC purity 99.6%, yield 95%.
Claims (10)
1. the preparation method of the clean intermediate of Yi Zhong Kan Gelie, is characterized in that, comprise the following steps:
One, with to fluorine halogen benzyl and 3-halogen propenal for raw material, under sulphur reagent exists, occur to react as follows,
Obtain 2-to fluorophenyl thiophene;
Two, gained 2-is to fluorophenyl thiophene and 5-halo-2-tolyl aldehyde under n-Butyl Lithium catalysis, occurs to react as follows,
Obtain product 2-(4-fluorophenyl)-5-[(5-halo-2-methyl phenyl carbinol)] thiophene.
2. the preparation method of the clean intermediate of a kind of Kan Gelie according to claim 1, it is characterized in that, step one, by sulphur reagent, is dissolved in organic solvent fluorine halogen benzyl and 3-halogen propenal, temperature control 10 ~ 80 DEG C respectively, add fluorine halogen benzyl solution in sulphur reagent solution, stirring reaction, then add 3-halogen acrolein solution, coreaction 3 ~ 6h, after reacting completely, product obtains 2-to fluorophenyl thiophene through aftertreatment.
3. the preparation method of the clean intermediate of a kind of Kan Gelie according to claim 2, it is characterized in that, step one aftertreatment is: product is cooled to 0 ~ 10 DEG C, adds water, and crystallization, filtration, obtain crude product, then obtains 2-to fluorophenyl thiophene through recrystallization.
4. the preparation method of the clean intermediate of a kind of Kan Gelie according to claim 1; it is characterized in that; step 2, is dissolved in aprotic solvent fluorophenyl thiophene and 5-halo-2-tolyl aldehyde respectively by 2-, and nitrogen protection borehole cooling is to-90 ~-50 DEG C; n-Butyl Lithium is added in fluorophenyl thiophene solution to 2-; stirring reaction, then add 5-halo-2-tolyl aldehyde solution, coreaction 1.5 ~ 3h; after reacting completely, product obtains 2-to fluorophenyl thiophene through aftertreatment.
5. the preparation method of the clean intermediate of a kind of Kan Gelie according to claim 4, it is characterized in that, step 2 aftertreatment is: slowly risen again by product to-20 ~-30 DEG C, add hydrochloric acid, termination reaction, continue to rise again to 20 ~ 30 DEG C, by product separatory, gained organic phase after washing, concentrating under reduced pressure, then adds methyl tertiary butyl ether, is warming up to 50 ~ 60 DEG C, after stirring for some time, slow cooling to 0 ~ 5 DEG C again, crystallization, filtration, gained solid obtains chemical compounds I after drying.
6. the preparation method of the clean intermediate of a kind of Kan Gelie according to claim 1, is characterized in that, described sulphur reagent is the one in potassium sulphide, lithium sulfide, aluminium sulfide, sodium sulphite, nine hydrated sodium sulfides.
7. the preparation method of the clean intermediate of a kind of Kan Gelie according to claim 2, is characterized in that, step one organic solvent is DMF, N-Methyl pyrrolidone, 1,3-dimethyl-imidazolinone, tetrahydrofuran (THF), toluene or methylene dichloride.
8. the preparation method of the clean intermediate of a kind of Kan Gelie according to claim 4, is characterized in that, described aprotic solvent is one or more in tetrahydrofuran (THF), 2-methyltetrahydrofuran, n-butyl ether, ether, toluene.
9. the preparation method of the clean intermediate of a kind of Kan Gelie according to claim 1, is characterized in that, in step one, 3-halogen propenal consumption is 1.0 ~ 2.0 molar equivalents to fluorine halogen benzyl, and sulphur reagent dosage is 1.0 ~ 3.0 molar equivalents to fluorine halogen benzyl.
10. the preparation method of the clean intermediate of a kind of Kan Gelie according to claim 1, is characterized in that, in step 2, n-Butyl Lithium consumption is 1.0 ~ 2.0 molar equivalents of 2-to fluorophenyl thiophene; 5-halo-2-tolyl aldehyde consumption is 1.0 ~ 1.5 molar equivalents of 2-to fluorophenyl thiophene.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2016035042A1 (en) * | 2014-09-05 | 2016-03-10 | Mylan Laboratories Ltd | Process for the preparation of canagliflozin |
| CN114835712A (en) * | 2021-02-01 | 2022-08-02 | 重庆恩联生物科技有限公司 | Synthesis method of epinastine |
| CN115260074A (en) * | 2022-08-02 | 2022-11-01 | 爱斯特（成都）生物制药股份有限公司 | Preparation method of Paxlovid intermediate of oral antiviral drug |
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| WO2016035042A1 (en) * | 2014-09-05 | 2016-03-10 | Mylan Laboratories Ltd | Process for the preparation of canagliflozin |
| CN114835712A (en) * | 2021-02-01 | 2022-08-02 | 重庆恩联生物科技有限公司 | Synthesis method of epinastine |
| CN115260074A (en) * | 2022-08-02 | 2022-11-01 | 爱斯特（成都）生物制药股份有限公司 | Preparation method of Paxlovid intermediate of oral antiviral drug |
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