CN105218329B - Intermediate of liflozin analogues and preparation method of intermediate - Google Patents
Intermediate of liflozin analogues and preparation method of intermediate Download PDFInfo
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- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
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- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
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- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
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Abstract
The invention provides an intermediate of liflozin analogues and a preparation method of the intermediate. The structural formula of the intermediate is shown in the specification. The invention further provides a preparation method of the intermediate of the liflozin analogues. Firstly, 6-methyl-2-oxocycolhexyl-3-alkene methyl formate is prepared; then, 3- bromo-6-methyl salicylate is prepared; 2-methoxyl-3-bromo-6-methylbenzoic acid methyl ester is prepared; 2-methoxyl-3-bromo-6-methyl benzoic acid is prepared; 3-bromo-2-methoxyl-6-methyl-N,O-dimethyl hydroxybenzamide is prepared, (3-bromo-2-methoxyl-6-methyl phenyl) (4'-substituent phenyl) ketone is prepared; (3-bromo-2-methoxyl-methyl phenyl) (4'-substituent phenyl) methane is prepared. Formation of a para-isomer is avoided, and the yield is also higher than 90%.
Description
Technical field
The invention belongs to medicinal chemistry art, is related to a kind of net class compound of row, specifically a kind of net analog of row
Intermediate and preparation method thereof.
Background technology
In recent years, sodium glucose transporter 2 (sodium/glucose cotransporter 2, SGLT2) inhibitor quilt
It is described as the new hope for the treatment of diabetes, SGLT2 inhibitor Main Function renal proximal tubules sodium grape fortune body 2, by suppressing to turn
Fortune body, prevents the glucose for having filtered reabsorption in kidney, glucose to manage and ureter through the nephron, Bellini, most
Discharge by urine, so as to remove urine in excessive glucose, reach purpose (the Minireviews in of control hyperglycaemia
medicinal chemistry(2010):905-913.).At present, the medicine of SGLT2 inhibitor listing has canagliflozin
(Canagliflozin), Dapagliflozin (dapagliflozin) and empagliflozin.
These medicines are all modified on the basis of Dapagliflozin structure, especially to the transformation of C rings than larger, but
The more difficult synthesis of BC ring intermediates to the multiple functional groups of B ring upper bands, limits the diversity of such medicines structure.At present, arrange
The BC rings of net class medicine are mostly the ketone compounds that BC rings are obtained by F-C acylation reactions, Jing triethyl silicanes, borontrifluoride
Borate ether reduction system obtains BC rings (Patent US20020137903, US2004138439), and advantage is simple to operate, route
It is short, but adjacency pair position isomer is formed in F-C acylation reactions, it is more difficult to purify, yield also only has 65% or so.It is therefore desirable to grinding
Study carefully the new preparation method of the BC ring intermediates of the multiple functional groups of B ring upper bands.
The content of the invention
For above-mentioned technical problem of the prior art, the invention provides a kind of net analog intermediate of row and its preparation
Method, the net analog intermediate of described this row and preparation method thereof solve the net class medicine of row of the prior art and are preparing
During yield is low, purification difficult technical problem.
The invention provides a kind of arrange net analog intermediate, its structural formula is as follows：
Wherein, R group is hydrogen, halogen, cyano group, the low alkyl group of 1-6 carbon, 3-10 carbon
The alkenyl of alkoxycycloaikyl, the haloalkyl (needing to describe several C) of 1-6 carbon or 1-6 carbon.
Further, the trifluoro of described R group fluorine, double fluoro-alkyl alkoxyls of 3-10 carbon or 3-10 carbon
Substituted alkyl alkoxyl.
Present invention also offers the preparation method of the above-mentioned net analog intermediate of row, comprises the steps：
1) the step of preparation 6- methyl -2- oxocyclohexyl -3- zinecarboxylic acid methyl esters；Caustic alcohol is dissolved in without watery wine
In essence, methyl acetoacetate is added, be cooled to -2～2 DEG C, be subsequently adding the ethanol solution of E- crotonaldehydes, after addition is finished,
It is stirred overnight, gained yellow solution is cooled to -2～2 DEG C, is then passed through saturation with hydrogen chloride gas, in hydrogen spectrum 2.0 is shown
Hydrogen on the acetyl group at place disappears, and by rectification under vacuum oil product 6- methyl -2- oxocyclohexyl -3- zinecarboxylic acid first is obtained
Ester；Wherein, the mol ratio of caustic alcohol, methyl acetoacetate and E- crotonaldehydes is 1mmol：30～50mmol：25～45mmol；
2) one the step of prepare 3- bromo- 6- cresotinic acids methyl esters；By 6- methyl -2- oxocyclohexyl -3- zinecarboxylic acids
Methyl esters is placed in acetic acid liquid, and after adding bromine, addition to finish at -2～2 DEG C, back flow reaction 10～30 hours is subsequently poured into frozen water
In, extract, wash, be dried, concentrate, obtain the bromo- 6- cresotinic acids methyl esters of khaki solid chemical compound 3- after purification；Wherein,
The material ratio of 6- methyl -2- oxocyclohexyl -3- zinecarboxylic acid methyl esters, acetic acid and bromine is 15～18mol：8～15L：30～
35mol；
3) one the step of prepare 2- methoxyl group -3- bromo- 6 methyl toluates；By the bromo- 6- cresotinic acids methyl esters of 3-
Dissolving in acetone, adds iodomethane, potassium carbonate, is stirred at room temperature 10～20 hours, then filters, and washs filter cake with acetone,
By mother liquid obtained concentration, drying, purifying, bromo- 6 methyl toluates of grease 2- methoxyl group -3- are obtained；Wherein, the bromo- 6- of 3-
The dissolving of cresotinic acid methyl esters, iodomethane, the mol ratio of potassium carbonate are 1mol：3～4mol：3.5～5mol；
4) one the step of prepare 2- methoxyl group -3- bromo- 6- methyl benzoic acids；By the bromo- 6 methylbenzene first of 2- methoxyl group -3-
Sour methyl esters dissolves in ethanol, adds water, NaOH, heating reflux reaction 3～8 hours to be concentrated after reaction completely, then
It is dissolved in water and extracts, gained water mutually adjusts pH=1.0～3.0, then extracts, wash, after salt is washed, be dried, is concentrated to give white solid
The bromo- 6- methyl benzoic acids of body 2- methoxyl group -3-；Wherein, the bromo- 6 methyl toluate dissolvings of 2- methoxyl groups -3-, ethanol, water,
The material ratio of NaOH is 1～1.5mol：8～15L：1.5～2.5L:7～8mol；
5) one the step of prepare the bromo- 2- methoxyl groups -6- methyl-N of 3-, O- dimethyl Oxybenzamides；By 2- methoxyl groups-
The bromo- 6- methyl benzoic acids of 3- are dissolved in dichloromethane, are subsequently adding carbonyl dimidazoles, after addition is finished, are stirred at room temperature
Reaction 10～20 minutes, is subsequently adding triethylamine, adds N, is stirred overnight under O- dimethyl hydroxylamine hydrochlorides, and room temperature anti-
Should, then drying concentrated in vacuo obtains the bromo- 2- methoxyl groups -6- methyl-N of off-white powder 3-, O- dimethyl Oxybenzamides；
Wherein, rubbing the bromo- 6- methyl benzoic acids of 2- methoxyl group -3-, carbonyl dimidazoles, triethylamine and N, O- dimethyl hydroxylamine hydrochloride
You are than being 10mol：10～15mol：14～20mol：10～15mol；
6) the step of preparation (the bromo- 2- methoxyl groups -6- aminomethyl phenyls of 3-) (4 '-substituent phenyl) ketone；3- is bromo-
2- methoxyl group -6- methyl-N, O- dimethyl Oxybenzamides are dissolved in tetrahydrofuran, under nitrogen protection, are added to bromine second
Base benzene and RMgBr obtained in magnesium chips, after addition is finished, are stirred at room temperature 10～20 hours, and reaction is quenched, and extract, and merge organic
Phase, saturated common salt water washing, anhydrous sodium sulfate drying, drying concentrated in vacuo, purifying obtains thick grease (the bromo- 2- of 3-
Methoxyl group -6- aminomethyl phenyls) (4- substituent phenyl) ketone；Wherein, the bromo- 2- methoxyl groups -6- methyl-N of 3-, O- dimethyl oxybenzenes
Formamide, the material ratio of RMgBr be, 10mmol：10～30mmol；
7) the step of preparation (the bromo- 2- methoxyl groups -6- aminomethyl phenyls of 3-) (4 '-substituent phenyl) methane；By (3-
Bromo- 2- methoxyl groups -6- aminomethyl phenyls) (4 '-ethylphenyl) ketone is dissolved in acetonitrile, adds triethyl silicane, and system is cold
But -5～15 DEG C are arrived, BFEE is subsequently adding, keeping temperature is not higher than 20 DEG C, after addition is finished, at 20-25 DEG C instead
Should, the reaction time is 5～9 hours, extraction, and washing merges water phase, then extracts, and after merging organic phase, is washed with saturated common salt
Wash, organic phase concentrate drying, purifying obtains thick light yellow oil (the bromo- 2- methoxyl groups -6- aminomethyl phenyls of 3-) (4 '-substituent
Phenyl) methane；Wherein, (the bromo- 2- methoxyl groups -6- aminomethyl phenyls of 3-) (4 '-ethylphenyl) ketone, acetonitrile, triethyl silicane and
The material ratio of BFEE is 10mol：50～70L：25～30mol：20～25mol.
Further, in step 2) in, extracted using dichloromethane.
Further, in step 4) in, first extracted using dichloromethane, then extracted using ethyl acetate.
Further, in step 6) in, reaction is quenched using saturated ammonium chloride.
Further, in step 6) in, extracted using dichloromethane.
Further, in step 6) in, RMgBr is dissolved in tetrahydrofuran.
Further, in step 7) in, extracted using methyl tertiary butyl ether(MTBE).
The present invention is condensed by crotonaldehyde with methyl acetoacetate, then cyclization obtains compound 3 under chlorination hydrogen catalysis, is changed
Compound 3 and bromine addition, by elimination reaction aromatic cycle compound 4 is constructed, and compound 4 is raw under the effect of methylating reagent iodomethane
Into etherification product 5, the alkaline hydrolysis of compound 5 obtains carboxylic acid compound 6, compound 6 Jing after Weinreb amidatioons with grignard reagent reacting
Ketone compounds 9 are obtained, the Jing reduction reactions of compound 9 obtain alkylate BC rings 10.
Arrange the synthetic route of net analog BC rings
The present invention is compared with prior art, and its technological progress is significant.The present invention adopts F-C mostly with the net class medicine of row
Acylation reaction synthesis ketone 9 is compared, and this route substitutes F-C acylation reactions with Weinreb acid amides and grignard reagent reacting, keeps away
Exempt from the formation of adjacency pair position isomer, while yield is also above 90%.
Specific embodiment
In conjunction with embodiment, the invention will be further described, but the enforcement of the present invention is not limited to that.
The preparation of the 6- methyl -2- oxocyclohexyl -3- zinecarboxylic acid methyl esters of embodiment 1
During sodium silk (0.5g, 21.7mmol) is put into into the absolute alcohol of 150mL, after being completely dissolved, 97.5 grams of second are added
Methyl acetoacetate (97.5g, 840mmol), is cooled to 0 DEG C, then by the ethanol solution of E- crotonaldehydes (52.5g, 749mmol's
E- crotonaldehydes are dissolved in the absolute ethyl alcohol of 50mL), after completion of dropping, it is stirred overnight at room temperature, gained yellow solution is cooled to 0
DEG C, then saturation being passed through with hydrogen chloride gas, hydrogen-based this disappearances on the acetyl group for showing at 2.0 in hydrogen spectrum is logical
Crossing rectification under vacuum can obtain oil product 6- methyl -2- oxocyclohexyl -3- zinecarboxylic acid methyl esters (75g, content 80%, yield
48.7%).It is directly used in the next step.
The preparation of the bromo- 6- cresotinic acids methyl esters of the 3- of embodiment 2
Raw material 6- methyl -2- oxocyclohexyls -3- zinecarboxylic acid methyl esters (2.8g, 16.6mmol) is placed in into the acetic acid of 10mL
In, then bromine (bromine 1.7mL, 33.1mmol are dissolved in the acetic acid of 15mL), after completion of dropping, back flow reaction 24 is added dropwise at 0 DEG C
Hour.In being subsequently poured into frozen water, dichloromethane extraction, washing, saturated common salt washing, anhydrous sodium sulfate drying, after then concentrating,
Jing posts purify (Rf=0.75, PE：EA=10：1) the bromo- 6- cresotinic acids methyl esters of khaki solid chemical compound 3-, is obtained
(0.3g, 1.2mmol, yield 7.4%).1HNMR(CDCl3,300MHz)δ:11.98(s,1H),7.56(d,1H),6.66(d,
1H),4.00(s,3H),2.59(s,3H).
The preparation of bromo- 6 methyl toluates of the 2- methoxyl group -3- of embodiment 3
During the bromo- 6- cresotinic acids methyl esters (0.3g, 1.22mmol) of raw material 3- are dissolved in into the acetone of 10mL, iodine first is added
Alkane (0.6g, 3.61mmol), potassium carbonate (0.4g, 2.90mmol).It is stirred overnight at room temperature.Then filter, and filter is washed with acetone
Cake, mother liquid obtained concentration is dry, cross post purifying (Rf=0.70, PE：EA=10：1) grease 2- methoxyl group -3- bromo- 6, are obtained
Methyl toluate (0.3g, 1.16mmol, yield 95.1%).1HNMR(CDCl3,300MHz)δ:7.47(d,1H),6.86
(d, 1H), 3.94 (s, 3H), 3.88 (s, 3H), 2.28 (s, 3H).
The preparation of the bromo- 6- methyl benzoic acids of the 2- methoxyl group -3- of embodiment 4
During bromo- 6 methyl toluates (0.3g, 1.16mmol) of raw material 2- methoxyl group -3- are dissolved in into the ethanol of 10mL,
The water of addition 2mL, NaOH (0.3g, 7.5mmol), heating reflux reaction 5 hours, raw material reaction is complete.After concentration, add water
After dissolving and being extracted with dichloromethane, gained water phase acid adjustment pH=2, then be extracted with ethyl acetate, wash, saturated common salt water washing
Afterwards, it is dried, concentration can obtain white solid 2- methoxyl group -3- bromo- 6- methyl benzoic acids (0.25g, 1.02mmol, yield
89.7%).1HNMR(CDCl3,300MHz)δ:7.53(d,1H),6.92(d,1H),3.94(s,3H),2.41(s,3H).
The bromo- 2- methoxyl groups -6- methyl-N of the 3- of embodiment 5, the preparation of O- dimethyl Oxybenzamides
The bromo- 6- methyl benzoic acids (2.45g, 10mmol) of raw material 2- methoxyl group -3- are dissolved in into the dichloromethane of 20mL dryings
In alkane, carbonyl dimidazoles (1.78g, 11mmol) are then added portionwise into, after addition is finished, reaction 15 minutes are stirred at room temperature,
Triethylamine (1.5g, 15mmol) is subsequently adding, N is added, under O- dimethyl hydroxylamine hydrochlorides (1.17g, 12mmol) and room temperature
Reaction is stirred overnight, it is then concentrated in vacuo dry, obtain the bromo- 2- methoxyl groups -6- methyl-N of off-white powder 3-, O- dimethyl oxybenzenes
Formamide (2.90g), is directly used in the next step.
The preparation of embodiment 6 (the bromo- 2- methoxyl groups -6- aminomethyl phenyls of 3-) (4 '-ethylphenyl) ketone
The bromo- 2- methoxyl groups -6- methyl-N of upper step crude material 3-, O- dimethyl Oxybenzamides (2.9g) are dissolved in
In the tetrahydrofuran that 20mL is dried, under nitrogen protection, it is added dropwise to bromo ethyl phenenyl and RMgBr tetrahydrofuran obtained in magnesium chips
Solution (12mmol), after completion of dropping, is stirred overnight at room temperature, and then reaction, dichloromethane 30mL × 3 is quenched with saturated ammonium chloride
Extraction, merges organic phase, and saturated common salt water washing, anhydrous sodium sulfate drying is concentrated in vacuo dry, residue Jing posts purifying (Rf=
0.8,PE:EA=10:1) thick grease (the bromo- 2- methoxyl groups -6- aminomethyl phenyls of 3-) (4 '-ethylphenyl) first, is obtained
Ketone (3.1g, 9.3mmol, yield 93.0%).1HNMR(CDCl3,300MHz)δ:7.75(d,2H),7.53(d,1H),7.29(d,
2H), 6.93 (d, 1H), 3.73 (s, 3H), 2.72 (q, 2H), 2.12 (s, 3H), 1.28 (t, 3H).
The preparation of embodiment 7 (the bromo- 2- methoxyl groups -6- aminomethyl phenyls of 3-) (4- ethylphenyls) methane
Raw material (the bromo- 2- methoxyl groups -6- aminomethyl phenyls of 3-) (4 '-ethylphenyl) ketone (3.3g, 10mmol) is dissolved in
In the acetonitrile of 60mL, triethyl silicane (2.9g, 25mmol) is added, system is cooled to into 10 DEG C, be then slowly added dropwise borontrifluoride
Borate ether (2.8g, 20mmol), during dropwise addition, keeping temperature is not higher than 20 DEG C (dripping off within 0.5 hour), completion of dropping
Afterwards, in 20-25 DEG C of reaction, about 7 hours reaction time, the extraction of 60mL methyl tertiary butyl ether(MTBE)s is added, with 40 milliliters × 2 sodium carbonate
Washing, merges water phase, and with the methyl tertiary butyl ether(MTBE) aqueous phase extracted of 40mL, after merging organic phase, with the saturated aqueous common salt of 40mL
Washing, organic phase concentration dry (as far as possible completely dry, it may be considered that after concentration is dry, then with oil pump concentration a period of time of high vacuum).
Then silica column purification (Rf=0.7, PE are passed through：EA=50:1) thick light yellow oil (2.1g, yield 65.8%), is obtained.1HNMR(CDCl3,300MHz)δ:7.37(d,1H),7.10(d,2H),7.02(d,2H),6.86(d,1H),4.09,3.73(s,
3H), 2.62 (q, 2H), 2.19 (s, 3H), 1.22 (t, 3H).
General principle, principal character and the advantages of the present invention of the present invention has been shown and described above.The technology of the industry
Personnel it should be appreciated that the present invention is not restricted to the described embodiments, the simply explanation described in above-described embodiment and specification this
The principle of invention, of the invention without departing from the spirit and scope of the present invention also to have various changes and modifications, these changes
Change and improvement is both fallen within scope of the claimed invention.The claimed scope of the invention by appending claims and its
Equivalent is defined.
Claims (7)
1. the preparation method of the net analog intermediate of a kind of row, it is characterised in that comprise the steps：
1）The step of one preparation 6- methyl -2- oxocyclohexyl -3- zinecarboxylic acid methyl esters；Caustic alcohol is dissolved in into absolute alcohol
In, methyl acetoacetate is added, -2 ~ 2 DEG C are cooled to, the ethanol solution of E- crotonaldehydes is subsequently adding, after addition is finished, stirring
Overnight, gained yellow solution is cooled to -2 ~ 2 DEG C, is then passed through saturation with hydrogen chloride gas, shows at 2.0 in hydrogen spectrum
Hydrogen on acetyl group disappears, and by rectification under vacuum oil product 6- methyl -2- oxocyclohexyl -3- zinecarboxylic acid methyl esters is obtained；Its
In, the mol ratio of caustic alcohol, methyl acetoacetate and E- crotonaldehydes is 1：30~50 ：25~45；
2）One the step of prepare 3- bromo- 6- cresotinic acids methyl esters；By 6- methyl -2- oxocyclohexyl -3- zinecarboxylic acid methyl esters
In being placed in acetic acid liquid, after adding bromine, addition to finish at -2 ~ 2 DEG C, back flow reaction 10 ~ 30 hours, in being subsequently poured into frozen water, extraction
Take, wash, being dried, concentrating, obtaining the bromo- 6- cresotinic acids methyl esters of khaki solid chemical compound 3- after purification；Wherein, 6- first
The material ratio of base -2- oxocyclohexyl -3- zinecarboxylic acid methyl esters, acetic acid and bromine is 15 ~ 18mol：8~15L：30~35mol；
3）One the step of prepare 2- methoxyl group -3- bromo- 6 methyl toluates；By the bromo- 6- cresotinic acids methyl esters dissolvings of 3-
In acetone, iodomethane, potassium carbonate are added, is stirred at room temperature 10 ~ 20 hours, then filtered, and filter cake is washed with acetone, by gained
Mother liquor concentrations, drying, purifying, obtain bromo- 6 methyl toluates of grease 2- methoxyl group -3-；Wherein, the bromo- 6- methyl water of 3-
Poplar acid methyl esters dissolving, iodomethane, the mol ratio of potassium carbonate are 1：3~4 ：3.5~5.0 ；
4）One the step of prepare 2- methoxyl group -3- bromo- 6- methyl benzoic acids；By the bromo- 6 methyl benzoic acid first of 2- methoxyl group -3-
Ester dissolves in ethanol, adds water, NaOH, heating reflux reaction 3 ~ 8 hours to be concentrated after reaction completely, added water
Dissolve and extract, gained water mutually adjusts pH=1.0 ~ 3.0, then extracts, wash, salt is dried after washing, and is concentrated to give white solid 2- methoxies
The bromo- 6- methyl benzoic acids of base -3-；Wherein, the bromo- 6 methyl toluate dissolvings of 2- methoxyl groups -3-, ethanol, water, NaOH
Material ratio be 1 ~ 1.5 mol：8~15L：1.5~2.5L:7~8mol；
5）One the step of prepare the bromo- 2- methoxyl groups -6- methyl-N of 3-, O- dimethyl Oxybenzamides；By 2- methoxyl group -3-
Bromo- 6- methyl benzoic acids are dissolved in dichloromethane, are subsequently adding carbonyl dimidazoles, after addition is finished, are stirred at room temperature anti-
Answer 10 ~ 20 minutes, be subsequently adding triethylamine, add N, O- dimethyl hydroxylamine hydrochlorides, and 10 ~ 20 hours are stirred under room temperature instead
Should, then drying concentrated in vacuo obtains the bromo- 2- methoxyl groups -6- methyl-N of off-white powder 3-, O- dimethyl Oxybenzamides；
Wherein, the bromo- 6- methyl benzoic acids of 2- methoxyl groups -3-, carbonyl dimidazoles, triethylamine and N, O- dimethyl hydroxylamine hydrochloride mole
Than for 10：10~15：14~20：10~15 ；
6）One prepares (the bromo- 2- methoxyl groups -6- aminomethyl phenyls of 3-)（4 '-ethylphenyl）The step of ketone；By the bromo- 2- methoxies of 3-
Base -6- methyl-N, O- dimethyl Oxybenzamides are dissolved in tetrahydrofuran, under nitrogen protection, add to bromo ethyl phenenyl with
RMgBr obtained in magnesium chips, after addition is finished, is stirred overnight at room temperature, and reaction is quenched, and extracts, and merges organic phase, saturated common salt
Water washing, anhydrous sodium sulfate drying, drying concentrated in vacuo, purifying obtains thick grease (the bromo- 2- methoxyl groups -6- first of 3-
Base phenyl)（4 '-ethylphenyl）Ketone；Wherein, the bromo- 2- methoxyl groups -6- methyl-N of 3-, O- dimethyl Oxybenzamides, grignard
The material ratio of reagent is 10 mmol：10~30 mmol；
7）One prepares (the bromo- 2- methoxyl groups -6- aminomethyl phenyls of 3-)（4 '-ethylphenyl）The step of methane；By (the bromo- 2- first of 3-
Epoxide -6- aminomethyl phenyls)（4 '-ethylphenyl）Ketone is dissolved in acetonitrile, adds triethyl silicane, system is cooled to into -5 ~
15 DEG C, BFEE is subsequently adding, keeping temperature is not higher than 20 DEG C, after addition is finished, in 20-25 DEG C of reaction, during reaction
Between be 5 ~ 9 hours, extraction, washing merges water phase, then extracts, and after merging organic phase, uses saturated common salt water washing, and organic phase is dense
Contracting drying, purifying obtains thick light yellow oil (the bromo- 2- methoxyl groups -6- aminomethyl phenyls of 3-)（4 '-ethylphenyl）Methane；Its
In, (the bromo- 2- methoxyl groups -6- aminomethyl phenyls of 3-)（4 '-ethylphenyl）Ketone, acetonitrile, triethyl silicane and BFEE
Material ratio be 10 mol：50~70 L：25~30 mol：20~25 mol.
2. according to a kind of preparation method of the net analog intermediate of row of claim 1, it is characterised in that：In step 2）In, adopt
Dichloromethane is extracted.
3. according to a kind of preparation method of the net analog intermediate of row of claim 1, it is characterised in that：In step 4）In, first adopt
Extracted with dichloromethane, then extracted using ethyl acetate.
4. according to a kind of preparation method of the net analog intermediate of row of claim 1, it is characterised in that：In step 6）In, adopt
Saturated ammonium chloride is quenched reaction.
5. according to a kind of preparation method of the net analog intermediate of row of claim 1, it is characterised in that：In step 6）In, adopt
Dichloromethane is extracted.
6. according to a kind of preparation method of the net analog intermediate of row of claim 1, it is characterised in that：In step 6）In, by lattice
Family name's reagent is dissolved in tetrahydrofuran.
7. according to a kind of preparation method of the net analog intermediate of row of claim 1, it is characterised in that：In step 7）In, adopt
Methyl tertiary butyl ether(MTBE) is extracted.
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| CN201510665756.2A CN105218329B (en) | 2015-10-15 | 2015-10-15 | Intermediate of liflozin analogues and preparation method of intermediate |
| PCT/CN2016/075768 WO2017063327A1 (en) | 2015-10-15 | 2016-03-07 | Novel c-spiro-o-glycoside compound intermediate and preparation method therefor |
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| CN105218329B (en) * | 2015-10-15 | 2017-05-03 | 上海应用技术学院 | Intermediate of liflozin analogues and preparation method of intermediate |
| CN111592515B (en) * | 2020-06-22 | 2022-02-08 | 广州市力鑫药业有限公司 | Preparation method of SGLT2 inhibitor for reducing blood sugar |
| CN113461659B (en) * | 2021-07-19 | 2022-11-11 | 上海应用技术大学 | C-spirocyclic prostaglandin analogue intermediate and preparation method thereof |
| CN115820071B (en) * | 2022-08-08 | 2023-08-18 | 山东奔腾漆业股份有限公司 | Corrosion-resistant coating and preparation method thereof |
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| CN104341444A (en) * | 2014-09-30 | 2015-02-11 | 广西中医药大学 | Empagliflozin silicon-containing aglycone as well as preparation method and application thereof |
| CN104447678A (en) * | 2014-09-02 | 2015-03-25 | 江南大学 | Method for preparing Invokana key intermediate |
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| US6613806B1 (en) * | 1999-01-29 | 2003-09-02 | Basf Corporation | Enhancement of the efficacy of benzoylbenzenes |
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| CN105218329B (en) * | 2015-10-15 | 2017-05-03 | 上海应用技术学院 | Intermediate of liflozin analogues and preparation method of intermediate |
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| EP1023832A1 (en) * | 1999-01-29 | 2000-08-02 | American Cyanamid Company | Aqueous suspension concentrate |
| EP1023834A1 (en) * | 1999-01-29 | 2000-08-02 | American Cyanamid Company | Fungicidal mixtures |
| CN1653075A (en) * | 2002-05-20 | 2005-08-10 | 百时美施贵宝公司 | C-aryl glucoside SGLT2 inhibitors and method |
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| CN104059041A (en) * | 2013-03-20 | 2014-09-24 | 爱康药业有限公司 | Preparation method of antidiabetic dapagliflozin intermediate |
| CN104086379A (en) * | 2014-07-29 | 2014-10-08 | 安徽联创药物化学有限公司 | Method for synthesizing forxiga intermediate |
| CN104447678A (en) * | 2014-09-02 | 2015-03-25 | 江南大学 | Method for preparing Invokana key intermediate |
| CN104341444A (en) * | 2014-09-30 | 2015-02-11 | 广西中医药大学 | Empagliflozin silicon-containing aglycone as well as preparation method and application thereof |
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| CN105218329A (en) | 2016-01-06 |
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