[go: up one dir, main page]

CN104710486A - Method for synthesizing SGLT2 inhibitor drugs - Google Patents

Method for synthesizing SGLT2 inhibitor drugs Download PDF

Info

Publication number
CN104710486A
CN104710486A CN201510158948.4A CN201510158948A CN104710486A CN 104710486 A CN104710486 A CN 104710486A CN 201510158948 A CN201510158948 A CN 201510158948A CN 104710486 A CN104710486 A CN 104710486A
Authority
CN
China
Prior art keywords
compound
organic solvent
reaction
synthetic method
class medicine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN201510158948.4A
Other languages
Chinese (zh)
Inventor
洪健
刘国斌
朱磊
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
An Run Pharmaceutical Technology (suzhou) Co Ltd
Original Assignee
An Run Pharmaceutical Technology (suzhou) Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by An Run Pharmaceutical Technology (suzhou) Co Ltd filed Critical An Run Pharmaceutical Technology (suzhou) Co Ltd
Priority to CN201510158948.4A priority Critical patent/CN104710486A/en
Publication of CN104710486A publication Critical patent/CN104710486A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

The invention provides a method for synthesizing SGLT2 inhibitor drugs. The method comprises the following steps: (a) reacting a compound (1) with n-butyllithium in an organic solvent for 0.5-2 hours, and then dripping an organic solvent dissolved with a compound (2) to react for 1.5-4 hours to obtain a compound (3); or, in a nitrogen atmosphere, reacting the compound (1) with isopropylmagnesium chloride and lithium chloride in the organic solvent for 0.5-1 hour, and then dripping the organic solvent dissolved with the compound (2) to react for 1.5-4 hours to obtain the compound (3); (b) in the organic solvent, carrying out a reduction reaction on the compound (3) to obtain a compound (4); (c) in the organic solvent, carrying out an acetylation reaction on the compound (4), pyridine and acetic anhydride to obtain a compound (5); and (d) carrying out a hydrolysis reaction on the compound (5) to obtain a compound (6), namely the SGLT2 inhibitor drugs. The method provided by the invention is simple in steps, low in cost, high in yield and is suitable for industrial production. The reaction route is as follows in the specification.

Description

A kind of synthetic method arranging clean class medicine
Technical field
The present invention relates to small-molecule chemical pharmaceutical formulating art, relate more specifically to a kind of synthetic method arranging clean class medicine.
Background technology
Sodium relies on glucose cotransporter (SGLTs) and is divided into SGLT1-6, wherein, SGLT2 has heavy body and low-affinity, be responsible for the heavily absorption of 90% glucose, and SGLT1 only completes the heavily absorption of 10% glucose, therefore, the activity of SGLT2 is suppressed, increase kidney to the excretion of glucose, become the novel targets of Development of New Generation antidiabetic medicine.
FDA (Food and Drug Adminstration) (FDA) have approved three clean class medicine listings of row in recent years continuously, they are Da Gelie clean (Dapagliflozin) respectively, Ka Gelie clean (Canagliflozin) and Yi Gelie clean (Empagliflozin), they are all the white II inhibitor (SGLT2) of sodium glucose co-transporter 2, are used for the treatment of type ii diabetes.
Da Gelie clean (Dapagliflozin), chemical name is the chloro-5-of 2-(D-Glucopyranose-1-base)-4 '-ethoxy diphenyl methane.Da Gelie is the white II inhibitor (SGLT2) of a kind of sodium glucose co-transporter 2 of being developed jointly by Bristol-Myer-Squibb company of the U.S. and Sweden AstraZeneca only, in January, 2012 is in the granted listing of European Union, FDA (Food and Drug Adminstration) (FDA) announced on January 8th, 2014, ratified treatment Da Gelie being used for only type ii diabetes.
Ka Gelie is clean, chemical name is (1S)-1,5-dehydrogenation-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl] methyl]-4-aminomethyl phenyl]-D-Glucose alcohol, FDA (Food and Drug Adminstration) (FDA) in March, 2013 approval (Canagliflozin) listing, for improving the glycemic control of type ii diabetes adult patient.Ka Gelie is that (under Johnson & Johnson, Yang Sen (Janssen) drugmaker develops the white II inhibitor (SGLT2) of listing sodium glucose co-transporter 2 by Johnson & Johnson only.
Yi Gelie clean (Empagliflozin), chemical name is (1S)-1, 5-dewaters-1-C-[the chloro-3-of 4-[[4-[[(3S)-tetrahydrochysene-3-furyl] oxygen base] phenyl] methyl] phenyl]-D-Glucose alcohol, on August 3rd, 2014, come (Eli Lilly) diabetes alliance by Boehringer Ingelheim (Boering-Ingelheim) and-Li to develop jointly August 1, in August, 2014 Glucovance Yi Palie clean (Empagliflozin) obtains FDA approval, in conjunction with diet and motion for the treatment of type ii diabetes adult patient, to improve glycemic control.
Arrange clean class pharmacological agent and can improve glycolated hemoglobin (HbA1c), its mechanism of drug action is the SGLT2 by suppressing to be expressed in kidney, reduces renal glucose reabsorption, increases the excretion of glucose in urine, thus reduce plasma glucose levels.In vitro study shows, and arranges clean class medicine remarkable to the restraining effect of SGLT2, has highly selective, be all better than SGLT1; Experimentation on animals shows, they can reduce empty stomach and the postprandial blood sugar of type ii diabetes patient, and significantly can reduce glycolated hemoglobin.
These primary synthetic methods arranging clean class medicine of current bibliographical information are as follows:
1, use Gluconolactone to be starting raw material, after trimethylsilyl chloride process, obtain trimethyl silicon based protection Gluconolactone (2).Then, the chloro-5-bromo-benzoic acid of 2-is starting raw material, through Friedel-Craft acylation reaction, obtains intermediate benzophenone compound, then with triethyl silicane or NaBH 4/ AlCl 3for reduction, intermediate benzophenone is reduced to ditane compounds (1A).Compound (1A) is at-78 DEG C, after n-Butyl Lithium process, obtain its lithium salt solution, at-78 DEG C its lithium salt solution is added drop-wise in the toluene solution of compound (2) and carries out linked reaction, be obtained by reacting methoxy intermediate (7A) with anhydrous methanol/methylsulfonic acid more afterwards.Take triethyl silicane as reductive agent, compound (7A) sloughs methoxyl group, and acetylization reaction subsequently obtains acetic ester mixture, then removes alpha-isomer through crystallization purifying, obtains pure β-isomer (5A).Last hydrolysis reaction must arrive clean (6A) (W.Meng et al, J.Med.Chem., 2008,51,1145 of lattice row; WO2010022313 (2010)).
2, J.Z.Gougoutas report uses compound (1A) to be starting raw material ,-78 DEG C, after n-Butyl Lithium process, obtains its lithium salts.Its lithium salts is added drop-wise to in compound (2) toluene solution, and-78 DEG C are carried out coupling, obtain intermediate (3A).Finally, add anhydrous methanol/hydrochloric acid and obtain intermediate (7A).Intermediate (7A) is not separated, and after adding 2-butyne-Isosorbide-5-Nitrae-glycol, obtains intermediate (8).Reduction demethoxylation, acetylization reaction obtains intermediate (5A), and last hydrolysis reaction must arrive clean (6A) (J.Z.Gougoutas etal, US7919598, (2011)) of lattice row.
3, the report such as B.H.Xu, uses 2-chlorine-4-iodine phenylformic acid to be starting raw material, obtains iodo ditane intermediate (1D) through three-step reaction.Then, and i-PrMgCl/LiCl is obtained by reacting corresponding format reagent, then with compound (2) coupling, methoxylation obtains intermediate (7A).Same method, intermediate (7A) is reduced demethoxylation, and L-PROLINE process must arrive lattice and arrange clean mixture and carry out purifying (B.H.Xu et al, WO2013152476 (2013)).
4.Nomura etc. report the synthetic method that Ka Gelie is clean: same, use trimethyl silicon based protection Gluconolactone (2) to be starting raw material ,-78 DEG C, intermediate (1B), after n-Butyl Lithium process, obtains its lithium salts.Its lithium salts is added drop-wise to in compound (2) toluene solution, carries out coupling.Finally, add anhydrous methanol/methylsulfonic acid and obtain methoxy intermediate (7B).Use triethyl silicane is reductive agent, compound (7B) demethoxylation, obtains clean (6B) (Nomura, S.et al, J.Med.Chem., 2010,53,6355) of Ka Gelie.
People's reports such as 5.Weber are about the clean synthetic method of Yi Palie: use trimethyl silicon based protection Gluconolactone (2) to be starting raw material;-78 DEG C; intermediate (1C) and i-PrMgCl.LiCl are obtained by reacting corresponding format reagent; again with compound (2) coupling, methoxylation obtains intermediate (7C).Finally, use triethyl silicane is reductive agent, compound (7C) demethoxylation, obtains clean (6C) (Weber, D.et al, the US20110237526 (2011) of Yi Gelie; Eckhardt, M.et al, US7772191 (2010)).
So far, the synthetic method defect of bibliographical information is as follows:
(1) bibliographical information so far, after the lithium salts of (-78 DEG C) compound (1A-C) or grignard agent solution and compound (2) carry out linked reaction at low temperatures, add anhydrous methanol process, be converted into methoxy compound (7), then reduce demethoxylated reaction, reaction scheme is longer.
(2) existing method, needs at low temperatures (-78 DEG C), the lithium salt solution of compound (1A, B) is added drop-wise in the toluene/THF solution of compound (2) freezing in advance and carries out linked reaction.Need special very low temperature equipment and condition, the lithium salt solution poor stability of compound (1A, B), easily decomposes, and cause linked reaction productive rate low, side reaction is more, is difficult to carry out amplification and produces.
(3) for and the clean technique of Ka Gelie clean for Da Gelie, literature procedure so far, all at low temperatures (-78 DEG C), by compound (1A, B) lithium salt solution is added drop-wise in compound (2) solution and carries out linked reaction, due to severe reaction conditions, and operational difficulty, equipment requirements is higher, is difficult to carry out suitability for industrialized production.
Consider, at present the synthetic method of report, severe reaction conditions, operational difficulty and loaded down with trivial details, cannot produce in a large number, be not suitable for suitability for industrialized production.
Summary of the invention
For overcoming the problems referred to above of the prior art, the invention provides a kind of synthetic method arranging clean class medicine.The method step is simple, and cost is low, and yield is high, is applicable to suitability for industrialized production.
The technical solution used in the present invention is:
The synthetic method that Da Gelie is clean, comprises the following steps:
A () under nitrogen protection, compound (1) and n-Butyl Lithium stirring reaction 0.5-1 hour at-90 ~-50 DEG C in organic solvent, then the organic solvent being dissolved with compound (2) is dripped under nitrogen protection, and at-90 ~-50 DEG C of stirring reaction 1.5-4 hour, obtain compound (3); Or
Under nitrogen protection, compound (1) and isopropylmagnesium chloride and lithium chloride stirring reaction 0.5-1 hour at-20 ~ 0 DEG C in organic solvent, then the organic solvent being dissolved with compound (2) is dripped under nitrogen protection, and at-20 DEG C ~ 0 DEG C stirring reaction 1.5-4 hour, obtain compound (3);
B () in organic solvent, reduction reaction is there is in the compound (3) obtained in step (a) and reductive agent and boron trifluoride or aluminum chloride at-20 ~ 20 DEG C, obtain compound (4), described reductive agent is selected from triethyl silicane, tripropyl silane, tri isopropyl silane, t-butyldimethyl silane, one or more in diphenylmethylsilane;
C () in organic solvent, under 4-dimethylamino pyridine existent condition, there is acetylization reaction, obtain compound (5) in the compound (4) obtained in step (b) and pyridine and aceticanhydride at 20 ~ 50 DEG C;
Under the effect of alkaline solution, there is hydrolysis reaction in organic solvent at 20 ~ 50 DEG C and obtain target product compound (6), namely arrange clean class medicine in the compound (5) obtained in (d) step (c);
Further, in step (a), organic solvent is selected from one or more in ether, dioxane, methyl tertiary butyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran and benzene, toluene, ethylbenzene, trimethylphenylmethane and dimethylbenzene.
Further, after the reaction of step (a), use acid to carry out aftertreatment, the acid used is selected from one or more in hydrochloric acid, formic acid, acetic acid, trifluoracetic acid, methylsulfonic acid, ethyl sulfonic acid, trifluoromethanesulfonic acid, phosphoric acid and sodium bisulphate solution.
Preferably, in step (a), two step stirring reactions all carry out at-78 DEG C.
Further, in step (b), organic solvent is selected from one or more in methylene dichloride, acetonitrile, chloroform, tetracol phenixin and tetrahydrofuran (THF).
Further, in step (b), the time of reduction reaction is 3-8 hour, preferred 4-7 hour.
Further, in step (c), described organic solvent is selected from methylene dichloride, ethylene dichloride, tetrahydrofuran (THF), 2-methyltetrahydrofuran, ether, n-butyl ether, methyl tertiary butyl ether, one or more in dioxane.
Preferably, the time of acetylization reaction is 1-2 hour.
Further, in step (d), described organic solvent is selected from one or more in tetrahydrofuran (THF), 2-methyltetrahydrofuran, Isosorbide-5-Nitrae-dioxane, methyl alcohol, ethanol and Virahol.
Preferably, in step (d), alkaline solution is selected from one or more in aqueous sodium hydroxide solution, potassium hydroxide aqueous solution, lithium hydroxide aqueous solution and the cesium hydroxide aqueous solution.
More preferably, in step (d), the time of hydrolysis reaction is 10-24 hour.
Following innovation has been carried out: (1) linked reaction product (3) is reduced after being converted into methoxy compound (7) again in the present invention; linked reaction product (3) directly can be reduced into intermediate (4), then obtains arranging clean class medicine through acetylize and hydrolysis two-step reaction.(2) lithium salts or the grignard agent solution that at low temperatures (-78 DEG C), compound 2 are directly added drop-wise to compound (1A-C) carry out linked reaction.
The raw material used in method of the present invention can be bought by commercial sources, also can prepare according to the conventional chemical synthetic method of this area.Present invention also provides the preparation method of compound (2) and compound (5).
Compared with prior art, the present invention has the following advantages: the invention provides a kind of synthetic method arranging clean class medicine, the method the present invention is based on shortening reactions steps, simplify the operation method, key point is: (1) material order of addition: directly compound (2) solution is added drop-wise in the lithium salt solution of compound (5), carry out linked reaction under low temperature, after compound (2) and (5) need not being cooled to-78 DEG C, carry out linked reaction more simultaneously.(2) reactions steps is shortened: linked reaction product 3 without the need to being converted further as carrying out reduction reaction again after methoxy compound (7), but being directly reduced and being converted into intermediate 4.Method processing step of the present invention is simple, controllability strong, thus do not need loaded down with trivial details reaction and last handling process, and yield is high, cost is low, product purity is high, is applicable to suitability for industrialized production.
Embodiment
Below in conjunction with specific embodiment, the present invention is further elaborated.
Embodiment 1
The preparation of compound (1A) and compound (2) is with reference to reference literature US7919598 (2011).
Prepare compound (3A)
Example 1-1:
By compound (1A) (18g; 0.055mol) be dissolved in tetrahydrofuran (THF) and toluene Mixed Solvent (1:2; 150mL) lead in the there-necked flask of nitrogen protection; be cooled to-90 DEG C; drip the hexane solution (40mL of the n-Butyl Lithium of 2.0M; 0.08mol), 30min is stirred.Then under nitrogen protection, the toluene solution (50mL) of compound (2) (28.0g, 0.06mol) is dripped.After equality of temperature stirs 2 hours, add hydrochloric acid and be adjusted to pH 4.0-6.0, separate organic phase, aqueous phase is extracted with ethyl acetate, merge organic phase, with saturated common salt washing, filter after anhydrous sodium sulfate drying, filtrate concentrated 18.7g yellow oil (productive rate 80%, product is the mixture (α/β=15/85) of α-and β-isomer.
The HNMR data of main component β-isomer are as follows:
1H-NMR(400MHz,CD 3OD,400MHz,δppm)：1.34(t,J＝6.8Hz,3H),3.04(m,1H),3.38(d,J＝8.6Hz,1H),3.50(m,1H),3.72(t,J＝9.0Hz,1H),3.76(dd,J＝5.0Hz and 11.2Hz,1H),3.85(dd,J＝2.0 and 11.6Hz,1H),3.92(d,J＝14.6Hz,1H),4.08(d,J＝14.6Hz,1H),6.75(d,J＝8.4Hz,2H),7.00(d,J＝8.4Hz,2H),7.30(d,J＝8.4Hz,1H),7.40(dd,J＝2.2 and 8.2Hz,1H),7.50(d,J＝2.2Hz,1H)。
Example 1-2:
By compound (1A) (18g; 0.055mol) be dissolved in 2-methyltetrahydrofuran and benzene mixed solvent (1:1; 120mL) lead in the there-necked flask of nitrogen protection; be cooled to-78 DEG C; drip the hexane solution (40mL of the n-Butyl Lithium of 2.0M; 0.08mol), stir 1.5 hours.Then under nitrogen protection, the benzole soln (50mL) of compound (2) (28.0g, 0.06mol) is dripped.After equality of temperature stirs 3 hours, add acetic acid and be adjusted to pH4.0-6.0, separate organic phase, aqueous phase is extracted with ethyl acetate, merge organic phase, with saturated common salt washing, filter after anhydrous sodium sulfate drying, filtrate concentrated 18.0g yellow oil (productive rate 77%, product is the mixture (α/β=16/84) of α-and β-isomer.
Example 1-3:
By compound (1A) (18g; 0.055mol) be dissolved in ether and ethylbenzene mixed solvent (1:1; 140mL) lead in the there-necked flask of nitrogen protection; be cooled to-60 DEG C; drip the hexane solution (40mL of the n-Butyl Lithium of 2.0M; 0.08mol), stir 1 hour.Then under nitrogen protection, the ethylbenzene solution (60mL) of compound 2 (28.0g, 0.06mol) is dripped.After equality of temperature stirs 4 hours, add formic acid and be adjusted to pH4.0-6.0, separate organic phase, aqueous phase is extracted with ethyl acetate, merge organic phase, with saturated common salt washing, filter after anhydrous sodium sulfate drying, filtrate concentrated 17.4g yellow oil (productive rate 74%, product is the mixture (α/β=15/85) of α-and β-isomer.
Example 1-4:
By compound (1A) (18g; 0.055mol) be dissolved in dioxane and trimethylphenylmethane mixed solvent (1:2; 160mL) lead in the there-necked flask of nitrogen protection; be cooled to-50 DEG C; drip the hexane solution (40mL of the n-Butyl Lithium of 2.0M; 0.08mol), 45min is stirred.Then under nitrogen protection, the trimethylphenylmethane solution (60mL) of compound (2) (28.0g, 0.06mol) is dripped.After equality of temperature stirs 3 hours, add methylsulfonic acid and be adjusted to pH4.0-6.0, separate organic phase, aqueous phase is extracted with ethyl acetate, merge organic phase, with saturated common salt washing, filter after anhydrous sodium sulfate drying, filtrate concentrated 17.0g yellow oil (productive rate 73%, product is the mixture (α/β=17/83) of α-and β-isomer.
Example 1-5:
By compound (1A) (18g; 0.055mol) be dissolved in methyl tertiary butyl ether and toluene Mixed Solvent (1:1; 160mL) lead in the there-necked flask of nitrogen protection; be cooled to-65 DEG C; drip the hexane solution (40mL of the n-Butyl Lithium of 2.0M; 0.08mol), stir 1 hour.Then under nitrogen protection, the toluene solution (60mL) of compound (2) (28.0g, 0.06mol) is dripped.After equality of temperature stirs 3 hours, add ethyl sulfonic acid and be adjusted to pH4.0-6.0, separate organic phase, aqueous phase is extracted with ethyl acetate, merge organic phase, with saturated common salt washing, filter after anhydrous sodium sulfate drying, filtrate concentrated 16.5g yellow oil (productive rate 70.8%, product is the mixture (α/β=19/81) of α-and β-isomer.
Example 1-6:
By compound (1A) (18g; 0.055mol) be dissolved in methyl tertiary butyl ether and toluene Mixed Solvent (1:1; 160mL) lead in the there-necked flask of nitrogen protection; be cooled to-50 DEG C; drip the hexane solution (40mL of the n-Butyl Lithium of 2.0M; 0.08mol), 45min is stirred.Then under nitrogen protection, the toluene solution (60mL) of compound (2) (28.0g, 0.06mol) is dripped.After equality of temperature stirs 4 hours, add trifluoromethanesulfonic acid and be adjusted to pH4.0-6.0, separate organic phase, aqueous phase is extracted with ethyl acetate, merge organic phase, with saturated common salt washing, filter after anhydrous sodium sulfate drying, filtrate concentrated 16.0g yellow oil (productive rate 70%, product is the mixture (α/β=20/80) of α-and β-isomer.
Example 1-7:
By compound (1A) (18g; 0.055mol) be dissolved in ether and toluene Mixed Solvent (1:1; 160mL) lead in the there-necked flask of nitrogen protection; be cooled to-60 DEG C; drip the hexane solution (40mL of the n-Butyl Lithium of 2.0M; 0.08mol), stir 1 hour.Then under nitrogen protection, the toluene solution (80mL) of compound (2) (28.0g, 0.06mol) is dripped.After equality of temperature stirs 4 hours, add sodium bisulphate solution and be adjusted to pH4.0-6.0, separate organic phase, aqueous phase is extracted with ethyl acetate, merge organic phase, with saturated common salt washing, filter after anhydrous sodium sulfate drying, filtrate concentrated 15.2g yellow oil (productive rate 65.2%, product is the mixture (α/β=17/83) of α-and β-isomer.
Equally, also trifluoroacetic acid or phosphoric acid can be used during the aftertreatment of this step.
Embodiment 2
Synthetic compound (5A)
Example 2-1:
By compound (3A) (12g, 0.027mol) be dissolved in methylene dichloride and acetonitrile mixed solvent (1:1,90mL), be cooled to-10 DEG C and add triethyl silicane (5.8g, 0.05mol), then boron trifluoride ether solution (4mL, 0.03mol) is slowly dripped.React 3 hours, add saturated sodium bicarbonate solution (40mL), remove organic solvent under reduced pressure.Add ethyl acetate and water in residuum, leave standstill after stirring, separate organic phase, aqueous phase is extracted with ethyl acetate.Merge organic phase, use water and saturated common salt water washing successively, concentrated after anhydrous sodium sulfate drying, residuum is dissolved in methylene dichloride (50mL), add anhydrous pyridine (16mL, 0.20mol), aceticanhydride (20g, 0.2mol) and 4-dimethylamino pyridine (0.1g, 1mmol), stirring at normal temperature 1h.TLC detects, and raw material disappears.Water (40mL) is added, dichloromethane extraction under water bath condition.Merge organic phase, with 1N hydrochloric acid and saturated common salt water washing.Filter after anhydrous sodium sulfate drying, with ethyl alcohol recrystallization twice after filtrate is concentrated, obtain white solid 9.5g (two step total recovery 58%, HPLC purity >98%).
1H-NMR(400MHz,CDCl 3，400MHz，δppm)：1.40(t,J＝6.8Hz,3H),1.71(s,3H),1.99(s,3H),2.05(s,3H),2.08(s,3H),3.78-3.80(m,1H),3.90-4.01(m,4H),4.14(dd,J1＝2.4Hz,J2＝12.4Hz,1H),4.24～4.6(dd,J1＝8.4Hz,J2＝12.4Hz,1H),4.31(d,J＝9.6Hz,2H),5.05(t,J＝9.6Hz,1H),5.20(t,J＝9.6Hz,1H),5.28(t,J＝9.2Hz,1H),6.82(d,J＝8.4Hz,2H),7.05(d,J＝8.4Hz,2H),7.18(dd,J1＝2.0Hz,J2＝8.4Hz,1H),7.35(d,J＝8.0Hz,2H)。
Example 2-2:
By compound (3A) (12g, 0.027mol) be dissolved in methylene dichloride and acetonitrile mixed solvent (1:2,90mL), be cooled to-10 DEG C and add tri isopropyl silane (7.9g, 0.05mol), then slowly boron trifluoride acetonitrile solution (4mL, 0.03mol) is dripped.React 4 hours, add saturated sodium bicarbonate solution (40mL), remove organic solvent under reduced pressure, add ethyl acetate and water in residuum, leave standstill after stirring, separate organic phase, aqueous phase is extracted with ethyl acetate.Merge organic phase, use water and saturated common salt water washing successively, concentrated after anhydrous sodium sulfate drying, residuum is dissolved in dichloromethane ethane (50mL), add anhydrous pyridine (16mL, 0.20mol), aceticanhydride (20g, 0.2mol) and 4-dimethylamino pyridine (0.1g, 1mmol), stirring at normal temperature 1.5h.TLC detects, and raw material disappears.Water (40mL) is added, dichloromethane extraction under water bath condition.Merge organic phase, with 1N hydrochloric acid and saturated common salt water washing.Filter after anhydrous sodium sulfate drying, with ethyl alcohol recrystallization twice after filtrate is concentrated, obtain white solid 9.8g (two step total recovery 59%, HPLC purity >98%).
Example 2-3:
By compound (3A) (12g, 0.027mol) be dissolved in methylene dichloride and acetonitrile mixed solvent (1:3,90mL), be cooled to-10 DEG C, add t-butyldimethyl silane (5.8,0.05mol), then slowly boron trifluoride tetrahydrofuran solution (4mL, 0.03mol) is dripped.React 6 hours, add saturated sodium bicarbonate solution (40mL), remove organic solvent under reduced pressure, add ethyl acetate and water in residuum, leave standstill after stirring, separate organic phase, aqueous phase is extracted with ethyl acetate.Merge organic phase, use water and saturated common salt water washing successively, concentrated after anhydrous sodium sulfate drying, residuum is dissolved in tetrahydrofuran (THF) (50mL), add anhydrous pyridine (16mL, 0.20mol), aceticanhydride (20g, 0.2mol) and 4-dimethylamino pyridine (0.1g, 1mmol), stirring at normal temperature 2h.TLC detects, and raw material disappears.Water (40mL) is added, dichloromethane extraction under water bath condition.Merge organic phase, with 1N hydrochloric acid and saturated common salt water washing.Filter after anhydrous sodium sulfate drying, with ethyl alcohol recrystallization twice after filtrate is concentrated, obtain white solid 9.2g (two step total recovery 56%, HPLC purity >98%).
Example 2-4:
By compound (3A) (12g, 0.027mol) be dissolved in methylene dichloride and acetonitrile mixed solvent (1:2,90mL), be cooled to-10 DEG C, add tripropyl silane (7.9g, 0.05mol), then slowly boron trifluoride acetonitrile solution (4mL, 0.03mol) is dripped.React 7 hours, add saturated sodium bicarbonate solution (40mL), remove organic solvent under reduced pressure, add ethyl acetate and water in residuum, leave standstill after stirring, separate organic phase, aqueous phase is extracted with ethyl acetate.Merge organic phase, use water and saturated common salt water washing successively, concentrated after anhydrous sodium sulfate drying, residuum is dissolved in methylene dichloride methyl tertiary butyl ether (50mL), add anhydrous pyridine (16mL, 0.20mol), aceticanhydride (20g, 0.2mol) and 4-dimethylamino pyridine (0.1g, 1mmol), stirring at normal temperature 2h.TLC detects, and raw material disappears.Water (40mL) is added, dichloromethane extraction under water bath condition.Merge organic phase, with 1N hydrochloric acid and saturated common salt water washing.Filter after anhydrous sodium sulfate drying, with ethyl alcohol recrystallization twice after filtrate is concentrated, obtain white solid 9.0g (two step total recovery 54%, HPLC purity >98%).
Example 2-5:
By compound (3A) (12g, 0.027mol) be dissolved in methylene dichloride and acetonitrile mixed solvent (1:2,90mL), be cooled to-10 DEG C, add diphenylmethylsilane (9.9g, 0.05mol), then slowly boron trifluoride acetonitrile solution (4mL, 0.03mol) is dripped.React 8 hours, add saturated sodium bicarbonate solution (40mL), remove organic solvent under reduced pressure, add ethyl acetate and water in residuum, leave standstill after stirring, separate organic phase, aqueous phase is extracted with ethyl acetate.Merge organic phase, use water and saturated common salt water washing successively, concentrated after anhydrous sodium sulfate drying, residuum is dissolved in dioxane (50mL), add anhydrous pyridine (16mL, 0.20mol), aceticanhydride (19g, 0.2mol) and 4-dimethylamino pyridine (0.1g, 1mmol), stirring at normal temperature 1.5h.TLC detects, and raw material disappears.Water (40mL) is added, dichloromethane extraction under water bath condition.Merge organic phase, with 1N hydrochloric acid and saturated common salt water washing.Filter after anhydrous sodium sulfate drying, with ethyl alcohol recrystallization twice after filtrate is concentrated, obtain white solid 8.8g (two step total recovery 52.7%, HPLC purity >98%).
Embodiment 3
Prepare compound (6A)
Example 3-1:
Compound (5A) (4.5g, 7.8mmol), hydronium(ion) Lithium Oxide 98min (0.4g, 9.8mmol) and a tetrahydrofuran (THF), methyl alcohol, water mixed solvent (2:3:1,78mL) adds in 100mL there-necked flask successively.Stirring at normal temperature 10 hours.TLC detects, and raw material disappears.Concentrated, residuum is dissolved in ethyl acetate (65mL), use successively saturated brine, 5% aqueous potassium hydrogen sulfate (65mL) and saturated common salt water washing, filter after anhydrous sodium sulfate drying.Concentrated filtrate obtains pale yellow viscous liquid 3.0g (yield 94%, HPLC purity=99.5%).
1H-NMR(DMSO-d6,400MHz，δppm):1.29(t,J＝7.0Hz,3H),3.12～3.50(m,4H),3.73(d,J＝10.5,1H),3.94～4.06(m,6H),6.83(d,J＝8.6Hz,2H),7.11(d,J＝8.6Hz,2H),7.23(dd,J1＝1.7Hz,J2＝8.2Hz,1H),7.32(d,J＝1.7Hz,1H),7.37(d,J＝8.2Hz,1H)。
Example 3-2:
Compound (5A) (4.5g, 7.8mmol), sodium hydroxide (0.4g, 9.8mmol) and 2-methyltetrahydrofuran, ethanol, water mixed solvent (2:3:1,78mL) adds in 100mL there-necked flask successively.Stirring at normal temperature 15 hours.TLC detects, and raw material disappears.Concentrated, residuum is dissolved in ethyl acetate (60mL), use successively saturated brine, 5% aqueous potassium hydrogen sulfate (65mL) and saturated common salt water washing, filter after anhydrous sodium sulfate drying.Concentrated filtrate obtains pale yellow viscous liquid 3.1g (yield 97%, HPLC purity=99.2%).
Example 3-3:
Compound (5A) (4.5g, 7.8mmol), potassium hydroxide (0.4g, 9.8mmol) and Isosorbide-5-Nitrae-dioxane, methyl alcohol, water mixed solvent (2:3:1,78mL) adds in 100mL there-necked flask successively.Stirring at normal temperature 20 hours.TLC detects, and raw material disappears.Concentrated, residuum is dissolved in ethyl acetate (60mL), use successively saturated brine, 5% aqueous potassium hydrogen sulfate (65mL) and saturated common salt water washing, filter after anhydrous sodium sulfate drying.Concentrated filtrate obtains pale yellow viscous liquid 2.9g (yield 90.7%, HPLC purity=99.2%).
Example 3-4:
Compound (5A) (4.5g, 7.8mmol), cesium hydroxide (0.4g, 9.8mmol) and Isosorbide-5-Nitrae-dioxane, Virahol, water mixed solvent (2:3:1,78mL) adds in 100mL there-necked flask successively.Stirring at normal temperature 24 hours.TLC detects, and raw material disappears.Concentrated, residuum is dissolved in ethyl acetate (60mL), use successively saturated brine, 5% aqueous potassium hydrogen sulfate (65mL) and saturated common salt water washing, filter after anhydrous sodium sulfate drying.Concentrated filtrate obtains pale yellow viscous liquid 3.1g (yield 97%, HPLC purity=99.2%).
Embodiment 4
Synthetic compound (3B)
Example 4-1:
By compound (1B), (reference literature synthesizes: Nomura; S.et al, J.Med.Chem., 2010; 53; 6355) (28.9g, 0.080mol) is dissolved in the there-necked flask of tetrahydrofuran (THF) and the logical nitrogen protection of toluene Mixed Solvent (1:1,350mL); be cooled to-90 DEG C; drip the hexane solution (40mL, 0.080mol) of the n-Butyl Lithium of 2.0M, stir 30min.Then under nitrogen protection, the toluene solution (120mL) of compound (2) (34.0g, 0.0728mol) is dripped.After equality of temperature stirs two hours, add hydrochloric acid and be adjusted to pH4.0-6.0, separate organic phase, aqueous phase is extracted with ethyl acetate, merge organic phase, with saturated common salt washing, filter after anhydrous sodium sulfate drying, filtrate concentrated 27.2g yellow oil (productive rate 82%, product is the mixture (α/β=16/84) of α-and β-isomer.
The HNMR data of main component β-isomer are as follows
1H-NMR(DMSO-d6,400MHz，δppm):2.29(s,3H),2.90～3.72(m,6H),4.13(d,J＝15.5Hz,2H),4.50～4.96(m,5H),6.78(d,J＝3.6Hz,1H),7.14(d,J＝8.2Hz,1H),7.20(d,J＝8.2Hz,2H),7.26(d,J＝3.7Hz,1H),7.32(dd,J＝1.6and 8.2Hz,1H),7.42(dd,J＝1.6 and 8.2Hz,1H),7.58(m,2H)。
Example 4-2:
By compound (1B) (28.9g; 0.080mol) be dissolved in 2-methyltetrahydrofuran and benzene mixed solvent (1:1; 300mL) lead in the there-necked flask of nitrogen protection; be cooled to-78 DEG C; drip the hexane solution (40mL of the n-Butyl Lithium of 2.0M; 0.08mol), 45min is stirred.Then under nitrogen protection, the benzole soln (150mL) of compound (2) (34.0g, 0.0728mol) is dripped.After equality of temperature stirs two hours, add hydrochloric acid and be adjusted to pH 4.0-6.0, separate organic phase, aqueous phase is extracted with ethyl acetate, merge organic phase, with saturated common salt washing, filter after anhydrous sodium sulfate drying, filtrate concentrated 25.0g yellow oil (productive rate 75%, product is the mixture (α/β=19/81) of α-and β-isomer.
Example 4-3:
By compound (1B) (28.9g; 0.080mol) be dissolved in ether and ethylbenzene mixed solvent (1:1; 250mL) lead in the there-necked flask of nitrogen protection; be cooled to-60 DEG C; drip the hexane solution (40mL of the n-Butyl Lithium of 2.0M; 0.08mol), stir 1 hour.Then under nitrogen protection, the ethylbenzene solution (160mL) of compound 2 (34.0g, 0.0728mol) is dripped.After equality of temperature stirs two hours, add hydrochloric acid and be adjusted to pH 4.0-6.0, separate organic phase, aqueous phase is extracted with ethyl acetate, merge organic phase, with saturated common salt washing, filter after anhydrous sodium sulfate drying, filtrate concentrated 27.4g yellow oil (productive rate 81%, product is the mixture (α/β=15/85) of α-and β-isomer.
Example 4-4:
By compound (1B) (28.9g; 0.080mol) be dissolved in dioxane and trimethylphenylmethane mixed solvent (1:1; 260mL) lead in the there-necked flask of nitrogen protection; be cooled to-50 DEG C; drip the hexane solution (40mL of the n-Butyl Lithium of 2.0M; 0.08mol), stir 2 hours.Then under nitrogen protection, the trimethylphenylmethane solution (160mL) of compound 2 (34.0g, 0.0728mol) is dripped.After equality of temperature stirs two hours, add hydrochloric acid and be adjusted to pH 4.0-6.0, separate organic phase, aqueous phase is extracted with ethyl acetate, merge organic phase, with saturated common salt washing, filter after anhydrous sodium sulfate drying, filtrate concentrated 26.0g yellow oil (productive rate 76.9%, product is the mixture (α/β=17/83) of α-and β-isomer.
Embodiment 5
Synthetic compound (4B)
Example 5-1
By compound (3B) (12.5g, 0.027mol) be dissolved in methylene dichloride and acetonitrile mixed solvent (1:1,120mL), be cooled to-10 DEG C and add triethyl silicane (5.8g, 0.05mol), then boron trifluoride ether solution (4mL, 0.03mol) is slowly dripped.React 6 hours, add saturated sodium bicarbonate solution (40mL), remove solvent under reduced pressure, add ethyl acetate and water in residuum, leave standstill after stirring, separate organic phase, aqueous phase is extracted with ethyl acetate.Merge organic phase, use water and saturated common salt water washing successively, concentrated after anhydrous sodium sulfate drying, residuum is dissolved in ethyl acetate (60mL), then ether (120ml) is added, in water (1.5ml), crystallization obtains clear crystal 6g (yield 50%, HPLC purity >98%).
1H-NMR(DMSO-d6,400MHz,δppm):2.28(s,3H),3.10～3.30(m,4H),3.40-3.44(m,1H),3.60-3.66(m,1H),4.00(d,J＝9.2Hz,1H),4.12(d,J＝15.6Hz,2H),4.40～4.90(m,4H),6.80(d,J＝3.6Hz,1H),7.10-7.26(m,5H),7.30(d,J＝3.5Hz,1H),7.59(dd,J＝5.6 and 8.8Hz,2H)。
Example 5-2
By compound (3B) (12.5g, 0.027mol) be dissolved in methylene dichloride (120mL), be cooled to-10 DEG C and add tri isopropyl silane (7.9g, 0.05mol), then boron trifluoride ether solution (4mL, 0.03mol) is slowly dripped.React 4 hours, add saturated sodium bicarbonate solution (40mL), remove solvent under reduced pressure, add ethyl acetate and water in residuum, leave standstill after stirring, separate organic phase, aqueous phase is extracted with ethyl acetate.Merge organic phase, use water and saturated common salt water washing successively, concentrated after anhydrous sodium sulfate drying, residuum is dissolved in ethyl acetate (60mL), then ether (120ml) is added, in water (1.5ml), crystallization obtains clear crystal 6.5g (yield 55%, HPLC purity >98%).
Example 5-3
By compound (3B) (12.5g, 0.027mol) be dissolved in methylene dichloride (120mL), be cooled to-10 DEG C and add tripropyl silane (7.9g, 0.05mol), then boron trifluoride ether solution (4mL, 0.03mol) is slowly dripped.React 8 hours, add saturated sodium bicarbonate solution (40mL), remove organic solvent under reduced pressure, add ethyl acetate and water in residuum, leave standstill after stirring, separate organic phase, aqueous phase is extracted with ethyl acetate.Merge organic phase, use water and saturated common salt water washing successively, concentrated after anhydrous sodium sulfate drying, residuum is dissolved in ethyl acetate (60mL), then ether (120ml) is added, in water (1.5ml), crystallization obtains clear crystal 6.2g (yield 51.7%, HPLC purity >98%).
Embodiment 6
Synthetic compound 3C
Example 6-1:
By compound (1C), (reference literature synthesizes: Weber; D.et al; US20110237526 (2011)) (26.7g; 0.064mol) be dissolved in the there-necked flask of the logical nitrogen protection of tetrahydrofuran (THF) (200mL); be cooled to-20 DEG C, drip 14wt% isopropylmagnesium chloride/lithium chloride tetrahydrofuran solution (i-PrMgCl/LiCl=1/1 (mol/mol), 50g; 0.067mol), 30min is stirred.Then under nitrogen protection, the tetrahydrofuran solution (100mL) of compound (2) (31.7g, 0.068mol) is dripped.-20 DEG C are stirred after 1.5 hours, add hydrochloric acid and be adjusted to pH 4.0-5.0, separate organic phase, aqueous phase is extracted with ethyl acetate, merge organic phase, with saturated common salt washing, filter after anhydrous sodium sulfate drying, filtrate concentrated 25.2g yellow oil (productive rate 84.2%, product is the mixture (α/β=18/82) of α-and β-isomer.
The HNMR data of main component β-isomer are as follows:
1H-NMR(400MHz,CD 3OD,400MHz,δppm)：1.86-1.96(m,1H),2.15-2.20(m,1H),3.05-3.34(m,4H),3.50-3.56(m,1H),3.72-3.82(m,5H),3.92-4.02(m,3H),4.45(s,1H),4.82(1H,d,J＝4Hz),4.88-5.01(m,4H),6.74(d,J＝8.4Hz,2H),7.00(d,J＝8.4Hz,2H),7.32(d,J＝8.4Hz,1H),7.42(dd,J＝2.2and8.2Hz,1H),7.54(d,J＝2.2Hz,1H)。
Example 6-2:
By compound (1C) (26.7g; 0.064mol) be dissolved in the there-necked flask of the logical nitrogen protection of 2-methyltetrahydrofuran (200mL); be cooled to 0 DEG C; drip 14wt% isopropylmagnesium chloride/lithium chloride tetrahydrofuran solution (i-PrMgCl/LiCl=1/1 (mol/mol); 50g; 0.067mol), stir 1 hour.Then under nitrogen protection, the 2-methyltetrahydrofuran solution (100mL) of compound (2) (31.7g, 0.068mol) is dripped.0 DEG C is stirred after 4 hours, add hydrochloric acid and be adjusted to pH 4.0-5.0, separate organic phase, aqueous phase is extracted with ethyl acetate, merge organic phase, with saturated common salt washing, filter after anhydrous sodium sulfate drying, filtrate concentrated 23.8g yellow oil (productive rate 79.6%, product is the mixture (α/β=16/84) of α-and β-isomer.
Embodiment 7
Synthetic compound (4C)
Example 7-1
At 20 DEG C, triethyl silicane (5.8g, 0.05mol), aluminum chloride (4.64g, 0.035mol) is dissolved in methylene dichloride and acetonitrile mixed solvent (1:1,100mL).Under stirring, compound (3C) (8.1g, 0.027mol) be dissolved in methylene dichloride and acetonitrile mixed solvent (1:1,50mL), in the triethyl silicane/aluminum chloride methylene dichloride being then added drop-wise to above-mentioned preparation and acetonitrile mixed solvent.At 20 DEG C, react 3 hours, then add water (100mL), and toluene extracts.Merge organic phase, use water and saturated common salt water washing successively, concentrated after anhydrous sodium sulfate drying, add acetonitrile (10ml), water (140ml), stir at 20 DEG C.Then be cooled to 5 DEG C, crystallization obtains clear crystal 6.6g (yield 54%, HPLC purity >98%).
1H-NMR(400MHz,CD 3OD,400MHz,δppm)：1.83-1.94(m,1H),2.14-2.22(m,1H),3.02-3.36(m,3H),3.52-3.54(m,1H),3.70-3.80(m,5H),3.90-4.00(m,3H),4.44(s,1H),4.80(1H,d,J＝4Hz),4.86-5.00(m,4H),6.72(d,J＝8.4Hz,2H),7.02(d,J＝8.4Hz,2H),7.34(d,J＝8.4Hz,1H),7.40(dd,J＝2.2and8.2Hz,1H),7.56(d,J＝2.2Hz,1H)。
Above specific embodiment of the present invention is illustrated; but protection content of the present invention is not only limited to above embodiment; in art of the present invention, the usual knowledge of a GPRS, just can carry out diversified change within the scope of its technology main idea.

Claims (9)

1. arrange a synthetic method for clean class medicine, it is characterized in that, comprise the following steps:
A () under nitrogen protection, compound (1) and n-Butyl Lithium stirring reaction 0.5-1 hour at-90 ~-50 DEG C in organic solvent, then the organic solvent being dissolved with compound (2) is dripped under nitrogen protection, and at-90 ~-50 DEG C of stirring reaction 1.5-4 hour, obtain compound (3); Or
Under nitrogen protection, compound (1) and isopropylmagnesium chloride and lithium chloride stirring reaction 0.5-1 hour at-20 ~ 0 DEG C in organic solvent, then the organic solvent being dissolved with compound (2) is dripped under nitrogen protection, and at-20 DEG C ~ 0 DEG C stirring reaction 1.5-4 hour, obtain compound (3);
B () in organic solvent, reduction reaction is there is in the compound (3) obtained in step (a) and reductive agent and boron trifluoride or aluminum chloride at-20-20 DEG C, obtain compound (4), described reductive agent is selected from triethyl silicane, tripropyl silane, tri isopropyl silane, t-butyldimethyl silane, one or more in diphenylmethylsilane;
C () in organic solvent, under 4-dimethylamino pyridine existent condition, there is acetylization reaction, obtain compound (5) in the compound (4) obtained in step (b) and pyridine and aceticanhydride at 20-50 DEG C;
Under the effect of alkaline solution, there is hydrolysis reaction in organic solvent at 20-50 DEG C and obtain compound (6), namely arrange clean class medicine in the compound (5) obtained in (d) step (c);
2. the synthetic method of the clean class medicine of row according to claim 1, it is characterized in that: in step (a), described organic solvent is selected from one or more in ether, dioxane, methyl tertiary butyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran and benzene, toluene, ethylbenzene, trimethylphenylmethane and dimethylbenzene.
3. the synthetic method of the clean class medicine of row according to claim 1, it is characterized in that: in step (b), described organic solvent is selected from one or more in methylene dichloride, acetonitrile, chloroform, tetracol phenixin and tetrahydrofuran (THF).
4. the synthetic method of the clean class medicine of row according to claim 1, is characterized in that: in step (b), and the time of reduction reaction is 3-8 hour.
5. the synthetic method of the clean class medicine of row according to claim 1, it is characterized in that: in step (c), described organic solvent is selected from methylene dichloride, ethylene dichloride, tetrahydrofuran (THF), 2-methyltetrahydrofuran, ether, n-butyl ether, methyl tertiary butyl ether, one or more in dioxane.
6. the synthetic method of the clean class medicine of row according to claim 1, is characterized in that: in step (c), and the time of described acetylization reaction is 1-2 hour.
7. the synthetic method of the clean class medicine of row according to claim 1, it is characterized in that: in step (d), described organic solvent is selected from one or more in tetrahydrofuran (THF), 2-methyltetrahydrofuran, Isosorbide-5-Nitrae-dioxane, methyl alcohol, ethanol and Virahol.
8. the synthetic method of the clean class medicine of row according to claim 1, it is characterized in that: in step (d), described alkaline solution is selected from one or more in aqueous sodium hydroxide solution, potassium hydroxide aqueous solution, lithium hydroxide aqueous solution and the cesium hydroxide aqueous solution.
9. the synthetic method of the clean class medicine of row according to claim 1, is characterized in that: in step (d), and the time of hydrolysis reaction is 10-24 hour.
CN201510158948.4A 2015-04-07 2015-04-07 Method for synthesizing SGLT2 inhibitor drugs Pending CN104710486A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201510158948.4A CN104710486A (en) 2015-04-07 2015-04-07 Method for synthesizing SGLT2 inhibitor drugs

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201510158948.4A CN104710486A (en) 2015-04-07 2015-04-07 Method for synthesizing SGLT2 inhibitor drugs

Publications (1)

Publication Number Publication Date
CN104710486A true CN104710486A (en) 2015-06-17

Family

ID=53410263

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201510158948.4A Pending CN104710486A (en) 2015-04-07 2015-04-07 Method for synthesizing SGLT2 inhibitor drugs

Country Status (1)

Country Link
CN (1) CN104710486A (en)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105541816A (en) * 2016-01-20 2016-05-04 大连理工大学 A kind of synthetic method of Ipagliflozin
CN106632288A (en) * 2016-11-07 2017-05-10 安徽九华华源药业有限公司 Method for preparing empagliflozin
CN108610316A (en) * 2016-12-09 2018-10-02 江苏豪森药业集团有限公司 The preparation method of Dapagliflozin
CN108794548A (en) * 2017-04-28 2018-11-13 正大天晴药业集团股份有限公司 Prepare that En Gelie is net and its method of intermediate
CN112812107A (en) * 2019-11-18 2021-05-18 上海启讯医药科技有限公司 Preparation method of SGLT-2 inhibitor and intermediate
CN112955966A (en) * 2018-06-14 2021-06-11 阿斯利康(英国)有限公司 Method for lowering blood glucose using gliflozin Sodium (gliflozin Sodium) -glucose co-transporter 2 inhibitor pharmaceutical composition
CN113880796A (en) * 2021-10-14 2022-01-04 山东诚创蓝海医药科技有限公司 Preparation method of dapagliflozin
CN115232179A (en) * 2022-08-15 2022-10-25 江西天戌药业有限公司 Preparation method of empagliflozin intermediate impurity
CN119751398A (en) * 2024-11-27 2025-04-04 江苏阿尔法药业股份有限公司 Crystal form of acetylated dapagliflozin and preparation method thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101830876A (en) * 2009-03-12 2010-09-15 上海恒瑞医药有限公司 C-aryl glucoside derivative, preparation method thereof and application thereof in medicine
CN102516215A (en) * 2011-12-12 2012-06-27 天津药物研究院 Preparation method of C-glucoside containing saturated cyclohexane structure
CN104478839A (en) * 2014-11-24 2015-04-01 苏州乔纳森新材料科技有限公司 Synthesis method of dapagliflozin

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101830876A (en) * 2009-03-12 2010-09-15 上海恒瑞医药有限公司 C-aryl glucoside derivative, preparation method thereof and application thereof in medicine
CN102516215A (en) * 2011-12-12 2012-06-27 天津药物研究院 Preparation method of C-glucoside containing saturated cyclohexane structure
CN104478839A (en) * 2014-11-24 2015-04-01 苏州乔纳森新材料科技有限公司 Synthesis method of dapagliflozin

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
SHUO ZHANG，ET AL.: ""A practical synthetic approach to a trans-cyclohexane-bearing C-glucoside as potent SGLT2 inhibitor"", 《INDIAN JOURNAL OF CHEMISTRY》 *
任建国，等: ""达格列净的合成工艺改进"", 《中国药物化学杂志》 *
张帅阳，等: ""达格列净合成路线图解"", 《中国医药工业杂志》 *
肖鹏，等: ""坎格列净的合成"", 《中国医药工业杂志》 *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105541816A (en) * 2016-01-20 2016-05-04 大连理工大学 A kind of synthetic method of Ipagliflozin
CN106632288A (en) * 2016-11-07 2017-05-10 安徽九华华源药业有限公司 Method for preparing empagliflozin
CN106632288B (en) * 2016-11-07 2019-07-16 安徽九华华源药业有限公司 The preparation method of empagliflozin
CN108610316B (en) * 2016-12-09 2021-11-05 江苏豪森药业集团有限公司 Preparation method of dapagliflozin
CN108610316A (en) * 2016-12-09 2018-10-02 江苏豪森药业集团有限公司 The preparation method of Dapagliflozin
CN108794548A (en) * 2017-04-28 2018-11-13 正大天晴药业集团股份有限公司 Prepare that En Gelie is net and its method of intermediate
CN108794548B (en) * 2017-04-28 2023-06-16 正大天晴药业集团股份有限公司 Process for preparing enggliflozin and intermediates thereof
CN112955966A (en) * 2018-06-14 2021-06-11 阿斯利康(英国)有限公司 Method for lowering blood glucose using gliflozin Sodium (gliflozin Sodium) -glucose co-transporter 2 inhibitor pharmaceutical composition
CN112812107A (en) * 2019-11-18 2021-05-18 上海启讯医药科技有限公司 Preparation method of SGLT-2 inhibitor and intermediate
CN112812107B (en) * 2019-11-18 2024-03-15 上海启讯医药科技有限公司 Preparation method of SGLT-2 inhibitor and intermediate
CN113880796A (en) * 2021-10-14 2022-01-04 山东诚创蓝海医药科技有限公司 Preparation method of dapagliflozin
CN115232179A (en) * 2022-08-15 2022-10-25 江西天戌药业有限公司 Preparation method of empagliflozin intermediate impurity
CN119751398A (en) * 2024-11-27 2025-04-04 江苏阿尔法药业股份有限公司 Crystal form of acetylated dapagliflozin and preparation method thereof

Similar Documents

Publication Publication Date Title
CN104710486A (en) Method for synthesizing SGLT2 inhibitor drugs
CN101624390B (en) Preparation method of key intermediate of rosuvastatin calcium side chain
CN103450225B (en) The preparation method of cefoxitin sodium
CN104496952B (en) Synthesis method of dapagliflozin
CN106117192A (en) The synthetic method that a kind of En Gelie is clean
CN109988161A (en) A kind of preparation method that suitable industrialized production En Gelie is net
WO2022199378A1 (en) Synthetic method of bempedoic acid active pharmaceutical ingredient
CN101407513A (en) Method for synthesizing nucleoside analogue
CN109535210A (en) A kind of method of synthesizing and purifying Tulathromycin impurity E
JP5646706B2 (en) Method for producing C-glycoside derivative
CN114560901B (en) A preparation method of ergosterol or its derivatives
CN114262278B (en) Method for preparing oseltamivir phosphate
CN106749335B (en) A kind of preparation method and application of halogenated oxycephalosporins intermediate
CN105481913A (en) Method for synthesizing azithromycin
CN106317024A (en) Crizotinib intermediate, preparation method and crizotinib preparation method
Tsujimori et al. Synthesis and Absolute Configuration of Hongoquercin A, an Antibacterial Sesquiterpene‐Substituted Orsellinic Acid Isolated as a Fungal Metabolite
CN114717280B (en) A synthetic method of monopiravir
CN102268017B (en) Preparation method of broad-spectrum long-acting penicillin antibiotic ticarcillin sodium
CN106632453A (en) Preparation method for synthesizing key intermediate 4-BMA of 1beta-methyl carbapenem antibiotic bicyclic nucleus
CN109516964B (en) Preparation method of aprepitant intermediate
CN101497582A (en) N-substituted-1-deoxynojirimycin compound and preparation thereof
CN110016030B (en) Preparation method of 5-fluoro-1H-pyrrole- [2,3-b ] pyridine-4-formaldehyde
CN104530164A (en) Synthesis technology for capecitabine
CN105753827A (en) Method for preparing compound
CN111943891B (en) Rosuvastatin calcium impurity and rosuvastatin calcium quality control method

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
RJ01 Rejection of invention patent application after publication
RJ01 Rejection of invention patent application after publication

Application publication date: 20150617