CN105753910A - Preparation method of canagliflozin intermediate - Google Patents
Preparation method of canagliflozin intermediate Download PDFInfo
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Abstract
The invention relates to a preparation method of a canagliflozin intermediate methyl-1-C-(3-((5-(4-fluorophenyl)-2-thienyl)methyl)-4-methylphenyl)-D-glucopyranoside (I). The method comprises the following steps: preparing a Grignard reagent from initial raw materials comprising 2-[(5-halo-2-methylphenyl)methyl]-5-(4-fluorophenyl)thiophene (II) and 2,3,4,6-tetra-O-trimethylsilyl-D-glucolactone (III) and magnesium powder, carrying out nucleophilic substitution, and removing a trimethylsilyl group to obtain the canagliflozin intermediate. Compared with previously reported methods, the preparation method provided by the invention has the advantages of safety, high yield and easy control.
Description
Technical field
The present invention relates to pharmaceutical synthesis field.It is particularly used for a kind of intermediate of the medicine canagliflozin for the treatment of diabetes: methyl 1-C-(3-((5-(4-fluorophenyl)-2-thienyl) methyl)-4-aminomethyl phenyl)-D-pyranglucoside (I) preparation method.
Background technology
The chemistry of canagliflozin (canagliflozin) is called 1-(β-D-glycopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienyl methyl] benzene, and molecular formula is C24H25FO5S, molecular weight is 444.52.Canagliflozin is as a kind of sodium dependent glucose operating albumen (SGLT) inhibitor, ratified its tablet by food and drug administration (FDA) on March 29th, 2013 to coordinate with diet and motion, for Adult type II diabetes's Patients' rights blood glucose.
The molecular formula of methyl 1-C-(3-((5-(4-fluorophenyl)-2-thienyl) methyl)-4-aminomethyl phenyl)-D-pyranglucoside (I) is C25H27FO6S, molecular weight is 474.15, is a kind of important intermediate preparing canagliflozin, through demethoxylation, just can prepare canagliflozin.
The domestic and international relevant report of syntheti c route of current methyl 1-C-(3-((5-(4-fluorophenyl)-2-thienyl) methyl)-4-aminomethyl phenyl)-D-pyranglucoside (I) mainly have the following two kinds:
Article 1, route, uses n-BuLi, it is necessary to the ultralow temperature reaction condition of-78 DEG C, it is not easy to realizing and difficult control, n-butyllithium solution has very strong reproducibility, meets water, oxidant all easily burn, has certain production safety hidden danger.
Article 2 route, uses isopropylmagnesium chloride lithium chloride complexometric reagent, it is not necessary to the ultralow temperature reaction of-78 DEG C, reaction is easily controlled, but yield is on the low side.
Summary of the invention
Present invention aim to overcome that weak point of the prior art, research design one reaction condition easily realizes, easily-controlled operation, reaction yield is high, is suitable for a kind of intermediate of industrialized canagliflozin: the preparation method of methyl 1-C-(3-((5-(4-fluorophenyl)-2-thienyl) methyl)-4-aminomethyl phenyl)-D-pyranglucoside (I).
The preparation method of the present invention is as follows:
With 2-[(5-halo-2-aminomethyl phenyl) methyl]-5-(4-fluorophenyl) thiophene of formula (II) for initiation material,
Wherein X=chlorine, bromine, fluorine, iodine, it is preferred to bromine, iodine,
First 2-[(5-halo-2-aminomethyl phenyl) methyl]-5-(4-fluorophenyl) thiophene of formula (II) is prepared into Grignard reagent with magnesium powder under solvent condition, then the 2 of formula (III) are used, 3,4,6-tetra--O-is trimethyl silicon based-D-Glucose acid lactone nucleophilic displacement of fluorine
Remove trimethyl silicon based again, prepare methyl 1-C-(3-((5-(4-fluorophenyl)-2-thienyl) methyl)-4-the aminomethyl phenyl)-D-pyranglucoside of formula (I):
Reaction scheme is shown below:
2-[(5-X (halo)-2-aminomethyl phenyl) methyl]-5-(4-fluorophenyl) thiophene (II) prepares into Grignard reagent with magnesium powder under solvent condition, 5-X is 5-chlorine, 5-bromine, 5-fluorine, 5-iodine, it is preferred to 5-bromine, 5-iodine.Solvent can be ether solvent (such as ether, oxolane, dioxane etc.), Aliphatic hydrocarbon solvents (such as butane, pentane, hexane), cycloaliphatic hydrocarbon solvents (such as hexamethylene or cycloheptane) or aromatic hydrocarbons solvent (benzene, toluene etc.) etc..When X is bromine, chlorine or fluorine, when formula (II) compound and magnesium powder reaction, it is necessary to add iodine, it is therefore an objective to priming reaction, make reaction easily generate Grignard reagent；Preferably, the mol ratio of 2-[(5-X (halo)-2-aminomethyl phenyl) methyl]-5-(4-fluorophenyl) thiophene (II) and iodine is 1:0.005～0.2, more preferably 1:0.01～0.1, even more preferably 1:0.045～0.1.It is 0～50 DEG C that 2-[(5-X (halo)-2-aminomethyl phenyl) methyl]-5-(4-fluorophenyl) thiophene (II) prepares into the temperature of Grignard reagent with magnesium powder, it is preferable that 13～25 DEG C, more preferably 18～25 DEG C.It is 2～10h that 2-[(5-X (halo)-2-aminomethyl phenyl) methyl]-5-(4-fluorophenyl) thiophene (II) prepares into the response time of Grignard reagent with magnesium powder, it is preferred to 5～8h, more preferably 5.5～7.5h.
The solvent that 2-[(5-X (halo)-2-aminomethyl phenyl) methyl]-5-(4-fluorophenyl) thiophene (II) uses when preparing into Grignard reagent with magnesium powder is preferably ether, oxolane or 1,4-dioxane, more preferably oxolane.
Prepare in the reaction of Grignard reagent with magnesium powder at 2-[(5-X (halo)-2-aminomethyl phenyl) methyl]-5-(4-fluorophenyl) thiophene (II), the mol ratio of 2-[(5-X (halo)-2-aminomethyl phenyl) methyl]-5-(4-fluorophenyl) thiophene (II) and magnesium powder is: 1:1.1～10, it is preferably 1:3～8, more preferably 1:4～6
Preferably, 2-[(5-MgX (halo)-2-aminomethyl phenyl) methyl]-5-(4-fluorophenyl) thiophene (II) and 2,3,4,6-tetra--O-is trimethyl silicon based-and the mol ratio of D-Glucose acid lactone (III) is 1:0.6～3.0, preferred 1:1～2, more preferably 1:1.1～1.5；Response time is 1～5h, it is preferred to 2～3h.Preferably, nucleophilic displacement of fluorine is temperature-50～25 DEG C, it is preferable that-30～5 DEG C, more preferably carry out when-10～0 DEG C.De-trimethyl silicon based temperature-50～40 DEG C, it is preferable that-10～25 DEG C, more preferably carry out when 10～25 DEG C.
The de-trimethyl silicon based methanol solution of employing methanesulfonic acid or the alcoholic solution of methanesulfonic acid carry out, it is preferred that carry out with the methanol solution of methanesulfonic acid.The concentration of the methanol solution of methanesulfonic acid or the alcoholic solution of methanesulfonic acid is 0.8～2.5mol (methanesulfonic acid)/L, it is preferred to 1～2.2mol/L, more preferably 1.3～2.0mol/L.
Detailed description of the invention
Embodiment 1
nullBy magnesium powder (14.4g，600mmol)、Iodine (1.3g，10.0mmol) join in dry reaction bulb，Under nitrogen protection, dry oxolane (50mL) is joined in reaction bulb，It is cooled to 0 DEG C，Oxolane (100mL) solution of 2-[(the bromo-2-aminomethyl phenyl of 5-) methyl]-5-(4-fluorophenyl) thiophene (II) (36.1g100mmol) is slowly added dropwise in reaction bulb，Finish and be warming up to 25 DEG C，Stirring reaction 5～8h，It is cooled to 0 DEG C，By above-mentioned reaction solution at 0 DEG C，It is added dropwise over to 2,3,4,6-tetra--O-is trimethyl silicon based-D-Glucose acid lactone (III) (55.9g，In anhydrous tetrahydro furan (100mL) solution 120mmol)，Finish and reactant mixture is stirred 2～3h，And use will containing pyrovinic acid (26.4g in the cooling condition，Methanol (150mL) solution 275mmol) is added drop-wise in reactant liquor above，Drip to finish and be slowly warmed up to stirred overnight at room temperature，After reaction terminates，Cool the temperature to 0 DEG C，Add about 300mL saturated sodium bicarbonate solution to about pH7，Layering，Water layer is with 200mL extraction into ethyl acetate once，Merge organic layer，Saturated aqueous common salt (200mL) washs once，Anhydrous magnesium sulfate dries，Sucking filtration，Filtrate decompression distillation obtains light yellow solid powder methyl 1-C-(3-((5-(4-fluorophenyl)-2-thienyl) methyl)-4-aminomethyl phenyl)-D-pyranglucoside (I) 43.6g yield 91.8%.HPLC content 95.0%.
1HNMR(400MHz,CD3Cl) δ: 2.28 (s, 3H), 3.10 (s, 3H), 3.80 (s, 2H) 3.35～4.06 (m, 4H), 4.55 (s, 2H), 4.67 (s, 1H) 4.90 (s, 3H), 6.80～7.09 (m, 4H), 7.19 (s, 1H), 7.30 (d, J=8,2H), 8.02 (d, J=8,2H).
Embodiment 2
nullBy magnesium powder (14.4g，600mmol) join in dry reaction bulb，Under nitrogen protection, dry oxolane (50mL) is joined in reaction bulb，It is cooled to 0 DEG C，Oxolane (100mL) solution of 2-[(the iodo-2-aminomethyl phenyl of 5-) methyl]-5-(4-fluorophenyl) thiophene (II) (41.0g100mmol) is slowly added dropwise in reaction bulb，Finish and be warming up to 25 DEG C，Stirring reaction 5～8h，It is cooled to 0 DEG C，By above-mentioned reaction solution at 0 DEG C，It is added dropwise over to 2,3,4,6-tetra--O-is trimethyl silicon based-D-Glucose acid lactone (III) (55.9g，In anhydrous tetrahydro furan (100mL) solution 120mmol)，Finish and reactant mixture is stirred 2～3h，And use will containing pyrovinic acid (26.4g in the cooling condition，Methanol (150mL) solution 275mmol) is added drop-wise in reactant liquor above，Drip to finish and be slowly warmed up to stirred overnight at room temperature，After reaction terminates，Cool the temperature to 0 DEG C，Add the saturated NaHCO of about 300mL3Solution is to about pH7, layering, water layer is with 200mL extraction into ethyl acetate once, merge organic layer, saturated aqueous common salt (200mL) washs once, anhydrous magnesium sulfate dries, sucking filtration, and filtrate decompression distillation obtains light yellow solid powder methyl 1-C-(3-((5-(4-fluorophenyl)-2-thienyl) methyl)-4-aminomethyl phenyl)-D-pyranglucoside (I) 44.3g yield 93.4%., HPLC content 96.7%.
Embodiment 3
nullBy magnesium powder (14.4g，600mmol)、Iodine (1.3g，1.0mmol) join in dry reaction bulb，Under nitrogen protection, dry ether (50mL) is joined in reaction bulb，It is cooled to 0 DEG C，By 2-[(the bromo-2-aminomethyl phenyl of 5-) methyl]-5-(4-fluorophenyl) thiophene (II) (36.1g，Ether (100mL) solution 100mmol) is slowly added dropwise in reaction bulb，Finish and be warming up to 25 DEG C，Stirring reaction 5～8h，It is cooled to 0 DEG C，By above-mentioned reaction solution at 0 DEG C，It is added dropwise over to 2,3,4,6-tetra--O-is trimethyl silicon based-D-Glucose acid lactone (III) (55.9g，In anhydrous tetrahydro furan (100mL) solution 120mmol)，Finish and reactant mixture is stirred 2～3h，And use will containing pyrovinic acid (26.4g in the cooling condition，Methanol (150mL) solution 275mmol) is added drop-wise in reactant liquor above，Drip to finish and be slowly warmed up to stirred overnight at room temperature，After reaction terminates，Cool the temperature to 0 DEG C，Add about 300mL saturated sodium bicarbonate solution to about pH7，Layering，Water layer is with 200mL extraction into ethyl acetate once，Merge organic layer，Saturated aqueous common salt (200mL) washs once，Anhydrous magnesium sulfate dries，Sucking filtration，Filtrate decompression distillation obtains light yellow solid powder methyl 1-C-(3-((5-(4-fluorophenyl)-2-thienyl) methyl)-4-aminomethyl phenyl)-D-pyranglucoside (I) 42.7g，Yield 90.0%., HPLC content 95.5%.
Embodiment 4
nullBy magnesium powder (12.0g，500mmol)、Iodine (1.3g，10.0mmol) join in dry reaction bulb，Under nitrogen protection, dry oxolane (50mL) is joined in reaction bulb，It is cooled to 0 DEG C，By 2-[(the bromo-2-aminomethyl phenyl of 5-) methyl]-5-(4-fluorophenyl) thiophene (II) (36.1g，Oxolane (100mL) solution 100mmol) is slowly added dropwise in reaction bulb，Finish and be warming up to 25 DEG C，Stirring reaction 5～8h，It is cooled to 0 DEG C，By above-mentioned reaction solution at 0 DEG C，It is added dropwise over to 2,3,4,6-tetra--O-is trimethyl silicon based-D-Glucose acid lactone (III) (55.9g，In anhydrous tetrahydro furan (100mL) solution 120mmol)，Finish and reactant mixture is stirred 2～3h，And use will containing pyrovinic acid (26.4g in the cooling condition，Methanol (150mL) solution 275mmol) is added drop-wise in reactant liquor above，Drip to finish and be slowly warmed up to stirred overnight at room temperature，After reaction terminates，Cool the temperature to 0 DEG C，Add about 300mL saturated sodium bicarbonate solution to about pH7，Layering，Water layer is with 200mL extraction into ethyl acetate once，Merge organic layer，Saturated aqueous common salt (200mL) washs once，Anhydrous magnesium sulfate dries，Sucking filtration，Filtrate decompression distillation obtains light yellow solid powder methyl 1-C-(3-((5-(4-fluorophenyl)-2-thienyl) methyl)-4-aminomethyl phenyl)-D-pyranglucoside (I) 42.0g yield 92.1%，HPLC content 95.9%.
Comparative example 1
Method according to the embodiment 1 of US7943582.Take clean dry reaction bulb; under argon shield; add 2-[(the bromo-2-aminomethyl phenyl of 5-) methyl]-5-(4-fluorophenyl) thiophene (II) (28.9g) inside reaction bulb; put into temperature in-78 DEG C of low-temp reaction grooves; the temperature in reaction bulb is made to maintain-67～-70 DEG C; it is subsequently adding THF (480mL) and toluene (480mL); dissolve clarification; start to be slowly added dropwise n-BuLi hexane solution (1.6M; 50mL) in reaction bulb; dropwise, constant temperature stirring reaction 20min；By 2,3,4,6-tetra--O-are trimethyl silicon based-toluene (240mL) solution of D-Glucose acid lactone (III) (34.0g) in, be slowly added dropwise in reactant liquor above, finish, stirring reaction 1h at that same temperature, is finally added drop-wise in reactant liquor by methanol (480mL) solution containing pyrovinic acid (21.0g), is warmed up to and reaction 17h is stirred at room temperature, cool the temperature to about 0 DEG C, add saturated NaHCO3Solution, extraction into ethyl acetate, merges organic layer, brine It, anhydrous magnesium sulfate dries, decompression distillation obtains grease, uses 100mL toluene and 400mL normal hexane by adding in grease, and is stirred continuously, filter, dry, obtain methyl 1-C-(3-((5-(4-fluorophenyl)-2-thienyl) methyl)-4-aminomethyl phenyl)-D-pyranglucoside (I) 31.6g, yield 83.3%.
From above comparative example it can be seen that this comparative example needs to carry out under the ultralow temperature of-78 DEG C, it is not easy to control, n-BuLi is used to have certain potential safety hazard.
It is pointed out that above-described embodiment is only the technology design and feature that the present invention is described, its object is to allow person skilled in the art will appreciate that present disclosure and to implement according to this, can not limit the scope of the invention with this.All equivalences made according to spirit of the invention change or modify, and all should be encompassed within protection scope of the present invention.
Claims (10)
1. a preparation method for methyl 1-C-(3-((5-(4-fluorophenyl)-2-thienyl) methyl)-4-the aminomethyl phenyl)-D-pyranglucoside of formula (I),
It is characterized in that described method includes being made by step: with 2-[(5-halo-2-aminomethyl phenyl) methyl]-5-(4-fluorophenyl) thiophene of formula (II) for initiation material,
Wherein X=chlorine, bromine, fluorine, iodine, it is preferred to bromine, iodine,
First 2-[(5-halo-2-aminomethyl phenyl) methyl]-5-(4-fluorophenyl) thiophene of formula (II) is prepared into Grignard reagent with magnesium powder under solvent condition, then the 2 of formula (III) are used, 3,4,6-tetra--O-is trimethyl silicon based-D-Glucose acid lactone nucleophilic displacement of fluorine
Remove trimethyl silicon based again, obtain methyl 1-C-(3-((5-(4-fluorophenyl)-2-thienyl) methyl)-4-the aminomethyl phenyl)-D-pyranglucoside of formula (I).
2. preparation method according to claim 1, it is characterized in that, when X is bromine, chlorine or fluorine, iodine is added when preparing Grignard reagent, the mol ratio of 2-[(5-X (halo)-2-aminomethyl phenyl) methyl]-5-(4-fluorophenyl) thiophene (II) and iodine is 1:0.005～0.2, more preferably 1:0.01～0.1, even more preferably 1:0.045～0.1.
3. preparation method as claimed in claim 1 or 2, it is characterized in that during preparation Grignard reagent, solvent for use is ether solvent, for instance ether, oxolane or dioxane, Aliphatic hydrocarbon solvents, such as butane, pentane or hexane, cycloaliphatic hydrocarbon solvents, for instance hexamethylene or cycloheptane, or aromatic hydrocarbons solvent, such as benzene or toluene, it is preferably ether, oxolane or Isosorbide-5-Nitrae-dioxane, more preferably oxolane.
4. the preparation method as described in claim 1-3, it is characterized in that the mol ratio of 2-[(5-halo-2-aminomethyl phenyl) methyl]-5-(4-fluorophenyl) thiophene (II) and magnesium powder is: 1:1.1～10, it is preferably 1:3～8, more preferably 1:4～6.
5. the preparation method as described in claim 1-4, it is characterised in that the reaction temperature of preparation Grignard reagent is 0～50 DEG C, it is preferred to 13～25 DEG C, more preferably 18～25 DEG C；The response time of preparation Grignard reagent is 2～10h, it is preferred to 5～8h, more preferably 5.5～7.5h.
6. the preparation method as described in claim 1-5, it is characterized in that, 2-[(5-MgX (halo)-2-aminomethyl phenyl) methyl]-5-(4-fluorophenyl) thiophene (II) and 2,3,4,6-tetra--O-is trimethyl silicon based-and the mol ratio of D-Glucose acid lactone (III) is 1:0.6～3.0, it is preferable that 1:1～2, more preferably 1:1.1～1.5；The nucleophilic substitution time is 1～5h, it is preferred to 2～3h.
7. the preparation method according to any one of claim 1-6, it is characterised in that nucleophilic displacement of fluorine is temperature-50～25 DEG C, it is preferable that-30～5 DEG C, more preferably carry out when-10～0 DEG C.
8. the preparation method according to any one of claim 1-7, it is characterised in that de-trimethyl silicon based temperature-50～40 DEG C, it is preferable that-10～25 DEG C, more preferably carry out when 10～25 DEG C.
9. the preparation method according to any one of claim 1-8, it is characterised in that the de-methanol solution of trimethyl silicon based methanesulfonic acid or the alcoholic solution of methanesulfonic acid carry out, it is preferred that carry out with the methanol solution of methanesulfonic acid.
10. method according to claim 9, wherein methanesulfonic acid methanol solution or or the concentration of alcoholic solution of methanesulfonic acid be 0.8～2.5mol/L, it is preferred to 1～2.2mol/L, more preferably 1.3～2.0mol/L.
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| CN108033955A (en) * | 2017-12-15 | 2018-05-15 | 东南大学 | A kind of preparation method of antidiabetic drug canagliflozin |
| CN109553649A (en) * | 2017-09-26 | 2019-04-02 | 北大方正集团有限公司 | A kind of preparation method of canagliflozin intermediate |
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| CN109553649A (en) * | 2017-09-26 | 2019-04-02 | 北大方正集团有限公司 | A kind of preparation method of canagliflozin intermediate |
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| CN108033955A (en) * | 2017-12-15 | 2018-05-15 | 东南大学 | A kind of preparation method of antidiabetic drug canagliflozin |
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