CN105153137A - Preparation method of empagliflozin - Google Patents
Preparation method of empagliflozin Download PDFInfo
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- CN105153137A CN105153137A CN201510593600.8A CN201510593600A CN105153137A CN 105153137 A CN105153137 A CN 105153137A CN 201510593600 A CN201510593600 A CN 201510593600A CN 105153137 A CN105153137 A CN 105153137A
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- 0 *c1cc(C(C=C)=O)c(*)cc1 Chemical compound *c1cc(C(C=C)=O)c(*)cc1 0.000 description 6
- YURQCVXKSGLWMZ-UHFFFAOYSA-N COc(cc1)ccc1C(c1cc([Br-])ccc1Cl)=N Chemical compound COc(cc1)ccc1C(c1cc([Br-])ccc1Cl)=N YURQCVXKSGLWMZ-UHFFFAOYSA-N 0.000 description 1
- WEZCVPJNMDMFKU-UHFFFAOYSA-N OC(c1cc(N=[IH])ccc1Cl)=[U] Chemical compound OC(c1cc(N=[IH])ccc1Cl)=[U] WEZCVPJNMDMFKU-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The invention discloses a preparation method of empagliflozin. The preparation method comprises the steps of firstly, reacting 5-bromo-2-chlorobenzoic acid and anisole to obtain 5-bromo-2-chlorphenyl-4-methoxyphenyl-ketone V; carrying out reduction reaction on 5-bromo-2-chlorphenyl-4-methoxyphenyl-ketone to obtain 5-bromo-2-chloro-4'-methoxydiphenylmethane IV; carrying out coupling reaction on 5-bromo-2-chloro-4'-methoxydiphenylmethane and 2,3,4,6-O-tetrapivaloyl-ALPHA-D-bromo-glucopyranose to obtain a key intermediate III; demethylating the key intermediate III to obtain a key intermediate II; and forming ether by using the intermediate II and (S)-3-iodo-tetrahydrofuran under an alkaline condition, and removing pivaloyl to obtain empagliflozin. Empagliflozin is synthesized by using cheap and available 5-bromo-2-chlorobenzoic acid as a raw material, the synthesis route is simple, and the preparation method has the advantages of simplicity and convenience in operation, low cost, environment friendliness and the like.
Description
Technical field
The invention belongs to chemical field, relate to a kind of Ai Gelie clean, the preparation method that a kind of Ai Gelie is clean specifically.
Background technology
Diabetes are diseases of a kind of serious harm human health, and along with the raising of Living consumption, onset diabetes rate has the trend raised year by year, and the control of diabetes has caused the concern of world community government and hygiene department.Huge human and material resources and financial resources, all to the research and development of diabetes medicament, have been dropped in countries in the world.Diabetes are clinical point of two types: 1, insulin-dependent diabetes mellitus (i.e. type i diabetes).2, non insulin dependent diabetes (i.e. type II diabetes).Type ii diabetes sickness rate is very high, accounts for about 90% of onset diabetes number.
At present, the method for clinical treatment type ii diabetes importantly pharmacological agent.And the type ii diabetes medicine gone on the market has: Sulphonylurea, biguanides, alpha-glucosidase inhibitor, thiazolidinediones antidiabetic drug, Drugs Promoting Insulin Secretion, dipeptidyl peptidase-IV (DPP-4) inhibitor, sodium glucose co-transporter 2 white (SGLT) 2 inhibitor.
White (SGLT) 2 of sodium glucose co-transporter 2 is delivery systems of a class low-affinity, heavy body, and particular expression is in uriniferous tubules S1 section, and be the important transporter in kidney sodium glucose reabsorption, its dysfunction can cause occurring glucose in urine.For this novel targets, this novel therapeutic modality of SGLT2 inhibitor just arises at the historic moment, and by suppressing SGLT2, preventing uriniferous tubules to the heavily absorption of glucose, and discharging excessive glucose, thus reaches the object reducing blood sugar, treatment diabetes.Ai Gelie represents one of medicine as the up-to-date of SGLT2 inhibitor only, and Japanese Kotobuki ratifies its listing, for improving the glycemic control of type ii diabetes adult patient in January, 2014.
The people such as Xiao-junWang report one with 5-iodine (bromine)-2-tolyl acid for raw material; key intermediate VII is obtained after Friedel-Crafts reaction, substitution reaction and carbonyl reduction; the Gluconolactone that glucose Piece Selection TMS protects; after obtaining these two key intermediates; the Gluconolactone that intermediate VII protects with TMS under n-Butyl Lithium effect reacts; not cancellation is directly obtained by reacting compound VI with the methanol solution of methylsulfonic acid, reduces and obtain Compound I after ethanoyl protection hydroxyl under the condition of triethyl silicane and boron trifluoride diethyl etherate.This route protects the reaction of gluconolactone based on lithium reagent and TMS, and main drawback is that TMS protecting group is unstable, needs second protection hydroxyl to purify after linked reaction, the complex operation of reaction and in industrialization process quality product wayward.Its route is as follows:
reactioncondition：(a)TMSCl，NMM，DMAP，98％；(b)(COCl)
2，AlCl
3，DCM，95％；(c)KTB，87％；(d)NaBH
4，AlCl
3，93％；(e)iPrMgCl.LiCl，-10℃，85％；(f)AlCl
3，Et
3SiH，70％.
Summary of the invention
For above-mentioned technical problem of the prior art, the invention provides the preparation method that a kind of Ai Gelie is clean, the clean preparation method of described this Ai Gelie solves the technical problem preparing the clean method complex process of Ai Gelie, purification difficult of the prior art.
The invention provides the preparation method that a kind of Ai Gelie is clean, comprise the following steps:
1) first, reacted by the bromo-2-chloro-benzoic acid of 5-and methyl-phenoxide, obtain the bromo-2-chloro-phenyl-of 5--4-p-methoxy-phenyl-ketone V;
2) then, 5-bromo-2-chloro-phenyl--4-p-methoxy-phenyl-ketone obtains the bromo-2-of 5-chloro-4'-methoxyl group ditane IV through reduction reaction;
3) the bromo-2-of 5-chloro-4'-methoxyl group ditane and 2,3,4,6-O-tetra-pivaloyl group-ALPHA-D-bromo Glucopyranose obtain key intermediate III through linked reaction;
4) key intermediate III demethylation obtains key intermediate II;
5) intermediate II and (S)-3 iodo tetrahydrofuran (THF) become ether in the basic conditions and slough pivaloyl group to obtain Ai Gelie clean,
Further, in step 1) in, the bromo-2-chloro-benzoic acid of described 5-and methyl-phenoxide, through friedel-crafts acylation, obtain the bromo-2-chloro-phenyl-of 5--4-p-methoxy-phenyl-ketone.
Further, in a solvent, the bromo-2-chloro-benzoic acid of 5-is first prepared into acyl chlorides with sulfur oxychloride or oxalyl chloride, then react under lewis acidic effect with methyl-phenoxide, obtain the bromo-2-chloro-phenyl-of 5--4-p-methoxy-phenyl-ketone, control temperature is 0-80 DEG C, preferably 20 DEG C; Reaction 2-18h, preferred 6h; Described solvent is DMF, methylene dichloride, dithiocarbonic anhydride, ether, oil of mirbane, preferred methylene dichloride; The consumption of solvent, by solvent: the bromo-2-chloro-benzoic acid of 5-is 1-10L:1mol, preferred 1L:1mol; Described Lewis acid is aluminum chloride, zinc chloride, iron(ic) chloride, boron trifluoride, columbium pentachloride, preferred aluminum chloride; Described lewis acidic consumption, by Lewis acid: the mol ratio of the bromo-2-chloro-benzoic acid of 5-is 0.8-2mol:1mol, preferred 1.2mol:1mol.
Further, in step 2) in, the bromo-2-chloro-phenyl-of described 5--4-p-methoxy-phenyl-ketone in a solvent, by going back the effect of original reagent, the bromo-2-of 5-chloro-4'-methoxyl group ditane is obtained through reduction reaction, solvent be selected from tetrahydrofuran (THF), ether, isopropyl ether, n-butyl ether, 2-methyltetrahydrofuran or toluene one or more, preferred tetrahydrofuran (THF); Reaction times is 2-24h, preferred 6h; Also original reagent is selected from one or more in aluminum chloride, tin tetrachloride, sodium borohydride, trifluoroacetic acid, boron trifluoride diethyl etherate, iron trichloride, Lithium Aluminium Hydride, zinc dichloride, sulfuric acid, palladium chloride, aluminum oxide; Preferred sodium borohydride and aluminum chloride; Temperature of reaction is 0-100 DEG C, preferably 65 DEG C.
Further, in step 3) in, the bromo-2-of described 5-chloro-4'-methoxyl group ditane is first obtained by reacting compound IV with organometallic reagent ', the mol ratio of the bromo-2-of 5-chloro-4'-methoxyl group ditane and organometallic reagent is 1:0.3-1.0, control temperature is-20-35 DEG C, reaction times is 12-36h; The mol ratio of the mixture of compound IV ' carry out being obtained by reacting IV with the mixture of zinc bromide and lithiumbromide again "; described compound IV ' and zinc bromide and lithiumbromide is 1mol:0.3-1.2mol; the zinc bromide in molar ratio of the proportioning between described zinc bromide and the mixture of lithiumbromide: lithiumbromide is 1mol:1mol; reaction solvent is one or more in oil of mirbane, toluene, dibutyl ether, ether, tetrahydrofuran (THF), hexane or pentane, preferred toluene, dibutyl ether; Control temperature is-10-55 DEG C and reacts, preferably 0 DEG C; Reaction times 0.2-6h, preferred 1h; IV " again with 2; 3,4,6-O-tetra-pivaloyl group-ALPHA-D-bromo Glucopyranose is obtained by reacting key intermediate III; reaction solvent is one or more in oil of mirbane, toluene, dibutyl ether, ether, tetrahydrofuran (THF), hexane, pentane, preferred toluene, dibutyl ether; Temperature of reaction is 25-145 DEG C, preferably 100 DEG C; Reaction times 3-30h, preferred 12h.
Further, described organometallic reagent is n-Hex (n-Bu)
2mgLi, the i.e. bromo-2-of 5-chloro-4'-methoxyl group ditane and n-Hex (n-Bu)
2mgLi is obtained by reacting IV ' for 1mol:0.3-1.0mol in molar ratio, and preferred molar ratio is 1mol:0.5mol.
Further, in step (4), key intermediate III in a solvent, is obtained by reacting key intermediate II by demethylation reagent effect through demethylation, solvent for use is one or more in methylene dichloride, acetic acid, butyl ether or bromobenzene, preferred methylene dichloride; Described demethylation reagent is one or more in hydrogen bromide, hydrogenchloride, hydrogen iodide, boron tribromide, boron trichloride, sodium iodide, aluminum chloride, sodium amide, lithium chloride, preferred boron tribromide; Temperature of reaction is-30-100 DEG C, preferably-15 DEG C; Reaction times 0.5-25h, preferred 12h.
Further; in step 5) in; intermediate II and (S)-3 iodo tetrahydrofuran (THF) in a solvent; under the effect of alkali, become ether and slough pivaloyl group to obtain Ai Gelie clean; described alkali is one or more in sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, potassium hydride KH, calcium hydroxide, salt of wormwood, cesium carbonate, sodium carbonate, sodium methylate, sodium ethylate, sodium tert-butoxide or potassium tert.-butoxide, preferred cesium carbonate.Solvent for use is one or more in methyl alcohol, ethanol, Virahol, the trimethyl carbinol or water, particular methanol; Temperature of reaction is-30-100 DEG C, preferably 25 DEG C; Reaction times 0.5-25h, preferred 2h.
The synthetic route that above-mentioned Ai Gelie is clean, its reaction process equation is as follows:
Invention increases reaction yield, do not produce other isomer impurities.Purity reaches more than 99%, content can reach the standard of bulk drug.
The present invention compares with prior art, and its technical progress is significant.The present invention be utilize 5-bromo-2-chloro-benzoic acid that is cheap, that be easy to get for Material synthesis Ai Gelie clean, overcome in existing route the yield synthesizing Ai Gelie clean too low, the shortcomings such as stereoselectivity is wayward, synthetic route product of the present invention is easily purified, have easy and simple to handle, cost is low, advantages of environment protection.
Embodiment
Below by specific embodiment, the present invention is set forth further, but do not limit the present invention.
Nucleus magnetic resonance is measured by Mercury-Plus300/Bruker500 type nuclear magnetic resonance analyser, German Bruker company.Mass spectrum is measured by WatersUPLCMS, Waters, US.
Embodiment 1
The bromo-2-chloro-benzoic acid (29.45g, 125mmol) of 5-is added, CH in 500mL single port bottle
2cl
2(150mL), drip several DMF, slowly drip oxalyl chloride (13.1mL, 137.5mmol), bubbling is violent, drips complete room temperature reaction 2h, and methyl alcohol cancellation is used in sampling, and TLC finds that raw material reaction is complete, and concentrating under reduced pressure obtains colorless oil.
Methyl-phenoxide (12.2g, 112.5mmol) is added, aluminum chloride (18.4g, 137.5mmol), CH in the 1000mL there-necked flask that thermometer, constant pressure funnel and drying tube be housed
2cl
2(200mL), be down to-10 DEG C, drip the above-mentioned CH preparing acyl chlorides
2cl
2solution, controls dropping process and is no more than-5 DEG C, drips to finish slowly to rise to room temperature 20 DEG C, and reaction 6h, TLC detect and find that raw material reaction is complete, system are poured in the cryosel acid (about 2M) of 200mL, stratification, aqueous phase CH
2cl
2(50mL × 2) extract, merge the washing of organic phase saturated sodium bicarbonate solution to without the bromo-2-chloro-benzoic acid of 5-, concentrated that the bromo-2-chloro-phenyl-of 5--4-p-methoxy-phenyl-ketone V is colorless oil (36.2g after dry, 111mmol), low temperature is placed as clear crystal, and yield is 99%.
1HNMR(500MHz,CDCl
3)δ7.86(s,1H),7.78(s,1H),7.76–7.74(m,1H),7.73(s,1H),7.38(s,1H),7.01(s,2H),3.79(s,3H).ESI-MSm/z:324.9/326.9(M+1)+
Embodiment 2
In the 250mL there-necked flask that thermometer, reflux condensing tube, drying tube be housed, add the bromo-2-chloro-phenyl-of 5--4-p-methoxy-phenyl-ketone (20g, 62.02mmol), THF (100mL), adds NaBH under stirring at room temperature
4(39.33g, 310.08mmol), adds AlCl in batches
3(20.67g, 155.04mmol), system bubbling is violent, and it is complete that reinforced complete heating reflux reaction 6h, TLC detect raw material reaction, stopped reaction.System is slowly poured into after being down to room temperature in 80mL frozen water, vigorous stirring 0.5h, rises to room temperature naturally, stratification, aqueous phase ethyl acetate (30mL × 3) extracts, merge organic phase, with saturated sodium-chloride (100mL × 2) washing, obtaining the bromo-2-of 5-chloro-4'-methoxyl group ditane IV after drying is concentrated is colorless oil (18.35g, 58.89mmol), low temperature places to obtain white solid, and it is 99.0% that HPLC detects purity, and yield is 95.0%.
1HNMR(500MHz,CDCl
3)δ7.49(s,1H),7.28(d,J＝5.0Hz,1H),7.25(s,1H),7.12–7.09(m,1H),7.09–7.06(m,1H),6.85(s,1H),6.85(s,1H),3.99(s,2H),3.79(s,3H).ESI-MSm/z:310.9/311.9(M+1)+
Embodiment 3
N
2under protection, to adding the bromo-2-of 5-chloro-4'-methoxyl group ditane (10g, 32.09mmol) toluene 40mL in the there-necked flask of thermometer, being cooled to-10 DEG C, slowly adding n-Hex (n-Bu)
2mgLi20mL (16.05mmol).Add the butyl ether solution 16mL (16mmol) of zinc bromide/lithiumbromide after insulation 1h, 0 DEG C of insulation 1h, adds 2; 3,4,6-O-tetra-pivaloyl group-ALPHA-D-bromo Glucopyranose (14.87g; toluene solution 25.67mmol), is warming up to 95 DEG C.Detect after 12h that raw material reaction is complete adds 4NHCl40mL cancellation reaction, separatory, uses 50mLEA aqueous phase extracted, merges organic phase, dry concentrated, obtains dark oil thing, and filter III is white solid 13.13g after adding the making beating of 200mL sherwood oil, yield is 70%.
1hNMR (501MHz, CDCl
3) δ 7.34 (d, J=8.0Hz, 1H), 7.17 (d, J=7.7Hz, 2H), 7.09 (t, J=8.6Hz, 2H), 6.83 (t, J=7.2Hz, 2H), 5.41 (t, J=9.4Hz, 1H), 5.33 (d, J=9.8Hz, 1H), 5.27 (dd, J=18.0, 8.3Hz, 1H), 4.35 (d, J=9.9Hz, 1H), 4.22 – 4.18 (m, 1H), 4.16 – 4.07 (m, 2H), 4.01 (t, J=10.9Hz, 2H), 3.80 (d, J=5.6Hz, 3H), 1.25 – 1.20 (m, 9H), 1.20 – 1.15 (m, 9H), 1.14 – 1.09 (m, 19H), 0.87 (d, J=8.0Hz, 9H) .ESI-MSm/z:732.5 (M+1)+.
Embodiment 4
N
2in with the 50mL there-necked flask of thermometer, add III (2g, 2.73mmol) under protection, add DCM20mL, be cooled to-15 DEG C, slowly add BBr
3(2.74g, 10.92mmol) ,-10 DEG C of incubated overnight, add 2NHCl10mL after raw material reaction, separatory, and 15mLDCM extraction once, merges organic phase, dry, and concentrated, obtain faint yellow solid, column chromatography obtains II1.66g2.31mmol yield 85%.
1hNMR (501MHz, CDCl
3) δ 7.36 (d, J=8.1Hz, 1H), 7.28 (s, 1H), 7.27 (s, 1H), 7.22 – 7.17 (m, 2H), 7.02 (d, J=8.3Hz, 1H), 6.94 (d, J=8.3Hz, 1H), 5.46 (d, J=13.8Hz, 1H), 5.43 (t, J=9.4Hz, 1H), 5.33 (t, J=8.0Hz, 1H), 5.28 (dd, J=19.0, 9.4Hz, 1H), 4.37 (d, J=9.9Hz, 1H), 4.21 (d, J=11.9Hz, 1H), 4.12 (dd, J=12.4, 4.0Hz, 1H), 4.04 – 3.95 (m, 2H), 3.84 (dd, J=18.1, 10.4Hz, 1H), 1.26 – 1.21 (m, 9H), 1.19 (d, J=10.8Hz, 9H), 1.16 – 1.10 (m, 9H), 0.94 – 0.82 (m, 10H) .ESI-MSm/z:716.5 (M+1)+.
Embodiment 5
II (2.4g, 3.352mmol) is added, MeOH30mL, CsCO in the 50mL there-necked flask of thermometer
3(8.74g, 26.816mmol), adds (S)-3 iodo tetrahydrofuran (THF) (1.12g after stirring at room temperature 2h, 6.0336), room temperature for overnight, concentrated removing MeOH, adds DCM25mL, concentrated hydrochloric acid 10mL, separatory, 20mLDCM extraction once, merges organic phase, dry concentrated, obtaining the clean 1.16g yield of white solid Ai Gelie after methanol/water crystallization is 77%.
1hNMR (400MHz, DMSO) 7.70 (d, J=8.4Hz, 1H), 7.33 (d, J=2.0Hz, 1H), 7.24 (dd, J=2.0, 8.4Hz, 1H), 7.17 (ABq, J=8.8Hz, 2H), 6.82 (q, J=8.8Hz, 1H), 4.95 (m, 3H), 4.84 (d, J=6.4Hz, 1H), 4.46 (t, J=6.0Hz, 1H), 3.98 (m, 3H), 3.87-3.67 (m, 5H), 3.46-3.42 (m, 1H), 3.27-3.10 (m, 4H), 2.23-2.14 (m, 1H), 1.96-1.89 (m, 1H) .ESI-MSm/z:451.1 (M+1)+.
The above is only the citing of embodiments of the present invention; it should be pointed out that for those skilled in the art, under the prerequisite not departing from the technology of the present invention principle; can also make some improvement and modification, these improve and modification also should be considered as protection scope of the present invention.
Claims (8)
1. the preparation method that Yi Zhong Ai Gelie is clean, is characterized in that comprising the following steps:
1) first, reacted by the bromo-2-chloro-benzoic acid of 5-and methyl-phenoxide, obtain the bromo-2-chloro-phenyl-of 5--4-p-methoxy-phenyl-ketone V;
2) then, 5-bromo-2-chloro-phenyl--4-p-methoxy-phenyl-ketone obtains the bromo-2-of 5-chloro-4'-methoxyl group ditane IV through reduction reaction;
3) the bromo-2-of 5-chloro-4'-methoxyl group ditane and 2,3,4,6-O-tetra-pivaloyl group-ALPHA-D-bromo Glucopyranose obtain key intermediate III through linked reaction;
4) key intermediate III demethylation obtains key intermediate II;
5) intermediate II and (S)-3 iodo tetrahydrofuran (THF) become ether in the basic conditions and slough pivaloyl group to obtain Ai Gelie clean,
2. the preparation method that a kind of Ai Gelie as claimed in claim 1 is clean, is characterized in that: in step 1) in, the bromo-2-chloro-benzoic acid of described 5-and methyl-phenoxide, through friedel-crafts acylation, obtain the bromo-2-chloro-phenyl-of 5--4-p-methoxy-phenyl-ketone.
3. the preparation method that a kind of Ai Gelie as claimed in claim 2 is clean, it is characterized in that: in a solvent, the bromo-2-chloro-benzoic acid of 5-is first prepared into acyl chlorides with sulfur oxychloride or oxalyl chloride, then react under lewis acidic effect with methyl-phenoxide, control temperature is 0-80 DEG C, reaction 2-18h, obtains the bromo-2-chloro-phenyl-of 5--4-p-methoxy-phenyl-ketone; Described solvent is DMF, methylene dichloride, dithiocarbonic anhydride, ether or oil of mirbane; The consumption of solvent, by solvent: the bromo-2-chloro-benzoic acid of 5-is 1-10L:1mol; Described Lewis acid is aluminum chloride, zinc chloride, iron(ic) chloride, boron trifluoride or columbium pentachloride; Described lewis acidic consumption is by Lewis acid: the mol ratio of the bromo-2-chloro-benzoic acid of 5-is 0.8-2mol:1mol.
4. the preparation method that a kind of Ai Gelie as claimed in claim 1 is clean, it is characterized in that: in step 2) in, the bromo-2-chloro-phenyl-of described 5--4-p-methoxy-phenyl-ketone in a solvent, by going back the effect of original reagent, the bromo-2-of 5-chloro-4'-methoxyl group ditane is obtained through reduction reaction, solvent is selected from tetrahydrofuran (THF), ether, isopropyl ether, n-butyl ether, 2-methyltetrahydrofuran, or one or more in toluene, reaction times is 2-24h, also original reagent is selected from aluminum chloride, tin tetrachloride, sodium borohydride, trifluoroacetic acid, boron trifluoride diethyl etherate, iron trichloride, Lithium Aluminium Hydride, zinc dichloride, sulfuric acid, palladium chloride, or one or more in aluminum oxide, temperature of reaction is 0-100 DEG C.
5. the preparation method that a kind of Ai Gelie as claimed in claim 1 is clean, it is characterized in that: in step 3) in, the bromo-2-of described 5-chloro-4'-methoxyl group ditane is first obtained by reacting compound IV with organometallic reagent ', the mol ratio of the bromo-2-of 5-chloro-4'-methoxyl group ditane and organometallic reagent is 1:0.3-1.0, control temperature is-20-35 DEG C, and the reaction times is 12-36h; The mol ratio of the mixture of compound IV ' carry out being obtained by reacting IV with the mixture of zinc bromide and lithiumbromide again "; described compound IV ' and zinc bromide and lithiumbromide is 1mol:0.3-1.2mol; the proportioning between described zinc bromide and the mixture of lithiumbromide be 1mol:1mol in molar ratio; reaction solvent is one or more in oil of mirbane, toluene, dibutyl ether, ether, tetrahydrofuran (THF), hexane or pentane; control temperature is-10-55 DEG C and reacts, reaction times 0.2-6h; Compound IV " again with 2; 3; 4; 6-O-tetra-pivaloyl group-ALPHA-D-bromo Glucopyranose is obtained by reacting key intermediate III; reaction solvent is one or more in oil of mirbane, toluene, dibutyl ether, ether, tetrahydrofuran (THF), hexane, pentane; temperature of reaction is 25-145 DEG C, reaction times 3-30h.
6. the preparation method that a kind of Ai Gelie as claimed in claim 5 is clean, is characterized in that: described organometallic reagent is n-Hex (n-Bu)
2mgLi.
7. the preparation method that a kind of Ai Gelie as claimed in claim 1 is clean, it is characterized in that: in step (4), key intermediate III in a solvent, key intermediate II is obtained by reacting through demethylation by demethylation reagent effect, solvent for use is methylene dichloride, acetic acid, butyl ether, or one or more in bromobenzene, described demethylation reagent is hydrogen bromide, hydrogenchloride, hydrogen iodide, boron tribromide, boron trichloride, sodium iodide, aluminum chloride, sodium amide, one or more in lithium chloride, temperature of reaction is-30-100 DEG C, reaction times 0.5-25h.
8. the preparation method that a kind of Ai Gelie as claimed in claim 1 is clean, it is characterized in that: in step 5) in, intermediate II and (S)-3 iodo tetrahydrofuran (THF) in a solvent, under the effect of alkali, become ether and slough pivaloyl group to obtain Ai Gelie clean, described alkali is sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, potassium hydride KH, calcium hydroxide, salt of wormwood, cesium carbonate, sodium carbonate, sodium methylate, sodium ethylate, sodium tert-butoxide, or one or more in potassium tert.-butoxide, solvent for use is methyl alcohol, ethanol, Virahol, the trimethyl carbinol, or one or more in water, temperature of reaction is-30-100 DEG C, reaction times 0.5-25h.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017206808A1 (en) * | 2016-05-30 | 2017-12-07 | 上海医药工业研究院 | Process for preparing dapagliflozin eutectic matter |
| WO2018224957A1 (en) | 2017-06-05 | 2018-12-13 | Laurus Labs Limited | Novel process for preparation of empagliflozin or its co-crystals, solvates and their polymorphs thereof |
| CN111995507A (en) * | 2020-09-23 | 2020-11-27 | 浙江宏元药业股份有限公司 | Application of combined catalyst in specific Friedel-crafts reaction |
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| CN111995507A (en) * | 2020-09-23 | 2020-11-27 | 浙江宏元药业股份有限公司 | Application of combined catalyst in specific Friedel-crafts reaction |
| CN111995507B (en) * | 2020-09-23 | 2022-07-22 | 浙江宏元药业股份有限公司 | Application of combined catalyst in specific Friedel-crafts reaction |
| CN114716425A (en) * | 2022-04-11 | 2022-07-08 | 沧州那瑞化学科技有限公司 | Synthetic method of aromatic heterocyclic substituted methylene compound |
| CN114716425B (en) * | 2022-04-11 | 2023-09-01 | 沧州那瑞化学科技有限公司 | Synthesis method of aromatic heterocyclic substituted methylene compound |
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