CN104478670A - Preparation method of 5-bromine-2-chlorine-4'-ethyoxyl diphenylmethane - Google Patents
Preparation method of 5-bromine-2-chlorine-4'-ethyoxyl diphenylmethane Download PDFInfo
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Abstract
The invention relates to the chemical field and particularly relates to a novel synthesis method for preparing a key intermediate 5-bromine-2-chlorine-4'-ethyoxyl diphenylmethane of a drug dapagliflozin for treating diabetes mellitus II. The preparation method comprises the following steps: enabling a starting raw material ortho-toluidine to firstly perform bromization and then perform chlorination after diazotization on a benzene ring with N-bromo-succinimide; then, in the presence of a halogenating agent, performing halogenating reaction of beta-position; and finally, performing Friedel-Crafts alkylation synthesis with phenetole, thereby obtaining the key intermediate. The preparation method is simple and convenient, economical and relatively high in reaction yield in each step, and suitable for industrial production.
Description
Technical field:
The present invention relates to the synthetic method of the chloro-4 '-ethoxy diphenyl methane of the bromo-2-of the clean important intermediate 5-of a kind of Da Gelie.
Background technology:
Da Gelie clean (Dapagliflozin) is the white 2 (Sodium-glucoseco-transporter-2 of sodium glucose co-transporter 2, SGLT2) inhibitor, C-aryl glucoside compounds, chemistry is by name: (2S, 3R, 4R, 5S, 6R)-2-[3-(4-phenetole methyl)-4-chloro-phenyl-]-6-methylol tetrahydrochysene-2H-pyrans-3,4,5-triol.Da Gelie by suppressing kidney sodium glucose co-transporter 2 white 2, suppresses the heavily absorption of blood sugar only, thus glucose level in control agent; Can significantly reduce patient's glycated hemoglobin levels and body weight simultaneously.Da Gelie, only by Shi Guibao company and AstraZeneca cooperative research and development, is second SGLT2 inhibitor of U.S. FDA approval listing, is used for the treatment of diabetes B.
The clean synthetic method Relatively centralized of existing Da Gelie, all using the chloro-4 '-ethoxy diphenyl methane of the bromo-2-of 5-as its key intermediate.Comparatively classical synthetic method (patent US6414126B1) is: the chloro-4 '-ethoxy diphenyl methane warp of the bromo-2-of 5-is with 2,3,4, the condensation under butyllithium effect of 6-tetra--O-TMS-D-glucopyra saccharic acid-1,5-lactone, anomeric carbon etherification of hydroxyl groups and de-TMS protecting group obtain the chloro-5-of 2-(1-methoxy-D-glucopyranos-1-base)-4 '-ethoxy diphenyl methane; Then again through reduction, esterification, recrystallization removing end position epimer, be finally hydrolyzed arrive lattice row only.Therefore, 5-bromo-2
-chloro-4 '-ethoxy diphenyl methane is only most important for synthesis Da Gelie.But the synthetic method of the bromo-2-of 5-chloro-4 '-ethoxy diphenyl methane of bibliographical information is comparatively single.
Synthetic method (the Wei Meng of the chloro-4 '-ethoxy diphenyl methane of the bromo-2-of 5-of the report such as Wei Meng; J.Med.Chem.2008; 51.1145-1149) with raw material sources comparatively difficulty, the relatively costly chloro-phenylformic acid of the bromo-6-of 3-of price for starting raw material; first acidylate is carried out with oxalyl chloride; then carry out Fu-Ke acidylate with phenetole, finally carbonyl reduction is obtained.The advantage of this synthetic method is that synthetic route is shorter, and shortcoming is then that cost of material is more expensive, and yield is low, especially employ there is carcinogenesis 1,2-ethylene dichloride (EDC) as solvent.Its synthetic route is as follows:
(Yu Yankun, Chinese Journal of Pharmaceuticals, 2011 such as Yu Yankun, 42 (2)) improvement to above-mentioned route is reported, using sodium borohydride/aluminum chloride system instead is methylene radical by carbonyl reduction, and yield reaches 92%, but two-step reaction all uses aluminum trichloride (anhydrous).Because aluminum chloride is strict to anhydrous requirement, feed ratio is 2 times of equivalents of reduction substrate, like this, can form a large amount of alumine hydroxide colloids in last handling process, and particularly after industrial scale is amplified, this can bring very large difficulty to aftertreatment.
Summary of the invention:
Technical problem to be solved by this invention be to provide a kind of simple and easy to do, raw material is easy to get, respectively walk yield and total recovery is all higher, the synthetic method of the chloro-4 '-ethoxy diphenyl methane of the bromo-2-of Da Gelie clean key intermediate 5-that is easy to realize suitability for industrialized production.
The present invention includes following steps:
Step (1): with Ortho Toluidine 1 for starting raw material, in organic solvent, and there is the bromo-reaction on phenyl ring in N-bromo-succinimide (NBS), obtains the bromo-2-aminotoluene 2 of 4-:
Step (2): the product in step (1) is dissolved in hydrochloric acid soln, adds sodium nitrite in aqueous solution, obtains diazonium compound, under cuprous chloride and hydrochloric acid, through Sandmeyer reaction, obtains the bromo-2-toluene(mono)chloride 3 of 5-;
Step (3): the product in step (2), in organic solution, under the existence of 2,2-Diisopropyl azodicarboxylate (AIBN), and the halogenating reaction of halogenating agent generation benzyl position, generates compound 4;
Step (4): the product in step (3) is under the existence of Lewis acid, and phenyl ethyl ether reaction, obtains the chloro-4 '-ethoxy diphenyl methane 5 of the bromo-2-of Fu-Ke alkylate 5-.
In described step (1), the mol ratio of Ortho Toluidine and NBS is 1: 1 ~ 1.5, optimal selection 1: 1.1.Temperature of reaction is 0 DEG C ~ 25 DEG C, optimal selection 0 DEG C ~ 5 DEG C.Reaction times is 1 ~ 24h, optimal selection 4 ~ 6h, reaction solvent can be optional the formed mixed solvent of water, acetonitrile, toluene, chloroform, tetracol phenixin, tetrahydrofuran (THF), ethyl acetate, methylene dichloride, hexanaphthene, ether, dimethyl sulfoxide (DMSO), acetone, dimethyl formamide, N,N-DIMETHYLACETAMIDE, Isosorbide-5-Nitrae-dioxane or above-mentioned solvent.Preferential employing dimethyl formamide, N,N-DIMETHYLACETAMIDE.
In step (2), the bromo-2-aminotoluene of 4-forms the concentration of hydrochloric acid of hydrochloride is 1mol/L ~ 12mol/L, optimal selection 3mol/L, the mol ratio of the bromo-2-aminotoluene of 4-and hydrogenchloride is 1: 1 ~ 20, optimal selection 1: 3, the concentration of sodium nitrite in aqueous solution is 10% ~ 40%, prioritizing selection 20%, the mol ratio of the bromo-2-aminotoluene of 4-and Sodium Nitrite is 1: 1 ~ 3, optimal selection 1: 1.1, temperature of reaction is-20 DEG C ~ 10 DEG C, optimal selection-10 DEG C ~ 0 DEG C.In step (2), the concentration of hydrochloric acid of cuprous chloride hydrochloric acid soln is 1mol/L ~ 12mol/L, optimal selection 3mol/L, the mol ratio of cuprous chloride and hydrogenchloride is 1: 1 ~ 20, optimal selection 1: 3, the mol ratio of the bromo-2-aminotoluene of 4-and cuprous chloride is 1: 0.5 ~ 10, optimal selection 1: 1, and temperature of reaction is 50 DEG C ~ 100 DEG C, optimal selection 80 DEG C, the reaction times is 1 ~ 10h.
In step (3), X is chlorine, bromine, and halogenating agent is N-bromo-succinimide (NBS), N-chlorosuccinimide (NCS).Preferentially select N-bromo-succinimide.In step (3), the mol ratio of the bromo-2-toluene(mono)chloride of 5-and halogenating agent is 1: 1 ~ 3, optimal selection is 1: 1.2, the bromo-2-toluene(mono)chloride of 5-and 2, the mol ratio of 2-Diisopropyl azodicarboxylate (AIBN) is 1: 0.1 ~ 2, optimal selection is 1: 0.2, temperature of reaction is 25 DEG C ~ 80 DEG C, optimal selection 65 DEG C.Reaction times is 1 ~ 10h, and reaction solvent can be optional the formed mixed solvent of sherwood oil, methylene dichloride, chloroform, tetracol phenixin, ethyl acetate, acetonitrile, toluene, tetrahydrofuran (THF), hexanaphthene or above-mentioned solvent.Preferential employing chloroform.In step (3), the purification process of compound 4 is: compound 4 is dissolved in sherwood oil, methylene dichloride, ethyl acetate, hexanaphthene, normal hexane, N, dinethylformamide, N, in optional the formed mixed solvent of N-N,N-DIMETHYLACETAMIDE, toluene, acetonitrile, acetone or above-mentioned solvent, add optional the formed mixed solvent of ethanol, methyl alcohol, Virahol, propyl carbinol or this kind solvent wherein, the solid filtering formed, is highly purified compound 4.
In step (4), the mol ratio of compound 4 and phenyl ethyl ether is 1: 1 ~ 30, optimal selection 1: 5, the mol ratio of the bromo-2-of 4-(brooethyl)-chlorobenzene and zinc chloride is 1: 0.1 ~ 10, optimal selection 1: 1 ~ 2, temperature of reaction is 0 DEG C ~ 100 DEG C, optimal selection 75 DEG C, the reaction times is 1 ~ 24h, and reaction solvent can be optional the formed mixed solvent of phenyl ethyl ether, oil of mirbane, hexanaphthene, methylene dichloride, chloroform, ethyl acetate, tetracol phenixin or above-mentioned solvent.Preferential employing phenyl ethyl ether, chloroform.In step (4), the purification process of the bromo-2-of 5-chloro-4 '-ethoxy diphenyl methane is: chloro-for bromo-for 5-2-4 '-ethoxy diphenyl methane is dissolved in sherwood oil, methylene dichloride, ethyl acetate, hexanaphthene, normal hexane, N, dinethylformamide, N, in optional the formed mixed solvent of N-N,N-DIMETHYLACETAMIDE, toluene, acetonitrile, acetone or above-mentioned solvent, add optional the formed mixed solvent of ethanol, methyl alcohol, Virahol, propyl carbinol or this kind solvent wherein, the solid filtering formed, is the chloro-4 '-ethoxy diphenyl methane of the bromo-2-of highly purified 5-.
The present invention is with Ortho Toluidine cheap and easy to get for starting raw material, and the first step reaction conditions is gentle, and easy and simple to handle, yield is high; Second step is classical Sandmeyer reaction, and reaction conditions is gentle, and yield is high, and first two steps do not need to be further purified after reacting simple aftertreatment just to may be used for the next step, is applicable to industrial production.Four-step reaction is the alkylation of phenyl ethyl ether, and catalyzer zinc chloride used requires low compared to aluminum chloride is anhydrous, and aftertreatment is easy.The invention provides the synthetic method of the chloro-4 '-ethoxy diphenyl methane of the bromo-2-of a kind of brand-new Da Gelie clean key intermediate 5-, be applicable to industrialization, enrich the synthetic route of the chloro-4 '-ethoxy diphenyl methane of the bromo-2-of 5-, provide more more options to manufacturing enterprise.
Embodiment:
Below by embodiment, the present invention is described further, but embodiment does not limit the scope of the invention.
(1) preparation of the bromo-2-aminotoluene of 4-
The Ortho Toluidine of 8.1ml (75.4mmol) is placed in the dry mono-neck bottle of 250ml, ice-water bath lower magnetic force stirs.13.5g (75.8mmol) N-bromo-succinimide is dissolved in 60ml DMF, is placed in dropping funnel and slowly instillation, maintains reaction solution about 0 DEG C, dropwise reaction 5h.Poured into by reaction solution in 600ml frozen water, separate out solid, suction filtration obtains solid, aqueous phase 50ml extraction into ethyl acetate, concentrate to obtain a small amount of solid, combining solid sherwood oil (25ml*3) washing, obtains 13.2g solid,, yield is 95%, and product is not purified is directly used in the next step.m.p.50-52℃.
1H-NMR(DMSO-d
6，300MHz)δ：2.0(s，3H)，5.0(brs，2H)，6.5-7.0(m，3H)。
(2) preparation of the bromo-2-toluene(mono)chloride of 5-
The bromo-2-aminotoluene of 11.7g (63.2mmol) 4-is joined in the hydrochloric acid soln of 45ml (6mol/L), fully stirs evenly, make salify.The solution formed is placed in cryosel bath, is cooled to less than-5 DEG C, and slowly drip the sodium nitrite solution (4.8g, 69.5mmol, 20ml) of about 20%, holding temperature is lower than 0 DEG C.Drip, add the Isosorbide-5-Nitrae-dioxane of 12ml, stir evenly.Above-mentioned diazonium salt solution is slowly added the cuprous chloride (6.7g being in ice-water bath, in the hydrochloric acid soln (20ml) of 3mol/L 66.4mmol), and vigorous stirring, be added dropwise to complete rear stirring at room temperature 0.5h, be then warming up to 80 DEG C of reaction 3h.Cooling, methylene dichloride (75ml*2) extracts, and extraction liquid is through saturated NaHCO
3solution (150ml), water (150ml) and saturated aqueous common salt (100ml*2) wash, and anhydrous sodium sulfate drying spends the night, and concentrating under reduced pressure obtains reddish-brown liquid 11.2g (yield 87%).
1H-NMR(CDCl
3，300MHz)δ：2.3(s，3H)，7.1-7.2(m，3H)。
(3) preparation of the bromo-2-of 4-(brooethyl)-chlorobenzene
By bromo-for 4.1g (20mmol) 5-2-toluene(mono)chloride, 0.66g (4mmol) 2,2-Diisopropyl azodicarboxylate, 3.9g (22mmol) N-bromo-succinimide and 20ml chloroform drop in the dry two neck bottles of 50ml, backflow 5h.Sherwood oil (75ml) dilutes, filtering solid, and filtrate water (100ml), saturated aqueous common salt (100ml*2) wash, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, residuum ethyl alcohol recrystallization obtains 4.1g needle crystal (yield 72%).m.p.59-63℃.
1H-NMR(CDCl
3，300MHz)δ：4.5(s，2H)，7.2-7.5(m，3H)。
(4) preparation of the chloro-4 '-ethoxy diphenyl methane of the bromo-2-of 5-
The bromo-2-of 3.1g (10.9mmol) 4-(brooethyl)-chlorobenzene is joined in the phenyl ethyl ether (5ml) containing zinc chloride (21.9mmol), at 75 DEG C, react 6h.Cooling, after reaction solution adds hydrochloric acid soln acidifying, ethyl acetate (50ml*2) extracts, and organic layers with water (100ml), saturated aqueous common salt (100ml*2) wash, anhydrous sodium sulfate drying.Cross and filter siccative, filtrate reduced in volume, residue obtains solid 2.5g through ethyl alcohol recrystallization, yield 71%.m.p.38℃～40℃，ES-MS(m/z)：325.0[M
+]；
1H-NMR(CDCl
3，75MHz)δ：1.4(t，J＝6.99Hz，3H)，3.9(s，2H)，4.0(q，J＝6.99Hz，2H)，6.8(d，J＝8.67Hz，2H)，7.1(d，J＝8.67Hz，2H)，7.2-7.3(m，3H)；
13C-NMR(CDCl
3，300MHz)δ：157.5，141.9，133.9，132.8，132.1，131.7，131.5，131.2，130.8，130.1，1205，1148，634，376，151。
Claims (9)
1. the synthetic method of the clean key intermediate of Yi Zhong Da Gelie, is characterized in that, comprise the following steps:
Step (1): with Ortho Toluidine 1 for starting raw material, in organic solvent, and there is the bromo-reaction on phenyl ring in N-bromo-succinimide (NBS), obtains the bromo-2-aminotoluene 2 of 4-;
Step (2): the product in step (1) is dissolved in hydrochloric acid, adds sodium nitrite in aqueous solution, obtains diazonium compound, under cuprous chloride and hydrochloric acid condition, through Sandmeyer reaction, obtains the bromo-2-toluene(mono)chloride 3 of 5-;
Step (3): the product in step (2), in organic solution, under the existence of 2,2-Diisopropyl azodicarboxylate (AIBN), and the halogenating reaction of halogenating agent generation benzyl position, generates compound 4;
Step (4): the product in step (3) is under the existence of zinc chloride, and phenyl ethyl ether reaction, obtains the chloro-4 '-ethoxy diphenyl methane 5 of the bromo-2-of Fu-Ke alkylate 5-.
2. preparation method according to claim 1, is characterized in that, in step (1), the mol ratio of Ortho Toluidine and NBS is 1: 1 ~ 2.Temperature of reaction is 0 DEG C ~ 25 DEG C.Reaction times is 1 ~ 24h, reaction solvent can be optional the formed mixed solvent of water, acetonitrile, toluene, chloroform, tetracol phenixin, tetrahydrofuran (THF), ethyl acetate, methylene dichloride, hexanaphthene, ether, dimethyl sulfoxide (DMSO), acetone, dimethyl formamide, N,N-DIMETHYLACETAMIDE, Isosorbide-5-Nitrae-dioxane or above-mentioned solvent.Preferential employing dimethyl formamide, N,N-DIMETHYLACETAMIDE.
3. preparation method according to claim 1, it is characterized in that, in step (2), the bromo-2-aminotoluene of 4-forms the concentration of hydrochloric acid of hydrochloride is 1mol/L ~ 12mol/L, the mol ratio of the bromo-2-aminotoluene of 4-and hydrogenchloride is 1: 1 ~ 20, the concentration of sodium nitrite in aqueous solution is 10% ~ 40%, the mol ratio of the bromo-2-aminotoluene of 4-and Sodium Nitrite is 1: 1 ~ 3, and temperature of reaction is-20 DEG C ~ 10 DEG C.
4. the preparation method according to claim 1 and 3, it is characterized in that, in step (2), the concentration of hydrochloric acid of cuprous chloride hydrochloric acid soln is 1mol/L ~ 12mol/L, the mol ratio of cuprous chloride and hydrogenchloride is 1: 1 ~ 20, the mol ratio of the bromo-2-aminotoluene of 4-and cuprous chloride is 1: 0.5 ~ 10, temperature of reaction is 50 DEG C ~ 100 DEG C, and the reaction times is 1 ~ 10h.
5. preparation method according to claim 1, is characterized in that, in step (3), X is chlorine, bromine, and halogenating agent is N-chlorosuccinimide (NCS), N-bromo-succinimide (NBS).Preferentially select N-bromo-succinimide.
6. the preparation method according to claim 1 and 5, it is characterized in that, be 1: 1 ~ 3 in the mol ratio of the bromo-2-toluene(mono)chloride of step (3) 5-and halogenating agent, the bromo-2-toluene(mono)chloride of 5-and 2, the mol ratio of 2-Diisopropyl azodicarboxylate (AIBN) is 1: 0.1 ~ 2, and temperature of reaction is 25 DEG C ~ 80 DEG C.Reaction times is 1 ~ 10h, and reaction solvent can be optional the formed mixed solvent of sherwood oil, methylene dichloride, chloroform, tetracol phenixin, ethyl acetate, acetonitrile, toluene, tetrahydrofuran (THF), hexanaphthene or above-mentioned solvent.Preferential employing chloroform.
7. the preparation method according to claim 1,5 and 6, it is characterized in that, in step (3), the purification process of compound 4 is: compound 4 is dissolved in sherwood oil, methylene dichloride, ethyl acetate, hexanaphthene, normal hexane, N, dinethylformamide, N, in optional the formed mixed solvent of N-N,N-DIMETHYLACETAMIDE, toluene, acetonitrile, acetone or above-mentioned solvent, add optional the formed mixed solvent of ethanol, methyl alcohol, Virahol, propyl carbinol or this kind solvent wherein, the solid filtering formed, is highly purified compound 4.
8. preparation method according to claim 1, it is characterized in that, in step (4), the mol ratio of compound 4 and phenyl ethyl ether is 1: 1 ~ 30, the mol ratio of the bromo-2-of 4-(brooethyl)-chlorobenzene and zinc chloride is 1: 0.1 ~ 10, temperature of reaction is 0 DEG C ~ 100 DEG C, reaction times is 1h ~ 24h, and reaction solvent can be optional the formed mixed solvent of phenyl ethyl ether, oil of mirbane, hexanaphthene, methylene dichloride, chloroform, ethyl acetate, tetracol phenixin or above-mentioned solvent.Preferential employing phenyl ethyl ether, chloroform.
9. according to claim 1, preparation method described in 7 and 8, it is characterized in that, in step (4), the purification process of the bromo-2-of 5-chloro-4 '-ethoxy diphenyl methane is: chloro-for bromo-for 5-2-4 '-ethoxy diphenyl methane is dissolved in sherwood oil, methylene dichloride, ethyl acetate, hexanaphthene, normal hexane, N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, toluene, acetonitrile, in acetone or optional the formed mixed solvent of above-mentioned solvent, add ethanol wherein, methyl alcohol, Virahol, propyl carbinol or optional the formed mixed solvent of this kind solvent, the solid formed, be the chloro-4 '-ethoxy diphenyl methane of the bromo-2-of highly purified 5-.
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| WO2017063327A1 (en) * | 2015-10-15 | 2017-04-20 | 上海应用技术学院 | Novel c-spiro-o-glycoside compound intermediate and preparation method therefor |
| CN107652277A (en) * | 2017-08-09 | 2018-02-02 | 江苏工程职业技术学院 | A kind of preparation method net Yi Palie |
| CN107652276A (en) * | 2017-08-09 | 2018-02-02 | 江苏工程职业技术学院 | A kind of preparation method net SGLT2 inhibitor Yi Palie |
| CN107652278A (en) * | 2017-08-09 | 2018-02-02 | 江苏工程职业技术学院 | A kind of synthesis technique net Yi Palie |
| CN108084130A (en) * | 2017-12-15 | 2018-05-29 | 东南大学 | A kind of preparation method of antidiabetic drug Dapagliflozin |
| CN112920030A (en) * | 2021-02-05 | 2021-06-08 | 安庆奇创药业有限公司 | Method for preparing dapagliflozin intermediate by one-pot method |
| CN114577944A (en) * | 2022-03-10 | 2022-06-03 | 山东鲁抗医药股份有限公司 | Method for detecting related substances in 5-bromo-2-chloro-4' -ethoxy diphenylmethane |
| CN115710165A (en) * | 2022-11-17 | 2023-02-24 | 北京擎科生物科技有限公司 | Method for preparing 4,4' -bis (methoxy) trityl chloride by using oligonucleotide synthesis waste liquid |
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| CN105061177A (en) * | 2015-08-12 | 2015-11-18 | 黄石市利福达医药化工有限公司 | Preparation method of 10,10-dimethylanthrone |
| CN105061177B (en) * | 2015-08-12 | 2018-05-29 | 黄石市利福达医药化工有限公司 | A kind of preparation method of 10,10-- dimethyl anthrone |
| WO2017063327A1 (en) * | 2015-10-15 | 2017-04-20 | 上海应用技术学院 | Novel c-spiro-o-glycoside compound intermediate and preparation method therefor |
| CN107652277A (en) * | 2017-08-09 | 2018-02-02 | 江苏工程职业技术学院 | A kind of preparation method net Yi Palie |
| CN107652276A (en) * | 2017-08-09 | 2018-02-02 | 江苏工程职业技术学院 | A kind of preparation method net SGLT2 inhibitor Yi Palie |
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| CN108084130A (en) * | 2017-12-15 | 2018-05-29 | 东南大学 | A kind of preparation method of antidiabetic drug Dapagliflozin |
| CN112920030A (en) * | 2021-02-05 | 2021-06-08 | 安庆奇创药业有限公司 | Method for preparing dapagliflozin intermediate by one-pot method |
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| CN114577944B (en) * | 2022-03-10 | 2023-08-15 | 山东鲁抗医药股份有限公司 | Detection method for related substances in 5-bromo-2-chloro-4' -ethoxydiphenylmethane |
| CN115710165A (en) * | 2022-11-17 | 2023-02-24 | 北京擎科生物科技有限公司 | Method for preparing 4,4' -bis (methoxy) trityl chloride by using oligonucleotide synthesis waste liquid |
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