CN102942542B - The preparation method of 2,3-Dihydrobenzofuranes compounds - Google Patents
The preparation method of 2,3-Dihydrobenzofuranes compounds Download PDFInfo
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- ZPMNHBXQOOVQJL-UHFFFAOYSA-N COCCCN(CC1)CCC1NC(c(c1c2CCO1)cc(Cl)c2N)=O Chemical compound COCCCN(CC1)CCC1NC(c(c1c2CCO1)cc(Cl)c2N)=O ZPMNHBXQOOVQJL-UHFFFAOYSA-N 0.000 description 2
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Abstract
The invention discloses a kind of 2; the preparation method of 3-Dihydrobenzofuranes compounds, it is to replace to allyl group o-hydroxy methyl esters between amino for raw material, by reactions such as a series of oxidation, reduction, protection, replacement, Guan Huan, hydrolysis; prepare 2,3-Dihydrobenzofuranes compounds.This preparation method reacts simple, and cost is low, and transformation efficiency is high, and aftertreatment is simple, is easy to suitability for industrialized production.
Description
Technical field
The invention belongs to organic synthesis field, be specifically related to the preparation of prucalopride key intermediate 2,3-Dihydrobenzofuranes compounds.
Background technology
Succsinic acid prucalopride (Prucalopride succinate, chemical name 4-amino-5-chloro-2, 3-dihydro-N-[1-(3-methoxy-propyl)-4-piperidyl]-7-benzofuran carboxamides succinate), developed according to the authorization of Janssen company (under Johnson & Johnson Subsidiary Company) by Belgian Movetis company, in October, 2009 is used for the treatment of women's chronic constipation the U.S. is granted, in October, 2009 gets the Green Light in Europe, in January, 2010 goes on the market in Germany, in March, 2010 goes on the market in Britain, trade(brand)name Resolor.China ratifies the clinical trial of tablet in China of Janssen Pharmaceutica N.V. company, for the symptomatic treatment of women's chronic constipation that cathartic cannot fully be alleviated in April, 2010.Succsinic acid prucalopride is the first novel serotonin 5-HT4 receptor-selective, high-affinity antagonists, wriggling can be triggered, compared with similar drugs, have that 5-HT4 receptor-selective is high, avidity is strong, rapid-action, untoward reaction is few, the feature of better tolerance, have wide potential applicability in clinical practice in constipation therapy field.
Compound patent US5854260A disclose chloro-2, the 3-Dihydrobenzofuranes-7-carboxylic acids of 4-amino-5-directly and the condensation of 1-(3-methoxy-propyl)-4-piperylhydrazine, salify obtain the method for succsinic acid prucalopride.This route steps is simple, and yield is higher, is applicable to suitability for industrialized production.
The key intermediate of ambroid acid prucalopride is chloro-2, the 3-Dihydrobenzofuranes-7-carboxylic acids (compound 1) of 4-amino-5-, and synthetic method has following several:
Patent of invention US5374637 take m-anisidine as raw material; protect through pivaloyl group; hydroxyethylation, cyclization, chloro, bromo under butyllithium effect, finally obtain chloro-2, the 3-Dihydrobenzofuranes-7-carboxylic acids of 4-amino-5-under butyllithium effect with carbon dioxide reaction.This route uses butyllithium twice, needs-78 DEG C of low temperature, and the isomer that chloro produces need through pillar layer separation, operation inconvenience, and yield only has 18%.
Document [Synlett 1993, (4), 269-270] with 4-acetamido-2 hydroxybenzoic acid methyl esters for raw material, cyclization after chloro, iodo, trimethylsilyl acetylene, hydro-reduction under rhodium catalysis, finally hydrolysis obtains 4-amino-5-chloro-2,3-Dihydrobenzofuranes-7-carboxylic acid, yield 38%, uses silica reagent and the rhodium reagent of high price, is unsuitable for a large amount of preparation in route.
Document [Chem.Pharm.Bull.1998; 46 (1); 42-52] be raw material with para-aminosalicylic acid; after esterification, acetylize, on hydroxyl, reaction generates allyl group; allyl group moves to hydroxyl ortho position in a heated condition; then alkene is oxidized to the aldehyde of a few carbon atom, then becomes alcohol with sodium borohydride reduction.At catalysis ShiShimonoseki ring of triphenyl phosphorus, slough protecting group after chlorination and generate chloro-2, the 3-Dihydrobenzofuranes-7-carboxylic acids of 4-amino-5-.This highway route design is reasonable, and productivity ratio is more satisfactory, but has used hypertoxic perosmic anhydride reagent in reaction, there is labour protection problem, and has column chromatography to operate in the aftertreatment of a few step reaction, is not suitable for suitability for industrialized production.
Document [former friendly will; man of Tang Deng; Cen Junda. Chinese Journal of Pharmaceuticals 2012; 43 (1); 5-8] be raw material with para-aminosalicylic acid; chloro-2, the 3-Dihydrobenzofuranes-7-carboxylic acids of 4-amino-5-are obtained after esterification, acetylize and chloro, bromo, bromotrifluoromethane, cyclization and hydrolysis.Operation is easy, mild condition, but productive rate is on the low side, is not suitable for a large amount of production.
Therefore, the key intermediate seeking succsinic acid prucalopride is the synthetic method of chloro-2, the 3-Dihydrobenzofuranes-7-carboxylic acids (compound 1) of 4-amino-5-, is significant.
Summary of the invention
The object of the invention is to provide a kind of 2, the preparation method of 3-Dihydrobenzofuranes compounds [structure is as shown in formula I], to synthesize chloro-2, the 3-Dihydrobenzofuranes-7-carboxylic acids (compound 1) of 4-amino-5-, for the preparation of succsinic acid prucalopride, to meet the needs of related industries department.
The present invention also aims to the preparation method that another kind of 2,3-Dihydrobenzofuranes compounds [structure is such as formula III Suo Shi] is provided.
2,3-described Dihydrobenzofuranes compounds comprise the salt that the free alkali or its organic acid with formula I, formula (I ") and the compound shown in III or mineral acid are formed.
Object of the present invention can be reached by following measures:
A kind of preparation method of 2,3-Dihydrobenzofuranes compounds, adopts compound 7 to be starting raw material, selects ruthenium trichloride or its hydrate/periodate composite catalyst to promote reaction, obtains compound 6; Obtain compound 5 after aldehyde radical in compound 6 is reduced to hydroxyl, then be substituted leavings group Z on reaction forming, proceed ring closure reaction and obtain compound (I), then obtain compound 2 through chlorination, obtain compound 1 finally by hydrolysis reaction,
Wherein, R is C
1-6straight chained alkyl, benzyl, halogeno-benzyl, C
1-4alkyl benzyl, diphenyl-methyl or the tertiary butyl, be preferably methyl; X is carbobenzoxy-(Cbz), tertbutyloxycarbonyl or C
1-6straight chained alkyl acyl group, is preferably ethanoyl; Z is halogen, tolysulfonyl oxygen base, trimethyl fluoride sulfonyl oxygen base, mesyloxy or phenylsulfonyloxy; Wherein halogen is preferably chlorine.
Starting material compound 7 reference [Chem.Pharm.Bull.1998,46 (1), 42-52] method can be made by oneself or be purchased.
In the reaction preparing compound 6, catalyzer selects ruthenium trichloride or its hydrate/periodate composite catalyst, and wherein periodate can adopt sodium periodate or potassium periodate.Further, ruthenium trichloride/sodium periodate, ruthenium trichloride/potassium periodate, ruthenium trichloride hydrate/sodium periodate or ruthenium trichloride hydrate/potassium periodate composite catalyst selected by catalyzer.In composite catalyst, the mole dosage of ruthenium trichloride or its hydrate is 1% ~ 8% of compound 7, preferably 2% ~ 4%; The molar weight of periodate is 1 ~ 10 times of compound 7, preferably 3 ~ 6 times; This temperature of reaction is 0 ~ 80 DEG C, preferably 10 DEG C ~ 40 DEG C, and this reaction times is 1 ~ 12h.
The composite catalyst that this reaction is selected, cheap and easy to get, avoid the Cost Problems that the silica reagent of high price and rhodium reagent place bring, avoid the harm using the perosmic anhydride reagent of severe toxicity to cause environment simultaneously.
Present invention also offers the customary preparation methods of compound 5 and compound 4, but be not limited only to following method:
Adopting compound 6 under the effect of sodium borohydride, reduce aldehyde radical is hydroxyl, and prepare compound 5, its reaction solvent can select methyl alcohol or tetrahydrofuran (THF), and temperature of reaction is 20 DEG C ~ 30 DEG C, after reaction with acid for adjusting pH value to 5-6.
Adopt compound 5 or the reaction such as its salt and sulfur oxychloride, Tosyl chloride, trimethyl fluoride sulfonyl chlorine, methylsulfonyl chloride or benzene sulfonyl chloride, prepare compound 4 or its salt, reactant preferably adopts sulfur oxychloride or Tosyl chloride, most preferably sulfur oxychloride.Concrete grammar can adopt existing ordinary method, such as, after being dissolved by compound 5, drips sulfur oxychloride or Tosyl chloride under low temperature, chlorination obtains compound 4, this reaction solvent is DMF or methylene dichloride, and temperature of reaction is 0 DEG C ~ 30 DEG C.
In the reaction preparing compound (I), compound 4 carries out ring closure reaction under organic bases or mineral alkali catalysis, prepares compound (I); Wherein said organic bases or mineral alkali are selected from one or more in salt of wormwood, sodium carbonate, sodium bicarbonate, saleratus, potassium hydroxide, sodium hydroxide, triethylamine, tri-n-butylamine or tri-tert amine; The consumption of organic bases or mineral alkali is 1 ~ 4 times of compound 4 molar weight.This reaction can be carried out, in organic solvent as DMF or THF; The temperature of reaction controls in room temperature to reflux temperature, preferably 20 DEG C ~ 100 DEG C.
This reaction changes route in the past, alcoholic extract hydroxyl group is carried out substitution reaction, the leavings group connected, then carries out Guan Huan, be obtained by reacting target compound (I).This route comparatively other pass ring methods is compared, and reaction is simple, and cost is low, and transformation efficiency is high, and aftertreatment is simple, is easy to suitability for industrialized production.
Present invention also offers the customary preparation methods being obtained by reacting succsinic acid prucalopride key intermediate compound 1 by compound (I), but be not limited only to following method:
Compound (I) and N-chlorosuccinimide are obtained by reacting compound 2 at 30 DEG C ~ 100 DEG C.Compound 2 reacts under sodium hydroxide effect, then with acid for adjusting pH value to 6-7, obtains compound 1.Such as when R is methyl, when X is ethanoyl, compound 2 and sodium hydroxide can be reacted at 40 ~ 100 DEG C, after reaction again with acid for adjusting pH value to 6-7, to obtain final product.
When reacting preparation 2,3-Dihydrobenzofuranes compounds by compound 5, there are two kinds of routes: namely the phenolic hydroxyl group contraposition of the derivative of compound 7 first can go up chlorine before ring-closure reaction, also after closed loop, can go up chlorine again.After the alcoholic extract hydroxyl group of compound 5 is replaced by leavings group, ring-closure reaction, then phenolic hydroxyl group contraposition under the effect of the chlorinating agents such as sulfuryl chloride on chlorine time, namely obtain compound (I ").When the alcoholic extract hydroxyl group of compound 5 is replaced by leavings group, then ring-closure reaction, obtains compound (I), then under the effect of the chlorinating agents such as N-chlorosuccinimide, upper for phenolic hydroxyl group contraposition reaction chlorine is obtained compound 2.
Therefore present invention also offers the preparation method of another kind of 2,3-Dihydrobenzofuranes compounds, adopt compound 7 to be starting raw material, select ruthenium trichloride or its hydrate/periodate composite catalyst to promote reaction, obtain compound 6 or its salt; Compound 5 or its salt is obtained after aldehyde radical in compound 6 or its salt is reduced to hydroxyl, continue to be substituted leavings group Z on reaction forming after carrying out reaction chlorination with chlorination reagent again, obtain compound 4 " or its salt; compound 4 " or its salt carry out ring closure reaction and obtain compound (I "); obtain compound 1 finally by hydrolysis reaction
Wherein, the group in various and a same route of preparation of compound 6,5 and 1.
The invention provides compound 4 " customary preparation methods, but be not limited only to following method:
Preparing compound 4 " process in; compound 5 or its salt first carry out chlorination with sulfuryl chloride or N-chlorosuccinimide; react with sulfur oxychloride, Tosyl chloride, trimethyl fluoride sulfonyl chlorine, methylsulfonyl chloride or benzene sulfonyl chloride, leavings group Z in connection, prepares compound 4 again ".Such as compound 5 and N-chlorosuccinimide carry out chlorination by chlorine in phenolic hydroxyl group contraposition at 50 DEG C ~ 90 DEG C, and then are obtained by reacting compound 4 with sulfur oxychloride ".
In preparation Compound I " reaction in, compound 4 " under organic bases or mineral alkali catalysis, carry out ring closure reaction, prepare compound (I "); Wherein said organic bases or mineral alkali are selected from one or more in salt of wormwood, sodium carbonate, sodium bicarbonate, saleratus, potassium hydroxide, sodium hydroxide, triethylamine, tri-n-butylamine or tri-tert amine; The consumption of organic bases or mineral alkali is compound 4 " 1 ~ 4 times of molar weight; The temperature of reaction controls in room temperature to reflux temperature, and preferably 20 DEG C ~ 100 DEG C, the reaction times is 1 ~ 24h.
Present invention also offers compound 6 " preparation method; it is characterized in that adopt compound 7 " or its salt be starting raw material, ruthenium trichloride or its hydrate/periodate composite catalyst is selected to promote reaction, obtain compound 6 "; wherein the mole dosage of ruthenium trichloride or its hydrate is compound 7 " 1% ~ 8%, preferably 2% ~ 4%; The molar weight of periodate is compound 7 " 1 ~ 10 times, preferably 3 ~ 6 times, this temperature of reaction is 0 ~ 100 DEG C,
Wherein, X is carbobenzoxy-(Cbz), tertbutyloxycarbonyl or C
1-6straight chained alkyl acyl group.
Can by compound 6 " react with reference to the preparation method of above-mentioned two kind of 2,3-Dihydrobenzofuranes compounds, finally obtain compound 1.
Can to compound 6 " carboxyl carry out protection and obtain compound 6, then with reference to the preparation method of above-mentioned two kind of 2,3-Dihydrobenzofuranes compounds, finally obtain compound 1.
Also can by compound 6 " under the effect of the reductive agents such as sodium borohydride, aldehyde radical is reduced into hydroxyl, then protects carboxyl, obtains compound 5, then with reference to the preparation method of above-mentioned two kind of 2,3-Dihydrobenzofuranes compounds, finally obtains compound 1.
The invention provides the preparation method of another 2,3-Dihydrobenzofuranes compounds III, it is characterized in that adopting compound ii or its salt to be starting raw material, carry out ring closure reaction and obtain compound III,
Wherein, Y is chlorine or hydrogen; X is carbobenzoxy-(Cbz), tertbutyloxycarbonyl or C
1-6straight chained alkyl acyl group; Z is halogen, tolysulfonyl oxygen base, trimethyl fluoride sulfonyl oxygen base, mesyloxy or phenylsulfonyloxy.
Compound ii can be obtained by compound 4 de-R group under the condition of acid, also can pass through compound 6 " through aldehyde radical reduction reaction, hydroxyl substitution reaction obtains, but is not limited only to this method.
Compound ii or its salt carry out ring closure reaction under organic bases or mineral alkali catalysis, and wherein said organic bases or mineral alkali are selected from one or more in salt of wormwood, sodium carbonate, sodium bicarbonate, saleratus, potassium hydroxide, sodium hydroxide, triethylamine, tri-n-butylamine or tri-tert amine; The consumption of organic bases or mineral alkali is 1 ~ 4 times of compound ii molar weight.
" salt " in the present invention in compound 7 or its salt, compound 6 or its salt, compound 5 or its salt, compound 4 or its salt represents not to be had or less those salt dysgenic reaction process.This kind of salt can include but not limited to: the salt that (1) becomes with acid, comprise mineral acid, such as (but being not limited to) hydrochloric acid, Hydrogen bromide, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid and perchloric acid etc., organic acids is as (but being not limited to) acetic acid, propionic acid, vinylformic acid, oxalic acid, (D) or (L) oxysuccinic acid, fumaric acid, toxilic acid etc.(2) with salt formed by metal ion or organic bases, metal ion is alkalimetal ion, alkaline-earth metal ions or aluminum ion such as, and organic bases is as thanomin, diethanolamine, trolamine, Trometamol, N-METHYL-ALPHA-L-GLUCOSAMINE etc.
The present invention for raw material, by reactions such as a series of oxidation, reduction, protection, replacement, Guan Huan, hydrolysis, prepares 2,3-Dihydrobenzofuranes compounds to allyl group o-hydroxy methyl esters between amino to replace.Adopt 2,3-Dihydrobenzofuranes compounds of the present invention, chloro-2, the 3-Dihydrobenzofuranes-7-carboxylic acids (compound 1) of 4-amino-5-can be prepared easily, thus succsinic acid prucalopride can be prepared more easily, to meet the needs of medicine industry.This route reaction is simple, and cost is low, and transformation efficiency is high, and aftertreatment is simple, is easy to suitability for industrialized production.
Embodiment
Following examples further describe the present invention, but these embodiments are only for illustration of the present invention, instead of limitation of the scope of the invention.
Embodiment 12-hydroxyl-3-(2-aldehyde-base) (the preparation of compound 6 ') of-4-acetyl-amino-benzoic acid methyl ester
Chemical equation
Operation steps
In 10L reaction flask; under nitrogen protection; add 160g compound 7 ', 6.2g ruthenium trichloride monohydrate, 7.2g benzyltriethylammoinium chloride and 1142ml ethyl acetate; open and stir; drip the mixing solutions of 687g sodium periodate and 7140ml water; in controlling between temperature 20 ~ 30 DEG C; drip and finish; 1.5h is reacted under room temperature; TLC monitors reaction and carries out, developping agent: petrol ether/ethyl acetate=1/1, the Rf=0.5 of raw material (compound 7 '); it is complete that the Rf=0.4 of product, TLC show raw material primitive reaction.Stopped reaction, adds 3570ml ethyl acetate, stirs 10 minutes, separates ethyl acetate layer, aqueous layer with ethyl acetate 2140ml × 2 are extracted, combined ethyl acetate layer, with the washing of water 2140ml × 2, and ethyl acetate layer anhydrous sodium sulfate drying, be spin-dried for, obtain 142g black solid, be compound 6 '.
The compound 6 ' obtained is added 2035ml methyl alcohol, stir, be cooled to 0 DEG C, add 52.4g sodium borohydride in batches, finish, 15h is reacted between 20 ~ 25 DEG C, TLC monitor reaction carry out, developping agent: petrol ether/ethyl acetate=1/1, compound 6 ' Rf=0.4, product 5 ' Rf=0.3, it is complete that TLC shows primitive reaction.Stopped reaction, adjust between its pH value to 5 ~ 6 with 6mol/L aqueous hydrochloric acid under ice-water bath, continue to stir 1h, elimination insolubles, filtrate is spin-dried for, and obtains enriched material, adds 8900ml ethyl acetate, wash with water 2700ml × 3, combining water layer, then extract once with ethyl acetate 2700ml, merge organic layer anhydrous sodium sulfate drying, be spin-dried for, obtain gray solid, add 1250ml ethyl acetate inwards and be heated to backflow, slowly add 2500ml sherwood oil, continue backflow 10 minutes, then naturally cool to stirring at room temperature crystallization 12h.Suction filtration, filter cake 50ml ethyl acetate/petroleum ether=1/2 mixed solution washing, 40 DEG C of vacuum-dryings, obtain 121.7g gray solid, be compound 5 ', yield: 75%.
1HNMR(DMSO-d6)：δ11.09(1H,s)、δ9.61(1H,s)、δ7.64(1H,d)、δ7.39(1H,d)、δ5.22(1H,br)、δ3.89(3H,s)、δ3.59(2H,t)、δ2.85(2H,t)、δ2.09(3H,s)；
MS(ESI)：254.1([M+H]
+)，276.1([M+Na]
+)。
The preparation of embodiment 2 compound (I ') 4-acetylaminohydroxyphenylarsonic acid 2,3-Dihydrobenzofuranes-7-carboxylate methyl ester
Chemical equation
Operation steps
In 500ml four-hole bottle, add 48g compound 5 and ' with 288Ml DMF, stir clearly molten.Be cooled to 0 ~ 10 DEG C, instillation 22.6g sulfur oxychloride, drips and finishes for about 30 minutes.Rise to room temperature reaction 2h, TlC monitors reaction, developping agent: petrol ether/ethyl acetate=1/1, compound 5 ' Rf=0.3, the Rf=0.8 of product, TLC display reacts completely.Stopped reaction, reaction solution is evaporated to dry between 50 ~ 60 DEG C, obtain 51.5g gray solid be compound 4 '.
1HNMR(DMSO-d6)：δ11.14(1H,s)、δ9.57(1H,s)、δ7.68(1H,d)、δ7.22(1H,d)、δ3.90(3H,s)、δ3.69(2H,t)、δ3.12(2H,t)、δ2.11(3H,s)；
MS(ESI)：272.1([M+H]
+)，294.1([M+Na]
+)。
51.5g compound 4 ' is added in 2L reaction flask, and add 720ml tetrahydrofuran (THF) and 38.4g triethylamine, stir, be heated to back flow reaction 12h, TlC monitors reaction, developping agent: petrol ether/ethyl acetate=1/1, compound 4 ' Rf=0.8, (Rf=0.2 of I '), TLC display reacts completely compound.Stopped reaction, is cooled to room temperature, elimination insolubles, and filtrate is spin-dried for, and obtains residue, adds 960ml ethyl acetate inwards, uses water 360ml, 20% wet chemical 360ml and saturated sodium-chloride water solution 360ml × 2 to wash respectively.Combining water layer, water layer uses ethyl acetate 360ml × 2 to extract again, combined ethyl acetate layer, with 20g activated carbon decolorizing 1h, then uses anhydrous sodium sulfate drying.Filtering siccative, filtrate is spin-dried for, and obtains 45g solid-liquid.Add 80ml ethyl acetate inwards, be heated to backflow and make it dissolve, slowly add 96ml sherwood oil, finish and be incubated backflow again 5 minutes, then naturally cool to room temperature, then proceed to stirring and crystallizing 10h between 3 ~ 8 DEG C.Suction filtration, the ethyl acetate/petroleum ether=1/1 mixed solution washing that filter cake 30ml is cold, 40 DEG C of vacuum-dryings, obtain 37.9g off-white color solid, are compound (I '), yield 85%.
1HNMR(DMSO-d6)：δ9.54(1H,s)、δ7.56(1H,d)、δ7.41(1H,d)、δ4.63(2H,t)、δ3.75(3H,s)、δ3.15(2H,t)、δ2.10(3H,s)；
MS(ESI)：236.1([M+H]
+)，258.1([M+Na]
+)。
The preparation of chloro-2, the 3-Dihydrobenzofuranes-7-carboxylic acids (compound 1) of embodiment 34-amino-5-
Chemical equation
Operation steps
In 2L four-hole boiling flask, add 140g 4-acetylaminohydroxyphenylarsonic acid 2,3-Dihydrobenzofuranes-7-carboxylate methyl ester and 78.4g N-chlorosuccinimide, and 840ml DMF.Open and stir, be warming up to 70 DEG C of reactions, TLC monitoring reaction is carried out, developping agent: petrol ether/ethyl acetate=1/2, compound (Rf=0.3 of I '), compound 2 ' Rf=0.6.After reaction 3h, TLC display reacts completely.Stopped reaction, reaction solution decompression steams about 600mlDMF.Be warming up to 70 DEG C, slowly add 840ml water, 10-15 DEG C of stirring and crystallizing 2h is slowly cooled to after 70 DEG C of stirring 30min, suction filtration, appropriate frozen water washing leaching cake, 45 DEG C of vacuum-drying 12h, obtain 114.8g yellow solid, be chloro-2,3-Dihydrobenzofuranes-7-carboxylate methyl ester (compound 2 '), the yields 70% of 4-acetylaminohydroxyphenylarsonic acid 5-.
In 5L four-hole boiling flask, add 112g 4-acetylaminohydroxyphenylarsonic acid 5-chloro-2,3-Dihydrobenzofuranes-7-carboxylate methyl ester and 1120ml methyl alcohol, open and stir, slowly add 8mol/LNaOH aqueous solution 1120ml, be warming up to back flow reaction, TLC monitors reaction and carries out, developping agent: petrol ether/ethyl acetate=1/2, compound 2 ' Rf=0.6, the Rf=0.0 of compound 1.After reaction 10h, it is complete that TLC shows raw material reaction.Stopped reaction, is cooled to 5 ~ 10 DEG C and adjusts its pH value to 6-7 with the 8mol/L HCl aqueous solution, then insulated and stirred 1h, separates out solid.Suction filtration, 50ml frozen water washing leaching cake, 45 DEG C of vacuum-drying 12h.Filtrate is spin-dried for obtain solid, adds 500ml ethyl acetate, is warming up to 50 DEG C and stirs 30min, be cooled to room temperature, suction filtration.Filter cake adds about 300ml water and stirs at 50 DEG C, then stirring and crystallizing 2h between 10 ~ 15 DEG C is cooled to, suction filtration, 20ml frozen water washing leaching cake, 45 DEG C of vacuum-drying 12h, merge twice solid and obtain 78.7g gray solid, are succsinic acid prucalopride key intermediate 4-amino-5-chloro-2,3-Dihydrobenzofuranes-7-carboxylic acid (compound 1), yield: 89%.
1HNMR(DMSO-d6)：δ11.99(1H,s)、δ7.43(1H,s)、δ5.93(2H,s)、δ4.60(2H,t)、δ2.98(2H,t)；
MS(ESI)：212.1([M-H]
+)。
The preparation of embodiment 4 compound (12) 4-acetylaminohydroxyphenylarsonic acid 2,3-Dihydrobenzofuranes-7-carboxylic acid
Chemical equation
Operation steps
In 10L reaction flask; under nitrogen protection; add 160g compound 8,6.2g ruthenium trichloride monohydrate, 7.2g benzyltriethylammoinium chloride and 1142ml ethyl acetate; open and stir; the mixing solutions of 727g sodium periodate and 7140ml water is dripped under room temperature; drip and finish; react 2h under room temperature, stopped reaction, add 3570ml, 2140ml × 2 ethyl acetate and extract; combined ethyl acetate layer; with the washing of water 2140ml × 2, ethyl acetate layer anhydrous sodium sulfate drying, is spin-dried for; obtain 110g black solid, be compound 9.
The compound 9 obtained is added 2035ml methyl alcohol, stirs, be cooled to 0 DEG C, add 43.3g sodium borohydride in batches, finish, in room temperature reaction 15h.Stopped reaction, adjusts between its pH value to 5 ~ 6 with 6mol/L aqueous hydrochloric acid under ice-water bath, continues to stir 1h, elimination insolubles, filtrate is spin-dried for, and obtains enriched material, add 8900ml ethyl acetate, with the washing of water 2700ml × 3, combining water layer, extract once with ethyl acetate 2700ml again, merge organic layer, anhydrous sodium sulfate drying, be spin-dried for, obtain gray solid, add 1250ml ethyl acetate inwards and be heated to backflow, then naturally cool to stirring at room temperature crystallization 12h.Suction filtration, filter cake 50ml ethyl acetate washing, 40 DEG C of vacuum-dryings, obtain 97.6g gray solid, are compound 10, yield: 60%.MS(ESI)：240.1([M+H]
+)。
In 1000ml four-hole bottle, add 97.6g compound 10 and 580MLDMF, stir clearly molten.Be cooled to 0 ~ 10 DEG C, add 77.7g Tosyl chloride in batches, finish.Rise to room temperature reaction 2h.Stopped reaction, reaction solution is evaporated to dry between 50 ~ 60 DEG C, obtains 160.5g gray solid, with methylene dichloride: the moving phase of methyl alcohol=5:1 crosses pillar, obtains solid 40.2g, is compound 11.
40g compound 11 is added in 1L reaction flask, and adds 400ml tetrahydrofuran (THF) and 20.6g triethylamine, stir, be heated to back flow reaction 12h.Stopped reaction, is cooled to room temperature, elimination insolubles, and filtrate is spin-dried for, and obtains residue, adds 250ml ethyl acetate inwards, uses water 100ml, 15% aqueous hydrochloric acid 100ml and saturated sodium-chloride water solution 100ml × 2 to wash respectively.Ethyl acetate layer 8g activated carbon decolorizing 1h, then use anhydrous sodium sulfate drying.Filtering siccative, filtrate is spin-dried for, and obtains residue.Add 80ml ethyl acetate reflux inwards, then naturally cool to room temperature, suction filtration, filter cake cold ethyl acetate washing, 40 DEG C of vacuum-dryings, obtain 15.1g off-white color solid, are compound (12), yield 69%.MS(ESI)：222.08([M+H]
+)。
The preparation of embodiment 5 compound (17) 4-benzyloxycarbonyl amino-2,3-Dihydrobenzofuranes-7-carboxylic acid, ethyl ester
Chemical equation
Operation steps
In 10L reaction flask; under nitrogen protection; add 160g compound 13,6.2g ruthenium trichloride monohydrate, 7.2g benzyltriethylammoinium chloride and 1142ml ethyl acetate; open and stir; the mixing solutions of 481g sodium periodate and 5100ml water is dripped under room temperature; drip and finish; react 2h under room temperature, stopped reaction, add 3570ml, 2140ml × 2 ethyl acetate and extract; combined ethyl acetate layer; with the washing of water 2140ml × 2, ethyl acetate layer anhydrous sodium sulfate drying, is spin-dried for; obtain 120g black solid, be compound 14.
The compound 14 obtained is added 2035ml methyl alcohol, stirs, be cooled to 0 DEG C, add 34.1g sodium borohydride in batches, finish, in room temperature reaction 15h.Stopped reaction, adjusts between its pH value to 5 ~ 6 with 6mol/L aqueous hydrochloric acid under ice-water bath, continues to stir 1h, elimination insolubles, filtrate is spin-dried for, and obtains enriched material, add 8900ml ethyl acetate, with the washing of water 2700ml × 3, combining water layer, extract once with ethyl acetate 2700ml again, merge organic layer anhydrous sodium sulfate drying, be spin-dried for, obtain gray solid, add 1250ml ethyl acetate inwards and be heated to backflow, then naturally cool to stirring at room temperature crystallization 12h.
Suction filtration, filter cake 50ml ethyl acetate washing, 40 DEG C of vacuum-dryings, obtain 102g gray solid, are compound 15, yield: 63%.MS(ESI)：360.1([M+H]
+)。
In 1000ml four-hole bottle, add 102g compound 15 and 580MLDMF, stir clearly molten.Be cooled to 0 ~ 10 DEG C, instillation 33.8g sulfur oxychloride, drips and finishes.Rise to room temperature reaction 2h.Stopped reaction, reaction solution is evaporated to dry between 50 ~ 60 DEG C, obtains 107g gray solid and is compound 16.MS(ESI)：378.1([M+H]
+)。
107g compound 16 is added in 2L reaction flask, and adds 1500ml tetrahydrofuran (THF) and 57.3g triethylamine, stir, be heated to back flow reaction 12h.Stopped reaction, is cooled to room temperature, elimination insolubles, and filtrate is spin-dried for, and obtains residue, adds 1000ml ethyl acetate inwards, uses water 300ml, 20% wet chemical 300ml and saturated sodium-chloride water solution 300ml × 2 to wash respectively.Ethyl acetate layer 20g activated carbon decolorizing 1h, then use anhydrous sodium sulfate drying.Filtering siccative, filtrate is spin-dried for, and obtains residue.Add 80ml ethyl acetate reflux inwards, then naturally cool to room temperature, suction filtration, filter cake cold ethyl acetate washing, 40 DEG C of vacuum-dryings, obtain 63g off-white color solid, are compound (17), yield 65%.MS(ESI)：342.1([M+H]
+)。
Chloro-2, the 3-Dihydrobenzofuranes-7-carboxylate methyl ester (preparations of compound 2 ') of embodiment 64-acetylaminohydroxyphenylarsonic acid 5-
Chemical equation
Operation steps
In 2L four-hole boiling flask, add 140g compound 5 ' and 73.8g N-chlorosuccinimide, and 840ml DMF.Open and stir, be warming up to 70 DEG C of reaction 3h.Stopped reaction, removal of solvent under reduced pressure, adds 840ml water in residue, stirred at ambient temperature crystallization 2h, suction filtration, suitable quantity of water washing leaching cake, and 45 DEG C of vacuum-drying 12h, obtain 87.5g yellow solid, are compound 18, yield 55%.MS(ESI)：288.1([M+H]
+)。
In 1000ml four-hole bottle, add 87.5g compound 18 and 500MLDMF, stir clearly molten.Be cooled to 0 ~ 10 DEG C, instillation 36.2g sulfur oxychloride, drips and finishes.Rise to room temperature reaction 2h.Stopped reaction, reaction solution is evaporated to dry between 50 ~ 60 DEG C, obtains 93.1g gray solid and is compound 19.MS(ESI)：306.1([M+H]
+)。
93.1g compound 19 is added in 2L reaction flask, and adds 1400ml tetrahydrofuran (THF) and 61.5g triethylamine, stir, be heated to back flow reaction 12h.Stopped reaction, is cooled to room temperature, elimination insolubles, and filtrate is spin-dried for, and obtains residue, adds 1000ml ethyl acetate inwards, uses water 300ml, 20% wet chemical 300ml and saturated sodium-chloride water solution 300ml × 2 to wash respectively.Ethyl acetate layer 20g activated carbon decolorizing 1h, then use anhydrous sodium sulfate drying.Filtering siccative, filtrate is spin-dried for, and obtains residue.Add 80ml ethyl acetate reflux inwards, then naturally cool to room temperature, suction filtration, filter cake cold ethyl acetate washing, 40 DEG C of vacuum-dryings, obtain 55.7g off-white color solid, are compound (2 '), yield 68%.MS(ESI)：270.1([M+H]
+)。
Embodiment 72-hydroxyl-3-(2-aldehyde-base) (the preparation of compound 6 ') of-4-acetyl-amino-benzoic acid methyl ester
Chemical equation
Operation steps
In 10L reaction flask; under nitrogen protection; add 91.5g compound 20,3.5g ruthenium trichloride monohydrate, 3.6g benzyltriethylammoinium chloride and 600ml methylene dichloride; open and stir; drip the mixing solutions of 344g sodium periodate and 3600ml water; in controlling between temperature 20 ~ 30 DEG C; drip and finish; 2h is reacted under room temperature; TLC monitors reaction and carries out, developping agent: methyl alcohol oil ether/methylene dichloride=1/10, the Rf=0.7 of raw material (compound 20); it is complete that the Rf=0.5 of product, TLC show raw material primitive reaction.Stopped reaction, add 1700ml ethyl acetate, the hydrochloric acid soln of 200ml10% stirs 10 minutes, separate organic layer, aqueous layer with ethyl acetate 1000ml × 2 are extracted, and merge organic layer, wash with water 800ml × 2, ethyl acetate layer anhydrous sodium sulfate drying, be spin-dried for, obtain 68g black solid, be compound 6 '.MS(ESI)：252.1([M+H]
+)。
Claims (14)
1. one kind 2, the preparation method of 3-Dihydrobenzofuranes compounds, it is characterized in that adopting compound 7 or its salt to be starting raw material, ruthenium trichloride or its hydrate/periodate composite catalyst is selected to promote reaction, obtain compound 6 or its salt, in composite catalyst, the mole dosage of ruthenium trichloride or its hydrate is 1% ~ 8% of compound 7, and the molar weight of periodate is 1 ~ 10 times of compound 7; Compound 5 or its salt is obtained after aldehyde radical in compound 6 or its salt is reduced to hydroxyl, compound 5 or its salt and sulfur oxychloride, Tosyl chloride, trimethyl fluoride sulfonyl chlorine, methylsulfonyl chloride or benzene sulfonyl chloride react, prepare compound 4 or its salt, compound 4 or its salt are carried out ring closure reaction under organic bases or mineral alkali catalysis and obtains compound (I), compound 2 is obtained again through chlorination, compound 1 is obtained finally by hydrolysis reaction
Wherein, R is C
1-6straight chained alkyl, benzyl, halogeno-benzyl, C
1-4alkyl benzyl, diphenyl-methyl or the tertiary butyl; X is carbobenzoxy-(Cbz), tertbutyloxycarbonyl or C
1-6straight chained alkyl acyl group; Z is chlorine; Described organic bases or mineral alkali are selected from one or more in salt of wormwood, sodium carbonate, sodium bicarbonate, saleratus, potassium hydroxide, sodium hydroxide, triethylamine, tri-n-butylamine or tri-tert amine.
2. method according to claim 1, is characterized in that described R is methyl; X is ethanoyl.
3. method according to claim 1, is characterized in that preparing in the reaction of compound 6, and in composite catalyst, the mole dosage of ruthenium trichloride or its hydrate is 2% ~ 4% of compound 7; The molar weight of periodate is 3 ~ 6 times of compound 7; This temperature of reaction is 0 ~ 80 DEG C; Described periodate is potassium periodate and sodium periodate.
4. method according to claim 3, is characterized in that preparing in the reaction of compound 6, and temperature of reaction is 10 DEG C ~ 40 DEG C.
5. method according to claim 1, is characterized in that preparing in the reaction of compound 5 or its salt, and employing sodium borohydride is reductive agent.
6. method according to claim 1, is characterized in that compound 4 is prepared in the reaction of compound (I), and the consumption of organic bases or mineral alkali is 1 ~ 4 times of compound 4 molar weight; Temperature of reaction controls in room temperature to reflux temperature.
7. method according to claim 1, is characterized in that compound 4 is prepared in the reaction of compound (I), and temperature of reaction is 20 DEG C ~ 100 DEG C.
8. method according to claim 1, is characterized in that compound (I) and N-chlorosuccinimide are obtained by reacting compound 2 at 30 DEG C ~ 100 DEG C; Compound 2 reacts under sodium hydroxide effect at 40 ~ 100 DEG C, then with acid for adjusting pH value to 6-7, obtains compound 1.
9. one kind 2, the preparation method of 3-Dihydrobenzofuranes compounds, it is characterized in that adopting compound 7 or its salt to be starting raw material, ruthenium trichloride or its hydrate/periodate composite catalyst is selected to promote reaction, obtain compound 6 or its salt, in composite catalyst, the mole dosage of ruthenium trichloride or its hydrate is 1% ~ 8% of compound 7, and the molar weight of periodate is 1 ~ 10 times of compound 7; Compound 5 or its salt is obtained after aldehyde radical in compound 6 or its salt is reduced to hydroxyl, compound 5 or its salt first carry out chlorination with sulfuryl chloride or N-chlorosuccinimide, react with sulfur oxychloride, Tosyl chloride, trimethyl fluoride sulfonyl chlorine, methylsulfonyl chloride or benzene sulfonyl chloride again, leavings group Z in connection, obtain compound 4 " or its salt; compound 4 " or its salt carry out ring closure reaction and obtain compound (I "), obtain compound 1 finally by hydrolysis reaction
Wherein, R is C
1-6straight chained alkyl, benzyl, halogeno-benzyl, C
1-4alkyl benzyl, diphenyl-methyl or the tertiary butyl; X is carbobenzoxy-(Cbz), tertbutyloxycarbonyl or C
1-6straight chained alkyl acyl group; Z is chlorine.
10. method according to claim 9, is characterized in that compound 4 " under organic bases or mineral alkali catalysis, carry out ring closure reaction, prepare compound (I "); Wherein said organic bases or mineral alkali are selected from one or more in salt of wormwood, sodium carbonate, sodium bicarbonate, saleratus, potassium hydroxide, sodium hydroxide, triethylamine, tri-n-butylamine or tri-tert amine; The consumption of organic bases or mineral alkali is compound 4 " 1 ~ 4 times of molar weight.
11. methods according to claim 9, the temperature of reaction that it is characterized in that preparing compound (I ") controls in room temperature to reflux temperature.
12. methods according to claim 11, the temperature of reaction that it is characterized in that preparing compound (I ") is 20 DEG C ~ 100 DEG C.
13. 1 kinds of compounds 6 " preparation method; it is characterized in that adopt compound 7 " or its salt be starting raw material, ruthenium trichloride or its hydrate/periodate composite catalyst is selected to promote reaction, obtain compound 6 " or its salt; in composite catalyst, the mole dosage of ruthenium trichloride or its hydrate is 1% ~ 8% of compound 7, and the molar weight of periodate is 1 ~ 10 times of compound 7; ;
Wherein, X is carbobenzoxy-(Cbz), tertbutyloxycarbonyl or C
1-6straight chained alkyl acyl group.
14. methods according to claim 13, is characterized in that preparing compound 6 " in composite catalyst used the mole dosage of ruthenium trichloride or its hydrate be compound 7 " 2% ~ 4%; The molar weight of periodate is compound 7 " 3 ~ 6 times.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1045781A (en) * | 1989-03-22 | 1990-10-03 | 詹森药业有限公司 | N-(3-hydroxy-4-piperidinyl base) (Dihydrobenzofuranes, dihydro-2H-chromene or dihydrobenzo two English) carboxamides derivatives |
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|---|---|---|---|---|
| CN1045781A (en) * | 1989-03-22 | 1990-10-03 | 詹森药业有限公司 | N-(3-hydroxy-4-piperidinyl base) (Dihydrobenzofuranes, dihydro-2H-chromene or dihydrobenzo two English) carboxamides derivatives |
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| Title |
|---|
| Ruthenium-Catalyzed Oxidative Cleavage of Olefins to Aldehydes;Dan Yang;《J. Org. Chem.》;20010620;第66卷;4814-4818 * |
| Synthesis and Structure-Activity Relationship of 3-Substituted Benzamide, Benzo[b]furan-7-carboxamide, 2,3-Dihydrobenzo[b]furan-7-carboxamide, and Indole-5-carboxamide Derivatives as Selective Serotonin 5-HT4 Receptor Agonists;Takuji KaKrGamn;《Chem. Pharm. Bull.》;19980131;第46卷(第1期);42-52 * |
| 普卡必利的合成;刘宇;《药学与临床研究》;20110831;第19卷(第4期);306-307 * |
| 琥珀酸普卡必利的合成;原友志;《中国医药工业杂志》;20120131;第43卷(第1期);5-8 * |
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