CN102516252A - Preparation method of Nedocromil sodium - Google Patents
Preparation method of Nedocromil sodium Download PDFInfo
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Abstract
The invention discloses a preparation method of 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano[3,2-g] quinoline-2,8-sodium dicarboxylic acid (Nedocromil sodium). A raw material of m-anisidine (a compound A ) is treated with a condensation reaction to generate a compound B; the compound B is treated with a first Friedel-Crafts acylation to obtain a compound C1 and a compound C2; the compound C1 and the compound C2 are treated with demethylation, and isomer C2 is separated out to obtain a compound D; the compound D is treated with a second Friedel-Crafts acylation to obtain a diacetyl compound E; and the compound E is treated with a substitution reaction, ether formation, rearrangement, reduction, ring formation, hydrolysis and salt forming reaction to obtain the Nedocromil sodium (a compound L). The method of the invention increase synthesis yield of Nedocromil sodium.
Description
Technical field
The present invention relates to a kind of preparation method who prepares antiallergic property inflammation medicine sodium nedocromil from an amido methyl-phenoxide.
Background technology
9-ethyl-6; 9-dihydro-4; 6-dioxo-10-propyl group-4H-ratio mutters also [3; 2-g] quinoline-2,8-dicarboxylicacid sodium (Chinese: sodium nedocromil, English name: be Nedocromil sodium) in the successful antiallergic property inflammation medicine of the later development eighties in 20th century by Britain Fison drugmaker.This medicine is the strongest non-steroidal anti-inflammatory anti-asthmatic of present anti-inflammatory action, is the medicine of present antiallergic property inflammation of being gazed at most in the world.The asthma that U.S. sanitary and human health care portion, American-European all states formulate is prevented and treated in the standard, all recommends sodium nedocromil as " a line medicine ".This kind is at present domestic declares and produces.
For synthesizing of sodium nedocromil; In the document, " organic drug synthesis method " P439～442 (calling document 1 in the following text) of Chinese Medicine science and technology press in 1999 publication have been described two kinds of different compound methods respectively with " modern medicines are with clinical " magazine 2011 the 25th volumes the 2nd phase P142-144 (calling document 2 in the following text) that Chinese Pharmaceutical Association sponsors at home.The method steps of document 1 is various, and mostly midbody is oily matter, and its technology is unfavorable for production quality control and is not suitable for suitability for industrialized production.The method steps that document 2 is listed is shorter relatively; But synthesize 3-acetamido-4 from 3-methoxyacetanilide (compd B) in its method; The process of 6-diacetyl phenol (compd E) is on same phenyl ring, to carry out Fu-Ke acylation reaction simultaneously twice, also has also incomplete problem of ether bond rupture, so cause the key intermediate compd E purity of building-up process of sodium nedocromil not high; Actual recovery is very low, only has about 15%.
Abroad in the document; EP0030423 (calling document 3 in the following text) has also disclosed a kind of compound method of sodium nedocromil; The method of its technological process and document 2 is unanimous on the whole, is to accomplish through two-step reaction although also mentioned diacetylation, does not isolate the isomeric compound C2 that acetylize for the first time produces; Ether bond rupture is also incomplete, also has the shortcoming of document 2.
EP0052280 (calling document 4 in the following text) specializes in to the acetylization reaction once more of phenyl ring; The reaction of pointing out to prepare the diacetylation compound is a difficult chemical reaction that carries out; And the compound that clearly shows the similar compound I that the acetylize first time is produced can make the diacetylation compound under given conditions, and the reaction of acetylize system diacetylation compound is difficult to realize and the compound of similar compound II carries out for the second time again.
Summary of the invention
In order to improve the key intermediate 3-acetamido-4 in the sodium nedocromil synthesis route; The quality and the yield of 6-diacetyl phenol (compd E); And then the production cost of reduction suitability for industrialized production sodium nedocromil; Increase economic efficiency, the invention discloses a kind of new compound method of sodium nedocromil, and make through reactions:
With an amido methyl-phenoxide (compd A) is raw material, makes 3-methoxyacetanilide (compd B) through amido is carried out acylation reaction, and compd B makes 3-methoxyl group-4-ethanoyl-Acetanilide (Compound C 1) and isomer 3-methoxyl group-6-ethanoyl-Acetanilide (Compound C 2) through friedel-crafts acylation reaction; Compound C 1 makes 3-acetamido-4-acetyl phenol (Compound D) through the carbon-oxygen bond cleavage reaction of ether, isolates the Compound C 2 that the carbon-oxygen bond cleavage reaction can not take place, and Compound D makes 3-acetamido-4 through friedel-crafts acylation reaction for the second time; 6-diacetyl phenol (compd E), compd E makes 3-ethylamino--4 through substitution reaction, 6-diacetyl phenol (compound F 17-hydroxy-corticosterone); Compound F 17-hydroxy-corticosterone makes 3-allyl group oxygen base-4 through becoming the ether reaction, and 6-diacetyl-N-ethylaniline (compound G), compound G are reset through Claisen and made compound 4; 6-diacetyl-3-ethylamino-2-chavicol (compound H), compound H makes 4 through catalytic hydrogenating reduction, 6-diacetyl-3-ethylamino-2-propylphenol (compound I); The reaction of compound I and oxalic acid diethyl ester cyclic condensation makes 9-ethyl-6, and 9-dihydro-4,6-dioxo-10-propyl group-4H-ratio mutter also [3; 2-g] quinoline-2,8-ethyl dicarboxylate (compound J), compound J makes 9-ethyl-6 through the ester hydrolysis; 9-dihydro-4,6-dioxo-10-propyl group-4H-ratio [3, the 2-g] quinoline-2 of muttering also; 8-dicarboxylicacid (compound K), compound K become sodium salt to make 9-ethyl-6,9-dihydro-4; 6-dioxo-10-propyl group-4H-pyrans also [3; 2-g] quinoline-2,8-dicarboxylicacid sodium (compound L), thus realized the preparation of sodium nedocromil.
Method of the present invention can be represented with the reactions formula:
The inventive method realizes through following step respectively:
In polar solvent, compd A and aceticanhydride are reacted 1～3h at 15～30 ℃, reaction is finished, and uses the alkaline aqueous solution neutralizing acid, separates out white solid, crosses to filter compd B.
Compd B, acylating agent Acetyl Chloride 98Min. and catalyzer aluminum chloride be 0～20 ℃ of Fu-Ke acylation reaction 2～4h in polar solvent, and reaction is finished, in the impouring water, organic solvent extraction, concentrate the mixture of Compound C 1 and Compound C 2.
In polar solvent, Compound C 1 and Compound C 2 mixtures and catalyzer Soiodin and aluminum chloride react complete at 20～30 ℃ of reaction 10～15h, and Compound C 1 is transformed into Compound D and Compound C 2 can remain unchanged.In the reaction solution impouring water; Adding Sulfothiorine keeps Soiodin to be soluble in the aqueous phase; Go out Compound C 1 and Compound C 2 with organic solvent extraction, use alkaline aqueous solution back extraction organic layer again, make Compound D be dissolved in that water layer becomes sodium phenolate and Compound C 2 still is retained in the organic layer and separate.Mineral acid (hydrochloric acid or sulfuric acid) transfers the buck layer to slightly acidic again, and white solid generates, and suction filtration gets Compound D.
In polar solvent, Compound D, acylating agent Acetyl Chloride 98Min. and catalyzer aluminum chloride carry out Fu Ke acylation reaction 60～120h at 36～41 ℃, then in the impouring frozen water, organic solvent extraction, concentrate compd E.
In polar solvent; Compd E, sodium hydride, halo ethane (iodoethane, monobromethane) are at-5～0 ℃ of reaction 1～2h, and the primary amine groups of compd E is transformed into tertiary amine groups, and 2～4h amido linkage that in strongly acidic solution, refluxes again decomposes; Slough the ethanoyl on the amido, obtain compound F 17-hydroxy-corticosterone.
In polar solvent, compound F 17-hydroxy-corticosterone, Anhydrous potassium carbonate, allyl bromine are at 60～70 ℃ of reaction 1～4h, and in the reaction solution impouring water, suction filtration gets compound G.
Compound G is 180～220 ℃ of reaction 1～3h in polar solvent, and allylic rearrangement obtains compound H.Compound H is in polar solvent, and 20～40 ℃ with catalyzer normal pressure catalytic hydrogenation reaction 7～12h, recommends catalyzer: Pd/C, and reaction is finished, and in the reaction solution impouring water, solid is separated out, and crosses to filter compound I.
Compound I is in polar solvent; React 2～5h with strong alkali catalyst (sodium ethylate, sodium methylate or sodium hydride) and oxalic acid diethyl ester at 70～85 ℃, react 0.5～1h at 70～85 ℃ in the strong acid (concentrated hydrochloric acid or 40% vitriol oil) then, reaction is finished; Pour in the water; Solid is separated out, and filters, and gets compound J.
Compound J uses alkaline aqueous solution in polar solvent, the sodium bicarbonate aqueous solution, and two ester groups of hydrolysis compound J are at 75～85 ℃ of back flow reaction 2～8h.Reaction is finished, in the impouring water, and acidifying, suction filtration gets compound K.
Compound K is carried out to reactant salt with the aqueous solution of sodium hydroxide or sodium hydrogencarbonate and obtains compound L in polar solvent, i.e. sodium nedocromil.
Polar solvent that the present invention is used and organic solvent are acetate, ethanol, methylene dichloride, ETHYLE ACETATE, acetonitrile, n-formyl sarcolysine base pyrrolidone, N, one or more in the middle of the dinethylformamide.
The used alkaline aqueous solution of the present invention is the aqueous solution of sodium hydroxide, Pottasium Hydroxide, yellow soda ash, salt of wormwood or sodium hydrogencarbonate etc.
The reported method reactions step is many in document 1 (" organic drug synthesis method " P439～442 of Chinese Medicine science and technology press in 1999 publication), ten four-step reactions; Mostly midbody is oily matter, is unfavorable for purifying; Repeatedly use ether in the process, use the column chromatography purification midbody, can't realize industriallization.
(2011 the 25th volumes of " modern medicines and clinical " magazine that Chinese Pharmaceutical Association sponsors the 2nd phase P142-144) reported the compound method of simplifying relatively at document 2, and its route is following:
Be different from the present invention, its compd B is to accomplish in a step to compd E in document 2.Yet, show through our practice, low by the method yield of the direct one-step synthesis compd E of compd B, be about 15%, impurity is a lot of in the compd E, purifying complex.Analyze the method for document 2, following weak point arranged:
One of not enough: compd B is through Fu-Ke acylations, and reaction is a last ethanoyl earlier, with an acyl substituted phenyl ring hydrogen, according to orientation effect, can generate two kinds of isomer, Compound C 1 and Compound C 2.Owing to introduced the ethanoyl of passivation phenyl ring; Carry out the more reaction conditions of harshness of acetylize once more; By in document 4 (EP0052280) page 2, describing; Compound C 1 can make the diacetylation compound under certain condition, and Compound C 2 to carry out second time acetylize system diacetylation compound again be almost impossible.Remove so the method for the direct one-step synthesis compd E of compd B in the document 2, Compound C 2 can be present in the compd E and be difficult to a kind of form of impurity, reduce the midbody quality.
Two of deficiency: making the diacetylation compound from Compound C 1 is the harsh reaction of a conditional request, and all substituting groups on its phenyl ring are all influential to the phenyl ring activity, carry out thereby influence successful reaction.Hydroxyl and methoxyl group all are ortho-para directing groups, and hydroxyl has very strong given the electronic induction effect and give electron conjugated effect, and methoxyl group has weak electrophilic inductive effect and certain to give electron conjugated effect.So for carrying out acetylization reaction under identical reaction conditions, Compound C 1 more is difficult to carry out the diacetylation reaction than Compound D.So in preparation compd E process, with respect to diacetyl method of the present invention, the diacetylation method of document 2 make reaction more difficulty carry out.
Three of deficiency: in the process of the preparation compd E that document 2 is reported; The methoxyl group of compd B has only part can change into hydroxyl; Major cause is that the reaction conditions of Fu-Ke acylations is not the top condition of the carbon-oxygen bond cleavage reaction of ether, so the carbon-oxygen bond cleavage reaction of compd B ehter bond is incomplete.So the methoxyl group that can contain Compound C 1 in the compd E that document 2 methods make is not transformed into the impurity of hydroxyl.
Document 3 (EP0030423) has been reported two kinds of method synthetic compound E, and a kind of method is identical with document 2; Another kind method is to make compd E with twice Fu-Ke reaction; Separate the isomer that the first time, acidylate obtained; Simultaneously also can not be as this bibliographical information through the first time acidylate just can obtain the product that ether bond rupture becomes hydroxyl simultaneously, so there are all shortcomings of document 2 equally.
To above deficiency, the present invention has done following improvement to compd B synthetic compound E: compd B carries out earlier first time friedel-crafts acylation reaction and generates an acyl compounds C1 and Compound C 2 under relatively low temperature; Compound C 1 is reacted under Soiodin and aluminum chloride catalysis with Compound C 2, and the methoxyl group of Compound C 1 changes into hydroxyl fully, and the methoxyl group of having avoided can containing in the compd E Compound C 1 is not transformed into the impurity of hydroxyl, just avoided document 2 deficiency three;
Through experiment showed, that its methoxyl group then keeps steady state under Compound C 2 similarity conditions, can not change into hydroxyl.When aftertreatment; Utilize Compound C 1 that phenolic hydroxyl group is arranged; Compound C 2 does not then have the phenolic hydroxyl group characteristic, and their deliquescent difference in buck that cause are removed Compound C 2 dexterously from Compound C 1; Just do not have Compound C 2 impurity in the compd E, so just avoided one of deficiency of document 2;
Compound D is carried out the friedel-crafts acylation reaction second time again, and with respect to the Compound C that contains methoxyl group 1, the Compound D of hydroxyl more is prone to carry out diacetylation reaction, so just avoided document 2 deficiency two.
In the present invention, be 98% by the yield of compd B synthetic compound C1 and Compound C 2 mixtures, be 76% by the yield of Compound C 1 and Compound C 2 mixture synthetic compound D, be 54% by the yield of Compound D synthetic compound E.Like this, in the present invention, be about 40% by the total recovery of the three-step reaction of compd B synthetic compound E.And with the compound method of document 2 or document 3, the actual total recovery of compd B synthetic compound E only has about 15%.Method of the present invention will be synthesized the committed step of sodium nedocromil, and compd B improves to the synthesis yield of compd E greatly, be 2.6～2.7 times of corresponding yield of document 2.
So, with the big production cost that reduces compd E of method of synthetic compound E among the present invention, because compd E is the key intermediate of synthetic sodium nedocromil, so the method among the present invention can reduce the production cost of sodium nedocromil greatly.
Embodiment
The preparation of embodiment 1 3-methoxyacetanilide (compd B)
In 2000ml round bottom there-necked flask, add amido methyl-phenoxide 700g between starting compound A, mechanical stirring drips Glacial acetic acid min. 99.5 600ml about 5 ℃.Finish, stir 10min, equality of temperature drips aceticanhydride 595ml.Drip and finish, continue to stir 10min, rise to 20 ℃ of reaction 2h.With in the reaction solution alkali lye that slowly impouring 800g sodium hydroxide and 3L water are made into, white solid is separated out below the room temperature.Filter, washing, vacuum-drying gets solid 3-methoxyacetanilide (compd B) 890g of off-white color, yield: 94%, fusing point: 77-80 ℃.
Embodiment 2 3-methoxyl group-4-ethanoyl-Acetanilide (Compound C
1) preparation
In the 5000ml there-necked flask, add aluminum chloride 860g, argon shield; Add methylene dichloride 1.2L, mechanical stirring is added dropwise to the 473ml Acetyl Chloride 98Min. about 0 ℃; After adding; The mixing solutions of Dropwise 35 0g3-methoxyacetanilide (compd B) and 2.3L methylene dichloride under the equality of temperature drips and finishes again, reacts 4h about 0 ℃.Reaction is finished; Below the room temperature reaction solution is carefully poured in the 4L frozen water; Dichloromethane extraction, behind the vacuum concentration the mixture 423g of faint yellow 3-methoxyl group-4-ethanoyl-Acetanilide (Compound C 1) and isomer 3-methoxyl group-6-ethanoyl-Acetanilide (Compound C 2), yield 96.3%
(Compound D) preparation of embodiment 3 3-acetamido-4-acetyl phenol
In the 5000ml there-necked flask, add the mixture 423g of 3-methoxyl group-4-ethanoyl-Acetanilide (Compound C 1) and isomer 3-methoxyl group-6-ethanoyl-Acetanilide (Compound C 2), acetonitrile 4000ml; Be stirred to dissolving fully; Argon shield is adding aluminum trichloride (anhydrous) 600g in batches below 15 ℃, add Soiodin 400g about 0 ℃ fast; Be warming up to 20 ℃, stirring reaction 15h.Reaction is finished, and the reaction solution impouring is dissolved with in the 7L water of 380g Sulfothiorine, and ethyl acetate extraction gets organic layer, with 20% aqueous sodium hydroxide solution back extraction organic layer.Get the alkali lye layer, concentrated hydrochloric acid is transferred alkali lye layer pH=3-4, has a large amount of white solids to generate, and suction filtration gets faint yellow solid 3-acetamido-4-acetyl phenol (Compound D) 388g, yield: 72%, and fusing point: 140-143 ℃.
Embodiment 4 3-acetamidos-4, the preparation of 6-diacetyl phenol (compd E)
In the 5000ml three-necked bottle, add 3-acetamido-4-acetyl phenol (Compound D) 220g, aluminum trichloride (anhydrous) 1500g, argon shield.Add methylene dichloride 3500ml, 15 ℃ of left and right sides dripping acetyl chloride 810ml.Drip and finish, be warming up to 36 ℃ of reaction 100h.Reaction is cooled to room temperature after finishing.Room temperature is following with in the reaction solution impouring 8L frozen water, dichloromethane extraction, drying; Be concentrated into driedly, add methyl alcohol 1200ml and reflux to boil and wash twice, cooling; Suction filtration, drying under reduced pressure gets white powder solid 3-acetamido-4; 6-diacetyl phenol (compd E) 133g, yield: 51%, fusing point: 190-192 ℃.
Embodiment 5 3-ethylamino-s-4, the preparation of 6-diacetyl phenol (compound F 17-hydroxy-corticosterone)
In the 5000ml three-necked bottle, add sodium hydride 43g, argon shield.Add N-Methyl pyrrolidone 240ml ,-5 ℃ slowly drip 160g 3-acetamidos-4, and the solution of 6-diacetyl phenol (compd E) and 1400mlN-SL 1332 ℃ drips iodoethane 112ml, 0 ℃ of stirring reaction 2h again-5.Reaction is finished, and in reaction solution, adds the mixed solution of 880ml ethanol and 880ml concentrated hydrochloric acid below the room temperature, and 80 ℃ of left and right sides refluxing and stirring reaction 3h are cooled to room temperature; Pour in the 4000ml frozen water, slowly regulating about pH=4 with the sodium hydroxide saturated solution below the room temperature, generate a large amount of solids, filter; Petroleum ether, oven dry gets greyish white needle-like 3-ethylamino--4; 6-diacetyl phenol (compound F 17-hydroxy-corticosterone) 96.2g, yield: 63%, fusing point: 102-104.
Embodiment 6 3-allyl group oxygen bases-4, the preparation of 6-diacetyl-N-ethylaniline (compound G)
In the 2000ml there-necked flask, mechanical stirring adds 3-ethylamino--4,6-diacetyl phenol (compound F 17-hydroxy-corticosterone) 150g, DMF 1280ml; Anhydrous potassium carbonate 96g, argon shield drips allyl bromine 60ml under the room temperature, be warming up to 70 ℃ of heated and stirred reaction 4h, and reaction is finished; Reduce to room temperature, in reaction solution impouring frozen water, solid is separated out, and filters; With getting 3-allyl group oxygen base-4,6-diacetyl-N-ethylaniline (compound G) 139g, yield 76.5%, fusing point: 83-86 ℃ after the recrystallizing methanol.
Embodiment 74, the preparation of 6-diacetyl-3-ethylamino-2-propylphenol (compound I)
In the 2000ml there-necked flask, add 3-allyl group oxygen base-4,6-diacetyl-N-ethylaniline (compound G) 100g, argon shield adds N-Methyl pyrrolidone 740ml, is warming up to about 200 ℃ and reacts 1h.Be cooled to 30 ℃, compound G changes into 4, and 6-diacetyl-3-ethylamino-2-chavicol (compound H) adds ethanol 850ml, 10% palladium carbon 5g, 30 ℃ of following normal pressure high degree of agitation catalytic hydrogenation 12h again in above-mentioned reaction solution.Reaction is finished, and filtering recovering catalyst in the filtrating impouring 4L water, has a large amount of solids to separate out.Filter, oven dry gets yellow solid 4,6-diacetyl-3-ethylamino-2-propylphenol (compound I) 88g, and yield: 87%, fusing point: 111-115 ℃.
Embodiment 8 9-ethyls-6,9-dihydro-4,6-dioxo-10-propyl group-4H-ratio [3, the 2-g] quinoline-2 of muttering also, 8-ethyl dicarboxylate's (compound J) preparation
In the 5000ml three-necked bottle, add 4,6-diacetyl-3-ethylamino-2-propylphenol (compound I) 105g, argon shield.Add absolute ethyl alcohol 2500ml, about 0 ℃, drip the alcohol sodium solution that makes with sodium Metal 99.5 105g and 1500ml ethanol in advance.Drip and finish, rise to and drip oxalic acid diethyl ester 378ml about 25 ℃, be warming up to 80 ℃ of reaction 3h again.Reaction is finished, and slowly splashes into concentrated hydrochloric acid 900ml, and 80 ℃ are reacted 0.5h again.Reaction is finished, and reduces to room temperature, and reaction solution is poured in the water, has a large amount of solids to separate out; Filter, ethyl alcohol recrystallization gets yellow needle-like solid 9-ethyl-6; 9-dihydro-4,6-dioxo-10-propyl group-4H-ratio [3, the 2-g] quinoline-2 of muttering also; 8-ethyl dicarboxylate (compound J) 140g, yield 79%, fusing point: mp 131-134 ℃.
Embodiment 9 9-ethyls-6,9-dihydro-4,6-dioxo-10-propyl group-4H-ratio [3, the 2-g] quinoline-2 of muttering also, the preparation of 8-dicarboxylicacid (compound K)
In the 5000ml there-necked flask, add 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl group-4H-pyrans also [3; 2-g] quinoline-2,8-ethyl dicarboxylate (compound J) 100g, argon shield; Add ethanol 2700ml, sodium hydrogencarbonate 80g and 1700ml water are warming up to 80 ℃ of reaction 4h.Reduce to room temperature, in reaction solution impouring water, concentrated hydrochloric acid is acidified to pH=2, suction filtration; Oven dry, yellow solid 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl group-4H-ratio mutter also [3; 2-g] quinoline-2,8-dicarboxylicacid (compound K) 75g, yield: 84%, fusing point: 193-194 ℃.
The preparation of embodiment 10 sodium nedocromils (compound L)
In the 5000ml there-necked flask, add 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl group-4H-pyrans is [3,2-g] quinoline-2 also; 8-dicarboxylicacid (compound K) 100g, pure water 1500ml, sodium hydrogencarbonate 43g and 1000ml pure water stir fully dissolving 3h; The elimination insolubles adds acetone 12L, separates out solid, 0 ℃ of crystallization 2h; Suction filtration obtains the faint yellow solid nedocromil and receives (compound L) 93.3g, yield: 82.5% after the drying.
Embodiment 11 3-methoxyl group-4-ethanoyl-Acetanilide (Compound C
1) preparation
In the 5000ml there-necked flask, add aluminum chloride 800g, argon shield; Add methylene dichloride 1.1L, mechanical stirring is added dropwise to the 450ml Acetyl Chloride 98Min. about 10 ℃; After adding; Drip the mixing solutions of 315g3-methoxyacetanilide (compd B) and 2.1L methylene dichloride again under the equality of temperature, drip and finish, react 2h about 20 ℃.Reaction is finished; Below the room temperature reaction solution is carefully poured in the 4L frozen water; Dichloromethane extraction, behind the vacuum concentration the mixture 376g of faint yellow 3-methoxyl group-4-ethanoyl-Acetanilide (Compound C 1) and isomer 3-methoxyl group-6-ethanoyl-Acetanilide (Compound C 2), yield 95.3%
The preparation of embodiment 12 3-acetamido-4-acetyl phenol (Compound D)
In the 5000ml there-necked flask, add the mixture 360g of 3-methoxyl group-4-ethanoyl-Acetanilide (Compound C 1) and isomer 3-methoxyl group-6-ethanoyl-Acetanilide (Compound C 2), acetonitrile 3400ml; Be stirred to dissolving fully; Argon shield is adding aluminum trichloride (anhydrous) 490g in batches below 15 ℃, add Soiodin 320g about 0 ℃ fast; Be warming up to 25 ℃, stirring reaction 13h.Reaction is finished, and the reaction solution impouring is dissolved with in the 6L water of 310g Sulfothiorine, and ethyl acetate extraction gets organic layer, with 20% aqueous sodium hydroxide solution back extraction organic layer.Get the alkali lye layer, concentrated hydrochloric acid is transferred alkali lye layer pH=3-4, has a large amount of white solids to generate, and suction filtration gets faint yellow solid 3-acetamido-4-acetyl phenol (Compound D) 333g, yield: 73%, and fusing point: 140-142 ℃.
Embodiment 13 3-acetamidos-4, the preparation of 6-diacetyl phenol (compd E)
In the 5000ml three-necked bottle, add 3-acetamido-4-acetyl phenol (Compound D) 210g, aluminum trichloride (anhydrous) 1300g, argon shield.Add methylene dichloride 3400ml, 15 ℃ of left and right sides dripping acetyl chloride 720ml.Drip and finish, be warming up to 38 ℃ of reaction 90h.Reaction is cooled to room temperature after finishing.Room temperature is following with in the reaction solution impouring 7L frozen water, dichloromethane extraction, drying; Be concentrated into driedly, add methyl alcohol 1100ml and reflux to boil and wash twice, cooling; Suction filtration, drying under reduced pressure gets white powder solid 3-acetamido-4; 6-diacetyl phenol (compd E) 124.8g, yield: 50%, fusing point: 190-192.5 ℃.
Embodiment 14 3-methoxyl group-4-ethanoyl-Acetanilide (Compound C
1) preparation
In the 5000ml there-necked flask, add aluminum chloride 817g, argon shield; Add methylene dichloride 1.1L, mechanical stirring is added dropwise to the 450ml Acetyl Chloride 98Min. about 10 ℃; After adding; Drip the mixing solutions of 330g3-methoxyacetanilide (compd B) and 2.2L methylene dichloride again under the equality of temperature, drip and finish, react 2h about 10 ℃.Reaction is finished; Below the room temperature reaction solution is carefully poured in the 3.7L frozen water; Dichloromethane extraction, behind the vacuum concentration the mixture 406g of faint yellow 3-methoxyl group-4-ethanoyl-Acetanilide (Compound C 1) and isomer 3-methoxyl group-6-ethanoyl-Acetanilide (Compound C 2), yield 97.3%
The preparation of embodiment 15 3-acetamido-4-acetyl phenol (Compound D)
In the 5000ml there-necked flask, add the mixture 338g of 3-methoxyl group-4-ethanoyl-Acetanilide (Compound C 1) and isomer 3-methoxyl group-6-ethanoyl-Acetanilide (Compound C 2), acetonitrile 3700ml; Be stirred to dissolving fully; Argon shield is adding aluminum trichloride (anhydrous) 480g in batches below 15 ℃, add Soiodin 320g about 0 ℃ fast; Be warming up to 30 ℃, stirring reaction 10h.Reaction is finished, and the reaction solution impouring is dissolved with in the 5.5L water of 304g Sulfothiorine, and ethyl acetate extraction gets organic layer, with 20% aqueous sodium hydroxide solution back extraction organic layer.Get the alkali lye layer, concentrated hydrochloric acid is transferred alkali lye layer pH=3-4, has a large amount of white solids to generate, and suction filtration gets faint yellow solid 3-acetamido-4-acetyl phenol (Compound D) 322g, yield: 73%, and fusing point: 140.5-143 ℃.
Embodiment 16 3-acetamidos-4, the preparation of 6-diacetyl phenol (compd E)
In the 5000ml three-necked bottle, add 3-acetamido-4-acetyl phenol (Compound D) 191g, aluminum trichloride (anhydrous) 1430g, argon shield.Add methylene dichloride 3000ml, 15 ℃ of left and right sides dripping acetyl chloride 770ml.Drip and finish, be warming up to 41 ℃ of reaction 100h.Reaction is cooled to room temperature after finishing.Room temperature is following with in the reaction solution impouring 8L frozen water, dichloromethane extraction, drying; Be concentrated into driedly, add methyl alcohol 1050ml and reflux to boil and wash twice, cooling; Suction filtration, drying under reduced pressure gets white powder solid 3-acetamido-4; 6-diacetyl phenol (compd E) 124g, yield: 54%, fusing point: 190.5-193 ℃.
Comparative example 1 (document 2 methods one step acidylate method)
3-acetamido-4, the preparation of 6-diacetyl phenol (compd E)
In the 2000ml three-necked bottle, add aluminum trichloride (anhydrous) 300g, argon shield adds methylene dichloride 310ml, 0 ℃ of following dripping acetyl chloride 216ml.Drip and finish, drip the solution of 37g 3-methoxyacetanilide (compd B) and 270ml methylene dichloride again, be warming up to backflow, reaction 70h.Reaction is cooled to room temperature after finishing.With in the reaction solution impouring 1.6L frozen water, filter below the room temperature, filtrating use dichloromethane extraction, and the washing organic layer is to neutral, and drying is concentrated into driedly, add ethanol 400ml and reflux to boil and wash twice, suction filtration, dry yellow powder, 155-182 ℃ of survey fusing point.Again with methyl alcohol 240ml reflux boil after giving a baby a bath on the third day after its birth time off-white powder shape solid 3-acetamido-4,6-diacetyl phenol (compd E) 7.9g, yield: 15.2%, fusing point: 188-191 ℃.
Comparative example 2 (document 3 method twos step acidylate method)
1.3-methoxyl group-4-ethanoyl-Acetanilide (Compound C
1) preparation
In the 2000ml there-necked flask, add aluminum chloride 344g, argon shield adds methylene dichloride 1500ml; 140g3-methoxyacetanilide (compd B), mechanical stirring is added dropwise to the 190ml Acetyl Chloride 98Min. about 8 ℃; After adding, react 1h about 5 ℃, be warming up to back flow reaction 2h; The TLC detection reaction is complete, and cooling is carefully poured reaction solution in the 1.6L frozen water below the room temperature; Dichloromethane extraction, behind the vacuum concentration the mixture 151g of faint yellow 3-methoxyl group-4-ethanoyl-Acetanilide (Compound C 1) and isomer 3-methoxyl group-6-ethanoyl-Acetanilide (Compound C 2), yield 86.3%
2.3-acetamido-4, the preparation of 6-diacetyl phenol (compd E)
In the 2000ml three-necked bottle, add the mixture 88g of 3-methoxyl group-4-ethanoyl-Acetanilide (Compound C 1) and isomer 3-methoxyl group-6-ethanoyl-Acetanilide (Compound C 2), aluminum trichloride (anhydrous) 600g, argon shield.Add methylene dichloride 1400ml, 15 ℃ of left and right sides dripping acetyl chloride 325ml.Drip and finish, temperature rising reflux reaction 40h.Reaction is cooled to 20 ℃ after finishing.Room temperature is following with in the reaction solution impouring 3L frozen water, dichloromethane extraction (filtration method in the document can not get product), drying; Be concentrated into driedly, add methyl alcohol 500ml again and reflux to boil and wash twice, cooling; Suction filtration, drying under reduced pressure gets white powder solid 3-acetamido-4; 6-diacetyl phenol (compd E) 17g, yield: 17%, fusing point: 187-190 ℃.
Claims (7)
1. 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl group-4H-ratio [3,2-g] quinoline-2 of muttering also, the preparation method of 8-dicarboxylicacid (nedocromil) and sodium salt (sodium nedocromil) thereof is made by the reactions step:
With an amido methyl-phenoxide is raw material, makes the 3-methoxyacetanilide through the amido acylation reaction; Make 3-methoxyl group-4-ethanoyl-Acetanilide and isomer 3-methoxyl group-6-ethanoyl-Acetanilide through friedel-crafts acylation reaction again; 3-methoxyl group-4-ethanoyl-Acetanilide is removed isomer 3-methoxyl group-6-ethanoyl-Acetanilide through the carbon-oxygen bond cleavage reaction and the separation of ether, makes 3-acetamido-4-acetyl phenol; 3-acetamido-4-acetyl phenol is through making 3-acetamido-4 through friedel-crafts acylation reaction, 6-diacetyl phenol for the second time; 3-acetamido-4-acetyl phenol makes 3-ethylamino--4 through substitution reaction, 6-diacetyl phenol; 3-ethylamino--4,6-diacetyl phenol makes 3-allyl group oxygen base-4,6-diacetyl-N-ethylaniline through becoming the ether reaction; 3-allyl group oxygen base-4,6-diacetyl-N-ethylaniline are reset through Claisen and are made compound 4,6-diacetyl-3-ethylamino-2-chavicol; 4,6-diacetyl-3-ethylamino-2-chavicol makes 4 through catalytic hydrogenating reduction, 6-diacetyl-3-ethylamino-2-propylphenol; 4,6-diacetyl-3-ethylamino-2-propylphenol and oxalic acid diethyl ester cyclic condensation make 9-ethyl-6,9-dihydro-4, and 6-dioxo-10-propyl group-4H-pyrans is [3,2-g] quinoline-2 also, the 8-ethyl dicarboxylate; 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl group-4H-ratio mutter also [3; 2-g] quinoline-2, the 8-ethyl dicarboxylate makes 9-ethyl-6 through the ester hydrolysis, 9-dihydro-4; 6-dioxo-10-propyl group-4H-ratio [3,2-g] quinoline-2 of muttering also, 8-dicarboxylicacid (being nedocromil); 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl group-4H-ratio mutter also [3; 2-g] quinoline-2,8-dicarboxylicacid and sodium ion salify make 9-ethyl-6,9-dihydro-4; 6-dioxo-10-propyl group-4H-ratio [3,2-g] quinoline-2 of muttering also, 8-dicarboxylicacid sodium (being sodium nedocromil).
2. method according to claim 1; It is characterized in that 3-methoxyacetanilide, Acetyl Chloride 98Min. and catalyzer aluminum chloride in polar solvent 0～20 ℃ carry out Fu-Ke acylation reaction 2～4h; Reaction finishes in the reaction solution impouring water; Organic solvent extraction is concentrated into the mixture of dried 3-methoxyl group-4-ethanoyl-Acetanilide and 3-methoxyl group-6-ethanoyl-Acetanilide; Reaction formula is following:
3. method according to claim 1; It is characterized in that 3-methoxyl group-4-ethanoyl-Acetanilide and 3-methoxyl group-6-ethanoyl-Acetanilide mixture and catalyzer Soiodin, aluminum chloride are at 20～30 ℃ of reaction 10～15h in polar solvent; Reaction is finished, and 3-methoxyl group-4-ethanoyl-Acetanilide is transformed into 3-acetamido-4-acetyl phenol, in reaction solution impouring water; Add Sulfothiorine; Go out 3-acetamido-4-acetyl phenol and 3-methoxyl group-6-ethanoyl-Acetanilide with organic solvent extraction, separate and remove 3-methoxyl group-6-ethanoyl-Acetanilide, obtain the alkaline aqueous solution of 3-acetamido-4-acetyl phenol; Mineral acid (hydrochloric acid, sulfuric acid) transfers to slightly acidic, and suction filtration gets 3-acetamido-4-acetyl phenol; Reaction formula is following:
4. method according to claim 1; It is characterized in that in polar solvent; 3-acetamido-4-acetyl phenol, acylating agent Acetyl Chloride 98Min. and catalyzer aluminum chloride carry out Fu Ke acylation reaction 60～120h at 36～41 ℃, then in the impouring frozen water, and organic solvent extraction; Concentrate 3-acetamido-4,6-diacetyl phenol; Reaction formula is following:
5. method according to claim 3; It is characterized in that separating the method for removing 3-methoxyl group-6-ethanoyl-Acetanilide; Be dissolved with the organic solvent of 3-acetamido-4-acetyl phenol and 3-methoxyl group-two kinds of mixtures of 6-ethanoyl-Acetanilide with the alkaline aqueous solution back extraction; 3-acetamido-4-acetyl phenol becomes sodium phenolate and is dissolved in water layer; And 3-methoxyl group-6-ethanoyl-Acetanilide still is retained in the organic layer, thereby separates 3-methoxyl group-6-ethanoyl-Acetanilide, is only contained the alkaline aqueous solution of 3-acetamido-4-acetyl phenol.
6. according to the described method of claim 2-5, it is characterized in that its described polar solvent or organic solvent are one or more in methylene dichloride, trichloromethane, ethylene dichloride, ETHYLE ACETATE, the acetonitrile.
7. according to claim 3,5 described methods, it is characterized in that its described alkaline aqueous solution is one or more the aqueous solution in sodium hydroxide, Pottasium Hydroxide, yellow soda ash, salt of wormwood, the sodium hydrogencarbonate.
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| CN103214380A (en) * | 2013-04-22 | 2013-07-24 | 浙江大学 | Synthesis method for m-hydroxy-N,N-diethyl aniline |
| CN113527250A (en) * | 2020-04-16 | 2021-10-22 | 广东东阳光药业有限公司 | Siponimod intermediate and preparation method thereof |
| CN113735721A (en) * | 2021-10-09 | 2021-12-03 | 上海昕凯医药科技有限公司 | Method for synthesizing 3-ethylamino-4-methylphenol |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103214380A (en) * | 2013-04-22 | 2013-07-24 | 浙江大学 | Synthesis method for m-hydroxy-N,N-diethyl aniline |
| CN103214380B (en) * | 2013-04-22 | 2014-10-08 | 浙江大学 | Synthesis method for m-hydroxy-N,N-diethyl aniline |
| CN113527250A (en) * | 2020-04-16 | 2021-10-22 | 广东东阳光药业有限公司 | Siponimod intermediate and preparation method thereof |
| CN113527250B (en) * | 2020-04-16 | 2024-01-05 | 广东东阳光药业股份有限公司 | Octabolmod intermediate and preparation method thereof |
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