CN103012337A - Synthetic technology for 4-acetamido-2,3-dihydrobenzofuran-7-methyl formate - Google Patents
Synthetic technology for 4-acetamido-2,3-dihydrobenzofuran-7-methyl formate Download PDFInfo
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- CN103012337A CN103012337A CN 201210560166 CN201210560166A CN103012337A CN 103012337 A CN103012337 A CN 103012337A CN 201210560166 CN201210560166 CN 201210560166 CN 201210560166 A CN201210560166 A CN 201210560166A CN 103012337 A CN103012337 A CN 103012337A
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- 0 COC(c1c2OCCc2c(*)c(Cl)c1)=O Chemical compound COC(c1c2OCCc2c(*)c(Cl)c1)=O 0.000 description 1
- KRMUVKSAOVLXLF-UHFFFAOYSA-N Nc(c1c(c(C(O)=O)c2)OCC1)c2Cl Chemical compound Nc(c1c(c(C(O)=O)c2)OCC1)c2Cl KRMUVKSAOVLXLF-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention discloses a synthetic technology for 4-acetamido-2,3-dihydrobenzofuran-7-methyl formate. The invention provides a method for synthesizing 4-acetamido-2,3dihydrobenzofuran-7-methyl formate, which comprises Steps (a), (b) and (c) as described in the specification, wherein Step (a) is executed under an ozone condition, and/or Step (c) is executed as described in the specification.
Description
Technical field
The present invention relates to 4-acetylaminohydroxyphenylarsonic acid 2, the synthesis technique of 3-Dihydrobenzofuranes-7-methyl-formiate.
Background technology
Prucalopride (prucalopride), chemistry 4-amino by name-5-chloro-2,3-dihydro-N-[1-(3-methoxy-propyl)-4-piperidyl]-the 7-benzofuran carboxamides, it is a kind of selectivity 5-HT4 receptor stimulant, the clinical female constipation that laxative can not be alleviated, the trade(brand)name Resolor of being used for the treatment of of its monosuccinic acid salt.
4-amino-5-chloro-2,3-Dihydrobenzofuranes-7-carboxylic acid are the important intermediate of synthetic prucalopride (prucalopride),
US5374637(CN1045781, EP389037)) and J.Het.Chem, 1980,17 (6): 1333-5. has reported its synthetic method.Its synthetic route is as follows:
These two steps of method all need be used butyllithium reagent, and its hexane solution is inflammable, and price is also relatively more expensive.Be unsuitable for scale operation.
Chem.Pharm.Bull 46 (1), 42-52 (1998) and pharmacy and clinical study 2011(4) 306-307 reported modified processing route:
Need to use hypertoxic, expensive reagent perosmic anhydride by compound 3 preparation compounds 4 in this synthetic route; Needed to use poisonous triphenylphosphine by compound 5 preparation compounds 6, product must be purified through column chromatography.These reagent and technique also all are not suitable for industrial mass production.
In addition, the key that obtains above-mentioned intermediate 8 is how to obtain compound 6, that is to say, above-claimed cpd 6 is key intermediates of above-mentioned intermediate 8, if can high yield, environmental friendliness ground obtains above-claimed cpd 6, also just can address the above problem.
Therefore, seek a suitable above-claimed cpd 6(4-acetylaminohydroxyphenylarsonic acid 2,, 3-Dihydrobenzofuranes-7-methyl-formiate) industrial new synthesis route, will have great importance.
Summary of the invention
The object of the invention is to provide a suitable industrial production 4-acetylaminohydroxyphenylarsonic acid 2,, the synthetic method of 3-Dihydrobenzofuranes-7-methyl-formiate, it can be used for effectively synthesizing 4-amino-5-chloro-2,3-Dihydrobenzofuranes-7-carboxylic acid and prucalopride is to satisfy the need of production of this medicine.
One aspect of the present invention provides a kind of synthetic 4-acetylaminohydroxyphenylarsonic acid 2, the method for 3-Dihydrobenzofuranes-7-methyl-formiate, and described method comprises the steps:
Step (a)
Step (b)
With
Step (c)
Wherein:
Above-mentioned steps (a) is to carry out under the condition that ozone exists; And/or
Above-mentioned steps (c) is following carries out:
In the formula: R represents (C1-C6) alkyl or (C1-C6) alkyl-phenyl;
X represents halogen.
In a preferred embodiment of the present invention, above-mentioned steps (a) is carried out-100 to 100 ℃ temperature, preferably-50 to 50 ℃, preferably carries out at-20 to 0 ℃.
In a preferred embodiment of the present invention, in step (a), pass into and contain O
3Oxygen, its ozone concn is more suitable with 10mg/L-100mg/L, preferably 20mg/L-80mg/L, preferably 40mg/L-60mg/L.
In a preferred embodiment of the present invention, the R in the formula represents (C1-C4) alkyl or (C1-C4) alkyl-phenyl, is preferably (C1-C2) alkyl or (C1-C2) alkyl-phenyl, more preferably methyl or tolyl.
In a preferred embodiment of the present invention, X is selected from fluorine, chlorine, bromine or iodine, is preferably selected from fluorine, chlorine or bromine, more preferably chlorine.
In a preferred embodiment of the present invention, compound 5 and formula R-SO
2The mol ratio of the compound of-X is more preferably 1:1.10-1:20 with 1:1.05-1:25, is more preferably 1:1.10-1:15.
In a preferred embodiment of the present invention, in above-mentioned steps (c), compound 5 and formula R-SO
2Add alkali in the reaction of the compound of-X, such as the mineral alkali of yellow soda ash, sodium bicarbonate, salt of wormwood and combination thereof etc.; The organic bases of diethylamine, triethylamine, pyridine, hexahydropyridine and combination thereof etc.; Preferably, described alkali is selected from diethylamine, triethylamine, pyridine, hexahydropyridine and combination thereof.
In a preferred embodiment of the present invention, in above-mentioned steps (c), compound 9 used alkali in the reaction of compound 6 comprises the mineral alkali of yellow soda ash, salt of wormwood and combination thereof etc.; The organic amine of diethylamine, triethylamine and combination thereof etc.; And/or the pyridine organic bases of pyridine, hexahydropyridine and combination thereof etc.; Preferably, described alkali is organic amine, for example diethylamine, triethylamine and combination thereof.
The present invention provides a kind of 4-of preparation amino-5-chloro-2 on the other hand, and the method for 3-Dihydrobenzofuranes-7-carboxylic acid said method comprising the steps of:
Step (a)
Step (b)
With
Step (c)
Step (d)
Step (e)
Wherein:
Above-mentioned steps (a) is to carry out under the condition that ozone exists; And/or
Above-mentioned steps (c) is following carries out:
In the formula: R represents (C1-C6) alkyl or (C1-C6) alkyl-phenyl;
X represents halogen.
A further aspect of the present invention provides a kind of method of synthetic following formula: compound,
Said method comprising the steps of:
Step (a)
Step (b)
With
Step (c)
Step (d)
Step (e)
Step (f)
Step (g)
Wherein:
Above-mentioned steps (a) is to carry out under the condition that ozone exists; And/or
Above-mentioned steps (c) is following carries out:
In the formula: R represents (C1-C6) alkyl or (C1-C6) alkyl-phenyl;
X represents halogen.
Embodiment
In the present invention, if not special explanation, percentage ratio (%) or part all refer to weight percentage or the weight part with respect to composition.
In the present invention, if not special explanation, each related component or its preferred ingredient can be combined to form new technical scheme mutually.
In the present invention, if not special explanation, all embodiments mentioned in this article and preferred implementation can be combined to form new technical scheme mutually.
In the present invention, if not special explanation, all technical characterictics mentioned in this article and preferred feature can be combined to form new technical scheme mutually.
In the present invention, if there is not opposite explanation, the content sum of each component is 100% in the composition.
In the present invention, if there is not opposite explanation, the umber sum of each component can be 100 weight parts in the composition.
In the present invention, unless other explanations are arranged, the breviary that numerical range " a-b " expression a closes to the arbitrary real array between the b represents that wherein a and b are real numbers.For example the whole real numbers between " 0-5 " have all been listed in numerical range " 0-5 " expression herein, and " 0-5 " just the breviary of these combinations of values represents.
In the present invention, unless other explanations are arranged, integer numerical range " a-b " expression a represents that to the breviary of the combination of the arbitrary integer between the b wherein a and b are integers.For example integer numerical range " 1-N " expression 1,2 ... N, wherein N is integer.
In the present invention, unless other explanations are arranged, the multicomponent mixture of " its combination " described each element of expression, for example two kinds, three kinds, four kinds and until the multicomponent mixture of maximum possible.
If do not particularly point out, the used term " a kind of " of this specification sheets refers to " at least a ".
If do not particularly point out, the benchmark of percentage ratio of the present invention (comprising weight percentage) all is the gross weight of described composition.
" scope " disclosed herein is with the form of lower limit and the upper limit.Can be respectively one or more lower limits, and one or more upper limit.Given range limits by a selected lower limit and a upper limit.The border that selected lower limit and the upper limit define special scope.All can carry out by this way restricted portion and comprise with capable of being combined, and namely any lower limit can be combined to form a scope with any upper limit.For example, listed the scope of 60-120 and 80-110 for special parameter, be interpreted as that the scope of 60-110 and 80-120 also expects.In addition, if the minimum extent value 1 and 2 of listing, and if listed maximum range value 3,4 and 5, the scope below then can all expect: 1-3,1-4,1-5,2-3,2-4 and 2-5.
In this article, except as otherwise noted, the ratio of each component or weight all refer to dry weight.
In this article, except as otherwise noted, term " halogen " or " halogen " etc. all represent fluorine, chlorine, bromine and iodine.
In this article, except as otherwise noted, term " alkyl " expression C1-C20 straight or branched alkyl, C1-C15 straight or branched alkyl preferably, more preferably C1-C10 straight or branched alkyl will be well C1-C6 straight or branched alkyl also, is preferably C1-C4 straight or branched alkyl.
In this article, except as otherwise noted, term " thiazolinyl " expression C2-C20 straight or branched thiazolinyl, C2-C15 straight or branched thiazolinyl preferably, more preferably C2-C10 straight or branched thiazolinyl will be well C2-C6 straight or branched thiazolinyl also, is preferably C2-C4 straight or branched thiazolinyl.
In this article, except as otherwise noted, term " alkynyl " expression C2-C20 straight or branched alkynyl, C2-C15 straight or branched alkynyl preferably, more preferably C2-C10 straight or branched alkynyl will be well C2-C6 straight or branched alkynyl also, is preferably C2-C4 straight or branched alkynyl.
In this article, except as otherwise noted, term " cycloalkyl " expression C3-C20 cycloalkyl, C2-C15 cycloalkyl preferably, more preferably the C2-C10 cycloalkyl will be the C2-C6 cycloalkyl well also, is preferably the C2-C4 cycloalkyl.
In this article, except as otherwise noted, term " aryl " expression C6-C20 aryl, C6-C15 aryl preferably, more preferably the C6-C10 aryl will be the C6-C8 aryl well also, is preferably the C6 aryl.
In this article, except as otherwise noted, term " is mixed " and is represented that the one or more carbon atoms in each group are obtained group by the heteroatoms replacement, include but not limited to Heterocyclylalkyl, heteroaryl etc.
In this article, except as otherwise noted, term " heteroatoms " expression is selected from the atom of O, S, N.
In this article, except as otherwise noted, each reaction is all carried out at normal temperatures and pressures.
In this article, except as otherwise noted, each reactions steps can sequentially be carried out, and also can not carry out in order.For example, can comprise other steps between each reactions steps, and also can the transposing order between the reactions steps.Preferably, herein reaction method is in sequence.
One aspect of the present invention provides a kind of synthetic 4-acetylaminohydroxyphenylarsonic acid 2,, the method for 3-Dihydrobenzofuranes-7-methyl-formiate, described method comprises the steps:
Step (a)
Step (b)
With
Step (c)
Wherein:
Above-mentioned steps (a) is to carry out under the condition that ozone exists; And/or
Above-mentioned steps (c) is following carries out:
In the formula: R represents (C1-C6) alkyl or (C1-C6) alkyl-phenyl;
X represents halogen.
In aforesaid method of the present invention, described compound 3 is conventional in the art, and it can synthesize or commercially available obtaining according to prior art.In a preferred embodiment of the present invention, described compound 3 is synthetic according to the method for Chem.Pharm.Bull 46 (1) 42-52 (1998).
In the above-mentioned steps (a) of the inventive method, above-mentioned steps (a) is carried out under the ozone existence condition.Ozonization is the good method that the fracture pendant double bonds prepares aldehyde.The advantages such as ozone is as a kind of oxygenant, and it is strong to have oxidation capacity, and selectivity is good, and speed of response is fast.And can decompose voluntarily after the reaction end, do not produce serious three-waste pollution problem, meet requirement and the trend of current Green Chemistry, cleaning procedure.The inventive method adopts ozonization to prepare compound 4, has low, the free of contamination advantage of cost.
In a preferred embodiment of the present invention, step of the present invention (a) can be carried out in alcoholic solvent, and used alcoholic solvent can be the C1-C6 alkyl alcohol, preferably C1-C3 alkyl alcohol, preferably methyl alcohol.
The temperature of step of the present invention (a) is concrete the restriction not, and those of ordinary skill in the art can direct derivation go out its actual temp in conjunction with its expertise again according to description of the invention.In a preferred embodiment of the present invention, above-mentioned steps (a) is carried out under-100 to 100 ℃ temperature usually, preferably-50 to 50 ℃, preferably carries out at-20 to 0 ℃.
Ozone concn in the step of the present invention (a) and reaction times is concrete the restriction not, those of ordinary skill in the art according to description of the invention again in conjunction with directly ozone and the reaction in the determining step (a) of its expertise.In a preferred embodiment of the present invention, in step (a), pass into by containing O
3Oxygen, its ozone concn is more suitable with 10mg/L-100mg/L, preferably 20mg/L-80mg/L minute, 40mg/L-60mg/L preferably.Generally speaking, the large the reaction time of ozone concn is short, ozone concn hour long reaction time.Consider safety factors, ozone concn is unsuitable excessive, and the reaction times is controlled at 5-10 hour better.
In aforesaid method of the present invention, described step (b) is conventional, those of ordinary skill in the art according to description of the invention again in conjunction with can directly determining above-mentioned steps (b) in the prior art.In a preferred embodiment of the present invention, the actual conditions of described step (b) can be referring to Chem.Pharm.Bull46 (1) 42-52 (1998).
In another preferred embodiment of the present invention, above-mentioned steps (b) is finished convenient operation with step (a) in same reactor.The about 40-80% of two step total yields.
In another preferred embodiment of the present invention, above-mentioned steps (b) is to carry out under the condition that sodium borohydride exists.For the not concrete restriction of the consumption of sodium borohydride, those of ordinary skill in the art goes out the consumption of sodium borohydride again in conjunction with direct derivation in the prior art according to description of the invention.In this another preferred embodiment, the mol ratio of sodium borohydride and compound 4 is 0.25-5, preferably 0.5-1.5, preferably 1.0-1.35.
In above-mentioned steps of the present invention (b), temperature of reaction also has no special requirements.In a preferred embodiment of the present invention, described step (b) is carried out in room temperature.
In above-mentioned steps of the present invention (b), the reaction times does not have special requirement, those of ordinary skill in the art according to description of the invention again in conjunction with can directly obtaining its concrete reaction times in the prior art.In a preferred embodiment of the present invention, the described reaction times is 0.5-5 hour, preferably 1.0-4.0 hour, and preferably 2-3 hour.
Above-mentioned steps (c) is following carries out:
In the formula: R represents (C1-C6) alkyl or (C1-C6) alkyl-phenyl;
X represents halogen.
In a preferred embodiment of the present invention, the R in the formula represents (C1-C4) alkyl or (C1-C4) alkyl-phenyl, is preferably (C1-C2) alkyl or (C1-C2) alkyl-phenyl, more preferably methyl or tolyl.
In a preferred embodiment of the present invention, X is selected from fluorine, chlorine, bromine or iodine, is preferably selected from fluorine, chlorine or bromine, more preferably chlorine.
The synthetic route via sulfonate compound 9 is selected in 6 the cyclization from compound 5 to compound.Sulfonic group is a good leavings group, sloughs under the effect of organic bases easily, ring-closure reaction occurs thereupon obtain compound 6.Reaction temperature and easy to control need not used more expensive and poisonous triphenylphosphine.
In step of the present invention (c), compound 5 and formula R-SO
2The consumption of the compound of-X is concrete the restriction not, and those of ordinary skill in the art can directly obtain their consumption again in conjunction with prior art according to description of the invention.In a preferred embodiment of the present invention, compound 5 and formula R-SO
2The mol ratio of the compound of-X is more preferably 1:1.10-1:20 with 1:1.05-1:25, is more preferably 1:1.10-1:15.
In step of the present invention (c), compound 5 and formula R-SO
2The reaction of the compound of-X can be carried out in the inert solvent of solubilizing reaction thing any.In a preferred embodiment of the present invention, employed solvent can be the aliphatic hydrocarbons such as pentane, hexane, heptane and combination thereof, also can be the aromatic solvents such as benzene,toluene,xylene and combination thereof, also can be the alcoholic solvents such as methyl alcohol, ethanol, Virahol and combination thereof, can also be the halogenated hydrocarbon solvents such as methylene dichloride, trichloromethane, ethylene dichloride and combination thereof, lower, the aliphatic halogenated hydrocarbon solvent with certain polarity of boiling point preferably, for example methylene dichloride, trichloromethane, ethylene dichloride and combination thereof.
In the above-mentioned steps (c) of the inventive method, compound 5 and the not concrete restriction of the consumption of solvent, those of ordinary skill in the art can directly determine compound 5 and solvent in conjunction with prior art again according to description of the invention.In a preferred embodiment of the present invention, the mol ratio of compound 5 and solvent is more preferably 1:8-1:12 between 1:5-1:15, preferably about 1:10.
In the above-mentioned steps (c) of the inventive method, compound 5 and formula R-SO
2The preferred alkali that adds in the reaction of the compound of-X, those of ordinary skill in the art can directly determine concrete alkali in conjunction with prior art again according to description of the invention, as long as it can provide alkaline environment to reaction.In a preferred embodiment of the present invention, described alkali can be the mineral alkali of yellow soda ash, sodium bicarbonate, salt of wormwood and combination thereof etc., also can be the organic bases of diethylamine, triethylamine, pyridine, hexahydropyridine and combination thereof etc.In another preferred embodiment of the present invention, described alkali is selected from diethylamine, triethylamine, pyridine, hexahydropyridine and combination thereof.
In the step of the present invention (c), compound 5 and formula R-SO
2The temperature of reaction of the compound of-X is concrete the restriction not, and those of ordinary skill in the art can direct derivation go out its actual temp in conjunction with its expertise again according to description of the invention.In a preferred embodiment of the present invention, described temperature better is between-50～50 ℃ between-100～100 ℃, is more preferably between-20～20 ℃.
6 is the reactions of closing ring from compound 9 to compound.Compound 9 is sloughed alkylsulfonyl under the effect of alkali, close ring with intramolecular phenolic hydroxyl group effect again.
In step of the present invention (c), compound 9 used alkali in the reaction of compound 6 is conventional, and those of ordinary skill in the art can directly determine concrete alkali in conjunction with prior art again according to description of the invention.In a preferred embodiment of the present invention, described alkali can be the mineral alkali of yellow soda ash, salt of wormwood and combination thereof etc., also can use the organic amine of diethylamine, triethylamine and combination thereof etc., also can be the pyridine organic bases of pyridine, hexahydropyridine and combination thereof etc.In another preferred embodiment of the present invention, described alkali is organic amine, for example diethylamine, triethylamine and combination thereof.
In step of the present invention (c), compound 9 is conventional with the consumption of alkali, and those of ordinary skill in the art can directly determine their concrete consumption again in conjunction with prior art according to description of the invention.In a preferred embodiment of the present invention, the mol ratio of described compound 9 and alkali is more preferably 1:8-1:15, preferably at 1:9-1:12 with 1:5-1:50.
In step of the present invention (c), compound 9 preferably carries out in solvent to the reaction of compound 6.Described solvent is conventional in the art, and those of ordinary skill in the art can directly determine concrete solvent in conjunction with prior art again according to description of the invention.In a preferred embodiment of the present invention, described solvent can be any not with the inert solvent of reactant effect, such as aliphatic hydrocarbons such as pentane, hexane, heptane and combinations thereof, also can be the aromatic solvents such as benzene,toluene,xylene and combination thereof, also can be the halogenated hydrocarbon solvents such as methylene dichloride, trichloromethane, ethylene dichloride and combination thereof, and the esters solvent of ethyl acetate, butylacetate and combination thereof etc.In another preferred embodiment of the present invention, described solvent is esters solvent, for example ethyl acetate, butylacetate and combination thereof.
The present invention provides a kind of 4-of preparation amino-5-chloro-2 on the other hand, and the method for 3-Dihydrobenzofuranes-7-carboxylic acid said method comprising the steps of:
Step (a)
Step (b)
With
Step (c)
Step (d)
Step (e)
Wherein:
Above-mentioned steps (a) is to carry out under the condition that ozone exists; And/or
Above-mentioned steps (c) is following carries out:
In the formula: R represents (C1-C6) alkyl or (C1-C6) alkyl-phenyl;
X represents halogen.
In aforesaid method of the present invention, step (d) and (e) be conventional, those of ordinary skill in the art can directly obtain concrete step (d) and (e) in conjunction with prior art again according to description of the invention, for example above-mentioned steps (d) but and (e) the method operation of reference literature Chem.Pharm.Bull 46 (1) 42-52 (1998).
In a preferred embodiment of the present invention, described step (d) is following carries out:
With compound 6, DMF(N, dinethylformamide) and the NCS(N-chlorosuccinimide) the 0.1kg reacting by heating obtained compound 7 in 1-2 hour.
In another preferred embodiment of the present invention, described step (e) is following carries out:
Compound 7 is added in the methyl alcohol; Then add sodium hydroxide and water; Reflux obtains compound 8.
The present invention provides a kind of method of synthetic following formula: compound on the other hand,
Said method comprising the steps of:
Step (a)
Step (b)
With
Step (c)
Step (d)
Step (e)
Step (f)
Step (g)
Wherein:
Above-mentioned steps (a) is to carry out under the condition that ozone exists; And/or
Above-mentioned steps (c) is following carries out:
In the formula: R represents (C1-C6) alkyl or (C1-C6) alkyl-phenyl;
X represents halogen.
In aforesaid method of the present invention, step (f) and (g) be conventional, those of ordinary skill in the art can directly obtain concrete step (f) and (g) in conjunction with prior art again according to description of the invention, for example above-mentioned steps (f) but and (g) the method operation of reference literature Chem.Pharm.Bull 46 (1) 42-52 (1998).
Adopt processing method of the present invention can prepare easily 4-amino-5-chloro-2,3-Dihydrobenzofuranes-7-carboxylic acid, thus can prepare easily the succsinic acid prucalopride, satisfy the needs of medicine industry.
In an embodiment, reaction reagent methylene dichloride, methyl alcohol, triethylamine, ethyl acetate, ethanol, pyridine, tetrahydrofuran (THF), DMF are full of chemical industry company limited available from the Shanghai Lay;
Reaction reagent sodium borohydride, Glacial acetic acid, methane sulfonyl chloride, N-chlorosuccinimide, sodium hydroxide, hydrochloric acid, Succinic Acid, trifluoroacetic acid, salt of wormwood are available from Shanghai experiment reagent company limited;
Oxygen is available from the firm intelligence gas in Shanghai company limited;
Uncle's N-fourth oxygen amino-4-piperidone is available from the sincere beneficial chemical in Xuzhou Science and Technology Ltd.;
Ozonizer is the CXF-20G type available from Beijing North reason first rays of the morning sun Science and Technology Ltd.;
N, N'-carbonyl dimidazoles (CDI) is available from Shanghai Aladdin reagent company.
Embodiment 1
Add compound 3(self-control in the 10L flask, method is referring to Chem.Pharm.Bull46 (1) 42-52 (1998)) 0.5kg, methyl alcohol 5L, cool to-20 ℃, begin to pass into by 0 of ozonizer generation
3, ozone concn is 41.23mg/L, keeps the reaction in 8 hours of this temperature and finishes.Add sodium borohydride 0.1kg after reaction finishes, reaction in about 2-3 hour finishes.Adding Glacial acetic acid after finishing transfers pH to neutral.Concentrating under reduced pressure methyl alcohol gets off-white color product compound 5 (0.3kg), fusing point: 170-175 ℃; 1HNMR(DMSO): δ 2.089(3H, s), 2.846 (2H, t), 3.580 (2H, t), (3.898 3H, s), 5.242 (1H, s), 7.385 (1H, d), (7.651 1H, d), 9.628(1H, s), 11.104 (1H, s).
Embodiment 2
Embodiment 1 gained compound 5 (0.3kg), methylene dichloride 300ml, pyridine 30ml join in the 5L bottle, cool to-10 ℃, add the 100ml methane sulfonyl chloride, keep-10 ℃ of reactions 8-10 hour.Concentrating under reduced pressure methylene dichloride after reaction finishes gets pink product, filters washing, drying.Get compound 9(0.32kg).Fusing point: 134.6-136.3 ℃; 1H NMR(CDCl 3): δ 2.223(3H, s), 2.992(3H, s), 3.160 (2H, t), (3.944 3H, s), 4.520 (2H, t), 7.614 (1H, d), (7.760 1H, d), 7.999 (1H, s), 11.274(1H, s).
Embodiment 3
Embodiment 2 gained compound 9(0.3kg), triethylamine 100ml and ethyl acetate 3L refluxed 10 hours.After should finish rear concentrating under reduced pressure triethylamine, get the off-white color solid.Use re-crystallizing in ethyl acetate, get 0.18kg compound 6.Fusing point: 125.8-128.9 ℃; 1H NMR(CDCl 3): δ 2.216(3H, s), 3.138(2H, t), 3.889 (3H, s), 4.771 (2H, t), 6.997 (1H, s), 7.489 (1H, d), 7.264 (1H, d).
Embodiment 4
Embodiment 3 gained compounds 6 0.18kg, DMF(N, dinethylformamide) 1.8L and NCS(N-chlorosuccinimide) 0.1kg slowly is heated to 70-80 ℃ of reaction 1-2 hour.Pour in the 5L frozen water, leave standstill and filtered to such an extent that compound 7 need not dryly directly drop into next step in 2-3 hour.
Embodiment 5
Embodiment 4 gained compounds 7 add 5L methyl alcohol, then add sodium hydroxide 0.08kg and 1L water, reflux 3-5 hour.Reaction boils off methyl alcohol after finishing, and has solid to separate out, and uses the concentrated hydrochloric acid adjust pH to 4-5.Separate out a large amount of solids.Filter, with the washing of 50% ethanol, the dry 0.12kg compound 8 that gets.Fusing point: 210-215 ℃; 1HNMR(DMSO): δ 2.959 (2H, t), 4.565 (2H, t), 5.759 (2H, s), 7.431 (1H, s).
MS（ESI）M+H=214
Embodiment 6
With reference to J.Med.CHem.2007,50,3561-3572 synthetic compound 10 (1-(3-methoxy-propyl)-4-piperylhydrazine), concrete synthetic method is as follows: uncle's N-fourth oxygen amino of 0.2kg-4-piperidone and 1kg salt of wormwood are joined 1.5L N, dissolve in the dinethylformamide, then add the 1-bromo-3-methoxy propane of 0.18kg.Then, be warmed up to 70-80 ℃ of reaction 5-6 hour.Be down to room temperature, then the 0-5 ℃ of frozen water crystallization of adding 5L 3-4 hour filter drying.
Above-mentioned raw materials joined in the 2L methylene dichloride dissolve, then added the about 2-3 of 200ml trifluoroacetic acid and temperature rising reflux hour, decompression evaporated solvent and gets oily matter 1-(3-methoxy-propyl)-4-piperylhydrazine (10) 101g, 1HNMR(CDCl3 after reaction finished): δ 3.38(2H, t), 3.29(3H, s), 2.85(2H, m), 2.62(1H, m), 2.35(2H, m), 1.95 (2H, m), 1.76(4H, m), (1.37 2H, m), MS(ESI) M+H=173.
With embodiment 5 gained compound 8(120g) be suspended among the 1.2L THF, ice bath is cooled to 0-5 ℃, disposable adding CDI(93g), stirring at room adds compound 10(98g after one hour) THF (980ml solution, reflux is after 5 hours, adds water 1L after boiling off THF, separate out solid, stir after 2 hours and filter, the dry 123g off-white color solid prucalopride (compound 11) that gets, 1HNMR(DMSO): δ 7.46 (1H, s), 7.25 (1H, d), 5.88 (2H, s), (4.70 2H, t), 3.71 (1H, br), 3.21 (3H, s), (3.05 2H, t), 2.70 (2H, d), 2.37 (2H, t), (2.03 2H, t), 1.80 (2H, d), 1.62 (2H, m), (1.40 2H, m).
MS（ESI）M+H=368
Embodiment 7
With embodiment 6 described compound 11(123g) add in the 600ml ethanol, gac 6g adds backflow and filters after 30 minutes.Be chilled to the mixing solutions that adds 39.3g Succinic Acid and (200ml ethanol, 80ml water) in the backward filtrate in chamber.Then stirring at room 3-5 hour, filtration, 60 ℃ of vacuum-dryings got off-white powder shape Succinic Acid prucalopride (compound 12) 125g.Fusing point: 196-197 ℃, 1HNMR(DMSO): δ 7.46 (1H, s), 7.28 (1H, d), (5.87 2H, s), 4.73 (2H, t), (3.80 1H, br), 3.34 (2H, t), (3.22 3H, s), 3.04 (2H, t), 2.29 ~ 2.39 (6H, m), 1.87 (2H, d), (1.72 2H, m), 1.55 (2H, m).
Claims (10)
1. synthetic 4-acetylaminohydroxyphenylarsonic acid 2, the method for 3-Dihydrobenzofuranes-7-methyl-formiate, described method comprises the steps:
Step (a)
Step (b)
Step (c)
Wherein:
Above-mentioned steps (a) is to carry out under the condition that ozone exists; And/or
Above-mentioned steps (c) is following carries out:
In the formula: R represents (C1-C6) alkyl or (C1-C6) alkyl-phenyl;
X represents halogen.
2. the method for claim 1 is characterized in that, above-mentioned steps (a) is carried out-100 to 100 ℃ temperature, preferably-50 to 50 ℃, preferably carries out at-20 to 0 ℃.
3. the method for claim 1 is characterized in that, passes into to contain O in step (a)
3Oxygen, its ozone concn is more suitable with 10mg/L-100mg/L, preferably 20mg/L-80mg/L, preferably 40mg/L-60mg/L.
4. the method for claim 1 is characterized in that, the R in the formula represents (C1-C4) alkyl or (C1-C4) alkyl-phenyl, is preferably (C1-C2) alkyl or (C1-C2) alkyl-phenyl, more preferably methyl or tolyl.
5. the method for claim 1 is characterized in that, X is selected from fluorine, chlorine, bromine or iodine, is preferably selected from fluorine, chlorine or bromine, more preferably chlorine.
6. the method for claim 1 is characterized in that, compound 5 and formula R-SO
2The mol ratio of the compound of-X is more preferably 1:1.10-1:20 with 1:1.05-1:25, is more preferably 1:1.10-1:15.
7. the method for claim 1 is characterized in that, in above-mentioned steps (c), and compound 5 and formula R-SO
2Add alkali in the reaction of the compound of-X, such as the mineral alkali of yellow soda ash, sodium bicarbonate, salt of wormwood and combination thereof etc.; The organic bases of diethylamine, triethylamine, pyridine, hexahydropyridine and combination thereof etc.; Preferably, described alkali is selected from diethylamine, triethylamine, pyridine, hexahydropyridine and combination thereof.
8. the method for claim 1 is characterized in that, in above-mentioned steps (c), compound 9 used alkali in the reaction of compound 6 comprises the mineral alkali of yellow soda ash, salt of wormwood and combination thereof etc.; The organic amine of diethylamine, triethylamine and combination thereof etc.; And/or the pyridine organic bases of pyridine, hexahydropyridine and combination thereof etc.; Preferably, described alkali is organic amine, for example diethylamine, triethylamine and combination thereof.
9. one kind prepares 4-amino-5-chloro-2, and the method for 3-Dihydrobenzofuranes-7-carboxylic acid said method comprising the steps of:
Step (a)
Step (b)
Step (c)
Step (d)
Step (e)
Wherein:
Above-mentioned steps (a) is to carry out under the condition that ozone exists; And/or
Above-mentioned steps (c) is following carries out:
In the formula: R represents (C1-C6) alkyl or (C1-C6) alkyl-phenyl;
X represents halogen.
10. the method for a synthetic following formula: compound,
Said method comprising the steps of:
Step (a)
Step (b)
Step (c)
Step (d)
Step (e)
Step (f)
Step (g)
Wherein:
Above-mentioned steps (a) is to carry out under the condition that ozone exists; And/or
Above-mentioned steps (c) is following carries out:
In the formula: R represents (C1-C6) alkyl or (C1-C6) alkyl-phenyl;
X represents halogen.
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