CN106699557A - Method for synthesizing medicine intermediate - Google Patents

Method for synthesizing medicine intermediate Download PDF

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Publication number
CN106699557A
CN106699557A CN201710001358.XA CN201710001358A CN106699557A CN 106699557 A CN106699557 A CN 106699557A CN 201710001358 A CN201710001358 A CN 201710001358A CN 106699557 A CN106699557 A CN 106699557A
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basic hydrolysis
reaction
esterification
halomethane
equivalents
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陈本顺
周长岳
徐秋斌
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NANJING OCEAN PHARMACEUTICAL TECHNOLOGY Co Ltd
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NANJING OCEAN PHARMACEUTICAL TECHNOLOGY Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
    • C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/10—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with ester groups or with a carbon-halogen bond
    • C07C67/11—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with ester groups or with a carbon-halogen bond being mineral ester groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)

Abstract

The invention relates to the field of chemical synthesis, and in particular relates to a method for synthesizing a medicine intermediate. Aiming at the problems that a conventional synthesis route is large in raw material cost investment in industrial production, complex in industrial process and high in product cost, the invention provides a completely novel method for synthesizing a series of compounds, so that not only is the production cost remarkably lowered, but also the production process is simple, and industrial production can be easily achieved.

Description

The synthetic method of pharmaceutical intermediate
The application is application number 201310448175.4, and the applying date is September in 2013 27, a kind of entitled " medicine The divisional application of the synthetic method of thing intermediate ".
Technical field
The present invention relates to the field of chemical synthesis, the more particularly to synthetic method of pharmaceutical intermediate.
Background technology
2- (dioxane -4- bases of (4R, 6S) -6- carboxaldehyde radicals -2,2- dimethyl -1,3)-methyl acetate is a kind of important Drug synthesis intermediate, its synthesis cost and finished product in target product purity directly affect pharmaceutical synthesis cost and The generalization of synthetic route industrialized production.
At present, conventional synthesis mode, is still the disclosed synthesis mode between 95~97 years.
A kind of mode is：
Not only processing step is complicated for this mode, and needs to carry out ozone oxidation scission of link to double bond in step 6, so that Obtain target product.Preparation cost is high, conversion efficiency is low, and the product purity for obtaining is not high.Simultaneously as raw material mix is difficult Obtain, Material synthesis are also complex in itself, further increase the cost input of industrialized production under this synthetic route.
Another mode is：
It is raw material from 3,5- dicarbapentaborane methyl caproate and (1S, 2R, 5S)-(+)-menthol (S)-p-methyl benzenesulfonic acid, passes through Upper chiral auxiliary, once reduction, secondary reduction, acetonylidene protection, Pummererreaction, desulphurization reaction, de- acetate, Swern oxidations obtain target product.To multiple highly difficult reactions, reaction condition is harsher, the product for obtaining for the highway route design Impurity is more, purity difference, yield are low.
The content of the invention
The purpose of the present invention is directed to current synthetic route in industrialized production, and cost of material input is big, industrialization stream Journey is complicated, the relatively costly problem of production, there is provided a kind of brand-new 2- ((4R, 6S) -6- carboxaldehyde radicals -2,2- dimethyl -1, 3 dioxane -4- bases)-methyl acetate preparation method, synthetic route is as follows：
First, using the chloro- 5- hydroxyls -3- carbonyls-methyl caproates of 6- as initiation material, due to its be a kind of synthesis technique into The simple chemical raw material of ripe, synthetic method, therefore its purchasing price is relatively low, can greatly reduce putting into industrialized production This.
Therefore, synthetic route and synthesis technique are studied, 2- is synthesized by the chloro- 5- hydroxyls -3- carbonyls of 6--methyl caproate ((4R, 6S) -6- carboxaldehyde radicals -2,2- dimethyl -1,3 dioxane -4- bases)-methyl acetate, for 2- ((4R, 6S) -6- formaldehyde Dioxane -4- the bases of base -2,2- dimethyl -1,3) there is for-methyl acetate industrialized production great reform meaning.
The present invention is based on such thinking, discloses a kind of brand-new 2- ((4R, 6S) -6- carboxaldehyde radicals -2,2- diformazans Base -1,3 dioxane -4- bases)-methyl acetate synthetic route, such that it is able to the popularization and application in industrialized production.
Further, the invention also discloses using this synthetic route synthesis 2- ((4R, 6S) -6- carboxaldehyde radicals -2,2- bis- Methyl isophthalic acid, 3 dioxane -4- bases)-methyl acetate specific synthesis step,
The first step, D-2-Me under cryogenic conditions, is reduced in the reduction system of alkyl methoxyborane-boron hydride D-3-Me；
Second step, D-3-Me in the presence of 2,2-dimethoxypropane protective agent, with p-methyl benzenesulfonic acid or to toluene sulphur There is reduction reaction in sour pyridiniujm, generate D-4-Me；
There is exchange reaction and generate D-5- in the 3rd step, D-4-Me under the catalysis of tetrabutylammonium chloride and with acetate ion Me；
4th step, under conditions of 0~50 DEG C, basic hydrolysis generates D-6-Me to D-5-Me；
5th step, D-6-Me is through polite (swern) oxidation reaction oxidation generation D-7-Me.
In order to adapt to industrialized Production requirement, reaction yield is further improved, the present invention is also further in above-mentioned reaction Preferred following technical scheme in step：
In the first step, the solvent medium for there is reduction reaction is tetrahydrofuran, dioxane, isopropyl ether, uncle Butyl dimethyl ether, dichloromethane one or two；
In the first step, the temperature of reaction is -50~-80 DEG C；
In the first step, reduced using the lower hydride-ion-transfer of alkyl methoxyl group boron complexing, the choosing of alkyl methoxyborane From diethyl ylmethoxy boron, dipropyl ylmethoxy boron, dibutyl methoxyl group boron, diisobutyl methoxyl group boron, two (1,2- dimethyl Propyl group) methoxyl group boron, dicyclohexyl methoxyl group boron etc.；
In the first step, boron hydride is any one in sodium borohydride, potassium borohydride, zinc borohydride etc.；
In the first step, D-2-Me, reducing agent, alkyl methoxyl group boron substance amount ratio preferably 1：1~2：0.5~1；
In the second step, solvent medium be acetone, toluene, dichloromethane, DMF, dimethyl sulfoxide, One or two in tetrahydrofuran；
In the second step, D-3-Me, 2,2-dimethoxypropane, the amount ratio of catalyst material are 1：1~10：0.01 ~0.1；
Reaction temperature is 0-70 DEG C in the second step；
In 3rd step, solvent medium is DMF, dimethyl sulfoxide, N- methylpyrroles in the reaction In alkanone any one or it is solvent-free；
The temperature reacted in 3rd step is 80-120 DEG C；
D-4-Me, sodium acetate, the amount of substance ratio of tetrabutylammonium chloride are 1 in 3rd step：1~4：0.1~0.5；
In 4th step, the solvent of basic hydrolysis is methyl alcohol, in ethanol, tetrahydrofuran, dioxane, water, acetonitrile one Plant or two kinds；
Alkali preferably is selected from being any one in sodium carbonate, potassium carbonate, sodium acid carbonate, saleratus in 4th step, institute The consumption for stating alkali is 0.1-2.0 equivalents；
In 5th step, reaction medium is the triethylamine solution of dichloromethane and dimethyl sulfoxide mixed solvent, described anti- It is -78-0 DEG C to answer temperature；Activator is also included, the activator is oxalyl chloride.
Further, we carry out recrystallization purifying process to product first further preferably on the basis of the synthesis of the 3rd step, Recrystallization solvent is the mixed solvent of ethyl acetate and n-hexane, and wherein ethyl acetate and the mixed proportion of n-hexane is 1：(5- 20), the recrystallization temperature is -20-30 DEG C.It is recrystallized to give compound and is further carried out the 4th step and is reacted with the 5th step.
Meanwhile, we also disclosed the preparation method of D-3-Me, its synthetic route is as follows：
The first step, D-3 basic hydrolysis generation D-3-Na；
Second step, D-3-Na is through halomethane esterification generation D-3-Me.
Further, in order to improve industrial production efficiency, we further disclose in the step independently preferably with Any one or multiple optimum conditions are descended,
In the first step, for solvent medium that basic hydrolysis occurs be methyl alcohol, ethanol, tetrahydrofuran, dioxane, One or two in water, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide (DMSO)；
In the first step, the temperature of reaction is 20-100 DEG C；
In the first step, the alkali for basic hydrolysis is preferably in potassium hydroxide, NaOH, sodium carbonate, potassium carbonate Any one；In the first step, the consumption for the alkali of basic hydrolysis is 1-2 equivalents.
In the second step, the solvent medium of esterification is dichloromethane, DMF, dimethyl sulfoxide, One or two in tetrahydrofuran；
In the second step, methylating reagent is iodomethane or bromomethane；
In the second step, the consumption of methylating reagent halomethane is 1.0-5 equivalents；
The reaction temperature of the second step esterification is 0-70 DEG C.
Meanwhile, we also disclosed the preparation method of D-4-Me, its synthetic route is as follows：
The first step, D-4 hydrolysis generations D-3-Na.
Second step, D-4-Na esterification generations D-3-Me.
Further, it is we also disclosed the optimum condition in D-4-Me building-up processes：
In the first step, for solvent medium that basic hydrolysis occurs be methyl alcohol, ethanol, tetrahydrofuran, dioxane, One or two in water, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide (DMSO)；
In the first step, the temperature of reaction is 20-100 DEG C；
In the first step, the alkali for basic hydrolysis is preferably in potassium hydroxide, NaOH, sodium carbonate, potassium carbonate Any one；In the first step, the consumption for the alkali of basic hydrolysis is 1-2 equivalents.
In the second step, the solvent medium of esterification is dichloromethane, DMF, dimethyl sulfoxide, One or two in tetrahydrofuran；
In the second step, methylating reagent halomethane is preferably iodomethane or bromomethane；
In the second step, the consumption of methylating reagent halomethane is 1.0-5 equivalents；
The reaction temperature of the second step esterification is 0-70 DEG C.
Meanwhile, we also disclosed the preparation method of D-6-Me, it is characterized in that synthetic route is as follows：
The first step, D-6 basic hydrolysis generation D-6-Na.
Second step, D-6-Na is through halomethane esterification generation D-6-Me.
In order to further improve yield, we further disclose in the step independently preferably it is following any one Or multiple optimum conditions,
In the first step, for solvent medium that basic hydrolysis occurs be methyl alcohol, ethanol, tetrahydrofuran, dioxane, One or two in water, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide (DMSO)；
In the first step, the temperature of reaction is 20-100 DEG C；
In the first step, the alkali for basic hydrolysis is any in potassium hydroxide, NaOH, sodium carbonate, potassium carbonate It is a kind of；
In the first step, the consumption for the alkali of basic hydrolysis is 1-2 equivalents；
In the second step, the solvent medium of esterification is dichloromethane, DMF, dimethyl sulfoxide, One or two in tetrahydrofuran；
In the second step, methylating reagent halomethane is preferably iodomethane or bromomethane；
In the second step, the consumption of methylating reagent halomethane is 1.0-5 equivalents；
The reaction temperature of the second step esterification is 0-70 DEG C.
Finally, we also disclosed the preparation method of D-7-Me, it is characterized in that synthetic route is as follows：
The first step, D-7 basic hydrolysis generation D-7-Na.
Second step, D-7-Na is through halomethane esterification generation D-7-Me.
Further, it is preferable to independently preferably following any one or multiple optimum conditions in the step,
In the first step, for solvent medium that basic hydrolysis occurs be methyl alcohol, ethanol, tetrahydrofuran, dioxane, One or two in water, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide (DMSO)；
In the first step, the temperature of reaction is 20-100 DEG C；
In the first step, the alkali for basic hydrolysis is preferably in potassium hydroxide, NaOH, sodium carbonate, potassium carbonate Any one；In the first step, the base amount for basic hydrolysis is 1-2 equivalents.
In the second step, the solvent medium of esterification is dichloromethane, DMF, dimethyl sulfoxide, One or two in tetrahydrofuran；
In the second step, methylating reagent halomethane is preferably iodomethane or bromomethane；
In the second step, the consumption of methylating reagent halomethane is 1.0-5 equivalents；
The reaction temperature of the second step esterification is 0-70 DEG C.
The present invention synthesizes 2- ((4R, 6S) -6- formaldehyde with the chloro- 5- hydroxyls -3- carbonyls-methyl caproates of 6- as initiation material Base -2,2- dimethyl -1,3 dioxane -4- bases)-methyl acetate, not only low production cost, and also production procedure is simple, it is easy to Industrialized production.
Specific embodiment
The synthesis of the D-3-Me of embodiment 1
Dry and add in there-necked flask 252mlTHF, -80 degree are down in 45.2g D-2-Me, 124ml methyl alcohol, nitrogen protection.Drop Plus the THF solution of diethylmethoxyborane, 10min drips off, -75 degree reaction 20min.It is disposable to add 14.4g KBH4, control Temperature -75~-80 is spent, the plate detection of reaction 4h points, ambient temperature overnight reaction 10h.Glacial acetic acid regulation PH=6 is added dropwise, depressurize precipitation.Obtain oily Shape thing 79.5g.
The synthesis of the D-3-Na of embodiment 2
D-329g is added in 250ml there-necked flasks, NaOH 5g, 60ml methyl alcohol, 30ml water, reaction system is heated to 40 ℃.Monitoring to raw material disappears, and system concentration is dry, obtains 22.2g target products, yield 92%.
The synthesis of the D-3-Me of embodiment 3
Addition D-3-Na 18g in 250ml there-necked flasks, addition 24g iodomethane, 100mL acetone, 2.6g TBABs, Reaction system is heated to 70 DEG C.Monitoring to raw material disappears, and system concentration is dry, adds 100ml ethyl acetate and 50ml moisture liquid, has Machine layer anhydrous sodium sulfate drying, filtering, organic layer is concentrated to give 15g target products, yield 88%.
The synthesis of the D-4-Me of embodiment 4
D-3-Me 78.7g, the mixing of 2,2-dimethoxypropane 103g, 3.14g p-methyl benzenesulfonic acid are stirred at room temperature, 24h Point plate reaction afterwards terminates, and saturated sodium bicarbonate solution washing is concentrated to give grease 52.6g.
The synthesis of the D-4-Na of embodiment 5
D-426g is added in 250ml there-necked flasks, NaOH 5g, 60ml methyl alcohol, 30ml water, reaction system is heated to 40 ℃.Monitoring to raw material disappears, and system concentration is dry, obtains 21.6g target products, yield 95%.
The synthesis of the D-4-Me of embodiment 6
Addition D-4-Na 18g in 250ml there-necked flasks, addition 24g iodomethane, 100mL acetone, 2.6g TBABs, Reaction system is heated to 70 DEG C.Monitoring to raw material disappears, and system concentration is dry, adds 100ml ethyl acetate and 50ml moisture liquid, has Machine layer anhydrous sodium sulfate drying, filtering, organic layer is concentrated to give 15.6g target products, yield 91%.
The synthesis of the D-5-Me of embodiment 7
10.7g D-4-Me, 14.1g sodium acetates are added in reaction bulb, 3.69g tetrabutylammonium chlorides, stirring is warming up to 120 Degree.Reaction 22h point plate reaction raw materials are varied less, cooling down to room temperature, plus 40ml water, the stirring of 60ml n-hexanes, are stood and are divided Liquid, the water layer n-hexane extraction of 30ml*2 twice, merges organic phase, and saturated sodium-chloride washing is concentrated to give 10.6g targets product Thing.Yield 91%.
The synthesis of the D-6-Me of embodiment 8
Taking 10.4g D-5-Me adds 83.88ml methyl alcohol molten clear, obtains yellow clarification system, adds 2.9g potassium carbonate, room Temperature stirring.2h points board monitoring reaction terminates, and filters, and obtains faint yellow clarified mother liquor, PH=9.0.5N glacial acetic acid adjusts PH=8 or so, 55ml frozen water is added, PH=10 or so is surveyed.30 degree are concentrated under reduced pressure, and are extracted with the EA of 100ml*4, merge organic phase, saturated common salt Water washing, dries precipitation and obtains 7.8g pale yellow oils.Yield 89%.
The synthesis of the D-6-Na of embodiment 9
D-631g is added in 250ml there-necked flasks, NaOH 5g, 60ml methyl alcohol, 30ml water, reaction system is heated to 40 ℃.Monitoring to raw material disappears, and system concentration is dry, obtains 25.6g target products, yield 94%.
The synthesis of the D-6-Me of embodiment 10
Addition D-6-Na 20g in 250ml there-necked flasks, addition 24g iodomethane, 100mL acetone, 2.6g TBABs, Reaction system is heated to 70 DEG C.Monitoring to raw material disappears, and system concentration is dry, adds 100ml ethyl acetate and 50ml moisture liquid, has Machine layer anhydrous sodium sulfate drying, filtering, organic layer is concentrated to give 16.7g target products, yield 87%.
The synthesis of the D-7-Me of embodiment 11
Add 60ml dichloromethane, 2.5g oxalyl chlorides to be cooled to -78 DEG C in there-necked flask, 3.7g dimethyl sulfoxides are added dropwise, then The solution of 6g D-6-Me and 20ml dichloromethane composition is added dropwise, monitoring to raw material disappears, and adds 20ml triethylamines, is warming up to -30 DEG C, reaction solution being poured into the water of 100ml, point liquid, water layer is extracted with 100ml dichloromethane, combined dichloromethane layer, washing Wash to neutrality, add anhydrous sodium sulfate drying, concentration removal dichloromethane obtains 5.5g target products, yield 93%.
The synthesis of the D-7-Na of embodiment 12
D-730g is added in 250ml there-necked flasks, NaOH 5g, 60ml methyl alcohol, 30ml water, reaction system is heated to 40 ℃.Monitoring to raw material disappears, and system concentration is dry, obtains 20.1g target products, yield 77%.
The synthesis of the D-7-Me of embodiment 13
Addition D-7-Na 19g in 250ml there-necked flasks, addition 24g iodomethane, 100mL acetone, 2.6g TBABs, Reaction system is heated to 70 DEG C.Monitoring to raw material disappears, and system concentration is dry, adds 100ml ethyl acetate and 50ml moisture liquid, has Machine layer anhydrous sodium sulfate drying, filtering, organic layer is concentrated to give 15.0g target products, yield 82%.
The D-2-Me of embodiment 14 prepares D-7-Me
Respectively according to following steps：
(1) addition 252ml THF, 45.2g D-2-Me, 124ml methyl alcohol in there-necked flask is dried, nitrogen protection is down to -80 Degree.
The THF solution of diethylmethoxyborane is added dropwise, 10min is dripped off, -75 degree reaction 20min.It is disposable to add 14.4gKBH4, the degree of temperature control -75~-80, the plate detection of reaction 4h points, ambient temperature overnight reaction 10h.Glacial acetic acid regulation PH=6 is added dropwise, Decompression precipitation, obtains 79.5g D-3-Me.
(2) D-3-Me that will be obtained in step (1), the mixing of 2,2-dimethoxypropane 110g, 3.2g p-methyl benzenesulfonic acid, It is stirred at room temperature, plate reaction is put after 24h and is terminated, saturated sodium bicarbonate solution washing is concentrated to give grease 59.1g.
(3) in grease 59.1g being put into reaction bulb, and 70.1g sodium acetates are added, 18g tetrabutylammonium chlorides, stirring rises Temperature is to 120 degree.Reaction 22h point plate reaction raw materials are varied less, cooling down to room temperature, plus 100ml water, and 300ml n-hexanes are stirred Mix, stand a point liquid, the water layer n-hexane extraction of 60ml*2 twice, merges organic phase, and saturated sodium-chloride washing is being evaporated off 90% just Hexane, adds 4ml ethyl acetate, and -20 DEG C obtain white solid 44g.
(4) add 400ml methyl alcohol molten clear 44g D-5-Me, obtain yellow clarification system, add 15g potassium carbonate, room temperature Stirring.2h points board monitoring reaction terminates, and filters, and obtains faint yellow clarified mother liquor, PH=9.0.5N glacial acetic acid adjusts PH=8 or so, plus Enter 250ml frozen water, survey PH=10 or so.30 degree are concentrated under reduced pressure, and are extracted with the EA of 250ml*4, merge organic phase, saturated aqueous common salt Washing, dries precipitation and obtains 36g pale yellow oils, i.e. D-6-Me.
(5) 360ml dichloromethane, 15g oxalyl chlorides is added to be cooled to -78 DEG C, 22.2g diformazans are added dropwise sub- in there-necked flask Sulfone, then the solution of the D-6-Me and 120ml dichloromethane composition obtained in step (4) is added dropwise, monitoring to raw material disappears, adds 120ml triethylamines, are warming up to -30 DEG C, reaction solution are poured into the water of 600ml, and point liquid, water layer is extracted with 500ml dichloromethane Take, combined dichloromethane layer, water washing to neutrality, add anhydrous sodium sulfate drying, concentration removal dichloromethane obtains 30g mesh Mark product D-7-Me.Reaction gross production rate is 60%.
The D-3-Me of embodiment 15 prepares D-7-Me
(1) by 45g D-3-Me, the mixing of 2,2-dimethoxypropane 103g, 3.14g p-methyl benzenesulfonic acid is stirred at room temperature, Put plate reaction after 24h to terminate, saturated sodium bicarbonate solution washing is concentrated to give grease 54.6g.
(2) in grease 54.6g being put into reaction bulb, and 150.1g sodium acetates are added, 31g tetrabutylammonium chlorides, stirring It is warming up to 120 degree.Reaction 22h point plate reaction raw materials are varied less, cooling down to room temperature, plus 100ml water, 300ml n-hexanes Stirring, stands a point liquid, and the water layer n-hexane extraction of 60ml*2 twice, merges organic phase, and saturated sodium-chloride washing is evaporated off 90% N-hexane, adds 4ml ethyl acetate, and -20 DEG C obtain white solid 40g.
(3) add 400ml methyl alcohol molten clear D-5-Me, obtain yellow clarification system, add 15g potassium carbonate, be stirred at room temperature. 2h points board monitoring reaction terminates, and filters, and obtains faint yellow clarified mother liquor, PH=9.0.5N glacial acetic acid adjusts PH=8 or so, adds 250ml frozen water, surveys PH=10 or so.30 degree are concentrated under reduced pressure, and are extracted with the EA of 250ml*4, merge organic phase, saturated common salt washing Wash, dry precipitation and obtain 30g pale yellow oils, i.e. D-6-Me.
(4) 300ml dichloromethane, 12.5g oxalyl chlorides is added to be cooled to -78 DEG C, 18.5g diformazans are added dropwise in there-necked flask Sulfoxide, then the solution of the D-6-Me and 100ml dichloromethane composition obtained in step (3) is added dropwise, monitoring to raw material disappears, adds 100ml triethylamines, are warming up to -30 DEG C, reaction solution are poured into the water of 500ml, and point liquid, water layer is extracted with 500ml dichloromethane Take, combined dichloromethane layer, water washing to neutrality, add anhydrous sodium sulfate drying, concentration removal dichloromethane obtains 26g mesh Mark product D-7-Me.Reaction gross production rate is 52%.
The D-4-Me of embodiment 16 prepares D-7-Me
(1) in D-4-Me 52.6g being put into reaction bulb, and 150g sodium acetates are added, 30g tetrabutylammonium chlorides, stirring rises Temperature is to 120 degree.Reaction 22h point plate reaction raw materials are varied less, cooling down to room temperature, plus 100ml water, and 300ml n-hexanes are stirred Mix, stand a point liquid, the water layer n-hexane extraction of 60ml*2 twice, merges organic phase, and saturated sodium-chloride washing is being evaporated off 90% just Hexane, adds 4ml ethyl acetate, and -20 DEG C obtain white solid 45g.
(2) add 400ml methyl alcohol molten clear D-5-Me, obtain yellow clarification system, add 15g potassium carbonate, be stirred at room temperature. 2h points board monitoring reaction terminates, and filters, and obtains faint yellow clarified mother liquor, PH=9.0.5N glacial acetic acid adjusts PH=8 or so, adds 250ml frozen water, surveys PH=10 or so.30 degree are concentrated under reduced pressure, and are extracted with the EA of 250ml*4, merge organic phase, saturated common salt washing Wash, dry precipitation and obtain 36g pale yellow oils, i.e. D-6-Me.
(3) 360ml dichloromethane, 15g oxalyl chlorides is added to be cooled to -78 DEG C, 22.2g diformazans are added dropwise sub- in there-necked flask Sulfone, then the solution of the D-6-Me and 120ml dichloromethane composition obtained in step (4) is added dropwise, monitoring to raw material disappears, adds 120ml triethylamines, are warming up to -30 DEG C, reaction solution are poured into the water of 600ml, and point liquid, water layer is extracted with 500ml dichloromethane Take, combined dichloromethane layer, water washing to neutrality, add anhydrous sodium sulfate drying, concentration removal dichloromethane obtains 30g mesh Mark product D-7-Me.Reaction yield is 60%.
The D-5-Me of embodiment 17 prepares D-7-Me
(1) add 400ml methyl alcohol molten clear 60g D-5-Me, obtain yellow clarification system, add 15g potassium carbonate, room temperature Stirring.2h points board monitoring reaction terminates, and filters, and obtains faint yellow clarified mother liquor, PH=9.0.5N glacial acetic acid adjusts PH=8 or so, plus Enter 250ml frozen water, survey PH=10 or so.30 degree are concentrated under reduced pressure, and are extracted with the EA of 250ml*4, merge organic phase, saturated aqueous common salt Washing, dries precipitation and obtains 46g pale yellow oils, i.e. D-6-Me.
(2) 360ml dichloromethane, 19g oxalyl chlorides is added to be cooled to -78 DEG C, 28g dimethyl sulfoxides are added dropwise in there-necked flask, The solution of the D-6-Me and 120ml dichloromethane composition obtained in step (4) is added dropwise again, monitoring to raw material disappears, and adds 150ml Triethylamine, is warming up to -30 DEG C, reaction solution is poured into the water of 600ml, and point liquid, water layer is extracted with 500ml dichloromethane, is closed And dichloromethane layer, water washing to neutrality, anhydrous sodium sulfate drying is added, concentration removal dichloromethane obtains 40g target products D-7-Me.Reaction yield is 80%.

Claims (8)

  1. The preparation method of 1.D-3-Me, it is characterized in that synthetic route is as follows：
    The first step, D-3 basic hydrolysis generation D-3-Na；
    Second step, D-3-Na is through halomethane esterification generation D-3-Me.
  2. 2. the preparation method of D-3-Me according to claim 1, it is characterized in that：It is independently preferably following in the step to appoint Anticipate one or more optimum condition,
    In the first step, the solvent medium for there is basic hydrolysis is methyl alcohol, ethanol, tetrahydrofuran, dioxane, water, second One or two in nitrile, N,N-dimethylformamide, dimethyl sulfoxide (DMSO)；
    In the first step, the temperature of reaction is 20-100 DEG C；
    In the first step, for basic hydrolysis alkali be preferably it is any in potassium hydroxide, NaOH, sodium carbonate, potassium carbonate It is a kind of；
    In the first step, the consumption for the alkali of basic hydrolysis is 1-2 equivalents；
    In the second step, the solvent medium of esterification is dichloromethane, DMF, dimethyl sulfoxide, tetrahydrochysene One or two in furans；
    In the second step, methylating reagent is iodomethane or bromomethane；
    In the second step, the consumption of methylating reagent halomethane is 1.0-5 equivalents；
    The reaction temperature of the second step esterification is 0-70 DEG C.
  3. The preparation method of 3.D-4-Me, it is characterized in that synthetic route is as follows：
    The first step, D-4 basic hydrolysis generation D-4-Na；
    Second step, D-4-Na is through halomethane esterification generation D-4-Me.
  4. 4. the preparation method of D-4-Me according to claim 3, it is characterized in that, it is independently preferably following in the step to appoint Anticipate one or more optimum condition,
    In the first step, the solvent medium for there is basic hydrolysis is methyl alcohol, ethanol, tetrahydrofuran, dioxane, water, second One or two in nitrile, N,N-dimethylformamide, dimethyl sulfoxide (DMSO)；
    In the first step, the temperature of reaction is 20-100 DEG C；
    In the first step, for basic hydrolysis alkali be preferably it is any in potassium hydroxide, NaOH, sodium carbonate, potassium carbonate It is a kind of；
    In the first step, the consumption for the alkali of basic hydrolysis is 1-2 equivalents；
    In the second step, the solvent medium of esterification is dichloromethane, DMF, dimethyl sulfoxide, tetrahydrochysene One or two in furans；
    In the second step, methylating reagent halomethane is preferably iodomethane or bromomethane；
    In the second step, the consumption of methylating reagent halomethane is 1.0-5 equivalents；
    The reaction temperature of the second step esterification is 0-70 DEG C.
  5. The preparation method of 5.D-6-Me, it is characterized in that synthetic route is as follows：
    The first step, D-6 basic hydrolysis generation D-6-Na；
    Second step, D-6-Na is through halomethane esterification generation D-6-Me.
  6. 6. the preparation method of D-6-Me according to claim 5, it is characterized in that, it is independently preferably following in the step to appoint Anticipate one or more optimum condition,
    In the first step, the solvent medium for there is basic hydrolysis is methyl alcohol, ethanol, tetrahydrofuran, dioxane, water, second One or two in nitrile, N,N-dimethylformamide, dimethyl sulfoxide (DMSO)；
    In the first step, the temperature of reaction is 20-100 DEG C；
    In the first step, the alkali for basic hydrolysis is any one in potassium hydroxide, NaOH, sodium carbonate, potassium carbonate；
    In the first step, the consumption for the alkali of basic hydrolysis is 1-2 equivalents；
    In the second step, the solvent medium of esterification is dichloromethane, DMF, dimethyl sulfoxide, tetrahydrochysene One or two in furans；
    In the second step, methylating reagent halomethane is preferably iodomethane, chloromethanes or bromomethane；
    In the second step, the consumption of methylating reagent halomethane is 1.0-5 equivalents；The reaction temperature of the second step esterification Spend is 0-70 DEG C.
  7. The preparation method of 7.D-7-Me, it is characterized in that synthetic route is as follows：
    The first step, D-7 basic hydrolysis generation D-7-Na；
    Second step, D-7-Na is through halomethane esterification generation D-7-Me.
  8. 8. the preparation method of D-7-Me according to claim 7, it is characterized in that, it is independently preferably following in the step to appoint Anticipate one or more optimum condition,
    In the first step, the solvent medium for there is basic hydrolysis is methyl alcohol, ethanol, tetrahydrofuran, dioxane, water, second One or two in nitrile, N,N-dimethylformamide, dimethyl sulfoxide (DMSO)；
    In the first step, the temperature of reaction is 20-100 DEG C；
    In the first step, for basic hydrolysis alkali be preferably it is any in potassium hydroxide, NaOH, sodium carbonate, potassium carbonate It is a kind of；
    In the first step, the base amount for basic hydrolysis is 1-2 equivalents；
    In the second step, the solvent medium of esterification is dichloromethane, DMF, dimethyl sulfoxide, tetrahydrochysene One or two in furans；
    In the second step, methylating reagent halomethane is preferably iodomethane, chloromethanes or bromomethane；
    In the second step, the consumption of methylating reagent halomethane is 1.0-5 equivalents；
    The reaction temperature of the second step esterification is 0-70 DEG C.
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