CN1328240C - Preparation of benzoyl oxy-aldehyde - Google Patents
Preparation of benzoyl oxy-aldehyde Download PDFInfo
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- CN1328240C CN1328240C CNB2005100215714A CN200510021571A CN1328240C CN 1328240 C CN1328240 C CN 1328240C CN B2005100215714 A CNB2005100215714 A CN B2005100215714A CN 200510021571 A CN200510021571 A CN 200510021571A CN 1328240 C CN1328240 C CN 1328240C
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Abstract
The present invention provides a new method for preparing benzoyloxyacetaldehyde (I), which uses sodium benzoate and epichlorohydrin as starting raw material, and 1, 2-bioxhydryl-3-benzoyloxypropane (III) is obtained through esterification and hydrolysis; glycerol and boric acid can also be used as the starting raw material, and III is obtained through complex, the esterification and the hydrolysis; (I) is prepared by III through the oxidation of periodic acid or periodate absorbed on silica gel. The present invention has the advantages of easily obtained raw material, mild reaction condition, convenient operation, high product yield and friendly reaction environment.
Description
Technical field
The invention belongs to the pharmaceutical chemistry field, is the novel preparation method of O-Benzoylglycolaldehyde (I).
Background technology
O-Benzoylglycolaldehyde (I) is the important intermediate of synthetic lamivudine (Lamivudine), emtricitabine nucleoside medicines such as (Emtricitabine).Foreign literature: J Am Chem Soc1939,61:1156～1159 have reported that with the phenylformic acid allyl ester be starting raw material, feed ozone (O in pyruvic acid aqueous solution
3), oxygenolysis obtains O-Benzoylglycolaldehyde; This method operation steps is few, but starting raw material is not easy to obtain, and reaction yield is also lower, and the crude product yield only is 56%; And to use the ozone (O of the big and seriously corroded of toxicity in the reaction
3), bring difficulty for a large amount of preparations, also environment is worked the mischief.Swiss Patent 683613 (CH683613) is with 2-butylene-1, and the two benzoic ethers of 4-glycol are starting raw material, feed ozone (O in ethyl acetate solution
3) oxidation, obtain O-Benzoylglycolaldehyde, though this method operation steps is few, yield height (94.8%), but still have the drawback of using ozone, and the feedstock production difficulty.United States Patent (USP) 5047407 (US5047407) and world patent/9529176 (WO95/29176) have reported that with 1 2-dihydroxyl-3-benzoyloxy propane is raw material, uses NaIO in methylene dichloride/water mixed solvent
4Oxidation makes O-Benzoylglycolaldehyde; This method has overcome the drawback of using ozone, but oxidization-hydrogenation ratio is on the low side, only is 62.14%.Document Can J Research 1933,8:129～136 and Ber 1920,53:1589～1605 have described 1, the synthetic method of 2-dihydroxyl-3-benzoyloxy propane, this method is a starting raw material with glycerol acetonide acetone, under quinoline or triethylamine existence condition with the Benzoyl chloride condensation, obtain glycerol acetonide acetone benzoic ether, in the HCl aqueous solution, take off the acetone protecting group again, promptly get 1,2-dihydroxyl-3-benzoyloxy propane; Because raw materials used glycerol acetonide acetone is not easy to obtain, also need further preparation, so this method exists that synthesis step is many, at the bottom of the complex operation, yield, " three wastes " seriously polluted, high deficiency of cost.
Summary of the invention
The objective of the invention is to be to avoid the deficiency of existing method, the novel method of a kind of yield height, cost is low, reaction conditions is gentle, aftertreatment is easy, reaction environment is friendly preparation O-Benzoylglycolaldehyde (I) is provided.
O-Benzoylglycolaldehyde proposed by the invention (I) novel preparation method is to be starting raw material with Sodium Benzoate cheap and easy to get, epoxy chloropropane or glycerol, boric acid, phenylformic acid, and its synthetic route is as follows:
Method one:
Method two:
For above-mentioned two synthetic routes, its concrete steps are:
A) Sodium Benzoate and epoxy chloropropane esterification make phenylformic acid glycidyl ester (II).
B) compound that is obtained by step a) (II) hydrolysis in acidic aqueous solution gets 1,2-dihydroxyl-3-benzoyloxy propane (III).
C) glycerol and boric acid condensation make boric acid double glyceride (IV).
D) compound that is obtained by step c) (IV) and phenylformic acid esterification get benzoyl boric acid double glyceride (V).
E) compound that is obtained by step d) (V) hydrolysis in acidic aqueous solution gets 1,2-dihydroxyl-3-benzoyloxy propane (III).
F) compound that is obtained by step b) or step e) (III) obtains O-Benzoylglycolaldehyde (I) through oxidation.
Wherein, step (c), step (d) and step (e) but one pot reaction finish.
Each step of this synthetic method specifically describes as follows:
Step a): Sodium Benzoate and epoxy chloropropane through the phase-transfer catalysis esterification, make phenylformic acid glycidyl ester (II) in suitable solvent.Wherein, the solvent that esterification is suitable can be low-molecular-weight ketone as acetone, butanone, methyl isopropyl Ketone, and low-molecular-weight halohydrocarbon is as methylene dichloride, chloroform, 1,2-ethylene dichloride, and aromatic hydrocarbons as: benzene, toluene, chlorobenzene, dimethylbenzene, preferred solvent are toluene and chlorobenzene; Suitable phase-transfer catalyst can be quaternary ammonium salt as Tetrabutylammonium bromide (TBAB), benzyl triethyl ammonium ammonium (TEBA), benzyl tributyl ammonium (TBBA), bromogeramine, polyoxyethylene glycol is as polyoxyethylene glycol-400 (PEG-400), polyoxyethylene glycol-600 (PEG-600), polyoxyethylene glycol-800 (PEG-800), or the composition of quaternary ammonium salt and polyoxyethylene glycol, preferred phase-transfer catalyst is Tetrabutylammonium bromide, polyoxyethylene glycol-400; The mole proportioning of Sodium Benzoate, epoxy chloropropane and phase-transfer catalyst is 1: 1～2.5: 0.01～0.2, and preferred mole proportioning is 1: 1.5: 0.1; Temperature of reaction is room temperature～180 ℃, and preferable reaction temperature is a reflux temperature.
Step b): phenylformic acid glycidyl ester (II) hydrolysis in dilute acid solution gets 1,2-dihydroxyl-3-benzoyloxy propane (III).Wherein, used acid can be mineral acid as sulfuric acid, hydrochloric acid, phosphoric acid, H type Zeo-karb as: 732 types, Dowex-50 type, preferred acid be sulfuric acid and H type 732 Zeo-karbs; Hydrolysising reacting temperature is room temperature～80 ℃, and preferable reaction temperature is 40～60 ℃.
Step c): glycerol and boric acid back flow reaction in solvent makes complex compound boric acid double glyceride (IV) through dehydrating condensation.Wherein, the suitable solvent of complex reaction can be toluene, dimethylbenzene, chlorobenzene, heptane, and preferred solvent is a toluene; The mole proportioning of glycerol and boric acid is 2～2.2: 1, and preferred mole proportioning is 2: 1.
Step d): compound (IV) is without separation, directly with phenylformic acid under acid catalysis, reflux dewatering must benzoyl boric acid double glyceride (V).Wherein, the esterification appropriate catalyst can be protonic acid as HCl, H
2SO
4, tosic acid, or Lewis acid as: FeCl
3, SnCl
4, CuCl
2, preferred catalyst is tosic acid and SnCl
4
Step e): compound (V) is without separation, and directly hydrolysis in acidic aqueous solution gets 1,2-dihydroxyl-3-benzoyloxy propane (III).Wherein, the acid that hydrolysis reaction is suitable is protonic acid as HCl, H
2SO
4, tosic acid, preferred acid is HCl and H
2SO
4Hydrolysising reacting temperature is room temperature～150 ℃, and preferred temperature is a room temperature.
Step f): the compound that step b) or step e) obtain (III) in appropriate solvent, gets O-Benzoylglycolaldehyde (I) through oxidizing reaction.Wherein, the solvent that oxidizing reaction is suitable can be low-molecular-weight halohydrocarbon as methylene dichloride, chloroform, 1, the 2-ethylene dichloride, and preferred solvent is methylene dichloride and chloroform; Used oxygenant can be the Periodic acid that is adsorbed on the silica gel or periodate as NaIO
4, KIO
4Temperature of reaction is a room temperature.
The invention has the advantages that: compared with prior art, this method raw materials used cheap and easy to get, reaction conditions is gentle, easy and simple to handle, yield is high, cost is low, reaction environment is friendly, is fit to a large amount of preparation O-Benzoylglycolaldehydes.
Embodiment
One. the preparation of phenylformic acid glycidyl ester (II)
Embodiment 1
Sodium Benzoate 14.4g (0.1mol), epoxy chloropropane 13.9g (0.15mol), Tetrabutylammonium bromide 3.2g (0.01mol) and toluene 50ml are mixed temperature rising reflux stirring reaction 2 hours.After reaction finishes, filter, filtrate is used 15mL * 2 deionized water wash, and toluene liquid is through anhydrous Na
2SO
4Drying removes solvent and excessive epoxy chloropropane under reduced pressure, gets faint yellow phenylformic acid glycidyl ester oily liquids 16.67g, yield 93.5%.
Embodiment 2
Sodium Benzoate 14.4g (0.1mol), epoxy chloropropane 13.9g (0.15mol), polyoxyethylene glycol-4004.0g (0.01mol) and chlorobenzene 60ml are mixed temperature rising reflux stirring reaction 1.5 hours.Reaction removes by filter small amount of solid after finishing, and filtrate is used 15mL * 2 deionized water wash, and organic layer is through anhydrous Na
2SO
4Drying removes solvent and excessive epoxy chloropropane under reduced pressure, gets faint yellow phenylformic acid glycidyl ester oily liquids 17.08g, yield 95.8%.
Two .1, the preparation of 2-dihydroxyl-3-benzoyloxy propane (III)
Embodiment 1
The aqueous sulfuric acid 120ml that adds phenylformic acid glycidyl ester 21.4g (0.12mol) and 0.05mol/L in reaction flask in 50～55 ℃ of stirring reactions, till oily liquid disappears, needs 3.5 hours approximately.Reaction is cooled to room temperature after finishing, and uses Na
2CO
3Neutralization solution pH adds NaCl to saturated to neutral in solution, mixed solution extracts with ether 60mL * 3, and ether solution is through anhydrous Na
2SO
4After the drying, remove solvent under reduced pressure, get off-white color low melting point solid 20.4g, yield 86.5% after the cooling.
1H-NMR(CDCl
3)δ：8.06(m，2H，Ar-H)，7.56(m，1H，Ar-H)，7.48(m，2H，Ar-H)，4.44(m，2H，PhCOOCH
2)，4.10(t，1H，J＝4.8Hz，CH)，3.81(dd，1H，J＝4.8Hz，7.6Hz，CH
2OH)，3.70(dd，1H，J＝5.6Hz，7.6Hz，CH
2OH)；MS(EI)m/e：196(M
+)。
Embodiment 2
Phenylformic acid glycidyl ester 21.4g (0.12mol), deionized water 120ml and the 732 Zeo-karb 10.0g that are processed into the H type are added in the reaction flask, in 50 ℃ of stirring reactions 2.5 hours.Reaction is cooled to room temperature after finishing, and filters, and adds NaCl in the filtrate to saturated, and mixed solution extracts with ether 60mL * 3, and ether solution is through anhydrous Na
2SO
4After the drying, remove solvent under reduced pressure, cooling gets off-white color low melting point solid 22.72g, yield 96.5%.
Embodiment 3
Glycerol 18.4g (0.2mol), boric acid 6.18g (0.1mol) and toluene 80mL are mixed, and reflux water-dividing reaction under agitation finishes reaction after 5 hours, tell about 5.5mL water.After reaction solution cools off slightly, add phenylformic acid 24.4g (0.2mol) and tosic acid 1.9g (0.01mol), continue reflux water-dividing to reaction and finish, need 7 hours approximately.Reaction removes solvent under reduced pressure after finishing, and remaining oily matter is cooled to room temperature, adds 1.0mol/L aqueous hydrochloric acid 160mL, and the stirring at room reaction was used Na after 2 hours
2CO
3In and pH to neutral, extract ether 100mL * 3, ether solution is through anhydrous Na
2SO
4After the drying, remove solvent under reduced pressure, get off-white color low melting point solid 33.83g, total recovery 86.2% after the cooling.
Embodiment 4
Glycerol 9.2g (0.1mol), boric acid 3.09g (0.05mol) and toluene 50mL are mixed, and reflux water-dividing reaction under agitation finishes reaction after 4 hours, tell about 2.7mL water.After reaction solution cools off slightly, add phenylformic acid 12.2g (0.1mol) and stannic chloride pentahydrate 1.0g, continue reflux water-dividing to reaction and finish, need 5 hours approximately.Reaction removes solvent under reduced pressure after finishing, and remaining oily matter is cooled to room temperature, adds 0.5mol/L aqueous sulfuric acid 100mL, and the stirring at room reaction was used Na after 1.5 hours
2CO
3In and pH to neutral, extract ether 50mL * 3, extracting solution is through anhydrous Na
2SO
4After the drying, remove solvent under reduced pressure, get off-white color low melting point solid 17.52g, total recovery 89.3% after the cooling.
Three. the preparation of O-Benzoylglycolaldehyde (I)
Embodiment 1
In reaction flask, add NaIO
4/ silica gel adsorption thing 30.0g (about 0.04mol) and methylene dichloride 150ml, after stirring, add 1,2-dihydroxyl-3-benzoyloxy propane 3.92g (0.02mol), stirring at room reaction 40 minutes, after reaction finishes, filter a small amount of washed with dichloromethane filter cake, filtrate and washing lotion merge, decompression steams solvent, gets almost colourless oily liquids 3.18g, yield 97.0%.
1H-NMR(CDCl
3)δ：9.72(s，1H，CHO)，8.10(m，2H，Ar-H)，7.61(d，1H，Ar-H)，7.48(m，2H，Ar-H)，4.90(s，2H，CH
2)；MS(EI)m/e：164(M
+)。
Embodiment 2
In reaction flask, add HIO
4/ silica gel adsorption thing 28.0g (about 0.04mol) and chloroform 150ml, after stirring, add 1,2-dihydroxyl-3-benzoyloxy propane 3.92g (0.02mol), stirring at room reaction 1 hour, after reaction finishes, filter the minimum of chloroform washing leaching cake, filtrate and washing lotion merge, decompression steams solvent, gets almost colourless oily liquids 3.05g, yield 92.8%.
The foregoing description only is used to illustrate embodiments of the present invention, but the present invention is not limited only to above-mentioned example.
Claims (5)
1. the novel preparation method of an O-Benzoylglycolaldehyde (I)
It is characterized in that:
A) be starting raw material with Sodium Benzoate and epoxy chloropropane, in solvent,, make phenylformic acid glycidyl ester (II) through the phase-transfer catalysis esterification;
B) compound that is obtained by step a) (II) hydrolysis in dilute acid solution gets 1,2-dihydroxyl-3-benzoyloxy propane (III);
C) compound that is obtained by step b) (III) in appropriate solvent, gets O-Benzoylglycolaldehyde (I) through oxidizing reaction.
2. according to the described method of claim 1, it is characterized in that the suitable solvent of step a) is acetone, butanone, methyl isopropyl Ketone, methylene dichloride, chloroform, 1,2-ethylene dichloride, benzene, toluene, chlorobenzene, dimethylbenzene; Suitable phase-transfer catalyst is the composition of quaternary ammonium salt, polyoxyethylene glycol or quaternary ammonium salt and polyoxyethylene glycol.
3. according to the described method of claim 1, the mole proportioning that it is characterized in that Sodium Benzoate in the step a), epoxy chloropropane and phase-transfer catalyst is 1: 1～2.5: 0.01～0.2; Temperature of reaction is room temperature～180 ℃.
4. according to the described method of claim 1, it is characterized in that the used acid of step b) is mineral acid or H type Zeo-karb; Temperature of reaction is room temperature～80 ℃.
5. according to the described method of claim 1, it is characterized in that the suitable solvent of step c) reaction is methylene dichloride, chloroform, 1, the 2-ethylene dichloride; Used oxygenant is Periodic acid or the periodate that is adsorbed on the silica gel; Temperature of reaction is a room temperature.
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|---|---|---|---|
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| CN101318885B (en) * | 2008-06-27 | 2011-07-20 | 烟台海岸带可持续发展研究所 | Preparation method for converting organic carboxylic acid into organic aldehyde |
| CN103450024A (en) * | 2013-09-09 | 2013-12-18 | 辽宁石油化工大学 | Preparation method of glycerol monostearate p-hydroxybenzoate |
| CN109439707A (en) * | 2018-12-07 | 2019-03-08 | 武汉工程大学 | The enzymatic preparation method of emtricitabine |
Citations (5)
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|---|---|---|---|---|
| CN1044817A (en) * | 1989-02-08 | 1990-08-22 | Iaf生物化学国际公司 | The replacement 1 of antiviral performance is arranged, 3-oxygen thia alkane |
| JPH05155815A (en) * | 1991-12-04 | 1993-06-22 | Mitsui Petrochem Ind Ltd | Production of glycerol derivative |
| CH683613A5 (en) * | 1992-05-22 | 1994-04-15 | Lonza Ag | Oxo:ethyl benzoate ester prodn. - by ozonolysis of benzoic acid 2-en-1,4-di:yl ester(s) followed by redn. useful as intermediate for antiviral pharmaceuticals |
| US6228860B1 (en) * | 1990-11-13 | 2001-05-08 | Biochem Pharma Inc. | Substituted 1,3-oxathiolanes with antiviral properties |
| CN1620295A (en) * | 2001-12-14 | 2005-05-25 | 法玛塞特有限公司 | Preparation of intermediates useful in the synthesis of antiviral nucleosides |
-
2005
- 2005-08-31 CN CNB2005100215714A patent/CN1328240C/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1044817A (en) * | 1989-02-08 | 1990-08-22 | Iaf生物化学国际公司 | The replacement 1 of antiviral performance is arranged, 3-oxygen thia alkane |
| US6228860B1 (en) * | 1990-11-13 | 2001-05-08 | Biochem Pharma Inc. | Substituted 1,3-oxathiolanes with antiviral properties |
| JPH05155815A (en) * | 1991-12-04 | 1993-06-22 | Mitsui Petrochem Ind Ltd | Production of glycerol derivative |
| CH683613A5 (en) * | 1992-05-22 | 1994-04-15 | Lonza Ag | Oxo:ethyl benzoate ester prodn. - by ozonolysis of benzoic acid 2-en-1,4-di:yl ester(s) followed by redn. useful as intermediate for antiviral pharmaceuticals |
| CN1620295A (en) * | 2001-12-14 | 2005-05-25 | 法玛塞特有限公司 | Preparation of intermediates useful in the synthesis of antiviral nucleosides |
Non-Patent Citations (3)
| Title |
|---|
| Enantioselective allyltitanations.Synthesis of optically active1,2-diol units: useful intermediates for the preparation ofbiologically active compounds.Cossy,Janine,Bouzbouz,Samir,Caille,Jean Claude,Tetrahedron: Asymmetry,Vol.10 No.20 1999 * |
| Enantioselective allyltitanations.Synthesis of optically active1,2-diol units: useful intermediates for the preparation ofbiologically active compounds.Cossy,Janine,Bouzbouz,Samir,Caille,Jean Claude,Tetrahedron: Asymmetry,Vol.10 No.20 1999;The synthetic methodology of nonracemic glycidol and related2,3-epoxy alcohols Hanson M. R,Chemical Reviews,Vol.91 No.4 1991 * |
| The synthetic methodology of nonracemic glycidol and related2,3-epoxy alcohols Hanson M. R,Chemical Reviews,Vol.91 No.4 1991 * |
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