CN103864610A - Preparation method of phenyl malonic acid monoester compound - Google Patents
Preparation method of phenyl malonic acid monoester compound Download PDFInfo
- Publication number
- CN103864610A CN103864610A CN201210527891.7A CN201210527891A CN103864610A CN 103864610 A CN103864610 A CN 103864610A CN 201210527891 A CN201210527891 A CN 201210527891A CN 103864610 A CN103864610 A CN 103864610A
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- China
- Prior art keywords
- alkali metal
- metal salt
- compound
- preparation
- malonic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/313—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of doubly bound oxygen containing functional groups, e.g. carboxyl groups
Abstract
The invention discloses a method for preparing a phenyl malonic acid monoester compound by benzyl acetate compound carboxylation adopting an organic amine alkali metal salt and carbon dioxide. In the preparation, under the action of the organic amine alkali metal salt, an alpha-site hydrogen atom of a benzyl acetate compound is replaced and a carbanion compound is produced, the carbanion compound undergoes a carboxylation reaction with carbon dioxide to produce phenyl malonic acid monoester alkali metal salt solids, and the phenyl malonic acid monoester alkali metal salt solids can be directly acidified by an inorganic acid solution so that the phenyl malonic acid monoester compound solids are obtained. The preparation method has simple processes, simplifies organic solvent extraction and crystallization steps, reduces an organic solvent use amount, utilizes the organic amine alkali metal salt raw-material having a low price, realizes a high product yield and has a low production cost and a high economic value in industrialized application. The preparation method belongs to the field of chemical synthesis.
Description
Technical field
The invention belongs to the field of chemical synthesis, particularly a kind of preparation method of phenylmalonate monoester class compound.
Background technology
Phenylmalonate monoester class compound is the important intermediate of for example penicillin of raw materials medicine and cynnematin, in this compounds, 4-(4-methoxy-benzyl oxygen base) phenylmalonate-4-methoxy-benzyl monoesters is the important intermediate of the preparation beta-lactam antibiotics that contains 4-hydroxybenzene CoA malonyl CoA amine side chain.
In Japanese Patent JP54-106447, introduce the preparation method of phenylmalonate monoester class compound, in the method, by an alkali metal salt reaction of phenylacetate compounds and six alkyl disilazanes, the α position hydrogen atom of basic metal substituted phenylacetic acid ester compound, generate carbanion compound, then maintain lesser temps, react in inert solvent with carbonic acid gas and generate an alkali metal salt of phenylmalonate monoester class compound, last acidifying, solvent extraction, condensing crystal obtains phenylmalonate monoester class compound.
Japanese Patent JP61-165351 provides and above-mentioned basically identical method.
In above preparation method, need to use expensive silylating reagent six alkyl disilazanes, and also aftertreatment complexity, increase the usage quantity of organic solvent, and then increased solvent cost recovery, produce disadvantageous effect for industrialized application.
In English Patent GB2056444, used the organic basess such as sodium carbide, side reaction easily occurs, yield is lower.
Summary of the invention
Object of the present invention is exactly the above-mentioned defect for existing synthetic method, provide a kind of simple to operate, yield is higher, the preparation method of with low cost, the phenylmalonate monoester class compound that is more suitable for scale production.
The present invention is achieved through the following technical solutions:
A kind of phenylmalonate monoester class compound (I)
(wherein R
1for: the alkoxyl group that contains 1 ~ 3 carbon atom; The acyloxy that contains 2 ~ 4 carbon atoms; The aromatic ring alkoxyl group that contains a phenyl or a hexichol methoxycarbonyl methoxyl group; The benzyloxy being replaced by a nitro or the alkoxyl group that contains 1 ~ 3 carbon atom; Or in ring system, there is the saturated heterocyclyl oxygen base of heteroatoms oxygen or sulphur.R
2for: the alkyl that contains 1 ~ 4 carbon atom; The aralkyl that contains phenyl; Diphenyl-methyl; The benzyloxy being replaced by a nitro or the alkoxyl group that contains 1 ~ 3 carbon atom; Indanyl)
The preparation method of this compound (I), is characterized in that comprising the following steps:
(1) by phenylacetate compounds (II)
（Ⅱ）
(wherein R
1and R
2define the same)
In organic solvent, react with an alkali metal salt of organic amine, mixeding liquid temperature is-30 ~ 50 DEG C, generates transition state carbanion compound (III);
（Ⅲ）
(wherein R
1and R
2define the same)
(2) then add carbonic acid gas, reaction obtains phenylmalonate monoesters an alkali metal salt solid (IV)
（Ⅳ）
(wherein R
1and R
2define the samely, M is that basic metal comprises: sodium, lithium, potassium etc.)
(3) by (IV) with the direct acidifying of inorganic acid solution, stir, crystallization, obtains phenylmalonate monoester class compound solid (I);
More prioritization scheme of the present invention is: in step (1), organic amine used comprises: tetramethyleneimine, and diethylamine, Diisopropylamines etc., are preferably tetramethyleneimine, Diisopropylamine; Basic metal used comprises: sodium, lithium, potassium etc.; The phenylacetate compounds of every corresponding 1 molar fraction, the umber of organic amine an alkali metal salt used is 1 ~ 10 part, is preferably 1 ~ 5 part; Optimal reaction temperature is-10 ~ 10 DEG C; In step (2), carbonic acid gas used is carbon dioxide or dry ice, preferably carbon dioxide gas, and optimal reaction temperature is-25 ~-10 DEG C; In step (3), optimum temps is 5 ~ 25 DEG C, and mineral acid used can be hydrochloric acid, sulfuric acid, nitric acid, Hydrogen bromide, acetic acid etc.The present invention reacts the solvent using and is not particularly limited, as long as they do not produce harmful effect to this reaction, can select as follows: the halogenated alkane of C1 ~ C4, and as methylene dichloride, chloroform, ethylene dichloride etc.; The nitrile of C1 ~ C4, as acetonitrile or propionitrile etc.; C1 ~ C8 acetic ester, as ethyl acetate, methyl acetate etc.; The ether of C1 ~ C4.As ether, tetrahydrofuran (THF) etc.; The acid amides of C3 ~ C4, as dimethyl formamide, N,N-DIMETHYLACETAMIDE etc.; C6 ~ C10 containing benzene solvent, as toluene, dimethylbenzene, one or more in chlorobenzene equal solvent, preferably tetrahydrofuran (THF).
It is simple to operate in the present invention, preparing the outstanding advantages that the method for phenylmalonate monoester class compound has, organic amine an alkali metal salt cost of material used is cheap, reduce the use of organic solvent, product yield is high, production cost is low, there is good practicality, be suitable for large-scale industrial production, can produce good economic benefit and social benefit.
Embodiment
Be below specific embodiment of the invention case, further describe the present invention, but the present invention be not limited only to this.
Embodiment 1
Under nitrogen protection; in 500ml four-hole bottle, add successively 4-(4-methoxy-benzyl oxygen base) toluylic acid-4-methoxy-benzyl ester 8g and tetrahydrofuran (THF) 70ml; be cooled to-10 ~-5 DEG C, in 20min, drip the hexane solution 15ml of 2mol/L pyrrolidyl lithium, dropwise; slowly be warming up to 0 ~ 5 DEG C; reaction 50min, is cooled to-25 DEG C, slowly passes into carbonic acid gas; stirring reaction 1h, reacts completely.Then add saturated brine 150ml, generate 4-(4-methoxy-benzyl oxygen base) phenylmalonate-4-methoxy-benzyl monoesters lithium salts white precipitate, filters.Gained solid is added in 1N HCl water 30ml, stirs, filter and obtain 4-(4-methoxy-benzyl oxygen base) the white crystal 7.92g of phenylmalonate-4-methoxy-benzyl monoesters, yield 89%.
1H NMR(CDCl
3，400MH
Z)δ：6.87～7.24（m，PhH，12H），5.16（s，OCH
2，2H），5.00（s，CH
2O，2H），4.62 (s，CH，1H），3.83（s，OCH
3，6H）。
Embodiment 2
Under nitrogen protection; in 500ml four-hole bottle, add successively 4-(4-methoxy-benzyl oxygen base) toluylic acid-4-methoxy-benzyl ester 8g and tetrahydrofuran (THF) 80ml; be cooled to-5 ~ 0 DEG C, in 20min, drip the n-heptane solution 20ml of 2mol/L diisopropylaminoethyl sodium, dropwise; slowly be warming up to 0 ~ 5 DEG C; reaction 50min, is cooled to-20 DEG C, slowly passes into carbonic acid gas; stirring reaction 1h, reacts completely.Then add saturated brine 150ml, generate 4-(4-methoxy-benzyl oxygen base) phenylmalonate-4-methoxy-benzyl monoester sodium salt white precipitate, filters.Gained solid is added in 1N HCl water 30ml, stirs, filter and obtain 4-(4-methoxy-benzyl oxygen base) the white crystal 7.85g of phenylmalonate-4-methoxy-benzyl monoesters, yield 88%.
1H NMR(CDCl
3，400MH
Z)δ：6.87～7.24（m，PhH，12H），5.18（s，OCH
2，2H）, 5.05(s，CH
2O，2H），4.64 (s，CH，1H），3.81（s，OCH
3，6H）。
Claims (4)
1. a preparation method for phenylmalonate monoester class compound (I), is characterized in that, comprises the following steps:
(wherein R
1for: the alkoxyl group that contains 1 ~ 3 carbon atom; The acyloxy that contains 2 ~ 4 carbon atoms; The aromatic ring alkoxyl group that contains a phenyl or a hexichol methoxycarbonyl methoxyl group; The benzyloxy being replaced by a nitro or the alkoxyl group that contains 1 ~ 3 carbon atom; Or in ring system, there is the saturated heterocyclyl oxygen base of heteroatoms oxygen or sulphur; R
2for: the alkyl that contains 1 ~ 4 carbon atom; The aralkyl that contains phenyl; Diphenyl-methyl; The benzyloxy being replaced by a nitro or the alkoxyl group that contains 1 ~ 3 carbon atom; Indanyl)
(1) by phenylacetate compounds (II)
(wherein R
1and R
2define the same)
In organic solvent, react with an alkali metal salt of organic amine, generate transition state carbanion compound (III),
(wherein R
1and R
2define the same)
(2) then with carbonic acid gas generation carboxylation reaction, obtain phenylmalonate monoesters an alkali metal salt solid (IV),
(wherein R
1and R
2define the samely, M is that basic metal comprises: sodium, lithium, potassium etc.)
(3) finally obtain phenylmalonate monoester class compound solid with the direct acidifying of inorganic acid solution.
2. method according to claim 1, is characterized in that organic amine used comprises: tetramethyleneimine, and diethylamine, Diisopropylamines etc., are preferably tetramethyleneimine, Diisopropylamine.
3. method according to claim 1, is characterized in that basic metal used comprises: sodium, lithium, potassium etc.
4. method according to claim 1, is characterized in that the temperature of reaction of step (1) is-30 ~ 50 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210527891.7A CN103864610A (en) | 2012-12-11 | 2012-12-11 | Preparation method of phenyl malonic acid monoester compound |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210527891.7A CN103864610A (en) | 2012-12-11 | 2012-12-11 | Preparation method of phenyl malonic acid monoester compound |
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| Publication Number | Publication Date |
|---|---|
| CN103864610A true CN103864610A (en) | 2014-06-18 |
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ID=50903687
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|---|---|---|---|
| CN201210527891.7A Pending CN103864610A (en) | 2012-12-11 | 2012-12-11 | Preparation method of phenyl malonic acid monoester compound |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110003006A (en) * | 2019-04-23 | 2019-07-12 | 山西千岫制药有限公司 | A kind of preparation method of sour 7 side chains of latamoxef |
| CN110950761A (en) * | 2019-12-16 | 2020-04-03 | 山东金城柯瑞化学有限公司 | Synthesis method of latamoxef 7-site side chain |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102229531A (en) * | 2011-05-09 | 2011-11-02 | 山东睿鹰先锋制药有限公司 | Preparation method of p-hydroxy benzal propane diacid derivative |
-
2012
- 2012-12-11 CN CN201210527891.7A patent/CN103864610A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102229531A (en) * | 2011-05-09 | 2011-11-02 | 山东睿鹰先锋制药有限公司 | Preparation method of p-hydroxy benzal propane diacid derivative |
Non-Patent Citations (1)
| Title |
|---|
| 刘相奎等: "4-(4-甲氧基苄基氧基)苯丙二酸-4-甲氧基苄基单酯的工艺改进", 《中国抗生素杂志》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110003006A (en) * | 2019-04-23 | 2019-07-12 | 山西千岫制药有限公司 | A kind of preparation method of sour 7 side chains of latamoxef |
| CN110950761A (en) * | 2019-12-16 | 2020-04-03 | 山东金城柯瑞化学有限公司 | Synthesis method of latamoxef 7-site side chain |
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Application publication date: 20140618 |