CN103086910A - Preparation method of optically active amide - Google Patents
Preparation method of optically active amide Download PDFInfo
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- CN103086910A CN103086910A CN2011103446913A CN201110344691A CN103086910A CN 103086910 A CN103086910 A CN 103086910A CN 2011103446913 A CN2011103446913 A CN 2011103446913A CN 201110344691 A CN201110344691 A CN 201110344691A CN 103086910 A CN103086910 A CN 103086910A
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Abstract
The invention provides a preparation method of amide with high efficiency rate and high optical purity. The method comprises: (a) performing an esterification reaction for 2,2'-dimethyl cyclopropane carboxylic acid and a chiral reagent under a condition of using an inorganic catalyst potash, thereby preparing (S)-(+)-2,2'-dimethyl cyclopropane ester; (b) adding water and then performing a hydrolysis for the (S)-(+)-2,2'-dimethyl cyclopropane ester, thereby preparing (S)-(+)-2,2'-dimethyl cyclopropane carboxylic acid; and (c) performing chlorination and amination additional reactions for the (S)-(+)-2,2'- dimethyl cyclopropane carboxylic acid, thereby preparing the amide with optical activity. The method provided by the invention uses the cheap inorganic catalyst to substitute expensive biochemical catalysts, and thus can not only promote the esterification reaction, but also reduce production cost, and obtain a high earning rate among various racemisation reactions.
Description
Technical field
The present invention relates to a kind of manufacture method of optically active amides.Further, the present invention relates to use the organic catalyst manufacturing as the manufacture method of the acid amides of Sai Latating intermediate.
Background technology
Sai Latating (sheila statin) is a kind of compound, its with belong to the antibiotic imipenum of carbapenems (carbapenem) (imipenem) and mix mutually after, can stop imipenum (imipenem) to be decomposed by microorganism, thereby can improve its germ resistance.European patent discloses the manufacture method of a kind of Sai Latating for No. 48301.Can find out from following chemical equation, Sai Latating utilizes the compound with following chemical structural formula 1 to make, as shown in following chemical equation, the compound shown in chemical structural formula 1 and alpha keto acid compound are carried out adding amino acid Cys (cysteine) after polyreaction again get final product.
Chemical structural formula 1
Chemical equation
Compound with above-mentioned chemical structural formula 1 also has optical activity (opticity), depends on the optical purity of above-claimed cpd due to the product purity of the finished product Sai Latating.Therefore, chirality (chiral) midbody compound with above-mentioned chemical structural formula 1 is to make the necessary core substance of Sai Latating, can make with comparalive ease Sai Latating by it.People have worked out various manufacture method now.
The main method of making above-claimed cpd is with racemic modification (recemate) and the method for separating again after chiral separation reagent combines.At this moment, in order to obtain object, need the sepn process through more complicated.That is, racemic modification (recemate) after being combined, is isolated by chiral separation reagent each isomers again, and then separating chiral separation agent and each isomers etc.In the ordinary course of things, reach more than 98% if racemic modification (recemate) is separated into our desirable optical purity, must satisfy its row yielding is below 20%, just can obtain object.
In addition, record a kind of method of separating by biology on No. the 5273903rd, United States Patent (USP) and make the method for the compound with above-mentioned chemical structural formula 1 with racemic modification.It utilizes acylase, optionally adds water and decomposes racemic modification (recemate), makes thus the compound with above-mentioned chemical structural formula 1.But when manufacturing a product by the method, its optical purity is also 93%, therefore, intactly use the pharmaceuticals intermediate if adopt foregoing biology partition method, in contrast, enantiomorph impurity content just can reach 3.5%, so be unsuitable for adopting above-mentioned biology partition method.
Record a kind of method that manufacturing has the compound of above-mentioned chemical structural formula 1 on No. the 10-0654923rd, Korean Patent.It is with levorotatory menthol (L-menthol) combination of racemic modification (recemate) with less expensive chiral separation reagent, separate each diastereomer isomers by the simple method of recrystallize more afterwards, and then produce our needed S-FIRM product.In contrast, because isomers is can not separate with the levorotatory menthol (L-menthol) as chiral separation reagent, but it is carried out the racemic modification of isomers in identical reaction vessel.Then can adopt continuously the method for recrystallize to continue to produce our needed S-FIRM product.Content according to record, by this method, can obtain our its required chiral purity and reach 90～95% S-FIRM product, but because the row yielding of the ester mixture that obtains by the initial stage esterification in aforesaid method only reaches 25%, so cause the row yielding of the finished product also not high.In a word, all there is the lower problem of economic benefit in aforesaid method.
Summary of the invention
In order to address the above problem, the object of the invention is to, a kind of manufacture method of optically active amides is provided, can also can produce the superior returns optically active amides in the situation that do not use existing high price biocatalyst, greatly increase economic efficiency.
Another object of the present invention is by using organic catalyst, esterification to be carried out smoothly, thereby obtain higher row yielding in various racemizations.Therefore, the present invention is applicable in various chiral reagent reactions.
To achieve these goals, manufacture method of the present invention comprises the following steps:
(a) using organic catalyst salt of wormwood (K
2CO
3) situation under, make 2,2-dimethyl cyclopropane carboxylic acid (dimethyl cyclo propane carboxyl acid) and chiral reagent carry out esterification, thereby produce (S)-(+)-2,2-dimethylcyclopropane ester;
(b) to above-mentioned (S)-(+)-2,2-dimethylcyclopropane ester adds water decomposition to be processed, thereby produces 2,2-dimethyl cyclopropane carboxylic acid (dimethyl cyclo propane carboxyl acid);
(c) to above-mentioned (S)-(+)-2,2-dimethyl cyclopropane carboxylic acid (dimethyl cyclo propane carboxyl acid) carries out chlorination and ammonification addition reaction, thereby produces the have optical activity acid amides of (opticity).This manufacturing processed is (S)-(+)-2, the manufacturing step of 2-dimethyl-cyclopropane carboxamide (dimethyl cyclo propane carbox amide).
In addition, the above-mentioned chiral reagent mixture that adopts one of following reagent or mixed by them:
4-fluorobenzaldehyde (fluor benzaldehyde); 4-chlorobenzaldehyde (chloro benzaldehyde); 2,4 dichloro benzene formaldehyde (chloro benzaldehyde); 2,3 dichloro benzaldehyde (chloro benzaldehyde); 2,6-dichlorobenzaldehyde (chloro benzaldehyde); 4-chloro-3-fluorobenzaldehyde (fluor benzaldehyde); 2-chloro-4-fluorobenzaldehyde (fluor benzaldehyde); 4-bromobenzaldehyde (brom benzaldehyde); Or 2-naphthaldehyde (Naphthaldehyde).
The solvent that adds in above-mentioned manufacture method is more than one the solvent of selecting from the component that following material forms.That is, from the component that methylene dichloride, ethylene dichloride, trichloromethane, tetracol phenixin, zellon, tetrachloroethane etc. form, select wherein more than one solvent add and use.
In above-mentioned manufacture method, selected siccative is sal epsom, sodium sulfate or calcium chloride.
Use SOCl when carrying out above-mentioned chlorination reaction
2Or SO
2Cl
2
Use NH when carrying out above-mentioned ammonification addition reaction
3
[invention effect]
In the situation that substitute the high price biocatalyst with organic catalyst, the present invention also can produce the desirable acid amides product that has high-optical-purity and superior returns and have the good optical activity.Can reduce production costs when adopting manufacture method of the present invention, that is, the present invention can increase economic efficiency greatly.
Embodiment
Manufacture method of the present invention has high-optical-purity and superior returns (S)-(+)-2, the method for 2-dimethyl-cyclopropane carboxamide (dimethyl cyclo propane carbox amide) isomers about manufacturing.That is, the present invention is used for making the compound with chemical structural formula 1, and its manufacture method comprises the following steps:
Chemical structural formula 1
Using organic catalyst K
2CO
3Situation under, make and have 2 of chemical structural formula 2,2-dimethyl cyclopropane carboxylic acid (dimethyl cyclo propane carboxyl acid) and chirality (Chiral) reagent carry out esterification, make (S)-(+)-2, the stage of 2-dimethylcyclopropane ester (dimethyl cyclo propane ester):
Chemical structural formula 2
To above-mentioned (S)-(+)-2,2-dimethylcyclopropane ester (dimethyl cyclo propane ester) adds water decomposition to be processed, thereby produce (S)-(+)-2,2-dimethyl cyclopropane carboxylic acid (dimethyl cyclo propane carboxyl acid);
To above-mentioned (S)-(+)-2,2-dimethyl cyclopropane carboxylic acid (dimethyl cyclo propane carboxyl acid) carries out chlorination and ammonification addition reaction, has optically active acid amides thereby produce.(S)-(+)-2 that has above-mentioned chemical structural formula 1 comprising manufacturing, the stage of 2-dimethylcyclopropane ester (dimethyl cyclo propane ester).
Respectively one of the following or the mixture that mixed by them at chiral reagent used in the present invention (chiral reagent):
4-fluorobenzaldehyde (fluor benzaldehyde); 4-chlorobenzaldehyde (chloro benzaldehyde); 2,4 dichloro benzene formaldehyde (chloro benzaldehyde); 2,3 dichloro benzaldehyde (chloro benzaldehyde); 2,6-dichlorobenzaldehyde (chloro benzaldehyde); 4-chloro-3-fluorobenzaldehyde (fluor benzaldehyde); 2-chloro-4-fluorobenzaldehyde (fluor benzaldehyde); 4-bromobenzaldehyde (brom benzaldehyde); 2-naphthaldehyde (Naphthaldehyde).
The below introduces the present invention in detail, that is, and and the manufacture method of optically active amides.
(a) using salt of wormwood (K
2CO
3) situation under carry out esterification, thereby produce (S)-(+)-2, the 2-dimethylcyclopropane;
Above-mentioned reaction formula is to use salt of wormwood (K
2CO
3) situation under make raw material 2,2-dimethyl cyclopropane carboxylic acid (dimethyl cyclo propane carboxyl acid) and chiral reagent (chiral reagent) carry out esterification.Can find out from reaction formula, chiral reagent used in the present invention (Chiral reagent) is 4-fluorobenzaldehyde (fluor benzaldehyde).The 4-fluorobenzaldehyde that uses in above-mentioned reaction (fluor benzaldehyde), the chiral reagent that can use in the present invention (Chiral reagent) can be with reference to＜table 1〉in 4a～4h, carrying out the formed material of esterification with chiral reagent (chiral reagent) can be with reference to＜table 1〉in 3a～3h.
4a:4-chlorobenzaldehyde (chloro benzaldehyde);
4b:2,4-dichlorobenzaldehyde (chloro benzaldehyde);
4c:2,3-dichlorobenzaldehyde (chloro benzaldehyde);
4d:2,6-dichlorobenzaldehyde (chloro benzaldehyde);
4e:4-chloro-3-fluorobenzaldehyde (fluor benzaldehyde);
4f:2-chloro-4-fluorobenzaldehyde (fluor benzaldehyde);
4g:4-bromobenzaldehyde (brom benzaldehyde);
4h:2-naphthaldehyde (Naphthaldehyde)
＜table 1 〉
At this moment, owing to using salt of wormwood (K
2CO
3) replace existing biocatalyst, so the present invention can promote esterification, so, the row yielding of the formed product of process esterification reaches 40% unexpectedly, and so just the row yielding 25% than the formed product of existing esterification improves a lot.In addition, due to salt of wormwood (K
2CO
3) want cheap more than biocatalyst.So the present invention can be called an epoch-making invention.
Spendable solvent can be that methylene dichloride, ethylene dichloride, trichloromethane, tetracol phenixin, zellon, tetrachloroethane, the spendable siccative of four water furans (tetra hydro furan) can be sal epsom, sodium sulfate, calcium chloride etc. in above-mentioned reaction.
(b) to (S)-(+)-2,2-dimethylcyclopropane ester (dimethyl cyclo propane ester) adds the water decomposition reaction treatment, thereby produce (S)-(+)-2,2-dimethyl cyclopropane carboxylic acid (dimethyl cyclo propane carboxyl acid):
From above-mentioned chemical structural formula 3 as seen, to (S)-(+)-2,2-dimethylcyclopropane ester (dimethyl cyclo propane ester) adds the water decomposition reaction treatment, can produce (S)-(+)-2,2-dimethyl cyclopropane carboxylic acid (dimethyl cyclo propane carboxyl acid).Can certainly use＜table 1 in above-mentioned chemical structural formula 3〉in the chiral reagent of listed 3a～3h.
In above reaction, the solvent of use can be methylene dichloride, ethylene dichloride, trichloromethane, tetracol phenixin, zellon, tetrachloroethane etc.
As above-mentioned (a) stage, the siccative that use this moment can be sal epsom, sodium sulfate, calcium chloride etc.
(c) to (S)-(+)-2,2-dimethyl cyclopropane carboxylic acid (dimethyl cyclo propane carboxyl acid) carries out chlorination and ammonification addition reaction, thereby produce (S)-(+)-2,2-dimethylcyclopropane ester (dimethyl cyclo propane ester).
In above-mentioned chlorination reaction, the reagent of use can be SOCl
2SO2Cl
2Deng.The solvent that uses in above-mentioned reaction can be methylene dichloride, ethylene dichloride, trichloromethane, tetracol phenixin, zellon, tetrachloroethane etc.
Adopt with the method that is same as aforesaid method and make (S)-(+)-2,2-dimethyl-cyclopropane carboxamide (dimethyl cyclo propane carbox amide).Select afterwards the suitable prepared mucus of recrystallisation solvent purification.So, just can produce the optically active amides with high-optical-purity.
The below illustrates above-mentioned manufacture method.Its purpose is to be described more specifically content of the present invention.And protection scope of the present invention comprises claims restricted portion and the modification in equivalency range with it thereof, and the present invention is not limited to following illustrative scope.
[experimental example 1]
(a) using organic catalyst K
2CO
3Situation under, produce (S)-(+)-2 by esterification, 2-dimethylcyclopropane ester (dimethyl cyclo propane ester) is with 4.5g (3.2mmol) salt of wormwood (K
2CO
3), the 50ml ethylene dichloride puts in 500ml capacity flask, at the temperature below 10 ℃, splashes into 37g (32.4mmol) 2,2-dimethyl cyclopropane carboxylic acid (dimethyl cyclo propane carboxyl acid).After one hour, more slowly splash into 42.1g (35.4mmol) thionyl chloride (thionyl chloride), and at the temperature of 20 ℃ of maintenances, slowly splash into the mixed solution of 41.5g (32.4mmol) 4-fluorobenzaldehyde and 50ml ethylene dichloride.Then, carry out the esterification of 4 hours.After splashing into 200ml reaction water and 40ml ethylene dichloride, carry out layering and process.After the dried over mgso organic layer, carry out concentrating under reduced pressure and purify with methyl alcohol.Then carry out filtration treatment, then at 40 ℃ of temperature dry 2 hours, thereby can obtain 29.5g intermediate material (S)-(+)-2,2-dimethylcyclopropane ester (dimethyl cyclo propane ester) (row yielding is 41.3%).The keeping of R-FORM filtered liquid is preserved, so that when carrying out racemization reaction next time, mix use with its filtered liquid.By the result demonstration that the gc analysis instrument is analyzed, the turnover ratio of this moment is 97.5%, and optical purity is 99.1%ee.
(b) to (S)-(+)-2,2-dimethylcyclopropane ester (dimethyl cyclo propane ester) adds the water decomposition reaction treatment, just can produce (S)-(+)-2,2-dimethyl cyclopropane carboxylic acid (dimethyl cyclo propane carboxy acid);
With 29.5g (13.4mmol) (S)-(+)-2,2-dimethylcyclopropane ester (dimethyl cyclo propane ester), 150ml concentration be 95% ethanol, the anhydrous potassium hydroxide of 10.6g (18.9mmol), 8.3g water to put into capacity be in the 500ml flask, refluxed 12 hours at 80 ℃ of temperature greatly.Then it is carried out cooling process concentrating under reduced pressure to the normal temperature.Then add 15ml reaction water, 15ml ethylene dichloride, carry out drying treatment with sal epsom again after extracting its organic layer, then filter and concentrating under reduced pressure is processed and can obtain the pure 4-fluorobenzaldehyde of 20.5g (fluor benzaldehyde), being used for the water layer composition of layering is concentrated hydrochloric acid water, makes its hydrogen ion concentration near 1.Splashing into the 30ml ethylene dichloride carries out with sal epsom, its organic layer being carried out drying treatment after the layering processing, at last it is filtered and concentrating under reduced pressure is processed and can obtain pure (S)-(+)-2 of 14.8g, 2-dimethyl cyclopropane carboxylic acid (dimethyl cyclo propane carboxyl acid) (row yielding is 40.0%).By the result demonstration that the gc analysis instrument is analyzed, the turnover ratio of this moment is 98.8%, and optical purity is 99.6%ee.
(c) to (S)-(+)-2,2-dimethyl cyclopropane carboxylic acid (dimethyl cyclo propane carboxyl acid) carries out chlorination and ammonification addition reaction, just can produce (S)-(+)-2,2-dimethylcyclopropane ester (dimethyl cyclo propane ester);
With 14.8g (13.0mmol) (S)-(+)-2,2-dimethyl cyclopropane carboxylic acid (dimethyl cyclo propane carboxyl acid), 15ml ethylene dichloride and 16.8g (14.0mmol) thionyl chloride are put into the round flask that capacity is 250ml, approximately stirred 5 hours at normal temperatures, afterwards it is placed on to distinguish on plate (panel) and takes care of.
The 150ml ethylene dichloride is dripped in the round flask that capacity is 500ml, with ice bath (ice bath) device, its internal temperature is cooled to below 0 ℃, then slowly add 11.3g (60.0mmol) ammonia.At 0～5 ℃ of temperature, will certainly slowly splash into wherein at the chlorination reaction thing of distinguishing on plate in 2 hours, to note muriatic heating during operation.Its stirring was splashed into the 60ml reaction water after 1 hour, and then stirred 30 minutes.So, the phenomenon that organic layer separates with water layer will occur., the organic layer of collecting is put together and with sal epsom, it is carried out drying treatment several times after water layer with the ethylene dichloride repetitive scrubbing.Then filter and concentrating under reduced pressure, the 20ml ethanol that reinjects afterwards also carries out the reflow treatment of 2 hours.Then carry out again filtration treatment after it being cooled to 10～15 ℃, carry out afterwards the drying treatment of 2 hours at the temperature of 40 ℃.So just can obtain 13.6g (S)-(+)-2,2-dimethyl-cyclopropane carboxamide (dimethyl cyclo propane carbox amide), its row yielding can reach 37.1%.By the result demonstration that the gc analysis instrument is analyzed, the turnover ratio of this moment is 98.5%, and optical purity is 99.5%ee.
Above-mentioned optical purity is calculated with following calculation formula.
Optical purity (enantiometric excess, %ee)=[(concentration of concentration-R-FORM of S-FORM)/(concentration of concentration+R of S)] * 100
[experimental example 2]
(a) use 41.5g (32.4mmol) the 4-fluorobenzaldehyde that 45.5g (32.4mmol) 4-chlorobenzaldehyde replaces (a) in experimental example 1 to use this moment, replace the condition of dry 2 hours at 40 ℃ of temperature originally in the drying condition of 5 hours at 35 ℃ of temperature.In addition the other guide all content of operation with experimental example 1 is identical.Result obtains 29.5g (S)-(+)-2,2-dimethylcyclopropane ester (dimethyl cyclo propane ester) (row yielding is 38.2%).By the result demonstration that the gc analysis instrument is analyzed, the turnover ratio of this moment is 97.5%.
(b) obtain the 20.5g4-fluorobenzaldehyde in (b) of experimental example 1, and acquisition 22.5g4-chlorobenzaldehyde in (b) of this test, and obtain pure (S)-(+)-2 of 14.8g, 2-dimethyl cyclopropane carboxylic acid (dimethyl cyclo propane carboxyl acid) (row yielding is 40.0%).By the result demonstration that the gc analysis instrument is analyzed, the turnover ratio of this moment is 98.5%, and optical purity is 99.1%ee.
[experimental example 3]
(a) use 56.7g (32.4mmol) 2 this moment, the 4-dichlorobenzaldehyde replaces 41.5g (32.4mmol) the 4-fluorobenzaldehyde of use in (a) of experimental example 1, replaces the condition of dry 2 hours at 40 ℃ of temperature originally in the drying condition of 3 hours at 40 ℃ of temperature.In addition the other guide all content of operation with experimental example 1 is identical.Result acquisition 31.2g intermediate material (S)-(+)-2,2-dimethylcyclopropane ester (dimethyl cyclo propane ester) (row yielding is 38.2%).By the result demonstration that the gc analysis instrument is analyzed, the turnover ratio of this moment is 96.8%.
(b) obtain the 20.5g4-fluorobenzaldehyde in (b) in experimental example 1, and obtain 25.5g2 in (b) of this test, the 4-dichlorobenzaldehyde, and obtain pure (S)-(+)-2 of 15.1g, 2-dimethyl cyclopropane carboxylic acid (dimethyl cyclo propane carboxyl acid) (row yielding is 40.8%).By the result demonstration that the gc analysis instrument is analyzed, the turnover ratio of this moment is 98.1%, and optical purity is 98.9%ee.
[experimental example 4]
(a) use 56.7g (32.4mmol) 2 this moment, 41.5g (32.4mmol) the 4-fluorobenzaldehyde that the replacement of 3-dichlorobenzaldehyde is used in (a) of experimental example 1 replaces the condition of dry 2 hours at 40 ℃ of temperature originally in the drying condition of 3 hours at 40 ℃ of temperature.In addition the other guide all content of operation with experimental example 1 is identical.Result acquisition 31.5g intermediate material (S)-(+)-2,2-dimethylcyclopropane ester (dimethyl cyclo propane ester) (row yielding is 35.7%), by the result demonstration that the gc analysis instrument is analyzed, the turnover ratio of this moment is 97.2%.
(b) obtain the 20.5g4-fluorobenzaldehyde in (b) of experimental example 1, and obtain 24.6g2 in (b) of this test, the 3-dichlorobenzaldehyde, and obtain pure (S)-(+)-2 of 15.0g, 2-methyl cyclopropane carboxylic acid (dimethyl cyclo propane carboxy acid) (row yielding is 40.5%).By the result demonstration that the gc analysis instrument is analyzed, the turnover ratio of this moment is 97.7%, and optical purity is 98.4%ee.
[experimental example 5]
(a) use 56.7g (32.4mmol) 2 this moment, 41.5g (32.4mmol) the 4-fluorobenzaldehyde that the replacement of 6-dichlorobenzaldehyde is used in (a) of experimental example 1 replaces the condition of dry 2 hours at 40 ℃ of temperature originally in the drying condition of 3 hours at 40 ℃ of temperature.In addition other guide is all identical with the operation of experimental example 1.Result acquisition 30.5g intermediate material (S)-(+)-2,2-dimethylcyclopropane ester (dimethyl cyclo propane ester) (row yielding is 34.6%).By the result demonstration that the gc analysis instrument is analyzed, the turnover ratio of this moment is 96.8%.
(b) obtain the 20.5g4-fluorobenzaldehyde in (b) of experimental example 1, and obtain 24.6g2 in (b) of this test, the 6-dichlorobenzaldehyde, and obtain pure (S)-(+)-2 of 14.7g, 2-dimethyl cyclopropane carboxylic acid (dimethyl cyclo propane carboxyl acid) (row yielding is 39.7%).By the result demonstration that the gc analysis instrument is analyzed, the turnover ratio of this moment is 97.5%, and optical purity is 98.8%ee.
[experimental example 6]
(a) use this moment 51.3g (32.4mmol) 4-chlorine 3-fluorobenzaldehyde to replace 41.5g (32.4mmol) the 4-fluorobenzaldehyde that uses in (a) of experimental example 1, replace the condition of dry 2 hours at 40 ℃ of temperature originally in the drying condition of 5 hours at 35 ℃ of temperature.In addition other guide is all identical with the operation of experimental example 1.Result acquisition 30.1g intermediate material (S)-(+)-2,2-dimethylcyclopropane ester (dimethyl cyclo propane ester) (row yielding is 36.3%).By the result demonstration that the gc analysis instrument is analyzed, the turnover ratio of this moment is 98.2%.
(b) obtain 20.5g 4-fluorobenzaldehyde in (b) of experimental example 1, and obtain 24.4g4-chloro-3-fluorobenzaldehyde in (b) of this test, and obtain pure (S)-(+)-2 of 14.5g, 2-dimethyl cyclopropane carboxylic acid (dimethyl cyclo propane carboxyl acid) (row yielding is 39.2%).By the result demonstration that the gc analysis instrument is analyzed, the turnover ratio of this moment is 97.8%, and optical purity is 98.5%ee.
[experimental example 7]
(a) use this moment 51.3g (32.4mmol) 2-chloro-4-fluorobenzaldehyde to replace 41.5g (32.4mmol) the 4-fluorobenzaldehyde that uses in (a) of experimental example 1, drying is 3 hours at 40 ℃ of temperature, replaced originally at 40 ℃ of temperature the content conditions of dry 2 hours.In addition, all the content of operation with experimental example 1 is identical for other guide.Result acquisition 30.5g intermediate material (S)-(+)-2,2-dimethylcyclopropane ester (dimethyl cyclo propane ester) (row yielding is 36.7%).By the result demonstration that the gc analysis instrument is analyzed, the turnover ratio of this moment is 97.2%.
(b) obtain 20.5g 4-fluorobenzaldehyde in (b) of experimental example 1, and obtain 24.8g2-chloro-4-fluorobenzaldehyde in (b) of this test, and obtain pure (S)-(+)-2 of 14.8g, 2-dimethyl cyclopropane carboxylic acid (dimethyl cyclo propane carboxyl acid) (row yielding is 39.2%).By the result demonstration that the gc analysis instrument is analyzed, the turnover ratio of this moment is 98.4%, and optical purity is 98.8%ee.
[experimental example 8]
(a) use this moment 59.9g (32.4mmol) 4-bromobenzaldehyde to replace 41.5g (32.4mmol) the 4-fluorobenzaldehyde that uses in (a) of [experimental example 1], replace the condition of dry 2 hours at 40 ℃ of temperature originally in the drying condition of 5 hours at 35 ℃ of temperature.In addition the other guide all content of operation with experimental example 1 is identical.Result acquisition 31.7g intermediate material (S)-(+)-2,2-dimethylcyclopropane ester (dimethyl cyclo propane ester) (row yielding is 34.5%).By the result demonstration that the gc analysis instrument is analyzed, the turnover ratio of this moment is 98.2%.
(b) obtain the 20.5g4-fluorobenzaldehyde in (b) of experimental example 1, and obtain the 26.7g4-bromobenzaldehyde in (b) of this test, and obtain pure (S)-(+)-2 of 15.1g, 2-dimethyl cyclopropane carboxylic acid (dimethyl cyclo propane carboxy acid) (row yielding is 40.8%).By the result demonstration that the gc analysis instrument is analyzed, the turnover ratio of this moment is 98.4%, and optical purity is 98.8%ee.
[experimental example 9]
(a) use this moment 50.6g (32.4mmol) 2-naphthaldehyde to replace 41.5g (32.4mmol) the 4-fluorobenzaldehyde that uses in (a) of experimental example 1, replace the condition of dry 2 hours at 40 ℃ of temperature originally in the drying condition of 3 hours at 50 ℃ of temperature.In addition other content of operation are all identical with experimental example 1.Result acquisition 30.4g intermediate material (S)-(+)-2,2-dimethylcyclopropane ester (dimethyl cyclo propane ester) (row yielding is 36.9%).By the result demonstration that the gc analysis instrument is analyzed, the turnover ratio of this moment is 98.7%.
(b) obtain the 20.5g4-fluorobenzaldehyde in (b) of experimental example 1, and obtain the 23.8g2-naphthaldehyde in (b) of this test, and obtain pure (S)-(+)-2 of 14.7g, 2-dimethyl cyclopropane carboxylic acid (dimethyl cyclo propane carboxy acid) (row yielding is 39.7%).By the result demonstration that the gc analysis instrument is analyzed, the turnover ratio of this moment is 97.6%, and optical purity is 98.9%ee.
Claims (6)
1. the manufacture method of an optically active amides, this optically active amides has following chemical structural formula 1,
Chemical structural formula 1
It is characterized in that, comprise the following steps: (a) in the situation that use organic catalyst salt of wormwood has 2 of following chemical structural formula 2,2-dimethyl cyclopropane carboxylic acid and chiral reagent carry out esterification, thereby make (S)-(+)-2,2-dimethylcyclopropane ester;
Chemical structural formula 2
(b) to described (S)-(+)-2,2-dimethylcyclopropane ester adds water decomposition to be processed, thereby makes (S)-(+)-2, the 2-dimethyl cyclopropane carboxylic acid;
(c) to described (S)-(+)-2, the 2-dimethyl cyclopropane carboxylic acid carries out chlorination and ammonification addition reaction, has optically active acid amides thereby make,
Described manufacturing processed comprises described (S)-(+)-2 with chemical structural formula 1, the manufacturing processed of 2-dimethylcyclopropane ester.
2. the manufacture method of optically active amides according to claim 1, is characterized in that, the mixture that it uses one of following chiral reagent or is mixed by them:
The 4-fluorobenzaldehyde; The 4-chlorobenzaldehyde; 2,4 dichloro benzene formaldehyde; 2,3 dichloro benzaldehyde; 2,6-dichlorobenzaldehyde; 4-chloro-3-fluorobenzaldehyde; 2-chloro-4-fluorobenzaldehyde; The 4-bromobenzaldehyde; The 2-naphthaldehyde.
3. the manufacture method of optically active amides according to claim 1, is characterized in that, selects more than one solvent from the component that methylene dichloride, ethylene dichloride, trichloromethane, tetracol phenixin, zellon, tetrachloroethane etc. form.
4. the manufacture method of optically active amides according to claim 1, is characterized in that, selects more than one solvent from the component that the siccative such as sal epsom, sodium sulfate, calcium chloride form.
5. the manufacture method of optically active amides according to claim 1, is characterized in that, in described step (c), uses SOCl for carrying out chlorination reaction
2Or SO
2Cl
2
6. the manufacture method of optically active amides according to claim 1, is characterized in that, in described step (c), uses NH for carrying out the ammonia addition reaction
3
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US4487956A (en) * | 1983-07-20 | 1984-12-11 | Sumitomo Chemical Company, Limited | Menthyl 2,2-dimethylcyclopropanecarboxylate and resolution of the same |
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