CN104478756B - A kind of synthetic method of (S)-metolachlor - Google Patents
A kind of synthetic method of (S)-metolachlor Download PDFInfo
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Abstract
The invention discloses the synthetic method of one (S)-metolachlor, for raw material with Pfansteihl ester, first carry out the halo of alcohol, chiral carbon generation configuration conversion, then the reduction of ester, the etherificate of alcohol is carried out, carry out nucleophilic substitution reaction with 2-methyl-6-ethylaniline again and generate secondary amine, last and chloroacetyl chloride reacts and generates target product (S)-metolachlor.Compared with existing synthetic route, the present invention has the advantages that starting raw material is cheap and easy to get, Atom economy good, cost is low, stereoselectivity is good and reaction conditions is gentle.
Description
One, technical field
The present invention relates to a kind of preparation method of known compound, specifically a kind of synthetic method of (S)-metolachlor, relates to chemistry of pesticide synthesis technical field.
Two, background technology
Nineteen fifty-two, About Monsanto Chemicals has found that chloroacetamide-based compounds has weeding activity, alachlor, metolachlor etc. become the representative of typical acetamide-group herbicides subsequently, wherein metolachlor (Metolachlor) is the maximum highly selective acetamide-group herbicides of the ground such as the U.S. and North America consumption, its chemical name is 2-ethyl-6-methyl-N-(l '-methyl-2 '-methoxyethyl) nitrogen-chloro acetanilide, there are R, S two kinds of configurations, wherein only have S type isomer to be active substance, there is herbicidal effect.(S)-metolachlor is also known as gold all you or S-metolachlors, and research shows in same amount situation, and the activity of (S)-metolachlor is 1.4-1.6 times of metolachlor.
At present, the primary synthetic methods of (S)-metolachlor has 3 kinds: (1) racemic modification enzyme Split Method [Can.J.ofChem., 2006,84 (8), 1058, " organic chemistry " (supplementary issue), 2005,25,541, US5002606A, 1991-03-26]: adopt chemistry or enzyme kinetics method to split N-(2-methyl-6-ethylphenyl) alanine ester, and then carry out reducing, acylations, methylating etc. obtains S-metolachlor, (2) chiral source synthesis method [CN102110346A, CN101367746B]: the complete synthesis route taking chiral raw material as initial substance, two patents of invention are had to report this method at present, synthetic route as shown in Figure 1, for raw material with (D)-lactate, first react with Tosyl chloride or methylsulfonyl chloride and generate (R)-2-(tolysulfonyl oxygen base/methylsulfonyl) propionic ester, (S)-N-(2-methyl-6-ethylphenyl) alanine ester is obtained by reacting again with 2-methyl-6-ethylaniline, then generation (S)-N-(1 '-methyl-2 '-hydroxyethyl)-2-methyl-6-ethylaniline is reduced, acylation reaction is carried out again with chloroacetyl chloride, finally carrying out methylates obtains (S)-metolachlor, (3) asymmetric catalytic hydrogenation reduction method [Adv.Synth. & Cat., 2002,344 (1), 17, J.ofOrganometallicChem., 1975,90 (3), 353, TetrahedronLett., 1990,31 (29), 4117, Chem.Reviews, 2003,103 (8), 3101, Tetrahedron:Asymmetry, 2000,11 (7), 1469, CN101857612A]: first generate imines, then apply chiral catalyst shortening and generate Chiral Amine, the composition of chiral catalytic system is the catalyst system that chiral diphosphine ligand and Rh (I), Ru, Ir etc. form, and is the focus of research at present.The Industrialized processing technique of external this method existing, domestic or blank.
These three kinds of synthetic methods of current report have certain limitation.Method (1) maximum difficulty is the preparation splitting enzyme, is difficult to realize industrialization; The advantage of method (2) be reaction process without the need to carrying out chiral separation, greatly reduce cost, but owing to using D-ALPHA-Hydroxypropionic acid as raw material; price; production cost is high, and also there is acylations selectivity simultaneously, introduce leavings group and produce the problems such as useless solid, overall yield is only 50%.The technological difficulties of method (3) are the reactions of imines asymmetric catalytic hydrogenation, and most crucial technology is the synthesis of chiral catalyst, and chiral catalyst exists instability and the shortcoming of costliness.
Three, summary of the invention
The present invention aims to provide the synthetic method of one (S)-metolachlor, and the inventive method has the features such as raw material is cheap and easy to get, stereoselectivity good, reaction conditions is gentle.
Technical solution problem of the present invention adopts following technical scheme to realize:
The synthetic method of the present invention (S)-metolachlor, comprises the following steps:
(1) Pfansteihl ester and ether solvent is added in nitrogen protection downhill reaction device, under condition of ice bath, (0-5 DEG C) drips phosphorus trichloride or phosphorus tribromide, after dripping off, under condition of ice bath, (0-5 DEG C) reacts 2h, is warming up to 25 DEG C subsequently and continues reaction 2-6h; Reaction terminates to add saturated aqueous sodium carbonate extraction in backward reaction solution, aqueous phase uses extracted with diethyl ether again, merge organic phase, after organic phase drying, column chromatography (elutriant is the mixing solutions of ethyl acetate and sherwood oil, volume ratio 1:10) is separated and obtains intermediate compound I-(R)-2-chloropropionate or (R)-2 bromopropionic acid ester.
Described in step (1), Pfansteihl ester is selected from Pfansteihl methyl esters, Pfansteihl ethyl ester, Pfansteihl propyl ester or Pfansteihl butyl ester; Described ether solvent is one or more in ether, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, preferred ether; Phosphorus trichloride or the mol ratio between phosphorus tribromide and Pfansteihl ester are 1:2-3, preferred 1:2; After being warming up to 25 DEG C, the reaction times is preferably 4h.
(2) in reactor, add dehydrated alcohol, sodium borohydride and lithium chloride successively, stirring at room temperature 30min, under cryosel bath, (-10 DEG C ~ 0 DEG C) drips intermediate compound I, is warming up to room temperature reaction 3-4h after dripping off; Reaction terminates rear filtration, is extracted with ethyl acetate, leaves and takes organic phase after filter cake washing, and organic phase successively drying, filtration, underpressure distillation obtains intermediate II-(R)-2-propylene chlorohydrin or (R)-2-bromopropyl alcohol except after desolventizing.
In step (2), the mol ratio of sodium borohydride and intermediate compound I is 3:1; The mol ratio of lithium chloride and sodium borohydride is 1:1.
(3) in reactor, add anhydrous tetrahydro furan, intermediate II and sodium hydride successively, under cryosel bath, (-10 DEG C) drip methyl-sulfate, drip off rear elder generation at-10 ~ 0 DEG C of reaction 1h, are then warming up to room temperature reaction 3h; Reaction terminates after washing, extraction into ethyl acetate, leaves and takes organic phase, and organic phase successively drying, filtration, underpressure distillation obtains intermediate III-(R)-2-chloropropyl ether or (R)-2-bromopropyl methyl ether except after desolventizing.
In step (3), the mol ratio of intermediate II, sodium hydride and methyl-sulfate is 1:1:1.2.
(4) in reactor, add intermediate III, 2-methyl-6-ethylaniline, anhydrous sodium carbonate and sodium iodide successively, be warming up to 130 DEG C of reaction 3.5h, 80 DEG C are cooled to after reaction terminates, add water and ethyl acetate, be separated organic phase, organic phase successively drying, filtration, underpressure distillation obtains intermediate compound IV-(S)-N-(1'-methyl-2'-methoxy ethyl)-2-methyl-6-ethylaniline except after desolventizing.
In step (4), the mol ratio of intermediate III, 2-methyl-6-ethylaniline, anhydrous sodium carbonate and sodium iodide is 1.2:1:0.5:0.1.
(5) in reactor, add toluene, intermediate compound IV and appropriate triethylamine successively, under cryosel bath, (-10 DEG C) drip the toluene solution of chloroacetyl chloride, first at-10 ~ 0 DEG C, react 3h, are warming up to room temperature subsequently and continue reaction 3h; Reaction terminates after washing, extraction into ethyl acetate, leaves and takes organic phase, and organic phase successively drying, filtration, underpressure distillation obtains target product-(S)-metolachlor except after desolventizing.
The mol ratio 1:1.1 of intermediate compound IV and chloroacetyl chloride in step (5).
Compared with the prior art, beneficial effect of the present invention is embodied in:
The present invention with chiral reagent Pfansteihl (price is 1/5th of D-ALPHA-Hydroxypropionic acid) cheap and easy to get for raw material, under given conditions, highly-solid selectively achieve configuration conversion, chiral intermediate (2R)-halopropyl methyl ether is obtained again through reduction and etherification reaction, then carry out with 2-methyl-6 ethylaniline the two times transfer that nucleophilic substitution reaction realizes chiral configuration, last and chloroacetyl chloride reacts and generates target product (S)-metolachlor.Compared with existing synthetic route, the present invention has the advantages that starting raw material is cheap and easy to get, Atom economy good, cost is low, stereoselectivity is good and reaction conditions is gentle.
Four, accompanying drawing explanation
Fig. 1 is with the synthetic route of chiral source synthesis method preparation (S)-metolachlor.
Five, embodiment
The technique means realized to make the present invention, creation characteristic, reaching object and effect is easy to understand, below in conjunction with specific embodiment, setting forth the present invention further.
Embodiment 1:
1) under nitrogen protection; Pfansteihl methyl esters 6.2g (0.06mol) and 30mL ether is added in there-necked flask; in there-necked flask, slowly phosphorus trichloride 2.74g (0.02mol) is dripped under condition of ice bath; control rate of addition; make temperature of reaction not higher than 5 DEG C; after dropwising; react 2h at 0 DEG C after, be warming up to 25 DEG C of reactions 2h, TLC and monitor reaction end; saturated aqueous sodium carbonate is added in reaction solution; separate organic phase, water layer extracted with diethyl ether 3 times, merges organic phase; wash three times, anhydrous MgSO
4drying, column chromatography for separation (elutriant is the mixing solutions of ethyl acetate and sherwood oil, volume ratio 1:10) obtains intermediate compound I-(R)-2-methyl chloropropionate 6.8g, and productive rate is 92.9%, ee value is 98%.
1HNMR(400MHz,CDCl
3,δ)：4.13(q,1H)；3.18(s,3H)；1.16(d,3H)。
2) in the there-necked flask that agitator, thermometer are housed, 100mL dehydrated alcohol is added successively, sodium borohydride 5.64g (0.15mol) and lithium chloride 6.36g (0.15mol), stirring at room temperature half an hour, icy salt solution temperature control is about-5 DEG C, start to drip (R)-2-methyl chloropropionate (6.1g, 0.05mol) be dissolved in 10mL ethanol, at 0 DEG C of reaction 1h after 15min dropwises, then be warmed up to 25 DEG C and continue reaction 3h, TLC monitoring reaction end; Reaction terminates rear filtration, steaming desolventizes, washing resistates, then be extracted with ethyl acetate water layer 3 times (20mLx3), merge organic phase, organic phase is with anhydrous sodium sulfate drying, filter, be spin-dried for solvent, underpressure distillation obtains intermediate II-(R)-2-propylene chlorohydrin 4.5g, and productive rate is 95.7%.
1HNMR(400MHz,CDCl
3,δ)：5.01(d,1H),3.85-3.74(m,1H),3.49(d,2H),1.12(d,3H)。
3) in the four-hole boiling flask that agitator, thermometer are housed, add the NaH1.8g (0.06mol) of 100mL anhydrous tetrahydro furan, (R)-2-propylene chlorohydrin 4.7g (0.05mol), content 80% successively, temperature control is at-10 DEG C, methyl-sulfate 7.56g (0.06mol) is dripped after stirring 2h, first at-10 ~ 0 DEG C of reaction 1h, then be warming up to room temperature reaction 3h, TLC monitors reaction end; Reaction terminates rear steaming and desolventizes, add 30mL water, be extracted with ethyl acetate again 3 times (20mLx3), merge organic phase, organic phase anhydrous sodium sulfate drying, filters, is spin-dried for solvent, underpressure distillation obtains intermediate III-(R)-2-chloropropyl ether 5.1g, and productive rate is 94.4%.
1HNMR(400MHz,CDCl
3,δ)：3.38(s,3H),3.51(m,2H),4.01(m,1H),1.56(d,3H)。
4) in the 200mL there-necked flask being furnished with agitator, thermometer and prolong, add (R)-2-chloropropyl ether 6.5g (0.06mol), 2-methyl-6-ethylaniline 6.75g (0.05mol), anhydrous sodium carbonate 2.65g (0.025mol) and NaI0.75g (5mmol) respectively, be heated to 130 DEG C of stirring reaction 3.5h, TLC monitors reaction end; 80 DEG C are cooled to after reaction terminates, add after 50ml water fully stirs and add extraction into ethyl acetate 3 times (30mLx3) again, merge organic phase, organic phase obtains intermediate compound IV-(S)-N-(1'-methyl-2'-methoxy ethyl)-2-methyl-6-ethylaniline 8.5g through anhydrous sodium sulfate drying, steaming after desolventizing, and productive rate is 82.1%.
1HNMR(400MHz,CDCl
3,δ)：7.01(dd,2H),6.88(t,1H),3.36(m,6H),2.66(q,2H),2.30(s,3H),1.24(t,3H),1.18(d,3H)。
5) in the 200mL four-hole boiling flask that agitator, thermometer are housed, add toluene 100mL, (S)-N-(1'-methyl-2'-methoxy ethyl)-2-methyl-6-ethylaniline 4.15g (0.02mol), triethylamine 5mL successively, temperature control is at about-10 DEG C, drip the solution of the chloroacetyl chloride 2.5g (0.022mol) be dissolved in 10mL toluene, continue reaction 3h, TLC under being warming up to room temperature react 3h at-10 ~ 0 DEG C after and monitor reaction end; Reaction terminates after washing, extraction into ethyl acetate 3 times (30mLx3), merges organic phase, organic phase, through anhydrous sodium sulfate drying, is filtered, is spin-dried for solvent, underpressure distillation obtains target product-(S)-metolachlor 5.1g, and productive rate is 90.1%, ee value is 92%.
1HNMR(400MHz,CDCl
3)：δ1.14(d,3H),1.25(t,3H),2.23(m,3H),2.56(m,2H),3.25(m,3H),3.47(m,1H),3.58(s,2H),3.73(m,1H),4.23(m,1H),7.11(m,1H),7.19(m,1H),7.24(m,1H)。
Embodiment 2:
1) under nitrogen protection; Pfansteihl methyl esters 6.2g (0.06mol) and 30mL ether is added in there-necked flask; in there-necked flask, slowly phosphorus tribromide 5.4g (0.02mol) is dripped under condition of ice bath; control rate of addition; make temperature of reaction not higher than 5 DEG C; after dropwising; react 2h at 0 DEG C after, be warming up to 25 DEG C of reactions 2h, TLC and monitor reaction end; saturated aqueous sodium carbonate is added in reaction solution; separate organic phase, water layer extracted with diethyl ether 3 times, merges organic phase; wash three times, anhydrous MgSO
4drying, column chromatography for separation (elutriant is the mixing solutions of ethyl acetate and sherwood oil, volume ratio 1:10) obtains intermediate compound I-(R)-2 bromopropionic acid methyl esters 9.5g, and productive rate is 94.8%, ee value is 97.6%.
1HNMR(400MHz,CDCl
3,δ)：4.39(m,1H),3.80(s,3H),1.84(d,3H)。
2) in the there-necked flask that agitator, thermometer are housed, 100mL dehydrated alcohol is added successively, sodium borohydride 5.64g (0.15mol) and lithium chloride 6.36g (0.15mol), stirring at room temperature half an hour, icy salt solution temperature control is about-5 DEG C, start to drip (R)-2 bromopropionic acid ester (8.35g, 0.05mol) be dissolved in 10mL ethanol, at 0 DEG C of reaction 1h after 15min dropwises, then be warmed up to 25 DEG C and continue reaction 3h, TLC monitoring reaction end; Reaction terminates rear filtration, steaming desolventizes, washing resistates, then be extracted with ethyl acetate water layer 3 times (20mLx3), merge organic phase, organic phase is with anhydrous sodium sulfate drying, filter, be spin-dried for solvent, underpressure distillation obtains intermediate II-(R)-2-bromopropyl alcohol 6.7g, and productive rate is 96.4%.
1HNMR(400MHz,CDCl
3,δ)：4.28(m,1H),3.71(m,2H),2.19(s,1H),1.62(d,3H)。
3) in the four-hole boiling flask that agitator, thermometer are housed, add the NaH1.8g (0.06mol) of 100mL anhydrous tetrahydro furan, (R)-2-bromopropyl alcohol 7.0g (0.05mol), content 80% successively, temperature control is at-10 DEG C, methyl-sulfate 7.56g (0.06mol) is dripped after stirring 2h, first at-10 ~ 0 DEG C of reaction 1h, then be warming up to room temperature reaction 3h, TLC monitors reaction end; Reaction terminates rear steaming and desolventizes, add 30mL water, be extracted with ethyl acetate again 3 times (20mLx3), merge organic phase, organic phase anhydrous sodium sulfate drying, filters, is spin-dried for solvent, underpressure distillation obtains intermediate III-(R)-2-bromopropyl methyl ether 7.2g, and productive rate is 94.1%.
1HNMR(400MHz,CDCl
3,δ)：3.96(m,1H),3.46(m,2H),3.35(s,33H),1.53(d,3H)。
4) in the 200mL there-necked flask being furnished with agitator, thermometer and prolong, add (R)-2-bromopropyl methyl ether 9.2g (0.06mol), 2-methyl-6-ethylaniline 6.75g (0.05mol), anhydrous sodium carbonate 2.65g (0.025mol) and NaI0.75g (5mmol) respectively, be heated to 130 DEG C of stirring reaction 3.5h, TLC monitors reaction end; 80 DEG C are cooled to after reaction terminates, add after 50ml water fully stirs and add extraction into ethyl acetate 3 times (30mLx3) again, merge organic phase, organic phase obtains intermediate compound IV-(S)-N-(1'-methyl-2'-methoxy ethyl)-2-methyl-6-ethylaniline 8.7g through anhydrous sodium sulfate drying, steaming after desolventizing, and productive rate is 84.0%.
5) in the 250mL four-hole boiling flask that agitator, thermometer are housed, add toluene 150mL, (S)-N-(1'-methyl-2'-methoxy ethyl)-2-methyl-6-ethylaniline 8.3g (0.02mol), triethylamine 10mL successively, temperature control is at about-10 DEG C, drip the solution of the chloroacetyl chloride 5.0g (0.044mol) be dissolved in 10mL toluene, continue reaction 3h, TLC under being warming up to room temperature react 3h at-10 ~ 0 DEG C after and monitor reaction end; Reaction terminates after washing, extraction into ethyl acetate 3 times (30mLx3), merges organic phase, organic phase, through anhydrous sodium sulfate drying, is filtered, is spin-dried for solvent, underpressure distillation obtains target product-(S)-metolachlor 5.1g, and productive rate is 91.9%, ee value is 92.5%.
Embodiment 3:
1) under nitrogen protection; Pfansteihl methyl esters 6.2g (0.06mol) and 30mL ether is added in there-necked flask; in there-necked flask, slowly phosphorus trichloride 4.11g (0.03mol) is dripped under condition of ice bath; control rate of addition; make temperature of reaction not higher than 5 DEG C; after dropwising; react 2h at 0 DEG C after, be warming up to 25 DEG C of reactions 2h, TLC and monitor reaction end; saturated aqueous sodium carbonate is added in reaction solution; separate organic phase, water layer extracted with diethyl ether 3 times, merges organic phase; wash three times, anhydrous MgSO
4drying, column chromatography for separation (elutriant is the mixing solutions of ethyl acetate and sherwood oil, volume ratio 1:10) obtains intermediate compound I-(R)-2-methyl chloropropionate 6.6g, and productive rate is 95.7%, ee value is 98.0%.
Step 2) to step 5) with embodiment 1, finally obtaining (S)-metolachlor 4.96g, the total recovery of building-up reactions is 65.1%, ee value is 93%.
Embodiment 4:
1) under nitrogen protection; Pfansteihl methyl esters 6.2g (0.06mol) and 30mL ether is added in there-necked flask; in there-necked flask, slowly phosphorus trichloride 5.48g (0.04mol) is dripped under condition of ice bath; control rate of addition; make temperature of reaction not higher than 5 DEG C; after dropwising; react 2h at 0 DEG C after, be warming up to 25 DEG C of reactions 2h, TLC and monitor reaction end; saturated aqueous sodium carbonate is added in reaction solution; separate organic phase, water layer extracted with diethyl ether 3 times, merges organic phase; wash three times, anhydrous MgSO
4drying, column chromatography for separation (elutriant is the mixing solutions of ethyl acetate and sherwood oil, volume ratio 1:10) obtains intermediate compound I-(R)-2-methyl chloropropionate 6.6g, and productive rate is 90.2%, ee value is 98.5%.
Step 2) to step 5) with embodiment 1, finally obtaining (S)-metolachlor 4.81g, the total recovery of building-up reactions is 63.5%, ee value is 93.2%.
Embodiment 5:
1) under nitrogen protection; Pfansteihl ethyl ester 7.08g (0.06mol) and 30mL ether is added in there-necked flask; in there-necked flask, slowly phosphorus trichloride 2.74g (0.02mol) is dripped under condition of ice bath; control rate of addition; make temperature of reaction not higher than 5 DEG C; after dropwising; react 2h at 0 DEG C after, be warming up to 25 DEG C of reactions 2h, TLC and monitor reaction end; saturated aqueous sodium carbonate is added in reaction solution; separate organic phase, water layer extracted with diethyl ether 3 times, merges organic phase; wash three times, anhydrous MgSO
4drying, column chromatography for separation (elutriant is the mixing solutions of ethyl acetate and sherwood oil, volume ratio 1:10) obtains intermediate compound I-(R)-2-methyl chloropropionate 6.7g, and productive rate is 91.5%, ee value is 97.5%.
Step 2) to step 5) with embodiment 1, finally obtaining (S)-metolachlor 5.19g, the total recovery of building-up reactions is 65.8%, ee value is 92.5%.
Embodiment 6:
1) under nitrogen protection; Pfansteihl methyl esters 6.2g (0.06mol) and 30mL tetrahydrofuran (THF) is added in there-necked flask; in there-necked flask, slowly phosphorus trichloride 4.11g (0.03mol) is dripped under condition of ice bath; control rate of addition; make temperature of reaction not higher than 5 DEG C; after dropwising; react 2h at 0 DEG C after, be warming up to 25 DEG C of reactions 2h, TLC and monitor reaction end; saturated aqueous sodium carbonate is added in reaction solution; separate organic phase, water layer extracted with diethyl ether 3 times, merges organic phase; wash three times, anhydrous MgSO
4drying, column chromatography for separation (elutriant is the mixing solutions of ethyl acetate and sherwood oil, volume ratio 1:10) obtains intermediate compound I-(R)-2-methyl chloropropionate 5.5g, and productive rate is 75.2%, ee value is 97.5%.
Step 2) to step 5) with embodiment 1, finally obtaining (S)-metolachlor 4.98g, the total recovery of building-up reactions is 65.1%, ee value is 92.7%.
Embodiment 7:
1) under nitrogen protection; Pfansteihl methyl esters 6.2g (0.06mol) and 30mL1 is added in there-necked flask; 4-dioxane; in there-necked flask, slowly phosphorus trichloride 4.11g (0.03mol) is dripped under condition of ice bath; control rate of addition; make temperature of reaction not higher than 5 DEG C, after dropwising, react 2h at 0 DEG C after; be warming up to 25 DEG C of reaction 2h; TLC monitors reaction end, adds saturated aqueous sodium carbonate, separate organic phase in reaction solution; water layer extracted with diethyl ether 3 times; merge organic phase, wash three times, anhydrous MgSO
4drying, column chromatography for separation (elutriant is the mixing solutions of ethyl acetate and sherwood oil, volume ratio 1:10) obtains intermediate compound I-(R)-2-methyl chloropropionate 4.3g, and productive rate is 58.8%, ee value is 96%.
Step 2) to step 5) with embodiment 1, finally obtaining (S)-metolachlor 4.26g, the total recovery of building-up reactions is 62.4%, ee value is 93.6%.
More than show and describe ultimate principle of the present invention and principal character and advantage of the present invention.The technician of the industry should understand; the present invention is not restricted to the described embodiments; what describe in above-described embodiment and specification sheets just illustrates principle of the present invention; without departing from the spirit and scope of the present invention; the present invention also has various changes and modifications, and these changes and improvements all fall in the claimed scope of the invention.Application claims protection domain is defined by appending claims and equivalent thereof.
Claims (9)
1. a synthetic method for (S)-metolachlor, is characterized in that comprising the following steps:
(1) add Pfansteihl ester and ether solvent in nitrogen protection downhill reaction device, at 0-5 DEG C, drip phosphorus trichloride or phosphorus tribromide, in 0-5 DEG C of reaction 2h after dripping off, be warming up to 25 DEG C subsequently and continue reaction 2-6h; Reaction terminates to add saturated aqueous sodium carbonate extraction in backward reaction solution, and aqueous phase uses extracted with diethyl ether again, and merge organic phase, after organic phase drying, column chromatography for separation obtains intermediate compound I-(R)-2-chloropropionate or (R)-2 bromopropionic acid ester;
(2) in reactor, add dehydrated alcohol, sodium borohydride and lithium chloride successively, stirring at room temperature 30min, at-10 DEG C ~ 0 DEG C, drip intermediate compound I, after dripping off, be warming up to room temperature reaction 3-4h; Reaction terminates rear filtration, is extracted with ethyl acetate, leaves and takes organic phase after filter cake washing, and organic phase successively drying, filtration, underpressure distillation obtains intermediate II-(R)-2-propylene chlorohydrin or (R)-2-bromopropyl alcohol except after desolventizing;
(3) in reactor, add anhydrous tetrahydro furan, intermediate II and sodium hydride successively, at-10 DEG C, drip methyl-sulfate, drip off rear elder generation at-10 ~ 0 DEG C of reaction 1h, be then warming up to room temperature reaction 3h; Reaction terminates after washing, extraction into ethyl acetate, leaves and takes organic phase, and organic phase successively drying, filtration, underpressure distillation obtains intermediate III-(R)-2-chloropropyl ether or (R)-2-bromopropyl methyl ether except after desolventizing;
(4) in reactor, add intermediate III, 2-methyl-6-ethylaniline, anhydrous sodium carbonate and sodium iodide successively, be warming up to 130 DEG C of reaction 3.5h, 80 DEG C are cooled to after reaction terminates, add water and ethyl acetate, be separated organic phase, organic phase successively drying, filtration, underpressure distillation obtains intermediate compound IV-(S)-N-(1'-methyl-2'-methoxy ethyl)-2-methyl-6-ethylaniline except after desolventizing;
(5) in reactor, add toluene, intermediate compound IV and appropriate triethylamine successively, at-10 DEG C, drip the toluene solution of chloroacetyl chloride, first at-10 ~ 0 DEG C, react 3h, be warming up to room temperature subsequently and continue reaction 3h; Reaction terminates after washing, extraction into ethyl acetate, leaves and takes organic phase, and organic phase successively drying, filtration, underpressure distillation obtains target product-(S)-metolachlor except after desolventizing.
2. the synthetic method of (S)-metolachlor according to claim 1, is characterized in that:
Described in step (1), Pfansteihl ester is selected from Pfansteihl methyl esters, Pfansteihl ethyl ester, Pfansteihl propyl ester or Pfansteihl butyl ester;
Ether solvent described in step (1) is one or more in ether, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane.
3. the synthetic method of (S)-metolachlor according to claim 1, is characterized in that:
In step (1), phosphorus trichloride or the mol ratio between phosphorus tribromide and Pfansteihl ester are 1:2-3.
4. the synthetic method of (S)-metolachlor according to claim 1 and 2, is characterized in that:
In step (1), phosphorus trichloride or the mol ratio between phosphorus tribromide and Pfansteihl ester are 1:2.
5. the synthetic method of (S)-metolachlor according to claim 1, is characterized in that:
After being warming up to 25 DEG C in step (1), the reaction times is 4h.
6. the synthetic method of (S)-metolachlor according to claim 1, is characterized in that:
In step (2), the mol ratio of sodium borohydride and intermediate compound I is 3:1; The mol ratio of lithium chloride and sodium borohydride is 1:1.
7. the synthetic method of (S)-metolachlor according to claim 1, is characterized in that:
In step (3), the mol ratio of intermediate II, sodium hydride and methyl-sulfate is 1:1:1.2.
8. the synthetic method of (S)-metolachlor according to claim 1, is characterized in that:
In step (4), the mol ratio of intermediate III, 2-methyl-6-ethylaniline, anhydrous sodium carbonate and sodium iodide is 1.2:1:0.5:0.1.
9. the synthetic method of (S)-metolachlor according to claim 1, is characterized in that:
The mol ratio 1:1.1 of intermediate compound IV and chloroacetyl chloride in step (5).
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