CN101367746B - Novel method for synthesizing -metolachlor - Google Patents
Novel method for synthesizing -metolachlor Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 19
- 230000002194 synthesizing effect Effects 0.000 title abstract 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 116
- 229940057867 methyl lactate Drugs 0.000 claims abstract description 24
- JJVKJJNCIILLRP-UHFFFAOYSA-N 2-ethyl-6-methylaniline Chemical compound CCC1=CC=CC(C)=C1N JJVKJJNCIILLRP-UHFFFAOYSA-N 0.000 claims abstract description 17
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims abstract description 15
- -1 2-methyl-6-ethylphenyl Chemical group 0.000 claims abstract description 9
- 235000004279 alanine Nutrition 0.000 claims abstract description 7
- 239000002994 raw material Substances 0.000 claims abstract description 7
- 229940116333 ethyl lactate Drugs 0.000 claims abstract description 5
- 230000001035 methylating effect Effects 0.000 claims abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 152
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 114
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 98
- 239000002904 solvent Substances 0.000 claims description 76
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 56
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 32
- 239000002585 base Substances 0.000 claims description 32
- 229910052760 oxygen Inorganic materials 0.000 claims description 32
- 239000001301 oxygen Substances 0.000 claims description 32
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 31
- WVQBLGZPHOPPFO-LBPRGKRZSA-N (S)-metolachlor Chemical compound CCC1=CC=CC(C)=C1N([C@@H](C)COC)C(=O)CCl WVQBLGZPHOPPFO-LBPRGKRZSA-N 0.000 claims description 28
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 27
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Inorganic materials [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 11
- 239000003513 alkali Substances 0.000 claims description 10
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 claims description 10
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- 239000012448 Lithium borohydride Substances 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- 230000002829 reductive effect Effects 0.000 claims description 6
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 5
- 229910052700 potassium Inorganic materials 0.000 claims description 5
- 239000011591 potassium Substances 0.000 claims description 5
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 5
- 235000015320 potassium carbonate Nutrition 0.000 claims description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 230000000694 effects Effects 0.000 claims description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 4
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 4
- 239000003921 oil Substances 0.000 claims description 4
- 239000003444 phase transfer catalyst Substances 0.000 claims description 4
- 239000012312 sodium hydride Substances 0.000 claims description 4
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 3
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 claims description 3
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 3
- 229910052782 aluminium Inorganic materials 0.000 claims description 3
- 239000004411 aluminium Substances 0.000 claims description 3
- CHQVQXZFZHACQQ-UHFFFAOYSA-M benzyl(triethyl)azanium;bromide Chemical compound [Br-].CC[N+](CC)(CC)CC1=CC=CC=C1 CHQVQXZFZHACQQ-UHFFFAOYSA-M 0.000 claims description 3
- OIRDBPQYVWXNSJ-UHFFFAOYSA-N methyl trifluoromethansulfonate Chemical class COS(=O)(=O)C(F)(F)F OIRDBPQYVWXNSJ-UHFFFAOYSA-N 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 claims description 3
- 229910000105 potassium hydride Inorganic materials 0.000 claims description 3
- 235000017550 sodium carbonate Nutrition 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 3
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical group [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 239000011230 binding agent Substances 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 238000007069 methylation reaction Methods 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 abstract description 28
- 230000008569 process Effects 0.000 abstract description 3
- 230000035484 reaction time Effects 0.000 abstract description 3
- 239000003638 chemical reducing agent Substances 0.000 abstract 1
- 230000003287 optical effect Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 72
- 206010013786 Dry skin Diseases 0.000 description 58
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 58
- 238000001035 drying Methods 0.000 description 58
- 239000012044 organic layer Substances 0.000 description 58
- 238000004821 distillation Methods 0.000 description 48
- 238000005406 washing Methods 0.000 description 44
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 38
- 239000010410 layer Substances 0.000 description 36
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 36
- 239000012266 salt solution Substances 0.000 description 33
- 238000000605 extraction Methods 0.000 description 24
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 description 22
- 238000003810 ethyl acetate extraction Methods 0.000 description 22
- DWKPPFQULDPWHX-VKHMYHEASA-N l-alanyl ester Chemical compound COC(=O)[C@H](C)N DWKPPFQULDPWHX-VKHMYHEASA-N 0.000 description 22
- 229940017219 methyl propionate Drugs 0.000 description 22
- 239000000243 solution Substances 0.000 description 19
- 238000003756 stirring Methods 0.000 description 18
- 238000009835 boiling Methods 0.000 description 13
- 238000001816 cooling Methods 0.000 description 12
- 239000012043 crude product Substances 0.000 description 12
- 239000013078 crystal Substances 0.000 description 12
- 239000000706 filtrate Substances 0.000 description 12
- 238000001914 filtration Methods 0.000 description 12
- 239000005457 ice water Substances 0.000 description 12
- 238000001953 recrystallisation Methods 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 238000006555 catalytic reaction Methods 0.000 description 4
- 229960000935 dehydrated alcohol Drugs 0.000 description 3
- 239000004009 herbicide Substances 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 238000010792 warming Methods 0.000 description 3
- WVQBLGZPHOPPFO-UHFFFAOYSA-N 2-chloro-N-(2-ethyl-6-methylphenyl)-N-(1-methoxypropan-2-yl)acetamide Chemical compound CCC1=CC=CC(C)=C1N(C(C)COC)C(=O)CCl WVQBLGZPHOPPFO-UHFFFAOYSA-N 0.000 description 2
- 239000003905 agrochemical Substances 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- ROBXZHNBBCHEIQ-BYPYZUCNSA-N ethyl (2s)-2-aminopropanoate Chemical compound CCOC(=O)[C@H](C)N ROBXZHNBBCHEIQ-BYPYZUCNSA-N 0.000 description 2
- 230000002363 herbicidal effect Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- 238000009333 weeding Methods 0.000 description 2
- 241001227713 Chiron Species 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- XCSGPAVHZFQHGE-UHFFFAOYSA-N alachlor Chemical compound CCC1=CC=CC(CC)=C1N(COC)C(=O)CCl XCSGPAVHZFQHGE-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- VXIVSQZSERGHQP-UHFFFAOYSA-N chloroacetamide Chemical compound NC(=O)CCl VXIVSQZSERGHQP-UHFFFAOYSA-N 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 229960004756 ethanol Drugs 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a novel method for synthesizing -metolachlor, and invents a full synthetic route adopting a chiral seed. The method specifically comprises the steps of using (D) -methyl lactate or (D) -ethyl lactate as a raw material to react with p-toluenesulfonyl chloride to generate (R) -2- (p-toluenesulfonyloxy) propionate, then reacting with 2-methyl-6-ethylaniline to obtain S- (-) -N- (2-methyl-6-ethylphenyl) alanine ester, then reacting with a reducing agent C to obtain S- (-) -N- (1 '-methyl-2' -hydroxyethyl) -2-methyl-6-ethylaniline, further acylating with chloroacetyl chloride, and finally methylating to obtain -metolachlor. The whole process does not need to be split, the reaction is mild, the yield is high, the optical purity is good, the reaction time is short, the raw materials are cheap and easy to obtain, and the cost is low.
Description
Technical field
The invention belongs to the research field of asymmetric synthesis in the organic chemistry, the present invention relates to the novel method of a kind of synthesis of chiral agricultural chemicals (S)-metolachlor.
Technical background
Nineteen fifty-two, U.S. Monsanto Company found that chloroacetamide-based compounds has weeding activity, and during 60 to the seventies, the acetamide-group herbicides development is rapid, the commercialization in the meantime of most of kinds.Alachlor, metolachlor etc. all are typical case's representatives.Along with the progress of society, the enhancing of environmental consciousness, the chirality agricultural chemicals also becomes in the chemistry of pesticide a very active research field.(S)-metolachlor is exactly typical products in the chloroacetyl amine weedicide, this product is to use wider a kind of weedicide now, the metolachlor of Shi Yonging is a racemic modification traditionally, have only half composition that the effect of weeding is arranged, effective constituent is its S isomer, account for 50%, other 50% R body has then slatterned [1].Its main synthetic method has the racemic modification enzyme process to split [2 at present, 3], asymmetry catalysis hydrogenating reduction [4], wherein the asymmetry catalysis hydrogenating reduction also is the method that large-scale industrial production on the our times (S)-metolachlor adopts, yet has only abroad the ripe production technology that (S)-metolachlor is arranged at present.
Reference
[1]ByungT?C，Yu?S?C.Enantioselective?synthesis?of?optically?activemetolachlor?via?asymmetric?reduction[J].Tetrahedron：Asymmetry，1992，3(3)：337-340.
[2]Zheng?L?Y，Zhang?S?Q，Wang?F，et?al.Chemoenzymatic?synthesis?of?thechiral?herbicide：(S)-metolachlor[J].Canadian?Journal?of?Chemistry，2006，84(8)：1058-1063.
[3]Magden?H?M，Binningen?C?V.Preparation?of?optically?activen-(1′-methyl-2′-methoxyethyl)-N-chloroacetyl-2-ethyl-6-methylanilineas?as?herbicide[P].US5002606A，1991-03-26.
[4]Blaser?H?U.The?chiral?switch?of(S)-metolachlor：a?personal?accountof?an?industrial?odyssey?in?asymmetric?catalysis[J].Advanced?Synthesis&Catalysis，2002，344(1)：17-31.
Summary of the invention
The objective of the invention is in order to overcome disadvantages of background technology, a kind of novel method of synthetic (S)-metolachlor is provided.The complete synthesis novel method of the chiron that the present invention adopts has mild condition, the yield height, and the e.e. value is high, and side reaction is few, and the reaction times is short, also significantly reduces the advantage of raw materials cost in addition.
Technical scheme of the present invention is: the first step, utilize that (D)-methyl lactate or (D)-ethyl lactate is a starting raw material, in the presence of alkali, with Tosyl chloride-10 ℃～30 ℃ down reaction generate (R)-2-(tolysulfonyl oxygen base) propionic esters; Second step added 2-methyl-6-ethylaniline in (R)-2-(tolysulfonyl oxygen base) propionic ester, and added alkali, reacted 1～4 hour down at 110 ℃～160 ℃, obtained S-(-)-N-(2-methyl-6-ethylphenyl) alanine ester; In the 3rd step, S-(-)-N-(2-methyl-6-ethylphenyl) alanine ester and reductive agent reacted 1～24 hour down at-10 ℃～30 ℃, obtained S-(-)-N-(1 '-methyl-2 '-hydroxyethyl)-2-methyl-6-ethylaniline; The 4th step, in S-(-)-N-(1 '-methyl-2 '-hydroxyethyl)-2-methyl-6-ethylaniline, add acid binding agent alkali, and dropping chloroacetyl chloride, temperature is controlled at-15 ℃～30 ℃, reacted 1～24 hour, and obtained S-(-)-2-chloro-N-(2-methyl-6-ethylphenyl)-N-(2-hydroxyl-1-methylethyl) ethanamide; The 5th step, with S-(-)-2-chloro-N-(2-methyl-6-ethylphenyl)-N-(2-hydroxyl-1-methylethyl) ethanamide and methylating reagent under the effect of triethylamine, pyridine, sodium hydride, potassium hydride KH, sodium hydroxide, potassium hydroxide or salt of wormwood and phase-transfer catalyst, temperature is controlled at-15 ℃～110 ℃ reactions 1～24 hour, obtains (S)-metolachlor.Each used amount ratio of second step reaction is (R)-2-(tolysulfonyl oxygen base) propionic ester: 2-methyl-6-ethylaniline is 1: 0.8～1.3, (R)-2-(tolysulfonyl oxygen base) propionic ester: alkali is 1: 0.9～1.5.The first step, second step and used alkali of the 4th step are triethylamine, pyridine, salt of wormwood or yellow soda ash.The used reductive agent of three-step reaction is red aluminium, Lithium Aluminium Hydride, lithium borohydride, sodium borohydride-lithium chloride or POTASSIUM BOROHYDRIDE-lithium chloride.Used each amount of three-step reaction is than S-(-)-N-(2-methyl-6-ethylphenyl) alanine ester: reductive agent is 1: 0.8～3, and the solvent that reacts used is methyl alcohol, ethanol, tetrahydrofuran (THF) or ether.The 5th step reaction methylating reagent can be trifluoromethanesulfonic acid methyl esters, methyl iodide, methyl-sulfate or diazomethane, used phase-transfer catalyst is tetrabutylammonium iodide, tetra-n-butyl ammonium bromide, benzyl triethyl ammonium bromide, benzyltriethylammoinium chloride or phenyl triethyl brometo de amonio, and the used solvent of methylation reaction is methylene dichloride, ethylene dichloride, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), sherwood oil, toluene or benzene.
Its synthetic route is as follows:
With existing method relatively, the present invention has the following advantages: whole process need not to split, reaction temperature and, yield height, e.e. value height, side reaction is few, the reaction times is short, each raw material and catalyzer are also cheap and easy to get.And present method can overcome because the racemization role that pyroreaction causes also significantly reduces raw materials cost in addition.
Embodiment
Embodiment one:
In 250 milliliters of there-necked flasks of agitator, thermometer are housed, add 125 milliliters of toluene, then respectively with Tosyl chloride 21 grams (0.11 mole), (D)-methyl lactate 10.4 gram (0.1 mole) puts in the reaction flask, drip triethylamine 15.2 grams (0.15 mole), ice-water bath temperature control-10 ℃～-5 ℃ is followed the tracks of reaction and being reacted completely until (D)-methyl lactate.Filter, filtrate is with 45 milliliters of washings, layering, and water layer merges organic layer with 45 milliliters of dichloromethane extractions, restrains anhydrous sodium sulfate dryings with 20, and filtration is spin-dried for solvent and gets faint yellow crude product.Use ether then: normal hexane=recrystallization obtained clear crystal (R)-2-(tolysulfonyl oxygen base) methyl propionate 22 grams, yield 85%, e.e. value 97.1% in 1: 1.Agitator is being housed, drop into 2-methyl-6-ethylaniline 14.1 grams (0.104 mole) in 100 milliliters of there-necked flasks of thermometer, (R)-2-(tolysulfonyl oxygen base) methyl propionate 21.7 grams (0.08 mole), intensification is heated to 110 ℃, beginning slowly drips pyridine 9.5 grams (0.12 mole), drip that Bi Houji is continuous to be warmed up to 150 ℃～160 ℃, react and finished in 1 hour, cooling is poured reaction solution in 100 milliliters of frozen water into, stirs, and add and be washed to neutrality, water layer merges organic layer with 100 milliliters of extractions of ethyl acetate, and restrains anhydrous sodium sulfate dryings with 25, filter, be spin-dried for solvent, underpressure distillation obtains S-(-)-N-(2-methyl-6-ethylphenyl) alanine methyl ester 15.8 grams, yield 89%, e.e. be worth 95%, specific rotatory power
(c=0.92, EtOH) (document
(c=0.92, EtOH)).
Agitator is being housed, add 200 milliliters of dehydrated alcohols successively in 250 milliliters of there-necked flasks of thermometer, sodium borohydride 7.9 grams (0.21 mole) and lithium chloride 8.9 grams (0.21 mole), stirring at room half an hour, icy salt solution temperature control-10 ℃～0 ℃, begin to drip S-(-)-N-(2-methyl-6-ethylphenyl) alanine methyl ester 15.5 grams (0.07 mole), dropwise the back reaction below 0 ℃ 1 hour, then at room temperature reaction until reacting completely, filter solvent evaporated, add 50 milliliters of washing resistatess, use 50 milliliters of aqueous layer extracted of ethyl acetate then, merge organic layer, and restrain anhydrous sodium sulfate dryings with 20, filter, be spin-dried for solvent, underpressure distillation obtains S-(-)-N-(1 '-methyl-2 '-hydroxyethyl)-2-methyl-6-ethylaniline 13.1 grams, yield 97%, record e.e. value 94%, specific rotatory power
(c=1.94, MeOH) (document
(c=1.941, MeOH)).
Agitator is being housed, add 30 milliliters of toluene successively in 100 milliliters of four-hole boiling flasks of thermometer, S-(-)-N-(1 '-methyl-2 '-hydroxyethyl)-2-methyl-6-ethylaniline 11.6 grams (0.06 mole), triethylamine 7.3 grams (0.072 mole), icy salt solution temperature control-15 ℃～0 ℃, begin to drip after dissolving in chloroacetyl chloride 5.4 grams (0.048 mole) in 50 milliliters of toluene, earlier after reacting 3 hours below 0 ℃, then at room temperature reaction until reacting completely, add 50 milliliters of washings, use 50 milliliters of ethyl acetate extractions again, merge organic layer, and with 20 gram anhydrous sodium sulfate dryings, filter, be spin-dried for solvent, underpressure distillation obtains S-(-)-2-chloro-N-(2-methyl-6-ethylphenyl)-N-(2-hydroxyl-1-methylethyl) ethanamide 9.8 grams, yield 76%, e.e. be worth 92%, specific rotatory power
(c=1.17, MeOH) (document
(c=1.166, MeOH)).
Agitator is being housed, in 100 milliliters of four-hole boiling flasks of thermometer, add 30 milliliters of anhydrous tetrahydro furans successively, S-(-)-2-chloro-N-(2-methyl-6-ethylphenyl)-N-(2-hydroxyl-1-methylethyl) ethanamide 16.2 grams (0.06 mole), content 70% sodium hydride 2.9 grams (0.085 mole), icy salt solution temperature control-15 ℃～0 ℃, stir after 3 hours, begin to drip after dissolving in methyl iodide 17 grams (0.12 mole) in 50 milliliters of tetrahydrofuran (THF)s, earlier after reacting 3 hours below 0 ℃, then at room temperature reaction until reacting completely, add 50 milliliters of washings, use 50 milliliters of ethyl acetate extractions again, merge organic layer, and restrain anhydrous sodium sulfate dryings with 20, filter, be spin-dried for solvent, underpressure distillation obtains (S)-metolachlor 14.6 grams, yield 86%, e.e. be worth 90%, specific rotatory power
(c=2.1, normal hexane) (document
(c=2.073, normal hexane))
Embodiment two:
In 250 milliliters of there-necked flasks of agitator, thermometer are housed, add 125 milliliters of methylene dichloride, then respectively with Tosyl chloride 21 grams (0.11 mole), (D)-methyl lactate 10.4 gram (0.1 mole) puts in the reaction flask, drip triethylamine 12.1 grams (0.12 mole), ice-water bath temperature control-10 ℃～-5 ℃ is followed the tracks of reaction and being reacted completely until (D)-methyl lactate.Filter, filtrate is with 45 milliliters of washings, layering, and water layer merges organic layer with 45 milliliters of dichloromethane extractions, restrains anhydrous sodium sulfate dryings with 20, and filtration is spin-dried for solvent and gets faint yellow crude product.Use ether then: normal hexane=recrystallization obtained clear crystal (R)-2-(tolysulfonyl oxygen base) methyl propionate 21.7 grams, yield 84%, e.e. value 98% in 1: 1.Agitator is being housed, drop into 2-methyl-6-ethylaniline 11.9 grams (0.088 mole) in 100 milliliters of there-necked flasks of thermometer, (R)-2-(tolysulfonyl oxygen base) methyl propionate 21.7 grams (0.08 mole), intensification is heated to 140 ℃, begin to drip triethylamine 12.2 grams (0.12 mole), drip that Bi Houji is continuous to be warmed up to 150 ℃～160 ℃, react and finished in 2.5 hours, cooling is poured reaction solution in 100 milliliters of frozen water into, stirs, and add and be washed to neutrality, water layer merges organic layer with 100 milliliters of extractions of ethyl acetate, and restrains anhydrous sodium sulfate dryings with 25, filter, be spin-dried for solvent, underpressure distillation obtains S-(-)-N-(2-methyl-6-ethylphenyl) alanine methyl ester 16.1 grams, yield 91%, e.e. be worth 95%, specific rotatory power
(c=0.92, EtOH) (document
(c=0.92, EtOH)).
Agitator is being housed, add 200 milliliters of anhydrous methanols successively in 250 milliliters of there-necked flasks of thermometer, sodium borohydride 7.9 grams (0.21 mole) and lithium chloride 8.9 grams (0.21 mole), stirring at room half an hour, icy salt solution temperature control-10 ℃～0 ℃, begin to drip S-(-)-N-(2-methyl-6-ethylphenyl) alanine methyl ester 15.5 grams (0.07 mole), dropwise the back reaction below 0 ℃ 1 hour, then at room temperature reaction until reacting completely, filter solvent evaporated, add 50 milliliters of washing resistatess, use 50 milliliters of aqueous layer extracted of ethyl acetate then, merge organic layer, and restrain anhydrous sodium sulfate dryings with 20, filter, be spin-dried for solvent, underpressure distillation obtains S-(-)-N-(1 '-methyl-2 '-hydroxyethyl)-2-methyl-6-ethylaniline 13.1 grams, yield 97%, record e.e. value 94%, specific rotatory power
(c=1.94, MeOH) (document
(c=1.941, MeOH)).
Agitator is being housed, add 30 milliliters of methylene dichloride successively in 100 milliliters of four-hole boiling flasks of thermometer, S-(-)-N-(1 '-methyl-2 '-hydroxyethyl)-2-methyl-6-ethylaniline 11.6 grams (0.06 mole), triethylamine 7.9 grams (0.078 mole), icy salt solution temperature control-15 ℃～0 ℃, begin to drip after dissolving in chloroacetyl chloride 7.5 grams (0.066 mole) in 50 milliliters of methylene dichloride, earlier after reacting 3 hours below 0 ℃, then at room temperature reaction until reacting completely, add 50 milliliters of washings, use 50 milliliters of ethyl acetate extractions again, merge organic layer, and with 20 gram anhydrous sodium sulfate dryings, filter, be spin-dried for solvent, underpressure distillation obtains S-(-)-2-chloro-N-(2-methyl-6-ethylphenyl)-N-(2-hydroxyl-1-methylethyl) ethanamide 13 grams, yield 80%, e.e. be worth 93.8%, specific rotatory power
(c=1.17, MeOH) (document
(c=1.166, MeOH)).
S-(-)-2-chloro-N-(2-methyl-6-ethylphenyl)-N-(2-hydroxyl-1-methylethyl) ethanamide 13 grams (0.048 mole) are put in 30 milliliters of benzene, add benzyl triethyl ammonium bromide 0.6 gram (0.0022 mole) again, add methyl-sulfate 12.1 grams (0.096 mole) again, icy salt solution temperature control-15 ℃～0 ℃, beginning Dropwise 5 0% sodium hydroxide solution 9.6 grams, dropwise the back reaction below 0 ℃ 2 hours, then 40 ℃ of reactions until reacting completely, after finishing, reaction adds 50 milliliters of washings, use 50 milliliters of ethyl acetate extractions again, merge organic layer, and restrain anhydrous sodium sulfate dryings with 20, filter, be spin-dried for solvent, underpressure distillation gets (S)-metolachlor 11.3 grams, yield 83%, e.e. be worth 93%, specific rotatory power
(c=2.1, normal hexane) (document
(c=2.073, normal hexane)).
Embodiment three:
In 250 milliliters of there-necked flasks of agitator, thermometer are housed, add 125 milliliter 1, the 2-ethylene dichloride, then respectively with Tosyl chloride 15.3 gram (0.08 mole), (D)-methyl lactate 10.4 grams (0.1 mole) put in the reaction flask, drip triethylamine 12.1 grams (0.12 mole), ice-water bath temperature control-10 ℃～-5 ℃, after drip finishing,, follow the tracks of reaction and reacting completely until Tosyl chloride 20 ℃～30 ℃ reactions.Filter, filtrate is with 45 milliliters of washings, layering, and water layer merges organic layer with 45 milliliters of dichloromethane extractions, restrains anhydrous sodium sulfate dryings with 20, and filtration is spin-dried for solvent and gets faint yellow crude product.Use ether then: normal hexane=recrystallization obtained clear crystal (R)-2-(tolysulfonyl oxygen base) methyl propionate 17 grams, yield 82%, e.e. value 94% in 1: 1.Agitator is being housed, drop into 2-methyl-6-ethylaniline 7.2 grams (0.053 mole) in 100 milliliters of there-necked flasks of thermometer, (R)-2-(tolysulfonyl oxygen base) methyl propionate 17 grams (0.066 mole), intensification is heated to 110 ℃, begin to drip triethylamine 7.35 grams (0.073 mole), drip that Bi Houji is continuous to be warmed up to 140 ℃～150 ℃, react and finished in 1 hour, cooling is poured reaction solution in 100 milliliters of frozen water into, stirs, and add and be washed to neutrality, water layer merges organic layer with 100 milliliters of extractions of ethyl acetate, and restrains anhydrous sodium sulfate dryings with 25, filter, be spin-dried for solvent, underpressure distillation obtains S-(-)-N-(2-methyl-6-ethylphenyl) alanine methyl ester 9.7 grams, yield 83%, e.e. be worth 93%, specific rotatory power
(c=0.92, EtOH) (document
(c=0.92, EtOH)).
Agitator is being housed, add 30 milliliters of anhydrous tetrahydro furans successively in 100 milliliters of there-necked flasks of thermometer, Lithium Aluminium Hydride 1.68 grams (0.044 mole), icy salt solution temperature control-10 ℃～0 ℃, begin to drip the anhydrous tetrahydrofuran solution of S-(-)-N-(2-methyl-6-ethylphenyl) alanine methyl ester 9.7 grams (0.044 mole), dropwise the back reaction below 0 ℃ 2 hours, then at room temperature reaction until reacting completely, add 30 ml water termination reactions, add 30 milliliters in 15% sodium hydroxide then, add 30 ml waters again, filter, solvent evaporated, use 30 milliliters of aqueous layer extracted of ethyl acetate then, merge organic layer, and restrain anhydrous sodium sulfate dryings with 20, filter, be spin-dried for solvent, underpressure distillation obtains S-(-)-N-(1 '-methyl-2 '-hydroxyethyl)-2-methyl-6-ethylaniline 6.9 grams, yield 81.2%, record e.e. value 92%, specific rotatory power
(c=1.94, MeOH) (document
(c=1.941, MeOH)).
Agitator is being housed, add 30 milliliters of benzene successively in 100 milliliters of four-hole boiling flasks of thermometer, S-(-)-N-(1 '-methyl-2 '-hydroxyethyl)-2-methyl-6-ethylaniline 5.8 grams (0.03 mole), salt of wormwood 6.2 grams (0.045 mole), icy salt solution temperature control-15 ℃～0 ℃, begin to drip after dissolving in chloroacetyl chloride 4.1 grams (0.036 mole) in 30 milliliters of benzene, earlier after reacting 3 hours below 0 ℃, then at room temperature reaction until reacting completely, filter, be spin-dried for solvent, underpressure distillation obtains S-(-)-2-chloro-N-(2-methyl-6-ethylphenyl)-N-(2-hydroxyl-1-methylethyl) ethanamide 5.5 grams, yield 68%, e.e. be worth 91.7%, specific rotatory power
(c=1.17, MeOH) (document
(c=1.166, MeOH)).
S-(-)-2-chloro-N-(2-methyl-6-ethylphenyl)-N-(2-hydroxyl-1-methylethyl) ethanamide 5.5 grams (0.02 mole) are put in 30 milliliters of toluene, add content 70% sodium hydride 2.4 grams (0.07 mole) again, be warming up to backflow, after 10 minutes, begin to drip methyl-sulfate 5 grams (0.04 mole) again, after dropwising, continue to reflux until reacting completely, add 15 milliliters of ammoniacal liquor after reaction finishes and wash and 30 milliliters of washings, use 50 milliliters of ethyl acetate extractions again, merge organic layer, and with 20 gram anhydrous sodium sulfate dryings, filter, be spin-dried for solvent, underpressure distillation gets (S)-metolachlor 5.3 grams, yield 94%, e.e. value 91.1%, specific rotatory power
(c=2.1, normal hexane) (document
(c=2.073, normal hexane)).
Embodiment four:
In 250 milliliters of there-necked flasks of agitator, thermometer are housed, add 125 milliliters of benzene, then respectively with Tosyl chloride 21 grams (0.11 mole), (D)-ethyl lactate 11.8 gram (0.1 mole) puts in the reaction flask, drip triethylamine 15.2 grams (0.15 mole), ice-water bath temperature control-10 ℃～-5 ℃ is followed the tracks of reaction and being reacted completely until (D)-ethyl lactate.Filter, filtrate is with 45 milliliters of washings, layering, and water layer merges organic layer with 45 milliliters of dichloromethane extractions, restrains anhydrous sodium sulfate dryings with 20, and filtration is spin-dried for solvent and gets faint yellow crude product.Use ether then: normal hexane=recrystallization obtained clear crystal (R)-2-(tolysulfonyl oxygen base) ethyl propionate 23.7 grams, yield 87% in 1: 1.Agitator is being housed, drop into 2-methyl-6-ethylaniline 8.7 grams (0.064 mole) in 100 milliliters of there-necked flasks of thermometer, (R)-2-(tolysulfonyl oxygen base) ethyl propionate 21.8 grams (0.08 mole), intensification is heated to 140 ℃, begin to drip triethylamine 7.3 grams (0.072 mole), drip that Bi Houji is continuous to be warmed up to 150 ℃, react and finished in 1.5 hours, cooling, reaction solution is poured in 100 milliliters of frozen water, stir, and add and be washed to neutrality, water layer is with 100 milliliters of extractions of ethyl acetate, merge organic layer, and with 25 gram anhydrous sodium sulfate dryings, filter, be spin-dried for solvent, underpressure distillation obtains S-(-)-N-(2-methyl-6-ethylphenyl) alanine ethyl ester 11.3 grams, yield 75%.
Agitator is being housed, add 30 milliliters of anhydrous diethyl ethers successively in 100 milliliters of there-necked flasks of thermometer, Lithium Aluminium Hydride 1.63 grams (0.043 mole), icy salt solution temperature control-10 ℃～0 ℃, begin to drip the anhydrous ether solution of S-(-)-N-(2-methyl-6-ethylphenyl) alanine ethyl ester 11.3 grams (0.048 mole), dropwise the back reaction below 0 ℃ 2 hours, then at room temperature reaction until reacting completely, add 30 ml water termination reactions, add 30 milliliters in 15% sodium hydroxide then, add 30 ml waters again, filter, solvent evaporated, use 30 milliliters of aqueous layer extracted of ethyl acetate then, merge organic layer, and restrain anhydrous sodium sulfate dryings with 20, filter, be spin-dried for solvent, underpressure distillation obtains S-(-)-N-(1 '-methyl-2 '-hydroxyethyl)-2-methyl-6-ethylaniline 6.9 grams, yield 74%, record e.e. value 87%, specific rotatory power
(c=1.94, MeOH) (document
(c=1.941, MeOH)).
Agitator is being housed, add 30 milliliters of benzene successively in 100 milliliters of four-hole boiling flasks of thermometer, S-(-)-N-(1 '-methyl-2 '-hydroxyethyl)-2-methyl-6-ethylaniline 5.8 grams (0.03 mole), yellow soda ash 4.77 grams (0.045 mole), icy salt solution temperature control-15 ℃～0 ℃, begin to drip after dissolving in chloroacetyl chloride 4.1 grams (0.036 mole) in 30 milliliters of benzene, earlier after reacting 3 hours below 0 ℃, then at room temperature reaction until reacting completely, filter, be spin-dried for solvent, underpressure distillation obtains S-(-)-2-chloro-N-(2-methyl-6-ethylphenyl)-N-(2-hydroxyl-1-methylethyl) ethanamide 5.5 grams, yield 68%, e.e. be worth 86%, specific rotatory power
(c=1.17, MeOH) (document
(c=1.166, MeOH)).
S-(-)-2-chloro-N-(2-methyl-6-ethylphenyl)-N-(2-hydroxyl-1-methylethyl) ethanamide 5.5 grams (0.02 mole) are put in 30 milliliters of toluene, add content 50% potassium hydride KH 3.2 grams (0.04 mole) again, be warming up to backflow, after 10 minutes, begin to drip methyl-sulfate 5 grams (0.04 mole) again, after dropwising, continue to reflux until reacting completely, add 15 milliliters of ammoniacal liquor after reaction finishes and wash and 30 milliliters of washings, use 50 milliliters of ethyl acetate extractions again, merge organic layer, and with 20 gram anhydrous sodium sulfate dryings, filter, be spin-dried for solvent, underpressure distillation gets (S)-metolachlor 5.1 grams, yield 90%, e.e. value 84.4%, specific rotatory power
(c=2.1, normal hexane) (document
(c=2.073, normal hexane))
Embodiment five:
In 250 milliliters of there-necked flasks of agitator, thermometer are housed, add 125 milliliters of methylene dichloride, then respectively with Tosyl chloride 21 grams (0.11 mole), (D)-methyl lactate 10.4 gram (0.1 mole) puts in the reaction flask, drip triethylamine 12.1 grams (0.12 mole), ice-water bath temperature control-10 ℃～-5 ℃ is followed the tracks of reaction and being reacted completely until (D)-methyl lactate.Filter, filtrate is with 45 milliliters of washings, layering, and water layer merges organic layer with 45 milliliters of dichloromethane extractions, restrains anhydrous sodium sulfate dryings with 20, and filtration is spin-dried for solvent and gets faint yellow crude product.Use ether then: normal hexane=recrystallization obtained clear crystal (R)-2-(tolysulfonyl oxygen base) methyl propionate 21.7 grams, yield 84%, e.e. value 98% in 1: 1.Agitator is being housed, drop into 2-methyl-6-ethylaniline 10.8 grams (0.08 mole) in 100 milliliters of there-necked flasks of thermometer, (R)-2-(tolysulfonyl oxygen base) methyl propionate 21.7 grams (0.08 mole), intensification is heated to 120 ℃, begin to drip triethylamine 10.5 grams (0.104 mole), drip that Bi Houji is continuous to be warmed up to 150 ℃～160 ℃, react and finished in 2 hours, cooling is poured reaction solution in 100 milliliters of frozen water into, stirs, and add and be washed to neutrality, water layer merges organic layer with 100 milliliters of extractions of ethyl acetate, and restrains anhydrous sodium sulfate dryings with 25, filter, be spin-dried for solvent, underpressure distillation obtains S-(-)-N-(2-methyl-6-ethylphenyl) alanine methyl ester 16.3 grams, yield 92%, e.e. be worth 96.7%, specific rotatory power
(c=0.92, EtOH) (document
(c=0.92, EtOH)).
Agitator is being housed, add 200 milliliters of dehydrated alcohol alcohol successively in 250 milliliters of there-necked flasks of thermometer, POTASSIUM BOROHYDRIDE 11.3 grams (0.21 mole) and lithium chloride 8.9 grams (0.21 mole), stirring at room half an hour, icy salt solution temperature control-10 ℃～0 ℃, begin to drip S-(-)-N-(2-methyl-6-ethylphenyl) alanine methyl ester 15.5 grams (0.07 mole), dropwise the back reaction below 0 ℃ 1 hour, then at room temperature reaction until reacting completely, filter solvent evaporated, add 50 milliliters of washing resistatess, use 50 milliliters of aqueous layer extracted of ethyl acetate then, merge organic layer, and restrain anhydrous sodium sulfate dryings with 20, filter, be spin-dried for solvent, underpressure distillation obtains S-(-)-N-(1 '-methyl-2 '-hydroxyethyl)-2-methyl-6-ethylaniline 13 grams, yield 96%, record e.e. value 94.2%, specific rotatory power
(c=1.94, MeOH) (document
(c=1.941, MeOH)).
Agitator is being housed, add 30 milliliters of methylene dichloride successively in 100 milliliters of four-hole boiling flasks of thermometer, S-(-)-N-(1 '-methyl-2 '-hydroxyethyl)-2-methyl-6-ethylaniline 11.6 grams (0.06 mole), triethylamine 7.9 grams (0.078 mole), icy salt solution temperature control-15 ℃～0 ℃, begin to drip after dissolving in chloroacetyl chloride 7.5 grams (0.066 mole) in 50 milliliters of methylene dichloride, earlier after reacting 3 hours below 0 ℃, then at room temperature reaction until reacting completely, add 50 milliliters of washings, use 50 milliliters of ethyl acetate extractions again, merge organic layer, and with 20 gram anhydrous sodium sulfate dryings, filter, be spin-dried for solvent, underpressure distillation obtains S-(-)-2-chloro-N-(2-methyl-6-ethylphenyl)-N-(2-hydroxyl-1-methylethyl) ethanamide 13 grams, yield 80%, e.e. be worth 93.3%, specific rotatory power
(c=1.17, MeOH) (document
(c=1.166, MeOH)).
S-(-)-2-chloro-N-(2-methyl-6-ethylphenyl)-N-(2-hydroxyl-1-methylethyl) ethanamide 13 grams (0.048 mole) are put in 30 milliliters of methylene dichloride, add benzyltriethylammoinium chloride 0.6 gram (0.0026 mole) again, add methyl-sulfate 7.3 grams (0.058 mole) again, icy salt solution temperature control-15 ℃～0 ℃, beginning Dropwise 5 0% sodium hydroxide solution 9.6 grams, dropwise the back reaction below 0 ℃ 2 hours, then 40 ℃ of reactions until reacting completely, after finishing, reaction adds 50 milliliters of washings, use 50 milliliters of ethyl acetate extractions again, merge organic layer, and restrain anhydrous sodium sulfate dryings with 20, filter, be spin-dried for solvent, underpressure distillation gets (S)-metolachlor 11.3 grams, yield 83%, e.e. be worth 92.2%, specific rotatory power
(c=2.1, normal hexane) (document
(c=2.073, normal hexane))
Embodiment six:
In 250 milliliters of there-necked flasks of agitator, thermometer are housed, add 125 milliliters of methylene dichloride, then respectively with Tosyl chloride 21 grams (0.11 mole), (D)-methyl lactate 10.4 gram (0.1 mole) puts in the reaction flask, drip triethylamine 12.1 grams (0.12 mole), ice-water bath temperature control-10 ℃～-5 ℃ is followed the tracks of reaction and being reacted completely until (D)-methyl lactate.Filter, filtrate is with 45 milliliters of washings, layering, and water layer merges organic layer with 45 milliliters of dichloromethane extractions, restrains anhydrous sodium sulfate dryings with 20, and filtration is spin-dried for solvent and gets faint yellow crude product.Use ether then: normal hexane=recrystallization obtained clear crystal (R)-2-(tolysulfonyl oxygen base) methyl propionate 21.7 grams, yield 84%, e.e. value 98% in 1: 1.Agitator is being housed, drop into 2-methyl-6-ethylaniline 11.9 grams (0.088 mole) in 100 milliliters of there-necked flasks of thermometer, (R)-2-(tolysulfonyl oxygen base) methyl propionate 21.7 grams (0.08 mole), intensification is heated to 140 ℃, begin to drip triethylamine 10.5 grams (0.104 mole), drip that Bi Houji is continuous to be warmed up to 150 ℃, react and finished in 1.5 hours, cooling is poured reaction solution in 100 milliliters of frozen water into, stirs, and add and be washed to neutrality, water layer merges organic layer with 100 milliliters of extractions of ethyl acetate, and restrains anhydrous sodium sulfate dryings with 25, filter, be spin-dried for solvent, underpressure distillation obtains S-(-)-N-(2-methyl-6-ethylphenyl) alanine methyl ester 16.6 grams, yield 94%, e.e. be worth 99.2%, specific rotatory power
(c=0.92, EtOH) (document
(c=0.92, EtOH)).
Agitator is being housed, add 60 milliliters of anhydrous diethyl ethers successively in 150 milliliters of there-necked flasks of thermometer, red aluminium 28.3 grams (0.14 mole), icy salt solution temperature control-10 ℃～0 ℃, begin to drip S-(-)-N-(2-methyl-6-ethylphenyl) alanine methyl ester 15.5 grams (0.07 mole), dropwise the back reaction below 0 ℃ 2 hours, then at room temperature reaction until reacting completely, filter, solvent evaporated adds 50 milliliters of washing resistatess, uses 50 milliliters of aqueous layer extracted of ethyl acetate then, merge organic layer, and with 20 gram anhydrous sodium sulfate dryings, filter, be spin-dried for solvent, underpressure distillation obtains S-(-)-N-(1 '-methyl-2 '-hydroxyethyl)-2-methyl-6-ethylaniline 13.1 grams, yield 97% records e.e. value 98%, specific rotatory power
(c=1.94, MeOH) (document
(c=1.941, MeOH)).
Agitator is being housed, add 30 milliliters of methylene dichloride successively in 100 milliliters of four-hole boiling flasks of thermometer, S-(-)-N-(1 '-methyl-2 '-hydroxyethyl)-2-methyl-6-ethylaniline 11.6 grams (0.06 mole), triethylamine 7.9 grams (0.078 mole), icy salt solution temperature control-15 ℃～0 ℃, begin to drip after dissolving in chloroacetyl chloride 7.5 grams (0.066 mole) in 50 milliliters of methylene dichloride, earlier after reacting 3 hours below 0 ℃, then at room temperature reaction until reacting completely, add 50 milliliters of washings, use 50 milliliters of ethyl acetate extractions again, merge organic layer, and with 20 gram anhydrous sodium sulfate dryings, filter, be spin-dried for solvent, underpressure distillation obtains S-(-)-2-chloro-N-(2-methyl-6-ethylphenyl)-N-(2-hydroxyl-1-methylethyl) ethanamide 13 grams, yield 80%, e.e. be worth 95%, specific rotatory power
(c=1.17, MeOH) (document
(c=1.166, MeOH)).
S-(-)-2-chloro-N-(2-methyl-6-ethylphenyl)-N-(2-hydroxyl-1-methylethyl) ethanamide 13 grams (0.048 mole) are put in 30 milliliters of sherwood oils (60 ℃～90 ℃), add tetrabutylammonium iodide 0.6 gram (0.0016 mole) again, icy salt solution temperature control-15 ℃～0 ℃, add 50% sodium hydroxide solution, 9.6 grams again, begin to drip methyl-sulfate 6.05 grams (0.048 mole), dropwise the back reaction below 0 ℃ 2 hours, then at room temperature reaction until reacting completely, after finishing, reaction adds 50 milliliters of washings, use 50 milliliters of ethyl acetate extractions again, merge organic layer, and restrain anhydrous sodium sulfate dryings with 20, filter, be spin-dried for solvent, underpressure distillation gets (S)-metolachlor 9 grams, yield 65%, e.e. be worth 92.2%, specific rotatory power
(c=2.073, normal hexane) (document
(c=2.073, normal hexane))
Embodiment seven:
In 250 milliliters of there-necked flasks of agitator, thermometer are housed, add 125 milliliters of methylene dichloride, then respectively with Tosyl chloride 21 grams (0.11 mole), (D)-methyl lactate 10.4 gram (0.1 mole) puts in the reaction flask, drip triethylamine 12.1 grams (0.12 mole), ice-water bath temperature control-10 ℃～-5 ℃ is followed the tracks of reaction and being reacted completely until (D)-methyl lactate.Filter, filtrate is with 45 milliliters of washings, layering, and water layer merges organic layer with 45 milliliters of dichloromethane extractions, restrains anhydrous sodium sulfate dryings with 20, and filtration is spin-dried for solvent and gets faint yellow crude product.Use ether then: normal hexane=recrystallization obtained clear crystal (R)-2-(tolysulfonyl oxygen base) methyl propionate 21.7 grams, yield 84%, e.e. value 98% in 1: 1.Agitator is being housed, drop into 2-methyl-6-ethylaniline 11.9 grams (0.088 mole) in 100 milliliters of there-necked flasks of thermometer, (R)-2-(tolysulfonyl oxygen base) methyl propionate 21.7 grams (0.08 mole), intensification is heated to 140 ℃, begin to drip triethylamine 10.5 grams (0.104 mole), drip that Bi Houji is continuous to be warmed up to 150 ℃, react and finished in 1.5 hours, cooling is poured reaction solution in 100 milliliters of frozen water into, stirs, and add and be washed to neutrality, water layer merges organic layer with 100 milliliters of extractions of ethyl acetate, and restrains anhydrous sodium sulfate dryings with 25, filter, be spin-dried for solvent, underpressure distillation obtains S-(-)-N-(2-methyl-6-ethylphenyl) alanine methyl ester 16.6 grams, yield 94%, e.e. be worth 99.2%, specific rotatory power
(c=0.92, EtOH) (document
(c=0.92, EtOH)).
Agitator is being housed, add 30 milliliters of anhydrous methanols successively in 100 milliliters of there-necked flasks of thermometer, lithium borohydride 3.8 grams (0.175 mole), icy salt solution temperature control-10 ℃～0 ℃, begin to drip S-(-)-N-(2-methyl-6-ethylphenyl) alanine methyl ester 15.5 grams (0.07 mole), dropwise the back reaction below 0 ℃ 2 hours, then at room temperature reaction until reacting completely, filter, solvent evaporated adds 50 milliliters of washing resistatess, uses 50 milliliters of aqueous layer extracted of ethyl acetate then, merge organic layer, and with 20 gram anhydrous sodium sulfate dryings, filter, be spin-dried for solvent, underpressure distillation obtains S-(-)-N-(1 '-methyl-2 '-hydroxyethyl)-2-methyl-6-ethylaniline 13 grams, yield 96.8% records e.e. value 97%, specific rotatory power
(c=1.94, MeOH) (document
(c=1.941, MeOH)).
Agitator is being housed, add 30 milliliters of methylene dichloride successively in 100 milliliters of four-hole boiling flasks of thermometer, S-(-)-N-(1 '-methyl-2 '-hydroxyethyl)-2-methyl-6-ethylaniline 11.6 grams (0.06 mole), triethylamine 7.9 grams (0.078 mole), icy salt solution temperature control-15 ℃～0 ℃, begin to drip after dissolving in chloroacetyl chloride 7.5 grams (0.066 mole) in 50 milliliters of methylene dichloride, earlier after reacting 3 hours below 0 ℃, then at room temperature reaction until reacting completely, add 50 milliliters of washings, use 50 milliliters of ethyl acetate extractions again, merge organic layer, and with 20 gram anhydrous sodium sulfate dryings, filter, be spin-dried for solvent, underpressure distillation obtains S-(-)-2-chloro-N-(2-methyl-6-ethylphenyl)-N-(2-hydroxyl-1-methylethyl) ethanamide 13 grams, yield 80%, e.e. be worth 95%, specific rotatory power
(c=1.17, MeOH) (document
(c=1.166, MeOH)).
S-(-)-2-chloro-N-(2-methyl-6-ethylphenyl)-N-(2-hydroxyl-1-methylethyl) ethanamide 13 grams (0.048 mole) are put into 30 milliliter 1, in the 2-ethylene dichloride, add phenyl triethyl brometo de amonio 0.6 gram (0.0023 mole) again, icy salt solution temperature control-15 ℃～0 ℃, add 50% sodium hydroxide solution, 9.6 grams again, begin to drip methyl-sulfate 6.05 grams (0.048 mole), dropwise the back reaction below 0 ℃ 2 hours, after react completely, reaction finishes, add 50 milliliters of washings at room temperature reaction then, use 50 milliliters of ethyl acetate extractions again, merge organic layer, and with 20 gram anhydrous sodium sulfate dryings, filter, be spin-dried for solvent, underpressure distillation gets (S)-metolachlor 8.7 grams, yield 63%, e.e. value 91.1%, specific rotatory power
(c=2.073, normal hexane) (document
(c=2.073, normal hexane))
Embodiment eight:
In 250 milliliters of there-necked flasks of agitator, thermometer are housed, add 125 milliliters of methylene dichloride, then respectively with Tosyl chloride 21 grams (0.11 mole), (D)-methyl lactate 10.4 gram (0.1 mole) puts in the reaction flask, drip triethylamine 12.1 grams (0.12 mole), ice-water bath temperature control-10 ℃～-5 ℃ is followed the tracks of reaction and being reacted completely until (D)-methyl lactate.Filter, filtrate is with 45 milliliters of washings, layering, and water layer merges organic layer with 45 milliliters of dichloromethane extractions, restrains anhydrous sodium sulfate dryings with 20, and filtration is spin-dried for solvent and gets faint yellow crude product.Use ether then: normal hexane=recrystallization obtained clear crystal (R)-2-(tolysulfonyl oxygen base) methyl propionate 21.7 grams, yield 84%, e.e. value 98% in 1: 1.Agitator is being housed, drop into 2-methyl-6-ethylaniline 11.9 grams (0.088 mole) in 100 milliliters of there-necked flasks of thermometer, (R)-2-(tolysulfonyl oxygen base) methyl propionate 21.7 grams (0.08 mole), intensification is heated to 140 ℃, begin to drip triethylamine 10.5 grams (0.104 mole), drip that Bi Houji is continuous to be warmed up to 150 ℃, react and finished in 1.5 hours, cooling is poured reaction solution in 100 milliliters of frozen water into, stirs, and add and be washed to neutrality, water layer merges organic layer with 100 milliliters of extractions of ethyl acetate, and restrains anhydrous sodium sulfate dryings with 25, filter, be spin-dried for solvent, underpressure distillation obtains S-(-)-N-(2-methyl-6-ethylphenyl) alanine methyl ester 16.6 grams, yield 94%, e.e. be worth 99.2%, specific rotatory power
(c=0.92, EtOH) (document
(c=0.92, EtOH)).
Agitator is being housed, add 30 milliliters of anhydrous tetrahydro furans successively in 100 milliliters of there-necked flasks of thermometer, lithium borohydride 3.8 grams (0.175 mole), icy salt solution temperature control-10 ℃～0 ℃, begin to drip S-(-)-N-(2-methyl-6-ethylphenyl) alanine methyl ester 15.5 grams (0.07 mole), dropwise the back reaction below 0 ℃ 2 hours, then at room temperature reaction until reacting completely, filter, solvent evaporated adds 50 milliliters of washing resistatess, uses 50 milliliters of aqueous layer extracted of ethyl acetate then, merge organic layer, and with 20 gram anhydrous sodium sulfate dryings, filter, be spin-dried for solvent, underpressure distillation obtains S-(-)-N-(1 '-methyl-2 '-hydroxyethyl)-2-methyl-6-ethylaniline 12.9 grams, yield 96% records e.e. value 95%, specific rotatory power
(c=1.94, MeOH) (document
(c=1.941, MeOH)).
Agitator is being housed, add 30 milliliters of methylene dichloride successively in 100 milliliters of four-hole boiling flasks of thermometer, S-(-)-N-(1 '-methyl-2 '-hydroxyethyl)-2-methyl-6-ethylaniline 11.6 grams (0.06 mole), triethylamine 7.9 grams (0.078 mole), icy salt solution temperature control-15 ℃～0 ℃, begin to drip after dissolving in chloroacetyl chloride 7.5 grams (0.066 mole) in 50 milliliters of methylene dichloride, earlier after reacting 3 hours below 0 ℃, then at room temperature reaction until reacting completely, add 50 milliliters of washings, use 50 milliliters of ethyl acetate extractions again, merge organic layer, and with 20 gram anhydrous sodium sulfate dryings, filter, be spin-dried for solvent, underpressure distillation obtains S-(-)-2-chloro-N-(2-methyl-6-ethylphenyl)-N-(2-hydroxyl-1-methylethyl) ethanamide 13 grams, yield 80%, e.e. be worth 95%, specific rotatory power
(c=1.17, MeOH) (document
(c=1.166, MeOH)).
S-(-)-2-chloro-N-(2-methyl-6-ethylphenyl)-N-(2-hydroxyl-1-methylethyl) ethanamide 13 grams (0.048 mole) are put into 30 milliliter 1, in the 2-ethylene dichloride, add tetra-n-butyl ammonium bromide 0.6 gram (0.0019 mole) again, icy salt solution temperature control-15 ℃～0 ℃, add 50% sodium hydroxide solution, 9.6 grams again, begin to drip methyl-sulfate 6.05 grams (0.048 mole), dropwise the back reaction below 0 ℃ 2 hours, after react completely, reaction finishes, add 50 milliliters of washings at room temperature reaction then, use 50 milliliters of ethyl acetate extractions again, merge organic layer, and with 20 gram anhydrous sodium sulfate dryings, filter, be spin-dried for solvent, underpressure distillation gets (S)-metolachlor 8.3 grams, yield 60%, e.e. value 90%, specific rotatory power
(c=2.073, normal hexane) (document
(c=2.073, normal hexane))
Embodiment nine:
In 250 milliliters of there-necked flasks of agitator, thermometer are housed, add 125 milliliters of methylene dichloride, then respectively with Tosyl chloride 21 grams (0.11 mole), (D)-methyl lactate 10.4 gram (0.1 mole) puts in the reaction flask, drip triethylamine 12.1 grams (0.12 mole), ice-water bath temperature control-10 ℃～-5 ℃ is followed the tracks of reaction and being reacted completely until (D)-methyl lactate.Filter, filtrate is with 45 milliliters of washings, layering, and water layer merges organic layer with 45 milliliters of dichloromethane extractions, restrains anhydrous sodium sulfate dryings with 20, and filtration is spin-dried for solvent and gets faint yellow crude product.Use ether then: normal hexane=recrystallization obtained clear crystal (R)-2-(tolysulfonyl oxygen base) methyl propionate 21.7 grams, yield 84%, e.e. value 98% in 1: 1.Agitator is being housed, drop into 2-methyl-6-ethylaniline 11.9 grams (0.088 mole) in 100 milliliters of there-necked flasks of thermometer, (R)-2-(tolysulfonyl oxygen base) methyl propionate 21.7 grams (0.08 mole), intensification is heated to 140 ℃, begin to drip triethylamine 10.5 grams (0.104 mole), drip that Bi Houji is continuous to be warmed up to 150 ℃, react and finished in 1.5 hours, cooling is poured reaction solution in 100 milliliters of frozen water into, stirs, and add and be washed to neutrality, water layer merges organic layer with 100 milliliters of extractions of ethyl acetate, and restrains anhydrous sodium sulfate dryings with 25, filter, be spin-dried for solvent, underpressure distillation obtains S-(-)-N-(2-methyl-6-ethylphenyl) alanine methyl ester 16.6 grams, yield 94%, e.e. be worth 99.2%, specific rotatory power
(c=0.92, EtOH) (document
(c=0.92, EtOH)).
Agitator is being housed, add 30 milliliters of anhydrous tetrahydro furans successively in 100 milliliters of there-necked flasks of thermometer, lithium borohydride 3.8 grams (0.175 mole), icy salt solution temperature control-10 ℃～0 ℃, begin to drip S-(-)-N-(2-methyl-6-ethylphenyl) alanine methyl ester 15.5 grams (0.07 mole), dropwise the back reaction below 0 ℃ 2 hours, then at room temperature reaction until reacting completely, filter, solvent evaporated adds 50 milliliters of washing resistatess, uses 50 milliliters of aqueous layer extracted of ethyl acetate then, merge organic layer, and with 20 gram anhydrous sodium sulfate dryings, filter, be spin-dried for solvent, underpressure distillation obtains S-(-)-N-(1 '-methyl-2 '-hydroxyethyl)-2-methyl-6-ethylaniline 12.9 grams, yield 96% records e.e. value 95%, specific rotatory power
(c=1.94, MeOH) (document
(c=1.941, MeOH)).
Agitator is being housed, add 30 milliliters of methylene dichloride successively in 100 milliliters of four-hole boiling flasks of thermometer, S-(-)-N-(1 '-methyl-2 '-hydroxyethyl)-2-methyl-6-ethylaniline 11.6 grams (0.06 mole), triethylamine 7.9 grams (0.078 mole), icy salt solution temperature control-15 ℃～0 ℃, begin to drip after dissolving in chloroacetyl chloride 7.5 grams (0.066 mole) in 50 milliliters of methylene dichloride, earlier after reacting 3 hours below 0 ℃, then at room temperature reaction until reacting completely, add 50 milliliters of washings, use 50 milliliters of ethyl acetate extractions again, merge organic layer, and with 20 gram anhydrous sodium sulfate dryings, filter, be spin-dried for solvent, underpressure distillation obtains S-(-)-2-chloro-N-(2-methyl-6-ethylphenyl)-N-(2-hydroxyl-1-methylethyl) ethanamide 13 grams, yield 80%, e.e. be worth 95%, specific rotatory power
(c=1.17, MeOH) (document
(c=1.166, MeOH)).
S-(-)-2-chloro-N-(2-methyl-6-ethylphenyl)-N-(2-hydroxyl-1-methylethyl) ethanamide 13 grams (0.048 mole) are put into 30 milliliter 1, in the 2-ethylene dichloride, add trifluoromethanesulfonic acid methyl esters 9.51 grams (0.058 mole) again, pyridine, icy salt solution temperature control-15 ℃～0 ℃, reaction below 0 ℃ 2 hours, be warming up to gradually then straight 80 ℃ to reacting completely, the reaction back that finishes adds 50 milliliters of washings, uses 50 milliliters of ethyl acetate extractions again, merge organic layer, and with 20 gram anhydrous sodium sulfate dryings, filter, be spin-dried for solvent, underpressure distillation gets (S)-metolachlor 9.7 grams, yield 70%, e.e. value 91.1%, specific rotatory power
(c=2.073, normal hexane) (document
(c=2.073, normal hexane))
Embodiment ten:
In 250 milliliters of there-necked flasks of agitator, thermometer are housed, add 125 milliliters of methylene dichloride, then respectively with Tosyl chloride 21 grams (0.11 mole), (D)-methyl lactate 10.4 gram (0.1 mole) puts in the reaction flask, drip triethylamine 12.1 grams (0.12 mole), ice-water bath temperature control-10 ℃～-5 ℃ is followed the tracks of reaction and being reacted completely until (D)-methyl lactate.Filter, filtrate is with 45 milliliters of washings, layering, and water layer merges organic layer with 45 milliliters of dichloromethane extractions, restrains anhydrous sodium sulfate dryings with 20, and filtration is spin-dried for solvent and gets faint yellow crude product.Use ether then: normal hexane=recrystallization obtained clear crystal (R)-2-(tolysulfonyl oxygen base) methyl propionate 21.7 grams, yield 84%, e.e. value 98% in 1: 1.Agitator is being housed, drop into 2-methyl-6-ethylaniline 10.8 grams (0.08 mole) in 100 milliliters of there-necked flasks of thermometer, (R)-2-(tolysulfonyl oxygen base) methyl propionate 21.7 grams (0.08 mole), intensification is heated to 120 ℃, begin to drip triethylamine 10.5 grams (0.104 mole), drip that Bi Houji is continuous to be warmed up to 150 ℃～160 ℃, react and finished in 2 hours, cooling is poured reaction solution in 100 milliliters of frozen water into, stirs, and add and be washed to neutrality, water layer merges organic layer with 100 milliliters of extractions of ethyl acetate, and restrains anhydrous sodium sulfate dryings with 25, filter, be spin-dried for solvent, underpressure distillation obtains S-(-)-N-(2-methyl-6-ethylphenyl) alanine methyl ester 16.3 grams, yield 92%, e.e. be worth 96.7%, specific rotatory power
(c=0.92, EtOH) (document
(c=0.92, EtOH)).
Agitator is being housed, add 200 milliliters of dehydrated alcohol alcohol successively in 250 milliliters of there-necked flasks of thermometer, POTASSIUM BOROHYDRIDE 11.3 grams (0.21 mole) and lithium chloride 8.9 grams (0.21 mole), stirring at room half an hour, icy salt solution temperature control-10 ℃～0 ℃, begin to drip S-(-)-N-(2-methyl-6-ethylphenyl) alanine methyl ester 15.5 grams (0.07 mole), dropwise the back reaction below 0 ℃ 1 hour, then at room temperature reaction until reacting completely, filter solvent evaporated, add 50 milliliters of washing resistatess, use 50 milliliters of aqueous layer extracted of ethyl acetate then, merge organic layer, and restrain anhydrous sodium sulfate dryings with 20, filter, be spin-dried for solvent, underpressure distillation obtains S-(-)-N-(1 '-methyl-2 '-hydroxyethyl)-2-methyl-6-ethylaniline 13 grams, yield 96%, record e.e. value 94.2%, specific rotatory power
(c=1.94, MeOH) (document
(c=1.941, MeOH)).
Agitator is being housed, add 30 milliliters of methylene dichloride successively in 100 milliliters of four-hole boiling flasks of thermometer, S-(-)-N-(1 '-methyl-2 '-hydroxyethyl)-2-methyl-6-ethylaniline 11.6 grams (0.06 mole), triethylamine 7.9 grams (0.078 mole), icy salt solution temperature control-15 ℃～0 ℃, begin to drip after dissolving in chloroacetyl chloride 7.5 grams (0.066 mole) in 50 milliliters of methylene dichloride, earlier after reacting 3 hours below 0 ℃, then at room temperature reaction until reacting completely, add 50 milliliters of washings, use 50 milliliters of ethyl acetate extractions again, merge organic layer, and with 20 gram anhydrous sodium sulfate dryings, filter, be spin-dried for solvent, underpressure distillation obtains S-(-)-2-chloro-N-(2-methyl-6-ethylphenyl)-N-(2-hydroxyl-1-methylethyl) ethanamide 13 grams, yield 80%, e.e. be worth 93.3%, specific rotatory power
(c=1.17, MeOH) (document
(c=1.166, MeOH)).
S-(-)-2-chloro-N-(2-methyl-6-ethylphenyl)-N-(2-hydroxyl-1-methylethyl) ethanamide 13 grams (0.048 mole) are put in 30 milliliters of dimethyl sulfoxide (DMSO), add potassium hydroxide 5.4 grams (0.096 mole) again, icy salt solution temperature control-15 ℃～0 ℃, begin to drip methyl iodide 8.2 grams (0.058 mole), dropwise the back reaction below 0 ℃ 1 hour, then 20 ℃ of reactions until reacting completely, after finishing, reaction adds 50 milliliters of washings, use 50 milliliters of ethyl acetate extractions again, merge organic layer, and with 20 gram anhydrous sodium sulfate dryings, filter, be spin-dried for solvent, underpressure distillation gets (S)-metolachlor 11.7 grams, yield 86%, e.e. value 90%, specific rotatory power
(c=2.1, normal hexane) (document
(c=2.073, normal hexane))
Embodiment 11:
In 250 milliliters of there-necked flasks of agitator, thermometer are housed, add 125 milliliters of methylene dichloride, then respectively with Tosyl chloride 21 grams (0.11 mole), (D)-methyl lactate 10.4 gram (0.1 mole) puts in the reaction flask, drip triethylamine 12.1 grams (0.12 mole), ice-water bath temperature control-10 ℃～-5 ℃ is followed the tracks of reaction and being reacted completely until (D)-methyl lactate.Filter, filtrate is with 45 milliliters of washings, layering, and water layer merges organic layer with 45 milliliters of dichloromethane extractions, restrains anhydrous sodium sulfate dryings with 20, and filtration is spin-dried for solvent and gets faint yellow crude product.Use ether then: normal hexane=recrystallization obtained clear crystal (R)-2-(tolysulfonyl oxygen base) methyl propionate 21.7 grams, yield 84%, e.e. value 98% in 1: 1.Agitator is being housed, drop into 2-methyl-6-ethylaniline 10.8 grams (0.08 mole) in 100 milliliters of there-necked flasks of thermometer, (R)-2-(tolysulfonyl oxygen base) methyl propionate 21.7 grams (0.08 mole), intensification is heated to 120 ℃, begin to drip triethylamine 10.5 grams (0.104 mole), drip that Bi Houji is continuous to be warmed up to 150 ℃～160 ℃, react and finished in 2 hours, cooling is poured reaction solution in 100 milliliters of frozen water into, stirs, and add and be washed to neutrality, water layer merges organic layer with 100 milliliters of extractions of ethyl acetate, and restrains anhydrous sodium sulfate dryings with 25, filter, be spin-dried for solvent, underpressure distillation obtains S-(-)-N-(2-methyl-6-ethylphenyl) alanine methyl ester 16.3 grams, yield 92%, e.e. be worth 96.7%, specific rotatory power
(c=0.92, EtOH) (document
(c=0.92, EtOH)).
Agitator is being housed, add 200 milliliters of dehydrated alcohol alcohol successively in 250 milliliters of there-necked flasks of thermometer, POTASSIUM BOROHYDRIDE 11.3 grams (0.21 mole) and lithium chloride 8.9 grams (0.21 mole), stirring at room half an hour, icy salt solution temperature control-10 ℃～0 ℃, begin to drip S-(-)-N-(2-methyl-6-ethylphenyl) alanine methyl ester 15.5 grams (0.07 mole), dropwise the back reaction below 0 ℃ 1 hour, then at room temperature reaction until reacting completely, filter solvent evaporated, add 50 milliliters of washing resistatess, use 50 milliliters of aqueous layer extracted of ethyl acetate then, merge organic layer, and restrain anhydrous sodium sulfate dryings with 20, filter, be spin-dried for solvent, underpressure distillation obtains S-(-)-N-(1 '-methyl-2 '-hydroxyethyl)-2-methyl-6-ethylaniline 13 grams, yield 96%, record e.e. value 94.2%, specific rotatory power
(c=1.94, MeOH) (document
(c=1.941, MeOH)).
Agitator is being housed, add 30 milliliters of methylene dichloride successively in 100 milliliters of four-hole boiling flasks of thermometer, S-(-)-N-(1 '-methyl-2 '-hydroxyethyl)-2-methyl-6-ethylaniline 11.6 grams (0.06 mole), triethylamine 7.9 grams (0.078 mole), icy salt solution temperature control-15 ℃～0 ℃, begin to drip after dissolving in chloroacetyl chloride 7.5 grams (0.066 mole) in 50 milliliters of methylene dichloride, earlier after reacting 3 hours below 0 ℃, then at room temperature reaction until reacting completely, add 50 milliliters of washings, use 50 milliliters of ethyl acetate extractions again, merge organic layer, and with 20 gram anhydrous sodium sulfate dryings, filter, be spin-dried for solvent, underpressure distillation obtains S-(-)-2-chloro-N-(2-methyl-6-ethylphenyl)-N-(2-hydroxyl-1-methylethyl) ethanamide 13 grams, yield 80%, e.e. be worth 93.3%, specific rotatory power
(c=1.17, MeOH) (document
(c=1.166, MeOH)).
S-(-)-2-chloro-N-(2-methyl-6-ethylphenyl)-N-(2-hydroxyl-1-methylethyl) ethanamide 13 grams (0.048 mole) are put in 30 milliliters of methylene dichloride, and icy salt solution temperature control-15 ℃～0 adds HBF
44.21 gram (0.048 mole) begins to feed diazomethane 4 grams (0.096 mole), reaction below 0 ℃ 1 hour, and drip triethylamine 4.8 grams (0.048 mole), then at room temperature reaction until reacting completely, add 50 milliliters of washings, use 50 milliliters of ethyl acetate extractions again, merge organic layer, and restrain anhydrous sodium sulfate dryings with 20, filter, be spin-dried for solvent, underpressure distillation gets (S)-metolachlor 10.9 grams, yield 8%, e.e. be worth 90%, specific rotatory power
(c=2.1, normal hexane) (document
(c=2.073, normal hexane))
Embodiment 12:
In 250 milliliters of there-necked flasks of agitator, thermometer are housed, add 125 milliliters of methylene dichloride, then respectively with Tosyl chloride 21 grams (0.11 mole), (D)-methyl lactate 10.4 gram (0.1 mole) puts in the reaction flask, drip triethylamine 12.1 grams (0.12 mole), ice-water bath temperature control-10 ℃～-5 ℃ is followed the tracks of reaction and being reacted completely until (D)-methyl lactate.Filter, filtrate is with 45 milliliters of washings, layering, and water layer merges organic layer with 45 milliliters of dichloromethane extractions, restrains anhydrous sodium sulfate dryings with 20, and filtration is spin-dried for solvent and gets faint yellow crude product.Use ether then: normal hexane=recrystallization obtained clear crystal (R)-2-(tolysulfonyl oxygen base) methyl propionate 21.7 grams, yield 84%, e.e. value 98% in 1: 1.Agitator is being housed, drop into 2-methyl-6-ethylaniline 11.9 grams (0.088 mole) in 100 milliliters of there-necked flasks of thermometer, (R)-2-(tolysulfonyl oxygen base) methyl propionate 21.7 grams (0.08 mole), intensification is heated to 140 ℃, begin to drip triethylamine 10.5 grams (0.104 mole), drip that Bi Houji is continuous to be warmed up to 150 ℃, react and finished in 1.5 hours, cooling is poured reaction solution in 100 milliliters of frozen water into, stirs, and add and be washed to neutrality, water layer merges organic layer with 100 milliliters of extractions of ethyl acetate, and restrains anhydrous sodium sulfate dryings with 25, filter, be spin-dried for solvent, underpressure distillation obtains S-(-)-N-(2-methyl-6-ethylphenyl) alanine methyl ester 16.6 grams, yield 94%, e.e. be worth 99.2%, specific rotatory power
(c=0.92, EtOH) (document
(c=0.92, EtOH)).
Agitator is being housed, add 30 milliliters of anhydrous tetrahydro furans successively in 100 milliliters of there-necked flasks of thermometer, lithium borohydride 3.8 grams (0.175 mole), icy salt solution temperature control-10 ℃～0 ℃, begin to drip S-(-)-N-(2-methyl-6-ethylphenyl) alanine methyl ester 15.5 grams (0.07 mole), dropwise the back reaction below 0 ℃ 2 hours, then at room temperature reaction until reacting completely, filter, solvent evaporated adds 50 milliliters of washing resistatess, uses 50 milliliters of aqueous layer extracted of ethyl acetate then, merge organic layer, and with 20 gram anhydrous sodium sulfate dryings, filter, be spin-dried for solvent, underpressure distillation obtains S-(-)-N-(1 '-methyl-2 '-hydroxyethyl)-2-methyl-6-ethylaniline 12.9 grams, yield 96% records e.e. value 95%, specific rotatory power
(c=1.94, MeOH) (document
(c=1.941, MeOH)).
Agitator is being housed, add 30 milliliters of methylene dichloride successively in 100 milliliters of four-hole boiling flasks of thermometer, S-(-)-N-(1 '-methyl-2 '-hydroxyethyl)-2-methyl-6-ethylaniline 11.6 grams (0.06 mole), triethylamine 7.9 grams (0.078 mole), icy salt solution temperature control-15 ℃～0 ℃, begin to drip after dissolving in chloroacetyl chloride 7.5 grams (0.066 mole) in 50 milliliters of methylene dichloride, earlier after reacting 3 hours below 0 ℃, then at room temperature reaction until reacting completely, add 50 milliliters of washings, use 50 milliliters of ethyl acetate extractions again, merge organic layer, and with 20 gram anhydrous sodium sulfate dryings, filter, be spin-dried for solvent, underpressure distillation obtains S-(-)-2-chloro-N-(2-methyl-6-ethylphenyl)-N-(2-hydroxyl-1-methylethyl) ethanamide 13 grams, yield 80%, e.e. be worth 95%, specific rotatory power
(c=1.17, MeOH) (document
(c=1.166, MeOH)).
S-(-)-2-chloro-N-(2-methyl-6-ethylphenyl)-N-(2-hydroxyl-1-methylethyl) ethanamide 13 grams (0.048 mole) are put in 30 milliliters of sherwood oils (60 ℃～90 ℃), add methyl-sulfate 6.05 grams (0.048 mole) again, back flow reaction is until reacting completely then, after finishing, reaction adds 50 milliliters of washings, use 50 milliliters of ethyl acetate extractions again, merge organic layer, and with 20 gram anhydrous sodium sulfate dryings, filter, be spin-dried for solvent, underpressure distillation gets (S)-metolachlor 12 grams, yield 88%, e.e. be worth 90%, specific rotatory power
(c=2.073, normal hexane) (document
(c=2.073, normal hexane))
Though the present invention has been described in detail in detail, yet it is not to be used to limit the present invention with preferred embodiment.Any those skilled in the art under the situation that does not break away from the spirit and scope of the present invention, should make various modifications and change.Therefore protection scope of the present invention should be considered as appended claims institute restricted portion.
Claims (6)
1. the method for synthetic (S)-metolachlor, it is characterized in that: the first step, utilize that (D)-methyl lactate or (D)-ethyl lactate is a starting raw material, in the presence of alkali, with Tosyl chloride-10 ℃～30 ℃ down reaction generate (R)-2-(tolysulfonyl oxygen base) propionic esters; Second step added 2-methyl-6-ethylaniline in (R)-2-(tolysulfonyl oxygen base) propionic ester, and added alkali, reacted 1～4 hour down at 110 ℃～160 ℃, obtained S-(-)-N-(2-methyl-6-ethylphenyl) alanine ester; In the 3rd step, S-(-)-N-(2-methyl-6-ethylphenyl) alanine ester and reductive agent reacted 1～24 hour down at-10 ℃～30 ℃, obtained S-(-)-N-(1 '-methyl-2 '-hydroxyethyl)-2-methyl-6-ethylaniline; The 4th step, in S-(-)-N-(1 '-methyl-2 '-hydroxyethyl)-2-methyl-6-ethylaniline, add acid binding agent alkali, and dropping chloroacetyl chloride, temperature is controlled at-15 ℃～30 ℃, reacted 1～24 hour, and obtained S-(-)-2-chloro-N-(2-methyl-6-ethylphenyl)-N-(2-hydroxyl-1-methylethyl) ethanamide; The 5th step, with S-(-)-2-chloro-N-(2-methyl-6-ethylphenyl)-N-(2-hydroxyl-1-methylethyl) ethanamide and methylating reagent under the effect of triethylamine, pyridine, sodium hydride, potassium hydride KH, sodium hydroxide, potassium hydroxide or salt of wormwood and phase-transfer catalyst, temperature is controlled at-15 ℃～110 ℃ reactions 1～24 hour, obtains (S)-metolachlor.
2. the method for synthetic (S)-metolachlor according to claim 1, it is characterized in that: each used amount ratio of second step reaction is (R)-2-(tolysulfonyl oxygen base) propionic ester: 2-methyl-6-ethylaniline is 1: 0.8～1.3, (R)-2-(tolysulfonyl oxygen base) propionic ester: alkali is 1: 0.9～1.5.
3. the method for synthetic (S)-metolachlor according to claim 1 is characterized in that: the first step, second step and used alkali of the 4th step are triethylamine, pyridine, salt of wormwood or yellow soda ash.
4. the method for synthetic (S)-metolachlor according to claim 1, it is characterized in that: the used reductive agent of three-step reaction is red aluminium, Lithium Aluminium Hydride, lithium borohydride, sodium borohydride-lithium chloride or POTASSIUM BOROHYDRIDE-lithium chloride.
5. the method for synthetic (S)-metolachlor according to claim 1, it is characterized in that: used each amount of three-step reaction is than S-(-)-N-(2-methyl-6-ethylphenyl) alanine ester: reductive agent is 1: 0.8～3, and the solvent that reacts used is methyl alcohol, ethanol, tetrahydrofuran (THF) or ether.
6. the method for synthetic (S)-metolachlor according to claim 1, it is characterized in that: the 5th step reaction methylating reagent can be trifluoromethanesulfonic acid methyl esters, methyl iodide, methyl-sulfate or diazomethane, used phase-transfer catalyst is tetrabutylammonium iodide, tetra-n-butyl ammonium bromide, benzyl triethyl ammonium bromide, benzyltriethylammoinium chloride or phenyl triethyl brometo de amonio, and the used solvent of methylation reaction is methylene dichloride, ethylene dichloride, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), sherwood oil, toluene or benzene.
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| CN104478756B (en) * | 2014-11-17 | 2016-01-06 | 合肥工业大学 | A kind of synthetic method of (S)-metolachlor |
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| CN108299221A (en) * | 2017-01-13 | 2018-07-20 | 中国科学院成都有机化学有限公司 | A kind of synthesis（S）Isopropyl methoxalamine（Jin Douer）And the like new method |
| CN108299249A (en) * | 2017-01-13 | 2018-07-20 | 中国科学院成都有机化学有限公司 | It is a kind of（S）Isopropyl methoxalamine（Jin Douer）The preparation method of key intermediate |
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