CN101948406B - Preparation method of pregabalin intermediate cyanodiester - Google Patents
Preparation method of pregabalin intermediate cyanodiester Download PDFInfo
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- CN101948406B CN101948406B CN2010101747019A CN201010174701A CN101948406B CN 101948406 B CN101948406 B CN 101948406B CN 2010101747019 A CN2010101747019 A CN 2010101747019A CN 201010174701 A CN201010174701 A CN 201010174701A CN 101948406 B CN101948406 B CN 101948406B
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Abstract
The invention relates to a preparation method of pregabalin intermediate cyanodiester, belonging to the technical field of medicine. The preparation method comprises the following steps: (1) reacting 3-methyl butyl aldehyde with sulfonyl chloride and alkali metal cyanide to obtain 4-methyl-2-sulfuryloxy butyl cyanide; (2) reacting the 4-methyl-2-sulfuryloxy butyl cyanide with alkali metal halide to obtain 2-halo-4-methyl butyl cyanide; (3) and reacting the 2-halo-4-methyl butyl cyanide with malonic ester in the presence of an alkaline reagent to obtain 2-(1-cyan-3-methyl butyl)malonic ester, namely the pregabalin intermediate cyanodiester. The preparation method of cyanodiester does not require special reaction equipment, reaction reagent and special reaction condition, and has the advantages of easy acquisition of required materials, easy processing of three wastes, convenient operation, moderate reaction condition, easy separation of product, high reaction yield, high product purity, less impurity and low cost, thereby being applicable to industrial production.
Description
Technical field
The present invention relates to a kind of preparation method who relates to medicine intermediate, particularly relate to the preparation method of a kind of lyrica midbody cyanogen diester (Cyanodiester), belong to medical technical field.
Background technology
(pregabalin PGB) is novel γ-An Jidingsuan (GABA) receptor stimulant by world drugmaker exploitation to lyrica, is a kind of analogue of neurotransmitter GABA, has fat-solublely, can pass through hemato encephalic barrier.In the neurotransmitter transmittance process; Increase with the release of calcium ion presynaptic; And neurotransmitter discharges increase, can reduce flow of calcium ions through suppressing a kind of subunit α 2-σ albumen of cns voltage-dependent ca channel; Thereby reduce the release of excitatory neurotransmitters such as glutaminate, sympathin, P material, thereby effectively control neuropathic pain.
Lyrica has advantages such as dosage is low, medicining times is few, spinoff is little, longer duration.Because have good anxiety, the treatment neurodynia and better to the epileptics result of treatment, administration is more convenient, is considered to a kind of medicine the most likely in the epilepsy therapy medicine, has good market outlook.
About the preparation of lyrica midbody cyanogen diester, following paper and patent report are arranged at present:
(1)Grote?TM，Huckabee?BK，Mulhern?T，Sobieray?DM，Titus?RD.Methodof?making?(S)-3-(aminomethyl)-5-methylhexanoic?acid.WO9640617，1996-12-19.
(2)Dhar?DS，Kumar?R，Rao?TT，Ambalal?DK.Preparation?of?crystallineform?of?pregabalin.WO2008062460，2008-05-29.
(3)Tou?JS，Schleppnik?AA.Method?of?producing?mono-subst?itutedterminal?diesters.US4428887，1984-01-31.
(4)Tou?JS，Schleppnik?AA.Novel?1，2-ester?transposition?reactions.J?Org?Chem，1983，48(5)：753-755.
WO9640617 and WO2008062460 report be that cyanogen diester preparing method's reaction formula is following:
Problems such as this method is to be raw material with 3-methyl butyraldehyde and ethyl malonate, through condensation, obtains with the prussiate addition again, and this method exists the condensation product productive rate low, and separation difficulty is difficult for purifying, and impurity is high, and yield is low.
US4428887 and J Org Chem, 1983,48 (5): 753-755 report be that cyanogen diester preparing method's reaction formula is following:
This method is to be raw material with 2-cyanic acid-2-isobutyl-diethyl succinate, in the presence of basic catalyst, resets to obtain, and this method exists raw material to be difficult for obtaining, and yield is low, problems such as cost height.
Summary of the invention
The object of the invention is exactly to existing in prior technology the problems referred to above, and a kind of new lyrica midbody cyanogen diester cyanogen diester preparation method with characteristics such as product operation is easy, reaction conditions is gentle, purity is high, cost is low, yield height is provided.
The technical solution that the present invention provides is: this lyrica midbody cyanogen diester cyanogen diester preparation method is characterized in that this method comprises the steps:
(1) the first step: equimolar SULPHURYL CHLORIDE and 3-methyl butyraldehyde are mixed in acetonitrile, and, under agitation condition, add the alkali metal cyanide aqueous solution with the mixture cooling; At room temperature continue then to stir; Reaction finishes the back and in mixture, adds entry, uses dichloromethane extraction, and organic layer spends the night with anhydrous sodium sulfate drying through the washing back; Boil off organic solvent behind the filtering siccative and obtain solid, with obtaining 4-methyl-2-sulfonyloxy valeronitrile behind the ethyl alcohol recrystallization;
(2) second steps: 4-methyl-2-sulfonyloxy valeronitrile and alkali metal chloride are blended in the anhydrous butanone; Heating under agitation; The cooling back adds entry to reaction mixture, uses dichloromethane extraction again, spends the night with anhydrous sodium sulfate drying; Boil off organic solvent behind the filtering siccative, underpressure distillation obtains 2-halo-4-methyl valeronitrile again.
(3) the 3rd steps: under nitrogen protection, slowly drip the tetrahydrofuran solution of malonic ester at ambient temperature in the tetrahydrofuran solution of alkalitropism reagent, constantly stirred reaction mixture; After 1 hour, in reaction mixture, drip the tetrahydrofuran solution of 2-halo-4-methyl valeronitrile, stirred overnight under nitrogen protection condition and room temperature; With the reaction mixture cooling, stop to feed nitrogen, add aqueous sodium carbonate; Use extracted with diethyl ether after the solution layering; Organic layer spends the night with anhydrous sodium sulfate drying through the washing back, boils off organic solvent behind the filtering siccative and obtains 2-(1-cyanic acid-3-methylbutyl) malonic ester weak yellow liquid, i.e. lyrica midbody.
Be better to realize the object of the invention, a kind of as in benzene sulfonyl chloride, Tosyl chloride, methylsulfonyl chloride or the ethyl sulfonyl chloride of the SULPHURYL CHLORIDE that uses in the 4-methyl of said step 1-2-sulfonyloxy valeronitrile reaction, alkali metal cyanide is sodium cyanide or Potssium Cyanide.
For better realizing the object of the invention; Temperature of reaction in the 4-methyl of said step 1-2-sulfonyloxy valeronitrile reaction is-20～20 ℃; In 0.5～24 hour reaction times, molar ratio is a 3-methyl butyraldehyde: SULPHURYL CHLORIDE: alkali metal cyanide=1: 0.1～5.0: 0.1～5.0.
Be better to realize the object of the invention, a kind of as in sodium-chlor, Repone K, Sodium Bromide, Potassium Bromide, Soiodin or the potassiumiodide of the alkali metal halide that uses in the 2-halo of said step 2-4-methyl valeronitrile reaction.
For better realizing the object of the invention; Temperature of reaction in the 2-halo of said step 2-4-methyl valeronitrile reaction is 20～100 ℃; In 0.5～24 hour reaction times, molar ratio is 4-methyl-2-sulfonyloxy valeronitrile: alkali metal halide=1: 0.1～5.0.
For better realizing the object of the invention; A kind of as in methyl-malonate, ethyl malonate, propanedioic acid methyl ethyl ester, dipropyl malonate, NSC 406716, TERT-BUTYL MALONATE or the propanedioic acid di tert butyl carbonate of the malonic ester that uses in the 2-of said step 3 (1-cyanic acid-3-methylbutyl) the malonic ester reaction, a kind of as in sodium hydride, potassium hydride KH, sodium methylate, sodium ethylate, potassium methylate, potassium ethylate, sodium tert-butoxide or the potassium tert.-butoxide of the alkaline reagents that uses in the reaction.
For better realizing the object of the invention, molar ratio is 2-halo-4-methyl valeronitrile in the reaction of the 2-of said step 3 (1-cyanic acid-3-methylbutyl) malonic ester: malonic ester=1: 0.1～5.0.
Compared with prior art, the invention has the beneficial effects as follows: the preparation method of cyanogen diester provided by the invention need not special reaction equipment, need not reaction reagent, need not the special reaction condition; Needed raw material is easy to get, and the three wastes are handled easily, and are easy and simple to handle, and reaction conditions is gentle, the product separate easily; Raw material is easy to get, and reaction yield is high, and product purity is high; Impurity is few, and cost is low, is suitable for suitability for industrialized production.
Embodiment
Below in conjunction with specific embodiment the present invention is described further, should be understood that following examples only are used to the present invention is described and are not used in the scope of the present invention that limits.
The preparation of embodiment 1:4-methyl-2-phenylsulfonyloxy valeronitrile
In 500 milliliters of three-necked bottles, add 88.3 gram (0.5 mole) benzene sulfonyl chlorides and 43.1 gram (0.5 mole) 3-methyl butyraldehyde and 200 milliliters of acetonitriles, place cryosel to bathe three-necked bottle and make the reaction flask mixture be cooled to-10 ℃, under violent stirring, drip 120 milliliters of aqueous solution that contain 36.8 gram (0.75 mole) sodium cyanides; Dropwised about 30 minutes, remove cryosel then and bathe, at room temperature continue to stir 1 hour; In mixture, add 100 ml waters; Use 100 milliliters of dichloromethane extractions three times again, merge organic layer, organic layer spends the night with anhydrous sodium sulfate drying through the washing back; Boil off organic solvent behind the filtering siccative and obtain solid; With obtaining 118 gram 4-methyl-2-phenylsulfonyloxy valeronitriles behind the ethyl alcohol recrystallization, reaction yield is 93.2%, and product detects through TLC and is single spot.
Similarly, Tosyl chloride, methylsulfonyl chloride or ethyl sulfonyl chloride are replaced benzene sulfonyl chloride, Potssium Cyanide is replaced sodium cyanide, change temperature of reaction, reaction times, reactant molar ratio, obtain 4-methyl-2-sulfonyloxy valeronitrile, the result converges and lists in table 1.
The preparation of table 1.4-methyl-2-sulfonyloxy valeronitrile
| Numbering | 3-methyl butyraldehyde consumption (mol) | SULPHURYL CHLORIDE and consumption thereof (mol) | Prussiate and consumption thereof (mol) | Temperature of reaction (℃) | 4-methyl-2-sulfonyloxy valeronitrile title | Productive rate (%) |
| 1 | 0.5 | Benzene sulfonyl chloride 0.5 | Sodium cyanide 0.75 | -10 | 4-methyl-2-phenylsulfonyloxy valeronitrile | 93.2 |
| 2 | 0.5 | Benzene sulfonyl chloride 0.5 | Potssium Cyanide 1.0 | -20 | 4-methyl-2-phenylsulfonyloxy valeronitrile | 91.4 |
| 3 | 0.5 | Benzene sulfonyl chloride 0.5 | Potssium Cyanide 0.5 | 15 | 4-methyl-2-phenylsulfonyloxy valeronitrile | 92.5 |
| 4 | 0.5 | Benzene sulfonyl chloride 0.5 | Sodium cyanide 0.5 | 20 | 4-methyl-2-phenylsulfonyloxy valeronitrile | 92.8 |
| 5 | 0.5 | Benzene sulfonyl chloride 0.5 | Sodium cyanide 0.5 | -10 | 4-methyl-2-phenylsulfonyloxy valeronitrile | 91.6 |
| 6 | 0.5 | Benzene sulfonyl chloride 0.5 | Sodium cyanide | 10 | 4-methyl-2-benzene sulfonyl | 90.3 |
| 1.0 | Oxygen base valeronitrile | |||||
| 7 | 0.5 | Benzene sulfonyl chloride 1.0 | Sodium cyanide 0.75 | -15 | 4-methyl-2-phenylsulfonyloxy valeronitrile | 91.6 |
| 8 | 0.5 | Benzene sulfonyl chloride 0.5 | Potssium Cyanide 1.0 | 5 | 4-methyl-2-phenylsulfonyloxy valeronitrile | 92.8 |
| 9 | 0.5 | Benzene sulfonyl chloride 0.5 | Potssium Cyanide 0.75 | 10 | 4-methyl-2-phenylsulfonyloxy valeronitrile | 92.6 |
| 10 | 0.5 | Benzene sulfonyl chloride 0.5 | Potssium Cyanide 0.75 | 20 | 4-methyl-2-phenylsulfonyloxy valeronitrile | 93.0 |
| 11 | 0.5 | Benzene sulfonyl chloride 0.5 | Sodium cyanide 0.75 | -18 | 4-methyl-2-phenylsulfonyloxy valeronitrile | 90.3 |
| 12 | 0.5 | Benzene sulfonyl chloride 0.5 | Sodium cyanide 1.0 | -10 | 4-methyl-2-phenylsulfonyloxy valeronitrile | 91.6 |
| 13 | 0.5 | Benzene sulfonyl chloride 0.5 | Potssium Cyanide 0.5 | -20 | 4-methyl-2-phenylsulfonyloxy valeronitrile | 90.4 |
| 14 | 0.5 | Benzene sulfonyl chloride 0.25 | Sodium cyanide 0.75 | 10 | 4-methyl-2-phenylsulfonyloxy valeronitrile | 92.0 |
| 15 | 0.5 | Benzene sulfonyl chloride 0.5 | Potssium Cyanide 0.75 | -5 | 4-methyl-2-phenylsulfonyloxy valeronitrile | 92.2 |
| 16 | 0.5 | Benzene sulfonyl chloride 0.5 | Sodium cyanide 0.8 | 10 | 4-methyl-2-phenylsulfonyloxy valeronitrile | 92.6 |
| 17 | 0.5 | Benzene sulfonyl chloride 0.5 | Potssium Cyanide | -10 | 4-methyl-2-benzene sulfonyl | 92.3 |
| 0.25 | Oxygen base valeronitrile | |||||
| 18 | 0.5 | Benzene sulfonyl chloride 0.15 | Sodium cyanide 0.5 | 15 | 4-methyl-2-phenylsulfonyloxy valeronitrile | 91.1 |
| 19 | 0.5 | Benzene sulfonyl chloride 1.0 | Potssium Cyanide 0.3 | -10 | 4-methyl-2-phenylsulfonyloxy valeronitrile | 92.6 |
| 20 | 0.5 | Benzene sulfonyl chloride 0.5 | Sodium cyanide 1.0 | 20 | 4-methyl-2-phenylsulfonyloxy valeronitrile | 91.7 |
| 21 | 0.5 | Benzene sulfonyl chloride 0.5 | Sodium cyanide 0.5 | 5 | 4-methyl-2-phenylsulfonyloxy valeronitrile | 92.2 |
| 22 | 0.5 | Benzene sulfonyl chloride 0.5 | Potssium Cyanide 0.4 | 0 | 4-methyl-2-phenylsulfonyloxy valeronitrile | 93.0 |
| 23 | 0.5 | Tosyl chloride 0.5 | Sodium cyanide 0.75 | 0 | 4-methyl-2-tolysulfonyl oxygen base valeronitrile | 92.7 |
| 24 | 0.5 | Tosyl chloride 0.5 | Potssium Cyanide 0.75 | -15 | 4-methyl-2-tolysulfonyl oxygen base valeronitrile | 91.2 |
| 25 | 0.5 | Tosyl chloride 0.35 | Sodium cyanide 0.75 | 0 | 4-methyl-2-tolysulfonyl oxygen base valeronitrile | 91.9 |
| 26 | 0.5 | Tosyl chloride 0.5 | Sodium cyanide 0.75 | -20 | 4-methyl-2-tolysulfonyl oxygen base valeronitrile | 91.5 |
| 27 | 0.5 | Tosyl chloride 0.05 | Potssium Cyanide 0.75 | -10 | 4-methyl-2-tolysulfonyl oxygen base valeronitrile | 92.8 |
| 28 | 0.5 | Tosyl chloride | Potssium Cyanide | 20 | 4-methyl-2-is to toluene | 90.7 |
| 0.05 | 0.75 | The sulfonyloxy valeronitrile | ||||
| 29 | 0.5 | Tosyl chloride 1.0 | Potssium Cyanide 0.75 | -20 | 4-methyl-2-tolysulfonyl oxygen base valeronitrile | 92.0 |
| 30 | 0.5 | Tosyl chloride 0.5 | Sodium cyanide 1.0 | -10 | 4-methyl-2-tolysulfonyl oxygen base valeronitrile | 91.6 |
| 31 | 0.5 | Tosyl chloride 0.2 | Sodium cyanide 0.5 | -15 | 4-methyl-2-tolysulfonyl oxygen base valeronitrile | 92.1 |
| 32 | 0.5 | Tosyl chloride 0.3 | Sodium cyanide 0.75 | 10 | 4-methyl-2-tolysulfonyl oxygen base valeronitrile | 91.3 |
| 33 | 0.5 | Tosyl chloride 0.4 | Sodium cyanide 1.0 | 0 | 4-methyl-2-tolysulfonyl oxygen base valeronitrile | 91.8 |
| 34 | 0.5 | Tosyl chloride 0.5 | Potssium Cyanide 0.5 | -10 | 4-methyl-2-tolysulfonyl oxygen base valeronitrile | 92.5 |
| 35 | 0.5 | Tosyl chloride 0.5 | Sodium cyanide 0.75 | 5 | 4-methyl-2-tolysulfonyl oxygen base valeronitrile | 92.6 |
| 36 | 0.5 | Tosyl chloride 1.0 | Sodium cyanide 0.75 | -10 | 4-methyl-2-tolysulfonyl oxygen base valeronitrile | 93.0 |
| 37 | 0.5 | Tosyl chloride 0.25 | Sodium cyanide 0.75 | -10 | 4-methyl-2-tolysulfonyl oxygen base valeronitrile | 92.5 |
| 38 | 0.5 | Tosyl chloride 0.3 | Potssium Cyanide 0.5 | 0 | 4-methyl-2-tolysulfonyl oxygen base valeronitrile | 92.1 |
| 39 | 0.5 | Tosyl chloride | Potssium Cyanide | 20 | 4-methyl-2-is to toluene | 90.0 |
| 0.4 | 0.6 | The sulfonyloxy valeronitrile | ||||
| 40 | 0.5 | Tosyl chloride 0.05 | Potssium Cyanide 0.05 | -10 | 4-methyl-2-tolysulfonyl oxygen base valeronitrile | 92.7 |
| 41 | 0.5 | Tosyl chloride 0.6 | Sodium cyanide 0.75 | -10 | 4-methyl-2-tolysulfonyl oxygen base valeronitrile | 92.6 |
| 42 | 0.5 | Methylsulfonyl chloride 0.4 | Potssium Cyanide 0.8 | 18 | 4-methyl-2-mesyloxy valeronitrile | 88.5 |
| 43 | 0.5 | Methylsulfonyl chloride 0.5 | Sodium cyanide 0.75 | -10 | 4-methyl-2-mesyloxy valeronitrile | 91.0 |
| 44 | 0.5 | Methylsulfonyl chloride 0.15 | Sodium cyanide 0.5 | -10 | 4-methyl-2-mesyloxy valeronitrile | 90.5 |
| 45 | 0.5 | Methylsulfonyl chloride 0.5 | Potssium Cyanide 0.75 | -10 | 4-methyl-2-mesyloxy valeronitrile | 90.5 |
| 46 | 0.5 | Methylsulfonyl chloride 0.2 | Potssium Cyanide 0.5 | -10 | 4-methyl-2-mesyloxy valeronitrile | 90.2 |
| 47 | 0.5 | Methylsulfonyl chloride 0.25 | Sodium cyanide 0.75 | -5 | 4-methyl-2-mesyloxy valeronitrile | 89.7 |
| 48 | 0.5 | Methylsulfonyl chloride 0.25 | Sodium cyanide 0.25 | 20 | 4-methyl-2-mesyloxy valeronitrile | 88.3 |
| 49 | 0.5 | Methylsulfonyl chloride 0.25 | Sodium cyanide 1.0 | -20 | 4-methyl-2-mesyloxy valeronitrile | 88.1 |
| 50 | 0.5 | Methylsulfonyl chloride 0.5 | Sodium cyanide | 5 | 4-methyl-2-methylsulfonyl | 89.1 |
| 0.75 | Oxygen base valeronitrile | |||||
| 51 | 0.5 | Methylsulfonyl chloride 0.5 | Sodium cyanide 0.75 | -15 | 4-methyl-2-mesyloxy valeronitrile | 90.0 |
| 52 | 0.5 | Methylsulfonyl chloride 0.6 | Potssium Cyanide 0.8 | -10 | 4-methyl-2-mesyloxy valeronitrile | 89.4 |
| 53 | 0.5 | Methylsulfonyl chloride 0.45 | Sodium cyanide 0.75 | -15 | 4-methyl-2-mesyloxy valeronitrile | 89.2 |
| 54 | 0.5 | Methylsulfonyl chloride 0.5 | Sodium cyanide 0.75 | -20 | 4-methyl-2-mesyloxy valeronitrile | 88.7 |
| 55 | 0.5 | Methylsulfonyl chloride 0.4 | Potssium Cyanide 0.4 | -10 | 4-methyl-2-mesyloxy valeronitrile | 89.3 |
| 56 | 0.5 | Methylsulfonyl chloride 0.35 | Sodium cyanide 0.75 | -10 | 4-methyl-2-mesyloxy valeronitrile | 90.2 |
| 57 | 0.5 | Methylsulfonyl chloride 0.4 | Potssium Cyanide 0.4 | 12 | 4-methyl-2-mesyloxy valeronitrile | 88.6 |
| 58 | 0.5 | Methylsulfonyl chloride 0.4 | Potssium Cyanide 0.7 | 5 | 4-methyl-2-mesyloxy valeronitrile | 88.2 |
| 59 | 0.5 | Methylsulfonyl chloride 0.25 | Sodium cyanide 0.7 | -15 | 4-methyl-2-mesyloxy valeronitrile | 89.4 |
| 60 | 0.5 | Ethyl sulfonyl chloride 0.5 | Sodium cyanide 0.5 | 0 | 4-methyl-2-ethanesulfonyloxy group valeronitrile | 87.6 |
| 61 | 0.5 | Ethyl sulfonyl chloride 0.5 | Sodium cyanide | -10 | 4-methyl-2-second sulphonyl | 89.7 |
| 0.75 | Oxygen base valeronitrile | |||||
| 62 | 0.5 | Ethyl sulfonyl chloride 0.25 | Sodium cyanide 0.75 | 10 | 4-methyl-2-ethanesulfonyloxy group valeronitrile | 87.5 |
| 63 | 0.5 | Ethyl sulfonyl chloride 0.25 | Potssium Cyanide 0.4 | -10 | 4-methyl-2-ethanesulfonyloxy group valeronitrile | 89.1 |
| 64 | 0.5 | Ethyl sulfonyl chloride 0.5 | Sodium cyanide 0.75 | -10 | 4-methyl-2-ethanesulfonyloxy group valeronitrile | 89.7 |
| 65 | 0.5 | Ethyl sulfonyl chloride 0.75 | Potssium Cyanide 0.75 | -12 | 4-methyl-2-ethanesulfonyloxy group valeronitrile | 88.6 |
| 66 | 0.5 | Ethyl sulfonyl chloride 0.6 | Potssium Cyanide 0.4 | -10 | 4-methyl-2-ethanesulfonyloxy group valeronitrile | 89.2 |
| 67 | 0.5 | Ethyl sulfonyl chloride 0.05 | Sodium cyanide 0.05 | 0 | 4-methyl-2-ethanesulfonyloxy group valeronitrile | 89.4 |
| 68 | 0.5 | Ethyl sulfonyl chloride 0.25 | Potssium Cyanide 0.75 | 20 | 4-methyl-2-ethanesulfonyloxy group valeronitrile | 88.5 |
| 69 | 0.5 | Ethyl sulfonyl chloride 0.2 | Potssium Cyanide 0.2 | 10 | 4-methyl-2-ethanesulfonyloxy group valeronitrile | 88.3 |
| 70 | 0.5 | Ethyl sulfonyl chloride 0.05 | Sodium cyanide 0.05 | -20 | 4-methyl-2-ethanesulfonyloxy group valeronitrile | 88.7 |
| 71 | 0.5 | Ethyl sulfonyl chloride 0.5 | Potssium Cyanide 0.75 | 5 | 4-methyl-2-ethanesulfonyloxy group valeronitrile | 88.7 |
| 72 | 0.5 | Ethyl sulfonyl chloride 2.5 | Potssium Cyanide | -10 | 4-methyl-2-second sulphonyl | 89.3 |
| 2.5 | Oxygen base valeronitrile | |||||
| 73 | 0.5 | Ethyl sulfonyl chloride 0.5 | Sodium cyanide 0.6 | -10 | 4-methyl-2-ethanesulfonyloxy group valeronitrile | 89.3 |
| 74 | 0.5 | Ethyl sulfonyl chloride 0.5 | Sodium cyanide 0.8 | -15 | 4-methyl-2-ethanesulfonyloxy group valeronitrile | 88.7 |
The preparation of embodiment 2:2-bromo-4-methyl valeronitrile
In 500 milliliters of three-necked bottles, add 200 milliliters of anhydrous butanone; 126.7 gram (0.5 mole) 4-methyl-2-phenylsulfonyloxy valeronitrile and 59.5 gram (0.5 mole) Potassium Bromides, reflux 4 hours under agitation then, the cooling back adds 200 ml waters; Use 100 milliliters of dichloromethane extractions three times again; Merge organic layer, spend the night, boil off organic solvent behind the filtering siccative with anhydrous sodium sulfate drying; Underpressure distillation obtains 76.5 gram 2-bromo-4-methyl valeronitriles again; Reaction yield is 86.9%, and boiling point is 80-83 ℃/25mmHg,
Similarly, sodium-chlor, Repone K, Sodium Bromide, Soiodin or potassiumiodide are replaced Potassium Bromide, change temperature of reaction, reaction times, reactant molar ratio, obtain 2-halo-4-methyl valeronitrile, the result converges and lists in table 2.
The preparation of table 2.2-halo-4-methyl valeronitrile
| Numbering | 4-methyl-2-sulfonyloxy valeronitrile and consumption (mol) thereof | Halogenide and consumption thereof (mol) | Temperature of reaction (℃) | Reaction times (hour) | 2-halo-4-methyl valeronitrile title | Productive rate (%) |
| 1 | 4-methyl-2-benzene sulfonyl | Potassium Bromide 0.5 | Reflux | 4 | 2-bromo-4- | 86.9 |
| Oxygen base valeronitrile 0.5 | The methyl valeronitrile | |||||
| 2 | 4-methyl-2-phenylsulfonyloxy valeronitrile 0.5 | Potassiumiodide 0.75 | Reflux | 1 | 2-iodo-4-methyl valeronitrile | 82.3 |
| 3 | 4-methyl-2-phenylsulfonyloxy valeronitrile 0.5 | Sodium-chlor 1.0 | Reflux | 10 | 2-chloro-4-methyl valeronitrile | 87.6 |
| 4 | 4-methyl-2-phenylsulfonyloxy valeronitrile 0.2 | Sodium-chlor 1.0 | Reflux | 24 | 2-chloro-4-methyl valeronitrile | 90.6 |
| 5 | 4-methyl-2-phenylsulfonyloxy valeronitrile 0.25 | Sodium Bromide 0.75 | Reflux | 15 | 2-bromo-4-methyl valeronitrile | 87.1 |
| 6 | 4-methyl-2-phenylsulfonyloxy valeronitrile 0.5 | Repone K 1.0 | Reflux | 20 | 2-chloro-4-methyl valeronitrile | 87.2 |
| 7 | 4-methyl-2-phenylsulfonyloxy valeronitrile 0.5 | Sodium-chlor 0.5 | Reflux | 10 | 2-chloro-4-methyl valeronitrile | 86.4 |
| 8 | 4-methyl-2-phenylsulfonyloxy valeronitrile 0.5 | Soiodin 0.5 | 80 | 0.5 | 2-iodo-4-methyl valeronitrile | 86.0 |
| 9 | 4-methyl-2-phenylsulfonyloxy valeronitrile 0.5 | Sodium-chlor 0.5 | Reflux | 6 | 2-chloro-4-methyl valeronitrile | 85.9 |
| 10 | 4-methyl-2-phenylsulfonyloxy valeronitrile 0.5 | Potassiumiodide 0.5 | Reflux | 1 | 2-iodo-4-methyl valeronitrile | 85.3 |
| 11 | 4-methyl-2-phenylsulfonyloxy valeronitrile 0.5 | Sodium-chlor 0.5 | Reflux | 3 | 2-chloro-4-methyl valeronitrile | 86.4 |
| 12 | 4-methyl-2-benzene sulfonyl | Soiodin 0.5 | Reflux | 4 | 2-bromo-4- | 86.0 |
| Oxygen base valeronitrile 0.5 | The methyl valeronitrile | |||||
| 13 | 4-methyl-2-phenylsulfonyloxy valeronitrile 0.5 | Soiodin 0.5 | Reflux | 10 | 2-iodo-4-methyl valeronitrile | 85.9 |
| 14 | 4-methyl-2-phenylsulfonyloxy valeronitrile 0.5 | Sodium Bromide 0.5 | 40 | 24 | 2-bromo-4-methyl valeronitrile | 86.3 |
| 15 | 4-methyl-2-phenylsulfonyloxy valeronitrile 0.5 | Sodium-chlor 0.5 | Reflux | 4 | 2-chloro-4-methyl valeronitrile | 86.3 |
| 16 | 4-methyl-2-phenylsulfonyloxy valeronitrile 0.5 | Sodium Bromide 0.5 | Reflux | 20 | 2-bromo-4-methyl valeronitrile | 85.9 |
| 17 | 4-methyl-2-phenylsulfonyloxy valeronitrile 0.5 | Sodium-chlor 1.0 | 80 | 1 | 2-chloro-4-methyl valeronitrile | 85.4 |
| 18 | 4-methyl-2-phenylsulfonyloxy valeronitrile 0.5 | Soiodin 0.5 | Reflux | 7 | 2-iodo-4-methyl valeronitrile | 85.9 |
| 19 | 4-methyl-2-phenylsulfonyloxy valeronitrile 0.5 | Sodium Bromide 0.5 | 50 | 12 | 2-bromo-4-methyl valeronitrile | 86.4 |
| 20 | 4-methyl-2-phenylsulfonyloxy valeronitrile 0.5 | Potassium Bromide 0.5 | Reflux | 7.5 | 2-bromo-4-methyl valeronitrile | 86.9 |
| 21 | 4-methyl-2-phenylsulfonyloxy valeronitrile 0.5 | Potassium Bromide 0.5 | Reflux | 4 | 2-bromo-4-methyl valeronitrile | 86.1 |
| 22 | 4-methyl-2-phenylsulfonyloxy valeronitrile 0.2 | Sodium-chlor 0.15 | Reflux | 1 | 2-chloro-4-methyl valeronitrile | 85.4 |
| 23 | 4-methyl-2-is to toluene | Potassiumiodide | 50 | 4 | 2-iodo-4- | 86.7 |
| Sulfonyloxy valeronitrile 0.5 | 0.05 | The methyl valeronitrile | ||||
| 24 | 4-methyl-2-tolysulfonyl oxygen base valeronitrile 0.5 | Sodium-chlor 0.7 | Reflux | 9 | 2-chloro-4-methyl valeronitrile | 85.7 |
| 25 | 4-methyl-2-tolysulfonyl oxygen base valeronitrile 0.5 | Soiodin 0.5 | Reflux | 4 | 2-iodo-4-methyl valeronitrile | 86.6 |
| 26 | 4-methyl-2-tolysulfonyl oxygen base valeronitrile 0.5 | Potassium Bromide 0.5 | Reflux | 6 | 2-bromo-4-methyl valeronitrile | 86.1 |
| 27 | 4-methyl-2-tolysulfonyl oxygen base valeronitrile 0.5 | Repone K 0.5 | 25 | 5 | 2-chloro-4-methyl valeronitrile | 86.1 |
| 28 | 4-methyl-2-tolysulfonyl oxygen base valeronitrile 0.5 | Potassiumiodide 0.5 | 60 | 2 | 2-iodo-4-methyl valeronitrile | 85.7 |
| 29 | 4-methyl-2-tolysulfonyl oxygen base valeronitrile 0.5 | Potassium Bromide 0.05 | Reflux | 7 | 2-bromo-4-methyl valeronitrile | 87.2 |
| 30 | 4-methyl-2-tolysulfonyl oxygen base valeronitrile 0.5 | Sodium Bromide 0.5 | Reflux | 4 | 2-bromo-4-methyl valeronitrile | 86.0 |
| 31 | 4-methyl-2-tolysulfonyl oxygen base valeronitrile 0.5 | Potassium Bromide 0.5 | Reflux | 1.5 | 2-bromo-4-methyl valeronitrile | 86.2 |
| 32 | 4-methyl-2-tolysulfonyl oxygen base valeronitrile 0.1 | Potassiumiodide 0.5 | Reflux | 4 | 2-iodo-4-methyl valeronitrile | 86.4 |
| 33 | 4-methyl-2-tolysulfonyl oxygen base valeronitrile 0.5 | Sodium Bromide 0.3 | Reflux | 4 | 2-bromo-4-methyl valeronitrile | 86.5 |
| 34 | 4-methyl-2-is to toluene | Potassium Bromide 0.6 | 80 | 9 | 2-bromo-4- | 86.2 |
| Sulfonyloxy valeronitrile 0.5 | The methyl valeronitrile | |||||
| 35 | 4-methyl-2-tolysulfonyl oxygen base valeronitrile 0.5 | Sodium Bromide 0.4 | Reflux | 17 | 2-bromo-4-methyl valeronitrile | 85.8 |
| 36 | 4-methyl-2-tolysulfonyl oxygen base valeronitrile 0.1 | Soiodin 0.4 | Reflux | 8 | 2-iodo-4-methyl valeronitrile | 86.3 |
| 37 | 4-methyl-2-tolysulfonyl oxygen base valeronitrile 0.5 | Repone K 0.4 | Reflux | 15 | 2-chloro-4-methyl valeronitrile | 85.0 |
| 38 | 4-methyl-2-tolysulfonyl oxygen base valeronitrile 0.1 | Sodium-chlor 0.75 | 30 | 4 | 2-chloro-4-methyl valeronitrile | 86.4 |
| 39 | 4-methyl-2-tolysulfonyl oxygen base valeronitrile 0.5 | Sodium-chlor 0.4 | Reflux | 5.5 | 2-chloro-4-methyl valeronitrile | 83.0 |
| 40 | 4-methyl-2-tolysulfonyl oxygen base valeronitrile 0.5 | Potassium Bromide 0.3 | 50 | 3.5 | 2-bromo-4-methyl valeronitrile | 85.9 |
| 41 | 4-methyl-2-mesyloxy valeronitrile 0.5 | Repone K 0.5 | Reflux | 24 | 2-chloro-4-methyl valeronitrile | 82.9 |
| 42 | 4-methyl-2-mesyloxy valeronitrile 0.5 | Potassium Bromide 0.5 | Reflux | 20 | 2-bromo-4-methyl valeronitrile | 82.5 |
| 43 | 4-methyl-2-mesyloxy valeronitrile 0.7 | Potassium Bromide 0.5 | Reflux | 4 | 2-bromo-4-methyl valeronitrile | 82.6 |
| 44 | 4-methyl-2-mesyloxy valeronitrile 0.3 | Repone K 0.5 | Reflux | 16 | 2-chloro-4-methyl valeronitrile | 82.6 |
| 45 | 4-methyl-2-methylsulfonyl | Sodium-chlor 0.5 | Reflux | 4 | 2-chloro-4- | 83.2 |
| Oxygen base valeronitrile 0.5 | The methyl valeronitrile | |||||
| 46 | 4-methyl-2-mesyloxy valeronitrile 0.1 | Repone K 0.5 | Reflux | 4 | 2-chloro-4-methyl valeronitrile | 82.8 |
| 47 | 4-methyl-2-mesyloxy valeronitrile 0.5 | Potassiumiodide 0.05 | Reflux | 2 | 2-iodo-4-methyl valeronitrile | 82.1 |
| 48 | 4-methyl-2-mesyloxy valeronitrile 0.1 | Sodium-chlor 0.6 | Reflux | 18 | 2-chloro-4-methyl valeronitrile | 81.9 |
| 49 | 4-methyl-2-mesyloxy valeronitrile 0.5 | Repone K 0.5 | Reflux | 1.5 | 2-chloro-4-methyl valeronitrile | 80.9 |
| 50 | 4-methyl-2-mesyloxy valeronitrile 0.5 | Sodium Bromide 0.5 | Reflux | 7 | 2-bromo-4-methyl valeronitrile | 83.0 |
| 51 | 4-methyl-2-mesyloxy valeronitrile 0.4 | Sodium Bromide 0.3 | Reflux | 5 | 2-bromo-4-methyl valeronitrile | 82.8 |
| 52 | 4-methyl-2-mesyloxy valeronitrile 0.5 | Potassiumiodide 0.15 | 50 | 9 | 2-iodo-4-methyl valeronitrile | 80.9 |
| 53 | 4-methyl-2-ethanesulfonyloxy group valeronitrile 0.5 | Potassiumiodide 0.05 | Reflux | 6 | 2-iodo-4-methyl valeronitrile | 80.4 |
| 54 | 4-methyl-2-mesyloxy valeronitrile 0.1 | Sodium-chlor 0.6 | 45 | 18 | 2-chloro-4-methyl valeronitrile | 79.9 |
| 55 | 4-methyl-2-mesyloxy valeronitrile 0.5 | Soiodin 0.35 | 35 | 4.5 | 2-iodo-4-methyl valeronitrile | 78.6 |
| 56 | 4-methyl-2-methylsulfonyl | Potassiumiodide | Reflux | 9 | 2-iodo-4- | 82.9 |
| Oxygen base valeronitrile 0.5 | 0.15 | The methyl valeronitrile | ||||
| 57 | 4-methyl-2-mesyloxy valeronitrile 0.3 | Sodium Bromide 1.0 | Reflux | 5 | 2-bromo-4-methyl valeronitrile | 83.8 |
| 58 | 4-methyl-2-mesyloxy valeronitrile 0.3 | Potassium Bromide 0.7 | Reflux | 3.5 | 2-bromo-4-methyl valeronitrile | 82.8 |
| 59 | 4-methyl-2-mesyloxy valeronitrile 0.5 | Soiodin 0.35 | Reflux | 8.5 | 2-iodo-4-methyl valeronitrile | 82.6 |
| 60 | 4-methyl-2-ethanesulfonyloxy group valeronitrile 0.5 | Soiodin 0.35 | 60 | 4 | 2-iodo-4-methyl valeronitrile | 79.8 |
| 61 | 4-methyl-2-ethanesulfonyloxy group valeronitrile 0.5 | Potassium Bromide 0.5 | Reflux | 8 | 2-bromo-4-methyl valeronitrile | 81.7 |
| 62 | 4-methyl-2-ethanesulfonyloxy group valeronitrile 0.3 | Potassiumiodide 0.5 | Reflux | 4 | 2-iodo-4-methyl valeronitrile | 79.6 |
| 63 | 4-methyl-2-ethanesulfonyloxy group valeronitrile 0.5 | Sodium Bromide 0.5 | Reflux | 4 | 2-bromo-4-methyl valeronitrile | 80.2 |
| 64 | 4-methyl-2-ethanesulfonyloxy group valeronitrile 0.5 | Potassium Bromide 0.5 | Reflux | 4 | 2-bromo-4-methyl valeronitrile | 80.7 |
| 65 | 4-methyl-2-ethanesulfonyloxy group valeronitrile 0.5 | Potassiumiodide 0.5 | 80 | 4 | 2-iodo-4-methyl valeronitrile | 80.8 |
| 66 | 4-methyl-2-ethanesulfonyloxy group valeronitrile 0.5 | Repone K 0.2 | Reflux | 10 | 2-chloro-4-methyl valeronitrile | 80.2 |
| 67 | 4-methyl-2-second sulphonyl | Sodium-chlor 1.0 | Reflux | 24 | 2-chloro-4- | 81.0 |
| Oxygen base valeronitrile 0.5 | The methyl valeronitrile | |||||
| 68 | 4-methyl-2-ethanesulfonyloxy group valeronitrile 0.25 | Sodium Bromide 0.5 | Reflux | 24 | 2-bromo-4-methyl valeronitrile | 80.2 |
| 69 | 4-methyl-2-ethanesulfonyloxy group valeronitrile 0.5 | Sodium-chlor 1.0 | Reflux | 0.5 | 2-chloro-4-methyl valeronitrile | 79.7 |
| 70 | 4-methyl-2-ethanesulfonyloxy group valeronitrile 0.5 | Potassium Bromide 0.5 | Reflux | 4 | 2-bromo-4-methyl valeronitrile | 80.7 |
| 71 | 4-methyl-2-ethanesulfonyloxy group valeronitrile 0.5 | Sodium Bromide 0.2 | Reflux | 8 | 2-bromo-4-methyl valeronitrile | 81.5 |
| 72 | 4-methyl-2-ethanesulfonyloxy group valeronitrile 0.25 | Soiodin 0.75 | Reflux | 15 | 2-iodo-4-methyl valeronitrile | 80.9 |
| 73 | 4-methyl-2-ethanesulfonyloxy group valeronitrile 0.5 | Potassium Bromide 0.5 | Reflux | 4 | 2-bromo-4-methyl valeronitrile | 80.7 |
| 74 | 4-methyl-2-ethanesulfonyloxy group valeronitrile 0.1 | Sodium-chlor 0.5 | Reflux | 4.5 | 2-chloro-4-methyl valeronitrile | 81.2 |
The boiling point and refractive index
data of the 2-halo-4-methyl valeronitrile that obtains are following:
2-chloro-4-methyl valeronitrile: 65-68 ℃/15mmHg,
2-bromo-4-methyl valeronitrile:
80-83 ℃/25mmHg,
2-iodo-4-methyl valeronitrile: 72-75 ℃/13mmHg.
The preparation of embodiment 3:2-(1-cyanic acid-3-methylbutyl) ethyl malonate
Under nitrogen protection, in 500 milliliters of three-necked bottles, in the tetrahydrofuran solution of 12.0 gram (0.5 mole) sodium hydrides, slowly drip the tetrahydrofuran solution of 80.0 gram (0.5 mole) ethyl malonates at ambient temperature, constantly stirred reaction mixture; After about 1 hour, in reaction mixture, drip the tetrahydrofuran solution of 88.0 gram (0.5 mole) 2-bromo-4-methyl valeronitriles, stirred overnight under nitrogen protection condition and room temperature; Reaction mixture is cooled to 0 ℃; Stop to feed nitrogen, add aqueous sodium carbonate, use extracted with diethyl ether after the solution layering; Organic layer spends the night with anhydrous sodium sulfate drying through the washing back; Boil off organic solvent behind the filtering siccative and obtain 115 gram 2-(1-cyanic acid-3-methylbutyl) ethyl malonate weak yellow liquids, reaction yield is 90.0%, is 98.5% through its purity of gas chromatographic detection.
1H-NMR(CDCl
3，300MHz)，δ：0.98(t，J＝6.0Hz，6H)，1.15～1.21(m，6H)，1.25～1.34(m，1H)，1.54～1.66(m，2H)，3.22～3.34(m，1H)，3.98(d，J＝6.5Hz，1H)，4.10～4.25(q，4H)。
Similarly; Methyl-malonate, propanedioic acid methyl ethyl ester, dipropyl malonate, NSC 406716, TERT-BUTYL MALONATE or propanedioic acid di tert butyl carbonate are replaced ethyl malonate; Potassium hydride KH, sodium methylate, sodium ethylate, potassium methylate, potassium ethylate, sodium tert-butoxide or potassium tert.-butoxide are replaced sodium hydride; Change the reactant molar ratio, obtain 2-(1-cyanic acid-3-methylbutyl) malonic ester, the result converges and lists in table 3.
The preparation of table 3.2-(1-cyanic acid-3-methylbutyl) malonic ester
| Numbering | 2-halo-4-methyl valeronitrile and consumption (mol) thereof | Alkaline reagents and consumption thereof (mol) | 2-(1-cyanic acid-3-methylbutyl) malonic ester title | Purity | Productive rate (%) |
| 1 | 2-bromo-4-methyl valeronitrile 0.5 | Sodium cyanide 0.5 | 2-(1-cyanic acid-3-methylbutyl) ethyl malonate | 98.5 | 90.0 |
| 2 | 2-iodo-4-methyl valeronitrile 0.5 | Sodium cyanide 0.5 | 2-(1-cyanic acid-3-methylbutyl) methyl-malonate | 98.4 | 88.4 |
| 3 | 2-chloro-4-methyl valeronitrile 0.1 | Sodium tert-butoxide 0.5 | 2-(1-cyanic acid-3-methylbutyl) methyl-malonate | 98.7 | 90.6 |
| 4 | 2-chloro-4-methyl valeronitrile 1.0 | Sodium methylate 0.5 | 2-(1-cyanic acid-3-methylbutyl) methyl-malonate | 98.4 | 92.8 |
| 5 | 2-bromo-4-methyl valeronitrile 0.5 | Sodium ethylate 0.5 | 2-(1-cyanic acid-3-methylbutyl) ethyl malonate | 98.8 | 91.0 |
| 6 | 2-chloro-4-methyl valeronitrile 1.0 | Sodium tert-butoxide 0.5 | 2-(1-cyanic acid-3-methylbutyl) dipropyl malonate | 98.4 | 89.6 |
| 7 | 2-chloro-4-methyl valeronitrile 0.5 | Potassium ethylate 0.25 | 2-(1-cyanic acid-3-methylbutyl) dipropyl malonate | 98.3 | 88.7 |
| 8 | 2-chloro-4-methyl valeronitrile 0.5 | Potassium hydride KH 0.5 | 2-(1-cyanic acid-3-methylbutyl) dipropyl malonate | 99.2 | 89.8 |
| 9 | 2-chloro-4-methyl valeronitrile 0.75 | Sodium methylate 0.5 | 2-(1-cyanic acid-3-methylbutyl) dipropyl malonate | 98.4 | 89.7 |
| 10 | 2-iodo-4-methyl valeronitrile 0.25 | Potassium methylate 0.5 | 2-(1-cyanic acid-3-methylbutyl) TERT-BUTYL MALONATE | 98.5 | 89.3 |
| 11 | 2-chloro-4-methyl valeronitrile 0.5 | Potassium tert.-butoxide 0.25 | 2-(1-cyanic acid-3-methylbutyl) TERT-BUTYL MALONATE | 98.2 | 88.6 |
| 12 | 2-bromo-4-methyl valeronitrile 0.75 | Potassium ethylate 0.25 | 2-(1-cyanic acid-3-methylbutyl) TERT-BUTYL MALONATE | 98.5 | 89.7 |
| 13 | 2-iodo-4-methyl valeronitrile 0.5 | Potassium tert.-butoxide 0.25 | 2-(1-cyanic acid-3-methylbutyl) propanedioic acid methyl ethyl ester | 98.5 | 89.1 |
| 14 | 2-bromo-4-methyl valeronitrile 0.5 | Potassium methylate 0.2 | 2-(1-cyanic acid-3-methylbutyl) propanedioic acid methyl ethyl ester | 98.5 | 89.7 |
| 15 | 2-chloro-4-methyl valeronitrile 0.5 | Potassium hydride KH 0.5 | 2-(1-cyanic acid-3-methylbutyl) TERT-BUTYL MALONATE | 98.2 | 88.5 |
| 16 | 2-bromo-4-methyl valeronitrile 0.8 | Sodium ethylate 0.25 | 2-(1-cyanic acid-3-methylbutyl) propanedioic acid methyl ethyl ester | 98.2 | 89.0 |
| 17 | 2-chloro-4-methyl valeronitrile 0.5 | Potassium hydride KH 0.25 | 2-(1-cyanic acid-3-methylbutyl) propanedioic acid di tert butyl carbonate | 98.5 | 89.5 |
| 18 | 2-iodo-4-methyl valeronitrile 0.3 | Sodium methylate 0.2 | 2-(1-cyanic acid-3-methylbutyl) propanedioic acid di tert butyl carbonate | 98.3 | 89.2 |
| 19 | 2-bromo-4-methyl valeronitrile 0.4 | Potassium ethylate 0.25 | 2-(1-cyanic acid-3-methylbutyl) propanedioic acid di tert butyl carbonate | 98.4 | 88.2 |
| 20 | 2-bromo-4-methyl valeronitrile 0.3 | Sodium tert-butoxide 0.15 | 2-(1-cyanic acid-3-methylbutyl) propanedioic acid di tert butyl carbonate | 98.5 | 88.0 |
| 21 | 2-bromo-4-methyl valeronitrile 0.5 | Sodium hydride 0.5 | 2-(1-cyanic acid-3-methylbutyl) NSC 406716 | 98.5 | 89.7 |
| 22 | 2-chloro-4-methyl valeronitrile 0.5 | Sodium methylate 0.2 | 2-(1-cyanic acid-3-methylbutyl) NSC 406716 | 98.4 | 89.3 |
| 23 | 2-bromo-4-methyl valeronitrile 0.5 | Potassium ethylate 0.5 | 2-(1-cyanic acid-3-methylbutyl) NSC 406716 | 98.5 | 89.3 |
| 24 | 2-iodo-4-methyl valeronitrile 0.25 | Potassium tert.-butoxide 0.1 | 2-(1-cyanic acid-3-methylbutyl) NSC 406716 | 98.2 | 89.0 |
| 25 | 2-iodo-4-methyl valeronitrile 0.5 | Sodium hydride 0.5 | 2-(1-cyanic acid-3-methylbutyl) dipropyl malonate | 98.3 | 89.7 |
| 26 | 2-bromo-4-methyl valeronitrile 0.1 | Sodium tert-butoxide 0.2 | 2-(1-cyanic acid-3-methylbutyl) dipropyl malonate | 98.0 | 89.1 |
| 27 | 2-chloro-4-methyl valeronitrile 0.5 | Potassium hydride KH 0.5 | 2-(1-cyanic acid-3-methylbutyl) ethyl malonate | 98.2 | 88.4 |
| 28 | 2-iodo-4-methyl valeronitrile 0.15 | Potassium methylate 0.2 | 2-(1-cyanic acid-3-methylbutyl) ethyl malonate | 98.2 | 86.7 |
| 29 | 2-bromo-4-methyl valeronitrile 0.3 | Sodium tert-butoxide 0.25 | 2-(1-cyanic acid-3-methylbutyl) ethyl malonate | 98.5 | 88.3 |
| 30 | 2-bromo-4-methyl valeronitrile 1.0 | Sodium methylate 0.1 | 2-(1-cyanic acid-3-methylbutyl) TERT-BUTYL MALONATE | 97.8 | 92.0 |
| 31 | 2-bromo-4-methyl valeronitrile 0.35 | Potassium tert.-butoxide 0.1 | 2-(1-cyanic acid-3-methylbutyl) propanedioic acid methyl ethyl ester | 98.3 | 89.0 |
| 32 | 2-iodo-4-methyl valeronitrile 0.25 | Potassium hydride KH 0.2 | 2-(1-cyanic acid-3-methylbutyl) propanedioic acid methyl ethyl ester | 98.5 | 87.5 |
| 33 | 2-bromo-4-methyl valeronitrile 0.45 | Sodium methylate 0.2 | 2-(1-cyanic acid-3-methylbutyl) NSC 406716 | 98.3 | 89.7 |
| 34 | 2-bromo-4-methyl valeronitrile 0.5 | Sodium hydride 0.5 | 2-(1-cyanic acid-3-methylbutyl) NSC 406716 | 98.4 | 89.5 |
| 35 | 2-bromo-4-methyl valeronitrile 0.5 | Sodium tert-butoxide 0.1 | 2-(1-cyanic acid-3-methylbutyl) NSC 406716 | 98.3 | 88.7 |
| 36 | 2-iodo-4-methyl valeronitrile 0.25 | Potassium hydride KH 0.15 | 2-(1-cyanic acid-3-methylbutyl) TERT-BUTYL MALONATE | 98.5 | 88.2 |
| 37 | 2-iodo-4-methyl valeronitrile 0.35 | Potassium methylate 0.2 | 2-(1-cyanic acid-3-methylbutyl) TERT-BUTYL MALONATE | 98.4 | 87.9 |
| 38 | 2-chloro-4-methyl valeronitrile 0.05 | Sodium tert-butoxide 0.1 | 2-(1-cyanic acid-3-methylbutyl) TERT-BUTYL MALONATE | 98.5 | 89.8 |
| 39 | 2-chloro-4-methyl valeronitrile 0.5 | Sodium methylate 0.5 | 2-(1-cyanic acid-3-methylbutyl) propanedioic acid di tert butyl carbonate | 98.3 | 87.0 |
| 40 | 2-bromo-4-methyl valeronitrile 0.45 | Potassium hydride KH 0.2 | 2-(1-cyanic acid-3-methylbutyl) propanedioic acid di tert butyl carbonate | 97.9 | 88.3 |
| 41 | 2-chloro-4-methyl valeronitrile 0.2 | Sodium tert-butoxide 0.1 | 2-(1-cyanic acid-3-methylbutyl) propanedioic acid di tert butyl carbonate | 98.4 | 89.2 |
| 42 | 2-chloro-4-methyl valeronitrile 0.5 | Sodium ethylate 0.25 | 2-(1-cyanic acid-3-methylbutyl) methyl-malonate | 98.3 | 88.4 |
| 43 | 2-iodo-4-methyl valeronitrile 0.1 | Potassium tert.-butoxide 0.15 | 2-(1-cyanic acid-3-methylbutyl) methyl-malonate | 98.5 | 87.4 |
| 44 | 2-chloro-4-methyl valeronitrile 0.3 | Potassium methylate 0.2 | 2-(1-cyanic acid-3-methylbutyl) methyl-malonate | 98.2 | 88.2 |
| 45 | 2-chloro-4-methyl valeronitrile 0.5 | Potassium hydride KH 0.5 | 2-(1-cyanic acid-3-methylbutyl) ethyl malonate | 98.2 | 91.5 |
| 46 | 2-chloro-4-methyl valeronitrile 0.5 | Sodium ethylate 0.5 | 2-(1-cyanic acid-3-methylbutyl) ethyl malonate | 98.5 | 91.7 |
| 47 | 2-iodo-4-methyl valeronitrile 0.4 | Potassium methylate 0.2 | 2-(1-cyanic acid-3-methylbutyl) ethyl malonate | 98.2 | 90.5 |
| 48 | 2-chloro-4-methyl valeronitrile 0.3 | Sodium hydride 0.5 | 2-(1-cyanic acid-3-methylbutyl) methyl-malonate | 98.5 | 91.0 |
| 49 | 2-chloro-4-methyl valeronitrile 0.25 | Sodium ethylate 0.2 | 2-(1-cyanic acid-3-methylbutyl) methyl-malonate | 98.6 | 91.3 |
| 50 | 2-bromo-4-methyl valeronitrile 0.45 | Sodium tert-butoxide 0.1 | 2-(1-cyanic acid-3-methylbutyl) methyl-malonate | 98.5 | 90.5 |
| 51 | 2-bromo-4-methyl valeronitrile 0.5 | Potassium tert.-butoxide 0.1 | 2-(1-cyanic acid-3-methylbutyl) dipropyl malonate | 98.5 | 91.0 |
| 52 | 2-iodo-4-methyl valeronitrile 0.5 | Potassium methylate 0.5 | 2-(1-cyanic acid-3-methylbutyl) dipropyl malonate | 98.5 | 90.4 |
| 53 | 2-bromo-4-methyl valeronitrile 0.4 | Potassium ethylate 0.5 | 2-(1-cyanic acid-3-methylbutyl) dipropyl malonate | 98.5 | 91.5 |
| 54 | 2-chloro-4-methyl valeronitrile 0.15 | Potassium methylate 0.4 | 2-(1-cyanic acid-3-methylbutyl) ethyl malonate | 98.5 | 90.2 |
| 55 | 2-iodo-4-methyl valeronitrile 0.4 | Sodium methylate 0.3 | 2-(1-cyanic acid-3-methylbutyl) TERT-BUTYL MALONATE | 98.5 | 91.1 |
| 56 | 2-iodo-4-methyl valeronitrile 0.5 | Potassium tert.-butoxide 0.05 | 2-(1-cyanic acid-3-methylbutyl) TERT-BUTYL MALONATE | 98.3 | 90.3 |
| 57 | 2-iodo-4-methyl valeronitrile 0.5 | Sodium hydride 0.5 | 2-(1-cyanic acid-3-methylbutyl) NSC 406716 | 98.6 | 89.4 |
| 58 | 2-bromo-4-methyl valeronitrile 0.5 | Potassium methylate 0.4 | 2-(1-cyanic acid-3-methylbutyl) NSC 406716 | 98.3 | 91.5 |
| 59 | 2-iodo-4-methyl valeronitrile 0.4 | Sodium ethylate 0.2 | 2-(1-cyanic acid-3-methylbutyl) NSC 406716 | 98.3 | 90.0 |
| 60 | 2-chloro-4-methyl valeronitrile 0.5 | Potassium ethylate 0.5 | 2-(1-cyanic acid-3-methylbutyl) propanedioic acid methyl ethyl ester | 98.5 | 89.6 |
| 61 | 2-bromo-4-methyl valeronitrile 0.5 | Potassium hydride KH 0.1 | 2-(1-cyanic acid-3-methylbutyl) propanedioic acid methyl ethyl ester | 98.5 | 91.3 |
| 62 | 2-bromo-4-methyl valeronitrile 0.25 | Potassium ethylate 0.2 | 2-(1-cyanic acid-3-methylbutyl) propanedioic acid di tert butyl carbonate | 99.4 | 89.2 |
| 63 | 2-iodo-4-methyl valeronitrile 0.5 | Sodium hydride 0.5 | 2-(1-cyanic acid-3-methylbutyl) propanedioic acid methyl ethyl ester | 98.2 | 91.3 |
| 64 | 2-bromo-4-methyl valeronitrile 0.5 | Sodium hydride 0.5 | 2-(1-cyanic acid-3-methylbutyl) methyl-malonate | 98.5 | 92.0 |
| 65 | 2-iodo-4-methyl valeronitrile 0.5 | Potassium tert.-butoxide 0.1 | 2-(1-cyanic acid-3-methylbutyl) methyl-malonate | 98.5 | 90.4 |
| 66 | 2-chloro-4-methyl valeronitrile 0.5 | Potassium hydride KH 0.5 | 2-(1-cyanic acid-3-methylbutyl) methyl-malonate | 98.3 | 91.6 |
| 67 | 2-chloro-4-methyl valeronitrile 0.1 | Sodium ethylate 0.5 | 2-(1-cyanic acid-3-methylbutyl) dipropyl malonate | 98.2 | 90.8 |
| 68 | 2-bromo-4-methyl valeronitrile 0.5 | Sodium ethylate 0.25 | 2-(1-cyanic acid-3-methylbutyl) dipropyl malonate | 98.5 | 91.0 |
| 69 | 2-chloro-4-methyl valeronitrile 1.0 | Sodium tert-butoxide 0.1 | 2-(1-cyanic acid-3-methylbutyl) dipropyl malonate | 98.5 | 89.4 |
| 70 | 2-bromo-4-methyl valeronitrile 0.4 | Potassium ethylate 0.25 | 2-(1-cyanic acid-3-methylbutyl) TERT-BUTYL MALONATE | 98.7 | 91.3 |
| 71 | 2-bromo-4-methyl valeronitrile 0.5 | Potassium methylate 0.2 | 2-(1-cyanic acid-3-methylbutyl) NSC 406716 | 98.4 | 90.7 |
| 72 | 2-iodo-4-methyl valeronitrile 0.25 | Potassium tert.-butoxide 0.1 | 2-(1-cyanic acid-3-methylbutyl) NSC 406716 | 98.4 | 91.2 |
| 73 | 2-bromo-4-methyl valeronitrile 0.2 | Potassium ethylate 0.2 | 2-(1-cyanic acid-3-methylbutyl) propanedioic acid di tert butyl carbonate | 98.7 | 88.2 |
| 74 | 2-iodo-4-methyl valeronitrile 0.5 | Potassium tert.-butoxide 0.15 | 2-(1-cyanic acid-3-methylbutyl) TERT-BUTYL MALONATE | 98.4 | 91.0 |
The proton nmr spectra data of 2-(1-cyanic acid-3-methylbutyl) malonic ester that obtains are following:
(1) 2-(1-cyanic acid-3-methylbutyl) methyl-malonate,
1H-NMR (CDCl
3, 300MHz), δ: 1.09～1.17 (m, 6H), 1.28～1.35 (m, 1H), 1.54～1.68 (m, 2H), 3.24～3.30 (m, 1H), 3.96 (d, J=6.5Hz, 1H), 4.18 (s, 6H).
(2) 2-(1-cyanic acid-3-methylbutyl) ethyl malonate,
1H-NMR (CDCl
3, 300MHz), δ: 0.98 (t, J=6.0Hz, 6H), 1.15～1.21 (m, 6H), 1.25～1.34 (m, 1H), 1.54～1.66 (m, 2H), 3.22～3.34 (m, 1H), 3.98 (d, J=6.5Hz, 1H), 4.10～4.25 (q, 4H).
(3) 2-(1-cyanic acid-3-methylbutyl) propanedioic acid methyl ethyl ester,
1H-NMR (CDCl
3, 300MHz), δ: 0.96 (t, J=6.0Hz, 3H), 1.00～1.12 (m, 6H), 1.28～1.34 (m, 1H), 1.54～1.67 (m, 2H), 3.23～3.32 (m, 1H), 3.95 (d, J=6.5Hz, 1H), 4.02 (s, 3H), 4.52～4.62 (q, J=6.0Hz, 4H).
(4) 2-(1-cyanic acid-3-methylbutyl) dipropyl malonate,
1H NMR (CDCl
3, 300MHz), δ: 0.86 (t, J=6.0Hz, 6H), 1.10～1.18 (m, 6H); 1.25～1.35 (m, 1H), 1.50～1.62 (m, 2H), 1.68～1.72 (m, 4H), 3.24～3.32 (m; 1H), 3.94 (d, J=6.5Hz, 1H), 4.10～4.20 (t, J=6.6Hz, 4H).
(5) 2-(1-cyanic acid-3-methylbutyl) NSC 406716,
1H-NMR (CDCl
3, 300MHz), δ: 1.04 (d, J=6.3Hz, 6H), 1.15～1.20 (m, 6H), 1.28～1.35 (m, 1H), 1.54～1.68 (m, 2H), 3.20～3.36 (m, 1H), 3.88 (d, J=6.5Hz, 1H), 4.56 (q, J=6.3Hz, 2H).
(6) 2-(1-cyanic acid-3-methylbutyl) TERT-BUTYL MALONATE,
1H-NMR (CDCl
3, 300MHz), δ: 0.84 (t, J=6.0Hz, 6H), 1.00 (m, 4H), 1.14～1.20 (m, 6H), 1.28～1.35 (m, 1H), 1.52～1.72 (m, 6H), 3.23～3.33 (m, 1H), 3.97 (d, J=6.5Hz, 1H), 4.10～4.18 (m, 4H).
(7) 2-(1-cyanic acid-3-methylbutyl) propanedioic acid di tert butyl carbonate,
1H-NMR (CDCl
3, 300MHz), δ: 1.02～1.18 (d, J=6.0Hz, 6H), 1.24～1.34 (m, 1H), 1.48 (s, 18H), 1.52～1.62 (m, 2H), 3.25～3.34 (m, 1H), 3.98 (d, J=6.6Hz, 1H).
Reference
Zhu Ping. the present Research of lyrica and new synthetic method thereof. Baoji College Of Arts And Science journal (natural science edition), 2008,28 (2): 127-133.
Ichimura?K，Ohta?M.Conversion?of?aldehydes?to?2-monosubstitutedaziridines.Reduction?of?α-chloro-，bromo-，andsulfonyloxycarbonitriles?with?lithium?aluminum?hydride.Bull?Chem?SocJapan，1970，43(5)：1443-1450.
Claims (7)
1.
OnePlant lyrica midbody cyanogen diester preparation method, it is characterized in that this method comprises the steps:
(1) the first step: equimolar SULPHURYL CHLORIDE and 3-methyl butyraldehyde are mixed in acetonitrile, and, under agitation condition, add the alkali metal cyanide aqueous solution with the mixture cooling; At room temperature continue then to stir; Reaction finishes the back and in mixture, adds entry, uses dichloromethane extraction, and organic layer spends the night with anhydrous sodium sulfate drying through the washing back; Boil off organic solvent behind the filtering siccative and obtain solid, with obtaining 4-methyl-2-sulfonyloxy valeronitrile behind the ethyl alcohol recrystallization;
(2) second steps: 4-methyl-2-sulfonyloxy valeronitrile and alkali metal halide are blended in the anhydrous butanone; Heating under agitation; The cooling back adds entry to reaction mixture, uses dichloromethane extraction again, spends the night with anhydrous sodium sulfate drying; Boil off organic solvent behind the filtering siccative, underpressure distillation obtains 2-halo-4-methyl valeronitrile again;
(3) the 3rd steps: under nitrogen protection, slowly drip the tetrahydrofuran solution of malonic ester at ambient temperature in the tetrahydrofuran solution of alkalitropism reagent, constantly stirred reaction mixture; After 1 hour, in reaction mixture, drip the tetrahydrofuran solution of 2-halo-4-methyl valeronitrile, stirred overnight under nitrogen protection condition and room temperature; With the reaction mixture cooling, stop to feed nitrogen, add aqueous sodium carbonate; Use extracted with diethyl ether after the solution layering, organic layer spends the night with anhydrous sodium sulfate drying through the washing back, boils off organic solvent behind the filtering siccative and obtains 2-(1-cyanic acid-3-methylbutyl) malonic ester weak yellow liquid; It is the lyrica midbody
A kind of as in sodium hydride, potassium hydride KH, sodium methylate, sodium ethylate, potassium methylate, potassium ethylate, sodium tert-butoxide or the potassium tert.-butoxide of the alkaline reagents that uses in the reaction.
2. lyrica midbody cyanogen diester preparation method according to claim 1; A kind of as in benzene sulfonyl chloride, Tosyl chloride, methylsulfonyl chloride or the ethyl sulfonyl chloride of the SULPHURYL CHLORIDE that it is characterized in that using in the 4-methyl of said step 1-2-sulfonyloxy valeronitrile reaction, alkali metal cyanide is sodium cyanide or Potssium Cyanide.
3. the described lyrica midbody of claim 1 cyanogen diester preparation method; It is characterized in that the temperature of reaction in the 4-methyl of said step 1-2-sulfonyloxy valeronitrile reaction is-20～20 ℃; In 0.5～24 hour reaction times, molar ratio is a 3-methyl butyraldehyde: SULPHURYL CHLORIDE: alkali metal cyanide=1:0.1～5.0:0.1～5.0.
4. lyrica midbody cyanogen diester preparation method according to claim 1, a kind of as in sodium-chlor, Repone K, Sodium Bromide, Potassium Bromide, Soiodin or the potassiumiodide of the alkali metal halide that it is characterized in that using in the 2-halo of said step 2-4-methyl valeronitrile reaction.
5. lyrica midbody cyanogen diester preparation method according to claim 1; It is characterized in that the temperature of reaction in the 2-halo of said step 2-4-methyl valeronitrile reaction is 20～100 ℃; In 0.5～24 hour reaction times, molar ratio is 4-methyl-2-sulfonyloxy valeronitrile: alkali metal halide=1:0.1～5.0.
6. lyrica midbody cyanogen diester preparation method according to claim 1, a kind of as in methyl-malonate, ethyl malonate, propanedioic acid methyl ethyl ester, dipropyl malonate, NSC 406716, TERT-BUTYL MALONATE or the propanedioic acid di tert butyl carbonate of the malonic ester that it is characterized in that using in 2-(1-cyanic acid-3-methylbutyl) the malonic ester reaction of said step 3.
7. lyrica midbody cyanogen diester preparation method according to claim 1 is characterized in that molar ratio is 2-halo-4-methyl valeronitrile in 2-(1-cyanic acid-3-methylbutyl) the malonic ester reaction of said step 3: malonic ester=1:0.1～5.0.
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