CN108409557A - Bu Waxitan new intermediates and its synthetic method and application - Google Patents
Bu Waxitan new intermediates and its synthetic method and application Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/58—Preparation of carboxylic acid halides
- C07C51/60—Preparation of carboxylic acid halides by conversion of carboxylic acids or their anhydrides or esters, lactones, salts into halides with the same carboxylic acid part
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
- C07C53/38—Acyl halides
- C07C53/46—Acyl halides containing halogen outside the carbonyl halide group
- C07C53/50—Acyl halides containing halogen outside the carbonyl halide group of acids containing three or more carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
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- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention discloses Bu Waxitan new intermediates and its synthetic method and applications.The structural formula of intermediate isUsing the intermediate synthesize Bu Waxitan reaction route be
Description
Technical field
The invention belongs to pharmaceutical fields, and in particular to Bu Waxitan new intermediates and its synthetic method and application.
Background technology
Bu Waxitan is a kind of novel antiepileptic of Belgian UCB exploitations, has good curative effect and tolerance
Property, it is expected to the third generation antiepileptic of substitution Levetiracetam, there are good medical value and market prospects.
So far, a plurality of synthetic route is disclosed both at home and abroad, it is specific as follows：
CN1882535A is disclosed with 5- hydroxyl -4- n-propyl -2- furanones and S-2- amino-butanamides in sodium borohydride
The lower reduction amination in left and right, then hydrogenated reduction obtain racemization Bu Waxitan, and Bu Waxitan, synthetic route are prepared through pillar layer separation
As shown in Equation 1：
CN101263113A discloses route as shown in Equation 2, and the route reaction is cumbersome, and production cost is excessively high, less suitable
Close industrialized production.
CN106279074A is disclosed using R-4- n-propyls-dihydrofuran -2- ketone as raw material, under the action of zinc chloride,
Be obtained by the reaction R-3- n-propyl -4- chlorobutanoylchlorides with thionyl chloride, then with S-2- amino-butanamides and its salt amidation, HOBT contractings
It closes and prepares Bu Waxitan.The route is big with amide condensed difficulty since chloro group is difficult to leave away, and causes yield low, impurity compared with
It is more.Route such as formula 3：
By R-3- n-propyl -4- chlorobutanoylchlorides, then with S-2- amino-butanamides and its salt amidation, HOBT condensations prepare cloth
The whole yield of Wa Xitan is only 30% or so.
Develop it is a kind of be readily synthesized and facilitate Bu Waxitan synthesize new intermediate have great importance.
Invention content
It is an object of the invention to overcome the deficiencies of the prior art and provide a kind of Bu Waxitan new intermediates.
It is yet a further object of the present invention to provide the synthetic methods of above-mentioned Bu Waxitan new intermediates.
It is another object of the present invention to provide the Bu Waxitan synthetic methods based on above-mentioned Bu Waxitan new intermediates.
The technical solution used in the present invention is：
A kind of compound, structural formula is as shown in formula III：
The synthetic method of compound, synthetic route shown in above-mentioned formula III are as follows：
Acyl chloride reaction is carried out in a solvent using chloride reagent and compound II, obtains III compound represented of formula.
As being further improved for above-mentioned synthetic method, the solvent of acyl chloride reaction is aprotic solvent.Further,
Aprotic solvent is selected from least one of tetrahydrofuran, toluene, dichloromethane, ether and methyl tertiary butyl ether(MTBE).
As being further improved for above-mentioned synthetic method, chloride reagent is in thionyl chloride, triphosgene, phosphorus oxychloride
At least one.
As being further improved for above-mentioned synthetic method, the temperature of acyl chloride reaction is not higher than the reflux temperature of solvent.More
Further, the temperature of acyl chloride reaction is 20~55 DEG C.
As being further improved for above-mentioned synthetic method,
Application of the compound shown in above-mentioned formula III in synthesizing Bu Waxitan.
A kind of synthetic method of Bu Waxitan, including use compound shown in above-mentioned formula III and (S) -2- aminobutyryl amine salt
Hydrochlorate in organic solvent, carries out phase transfer reaction in the presence of a base, obtains Bu Waxitan, and synthetic route is as follows：
As being further improved for above-mentioned synthetic method, organic solvent is selected from dichloromethane, chloroform, acetonitrile, methyl
At least one of tertbutyl ether, dimethyl sulfoxide (DMSO), N,N-dimethylformamide, tetrahydrofuran.
As being further improved for above-mentioned synthetic method, alkali is selected from sodium hydroxide, potassium hydroxide, potassium tert-butoxide, the tert-butyl alcohol
At least one of sodium, sodium hydride, lithium diisopropylamine.
As being further improved for above-mentioned synthetic method, phase transfer catalyst is selected from benzyltriethylammoinium chloride, the tetrabutyl
Ammonium bromide, tetrabutylammonium chloride, 4-butyl ammonium hydrogen sulfate, tri-n-octyl methyl ammonium chloride, dodecyl trimethyl ammonium chloride, 14
At least one of alkyl trimethyl ammonium chloride, polyethylene glycol.
As being further improved for above-mentioned synthetic method, the temperature of phase transfer reaction is -10~50 DEG C, preferably 20~30
℃。
The beneficial effects of the invention are as follows：
The Bu Waxitan new intermediates of the present invention, have following benefit for synthesizing Bu Waxitan：Low in raw material price is easy to get,
Reaction route is short, high income, and the Bu Waxitan of high-optical-purity can be obtained without carrying out chiral resolution or pillar layer separation.
The Bu Waxitan synthesis technologies of the present invention, low in raw material price are easy to get, and reaction route is short, high income, without carrying out
Chiral resolution or pillar layer separation can obtain the Bu Waxitan of high-optical-purity.
Specific implementation mode
A kind of compound, structural formula is as shown in formula III：
The synthetic method of compound, synthetic route shown in above-mentioned formula III are as follows：
Acyl chloride reaction is carried out in a solvent using chloride reagent and compound II, obtains III compound represented of formula.
As being further improved for above-mentioned synthetic method, the solvent of acyl chloride reaction is aprotic solvent.Further,
Aprotic solvent is selected from least one of tetrahydrofuran, toluene, dichloromethane, ether and methyl tertiary butyl ether(MTBE).
As being further improved for above-mentioned synthetic method, chloride reagent is in thionyl chloride, triphosgene, phosphorus oxychloride
At least one.
Temperature is excessively high, and side reaction may increase, and causes the impurity level in product more, increases the difficulty isolated and purified.And
Temperature is too low, and reaction speed is relatively low, and production efficiency is more low.As being further improved for above-mentioned synthetic method, chloride is anti-
The temperature answered is not higher than the reflux temperature of solvent.Further, the temperature of acyl chloride reaction is 20~55 DEG C.Substantially may be used in this way
To be reacted at ambient temperature, without being additionally heated or cooled, while production efficiency, product purity all have advantage.
Application of the compound shown in above-mentioned formula III in synthesizing Bu Waxitan.
A kind of synthetic method of Bu Waxitan, including use compound shown in above-mentioned formula III and (S) -2- aminobutyryl amine salt
Hydrochlorate in organic solvent, carries out phase transfer reaction in the presence of a base, obtains Bu Waxitan, and synthetic route is as follows：
The reaction principle of this route is acyl chlorides and organic amine amidation under alkaline condition, amide further with bromoalkane
The N- alkylation structure cyclization that base carries out amide obtains step Wa Xitan.
As long as organic solvent can preferably dissolve reactant, type all has each reactant without particular/special requirement
The solvent of higher solubility is more preferably to select.As being further improved for above-mentioned synthetic method, organic solvent is selected from dichloromethane
At least one in alkane, chloroform, acetonitrile, methyl tertiary butyl ether(MTBE), dimethyl sulfoxide (DMSO), N,N-dimethylformamide, tetrahydrofuran
Kind.
Alkali can use alkali commonly used in the art.As being further improved for above-mentioned synthetic method, alkali be selected from sodium hydroxide,
At least one of potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium hydride, lithium diisopropylamine.
Phase transfer catalyst can use phase transfer catalyst commonly used in the art.As the further of above-mentioned synthetic method
It improves, phase transfer catalyst is selected from benzyltriethylammoinium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutyl hydrogen sulfate
In ammonium, tri-n-octyl methyl ammonium chloride, dodecyl trimethyl ammonium chloride, tetradecyl trimethyl ammonium chloride, polyethylene glycol extremely
Few one kind.
Reaction temperature is higher than 50 DEG C, and by-product is more；Temperature is too low, and reaction rate is slow, and the reaction time is long.Take into account production
Purity, the production efficiency of product, as being further improved for above-mentioned synthetic method, the temperature of phase transfer reaction is -10~50 DEG C, -5
DEG C~40 DEG C, 10~30 DEG C, 15~30 DEG C, 20~30 DEG C.
With reference to embodiment, the technical solution that further illustrates the present invention.
Embodiment 1：
Formula II compoundPreparation：
1) it takes R-4- n-propyls-dihydrofuran -2- ketone (20g, 156mmol) to be dissolved in acetic acid, the acetic acid of 33%HBr is added dropwise
Solution (100ml) reacts 3h at 55 DEG C；
2) it is cooled to room temperature and toluene (120ml) and water (20ml), liquid separation after stirring is added, water phase extracts (2* with toluene
60ml), merge organic phase to be dried with anhydrous sodium sulfate with saturated common salt water washing, filter, be concentrated in vacuo to obtain faint yellow oily
Object 14.7g, as Formula II compound.
Yield is 90%, HPLC purity ＞ 97%, ee purity ＞ 99%,1H NMR (300MHz, CDCl3)：δ 11.0 (1H,
S), 3.20 (1H, dd), 3.10 (1H, dd), 2.32 (1H, dd), 2.20 (1H, dd), 1.25-1.33 (4H, m), 0.96 (3H,
t)。
Formula III compoundPreparation：
Modus ponens II compounds (20.8g, 100mmol) are dissolved in toluene (60ml), then be added dropwise thionyl chloride (35.7g,
300mmol), it is stirred at room temperature 6 hours, removes thionyl chloride and toluene under reduced pressure, obtain pale yellow oil 22.5g, as formula III
Close object.
Yield is 98%, HPLC purity ＞ 97%, ee purity ＞ 99%,1H NMR (300MHz, CDCl3)：δ3.28(1H,
Dd), 3.15 (1H, dd), 2.92 (1H, dd), 2.65 (1H, dd), 1.25-1.33 (4H, m), 0.98 (3H, t).
The preparation of Bu Waxitan：
1) S-2- amino-butanamides (6.7g, 48mmol), tetrabutylammonium bromide (1.4g, 4.39mmol), potassium hydroxide are taken
Formula III compound (10g, 43.9mmol) is added dropwise in (7.4g, 131.8mmol), anhydrous sodium sulfate (10g) at -10~0 DEG C
Dimethyl sulfoxide (DMSO) (20ml) solution, is stirred to react 4h after being warming up to 40~50 DEG C, filtering, and faint yellow oily is obtained after concentrated solvent
Object；
2) pale yellow oil is dissolved in methyl tertiary butyl ether(MTBE) (40ml), stirring and dissolving, is filtered to remove insoluble miscellaneous
Matter is concentrated in vacuo to dry；
3) it is added in isopropyl acetate (10ml), dissolves by heating complete, be cooled to 5 DEG C or less crystallizations 4 hours, filter, use
A small amount of isopropyl acetate washing, it is 4 hours dry at (40 DEG C, -0.08MPa), obtain white solid powder 4.9g, as Bu Waxi
It is smooth.
Yield is 53%, HPLC purity ＞ 97%, ee purity ＞ 99%,1H NMR (300MHz, CDCl3)：δ6.17(1H,
s)；5.32(1H,s)；4.43(1H,dd)；3.49 (1H, dd)；3.01 (1H, dd)；2.59(1H,dd)；2.34(1H,m)；2.08
(1H, dd)；1.95(1H,m)；1.70 (1H, m)；1.47-1.28 (4H, m)；0.91(6H,dt).
Embodiment 2：
Formula II compoundPreparation：
1) it takes R-4- n-propyls-dihydrofuran -2- ketone (40g, 312mmol) to be dissolved in acetic acid, the acetic acid of 33%HBr is added dropwise
Solution (200ml) reacts 4h at 40~50 DEG C；
2) it is cooled to room temperature and toluene (240ml) and water (40ml), liquid separation after stirring is added, water phase extracts (2* with toluene
120ml), merge organic phase to be dried with anhydrous sodium sulfate with saturated common salt water washing, filter, be concentrated in vacuo to obtain faint yellow oily
Object 29.7g, as Formula II compound.
Yield is 91%, HPLC purity ＞ 97%, ee purity ＞ 99%,1H NMR (300MHz, CDCl3)：δ 11.0 (1H,
S), 3.20 (1H, dd), 3.10 (1H, dd), 2.32 (1H, dd), 2.20 (1H, dd), 1.25-1.33 (4H, m), 0.96 (3H,
t)。
Formula III compoundPreparation：
Modus ponens II compounds (20.8g, 100mmol) are dissolved in dichloromethane (60ml), then be added dropwise triphosgene (44.5g,
150mmol), it is stirred at room temperature 6 hours, removes triphosgene and dichloromethane under reduced pressure, obtain pale yellow oil 21.3g, as formula III
Compound.
Yield is 93%, HPLC purity ＞ 97%, ee purity ＞ 99%,1H NMR (300MHz, CDCl3)：δ3.28(1H,
Dd), 3.15 (1H, dd), 2.92 (1H, dd), 2.65 (1H, dd), 1.25-1.33 (4H, m), 0.98 (3H, t).
The preparation of Bu Waxitan：
1) S-2- amino-butanamides (20.1g, 144mmol), tetrabutylammonium iodide (4.9g, 13.17mmol), the tert-butyl alcohol are taken
Potassium (44.4g, 395.4mmol), anhydrous sodium sulfate (10g) are added dropwise the four of formula III compound (30g, 131.7mmol) at 0 DEG C
Hydrogen furans (60ml) solution, is stirred to react 10h after being warming up to 25~35 DEG C, filtering, and pale yellow oil is obtained after concentrated solvent；
2) pale yellow oil is dissolved in methyl tertiary butyl ether(MTBE) (130ml), stirring and dissolving, is filtered to remove insoluble miscellaneous
Matter is concentrated in vacuo to dry；
3) it is added in isopropyl acetate (40ml), dissolves by heating complete, be cooled to 5 DEG C or less crystallizations 4 hours, filter, use
A small amount of isopropyl acetate washing, it is 4 hours dry at (40 DEG C, -0.08MPa), obtain white solid powder 15.2g, as Bu Waxi
It is smooth.
Yield is 55%, HPLC purity ＞ 97%, ee purity ＞ 99%,1H NMR (300MHz, CDCl3)：δ6.17(1H,
s)；5.32(1H,s)；4.43(1H,dd)；3.49 (1H, dd)；3.01 (1H, dd)；2.59(1H,dd)；2.34(1H,m)；2.08
(1H, dd)；1.95(1H,m)；1.70 (1H, m)；1.47-1.28 (4H, m)；0.91(6H,dt).
Embodiment 3：
Formula II compoundPreparation：
1) it takes R-4- n-propyls-dihydrofuran -2- ketone (5.0Kg, 39mol) to be dissolved in acetic acid, the acetic acid of 33%HBr is added dropwise
Solution (25L) reacts 6h at 20 DEG C；
2) it is cooled to room temperature and toluene (30L) and water (5L), liquid separation after stirring is added, water phase extracts (2*15L) with toluene, closes
And organic phase is dried with saturated common salt water washing with anhydrous sodium sulfate, filtering is concentrated in vacuo to obtain pale yellow oil 3.8Kg,
As Formula II compound.
Yield is 93%, HPLC purity ＞ 97%, ee purity ＞ 99%,1H NMR (300MHz, CDCl3)：δ 11.0 (1H,
S), 3.20 (1H, dd), 3.10 (1H, dd), 2.32 (1H, dd), 2.20 (1H, dd), 1.25-1.33 (4H, m), 0.96 (3H,
t)。
Formula III compoundPreparation：
Modus ponens II compounds (5.2Kg, 25mol) are dissolved in toluene (15L), then thionyl chloride (8.9kg, 75mol) is added dropwise,
It is stirred at room temperature 6 hours, removes thionyl chloride and toluene under reduced pressure, obtain pale yellow oil 5.5Kg, as formula III compound.
Yield is 96%, HPLC purity ＞ 97%, ee purity ＞ 99%,1H NMR (300MHz, CDCl3)：δ3.28(1H,
Dd), 3.15 (1H, dd), 2.92 (1H, dd), 2.65 (1H, dd), 1.25-1.33 (4H, m), 0.98 (3H, t).
The preparation of Bu Waxitan：
1) S-2- amino-butanamides (6.5Kg, 46mol), tetrabutylammonium bromide (1.4Kg, 4.4mol), potassium hydroxide are taken
The dichloromethane of formula III compound (10Kg, 43.9mol) is added dropwise in (4.9Kg, 87.9mol), anhydrous sodium sulfate (10Kg) at 0 DEG C
Alkane (20L) solution is stirred to react 10h after being warming up to room temperature (20~30 DEG C), filtering, and faint yellow oily is obtained after concentrated solvent
Object；
2) pale yellow oil is dissolved in methyl tertiary butyl ether(MTBE) (40L), stirring and dissolving, is filtered to remove insoluble miscellaneous
Matter is concentrated in vacuo to dry；
3) it is added in isopropyl acetate (8L), dissolves by heating complete, be cooled to 5 DEG C or less crystallizations 4 hours, filtering, with few
Isopropyl acetate washing is measured, it is 6 hours dry at (40 DEG C, -0.08MPa), obtain white solid powder 5.1Kg, as Bu Waxitan.
Yield is 57%, HPLC purity ＞ 97%, ee purity ＞ 99%,1H NMR (300MHz, CDCl3)：δ6.17(1H,
s)；5.32(1H,s)；4.43(1H,dd)；3.49 (1H, dd)；3.01 (1H, dd)；2.59(1H,dd)；2.34(1H,m)；2.08
(1H, dd)；1.95(1H,m)；1.70 (1H, m)；1.47-1.28 (4H, m)；0.91(6H,dt).
Embodiment 4
The preparation of Bu Waxitan：
1) S-2- amino-butanamides (10.1g, 72mmol), benzyltriethylammoinium chloride (4.9g, 6.8mmol), hydrogen-oxygen are taken
Change sodium (44.4g, 210mmol), the trichlorine of formula III compound (15g, 66mmol) is added dropwise in anhydrous sodium sulfate (5g) at -10 DEG C
Methane (30ml) solution is stirred to react after -10~0 DEG C for 24 hours, filtering, and pale yellow oil is obtained after concentrated solvent；
2) pale yellow oil is dissolved in methyl tertiary butyl ether(MTBE) (80ml), stirring and dissolving, is filtered to remove insoluble miscellaneous
Matter is concentrated in vacuo to dry；
3) it is added in isopropyl acetate (25ml), dissolves by heating complete, be cooled to 5 DEG C or less crystallizations 4 hours, filter, use
A small amount of isopropyl acetate washing, it is 6 hours dry at (40 DEG C, -0.08MPa), obtain white solid powder 7.3g, as Bu Waxi
It is smooth.
Yield is 53%, HPLC purity ＞ 97%, ee purity ＞ 99%.1H NMR (300MHz, CDCl3)：δ6.17(1H,
s)；5.32(1H,s)；4.43(1H,dd)；3.49 (1H, dd)；3.01 (1H, dd)；2.59(1H,dd)；2.34(1H,m)；2.08
(1H, dd)；1.95(1H,m)；1.70 (1H, m)；1.47-1.28 (4H, m)；0.91(6H,dt).
Embodiment 5
Walk the preparation of Wa Xitan
1) S-2- amino-butanamides (30.1g, 216mmol) are taken, tetradecyl trimethyl ammonium chloride (5.8g,
19.8mmol), sodium hydride (14.2g, 593mmol), anhydrous sodium sulfate (15g), be added dropwise at 5 DEG C formula III compound (45g,
Methyl tertiary butyl ether(MTBE) (90ml) solution 197mmol) is stirred to react 10h after 10~20 DEG C, filters, and is obtained after concentrated solvent light
Yellow oil；
2) pale yellow oil is dissolved in isopropyl ether (200ml), stirring and dissolving, is filtered to remove insoluble impurity, very
Sky is concentrated to dryness；
3) it is added in isopropyl acetate (60ml), dissolves by heating complete, be cooled to 5 DEG C or less crystallizations 4 hours, filter, use
A small amount of isopropyl acetate washing, it is 4 hours dry at (40 DEG C, -0.08MPa), obtain white solid powder 23.0g, as Bu Waxi
It is smooth.
Yield is 56%, HPLC purity ＞ 97%, ee purity ＞ 99%,1H NMR (300MHz, CDCl3)：δ6.17(1H,
s)；5.32(1H,s)；4.43(1H,dd)；3.49 (1H, dd)；3.01 (1H, dd)；2.59(1H,dd)；2.34(1H,m)；2.08
(1H, dd)；1.95(1H,m)；1.70 (1H, m)；1.47-1.28 (4H, m)；0.91(6H,dt).
Embodiment 6
Walk the preparation of Wa Xitan
1) S-2- amino-butanamides (40.2g, 288mmol) are taken, 4-butyl ammonium hydrogen sulfate (13.4g, 39.4mmol), two is different
Formula III compound (60g, 262mmol) is added dropwise in propylcarbamic lithium (84.5g, 790mmol), anhydrous sodium sulfate (20g) at 0 DEG C
N,N-Dimethylformamide (120ml) solution, be stirred to react 10h after 10~20 DEG C, filter, obtained after concentrated solvent faint yellow
Grease；
2) pale yellow oil is dissolved in methyl tertiary butyl ether(MTBE) (400ml), stirring and dissolving, is filtered to remove insoluble miscellaneous
Matter is concentrated in vacuo to dry；
3) it is added in isopropyl acetate (100ml), dissolves by heating complete, be cooled to 5 DEG C or less crystallizations 4 hours, filter, use
A small amount of isopropyl acetate washing, it is 6 hours dry at (40 DEG C, -0.08MPa), obtain white solid powder 32.2g, as Bu Waxi
It is smooth.
Yield is 59%, HPLC purity ＞ 97%, ee purity ＞ 99%,1H NMR (300MHz, CDCl3)：δ6.17(1H,
s)；5.32(1H,s)；4.43(1H,dd)；3.49 (1H, dd)；3.01 (1H, dd)；2.59(1H,dd)；2.34(1H,m)；2.08
(1H, dd)；1.95(1H,m)；1.70 (1H, m)；1.47-1.28 (4H, m)；0.91(6H,dt).
Further experiment shows using other aprotic solvent, such as tetrahydrofuran, ether and methyl tertiary butyl ether(MTBE)
Deng to compoundSynthesis do not make significant difference.Chloride reagent is thionyl chloride, triphosgene, phosphorus oxychloride to production
Object does not also make significant difference.Under other reaction temperatures, at especially 20~55 DEG C, do not make significant difference to the preparation of product.React item
Part can be optimized further by having method.
Using compoundSynthesize Bu Waxitan when, other organic solvents, as dichloromethane, chloroform,
Acetonitrile, methyl tertiary butyl ether(MTBE), dimethyl sulfoxide (DMSO), N,N-dimethylformamide, tetrahydrofuran do not make significant difference to product；Alkali is hydrogen
When sodium oxide molybdena, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium hydride, lithium diisopropylamine, do not make significant difference to product；Phase
Transfer catalyst is benzyltriethylammoinium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, 4-butyl ammonium hydrogen sulfate, trioctylphosphine
When ammonio methacrylate, dodecyl trimethyl ammonium chloride, tetradecyl trimethyl ammonium chloride, polyethylene glycol, to product without notable
It influences.
Comparative example 1：
With embodiment 1, the difference is that using equimolar amountsReplace compoundDetection
The result shows that being unable to get Bu Waxitan.
By the response data of embodiment it is found that the compound of the present inventionWhen for synthesizing Bu Waxitan, have
The advantages that reaction step is short, and product purity is high, other raw materials are easy to get, and reaction condition is easily controllable has unexpected effect.
Claims (13)
1. a kind of compound, structural formula is as shown in formula III：
2. the synthetic method of compound described in claim 1, synthetic route are as follows：
Acyl chloride reaction is carried out in a solvent using chloride reagent and compound II, obtains III compound represented of formula.
3. synthetic method according to claim 2, it is characterised in that：The solvent of acyl chloride reaction is aprotic solvent.
4. synthetic method according to claim 2 or 3, it is characterised in that：The temperature of acyl chloride reaction is not higher than solvent
Reflux temperature.
5. synthetic method according to claim 3, it is characterised in that：Aprotic solvent is selected from tetrahydrofuran, toluene, dichloro
At least one of methane, ether and methyl tertiary butyl ether(MTBE).
6. synthetic method according to claim 2, it is characterised in that：Chloride reagent is selected from thionyl chloride, triphosgene, three
At least one of chlorethoxyfos.
7. synthetic method according to claim 4, it is characterised in that：The temperature of acyl chloride reaction is 20~55 DEG C.
8. application of the compound described in claim 1 in synthesizing Bu Waxitan.
9. a kind of synthetic method of Bu Waxitan, including use compound described in claim 1 and (S) -2- aminobutyryl amine salt
Hydrochlorate in organic solvent, carries out phase transfer reaction in the presence of a base, obtains Bu Waxitan, and synthetic route is as follows：
10. synthetic method according to claim 9, it is characterised in that：Organic solvent be selected from dichloromethane, chloroform,
At least one of acetonitrile, methyl tertiary butyl ether(MTBE), dimethyl sulfoxide (DMSO), N,N-dimethylformamide, tetrahydrofuran.
11. synthetic method according to claim 9, it is characterised in that：Alkali is selected from sodium hydroxide, potassium hydroxide, the tert-butyl alcohol
At least one of potassium, sodium tert-butoxide, sodium hydride, lithium diisopropylamine.
12. synthetic method according to claim 9, it is characterised in that：Phase transfer catalyst is selected from benzyl triethyl ammonium chlorination
Ammonium, tetrabutylammonium bromide, tetrabutylammonium chloride, 4-butyl ammonium hydrogen sulfate, tri-n-octyl methyl ammonium chloride, trimethyl chlorine
Change at least one of ammonium, tetradecyl trimethyl ammonium chloride, polyethylene glycol.
13. synthetic method according to claim 9, it is characterised in that：The temperature of phase transfer reaction is -10~50 DEG C.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109655557A (en) * | 2019-01-08 | 2019-04-19 | 丽珠集团新北江制药股份有限公司 | A kind of detection method of Bu Waxitan and its impurity |
| CN114213305A (en) * | 2021-12-29 | 2022-03-22 | 苏州诚和医药化学有限公司 | Production process of brivaracetam |
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| CN105646319A (en) * | 2015-12-30 | 2016-06-08 | 佛山市隆信医药科技有限公司 | Preparation method of brivaracetam |
| WO2016191435A1 (en) * | 2015-05-25 | 2016-12-01 | Peng Wang | Processes to produce brivaracetam |
| CN106748748A (en) * | 2015-11-10 | 2017-05-31 | 成都国弘医药有限公司 | A kind of Preparation Method And Their Intermediate of Bu Waxitan |
| CN108503573A (en) * | 2017-02-24 | 2018-09-07 | 北京艾百诺医药股份有限公司 | A kind of new preparation method of Bu Waxitan |
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| WO2016191435A1 (en) * | 2015-05-25 | 2016-12-01 | Peng Wang | Processes to produce brivaracetam |
| CN106748748A (en) * | 2015-11-10 | 2017-05-31 | 成都国弘医药有限公司 | A kind of Preparation Method And Their Intermediate of Bu Waxitan |
| CN105646319A (en) * | 2015-12-30 | 2016-06-08 | 佛山市隆信医药科技有限公司 | Preparation method of brivaracetam |
| CN108503573A (en) * | 2017-02-24 | 2018-09-07 | 北京艾百诺医药股份有限公司 | A kind of new preparation method of Bu Waxitan |
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| CN109655557A (en) * | 2019-01-08 | 2019-04-19 | 丽珠集团新北江制药股份有限公司 | A kind of detection method of Bu Waxitan and its impurity |
| CN114213305A (en) * | 2021-12-29 | 2022-03-22 | 苏州诚和医药化学有限公司 | Production process of brivaracetam |
| CN114213305B (en) * | 2021-12-29 | 2023-08-22 | 苏州诚和医药化学有限公司 | Production process of brivaracetam |
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