CN108530402A - The preparation method of one kind (R) -3- propyl-gamma-butyrolacton - Google Patents
The preparation method of one kind (R) -3- propyl-gamma-butyrolacton Download PDFInfo
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Abstract
The invention discloses a kind of preparation methods of (R) 3 propyl gamma butyrolactone, including：Using (S) 3 hydroxyl gamma butyrolactone as starting material, after sulphonic acid ester activated hydroxyl groups, in copper catalyst, in the presence of co-catalyst and nitrogenous compound, 3 propyl gamma butyrolactone of generation (R) is reacted with Grignard Reagent, the preparation method of (R) provided by the invention 3 propyl gamma butyrolactone has process route simple, raw material is cheap and easy to get, synthesis path is short, reaction condition is mild, it is easy to operate, high income, the good advantage of stereoselectivity, overcoming reaction existing in the prior art needs chiral resolution, chiral post separation, yield is low, and chemo-selective it is bad the problems such as, important value is provided for the technical study of Bu Waxitan.
Description
Technical field
The invention belongs to pharmaceutical chemistry to synthesize field, and in particular to a kind of antiepileptic Bu Waxitan intermediates (R) -3-
The preparation method of propyl-gamma-butyrolacton.
Background technology
Bu Waxitan is the third generation antiepileptic of excellent when ratio (UCB) company of Belgium research and development, respectively in January, 2016 and
Obtain within 2 months EMEA and FDA approval listings, the part for treat adult and 16 years old or more teenager epileptic breaks out, with or
Without the auxiliary treatment of secondary generalized seizure.Bu Waxitan is that the structure of Levetiracetam (Levetiracetam) derives
Object is a kind of highly selective, high-affinity synaptophysin 2A ligands, by with maincenter synaptic vesicle proteins 2A (SV2A)
In conjunction with influence synaptic function, while as a kind of sodium channel inhibitor of high-affinity, significantly improving antiepileptic activity.Yin Buwa
The western smooth good tolerability with better safety and pharmacokinetics, especially central nervous system, application prospect are preferable.
Bu Waxitan (Brivaracetam), chemical name (2S) -2- [(4R) -2- oxo -4- propyl -1- pyrrolidinyls] fourth
Amide, trade name Briviact, molecular formula C11H20N202, molecular weight 212.15, fusing point is 76.38 DEG C, white crystalline.
Structural formula is as follows：
The preparation of Bu Waxitan intermediates (R) -3- propyl-gamma-butyrolacton has following several method at present：
Method one：One is proposed in patent WO2016191435, CN106279074, CN106365986 and CN106432030
The preparation method of kind (R) -3- propyl-gamma-butyrolacton：
With (R)-epoxychloropropane (4) for starting material, formation is reacted with diester malonate (5) under the action of sodium methoxide
Compound 6, then compound 7 is obtained by the reaction with ethylmagnesium bromide in the presence of cuprous iodide, last decarboxylation obtains (R) -3- propyl -
Gamma-butyrolacton (3).
This method severe reaction conditions, yield are relatively low.
Method two：Document (J Org Chem, 1987,52 (6):1078-1082 and J ChemSoc Perkin Trans1,
1989,(5):935-943.) elaborate specific preparation method：
With to toluenesulfinic acid (8) be raw material, with chiral ligand (1R, 2S, 5R) -2- isopropyl -5- methyl cyclohexanols (9,
Also known as menthol) (1R, 2S, 5R) -2- isopropyl -5- methylcyclohexyl -1- are esterified to toluenesulfinic acid ester (10), with 1- penta
Alkynes magnesium bromide (11) nucleo philic substitution reaction obtains 4- (1- pentyne -1- sulfinyls) toluene (12), then with three (triphen phosphorus) chlorinations
Rhodium [RhCl (PPh3)3] be catalyst reduction 12 in triple carbon-carbon bonds obtain cis-form olefin (Z) -4- (1- amylene -1- sulfinyls) first
Benzene (13), 13 reset -2 (3H) -one of bis- chloro- 4- n-propyls dihydrofuran of (4S, 5R) -3,3- with trichloro-acetic chloride through Pummer
(14), 14 (R) -4- n-propyl dihydrofuran -2- ketone (3) is obtained through restoring, eliminating two-step reaction.
The route steps are cumbersome, are related to Grignard Reagent, low-temp reaction, and solvent uses the toxic reagents such as benzene, and time-consuming, at
This height is not suitable for industrialized production.
Method three：Document (Org.Process Res.Dev.2016,20,1566-1575) offer is a kind of to utilize biological enzyme
Reach the method for chiral resolution purpose.The route with propylmalonic acid dimethyl ester (16) be raw material, through bromine iso-butyl formate (17)
Replace to obtain compound 18, then split through decarboxylation, enzyme to obtain compound 20, most obtains (R) -4- propyl dihydros through reduction, cyclization afterwards
Furans -2- ketone (3).
This method synthetic route complex steps, are related to biological enzyme, use poisonous reagent ethyl chloroformate, cost that time-consuming
Height is not suitable for industrialized production.
Method four：Document (Org.Process Res.Dev.2016,20,1566-1575) elaborates a kind of to be detached with salt
Then continue synthetic method with purification chiral raw material.This method is modified on the basis of method three, and chiral benzene is utilized
Ethamine separating-purifying compound 20, but separating effect is bad.
There is many deficiencies in above method：Including severe reaction conditions, yield is relatively low, step is longer, raw material is not easy to obtain
It takes, agents useful for same or solvent toxicity are stronger etc..Therefore exploitation new method is needed to prepare (R) -3- propyl-gamma-butyrolacton.
Invention content
The present invention provides the preparation method of one kind (R) -3- propyl-gamma-butyrolacton, simple with process route, raw material is honest and clean
The advantage that valence is easy to get, synthesis path is short, reaction condition is mild, easy to operate, high income, stereoselectivity are good overcomes existing
The problems such as reaction present in technology needs chiral resolution, chiral post separation, yield is low and chemo-selective is bad.
The preparation method of one kind (R) -3- propyl-gamma-butyrolacton, including：
Wherein, R is p-toluenesulfonyl, mesyl or p-nitrophenyl sulfonyl；
(a) (S) -3- hydroxy-gamma-butyrolactones are dissolved in organic solvent A, and alkali is added under condition of ice bath, after stirring evenly, are delayed
Slow that the chloride solution for being dissolved in organic solvent A is added dropwise, control temperature continues stirring 5~15 hours, waits reacting at -30~30 DEG C
After, it is post-treated to obtain (S) -3- sulphonyl ester group-gamma-butyrolacton；
(b) organic solvent B dissolving (S) -3- sulphonyl ester group-gamma-butyrolacton, cuprous halide, co-catalyst, nitrogenous chemical combination
Grignard Reagent is added into the solution for object, and -30~20 DEG C are reacted 10~24 hours, after complete reaction, with saturation ammonium salt solution
It is quenched, it is post-treated to obtain (R) -3- propyl-gamma-butyrolacton.
The present invention under base catalysis, is obtained by the reaction using (S) -3- hydroxy-gamma-butyrolactones as starting material with sulfonic acid chloride
(S) -3- sulphonyl ester group-gamma-butyrolacton；Hydroxyl in the compound after sulphonic acid ester activates, can under copper catalysis with grignard
Reagent reacts generation (R) -3- propyl-gamma-butyrolacton；To enhance the complexing power of catalyst, the activity of catalyst is improved；
Co-catalyst is added in step (b), the co-catalyst is lithium methoxide, isopropyl lithium alkoxide or tert-butyl alcohol lithium；The co-catalyst
It is 1 with the ratio between the amount of substance of (S) -3- sulphonyl ester group-gamma-butyrolacton:1~3.
The alkali is triethylamine, diisopropyl ethyl amine, diethylaniline, N-methylmorpholine, pyridine, sodium carbonate, carbon
Sour hydrogen sodium, potassium carbonate, saleratus, sodium hydroxide, lithium hydroxide or potassium hydroxide, preferably triethylamine；Described (the S) -3-
The ratio between amount of substance of hydroxy-gamma-butyrolactone and alkali is 1:1~3, preferably 1:2.
The sulfonic acid chloride be paratoluensulfonyl chloride, mesyl chloride, 4-Nitrobenzenesulfonyl chloride, preferably paratoluensulfonyl chloride,
The ratio between described amount of substance of (S) -3- hydroxy-gamma-butyrolactones and sulfonic acid chloride is 1:1~2, preferably 1：1.6.
The organic solvent A be dichloromethane, 1,2- dichloroethanes, chloroform, toluene, dimethylbenzene, 1,4- dioxane,
Tetrahydrofuran, ethyl acetate, methyl acetate or butyl acetate, preferably dichloromethane.
The volumetric usage of the organic solvent A is calculated as 3~10mL/g with the quality of (S) -3- hydroxy-gamma-butyrolactones.
The cuprous halide is one kind in stannous chloride, cuprous bromide or cuprous iodide, preferably cuprous iodide；Halogen
It is 0.05~0.5 to change the ratio between cuprous and (S) -3- sulphonyl ester group-gamma-butyrolacton amount of substance:1, preferably 0.2:1.
The nitrogenous compound is N, N, N', N'- tetramethylethylenediamines, N, N, N', N ", N "-pentamethyl diethylidenes
Triamine, 1,1,4,7,10,10- hexamethyls trien, 2,2'- bipyridyls ,-three pyridine of 2,2', 6', 2 ", Phen
Or one kind in diisopropylethylamine, preferably 2,2'- bipyridyls, this is because 2,2'- bipyridyls are cost-effective, reaction is three-dimensional
Selectivity is best；The ratio between nitrogenous compound and the amount of substance of (S) -3- sulphonyl ester group-gamma-butyrolacton are 0.025~1:1, it is excellent
Select 0.4:1.
The Grignard Reagent propyl magnesium chloride, propyl magnesium bromide, propyl magnesium iodide, preferably propyl magnesium chloride；(S)-3-
The ratio between amount of substance of sulphonyl ester group-gamma-butyrolacton and Grignard Reagent is 1:1~2, preferably 1:1.5.
The organic solvent B is ether, acetone, methyl tertiary butyl ether(MTBE), tetrahydrofuran, 2- methyltetrahydrofurans, 1,4- bis-
One kind, preferably tetrahydrofuran in six ring of oxygen or toluene, the volumetric usage of organic solvent B is with (S) -3- sulphonyl ester group-γ-Ding Nei
The quality of ester is calculated as 1.5~10mL/g.
Reaction temperature in the step a) is preferably 0~10 DEG C；Reaction temperature in step b) is preferably -5~0 DEG C.
Post-processing described in step a) includes sour processing, liquid separation, washing, drying, concentration, purifying；After described in step b)
Processing includes extraction, dry, concentration, silica gel column chromatography purifying.
The saturation ammonium salt solution is preferably saturated ammonium chloride solution.
There is no stringent restrictions for the dosage of reaction raw materials in the present invention, more anti-than carrying out generally according to chemical reaction metering
It answers, to improve product yield, sulfonic acid chloride, grignard reagent are excessively reacted.
The not special meaning of term " organic solvent A ", " organic solvent B " is only intended to distinguish not labeled as " A ", " B "
With the organic solvent being previously mentioned in reaction step.
Compared with prior art, the beneficial effects of the present invention are：
Present invention process route is simple, uses (S) -3- hydroxy-gamma-butyrolactones cheap and easy to get for raw material, is reacted through 2 steps
Bu Waxitan keys chiral intermediate (R) -3- propyl-gamma-butyrolacton is made:Mild with reaction condition, easy to operate, yield
Advantage high, stereoselectivity is good, there is preferable application value and economic benefit.
Specific implementation mode
Below by specific embodiment, the invention will be further described, but protection scope of the present invention is not limited in
This.
Embodiment 1：
(a) preparation of (S) -3- p-toluenesulfonyls-gamma-butyrolacton
In 250mL single-necked flasks, raw material (S) -3- hydroxy-gamma-butyrolactones (10.0g, 98mmol) are dissolved in 20.0mL
Dichloromethane is added triethylamine (20.0g, 198mmol), stirs evenly controlled at -30 DEG C.By paratoluensulfonyl chloride
(30.0g, 157mmol) is dissolved in 40.0mL dichloromethane, is slowly added dropwise into above-mentioned reaction system, is stirred overnight at room temperature (anti-
Answer 12 hours), TLC detects raw material, and the reaction was complete.PH to 5, liquid separation, organic phase washing, saturation food are adjusted with the hydrochloric acid of 3mol/L
Salt is washed, and anhydrous sodium sulfate drying is concentrated under reduced pressure, and column chromatography purifies to obtain white solid 20.3g, yield 81%.
1H NMR(DMSO,400MHz)δ:7.72-7.81 (d, 2H), 7.44-7.53 (d, 2H), 5.32-5.48 (m, 1H),
4.33-4.58 (m, 2H), 2.43-2.48 (s, 3H, 3), 2.33-2.58 (m, 2H)
ESI-MS(m/z):257[M+].Mp：159-161℃.
(b) preparation of (R) -3- propyl-gamma-butyrolacton
At 0 DEG C, be added into 250mL three neck round bottom flask (S) -3- p-toluenesulfonyls-gamma-butyrolacton (10.00g,
39.0mmol), cuprous iodide (1.50g, 7.8mmol), 2,2'- bipyridyls (2.40g, 15.6mmol), lithium methoxide (1.48g,
Tetrahydrofuran (15.6mL) solution 39.0mmol), is vigorously stirred, be slowly added dropwise Extemporaneous propyl magnesium bromide (8.54g,
58.5mmol).Drop finishes, and keeps the temperature at 0 DEG C, continues to be vigorously stirred 24 hours.
Then reaction mixture is quenched with saturated ammonium chloride solution, three times with ether extraction, is dried with anhydrous sodium sulfate,
Vacuum distillation concentration, is then purified by silica gel chromatography (petroleum ether solution of 5% gradient ethyl acetate), and 4.6g whites are obtained
Solid, yield 92%.
1H NMR(DMSO,e400MHz)δ:4.11-4.38 (m, 2H), 2.10-2.35 (m, 2H), 1.87-2.15 (m,
1H), 1.05-1.18 (m, 2H), 1.28-1.35 (m, 2H), 0.85-0.91 (t, 3H)
ESI-MS(m/z):129[M+].Mp：114~117 DEG C.
Embodiment 2：
(a) preparation of (S) -3- p-toluenesulfonyls-gamma-butyrolacton
In 250mL single-necked flasks, raw material (S) -3- hydroxy-gamma-butyrolactones (13.0g, 127mmol) are taken, are dissolved in
26.0mL toluene, ice bath are added N-methylmorpholine (25.8g, 255mmol), stir evenly.By paratoluensulfonyl chloride (48.5g,
It 254mmol) is dissolved in 70.0mL toluene, is slowly added dropwise into above-mentioned reaction system, it is solid that reaction generates a large amount of triethylamine hydrochlorides
Body, iodine need mechanical agitation, are stirred to react 12 hours, and TLC detects raw material, and the reaction was complete.
It filtering, filter cake is washed with 13mL toluene, filtrate adjusts PH to 5 with the hydrochloric acid of 3mol/L, neutralizes excessive triethylamine,
Continue to filter, liquid separation is carried out to filtrate, water layer is extracted 1~2 time with toluene (26.0mL), merges organic phase.Washing, then be saturated
Brine It twice, after anhydrous sodium sulfate drying, is concentrated under reduced pressure, column chromatography purifies to obtain white solid 27.4g, yield
84%.
(b) preparation of (R) -3- propyl-gamma-butyrolacton
At 0 DEG C, be added into 250mL three neck round bottom flask (S) -3- p-toluenesulfonyls-gamma-butyrolacton (10.00g,
39.0mmol), stannous chloride (0.77g, 7.8mmol), 2,2'- bipyridyls (2.40g, 15.6mmol), lithium methoxide (1.48g,
2- methyltetrahydrofurans (15.6mL) solution 39.0mmol), is vigorously stirred, the propyl magnesium bromide of Extemporaneous is slowly added dropwise
(8.54g, 58.5mmol).Drop finishes, and keeps the temperature at -30 DEG C, continues to be vigorously stirred 20 hours.
Then reaction mixture is quenched with saturated ammonium chloride solution, three times with ether extraction, is dried with anhydrous sodium sulfate,
Vacuum distillation concentration, is then purified by silica gel chromatography (petroleum ether solution of 5% gradient ethyl acetate), and 4.1g whites are obtained
Solid, yield 82%.
Embodiment 3：
(a) preparation of (S) -3- p-toluenesulfonyls-gamma-butyrolacton
In 250mL single-necked flasks, raw material (S) -3- hydroxy-gamma-butyrolactones (13.0g, 127mmol) are taken, are dissolved in
26.0mL tetrahydrofurans, ice bath are added pyridine (20.2g, 255mmol), stir evenly.By paratoluensulfonyl chloride (24.3g,
It 127mmol) is dissolved in 70.0mL tetrahydrofurans, is slowly added dropwise into above-mentioned reaction system, reaction generates a large amount of triethylamine hydrochloric acid
Salt solid, iodine need mechanical agitation, are stirred to react 15 hours, and TLC detects raw material, and the reaction was complete.
It filters, washs filter cake with 13mL tetrahydrofurans, filtrate adjusts PH to 5 with the hydrochloric acid of 3mol/L, neutralizes excessive three
Ethamine continues to filter, and carries out liquid separation to filtrate, water layer is extracted 1~2 time with tetrahydrofuran (26.0mL), merges organic phase.Water
It washes, then is washed twice with saturated salt solution, after anhydrous sodium sulfate drying, is concentrated under reduced pressure, column chromatography purifies to obtain white solid
26.4g, yield 81%.
(b) preparation of (R) -3- propyl-gamma-butyrolacton
At 0 DEG C, be added into 250mL three neck round bottom flask (S) -3- p-toluenesulfonyls-gamma-butyrolacton (12.00g,
46.9mmol), cuprous bromide (1.35g, 9.4mmol), 2,2'- bipyridyls (7.32g, 46.9mmol), isopropyl lithium alkoxide (3.11g,
Isosorbide-5-Nitrae-dioxane (18.8mL) solution 46.9mmol), is vigorously stirred, the propyl magnesium bromide of Extemporaneous is slowly added dropwise
(13.82g, 93.8mmol).Drop finishes, and keeps the temperature at 20 DEG C, continuous to be vigorously stirred 12 hours.
Then reaction mixture is quenched with saturated ammonium chloride solution, three times with ether extraction, is dried with anhydrous sodium sulfate,
Vacuum distillation concentration, is then purified by silica gel chromatography (petroleum ether solution of 5% gradient ethyl acetate), and 5.4g whites are obtained
Solid, yield 90%.
Embodiment 4：
(a) preparation of (S) -3- p-toluenesulfonyls-gamma-butyrolacton
In 250mL single-necked flasks, raw material (S) -3- hydroxy-gamma-butyrolactones (20.0g, 196mmol) are taken, are dissolved in
40.0mL dimethylbenzene, ice bath are added triethylamine (40.0g, 396mmol), stir evenly.By paratoluensulfonyl chloride (60.0g,
It 314mmol) is dissolved in 80.0mL dimethylbenzene, is slowly added dropwise into above-mentioned reaction system, reaction generates a large amount of triethylamine hydrochlorides
Solid, iodine need mechanical agitation, are stirred to react 15 hours, and TLC detects raw material, and the reaction was complete.
It filters, washs filter cake with 20mL dimethylbenzene, filtrate adjusts PH to 5 with the hydrochloric acid of 3mol/L, neutralizes excessive three second
Amine continues to filter, and carries out liquid separation to filtrate, water layer is extracted 1~2 time with dimethylbenzene (40.0mL), merges organic phase.Washing, then
It is washed twice with saturated salt solution, after anhydrous sodium sulfate drying, is concentrated under reduced pressure, column chromatography purifies to obtain white solid 43.2g, produces
Rate 86%.
(b) preparation of (R) -3- propyl-gamma-butyrolacton
At 0 DEG C, be added into 250mL three neck round bottom flask (S) -3- p-toluenesulfonyls-gamma-butyrolacton (12.00g,
46.9mmol), cuprous iodide (4.46g, 23.45mmol), 2,2'- bipyridyls (0.183g, 1.173mmol), tert-butyl alcohol lithium
Acetone (18.8mL) solution of (3.75g, 46.9mmol), is vigorously stirred, the propyl magnesium bromide of Extemporaneous is slowly added dropwise
(6.91g, 46.9mmol).Drop finishes, and keeps the temperature at 0 DEG C, continuous to be vigorously stirred 24 hours.
Then reaction mixture is quenched with saturated ammonium chloride solution, three times with ether extraction, is dried with anhydrous sodium sulfate,
Vacuum distillation concentration, is then purified by silica gel chromatography (petroleum ether solution of 5% gradient ethyl acetate), and 5.2g whites are obtained
Solid, yield 87%.
Embodiment 5：
(a) preparation of (S) -3- p-toluenesulfonyls-gamma-butyrolacton
In 250mL single-necked flasks, raw material (S) -3- hydroxy-gamma-butyrolactones (20.0g, 196mmol) are taken, are dissolved in
40.0mL ethyl acetate is added triethylamine (19.8g, 196mmol), stirs evenly controlled at 10 DEG C.By tolysulfonyl
Chlorine (60.0g, 314mmol) is dissolved in 80.0mL ethyl acetate, is slowly added dropwise into above-mentioned reaction system, and reaction generates a large amount of three
Ethylamine hydrochloride solid, iodine need mechanical agitation, are stirred to react 12 hours, and TLC detects raw material, and the reaction was complete.
It filters, washs filter cake with 20mL ethyl acetate, filtrate adjusts PH to 5 with the hydrochloric acid of 3mol/L, neutralizes excessive three
Ethamine continues to filter, and carries out liquid separation to filtrate, aqueous layer with ethyl acetate (40.0mL) extracts 1~2 time, merges organic phase.Water
It washes, then is washed twice with saturated salt solution, after anhydrous sodium sulfate drying, is concentrated under reduced pressure, column chromatography purifies to obtain white solid
44.2g, yield 88%.
(b) preparation of (R) -3- propyl-gamma-butyrolacton
At 0 DEG C, be added into 250mL three neck round bottom flask (S) -3- p-toluenesulfonyls-gamma-butyrolacton (15.00g,
58.6mmol), cuprous iodide (2.23g, 11.7mmol), N, N, N', N'- tetramethylethylenediamines (2.72g, 23.4mmol), first
Ether (23mL) solution of lithium alkoxide (2.23g, 58.6mmol), is vigorously stirred, the propyl magnesium bromide of Extemporaneous is slowly added dropwise
(12.83g, 87.9mmol).Drop finishes, and keeps the temperature at 0 DEG C, continues to be vigorously stirred 20 hours.
Then reaction mixture is quenched with saturated ammonium chloride solution, three times with ether extraction, is dried with anhydrous sodium sulfate,
Vacuum distillation concentration, is then purified by silica gel chromatography (petroleum ether solution of 5% gradient ethyl acetate), and 6.2g whites are obtained
Solid, yield 82%.
Embodiment 6：
(a) preparation of (S) -3- p-toluenesulfonyls-gamma-butyrolacton
In 250mL single-necked flasks, raw material (S) -3- hydroxy-gamma-butyrolactones (13.0g, 127mmol) are taken, are dissolved in
26.0mL1,2- dichloroethanes are added diisopropylethylamine (33.0g, 255mmol), stir evenly controlled at 10 DEG C.It will
Paratoluensulfonyl chloride (38.8g, 203mmol) is dissolved in 70.0mL1, in 2- dichloroethanes, is slowly added dropwise into above-mentioned reaction system,
Reaction generates a large amount of triethylamine hydrochloride solids, and iodine needs mechanical agitation, is stirred to react 10 hours, and TLC detects raw material
The reaction was complete.
It filters, with 13mL1,2- dichloroethanes washs filter cake, and filtrate adjusts PH to 5 with the hydrochloric acid of 3mol/L, neutralizes excessive
Triethylamine, continue to filter, to filtrate carry out liquid separation, water layer with 1,2- dichloroethanes (26.0mL) extraction 1~2 time, be associated with
Machine phase.Washing, then washed twice with saturated salt solution, it after anhydrous sodium sulfate drying, is concentrated under reduced pressure, column chromatography purifies to obtain white
Solid 27.8g, yield 85%.
(b) preparation of (R) -3- propyl-gamma-butyrolacton
At 0 DEG C, be added into 250mL three neck round bottom flask (S) -3- p-toluenesulfonyls-gamma-butyrolacton (15.00g,
58.6mmol), cuprous iodide (2.23g, 11.7mmol), Phen (4.64g, 23.4mmol), lithium methoxide (2.23g,
Tetrahydrofuran (23mL) solution 58.6mmol), is vigorously stirred, be slowly added dropwise Extemporaneous propyl magnesium bromide (12.83g,
87.9mmol).Drop finishes, and keeps the temperature at 0 DEG C, continues to be vigorously stirred 24 hours.
Then reaction mixture is quenched with saturated ammonium chloride solution, three times with ether extraction, is dried with anhydrous sodium sulfate,
Vacuum distillation concentration, is then purified by silica gel chromatography (petroleum ether solution of 5% gradient ethyl acetate), and 6.4g whites are obtained
Solid, yield 85%.
Embodiment 7：
(a) preparation of (S) -3- p-toluenesulfonyls-gamma-butyrolacton
In 250mL single-necked flasks, raw material (S) -3- hydroxy-gamma-butyrolactones (13.0g, 127mmol) are taken, are dissolved in
26.0mL dichloromethane, ice bath are added diethylaniline (38.1g, 255mmol), stir evenly.By paratoluensulfonyl chloride
(38.8g, 203mmol) is dissolved in 70.0mL dichloromethane, is slowly added dropwise into above-mentioned reaction system, and reaction generates a large amount of three second
Amine hydrochlorate solid, iodine need mechanical agitation, are stirred to react 12 hours, and TLC detects raw material, and the reaction was complete.
It filters, washs filter cake with 13mL dichloromethane, filtrate adjusts PH to 5 with the hydrochloric acid of 3mol/L, neutralizes excessive three
Ethamine continues to filter, and carries out liquid separation to filtrate, water layer is extracted 1~2 time with dichloromethane (26.0mL), merges organic phase.Water
It washes, then is washed twice with saturated salt solution, after anhydrous sodium sulfate drying, is concentrated under reduced pressure, column chromatography purifies to obtain white solid
27.5g, yield 84%.
(b) preparation of (R) -3- propyl-gamma-butyrolacton
At 0 DEG C, be added into 250mL three neck round bottom flask (S) -3- p-toluenesulfonyls-gamma-butyrolacton (15.00g,
58.6mmol), cuprous iodide (2.23g, 11.7mmol), 1, Isosorbide-5-Nitrae, 7,10,10- hexamethyl triens (5.39g,
23.4mmol), tetrahydrofuran (23mL) solution of lithium methoxide (2.23g, 58.6mmol), is vigorously stirred, is slowly added dropwise and matches temporarily
The propyl magnesium bromide (12.83g, 87.9mmol) of system.Drop finishes, and keeps the temperature at -5 DEG C, continues to be vigorously stirred 24 hours.
Then reaction mixture is quenched with saturated ammonium chloride solution, three times with ether extraction, is dried with anhydrous sodium sulfate,
Vacuum distillation concentration, is then purified by silica gel chromatography (petroleum ether solution of 5% gradient ethyl acetate), and 6.5g whites are obtained
Solid, yield 86%.
Embodiment 8：
(a) preparation of (S) -3- p-toluenesulfonyls-gamma-butyrolacton
In 250mL single-necked flasks, raw material (S) -3- hydroxy-gamma-butyrolactones (13.0g, 127mmol) are taken, are dissolved in
26.0mL methyl acetates, ice bath are added potassium carbonate (35.2g, 255mmol), stir evenly.By paratoluensulfonyl chloride (38.8g,
It 203mmol) is dissolved in 70.0mL methyl acetates, is slowly added dropwise into above-mentioned reaction system, reaction generates a large amount of triethylamine hydrochloric acid
Salt solid, iodine need mechanical agitation, are stirred to react 12 hours, and TLC detects raw material, and the reaction was complete.
It filters, washs filter cake with 13mL methyl acetates, filtrate adjusts PH to 5 with the hydrochloric acid of 3mol/L, neutralizes excessive three
Ethamine continues to filter, and carries out liquid separation to filtrate, water layer is extracted 1~2 time with methyl acetate (26.0mL), merges organic phase.Water
It washes, then is washed twice with saturated salt solution, after anhydrous sodium sulfate drying, is concentrated under reduced pressure, column chromatography purifies to obtain white solid
28.4g, yield 87%.
(b) preparation of (R) -3- propyl-gamma-butyrolacton
At 0 DEG C, be added into 250mL three neck round bottom flask (S) -3- p-toluenesulfonyls-gamma-butyrolacton (15.00g,
58.6mmol), cuprous iodide (2.23g, 11.7mmol) ,-three pyridine of 2,2', 6', 2 " (10.16g, 23.4mmol), lithium methoxide
Tetrahydrofuran (23mL) solution of (2.23g, 58.6mmol), is vigorously stirred, the propyl magnesium bromide of Extemporaneous is slowly added dropwise
(12.83g, 87.9mmol).Drop finishes, and keeps the temperature at 0 DEG C, continues to be vigorously stirred 24 hours.
Then reaction mixture is quenched with saturated ammonium chloride solution, three times with ether extraction, is dried with anhydrous sodium sulfate,
Vacuum distillation concentration, is then purified by silica gel chromatography (petroleum ether solution of 5% gradient ethyl acetate), and 6.3g whites are obtained
Solid, yield 84%.
Embodiment 9：
(a) preparation of (S) -3- p-toluenesulfonyls-gamma-butyrolacton
In 250mL single-necked flasks, raw material (S) -3- hydroxy-gamma-butyrolactones (13.0g, 127mmol) are taken, are dissolved in
26.0mL dichloromethane is added saleratus (25.5g, 255mmol), stirs evenly controlled at 30 DEG C.It will be to toluene sulphur
Acyl chlorides (38.8g, 203mmol) is dissolved in 70.0mL dichloromethane, is slowly added dropwise into above-mentioned reaction system, and reaction generates a large amount of
Triethylamine hydrochloride solid, iodine need mechanical agitation, are stirred to react 5 hours, and TLC detects raw material, and the reaction was complete.
It filters, washs filter cake with 13mL dichloromethane, filtrate adjusts PH to 5 with the hydrochloric acid of 3mol/L, neutralizes excessive three
Ethamine continues to filter, and carries out liquid separation to filtrate, water layer is extracted 1~2 time with dichloromethane (26.0mL), merges organic phase.Water
It washes, then is washed twice with saturated salt solution, after anhydrous sodium sulfate drying, is concentrated under reduced pressure, column chromatography purifies to obtain white solid
27.1g, yield 83%.
(b) preparation of (R) -3- propyl-gamma-butyrolacton
At 0 DEG C, be added into 250mL three neck round bottom flask (S) -3- p-toluenesulfonyls-gamma-butyrolacton (15.00g,
58.6mmol), cuprous iodide (2.23g, 11.7mmol), N, N, N', N ", N "-five methyl diethylentriamines (4.06g,
23.4mmol), tetrahydrofuran (23mL) solution of lithium methoxide (2.23g, 58.6mmol), is vigorously stirred, is slowly added dropwise and matches temporarily
The propyl magnesium bromide (12.83g, 87.9mmol) of system.Drop finishes, and keeps the temperature at 0 DEG C, continues to be vigorously stirred 24 hours.
Then reaction mixture is quenched with saturated ammonium chloride solution, three times with ether extraction, is dried with anhydrous sodium sulfate,
Vacuum distillation concentration, is then purified by silica gel chromatography (petroleum ether solution of 5% gradient ethyl acetate), and 6.5g whites are obtained
Solid, yield 86%.
Embodiment 10：
(a) preparation of (S) -3- p-toluenesulfonyls-gamma-butyrolacton
In 250mL single-necked flasks, raw material (S) -3- hydroxy-gamma-butyrolactones (13.0g, 127mmol) are taken, are dissolved in
26.0mL dichloromethane is added sodium hydroxide (10.2g, 255mmol), stirs evenly controlled at 20 DEG C.It will be to toluene sulphur
Acyl chlorides (38.8g, 203mmol) is dissolved in 70.0mL dichloromethane, is slowly added dropwise into above-mentioned reaction system, and reaction generates a large amount of
Triethylamine hydrochloride solid, iodine need mechanical agitation, are stirred to react 12 hours, and TLC detects raw material, and the reaction was complete.
It filters, washs filter cake with 13mL dichloromethane, filtrate adjusts PH to 5 with the hydrochloric acid of 3mol/L, neutralizes excessive three
Ethamine continues to filter, and carries out liquid separation to filtrate, water layer is extracted 1~2 time with dichloromethane (26.0mL), merges organic phase.Water
It washes, then is washed twice with saturated salt solution, after anhydrous sodium sulfate drying, is concentrated under reduced pressure, column chromatography purifies to obtain white solid
28.1g, yield 86%.
(b) preparation of (R) -3- propyl-gamma-butyrolacton
At 0 DEG C, be added into 250mL three neck round bottom flask (S) -3- p-toluenesulfonyls-gamma-butyrolacton (15.00g,
58.6mmol), cuprous iodide (2.23g, 11.7mmol), diisopropylethylamine (3.02g, 23.4mmol), lithium methoxide (2.23g,
Ether (23mL) solution 58.6mmol), is vigorously stirred, be slowly added dropwise Extemporaneous propyl magnesium bromide (12.83g,
87.9mmol).Drop finishes, and keeps the temperature at 0 DEG C, continues to be vigorously stirred 24 hours.
Then reaction mixture is quenched with saturated ammonium chloride solution, three times with ether extraction, is dried with anhydrous sodium sulfate,
Vacuum distillation concentration, is then purified by silica gel chromatography (petroleum ether solution of 5% gradient ethyl acetate), and 6.6g whites are obtained
Solid, yield 88%.
Embodiment 11：
(a) preparation of (S) -3- p-toluenesulfonyls-gamma-butyrolacton
In 250mL single-necked flasks, raw material (S) -3- hydroxy-gamma-butyrolactones (16.0g, 157mmol) are taken, are dissolved in
30.0mL chloroforms, ice bath are added triethylamine (31.7g, 313mmol), stir evenly.By mesyl chloride (28.8g, 251mmol)
It is dissolved in 60.0mL chloroforms, is slowly added dropwise into above-mentioned reaction system, reaction generates a large amount of triethylamine hydrochloride solids, and amplification is anti-
It answers, needs mechanical agitation, be stirred to react 10 hours, TLC detects raw material, and the reaction was complete.
It filters, with 15mL chloroform filter cakes, filtrate adjusts PH to 5 with the hydrochloric acid of 3mol/L, neutralizes excessive triethylamine,
Continue to filter, liquid separation is carried out to filtrate, water layer is extracted 1~2 time with chloroform (30.0mL), merges organic phase.Washing, then be saturated
Brine It twice, after anhydrous sodium sulfate drying, is concentrated under reduced pressure, column chromatography purifies to obtain white solid 34.1g, yield
85%.
(b) preparation of (R) -3- propyl-gamma-butyrolacton
At 0 DEG C, be added into 250mL three neck round bottom flask (S) -3- p-toluenesulfonyls-gamma-butyrolacton (22.00g,
85.9mol), cuprous iodide (0.82g, 4.30mmol), 2,2'- bipyridyls (5.37g, 34.4mmol), lithium methoxide (3.26g,
Toluene (34.0mL) solution 85.9mmol), is vigorously stirred, be slowly added dropwise Extemporaneous propyl magnesium bromide (18.80g,
128.9mmol).Drop finishes, and keeps the temperature at 0 DEG C, continues to be vigorously stirred 24 hours.
Then reaction mixture is quenched with saturated ammonium chloride solution, three times with ether extraction, is dried with anhydrous sodium sulfate,
Vacuum distillation concentration, is then purified by silica gel chromatography (petroleum ether solution of 5% gradient ethyl acetate), it is colourless to obtain 9.4g
Grease, yield 85%.
Embodiment 12：
(a) preparation of (S) -3- p-toluenesulfonyls-gamma-butyrolacton
In 250mL single-necked flasks, raw material (S) -3- hydroxy-gamma-butyrolactones (16.0g, 157mmol) are taken, are dissolved in
30.0mL1,4- dioxane, ice bath are added triethylamine (47.8g, 471mmol), stir evenly.By 4-Nitrobenzenesulfonyl chloride
(55.6g, 251mmol) is dissolved in 60.0mL1, in 4- dioxane, is slowly added dropwise into above-mentioned reaction system, and reaction generates a large amount of
Triethylamine hydrochloride solid, iodine need mechanical agitation, are stirred to react 10 hours, and TLC detects raw material, and the reaction was complete.
It filters, with 15mL1,4- dioxane washs filter cake, and filtrate adjusts PH to 5 with the hydrochloric acid of 3mol/L, neutralizes excessive
Triethylamine, continue to filter, to filtrate carry out liquid separation, water layer with Isosorbide-5-Nitrae-dioxane (30.0mL) extract 1~2 time, be associated with
Machine phase.Washing, then washed twice with saturated salt solution, it after anhydrous sodium sulfate drying, is concentrated under reduced pressure, column chromatography purifies to obtain white
Solid 34.5g, yield 86%.
(b) preparation of (R) -3- propyl-gamma-butyrolacton
At 0 DEG C, be added into 250mL three neck round bottom flask (S) -3- p-toluenesulfonyls-gamma-butyrolacton (22.00g,
85.9mol), cuprous iodide (3.27g, 17.2mmol), 2,2'- bipyridyls (5.37g, 34.4mmol), lithium methoxide (3.26g,
Methyl tertiary butyl ether(MTBE) (34.0mL) solution 85.9mmol), is vigorously stirred, the propyl magnesium bromide of Extemporaneous is slowly added dropwise
(18.80g, 128.9mmol).Drop finishes, and keeps the temperature at -5 DEG C, continues to be vigorously stirred 24 hours.
Then reaction mixture is quenched with saturated ammonium chloride solution, three times with ether extraction, is dried with anhydrous sodium sulfate,
Vacuum distillation concentration, is then purified by silica gel chromatography (petroleum ether solution of 5% gradient ethyl acetate), it is colourless to obtain 9.6g
Grease, yield 87%.
Embodiment 13：
(a) preparation of (S) -3- p-toluenesulfonyls-gamma-butyrolacton
In 250mL single-necked flasks, raw material (S) -3- hydroxy-gamma-butyrolactones (10.0g, 98mmol) are taken, 20.0mL is dissolved in
Butyl acetate is added triethylamine (20.0g, 198mmol), stirs evenly controlled at 10 DEG C.By paratoluensulfonyl chloride
(30.0g, 157mmol) is dissolved in 40.0mL butyl acetates, is slowly added dropwise into above-mentioned reaction system, and reaction generates a large amount of three second
Amine hydrochlorate solid, iodine need mechanical agitation, are stirred to react 10 hours, and TLC detects raw material, and the reaction was complete.
It filters, washs filter cake with 10mL butyl acetates, filtrate adjusts PH to 5 with 3mol/L HCl, neutralizes excessive three second
Amine continues to filter, and carries out liquid separation to filtrate, water layer is extracted 1~2 time with butyl acetate (20.0mL), merges organic phase.Washing,
It is washed twice with saturated salt solution, after anhydrous sodium sulfate drying, is concentrated under reduced pressure to give, column chromatography purifies to obtain white solid again
20.1g, yield 80%.
(b) preparation of (R) -3- propyl-gamma-butyrolacton
At 0 DEG C, be added into 250mL three neck round bottom flask (S) -3- p-toluenesulfonyls-gamma-butyrolacton (21.00g,
82.0mol), cuprous iodide (3.12g, 16.4mmol), 2,2'- bipyridyls (5.12g, 32.8mmol), lithium methoxide (3.11g,
Tetrahydrofuran (33.0mL) solution 82.0mmol), is vigorously stirred, be slowly added dropwise Extemporaneous propyl magnesium iodide (17.91g,
123.0mmol).Drop finishes, and keeps the temperature at -5 DEG C, continues to be vigorously stirred 10 hours.
Then reaction mixture is quenched with saturated ammonium chloride solution, three times with ether extraction, is dried with anhydrous sodium sulfate,
Vacuum distillation concentration, is then purified by silica gel chromatography (petroleum ether solution of 5% gradient ethyl acetate), and 8.4g whites are obtained
Solid, yield 80%.
It should be pointed out that the design only to illustrate the invention of above-mentioned experiment embodiment and feature, the purpose is to allow be familiar with this
The people of invention understands this experiment and implements according to this, can not limit the scope of the invention.It is all according to spirit of the invention
The equivalent change or modification made should all cover within the scope of the present invention.
Claims (10)
1. the preparation method of one kind (R) -3- propyl-gamma-butyrolacton, including：
Wherein, R is p-toluenesulfonyl, mesyl or p-nitrophenyl sulfonyl；
(a) (S) -3- hydroxy-gamma-butyrolactones are dissolved in organic solvent A, and alkali is added under condition of ice bath, after stirring evenly, are slowly dripped
Solubilization is in the chloride solution of organic solvent A, and control temperature continues stirring 5~15 hours at -30~30 DEG C, to the end of reaction
Afterwards, post-treated to obtain (S) -3- sulphonyl ester group-gamma-butyrolacton；
(b) after organic solvent B dissolving (S) -3- sulphonyl ester group-gamma-butyrolacton, cuprous halide, co-catalyst, nitrogenous compound,
Grignard Reagent is added into the solution, -30~20 DEG C are reacted 10~24 hours, after complete reaction, are quenched with saturation ammonium salt solution
It goes out, it is post-treated to obtain (R) -3- propyl-gamma-butyrolacton.
2. the preparation method of (R) -3- propyl-gamma-butyrolacton according to claim 1, which is characterized in that the alkali is
Triethylamine, diisopropyl ethyl amine, diethylaniline, N-methylmorpholine, pyridine, sodium carbonate, sodium bicarbonate, potassium carbonate, carbonic acid
The ratio between the amount of substance of hydrogen potassium, sodium hydroxide, lithium hydroxide or potassium hydroxide, (the S) -3- hydroxy-gamma-butyrolactones and alkali is
1:1~3.
3. the preparation method of (R) -3- propyl-gamma-butyrolacton according to claim 1, which is characterized in that the sulphonyl
Chlorine is paratoluensulfonyl chloride, mesyl chloride or 4-Nitrobenzenesulfonyl chloride, (the S) -3- hydroxy-gamma-butyrolactones and sulfonic acid chloride
The ratio between amount of substance is 1:1~2.
4. the preparation method of (R) -3- propyl-gamma-butyrolacton according to claim 1, which is characterized in that described is organic
Solvent A be dichloromethane, 1,2- dichloroethanes, chloroform, toluene, dimethylbenzene, 1,4- dioxane, tetrahydrofuran, ethyl acetate,
Methyl acetate or butyl acetate；The volumetric usage of the organic solvent A is calculated as 3 with the quality of (S) -3- hydroxy-gamma-butyrolactones
~10mL/g.
5. the preparation method of (R) -3- propyl-gamma-butyrolacton according to claim 1, which is characterized in that the halogenation
Cuprous one kind in stannous chloride, cuprous bromide or cuprous iodide, cuprous halide and (S) -3- sulphonyl ester group-gamma-butyrolacton
The ratio between the amount of substance be 0.05~0.5:1.
6. the preparation method of (R) -3- propyl-gamma-butyrolacton according to claim 1, which is characterized in that described helping is urged
Agent is lithium methoxide, isopropyl lithium alkoxide or tert-butyl alcohol lithium；The substance of the co-catalyst and (S) -3- sulphonyl ester group-gamma-butyrolacton
The ratio between amount be 1:1~3.
7. the preparation method of (R) -3- propyl-gamma-butyrolacton according to claim 1, which is characterized in that described is nitrogenous
Compound is N, N, N', N'- tetramethylethylenediamines, N, N, N', N ", N "-five methyl diethylentriamines, 1,1,4,7,10,10-
One in hexamethyl trien, 2,2'- bipyridyls ,-three pyridine of 2,2', 6', 2 ", Phen or diisopropylethylamine
Kind, the ratio between nitrogenous compound and the amount of substance of (S) -3- sulphonyl ester group-gamma-butyrolacton are 0.025~1:1.
8. the preparation method of (R) -3- propyl-gamma-butyrolacton according to claim 1, which is characterized in that the grignard examination
Agent is propyl magnesium chloride, propyl magnesium bromide or propyl magnesium iodide, the object of (S) -3- sulphonyl ester group-gamma-butyrolacton and Grignard Reagent
The ratio between amount of matter is 1:1~2.
9. the preparation method of (R) -3- propyl-gamma-butyrolacton according to claim 1, which is characterized in that described organic molten
Agent B is one kind in ether, acetone, methyl tertiary butyl ether(MTBE), tetrahydrofuran, 2- methyltetrahydrofurans, Isosorbide-5-Nitrae-dioxane or toluene,
The volumetric usage of organic solvent B is calculated as 1.5~10mL/g with the quality of (S) -3- sulphonyl ester group-gamma-butyrolacton.
10. the preparation method of (R) -3- propyl-gamma-butyrolacton according to claim 1, which is characterized in that step a) institutes
The post-processing stated includes sour processing, liquid separation, washing, drying, concentration, purifying；Post-processing described in step b) includes extraction, does
Dry, concentration, silica gel column chromatography purifying.
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