CN110885325B - Preparation method of (S) -glycidol phthalimide - Google Patents
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Abstract
The invention provides a preparation method of (S) -glycidol phthalimide (II). Phthalimide (III) and (S) -1-substituent epoxypropane (IV) are used as raw materials to react under the action of a catalyst to generate 2- ((S) -3-substituent-2-hydroxypropyl) isoindoline-1, 3-diketone (V), and finally (S) -glycidol phthalimide (II) is generated through a ring closure reaction. The method has the advantages of cheap and easily obtained raw materials, easily realized reaction conditions and low cost; the reaction route is short, the operation is simple and convenient, and the post-treatment is simple; less side reaction, high yield and purity of target product, and suitability for industrial production.
Description
Technical Field
The invention relates to a preparation method of (S) -glycidol phthalimide, belonging to the field of pharmaceutical biochemical industry.
Background
Rivaroxaban, known as Rivaroxaban in english, is a new oral anticoagulant; the composition is absorbed through oral administration, has long curative effect, is used for preventing and treating venous thrombosis, has wide treatment range and does not need conventional monitoring of blood coagulation function. Rivaroxaban, the first direct factor Xa inhibitor developed by bayer, was approved by the U.S. Food and Drug Administration (FDA) for marketing in 2011; the preparation is mainly used for preventing the formation of deep vein thrombosis and pulmonary thrombosis of patients after hip joint and knee joint replacement in clinic, can also prevent cerebral apoplexy and non-central nervous system embolism of patients with non-valvular atrial fibrillation, and reduces the recurrence risk of coronary artery syndrome. The market sales of rivaroxaban from 2011 to 2016 are $ 1.4, $ 6.5 $ 21.1 $ 37.5 $ 43.6 $ 55.6 billion respectively, and its rapidly increasing sales and superior performance will make it a new milestone in the development history of cardiovascular drugs. Therefore, the development of a preparation method of rivaroxaban with high purity and low cost is of great significance.
The structural formula of rivaroxaban (I) is shown in the specification.
Wherein, (S) -glycidylphthalimide (II) is an important intermediate for preparing rivaroxaban, novel antibiotic linezolid, antifungal thioxooxazolidone and oxazolidinedione.
The preparation method of (S) -glycidol phthalimide mainly comprises the following steps:
gutcait et al (Tetrahedron asym.1996,7,1641) use phthalimide and (S) -glycidol as starting materials in diethyl azodicarboxylate (DEAD) and triphenylphosphine (Ph) in tetrahydrofuran3P) in the presence of a catalyst, to prepare (S) -glycidylphthalimide. Depicted as scheme 1 below:
synthesis scheme 1
The method generates a large amount of triphenylphosphine oxide and urea byproducts, has complex post-treatment and lower reaction yield (80 percent), and is not beneficial to industrial production.
Bogda et al (Synlett, Vol.1996.873-874) use phthalimide and (S) -epichlorohydrin as raw materials to prepare (S) -glycidol phthalimide by a microwave method in the presence of tetrabutylammonium bromide and potassium carbonate, but the microwave method has high energy consumption and high cost and is not beneficial to industrial production.
Patent document WO2006031179 (astrazeneca) utilizes potassium phthalimide to react with (R) -3-chloro-1, 2-propanediol to obtain (S) -N-dihydroxypropyl phthalimide, which is then cyclized with trimethyl orthoacetate in the presence of an acid catalyst, and then cyclized with acetyl halide in an alkaline condition to form an oxirane ring, thereby preparing (S) -glycidylphthalimide. Depicted as scheme 2 below:
synthesis scheme 2
The method has long route and complicated operation, and in addition, trimethyl orthoacetate is used for protection and acetyl halide ring opening, so that the production cost is high, and the cost reduction and industrialization are not facilitated.
Patent document EP 1403267 describes the preparation of (S) -glycidylphthalimide by reacting (S) -epichlorohydrin with potassium phthalimide as starting material in the presence of isopropanol and trimethylbenzylammonium chloride. The method takes the phthalimide potassium as the raw material, and the raw material has high price; in addition, in the reaction process, the phthalimide negative ions carry out nucleophilic attack on the epoxy groups, so that the side reactions are more, the product is difficult to purify, the purification condition requirement is high, and the product production cost is high; and the product yield and purity are also low.
Chinese patent document CN103382200A also uses potassium phthalimide or phthalimide as a raw material, and reacts with (S) -epichlorohydrin in the presence of isopropanol, a large amount of benzyltriethylammonium chloride and potassium iodide to prepare (S) -glycidylphthalimide. Depicted as scheme 3 below:
synthesis scheme 3
Although the method has high product yield, the used benzyltriethylammonium chloride is as high as more than 12 percent of the phthalimide potassium, and the method is not easy to carry out post-treatment; in addition, the reaction selectable temperature is low because of the poor stability of the epoxy ring. In addition, although the invention takes phthalimide and (S) -epichlorohydrin as raw materials to carry out the reaction, potassium tert-butoxide needs to be added, and the reaction in the method is actually as follows: phthalimide and potassium tert-butoxide firstly form potassium phthalimide, and then the potassium phthalimide reacts with (S) -epoxy chloropropane, actually, phthalimide negative ions carry out nucleophilic attack on epoxy groups; SN of nitrogen negative ion and methyl chloride existing in reaction process of phthalimide potassium and (S) -epichlorohydrin2A side reaction, in which a small amount of (R) -glycidylphthalimide is produced while the target product is produced (the reaction mechanism is described as the following synthetic scheme 4), which is difficult to purify; in addition, due to the stronger nucleophilicity of the phthalimide negative ions, a tandem reaction byproduct of the phthalimide negative ions and the final product (S) -glycidol phthalimide can also be generated in the actual reaction; the above factors result in the purity of the target product being only 92% at most, and the yield of waste water is increased by the washing stepLarge, not beneficial to environmental protection and industrial production. In addition, the generated potassium phthalimide has slow reaction rate due to low solubility and low reaction temperature, the reaction time is 72 to 140 hours, the production period is longer and the cost is higher.
Synthesis scheme 4
Therefore, a preparation method of (S) -glycidol phthalimide, which is simple and convenient to operate, easy to realize, green and safe, low in cost, few in byproducts, high in purity and yield and suitable for industrial production, is sought, and has important significance for the production of rivaroxaban or other medical products; the invention is particularly proposed.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a preparation method of (S) -glycidol phthalimide with low cost and high purity. The method has the advantages of cheap and easily obtained raw materials, easily realized reaction conditions and low cost; the reaction route is short, the operation is simple and convenient, and the post-treatment is simple; less side reaction, high yield and purity of target product, and suitability for industrial production.
Description of terms:
a compound of formula II: (S) -glycidylphthalimide;
a compound of formula III: phthalimide;
a compound of formula IV: (S) -1-substituent propylene oxide;
a compound of formula V: 2- ((S) -3-substituent-2-hydroxypropyl) isoindoline-1, 3-dione.
In the specification, the compound numbers are completely consistent with the structural formula numbers, have the same reference relationship, and are based on the structural formula of the compound.
The technical scheme of the invention is as follows:
a method for preparing (S) -glycidylphthalimide (II), comprising the steps of:
(1) preparing a compound of formula v by reacting a compound of formula iii with a compound of formula iv;
in the structural formulas of the compound shown in the formula IV and the compound shown in the formula V, a substituent X is chlorine, bromine, methylsulfonyloxy, p-toluenesulfonyloxy or phenylsulfonyloxy;
(2) the compound of the formula V is subjected to ring closure reaction to prepare a compound of a formula II.
According to a preferred embodiment of the invention, in step (1), the reaction of the compound of formula III with the compound of formula IV is carried out in solvent A under the action of a catalyst.
Preferably, the solvent A is one or a combination of more than two of isopropanol, ethanol, Tetrahydrofuran (THF), 2-methyltetrahydrofuran or N, N-Dimethylformamide (DMF); the mass ratio of the solvent A to the compound of the formula III is (3.0-10.0): 1.
preferably, the catalyst is one or a combination of more than two of benzyltriethylammonium chloride, tetrabutylammonium iodide, tetrabutylammonium bromide, tetrabutylammonium chloride or dodecyltrimethylammonium chloride; the number of moles of said catalyst is 3-9% of the number of moles of the compound of formula III.
Preferably, according to the invention, the molar ratio of the compound of formula IV to the compound of formula III in step (1) is (1.0-3.0): 1.
preferably, according to the invention, the reaction temperature in step (1) is 30-80 ℃; preferably, the reaction temperature is 30-60 ℃. The reaction time is 2-24 hours; preferably, the reaction time is 5 to 15 hours.
According to a preferred embodiment of the invention, in step (2), the ring closure of the compound of formula V is carried out in solvent B under the action of a basic reagent.
Preferably, the solvent B is one or a combination of more than two of dichloromethane, toluene, tetrahydrofuran or methyl tert-butyl ether; the mass ratio of the solvent B to the compound of formula V is (2.0-10.0): 1.
preferably, the alkaline reagent is sodium hydride, 10-40 wt% sodium methoxide methanol solution, 10-40 wt% sodium hydroxide alcohol solution, 10-40 wt% potassium hydroxide alcohol solution or 10-40 wt% sodium ethoxide ethanol solution, wherein the alcohol solution is methanol, ethanol or isopropanol solution; the molar ratio of the basic agent to the compound of the formula V is (0.9-1.2): 1.
Preferably, the ring closure reaction of the compound of formula v comprises the steps of: mixing the compound of formula V and solvent B, dripping alkaline reagent at (-10) -40 deg.C, and performing ring closure reaction at (-10) -40 deg.C.
Preferably according to the invention, the temperature of the ring closure reaction in step (2) is (-10) to 40 ℃; preferably, the ring closure reaction temperature is 5-30 ℃. The ring closing reaction time is 0.5-10 hours; preferably, the ring closing reaction time is 0.5-2 hours;
the process of the present invention is depicted as the following reaction scheme (scheme 5):
Wherein X is chlorine, bromine, methylsulfonyloxy, p-toluenesulfonyloxy or phenylsulfonyloxy.
The invention has the technical characteristics and beneficial effects that:
1. the invention uses cheap and easily obtained phthalimide (III) and (S) -1-substituent epoxypropane (IV) as raw materials, the raw materials react under the action of a phase transfer catalyst to generate 2- ((S) -3-substituent-2-hydroxypropyl) isoindoline-1, 3-diketone (V), the obtained product is subjected to simple separation, hydrogen chloride is removed under an alkaline condition, and ring closure is carried out to generate (S) -glycidol phthalimide (II), wherein the alkali is preferably added into the system in a dropwise manner, and the yield and the purity of a target product are improved. The raw materials used in the invention are cheap and easily available, the reaction conditions are mild, the control and implementation are easy, and the cost is low; according to the invention, the target product can be prepared by only two steps, and the reaction intermediate 2- ((S) -3-substituent-2-hydroxypropyl) isoindoline-1, 3-diketone (IV) is directly subjected to the next reaction after being simply purified, so that the process route is simple, the operation is simple and convenient, and the post-treatment and purification of the target product are simple; the method is green and safe and is suitable for industrial production.
2. Compared with the prior art CN103382200A, the invention adopts a phase transfer catalyst to catalyze the nucleophilic substitution reaction of phthalimide and (S) -1-substituent epoxypropane: the amount of the used catalyst is small, the post-treatment is easy, and the cost is reduced; the stability of raw materials and intermediate products is high, the reaction temperature is proper, the problem of low solubility of potassium phthalimide is not involved, the reaction time is short, and the preparation period is short; the reaction does not relate to phthalimide negative ions, the nucleophilicity of the reaction is higher than that of the phthalimide, side reactions caused by high activity of the phthalimide negative ions are avoided, byproducts such as R-enantiomer and the like are avoided, the reaction selectivity is high, the side reactions and the byproducts are few, the total yield of products of the two-step reaction can reach 88.2 percent (calculated by taking the phthalimide as the starting material), the enantiomeric purity can reach 99.4 percent only by simple recrystallization purification, and the purity is higher; and the post-treatment does not need the steps of water washing and the like, the waste water generation amount is small, and the method is green and environment-friendly. In addition, the invention has higher reaction yield and purity than those of the method which takes the phthalimide potassium and the (S) -epichlorohydrin as raw materials.
3. The invention overcomes the defect that the nucleophilic activity of the phthalimide is improved by adding alkali (such as potassium carbonate, triethylamine and the like) into a phthalimide reaction system in the prior art; because the alkali also has nucleophilic activity, the alkali reacts with an epoxy group to generate a byproduct, and simultaneously phthalimide generates an anion form, the alkali also generates a side product in a series connection; the invention avoids the two side reactions, thereby improving the reaction selectivity of the phthalimide and improving the reaction yield and purity.
Drawings
FIG. 1 shows the nuclear magnetic spectrum of the product obtained in example 1 (deuterated CDCl)3)；
FIG. 2 is a liquid chromatogram of the product obtained in example 1;
FIG. 3 is a photograph of a film obtained by the preparation of example 2Nuclear magnetic hydrogen spectrum (deuterated CDCl) of (S) -glycidylphthalimide (ii)3)；
FIG. 4 is a liquid chromatogram of (S) -glycidylphthalimide (II) prepared in example 2;
FIG. 5 is a chiral liquid chromatogram of (S) -glycidylphthalimide (II) prepared in example 2.
Detailed Description
The present invention is described in detail below with reference to examples, but the present invention is not limited thereto.
The (S) -1-substituted cyclopropane (IV) used in the examples is either commercially available or can be prepared by condensation of 1-hydroxy-propylene oxide with the corresponding acid or sulfonyl chloride according to the prior art.
The rest raw materials and reagents are all commercial products.
In the examples, "%" is mass percent unless otherwise specified; the yields are all molar yields.
Example 1: 2- ((S) -3-chloro-2-hydroxypropyl) isoindoline-1, 3-dione (V)1) Preparation of
To a 500 ml four-necked flask equipped with a stirrer, a thermometer and a condenser were charged 160 g of isopropyl alcohol, 29.6 g (0.20 mol) of phthalimide (III) and 27.8 g (0.30 mol) of (S) -1-chloroepoxypropane (IV)1) 3.22 g (0.01 mol) of tetrabutylammonium bromide, and the mixture was heated and stirred at an internal temperature of 43 ℃ for 12 hours. Vacuum distilling to recover isopropanol, adding 80 g n-hexane into residue, stirring at room temperature for 1 hr, filtering, washing filter cake with 20 g n-hexane, and mixing filtrates. And (3) decompressing and distilling to recover the normal hexane and the excessive (S) -1-chloroepoxypropane. The filter cake is dried to give 49.7 g of crude 2- ((S) -3-chloro-2-hydroxypropyl) isoindoline-1, 3-dione (V)1) (ii) a Was used without further purification in example 2.
FIG. 1 shows the nuclear magnetic spectrum (deuterated CDCl) of the product obtained in this example3)；
The nuclear magnetic data of the product are as follows:
1HNMR (400MHz, deuterated CDCl)3)δ:2.95(br,1H),3.57-3.72(m,1H),3.02-3.84(m,2H),4.11-4.24(m,1H),7.71-7.77(m,2H),7.83-7.90(m,2H)
As can be seen from FIG. 1, the product prepared in this example is 2- ((S) -3-chloro-2-hydroxypropyl) isoindoline-1, 3-dione (V)1) And (S) -glycidylphthalimide (II). The peaks marked are partial peaks of the minor amount of (S) -glycidylphthalimide (II) produced in the reaction of this example, and the peaks of the two compounds of the aromatic hydrogen signal overlap and are not shown.
FIG. 2 is a liquid chromatogram of the product obtained in this example; as is clear from FIG. 2, the peak having a retention time of 13.410min is the peak of a small amount of (S) -glycidylphthalimide (II) produced in the reaction of this example; 2- ((S) -3-chloro-2-hydroxypropyl) isoindoline-1, 3-dione (V) in the crude product prepared in this example1) And the sum of the (S) -glycidylphthalimide (II) contents of the partially ring-closed products is 94% to 97%.
Example 2: preparation of (S) -glycidylphthalimide (II)
To a 500 ml four-necked flask equipped with a stirrer and a thermometer was added 200 g of toluene, 49.7 g of 2- ((S) -3-chloro-2-hydroxypropyl) isoindoline-1, 3-dione (V) obtained in example 11) And stirring the mixture at the temperature of between 20 and 25 ℃ to uniformly mix the mixture. 36 g of a 30% sodium methoxide methanol solution was added dropwise thereto over 15 minutes. The reaction was stirred at 25 ℃ for 0.5 hour. Filtration was carried out, 10 g of ice water was added to the filtrate, toluene was recovered by distillation, and the residue was recrystallized from 100 g of ethanol to give 34.6 g of (S) -glycidylphthalimide in a yield of 85.1% (based on phthalimide as a starting material). Optical purity 99.2% ee.
FIG. 3 shows the nuclear magnetic hydrogen spectrum (deuterated CDCl) of (S) -glycidylphthalimide (II) prepared in this example3)；
The nuclear magnetic data of the product are as follows:
1HNMR (400MHz, deuterated CDCl)3)δ:2.68(dd,J＝4.8,2.5Hz,1H),2.81(t,J＝4.4Hz,1H),3.20-3.26(m,1H),3.81(dd,J＝14.3,5.0Hz,1H),3.96(dd,J＝14.4,5.0Hz,1H),7.71-7.76(m,2H),7.83-7.90(m,2H)
As can be seen from FIG. 3, the product prepared in this example was (S) -glycidylphthalimide.
FIG. 4 is a liquid chromatogram of (S) -glycidylphthalimide (II) prepared in this example; as can be seen from FIG. 4, the purity of (S) -glycidylphthalimide (II) in the product obtained in this example was 99.1%, and the purity was high.
FIG. 5 is a chiral liquid chromatogram of (S) -glycidylphthalimide (II) prepared in this example; as can be seen from FIG. 5, the peak ascribed to (R) -glycidylphthalimide at a retention time of 13.954min in the graph; the peak at the retention time of 14.494min is assigned as (S) -glycidylphthalimide (II), and the optical purity of the target product (S) -glycidylphthalimide (II) is 99.2% ee, which has higher optical purity.
Example 3: 2- ((S) -3-bromo-2-hydroxypropyl) isoindoline-1, 3-dione (V)2) Preparation of
To a 500 ml four-necked flask equipped with a stirrer, a thermometer and a condenser were charged 160 g of isopropyl alcohol, 29.6 g (0.20 mol) of phthalimide (III) and 40.8 g (0.30 mol) of (S) -1-bromoepoxypropane (IV)2) 3.22 g (0.01 mol) of tetrabutylammonium bromide, and the mixture was heated and stirred at an internal temperature of 43 ℃ for 10 hours. Vacuum distilling to recover isopropanol, adding 80 g n-hexane into residue, stirring at room temperature for 1 hr, filtering, washing filter cake with 20 g n-hexane, and mixing filtrates. And (3) decompressing and distilling to recover the normal hexane and the excessive (S) -1-bromoepoxypropane. The filter cake is dried to give 59.8 g of crude 2- ((S) -3-bromo-2-hydroxypropyl) isoindoline-1, 3-dione (V)2) Was used without further purification in example 4. HPLC analysis of the crude product for 2- ((S) -3-bromo-2-hydroxypropyl) isoindoline-1, 3-dione (V)2) And the sum of the (S) -glycidylphthalimide (II) contents of the partially ring-closed products is from 90% to 93%.
Example 4: preparation of (S) -glycidylphthalimide (II)
200 g of toluene are added into a 500 ml four-mouth bottle connected with a stirring thermometer,59.8 g of 2- ((S) -3-bromo-2-hydroxypropyl) isoindoline-1, 3-dione (V) obtained in example 32) And cooling the system to 5 ℃, and stirring the system to be uniformly mixed. 36 g of a 30% sodium methoxide methanol solution was added dropwise thereto over 15 minutes. The reaction was stirred at 5 ℃ for 0.5 hour. Filtration was carried out, 10 g of ice water was added to the filtrate, toluene was recovered by distillation, and the residue was recrystallized from 100 g of ethanol to give 34.1 g of (S) -glycidylphthalimide. The yield was 83.9% (calculated on phthalimide as starting material), the HPLC purity was 99.2%, and the optical purity was 99.3% ee.
Example 5: 2- ((S) -3-chloro-2-hydroxypropyl) isoindoline-1, 3-dione (V)1) Preparation of
To a 500 ml four-necked flask equipped with a stirrer, a thermometer and a condenser were charged 160 g of isopropyl alcohol, 29.6 g (0.20 mol) of phthalimide (III) and 27.8 g (0.30 mol) of (S) -1-chloroepoxypropane (IV)1) 2.27 g (0.01 mol) of benzyltriethylammonium chloride, and the mixture was heated and stirred at an internal temperature of 43 ℃ for 10 hours. Vacuum distilling to recover isopropanol, adding 80 g n-hexane into residue, stirring at room temperature for 1 hr, filtering, washing filter cake with 20 g n-hexane, and mixing filtrates. And (3) decompressing and distilling to recover the normal hexane and the excessive (S) -1-chloroepoxypropane. The filter cake is dried to give 50.2 g of crude 2- ((S) -3-chloro-2-hydroxypropyl) isoindoline-1, 3-dione (V)1) Was used without further purification in example 6. HPLC analysis of the crude product for 2- ((S) -3-chloro-2-hydroxypropyl) isoindoline-1, 3-dione (V)1) And the sum of the (S) -glycidylphthalimide (II) contents of the partially ring-closed products is from 94% to 96%.
Example 6: preparation of (S) -glycidylphthalimide (II)
To a 500 ml four-necked flask equipped with a stirrer and a thermometer was added 200 g of toluene, 50.2 g of 2- ((S) -3-chloro-2-hydroxypropyl) isoindoline-1, 3-dione (V) obtained in example 51) And stirring the system at 25 ℃ to mix uniformly. 36 g of a 30% sodium methoxide methanol solution was added dropwise thereto over 15 minutes. The reaction was stirred at 25 ℃ for 0.5 hour. Filtering, adding 10 g of ice water into the filtrate, and distilling to recover the methanolBenzene, the residue was recrystallized from 100 g of ethanol to give 35.6 g of (S) -glycidylphthalimide. The yield was 87.6% (calculated on phthalimide as starting material), the HPLC purity was 99.2%, and the optical purity was 99.3% ee.
Example 7: 2- ((S) -3-P-toluenesulfonyloxy-2-hydroxypropyl) isoindoline-1, 3-dione (V)3) Preparation of
Into a 500 ml four-necked flask equipped with a stirrer, a thermometer and a condenser were charged 200 g of tetrahydrofuran, 29.6 g (0.20 mol) of phthalimide (III), and 50.2 g (0.22 mol) of (S) -1-p-toluenesulfonyloxypropylene oxide (IV)3) 2.27 g (0.01 mol) of benzyltriethylammonium chloride, and the mixture was heated and stirred at an internal temperature of 50 ℃ for 8 hours. The tetrahydrofuran was recovered by distillation under reduced pressure, 80 g of n-hexane was added to the residue, stirred at room temperature for 1 hour, filtered, the filter cake was washed with 20 g of n-hexane, and the filtrates were combined. Vacuum distillation to recover n-hexane and excess (S) -1-p-toluenesulfonyloxypropylene oxide (III)3). The filter cake is dried to obtain 75.4 g of crude product 2- ((S) -3-p-toluenesulfonyloxy-2-hydroxypropyl) isoindoline-1, 3-dione (V)3) Was used without further purification in example 8.
Example 8: preparation of (S) -glycidylphthalimide (II)
To a 500 ml four-necked flask equipped with a stirrer and a thermometer was added 200 g of toluene and 75.4 g of 2- ((S) -3-p-toluenesulfonyloxy-2-hydroxypropyl) isoindoline-1, 3-dione (V) obtained in example 73) And stirring at (-10) - (-5) deg.C to mix well. 36 g of a 30% sodium methoxide methanol solution was added dropwise thereto over 15 minutes. The temperature is restored to 15-20 ℃ and the reaction is stirred for 1 hour. Filtration was carried out, 10 g of ice water was added to the filtrate, toluene was recovered by distillation, and the residue was recrystallized from 100 g of ethanol to give 35.8 g of (S) -glycidylphthalimide. The yield was 88.2% (calculated on phthalimide as starting material), the HPLC purity was 99.5%, and the optical purity was 99.4% ee.
Comparative example 1: influence of the addition of bases on the reaction in the preparation of the Compounds of the formula V
Is connected with a stirrerA500 ml four-necked flask equipped with a stirrer, a thermometer and a condenser was charged with 160 g of isopropyl alcohol, 29.6 g (0.20 mol) of phthalimide (III) and 27.8 g (0.30 mol) of (S) -1-chloroepoxypropane (IV)1) 2.02 g (0.02 mol) of triethylamine and 3.22 g (0.01 mol) of tetrabutylammonium bromide, heating and stirring for 12 hours at the internal temperature of 43 ℃. The isopropanol was recovered by distillation under reduced pressure and filtered, the filter cake was washed with 20 g of n-hexane, and the filtrates were combined. And (3) decompressing and distilling to recover the normal hexane and the excessive (S) -1-chloroepoxypropane. The filter cake is dried to give 50.2 g of crude 2- ((S) -3-chloro-2-hydroxypropyl) isoindoline-1, 3-dione (V)1) (ii) a HPLC analysis of the crude product prepared in comparative example 1 for 2- ((S) -3-chloro-2-hydroxypropyl) isoindoline-1, 3-dione (V)1) And the sum of the (S) -glycidylphthalimide (II) contents of the partially ring-closed products is from 84% to 86%.
As can be seen from this comparative example, the addition of a base in the preparation of the compound of formula V leads to side reactions which produce by-products and to a reduction in the yield of the desired product.
Comparative example 2: phase transfer catalyst for catalyzing reaction of potassium phthalimide and (S) -1-chloroepoxypropane
Into a 500 ml four-necked flask equipped with a stirrer, a thermometer and a condenser were charged 160 g of isopropyl alcohol, 37.0 g (0.20 mol) of potassium phthalimide, and 27.8 g (0.30 mol) of (S) -1-chloroepoxypropane (IV)1) And 3.22 g (0.01 mol) of tetrabutylammonium bromide, heated and stirred at an internal temperature of 43 ℃ for 72 hours. The isopropanol was recovered by distillation under reduced pressure, the reaction mixture was heat-dissolved in 100 g of ethanol, filtered, and the filtrate was cooled and recrystallized to give 23.6 g of (S) -glycidylphthalimide in 58.0% yield (based on potassium phthalimide as the starting material). The optical purity was 95.2% ee.
As can be seen from the comparison of the comparative example, in the process of preparing (S) -glycidylphthalimide by the next reaction of potassium phthalimide and (S) -1-chloroepoxypropane under the action of a phase transfer catalyst, side reactions and byproducts are more, so that the yield and the optical purity of the target product are lower.
Comparative example 3: reaction step (2) Effect of the mode of addition of base on the reaction in the preparation of Compound of formula II
To a 500 ml four-necked flask equipped with a stirrer and a thermometer, 200 g of toluene and 49.7 g of the same were charged in the same manner as in example 1 (formula V was omitted here)1Preparation of Compound (I) the 2- ((S) -3-chloro-2-hydroxypropyl) isoindoline-1, 3-dione (V) obtained1) And stirring the mixture at the temperature of between 20 and 25 ℃ to uniformly mix the mixture. To this, 36 g of 30% sodium methoxide methanol solution was added in one portion. The reaction mixture was stirred at 25 ℃ for 0.5 hour. Filtration was carried out, 10 g of ice water was added to the filtrate, toluene was recovered by distillation, and the residue was recrystallized from 100 g of ethanol to give 20.6 g of (S) -glycidylphthalimide in a yield of 50.6% (based on phthalimide as a starting material) and an optical purity of 96.3% ee.
Compared with the prior art, the method has the advantages that the alkali is added into the reaction system at one time, the concentration is high, the generated target product further generates side reaction, byproducts are generated, and the yield and the purity of the target product are reduced; alkali is dripped into the reaction system, which is beneficial to improving the yield and the purity of the target product.
Claims (4)
1. A method for preparing (S) -glycidylphthalimide (II), comprising the steps of:
160 g of isopropanol, 0.20 mol of phthalimide (III), 0.30 mol of (S) -1-chloroepoxypropane and 0.01 mol of tetrabutylammonium bromide are added into a 500 ml four-neck flask which is connected with a stirring, thermometer and condenser pipe, heated and stirred for 12 hours at the internal temperature of 43 ℃; vacuum distilling to recover isopropanol, adding 80 g of n-hexane into the residue, stirring at room temperature for 1 hour, filtering, washing the filter cake with 20 g of n-hexane, and combining the filtrates; recovering n-hexane and excessive (S) -1-chloroepoxypropane by reduced pressure distillation; drying the filter cake to obtain a crude product 2- ((S) -3-chloro-2-hydroxypropyl) isoindoline-1, 3-diketone (V); used in the next step without further purification;
wherein, in the compound of formula V, the substituent X is chlorine;
200 g of toluene and 49.7 g of the crude product 2- ((S) -3-chloro-2-hydroxypropyl) isoindoline-1, 3-dione (V) are added into a 500 ml four-mouth bottle connected with a stirring thermometer, and the mixture is stirred and mixed uniformly at the temperature of between 20 and 25 ℃; 36 g of 30% sodium methoxide methanol solution is dripped into the solution for 15 minutes; stirring and reacting for 0.5 hour at 25 ℃; filtration was carried out, 10 g of ice water was added to the filtrate, toluene was recovered by distillation, and the residue was recrystallized from 100 g of ethanol to give (S) -glycidylphthalimide.
2. A method for preparing (S) -glycidylphthalimide (II), comprising the steps of:
160 g of isopropanol, 0.20 mol of phthalimide (III), 0.30 mol of (S) -1-bromoepoxypropane and 0.01 mol of tetrabutylammonium bromide are added into a 500 ml four-neck flask which is connected with a stirring, thermometer and condenser pipe, heated and stirred for 10 hours at the internal temperature of 43 ℃; vacuum distilling to recover isopropanol, adding 80 g of n-hexane into the residue, stirring at room temperature for 1 hour, filtering, washing the filter cake with 20 g of n-hexane, and combining the filtrates; recovering n-hexane and excessive (S) -1-bromoepoxypropane by reduced pressure distillation; drying the filter cake to obtain a crude product 2- ((S) -3-bromo-2-hydroxypropyl) isoindoline-1, 3-dione (V), which is directly used in the next step without further purification;
wherein, in the compound of formula V, the substituent X is bromine;
200 g of toluene and 59.8 g of 2- ((S) -3-bromo-2-hydroxypropyl) isoindoline-1, 3-dione (V) are added into a 500 ml four-mouth bottle connected with a stirring thermometer, and the mixture is cooled to 5 ℃ and stirred to be uniformly mixed; 36 g of 30% sodium methoxide methanol solution is dripped into the solution for 15 minutes; stirring and reacting for 0.5 hour at the temperature of 5 ℃; filtration was carried out, 10 g of ice water was added to the filtrate, toluene was recovered by distillation, and the residue was recrystallized from 100 g of ethanol to give (S) -glycidylphthalimide.
3. A method for preparing (S) -glycidylphthalimide (II), comprising the steps of:
160 g of isopropanol, 0.20 mol of phthalimide (III), 0.30 mol of (S) -1-chloroepoxypropane (IV) and 0.01 mol of benzyltriethylammonium chloride are added into a 500 ml four-neck flask which is connected with a stirring, thermometer and condenser pipe, heated and stirred for 10 hours at the internal temperature of 43 ℃; vacuum distilling to recover isopropanol, adding 80 g of n-hexane into the residue, stirring at room temperature for 1 hour, filtering, washing the filter cake with 20 g of n-hexane, and combining the filtrates; recovering n-hexane and excessive (S) -1-chloroepoxypropane by reduced pressure distillation; drying the filter cake to obtain a crude product 2- ((S) -3-chloro-2-hydroxypropyl) isoindoline-1, 3-diketone (V), and directly using the crude product in the next step without further purification;
wherein, in the compound of formula V, the substituent X is chlorine;
200 g of toluene and 50.2 g of 2- ((S) -3-chloro-2-hydroxypropyl) isoindoline-1, 3-dione (V) are added into a 500 ml four-mouth bottle connected with a stirring thermometer, and the mixture is stirred and mixed uniformly at 25 ℃; 36 g of 30% sodium methoxide methanol solution is dripped into the solution for 15 minutes; stirring and reacting for 0.5 hour at 25 ℃; filtration was carried out, 10 g of ice water was added to the filtrate, toluene was recovered by distillation, and the residue was recrystallized from 100 g of ethanol to give (S) -glycidylphthalimide.
4. A method for preparing (S) -glycidylphthalimide (II), comprising the steps of:
adding 200 g of tetrahydrofuran, 0.20 mol of phthalimide (III), 0.22 mol of (S) -1-p-toluenesulfonyloxyepoxypropane (IV) and 0.01 mol of benzyltriethylammonium chloride into a 500 ml four-neck flask which is connected with a stirring tube, a thermometer and a condensing tube, heating, and stirring for 8 hours at the internal temperature of 50 ℃; distilling under reduced pressure to recover tetrahydrofuran, adding 80 g of n-hexane into the residue, stirring at room temperature for 1 hour, filtering, washing the filter cake with 20 g of n-hexane, and combining the filtrates; distilling under reduced pressure to recover n-hexane and excess (S) -1-p-toluenesulfonyloxypropylene oxide (IV); drying the filter cake to obtain a crude product 2- ((S) -3-p-toluenesulfonyloxy-2-hydroxypropyl) isoindoline-1, 3-dione (V), which is directly used in the next step without further purification;
wherein, in the compound shown in the formula V, a substituent X is p-toluenesulfonyloxy;
adding 200 g of toluene, 75.4 g of 2- ((S) -3-p-toluenesulfonyloxy-2-hydroxypropyl) isoindoline-1, 3-dione (V) and (10) to (5) DEG C into a 500 ml four-neck bottle connected with a stirring thermometer, and uniformly mixing; 36 g of 30% sodium methoxide methanol solution is dripped into the solution for 15 minutes; the temperature is restored to 15 to 20 ℃, and the mixture is stirred and reacted for 1 hour; filtration was carried out, 10 g of ice water was added to the filtrate, toluene was recovered by distillation, and the residue was recrystallized from 100 g of ethanol to give (S) -glycidylphthalimide.
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