CN108440383B - Preparation method of rivaroxaban intermediate - Google Patents
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Abstract
The invention relates to a preparation method of rivaroxaban intermediate S-N-glycidol phthalimide. The method uses the alumina which can be recycled repeatedly for catalytic reaction in the preparation process of the S-N-glycidylphthalimide, reduces the production cost, reduces the emission requirement, solves the problem that the phase transfer catalyst is difficult to remove and influences the product quality, further shortens the reaction time, avoids the special requirement on equipment caused by the use of potassium tert-butoxide, reduces the production cost, and is particularly suitable for industrial production.
Description
Technical Field
The invention relates to the field of organic synthetic pharmaceutical chemistry, and particularly relates to a preparation method of rivaroxaban intermediate S-N-glycidol phthalimide.
Background
Rivaroxaban is currently the most promising antithrombotic agent, and the essential difference from the traditional antithrombotic heparin is that it does not require the participation of antithrombin III and can directly antagonize free and bound factor Xa. Heparin requires antithrombin iii to function and factor Xa in the prothrombin complex is ineffective. The two novel oral anticoagulant medicaments are praised by the medical community as a great progress in the fields of anticoagulant treatment and potential lethal thrombus prevention, and become a new milestone in the development history of cardiovascular medicaments. Rivaroxaban (Rivaroxaban) was successfully developed by bayer medicine, germany, and qiansheng, usa. In 10.2008, approval was obtained in canada and the european union for marketing under the trade name Xarelto. Rivaroxaban, the first oral direct factor Xa inhibitor worldwide, inhibits both free and bound factor Xa and prothrombin activity with high selectivity and competitively, and extends the activated partial thromboplastin time Plate (PT) and prothrombin time (aPTT) in a dose-dependent manner, thereby extending clotting time and reducing thrombin formation. It has the advantages of high bioavailability, broad spectrum, stable dose-effect relationship, convenient administration, and low bleeding risk. Rivaroxaban is also a drug for the prevention and treatment of venous thrombosis. The composition is mainly used for preventing the formation of Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE) of patients after hip joint and knee joint replacement in clinic. Can also be used for preventing cerebral apoplexy and non-central nervous system embolism of patients with non-valvular atrial fibrillation, reducing the risk of coronary artery syndrome recurrence, etc.
With the clinical application of rivaroxaban, the demand for rivaroxaban is gradually increased. Patent WO 0147919 discloses for the first time a process for the preparation of rivaroxaban
S-N-glycidol phthalimide is used as a starting material of rivaroxaban, and the quality and the cost of the S-N-glycidol phthalimide play a decisive role in synthesizing rivaroxaban; therefore, S-N-glycidol phthalimide which is cheap and high in quality is more and more valued by chemical engineers; the synthetic routes reported for this mainly include:
Tetrahedron 1996(7)1641-1648 reports that S-N-glycidylphthalimide is obtained by one-step Mitsunobu reactions using phthalimide and R-epichlorohydrin as starting materials.
The reaction condition of the process is harsh and must be carried out at-70 ℃, a large amount of triphenylphosphine oxide generated in the reaction process is difficult to remove, the yield is only 30%, the quality is poor, and the cost is high.
US7135576B2, US6875875B2 report the production of intermediate I under the action of sodium carbonate using phthalimide and chiral epichlorohydrin as starting materials; and (3) obtaining the S-N-glycidol phthalimide from the intermediate I under the action of strong base (potassium tert-butoxide).
The synthetic route has long reaction time and uses a large amount of phase transfer catalysts; the difficulty in removing the phase transfer catalyst in the post-treatment leads to poor quality of the finished product; in the ring closing process, potassium tert-butoxide which is strong in alkalinity and expensive is used, so that the industrial cost is high, the chiral purity of the obtained product is low, and the ee value is only 97-98%; it is difficult to meet the requirement of medical use.
U.S. Pat. No. 4, 6875875, 2 and Chinese patent No. 103382200B report the reaction of bis (phthalimide) salt and S-epichlorohydrin as raw materials in the presence of phase transfer catalyst to obtain S-N-glycidylphthalimide.
The method uses the bis (phthalimide) methyl salt which is expensive and easy to racemize in the reaction process, and the obtained product has the purity difference of only 92 percent of chemical purity and 97 to 98 percent of ee value and is difficult to meet the medicinal requirements.
Korean patent KR100612779B1 reports that S-N-glycidylphthalimide is obtained by N-alkylation and dehydrochlorination of chiral 1-amino-3-chloro-2-propanol hydrochloride and phthalic anhydride as starting materials.
The synthetic route takes expensive 1-amino-3-chloro-2-propanol hydrochloride as a raw material, has low yield and is not suitable for industrialization. Synthesis scheme 5
The Indian literature Der Pharma Chemica,2011,3(5):168-175 reports that the intermediate I is obtained by taking the phthalimide and the chiral epichlorohydrin as the starting materials under the action of potassium carbonate; and obtaining the S-N-glycidol phthalimide from the intermediate I under the action of potassium carbonate/toluene.
The synthetic process route is basically consistent with the synthetic route 2; the total yield of the reaction in the step 2 is only 60 percent; the industrialization cost is high.
Daichuan, Master thesis, reported in the study of rivaroxaban synthesis process; using bis-phthalimide and chiral epichlorohydrin as initial raw materials to obtain an intermediate I under the action of a large amount of phase transfer catalyst (TBAB tetrabutylammonium bromide); and (3) obtaining the S-N-glycidol phthalimide from the intermediate I under the action of strong base (potassium tert-butoxide).
The process route uses a large amount of phase transfer catalyst (close to 50% of the starting material); TBAB is difficult to be cleaned in the reaction, and the product quality is seriously influenced; the total yield of the two steps of the process route is only 58 percent, and the industrialization cost is high.
Synthesis scheme 7
Green chem, 2010,12,1380-1382 reports synthesis of S-N-glycidylphthalimide from phthalimide and epichlorohydrin under the action of immobilized KF-Al2O 3.
The mixture obtained by the process route is difficult to purify and has low yield, and only the target product with the chiral purity of about 95 percent is obtained.
In conclusion, the existing process for synthesizing S-N-glycidylphthalimide generally has the problems of harsh reaction conditions, low yield, high cost, poor quality, great industrialization difficulty and the like. Therefore, the industrialization needs to be improved to realize the industrialization of S-N-glycidylphthalimide.
The preparation method of the medicinal intermediate S-N-glycidylphthalimide (compound III) provided by the invention has the advantages of simple operation, high chemical reaction yield, less three wastes, low raw material cost and capability of obtaining a high-purity finished product.
Disclosure of Invention
The invention aims to provide a preparation method of a medicinal intermediate S-N-glycidol phthalimide, which is suitable for industrial production, simple to operate, relatively low in cost and relatively high in chiral purity. Therefore, the synthetic route adopted by the invention is as follows:
according to the invention, phthalimide is used as an initial raw material to react with chiral epichlorohydrin to synthesize a compound intermediate I, and the obtained compound I is used for obtaining S-N-glycidol phthalimide shown in a formula III under the action of an organic solvent and inorganic base.
According to one embodiment of the present invention, the present invention provides a process for the preparation of a rivaroxaban intermediate compound represented by formula I, comprising the steps of:
reacting compound II with phthalimide in the presence of aluminum trioxide and a phase transfer catalyst
Wherein X is chlorine, bromine or iodine, preferably chlorine.
According to one embodiment of the present invention, there is provided a process for the preparation of S-N-glycidylphthalimide of formula III, comprising the steps of:
in the presence of aluminum trioxide and a phase transfer catalyst, a chiral compound II reacts with phthalimide to obtain a compound I,
wherein X is chlorine, bromine or iodine, preferably chlorine;
the compound I is cyclized to obtain an S-N-glycidylphthalimide compound III,
according to a particular embodiment of the invention, the aluminium trioxide in the reaction leading to compound I is acidic alumina, neutral alumina or basic alumina, preferably basic alumina.
According to a particular embodiment of the invention, the step of obtaining compound I is carried out in a protic solvent, which is isopropanol, ethanol, methanol or water; preferably isopropanol or ethanol.
According to a specific embodiment of the present invention, the phase transfer catalyst in the step of obtaining compound I is benzyltriethylammonium chloride, benzyltrimethylammonium chloride (TMBAC), tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate; benzyltriethylammonium chloride or benzyltrimethylammonium chloride are preferred.
According to a specific embodiment of the invention, the reaction temperature in the step of obtaining the compound I is-5-30 ℃; preferably 20 to 25 ℃.
According to a particular embodiment of the invention, the aluminium trioxide of the step of obtaining compound I is recovered and reused.
According to a particular embodiment of the invention, in obtaining the S-N-glycidylphthalimide compound III: the compound I is subjected to the action of an organic solvent and an inorganic base to obtain an S-N-glycidylphthalimide compound III.
According to a specific embodiment of the present invention, the organic solvent used in obtaining the S-N-glycidylphthalimide compound III is tetrahydrofuran, toluene, xylene, chlorobenzene, or cyclohexane; xylene or toluene is preferred.
According to a specific embodiment of the present invention, the inorganic base used in obtaining the S-N-glycidylphthalimide compound III is sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium methoxide or sodium tert-butoxide; sodium carbonate is preferred.
Compared with the prior art, the invention has the technical advancement that:
the aluminum oxide which can be recycled is adopted for catalytic reaction, so that the production cost is reduced; alumina is used to replace Na used in conventional reaction2CO3、K2CO3、Cs2CO3、NaHCO3、KHCO3The problem that the reaction system becomes sticky along with the reaction due to the introduction of sodium ions is avoided, and the conventionally used alkali cannot be recycled, so that the reaction system needs further treatment to meet the emission requirement; the use of the alumina can also greatly reduce the use of the phase transfer catalyst, and solve the problem that the phase transfer catalyst is difficult to remove and influences the product quality; the reaction time is further shortened; the product obtained by the method has high chiral purity and can meet the medicinal requirements; in the conventional technology, potassium tert-butoxide and the like are used, the operation needs to strictly control moisture, the requirement on the anhydrous condition of equipment is higher, the special requirement on the equipment caused by the use of the potassium tert-butoxide is avoided, and the production cost is reduced; the method provided by the invention has the advantages of higher yield and low cost, and is particularly suitable for industrial production. The chiral purity of the obtained S-N-glycidol phthalimide is as high as 99.5 percent.
Drawings
FIG. 1: and (3) detecting a spectrogram of S-N-glycidol phthalimide.
FIG. 2: chiral purity spectrum of S-N-glycidylphthalimide.
Detailed Description
The present invention is further illustrated by the following examples, which are not intended to limit the scope of the present invention in any way.
Example 1: preparation of 2- ((S) -3-chloro-2-hydroxypropyl) isoindoline-1, 3-dione (Compound I)
Phthalimide (100.0g, 0.68mol), basic alumina (1.0 g), TMBAC (1.0 g), isopropanol (300 g), and S-epichlorohydrin (23.0 g) were put into a four-necked flask and stirred. Controlling the internal temperature to be 20-25 ℃, keeping the temperature and reacting for 12h, sampling and controlling until the residue of the phthalimide in the reaction liquid is less than or equal to 1.0%, and finishing the reaction. Concentrating to remove isopropanol, adding 400g of toluene to dissolve, filtering and recovering alumina for later use; the filtrate was washed with 2X 100g of water, concentrated and crystallized by addition of 450g of n-heptane to give compound I150g (yield 92.1%).
Example 2: preparation of 2- ((S) -3-chloro-2-hydroxypropyl) isoindoline-1, 3-dione (Compound I)
Phthalimide (100.0g, 0.8mol), basic aluminum trioxide (recovered from example 1)1.0g, TMBAC1.0g, isopropanol 300g, and S-epichlorohydrin 23.0g were put into a four-necked flask and stirred. Controlling the internal temperature to be 20-25 ℃, keeping the temperature and reacting for 12h, sampling and controlling until the residue of the phthalimide in the reaction liquid is less than or equal to 1.0%, and finishing the reaction. Concentrating to remove isopropanol, adding 400g of toluene to dissolve, filtering and recovering alumina for later use; the filtrate was washed with 2X 100g of water, concentrated and crystallized by adding 450g of n-heptane to give 149.4g of Compound I (yield 91.7%).
Example 3: preparation of 2- ((S) -3-chloro-2-hydroxypropyl) isoindoline-1, 3-dione (Compound I)
Phthalimide (100.0g, 0.8mol), basic aluminum trioxide (recovered from example 2) (1.0 g), TMBAC1.0g, isopropanol (300 g), and S-epichlorohydrin (23.0 g) were put into a four-necked flask and stirred. Controlling the internal temperature to be 20-25 ℃, keeping the temperature and reacting for 12h, sampling and controlling until the residue of the phthalimide in the reaction liquid is less than or equal to 1.0%, and finishing the reaction. Concentrating to remove isopropanol, adding 400g of toluene to dissolve, filtering and recovering alumina for later use; the filtrate was washed with 2X 100g of water, concentrated and crystallized by adding 450g of n-heptane to give 149.0g of Compound I (yield 91.5%).
Example 4: preparation of 2- ((S) -3-chloro-2-hydroxypropyl) isoindoline-1, 3-dione (Compound I)
Phthalimide (100.0g, 0.68mol), basic alumina (1.0 g), benzyltriethylammonium chloride (1.0 g), isopropyl alcohol (300 g), and S-epichlorohydrin (23.0 g) were put into a four-necked flask and stirred. Controlling the internal temperature to be 20-25 ℃, keeping the temperature and reacting for 12h, sampling and controlling until the residue of the phthalimide in the reaction liquid is less than or equal to 1.0%, and finishing the reaction. Concentrating to remove isopropanol, adding 400g of toluene to dissolve, filtering and recovering alumina for later use; the filtrate was washed with 2X 100g of water, concentrated and crystallized by adding 450g of n-heptane to give 152g of Compound I (yield 93.3%).
Example 5: preparation of 2- ((S) -3-chloro-2-hydroxypropyl) isoindoline-1, 3-dione (Compound I)
Phthalimide (100.0g, 0.8mol), basic aluminum trioxide (recovered from example 4) (1.0 g), benzyltriethylammonium chloride (1.0 g), isopropyl alcohol (300 g), and S-epichlorohydrin (23.0 g) were put into a four-necked flask and stirred. Controlling the internal temperature to be 20-25 ℃, keeping the temperature and reacting for 12h, sampling and controlling until the residue of the phthalimide in the reaction liquid is less than or equal to 1.0%, and finishing the reaction. Concentrating to remove isopropanol, adding 400g of toluene to dissolve, filtering and recovering alumina for later use; the filtrate was washed with 2X 100g of water, concentrated and crystallized by adding 450g of n-heptane to give 151.6g of Compound I (yield 93.1%).
Example 6: preparation of 2- ((S) -3-chloro-2-hydroxypropyl) isoindoline-1, 3-dione (Compound I)
Phthalimide (100.0g, 0.8mol), basic aluminum trioxide (recovered from example 5) (1.0 g), benzyltriethylammonium chloride (1.0 g), isopropyl alcohol (300 g), and S-epichlorohydrin (23.0 g) were put into a four-necked flask and stirred. Controlling the internal temperature to be 20-25 ℃, keeping the temperature and reacting for 12h, sampling and controlling until the residue of the phthalimide in the reaction liquid is less than or equal to 1.0%, and finishing the reaction. Concentrating to remove isopropanol, adding 400g of toluene to dissolve, filtering and recovering alumina for later use; the filtrate was washed with 2X 100g of water, concentrated and crystallized by adding 450g of n-heptane to give 151.0g of Compound I (yield 92.7%).
Example 7: preparation of 2- ((S) -3-chloro-2-hydroxypropyl) isoindoline-1, 3-dione (Compound I)
Phthalimide (100.0g, 0.68mol), neutral alumina (1.0 g), benzyltriethylammonium chloride (1.0 g), isopropyl alcohol (300 g) and S-epichlorohydrin (23.0 g) were put into a four-neck flask and stirred. Controlling the internal temperature to be 20-25 ℃, keeping the temperature and reacting for 12h, sampling and controlling until the residue of the phthalimide in the reaction liquid is less than or equal to 1.0%, and finishing the reaction. Concentrating to remove isopropanol, adding 400g of toluene to dissolve, filtering and recovering alumina for later use; the filtrate was washed with 2X 100g of water, concentrated and crystallized by adding 450g of n-heptane to obtain 150.0g of Compound I (yield 92.1%).
Example 8: preparation of 2- ((S) -3-chloro-2-hydroxypropyl) isoindoline-1, 3-dione (Compound I)
Phthalimide (100.0g, 0.8mol), neutral aluminum trioxide (recovered from example 7) (1.0 g), benzyltriethylammonium chloride (1.0 g), isopropyl alcohol (300 g), and S-epichlorohydrin (23.0 g) were put into a four-necked flask and stirred. Controlling the internal temperature to be 20-25 ℃, keeping the temperature and reacting for 12h, sampling and controlling until the residue of the phthalimide in the reaction liquid is less than or equal to 1.0%, and finishing the reaction. Concentrating to remove isopropanol, adding 400g of toluene to dissolve and filter, and recovering alumina for later use; the filtrate was washed with 2X 100g of water, concentrated and crystallized by adding 450g of n-heptane to give 149.2g of Compound I (yield 91.6%).
Example 9: S-N-glycidylphthalimide (Compound III formula)
Compound I from example 4 (50.0g 0.21mol), sodium carbonate 22.0g, xylene 250g were charged to a four-necked flask with a trap. Stirring; heating, refluxing and water diversion for 4 h. And ending the reaction until the residue of the compound I in the reaction solution is less than or equal to 1.0 percent. The sodium carbonate was removed by filtration, the filtrate was washed with 2X 100g of water, concentrated, and crystallized by adding 200g of methanol to give 38.0g of S-N-glycidylphthalimide (yield 89%; HPLC 99.49%; ee 99.75%).
The detection method in the examples is as follows:
method for detecting S-N-glycidol phthalimide related substances
The instrument comprises the following steps: agilent 1206
A chromatographic column: ZORBOA Eclipse XDB-C184.6 mm, 5.0 μm
A: 0.1% aqueous triethylamine solution, adjusted to pH 3.00 with 85% phosphoric acid
B: acetonitrile
| Time (min) | Mobile phase (V/V, A%) | Mobile phase (V/V, B%) |
| 0 | 80 | 20 |
| 15 | 55 | 45 |
| 20 | 10 | 90 |
Flow rate: 1.0mL/min
A detector: VWD, wavelength 220nm
Sample introduction amount: 10 μ L
Column temperature: 40 deg.C
Operating time: 20min
The balance time is as follows: 5min
Diluent agent: acetonitrile-water 50:50
Sample concentration: 1mg/5 ml.
Method for detecting chiral purity of S-N-glycidol phthalimide
The instrument comprises the following steps: shimadzu LC-20AD
A chromatographic column: CHIRALPAK AD-H4.6 x 250mm, 5.0 μm
Mobile phase: n-hexane-isopropanol 90:10
Flow rate: 1.0mL/min
A detector: VWD wavelength 254nm
Sample introduction amount: 20 μ L
Column temperature: 35 deg.C
Operating time: 25min
Diluent agent: methanol
Sample concentration: 1 mg/ml.
The above description is only an embodiment of the present invention, but the structural features of the present invention are not limited thereto, and any changes or modifications within the scope of the present invention by those skilled in the art are covered by the present invention.
Claims (5)
1. A preparation method of a rivaroxaban intermediate compound shown as a formula I comprises the following steps:
in the presence of aluminium oxide and phase transfer catalyst, chiral compound II reacts with phthalimide
Wherein X is chlorine, bromine or iodine,
the reaction is carried out in a protic solvent, which is isopropanol or ethanol,
the reaction temperature is 20-25 ℃,
the alumina is alkaline alumina or neutral alumina,
the phase transfer catalyst is benzyl trimethyl ammonium chloride or benzyl triethyl ammonium chloride.
2. A preparation method of S-N-glycidylphthalimide shown in formula III comprises the following steps:
in the presence of aluminum oxide and a phase transfer catalyst, a chiral compound II reacts with phthalimide to obtain a compound I
Wherein X is chlorine, bromine or iodine,
the reaction is carried out in a protic solvent, which is isopropanol or ethanol,
the reaction temperature is 20-25 ℃,
the alumina is alkaline alumina or neutral alumina,
the phase transfer catalyst is benzyl trimethyl ammonium chloride or benzyl triethyl ammonium chloride;
the compound I is reacted with dimethylbenzene and sodium carbonate to obtain S-N-glycidylphthalimide compound III
3. The method according to claim 1 or 2, wherein X is chlorine.
4. The method according to claim 1, characterized in that the alumina is a basic alumina.
5. The method according to claim 1 or 2, wherein the alumina is recycled.
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