CN111087380A - Preparation method of ticagrelor intermediate - Google Patents
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Abstract
The invention belongs to the field of chemical pharmacy, and particularly discloses a preparation method of a ticagrelor intermediate, which comprises the steps of using ((4R,6S) -6-hydroxy-2, 2-dimethyltetrahydro-3 aH-penta [ d ] [1,3] dioxa-4-yl) benzyl carbamate (II) and glycol as raw materials, and reacting by using an acid catalyst to obtain the ticagrelor intermediate. The preparation method adopts a one-step method, and complicated steps such as protection, deprotection and the like are not needed during the reaction, so that manpower, material resources and energy consumption can be greatly saved. In addition, the raw materials such as ethylene glycol required by the method are all commercially available raw materials, so that the method is economical in price, and is beneficial to improving the production safety and reducing the production cost.
Description
Technical Field
The invention belongs to the field of chemical pharmacy, and particularly relates to a preparation method of a ticagrelor intermediate.
Background
Ticagrelor, a novel, selective small molecule anticoagulant developed by the company asikang and successfully marketed by the FDA in 2011, has pharmacological activity, enables the drug to exert drug efficacy without liver activation, has a fast onset of action, exerts pharmacological action without liver metabolism after oral administration, has reversibility with platelet ADP receptors, and rapidly recovers platelet function in blood after drug withdrawal. These significant advantages make ticagrelor a very promising drug with good clinical efficacy and reasonable safety.
At present, the main domestic production method of ticagrelor is to obtain a double-protected ticagrelor intermediate by taking D-ribose as a raw material and carrying out 6-7 steps of reaction, wherein hydroxyethyl needs to be introduced through multiple steps of protection, condensation and the like, and the total yield is lower.
Disclosure of Invention
The purpose of the invention is as follows: aiming at the defects in the prior art, the invention provides a preparation method of a novel intermediate of an antiplatelet aggregation medicine ticagrelor, which has the advantages of mild reaction conditions, simple process, convenient operation and no environmental pollution. The method adopts a one-step method to directly introduce the hydroxyethyl group by the ethylene glycol, and realizes more ideal yield and product purity by exploring and optimizing conditions. The ticagrelor intermediate prepared by the method can be directly used for the next reaction, and the production cost of the whole process can be reduced to the maximum extent.
The technical scheme is as follows: in order to achieve the above object, the present invention provides a preparation method of a ticagrelor intermediate, which comprises using ((4R,6S) -6-hydroxy-2, 2-dimethyltetrahydro-3 aH-penta [ d ] [1,3] dioxa-4-yl) carbamic acid benzyl ester (ii) and ethylene glycol as raw materials, and reacting with an acid catalyst to obtain the ticagrelor intermediate. The method only needs one-step reaction, and complex intermediate steps such as protection and deprotection are not needed in the reaction process, so that manpower, material resources and energy consumption can be greatly saved.
Further, the preparation method of the ticagrelor intermediate comprises the following steps:
s1 charging: adding ((4R,6S) -6-hydroxy-2, 2-dimethyltetrahydro-3 aH-pento [ d ] [1,3] dioxa-4-yl) benzyl carbamate (II), ethylene glycol, an acid catalyst and a solvent into a reactor, and uniformly stirring to obtain a mixture A1;
s2 reaction: keeping stirring, heating the mixture A1 to 100 ℃, preserving heat for 2-6 hours, and cooling to room temperature to obtain a mixture A2;
s3 purification: and purifying the mixture A2 to obtain a ticagrelor intermediate.
Further, in the preparation method of the ticagrelor intermediate, the purification process in step S3 includes: and (3) crude extracting the mixture A2 to obtain a crude ticagrelor intermediate product, and refining the crude ticagrelor intermediate product to obtain a refined ticagrelor intermediate product. Through the crude extraction step, the purity of the ticagrelor intermediate can reach 95 percent, and the process requirement of directly preparing the ticagrelor is met. Further refining the crude ticagrelor intermediate product to obtain a high-purity ticagrelor intermediate product.
Preferably, the crude extraction step comprises: filtering the mixture A2 to remove insoluble substances, washing with saturated brine, and distilling under normal pressure to reduce the volume by 55-85% to obtain a mixture A3; mixture a3 was added to petroleum ether and stirred for 3 hours to give an off-white solid powder as crude ticagrelor intermediate.
Preferably, the refining step comprises: and (4) recrystallizing the crude ticagrelor intermediate product by using methanol to obtain a refined ticagrelor intermediate product.
Further, in the above preparation method of the ticagrelor intermediate, in step S1, the solvent is preferably, but not limited to, toluene.
Preferably, in the preparation method of the ticagrelor intermediate, step S1, the ratio of benzyl ((4R,6S) -6-hydroxy-2, 2-dimethyltetrahydro-3 aH-penta [ d ] [1,3] dioxa-4-yl) carbamate (ii), ethylene glycol, acidic catalyst and solvent is 1:0.23-0.26:0.014-0.016:2-6 by weight.
Preferably, in the above preparation method of the ticagrelor intermediate, in step S1, the acidic catalyst is one of Nafion-H acidic resin, calix [4] arenesulfonic acid, and 1, 5-naphthalenedisulfonic acid.
The invention has the beneficial effects that:
1. the invention adopts a one-step method, and does not need complicated steps such as protection, deprotection and the like, thereby greatly saving manpower, material resources and energy consumption.
2. The raw materials such as ethylene glycol and the like adopted by the invention are commercially available, the price is economic, and the production safety can be effectively improved and the product cost can be reduced.
Drawings
Fig. 1 is a chemical reaction formula of a preparation method of a ticagrelor intermediate according to the present invention.
Detailed Description
The invention will be further illustrated by the following specific examples, which are given for the purpose of illustration only and are not intended to be limiting.
Example 1
Benzyl ((4R,6S) -6-hydroxy-2, 2-dimethyltetrahydro-3 aH-penta [ d ] [1,3] dioxa-4-yl) carbamate (II) (307 g, 1.0 mol), toluene (1800 g), ethylene glycol (79.2 g, 1.2 mol) and Nafion-H acid resin (4.9 g) were added to a reactor, stirred uniformly, heated to 100 ℃, stirred for 6 hours, cooled to room temperature after the reaction was completed, filtered to remove insoluble substances, washed with saturated brine, distilled at normal pressure to reduce the volume by 55%, and after cooling, the residue was added to petroleum ether and stirred for 3 hours to obtain an off-white solid powder which is a crude ticagrelor intermediate, about 324.6g, with a yield of about 92.5%. The content is more than 95 percent by HPLC detection, and the method can be directly used in the next step of the ticagrelor preparation process.
And recrystallizing a small amount of product by using methanol to obtain (I) a refined product of benzyl ((4R,6S) -6- (2-hydroxyethoxy) -2, 2-dimethyltetrahydro-3 aH-pento [ d ] [1,3] dioxa-4-yl) carbamate (ticagrelor intermediate).
1H NMR (d-DMSO，400MHz) δ：1.28（6H，s），1.78-1.95（2H，m），3.14-3.19（1H，q），3.52-3.72（4H，m），3.93-3.96（1H，q），4.18-4.21（1H，t），4.51-4.54（1H，t），5.11（2H，s），7.36-7.49（5H，m）。FAB-MS(m/z)：352 (M+H)。
Example 2
Benzyl ((4R,6S) -6-hydroxy-2, 2-dimethyltetrahydro-3 aH-penta [ d ] [1,3] dioxa-4-yl) carbamate (II) (307 g, 1.0 mol), toluene (615 g), ethylene glycol (72.6 g, 1.1 mol) and Nafion-H acid resin (4.3 g) were charged into a reactor, stirred uniformly, heated to 100 ℃, stirred for 2 hours, cooled to room temperature after the reaction was completed, filtered to remove insoluble matter, washed with saturated brine and distilled at normal pressure to reduce the volume by 85%, and after cooling, the residue was added to petroleum ether and stirred for 3 hours to obtain an off-white solid powder which is a crude ticagrelor intermediate, about 263.8g, with a yield of about 75.2%. The content is more than 95 percent by HPLC detection, and the method can be directly used in the next step of the ticagrelor preparation process.
And recrystallizing a small amount of product by using methanol to obtain (I) a refined product of benzyl ((4R,6S) -6- (2-hydroxyethoxy) -2, 2-dimethyltetrahydro-3 aH-pento [ d ] [1,3] dioxa-4-yl) carbamate (ticagrelor intermediate).
1H NMR (d-DMSO，400MHz) δ：1.28（6H，s），1.78-1.95（2H，m），3.14-3.19（1H，q），3.52-3.72（4H，m），3.93-3.96（1H，q），4.18-4.21（1H，t），4.51-4.54（1H，t），5.11（2H，s），7.36-7.49（5H，m）。FAB-MS(m/z)：352 (M+H)。
Example 3
Benzyl ((4R,6S) -6-hydroxy-2, 2-dimethyltetrahydro-3 aH-penta [ d ] [1,3] dioxa-4-yl) carbamate (II) (307 g, 1.0 mol), toluene (1200 g), ethylene glycol (75.9 g, 1.15 mol) and Nafion-H acid resin (4.6 g) were charged into a reactor, stirred uniformly, heated to 100 ℃, stirred for 4 hours, cooled to room temperature after the reaction was completed, filtered to remove insoluble matter, washed with saturated brine and distilled at normal pressure to remove most of the solvent, and after cooling, the residue was added to petroleum ether and stirred for 3 hours to obtain an off-white solid powder which is a crude ticagrelor intermediate, about 300.7g, with a yield of about 85.7%. The content is more than 95 percent by HPLC detection, and the method can be directly used in the next step of the ticagrelor preparation process.
And recrystallizing a small amount of product by using methanol to obtain (I) a refined product of benzyl ((4R,6S) -6- (2-hydroxyethoxy) -2, 2-dimethyltetrahydro-3 aH-pento [ d ] [1,3] dioxa-4-yl) carbamate (ticagrelor intermediate).
1H NMR (d-DMSO，400MHz) δ：1.28（6H，s），1.78-1.95（2H，m），3.14-3.19（1H，q），3.52-3.72（4H，m），3.93-3.96（1H，q），4.18-4.21（1H，t），4.51-4.54（1H，t），5.11（2H，s），7.36-7.49（5H，m）。FAB-MS(m/z)：352 (M+H)。
Example 4
Benzyl ((4R,6S) -6-hydroxy-2, 2-dimethyltetrahydro-3 aH-penta [ d ] [1,3] dioxa-4-yl) carbamate (II) (307 g, 1.0 mol), toluene (1800 g), ethylene glycol (79.2 g, 1.2 mol) and calix [4] arenesulfonic acid (4.9 g) were charged into a reactor, stirred uniformly, heated to 100 ℃, stirred for 6 hours, cooled to room temperature after the reaction was completed, filtered to remove insoluble matter, washed with saturated brine and distilled at normal pressure to remove most of the solvent, and after cooling, the residue was added to petroleum ether and stirred for 3 hours to obtain an off-white solid powder which was a crude ticagrelor intermediate, about 310.3g, and the yield was about 88.4%. The content is more than 95 percent by HPLC detection, and the method can be directly used in the next step of the ticagrelor preparation process.
And recrystallizing a small amount of product by using methanol to obtain (I) a refined product of benzyl ((4R,6S) -6- (2-hydroxyethoxy) -2, 2-dimethyltetrahydro-3 aH-pento [ d ] [1,3] dioxa-4-yl) carbamate (ticagrelor intermediate).
1H NMR (d-DMSO，400MHz) δ：1.28（6H，s），1.78-1.95（2H，m），3.14-3.19（1H，q），3.52-3.72（4H，m），3.93-3.96（1H，q），4.18-4.21（1H，t），4.51-4.54（1H，t），5.11（2H，s），7.36-7.49（5H，m）。FAB-MS(m/z)：352 (M+H)。
Example 5
Benzyl ((4R,6S) -6-hydroxy-2, 2-dimethyltetrahydro-3 aH-penta [ d ] [1,3] dioxa-4-yl) carbamate (II) (307 g, 1.0 mol), toluene (615 g), ethylene glycol (72.6 g, 1.1 mol) and calix [4] arenesulfonic acid (4.3 g) were charged into a reactor, stirred uniformly, heated to 100 ℃, stirred for 2 hours, cooled to room temperature after the reaction was completed, filtered to remove insoluble materials, washed with saturated brine and distilled at normal pressure to remove most of the solvent, and after cooling, the residue was added to petroleum ether and stirred for 3 hours to obtain an off-white solid powder which was a crude ticagrelor intermediate, about 248.1g, with a yield of about 70.7%. The content is more than 95 percent by HPLC detection, and the method can be directly used in the next step of the ticagrelor preparation process.
And recrystallizing a small amount of product by using methanol to obtain (I) a refined product of benzyl ((4R,6S) -6- (2-hydroxyethoxy) -2, 2-dimethyltetrahydro-3 aH-pento [ d ] [1,3] dioxa-4-yl) carbamate (ticagrelor intermediate).
1H NMR (d-DMSO，400MHz) δ：1.28（6H，s），1.78-1.95（2H，m），3.14-3.19（1H，q），3.52-3.72（4H，m），3.93-3.96（1H，q），4.18-4.21（1H，t），4.51-4.54（1H，t），5.11（2H，s），7.36-7.49（5H，m）。FAB-MS(m/z)：352 (M+H)。
Example 6
Benzyl ((4R,6S) -6-hydroxy-2, 2-dimethyltetrahydro-3 aH-penta [ d ] [1,3] dioxa-4-yl) carbamate (II) (307 g, 1.0 mol), toluene (1200 g), ethylene glycol (75.9 g, 1.15 mol) and calix [4] arenesulfonic acid (4.6 g) were charged into a reactor, stirred uniformly, heated to 100 ℃, stirred for 4 hours, cooled to room temperature after the reaction was completed, filtered to remove insoluble materials, washed with saturated brine and distilled at normal pressure to remove most of the solvent, and after cooling, the residue was added to petroleum ether and stirred for 3 hours to obtain an off-white solid powder, which is a crude ticagrelor intermediate, about 293.5g, with a yield of about 83.6%. The content is more than 95 percent by HPLC detection, and the method can be directly used in the next step of the ticagrelor preparation process.
And recrystallizing a small amount of product by using methanol to obtain (I) a refined product of benzyl ((4R,6S) -6- (2-hydroxyethoxy) -2, 2-dimethyltetrahydro-3 aH-pento [ d ] [1,3] dioxa-4-yl) carbamate (ticagrelor intermediate).
1H NMR (d-DMSO，400MHz) δ：1.28（6H，s），1.78-1.95（2H，m），3.14-3.19（1H，q），3.52-3.72（4H，m），3.93-3.96（1H，q），4.18-4.21（1H，t），4.51-4.54（1H，t），5.11（2H，s），7.36-7.49（5H，m）。FAB-MS(m/z)：352 (M+H)。
Example 7
Benzyl ((4R,6S) -6-hydroxy-2, 2-dimethyltetrahydro-3 aH-penta [ d ] [1,3] dioxa-4-yl) carbamate (II) (307 g, 1.0 mol), toluene (1800 g), ethylene glycol (79.2 g, 1.2 mol) and 1, 5-naphthalenedisulfonic acid (4.9 g) were charged into a reactor, and after stirring well, the mixture was heated to 100 ℃ and the reaction was continued for 6 hours with stirring, after the reaction was completed, the mixture was cooled to room temperature, insoluble matter was removed by filtration, most of the solvent was removed by distillation under normal pressure after washing with saturated brine, and after cooling, the residue was added to petroleum ether and stirred for 3 hours to obtain an off-white solid powder which was a crude ticagrelor intermediate, about 303.9g, with a yield of about 86.6%. The content is more than 95 percent by HPLC detection, and the method can be directly used in the next step of the ticagrelor preparation process.
And recrystallizing a small amount of product by using methanol to obtain (I) a refined product of benzyl ((4R,6S) -6- (2-hydroxyethoxy) -2, 2-dimethyltetrahydro-3 aH-pento [ d ] [1,3] dioxa-4-yl) carbamate (ticagrelor intermediate).
1H NMR (d-DMSO，400MHz) δ：1.28（6H，s），1.78-1.95（2H，m），3.14-3.19（1H，q），3.52-3.72（4H，m），3.93-3.96（1H，q），4.18-4.21（1H，t），4.51-4.54（1H，t），5.11（2H，s），7.36-7.49（5H，m）。FAB-MS(m/z)：352 (M+H)。
Example 8
Benzyl ((4R,6S) -6-hydroxy-2, 2-dimethyltetrahydro-3 aH-penta [ d ] [1,3] dioxa-4-yl) carbamate (II) (307 g, 1.0 mol), toluene (615 g), ethylene glycol (72.6 g, 1.1 mol) and 1, 5-naphthalenedisulfonic acid (4.3 g) were charged into a reactor, stirred uniformly, heated to 100 ℃, stirred for 2 hours, cooled to room temperature after the reaction was completed, filtered to remove insoluble matter, washed with saturated brine, distilled under normal pressure to remove most of the solvent, and after cooling, the residue was added to petroleum ether and stirred for 3 hours to obtain an off-white solid powder which was a crude ticagrelor intermediate, about 241.2g, with a yield of about 68.7%. The content is more than 95 percent by HPLC detection, and the method can be directly used in the next step of the ticagrelor preparation process.
And recrystallizing a small amount of product by using methanol to obtain (I) a refined product of benzyl ((4R,6S) -6- (2-hydroxyethoxy) -2, 2-dimethyltetrahydro-3 aH-pento [ d ] [1,3] dioxa-4-yl) carbamate (ticagrelor intermediate).
1H NMR (d-DMSO，400MHz) δ：1.28（6H，s），1.78-1.95（2H，m），3.14-3.19（1H，q），3.52-3.72（4H，m），3.93-3.96（1H，q），4.18-4.21（1H，t），4.51-4.54（1H，t），5.11（2H，s），7.36-7.49（5H，m）。FAB-MS(m/z)：352 (M+H)。
Example 9
Benzyl ((4R,6S) -6-hydroxy-2, 2-dimethyltetrahydro-3 aH-penta [ d ] [1,3] dioxa-4-yl) carbamate (II) (307 g, 1.0 mol), toluene (1200 g), ethylene glycol (75.9 g, 1.15 mol) and 1, 5-naphthalenedisulfonic acid (4.6 g) were charged into a reactor, and after stirring well, the mixture was heated to 100 ℃ and stirred for 4 hours, after completion of the reaction, the mixture was cooled to room temperature, insoluble matter was removed by filtration, most of the solvent was removed by atmospheric distillation after washing with saturated brine, and after cooling, the residue was added to petroleum ether and stirred for 3 hours to obtain an off-white solid powder which was a crude ticagrelor intermediate, about 287.6g, and the yield was about 81.9%. The content is more than 95 percent by HPLC detection, and the method can be directly used in the next step of the ticagrelor preparation process.
And recrystallizing a small amount of product by using methanol to obtain (I) a refined product of benzyl ((4R,6S) -6- (2-hydroxyethoxy) -2, 2-dimethyltetrahydro-3 aH-pento [ d ] [1,3] dioxa-4-yl) carbamate (ticagrelor intermediate).
1H NMR (d-DMSO，400MHz) δ：1.28（6H，s），1.78-1.95（2H，m），3.14-3.19（1H，q），3.52-3.72（4H，m），3.93-3.96（1H，q），4.18-4.21（1H，t），4.51-4.54（1H，t），5.11（2H，s），7.36-7.49（5H，m）。FAB-MS(m/z)：352 (M+H)。
The foregoing is only a preferred embodiment of the present invention, and it should be noted that modifications can be made by those skilled in the art without departing from the principle of the present invention, and these modifications should also be construed as the protection scope of the present invention.
Claims (8)
1. A preparation method of a ticagrelor intermediate is characterized by comprising the following steps: comprises the steps of using ((4R,6S) -6-hydroxy-2, 2-dimethyl tetrahydro-3 aH-pento [ d ] [1,3] dioxa-4-yl) carbamic acid benzyl ester (II) and ethylene glycol as raw materials, and reacting by using an acid catalyst to obtain a ticagrelor intermediate.
2. A method for preparing a ticagrelor intermediate according to claim 1, wherein: the method comprises the following steps:
s1 charging: adding ((4R,6S) -6-hydroxy-2, 2-dimethyltetrahydro-3 aH-pento [ d ] [1,3] dioxa-4-yl) benzyl carbamate (II), ethylene glycol, an acid catalyst and a solvent into a reactor, and uniformly stirring to obtain a mixture A1;
s2 reaction: keeping stirring, heating the mixture A1 to 100 ℃, preserving heat for 2-6 hours, and cooling to room temperature to obtain a mixture A2;
s3 purification: and purifying the mixture A2 to obtain a ticagrelor intermediate.
3. A method for preparing a ticagrelor intermediate according to claim 2, wherein: the purification process of step S3 includes: and (3) crude extracting the mixture A2 to obtain a crude ticagrelor intermediate product, and refining the crude ticagrelor intermediate product to obtain a refined ticagrelor intermediate product.
4. A method for preparing a ticagrelor intermediate according to claim 3, wherein: the crude extraction step comprises: filtering the mixture A2 to remove insoluble substances, washing with saturated brine, and distilling under normal pressure to reduce the volume by 55-85% to obtain a mixture A3; mixture a3 was added to petroleum ether and stirred for 3 hours to give an off-white solid powder as crude ticagrelor intermediate.
5. A method for preparing a ticagrelor intermediate according to claim 3, wherein: the refining step comprises: and (4) recrystallizing the crude ticagrelor intermediate product by using methanol to obtain a refined ticagrelor intermediate product.
6. A method for preparing a ticagrelor intermediate according to any of claims 2 to 5, wherein: in step S1, the solvent is toluene.
7. A method for preparing a ticagrelor intermediate according to claim 6, wherein: in step S1, the ratio of benzyl ((4R,6S) -6-hydroxy-2, 2-dimethyltetrahydro-3 aH-penta [ d ] [1,3] dioxa-4-yl) carbamate (II), ethylene glycol, acidic catalyst and solvent is 1:0.23-0.26:0.014-0.016:2-6 by weight.
8. A method for preparing a ticagrelor intermediate according to claim 6, wherein: in step S1, the acidic catalyst is one of Nafion-H acidic resin, calix [4] arenesulfonic acid, and 1, 5-naphthalenedisulfonic acid.
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| WO2011017108A2 (en) * | 2009-07-27 | 2011-02-10 | Auspex Pharmaceuticals, Inc. | Cyclopropyl modulators of p2y12 receptor |
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| WO2011017108A2 (en) * | 2009-07-27 | 2011-02-10 | Auspex Pharmaceuticals, Inc. | Cyclopropyl modulators of p2y12 receptor |
| CN103351372A (en) * | 2013-07-15 | 2013-10-16 | 深圳致君制药有限公司 | Preparation method of ticagrelor intermediate |
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