CN113461656A - Preparation method of ticagrelor key chiral intermediate isomer impurity TGAD2 - Google Patents
Preparation method of ticagrelor key chiral intermediate isomer impurity TGAD2 Download PDFInfo
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- CN113461656A CN113461656A CN202110921582.7A CN202110921582A CN113461656A CN 113461656 A CN113461656 A CN 113461656A CN 202110921582 A CN202110921582 A CN 202110921582A CN 113461656 A CN113461656 A CN 113461656A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention relates to a method for preparing an isomer impurity TGAD2 of a key optically active intermediate TGA of ticagrelor. The TGAD2 is prepared by the steps of Cbz protection, esterification reaction, deprotection reaction, oxidation reaction, reduction reaction and the like, the method has the advantages of simple and mild reaction conditions, convenient post-treatment and higher refining yield and purity, and the prepared sample can be further used as an impurity reference substance of a ticagrelor intermediate, thereby being beneficial to improving the quality control of ticagrelor.
Description
Technical Field
The invention relates to the field of medicinal chemistry, and in particular relates to a preparation method of a key chiral intermediate isomer impurity TGAD2 of ticagrelor.
Background
Impurities in the medicine are main factors influencing the purity of the medicine, and if the impurities in the medicine exceed the limited requirements specified by quality standards, the appearance and the physical and chemical parameters of the medicine are possibly changed, even the stability of the medicine is influenced, so that the activity of the medicine is reduced, the toxic and side effects are increased, and the product quality of the medicine and the medication safety of patients are seriously damaged.
Ticagrelor is a novel selective small molecule anticoagulant developed by astrazep, and the key chiral intermediate TGA structure of ticagrelor is as follows:
TGA has four chiral centers, and various isomer impurities are generated in the actual synthesis process and the storage process, so that the directional synthesis of an isomer impurity reference substance becomes very important in order to improve the product quality and the medication safety of patients.
There is no report about the preparation of the isomer impurity TGAD2 from TGA as the starting material.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: the preparation method of the key chiral intermediate isomer impurity TGAD2 of ticagrelor has the advantages of simple and mild reaction conditions, high refining yield and purity and the like.
The technical scheme for solving the technical problems is as follows:
the invention provides a preparation method of a key chiral intermediate isomer impurity TGAD2 of ticagrelor, which comprises the following steps:
(1) TGA is protected by Cbz in the presence of a basic reagent to obtain a compound 11;
(2) carrying out esterification reaction on the compound 11 to obtain a compound 18;
(3) removing the protecting group of the compound 18 to obtain a compound 19;
(4) carrying out oxidation reaction on the compound 19 to obtain a compound 20;
(5) asymmetric reduction of compound 20 to give compound TGAD 2;
further, the alkaline reagent used in the step (1) is one or more of potassium carbonate, sodium carbonate, potassium hydroxide, sodium bicarbonate and/or potassium bicarbonate, preferably potassium carbonate; the molar ratio of the alkaline reagent to the TGA is 1.5: 1-2.5: 1, preferably 2: 1; the protective agent used in the step (1) is benzyl chloroformate, and the molar ratio of the protective agent to the TGA is 1.4: 1-1.6: 1, preferably 1.5: 1;
further, the esterification reagent used in the step (2) is acetic anhydride, acetic acid or acetyl chloride, preferably acetic anhydride; the molar ratio of the esterification reagent to the compound 11 is 1: 1-1.5: 1, preferably 1.2: 1;
further, the deprotection agent used in the step (3) is H2/Pd-C、H2/Pd(OH)2、H2/PdCl2、HCOOH/Pd-C、NH2NH2Pd-C or cyclohexene/Pd-C, preferably H2/Pd-C；
Further, the oxidant used in the step (4) is sodium tungstate-hydrogen peroxide, potassium tungstate-hydrogen peroxide, ammonium tungstate-hydrogen peroxide, tungsten nitrate-hydrogen peroxide or tungsten sulfate-hydrogen peroxide, preferably sodium tungstate-hydrogen peroxide; the reaction temperature of the step (4) is not more than 50 ℃, preferably not more than 45 ℃;
further, the reducing agent used in the step (5) is lithium aluminum hydride, sodium borohydride, H2Pd-C or zinc powder/acetic acid, preferably lithium aluminum hydride; the molar ratio of lithium aluminum hydride to compound 20 is preferably 1: 1; the reaction temperature of the step (5) is not more than 35 ℃, and preferably not more than 30 ℃;
further, the preparation method of the TGAD2 provided by the invention also comprises the following purification steps:
(6) TGAD2 was reacted with benzyl chloroformate to afford compound 21 and purified;
(7) deprotection of compound 21 yields purified TGAD 2;
further, the deprotection agent used in the step (7) is H2/Pd-C、H2/Pd(OH)2、H2/PdCl2、HCOOH/Pd-C、NH2NH2Pd-C or cyclohexene/Pd-C, preferably H2/Pd-C；
The invention also provides application of the key chiral intermediate isomer impurity TGAD2 of ticagrelor obtained by the preparation method in serving as an impurity reference substance.
The Chinese naming of the compound of the invention conflicts with the structural formula, and the structural formula is taken as the standard; except for obvious errors in the formula.
The invention has the beneficial effects that: the preparation method of the brand new ticagrelor key chiral intermediate isomer impurity TGAD2 is provided, the reaction conditions are simple and mild, the post-treatment is convenient, the refining yield and the purity are high, and the prepared sample can be further used as an impurity reference substance of a ticagrelor intermediate.
Detailed Description
The invention is illustrated but not limited by the following examples. The technical solutions protected by the present invention are all the simple replacements or modifications made by the skilled person in the art.
Example 1:
(1) preparation of Compounds of formula 11
TGA (80g,0.4624mol) was dissolved in 250mL tetrahydrofuran, 200mL water was added, and potassium carbonate (127.62g,0.9248mol) was added. Stirring to dissolve, cooling to 0 ℃, dropwise adding benzyl chloroformate (118.33g,0.6936mol), stirring at room temperature for 5min after dropwise adding, completely converting the raw materials, layering, adding 150mL of ethyl acetate to extract an aqueous layer, combining organic layers, drying with anhydrous sodium sulfate, and concentrating to obtain 106g of a product (HPLC: 95%);
(2) preparation of Compounds of formula 18
The compound of formula 11 (100g,0.3256mol) was dissolved in 600mL of dichloromethane, triethylamine (65.85g,0.6508mol) was added, acetic anhydride (39.86g,0.3905mol) was added under stirring at room temperature, and after the addition, the mixture was refluxed for 24 hours. TLC detection, complete conversion of the raw material. The developing agent is n-hexane and ethyl acetate which are 2: 1. The reaction was quenched by adding 500mL of saturated sodium bicarbonate and stirring at room temperature for 30 min. The layers were separated, the aqueous layer was extracted with 500mL of dichloromethane, the organic layers were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and spin-dried to give 111g of a brown oil. (purification after oxime formation, directly in the next step)
(3) Preparation of Compounds of formula 19
The compound of formula 18 (111g crude) was dissolved in 1L methanol, 10g 10% Pd/C was added, hydrogen was substituted three times, and the mixture was stirred at room temperature overnight. TLC detection shows iodine, and the raw materials are completely converted. The developing solvent is dichloromethane-methanol 5: 1. And (4) carrying out suction filtration, rinsing a filter cake by using a proper amount of methanol, and carrying out spin drying to obtain 64g of light yellow oily matter. (purification after oxime formation, directly in the next step)
(4) Preparation of Compounds of formula 20
Dissolving the compound (64g crude product) shown in the formula 19 in 600mL of methanol and 60mL of water, adding sodium tungstate (191.22g, 0.6508mol), stirring for dissolving, cooling in an ice-water bath, dropwise adding hydrogen peroxide, controlling the temperature to be not more than 45 ℃, and stirring for 4 hours at room temperature after adding. TLC detection, potassium permanganate color development, dichloromethane and methanol 5:1 as developing agent and one drop of triethylamine. Adding 250mL of water and 113g of ammonium sulfite, stirring at room temperature for 30min, controlling the temperature not to exceed 45 ℃, and developing the color by using a starch potassium iodide test paper. The mixture was rotary-evaporated to no drop, extracted three times with 500mL of dichloromethane, and the organic layers were combined, washed with 500mL of saturated brine, and dried over anhydrous sodium sulfate. And (3) spin-drying, pulping by 60mL of methyl tert-ether, adding 60mL of n-hexane, and stirring for crystallization for 1 h. Suction filtration, rinsing of the filter cake with 50mL of n-hexane, forced air drying at 50 ℃ to give 30g (HPLC: 98%) of a pale yellow powder.
(5) Preparation of TGAD2
Suspending lithium aluminum hydride (4.636g,0.1221mol) in 50mL tetrahydrofuran, reducing the temperature to 0 ℃ under the protection of nitrogen, and adding 280mL tetrahydrofuran solution of the compound (28g,0.1221mol) of the formula 20 dropwise, wherein the temperature is controlled not to exceed 30 ℃. After dropping, the mixture was stirred at room temperature for 24 hours. TLC detection, and a developing solvent of dichloromethane: methanol 3: 1. The temperature is reduced to 0 ℃, and 80mL of ethyl acetate, 80mL of 10% sodium hydroxide aqueous solution and 280mL of water are added in turn to quench and react. A large amount of bubbles are generated, the heat is intensely released, and the temperature is controlled not to exceed 30 ℃. After dripping, stirring for 30min at room temperature, performing suction filtration, rinsing a filter cake by using a large amount of 300mL tetrahydrofuran until no product exists on the plate; the filtrate was spin-dried to obtain 50g of oil, which was crude TGAD 2.
(6) Preparation of Compounds of formula 21
TGAD2(50g crude) was dissolved in 300mL tetrahydrofuran, 50mL water was added, and potassium carbonate (33.75g,0.2442mol) was added. Stirring to dissolve, cooling to 0 ℃, dropwise adding benzyl chloroformate (27.08g,0.1587mol), stirring at room temperature for 5min after dropwise adding, completely converting the raw materials, demixing, extracting the water layer with 250mL of ethyl acetate, and combining the organic layers. Dried over anhydrous sodium sulfate. Column chromatography, conditions: ethyl n-hexane acetate 4:1 → ethyl n-hexane acetate 3:1 → ethyl n-hexane acetate 2: 1. 18g of the compound of formula 21 is obtained. N-hexane: ethyl acetate 10:1 was slurried, suction filtered, and air-dried at 45 ℃ to give 16.5g (HPLC: 97%) of a white solid.
(7) Preparation of TGAD2
The compound of formula 21 (15g,0.04883mol) was dissolved in 150mL of methanol, 1.5g of 10% Pd/C was added, hydrogen gas was substituted three times, and the mixture was stirred at room temperature overnight. TLC detection shows iodine, and the raw materials are completely converted. The developing solvent is dichloromethane methanol 3: 1. And (4) carrying out suction filtration, rinsing a filter cake by using a proper amount of methanol, and carrying out spin drying to obtain 5.5g of colorless oily matter. N-hexane is pulped, the white solid is filtered by suction, and vacuum drying is carried out to obtain 5.2g of white solid (the optical purity is 99.1 percent) which is a TGAD2 refined product, and the one-step reaction yield is as follows: 61.5 percent.
MS:m/z＝174.2(M+H+)；
1H-NMR(400MHz,DMSO-d6)δ4.63(t,1H),4.37(d,1H),3.93(d,1H),3.51(m,1H),1.85–1.77(m,2H),1.36(s,3H),1.25(s,3H)。
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various changes and modifications can be made without departing from the inventive concept of the present invention, and these changes and modifications are all within the scope of the present invention.
Claims (9)
1. A preparation method of a key chiral intermediate isomer impurity TGAD2 of ticagrelor comprises the following steps:
(1) TGA is protected by Cbz in the presence of a basic reagent to obtain a compound 11;
(2) carrying out esterification reaction on the compound 11 to obtain a compound 18;
(3) removing the protecting group of the compound 18 to obtain a compound 19;
(4) carrying out oxidation reaction on the compound 19 to obtain a compound 20;
(5) asymmetric reduction of compound 20 occurs to give compound TGAD 2.
2. The preparation method according to claim 1, wherein the alkaline reagent used in step (1) is one or more of potassium carbonate, sodium carbonate, potassium hydroxide, sodium bicarbonate and/or potassium bicarbonate, and the molar ratio of the alkaline reagent to the TGA is 1.5: 1-2.5: 1; the protective agent used in the step (1) is benzyl chloroformate, and the molar ratio of the protective agent to the TGA is 1.4: 1-1.6: 1.
3. The preparation method of claim 1, wherein the esterification reagent used in the step (2) is acetic anhydride, acetic acid or acetyl chloride, and the molar ratio of the esterification reagent to the compound 11 is 1:1 to 1.5: 1.
4. The production method according to claim 1, wherein the deprotection agent used in the step (3) is H2/Pd-C、H2/Pd(OH)2、H2/PdCl2、HCOOH/Pd-C、NH2NH2Pd-C or cyclohexene/Pd-C.
5. The preparation method according to claim 1, wherein the oxidant used in step (4) is sodium tungstate-hydrogen peroxide, potassium tungstate-hydrogen peroxide, ammonium tungstate-hydrogen peroxide, tungsten nitrate-hydrogen peroxide, or tungsten sulfate-hydrogen peroxide; the reaction temperature of the step (4) is not more than 50 ℃.
6. The method according to claim 1, wherein the reducing agent used in the step (5) is lithium aluminum hydride, sodium borohydride, or H2Pd-C or zinc powder/acetic acid; the reaction temperature of the step (5) is not more than 35 ℃.
7. The method of claim 1, further comprising the step of purifying:
(6) TGAD2 was reacted with benzyl chloroformate to afford compound 21 and purified;
(7) deprotection of compound 21 affords purified TGAD 2.
8. The production method according to claim 7, wherein the deprotection agent used in the step (7) is H2/Pd-C、H2/Pd(OH)2、H2/PdCl2、HCOOH/Pd-C、NH2NH2Pd-C or cyclohexene/Pd-C.
9. Use of the key chiral intermediate isomer of ticagrelor, TGAD2, obtained according to any one of claims 1 to 8, as an impurity control.
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Citations (7)
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| WO2012142983A1 (en) * | 2011-04-19 | 2012-10-26 | Zentiva, K.S. | Optically active salts of (3ar,4s,6r,6as)-6-amino-2,2-dimethyltetrahydro-3ah- cyclopenta-[d] [1,3]dioxol-4-ol and a method of their preparation |
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2021
- 2021-08-11 CN CN202110921582.7A patent/CN113461656A/en active Pending
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