CN112047919A - Ticagrelor intermediate and preparation method thereof - Google Patents
Ticagrelor intermediate and preparation method thereof Download PDFInfo
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Abstract
The invention relates to the technical field of medicines, in particular to a ticagrelor intermediate shown as a structural formula III and a preparation method thereof. According to the ticagrelor intermediate and the preparation method thereof provided by the invention, the chiral center is introduced from the raw material, racemization does not occur in subsequent reaction, the prepared product has high chiral purity, the raw material is cheap and easily available visolactone, and is prepared by separating recyclable biological enzyme, the enzyme separation efficiency is far higher than that of the traditional chiral substrate induction, the chiral center is constructed at the early stage of the route, the material waste of the later-stage separation is avoided, and the production cost is effectively reduced; the synthesis steps are greatly shortened, chiral auxiliary groups do not need to be used, the atom economy is high, the used materials are cheap and easy to obtain, the use of expensive palladium catalysts is avoided, and the production cost is effectively reduced; dangerous irritant reagents such as cyclopentadiene, potassium tert-butoxide, lithium borohydride and the like are avoided, and the production safety is improved.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a ticagrelor intermediate and a preparation method thereof.
Background
Ticagrelor, developed by AstraZeneca (AstraZeneca), was FDA approved at 7/20 days 2011 for reducing the incidence of thrombotic events in patients with Acute Coronary Syndrome (ACS). It is a novel, selective anticoagulant, and is the first reversible binding P2Y12 adenosine diphosphate receptor (ADP) antagonist, can act on purine 2 receptor subtype P2Y12 on Vascular Smooth Muscle Cells (VSMC) reversibly, has obvious inhibition effect on platelet aggregation caused by ADP, and can effectively improve the symptoms of patients with acute coronary heart disease. Ticagrelor (or ticagrelor) was sold under the trade name of dilinda in 2012 and has acquired an imported drug license issued by the national food and drug administration (SFDA), meaning that this drug for patients with Acute Coronary Syndrome (ACS) has been approved for formal marketing in china. The compound of formula IV is a key intermediate for synthesizing ticagrelor, contains four chiral centers and has great synthesis difficulty, so that the development of a new route suitable for industrial production becomes particularly important.
WO2011017108A discloses a preparation method of a ticagrelor intermediate, which comprises the following synthetic route:
the key intermediate is prepared from D-alanine serving as a raw material through Boc protection, condensation reaction, oxidation reaction, Diels-Alder reaction, dihydroxylation reaction, acetonylidene protection, sodium borohydride reduction and palladium-carbon catalytic hydrogenation. The route has long steps, expensive sodium periodate is used in the third step of oxidation, the molecular weight of iodine atoms is very large, an oxidant needs to be used in an equivalent amount, and the cost is very high; in the fourth step, cyclopentadiene is needed, which has anesthetic action and strong stimulation to skin and mucous membrane. Flammable, the vapors of which can form explosive mixtures with air. When exposed to open fire, high heat or contact with an oxidant, the flame-retardant material has the danger of causing combustion and explosion, can be strongly decomposed at high temperature and can have strong reaction with the oxidant, after high-speed impact, flow and agitation, the flame-retardant material can cause combustion and explosion due to electrostatic spark discharge, and steam of the flame-retardant material is heavier than air and can be diffused to a far place at a lower part and can cause backfire when exposed to open fire; the substrate induction effect of the D-alanine is general, the de value is only about 40%, partial diastereomer impurities can be removed through refining, the refining effect is limited, the acceptable quality can be achieved only by multiple times, meanwhile, the reverse Diels-Alder reaction can occur in the refining process, the product is racemized, and the yield is low; in the seventh step, sodium borohydride is used, which strongly stimulates mucous membrane, upper respiratory tract, eyes and skin, and can cause death due to spasm, inflammation and edema of larynx and bronchus, chemical pneumonia and pulmonary edema after inhalation. Oral administration erodes the digestive tract. After contacting with sodium borohydride, symptoms such as sore throat, cough, shortness of breath, headache, abdominal pain, diarrhea, dizziness, conjunctival congestion, pain and the like exist, and the symptoms can cause burning when meeting water, humid air, acids, oxidants, high heat and open fire; the Pd/C catalyst is used in the catalytic hydrogenation in the eighth step, so the cost is higher; the tenth reaction needs potassium tert-butoxide, which is easy to absorb moisture and has a risk of ignition, thus bringing great inconvenience to production; and the eleventh step uses lithium borohydride, so that the solid is easy to burn and dust explosion can occur. In conclusion, the route has the advantages of longer steps, lower yield, higher cost and difficult quality control, and is not suitable for industrial production.
WO9905143A also discloses a preparation method of a ticagrelor intermediate, which comprises the following synthetic route:
the route takes cyclopentadiene as a raw material, and has pungent smell though being cheap and easy to obtain through epoxidation reaction and coupling reaction; the epoxidation yield in the first step is low; the second step of reaction needs an unrecoverable homogeneous palladium catalyst, the yield is low, the obtained product is a racemate, and the cost of later chiral resolution is high; the selectivity of the double hydroxylation is not high, and the purification is difficult. The eighth step of reaction needs potassium tert-butoxide, which is easy to absorb moisture and has a risk of ignition, thus bringing great inconvenience to production; and in the ninth step, lithium borohydride is used, so that the solid is easy to burn and dust explosion can occur. In conclusion, the route has the advantages of longer steps, lower yield, higher cost and difficult quality control, and is not suitable for industrial production.
In view of the good medicinal prospect of ticagrelor, there is a need to develop an economical and safe preparation method of ticagrelor.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: provides an economic and safe ticagrelor intermediate and a preparation method thereof.
The technical scheme for solving the technical problems is as follows:
an intermediate for preparing ticagrelor has a structure shown as formula III:
a second aspect of the present invention provides a preparation method of the intermediate iii of ticagrelor, including the following steps:
(1) the compound of formula II is subjected to oxidation reaction to prepare a compound of formula III, and the specific reaction formula is as follows:
preferably, the preparation method of the intermediate for preparing ticagrelor further comprises the following steps:
(2) reacting a compound of formula I with a Grignard reagent to prepare a compound of formula II, wherein the reaction formula is as follows:
the third aspect of the present invention provides a method for preparing a ticagrelor key intermediate iv from the ticagrelor intermediate iii, comprising the following steps:
(i) the compound of formula III is subjected to reduction reaction to prepare a compound of formula IV, and the specific reaction formula is as follows:
preferably, the oxidizing agent in step (1) is selected from m-chloroperoxybenzoic acid, peracetic acid or peroxytrifluoroacetic acid.
Preferably, the molar ratio of the compound of formula ii to the oxidizing agent in step (1) is 1: 1-10; further, the molar ratio of the compound of formula II to the oxidant is 1: 2 to 5.
Preferably, the Grignard reagent in step (2) is selected from 4-methoxybenzyl magnesium chloride.
Preferably, the molar ratio of the compound of formula I to the grignard reagent in step (2) is 1: 1 to 1.2; further, the molar ratio of the compound of formula I to the Grignard reagent in the step (2) is 1: 1.05 to 1.2.
Preferably, the reducing agent in step (i) is selected from diphenylsilanes.
Preferably, a ruthenium-silicon composite ligand is also selected as a catalyst in the step (i), and the structural formula of the ruthenium-silicon composite ligand is as follows:
preferably, the molar ratio of the compound of formula III, the reducing agent and the ruthenium-silicon composite ligand in the step (i) is 1: 1-10: 0.001 to 0.1; further, the molar ratio of the compound of formula III in the step (i), the reducing agent and the ruthenium-silicon composite ligand is 1: 2-5: 0.01 to 0.05.
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 chiral center of the ticagrelor intermediate and the preparation method thereof provided by the invention is introduced from the raw material, racemization does not occur in the subsequent reaction, the prepared product has high chiral purity, the raw material is cheap and easily available visolactone, and is prepared by separating recyclable biological enzyme, the enzyme separation efficiency is far higher than that of the traditional chiral substrate induction, the chiral center is constructed at the early stage of the route, the material waste of the later-stage separation is avoided, and the production cost is effectively reduced; the synthesis steps are greatly shortened, chiral auxiliary groups do not need to be used, the atom economy is high, the used materials are cheap and easy to obtain, the use of expensive palladium catalysts is avoided, and the production cost is effectively reduced; dangerous irritant reagents such as cyclopentadiene, potassium tert-butoxide, lithium borohydride and the like are avoided, and the production safety is improved.
Drawings
FIG. 1 is a hydrogen spectrum of compound III prepared according to the present embodiment.
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:
reacting a compound of formula I with a Grignard reagent to prepare a compound of formula II:
the compound of formula I (5.03g, 17.65mmol) is dissolved in 50mL of methyltetrahydrofuran, cooled to-10 ℃ and 19.3mL of 4-methoxybenzylmagnesium chloride in tetrahydrofuran (1M) are added dropwise at a temperature not exceeding 0 ℃. After dropping, keeping the temperature for 1 hour, detecting the complete conversion of the raw material by TLC, dropping 15% acetic acid aqueous solution to adjust the pH to 7, controlling the temperature not to exceed 5 ℃, demixing, washing twice with 20mL of water, drying the organic layer with anhydrous sodium sulfate, spin-drying, adding 25mL of n-hexane, pulping for 1 hour, performing suction filtration, rinsing the solid with a proper amount of n-hexane, and drying for 6 hours by blowing at 40 ℃ to obtain a crude product (5.87g) of the compound of the formula II, wherein the crude product is not purified and is directly reacted in the next step, and the yield of.
Preparing a compound shown in the formula III by oxidizing a compound shown in the formula II:
dissolving the compound (4.33g, 10.68mmol) of the formula II obtained in the reaction in the previous step in 30mL of toluene, adding m-CPBA (5.53g, 32.04mmol) in portions at room temperature, controlling the temperature not to exceed 30 ℃, stirring at room temperature for 16h, detecting the complete conversion of the raw material by TLC, adding 20% sodium sulfite aqueous solution, controlling the temperature not to exceed 30 ℃, adding 30mL of saturated sodium bicarbonate aqueous solution, stirring for 30min, carrying out layering, washing an organic layer with 15mL of water, drying with anhydrous sodium sulfate, carrying out spin drying, and recrystallizing with n-hexane/ethyl acetate to obtain a white solid (3.71g, 98.3% purity, 8.65mmol) with the yield of 81%.
1H NMR(400MHz,DMSO-d6)7.43-7.28(m,5H),6.63(d,J＝6.0Hz,1H),5.00-4.90(m,1H),4.58(s,2H),4.56-4.45(m,2H),4.18(s,2H),3.81(s,1H),2.29(dt,J＝14.2,6.2Hz,1H),1.80(d,J＝14.5Hz,1H),1.38(s,12H),1.22(s,3H).
[M+H]+422.2；[M+Na]+444.2
③ the compound of the formula III is reduced to prepare the compound of the formula IV
The compound of formula III (7.52g, 17.84mmol) was dissolved in 40mL of tetrahydrofuran, and ruthenium silicon complex ligand (0.20g, 0.36mmol) was added. Adding diphenylsilane (6.58g, 35.68mmol) in tetrahydrofuran (20mL), controlling the temperature not to exceed 25 ℃, stirring at room temperature for 30min, detecting the complete conversion of the raw material by TLC, cooling to 0 ℃, adding 10mL of isopropanol, stirring at room temperature for 10min, and performing column chromatography to obtain a white solid (6.47g, purity 97.7%, 15.52mmol) with yield of 87%.
1H NMR(500MHz,Chloroform-d)7.30(s,5H),4.70(d,J＝12.4Hz,1H),4.43(s,1H),4.35–4.23(m,2H),4.00-3.92(m,2H),3.95-3.83(m,2H),3.74(ddd,J＝12.3,8.0,1.3Hz,1H),3.42(ddd,J＝12.5,8.0,1.2Hz,1H),3.32(ddd,J＝12.3,3.4,1.3Hz,1H),3.09(ddd,J＝12.5,3.5,1.3Hz,1H),2.01(dt,J＝13.0,7.0Hz,1H),1.61(dt,J＝13.0,7.0Hz,1H),1.48(s,3H),1.44(d,J＝2.4Hz,12H).
[M+H]+408.2；[M+Na]+430.2
Example 2:
reacting a compound of formula I with a Grignard reagent to prepare a compound of formula II:
the compound of formula I (5.03g, 17.65mmol) is dissolved in 50mL of methyltetrahydrofuran, cooled to-10 ℃ and 21.2mL of 4-methoxybenzylmagnesium chloride in tetrahydrofuran (1M) are added dropwise at a temperature not exceeding 0 ℃. After dropping, keeping the temperature for 1 hour, detecting the complete conversion of the raw material by TLC, dropping 15% acetic acid aqueous solution to adjust the pH to 7, controlling the temperature not to exceed 5 ℃, demixing, washing twice with 20mL of water, drying the organic layer with anhydrous sodium sulfate, spin-drying, adding 25mL of n-hexane, pulping for 1 hour, performing suction filtration, rinsing the solid with a proper amount of n-hexane, and drying for 6 hours by blowing at 40 ℃ to obtain a crude product (5.95g) of the compound of the formula II, wherein the crude product is not purified and is directly reacted in the next step, and the yield of.
Preparing a compound shown in the formula III by oxidizing a compound shown in the formula II:
dissolving the compound (4.33g, 10.68mmol) of the formula II obtained in the above reaction in 30mL of toluene, adding peroxytrifluoroacetic acid (2.78g, 21.36mmol) in portions at room temperature, controlling the temperature not to exceed 20 ℃, stirring at room temperature for 12h, detecting the complete conversion of the raw material by TLC, adding 20% of sodium sulfite aqueous solution, controlling the temperature not to exceed 20 ℃, adding 30mL of saturated sodium bicarbonate aqueous solution, stirring for 30min, carrying out layering, washing the organic layer with 15mL of water, drying with anhydrous sodium sulfate, carrying out spin drying, and recrystallizing with n-hexane/ethyl acetate to obtain a white solid (3.76g, 98.1% of purity, 8.76mmol) with the yield of 82%.
1H NMR(400MHz,DMSO-d6)7.43-7.28(m,5H),6.63(d,J＝6.0Hz,1H),5.00-4.90(m,1H),4.58(s,2H),4.56-4.45(m,2H),4.18(s,2H),3.81(s,1H),2.29(dt,J＝14.2,6.2Hz,1H),1.80(d,J＝14.5Hz,1H),1.38(s,12H),1.22(s,3H).
[M+H]+422.2；[M+Na]+444.2
③ the compound of the formula III is reduced to prepare the compound of the formula IV
Dissolving the compound of formula III (7.52g, 17.84mmol) in 40mL of tetrahydrofuran, and adding a ruthenium-silicon complex ligand (0.10g, 0.18 mmol); adding diphenylsilane (9.87g, 53.52mmol) in tetrahydrofuran (20mL), controlling the temperature not to exceed 25 ℃, stirring at room temperature for 30min, detecting the complete conversion of the raw material by TLC, cooling to 0 ℃, adding 10mL of isopropanol, stirring at room temperature for 10min, and performing column chromatography to obtain a white solid (6.52g, purity 98.0%, 15.69mmol) with yield of 88%.
1H NMR(500MHz,Chloroform-d)7.30(s,5H),4.70(d,J＝12.4Hz,1H),4.43(s,1H),4.35–4.23(m,2H),4.00-3.92(m,2H),3.95-3.83(m,2H),3.74(ddd,J＝12.3,8.0,1.3Hz,1H),3.42(ddd,J＝12.5,8.0,1.2Hz,1H),3.32(ddd,J＝12.3,3.4,1.3Hz,1H),3.09(ddd,J＝12.5,3.5,1.3Hz,1H),2.01(dt,J＝13.0,7.0Hz,1H),1.61(dt,J＝13.0,7.0Hz,1H),1.48(s,3H),1.44(d,J＝2.4Hz,12H).
[M+H]+408.2；[M+Na]+430.2
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 (10)
1. An intermediate for preparing ticagrelor is characterized in that the structure is shown as formula III:
2. a process for the preparation of an intermediate of ticagrelor according to claim 1, comprising the steps of:
(1) the compound of formula II is subjected to oxidation reaction to prepare a compound of formula III, and the specific reaction formula is as follows:
3. the method of claim 2, further comprising the steps of:
(2) reacting a compound of formula I with a Grignard reagent to prepare a compound of formula II, wherein the reaction formula is as follows:
4. a method for preparing a key intermediate IV of ticagrelor is characterized by comprising the following steps:
(i) the compound of formula III is subjected to reduction reaction to prepare a compound of formula IV, and the specific reaction formula is as follows:
5. the method according to claim 2, wherein the oxidizing agent in step (1) is selected from m-chloroperoxybenzoic acid, peracetic acid, or peroxytrifluoroacetic acid.
6. The process of claim 2, wherein the molar ratio of the compound of formula ii to the oxidizing agent in step (1) is 1: 1 to 10.
7. The method according to claim 3, wherein the Grignard reagent in the step (2) is selected from 4-methoxybenzylmagnesium chloride and the like.
8. The method of claim 3, wherein the molar ratio of the compound of formula I to Grignard reagent in step (2) is 1: 1 to 1.2.
9. The method of claim 4, wherein the reducing agent in step (i) is selected from diphenylsilanes; and (i) a ruthenium-silicon composite ligand is also selected as a catalyst.
10. The method of claim 9, wherein the compound of formula iii, the reducing agent, and the ruthenium silicon complex ligand in step (i) are present in a molar ratio of 1: 1-10: 0.001 to 0.1.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1228770A (en) * | 1996-07-08 | 1999-09-15 | 罗纳·布朗克罗尔药制品有限公司 | Compounds having antihypertensive, cardioprotective, anti-ischemic and antilipolytic properties |
| WO2011017108A2 (en) * | 2009-07-27 | 2011-02-10 | Auspex Pharmaceuticals, Inc. | Cyclopropyl modulators of p2y12 receptor |
| CN104114542A (en) * | 2011-12-23 | 2014-10-22 | 力奇制药公司 | Synthesis of triazolopyrimidine compounds |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1228770A (en) * | 1996-07-08 | 1999-09-15 | 罗纳·布朗克罗尔药制品有限公司 | Compounds having antihypertensive, cardioprotective, anti-ischemic and antilipolytic properties |
| WO2011017108A2 (en) * | 2009-07-27 | 2011-02-10 | Auspex Pharmaceuticals, Inc. | Cyclopropyl modulators of p2y12 receptor |
| CN104114542A (en) * | 2011-12-23 | 2014-10-22 | 力奇制药公司 | Synthesis of triazolopyrimidine compounds |
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