CN117720504A - Preparation method of ticagrelor intermediate - Google Patents
Preparation method of ticagrelor intermediate Download PDFInfo
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- CN117720504A CN117720504A CN202211531413.3A CN202211531413A CN117720504A CN 117720504 A CN117720504 A CN 117720504A CN 202211531413 A CN202211531413 A CN 202211531413A CN 117720504 A CN117720504 A CN 117720504A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- PYEJQVYISBUGDU-UHFFFAOYSA-N 2-(3,4-difluorophenyl)cyclopropane-1-carboxamide Chemical compound NC(=O)C1CC1C1=CC=C(F)C(F)=C1 PYEJQVYISBUGDU-UHFFFAOYSA-N 0.000 title claims description 13
- 238000000034 method Methods 0.000 claims abstract description 7
- 230000008569 process Effects 0.000 claims abstract description 4
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 23
- 238000006243 chemical reaction Methods 0.000 claims description 20
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 20
- 150000001875 compounds Chemical class 0.000 claims description 16
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 11
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 9
- 239000003513 alkali Substances 0.000 claims description 9
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- 239000002585 base Substances 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 5
- 230000009471 action Effects 0.000 claims description 4
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 229940043279 diisopropylamine Drugs 0.000 claims description 3
- 230000002194 synthesizing effect Effects 0.000 claims description 3
- -1 ticagrelor intermediate compound Chemical class 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- 238000005660 chlorination reaction Methods 0.000 claims description 2
- 230000026030 halogenation Effects 0.000 claims description 2
- 238000005658 halogenation reaction Methods 0.000 claims description 2
- 239000002994 raw material Substances 0.000 claims description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims 5
- FEWJPZIEWOKRBE-LWMBPPNESA-N levotartaric acid Chemical compound OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 claims 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims 2
- 230000003301 hydrolyzing effect Effects 0.000 claims 1
- 150000004702 methyl esters Chemical class 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 12
- 230000015572 biosynthetic process Effects 0.000 abstract description 11
- 238000010511 deprotection reaction Methods 0.000 abstract description 3
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 abstract description 3
- 238000001308 synthesis method Methods 0.000 abstract description 3
- 238000005904 alkaline hydrolysis reaction Methods 0.000 abstract description 2
- 238000005984 hydrogenation reaction Methods 0.000 abstract description 2
- YSNXOQGDHGUKCZ-UHFFFAOYSA-N n-benzylhydroxylamine;hydron;chloride Chemical class Cl.ONCC1=CC=CC=C1 YSNXOQGDHGUKCZ-UHFFFAOYSA-N 0.000 abstract description 2
- 238000005809 transesterification reaction Methods 0.000 abstract description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 abstract 2
- 125000006239 protecting group Chemical group 0.000 abstract 1
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- OEKWJQXRCDYSHL-FNOIDJSQSA-N ticagrelor Chemical compound C1([C@@H]2C[C@H]2NC=2N=C(N=C3N([C@H]4[C@@H]([C@H](O)[C@@H](OCCO)C4)O)N=NC3=2)SCCC)=CC=C(F)C(F)=C1 OEKWJQXRCDYSHL-FNOIDJSQSA-N 0.000 description 4
- 229960002528 ticagrelor Drugs 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical group CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 3
- 208000010125 myocardial infarction Diseases 0.000 description 3
- 208000004476 Acute Coronary Syndrome Diseases 0.000 description 2
- 239000012448 Lithium borohydride Substances 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910000272 alkali metal oxide Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000010100 anticoagulation Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000006317 cyclopropyl amino group Chemical group 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- VEUUMBGHMNQHGO-CQDYUVAPSA-N ethyl 2-chloroacetate Chemical group CCO[13C](=O)[13CH2]Cl VEUUMBGHMNQHGO-CQDYUVAPSA-N 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000010118 platelet activation Effects 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 108091006082 receptor inhibitors Proteins 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000004035 thiopropyl group Chemical group [H]SC([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the field of organic synthesis, in particular to the field of pharmaceutical chemistry, and more particularly relates to a preparation method of ticagrelor intermediates, which adopts transesterification to form amide, and can be completed by direct alkaline hydrolysis after removing protecting groups without hydrogenation deprotection of palladium carbon. Meanwhile, according to the technical scheme disclosed by the invention, the target product can be obtained in three steps, the synthesis process is simpler, the treatment is easier, and the method is an improved synthesis method suitable for industrial popularization.
Description
Technical Field
The invention relates to the field of organic synthesis, in particular to the field of pharmaceutical chemistry, and more particularly relates to a preparation method of ticagrelor intermediates.
Background
Ticagrelor is an oral selective P2Y12 receptor inhibitor that prevents ADP-mediated platelet activation and aggregation, while reducing the probability of cardiovascular death, acute Coronary Syndrome (ACS) in patients with myocardial infarction and stroke, and the historical rate of Myocardial Infarction (MI).
Ticagrelor Lei Huaxue is (1S, 2S,3R, 5S) -3- [7- [ (1R, 2S) -2- (3, 4-difluorophenyl) cyclopropylamino ] -5- (thiopropyl) -3H- [1,2,3] triazol [4,5-d ] pyrimidin-3-yl ] -5- (2-hydroxyethoxy) cyclopentane-1, 2-diol having a chemical structure represented by formula (A):
the synthesis and preparation method of ticagrelor are hot problems of research of those skilled in the field of anticoagulation medicine research and development. In the synthesis and preparation of ticagrelor, most of them are obtained through intermediates A, B, C according to different orders and different linking modes;
the invention relates to a ticagrelor intermediate C, which is a compound IV with a structural formula as follows:
the preparation of this intermediate is reported in patent US7067663,
the scheme needs expensive lithium borohydride and palladium carbon, and the whole preparation process has high cost. Meanwhile, the scheme has the disadvantages of more steps of the process flow, high process operation difficulty, low yield and the like.
Disclosure of Invention
The invention aims to provide a preparation method of a novel ticagrelor intermediate compound IV, which takes a compound I as an initial raw material, wherein the compound I firstly reacts with methyl alkyl acid to synthesize a compound II, then the compound II reacts with 2-halogenated ethyl alkyl acid under the action of alkali to synthesize a compound III, and finally the compound III is hydrolyzed in an alkaline environment to obtain a target compound IV;
wherein: r is R 1 、R 2 Optionally and independently selected from C1-C4 alkyl groups.
Methyl alkyl acid esters are used as both the reactant and solvent in the present embodiment.
In a preferred embodiment, the R 1 Is ethyl. When R is 1 When ethyl, methyl alkyl acetate is methyl acetate, which can be used as a reaction reagent and also can be used as a solvent.
Preferably, the mass volume ratio of the compound I to the methyl alkyl acid ester is 1 (1-5) g/ml.
The reaction temperature for synthesizing the compound II by the reaction of the compound I and the methyl alkyl acid ester is preferably 55-60 ℃.
In a preferred embodiment, the R 2 Is ethyl. When R is 2 When ethyl, the alkyl acid-2-haloethyl ester is 2-haloethyl acetate.
Further preferably, the halogenation is preferably a chlorination. Under this preferred condition, the alkyl acid-2-haloethyl ester is alkyl acid-2-chloroethyl ester. Further, when R 2 While ethyl is preferred, the alkyl acid-2-haloethyl ester is ethyl 2-chloroacetate.
Further preferably, the molar ratio of the compound II, the alkyl acid-2-halogenated ethyl ester and the alkali is 1: (1-3): (2 to 5), preferably 1:1.5:3.
in a preferred technical scheme, the compound II is synthesized with alkyl acid-2-halogenated ethyl ester under the action of alkali, wherein the alkali is one or more of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium tert-butoxide, sodium methoxide, triethylamine and diisopropylamine, and preferably potassium carbonate.
The compound III is hydrolyzed in an alkaline environment to obtain the target compound IV, wherein the base may be an alkali metal or alkaline earth metal hydroxide, an alkali metal or alkaline earth metal carbonate or an organic amine or a combination thereof, and in some embodiments, the base may be, without limitation, one or more of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium tert-butoxide, sodium methoxide, triethylamine, diisopropylamine.
Further preferably, the molar ratio of compound iii to base is 1:2 to 5, preferably 1:3.
meanwhile, the invention further discloses that the compound V is prepared from the compound IV and L tartaric acid through salification reaction, and any one of the following conditions is preferable or two preferable conditions are simultaneously provided,
a. the molar ratio of the compound IV to the L tartaric acid is 1:1-2, preferably 1:1.2; b. the reaction temperature is 40-55 ℃, and the crystallization temperature is 5-20 ℃.
According to the invention, the amide is formed by transesterification, the deprotection group is removed and then the amide is directly subjected to alkaline hydrolysis, the hydrogenation deprotection by palladium carbon is not needed, meanwhile, the alkyl acid-2-halogenated ethyl ester is adopted in the invention, the synthesis mode of the prior art for forming the ester and then reducing is changed, the original synthesis thought is jumped, the ester group is not needed to be reduced, and further lithium borohydride is not needed to be added, so that the synthesis cost is effectively saved. Meanwhile, according to the technical scheme disclosed by the invention, the target product can be obtained in three steps, the synthesis process is simpler, the treatment is easier, and the method is an improved synthesis method suitable for industrial popularization.
Drawings
FIG. 1 shows the compound III prepared in example 2 1 H-NMR spectrum.
Detailed Description
For a better understanding of the present invention, we will further describe the present invention with reference to specific examples.
EXAMPLE 1 Synthesis of Compound II
Compound I (52 g,0.3 mol) was added to the reactor, methyl acetate (156 ml) was added, the air in the vessel was replaced with nitrogen three times, the temperature was raised to reflux, methanol was separated by a water separator, and the reaction was carried out for 6 hours.
After the reaction of the spot plate material was completed, the solvent was distilled completely under reduced pressure, and the residue was collected to give Compound II (60.2 g,0.28 mol), yield 93.3%
EXAMPLE 2 Synthesis of Compound III
To the reactor was added compound II (30 g,0.14 mol), ethyl 2-chloroacetate (25.7 g,0.21 mol), toluene (150 ml) and stirred to dissolve, and potassium carbonate solid (58 g,0.42 mol) was added, stirred and heated to reflux, and reacted for 16 hours.
After the reaction was completed, water (100 ml) was added to the system and washed twice, the organic layer was separated, the dry solvent was recovered under reduced pressure, and the residue was collected to give Compound III (31.4 g,0.121 mol), whose yield was 86.3%, and whose nuclear magnetic resonance spectrum was shown in FIG. 1.
EXAMPLE 3 Synthesis of Compound IV
To the reactor was added compound III (25.9 g,0.1 mol), ethanol (200 ml) was added and mixed with stirring, 100ml of an aqueous potassium carbonate solution was added dropwise, wherein the potassium carbonate content was 41.5g, the potassium carbonate concentration was 3mol/L, the temperature was raised to 40 to 50℃and the reaction was continued at a constant temperature for 16 hours.
After the completion of the reaction, ethanol was recovered from the dry system under reduced pressure, ethyl acetate (200 ml) was added to extract 2 times, the organic layers were combined, and the solvent was evaporated after drying to give compound IV (19.9 g,0.0916 mol) in a yield of 91.6%.
EXAMPLE 4 Synthesis of Compound V
To the reactor were added compound IV (15.2 g,0.07 mol) and ethanol (100 ml), and the mixture was stirred for complete dissolution. Heating the system to 45-50 ℃; uniformly adding tartaric acid into three batches, wherein the intervals between the batches are 5min; tartaric acid (12.6 g,0.084 mol) was added in total, the temperature was kept at 45-50℃and stirred for 1h.
After the reaction is finished, slowly cooling to 30-40 ℃; the temperature reaches 30 ℃, the temperature is further reduced, the system is gradually separated out of solids, the temperature of the system is reduced to 10-15 ℃, and the mixture is stirred and crystallized for 10-12 hours;
after crystallization, centrifuging, and leaching the filter cake with cold ethanol (30 ml) for 2 times;
after centrifugation, the wet product was transferred to a vacuum oven and dried at 40-50℃to give Compound V (22.86 g,0.0622 mol), yield 88.9%, purity of liquid phase 99.6%.
Examples 5 to 6
Other conditions were the same as in example 1, except that the mass to volume ratio of compound I to methyl acetate was changed, and the reaction conditions and yields of example 1 and examples 5 to 6 are shown in Table 1.
TABLE 1 different conditions and results for example 1, examples 5-6
Examples | m(g):V(ml) | Reaction time/h | Yield/% |
1 | 1:3 | 6 | 93.3 |
5 | 1:1 | 6 | 89.5 |
6 | 1:5 | 6 | 92.3 |
Examples 7 to 10
Other conditions were the same as in example 2 except that the molar ratio of compound ii, ethyl 2-chloroacetate, base was varied; the base types, reaction conditions and yields of examples 2 and examples 7-10 are shown in Table 2.
TABLE 2 different conditions and results for example 2, examples 7-10
Examples 11 to 14
Other conditions are the same as in example 3, except that the molar ratio of compound III to base is changed, and the reaction conditions and yields of example 3 and examples 11 to 14 are shown in Table 3.
TABLE 3 different conditions and results for example 3, examples 11-14
Examples 15 to 20
Other conditions were the same as in example 4 except that the molar ratio of compound IV to L tartaric acid, the reaction temperature and the crystallization temperature were changed, and the reaction conditions and results of example 4 and examples 15 to 20 are detailed in table 4.
TABLE 4 different conditions and results for example 4, examples 15-20
Examples 21 to 23
Other conditions are the same as in example 1 and example 2, except that the kinds of R1 and R2 groups are changed, and the reaction conditions and results of examples 1 and 2 and examples 21 to 23 are shown in Table 5.
TABLE 5 different conditions and results for examples 1,2, and examples 21-23
What has been described above is a specific embodiment of the present invention. It should be noted that modifications and adaptations to the invention may occur to one skilled in the art without departing from the principles of the present invention and are intended to be within the scope of the present invention.
Claims (10)
1. The preparation method of the ticagrelor intermediate compound IV is characterized by comprising the following steps of: the method comprises the steps of taking a compound I as an initial raw material, firstly reacting the compound I with methyl alkyl acid to synthesize a compound II, then synthesizing the compound II with 2-halogenated ethyl alkyl acid under the action of alkali to synthesize a compound III, and finally hydrolyzing the compound III in an alkaline environment to obtain a target compound IV;
wherein: r is R 1 、R 2 Is optionally and independently selected from C1-C4 alkyl.
2. The preparation method of ticagrelor intermediate compound IV according to claim 1, wherein: the R is 1 Is ethyl.
3. The preparation method of ticagrelor intermediate compound IV according to claim 2, wherein: the mass volume ratio of the compound I to the alkyl acid methyl ester is 1 (1-5) g/ml.
4. The preparation method of ticagrelor intermediate compound IV according to claim 1, wherein: the reaction temperature for synthesizing the compound II by the reaction of the compound I and the methyl alkyl acid ester is 55-60 ℃.
5. The preparation method of ticagrelor intermediate compound IV according to claim 1, wherein: the halogenation is preferably a chlorination.
6. The process for the preparation of ticagrelor intermediate compound IV according to claim 1 or 2 or 5, characterized in that: the R is 2 Is ethyl.
7. The preparation method of ticagrelor intermediate compound IV according to claim 1, wherein: the molar ratio of the compound II to the alkyl acid-2-halogenated ethyl ester to the alkali is 1: (1-3): (2-5); preferably 1:1.5:3.
8. the preparation method of ticagrelor intermediate compound IV according to claim 1, wherein: the compound II and alkyl acid-2-halogenated ethyl ester are synthesized under the action of alkali, wherein the alkali is one or more of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium tert-butoxide, sodium methoxide, triethylamine and diisopropylamine, and is preferably potassium carbonate.
9. The preparation method of ticagrelor intermediate compound IV according to claim 1, wherein: the compound III is hydrolyzed in an alkaline environment to obtain a target compound IV, wherein the alkali is one or more of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium tert-butoxide, sodium tert-butoxide and sodium methoxide, and is preferably potassium carbonate;
further preferably, the molar ratio of compound iii to base is 1:2 to 5, preferably 1:3.
10. the preparation method of the ticagrelor intermediate compound V is characterized by comprising the following steps of: is prepared by salifying compound IV and L tartaric acid, and preferably has any one of the following conditions or two preferred conditions at the same time,
a. the molar ratio of the compound IV to the L tartaric acid is 1:1-2, preferably 1:1.2;
b. the reaction temperature is 40-55 ℃, and the crystallization temperature is 5-20 ℃;
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