CN103360408A - Novel thienopyridine compounds and use thereof in medicine - Google Patents
Novel thienopyridine compounds and use thereof in medicine Download PDFInfo
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Abstract
The invention relates to novel thienopyridine compounds or pharmaceutically acceptable salts of the novel thienopyridine compounds, medicine compositions comprising the thienopyridine compounds as active ingredients, and an application of the novel thienopyridine compounds or pharmaceutically acceptable salts of the novel thienopyridine compounds to the preparation of an antiplatelet drug. Het is trimethylpyrazinyl, pyrazinyl, pyridyl, thienyl, or indolyl; R1 is H or cyclopropylethanone; R2 is H or acetoxyl.
Description
Technical field
The present invention relates to new Thienopyridines or its pharmacy acceptable salt, contain these compounds as the pharmaceutical composition of activeconstituents, and described Thienopyridines or its pharmacy acceptable salt are for the preparation of the application of antiplatelet drug.
Wherein, Het is trimethylpyrazine base, pyrazinyl, pyridyl, thienyl, indyl; R
1Be H or cyclopropyl ketone base; R
2Be H or acetoxyl group.
Background technology
Thrombotic diseases is a kind of common disease, often shows as myocardial infarction, Ischemic Cerebral Infarction, venous thromboembolism.Thromboembolic disorders lethality rate and disability rate are all higher, and the arteriovenous thrombus is to cause the morbidity of cardiovascular disorder and dead first cause, also is one of first cause of cancer patients's death simultaneously; There is the 6500000 people deep venous thrombosis of getting involved in the whole world every year, and nearly 300,000 people die from pulmonary infarction, and atrial fibrillation can make cerebral apoplexy increase by 500.
The drug main for the treatment of clinically thrombotic diseases at present will be divided into anti-platelet drug, anticoagulation medicine and thrombolytic three major types.Wherein antiplatelet drug has treatment and prophylactic effect concurrently, is the main category of antithrombotic reagent always.
Oral antiplatelet drug commonly used has at present: (1) thromboxane A
2/ PGH
2Receptor antagonist; (2) GP II
b/ III
aReceptor antagonist; (3) adenosine diphosphate (ADP) (ADP) P2Y
12Receptor antagonist (such as the Thienopyridines medicine).Thienopyridines ADP P2Y wherein
12Receptor antagonist has become present antiplatelet main flow medicine.
Ticlopidine is that first is applied to clinical Thienopyridines ADP P2Y12 receptor antagonist, owing to there are the serious untoward reactions such as bone marrow depression, oligoleukocythemia, aplastic anemia, thrombocytopenia, withdraws from gradually antithrombotic market.S-generation Thienopyridines ADP P2Y12 receptor antagonist clopidogrel is present platelet aggregation-against standard care medicine clinically; But this medicine treatment is renderd a service lower, and owing to must pass through in its metabolic process in vivo after the two step metabolism of liver cytochrome P 450, just can obtain active metabolite, resulting active metabolite irreversibly with the P2Y12 receptors bind, thereby caused the drug effect of clopidogrel can reach 4-5 days, increased the risk of profuse bleeding.Prasugrel is third generation Thienopyridines ADP P2Y12 receptor antagonist, in its metabolism activation process, only have a step to depend on liver cytochrome P 450, and the cyclopropyl ketone base in the molecular structure substituted the ester group that originally can cause clopidogrel partial hydrolysis inactivation, thereby the ability of its anticoagulant is stronger, more effective; Yet incident then is obviously to have increased bleeding risk, and will be at a very long time run at high level.Therefore, safer and more effective ground of clinical needs antithrombotic reagent.
Summary of the invention
The invention provides by the Thienopyridines shown in the structural formula I its pharmacy acceptable salt class:
Wherein, Het is trimethylpyrazine base, pyrazinyl, pyridyl, thienyl, indyl; R
1Be H or cyclopropyl ketone base; R
2Be H or acetoxyl group.
Particularly, the invention provides the Thienopyridines that Het is the trimethylpyrazine base, structural formula is as follows:
Wherein, R
1Be H or cyclopropyl ketone base, R
2Be H or acetoxyl group.
It is the Thienopyridines of pyrazinyl that the present invention also provides Het, and structural formula is as follows:
Wherein, R
1Be H or cyclopropyl ketone base, R
2Be H or acetoxyl group.
It is the Thienopyridines of pyridyl that the present invention also provides Het, and structural formula is as follows:
Wherein, R
1Be H or cyclopropyl ketone base, R
2Be H or acetoxyl group.It is the Thienopyridines of thienyl that the present invention also provides Het, and structural formula is as follows:
It is the Thienopyridines of indyl that the present invention also provides Het, and structural formula is as follows:
Wherein, R
1Be H or cyclopropyl ketone base, R
2Be H or acetoxyl group.
The present invention relates to the preparation method of formula I compound or its pharmacy acceptable salt class.
The invention still further relates to above-mentioned formula I compound or its pharmacy acceptable salt class for the preparation of the application of antiplatelet drug.
The preferred following compounds of the present invention:
1) Compound I
1: 5-(2-methylene radical-3,5,6-trimethylpyrazine)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine also, and the concrete structure formula is as follows:
2) Compound I
2: 5-(2-methylene radical pyrazine)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine also, and the concrete structure formula is as follows:
3) Compound I
3: 5-(2-methylene radical pyridine)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine also, and the concrete structure formula is as follows:
4) Compound I
4: 5-(2-methylene radical thiophene)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine also, and the concrete structure formula is as follows:
5) Compound I
5: 5-(2-methylene radical indoles)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine also, and the concrete structure formula is as follows:
6) Compound I
6: 2-acetoxyl group-5-(2-methylene radical-3,5,6-trimethylpyrazine)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine also, and the concrete structure formula is as follows:
7) Compound I
7: 2-acetoxyl group-5-(2-methylene radical pyrazine)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine also, and the concrete structure formula is as follows:
8) Compound I
8: 2-acetoxyl group-5-(2-methylene radical pyridine)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine also, and the concrete structure formula is as follows:
9) Compound I
9: 2-acetoxyl group-5-(2-methylene radical thiophene)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine also, and the concrete structure formula is as follows:
10) Compound I
10: cyclopropyl ketone base-5-(2-methylene radical-3,5,6-trimethylpyrazine)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine also, and the concrete structure formula is as follows:
11) Compound I
11: cyclopropyl ketone base-5-(2-methylpyrazine)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine also, and the concrete structure formula is as follows:
12) Compound I
12: cyclopropyl ketone base-5-(2-picoline)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine also, and the concrete structure formula is as follows:
13) Compound I
13: 2-acetoxyl group-cyclopropyl ketone base-5-(2-methylene radical-3,5,6-trimethylpyrazine)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine also, and the concrete structure formula is as follows:
14) Compound I
14: 2-acetoxyl group-cyclopropyl ketone base-5-(2-methylene radical pyrazine)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine also, and the concrete structure formula is as follows:
15) Compound I
15: 2-acetoxyl group-cyclopropyl ketone base-5-(2-methylene radical pyridine)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine also, and the concrete structure formula is as follows:
Take Het as the trimethylpyrazine base as representative, target compound I
1-I
5Can prepare according to following route:
Take Het as the trimethylpyrazine base as representative, target compound I
6-I
9Can prepare according to following route:
Take Het as the trimethylpyrazine base as representative, target compound I
10-I
12Can prepare according to following route:
Take Het as the trimethylpyrazine base as representative, target compound I
13-I
15Can prepare according to following route:
Comprehensive above syntheti c route, Tetramethylpyrazine obtains a bromo product II through the N-bromosuccinimide bromo under catalyzed
1, obtain product I under the alkaline condition with after the tetrahydrothieno pyridines condensation
1And in order to introduce acetoxyl group, at first obtain intermediate III with active aldol tautomeric structure in the TERT-BUTYL DIMETHYL CHLORO SILANE protection raw material
6, again with a bromo product II
1/ II
6After the condensation, one kettle way removes the TBDMS protecting group and introduces ethanoyl and obtains product I
6When introducing the cyclopropyl ketone group ethylene-acetic acid is carried out structure of modification, obtain the Weinreb acid amides, further under the anhydrous and oxygen-free condition, the cyclopropyl ketone base is incorporated into the Tetramethylpyrazine molecule and obtains II
10/ II
13Then bromo obtains III
10/ III
13, next under alkaline condition with after the corresponding thienopyridine intermediate condensation, obtain Compound I
10/ IV
13, compound IV
13Acquisition end product I after removing the TBDMS protecting group and carrying out the ethanoyl protection
13
The free alkali of target compound acts on corresponding acid, obtains the salt of target compound.
Thienopyridines shown in the formula I of the present invention or its pharmacy acceptable salt and pharmaceutical composition thereof can be used for Antiplatelet therapy.
Embodiment
Can conduct further description the present invention by the following examples, yet scope of the present invention is not limited to following embodiment.One of skill in the art can understand, and under the prerequisite that does not deviate from the spirit and scope of the present invention, can carry out various variations and modification to the present invention.
Embodiment 1 5-(2-methylene radical-3,5,6-trimethylpyrazine)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine hydrochloride (Compound I also
1) synthetic
With 1.5g (11mmol) 2,3,5, the 6-Tetramethylpyrazine is dissolved in the 50mL tetracol phenixin, adds 2.0g (11mmol) NBS and catalytic amount benzoyl peroxide, back flow reaction under the illumination, reaction overnight 8-16 hour, TLC monitoring reaction (ethyl acetate/petroleum ether=1/1), the raw material rear termination reaction that substantially disappears, be cooled to below 50 ℃, suction filtration, concentrating under reduced pressure filtrate, column chromatography for separation gets white solid 2-brooethyl-3,5,6-trimethylpyrazine.
1.75g (10mmol) tetrahydrothieno pyridines (THTP) hydrochloride is dissolved in the methylene dichloride of 30mL, adds the triethylamine (TEA) of 1.2 equivalents, 25 ℃ of lower stirring reactions one hour obtain mixing solutions.In above-mentioned mixing solutions, add 2.14g (10mmol) 2-brooethyl-3,5, the 6-trimethylpyrazine, the triethylamine of 2.0 equivalents and catalytic amount sodium iodide, 45 ℃ of lower stirring reactions one hour are warming up to 52 ℃ of lower stirrings and continue about 5 hours of reaction.TLC monitoring reaction (ethyl acetate/petroleum ether=1/1), the raw material rear termination reaction that substantially disappears, add phosphate buffer solution under the whipped state, tell organic phase, dichloromethane extraction water three times, merge organic phase, use anhydrous sodium sulfate drying, carry out column chromatography for separation after the underpressure distillation desolventizing.(the preparation of phosphoric acid buffer: 9.5g KH
2PO
4With 0.95g NaHPO
412H
2Adding distilled water to total solution weight among the O is 358g).Obtain the pale yellow oily liquid body, in the salt acid ether, obtain white solid 0.96g behind the salify.
1H NMR (CDCl
3, 400MHz): δ 7.06 (dd, 1H, J=2.8,5.2Hz), 6.70 (dd, 1H, J=2.4,4.8Hz), 3.81 (s, 2H), 3.61 (s, 2H), 2.84 (s, 4H), 2.59 (s, 3H), 2.51 (s, 3H), 2.50 (s, 3H).
13C NMR:(CDCl
3, 100MHz): δ 150.0,149.7,148.0,147.8,133.7,133.4,125.2,122.5,61.2,53.2,50.5,25.4,21.6,21.5,20.9.LC-MS calculated value C
15H
19N
3S+H
+: 274.1; Measured value is 274.2.
Embodiment 2 5-(2-methylene radical pyrazine)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine hydrochloride (Compound I also
2) synthetic
1.0g (11mmol) 2-methylpyrazine is dissolved in the 50mL tetracol phenixin, add 2.0g (11mmol) NBS and catalytic amount benzoyl peroxide, back flow reaction under the illumination, reaction overnight 8-16 hour, TLC monitoring reaction (ethyl acetate/petroleum ether=1/1), the raw material rear termination reaction that substantially disappears, be cooled to below 50 ℃, suction filtration, concentrating under reduced pressure filtrate, column chromatography for separation gets weak yellow liquid 2-brooethyl pyrazine.
1.75g (10mmol) tetrahydrothieno pyridines (THTP) hydrochloride is dissolved in the methylene dichloride of 30mL, adds the triethylamine (TEA) of 1.2 equivalents, 25 ℃ of lower stirring reactions one hour obtain mixing solutions.In above-mentioned mixing solutions, add 1.71g (10mmol) 2-brooethyl pyrazine, the TEA of 2.0 equivalents and catalytic amount NaI, 45 ℃ of lower stirring reactions one hour are warming up to 52 ℃ of lower stirrings and continue about 5 hours of reaction.TLC monitoring reaction (ethyl acetate/petroleum ether=1/1), the raw material rear termination reaction that substantially disappears, add phosphate buffer solution under the whipped state, tell organic phase, dichloromethane extraction water three times, merge organic phase, anhydrous sodium sulfate drying carries out column chromatography for separation after the underpressure distillation desolventizing.Obtain the pale yellow oily liquid body, in the salt acid ether, obtain white solid 2.0g behind the salify.
1H NMR (DMSO-d
6, 400MHz): δ 12.0 (br, 1H), 9.05 (s, 1H), 8.76 (s, 2H), (7.47 s, 1H), 6.92 (s, 1H), 4.68 (s, 2H), (4.38 s, 2H), 3.80-3.43 (m, 2H), 3.24-3.14 (m, 2H).
13C NMR (DMSO-d
6, 100MHz): δ 147.0,146.5,145.3,144.4,131.4,128.0,125.3,125.1,56.3,50.3,49.2,21.6.LC-MS calculated value C
12H
13N
3S+H
+: 232.1; Measured value is 232.2.
Embodiment 3 5-(2-methylene radical pyridine)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine hydrochloride (Compound I also
3) synthetic
1.0g (11mmol) 2-picoline is dissolved in the 50mL tetracol phenixin, add 2.0g (11mmol) NBS and catalytic amount benzoyl peroxide, back flow reaction under the illumination, reaction overnight 8-16 hour, TLC monitoring reaction (ethyl acetate/petroleum ether=1/1), the raw material rear termination reaction that substantially disappears, be cooled to below 50 ℃, suction filtration, concentrating under reduced pressure filtrate, column chromatography for separation gets yellow liquid 2-bromo methyl cycloheptapyridine.
1.75g (10mmol) tetrahydrothieno pyridines (THTP) hydrochloride is dissolved in the methylene dichloride of 30mL, adds the triethylamine (TEA) of 1.2 equivalents, 25 ℃ of lower stirring reactions one hour obtain mixing solutions.In above-mentioned mixing solutions, add 1.70g (10mmol) bromo methyl cycloheptapyridine, the triethylamine of 2.0 equivalents and catalytic amount sodium iodide, 45 ℃ of lower stirring reactions one hour are warming up to 52 ℃ of lower stirrings and continue about 5 hours of reaction.TLC monitoring reaction (ethyl acetate/petroleum ether=1/1), the raw material rear termination reaction that substantially disappears, add phosphate buffer solution under the whipped state, tell organic phase, dichloromethane extraction water three times, merge organic phase, anhydrous sodium sulfate drying carries out column chromatography for separation after the underpressure distillation desolventizing.Obtain the pale yellow oily liquid body, in the salt acid ether, obtain white solid 1.55g behind the salify.
1HNMR (CDCl
3, 400MHz): δ 8.49 (d, J=8.0Hz, 1H), 7.59 (t, J=3.6Hz, 1H), 7.42 (d, J=7.6Hz, 1H), 7.10 (t, J=6.8Hz, 1H), (6.99 d, J=5.2Hz, 1H), 6.62 (t, J=5.2Hz, 1H), 3.80 (s, 2H), (3.56 s, 2H), 2.84-2.80 (m, 4H).
13C NMR (CDCl
3, 100MHz): δ 158.8,149.3,136.7,133.8,133.4,125.3,123.3,122.8,122.3,63.9,53.3,51.0,25.6.LC-MS calculated value C
13H
14N
2S+H
+: 231.1; Measured value is 231.1.
Embodiment 4 5-(2-methylene radical thiophene)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine hydrochloride (Compound I also
4) synthetic
0.98g (10mmol) 2-thiotolene is dissolved in the 50mL tetracol phenixin, add 2.0g (11mmol) NBS and catalytic amount benzoyl peroxide, back flow reaction under the illumination, reaction was spent the night 8-16 hour, TLC monitoring reaction (ethyl acetate/petroleum ether=1/1), the raw material rear termination reaction that substantially disappears, be cooled to below 50 ℃, suction filtration, concentrating under reduced pressure filtrate, column chromatography for separation obtains the 2-bromomethyl thiophene.
1.75g (10mmol) tetrahydrothieno pyridines (THTP) hydrochloride is dissolved in the methylene dichloride of 30mL, adds the triethylamine (TEA) of 1.2 equivalents, 25 ℃ of lower stirring reactions one hour obtain mixing solutions.In above-mentioned mixing solutions, add 1.76g (10mmol) 2-bromomethyl thiophene, the triethylamine of 2 equivalents and catalytic amount sodium iodide, 45 ℃ of lower stirring reactions one hour are warming up to 52 ℃ of lower stirrings and continue about 5 hours of reaction.TLC monitoring reaction (ethyl acetate/petroleum ether=1/1), the raw material rear termination reaction that substantially disappears, add phosphate buffer solution under the whipped state, tell organic phase, dichloromethane extraction water three times, merge organic phase, anhydrous sodium sulfate drying carries out column chromatography for separation after the underpressure distillation desolventizing.Obtain the pale yellow oily liquid body, in the salt acid ether, obtain white solid 1.50g behind the salify.
1H NMR (DMSO-d
6, 400MHz): δ 11.80 (br, 1H), 7.72 (d, J=4.4Hz, 1H), 7.50 (d, J=2.8Hz, 1H), 7.46 (d, J=5.2Hz, 1H), (7.16 m, 1H), 6.92 (m, 1H), (4.70 s, 2H), 4.19 (s, 2H), (3.72-3.37 m, 2H), 3.29-3.09 (m, 2H).
13C NMR (DMSO-d
6, 100MHz): δ 132.6,131.6,129.4,128.0,127.6,125.4,125.2,51.6,49.1,48.4,21.7.LC-MS calculated value C
12H
14NS
2+ H
+: 236.1; Measured value is 236.2.
Embodiment 5 5-(2-methylene radical indoles)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine hydrochloride (Compound I also
5) synthetic
With 6.56g (50mmol) 5-skatole, 6.10g (50mmol) DMAP and 12.0g (50mmol) Boc
2O is dissolved in the acetonitrile of 300mL, stirring reaction under the room temperature, TLC monitoring reaction (ethyl acetate/petroleum ether=1/5), the raw material rear termination reaction that substantially disappears, and concentrating under reduced pressure filtrate, column chromatography for separation gets white foam shape solid product.2.31g (10mmol) N-tert.-butoxy-5-skatole is dissolved in the 50mL tetracol phenixin, add 2.0g (11mmol) NBS and catalytic amount benzoyl peroxide, back flow reaction under the illumination, reaction overnight 8-16 hour, TLC monitoring reaction (ethyl acetate/petroleum ether=1/1), the raw material rear termination reaction that substantially disappears, be cooled to below 50 ℃, suction filtration, concentrating under reduced pressure filtrate, column chromatography for separation obtains N-tert.-butoxy-5-brooethyl indoles.
1.75g (10mmol) tetrahydrothieno pyridines (THTP) hydrochloride is dissolved in the methylene dichloride of 30mL, adds the triethylamine (TEA) of 1.2 equivalents, 25 ℃ of lower stirring reactions one hour obtain mixing solutions.In above-mentioned mixing solutions, add 1.76g (10mmol) N-tert.-butoxy-5-brooethyl indoles, the triethylamine of 2.0 equivalents and catalytic amount sodium iodide, 45 ℃ of lower stirring reactions one hour are warming up to 52 ℃ of lower stirrings and continue about 5 hours of reaction.TLC monitoring reaction (ethyl acetate/petroleum ether=1/4), the raw material rear termination reaction that substantially disappears, add phosphate buffer solution under the whipped state, tell organic phase, dichloromethane extraction water three times, merge organic phase, anhydrous sodium sulfate drying carries out column chromatography for separation after the underpressure distillation desolventizing.Obtain the pale yellow oily liquid body, pass into dry salt acid gas deprotection base after being dissolved in methylene dichloride, salify precipitation simultaneously obtains white solid 0.09g after after filtering.LC-MS calculated value C
16H
16N
2S+H
+: 269.1; Measured value is 269.3.
Embodiment 6 2-acetoxyl group-5-(2-methylene radical-3,5,6-trimethylpyrazine)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine hydrochloride (Compound I also
6) synthetic
With 7.2g (53mmol) 2,3,5, the 6-Tetramethylpyrazine is dissolved in the 50mL tetracol phenixin, adds 9.9g (53mmol) NBS and catalytic amount benzoyl peroxide, back flow reaction under the illumination, reaction overnight (8-16 hour), TLC monitoring reaction (ethyl acetate/petroleum ether=1/1), the raw material rear termination reaction that substantially disappears, be cooled to below 50 ℃, suction filtration, concentrating under reduced pressure filtrate, column chromatography for separation obtains 2-brooethyl-3,5,6-trimethylpyrazine.1.91g (10mmol) prasugrel intermediate hydrochloride, 1.65g (11mmol) TERT-BUTYL DIMETHYL CHLORO SILANE TBDMSCl and 30mL methylene dichloride are mixed, the triethylamine that adds 1.1 equivalents stirring reaction one hour under room temperature obtains mixing solutions.In above-mentioned mixing solutions, add 2.14g (10mmol) 2-brooethyl-3,5, the 6-trimethylpyrazine, the triethylamine of 2 equivalents and catalytic amount sodium iodide, 45 ℃ of lower stirring reactions one hour are warming up to 52 ℃ of lower stirrings and continue about 5 hours of reaction.TLC monitoring reaction (ethyl acetate/petroleum ether=1/1), the raw material rear termination reaction that substantially disappears, add phosphate buffer solution under the whipped state, tell organic phase, dichloromethane extraction water three times, merge organic phase, anhydrous sodium sulfate drying carries out column chromatography for separation and obtains oily liquids after the underpressure distillation desolventizing.Add triethylamine and the catalytic amount dimethyl aminopyridine of 1.1 equivalents in the above-mentioned 20mL acetonitrile solution that obtains product, stirred 30 minutes under the room temperature, drip the acetonitrile solution of the diacetyl oxide of 1.1 equivalents under the ice-water bath, continued stirring reaction one hour.Concentration of reaction solution after reaction finishes, column chromatography for separation obtains the oily product.In the salt acid ether, obtain white solid 0.38g behind the salify.
1H NMR (CDCl
3, 400MHz): 6.29 (s, 1H), 3.78 (s, 2H), 3.50 (s, 2H), 2.73-2.84 (m, 4H), 2.58 (s, 3H), 2.51 (s, 3H), 2.50 (s, 3H), 2.27 (s, 3H).
13C NMR (CDCl
3, 100MHz): δ 167.8,150.0,149.7,149.3,148.0,147.7,129.6,125.9,112.0,61.1,52.8,50.4,24.8,21.5,21.4,20.9,20.7.LC-MS calculated value C
17H
21N
3O
2S+H
+: 332.1; Measured value is 332.4.
Embodiment 7 2-acetoxyl group-5-(2-methylene radical pyrazine)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine hydrochloride (Compound I also
7) synthetic
1.0g (11mmol) 2-methylpyrazine is dissolved in the 50mL tetracol phenixin, add 2.0g (11mmol) NBS and catalytic amount benzoyl peroxide, back flow reaction under the illumination, reaction overnight 8-16 hour, TLC monitoring reaction (ethyl acetate/petroleum ether=1/1), the raw material rear termination reaction that substantially disappears, be cooled to below 50 ℃, suction filtration, concentrating under reduced pressure filtrate, column chromatography for separation obtains 2-brooethyl pyrazine.1.91g (10mmol) prasugrel intermediate hydrochloride, 1.65g (11mmol) TERT-BUTYL DIMETHYL CHLORO SILANE TBDMSCl and 30mL methylene dichloride are mixed, the triethylamine that adds 1.1 equivalents stirring reaction one hour under room temperature obtains mixing solutions.In above-mentioned mixing solutions, add 1.70g (10mmol) 2-brooethyl pyrazine, the triethylamine of 2.0 equivalents and catalytic amount sodium iodide, 45 ℃ of lower stirring reactions one hour are warming up to 52 ℃ of lower stirrings and continue about 5 hours of reaction.TLC monitoring reaction (ethyl acetate/petroleum ether=1/1), the raw material rear termination reaction that substantially disappears, add phosphate buffer solution under the whipped state, tell organic phase, dichloromethane extraction water three times, merge organic phase, anhydrous sodium sulfate drying carries out column chromatography for separation and gets oily matter after the underpressure distillation desolventizing.Add triethylamine and the catalytic amount dimethyl aminopyridine of 1.1 equivalents in the 20mL acetonitrile solution of above-mentioned product, stirred 30 minutes under the room temperature, drip the acetonitrile solution of the diacetyl oxide of 1.1 equivalents under the ice-water bath, continued stirring reaction one hour.Concentration of reaction solution after reaction finishes, column chromatography for separation obtains the oily product.In the salt acid ether, obtain white solid 0.40g behind the salify.
1H NMR (DMSO-d
6, 400MHz): δ 11.99 (br, 1H), 9.05 (s, 1H), 8.76 (s, 2H), 7.47 (t, J=4.8Hz, 1H), 6.92 (d, J=4.8Hz, 1H), 4.69 (s, 2H), (4.38 s, 2H), 3.80-3.14 (m, 2H), 2.25 (s, 3H) .LC-MS calculated value C
14H
15N
3O
2S+H
+: 290.1; Measured value is 290.1.
Embodiment 8 2-acetoxyl group-5-(2-methylene radical pyridine)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine hydrochloride (Compound I also
8) synthetic
1.0g (11mmol) 2-picoline is dissolved in the 50mL tetracol phenixin, add 2.0g (11mmol) NBS and catalytic amount benzoyl peroxide, back flow reaction under the illumination, reaction overnight 8-16 hour, TLC monitoring reaction (ethyl acetate/petroleum ether=1/1), the raw material rear termination reaction that substantially disappears, be cooled to below 50 ℃, suction filtration, concentrating under reduced pressure filtrate, column chromatography for separation obtains the 2-bromo methyl cycloheptapyridine.1.91g (10mmol) prasugrel intermediate hydrochloride, 1.65g (11mmol) TERT-BUTYL DIMETHYL CHLORO SILANE TBDMSCl and 30mL methylene dichloride are mixed, the triethylamine that adds 1.1 equivalents stirring reaction one hour under room temperature obtains mixing solutions.In above-mentioned mixing solutions, add 1.70g (10mmol) 2-bromo methyl cycloheptapyridine, the triethylamine of 2 equivalents and catalytic amount sodium iodide, 45 ℃ of lower stirring reactions one hour are warming up to 52 ℃ of lower stirrings and continue about 5 hours of reaction.TLC monitoring reaction (ethyl acetate/petroleum ether=1/1), the raw material rear termination reaction that substantially disappears, add phosphate buffer solution under the whipped state, tell organic phase, dichloromethane extraction water three times, merge organic phase, anhydrous sodium sulfate drying carries out column chromatography for separation and obtains oily matter after the underpressure distillation desolventizing.Add triethylamine and the catalytic amount dimethyl aminopyridine of 1.1 equivalents in the 20mL acetonitrile solution of above-mentioned product, stirred 30 minutes under the room temperature, drip the acetonitrile solution of the diacetyl oxide of 1.1 equivalents under the ice-water bath, continued stirring reaction one hour.Concentration of reaction solution after reaction finishes, column chromatography for separation obtains the oily product.In the salt acid ether, obtain white solid 0.05g behind the salify.
1H NMR (CDCl
3, 400MHz): 8.58 (dd, J=5.6,0.8Hz, 1H), 7.70-7.66 (m, 1H), (7.50 d, J=7.6Hz, 1H), 7.19-7.20 (m, 1H), 3.87 (s, 2H), (3.54 s, 2H), 2.88-2.82 (m, 4H), 2.27 (s, 3H).
13C NMR (CDCl
3, 100MHz): δ 167.7,158.3,149.3,149.0,136.5,129.4,125.7,123.0,122.1,111.8,63.6,52.6,50.5,24.8,20.6.LC-MS calculated value C
15H
16N
2O
2S+H
+: 289.1; Measured value is 289.1.
Embodiment 9 2-acetoxyl group-5-(2-methylene radical thiophene)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine hydrochloride (Compound I also
9) synthetic
0.98g (10mmol) 2-thiotolene is dissolved in the 50mL tetracol phenixin, add 2.0g (11mmol) NBS and catalytic amount benzoyl peroxide, back flow reaction under the illumination, reaction overnight 8-16 hour, TLC monitoring reaction (ethyl acetate/petroleum ether=1/1), the raw material rear termination reaction that substantially disappears, be cooled to below 50 ℃, suction filtration, concentrating under reduced pressure filtrate, column chromatography for separation obtains the 2-bromomethyl thiophene.1.91g (10mmol) prasugrel intermediate hydrochloride, 1.65g (11mmol) TERT-BUTYL DIMETHYL CHLORO SILANE TBDMSCl and 30mL methylene dichloride are mixed, the triethylamine that adds 1.1 equivalents stirring reaction one hour under room temperature obtains mixing solutions.In above-mentioned mixing solutions, add 1.75g (10mmol) 2-bromomethyl thiophene, the triethylamine of 2 equivalents and catalytic amount sodium iodide, 45 ℃ of lower stirring reactions one hour are warming up to 52 ℃ of lower stirrings and continue about 5 hours of reaction.TLC monitoring reaction (ethyl acetate/petroleum ether=1/1), the raw material rear termination reaction that substantially disappears, add phosphate buffer solution under the whipped state, tell organic phase, dichloromethane extraction water three times, merge organic phase, anhydrous sodium sulfate drying carries out column chromatography for separation and obtains the oily product after the underpressure distillation desolventizing.Add triethylamine and the catalytic amount dimethyl aminopyridine of 1.1 equivalents in the 20mL acetonitrile solution of above-mentioned product, stirred 30 minutes under the room temperature, drip the acetonitrile solution of the diacetyl oxide of 1.1 equivalents under the ice-water bath, continued stirring reaction one hour.Concentration of reaction solution after reaction finishes, column chromatography for separation obtains the oily product.In the salt acid ether, obtain white solid 0.25g behind the salify.
1H NMR (DMSO-d
6, 400MHz): δ 11.23 (br, 1H), 7.75 (d, J=5.2Hz, 1H), (7.17-7.10 m, 1H), 6.62 (s, 1H), 4.70-4.68 (m, 2H), (4.12 s, 2H), 3.43-3.34 (m, 4H), 2.29 (m, 2H).
13C NMR (DMSO-d
6, 100MHz): δ 167.8,14.9,132.6,130.4,129.5,127.7,124.3,123.7,111.9,48.8,48.4,40.1,21.3,20.5.LC-MS calculated value C
14H
15NO
2S
2+ H
+: 294.1; Measured value is 294.2.
Embodiment 10 cyclopropyl ketone base-5-(2-methylene radical-3,5,6-trimethylpyrazine)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine hydrochloride (Compound I also
10) synthetic
Under 0 ℃, the LDA of 15mL (2M THF solution) is dissolved in the 100mL anhydrous diethyl ether, drip 2.72g (20mmol) 2 in the whipping process, 3, the 10mL anhydrous ether solution of 5,6-Tetramethylpyrazine reacted 30 minutes, drip 3mL (30mmol) ethylene-acetic acid methyl esters, continue reaction 90 minutes.After adding saturated ammonium chloride solution cancellation reaction, use ethyl acetate extraction three times, merging organic phase and dry, concentrated rear pillar chromatographic separation obtain 1-cyclopropyl-2-(3,5,6-trimethylpyrazine)-ethyl ketone.With 2.2g (11mmol) 1-cyclopropyl-2-(3,5, the 6-trimethylpyrazine)-ethyl ketone is dissolved in the 50mL tetracol phenixin, add 2.0g (11mmol) NBS and catalytic amount benzoyl peroxide, back flow reaction under the illumination, reaction was spent the night 8-16 hour, TLC monitoring reaction (ethyl acetate/petroleum ether=1/1), the raw material rear termination reaction that substantially disappears is cooled to below 50 ℃ suction filtration, concentrating under reduced pressure filtrate, column chromatography for separation obtains 2-bromo-1-cyclopropyl-2-(3,5,6-trimethylpyrazine)-ethyl ketone.1.75g (10mmol) tetrahydrothieno pyridines (THTP) hydrochloride is dissolved in the methylene dichloride of 30mL, adds the triethylamine (TEA) of 1.2 equivalents, 25 ℃ of lower stirring reactions one hour obtain mixing solutions.In above-mentioned mixing solutions, add 2.82g (10mmol) 2-bromo-1-cyclopropyl-2-(3,5,6-trimethylpyrazine)-and ethyl ketone, the triethylamine of 2.0 equivalents and catalytic amount sodium iodide, 45 ℃ of lower stirring reactions one hour are warming up to 52 ℃ of lower stirrings and continue about 5 hours of reaction.TLC monitoring reaction (ethyl acetate/petroleum ether=1/1), the raw material rear termination reaction that substantially disappears, add phosphate buffer solution under the whipped state, tell organic phase, dichloromethane extraction water three times, merge organic phase, anhydrous sodium sulfate drying carries out column chromatography for separation after the underpressure distillation desolventizing.(the preparation of phosphoric acid buffer: 9.5g KH
2PO
4With 0.95g NaHPO
412H
2Adding distilled water to total solution weight among the O is 358g).The pale yellow oily liquid body that obtains obtains white solid 0.70g behind the salify in the salt acid ether.
1H NMR (CDCl
3, 400MHz): δ 7.05 (d, J=5.2Hz, 2H), 6.65 (d, J=5.2Hz, 1H), 4.79 (s, 1H), (3.73 s, 2H), 3.00-2.98 (m, 2H), (2.85-2.84 m, 2H), 2.58 (s, 3H), (2.49 s, 6H), 2.66-2.42 (m, 1H), (1.06-1.03 m, 2H), 0.84-0.81 (m, 2H).
13C NMR (CDCl
3, 100MHz): δ 208.4,150.4,150.1,149.2,146.1,133.6,133.4,125.3,122.6,50.6,48.2,25.5,21.7,21.6,21.1,19.0,11.6.LC-MS calculated value C
19H
23N
3OS+H
+: 342.2; Measured value is 342.3.
Embodiment 11 cyclopropyl ketone base-5-(2-methylpyrazine)-4,5,6,7-tetramethylene sulfide are [3,2-c] pyridine hydrochloride (Compound I also
11) synthetic
Under 0 ℃, the LDA of 15mL (2M THF solution) is dissolved in the 100mL anhydrous diethyl ether, drips the 10mL anhydrous ether solution of 1.88g (20mmol) 2-methylpyrazine in the whipping process, reacted 30 minutes, drip 3mL (30mmol) ethylene-acetic acid methyl esters, continue reaction 90 minutes.After adding saturated ammonium chloride solution cancellation reaction, use ethyl acetate extraction three times, merging organic phase and dry, concentrated rear pillar chromatographic separation obtain 1-cyclopropyl-2-methylpyrazine-ethyl ketone.1.62g (11mmol) 1-cyclopropyl-2-methylpyrazine-ethyl ketone is dissolved in the 50mL tetracol phenixin, add 2.0g (11mmol) NBS and catalytic amount benzoyl peroxide, back flow reaction under the illumination, reaction was spent the night 8-16 hour, TLC monitoring reaction (ethyl acetate/petroleum ether=1/1), the raw material rear termination reaction that substantially disappears, be cooled to below 50 ℃, suction filtration, concentrating under reduced pressure filtrate, column chromatography for separation obtains 2-bromo-1-cyclopropyl-2-(2-methylpyrazine)-ethyl ketone.1.75g (10mmol) tetrahydrothieno pyridines (THTP) hydrochloride is dissolved in the methylene dichloride of 30mL, adds the triethylamine (TEA) of 1.2 equivalents, 25 ℃ of lower stirring reactions one hour obtain mixing solutions.In above-mentioned mixing solutions, add 2.82g (10mmol) 2-bromo-1-cyclopropyl-2-(2-methylpyrazine)-ethyl ketone, 2.0 the triethylamine of equivalent and catalytic amount sodium iodide, 45 ℃ of lower stirring reactions one hour are warming up to 52 ℃ of lower stirrings and continue about 5 hours of reaction.TLC monitoring reaction (ethyl acetate/petroleum ether=1/1), the raw material rear termination reaction that substantially disappears, add phosphate buffer solution under the whipped state, tell organic phase, dichloromethane extraction water three times, merge organic phase, anhydrous sodium sulfate drying carries out column chromatography for separation after the underpressure distillation desolventizing.(the preparation of phosphoric acid buffer: 9.5g KH
2PO
4With 0.95g NaHPO
412H
2Adding distilled water to total solution weight among the O is 358g).Obtain the pale yellow oily liquid body, in the salt acid ether, obtain white solid 0.96g behind the salify.
1H NMR (CDCl
3, 400MHz): δ 8.79-8.78 (m, 1H), 8.63-8.62 (m, 1H), 8.56-8.55 (m, 1H), 7.08 (d, 1H, J=5.6Hz), 6.68 (d, 1H, J=4.8Hz), 3.70 (q, 2H, J=14.0Hz), (2.96-2.89 m, 4H), 2.53-2.50 (m, 1H), 1.25-0.92 (m, 1H).
13C NMR (CDCl
3, 100MHz): δ 207.7,151.7,145.4,144.4,143.9,133.1,132.9,125.1,122.9,79.3,50.9,48.6,25.4,18.4,12.5,11.9.LC-MS calculated value: C
16H
17N
3OS+H
+: 300.1; Measured value: 300.2.
Embodiment 12 cyclopropyl ketone base-5-(2-picoline)-4,5,6,7-tetramethylene sulfide are [3,2-c] pyridine hydrochloride (Compound I also
12) synthetic
Under 0 ℃, the LDA of 15mL (2M THF solution) is dissolved in the 100mL anhydrous diethyl ether, drips the 10mL anhydrous ether solution of 1.86g (20mmol) 2-picoline in the whipping process, reacted 30 minutes, drip 3mL (30mmol) ethylene-acetic acid methyl esters, continue reaction 90 minutes.After adding saturated ammonium chloride solution cancellation reaction, use ethyl acetate extraction three times, merging organic phase and dry, concentrated rear pillar chromatographic separation obtain 1-cyclopropyl-2-picoline-ethyl ketone.1.77g (11mmol) 1-cyclopropyl-2-(2-picoline)-ethyl ketone is dissolved in the 50mL tetracol phenixin, add 2.0g (11mmol) NBS and catalytic amount benzoyl peroxide, back flow reaction under the illumination, reaction was spent the night 8-16 hour, TLC monitoring reaction (ethyl acetate/petroleum ether=1/1), the raw material rear termination reaction that substantially disappears, be cooled to below 50 ℃, suction filtration, concentrating under reduced pressure filtrate, column chromatography for separation obtains 2-bromo-1-cyclopropyl-2-(2-picoline)-ethyl ketone.1.75g (10mmol) tetrahydrothieno pyridines (THTP) hydrochloride is dissolved in the methylene dichloride of 30mL, adds the triethylamine (TEA) of 1.2 equivalents, 25 ℃ of lower stirring reactions one hour obtain mixing solutions.In above-mentioned mixing solutions, add 2.40g (10mmol) 2-bromo-1-cyclopropyl-2-(2-picoline)-ethyl ketone, 2.0 the triethylamine of equivalent and catalytic amount sodium iodide, 45 ℃ of lower stirring reactions one hour are warming up to 52 ℃ of lower stirrings and continue about 5 hours of reaction.TLC monitoring reaction (ethyl acetate/petroleum ether=1/1), the raw material rear termination reaction that substantially disappears, add phosphate buffer solution under the whipped state, tell organic phase, dichloromethane extraction water three times, merge organic phase, anhydrous sodium sulfate drying carries out column chromatography for separation after the underpressure distillation desolventizing.(the preparation of phosphoric acid buffer: 9.5g KH
2PO
4With 0.95g NaHPO
412H
2Adding distilled water to total solution weight among the O is 358g).Obtain the pale yellow oily liquid body, in the salt acid ether, obtain white solid 0.54g behind the salify.
1HNMR(CDCl
3，400MHz)：δ8.65-8.64(m，1H)，7.72-7.70(m，1H)，7.55-7.52(m，1H)，7.28-7.26(m，1H)，7.06(d，J＝5.2Hz，1H)，6.67(s，J＝5.2Hz，1H)，4.63(s，1H)，3.71-3.65(m，2H)，2.92-2.90(m，4H)，1.42-1.19(m，1H)，1.08-0.98(m，2H)，0.88-0.85(m，2H).
13C?NMR(CDCl
3，100MHz)：δ208.3，155.8，149.7，136.8，133.2，127.8，125.2，123.8，123.0，122.7，81.7，51.0，48.8，25.3，18.6，12.2，11.6。LC-MS calculated value C
17H
18N
2OS+H
+: 299.1; Measured value is 299.2.
Embodiment 13 2-acetoxyl group-cyclopropyl ketone base-5-(2-methylene radical-3,5,6-trimethylpyrazine)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine hydrochloride (Compound I also
13) synthetic
Under 0 ℃, the LDA of 15mL (2M THF solution) is dissolved in the 100mL anhydrous diethyl ether, drip 2.72g (20mmol) 2 in the whipping process, 3, the 10mL anhydrous ether solution of 5,6-Tetramethylpyrazine reacted 30 minutes, drip 3mL (30mmol) ethylene-acetic acid methyl esters, continue reaction 90 minutes.After adding saturated ammonium chloride solution cancellation reaction, use ethyl acetate extraction three times, merge organic phase and obtain 1-cyclopropyl-2-(3,5,6-trimethylpyrazine)-ethyl ketone with anhydrous sodium sulfate drying, concentrated rear pillar chromatographic separation.With 2.2g (11mmol) 1-cyclopropyl-2-(3,5, the 6-trimethylpyrazine)-ethyl ketone is dissolved in the 50mL tetracol phenixin, add 2.0g (11mmol) NBS and catalytic amount benzoyl peroxide, back flow reaction under the illumination, react spend the night (8-16 hour), TLC monitoring reaction (ethyl acetate/petroleum ether=1/1), the raw material rear termination reaction that substantially disappears is cooled to below 50 ℃ suction filtration, concentrating under reduced pressure filtrate, column chromatography for separation obtains 2-bromo-1-cyclopropyl-2-(3,5,6-trimethylpyrazine)-ethyl ketone.1.91g (10mmol) prasugrel intermediate hydrochloride, 1.65g (11mmol) TERT-BUTYL DIMETHYL CHLORO SILANE TBDMSCl and 30mL methylene dichloride are mixed, the triethylamine that adds 1.1 equivalents stirring reaction one hour under room temperature obtains mixing solutions.In above-mentioned mixing solutions, add 1.70g (10mmol) 2-bromo-1-cyclopropyl-2-(3,5,6-trimethylpyrazine)-and ethyl ketone, the triethylamine of 2 equivalents and catalytic amount sodium iodide, 45 ℃ of lower stirring reactions one hour are warming up to 52 ℃ of lower stirrings and continue about 5 hours of reaction.TLC monitoring reaction (ethyl acetate/petroleum ether=1/1), the raw material rear termination reaction that substantially disappears, add phosphate buffer solution under the whipped state, tell organic phase, dichloromethane extraction water three times, merge organic phase, anhydrous sodium sulfate drying carries out column chromatography for separation and gets oily matter after the underpressure distillation desolventizing.Add triethylamine and the catalytic amount dimethyl aminopyridine of 1.1 equivalents in the 20mL acetonitrile solution of above-mentioned product, stirred 30 minutes under the room temperature, drip the acetonitrile solution of the diacetyl oxide of 1.1 equivalents under the ice-water bath, continued stirring reaction one hour.Concentration of reaction solution after reaction finishes, column chromatography for separation obtains the oily product.In the salt acid ether, obtain white solid behind the salify.LC-MS calculated value C
21H
25N
3O
3S+H
+: 400.2; Measured value is 400.3.
Embodiment 14 2-acetoxyl group-cyclopropyl ketone base-5-(2-methylene radical pyrazine)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine hydrochloride (Compound I also
14) synthetic
Under 0 ℃, the LDA of 15mL (2M THF solution) is dissolved in the 100mL anhydrous diethyl ether, drips the 10mL anhydrous ether solution of 2.72g (20mmol) 2-methylpyrazine in the whipping process, reacted 30 minutes, drip 3mL (30mmol) ethylene-acetic acid methyl esters, continue reaction 90 minutes.After adding saturated ammonium chloride solution cancellation reaction, use ethyl acetate extraction three times, merge organic phase and obtain 1-cyclopropyl-2-methylene radical pyrazine-ethyl ketone with anhydrous sodium sulfate drying, concentrated rear pillar chromatographic separation.2.2g (11mmol) 1-cyclopropyl-2-methylene radical pyrazine-ethyl ketone is dissolved in the 50mL tetracol phenixin, add 2.0g (11mmol) NBS and catalytic amount benzoyl peroxide, back flow reaction under the illumination, reaction is spent the night (8-16 hour), TLC monitoring reaction (ethyl acetate/petroleum ether=1/1), the raw material rear termination reaction that substantially disappears, be cooled to below 50 ℃, suction filtration, concentrating under reduced pressure filtrate, column chromatography for separation obtains 2-bromo-1-cyclopropyl-2-methylene radical pyrazine-ethyl ketone.1.91g (10mmol) prasugrel intermediate hydrochloride, 1.65g (11mmol) TERT-BUTYL DIMETHYL CHLORO SILANE TBDMSCl and 30mL methylene dichloride are mixed, the triethylamine that adds 1.1 equivalents stirring reaction one hour under room temperature obtains mixing solutions.In above-mentioned mixing solutions, add 1.70g (10mmol) 2-bromo-1-cyclopropyl-2-methylene radical pyrazine-ethyl ketone, the triethylamine of 2 equivalents and catalytic amount sodium iodide, 45 ℃ of lower stirring reactions one hour are warming up to 52 ℃ of lower stirrings and continue about 5 hours of reaction.TLC monitoring reaction (ethyl acetate/petroleum ether=1/1), the raw material rear termination reaction that substantially disappears, add phosphate buffer solution under the whipped state, tell organic phase, dichloromethane extraction water three times, merge organic phase, anhydrous sodium sulfate drying carries out column chromatography for separation and gets oily matter after the underpressure distillation desolventizing.Add triethylamine and the catalytic amount dimethyl aminopyridine of 1.1 equivalents in the 20mL acetonitrile solution of above-mentioned product, stirred 30 minutes under the room temperature, drip the acetonitrile solution of the diacetyl oxide of 1.1 equivalents under the ice-water bath, continued stirring reaction one hour.Concentration of reaction solution after reaction finishes, column chromatography for separation obtains the oily product.In the salt acid ether, obtain white solid behind the salify.
1HNMR(CDCl
3，400MHz)：δ8.60-8.57(m，1H)，8.50-8.45(m，1H)，8.40-8.38(m，1H)，5.78(s，1H)，4.77(s，1H)，3.65-3.62(m，2H)，2.64-2.70(m，4H)，2.08(s，3H)，1.12-1.08(m，1H)，0.58-0.46(m，2H).
13C?NMR(CDCl
3，100MHz)：δ210.2，168.0，153.7，146.7，144.4，144.5，141.9，133.9，122.7，107.4，71.3，56.1，47.5，25.9，16.9，15.4，7.2，7.0。LC-MS calculated value C
19H
21N
2O
3S+H
+: 299.1; Measured value is 299.2.LC-MS calculated value C
18H
19N
3O
3S+H
+: 358.1; Measured value is 358.2.
Embodiment 15 2-acetoxyl group-cyclopropyl ketone base-5-(2-picoline)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine hydrochloride (Compound I also
15) synthetic
Under 0 ℃, the LDA of 15mL (2M THF solution) is dissolved in the 100mL anhydrous diethyl ether, drips the 10mL anhydrous ether solution of 2.72g (20mmol) 2-picoline in the whipping process, reacted 30 minutes, drip 3mL (30mmol) ethylene-acetic acid methyl esters, continue reaction 90 minutes.After adding saturated ammonium chloride solution cancellation reaction, use ethyl acetate extraction three times, merge organic phase and obtain 1-cyclopropyl-2-picoline-ethyl ketone with anhydrous sodium sulfate drying, concentrated rear pillar chromatographic separation.2.2g (11mmol) 1-cyclopropyl-2-picoline-ethyl ketone is dissolved in the 50mL tetracol phenixin, add 2.0g (11mmol) NBS and catalytic amount benzoyl peroxide, back flow reaction under the illumination, reaction is spent the night (8-16 hour), TLC monitoring reaction (ethyl acetate/petroleum ether=1/1), the raw material rear termination reaction that substantially disappears, be cooled to below 50 ℃, suction filtration, concentrating under reduced pressure filtrate, column chromatography for separation obtains 2-bromo-1-cyclopropyl-2-picoline-ethyl ketone.1.91g (10mmol) prasugrel intermediate hydrochloride, 1.65g (11mmol) TERT-BUTYL DIMETHYL CHLORO SILANE TBDMSCl and 30mL methylene dichloride are mixed, the triethylamine that adds 1.1 equivalents stirring reaction one hour under room temperature obtains mixing solutions.In above-mentioned mixing solutions, add 1.70g (10mmol) 2-bromo-1-cyclopropyl-2-picoline-ethyl ketone, the triethylamine of 2 equivalents and catalytic amount sodium iodide, 45 ℃ of lower stirring reactions one hour are warming up to 52 ℃ of lower stirrings and continue about 5 hours of reaction.TLC monitoring reaction (ethyl acetate/petroleum ether=1/1), the raw material rear termination reaction that substantially disappears, add phosphate buffer solution under the whipped state, tell organic phase, dichloromethane extraction water three times, merge organic phase, anhydrous sodium sulfate drying carries out column chromatography for separation and gets oily matter after the underpressure distillation desolventizing.Add triethylamine and the catalytic amount dimethyl aminopyridine of 1.1 equivalents in the 20mL acetonitrile solution of above-mentioned product, stirred 30 minutes under the room temperature, drip the acetonitrile solution of the diacetyl oxide of 1.1 equivalents under the ice-water bath, continued stirring reaction one hour.Concentration of reaction solution after reaction finishes, column chromatography for separation obtains the oily product.In the salt acid ether, obtain white solid behind the salify.
1H?NMR(CDCl
3，400MHz)：δ8.65-8.64(m，1H)，7.82-7.80(m，1H)，7.58-7.56(m，1H)，7.29-7.27(m，1H)，5.78(s，1H)，4.77(s，1H)，3.69-3.62(m，2H)，2.62-2.80(m，4H)，2.08(s，3H)，1.12-1.09(m，1H)，0.68-0.45(m，2H).
13C?NMR(CDCl
3，100MHz)：δ210.2，168.0，158.6，149.4，146.7，135.9，133.9，123.0，122.7，120.6，107.4，71.3，56.1，47.5，25.9，16.9，15.4，7.8，7.0。LC-MS calculated value C
19H
21N
2O
3S+H
+: 299.1; Measured value is 299.2.LC-MS calculated value C
19H
20N
2O
3S+H
+: 357.1; Measured value is 357.2.
The experiment of embodiment 16 compound anticoagulations
This patent also provides the effect (the results are shown in following table) to kunming mice (male) abdominal injection and continuous three days cruor time extending of gavage, can find that all test-compounds all can prolong the clotting time.
Table 1. clotting time the selection result
Claims (9)
1. the Thienopyridines shown in the formula I, or its pharmacy acceptable salt class:
Wherein, Het is trimethylpyrazine base, pyrazinyl, pyridyl, thienyl, indyl; R
1Be H or cyclopropyl ketone base; R
2Be H or acetoxyl group.
2. the compound of claim 1, wherein Het is the trimethylpyrazine base, R
1Be H or cyclopropyl ketone base, R
2Be H or acetoxyl group, the concrete structure formula is as follows:
3. the compound of claim 1, Het is pyrazinyl, R
1Be H or cyclopropyl ketone base, R
2Be H or acetoxyl group, the concrete structure formula is as follows:
4. the compound of claim 1, Het is pyridyl, R
1Be H or cyclopropyl ketone base, R
2Be H or acetoxyl group, the concrete structure formula is as follows:
5. the compound of claim 1, Het is thienyl, R
1Be H or cyclopropyl ketone base, R
2Be H or acetoxyl group, the concrete structure formula is as follows:
6. the compound of claim 1, Het is indyl, R
1Be H or cyclopropyl ketone base, R
2Be H or acetoxyl group, the concrete structure formula is as follows:
7. the compound of claim 1 is selected from:
5-(2-methylene radical-3,5,6-trimethylpyrazine)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine also, and structure is as follows:
5-(2-methylene radical pyrazine)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine also, and structure is as follows:
5-(2-methylene radical pyridine)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine also, and structure is as follows:
5-(2-methylene radical thiophene)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine also, and structure is as follows:
5-(2-methylene radical indoles)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine also, and structure is as follows:
2-acetoxyl group-5-(2-methylene radical-3,5,6-trimethylpyrazine)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine also, and structure is as follows:
2-acetoxyl group-5-(2-methylene radical-pyrazine)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine also, and structure is as follows:
2-acetoxyl group-5-(2-methylene radical pyridine)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine also, and structure is as follows:
2-acetoxyl group-5-(2-methylene radical thiophene)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine also, and structure is as follows:
Cyclopropyl ketone base-5-(2-methylene radical-3,5,6-trimethylpyrazine)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine also, and structure is as follows:
Cyclopropyl ketone base-5-(2-methylpyrazine)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine also, and structure is as follows:
Cyclopropyl ketone base-5-(2-picoline)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine also, and structure is as follows:
2-acetoxyl group-cyclopropyl ketone base-5-(2-methylene radical-3,5,6-trimethylpyrazine)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine also, and structure is as follows:
2-acetoxyl group-cyclopropyl ketone base-5-(2-methylene radical pyrazine)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine also, and structural formula is as follows:
2-acetoxyl group-cyclopropyl ketone base-5-(2-methylene radical pyridine)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine also, and structural formula is as follows:
8. pharmaceutical composition, it contains the formula I compound described in the claim 1-7 or its pharmacy acceptable salt class, and one or more pharmaceutical carriers or vehicle.
9. the formula I compound described in the claim 1-7 or its pharmacy acceptable salt class are for the preparation of the application for the treatment of antiplatelet drug.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109646442A (en) * | 2019-01-29 | 2019-04-19 | 军事科学院军事医学研究院生物医学分析中心 | Acetate compounds are preparing the purposes in ring bird adenosine synzyme acetylation drug |
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| US4537894A (en) * | 1978-12-29 | 1985-08-27 | Sanofi, S.A. | Methods of using compositions having antithrombotic and anti-blood-platelet-aggregating activity |
| JPH0753561A (en) * | 1993-08-09 | 1995-02-28 | Toa Boshoku Kk | Tetrahydrothienopyridine derivative, its production and hematocyte coagulation inhibitor |
| CN101845051A (en) * | 2010-06-11 | 2010-09-29 | 天津药物研究院 | Nitrogen-containing heterocyclic thienopyridine compounds and preparation method and application thereof |
| CN102234284A (en) * | 2010-04-20 | 2011-11-09 | 严洁 | Fluorine-containing ticlopidine analogues, and preparation method and application thereof |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4537894A (en) * | 1978-12-29 | 1985-08-27 | Sanofi, S.A. | Methods of using compositions having antithrombotic and anti-blood-platelet-aggregating activity |
| JPH0753561A (en) * | 1993-08-09 | 1995-02-28 | Toa Boshoku Kk | Tetrahydrothienopyridine derivative, its production and hematocyte coagulation inhibitor |
| CN102234284A (en) * | 2010-04-20 | 2011-11-09 | 严洁 | Fluorine-containing ticlopidine analogues, and preparation method and application thereof |
| CN101845051A (en) * | 2010-06-11 | 2010-09-29 | 天津药物研究院 | Nitrogen-containing heterocyclic thienopyridine compounds and preparation method and application thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109646442A (en) * | 2019-01-29 | 2019-04-19 | 军事科学院军事医学研究院生物医学分析中心 | Acetate compounds are preparing the purposes in ring bird adenosine synzyme acetylation drug |
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