CN105968049A - Method for preparing 1-(2,6-dichlorobenzyl-3-(pyrrolidine-1-methyl)-6-aminoindazole - Google Patents
Method for preparing 1-(2,6-dichlorobenzyl-3-(pyrrolidine-1-methyl)-6-aminoindazole Download PDFInfo
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- CN105968049A CN105968049A CN201610219341.7A CN201610219341A CN105968049A CN 105968049 A CN105968049 A CN 105968049A CN 201610219341 A CN201610219341 A CN 201610219341A CN 105968049 A CN105968049 A CN 105968049A
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- pyrrolidine
- sodium
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- dichloromethane
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
Abstract
The invention provides a method for preparing 1-(2,6-dichlorobenzyl-3-(pyrrolidine-1-methyl)-6-aminoindazole. The method comprises the following steps: Step 1, a starting material 6-nitroindoline reacts with acidic nitrite to generate an indazole intermediate I; Step 2, the intermediate I reacts with 2,6-dichlorobenzylbromide under an alkaline condition to generate an intermediate II; Step 3, the intermediate II and pyrrolidine react to generate enamine, and enamine directly undergoes in-situ reduction to obtain an intermediate III; and Step 4, a nitro group of the intermediate III is reduced into an amino group so as to obtain the target product TM. By the TM preparation method provided by the invention, generation of a by-product compound 3 is avoided, yield is increased, and a purification method is simplified.
Description
Technical field
The present invention relates to pharmaceutical technology field, particularly relate to the preparation method of a kind of TM.
Background technology
Suppressing hematoblastic activation and gathering is prevention and treatment atherosclerotic blood vessel Cardioversion
One of important means formed.Existing antiplatelet drug include aspirin, thiophene pyridine,
Glycoprotein (GP) IIb/IIIa receptor anticaking agents and cilostazol.Although alone or in combination should
With reducing the incidence rate of vascular events, but inhibit platelet to coagulate normally due to medicine simultaneously
Blood function, adds the probability of patient's bleeding.Another being in the clinical experimental study stage is big
Class antiplatelet thing: PAR-1 antagonist RWJ-58259, PAR-1 antagonist RWJ-58259
There is antithrombotic, atherosis, anti-inflammatory and anticancer function.By optionally blocking blood coagulation
The platelet activation effect of enzyme mediation, suppresses hematoblastic activation and gathering.It could be theoretically argued that not
The coagulation pathway of interference orthoplastocyte protectiveness, being expected to become does not increases blood risk but possesses
The good Novel anti-platelet agent thing reducing vascular events.PAR-1 antagonist RWJ-58259
Its chemical formula C40H42Cl2F2N8O3, molecular weight: 791.71, chemical name:
(S)-4-amino-N-benzyl-2-((S)-2-(3-(1-(2,6-dichlorobenzyl)-3-
(pyrrolidin-1-ylmethyl)-1H-indazol-6-yl)ureido)-3-(3,4-difl
Uorophenyl) propanamido) butanamide (s)-4-Amino-N-benzyl
-2-((s)-2-(3-(1-(2,6-dichloro benzyl)-3-(1-pyrrolidinomethyl)-1H-indazole)
Urea-3-(3,4)-difluorophenyl) propionamido-butyramide, molecular structural formula is as follows:
TM is as RWJ-58259 compound
Important fragment, it plays very important effect during preparing RWJ-58259.
The molecular formula of TM is: C19H20Cl2N4, chemical name is: 1-(2,6-dichloro benzyl-3-(pyrroles
Cough up alkane-1-methyl)-6-Aminoindazole, its molecular structural formula is as follows:
But, at present, relevant synthesis this important indazole sheet of TM
The report of section is little, and synthetic method needs to pass through column chromatography, it is difficult to realize
Industrialization.Prior art utilizes TM synthesis RWJ-58259 route map as it is shown in figure 1,
According to route map 1, compound 1 preparing compound 2 can produce pair the most in a large number
Product Compound 3, document is also with changing the alkali of four kinds respectively: sodium hydroxide, cesium carbonate,
Triethylamine and sodium hydride, the content of by-product compounds 3 respectively from 13%-60%, this
To seriously reduce the productivity of compound 2 and bring great difficulty to purification.
Summary of the invention
It is an object of the invention to solve the defect that above-mentioned prior art exists, it is provided that Yi Zhongjian
Easy and that industrialized production indazole compound (TM) can be realized method.
A kind of method preparing TM, it is characterised in that comprise the following steps:
Step 1: raw through acid nitrite reaction by initiation material 6-nitroindoline quinoline
Become indazole intermediate I；
Step 2: intermediate compound I in the basic conditions with 2,6-benzyl dichloride bromine generates intermediate
II；
Step 3: intermediate II and pyrrolidine generate enamine direct in-situ reducing agent and reduce
Become intermediate III；
Step 4: the nitro of intermediate III is reduced into amino and obtains target product TM.
Further, the method for TM prepared as described above, in the synthesis of described intermediate compound I,
Described nitrite is: sodium nitrite；
Its synthetic schemes specifically includes:
Add 6-nitroindoline quinoline, water, sodium nitrite in a kettle., under mechanical agitation,
Dropping concentrated hydrochloric acid, after completion of the reaction, through extracting, wash, being dried to obtain intermediate
I。
Further, the method for TM prepared as described above, the synthesis bag of described mesosome II
Include following steps:
Intermediate compound I is added in reactor, be subsequently added DMF, alkali cpd, room temperature
Stirring, is slowly added dropwise 2, and 6-benzyl dichloride bromine is heated to 50 DEG C, stirs 16 hours, TLC
Display reaction completely, with water dissolution DMF and inorganic salt, adds dichloromethane afterwards and enters
Row layering extraction, merges organic facies, then H2O washs, and saturated aqueous common salt washs, dry
Dry intermediate II, and after carrying out recrystallization, it is directly used in next step.
Further, the method for TM prepared as described above, described alkali cpd is: nothing
Machine alkali or organic base.
Further, the method for TM prepared as described above, described inorganic base be NaOH,
One in KOH, sodium carbonate or potassium carbonate, cesium carbonate.
Further, the method for TM prepared as described above, described organic base is triethylamine
Or DBU.
Further, the method for TM prepared as described above, the synthesis of described intermediate III
Comprise the following steps:
Intermediate II is added in reactor, be subsequently added dichloromethane, DMF, acetic acid,
Pyrrolidine, is stirred at room temperature 1 hour, is dividedly in some parts reducing agent, and TLC display reaction is complete,
Adding saturated sodium bicarbonate solution, separatory collects dichloromethane layer, water layer dichloromethane
Extraction several times, merges organic facies, and saturated sodium bicarbonate washing, saturated aqueous common salt wash,
It is dried to obtain intermediate III.
Further, the method for TM prepared as described above, described reducing agent is triacetyl
One in epoxide sodium borohydride, sodium borohydride, sodium cyanoborohydride or borine.
Further, the method for TM prepared as described above, the conjunction of TM described in step 4
One-tenth includes: intermediate III added in reactor, ethanol, and catalyst, hydrogen donor heat
Backflow, TLC display reaction is complete, and removal of solvent under reduced pressure obtains crude product, and recrystallization obtains this
Invention TM.
Further, the method for TM prepared as described above, described catalyst be palladium carbon,
One in Raney's nickel, rhodium carbon, platinum carbon or platinum dioxide；Described palladium carbon can be by using
Zinc powder, iron powder, stannous chloride, ferrous chloride, ammonium sulfide is alternatively；Described hydrogen supply
Body is hydrazine hydrate, hydrogen, formic acid or 1，4-cyclohexadiene.
The TM preparation method that the present invention provides, not only avoids the product of by-product compounds 3
Raw, and improve productivity, also simplify purification process.
Accompanying drawing explanation
Fig. 1 is the route map of prior art synthesis PAR-1 antagonist RWJ-58259；
Fig. 2 is the route map that the present invention synthesizes TM；
Fig. 3 is 1-(2,6-dichloro benzyl-3-(pyrrolidine-1-methyl)-6-Aminoindazole1H nuclear-magnetism figure；
Fig. 4 is 1-(2,6-dichloro benzyl-3-(pyrrolidine-1-methyl)-6-Aminoindazole13C nuclear-magnetism figure.
Detailed description of the invention
For making the object, technical solutions and advantages of the present invention clearer, below the present invention
In technical scheme be clearly and completely described, it is clear that described embodiment is
The a part of embodiment of the present invention rather than whole embodiments.Based on the reality in the present invention
Executing example, those of ordinary skill in the art are obtained under not making creative work premise
Every other embodiment, broadly fall into the scope of protection of the invention.
Embodiment:
Indazole is generated through acid nitrite reaction by initiation material (1) 6-nitroindoline
Intermediate (2), intermediate (2) in the basic conditions with 2,6-benzyl dichloride bromine generates middle
Body (3), intermediate (3) and pyrrolidine generate enamine direct in-situ reducing agent and reduce
Becoming intermediate (4), the nitro of last intermediate (4) is reduced into amino and obtains target product
Thing (TM).
Comparison through different experiments obtains optimization route as shown in Figure 2.It is specifically
Synthetic method step is:
Step 1: the synthesis of intermediate (2)
Addition 6-nitroindoline (515.6g, 3mol) in 50L reactor, water (40L),
Sodium nitrite (1416g, 20mol), under mechanical agitation, dropping 6N concentrated hydrochloric acid (4L,
24mol), detecting through TLC or HPLC, reaction in about 6 hours is complete, dichloromethane
Alkane three times (10L*3) of extraction, washing, saturated aqueous common salt washs, be dried in 520g
Mesosome (2), productivity 89.8%.
1H NMR (DMSO, 400MHz) δ 8.15,8,26,8.63 (phenyl ring 3H,
Unimodal), 10.20 (aldehyde radical 1H, unimodal), 15.01 (indazole 1H, unimodal).
Step 2: the synthesis of intermediate (3)
Above-mentioned (520g, the 2.72mol) intermediate (2) that is dried is added in 10L reactor,
It is subsequently added DMF (5L), and cesium carbonate (1329.3g, 4.08mol) room temperature is stirred
Mix, be slowly added dropwise 2,6-benzyl dichloride bromine (879.4g, 2.992mol), be heated to 50 DEG C
Stirring 16 hours, TLC display reaction is complete, 20L water dissolution DMF and inorganic salt,
Reactant liquor dichloromethane (5L*3) extracts, and merges organic facies, H2O (5L*2) washes
Washing, saturated aqueous common salt (2L*4) washs, and is dried to obtain 761.9g intermediate (3), productivity
80.0%, after recrystallization, it is directly used in next step.
1H NMR (DMSO, 400MHz) δ 5.76 (s, 2H, methylene-dichloro-benzenes),
7.25-7.43 and 7.40-7.57 (2m, 3H, dichloro-benzenes), 8.10 [s, 2H, 4-H and
5-H (indazole)], 8.25 [s, 1H, 7-H (indazoles)], 9.98 (aldehyde radical 1H, unimodal)
Step 3: the synthesis of intermediate (4)
Above-mentioned (761.9g, the 2.18mol) intermediate (3) that is dried is added in 50L reactor,
It is subsequently added 30L dichloromethane, DMF (3L), acetic acid (400ml), pyrrolidine (322.4g,
4.53mol), be stirred at room temperature 1 hour, be dividedly in some parts sodium triacetoxy borohydride (1438.3g,
6.79mol), TLC display reaction completely, adds saturated sodium bicarbonate solution, and separatory is received
Collection dichloromethane layer, water layer dichloromethane (5L*2) is extracted twice, and merges organic facies,
Saturated sodium bicarbonate washs 2 times, and saturated aqueous common salt washs 4 times, is dried to obtain 667.9g intermediate
(4), productivity 75.6%.
1H NMR (DMSO, 400MHz) δ 1.64-2.41, (2s, 8H, pyrrolidine),
3.87 (s, 2H, methylene-pyrrolidines), 5.92 (s, 2H, methylene-dichloro-benzenes),
7.42-7.46and 7.54-7.57 (2m, 3H, dichloro-benzenes), 7.95-8.06 [m, 2H, 4-H and
5-H (indazole)], 8.80 [s, 1H, 7-H (indazoles)]
Step 4: the synthesis of final products (TM)
Above-mentioned (667.9g, 1.65mol) intermediate (4) are added in 50L reactor, 30L
Ethanol, 50g Pd/C, hydrazine hydrate (200ml, 3.30mol), it is heated to reflux, TLC shows
Show reaction completely, cold filtration Pd/C, removal of solvent under reduced pressure, obtain crude product 600g, heavily tie
Brilliant 450g sterling, productivity 72.6%.
1H NMR (400MHz, DMSO-d6) δ 1.62-2.49 [4m, 8H, (pyrrolidine)],
3.66 (s, 2H, methylene-pyrrolidines), 5.32 (s, 2H, amino-indazoles), 5.45 (s, 2H,
Methylene-dichloro-benzenes), 6.46-7.40 (m, 3H, dichloro-benzenes), 7.41-7.52 [m, 3H, Yin
Azoles], (pyrrolidine does not connect amino methylene to 13C NMR (400MHz, DMSO-d6) δ 23.0
Base)], 46.6 (methylene-dichloro-benzenes), 51.3 (methylene-pyrrolidines), 53.3 [pyrrolidine connects
Aminomethylene],
111.7,114.9,120.9,128.6,130.4,132.1,135.9,142.4,142.6,147.9。
Fig. 3 is 1-(2,6-dichloro benzyl-3-(pyrrolidine-1-methyl)-6-Aminoindazole1H core
Magnetic chart；Fig. 4 is 1-(2,6-dichloro benzyl-3-(pyrrolidine-1-methyl)-6-Aminoindazole13C
Nuclear-magnetism figure, as it is shown on figure 3, may determine that 1-(2,6-dichloro benzyl-3-(pyrroles by Fig. 3
Cough up alkane-1-methyl)-6-Aminoindazole hydrogen number and type is consistent with structure coincide；Logical
Cross Fig. 4 and may determine that 1-(2,6-dichloro benzyl-3-(pyrrolidine-1-methyl)-6-amino
Indazole carbon atom type is consistent with structure coincide.
There is advantages that
1, route is brief, and unit is simple to operate, easily realizes amplifying, and overall productivity improves about
20%.
Avoid 1-(2,6-dichloro benzyl)-1-((1-(2,6-dichloro benzyl)-6-nitro
-1H-indazole)-3-methyl) generation of pyrroles's bromination this impurity of ammonium salt.
2, use callable palladium catalyst carbon, replace the reduction nitre producing industrial solid waste residue
Based method, protects environment.Use zinc powder, iron powder, stannous chloride, ferrous chloride, ammonium sulfide
Deng reduction nitro, it is typically all and reacts in acid condition, produce bigger industrial wastes and waste residue.
The synthesis of final products (TM) can use palladium carbon as catalyst, and hydrazine hydrate is as confession
Hydrogen body, it is possible to use zinc powder, iron powder, stannous chloride, ferrous chloride, ammonium sulfide directly does
Reducing agent, without palladium carbon, can also use palladium carbon, rhodium carbon, platinum carbon and platinum dioxide etc. to urge simultaneously
Agent carries out catalytic hydrogenation, and hydrogen donor can also be hydrogen except hydrazine hydrate, formic acid, and Isosorbide-5-Nitrae-
Cyclohexadiene etc..But wherein using palladium carbon as catalyst, hydrazine hydrate is as the reduction bar of hydrogen donor
Part is optimal.
Last it is noted that above example is only in order to illustrate technical scheme, and
Non-to its restriction；Although the present invention being described in detail with reference to previous embodiment, ability
The those of ordinary skill in territory is it is understood that it still can be to the skill described in foregoing embodiments
Art scheme is modified, or wherein portion of techniques feature is carried out equivalent；And these are repaiied
Change or replace, not making the essence of appropriate technical solution depart from various embodiments of the present invention technical side
The spirit and scope of case.
Claims (10)
1. prepare 1-(2,6-dichloro benzyl-3-(pyrrolidine-1-methyl)-6-amino Yin for one kind
The method of azoles, it is characterised in that comprise the following steps:
Step 1: raw through acid nitrite reaction by initiation material 6-nitroindoline quinoline
Become indazole intermediate I；
Step 2: intermediate compound I in the basic conditions with 2,6-benzyl dichloride bromine generates intermediate
II；
Step 3: intermediate II and pyrrolidine generate enamine direct in-situ reducing agent and reduce
Become intermediate III；
Step 4: the nitro of intermediate III is reduced into amino and obtains target product TM.
Method the most according to claim 1, it is characterised in that described intermediate compound I
Synthesis in, described nitrite is: sodium nitrite；
Its synthetic schemes specifically includes:
Add 6-nitroindoline quinoline, water, sodium nitrite in a kettle., under mechanical agitation,
Dropping concentrated hydrochloric acid, after completion of the reaction, through extracting, wash, being dried to obtain intermediate
I。
Method the most according to claim 1, it is characterised in that described mesosome II's
Synthesis comprises the following steps:
Intermediate compound I is added in reactor, be subsequently added DMF, alkali cpd, room temperature
Stirring, is slowly added dropwise 2, and 6-benzyl dichloride bromine is heated to 50 DEG C, stirs 16 hours, TLC
Display reaction completely, with water dissolution DMF and inorganic salt, adds dichloromethane afterwards and enters
Row layering extraction, merges organic facies, then H2O washs, and saturated aqueous common salt washs, dry
Dry intermediate II, and after carrying out recrystallization, it is directly used in next step.
Method the most according to claim 3, it is characterised in that described alkali cpd
For: inorganic base or organic base.
Method the most according to claim 4, it is characterised in that described inorganic base is
One in NaOH, KOH, sodium carbonate or potassium carbonate, cesium carbonate.
Method the most according to claim 4, it is characterised in that described organic base is
Triethylamine or DBU.
7. according to the method described in claim 3, it is characterised in that described intermediate III
Synthesis comprise the following steps:
Intermediate II is added in reactor, be subsequently added dichloromethane, DMF, acetic acid,
Pyrrolidine, is stirred at room temperature 1 hour, is dividedly in some parts reducing agent, and TLC display reaction is complete,
Adding saturated sodium bicarbonate solution, separatory collects dichloromethane layer, water layer dichloromethane
Extraction several times, merges organic facies, and saturated sodium bicarbonate washing, saturated aqueous common salt wash,
It is dried to obtain intermediate III.
8. according to the method described in claim 7, it is characterised in that described reducing agent is three
One in acetoxyl group sodium borohydride, sodium borohydride, sodium cyanoborohydride or borine.
9. according to the method described in claim 1, it is characterised in that TM described in step 4
Synthesis include: intermediate III is added in reactor, ethanol, catalyst, hydrogen donor
Being heated to reflux, TLC display reaction is complete, and removal of solvent under reduced pressure obtains crude product, recrystallization
Obtain TM of the present invention.
10. according to the method described in claim 9, it is characterised in that described catalyst is palladium
One in carbon, Raney's nickel, rhodium carbon, platinum carbon or platinum dioxide；Described palladium carbon can be by
Using zinc powder, iron powder, stannous chloride, ferrous chloride, ammonium sulfide is alternatively；Described
Hydrogen donor is hydrazine hydrate, hydrogen, formic acid or 1，4-cyclohexadiene.
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| CN201610219341.7A CN105968049A (en) | 2016-04-08 | 2016-04-08 | Method for preparing 1-(2,6-dichlorobenzyl-3-(pyrrolidine-1-methyl)-6-aminoindazole |
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| CN201610219341.7A CN105968049A (en) | 2016-04-08 | 2016-04-08 | Method for preparing 1-(2,6-dichlorobenzyl-3-(pyrrolidine-1-methyl)-6-aminoindazole |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108273523A (en) * | 2018-04-02 | 2018-07-13 | 张逸强 | A kind of production method of anticoagulation medicine intermediate |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001000656A2 (en) * | 1999-06-29 | 2001-01-04 | Ortho-Mcneil Pharmaceutical, Inc. | Novel indazole peptidomimetics as thrombin receptor antagonists |
| JP2008247781A (en) * | 2007-03-29 | 2008-10-16 | Dainippon Sumitomo Pharma Co Ltd | New fused pyrazole derivative |
| WO2015042052A1 (en) * | 2013-09-17 | 2015-03-26 | Pharmakea, Inc. | Heterocyclic vinyl autotaxin inhibitor compounds |
-
2016
- 2016-04-08 CN CN201610219341.7A patent/CN105968049A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001000656A2 (en) * | 1999-06-29 | 2001-01-04 | Ortho-Mcneil Pharmaceutical, Inc. | Novel indazole peptidomimetics as thrombin receptor antagonists |
| JP2008247781A (en) * | 2007-03-29 | 2008-10-16 | Dainippon Sumitomo Pharma Co Ltd | New fused pyrazole derivative |
| WO2015042052A1 (en) * | 2013-09-17 | 2015-03-26 | Pharmakea, Inc. | Heterocyclic vinyl autotaxin inhibitor compounds |
Non-Patent Citations (2)
| Title |
|---|
| ÁNGEL M. VALDIVIELSO ET AL.,: "Improved synthesis of the PAR-1 thrombin receptor antagonist RWJ-58259", 《ARKIVOC》 * |
| MANAS CHAKRABARTY ET AL.,: "An expedient, regioselective synthesis of novel 2-alkylamino- and 2-alkylthiothiazolo[5,4-e]- and -[4,5-g]indazoles and their anticancer potential", 《TETRAHEDRON》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108273523A (en) * | 2018-04-02 | 2018-07-13 | 张逸强 | A kind of production method of anticoagulation medicine intermediate |
| CN108273523B (en) * | 2018-04-02 | 2020-09-22 | 暨南大学附属第一医院 | Production method of anticoagulant drug intermediate |
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