CN107151251A - A kind of preparation method of ACC inhibitor medicaments key intermediate - Google Patents
A kind of preparation method of ACC inhibitor medicaments key intermediate Download PDFInfo
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- CN107151251A CN107151251A CN201710323740.2A CN201710323740A CN107151251A CN 107151251 A CN107151251 A CN 107151251A CN 201710323740 A CN201710323740 A CN 201710323740A CN 107151251 A CN107151251 A CN 107151251A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Abstract
The present invention relates to a kind of method of synthesis ACC inhibitor medicaments key intermediates, belong to the field of chemical synthesis, the method of the present invention obtains target compound, it is not necessary to the alkaline hydrolysis step of group-4 ethyl formate mainly by improving initiation material by the reaction such as the reaction of Gewald aminothiophenes, acid amides synthesis, closed loop, bromo, the decarboxylation reaction of next step is also avoided the need for simultaneously, shorten reaction process short, with the stable safety of route, cost is low, raw material is cheap and easy to get, the advantage such as yield height.
Description
Technical field
The present invention relates to a kind of preparation method of compound, and in particular to a kind of ACC inhibitor medicaments key intermediate
Preparation method, is related to the field of chemical synthesis.
Background technology
Acetyl-CoA carboxylase（Abbreviation ACC）By being catalyzed the condensation of acetyl coenzyme A and malonyl coenzyme A, reduce, take off
Series reaction that water is restored and progressively synthesize various saturated fatty acids.ACC inhibitor is can to suppress ACC activity, from
And block the material of fatty acid synthesis process.Therefore, such material is usually used in treatment human obesity, dyslipidemia and hyperlipidemia
The diseases such as disease.
Patent US2015203510A1 protects a kind of ACC inhibitor of Thienopyrimidine derivative, and the material is in prevention
There is curative effect with the metabolic syndrome aspect of the treatment mankind, also have suppression to make the ACC enzymes in plant, parasite and bacterium in addition
With.
Wherein chemical compounds I is considered as the key intermediate in the material synthesis processes, disclosed in patent US2015203510A1
Synthesis chemical compounds I method be use following initiation material and route, by Gewald aminothiophenes reaction, acid amides synthesis,
The reaction such as closed loop, alkaline hydrolysis, decarboxylation, bromo obtains target compound I；The reaction scheme is long, and low total recovery is only 8.3%, and also
Using to precious metal raw materials such as silver acetates, cost is synthesized also high.
The content of the invention
For problem above, the invention provides a kind of novel synthesis of ACC inhibitor intermediate, by Gewald ammonia
The reaction such as the reaction of base thiophene, acid amides synthesis, closed loop, bromo obtains target compound I.Acetone generation is used in the selection of initiation material
For original raw material ethyl acetoacetate, it is possible to prevente effectively from Ethyl formate substituent is introduced in thiphene ring, without first
The alkaline hydrolysis step of acetoacetic ester base, while also avoiding the need for the decarboxylation reaction of next step, the technological reaction flow shortens, and route is steady
Dingan County is complete, and the yield of target product is significantly improved, and yield reaches more than 13%, and raw material uses acetone, cheap.
The synthetic route of the present invention is as follows：
1）By raw material of cyan-acetic ester, acetone and sulphur, reaction obtains intermediate formula（II）Compound；
2）By step 1）In obtained intermediate formula（II）Compound, which is dissolved in organic solvent, forms solution, is added into the solution
Triphosgene, is added dropwise after triethylamine reacts at -5 ~ 5 DEG C and adds raw material 2- methyl-2-amino propanoic acid tert-butyl ester hydrochlorides, occur
Amidation process, obtains intermediate formula（Ⅲ）Compound；
3）By step 2）In obtained intermediate formula（Ⅲ）Compound is dissolved in organic solvent into solution, and hydrogen is added into the solution
Change sodium, occur ring-closure reaction, obtain intermediate formula（Ⅳ）Compound；
4）By step 3）In obtained intermediate formula（Ⅳ）Compound is dissolved in organic solvent into solution, and vinegar is added into the solution
Sour sodium, is added dropwise bromine, occurs bromination reaction, obtains product Intermediate formula（Ⅰ）Compound；
Step 1）In, the molar ratio of described cyan-acetic ester, acetone and sulphur is 0.8 ~ 1.2：1：1, reaction temperature
For 50 ~ 70 DEG C, catalysts and solvents are carried out under conditions of existing；Described catalyst is morpholine or ethylenediamine；Described solvent
For methanol, absolute ethyl alcohol, isopropanol.
Step 2）In, described 2- methyl-2-amino propanoic acid tert-butyl esters hydrochloride, intermediate（II）, triphosgene and three second
The molar ratio of amine is 1：1：1：3~5；Described organic solvent is dichloromethane, chloroform.
Step 3）In, described sodium hydride and intermediate（Ⅲ）Molar ratio be 2 ~ 4:1, system back flow reaction；Institute
The organic solvent stated is 1,4- dioxane, tetrahydrofuran.
Step 4）In, described sodium acetate, bromine and intermediate（Ⅳ）Molar ratio be 1 ~ 3：1：1, reaction temperature
For 20 ~ 25 DEG C, reacted in solvent；Described organic solvent is acetic acid.
Embodiment
Embodiment 1
Step one：
Acetone is added into tetra- mouthfuls of reaction bulbs of 2L（200g, 3.444mol, 1eq）, cyan-acetic ester（389.5g, 3.444mol,
1eq）, sulphur（110.4g, 3.444mol, 1eq）, absolute ethyl alcohol 400ml, stirring is warming up to interior 30 DEG C of temperature, 30 ~ 40 DEG C of drops of temperature control
Plus morpholine（300g, 3.444mol, 1eq）, completion of dropping is warming up to 60 DEG C, insulation reaction 5h, TLC detection（EA:PE=1:3）,
It is complete to raw material reaction, stop reaction, cool to 30 DEG C or so, reaction solution is poured into 2L water, there is solid precipitation, stir
15min, filtering, filter cake is eluted with 200ml50% ethanol waters, and 50 DEG C of forced air drying 4h obtain yellow solid II：454.2g,
Yield：71.2%；Yellow solid II is subjected to nuclear-magnetism detection, 1 H-NMR（500MHz, CDCl 3 ）：δ 7.25（S, 2H）, 6.53（S, 1H）, 4.14-4.19（Q, 2H）, 2.12（S, 3H）, 1.28-1.25（T, 3H）。
Step 2：
Dry clean tetra- mouthfuls of reaction bulbs of 2L, plus drying tube are taken, leads to nitrogen protection, II is added into reaction bulb（100g, 0.540mol,
1eq）, dichloromethane 1L, stirring, the interior temperature of drop is to 0 DEG C, addition triphosgene（160.2g, 0.540mol, 1eq）, stirring is lower to be added dropwise three
Ethamine（191.2g, 1.890mol, 3.5eq）, Nei Wen -5 ~ 0 DEG C is controlled, completion of dropping is incubated 0 DEG C of stirring reaction 3h；Add into bottle
Enter 2- methyl-2-amino propanoic acid tert-butyl ester hydrochlorides（105.7g, 0.540mol, 1eq）, charging finishes, and warms naturally to room temperature,
It is stirred overnight, TLC detections（EA:PE=1:3）, it is complete to raw material reaction, 500ml water is added into system, 10min is stirred, stood
Layering, divides and takes organic phase, and aqueous phase is extracted with 200ml dichloromethane, merges organic phase, adds 80g anhydrous magnesium sulfates and dries 1h, mistake
Filter, 35 DEG C of filtrate is concentrated under reduced pressure into dry, obtains crude product, crude product 500ml ethyl acetate and petroleum ether（1:10）Mashing, filtering, 40
DEG C forced air drying 4h, obtains faint yellow solid III：148.8g, yield：74.4%；Yellow solid III is subjected to nuclear-magnetism detection, 1 H-NMR （500MHz, CDCl 3 ）：δ 11.22（S, 1H）, 6.55（S, 1H）, 5.93（S, 1H）, 4.15-4.20（Q, 2H）, 2.14（S, 3H）, 1.58（S, 6H）, 1.35（S, 9H）, 1.27-1.24（T, 3H）。
Step 3：
Dry clean tetra- mouthfuls of reaction bulbs of 2L, plus drying tube are taken, leads to nitrogen protection, III is added into bottle（100g, 0.270mol, 1eq）,
10 DEG C of temperature in Isosorbide-5-Nitrae-dioxane 1000ml, stirring, control, is slowly added into sodium hydride（12.96g, 0.540mol, 2eq）, finish,
10min is stirred, backflow is warming up to, reaction is stayed overnight, TLC detections（EA:PE=1:4）, it is complete to raw material reaction, cool to 30 DEG C of left sides
The right side, 500ml saturated aqueous ammonium chlorides are added dropwise into system, and drop finishes, and reaction solution is extracted with 3*500ml ethyl acetate, is associated with
Machine phase, with anhydrous sodium sulfate drying, filtering, 40 DEG C of filtrate is concentrated under reduced pressure into dry, obtains crude product, crude product with 200ml ethyl acetate and
Petroleum ether（1:10）Mashing, filtering, 40 DEG C of forced air drying 4h obtain off-white powder IV：30.5g, yield：34.8%；By white
Solid IV carries out nuclear-magnetism detection, 1 H-NMR（500MHz, CDCl 3 ）：δ 6.66（S, 1H）, 5.96（S, 1H）, 2.16（S, 3H）, 1.57（S, 6H）, 1.34（S, 9H）.
Step 4：
IV is added into tetra- mouthfuls of reaction bulbs of 1L（30g, 0.092mol, 1eq）, sodium acetate（16.65g, 0.203mol, 2.2eq）, vinegar
Sour 600ml, opens stirring, and bromine is added dropwise in 20 ~ 25 DEG C of temperature control（16.3g, 0.102mol, 1.1eq）, drip and finish, be incubated 20 ~ 25 DEG C
React 1h, TLC detections（EA:PE=1:2）, complete to raw material reaction, by reaction solution, 60 ~ 70 DEG C are concentrated under reduced pressure into dry, addition 1L water
30min is beaten, filtering, 50 DEG C of forced air drying 8h obtain off-white powder I：28.3g, yield：75.8%；White solid I is carried out
Nuclear-magnetism detection, 1 H-NMR（500MHz, CDCl 3 ）：5.95（S, 1H）, 2.15（S, 3H）, 1.56（S, 6H）, 1.33（S, 9H）。
Claims (6)
1. a kind of preparation method of ACC inhibitor medicaments key intermediate, the structure such as Formulas I of the intermediate, it is characterised in that
Comprise the following steps：
1）By raw material of cyan-acetic ester, acetone and sulphur, reaction obtains intermediate formula（II）Compound；
2）By step 1）In obtained intermediate formula（II）Compound, which is dissolved in organic solvent, forms solution, is added into the solution
Triphosgene, is added dropwise after triethylamine reacts at -5 ~ 5 DEG C and adds raw material 2- methyl-2-amino propanoic acid tert-butyl ester hydrochlorides, occur
Amidation process, obtains intermediate formula（Ⅲ）Compound；
3）By step 2）In obtained intermediate formula（Ⅲ）Compound is dissolved in organic solvent into solution, and hydrogen is added into the solution
Change sodium, occur ring-closure reaction, obtain intermediate formula（Ⅳ）Compound；
4）By step 3）In obtained intermediate formula（Ⅳ）Compound is dissolved in organic solvent into solution, and vinegar is added into the solution
Sour sodium, is added dropwise bromine, occurs bromination reaction, obtains product Intermediate formula（Ⅰ）Compound；
。
2. the preparation method of ACC inhibitor medicaments key intermediate according to claim 1, it is characterised in that：Step 1）
In, the molar ratio of described cyan-acetic ester, acetone and sulphur is 0.8 ~ 1.2：1：1, reaction temperature is 50 ~ 70 DEG C,
Catalysts and solvents are carried out under conditions of existing；Described catalyst is morpholine or ethylenediamine；Described solvent is alcohols solvent.
3. the preparation method of ACC inhibitor medicaments key intermediate according to claim 1, it is characterised in that：Step 2）
In, described 2- methyl-2-amino propanoic acid tert-butyl esters hydrochloride, intermediate（II）, triphosgene and triethylamine molar ratio
For 1：1：1：3~5；Described organic solvent is dichloromethane, chloroform.
4. the preparation method of ACC inhibitor medicaments key intermediate according to claim 1, it is characterised in that：Step 3）
In, described sodium hydride and intermediate（Ⅲ）Molar ratio be 2 ~ 4:1, system back flow reaction；Described organic solvent is
1,4- dioxane, tetrahydrofuran.
5. the preparation method of ACC inhibitor medicaments key intermediate according to claim 1, it is characterised in that：Step 4）
In, described sodium acetate, bromine and intermediate（Ⅳ）Molar ratio be 1 ~ 3：1：1, reaction temperature is 20 ~ 25 DEG C, solvent
Middle reaction；Described organic solvent is acetic acid.
6. preparation method according to claim 2, it is characterised in that：The alcohols solvent be selected from methanol or absolute ethyl alcohol or
Any one in isopropanol.
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| CN201710323740.2A CN107151251A (en) | 2017-05-10 | 2017-05-10 | A kind of preparation method of ACC inhibitor medicaments key intermediate |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102015712A (en) * | 2008-03-26 | 2011-04-13 | 阿德维纳斯治疗私人有限公司 | Heterocyclic compounds as adenosine receptor antagonist |
| CN104105485A (en) * | 2011-11-11 | 2014-10-15 | 尼普斯阿波罗有限公司 | Acc inhibitors and uses thereof |
-
2017
- 2017-05-10 CN CN201710323740.2A patent/CN107151251A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102015712A (en) * | 2008-03-26 | 2011-04-13 | 阿德维纳斯治疗私人有限公司 | Heterocyclic compounds as adenosine receptor antagonist |
| CN104105485A (en) * | 2011-11-11 | 2014-10-15 | 尼普斯阿波罗有限公司 | Acc inhibitors and uses thereof |
Non-Patent Citations (1)
| Title |
|---|
| SUNDER KUMAR KOLLI ET AL.: "Ligand-free Pd-catalyzed CeN cross-coupling/cyclization strategy: An unprecedented access to 1-thienyl pyrroloquinoxalines for the new approach towards apoptosis", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
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