A kind of synthetic method of chirality nafoxidine -3- carboxylic acid
阅读说明：本技术 一种手性四氢吡咯-3-羧酸的合成方法 (A kind of synthetic method of chirality nafoxidine -3- carboxylic acid ) 是由 杨杰 方卫国 施国强 于 2019-09-10 设计创作，主要内容包括：本发明涉及有机合成技术领域,为解决传统手性四氢吡咯-3-羧酸的合成方法制备路线长、收率低的问题,提供了一种手性四氢吡咯-3-羧酸的合成方法,包括：(1)硝基烯烃化合物与1～6碳的烷烃基酯在手性催化剂作用下合成式(II)；(2)将式(II)经硝基还原成胺基反应,同时环合反应得到式(III)；(3)将式(III)经脱去酯基反应得到式(IV)所示的化合物；(4)将式(IV)的内酰胺还原成胺,胺基NH进行保护后生成式(V)；(5)将式(V)的呋喃环氧化生成羧基得到式(VI)。本发明可以立体专一性的合成R或S构型的手性四氢吡咯-3-羧酸,降低了手性副产物的生成,提高了手性合成工艺的效率。(The present invention relates to technical field of organic synthesis, synthetic method preparation route to solve the problems, such as traditional chiral nafoxidine -3- carboxylic acid is long, yield is low, provide a kind of synthetic method of chiral nafoxidine -3- carboxylic acid, comprising: (1) the alkane base ester of nitroolefin compound and 1~6 carbon synthesizes formula (II) under chiral catalyst effect；(2) formula (II) is reduced into amido reaction through nitro, while cyclization reaction obtains formula (III)；(3) formula (III) ester group is sloughed to react to obtain formula (IV) compound represented；(4) by the lactam reduction of formula (IV) at amine, amido NH generates formula (V) after being protected；(5) the furans epoxidation of formula (V) is generated into carboxyl and obtains formula (VI).The present invention can be reduced the generation of chiral by-product, be improved the efficiency of chiral synthesis techniques with the chiral nafoxidine -3- carboxylic acid of the synthesis R or S configuration of stereocpecificity.)
1. a kind of synthetic method of chirality nafoxidine -3- carboxylic acid, which comprises the following steps:
(1) the alkane base ester of nitroolefin compound and 1~6 carbon shown in formula (I) synthesizes formula under chiral catalyst effect (II) compound represented；Reaction temperature is controlled at -20~100 DEG C；
(2) formula (II) compound represented is reduced into amido reaction through nitro, while cyclization reaction obtains shown in formula (III) Compound, reaction temperature control at 0~60 DEG C；
(3) formula (III) compound represented ester group is sloughed to react to obtain formula (IV) compound represented, reaction temperature control At 90~150 DEG C；
(4) lactam reduction of formula (IV) compound represented is obtained into intermediate reduction product amine at amine, then also original The amido NH of object amine generates formula (V) compound represented after being protected；
(5) the furans epoxidation of formula (V) compound represented is generated into carboxyl and obtains formula (VI) compound represented, it is as chiral Nafoxidine -3- carboxylic acid；Chirality nafoxidine -3- the carboxylic acid includes R isomers and S isomers；
It is reacted in an inert atmosphere step (1)~(5)；
The formula (I)~formula (VI) is as follows:
The wherein alkyl of R=1-4, P=protecting group, the protecting group are alkoxy carbonyl group or-CH2Ar；
The structural formula of the alkoxy carbonyl group are as follows:In formula: R=1-8 carbon alkane base；
- the CH2Ar, Ar is aromatic rings in formula.
2. a kind of synthetic method of chiral nafoxidine -3- carboxylic acid according to claim 1, which is characterized in that step (1) In, the chiral catalyst is chiral adjacent diamines and NiX2Shown in the formula (VII) or formula (VIII) that (X=I, Br, Cl) is generated Complex:
With (R, R) aglucon for representative, the formula (VII) and formula (VIII) are as follows:
Wherein, X=I, Br or Cl；
R1=H, 1-6 carbon alkyl or-CH2Ar；
R2=H, 1-6 carbon alkyl.
3. a kind of synthetic method of chiral nafoxidine -3- carboxylic acid according to claim 1, which is characterized in that step (2) In, it is that catalytic hydrogen reduction reacts that nitro, which is reduced into amido reaction, and catalyst is gold in the catalytic hydrogen reduction reaction system Metal catalyst, solvent are the alcohol of 1-4 carbon；Hydrogen Vapor Pressure is controlled in 1~5 atmospheric pressure.
4. a kind of synthetic method of chiral nafoxidine -3- carboxylic acid according to claim 1, which is characterized in that step (3) In, the reaction for sloughing ester group is that first then hydrolysis ester group heats decarboxylize at carboxyl in acid condition.
5. a kind of synthetic method of chiral nafoxidine -3- carboxylic acid according to claim 1, which is characterized in that step (4) In, it is LiAlH that lactam reduction, which reacts reducing agent used at amine,4, LiBH4, NaBH4, KBH4Or borine is combined with lewis acid and is answered With；Reaction dissolvent is non-protonic solvent.
6. a kind of synthetic method of chiral nafoxidine -3- carboxylic acid according to claim 1, which is characterized in that step (5) In, it is KMnO that furans epoxidation, which generates oxidant used in carboxyl reaction,4；Reaction dissolvent is acetone, one in the tert-butyl alcohol and water Kind or several mixing.
7. a kind of synthetic method of chiral nafoxidine -3- carboxylic acid according to claim 1, which is characterized in that
In step (1), the alkane base ester of 1~6 carbon is diester malonate；The chiral catalyst is to match shown in formula (IX) Close object:
Bn is benzyl in formula, with (R, R) aglucon for representative；
In step (2), it is Raney's nickel that nitro, which is reduced into amido reaction used catalyst, and reaction temperature is 25 DEG C~40 DEG C；
In step (3), the reaction of ester group is sloughed are as follows: formula (III) compound represented is dissolved in the mixed solvent of first alcohol and water In, enriching hydrochloric acid tune pH=2~3 after 0~5 DEG C of ester group is hydrolyzed completely with NaOH, obtained intermediate acid dissolution is in Isosorbide-5-Nitrae-two The in the mixed solvent of oxygen six rings and toluene is heated to 100~110 DEG C of back flow reactions and obtains formula (IV) compound represented；It is described The structural formula of intermediate acid are as follows:
In step (4), it is LiAlH that lactam reduction, which reacts reducing agent used at amine,4, BH3·Me2S or NaBH4/BF3·Et2O； Reaction dissolvent is tetrahydrofuran；The structural formula of the intermediate reduction product amine is formula (X):
Protection is carried out to the NH base of intermediate reduction product amine shown in formula (X) and generates formula (V) compound represented；
In step (5), it is KMnO that furans epoxidation, which generates oxidant used in carboxyl reaction,4；Reaction dissolvent is the tert-butyl alcohol and water Mixed solvent；Reaction temperature is controlled at 15~25 DEG C.
8. a kind of synthetic method of chiral nafoxidine -3- carboxylic acid according to claim 7, which is characterized in that step (1) In, the molar ratio of nitroolefin compound shown in the formula (I) and diester malonate is 1.2~1.5；The chiral catalyst Additional amount be formula (I) compound represented 0.5~5.0%mol；The volume of solvent usage and formula (I) compound represented Than for (5.0~10.0): 1.
9. a kind of synthetic method of chiral nafoxidine -3- carboxylic acid according to claim 7, which is characterized in that step (2) In, the dosage of the Raney's nickel is the 10~30wt% of formula (II) compound represented；Hydrogen Vapor Pressure is controlled in 1~5 atmosphere Pressure；The volume of solvent usage and formula (II) compound represented is (5.0~10.0): 1.
10. a kind of synthetic method of chiral nafoxidine -3- carboxylic acid according to claim 7, which is characterized in that
In step (3), the dosage of NaOH is 1.5~3.0 equivalents of formula (III) compound represented；The mixing of the first alcohol and water The volume ratio of methanol and water is (1~5) in solvent: 1, shown in the dosage of the mixed solvent of the first alcohol and water and formula (III) The volume ratio of compound is (3~10): 1；In the mixed solvent Isosorbide-5-Nitrae-the dioxane and first of the Isosorbide-5-Nitrae-dioxane and toluene The volume ratio of benzene is (1~3): 1；In reaction system, the volume ratio of the total amount and formula (III) compound represented of solvent for use is (5~15): 1；
In step (4), lactam reduction at amine react reducing agent used and formula (IV) compound represented equivalent proportion be (2~ 3.5): 1；Protect protecting group reagent used in the NH base of intermediate formula (X) compound represented and formula (X) compound represented Equivalent proportion is (1.1~2.0): 1, the volume ratio of the tetrahydrofuran and formula (X) compound represented is (5~10): 1；
In step (5), the KMnO4Dosage be formula (V) compound represented 4.0~6.5 equivalents；The tert-butyl alcohol and water The in the mixed solvent tert-butyl alcohol and water volume ratio be 1:(1~4), the dosage and formula of the mixed solvent of the tert-butyl alcohol and water (V) volume ratio of compound represented is (10~50): 1.
Technical field
The present invention relates to technical field of organic synthesis more particularly to a kind of synthetic methods of chiral nafoxidine -3- carboxylic acid.
Background technique
Chiral nafoxidine -3- carboxylic acid is a kind of important medicine intermediate, is widely used: can be applied to synthesize CDK8/19 inhibitor, this kind of compound can be used for treating tumour patient (WO2019068613A1)；Report can also be used to close recently At CDK12 inhibitor, for treating tumour (WO2019058132A1)；Also it is used to synthesize immunosuppressor for treating tumour (US10308644B2)；The structural modification that chiral nafoxidine -3- carboxylic acid is also applied to Diprovocim class compound is resisted The better compound adjuvant (WO2018005812A1) of cancer effect；It is also applied to synthesize a series of naphthalene sulfonamide pyrrolidines derivatives Object acts on KEAP-1, can be used for preventing and/or treating diabetes, obesity, dyslipidemia and associated disease (EP2997966)。
Summary of the invention
The present invention is in order to overcome the synthetic method preparation route of traditional chiral nafoxidine -3- carboxylic acid is long, yield is low to ask Topic provides a kind of synthetic method of chiral nafoxidine -3- carboxylic acid, and this method is easy to operate, simple process, and raw material is simply easy , it is at low cost, not only laboratory was suitble to prepare on a small scale, but also be suitble to industrialized production.
To achieve the goals above, the invention adopts the following technical scheme:
A kind of synthetic method of chirality nafoxidine -3- carboxylic acid, comprising the following steps:
(1) the alkane base ester of nitroolefin compound and 1~6 carbon shown in formula (I) synthesizes formula under chiral catalyst effect (II) compound represented；Reaction temperature is controlled at -20~100 DEG C；
(2) formula (II) compound represented is reduced into amido reaction through nitro, while cyclization reaction obtains shown in formula (III) Compound, reaction temperature control at 0~60 DEG C；
(3) formula (III) compound represented ester group is sloughed to react to obtain formula (IV) compound represented, reaction temperature control At 90~150 DEG C；
(4) lactam reduction of formula (IV) compound represented is obtained into intermediate reduction product amine at amine, then also original The amido NH of object amine generates formula (V) compound represented after being protected；
(5) the furans epoxidation of formula (V) compound represented is generated into carboxyl and obtains formula (VI) compound represented, it is as chiral Nafoxidine -3- carboxylic acid；Chirality nafoxidine -3- the carboxylic acid includes R isomers and S isomers；
It is reacted in an inert atmosphere step (1)~(5)；
The formula (I)~formula (VI) is as follows:
The wherein alkyl of R=1-4, P=protecting group；The protecting group is alkoxy carbonyl group or-CH2Ar；
The structural formula of the alkoxy carbonyl group are as follows:In formula: R=1-8 carbon alkane base；
- the CH2Ar, Ar is aromatic rings in formula.
The reaction equation of synthetic method of the invention is following (being representative with the catalysate that (R, R) is aglucon):
The chiral control generated of the invention is that 1,3- dicarbonyl compound is catalyzed by Ni (II)-chiral ligands to nitro compds The Michael's addition of hydrocarbon is realized.
Preferably, the chiral catalyst is chiral adjacent diamines and NiX in step (1)2(X=I, Br, Cl) is generated Complex shown in formula (VII) or formula (VIII):
With (R, R) aglucon for representative, the formula (VII) and formula (VIII) are as follows:
Wherein, X=I, Br or Cl；
R1=H, 1-6 carbon alkyl or-CH2Ar；
R2=H or 1-6 carbon alkyl.
Preferably, the chiral adjacent diamines hand is property cyclohexanediamine or nuclear substituted chiral cyclohexanediamine；Or N All substituted chiral cyclohexanediamine on the chiral cyclohexanediamine or N of upper substituted base and on ring.The chirality cyclohexanediamine For (S, S) or (R, R) aglucon.When using (S, S) aglucon, obtaining formula (II) compound represented is R isomers；And it uses When (R, R) aglucon, obtaining formula (II) compound represented is S isomers.
Preferably, it is that catalytic hydrogen reduction reacts that nitro, which is reduced into amido reaction, the catalytic hydrogenation in step (2) Catalyst is metallic catalyst in reduction reaction system, and solvent is the alcohol of 1-4 carbon；Hydrogen Vapor Pressure is controlled in 1~5 atmospheric pressure.
Preferably, the reaction for sloughing ester group is that first hydrolysis ester group is at carboxyl, then in acid condition in step (3) Heat decarboxylize.The alkali of hydrolysis of ester group is NaOH, KOH, CsOH or carbonic acid Na2CO3, K2CO3, Cs2CO3Deng；In reaction Acid is HCl, HBr, H2SO4, H3PO4Equal inorganic acids.
Preferably, it is LiAlH that lactam reduction, which reacts reducing agent used at amine, in step (4)4, LiBH4, NaBH4, KBH4Or borine and lewis acid use in conjunction, such as BH3·Me2S or NaBH4/BF3·Et2O；Reaction dissolvent is that aprotic is molten Agent.
Preferably, the non-protonic solvent be tetrahydrofuran (THF), methyl tertiary butyl ether(MTBE) (MTBE), methylene chloride, Chloroform or toluene.
Preferably, in step (5), it is KMnO that furans epoxidation, which generates oxidant used in carboxyl reaction,4；Reaction dissolvent For acetone, the mixing of one or more of the tert-butyl alcohol and water.
Preferably, the alkane base ester of 1~6 carbon is diester malonate in step (1)；The chiral catalyst is Complex shown in formula (IX):
IX, Bn is benzyl in formula, with (R, R) aglucon for representative；
In step (2), it is Raney's nickel that nitro, which is reduced into amido reaction used catalyst, and reaction temperature is 25 DEG C~40 DEG C；
In step (3), the reaction of ester group is sloughed are as follows: formula (III) compound represented is dissolved in the mixed solvent of first alcohol and water In, enriching hydrochloric acid tune pH=2~3 after 0~5 DEG C of ester group is hydrolyzed completely with NaOH, obtained intermediate acid dissolution is in Isosorbide-5-Nitrae-two The in the mixed solvent of oxygen six rings and toluene is heated to 100~110 DEG C of back flow reactions and obtains formula (IV) compound represented；It is described The structural formula of intermediate acid are as follows:
In step (4), it is LiAlH that lactam reduction, which reacts reducing agent used at amine,4, BH3·Me2S or NaBH4/BF3·Et2O； Reaction dissolvent is tetrahydrofuran；
The structural formula of the intermediate reduction product amine is formula (X):
Protection is carried out to the NH base of intermediate reduction product amine shown in formula (X) and generates formula (V) compound represented.Protecting group can To use alkoxy carbonyl group；The structural formula of the alkoxy carbonyl group are as follows:In formula: R=1-8 carbon alkane base；Or use- CH2Ar protects amino N H, and Ar is aromatic rings in formula.
In step (5), it is KMnO that furans epoxidation, which generates oxidant used in carboxyl reaction,4；Reaction dissolvent is the tert-butyl alcohol With the mixed solvent of water；Reaction temperature is controlled at 15~25 DEG C.
Preferably, in step (1), the molar ratio of nitroolefin compound and diester malonate shown in the formula (I) It is 1.2~1.5；The additional amount of the chiral catalyst is the 0.5~5.0%mol of formula (I) compound represented；Solvent usage Volume ratio with formula (I) compound represented is (5.0~10.0): 1.
Preferably, the dosage of the Raney's nickel is the 10~30wt% of formula (II) compound represented in step (2)； Hydrogen Vapor Pressure is controlled in 1~5 atmospheric pressure；The volume of solvent usage and formula (II) compound represented is (5.0~10.0): 1.
Preferably, the dosage of NaOH is 1.5~3.0 equivalents of formula (III) compound represented in step (3)；It is described The volume ratio of the in the mixed solvent methanol of first alcohol and water and water is (1~5): 1, the dosage of the mixed solvent of the first alcohol and water with The volume ratio of formula (III) compound represented is (3~10): 1；The in the mixed solvent Isosorbide-5-Nitrae-of the Isosorbide-5-Nitrae-dioxane and toluene The volume ratio of dioxane and toluene is (1~3): 1；In reaction system, chemical combination shown in the total amount and formula (III) of solvent for use The volume ratio of object is (5~15): 1.
Preferably, lactam reduction reacts reducing agent used at amine and works as with formula (IV) compound represented in step (4) Amount is than being (2~3.5): 1；It protects shown in protecting group reagent used in the NH base of intermediate formula (X) compound represented and formula (X) The equivalent proportion of compound be (1.1~2.0): 1, the volume ratio of the tetrahydrofuran and formula (X) compound represented be (5~ 10): 1.
Preferably, in step (5), the KMnO4Dosage be formula (V) compound represented 4.0~6.5 equivalents； The volume ratio of the in the mixed solvent tert-butyl alcohol and water of the tert-butyl alcohol and water is 1:(1~4), the mixing of the tert-butyl alcohol and water is molten The dosage of agent and the volume ratio of formula (V) compound represented are (10~50): 1.
Therefore, the invention has the following beneficial effects:
(1) this method can reduce chiral by-product with the chiral nafoxidine -3- carboxylic acid of the synthesis R or S configuration of stereocpecificity The generation of object improves the efficiency of chiral synthesis techniques.
(2) raw material is simple and easy to get, at low cost, and synthesis step is easy to operate, and laboratory has not only been suitble to prepare but also be suitble on a small scale Industrialized production.
Detailed description of the invention
Fig. 1 is the hydrogen spectrogram of formula made from embodiment 1 (VI) compound represented1HNMR spectrogram.
Specific embodiment
Below by specific embodiment, and in conjunction with attached drawing, the technical solutions of the present invention will be further described.
In the present invention, if not refering in particular to, all devices and raw material is commercially available or the industry is common are following Method in embodiment is unless otherwise instructed conventional method in that art.
It is representative with the catalysate that (R, R) is aglucon, following embodiment of the present invention is according to following reaction formula synthesis of chiral Nafoxidine -3- carboxylic acid: