CN107744831B - Quinidine derivative catalyst, preparation method and application - Google Patents

Quinidine derivative catalyst, preparation method and application Download PDF

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CN107744831B
CN107744831B CN201710774014.2A CN201710774014A CN107744831B CN 107744831 B CN107744831 B CN 107744831B CN 201710774014 A CN201710774014 A CN 201710774014A CN 107744831 B CN107744831 B CN 107744831B
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alkoxy
quinidine derivative
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quinidine
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CN107744831A (en
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张惠明
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Brassinolide Suzhou Bio Tech Co ltd
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
    • B01J31/0235—Nitrogen containing compounds
    • B01J31/0244—Nitrogen containing compounds with nitrogen contained as ring member in aromatic compounds or moieties, e.g. pyridine
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
    • B01J31/1805—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing nitrogen
    • B01J31/181—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine
    • B01J31/1825—Ligands comprising condensed ring systems, e.g. acridine, carbazole
    • B01J31/183—Ligands comprising condensed ring systems, e.g. acridine, carbazole with more than one complexing nitrogen atom, e.g. phenanthroline
    • B01J31/1835—Ligands comprising condensed ring systems, e.g. acridine, carbazole with more than one complexing nitrogen atom, e.g. phenanthroline comprising aliphatic or saturated rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • C07D453/04—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems having a quinolyl-4, a substituted quinolyl-4 or a alkylenedioxy-quinolyl-4 radical linked through only one carbon atom, attached in position 2, e.g. quinine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/02—Compositional aspects of complexes used, e.g. polynuclearity
    • B01J2531/0238—Complexes comprising multidentate ligands, i.e. more than 2 ionic or coordinative bonds from the central metal to the ligand, the latter having at least two donor atoms, e.g. N, O, S, P
    • B01J2531/0241—Rigid ligands, e.g. extended sp2-carbon frameworks or geminal di- or trisubstitution

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Abstract

The invention discloses a quinidine derivative catalyst, the structural formula of which is shown as formula I:

Description

Quinidine derivative catalyst, preparation method and application
Technical Field
The invention belongs to the technical field of application of alkaloids in organic catalysis, and particularly relates to a quinidine derivative catalyst, a preparation method and application thereof.
Background
Since brassinolide was isolated from canola pollen in 1979 by Grove et al, usa and its structure was determined by light diffraction and ultra-trace analysis, more than thirty analogs, collectively known as brassinosteroids (brs), were isolated from plants or synthesized artificially. It is now well established that the physiological functions of BRs are a novel class of highly active plant endogenous hormones, unlike the five major classes of phytohormones previously used.
The basic structure of BRs is a cholestene derivative, and it is believed that 22(R), 23(R) -dihydroxy, 24(S) methyl or ethyl, 7-oxo-lactone and 6-keto in B ring, 3(α) -hydroxy, 2(α), 3(α) -dihydroxy and 3(α), 4(β) -dihydroxy, and trans-linkage of A/B ring are important for biological activity through various biological tests.
The process route for chemically synthesizing 28 epi-brassinolide from stigmasterol is shown in figure 1, the reaction of double bond oxidation at step 6 determines the steric configuration and biological activity of the final product, osmium tetroxide can be effectively added with olefin, and the olefin is completely converted into cis-dihydroxy compound in the presence of other oxidant, which is one of the most selective and effective reactions in organic reaction, in the above step 6, osmium tetroxide can convert two double bonds into cis-dihydroxy with high selectivity, so that the ideal 2(α), 3(α) -dihydroxy is generated on the A ring of the product, but at the position of the double bond of the side chain, 22(S), 23(S) -dihydroxy.2 (α), 3(α), 22(S), 23(S) -tetrahydroxy alcohol is mainly generated, and the 2(α), 3(α), 22(S), 23(S) configuration of 28 epi-brassinolide product generated by the step 7 is called S-epi-brassinolide, and the bio-epi-brassinolide product is also called S28 epi-brassinolide, and the bio-brassinolide product is proved to have high biological activity as shown in figure 28, as well as the test result that the bio-epi-brassinolide has high bioactivity as compared with 22, R23 (3923).
An asymmetric cis-dihydroxy product can be obtained by adding a chiral ligand in the olefin oxidation reaction of osmium tetroxide, 2(α), 3(α), 22(R), 23(R) -tetrahydroxy alcohol with high selectivity can be generated by adding a quinidine derivative ligand in the 6 th step of the 28-epi-brassinolide synthesis process, and then a high-bioactivity R28 epi-brassinolide, namely high brassinolide, can be obtained by the 7 th step of reaction.
Disclosure of Invention
In view of the defects of the prior art, the invention aims to provide a quinidine derivative catalyst which has rich sources and low price, is used as a chiral ligand for the double-hydroxylation reaction of double bonds in the synthesis of 28-epi-brassinolide and can show higher asymmetric selectivity of R body configuration.
The purpose of the invention is realized by the following technical scheme:
a quinidine derivative catalyst has a structural formula shown in formula I:
Figure GDA0001490963200000031
the quinidine derivative catalyst is prepared by reacting quinidine with a catalyst, wherein R is1Selected from halogensAlkyl or alkoxy; the R is2Selected from halogen, alkyl or alkoxy; the R is3Selected from halogen, alkyl or alkoxy; the R is4Selected from halogen, alkyl or alkoxy; the R is5Selected from halogen, alkyl or alkoxy.
The quinidine derivative catalyst is characterized in that the alkyl is selected from C1-C5, and the alkoxy is selected from C1-C5.
The second purpose of the invention is to provide a preparation method of the quinidine derivative catalyst, and the preparation process is mature and simple.
The preparation method of the quinidine derivative catalyst comprises the following steps: 1) carrying out reduction reaction on the compound 18 to obtain a compound 19; 2) the compound 14 is subjected to substitution reaction to obtain a compound 15; cyclizing the compound 15 and diethyl malonate to generate a compound 16; compound 16 is chloridized by phosphorus oxychloride to generate compound 17; 3) carrying out condensation reaction on a compound 17 and a compound 19 to obtain the formula I;
Figure GDA0001490963200000041
the preparation method of the quinidine derivative catalyst comprises the following specific operation steps of the step 3): introducing inert gas into a compound 19, adding DMSO, stirring to dissolve, adding NaH at room temperature, reacting for 1h, adding a compound 17, heating to 90-110 ℃, reacting for 7-10h, cooling, adding EDTANa, ammonia water, ethyl acetate and water, stirring for 1h, separating to obtain an organic phase and a water phase, and allowing the organic phase to pass through a column to obtain the formula I.
In the preparation method of the quinidine derivative catalyst, the ammonia water is 30% ammonia water.
The preparation method of the quinidine derivative catalyst comprises the following steps of mixing EDTANA, ammonia water, ethyl acetate and water according to the dosage ratio of 10g to 7ml to 50 ml.
The application of the quinidine derivative catalyst in asymmetric synthesis of 28 epilabyrin lactone.
Compared with the prior art, the quinidine derivative catalyst, the preparation method and the application provided by the invention have the following technical effects: the quinidine derivative catalyst has rich sources, low cost and mature and simple preparation process, and is obtained by condensing 4, 6-dichloro-2-substituted phenyl pyrimidine and dihydroquinidine; experiments show that the compound can be used as a chiral ligand for double hydroxylation reaction of double bonds in 28-table brassinolide synthesis, and can show higher asymmetric selectivity of R body configuration.
Drawings
FIG. 1 is a schematic diagram of a process for the chemical synthesis of 28 epi-brassinolide starting from stigmasterol;
FIG. 2 is a structural formula of a single molecule quinidine derivative ligand;
FIG. 3 is a structural formula of bimolecular quinidine derivative ligands;
FIG. 4 is a structural formula of a quinidine derivative ligand DHQD-CLB;
FIG. 5 is a structural formula of a quinidine derivative ligand DHQD-PHN;
FIG. 6 is a structural formula of a quinidine derivative ligand DHQD-MEQ;
FIG. 7 is a synthesis scheme for quinidine derivative catalysts (formula I);
FIG. 8 is a structural formula of quinidine derivative catalyst BDHQD-PP.
The following detailed description of the embodiments of the present invention is provided in connection with the accompanying drawings and examples to make the technical solutions easier to understand and understand.
Detailed Description
The present invention will be described below with reference to specific examples, but the present invention is not limited thereto. The experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents and materials are commercially available without specific reference, and the following examples are not intended to limit the scope of the present invention, and all equivalent implementations or modifications without departing from the scope of the present invention are intended to be included in the scope of the present invention.
The quinidine derivative catalyst provided by the invention can be prepared by the following synthetic route (as shown in figure 7): the raw material substituted benzonitrile (compound 14) is firstly prepared into substituted phenylamidine (compound 15) through substitution reaction; substituted phenylamidine (compound 15) and diethyl malonate are cyclized to generate substituted phenylpyrimidinedione (compound 16), 4, 6-dichloro-2-substituted phenylpyrimidine (compound 17) generated by chlorination of phosphorus oxychloride and dihydroquinidine (compound 19) obtained by reduction reaction of quinidine (compound 18) are subjected to condensation reaction to obtain a quinidine derivative catalyst (formula I), and the chemical name is as follows: 6-bis [ (S) - ((2R, 4S, 5R) -5-ethyl-quinuclidin-2-yl) (6-methoxyquinolin-4-yl) methoxy ] -2-substituted phenylpyrimidine.
Various 4, 6-dichloro-2-substituted phenylpyrimidines (compound 17) are commonly used chemical intermediates, especially R 1-54, 6-dichloro-2-phenylpyrimidine as a herbicide protectant has been industrially produced on a relatively large scale and is readily available on the market.
Wherein R is1-54, 6-dichloro-2-phenylpyrimidine, being a hydrogen atom, having the chemical name: 4, 6-bis [ (S) - ((2R, 4S, 5R) -5-ethyl-quinuclidin-2-yl) (6-methoxyquinolin-4-yl) methoxy]2-phenyl pyrimidine, BDHQD-PP for short, and the structure of the derivative is shown in figure 8.
EXAMPLE 1 preparation of BDHQD-PP (Compound 20)
Adding 50g (153.17mmol) of dihydroquinidine (DHQD, compound 19), introducing argon, adding 600ml of DMSO, stirring to dissolve, adding 3.7g (154.17mmol) of NaH in portions at room temperature to generate bubbles, reacting for 1h after the addition is finished, and adding 4, 6-dichloro-2-phenylpyrimidine (17, R)1-5H)17.2g (76.44mmol), heating to 100 ℃ to react for 8H, stopping the reaction, cooling to room temperature, adding 100g of edtama, 70ml of ammonia (30%), 500ml of ethyl acetate and 500ml of water, stirring for 1H, separating, extracting the aqueous phase twice with 500ml of ethyl acetate, combining the organic phases, washing with 300ml of ammonia (5%) each time until the aqueous phase is colorless, and extracting the organic phase with 500ml of sulfuric acid (5%) each time until the organic phase is free of ligand. Mixing the aqueous phases of sulfuric acid, adjusting the pH value of the aqueous phases to 7-8 by using sodium carbonate, then adding ethyl acetate 1L for each extraction until the point plate of the aqueous phases is free from ligand, mixing the organic phases, adding silica gel (100-200 meshes) 120g for sample mixing, passing through a column by using silica gel (300-400 meshes) 1000g for column passing, and passing through the columnPolar dichloromethane and ethanol (50: 1) to obtain 40g of white ligand BDHQD-PP (compound 20).
Example 2 use of BDHQD-PP (Compound 20) in the asymmetric Synthesis of 28 epipladienolide
Preparation of the Tetrahydric alcohol (Compound 6): to a reaction flask were added 25g of diketene (compound 5), 250g of potassium ferricyanide, 105g of potassium carbonate, 50g of methylsulfonamide, 750mL of t-butanol, 750mL of water, 10g of BDHQD-PP (compound 20), and 0.9g of potassium osmate, and the mixture was stirred at 30 ℃ for 72 hours and the end of the reaction was monitored by TLC plate.
The reaction was stopped, 25g of sodium sulfite and 200ml of water were added to the system, and after stirring for 1 hour, the mixture was desolventized under reduced pressure to precipitate a solid, which was filtered, and the filter cake was washed with 3X 50ml of water, and then the obtained solid was dissolved in 800ml of ethyl acetate and washed with 0.25M aqueous sulfuric acid several times until the organic phase point plate was free of ligand. The organic phase was concentrated by adding 50g of silica gel and the column was eluted with ethyl acetate tetrahydrofuran 2: 1 to give about 22g of tetrahydroxy alcohol (compound 6) as a white solid.
The aqueous phase is adjusted to neutral pH with a suitable amount of sodium carbonate, a white thick liquid is precipitated and extracted each time with 3X 100ml of ethyl acetate. The organic phases were combined, washed once with 50ml of water, dried over anhydrous sodium sulfate and then concentrated to dryness to obtain about 9g of the recovered ligand BDHQD-PP.
The product tetrahydroxy alcohol (compound 6) is derived by naphthalene boric acid and then is detected by high performance liquid chromatography, and the result shows that 22(R), 23(R) -body: 22(S), 23(S) -body is more than 9: 1.
Comparative example
Preparation of the Tetrahydric alcohol (Compound 6): to the reaction flask were added 25g of diketene (Compound 5), 250g of potassium ferricyanide, 105g of potassium carbonate, 50g of methylsulfonamide, 750mL of t-butanol, 750mL of water, 0.9g of potassium osmate, and stirred at 30 ℃ for 72h, and the end point of the reaction was monitored by TLC plate.
The reaction was stopped, 25g of sodium sulfite and 200ml of water were added to the system, and after stirring for 1 hour, the mixture was desolventized under reduced pressure to precipitate a solid, which was filtered, and the cake was washed with 3X 50ml of water, and then the obtained solid was dissolved in 800ml of ethyl acetate, 50g of silica gel was added to concentrate the solution, and the column was washed with ethyl acetate/tetrahydrofuran 2: 1 to obtain about 26g of tetrahydroxy alcohol (compound 6) as a white solid.
The product tetrahydroxy alcohol (compound 6) is derived by naphthalene boric acid and then is detected by high performance liquid chromatography, and the result shows that 22(R), 23(R) -body: 22(S) and 23(S) -body are less than 1: 9.
The foregoing description shows and describes several preferred embodiments of the invention, but as aforementioned, it is to be understood that the invention is not limited to the forms disclosed herein, but is not to be construed as excluding other embodiments and is capable of use in various other combinations, modifications, and environments and is capable of changes within the scope of the inventive concept as expressed herein, commensurate with the above teachings, or the skill or knowledge of the relevant art. And that modifications and variations may be effected by those skilled in the art without departing from the spirit and scope of the invention as defined by the appended claims.

Claims (8)

1. A quinidine derivative catalyst is characterized in that the structural formula of the quinidine derivative is shown as a formula I:
Figure FDA0001490963190000011
2. the class of quinidine derivative catalysts of claim 1, wherein R is selected from the group consisting of1Selected from halogen, alkyl or alkoxy; the R is2Selected from halogen, alkyl or alkoxy; the R is3Selected from halogen, alkyl or alkoxy; the R is4Selected from halogen, alkyl or alkoxy; the R is5Selected from halogen, alkyl or alkoxy.
3. The class of quinidine derivative catalysts of claim 2, wherein said alkyl group is selected from the group consisting of C1-C5 alkyl groups, and said alkoxy group is selected from the group consisting of C1-C5 alkoxy groups.
4. The process for preparing a class of quinidine derivative catalysts of claim 1, comprising the steps of: 1) carrying out reduction reaction on the compound 18 to obtain a compound 19; 2) the compound 14 is subjected to substitution reaction to obtain a compound 15; cyclizing the compound 15 and diethyl malonate to generate a compound 16; compound 16 is chloridized by phosphorus oxychloride to generate compound 17; 3) carrying out condensation reaction on a compound 17 and a compound 19 to obtain the formula I;
Figure FDA0001490963190000021
5. the method for preparing a class of quinidine derivative catalysts according to claim 4, wherein the specific operation steps of step 3) include the following: introducing inert gas into a compound 19, adding DMSO, stirring to dissolve, adding NaH at room temperature, reacting for 1h, adding a compound 17, heating to 90-110 ℃, reacting for 7-10h, cooling, adding EDTANa, ammonia water, ethyl acetate and water, stirring for 1h, separating to obtain an organic phase and a water phase, and allowing the organic phase to pass through a column to obtain the formula I.
6. The method of claim 5, wherein the aqueous ammonia is 30% strength aqueous ammonia.
7. The method of claim 5, wherein the ratio of EDTANA, ammonia, ethyl acetate and water is 10g, 7ml, 50ml and 50 ml.
8. The use of a class of quinidine derivative catalysts of claim 1 in the asymmetric synthesis of 28 epilabyrin lactone.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6326327B1 (en) * 1996-11-20 2001-12-04 Degussa Ag Process for preparing MeO-Peg-protected dihydroquinine or dihydroquinidine derivatives, new dihydroquinine or dihydroquinidine derivatives and their use
CN101511795A (en) * 2006-07-05 2009-08-19 安万特农业公司 1-aryl-5-alkylpyrazole derivative compounds, methods of making and methods of use thereof
CN105461699A (en) * 2014-09-25 2016-04-06 广东东阳光药业有限公司 Substituted heterocyclic compound, and use method and use thereof

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EP1928878A1 (en) * 2005-08-24 2008-06-11 Pfizer Inc. Methods for the preparation of hcv polymerase inhibitors

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6326327B1 (en) * 1996-11-20 2001-12-04 Degussa Ag Process for preparing MeO-Peg-protected dihydroquinine or dihydroquinidine derivatives, new dihydroquinine or dihydroquinidine derivatives and their use
CN101511795A (en) * 2006-07-05 2009-08-19 安万特农业公司 1-aryl-5-alkylpyrazole derivative compounds, methods of making and methods of use thereof
CN105461699A (en) * 2014-09-25 2016-04-06 广东东阳光药业有限公司 Substituted heterocyclic compound, and use method and use thereof

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