CN117603205A - Synthesis method and application of quinidine derivative chiral phase transfer catalyst - Google Patents
Synthesis method and application of quinidine derivative chiral phase transfer catalyst Download PDFInfo
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- CN117603205A CN117603205A CN202311762818.2A CN202311762818A CN117603205A CN 117603205 A CN117603205 A CN 117603205A CN 202311762818 A CN202311762818 A CN 202311762818A CN 117603205 A CN117603205 A CN 117603205A
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- 239000003444 phase transfer catalyst Substances 0.000 title claims abstract description 29
- LOUPRKONTZGTKE-LHHVKLHASA-N quinidine Chemical class C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 title claims abstract description 24
- 238000001308 synthesis method Methods 0.000 title claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 108
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000000126 substance Substances 0.000 claims abstract description 16
- 125000003003 spiro group Chemical group 0.000 claims abstract description 12
- 238000010189 synthetic method Methods 0.000 claims abstract description 9
- 230000002152 alkylating effect Effects 0.000 claims abstract description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 6
- 230000002194 synthesizing effect Effects 0.000 claims abstract 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 78
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 49
- 238000006243 chemical reaction Methods 0.000 claims description 35
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 28
- 238000001035 drying Methods 0.000 claims description 23
- 238000003756 stirring Methods 0.000 claims description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 18
- 238000001914 filtration Methods 0.000 claims description 15
- 239000012074 organic phase Substances 0.000 claims description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- 238000003786 synthesis reaction Methods 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 230000015572 biosynthetic process Effects 0.000 claims description 13
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 13
- 239000000243 solution Substances 0.000 claims description 11
- -1 2-bromo-5-methoxybromobenzyl Chemical group 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
- 239000007787 solid Substances 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 9
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 9
- 239000003513 alkali Substances 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 7
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 6
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 6
- 230000001105 regulatory effect Effects 0.000 claims description 6
- 238000010009 beating Methods 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 239000002994 raw material Substances 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- 239000002168 alkylating agent Substances 0.000 claims description 2
- 229940100198 alkylating agent Drugs 0.000 claims description 2
- 238000003810 ethyl acetate extraction Methods 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 238000003809 water extraction Methods 0.000 claims description 2
- 125000006278 bromobenzyl group Chemical group 0.000 abstract description 3
- 230000003197 catalytic effect Effects 0.000 abstract description 2
- 229940127597 CGRP antagonist Drugs 0.000 abstract 1
- 230000001335 demethylating effect Effects 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 abstract 1
- 239000012043 crude product Substances 0.000 description 22
- 239000007788 liquid Substances 0.000 description 20
- 241000157855 Cinchona Species 0.000 description 13
- 229930013930 alkaloid Natural products 0.000 description 12
- 235000021513 Cinchona Nutrition 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- 150000003797 alkaloid derivatives Chemical class 0.000 description 10
- 239000008346 aqueous phase Substances 0.000 description 9
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 8
- 239000012452 mother liquor Substances 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 6
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 6
- 238000007792 addition Methods 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 235000001258 Cinchona calisaya Nutrition 0.000 description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 3
- 238000011914 asymmetric synthesis Methods 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 229960000948 quinine Drugs 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 2
- 150000003863 ammonium salts Chemical group 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 2
- 229960001404 quinidine Drugs 0.000 description 2
- 150000003413 spiro compounds Chemical class 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- MPPPKRYCTPRNTB-UHFFFAOYSA-N 1-bromobutane Chemical compound CCCCBr MPPPKRYCTPRNTB-UHFFFAOYSA-N 0.000 description 1
- CYNYIHKIEHGYOZ-UHFFFAOYSA-N 1-bromopropane Chemical compound CCCBr CYNYIHKIEHGYOZ-UHFFFAOYSA-N 0.000 description 1
- FYELSNVLZVIGTI-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-5-ethylpyrazol-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C=1C=NN(C=1CC)CC(=O)N1CC2=C(CC1)NN=N2 FYELSNVLZVIGTI-UHFFFAOYSA-N 0.000 description 1
- UZGLOGCJCWBBIV-UHFFFAOYSA-N 3-(chloromethyl)pyridin-1-ium;chloride Chemical compound Cl.ClCC1=CC=CN=C1 UZGLOGCJCWBBIV-UHFFFAOYSA-N 0.000 description 1
- 238000005698 Diels-Alder reaction Methods 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 238000006683 Mannich reaction Methods 0.000 description 1
- 238000006845 Michael addition reaction Methods 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 150000001450 anions Chemical group 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 238000007247 aza-Henry reaction Methods 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- KMPWYEUPVWOPIM-UHFFFAOYSA-N cinchonidine Natural products C1=CC=C2C(C(C3N4CCC(C(C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-UHFFFAOYSA-N 0.000 description 1
- KMPWYEUPVWOPIM-LSOMNZGLSA-N cinchonine Chemical compound C1=CC=C2C([C@@H]([C@H]3N4CC[C@H]([C@H](C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-LSOMNZGLSA-N 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- OUUQCZGPVNCOIJ-UHFFFAOYSA-N hydroperoxyl Chemical group O[O] OUUQCZGPVNCOIJ-UHFFFAOYSA-N 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 238000005935 nucleophilic addition reaction Methods 0.000 description 1
- 239000005416 organic matter Substances 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
Classifications
-
- 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/20—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a synthetic method and application of a chiral phase transfer catalyst of quinidine derivatives, wherein the synthesis method comprises the following steps: (a) Demethylating a substance shown in the formula (I) under the action of boron tribromide to obtain a compound shown in the formula (II); (b) Reacting a compound represented by a formula (II) with an alkylating reagent to obtain a compound represented by a formula (III); (c) The compound shown in the formula (III) reacts with bromobenzyl or substituted bromobenzyl to obtain the chiral phase transfer catalyst shown in the formula (IV). The chiral phase transfer catalyst shows higher catalytic efficiency and chiral selectivity in synthesizing key spiro chiral intermediates of gemant CGRP antagonists.
Description
Technical Field
The invention belongs to the technical field of organic matter synthesis, relates to quinidine derivatives, and particularly relates to a synthesis method of a quinidine derivative chiral phase transfer catalyst and application of the quinidine derivative chiral phase transfer catalyst in chiral spiro compound synthesis.
Background
The cinchona alkaloid is main alkaloid in the bark of the cinchona tree and the plants of the same genus, widely exists in the nature, has good biological activity and medical value, and contains quinine, quinidine, cinchonine and other alkaloids accounting for 30-60% of all alkaloids, wherein quinine is a special drug for treating malaria, quinidine can be used for treating arrhythmia, but has certain side effects.
Because cinchona alkaloid has a chiral framework with natural advantages and strong later-period modification capability, cinchona alkaloid and derivatives thereof are widely used as organic catalysts and chiral ligands for catalyzing asymmetric synthesis, and have become an important research field in asymmetric synthesis chemistry, and have attracted extensive attention and research of organic synthesis scientists.
Structure and configuration of cinchona alkaloid:
the cinchona alkaloid and the derivative thereof are used as chiral catalysts in asymmetric synthesis, are mainly converted into amino groups by hydroxyl groups, are further derived into thiourea (urea), sulfonamide or tetragonal amide derivatives and the like, are applied to asymmetric Diels-Alder reactions, asymmetric Aza-Henry reactions, asymmetric Mannich reactions, asymmetric nucleophilic addition and asymmetric Michael addition reactions, and have good ee values.
The cinchona alkaloid and the derivative thereof are used as chiral ligands, N atoms and hydroxyl oxygen atoms on the bridge ring are provided with unpaired lone pair electrons, the cinchona alkaloid can be coordinated with metal with empty orbitals, the purposes of regulating and controlling the space and electronic effects of a catalytic center can be achieved through reasonable structural modification, and the coordination atoms in the ligands can form bonds with the metal in an anion form or provide lone pair electrons to form Lewis acid-base adducts with the metal to carry out a series of asymmetric reactions.
The quaternary ammonium salt phase transfer catalyst of cinchona alkaloid and the derivative thereof is used for asymmetric alkylation reaction, and the quaternary ammonium salt phase transfer catalyst of the derivative which is gradually converted into hydroxyl through the monoquaternary ammonium salt on the initial bridgehead N is used for the asymmetric alkylation reaction, so that a better ee value is obtained.
Disclosure of Invention
In order to find out an efficient cinchona alkaloid bisquaternary ammonium salt chiral phase transfer catalyst, the invention provides a synthetic method of a quinine Ding Shou chiral phase transfer catalyst, and application of the catalyst in chiral spiro synthesis, and a product has a very high ee value.
The invention comprises a synthetic method of a series of chiral phase transfer catalysts with different substituent groups R, and is applied to the synthesis of a gement key chiral spiro intermediate, and the chiral phase transfer catalyst shows better chiral selectivity.
Synthesis of chiral spiro ring:
in order to achieve the above purpose, the present invention adopts the following technical scheme:
the invention provides a synthetic method of a chiral phase transfer catalyst of a quinidine derivative, which comprises the following steps:
(a) Adding boron tribromide into a compound shown in a formula (I) in methylene dichloride serving as a solvent to generate a compound shown in a formula (II), wherein the reaction temperature is controlled to be between-20 ℃ and 40 ℃; post-treatment: filtering the compound shown in the formula (II) obtained by the reaction by MTBE, dissolving solid in methanol/dichloromethane, regulating alkali by ammonia water, layering, extracting, drying and drying to obtain the compound;
(b) Adding alkali and an alkylating reagent into a compound shown in a formula (II) in a solvent to react to obtain a compound shown in a formula (III); post-treatment: extracting and layering the compound shown in the formula (III) obtained by the reaction, and drying and desolventizing an organic phase to obtain the compound shown in the formula (III);
(c) Adding 2-bromo-5-methoxybromobenzyl into a solvent for reaction to obtain a compound represented by a formula (IV); post-treatment: filtering the compound shown in the formula (IV) obtained by the reaction, and drying to obtain the compound;
a compound of formula (i):
a compound represented by the formula (ii):
a compound represented by formula (iii):
a compound represented by the formula (iv):
wherein R is 1 ＝H，-CH 2 CH 3 ，-(CH 2 ) 2 CH 3 ，-CH(CH 3 ) 2 ，-(CH 2 ) 3 CH 3 ，-Bn，
-CH 3 CH＝CH 2 ，-CH 2 CF 3 Or-3-methyl-pyridine; x is X 1 =cl, br, I or-OTf; x is X 2 =cl, br or I. In the invention, the synthetic route of the chiral phase transfer catalyst of the quinidine derivative is as follows:
as a preferable scheme of the invention, the specific steps of the synthesis method are as follows:
(a) Dissolving a substance shown in a formula (I) in dichloromethane, slowly dropwise adding boron tribromide at the temperature of-20-0 ℃, after the dropwise adding, keeping the temperature of the reaction solution at-20-0 ℃ and stirring for 1 hour, slowly heating to room temperature, and keeping the temperature of 35-40 ℃ and stirring for 2 hours;
the post-treatment is as follows: adding MTBE into the compound shown in the formula (II) obtained by the reaction, filtering to obtain a solid, dissolving the solid with methanol/dichloromethane, regulating alkali with ammonia water, layering, extracting, drying and drying to obtain the compound shown in the formula (II);
(b) Dissolving a compound shown in a formula (II) in DMF, adding cesium carbonate or potassium carbonate, adding an alkylating reagent at room temperature, stirring at room temperature for 5 hours, and carrying out reaction and post-treatment to obtain a compound shown in a formula (III);
the post-treatment process comprises the following steps: layering the compound shown in the formula (III) obtained by the reaction through ethyl acetate and water extraction, washing an organic phase with water and saturated brine, drying, and removing the dry matter to obtain the compound;
(c) Adding 2-bromo-5-methoxybromobenzyl into DMF/IPA, heating to 70 ℃, preserving heat, stirring for 12 hours, and performing post-treatment to obtain a compound shown in formula (IV);
the post-treatment is as follows: cooling the compound shown in the formula (IV) obtained by the reaction, adding ethyl acetate, filtering and drying to obtain the compound.
As a preferable mode of the invention, the molar ratio of the substance shown in the formula (I) to the boron tribromide is 1:2.0 to 4.0; 10g of the substance of formula (I) was added to 100mL of methylene chloride, and a methylene chloride solution of boron tribromide was added dropwise at a molar concentration of 1.0M.
As a preferable scheme of the invention, the mass ratio of the substance shown in the formula (II), cesium carbonate or potassium carbonate and the alkylating agent is 1:1 to 1.5:1.1 to 2; 20g of the substance of formula (II) are added per 100mL of DMF.
As a preferable scheme of the invention, the mass ratio of the substance shown in the formula (III) to the 2-bromo-5-methoxybromobenzyl is 1:2 to 2.5; 25g of a substance represented by the formula (III) is added into every 100mL of a mixed solution of DMF and IPA, wherein the volume ratio of DMF to IPA is as follows: 3.5:0.5.
as a preferable scheme of the invention, the beating solvent in the post-treatment process of the step (c) is DMF, IPA and ethyl acetate, and the volume ratio is 3.5:0.5:40, a step of performing a; the mass volume ratio of the compound represented by the formula (III) to the beating solvent is 1:44.
the invention also provides application of the quinidine derivative chiral phase transfer catalyst prepared by the synthesis method in chiral spiro synthesis.
As a preferable scheme of the invention, the synthesis method of the chiral spiro ring comprises the following steps: adding raw materials into toluene, stirring and dissolving, adding the chiral phase transfer catalyst prepared by the synthesis method of any one of claims 1-6 under the protection of nitrogen, dropwise adding a 1N sodium hydroxide aqueous solution at low temperature, layering, drying, filtering, and crystallizing to obtain the chiral spiro ring product.
Compared with the prior art, the invention has the following beneficial effects:
the post-treatment of the invention does not need to use column chromatography to purify and separate the product, because the raw materials and the process route of the invention are selected so that the post-treatment is simpler and more convenient, the purification is easy, the use of column chromatography purification is avoided, the production cost is saved, the time is greatly shortened, and the invention is suitable for industrialized mass production and also suitable for small-scale preparation in a laboratory.
Drawings
FIG. 1 is a synthetic route diagram of the present invention.
FIG. 2 is a chiral spiro compound prepared in example 11 1 HNMR profile.
Fig. 3 is a liquid chromatogram of the racemate.
FIG. 4 is a compound R represented by the formula (IV) 1 ＝H，X 2 Liquid chromatogram of the prepared crude product of Br.
FIG. 5 is a compound R represented by the formula (IV) 1 ＝-CH 2 CH 3 ，X 2 Liquid chromatogram of the prepared crude product of Br.
FIG. 6 is a compound R represented by the formula (IV) 1 ＝-(CH 2 ) 2 CH 3 ，X 2 Liquid chromatogram of the prepared crude product of Br.
FIG. 7 is a compound R represented by the formula (IV) 1 ＝-CH(CH 3 ) 2 ，X 2 Liquid chromatogram of the prepared crude product of Br.
FIG. 8 is a compound R represented by the formula (IV) 1 ＝-(CH 2 ) 3 CH 3 ，X 2 Liquid chromatogram of the prepared crude product of Br.
FIG. 9 is a compound R represented by the formula (IV) 1 ＝-Bn，X 2 Liquid chromatogram of the prepared crude product of Br.
FIG. 10 is a compound R represented by the formula (IV) 1 ＝-CH 3 CH＝CH 2 ，X 2 Liquid chromatogram of the prepared crude product of Br.
FIG. 11 is a compound R represented by the formula (IV) 1 ＝-CH 2 CF 3 ，X 2 Liquid chromatogram of the prepared crude product of Br.
FIG. 12 is a compound R represented by the formula (IV) 1 ＝-3-methyl-pyridine，X 2 Liquid chromatogram of the prepared crude product of Br.
Detailed Description
The technical solutions of the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention, and it is apparent that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Referring to fig. 1, the invention firstly provides a synthesis method of a chiral phase transfer catalyst of quinidine derivatives, which comprises the following steps:
(a) Dissolving a substance shown in a formula (I) in dichloromethane, slowly dropwise adding boron tribromide at the temperature of-20-0 ℃, after the dropwise adding, keeping the temperature of the reaction solution at-20-0 ℃ and stirring for 1 hour, slowly heating to room temperature, and keeping the temperature of 35-40 ℃ and stirring for 2 hours.
The post-treatment process of the step (a) comprises the following steps: and (3) adding MTBE into the compound shown in the formula (II) obtained by the reaction, filtering to obtain a solid, dissolving the solid by using methanol/dichloromethane, regulating alkali by using ammonia water, layering, extracting, drying and drying to obtain the compound shown in the formula (II).
(b) Dissolving a compound shown in a formula (II) in DMF, adding cesium carbonate or potassium carbonate, adding an alkylating reagent at room temperature, stirring at room temperature for 5 hours, and carrying out reaction and post-treatment to obtain the compound shown in the formula (III).
The post-treatment process of the step (b) comprises the following steps: and (3) extracting and layering the compound shown in the formula (III) obtained by the reaction by using ethyl acetate and water, washing an organic phase by using water and saturated brine, drying and removing the dryness to obtain the compound.
(c) And adding 2-bromo-5-methoxybromobenzyl into DMF/IPA, heating to 70 ℃, preserving heat, stirring for 12 hours, and performing post-treatment on the reaction to obtain the compound shown in the formula (IV).
The post-treatment process of the step (c) comprises the following steps: cooling the compound shown in the formula (IV) obtained by the reaction, adding ethyl acetate, filtering and drying to obtain the compound.
A compound of formula (i):
a compound represented by the formula (ii):
a compound represented by formula (iii):
a compound represented by the formula (iv):
wherein R is 1 ＝H，-CH 2 CH 3 ，-(CH 2 ) 2 CH 3 ，-CH(CH 3 ) 2 ，-(CH 2 ) 3 CH 3 ，-Bn，
-CH 3 CH＝CH 2 ，-CH 2 CF 3 Or-3-methyl-pyridine; x is X 1 =cl, br, I or-OTf; x is X 2 =cl, br or I.
Example 1
Synthesis of Compound of formula (II) (30.0 g,1 eq) was dissolved in dichloromethane (300 mL, 10V) under nitrogen protection, the reaction solution was cooled to-20℃and boron tribromide (91.7 g,4.0 eq) was slowly added dropwise, and after the addition, the reaction solution was allowed to react at-20-15℃for 1 hour at a temperature of-20℃and then at room temperature for 1 hour under reflux. The reaction solution was cooled to-10 to 0 ℃, MTBE (180 ml,6 v) was added, filtration was performed, the solid was added to methanol (90 ml,3 v) and methylene chloride (300 ml,10 v), stirring was performed at room temperature, water (180 ml,6 v) was added, the pH was adjusted to 12 with ammonia water, stirring was performed for 30 minutes, the layers were separated, the aqueous phase was extracted once with methylene chloride (300 ml,10 v), the organic phases were combined, washed once with saturated brine (90 ml,3 v), dried over anhydrous sodium sulfate, filtration was performed, and the filtrate was dried to obtain 22.1g of compound ii.
Example 2
Compounds of formula (III), R 1 ＝-CH 2 CH 3 Compound II (2.0 g,1.0 eq) was dissolved in DMF (10 mL) under nitrogen, and potassium carbonate (0.9 g,1.0 eq) and ethyl iodide (1.2 g,1.2 eq) were added at room temperature and reacted for 5 hours with stirring at room temperature. The reaction mixture was added with ethyl acetate (20 mL, 10V) and water (10 mL, 5V), the layers were separated, the aqueous phase was extracted once with ethyl acetate (10 mL, 10V), the organic phases were combined, washed once with saturated brine (10 mL, 5V), dried over anhydrous sodium sulfate, filtered, and the mother liquor was dried under reduced pressure to give 1.5g of the compound of formula (III), R 1 ＝-CH 2 CH 3 。
Example 3
Compounds of formula (III), R 1 ＝-(CH 2 ) 2 CH 3 Compound II (2.0 g,1.0 eq) was dissolved in DMF (10 mL) under nitrogen, cesium carbonate (2.1 g,1.0 eq) and bromopropane (1.2 g,1.5 eq) were added at room temperature, and the reaction was stirred at room temperature for 5 hours. The reaction mixture was added with ethyl acetate (20 mL, 10V) and water (10 mL, 5V), the layers were separated, the aqueous phase was extracted once with ethyl acetate (10 mL, 10V), the organic phases were combined, washed once with saturated brine (10 mL, 5V), dried over anhydrous sodium sulfate, filtered, and the mother liquor was dried under reduced pressure to give 1.8g of the compound of formula (III), R 1 ＝-(CH 2 ) 2 CH 3 。
Example 4
Compounds of formula (III), R 1 ＝-CH(CH 3 ) 2 Compound II (2.0 g,1.0 eq) was dissolved in DMF (10 mL) under nitrogen, cesium carbonate (2.1 g,1.0 eq) and bromoisopropyl (1.2 g,1.5 eq) were added at room temperature and the reaction was stirred at room temperature for 5 hours. The reaction mixture was added with ethyl acetate (20 mL, 10V) and water (10 mL, 5V), the layers were separated, the aqueous phase was extracted once with ethyl acetate (10 mL, 10V), the organic phases were combined, washed once with saturated brine (10 mL, 5V), dried over anhydrous sodium sulfate, filtered, and the mother liquor was dried under reduced pressure to give 1.7g of the compound of formula (III), R 1 ＝-CH(CH 3 ) 2 。
Example 5
Compounds of formula (III), R 1 ＝-(CH 2 ) 3 CH 3 Compound II (2.0 g,1.0 eq) was dissolved in DMF (10 mL) under nitrogen, cesium carbonate (2.1 g,1.0 eq) and 1-bromobutane (1.6 g,1.8 eq) were added at room temperature, and the reaction was stirred at room temperature for 5 hours. The reaction mixture was added with ethyl acetate (20 mL, 10V) and water (10 mL, 5V), the layers were separated, the aqueous phase was extracted once with ethyl acetate (10 mL, 10V), the organic phases were combined, washed once with saturated brine (10 mL, 5V), dried over anhydrous sodium sulfate, filtered, and the mother liquor was dried under reduced pressure to give 1.6g of the compound of formula (III), R 1 ＝-(CH 2 ) 3 CH 3 。
Example 6
Compounds of formula (III), R 1 Synthesis of= -Bn Compound II (2.0 g,1.0 eq) was dissolved in DMF (10 mL) under nitrogen protection, and potassium carbonate (0.9 g,1.0 eq) and bromobenzyl (1.4 g,1.3 eq) were added at room temperature and reacted for 5 hours with stirring at room temperature. The reaction mixture was added with ethyl acetate (20 mL, 10V) and water (10 mL, 5V), the layers were separated, the aqueous phase was extracted once with ethyl acetate (10 mL, 10V), the organic phases were combined, washed once with saturated brine (10 mL, 5V), dried over anhydrous sodium sulfate, filtered, and the mother liquor was dried under reduced pressure to give 1.9g of the compound of formula (III), R 1 ＝-Bn。
Example 7
Compounds of formula (III), R 1 ＝-CH 3 CH＝CH 2 Compound II (2.0 g,1.0 eq) was dissolved in DMF (10 mL) under nitrogen, and potassium carbonate (0.9 g,1.0 eq) and allyl bromide (1.0 g,1.2 eq) were added at room temperature and reacted for 5 hours with stirring at room temperature. The reaction mixture was added with ethyl acetate (20 mL, 10V) and water (10 mL, 5V), the layers were separated, the aqueous phase was extracted once with ethyl acetate (10 mL, 10V), the organic phases were combined, washed once with saturated brine (10 mL, 5V), dried over anhydrous sodium sulfate, filtered, and the mother liquor was dried under reduced pressure to give 1.3g of the compound of formula (III), R 1 ＝-CH 3 CH＝CH 2 。
Example 8
Compounds of formula (III), R 1 ＝-CH 2 CF 3 Compound II (2.0 g,1.0 eq) was dissolved in DMF (10 mL) under nitrogen, and potassium carbonate (0.9 g,1.0 eq) and trifluoromethanesulfonic acid-2, 2-trifluoroethyl ester (1.6 g,1.1 eq) were added at room temperature and reacted for 5 hours with stirring at room temperature. The reaction mixture was added with ethyl acetate (20 mL, 10V) and water (10 mL, 5V), the layers were separated, the aqueous phase was extracted once with ethyl acetate (10 mL, 10V), the organic phases were combined, washed once with saturated brine (10 mL, 5V), dried over anhydrous sodium sulfate, filtered, and the mother liquor was dried under reduced pressure to give 2.1g of the compound of formula (III), R 1 ＝-CH 2 CF 3 。
Example 9
Compounds of formula (III), R 1 Synthesis of= -3-methyl-pyridine Compound II (2.0 g,1.0 eq) was dissolved in DMF (10 mL) under nitrogen protection, cesium carbonate (2.1 g,1.0 eq), 3-chloromethylpyridine hydrochloride (1.4 g,1.3 eq) were added at room temperature, room temperatureThe reaction was stirred for 5 hours. The reaction mixture was added with ethyl acetate (20 mL, 10V) and water (10 mL, 5V), the layers were separated, the aqueous phase was extracted once with ethyl acetate (10 mL, 10V), the organic phases were combined, washed once with saturated brine (10 mL, 5V), dried over anhydrous sodium sulfate, filtered, and the mother liquor was dried under reduced pressure to give 2.2g of the compound of formula (III), R 1 ＝-3-methyl-pyridine。
Example 10
A compound represented by the formula (IV), R 1 ＝H，-CH 2 CH 3 ，-(CH 2 ) 2 CH 3 ，-CH(CH 3 ) 2 ，-(CH 2 ) 3 CH 3 ，-Bn，-CH 3 CH＝CH 2 ，-CH 2 CF 3 ，-3-methyl-pyridine；X 2 ＝Cl，Br，I。
The general preparation method comprises the following steps:
under the protection of nitrogen, dissolving (5 mmol) of a compound (III) in DMF/IPA (3.5V/0.5V), adding 2-bromo-5-methoxybromobenzyl (12.5 mmol), heating the reaction solution to 70 ℃, keeping the temperature and stirring for 12 hours, cooling to room temperature, adding ethyl acetate (40V), pulping and stirring at room temperature for 3 hours, filtering, rinsing the solid with ethyl acetate, and drying to obtain the compound represented by (IV), wherein the feeding amount and the output are shown in Table 1.
TABLE 1 production of the compounds of formula IV) from example 10
Example 11:
the application of the quinidine derivative chiral phase transfer catalyst in chiral spiro synthesis:
raw material (100)mmol), toluene (25V) is added, nitrogen is replaced for three times, the temperature is reduced to minus 2 ℃ under the protection of nitrogen, the compound (3 mmol) of the formula (IV) is added, stirring is carried out for 10 minutes, 0.3N sodium hydroxide aqueous solution (120 mmol) is dropwise added, the control temperature is between minus 2 and 5 ℃ after the dropwise addition, the mixture is kept warm and stirred for 2 hours after the dropwise addition is finished, water (10V) is added, layering is carried out, the organic phase is washed once by saturated brine (5V), anhydrous sodium sulfate is dried, filtered and dehydrated to obtain crude products, ee values of the crude products are shown in table 2 1 HNMR profile see fig. 2.
TABLE 2 ee value of crude product
Fig. 3 is a liquid chromatogram of the racemate.
FIG. 4 is a compound R represented by the formula (IV) 1 ＝H，X 2 Liquid chromatogram of the prepared crude product of Br.
FIG. 5 is a compound R represented by the formula (IV) 1 ＝-CH 2 CH 3 ，X 2 Liquid chromatogram of the prepared crude product of Br.
FIG. 6 is a compound R represented by the formula (IV) 1 ＝-(CH 2 ) 2 CH 3 ，X 2 Liquid chromatogram of the prepared crude product of Br.
FIG. 7 is a compound R represented by the formula (IV) 1 ＝-CH(CH 3 ) 2 ，X 2 Liquid chromatogram of the prepared crude product of Br.
FIG. 8 is a compound R represented by the formula (IV) 1 ＝-(CH 2 ) 3 CH 3 ，X 2 Liquid chromatogram of the prepared crude product of Br.
FIG. 9 is a compound R represented by the formula (IV) 1 ＝-Bn，X 2 Liquid chromatogram of the prepared crude product of Br.
FIG. 10 is a diagram of formula (IV)Compound R of (2) 1 ＝-CH 3 CH＝CH 2 ，X 2 Liquid chromatogram of the prepared crude product of Br.
FIG. 11 is a compound R represented by the formula (IV) 1 ＝-CH 2 CF 3 ，X 2 Liquid chromatogram of the prepared crude product of Br.
FIG. 12 is a compound R represented by the formula (IV) 1 ＝-3-methyl-pyridine，X 2 Liquid chromatogram of the prepared crude product of Br.
Therefore, the quinidine derivative chiral phase transfer catalyst prepared by the synthesis method is used for chiral spiro synthesis, and the obtained crude product has a high ee value.
While the invention has been described with respect to preferred embodiments thereof, it will be understood by those skilled in the art that various modifications and additions may be made without departing from the scope of the invention. Equivalent embodiments of the present invention will be apparent to those skilled in the art having the benefit of the teachings disclosed herein, when considered in the light of the foregoing disclosure, and without departing from the spirit and scope of the invention; meanwhile, any equivalent changes, modifications and evolution of the above embodiments according to the essential technology of the present invention still fall within the scope of the technical solution of the present invention.
Claims (8)
1. A synthetic method of a chiral phase transfer catalyst of quinidine derivatives, which is characterized by comprising the following steps:
(a) Adding boron tribromide into a compound shown in a formula (I) in methylene dichloride serving as a solvent to generate a compound shown in a formula (II), wherein the reaction temperature is controlled to be between-20 ℃ and 40 ℃; post-treatment: filtering the compound shown in the formula (II) obtained by the reaction by MTBE, dissolving solid in methanol/dichloromethane, regulating alkali by ammonia water, layering, extracting, drying and drying to obtain the compound;
(b) Adding alkali and an alkylating reagent into a compound shown in a formula (II) in a solvent to react to obtain a compound shown in a formula (III); post-treatment: extracting and layering the compound shown in the formula (III) obtained by the reaction, and drying and desolventizing an organic phase to obtain the compound shown in the formula (III);
(c) Adding 2-bromo-5-methoxybromobenzyl into a solvent for reaction to obtain a compound represented by a formula (IV); post-treatment: filtering the compound shown in the formula (IV) obtained by the reaction, and drying to obtain the compound;
a compound of formula (i):
a compound represented by the formula (ii):
a compound represented by formula (iii):
a compound represented by the formula (iv):
wherein R is 1 ＝H，-CH 2 CH 3 ，-(CH 2 ) 2 CH 3 ，-CH(CH 3 ) 2 ，-(CH 2 ) 3 CH 3 ，-Bn，
-CH 3 CH＝CH 2 ，-CH 2 CF 3 Or-3-methyl-pyridine; x is X 1 =cl, br, I or-OTf; x is X 2 =cl, br or I.
2. The synthetic method of the chiral phase transfer catalyst of the quinidine derivative according to claim 1, wherein the synthetic method comprises the following specific steps:
(a) Dissolving a substance shown in a formula (I) in dichloromethane, slowly dropwise adding boron tribromide at the temperature of-20-0 ℃, after the dropwise adding, keeping the temperature of the reaction solution at-20-0 ℃ and stirring for 1 hour, slowly heating to room temperature, and keeping the temperature of 35-40 ℃ and stirring for 2 hours;
the post-treatment is as follows: adding MTBE into the compound shown in the formula (II) obtained by the reaction, filtering to obtain a solid, dissolving the solid with methanol/dichloromethane, regulating alkali with ammonia water, layering, extracting, drying and drying to obtain the compound shown in the formula (II);
(b) Dissolving a compound shown in a formula (II) in DMF, adding cesium carbonate or potassium carbonate, adding an alkylating reagent at room temperature, stirring at room temperature for 5 hours, and carrying out reaction and post-treatment to obtain a compound shown in a formula (III);
the post-treatment process comprises the following steps: layering the compound shown in the formula (III) obtained by the reaction through ethyl acetate and water extraction, washing an organic phase with water and saturated brine, drying, and removing the dry matter to obtain the compound;
(c) Adding 2-bromo-5-methoxybromobenzyl into DMF/IPA, heating to 70 ℃, preserving heat, stirring for 12 hours, and performing post-treatment to obtain a compound shown in formula (IV);
the post-treatment is as follows: cooling the compound shown in the formula (IV) obtained by the reaction, adding ethyl acetate, filtering and drying to obtain the compound.
3. The method for synthesizing the chiral phase transfer catalyst of the quinidine derivative according to claim 1 or 2, wherein the molar ratio of the substance represented by formula (i) to the boron tribromide is 1:2.0 to 4.0; 10g of the substance of formula (I) was added to 100mL of methylene chloride, and a methylene chloride solution of boron tribromide was added dropwise at a molar concentration of 1.0M.
4. The synthetic method of the chiral phase transfer catalyst of the quinidine derivative according to claim 1 or 2, wherein the mass ratio of the substance shown in the formula (II), cesium carbonate or potassium carbonate and the alkylating agent is 1:1 to 1.5:1.1 to 2; 20g of the substance of formula (II) are added per 100mL of DMF.
5. The synthetic method of the chiral phase transfer catalyst of the quinidine derivative according to claim 1 or 2, wherein the mass ratio of the substance shown in the formula (III) to the 2-bromo-5-methoxybromobenzyl is 1:2 to 2.5; 25g of a substance represented by the formula (III) is added into every 100mL of a mixed solution of DMF and IPA, wherein the volume ratio of DMF to IPA is as follows: 3.5:0.5.
6. the method for synthesizing the chiral phase transfer catalyst of the quinidine derivative according to claim 1 or 2, wherein the beating solvent in the post-treatment process of step (c) is DMF, IPA and ethyl acetate, and the volume ratio is 3.5:0.5:40, a step of performing a; the mass volume ratio of the compound represented by the formula (III) to the beating solvent is 1:44.
7. the use of a quinidine derivative chiral phase transfer catalyst obtained by a synthesis method according to any of claims 1-6, wherein the quinidine derivative chiral phase transfer catalyst is used in chiral spiro synthesis.
8. The use according to claim 7, wherein the chiral spiro synthesis is: adding raw materials into toluene, stirring and dissolving, adding the chiral phase transfer catalyst prepared by the synthesis method of any one of claims 1-6 under the protection of nitrogen, dropwise adding a 1N sodium hydroxide aqueous solution at low temperature, layering, drying, filtering, and crystallizing to obtain the chiral spiro ring product.
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