CN112142663A - Synthesis method of (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline - Google Patents

Synthesis method of (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline Download PDF

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CN112142663A
CN112142663A CN202011142114.1A CN202011142114A CN112142663A CN 112142663 A CN112142663 A CN 112142663A CN 202011142114 A CN202011142114 A CN 202011142114A CN 112142663 A CN112142663 A CN 112142663A
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tetrahydroisoquinoline
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acid
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CN112142663B (en
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李彦雄
徐亮
蒙发明
于永海
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Foshan Yiansai Pharmaceutical Technology Co ltd
Enantiotech Corp Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • 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
    • B01J31/0245—Nitrogen containing compounds being derivatives of carboxylic or carbonic acids
    • B01J31/0247—Imides, amides or imidates (R-C=NR(OR))
    • 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
    • B01J31/0271—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds also containing elements or functional groups covered by B01J31/0201 - B01J31/0231
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • 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
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/60—Reduction reactions, e.g. hydrogenation
    • B01J2231/64—Reductions in general of organic substrates, e.g. hydride reductions or hydrogenations
    • B01J2231/641—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes
    • B01J2231/643—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes of R2C=O or R2C=NR (R= C, H)

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Abstract

The invention relates to a synthetic method of (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline. The method comprises the following steps: mixing 1-phenyl-3, 4-dihydroisoquinoline, a chiral catalyst, an acid and a solvent for reaction; the structural formula of the chiral catalyst is shown as a formula (I). In the hydrogenation reduction process, (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline with high chiral purity can be generated in one step, and meanwhile, the product is easy to separate and purify and has high yield. In addition, the method has the advantages of mild reaction conditions, stable process, simple, convenient and safe reaction operation, low production cost, simple and feasible three-waste treatment, environmental friendliness, simple equipment used in the reaction process, easily obtained raw materials and low production cost, and is suitable for industrial production.

Description

Synthesis method of (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a synthesis method of (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline.
Background
Solifenacin is a selective muscarinic M3 receptor antagonist developed by Astellas, Japan, and is mainly used for treating overactive bladder with symptoms of urgent micturition and frequent micturition. The chemical name of the solifenacin is (3R) -1-azabicyclo [2, 2, 2] octane-3-yl (1S) -1-phenyl-1, 4-dihydro-isoquinine-2- (1H) -carboxylate, and the structure is shown as the following formula (1):
Figure BDA0002737210110000011
from formula (1), solifenacin contains two chiral centers, one chiral center being located on the isoquinoline (2) structural unit and the other chiral center being located on the quinuclidinol structural unit. Therefore, the synthesis method of solifenacin is generally prepared by using (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline (formula (2)) and quinuclidinol (formula (3)) as raw materials, wherein (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline is an important intermediate for preparing solifenacin.
Figure BDA0002737210110000012
At present, (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline is synthesized mainly by borohydride reduction and then is obtained by resolution by a resolving agent, such as tartaric acid or a biological resolving agent. However, the method has low yield and poor optical purity of the product, and needs to be purified for many times.
Disclosure of Invention
Based on this, it is necessary to provide a method for synthesizing (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline. The synthesis method can generate the (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline with high chiral purity in one step, and simultaneously, the product is easy to separate and purify, and the product is easy to separate and purify and has high yield.
A synthetic method of (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline comprises the following steps:
mixing 1-phenyl-3, 4-dihydroisoquinoline, a chiral catalyst, an acid and a solvent for reaction;
the structural formula of the chiral catalyst is shown as the formula (I):
Figure BDA0002737210110000021
r is selected from a hydrogen atom, a straight chain alkyl group having 1 to 20 carbon atoms, a branched alkyl group having 3 to 20 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, a heterocyclic group having 3 to 10 ring atoms, an alkoxy group having 1 to 20 carbon atoms, a trifluoromethyl group, a halogen, an amino group, a cyano group, a hydroxyl group, a nitro group, an ester group, an amide group, a substituted or unsubstituted aryl group having 6 to 20 ring atoms, and a substituted or unsubstituted heteroaryl group having 5 to 20 ring atoms.
In one embodiment, the molar ratio of the 1-phenyl-3, 4-dihydroisoquinoline to the chiral catalyst is 1:0.8 to 1: 1.5.
In one embodiment, the molar ratio of the 1-phenyl-3, 4-dihydroisoquinoline to the chiral catalyst is 1:1.0 to 1: 1.3.
In one embodiment, the acid is selected from at least one of trifluoroacetic acid, acetic acid, benzoic acid, sulfonic acid, hydrochloric acid, and phosphoric acid.
In one embodiment, the molar ratio of the 1-phenyl-3, 4-dihydroisoquinoline to the acid is 1:0.2 to 1: 0.6.
In one embodiment, the molar ratio of the 1-phenyl-3, 4-dihydroisoquinoline to the acid is 1:0.3 to 1: 0.4.
In one embodiment, the reaction temperature is 10-60 ℃ and the reaction time is 5-40 h.
In one embodiment, the reaction temperature is 20-40 ℃ and the reaction time is 15-30 h.
In one embodiment, the solvent is selected from at least one of chloroform, dichloromethane, toluene, tetrahydrofuran, and acetonitrile.
In one embodiment, the reaction is followed by extraction, concentration and refining.
In one embodiment, R is selected from the group consisting of a hydrogen atom, a straight chain alkyl group having 1 to 12 carbon atoms, a straight chain alkyl group having 3 to 7 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, a straight chain alkoxy group having 1 to 6 carbon atoms, an isopropoxy group, a tert-butoxy group, an amino group, a cyano group, a hydroxyl group, a substituted or unsubstituted phenyl group.
In one embodiment, the alkyl group is selected from methyl, ethyl, isopropyl, or tert-butyl; the cycloalkyl is selected from cyclopropyl, cyclopentyl and cyclohexyl.
In one embodiment, the substituent in the aryl group having 6 to 20 ring atoms is selected from a halogen atom, a nitro group, a cyano group, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a tert-butyl group, an isobutyl group, a pentyl group, an isopentyl group, a neopentyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a methoxy group, a trifluoromethoxy group, or a trifluoromethyl group.
In one embodiment, the substituent in the substituted heteroaryl group having 5 to 20 ring atoms is selected from a halogen atom, a nitro group, a cyano group, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a tert-butyl group, an isobutyl group, a pentyl group, an isopentyl group, a neopentyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a methoxy group, a trifluoromethoxy group, or a trifluoromethyl group.
In one embodiment, R is selected from hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclohexyl, methoxy, ethoxy, isopropoxy, tert-butoxy, amino, cyano, hydroxy, phenyl, pyridyl, benzyl, or trifluoromethyl.
Compared with the prior art, the invention has the following beneficial effects:
the invention provides a method for synthesizing (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline, which takes 1-phenyl-3, 4-dihydroisoquinoline as a reaction raw material, and carries out hydrogenation reduction by matching with a proper chiral catalyst and acid, and in the process of hydrogenation reduction, (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline with high chiral purity can be generated in one step, and simultaneously, the product is easy to separate and purify, and the yield is high.
In addition, the synthesis method has the advantages of mild reaction conditions, stable process, simple, convenient and safe reaction operation, low production cost, simple and feasible three-waste treatment, environmental friendliness, simple equipment used in the reaction process, easily obtained raw materials and low production cost, and is suitable for industrial production.
Detailed Description
The present invention will be described in further detail with reference to specific examples. The present invention may be embodied in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
The existing (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline is synthesized mainly by borohydride reduction and then is obtained by resolution through a resolving agent, and the method has the advantages of low yield, poor optical purity of the product and multiple purification.
The invention provides a synthesis method of (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline, which can generate high chiral purity in one step, is easy to separate and purify the product, and has high yield. The technical scheme is as follows:
a synthetic method of (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline comprises the following steps:
mixing 1-phenyl-3, 4-dihydroisoquinoline, a chiral catalyst, an acid and a solvent for reaction;
the structural formula of the chiral catalyst is shown as the formula (I):
Figure BDA0002737210110000051
r is selected from a hydrogen atom, a straight chain alkyl group having 1 to 20 carbon atoms, a branched alkyl group having 3 to 20 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, a heterocyclic group having 3 to 10 ring atoms, an alkoxy group having 1 to 20 carbon atoms, a trifluoromethyl group, a halogen, an amino group, a cyano group, a hydroxyl group, a nitro group, an ester group, an amide group, a substituted or unsubstituted aryl group having 6 to 20 ring atoms, and a substituted or unsubstituted heteroaryl group having 5 to 20 ring atoms.
The reaction route comprises:
Figure BDA0002737210110000052
in one embodiment, the alkyl group is selected from methyl, ethyl, isopropyl, or tert-butyl; the cycloalkyl is selected from cyclopropyl, cyclopentyl and cyclohexyl.
Preferably, the aryl group is selected from phenyl, naphthyl, anthryl and pyrenyl. Preferably, said heteroaryl is selected from pyridyl, thienyl, furyl, pyrimidinyl.
In one embodiment, the substituent in the aryl group having 6 to 20 ring atoms is selected from a halogen atom, a nitro group, a cyano group, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a tert-butyl group, an isobutyl group, a pentyl group, an isopentyl group, a neopentyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a methoxy group, a trifluoromethoxy group, or a trifluoromethyl group.
In one embodiment, the substituent in the substituted heteroaryl group having 5 to 20 ring atoms is selected from a halogen atom, a nitro group, a cyano group, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a tert-butyl group, an isobutyl group, a pentyl group, an isopentyl group, a neopentyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a methoxy group, a trifluoromethoxy group, or a trifluoromethyl group.
In one preferred embodiment, R is selected from hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclohexyl, methoxy, ethoxy, isopropoxy, tert-butoxy, amino, cyano, hydroxy, phenyl, pyridyl, benzyl or trifluoromethyl.
In the present invention, the chiral catalyst can be selected from one of the following compounds:
catalyst I:
Figure BDA0002737210110000061
catalyst II:
Figure BDA0002737210110000062
catalyst III:
Figure BDA0002737210110000063
catalyst IV:
Figure BDA0002737210110000064
catalyst V:
Figure BDA0002737210110000071
catalyst VI:
Figure BDA0002737210110000072
catalyst VII:
Figure BDA0002737210110000073
catalyst IIX:
Figure BDA0002737210110000074
or catalyst IX:
Figure BDA0002737210110000075
preferably, the chiral catalyst is selected from catalysts I-II.
The general reaction formula of the chiral catalyst is shown as follows:
Figure BDA0002737210110000076
the preparation method of the chiral catalyst comprises the following steps:
s1, taking toluene as a solvent, taking chiral alpha-hydroxyphenylacetamide and 2,2, 6-trimethyl-1, 3-dioxin-4-ketone as reaction raw materials, wherein the molar ratio of the two is 1: (0.5-2), reacting to obtain chiral alpha-hydroxyphenylacetamide derivatives;
s2, at the temperature of 50-180 ℃, taking chiral alpha-hydroxyphenylacetamide derivatives, hexamethylenetetramine and ammonium acetate as reaction raw materials, wherein the molar ratio of the chiral alpha-hydroxyphenylacetamide derivatives to the hexamethylenetetramine to the ammonium acetate is 2: (0.5-2): (0.5-2) reacting for 2-24h to obtain the chiral catalyst.
In one embodiment, the molar ratio of the 1-phenyl-3, 4-dihydroisoquinoline to the chiral catalyst is 1:0.8 to 1: 1.5. It is understood that, in the present invention, the molar ratio of the 1-phenyl-3, 4-dihydroisoquinoline to the chiral catalyst can be set as, but is not limited to: 1:0.8, 1:0.82, 1:0.85, 1:0.88, 1:0.9, 1:0.92, 1:0.95, 1:0.98, 1:1.0, 1:1.05, 1:1.1, 1:1.12, 1:1.15, 1:1.18, 1:1.2, 1:1.21, 1:1.23, 1:1.25, 1:1.3, 1:1.38, 1:1.4, 1:1.45, 1:1.18, and 1: 1.5. Preferably, the molar ratio of the 1-phenyl-3, 4-dihydroisoquinoline to the chiral catalyst is 1: 1.0-1: 1.3.
In one embodiment, the acid is selected from at least one of trifluoroacetic acid, acetic acid, benzoic acid, sulfonic acid, hydrochloric acid, and phosphoric acid. Preferably, the acid is trifluoroacetic acid, acetic acid or phosphoric acid.
In one embodiment, the molar ratio of the 1-phenyl-3, 4-dihydroisoquinoline to the acid is 1:0.2 to 1: 0.6. It is understood that, in the present invention, the molar ratio of the 1-phenyl-3, 4-dihydroisoquinoline to the acid can be set as, but is not limited to: 1:0.2, 1:0.25, 1:0.28, 1:0.3, 1:0.31, 1:0.32, 1:0.333, 1:0.35, 1:0.38, 1:0.40, 1:0.45, 1:0.48, 1:0.5, 1:0.51, 1:0.55 and 1: 0.6. Preferably, the molar ratio of the 1-phenyl-3, 4-dihydroisoquinoline to the acid is 1:0.3 to 1: 0.4.
In one embodiment, the reaction temperature is 10-60 ℃ and the reaction time is 5-40 h.
In one preferable embodiment, the reaction temperature is 20-40 ℃ and the reaction time is 15-30 h.
In one embodiment, the solvent is at least one selected from chloroform, dichloromethane, toluene, tetrahydrofuran and acetonitrile, and preferably, the solvent is toluene, so that the reaction efficiency is high.
In one embodiment, after the reaction, the method further comprises the steps of extraction and concentration.
Preferably, the solvent used for quenching the reaction is water. The solvent used for the extraction was ethyl acetate.
Preferably, the method for synthesizing (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline according to the present invention comprises the following steps:
dissolving 1-phenyl-3, 4-dihydroisoquinoline, a chiral catalyst and trifluoroacetic acid in toluene, violently stirring at 30 ℃ for reaction for 24 hours, adding water for quenching reaction, and extracting with ethyl acetate. And concentrating the organic phase to obtain a white crude product.
In one embodiment, after the concentration, a refining step is further included.
Refining refers to the recrystallization purification operation of the crude product.
The following are specific examples.
Unless otherwise specified, the starting materials used in the present invention are all commercially available products.
Example 1
This example provides a method for synthesizing (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline, comprising the following steps:
(1) preparation of chiral catalyst I:
2,2, 6-trimethyl-1, 3-dioxin-4-one (142.2mg,1mmol) was added dropwise to a solution of (S) - α -hydroxy-N-methyl-2-phenylacetamide (165.1mg,1mmol) in toluene (0.5 mL). Reflux with stirring overnight, cool the reaction mixture to 50 ℃ and remove the solvent in vacuo. The crude product was isolated and purified by silica gel column chromatography (n-hexane: ethyl acetate in a volume ratio of 20: 1) to give 187.0mg of a white solid compound in a yield of 75%.
The above-mentioned white solid compound (498.6mg,2mmol), ammonium acetate (77.1mg,1mmol) and hexamethylenetetramine (140.2mg) were dissolved in 5mL of dioxane and reacted by heating at 100 ℃ for 30 minutes. Cooling to normal temperature, adding water, extracting with dichloromethane, and collecting organic phase. After the organic phase was concentrated, it was purified by silica gel column chromatography (n-hexane: ethyl acetate in a volume ratio of 10: 1) to obtain 368.7mg of pale yellow chiral catalyst I with a yield of 75%.
(2) Preparation of (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline:
dissolving 1-phenyl-3, 4-dihydroisoquinoline (1.0equiv), catalyst I (1.2equiv) and trifluoroacetic acid (0.3equiv) in 200mL of toluene, reacting at 30 ℃ with vigorous stirring for 24h, adding water to quench the reaction, extracting with ethyl acetate, and collecting an organic phase. The organic phase is concentrated to obtain a white crude product, and 185g of (S) -1-phenyl-1, 2,3, 4-tetrahydroquinoline product is obtained after recrystallization and refining, wherein the yield is 89%, the purity is 99.3%, and the chiral purity is 99.6%.
Example 2
This example is a method for synthesizing (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline, which has the same steps as example 1, except that: the chiral catalyst used was catalyst II.
(1) Preparing a chiral catalyst II:
2,2, 6-trimethyl-1, 3-dioxin-4-one (142.2mg,1mmol) was added dropwise to a solution of (S) - α -hydroxy-N-ethyl-2-phenylacetamide (179.2mg,1mmol) in toluene (0.5 mL). Reflux with stirring overnight, cool the reaction mixture to 50 ℃ and remove the solvent in vacuo. The crude product was isolated and purified by silica gel column chromatography (n-hexane: ethyl acetate in a volume ratio of 20: 1) to give 243.0mg of a white solid compound in a yield of 82%.
The above-mentioned white solid compound (526.6mg,2mmol), ammonium acetate (77.1mg,1mmol) and hexamethylenetetramine (140.2mg) were dissolved in 5mL of dioxane and reacted by heating at 100 ℃ for 30 minutes. Cooling to normal temperature, adding water, extracting with dichloromethane, and collecting organic phase. After the organic phase was concentrated, it was purified by silica gel column chromatography (n-hexane: ethyl acetate in a volume ratio of 10: 1) to obtain 426.1mg of pale yellow chiral catalyst II with a yield of 82%.
(2) Preparation of (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline:
dissolving 1-phenyl-3, 4-dihydroisoquinoline (1.0equiv), catalyst II (1.2equiv) and trifluoroacetic acid (0.3equiv) in 200mL of toluene, reacting at 30 ℃ with vigorous stirring for 24h, adding water to quench the reaction, extracting with ethyl acetate, and collecting an organic phase. The organic phase was concentrated to obtain a white crude product, which was recrystallized to obtain 176g of (S) -1-phenyl-1, 2,3, 4-tetrahydroquinoline with a yield of 85%, a purity of 98.5% and a chiral purity of 99.0%.
Example 3
This example is a method for synthesizing (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline, which has the same steps as example 1, except that: the molar ratio of the 1-phenyl-3, 4-dihydroisoquinoline to the chiral catalyst is different.
(1) Preparation of chiral catalyst I:
2,2, 6-trimethyl-1, 3-dioxin-4-one (142.2mg,1mmol) was added dropwise to a solution of (S) - α -hydroxy-N-methyl-2-phenylacetamide (165.1mg,1mmol) in toluene (0.5 mL). Reflux with stirring overnight, cool the reaction mixture to 50 ℃ and remove the solvent in vacuo. The crude product was isolated and purified by silica gel column chromatography (n-hexane: ethyl acetate in a volume ratio of 20: 1) to give 187.0mg of a white solid compound in a yield of 75%.
The above-mentioned white solid compound (498.6mg,2mmol), ammonium acetate (77.1mg,1mmol) and hexamethylenetetramine (140.2mg) were dissolved in 5mL of dioxane and reacted by heating at 100 ℃ for 30 minutes. Cooling to normal temperature, adding water, extracting with dichloromethane, and collecting organic phase. After the organic phase was concentrated, it was purified by silica gel column chromatography (n-hexane: ethyl acetate in a volume ratio of 10: 1) to obtain 368.7mg of pale yellow chiral catalyst I with a yield of 75%.
(2) Preparation of (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline:
dissolving 1-phenyl-3, 4-dihydroisoquinoline (1.0equiv), catalyst I (1.0equiv) and trifluoroacetic acid (0.3equiv) in 200mL of toluene, reacting at 30 ℃ for 24h under vigorous stirring, adding water to quench the reaction, extracting with ethyl acetate, and collecting an organic phase. The organic phase is concentrated to obtain a white crude product, and the white crude product is recrystallized and refined to obtain 181g of (S) -1-phenyl-1, 2,3, 4-tetrahydroquinoline product with the yield of 87 percent, the purity of 99.2 percent and the chiral purity of 99 percent.
Example 4
This example is a method for synthesizing (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline, which has the same steps as example 1, except that: the molar ratio of the 1-phenyl-3, 4-dihydroisoquinoline to the chiral catalyst is different.
(1) Preparation of chiral catalyst I:
2,2, 6-trimethyl-1, 3-dioxin-4-one (142.2mg,1mmol) was added dropwise to a solution of (S) - α -hydroxy-N-methyl-2-phenylacetamide (165.1mg,1mmol) in toluene (0.5 mL). Reflux with stirring overnight, cool the reaction mixture to 50 ℃ and remove the solvent in vacuo. The crude product was isolated and purified by silica gel column chromatography (n-hexane: ethyl acetate in a volume ratio of 20: 1) to give 187.0mg of a white solid compound in a yield of 75%.
The above-mentioned white solid compound (498.6mg,2mmol), ammonium acetate (77.1mg,1mmol) and hexamethylenetetramine (140.2mg) were dissolved in 5mL of dioxane and reacted by heating at 100 ℃ for 30 minutes. Cooling to normal temperature, adding water, extracting with dichloromethane, and collecting organic phase. After the organic phase was concentrated, it was purified by silica gel column chromatography (n-hexane: ethyl acetate in a volume ratio of 10: 1) to obtain 368.7mg of pale yellow chiral catalyst I with a yield of 75%.
(2) Preparation of (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline:
dissolving 1-phenyl-3, 4-dihydroisoquinoline (1.0equiv), catalyst I (1.3equiv) and trifluoroacetic acid (0.3equiv) in 200mL of toluene, reacting at 30 ℃ with vigorous stirring for 24h, adding water to quench the reaction, extracting with ethyl acetate, and collecting an organic phase. The organic phase is concentrated to obtain a white crude product, and 183g of (S) -1-phenyl-1, 2,3, 4-tetrahydroquinoline product is obtained after recrystallization and refining, wherein the yield is 88%, the purity is 99.2%, and the chiral purity is 99%.
Example 5
This example is a method for synthesizing (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline, which has the same steps as example 1, except that: the molar ratio of 1-phenyl-3, 4-dihydroisoquinoline to acid is different.
(1) Preparation of chiral catalyst I:
2,2, 6-trimethyl-1, 3-dioxin-4-one (142.2mg,1mmol) was added dropwise to a solution of (S) - α -hydroxy-N-methyl-2-phenylacetamide (165.1mg,1mmol) in toluene (0.5 mL). Reflux with stirring overnight, cool the reaction mixture to 50 ℃ and remove the solvent in vacuo. The crude product was isolated and purified by silica gel column chromatography (n-hexane: ethyl acetate in a volume ratio of 20: 1) to give 187.0mg of a white solid compound in a yield of 75%.
The above-mentioned white solid compound (498.6mg,2mmol), ammonium acetate (77.1mg,1mmol) and hexamethylenetetramine (140.2mg) were dissolved in 5mL of dioxane and reacted by heating at 100 ℃ for 30 minutes. Cooling to normal temperature, adding water, extracting with dichloromethane, and collecting organic phase. After the organic phase was concentrated, it was purified by silica gel column chromatography (n-hexane: ethyl acetate in a volume ratio of 10: 1) to obtain 368.7mg of pale yellow chiral catalyst I with a yield of 75%.
(2) Preparation of (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline:
dissolving 1-phenyl-3, 4-dihydroisoquinoline (1.0equiv), catalyst I (1.2equiv) and trifluoroacetic acid (0.2equiv) in 200mL of toluene, reacting at 30 ℃ with vigorous stirring for 24h, adding water to quench the reaction, extracting with ethyl acetate, and collecting an organic phase. The organic phase was concentrated to obtain a white crude product, which was recrystallized to obtain 170.4g of (S) -1-phenyl-1, 2,3, 4-tetrahydroquinoline product with a yield of 82%, a purity of 98.7% and a chiral purity of 98.9%.
Example 6
This example is a method for synthesizing (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline, which has the same steps as example 2, except that: the kind of acid is different.
(1) Preparing a chiral catalyst II:
2,2, 6-trimethyl-1, 3-dioxin-4-one (142.2mg,1mmol) was added dropwise to a solution of (S) - α -hydroxy-N-ethyl-2-phenylacetamide (179.2mg,1mmol) in toluene (0.5 mL). Reflux with stirring overnight, cool the reaction mixture to 50 ℃ and remove the solvent in vacuo. The crude product was isolated and purified by silica gel column chromatography (n-hexane: ethyl acetate in a volume ratio of 20: 1) to give 243.0mg of a white solid compound in a yield of 82%.
The above-mentioned white solid compound (526.6mg,2mmol), ammonium acetate (77.1mg,1mmol) and hexamethylenetetramine (140.2mg) were dissolved in 5mL of dioxane and reacted by heating at 100 ℃ for 30 minutes. Cooling to normal temperature, adding water, extracting with dichloromethane, and collecting organic phase. After the organic phase was concentrated, it was purified by silica gel column chromatography (n-hexane: ethyl acetate in a volume ratio of 10: 1) to obtain 426.1mg of pale yellow chiral catalyst II with a yield of 82%.
(2) Preparation of (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline:
dissolving 1-phenyl-3, 4-dihydroisoquinoline (1.0equiv), catalyst V (1.2equiv) and phosphoric acid (0.3equiv) in 200mL of toluene, reacting at 30 ℃ under vigorous stirring for 24h, adding water to quench the reaction, extracting with ethyl acetate, and collecting an organic phase. The organic phase was concentrated to obtain a white crude product, which was recrystallized to obtain 174.6g of (S) -1-phenyl-1, 2,3, 4-tetrahydroquinoline product with a yield of 84%, a purity of 98.3% and a chiral purity of 98.5%.
Example 7
This example is a method for synthesizing (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline, which has the same steps as example 2, except that: the kind of acid is different.
(1) Preparing a chiral catalyst II:
2,2, 6-trimethyl-1, 3-dioxin-4-one (142.2mg,1mmol) was added dropwise to a solution of (S) - α -hydroxy-N-ethyl-2-phenylacetamide (179.2mg,1mmol) in toluene (0.5 mL). Reflux with stirring overnight, cool the reaction mixture to 50 ℃ and remove the solvent in vacuo. The crude product was isolated and purified by silica gel column chromatography (n-hexane: ethyl acetate in a volume ratio of 20: 1) to give 243.0mg of a white solid compound in a yield of 82%.
The above-mentioned white solid compound (526.6mg,2mmol), ammonium acetate (77.1mg,1mmol) and hexamethylenetetramine (140.2mg) were dissolved in 5mL of dioxane and reacted by heating at 100 ℃ for 30 minutes. Cooling to normal temperature, adding water, extracting with dichloromethane, and collecting organic phase. After the organic phase was concentrated, it was purified by silica gel column chromatography (n-hexane: ethyl acetate in a volume ratio of 10: 1) to obtain 426.1mg of pale yellow chiral catalyst II with a yield of 82%.
(2) Preparation of (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline:
dissolving 1-phenyl-3, 4-dihydroisoquinoline (1.0equiv), catalyst V (1.2equiv) and acetic acid (0.3equiv) in 200mL of toluene, reacting at 30 ℃ under vigorous stirring for 24h, adding water to quench the reaction, extracting with ethyl acetate, and collecting an organic phase. The organic phase is concentrated to obtain a white crude product, and the white crude product is recrystallized and refined to obtain 176.6g of (S) -1-phenyl-1, 2,3, 4-tetrahydroquinoline product, wherein the yield is 85%, the purity is 98.6%, and the chiral purity is 99%.
Example 8
This embodiment provides a method for synthesizing (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline, which includes the following steps:
(1) preparation of chiral catalyst III:
2,2, 6-trimethyl-1, 3-dioxin-4-one (142.2mg,1mmol) was added dropwise to a solution of (S) - α -hydroxy-N-isopropyl-2-phenylacetamide (193.2mg,1mmol) in toluene (0.5 mL). Reflux with stirring overnight, cool the reaction mixture to 50 ℃ and remove the solvent in vacuo. The crude product was isolated and purified by silica gel column chromatography (n-hexane: ethyl acetate in a volume ratio of 20: 1) to give 221.9mg of a white solid compound in a yield of 80%.
The above-mentioned white solid compound (554.2mg,2mmol), ammonium acetate (77.1mg,1mmol) and hexamethylenetetramine (140.2mg) were dissolved in 5mL of dioxane and reacted by heating at 100 ℃ for 30 minutes. Cooling to normal temperature, adding water, extracting with dichloromethane, and collecting organic phase. After the organic phase was concentrated, it was purified by silica gel column chromatography (n-hexane: ethyl acetate in a volume ratio of 10: 1) to obtain 431.1mg of pale yellow chiral catalyst III with a yield of 81%.
(2) Preparation of (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline:
dissolving 1-phenyl-3, 4-dihydroisoquinoline (1.0equiv), catalyst III (1.2equiv) and hydrochloric acid (0.5equiv) in 200mL of dichloromethane, reacting at 20 ℃ with vigorous stirring for 15h, adding water to quench the reaction, extracting with ethyl acetate, and collecting an organic phase. The organic phase was concentrated to obtain a white crude product, which was refined by recrystallization to obtain 155.8g of (S) -1-phenyl-1, 2,3, 4-tetrahydroquinoline product with a yield of 75%, a purity of 97%, and a chiral purity of 98%.
Example 9
This embodiment provides a method for synthesizing (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline, which includes the following steps:
dissolving 1-phenyl-3, 4-dihydroisoquinoline (1.0equiv), catalyst II (0.8equiv) and trifluoroacetic acid (0.2equiv) in 200mL of tetrahydrofuran, reacting at 55 ℃ with vigorous stirring for 15h, adding water to quench the reaction, extracting with ethyl acetate, and collecting an organic phase. The organic phase was concentrated to obtain a white crude product, which was recrystallized to obtain 149.7g of (S) -1-phenyl-1, 2,3, 4-tetrahydroquinoline product with a yield of 72%, a purity of 97%, and a chiral purity of 98%.
Comparative example 1
This comparative example provides a synthesis method of (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline, the steps are the same as example 1, except that: the structural formula of the adopted chiral catalyst is shown as a formula (II).
Figure BDA0002737210110000161
The method comprises the following specific steps:
this example provides a method for synthesizing (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline, comprising the following steps:
dissolving 1-phenyl-3, 4-dihydroisoquinoline (1.0equiv), a catalyst (1.2equiv) shown in a formula (II) and trifluoroacetic acid (0.3equiv) in 200mL of toluene, vigorously stirring for reaction at 30 ℃ for 24h, adding water for quenching reaction, extracting with ethyl acetate, and collecting an organic phase. After the organic phase was concentrated, the (S) -1-phenyl-1, 2,3, 4-tetrahydroquinoline product could not be obtained in 0% yield.
Comparative example 2
This comparative example provides a synthesis method of (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline, the steps are the same as example 1, except that: the structural formula of the adopted chiral catalyst is shown as a formula (III).
Figure BDA0002737210110000162
The method comprises the following specific steps:
this example provides a method for synthesizing (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline, comprising the following steps:
dissolving 1-phenyl-3, 4-dihydroisoquinoline (1.0equiv), a catalyst (1.2equiv) shown in a formula (III) and trifluoroacetic acid (0.3equiv) in 200mL of toluene, violently stirring at 30 ℃ for reacting for 24h, adding water for quenching reaction, extracting with ethyl acetate, and collecting an organic phase. After the organic phase was concentrated, the (S) -1-phenyl-1, 2,3, 4-tetrahydroquinoline product could not be obtained in 0% yield.
Comparative example 3
This comparative example provides a synthesis method of (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline, the steps are the same as example 1, except that: trifluoroacetic acid was omitted. The method comprises the following specific steps:
dissolving 1-phenyl-3, 4-dihydroisoquinoline (1.0equiv) and catalyst I (1.2equiv) in 200mL of toluene, reacting at 30 ℃ with vigorous stirring for 24h, adding water to quench the reaction, extracting with ethyl acetate, and collecting the organic phase. The organic phase is concentrated to obtain a white crude product, and the white crude product is recrystallized and refined to obtain 99.8g of (S) -1-phenyl-1, 2,3, 4-tetrahydroquinoline product with the yield of 48 percent, the purity of 86 percent and the chiral purity of 92 percent.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.

Claims (10)

1. A synthetic method of (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline is characterized by comprising the following steps:
mixing 1-phenyl-3, 4-dihydroisoquinoline, a chiral catalyst, an acid and a solvent for reaction;
the structural formula of the chiral catalyst is shown as the formula (I):
Figure FDA0002737210100000011
r is selected from a hydrogen atom, a straight chain alkyl group having 1 to 20 carbon atoms, a branched alkyl group having 3 to 20 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, a heterocyclic group having 3 to 10 ring atoms, an alkoxy group having 1 to 20 carbon atoms, a trifluoromethyl group, a halogen, an amino group, a cyano group, a hydroxyl group, a nitro group, an ester group, an amide group, a substituted or unsubstituted aryl group having 6 to 20 ring atoms, and a substituted or unsubstituted heteroaryl group having 5 to 20 ring atoms.
2. The method for synthesizing (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline according to claim 1, wherein the molar ratio of the 1-phenyl-3, 4-dihydroisoquinoline to the chiral catalyst is 1:0.8 to 1: 1.5.
3. The method for synthesizing (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline according to claim 1, wherein the molar ratio of the 1-phenyl-3, 4-dihydroisoquinoline to the chiral catalyst is 1:1.0 to 1: 1.3.
4. The method for synthesizing (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline according to claim 1, wherein the acid is at least one selected from trifluoroacetic acid, acetic acid, benzoic acid, sulfonic acid, hydrochloric acid, and phosphoric acid.
5. The method for synthesizing (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline according to claim 4, wherein the molar ratio of the 1-phenyl-3, 4-dihydroisoquinoline to the acid is 1:0.2 to 1: 0.6.
6. The method for synthesizing (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline according to any one of claims 1 to 5, wherein the reaction temperature is 10 to 60 ℃ and the reaction time is 5 to 40 hours.
7. The method for synthesizing (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline according to any one of claims 1 to 5, wherein the solvent is at least one selected from the group consisting of chloroform, dichloromethane, toluene, tetrahydrofuran and acetonitrile.
8. The method for synthesizing (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline according to any one of claims 1 to 5, wherein R is selected from a hydrogen atom, a straight-chain alkyl group having 1 to 12 carbon atoms, a straight-chain alkyl group having 3 to 7 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, a straight-chain alkoxy group having 1 to 6 carbon atoms, an isopropoxy group, a tert-butoxy group, an amino group, a cyano group, a hydroxyl group, and a substituted or unsubstituted phenyl group.
9. The method for synthesizing (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline according to claim 8, wherein R is selected from a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a cyclopropyl group, a cyclohexyl group, a methoxy group, an ethoxy group, an isopropoxy group, a tert-butoxy group, an amino group, a cyano group, a hydroxyl group, a phenyl group, a pyridyl group, a benzyl group, or a trifluoromethyl group.
10. The method for synthesizing (S) -1-phenyl-1, 2,3, 4-tetrahydroisoquinoline according to any one of claims 1 to 5, further comprising the steps of extraction, concentration, and purification after the completion of the reaction.
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CN110683986A (en) * 2019-11-04 2020-01-14 中山奕安泰医药科技有限公司 Synthesis method of (S) 1-phenyl-1, 2,3, 4-tetrahydroisoquinoline

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103214493A (en) * 2013-05-10 2013-07-24 南京友杰医药科技有限公司 Method for generating narcotine by selective reduction utilizing chiral boron catalyst
CN109824652A (en) * 2019-03-04 2019-05-31 广西九圣新材料有限公司 A kind of Isosorbide-5-Nitrae-dihydropyridines difunctionality chiral catalyst and its preparation method and application
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