CN111233601A - Chiral resolution method of aryl halogen compound - Google Patents

Chiral resolution method of aryl halogen compound Download PDF

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CN111233601A
CN111233601A CN202010172925.XA CN202010172925A CN111233601A CN 111233601 A CN111233601 A CN 111233601A CN 202010172925 A CN202010172925 A CN 202010172925A CN 111233601 A CN111233601 A CN 111233601A
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methyl
furo
bromophenyl
dihydro
pyrrol
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陶鑫
韩加齐
史鹤峰
季翔
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CHANGZHOU YINSHENG PHARMACEUTICAL CO LTD
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B57/00—Separation of optically-active compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • 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

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Abstract

The invention relates to a chiral resolution method of an aryl halogen compound, which successfully resolves an R-S type isomer and an S-S type isomer without using an expensive SFC preparation column for separation, and has the advantages of simple operation, convenient industrial amplification and low cost by utilizing the solubility difference of the R-S type isomer and ((S) -1- ((S) -2- (6- (4-bromophenyl) -3, 5-dihydro-1H-furo [3, 4-c ] pyrrol-4-yl) pyrrolidine-1-yl) -3 methyl-1-oxobutane-2-yl) methyl carbamate of the S-S type isomer in ethyl acetate; the resolved S-S isomer of ((S) -1- ((S) -2- (6- (4-bromophenyl) -3, 5-dihydro-1H-furo [3, 4-c ] pyrrol-4-yl) pyrrolidine-1-yl) -3 methyl-1-oxobutane-2-yl) methyl carbamate is purified by a methanol recrystallization mode, the operation is simple, and the content and chiral purity of the obtained product can reach more than 99.5 percent.

Description

Chiral resolution method of aryl halogen compound
Technical Field
The invention relates to resolution of chiral isomers of a pharmaceutical compound, in particular to a chiral resolution method of an aryl halogen compound.
Background
The fubitasvir is a novel HCV NS5A inhibitor, and the main action mechanism of the fubitasvir is to prevent HCV replication by inhibiting NS5A protein so as to achieve the effect of treating chronic hepatitis C. The fubitasvir is prepared by Suzuki coupling reaction of an organic boric acid (ester) compound and an aryl halogen compound, wherein the aryl halogen compound is ((S) -1- ((S) -2- (6- (4-bromophenyl) -3, 5-dihydro-1H-furo [3, 4-c ] pyrrol-4-yl) pyrrolidin-1-yl) -3-methyl-1-oxobutan-2-yl) carbamic acid methyl ester, and the structural formula is as follows:
Figure BDA0002409825350000011
the aryl halogen compound has two isomers which are respectively R-S type and S-S type, wherein the R-S type is impurity isomer, in the prior art, the impurity isomer is removed mainly by SFC preparation column separation, and the separation method is only used in a small amount of laboratory research stages and cannot be amplified to batch production; therefore, designing a chiral resolution method of ((S) -1- ((S) -2- (6- (4-bromophenyl) -3, 5-dihydro-1H-furo [3, 4-c ] pyrrol-4-yl) pyrrolidin-1-yl) -3 methyl-1-oxobutan-2-yl) methyl carbamate, which is low in cost and easy to implement, is a technical problem which needs to be solved by the technical personnel in the field.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a chiral resolution method of an aryl halogen compound, which has simple process flow and low cost.
In order to solve the above technical problems, the present invention provides a chiral resolution method of aryl halogen compound, wherein the aryl halogen compound is ((S) -1- ((S) -2- (6- (4-bromophenyl) -3, 5-dihydro-1H-furo [3, 4-c ] pyrrol-4-yl) pyrrolidin-1-yl) -3-methyl-1-oxobutan-2-yl) carbamic acid methyl ester, and ((S) -1- ((S) -2- (6- (4-bromophenyl) -3, 5-dihydro-1H-furo [3, 4-c ] pyrrol-4-yl) pyrrolidin-1-yl) -3-methyl-1-yl) containing R-S type isomer and S-S type isomer Oxobutan-2-yl) carbamic acid methyl ester is slurried with an ethyl acetate solution and left to stand for not less than 12 hours, wherein ((S) -1- ((S) -2- (6- (4-bromophenyl) -3, 5-dihydro-1H-furo [3, 4-c ] pyrrol-4-yl) pyrrolidin-1-yl) -3 methyl-1-oxobutan-2-yl) carbamic acid methyl ester of the S-S isomer is dissolved in the ethyl acetate solution, and ((S) -1- ((S) -2- (6- (4-bromophenyl) -3, 5-dihydro-1H-furo [3, 4-c ] pyrrol-4-yl) pyrrolidin-1-yl) -3 methyl Methyl 1-oxobutan-2-yl) carbamate is insoluble in ethyl acetate solution, and filtration is carried out to obtain a cake of solid methyl ((S) -1- ((S) -2- (6- (4-bromophenyl) -3, 5-dihydro-1H-furo [3, 4-c ] pyrrol-4-yl) pyrrolidin-1-yl) -3-methyl-1-oxobutan-2-yl) carbamate of R-S isomer and a filtrate of ((S) -1- ((S) -2- (6- (4-bromophenyl) -3, 5-dihydro-1H-furo [3, 4-c ] pyrrol-4-yl) pyrrolidin-1-yl) -3 methyl-1-oxobutan-2-yl carbamate solution, the filtrate is concentrated to give a crude product, which is recrystallized from methanol to give methyl ((S) -1- ((S) -2- (6- (4-bromophenyl) -3, 5-dihydro-1H-furo [3, 4-c ] pyrrol-4-yl) pyrrolidin-1-yl) -3 methyl-1-oxobutan-2-yl) carbamate as S-S isomer.
Further, the aryl halogen compound methyl ((S) -1- ((S) -2- (6- (4-bromophenyl) -3, 5-dihydro-1H-furo [3, 4-c ] pyrrol-4-yl) pyrrolidin-1-yl) -3 methyl-1-oxobutan-2-yl) carbamate is prepared from compound II and compound III, the chemical reaction formula of which is formula I:
Figure BDA0002409825350000021
wherein the mol ratio of the compound II to the compound III is 1: 1, in the reaction, Moc-L-valine serving as a compound III, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride serving as a condensing agent and 1-hydroxybenzotriazole serving as a catalyst are dissolved in dichloromethane, a compound II is added at normal temperature, the reaction liquid is cooled to 0-5 ℃, N-diisopropylethylamine serving as an acid-binding agent is added, the reaction liquid is stirred at room temperature for 12 hours, after the reaction is detected to be complete, the reaction liquid is diluted by dichloromethane and water, the pH value is adjusted to 4-5 by diluted hydrochloric acid, an organic phase and an aqueous phase are separated, the aqueous phase is extracted by dichloromethane for multiple times to obtain an organic phase again, the obtained organic phases are combined, the organic phases are washed by saturated sodium bicarbonate solution and salt water for multiple times and are dried by anhydrous sodium sulfate, and then a drying agent is removed after filtration, concentrating under reduced pressure to obtain crude oily matter, namely ((S) -1- ((S) -2- (6- (4-bromophenyl) -3, 5-dihydro-1H-furo [3, 4-c ] pyrrol-4-yl) pyrrolidine-1-yl) -3 methyl-1-oxobutane-2-yl) carbamic acid methyl ester containing R-S type isomer and S-S type isomer.
Further, the mol ratio of the added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole and Moc-L-valine was 1.2:0.2: 1.
Further, the obtained aqueous phase was extracted at least 3 times with dichloromethane to obtain a residual organic phase, ensuring the extraction effect.
Further, the organic phases obtained were combined and washed at least 2 times with saturated sodium bicarbonate solution and at least 2 times with brine.
The invention has the technical effects that: compared with the prior art, the chiral resolution method of the aryl halogen compound successfully resolves the R-S type isomer and the S-S type isomer by utilizing the solubility difference of ((S) -1- ((S) -2- (6- (4-bromophenyl) -3, 5-dihydro-1H-furo [3, 4-c ] pyrrole-4-yl) pyrrolidine-1-yl) -3 methyl-1-oxobutane-2-yl) methyl carbamate of the R-S type isomer and the S-S type isomer in ethyl acetate, does not need to use an SFC preparation column with high cost for separation, and has the advantages of simple operation, convenient industrial amplification and low cost; the resolved S-S isomer of ((S) -1- ((S) -2- (6- (4-bromophenyl) -3, 5-dihydro-1H-furo [3, 4-c ] pyrrol-4-yl) pyrrolidine-1-yl) -3 methyl-1-oxobutane-2-yl) methyl carbamate is purified by a methanol recrystallization mode, the operation is simple, and the content and chiral purity of the obtained product can reach more than 99.5 percent.
Detailed Description
To further illustrate the present invention, some specific embodiments are described below, and some implementation methods of the present invention are described in conjunction with specific operation procedures.
Example 1
As the original chiral resolution process of the aryl halogen compound adopts SFC preparation column separation, the separation method is only used in a small amount of laboratory research stages and cannot be amplified to production, and therefore, a new separation and purification method needs to be tried and developed; the product was attempted to react chemically with various resolving agents and then isolated, the data are shown in table 1:
TABLE 1 results of different resolution reagents
Experiment number Resolution reagent Splitting results
1 (+) -tartaric acid Can not be separated
2 (+) -camphoric acid Can not be separated
3 (+) -Glycine Can not be separated
4 Isopropanol (I-propanol) Can be separated, and has chiral purity (ee% value) of 85%
5 Ethyl acetate Can be separated, and has chiral purity (ee% value) of 99.5%
As can be seen from the above table data, the conventional acidic resolving agent cannot achieve the resolving effect, and the R-S isomer impurities and the S-S product cannot be separated by using the acidic resolving agent; although isopropanol can realize separation, the separation purity is low, the ee value of chiral purity is only about 85%, and the requirement of mass production cannot be met; the R-S isomer impurity and the S-S product can be dissolved and separated only by adopting ethyl acetate.
Specifically, the chiral resolution method of the aryl halogen compound is that ((S) -1- ((S) -2- (6- (4-bromophenyl) -3, 5-dihydro-1H-furo [3, 4-c ] pyrrol-4-yl) pyrrolidin-1-yl) -3 methyl-1-oxobutan-2-yl) carbamic acid methyl ester, and the ((S) -1- ((S) -2- (6- (4-bromophenyl) -3, 5-dihydro-1H-furo [3, 4-c ] pyrrol-4-yl) pyrrolidin-1-yl) -3 methyl-1-oxobutan-2-yl) carbamic acid methyl ester is prepared from a compound II and a compound III, the chemical reaction formula is as follows:
Figure BDA0002409825350000041
using Moc-L-valine with the weight of 105.14g and 600.2mmol as a compound III, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride with the weight of 138.07g and 720.24mmol as a condensing agent, 1-hydroxybenzotriazole with the weight of 16.22g and 120.04mmol as a catalyst to dissolve in 4000mL of dichloromethane, adding 200g and 600.2mmol of a compound II at normal temperature, cooling the reaction solution to 0-5 ℃, adding 232.71g and 1.8mol of N, N-diisopropylethylamine as an acid binding agent, stirring at room temperature for 12 hours, detecting the reaction completion, diluting the reaction solution with 4000mL of dichloromethane and 4000mL of water, adjusting the pH value of the reaction solution to 4-5 with diluted hydrochloric acid with the density of 1mol/L, and separating an organic phase and an aqueous phase, extracting the separated water phase with 2000mL of dichloromethane to obtain an organic phase, repeatedly extracting for 3 times, wherein 2000mL of dichloromethane is used each time, combining the organic phase obtained by extraction with the organic phase obtained after reaction, washing the combined organic phase with 2000mL of saturated sodium bicarbonate solution, and repeatedly washing for 2 times; washing the combined organic phase with 2000mL of saline solution, repeating the washing for 2 times, and drying the organic phase with anhydrous sodium sulfate to remove water; the drying agent anhydrous sodium sulfate was removed by filtration, and the crude product was concentrated under reduced pressure to obtain 250g of crude oily substance, i.e., ((S) -1- ((S) -2- (6- (4-bromophenyl) -3, 5-dihydro-1H-furo [3, 4-c ] pyrrol-4-yl) pyrrolidin-1-yl) -3-methyl-1-oxobutan-2-yl) carbamic acid methyl ester containing R-S isomer and S-S isomer.
Adding methyl ((S) -1- ((S) -2- (6- (4-bromophenyl) -3, 5-dihydro-1H-furo [3, 4-c ] pyrrol-4-yl) pyrrolidin-1-yl) -3 methyl-1-oxobutan-2-yl) carbamate containing R-S type isomer and S-S type isomer to the ethyl acetate solution for beating and standing for not less than 12 hours, wherein ((S) -1- ((S) -2- (6- (4-bromophenyl) -3, 5-dihydro-1H-furo [3, 4-c ] pyrrol-4-yl) pyrrolidin-1-yl) -3 methyl-1-oxobutan- Dissolving methyl 2-yl) carbamate in ethyl acetate solution, and dissolving methyl ((S) -1- ((S) -2- (6- (4-bromophenyl) -3, 5-dihydro-1H-furo [3, 4-c ] pyrrol-4-yl) pyrrolidin-1-yl) -3 methyl-1-oxobutan-2-yl) carbamate of R-S type isomer in ethyl acetate solution, filtering to obtain filter cake and filtrate, wherein the filter cake is solid ((S) -1- ((S) -2- (6- (4-bromophenyl) -3, 5-dihydro-1H-furo [3, 4-c ] pyrrol-4-yl) pyrrolidin-1-yl) -3 methyl -1-oxobutan-2-yl) carbamic acid methyl ester, the filtrate obtained is a solution of ((S) -1- ((S) -2- (6- (4-bromophenyl) -3, 5-dihydro-1H-furo [3, 4-c ] pyrrol-4-yl) pyrrolidin-1-yl) -3-methyl-1-oxobutan-2-yl) carbamic acid methyl ester of the S-S isomer, the filtrate is concentrated to give a crude product, which is recrystallized from methanol to give ((S) -1- ((S) -2- (6- (4-bromophenyl) -3, 5-dihydro-1H-furo [ 3), 4-c ] pyrrol-4-yl) pyrrolidin-1-yl) -3 methyl-1-oxobutan-2-yl) carbamic acid methyl ester. The reaction formula is shown as formula III:
Figure BDA0002409825350000061
the chiral resolution of the aryl halogen compounds of R-S type and S-S type isomers by adopting ethyl acetate has obvious advantages compared with the separation by adopting an SFC preparation column method, and the resolution yield and the resolution effect are both obviously improved, which is shown in table 2.
TABLE 2 comparison of the results of chiral resolution of ethyl acetate and separation in SFC preparative column
Figure BDA0002409825350000062
It should be understood that the above examples are only for clearly illustrating the present invention and are not intended to limit the embodiments of the present invention. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. And such obvious variations or modifications which fall within the spirit of the invention are intended to be covered by the scope of the present invention.

Claims (5)

1. A chiral resolution method of aryl halogen compound is characterized in that the aryl halogen compound is ((S) -1- ((S) -2- (6- (4-bromophenyl) -3, 5-dihydro-1H-furo [3, 4-c ] pyrrol-4-yl) pyrrolidin-1-yl) -3 methyl-1-oxobutane-2-yl) carbamic acid methyl ester, and ((S) -1- ((S) -2- (6- (4-bromophenyl) -3, 5-dihydro-1H-furo [3, 4-c ] pyrrol-4-yl) pyrrolidin-1-yl) -3 methyl-1-oxobutane-containing R-S type isomer and S-S type isomer Adding methyl 2-yl) carbamate into ethyl acetate solution, pulping and standing for not less than 12 hours, wherein methyl ((S) -1- ((S) -2- (6- (4-bromophenyl) -3, 5-dihydro-1H-furo [3, 4-c ] pyrrol-4-yl) pyrrolidin-1-yl) -3 methyl-1-oxobutan-2-yl) carbamate of S-type isomer is dissolved in ethyl acetate solution, and ((S) -1- ((S) -2- (6- (4-bromophenyl) -3, 5-dihydro-1H-furo [3, 4-c ] pyrrol-4-yl) pyrrolidin-1-yl) -3 methyl-1-yl) pyrrolidin-1-yl) of R-S type isomer is dissolved in ethyl acetate solution -oxobutan-2-yl) carbamic acid methyl ester is insoluble in ethyl acetate solution, and filtration is carried out to obtain a cake which is solid ((S) -1- ((S) -2- (6- (4-bromophenyl) -3, 5-dihydro-1H-furo [3, 4-c ] pyrrol-4-yl) pyrrolidin-1-yl) -3 methyl-1-oxobutan-2-yl) carbamic acid methyl ester of the R-S isomer and a filtrate which is ((S) -1- ((S) -2- (6- (4-bromophenyl) -3, 5-dihydro-1H-furo [3, 4-c ] pyrrol-4-yl) pyrrolidin-1-yl) -3 methyl-1-oxobutan-2-yl carbamate solution, the filtrate is concentrated to give a crude product, which is recrystallized from methanol to give methyl ((S) -1- ((S) -2- (6- (4-bromophenyl) -3, 5-dihydro-1H-furo [3, 4-c ] pyrrol-4-yl) pyrrolidin-1-yl) -3 methyl-1-oxobutan-2-yl) carbamate as S-S isomer.
2. The process for chiral resolution of aryl halogen compounds according to claim 1, wherein said aryl halogen compound methyl ((S) -1- ((S) -2- (6- (4-bromophenyl) -3, 5-dihydro-1H-furo [3, 4-c ] pyrrol-4-yl) pyrrolidin-1-yl) -3-methyl-1-oxobutan-2-yl) carbamate is prepared from compound II and compound III, the chemical reaction formula of which is as shown in formula I:
Figure DEST_PATH_IMAGE002
(formula I) is shown in the specification,
wherein the mol ratio of the compound II to the compound III is 1: 1, in the reaction, Moc-L-valine serving as a compound III, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride serving as a condensing agent and 1-hydroxybenzotriazole serving as a catalyst are dissolved in dichloromethane, a compound II is added at normal temperature, the reaction liquid is cooled to 0-5 ℃, N-diisopropylethylamine serving as an acid-binding agent is added, the reaction liquid is stirred at room temperature for 12 hours, after the reaction is detected to be complete, the reaction liquid is diluted by dichloromethane and water, the pH value is adjusted to 4-5 by diluted hydrochloric acid, an organic phase and an aqueous phase are separated, the aqueous phase is extracted by dichloromethane for multiple times to obtain an organic phase again, the obtained organic phases are combined, the organic phases are washed by saturated sodium bicarbonate solution and salt water for multiple times and are dried by anhydrous sodium sulfate, and then a drying agent is removed after filtration, concentrating under reduced pressure to obtain crude oily matter, namely ((S) -1- ((S) -2- (6- (4-bromophenyl) -3, 5-dihydro-1H-furo [3, 4-c ] pyrrol-4-yl) pyrrolidine-1-yl) -3 methyl-1-oxobutane-2-yl) carbamic acid methyl ester containing R-S type isomer and S-S type isomer.
3. The method for chiral resolution of aryl halogen compounds according to claim 2, wherein the mol ratio of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole and Moc-L-valine added is 1.2:0.2: 1.
4. The process for chiral resolution of aryl halogen compounds according to claim 2 or 3, characterized in that the obtained aqueous phase is extracted at least 3 times with dichloromethane to obtain a residual organic phase.
5. The process for chiral resolution of aryl halogen compounds according to claim 4, wherein the combined organic phases are washed at least 2 times with saturated sodium bicarbonate solution and at least 2 times with brine.
CN202010172925.XA 2019-12-24 2020-03-13 Chiral resolution method of aryl halogen compound Pending CN111233601A (en)

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