CN117430540A - Pyrrolidine compound and preparation method thereof - Google Patents

Pyrrolidine compound and preparation method thereof Download PDF

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CN117430540A
CN117430540A CN202210834303.8A CN202210834303A CN117430540A CN 117430540 A CN117430540 A CN 117430540A CN 202210834303 A CN202210834303 A CN 202210834303A CN 117430540 A CN117430540 A CN 117430540A
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张强
李恩德
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Shanghai Allist Medicine Polytron Technologies Inc
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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
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    • C07C55/10—Succinic acid
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    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
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    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
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    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
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    • C07F7/1872—Preparation; Treatments not provided for in C07F7/20
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    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
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Abstract

The invention discloses a pyrrolidine compound and a preparation method thereof. Specifically discloses a preparation method of a compound III-1, which comprises the following steps: in a solvent, reacting the compound IV with fumaric acid to form a salt to obtain a compound III-1; the compound IVIs thatAndmixtures in any ratio. The pyrrolidine compound and the preparation method thereof are applied to the preparation of (S) -2- ((tert-butyldimethylsilyl) oxo) -1- ((S) -1-methylpyrrolidin-2-yl) ethanol, and can improve the purity of a target product and obtain higher yield;

Description

Pyrrolidine compound and preparation method thereof
Technical Field
The invention relates to a pyrrolidine compound and a preparation method thereof.
Background
About 30% of human tumors carry some mutated RAS genes. Among RAS family members, oncogenic mutations are most commonly found in the V-Ki-RAS2 Kirsten rat sarcoma virus oncogene homolog (KRAS) (85%), while neuroblastoma RAS virus oncogene homolog (NRAS) (12%) and the V-Ha-RAS murine Harvey sarcoma virus oncogene Homolog (HRAS) (3%) are less common. For KRAS mutations, the most common mutations occur at residues 12 glycine (G12), 13 glycine (G13) and 61 glutamine (Q61), with the G12 mutation accounting for 83%. The G12C mutation is one of the most common KRAS mutations, specifically a mutation of glycine (glycine) to cysteine (cysteine) at KRAS position 12, which is present in about 14% of non-small cell lung cancers (NSCLC), 4% of colorectal cancers, and 2% of pancreatic cancers. Other common KRAS mutations include G12D, G V, which are expressed at high levels in colorectal and pancreatic cancers.
Compound (S) -2- ((tert-butyldimethylsilyl) oxo) -1- ((S) -1-methylpyrrolidin-2-yl) ethanolIs an important intermediate for synthesizing KRAS G12C inhibitor. Because the compound has two chiral centers, the production method of the synthesis process has certain difficulty.
The following synthetic route is reported in patent PCT/CN 2022/074955:
in the product obtained in step 2 of the routeAnd->Isomer content ratio about 3:2 to 2:1, and is provided withThe purification step of the synthesis process is column chromatography separation and purification. In order to improve the purity of the target product (S) -2- ((tert-butyldimethylsilyl) oxo) -1- ((S) -1-methylpyrrolidin-2-yl) ethanol, obtain higher yield, and improve the separation and purification method so as to carry out industrial production, a synthetic process route needs to be redesigned.
Disclosure of Invention
The invention aims to solve the technical problem that the yield and purity of an important intermediate (S) -2- ((tert-butyldimethylsilyl) oxo) -1- ((S) -1-methylpyrrolidin-2-yl) ethanol synthesis route of a KRAS G12C inhibitor in the prior art are low, and therefore, the invention provides a pyrrolidine compound and a preparation method thereof. The pyrrolidine compound and the preparation method thereof are applied to the preparation of (S) -2- ((tert-butyldimethylsilyl) oxo) -1- ((S) -1-methylpyrrolidin-2-yl) ethanol, and can improve the purity of a target product; higher yields are obtained.
The invention solves the technical problems through the following technical scheme.
The invention provides a preparation method of a compound III-1, which comprises the following steps: in a solvent, reacting the compound IV with fumaric acid to form a salt to obtain a compound III-1;
the compound IVIs->Any ratio of the mixture of (c) to (c).
In the salt-forming reaction, the solvent is conventional in the art, preferably an alcoholic solvent, for example C 1-4 The alcohol solvent of (2) is, for example, isopropyl alcohol.
In the salification reaction, the volume to mass ratio of the solvent to the compound IV is conventional in the art, preferably 3-10mL/g, more preferably 6-8mL/g, for example 5mL/g.
In the salt formation reaction, the molar ratio of fumaric acid to the compound IV is conventional in the art, preferably from 0.1 to 10:1, more preferably from 0.1 to 1:1, for example 0.5:1.
The temperature of the salt forming reaction is conventional in the art, preferably 10-60 ℃, for example 50 ℃ or 20-25 ℃; for example, the reaction is carried out for 1-2 hours at 20-25 ℃, the temperature is raised to 50-60 ℃ for 2-3 hours, and the temperature is lowered to 20-25 ℃ for 8-12 hours.
The reaction time of the salification reaction can be monitored by conventional monitoring means until the reaction is completed, preferably 0.5 to 120 hours, for example 12 hours.
The salification reaction preferably comprises the steps of: mixing the compound IV with the solvent at 20-25 ℃, adding fumaric acid, reacting for 0.5-4h, heating to 50-60 ℃, reacting for 1-4h, cooling to 20-25 ℃, reacting for 8-16h, filtering, and drying to obtain the compound III-1.
The compound IVCan be->The proportion is 1-10:1, a mixture of two or more of the above-mentioned materials; for example 5-7:1; and for example 6:1.
In the salification reaction, the purity of the compound III-1 is 96.7 percent.
The invention also provides a preparation method of the compound III-2, which comprises the following steps: in a solvent, carrying out salt formation reaction on the compound IV and R-binaphthol phosphate ((R) - (-) -BNP) to obtain a compound III-2;
the compound IVIs->Mixtures in any ratio.
In the salt-forming reaction, the solvent is conventional in the art, preferably an alcoholic solvent, for example C 1-4 The alcohol solvent of (2) is, for example, methanol.
In the salification reaction, the volume to mass ratio of the solvent to the compound IV is conventional in the art, preferably 2-10mL/g, more preferably 2-6mL/g, for example 3mL/g or 5mL/g.
In the salt-forming reaction, the molar ratio of the R-binaphthol phosphate to the compound IV is conventional in the art, preferably 0.1 to 1:1, more preferably 0.5 to 0.9:1, for example 0.83:1.
The temperature of the salt-forming reaction is conventional in the art, preferably 10-80 ℃, for example 70 ℃, 30-35 ℃ or 20-25 ℃.
The reaction time of the salification reaction can be monitored by conventional monitoring means until the reaction is completed, preferably 0.5 to 48 hours, for example 12 hours.
The salification reaction can comprise the following steps: in a solvent, the compound IV is mixed with R-binaphthol phosphate and reacted for 8-12h at 20-25 ℃.
The salification reaction preferably further comprises the following post-treatment steps: after the reaction is finished, filtering, pulping by using an organic solvent, and filtering; the organic solvent is C 1-4 The alcohol solvent of (2) is, for example, methanol.
The compound IV may beThe proportion is 1-10:1, a mixture of two or more of the above-mentioned materials; for example 5-7:1; and for example 6:1.
The purity of the compound III-2 may be 93.97%.
The preparation method of the compound III-1 or III-2 can further comprise the following steps: in a solvent, in the presence of a reducing agent, carrying out a reduction reaction on the compound V to obtain a compound IV;
the compound VIs->Mixtures in any ratio; said compound IV->Is->Mixtures in any ratio.
In the reduction reaction, the reducing agent is conventional in the art, preferably an organometallic reducing agent, more preferably lithium aluminum tetrahydroide and/or red aluminum, for example lithium aluminum tetrahydroide.
In the reduction reaction, the molar ratio of the reducing agent to the compound V is conventional in the art, preferably 2-5:1, for example 3:1.
In the reduction reaction, the solvent is conventional in the art, preferably an ether solvent such as tetrahydrofuran.
In the reduction reaction, the volume to mass ratio of the solvent to the compound V is conventional in the art, preferably 2 to 20mL/g, for example 5mL/g or 17.7mL/g.
The temperature of the reduction reaction is conventional in the art, preferably 10-80 ℃, for example 70 ℃.
The reaction time of the reduction reaction may be monitored by conventional monitoring means until the reaction is completed, preferably 0.5 to 48 hours, for example 12 hours.
The compound VCan be->The proportion is 5-7:1, for example 5.6:1.
the compound IVCan be->The proportion is 1-10:1, a mixture of two or more of the above-mentioned materials; for example 6-7:1; and for example 6:1.
The preparation method of the compound III-1 or III-2 can further comprise the following steps: in the solvent, in (DHQD) 2 In the presence of PHAL, potassium osmium sulfate and a co-oxidant, the compound VI undergoes asymmetric dihydroxylation; the solvent is a mixed solvent of tetrahydrofuran and water; obtaining a compound V;
The compound VIs->Mixtures in any ratio.
In the asymmetric dihydroxylation reaction, the volume ratio of the tetrahydrofuran to the water in the mixed solvent is preferably 1-20:1; more preferably 4-8:1; for example 6.5:1.
In the asymmetric dihydroxylation reaction, preferably, the volume-mass ratio of the tetrahydrofuran to the compound VI is 1-50mL/g; for example 13mL/g.
In the asymmetric dihydroxylation reaction, preferably, the potassium osmium is a hydrate of potassium osmium, for example, potassium osmium dihydrate.
In the asymmetric dihydroxylation reaction, the auxiliary oxidant is conventional in the art, such as 4-methylmorpholine oxide and/or potassium ferricyanide; and for example, 4-methylmorpholine oxide.
In the asymmetric dihydroxylation reaction, the compounds VI and (DHQD) 2 The molar ratio of PHAL is conventional in the art, preferably 1:0.0001-1; more preferably, 1:0.01-0.5; for example 1:0.02.
In the asymmetric dihydroxylation reaction, the molar ratio of the compound VI to the pro-oxidant is conventional in the art, preferably 1:1-10; more preferably, 1:2-4; for example 1:3.
In the asymmetric dihydroxylation reaction, the molar ratio of the compound VI to potassium hundredthate is conventional in the art, and is preferably 1:0.0001-1; more preferably, 1:0.005-0.02; for example 1:0.02.
The reaction temperature of the asymmetric dihydroxylation reaction is conventional in the art, preferably-30 to 50 ℃, for example-10 to 0 ℃.
The reaction time of the asymmetric dihydroxylation reaction may be monitored by conventional monitoring means (e.g., TLC thin layer chromatography, gas chromatography) until the reaction is complete, preferably 1 to 50 hours, for example 12 hours.
The asymmetric dihydroxylation reaction preferably further comprises the following post-treatment steps: the sodium sulfite is quenched for reaction and extracted with organic solvent.
The asymmetric dihydroxylation reaction is preferably carried out by the steps of:
step 1: preparation of aqueous potassium osmium acid solutions, said aqueous potassium osmium acid solutions and (DHQD) 2 Mixing PHAL and tetrahydrofuran to obtain a mixture A;
step 2: the mixture a is mixed with the pro-oxidant and the compound VI.
In step 1, preferably, the aqueous solution of potassium osmium is combined with (DHQD) at a temperature of-10 to 0 DEG C 2 Mixing PHAL and tetrahydrofuran, and stirring for 10-20min to obtain mixture A.
In step 2, preferably, the mixture a is mixed with the pro-oxidant and the compound VI sequentially, for example, after the mixture a is mixed with the pro-oxidant, a mixture B is obtained, and the compound VI is added to the mixture B; for another example, the compound VI is added to the mixture B in such a manner that a tetrahydrofuran solution of the compound VI is added dropwise to the mixture B.
The compound VCan be->The proportion is 5-7:1, for example 5.6:1.
the preparation method of the compound III-1 or III-2 can further comprise the following steps that in a solvent, in the presence of alkali, nucleophilic addition reaction is carried out between the compound VII and a phosphorus ylide reagent to obtain a compound VI;
in the nucleophilic addition reaction, the solvent is conventional in the art, preferably a polar solvent, such as a polar ether solvent, and further such as tetrahydrofuran.
In the nucleophilic addition reaction, the volume to mass ratio of the solvent to the compound VII is conventional in the art, preferably 5 to 30mL/g, for example 20mL/g.
In the nucleophilic addition reaction, the phosphorus ylide reagent is conventional in the art, preferably, methyltriphenyl phosphorus bromide.
In the nucleophilic addition reaction, the molar ratio of the phosphorus ylide reagent to the compound VII is conventional in the art, preferably 1-5:1, more preferably 2-3:1, for example 2.05:1.
In the nucleophilic addition reaction, the base is conventional in the art, preferably an organic base, such as an alkali metal alkoxide, and further such as potassium t-butoxide and/or sodium t-butoxide.
In the nucleophilic addition reaction, the molar ratio of the base to the compound VII is conventional in the art, preferably 1-5:1, more preferably 2-3:1, for example 2:1.
The reaction temperature of the nucleophilic addition reaction is conventional in the art, preferably 0-50 ℃, for example 20-25 ℃.
The reaction time of the nucleophilic addition reaction can be monitored by conventional monitoring means until the reaction is completed, preferably 0.5 to 5 hours, for example 1 to 3 hours.
The nucleophilic addition reaction is preferably carried out under anhydrous and anaerobic conditions.
The nucleophilic addition reaction preferably further comprises the following post-treatment steps: quenching, extracting and concentrating.
The nucleophilic addition reaction preferably comprises the steps of:
s1: mixing alkali, phosphorus ylide reagent and organic solvent to obtain a mixture, and reacting the mixture for 1-2h;
S2: to the mixture, compound VII is added; the compound VII is preferably added dropwise to the mixture after the compound VII forms a solution with the organic solvent.
The invention also provides a preparation method of the compound I, which comprises the following steps: in a solvent, in the presence of alkali, carrying out substitution reaction on the compound III-1 or III-2 and PGCl to obtain a compound I;
the PG isWherein R is 1 、R 2 And R is 3 Each independently is C 1-4 An alkyl group.
In the substitution reaction, the PGCl may be trimethylchlorosilane, triethylchlorosilane, tri-t-butylchlorosilane, t-butyldiphenylchlorosilane, triisopropylchlorosilane, dimethylisopropylchlorosilane, t-butyldimethylchlorosilane, methyldiisopropylchlorosilane, or triisopropylchlorosilane; t-butyldimethylchlorosilane is preferred.
In the substitution reaction, PG is trimethyl silicon base, triethyl silicon base, tri-tertiary butyl silicon base, tertiary butyl diphenyl silicon base, triisopropyl silicon base, dimethyl isopropyl silicon base, tertiary butyl dimethyl silicon base, methyl diisopropyl silicon base or triisopropyl silicon base; preferably tert-butyldimethylsilyl, i.e. the compound I is
In the substitution reaction, the base is conventional in the art, for example, an organic base, and further, for example, imidazole.
In the substitution reaction, the molar ratio of the base to the compound III-1 or III-2 is conventional in the art, for example, 2 to 5:1, and further for example, 3:1.
In the substitution reaction, the solvent is conventional in the art, for example, halogenated hydrocarbon, and further, for example, chlorinated hydrocarbon; and for example dichloromethane.
In the substitution reaction, the volume to mass ratio of the solvent to the III-1 or III-2 is conventional in the art, for example, 8 to 16mL/g, and further for example, 12mL/g.
In the substitution reaction, the molar ratio of PGCl to III-1 or III-2 is conventional in the art, for example, 0.8-2:1, and further for example, 1.2:1.
The preparation method of the compound I can further comprise the following steps: the steps are method 1 or method 2:
in the method 1, in a solvent, a compound IV reacts with fumaric acid to form a salt to obtain a compound III-1;
the salification reaction may be as described in any of the previous schemes;
in the method 2 and in a solvent, the compound IV and R-binaphthol phosphate react to form a salt to obtain a compound III-2;
the salt formation reaction may be as described in any of the previous schemes.
The invention also provides a preparation method of the compound II: which comprises the following steps: in a solvent, reacting the compound I with succinic acid to form salt to obtain a compound II;
the definition of PG is as described in any one of the previous schemes.
In the salt forming reaction, the compound II is preferably
In the salification reaction, the solvent can be an ether solvent and/or an alcohol solvent; the ether solvent can be C 3-7 An ether solvent of (2); the alcohol solvent can be C 1-4 Alcohol solvents; for example, the solvent is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, and methanol.
In the salification reaction, the volume to mass ratio of the solvent to the compound I is conventional in the art, preferably 2-20mL/g, more preferably 2-15mL/g, for example 3mL/g or 13mL/g.
In the salification reaction, the molar ratio of the succinic acid to the compound I is conventional in the art, preferably 0.1-2:1; for example 1.2:1.
The temperature of the salt forming reaction is conventional in the art, preferably 10-80 ℃, for example 50 ℃ or 20-25 ℃.
The reaction time of the salt formation reaction may be monitored by conventional monitoring means until the reaction is completed, preferably for 0.5 to 48 hours, for example for 4 to 10 hours.
The salification reaction may include the steps of: and mixing the compound I with the solvent at 20-25 ℃, adding an alcohol solution of succinic acid, heating to 50-60 ℃, reacting for 0.5-4h, and cooling to 20-25 ℃.
The salification reaction may further comprise the following post-treatment steps: concentrating to obtain concentrate after the reaction is finished; pulping; preferably, the solvent for beating is preferably 2-methyltetrahydrofuran and methyl tertiary butyl ether; preferably, the concentration further comprises a process of adding 2-methyltetrahydrofuran for rotary evaporation; more preferably, the pulping process is to add 2-methyltetrahydrofuran, react for 1-3 hours, then add methyl tertiary butyl ether, react for 3-5 hours; for example, the volume to mass ratio of the 2-methyltetrahydrofuran to the concentrate is 10-20mL/g, and the volume to mass ratio of the methyl tertiary butyl ether to the concentrate is 10-20mL/g; the methyl tertiary butyl ether is added dropwise.
The preparation method of the compound II can further comprise the following steps: in a solvent, in the presence of alkali, carrying out substitution reaction on the compound III-1 or III-2 and PGCl to obtain a compound I;
the definition of PG is as described in any one of the previous schemes;
the substitution reaction may be as described in any of the previous schemes.
The invention also provides a preparation method of the compound I: which comprises the following steps: in a solvent, in the presence of alkali, performing hydrolysis reaction on the compound II to obtain a compound I;
the definition of PG is as described in any one of the previous schemes.
In the hydrolysis reaction, the solvent is conventional in the art, for example, halogenated hydrocarbon, and further, for example, chlorinated hydrocarbon; and for example dichloromethane.
In the hydrolysis reaction, the base is conventional in the art, for example, an inorganic base, for example, a metal carbonate, for example, sodium carbonate; the base may be in the form of an aqueous base solution; the amount of base is conventional in the art to adjust the pH of the system to 8-10, e.g., to 8-9.
The temperature of the hydrolysis reaction is conventional in the art, preferably 10-80 ℃, for example 10-35 ℃; and still more for example 20-25 deg.c.
The reaction time of the hydrolysis reaction may be monitored by conventional monitoring means until the reaction is completed, preferably 0.5 to 48 hours, for example 4 to 10 hours.
The hydrolysis reaction preferably further comprises the following post-treatment steps: extracting, concentrating to obtain concentrate, pulping with organic solvent, and filtering. The organic solvent may be a hydrocarbon solvent, such as n-heptane; the amount of the organic solvent is conventional in the art, for example, the volume mass of the organic solvent and the concentrate is 6-12mL/g; for example 10mL/g.
The preparation method of the compound I can further comprise the following steps: in a solvent, reacting the compound I with succinic acid to generate salt to obtain a compound II;
the definition of PG is as described in any one of the previous schemes;
the salt formation reaction may be as described in any of the previous schemes.
The preparation method of the compound I can further comprise the following steps: in a solvent, in the presence of alkali, carrying out substitution reaction on the compound III-1 or III-2 and PGCl to obtain a compound I;
the definition of PG is as described in any one of the previous schemes;
the substitution reaction may be as described in any of the previous schemes.
The preparation method of the compound I can further comprise the following steps: the step is a method 1 or a method 2;
in the method 1, in a solvent, a compound IV reacts with fumaric acid to form a salt to obtain a compound III-1;
the compound IVIs->Mixtures in any ratio; the salification reaction may be as described in any of the previous schemes; />
In the method 2 and in a solvent, the compound IV and or R-binaphthol phosphate react to form salt, so as to obtain a compound III-2;
the compound IVIs->Mixtures in any ratio; the salt formation reaction may be as described in any of the previous schemes.
The preparation method of the compound I can further comprise the following steps: in a solvent, in the presence of a reducing agent, carrying out a reduction reaction on the compound V to obtain a compound IV;
The compound VIs->Mixtures in any ratio; said compound IV->Is->Mixtures in any ratio; the reduction reaction may be as described in any of the previous schemes.
The preparation method of the compound I can further comprise the following steps: in the solvent, in (DHQD) 2 In the presence of PHAL, potassium osmium sulfate and a co-oxidant, the compound VI undergoes asymmetric dihydroxylation; the solvent is a mixed solvent of tetrahydrofuran and water; obtaining a compound V;
the compound VIs->Mixtures in any ratio; the asymmetric dihydroxylation reaction may be as described in any of the previous schemes.
The preparation method of the compound I can further comprise the following steps: in a solvent, in the presence of alkali, performing nucleophilic addition reaction on the compound VII and a phosphorus ylide reagent to obtain a compound VI;
the nucleophilic addition reaction may be as described in any of the preceding schemes.
The invention also provides a pyrrolidine compound, which is characterized by being any one of the following compounds:
wherein the PG is as defined in any one of the preceding schemes;a mixture of III-1 and III-1' in any proportion;Is a mixture of III-2 and III-2' in any proportion.
The invention also provides a preparation method of the pyrrolidine compound, which is characterized by comprising the following steps:
The steps are method 1 or method 2:
in the method 1, in a solvent, reacting a compound IV-1 with fumaric acid to form a salt to obtain a compound III-1;
the salification reaction may be as described in any of the previous schemes; or (b)
In the method 2 and in a solvent, the compound IV-1 and R-binaphthol phosphate react to form a salt to obtain a compound III-2;
the salt formation reaction may be as described in any of the previous schemes.
The invention also provides application of fumaric acid as chiral resolving agent of pyrrolidine compound, wherein the pyrrolidine compound isSaid->Is->Mixtures in any ratio; preferably, in such applications, the pyrrolidine compound is reacted with fumaric acid to form a salt, which may be as described in any of the previous schemes.
The invention also provides application of the R-binaphthol phosphate or the S-binaphthol phosphate as chiral resolving agent of pyrrolidine compounds, wherein the pyrrolidine compounds areSaid->Is->Mixtures in any ratio; preferably, in such applications, the pyrrolidine compound is reacted with the R-binaphthol phosphate to form a salt, which may be as described in any of the previous schemes.
The invention also provides a preparation method of the compound V, which comprises the following steps: in the solvent, in (DHQD) 2 In the presence of PHAL, potassium osmium sulfate and a co-oxidant, the compound VI undergoes asymmetric dihydroxylation; obtaining a compound V; the solvent is a mixed solvent of tetrahydrofuran and water;
the compound VIs->Mixtures in any ratio.
The asymmetric dihydroxylation reaction may be as described in any of the preceding schemes.
The preparation method of the compound V can further comprise the following steps: in a solvent, in the presence of alkali, performing nucleophilic addition reaction on the compound VII and a phosphorus ylide reagent to obtain a compound VI;
the nucleophilic addition reaction may be as described in any of the preceding schemes.
The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.
The reagents and materials used in the present invention are commercially available.
The invention has the positive progress effects that: the pyrrolidine compound and the preparation method thereof are applied to the preparation of (S) -2- ((tert-butyldimethylsilyl) oxo) -1- ((S) -1-methylpyrrolidin-2-yl) ethanol, and can improve the purity of a target product and obtain higher yield.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
PCT patent application PCT/CN2022/074955 is incorporated herein by reference in its entirety.
V in the embodiment represents the volume of the solvent corresponding to the mass of the material, wherein the material is 1eq of the material; for example, if the mass of the material is 10g,5V indicates a solvent volume of 50mL; if the mass of the material is 1kg,5V means that the volume of the solvent is 5L.
EXAMPLE 1 preparation of Compound VI
Preparation of (S) -tert-butyl-2-vinylpyrrolidine-1-carboxylic acid ester
Potassium tert-butoxide (1103.8 g,9.84mol,2 eq.) was dissolved in tetrahydrofuran (9.8L, 10V), methyltriphenylphosphorous bromide (3601.78 g,10.08mol,2.05 eq.) was added, and after nitrogen substitution, the reaction was carried out at 80℃for 1-2 hours and cooled to 0 ℃. A solution of (S) -tert-butyl-2-formylpyrrolidine-1-carboxylate (480 g,4.92mol,1 eq.) in tetrahydrofuran (9.8L, 10V) was added dropwise. The reaction was warmed to room temperature (20-25 ℃) and monitored by TLC (petroleum ether: ethyl acetate=4:1) for completion. The reaction solution was quenched with water (6L, 6V), extracted with methyl tert-butyl ether (5L, 5V), filtered and concentrated to give an oil, tetrahydrofuran (1L, 1V) was added dropwise with stirring at room temperature, n-heptane (5L, 5V) was added dropwise, the solid residue was removed by suction filtration, the filtrate was further separated into layers, the lower oil phase was extracted with n-heptane 2L, the organic n-heptane phases were combined, and concentrated under reduced pressure to give crude (S) -tert-butyl-2-vinylpyrrolidine-1-carboxylate oil (1050.6 g, crude yield 99%) which was directly fed to the next reaction.
EXAMPLE 2 preparation of Compound V
Preparation of (2S) -tert-butyl-2- (1, 2-dihydroxyethyl) pyrrolidine-1-carboxylic acid ester
Purified water (200 ml,2 v) was added to the reaction vessel, stirring was started, and potassium osmium sulfate dihydrate (3.7 g,0.02 eq.) was added, and stirring was continued for 10 to 20 minutes (it was observed that the potassium osmium sulfate dihydrate was completely dissolved). The temperature of the reaction system is reduced to-10 to 0 ℃, and the DHQD is added into the reaction system when the temperature is kept within the temperature range 2 PHAL (7.9 g,0.02 eq.) was added to tetrahydrofuran (800 mL, 8V) and stirring was continued for 10-20 minutes after addition was complete. 4-methylmorpholine oxide co-oxidant (178.1 g,3 eq.) was added thereto and stirring continued for 10-20 minutes after addition was completed. (S) -tert-butyl-2 obtained in example 1 was continuously added dropwise thereto at-10 to 0 ℃A mixed solution of vinylpyrrolidine-1-carboxylate (100 g,1 eq.) in tetrahydrofuran (500 mL, 5V). After the dripping is finished, the temperature is kept at-10 to 0 ℃ and the mixture is stirred overnight.
TLC (petroleum ether: tetrahydrofuran=2:1) and GC monitored the reaction. The reaction solution was quenched by adding sodium sulfite solution (1 l, w/w=20%, 10V), then adding purified water (1 l, 10V), standing for demixing, extracting aqueous phase ethyl acetate (1 l×2, 10v×2) twice, combining organic phases, washing with saturated sodium chloride solution (1 l, 10V), separating liquid, and concentrating twice with water using acetonitrile (500 ml×2,5v×2) to obtain (2S) -tert-butyl-2- (1, 2-dihydroxyethyl) pyrrolidine-1-carboxylate crude product (118 g, ss: sr=5.6:1), as a pale yellow oil, which was directly put into the next reaction.
Analysis of the isomer content in the crude product by GC (column type: shimadzu SH-Rtx-225,30m x 0.25mm,0.25 μm, retention time of product SS 16.237min, retention time of isomer impurity SR 16.509 min) shows SS: SR is 5.6:1, wherein the SS configuration, i.e.The content is 81.82%; SR configuration is->The content was 14.65%.
EXAMPLE 3 preparation of Compound IV
Preparation of 1- ((S) -1-methylpyrrolidin-2-yl) ethane-1, 2-diol
After nitrogen substitution of lithium aluminum hydride tetrahydrofuran solution (5 l,5.04mol,3.0 eq.) the temperature was reduced to 0 ℃. (2S) -tert-butyl-2- (1, 2-dihydroxyethyl) pyrrolidine-1-carboxylic acid ester (1.68 mol,1 eq.) obtained in example 2 was dissolved in tetrahydrofuran (5V) and slowly added dropwise to the reaction solution at 0deg.C. The reaction was carried out overnight at 70 ℃. TLC (dichloromethane: methanol: ammonia = 10:1:0.02) monitored reaction was complete. The reaction mixture was quenched with water (0.33V), 15% sodium hydroxide solution (0.33V) and water (1V) at 0deg.C, warmed to room temperature, dried with sodium sulfate (1980 g,13.94 mol), filtered and concentrated to give a crude product as a pale yellow oil.
Analysis of the isomer content in the crude product by GC (column type: agilent DB-WAX,30m x 0.32mm,0.25 μm, retention time of product SS 19.896min, retention time of isomer impurity SR 20.232 min) gave SS: SR is 6:1, wherein the SS configuration refers to SR configuration finger->
1 H NMR(400MHz,MeOD)δ3.75-3.72(m,1H),3.55-3.47(m,2H),3.06-3.01(m,1H),2.38-2.33(m,4H),2.27-2.19(m,1H),1.89-1.67(m,4H).
EXAMPLE 4 Synthesis of Compound III-1
Preparation of 1- ((S) -1-methylpyrrolidin-2-yl) ethane-1, 2-diol fumarate
10 g of crude compound IV obtained in example 3 is dissolved in 5V isopropanol, 0.5eq. Fumaric acid is added at 20-25 ℃, after mechanical stirring for 1-2h, solid is separated out, stirring is continued for 2-3h after heating to 50 ℃, cooling to 20-25 ℃ again, stirring is carried out overnight, filtration (the product is easy to absorb moisture and the suction filtration time is not too long), and air drying is carried out at 50 ℃ to obtain light yellow sandy solid, about 7.18 g (HNMR shows that the purity of the product is 96.7%).
Nuclear magnetic data of compound III-1:
1 H NMR(400MHz,MeOD)δ6.66(s,1H),4.04-4.00(dt,1H),3.65-3.61(m,1H),3.58-3.52(m,1H),3.50-3.46(m,1H),3.38-3.34(dt,1H),3.05-2.95(m,1H),2.84(s,3H),2.11-1.94(m,4H).
from the above nuclear magnetic data, it was confirmed that the obtained product was
EXAMPLE 5 Synthesis of Compound III-2
After 1 g of compound IV obtained in example 3 was mixed with 0.83 equivalent of R-binaphthol phosphate in 5V methanol solvent, stirred overnight at room temperature, gradually precipitating phosphate (R-BNP) solid, filtering to obtain phosphate solid, HNMR test result shows that: the purity of the product was 91.67%. The phosphate solid is subjected to methanol pulping and purification, and the HNMR test result shows that: the purity of the product was 93.97%.
Nuclear magnetic data of compound III-2:
1 HNMR(400MHz,D 2 O)δ7.94(d,J＝12Hz,2H),7.87(d,J＝12Hz,2H),7.45(dd,J＝4,8Hz,2H),7.34-7.30(m,2H),7.19-7.12(m,4H),3.91-3.87(m,1H),3.53-3.48(m,1H),3.43-3.30(m,3H),3.21-3.20(m,2H),2.95-2.88(m,1H),2.73(s,3H),1.96-1.76(m,4H)。
EXAMPLE 6 preparation of Compound I
Preparation of (S) -2- ((tert-butyldimethylsilyl) oxo) -1- ((S) -1-methylpyrrolidin-2-yl) ethanol
Dichloromethane (10V) was added to the compound III-1 (7.18 g,1.0 eq.) obtained in example 4, imidazole (3 eq.) was added, and after stirring well, a solution of t-butyldimethylchlorosilane (1.2 eq.) in DCM (2V) was added dropwise at 20-25 ℃ and reacted for 2-3h. TLC (dichloromethane: methanol: ammonia water=10:1:0.02) monitored the reaction was complete, saturated aqueous sodium bicarbonate (10V) was added and stirred for 10-20min, the aqueous phase was separated, dichloromethane (5V) extracted, the organic phases were combined and concentrated to give 10.9g of a pale yellow oil, and the purity of the compound of formula I was 96.7% as measured by GC (column type: shimadzu SH-Rtx-225,30m 0.25mm,0.25 μm, retention time of product SS was 11.573min, retention time of isomer impurity SR was 12.332 min.).
EXAMPLE 7 preparation of Compound II
Crude (S) -2- ((tert-butyldimethylsilyl) oxo) -1- ((S) -1-methylpyrrolidin-2-yl) ethanol (10.9 g,1 eq.) obtained in example 6 was dissolved in tetrahydrofuran (3V), and a solution of succinic acid (1.2 eq.) in methanol (10V) was added dropwise at 20-25℃and after the addition was completed, the temperature was raised to 50℃and stirred for 1.5-2 hours, and then cooled to 20-25 ℃. Concentrating to 1-2V, adding 5V 2-MeTHF, steaming to 1-2V, adding 10V 2-MeTHF, stirring at 20-25deg.C for 2-3 hr, dripping MTBE (10V), stirring for 3-5 hr, and filtering to obtain 13.2g (S) -2- ((tert-butyldimethylsilyl) oxo) -1- ((S) -1-methylpyrrolidin-2-yl) ethanol succinate wet product as light yellow solid.
Nuclear magnetic data for compound II:
1H NMR(400MHz,DMSO-d6)δ9.351-8.066(br,2H),3.741-3.706(m,1H),3.543-3.503(m,1H),3.399-3.357(m,1H),3.237-3.116(m,1H),2.783-2.750(m,1H),2.578-2.514(m,1H),2.459(s,1H),2.297(s,4H),1.825-1.611(m,4H),0.821(s,9H),-0.001(s,6H).
EXAMPLE 8 purification of Compound I
The wet (S) -2- ((tert-butyldimethylsilyl) oxo) -1- ((S) -1-methylpyrrolidin-2-yl) ethanolate obtained in example 7 was mixed with DCM (10V) in a reaction flask, stirred at room temperature, 10V saturated aqueous sodium carbonate was added dropwise to the system to pH 8-9, left to stand, the aqueous phase was extracted with DCM (5V) each time, and TLC (dichloromethane: methanol: ammonia = 100:10:1) monitored for aqueous phase free of (S) -2- ((tert-butyldimethylsilyl) oxo) -1- ((S) -1-methylpyrrolidin-2-yl) ethanol. The organic phases were combined, dried over anhydrous sodium sulfate and filteredConcentrating the filtrate under reduced pressure until no solvent is distilled off, pulping with 10V n-heptane for 0.5-1h, filtering, removing insoluble substances, collecting filtrate, concentrating the filtrate to dryness to obtain (S) -2- ((tert-butyldimethylsilyl) oxo) -1- ((S) -1-methylpyrrolidin-2-yl) ethanol (5.1 g, 56% from example 8 two steps), analyzing the content by GC (column type: shimadzu SH-Rtx-225,30m 0.25mm,0.25 μm, retention time of product SS is 11.573min, retention time of isomer impurity SR is 12.332 min), finding SS%>99%, wherein SS means
Nuclear magnetic data of compound I:
1 H NMR(400MHz,MeOD)δ3.76-3.72(m,1H),3.65-3.61(m,1H),3.55-3.50(m,1H),3.06-3.02(m,1H),2.41-2.36(m,1H),2.34(s,3H),2.26-2.19(m,1H),1.90-1.82(m,1H),1.78-1.67(m,3H),0.92-0.88(m,9H),0.10-0.08(m,6H).
comparative examples
Comparative example 1: preparation of Compound V
Compound V was prepared by repeating New proline analogues for organocatalysis the experimental conditions in Table1 Entry3 in Tetrahedron with very low conversion and almost no product, and the reaction was in the form of a black oil.
Comparative example 2: preparation of Compound V (reaction conditions are as follows, experimental procedure is as in example 2)
K 2 OsO 4. 2H 2 O (DHQD) 2 PHAL NMO Solvent(s) Temperature (temperature) Reaction time
3.0eq. 0.02eq. Without any means for t-BuOH/THF/H 2 O 20-25℃ 14h
The results show that: the reaction solution was in the form of a black oil, which was difficult to work up. The SS/SR in the product is 3.6:1; wherein SS meansSR means->
Comparative example 3:
2V of methanol and 10% of W of active carbon are put into a reaction bottle, stirred, 7Kg of crude product of the compound IV obtained in the example 3 is slowly added into the reaction bottle, stirred for 2 hours, filtered by suction, and a filter cake is leached by 0.5V of methanol, and filtrate is reserved. Adding 0.4 equivalent of S-binaphthol phosphate and 3V of methanol into a reaction bottle, protecting with nitrogen, stirring, heating to an internal temperature of 70 ℃, slowly dropwise adding a methanol solution of a treated crude product of the compound IV for about 1.5 hours, controlling the temperature of 70 ℃ after dropwise adding, stirring for 2 hours, gradually cooling to 30-35 ℃, carrying out suction filtration, adding 1V of MTBE into a filter cake for leaching, and carrying out filter cake: white crystals, weighing about 6.32kg. The filtered mother liquor is concentrated to 1V volume under reduced pressure at the temperature of 45 ℃, 3V MTBE is used for steaming three times, 5V MTBE is added for stirring for 15min, the solution is sticky and cannot be filtered by suction, and the supernatant is filtered by suction. The filtrate was a reddish brown oil, more viscous, concentrated and weighed approximately 1388g. KF moisture content 0.56%; GC (soluble residue): tetrahydrofuran solvent content 0.36%, dichloromethane solvent content 0.098%; NMR showed the purity of compound IV to be 84%.
Comparative example 4: purification of Compound I
The crystallization experiment is carried out on the compound I, and the fact that the compound I can not be precipitated by using water and hydrochloric acid to form oil, a small amount of solid can be precipitated by using n-heptane as a single solvent to dissolve the compound I, the temperature is reduced to minus 15 ℃, white solid with sticky wall appears, and the oil is solidified after the temperature is increased to 30 ℃, so that the solidified compound I is a low-melting-point solid and is difficult to purify by recrystallization.
Comparative example 5 purification of Compound I
The compound I is respectively subjected to salt formation reaction with maleic acid, tartaric acid, citric acid, fumaric acid, phosphoric acid, benzenesulfonic acid, hydrochloric acid and methanesulfonic acid, the materials are added according to the proportion of 0.98 of the mole ratio of acid to alkali, the materials are salified in different solvent systems (THF-ethanol, THF-water, THF-methanol and THF-acetone) at 30 ℃, n-heptane is dropwise added after stirring for 2 hours, stirring is carried out at room temperature overnight, no spontaneous nucleation phenomenon occurs in all the systems, and the solvent in a reaction bottle is blown off by argon, so that the result is found: the fumaric acid salt-forming system gave a paste, the remaining salt-forming systems gave an oil, and the oil was not solidified even after long stirring in an n-heptane system at low temperatures.
Therefore, compound I does not form a suitable salt form with the above acids, and cannot be purified by salt formation recrystallization with the above acids for subsequent isolation and purification.
A second part: related content of PCT/CN2022/074955
Intermediate 1: (2R, 4 aR) -tert-butyl-10-bromo-7, 11-dichloro-9-fluoro-2-methyl-5-carbonyl-4, 4a,5, 6-tetrahydro-1H-pyran-biazino [1',2':4,5] pyran-biazino [2,3-c ] quinoline-3 (2H) -carboxylic acid ester
Step 1 3-bromo-4-chloro-2-fluoroaniline
3-bromo-2-fluoroaniline (210 g,1.11mol,1 eq) was dissolved in N, N-dimethylformamide (2000 mL), and N-chlorosuccinimide (154.96 g,1.16mol,1.05 eq) was added thereto and reacted overnight at 70 ℃. LCMS detected complete reaction. After the reaction was cooled to room temperature, it was poured into ice water, water and ethyl acetate were added to extract, and the organic phase was washed three times with saturated aqueous sodium hydrogencarbonate, anhydrous aqueous sodium sulfite and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product (240 g).
MS m/z:223.9/225.9[M+H] + .
Step 2:3- ((3-bromo-4-chloro-2-fluorophenyl) amino) -3-carbonylpropionic acid
3-bromo-4-chloro-2-fluoroaniline (240 g) was dissolved in toluene (2400 mL), and isopropylidene malonate (184.93 g,1.28mol,1.2 eq) was added. The reaction was carried out at 90℃overnight. LCMS detection was complete, and after cooling to room temperature, filtration, the filter cake was the product, giving crude 3- ((3-bromo-4-chloro-2-fluorophenyl) amino) -3-carbonylpropionic acid (175 g), off-white product.
MS m/z:309.9/311.9[M+H] + .
Step 3 7-bromo-6-chloro-8-fluoroquinoline-2, 4-diol
3- ((3-bromo-4-chloro-2-fluorophenyl) amino) -3-carbonylpropionic acid (174 g,560.38mmol,1 eq) was mixed with polyphosphoric acid (1.89 kg,5.60mol,10 eq) and reacted at 135℃for 16 hours. LCMS monitored completion of the reaction, the reaction was poured into ice (1.9 kg), sodium hydroxide was added to adjust the ph=4 of the reaction, filtered, and the filter cake was slurried with water, acetonitrile, and ethyl acetate in sequence to give 7-bromo-6-chloro-8-fluoroquinoline-2, 4-diol (130 g, 79.31% yield) as a yellow solid.
MS m/z:292.0/294.0[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ7.74(d,J＝1.63Hz,1H),5.81(s,1H).
Step 4 7-bromo-6-chloro-8-fluoro-3-nitroquinoline-2, 4-diol
7-bromo-6-chloro-8-fluoroquinoline-2, 4-diol (129 g,441.03mmol,1 eq) was dissolved in concentrated nitric acid (430 mL) and reacted at 75℃for 1 hour. LCMS monitored completion of the reaction, the reaction was poured into ice (1.3 kg), filtered and the filter cake washed with water to give crude 7-bromo-6-chloro-8-fluoro-3-nitroquinoline-2, 4-diol (106 g) as a yellow solid.
MS m/z:337.0/339.0[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ11.82(br s,1H),7.96(d,J＝1.83Hz,1H).
Step 5 7-bromo-2, 4, 6-trichloro-8-fluoro-3-nitroquinoline
7-bromo-6-chloro-8-fluoro-3-nitroquinoline-2, 4-diol (25 g,74.08mmol,1 eq) was added to phosphorus oxychloride (340.75 g,2.22mol,30 eq) and N, N-diisopropylethylamine (28.72 g,222.23mmol,3 eq) was slowly added dropwise at room temperature and reacted at 100℃for 10 hours. LCMS detected complete reaction. Distillation under reduced pressure, column chromatography of the residue on silica gel (ethyl acetate/petroleum ether: 0-10%) gave the product (25 g, yield: 72.12%) as a yellow solid. The product was used directly in the next step.
Step 6 (3R, 6R) -1-tert-butyl-3-methyl-4- (7-bromo-2, 6-dichloro-8-fluoro-3-nitroquinolin-4-yl) -6-methylpiperazine-1, 3-dicarboxylic acid ester
7-bromo-2, 4, 6-trichloro-8-fluoro-3-nitroquinoline (10.2 g,27.25mmol,1 eq), (3R, 6R) -1-tert-butyl-3-methyl-6-methylpiperazine-1, 3-dicarboxylic acid ester (7.74 g,29.97mmol,1.1 eq) was dissolved in N, N-dimethylacetamide (125 mL), and N, N-diisopropylethylamine (7.04 g,54.49mmol,9.49mL,2 eq) was added and reacted at room temperature for 3 days. TLC (petroleum ether: ethyl acetate=5:1) monitored completion of the reaction, the reaction was diluted with water, extracted twice with ethyl acetate, the organic phase was washed 3 times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was chromatographed on silica gel (ethyl acetate: petroleum ether=0-10%) to give (3 r,6 r) -1-tert-butyl-3-methyl-4- (7-bromo-2, 6-dichloro-8-fluoro-3-nitroquinolin-4-yl) -6-methylpiperazine-1, 3-dicarboxylic acid ester (5.47 g, yield: 16.84%) as a yellow solid.
1 H NMR(400MHz,CDCl 3 )δ8.37(br s,1H),6.99(s,1H),5.02(s,1H),4.54(br d,J＝13.9Hz,1H),4.44(br s,1H),4.30(br d,J＝3.1Hz,1H),4.17(br s,1H),3.79-3.70(m,1H),3.75(s,2H),3.58-3.41(m,1H),3.15(br d,J＝11.8Hz,1H),2.63(s,1H),2.28(s,1H),1.49(s,9H),1.26(br d,J＝6.8Hz,3H).
Step 7 (2R, 4 aR) -tert-butyl-10-bromo-7, 11-dichloro-9-fluoro-2-methyl-5-carbonyl-4, 4a,5, 6-tetrahydro-1H-pyran-diazido [1',2':4,5] pyran-diazido [2,3-c ] quinoline-3 (2H) -carboxylic acid ester
(3R, 6R) -1-tert-butyl-3-methyl-4- (7-bromo-2, 6-dichloro-8-fluoro-3-nitroquinolin-4-yl) -6-methylpiperazine-1, 3-dicarboxylic acid ester (29.89 g,50.13mmol,1 eq) was dissolved in acetic acid (250 mL), and iron powder (11.20 g,200.53mmol,4 eq) was added to react at 80℃for 1 hour. LCMS monitored completion of the reaction, the reaction was concentrated, the residue was dissolved with dichloromethane, pH adjusted to 8 with saturated sodium bicarbonate solution and filtered. The filtrate was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was slurried at room temperature (petroleum ether: methyl tert-butyl ether=3:1). The filter cake was collected to give the product (22 g, yield: 82.15%) as a yellow solid.
MS m/z:533.0/535.0[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ8.02(br s,1H),7.94(d,J＝1.76Hz,1H),4.95(br d,J＝13.30Hz,1H),4.55(br s,1H),3.75-3.41(m,2H),3.13-2.94(m,2H),1.60(s,9H),1.57-1.55(m,3H).
Preparation of Compounds 22-P1, 22-P2, 22-P3 and 22-P4 step 1 (S) -tert-butyl-2-vinylpyrrolidine-1-carboxylate
Potassium tert-butoxide (27.03 g,240.91mmol,2 eq) was dissolved in tetrahydrofuran (240 mL), and methyltriphenylphosphorous bromide (88.21 g,246.93mmol,2.05 eq) was added, and after nitrogen substitution, the reaction was allowed to proceed at 80℃for 1 hour and cooled to 0 ℃. A solution of (S) -tert-butyl-2-formylpyrrolidine-1-carboxylate (24 g,120.45mmol,1 eq) in tetrahydrofuran (240 mL) was added dropwise. The reaction was carried out at room temperature for 2.5 hours. TLC (petroleum ether: ethyl acetate=5:1) monitored reaction completion. The reaction solution was quenched with water (150 mL), extracted with methyl tert-butyl ether, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column (ethyl acetate/petroleum ether: 0-5%) to give (S) -tert-butyl-2-vinylpyrrolidine-1-carboxylate (44 g, 97% yield) as a colorless oil.
1 H NMR(400MHz,CDCl 3 )δ5.66(br s,1H),4.97(br d,J＝9.6Hz,2H),4.35-4.09(m,1H),3.32(br s,2H),2.01-1.84(m,1H),1.83-1.68(m,2H),1.67-1.55(m,1H),1.37(br s,9H).
Step 2 (2S) -tert-butyl-2- (1, 2-dihydroxyethyl) pyrrolidine-1-carboxylic acid ester
To a mixed solution of (S) -tert-butyl-2-vinylpyrrolidine-1-carboxylate (8 g,40.55mmol,1 eq) in tert-butanol (168 mL), tetrahydrofuran (48 mL) and water (24 mL) was added 4-methylmorpholine tetraoxide (14.25 g,121.66mmol,3 eq) and potassium osmium dihydrate (1.49 g,4.06mmol,0.1 eq) and reacted overnight at room temperature. TLC (petroleum ether: tetrahydrofuran=2:1) monitored the reaction was complete. The reaction solution was quenched with saturated sodium sulfite solution (480 mL), extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated to give crude (2S) -tert-butyl-2- (1, 2-dihydroxyethyl) pyrrolidine-1-carboxylate (9.5 g), as a pale yellow oil, which was directly put into the next reaction.
1 H NMR(400MHz,CDCl 3 )δ4.03-3.80(m,1H),3.70-3.01(m,7H),2.12-1.65(m,4H),1.50-1.44(m,9H).
Step 3 Compounds 22-3-1 and 22-3-2
(S) -tert-butyl-2- ((S) -2- ((tert-butyldimethylsilyl) oxo) -1-hydroxyethyl) pyrrolidine-1-carboxylate and (S) -tert-butyl-2- ((R) -2- ((tert-butyldimethylsilyl) oxo) -1-hydroxyethyl) pyrrolidine-1-carboxylate
Crude (2S) -tert-butyl-2- (1, 2-dihydroxyethyl) pyrrolidine-1-carboxylate (9.50 g,40.56mmol,1 eq) was dissolved in dichloromethane (300 mL) and imidazole (5.52 g,81.11mmol,2 eq) and tert-butyldimethylchlorosilane (6.72 g,44.61mmol,1.1 eq) were added and reacted overnight at room temperature. TLC (petroleum ether: tetrahydrofuran=3:1) monitored completion of the reaction, the reaction mixture was quenched with water (300 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by filtration, and the residue was purified by column (tetrahydrofuran/petroleum ether: 0-10%) to give first fraction compound 22-3-1 (6.5 g, yield 46.38%, pale yellow solid) and second fraction compound 22-3-2 (4.2 g, yield 29.97%, pale yellow solid).
Compound 22-3-1:
1 H NMR(400MHz,CDCl 3 )δ4.05-3.68(m,3H),3.68-3.59(m,1H),3.58-3.38(m,2H),3.34-3.22(m,1H),2.06(br s,1H),1.98-1.69(m,3H),1.46(s,9H),0.89(s,9H),0.07(s,6H).
compound 22-3-2:
1 H NMR(400MHz,CDCl 3 )δ4.53(br s,1H),4.03-3.90(m,1H),3.74-3.36(m,4H),3.35-3.25(m,1H),2.00-1.71(m,4H),1.46(s,9H),0.91-0.88(m,9H),0.11-0.05(m,6H).
step 4 Compounds 22-4-1 and 22-4-2
(S) -2- ((tert-Butyldimethylsilyl) oxo) -1- ((S) -1-methylpyrrolidin-2-yl) ethanol and (R) -2- ((tert-Butyldimethylsilyl) oxo) -1- ((S) -1-methylpyrrolidin-2-yl) ethanol
Lithium aluminum hydride (1.27 g,33.43mmol,3 eq) was dissolved in tetrahydrofuran (40 mL), replaced with nitrogen, and cooled to 0deg.C. Compound 22-3-1 (3.85 g,11.14mmol,1 eq) was dissolved in tetrahydrofuran (20 mL) and slowly added dropwise to the reaction solution at 0deg.C. The reaction was carried out overnight at 70 ℃. TLC (petroleum ether: tetrahydrofuran: ammonia = 2:1:0.015) monitored the reaction was complete. Water, 15% sodium hydroxide solution and water were added to the reaction mixture in this order at 0℃to quench the reaction, the mixture was warmed to room temperature, dried over sodium sulfate, and concentrated by filtration to give a crude product (1.65 g) as a pale yellow oil. The crude product was dissolved in dichloromethane (32 mL), imidazole (1.52 g,22.31mmol,2 eq) and t-butyldimethylchlorosilane (1.85 g,12.27mmol,1.1 eq) were added and reacted overnight at room temperature. TLC (petroleum ether: tetrahydrofuran: ammonia=3:1:0.02) monitored the reaction was complete, the reaction was quenched with water, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column [ tetrahydrofuran (0.5% ammonia)/petroleum ether: 0-50% ], to give compound 22-4-1 (2 g, yield 69.09%) as a pale yellow oil.
1 H NMR(400MHz,CDCl 3 )δ3.76(dt,J＝2.9,6.1Hz,1H),3.71-3.63(m,1H),3.51(dd,J＝5.9,10.0Hz,1H),3.18-2.94(m,2H),2.35-2.27(m,4H),2.26-2.18(m,1H),1.85-1.74(m,1H),1.72-1.57(m,3H),0.88(s,9H),0.05(s,6H).
Lithium aluminum hydride (329.48 mg,8.68mmol,3 eq) was dissolved in tetrahydrofuran (10 mL), replaced with nitrogen, and the temperature was lowered to 0 ℃. Compound 22-3-2 (1 g,2.89mmol,1 eq) was dissolved in tetrahydrofuran (5 mL) and slowly added dropwise to the reaction solution at 0deg.C. The reaction was carried out overnight at 70 ℃. TLC (petroleum ether: tetrahydrofuran: ammonia = 2:1:0.015) monitored the reaction was complete. Water, 15% sodium hydroxide solution and water were added to the reaction mixture in this order at 0℃to quench the reaction, the mixture was warmed to room temperature, dried over sodium sulfate, and concentrated by filtration to give a crude product (350 mg) as a pale yellow oil. The crude product was dissolved in dichloromethane (7 mL), imidazole (328.21 mg,4.82mmol,2 eq) and t-butyldimethylchlorosilane (1.399 g,2.65mmol,1.1 eq) were added and reacted overnight at room temperature. TLC (petroleum ether: tetrahydrofuran: ammonia=3:1:0.02) monitored the reaction was complete, the reaction was quenched with water, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column [ tetrahydrofuran (0.5% ammonia)/petroleum ether: 0-50% ], to give compound 22-4-2 (400 mg, yield 63.96%) as a pale yellow oil.
1 H NMR(400MHz,CDCl 3 )δ3.57(d,J＝6.0Hz,2H),3.46-3.40(m,1H),3.05(td,J＝4.7,9.5Hz,1H),2.60-2.52(m,1H),2.44(s,3H),2.36-2.26(m,1H),1.97-1.85(m,1H),1.78-1.67(m,2H),1.66-1.56(m,1H),0.90-0.87(m,9H),0.06(s,6H).
Step 5 Compounds 22-5-1 and 22-5-2
(2R, 4 aR) -tert-butyl-10-bromo-7- ((S) -2- ((tert-butyldimethylsilyl) oxo) -1- ((S) -1-methylpyrrolidin-2-yl) ethoxy) -11-chloro-9-fluoro-2-methyl-5-carbonyl-4, 4a,5, 6-tetrahydro-1H-pyran-biazino [1',2':4,5] pyran biazino [2,3-c ] quinoline-3 (2H) -carboxylate and (2R, 4 aR) -tert-butyl-10-bromo-7- ((R) -2- ((tert-butyldimethylsilyl) oxo) -1- ((S) -1-methylpyrrolidin-2-yl) ethoxy) -11-chloro-9-fluoro-2-methyl-5-carbonyl-4, 4a,5, 6-tetrahydro-1H-pyran biazino [1',2':4,5] pyran biazino [2,3-c ] quinoline-3 (2H) -carboxylate
Sodium hydride (751.49 mg,18.79mmol,60% content, 3 eq) was dissolved in toluene (50 mL), replaced with nitrogen and cooled to 0deg.C. Compound 22-4-1 (1.95 g,7.52mmol,1.2 eq) was dissolved in toluene (25 mL) and slowly added dropwise to the reaction solution at 0deg.C. (2R, 4 aR) -tert-butyl-10-bromo-7, 11-dichloro-9-fluoro-2-methyl-5-carbonyl-4, 4a,5, 6-tetrahydro-1H-pyran-azino [1',2':4,5] pyran-azino [2,3-c ] quinoline-3 (2H) -carboxylic acid ester (3.35 g,6.26mmol,1 eq) was added and reacted overnight at 50 ℃. LCMS monitored completion of the reaction, the reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column [ tetrahydrofuran (0.5% aqueous ammonia)/petroleum ether: 0-70% ], to give compound 22-5-1 (3.7 g, yield 78.02%) as a brown solid.
MS m/z:756.1/758.1[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ7.79(s,1H),5.81(br s,1H),4.71-4.50(m,1H),4.34-4.10(m,1H),3.83(br d,J＝5.6Hz,2H),3.48-3.36(m,1H),3.27(br d,J＝13.5Hz,1H),3.06-2.93(m,1H),2.90-2.75(m,2H),2.39-2.33(m,3H),2.23(br s,1H),2.06(q,J＝8.3Hz,1H),1.73-1.53(m,4H),1.44(br d,J＝11.5Hz,12H),0.71(s,9H),-0.03(d,J＝11.3Hz,6H).
Sodium hydride (4.09 g,102.14mmol,60% purity, 3 eq) was dissolved in toluene (150 mL), replaced with nitrogen, and cooled to 0deg.C. Compound 22-4-2 (10.6 g,40.85mmol,1.2 eq) was dissolved in toluene (50 mL) and slowly added dropwise to the reaction solution at 0deg.C. (2R, 4 aR) -tert-butyl-10-bromo-7, 11-dichloro-9-fluoro-2-methyl-5-carbonyl-4, 4a,5, 6-tetrahydro-1H-pyran-azino [1',2':4,5] pyran-azino [2,3-c ] quinoline-3 (2H) -carboxylic acid ester (18.19 g,34.05mmol,1 eq) was added and reacted overnight at 50 ℃. LCMS monitored completion of the reaction, the reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography [ methanol (0.5% aqueous ammonia)/petroleum ether: 0-5% ], to give compound 22-5-2 (4.3 g, 16.68% yield) as a yellow solid.
MS m/z:756.3/758.3[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ8.56-8.33(m,1H),7.81(d,J＝1.3Hz,1H),5.54(br s,1H),4.92(br d,J＝13.6Hz,1H),4.52(br s,1H),4.30(br s,1H),4.08-3.85(m,2H),3.72-3.35(m,3H),3.21-2.81(m,4H),2.50(br s,2H),2.30(br s,1H),2.05-1.68(m,3H),1.57-1.43(m,12H),0.90-0.69(m,9H),0.13-0.06(m,6H).
Step 6 Compounds 22-6-1 and 22-6-2
(2R, 4 aR) -tert-butyl-10-bromo-11-chloro-9-fluoro-7- ((S) -2-hydroxy-1- ((S) -1-methylpyrrolidin-2-yl) ethoxy) -2-methyl-5-carbonyl-4, 4a,5, 6-tetrahydro-1H-pyran-biazino [1',2':4,5] pyran-biazino [2,3-c ] quinoline-3 (2H) -carboxylic acid ester and (2R, 4 aR) -tert-butyl-10-bromo-11-chloro-9-fluoro-7- ((R) -2-hydroxy-1- ((S) -1-methylpyrrolidin-2-yl) ethoxy) -2-methyl-5-carbonyl-4, 4a,5, 6-tetrahydro-1H-pyran biazino [1',2':4,5] pyran biazino [2,3-c ] quinoline-3 (2H) -carboxylic acid ester
Compound 22-5-1 (3.5 g,4.62mmol,1 eq) was dissolved in tetrahydrofuran (42 mL), tetrabutylammonium fluoride solution (1M, 6.93mL,1.5 eq) was added, stirred at room temperature for 4 hours, LCMS detection was complete, the reaction was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give crude compound 22-6-1 (3.2 g), as a pale brown solid, which was directly put into the next reaction.
MS m/z:642.2/644.2[M+H] + .
Compound 22-5-2 (1 g,1.32mmol,1 eq) was dissolved in tetrahydrofuran (5 mL), tetrabutylammonium fluoride solution (1M, 2.38mL,1.8 eq) was added, stirred at room temperature for 1 hour, the reaction was checked for completion by LCMS, the reaction solution was extracted with water and ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography [ methanol (0.5% aqueous ammonia)/dichloromethane: 0-5% ], to give compound 22-6-2 (550 mg, yield 64.77%) as a yellow solid.
MS m/z:642.0/644.0[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ8.86(br s,1H),7.82(br s,1H),5.72(br s,1H),5.00-4.70(m,1H),4.55-4.25(m,1H),4.14(dd,J＝6.4,11.7Hz,1H),3.93(dd,J＝4.0,11.5Hz,1H),3.82-3.19(m,4H),3.14-2.82(m,3H),2.75(br s,3H),2.62-2.40(m,1H),2.19-1.69(m,4H),1.62-1.46(m,12H).
Step 7 Compounds 22-7-1 and 22-7-2
(2R, 4aR, 7R) -tert-butyl-11-bromo-12-chloro-10-fluoro-2-methyl-7- ((S) -1-methylpyrrolidin-2-yl) -5-carbonyl-1, 2,4a,5,6, 7-hexahydro-8-oxa-3, 5a,9,13 c-tetraazanaphtho [3,2,1-de ] anthracene-3 (4H) -carboxylic acid ester and (2R, 4aR, 7S) -tert-butyl-11-bromo-12-chloro-10-fluoro-2-methyl-7- ((S) -1-methylpyrrolidin-2-yl) -5-carbonyl-1, 2,4a,5,6, 7-hexahydro-8-oxa-3, 5a,9,13 c-tetraazanaphtho [3,2,1-de ] anthracene-3 (4H) -carboxylic acid ester
Triphenylphosphine (1.41 g,5.37mmol,3 eq) was dissolved in tetrahydrofuran (30 mL) and diisopropyl azodicarboxylate (1.09 g,5.37mmol,3 eq) was added at 0deg.C and reacted for 30 min at 0deg.C. The crude compound 22-6-1 (1.15 g,1.79mmol,1 eq) was dissolved in tetrahydrofuran (6 mL), added dropwise to the reaction at 0deg.C, and stirred overnight at room temperature. LCMS monitored completion of the reaction, extraction of the reaction with water, washing with saturated brine, drying over anhydrous sodium sulfate, filtration and concentration, and purification of the residue by HPLC gave compound 22-7-1 (260 mg, 23.26% yield) as a pale yellow solid.
MS m/z:624.2/626.2[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ7.82(s,1H),4.72-4.52(m,2H),4.38-4.10(m,2H),3.96-3.80(m,1H),3.48(br d,J＝11.0Hz,1H),3.09-2.94(m,2H),2.87(br d,J＝12.0Hz,1H),2.73(td,J＝4.7,9.0Hz,1H),2.42-2.37(m,3H),2.31-2.23(m,1H),2.04-1.91(m,1H),1.88-1.67(m,3H),1.47-1.41(m,12H).
HPLC separation conditions:
column YMC Triart C18.times.50 mm.times.7um;
mobile phase A Water (0.05%ammonia hydroxide v/v) mobile phase B ACN;
54% -94% of mobile phase B, 9min
Triphenylphosphine (673.11 mg,2.57mmol,3 eq) was dissolved in tetrahydrofuran (3 mL), diisopropyl azodicarboxylate (518.93 mg,2.57mmol,3 eq) was added at 0deg.C and reacted for 30 min at 0deg.C. Compound 22-6-2 (550 mg,0.855mmol,1 eq) was dissolved in tetrahydrofuran (4.5 mL) and added dropwise to the reaction at 0deg.C and stirred overnight at room temperature. LCMS monitored completion of the reaction, the reaction was concentrated by filtration and the residue was purified by column chromatography [ methanol (0.5% aqueous ammonia)/dichloromethane: 0-5% ], and further purification by HPLC gave compound 22-7-2 (435 mg, yield 81.37%) as a white solid.
MS m/z:624.1/626.1[M+H] + .
1 H NMR(400MHz,CDCl 3 )δ7.82(d,J＝1.8Hz,1H),5.02-4.90(m,1H),4.83(br s,1H),4.59-4.24(m,1H),4.12(br dd,J＝5.8,13.8Hz,1H),3.94(dd,J＝3.3,13.8Hz,1H),3.79-3.19(m,3H),3.08-2.93(m,2H),2.88(q,J＝7.5Hz,1H),2.61(br s,3H),2.50-2.35(m,1H),2.10-1.74(m,4H),1.52(br s,9H),1.26(d,J＝6.3Hz,3H).
HPLC separation conditions:
column YMC Triart C18.times.50 mm.times.7um;
mobile phase A Water (0.225% FA), mobile phase B ACN;
mobile phase B percent is 29-69 percent and 9min.
Step 8-Compounds 22-8-1, 22-8-2 and 22-8-3
(2R, 4aR, 7R) -tert-butyl-12-chloro-10-fluoro-11- ((R) -2-fluoro-6-hydroxyphenyl) -2-methyl-7- ((S) -1-methylpyrrolidin-2-yl) -5-carbonyl-1, 2,4a,5,6, 7-hexahydro-8-oxa-3, 5a,9,13 c-tetralinimidazo [3,2,1-de ] anthracene-3 (4H) -carboxylate (2R, 4aR, 7R) -tert-butyl-12-chloro-10-fluoro-11- ((S) -2-fluoro-6-hydroxyphenyl) -2-methyl-7- ((S) -1-methylpyrrolidin-2-yl) -5-oxo-1, 2,4a,5,6, 7-hexahydro-8-oxa-3, 5a,9,13 c-tetralino [3,2,1-de ] anthracene-3 (4H) -carboxylic acid ester and (2R, 4aR, 7S) -tert-butyl-12-chloro-10-fluoro-11- (2-fluoro-6-hydroxyphenyl) -2-methyl-7- ((S) -1-methylpyrrolidin-2-yl) -5-oxo-1, 2,4a,5,6, 7-hexahydro-8-oxa-3, 5a,9,13 c-tetralino [3,2,1-de ] anthracene-3 (4H) -carboxylic acid ester
To a mixed solution of compound 22-7-1 (280 mg, 0.447 mmol,1 eq), potassium trifluoroborate (2-fluoro-6-hydroxyphenyl) (390.70 mg,1.79mmol,4 eq), potassium carbonate (185.77 mg,1.34mmol,3 eq), and water (1.5 mL) was dissolved, and methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (74.95 mg,0.090mmol,0.2 eq) was added, followed by nitrogen substitution, and the mixture was reacted at 80℃for 2 hours. LCMS monitored reaction was complete. The reaction solution was concentrated, and the crude product was purified by plate separation (petroleum ether: tetrahydrofuran: ammonia water=1:2:0.015) to give compound 22-8-1 (80 mg, yield 27.21%, pale yellow solid) and compound 22-8-2 (100 mg, yield 34.02%, pale yellow solid).
Compound 22-8-1:
MS m/z:656.3/658.3[M+H] + .
compound 22-8-2:
MS m/z:656.3/658.3[M+H] + .
to a mixed solution of 22-7-2 (400 mg, 0.6407 mmol,1 eq), potassium trifluoroborate (2-fluoro-6-hydroxyphenyl) salt (558.14 mg,2.56mmol,4 eq), potassium carbonate (265.39 mg,1.92mmol,3 eq), dissolved in dioxane (4.5 mL) and water (1.5 mL), methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (ii) (107.07 mg,0.12801mmol,0.2 eq) was added, and after nitrogen substitution, the mixture was reacted at 80℃for 5 hours. LCMS monitored reaction was complete. The reaction solution was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography [ tetrahydrofuran (containing 0.5% aqueous ammonia)/petroleum ether: 0-66% ], to give compound 22-8-3 (220 mg, yield 52.39%) as a yellow solid.
MS m/z:656.3/658.3[M+H] + .
Step 9 Compounds 22-9-1, 22-9-2 and 22-9-3
(2R, 4aR, 7R) -12-chloro-10-fluoro-11- ((R) -2-fluoro-6-hydroxyphenyl) -2-methyl-7- ((S) -1-methylpyrrolidin-2-yl) -2,3, 4a,6, 7-hexahydro-8-oxa-3, 5a,9,13 c-tetrazino [3,2,1-de ] anthracene-5 (1H) -one, (2R, 4aR, 7R) -12-chloro-10-fluoro-11- ((S) -2-fluoro-6-hydroxyphenyl) -2-methyl-7- ((S) -1-methylpyrrolidin-2-yl) -2,3, 4a,6, 7-hexahydro-8-oxa-3, 5a,9,13 c-tetrazino [3,2,1-de ] anthracene-5 (1H) -one and (2R, 4aR, 7S) -12-chloro-10-fluoro-11- (2-fluoro-6-hydroxyphenyl) -2-methyl-7- ((S) -1-methylpyrrolidin-2-yl) -2,3, 4a,6, 7-hexahydro-8-oxa-3, 9,13 c-tetrazino [3,2, 1-H) -one
Compound 22-8-1 (80 mg,0.122mmol,1 eq) was dissolved in dichloromethane (1.2 mL), trifluoroacetic acid (0.4 mL) was added, and the mixture was stirred at room temperature for 1 hour. LCMS monitored completion of the reaction and concentrated the reaction to give crude compound 22-9-1 (120 mg) as a pale brown oil which was directly taken to the next reaction.
MS m/z:556.3/558.3[M+H] + .
The compound 22-9-2 crude product (135 mg) is prepared by adopting a synthesis method of the compound 22-9-1 and taking the compound 22-8-2 as a raw material.
MS m/z:556.3/558.3[M+H] + .
The compound 22-9-3 crude product (260 mg) is prepared by adopting a synthesis method of the compound 22-9-1 and taking the compound 22-8-3 as a raw material.
MS m/z:556.3/558.3[M+H] + .
Step 10 Compounds 22-P1, 22-P2, 22-P3 and 22-P4
(2R, 4aR, 7R) -3-propenoyl-12-chloro-11- ((R) -2-fluoro-6-hydroxyphenyl) -2-methyl-7- ((S) -1-methylpyrrolidin-2-yl) -2,3, 4a,6, 7-hexahydro-8-oxa-3, 5a,9,13 c-tetrazino [3,2,1-de ] anthracene-5 (1H) -one, (2R, 4aR, 7R) -3-propenoyl-12-chloro-10-fluoro-11- ((S) -2-fluoro-6-hydroxyphenyl) -2-methyl-7- ((S) -1-methylpyrrolidin-2-yl) -2,3, 4a,6, 7-hexahydro-8-oxa-3, 5a,9,13 c-tetrazino [3,2,1-de ] anthracene-5 (1H) -one, (2R, 4aR, 7S) -3-propenoyl-12-chloro-10-fluoro-11- ((R) -2-fluoro-6-hydroxyphenyl) -2-methyl-7- ((S) -1-methylpyrrolidin-2-yl) -2,3, 4a,6, 7-hexahydro-8-oxa-3, 5a,9,13 c-tetrazino [3,2,1-de ] anthracene-5 (1H) -one and (2R, 4aR, 7S) -3-propenoyl-12-chloro-10-fluoro-11- ((S) -2-fluoro-6-hydroxyphenyl) -2-methyl-7- ((S) -1-methylpyrrolidin-2-yl) -2,3, 4a,6, 7-hexahydro-8-oxa-3, 5a,9,13 c-tetrazino [3,2,1-de ] anthracene-5 (1H) -one
The crude compound 22-9-1 (120 mg,0.122mmol,1 eq) and triethylamine (98.70 mg,0.975mmol,8 eq) were dissolved in dichloromethane (2 mL) and acryloyl chloride (11.04 mg,0.122mmol,1 eq) was slowly added at-70℃and reacted at-70℃for 30 min. LCMS detected complete reaction. The reaction mixture was quenched with saturated brine, extracted with dichloromethane and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate, addition of methanolic amine (7M, 2mL,14 mmol) to the residue at room temperature, half an hour of reaction, LCMS monitored completion of the reaction. The reaction solution was concentrated, and the residue was purified by HPLC to give compound 22-P1 (16.5 mg, yield: 22.1%) as a white solid.
MS m/z:610.3/612.3[M+H] + .
19 F NMR(376MHz,CDCl 3 )δ-112.10(s,1F),-116.84(s,1F).
1 H NMR(400MHz,CDCl 3 )δ7.86(s,1H),7.37-7.28(m,1H),6.99(br dd,J＝10.8,16.7Hz,1H),6.87(br d,J＝8.1Hz,1H),6.78(br t,J＝8.4Hz,1H),6.36(br d,J＝17.0Hz,1H),5.81(br d,J＝11.1Hz,1H),4.95(br s,1H),4.85-4.68(m,2H),4.24(br s,1H),3.89-3.77(m,1H),3.74(br s,1H),3.37-2.85(m,5H),2.67-2.32(m,4H),2.16-1.75(m,4H),1.68-1.61(m,3H).
HPLC separation conditions:
column Phenomenex Gemini-NX 80 x 40mm x 3um;
mobile phase A Water (0.05%ammonia hydroxide v/v) mobile phase B ACN;
mobile phase B percent of 29 to 69 percent for 9 minutes
The compound 22-P2 (15.8 mg, yield 17.0%) was obtained as a white solid by using the synthesis method of the compound 22-P1, preparing the crude compound 22-9-2 as a raw material and purifying the crude compound by HPLC.
MS m/z:610.3/612.3[M+H] + .
19 F NMR(376MHz,CDCl 3 )δ-112.30(s,1F),-116.53(s,1F).
1 H NMR(400MHz,CDCl 3 )δ7.79(s,1H),7.33-7.27(m,1H),7.06-6.83(m,2H),6.75(br t,J＝8.6Hz,1H),6.34(br d,J＝16.6Hz,1H),5.78(br d,J＝10.9Hz,1H),5.48-4.87(m,1H),4.77(br t,J＝12.4Hz,2H),4.28(br s,1H),3.86-3.61(m,2H),3.41-2.85(m,5H),2.70-2.40(m,4H),2.16-1.78(m,4H),1.63(br d,J＝6.5Hz,3H).
HPLC separation conditions:
column Phenomenex Gemini-NX 80 x 40mm x 3um;
mobile phase A Water (0.05%ammonia hydroxide v/v) mobile phase B ACN;
28% -68% of mobile phase B, 9min
The crude compound 22-9-3 (186 mg,0.3345mmol,1 eq) and triethylamine (270.81 mg,2.68mmol,8 eq) were dissolved in dichloromethane (3 mL), and acryloyl chloride (60.56 mg,0.6691mmol,2 eq) was slowly added at-70℃and reacted at-70℃for 30 min. LCMS detected complete reaction. The reaction solution was quenched with saturated brine, extracted with dichloromethane, washed with saturated sodium bicarbonate, and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate, addition of methanolic amine (7M, 2mL,14 mmol) to the residue at room temperature, half an hour of reaction, LCMS monitored completion of the reaction. The reaction solution was concentrated, and the residue was purified by two HPLC to give compound 22-P3 (30 mg, yield 13.92%, white solid) and compound 22-P4 (35 mg, yield 17.02%, white solid).
HPLC separation conditions:
columns Phenomenex Gemini NX-C18 (75 x 30mm x 3 um);
mobile phase A Water (0.05%ammonia hydroxide v/v) mobile phase B ACN;
36% -76% of mobile phase B and 9min.
Columns Phenomenex Gemini NX-C18 (75 x 30mm x 3 um);
mobile phase A Water (0.225% FA), mobile phase B ACN;
10% -50% of mobile phase B and 9min.
Compound 22-P3:
MS m/z:610.0/612.0[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ10.21(br s,1H),7.83(br s,1H),7.41-7.28(m,1H),7.07-6.74(m,3H),6.14(dd,J＝2.1,16.7Hz,1H),5.81-5.66(m,1H),5.17-4.35(m,3H),4.16-3.98(m,2H),3.87-3.68(m,2H),3.33-2.92(m,3H),2.73-2.59(m,1H),2.33(br s,3H),2.25-2.10(m,1H),1.84(br s,1H),1.75-1.61(m,3H),1.57-1.39(m,3H).
19 F NMR(376MHz,DMSO-d 6 )δ-113.71(s,1F),-119.41(s,1F).
compound 22-P4:
MS m/z:610.0/612.0[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ10.32(br s,1H),7.84(br s,1H),7.33(q,J＝7.9Hz,1H),7.08-6.73(m,3H),6.15(dd,J＝2.1,16.7Hz,1H),5.83-5.67(m,1H),5.19-4.36(m,3H),4.17-3.99(m,2H),3.89-3.71(m,2H),3.22-2.83(m,3H),2.71-2.57(m,1H),2.33(s,3H),2.24-2.10(m,1H),1.83(br d,J＝4.0Hz,1H),1.75-1.60(m,3H),1.59-1.43(m,3H).
19 F NMR(376MHz,DMSO-d 6 )δ-113.71(s,1F),-119.63(s,1F).
retention time (Compound 22-P3): 1.238min; retention time (Compound 22-P4): 0.927min.
Column: chiralpak IG-3 50*4.6mm I.D,3um
Mobile phase: a is CO 2 Ethanol (0.05% DEA); isocratic 40% B
Flow rate of 4mL/min
Column temperature of 35 DEG C
ABPR:1500psi
Test example 1: proliferation inhibitory Activity against Ba/F3KRAS-G12C, NCI-H358 and MIA PaCa-2 cells containing KRAS G12C mutations
The method is used for determining proliferation inhibition activity of the compound or salt thereof on a mouse primordial B cell Ba/F3KRAS-G12C cell strain which stably expresses KRAS G12C mutant protein and a non-small cell lung cancer NCI-H358 cell strain and pancreatic cancer MIA PaCa-2 cell strain which express the KRAS G12C mutant protein in vitro.
Cell source: ba/F3KRAS-G12C is purchased from Kang Yuanbo Biotechnology (Beijing) Inc., cat# KC-1260; NCI-H358 was purchased from Shanghai Dijin Biotechnology Co., ltd; MIA PaCa-2 was purchased from Shanghai Diaoko biotechnology Co.
Inoculating cells in logarithmic phase into 96-well plate (Ba/F3 KRAS-G12C, NCI-H358, MIA PaCa-2 cells 5000,3000,1000/well, 90 μl/well, respectively), 37℃and 5% CO 2 After 1 day of incubation, a gradient of the test compound or salt thereof is added. The method comprises the following steps: stock solutions (10 mM) of the compound or its salt dissolved in DMSO beforehand were diluted to 10 gradient concentrations at a ratio of 4 times and diluted to 10 times the target concentration in another 96-well plate with medium, and then 10. Mu.l/well of the solution of the compound or its salt was added to the 96-well plate inoculated with cells, i.e., the target concentration (10000, 2500,625,156,39,10,2.5,0.6,0.15,0.04 nM) was reached. 3 duplicate wells were set for each concentration, and a blank was set. Placing in 37 ℃ and 5% CO 2 After a further incubation of 72h, 50. Mu.l CellTiter-2.0 reagent (luciferase ATP bioluminescence detection reagent, available from Promega, cat No. G9243), shaking for 2min, incubating at room temperature for 8min, and detecting fluorescence intensity (light receiving time 100 ms). Calculating the inhibition ratio of each concentration of the compound or the salt thereof to cell proliferation (inhibition ratio of cell proliferation= [ (luminous intensity) 72 hour Medium control group Luminous intensity 72 hour group of compounds or salts thereof ) (luminous intensity) 72 hour Medium control group Luminous intensity Control group of 0 hour medium )]X 100%) data were analyzed using GraphPad Prism 5.0 software, non-linear S-curve regression was used to fit the data to derive the dose-response curve, and IC was calculated therefrom 50 Values, results are shown in Table 1.
TABLE 1

Claims (21)

1. A process for the preparation of compound III-1, characterized in that it comprises the steps of: in a solvent, reacting the compound IV with fumaric acid to form a salt to obtain a compound III-1;
the compound IVIs->Mixtures in any ratio.
2. The process for the preparation of compound III-1 according to claim 1, characterized in that it satisfies one or more of the following conditions:
(1) The solvent being an alcoholic solvent, e.g. C 1-4 Alcohol solvents of (2) are, for example, isopropanol;
(2) The volume to mass ratio of the solvent to the compound IV is 3-10mL/g, preferably 6-8mL/g, for example 5mL/g;
(3) The molar ratio of fumaric acid to the compound IV is from 0.1 to 10:1, preferably from 0.1 to 1:1, for example 0.5:1;
(4) The temperature of the salification reaction is 10-60 ℃, such as 50 ℃ or 20-25 ℃; for example, the reaction is carried out for 1 to 2 hours at the temperature of 20 to 25 ℃, the reaction is carried out for 2 to 3 hours at the temperature of 50 to 60 ℃, and the reaction is carried out for 8 to 12 hours at the temperature of 20 to 25 ℃;
(5) The reaction time of the salification reaction is 0.5-120h, for example 12h;
(6) The compound IV isThe proportion is 1-10:1, a mixture of two or more of the above-mentioned materials; for example 5-7:1; for example, 6:1; and
(7) The purity of the compound III-1 is 96.7%.
3. A process for the preparation of compound III-2, characterized in that it comprises the steps of: in a solvent, carrying out salt formation reaction on the compound IV and R-binaphthol phosphate to obtain a compound III-2;
the compound IVIs->Mixtures in any ratio.
4. A process for the preparation of compound III-2 according to claim 3, characterized in that it satisfies one or more of the following conditions:
(1) In the salt forming reaction, the solvent is an alcohol solvent, such as C 1-4 Alcohol solvents of (2) are, for example, methanol;
(2) In the salification reaction, the volume-mass ratio of the solvent to the compound IV is 2-10mL/g, preferably 2-6mL/g, for example 3mL/g or 5mL/g;
(3) The molar ratio of said R-binaphthol phosphate to said compound IV is from 0.1 to 1:1, preferably from 0.5 to 0.9:1, for example 0.83:1;
(4) The salt forming reaction temperature is 10-80 ℃, such as 70 ℃, 30-35 ℃ or 20-25 ℃; for another example, the salification reaction includes the steps of: in a solvent, mixing the compound IV with R-binaphthol phosphate, and reacting for 8-12h at 20-25 ℃;
(5) The reaction time of the salification reaction is 0.5-48h, for example 12h;
(6) The salification reaction comprises the following post-treatment steps: after the reaction is finished, filtering, pulping by using an organic solvent, and filtering; the organic solvent is C 1-4 Alcohol solvents of (2) such as methanol;
(7) The compound IV isThe proportion is 1-10:1, a mixture of two or more of the above-mentioned materials; for example 5-7:1; for example, 6:1; and
(8) The purity of the compound III-2 is 93.97%.
5. The process for the preparation of compound III-1 or III-2 according to any one of claims 1 to 4, further comprising the steps of: in a solvent, in the presence of a reducing agent, carrying out a reduction reaction on the compound V to obtain a compound IV;
the compound VIs->Mixtures in any ratio; the compound IVIs->Mixtures in any ratio.
6. The process for the preparation of compound III-1 or III-2 according to claim 5, wherein one or more of the following conditions are satisfied:
(1) In the reduction reaction, the reducing agent is an organometallic reducing agent, more preferably lithium aluminum tetrahydroide and/or red aluminum, for example lithium aluminum tetrahydroide;
(2) In the reduction reaction, the molar ratio of the reducing agent to the compound V is 2-5:1, for example 3:1;
(3) In the reduction reaction, the solvent is an ether solvent, such as tetrahydrofuran;
(4) In the reduction reaction, the volume-mass ratio of the solvent to the compound V is 2-20mL/g, for example, 5mL/g or 17.7mL/g;
(5) The temperature of the reduction reaction is 10-80 ℃, for example 70 ℃;
(6) The reaction time of the reduction reaction is 0.5-48h, for example 12h;
(7) The compound VIs->The proportion is 5-7:1, for example 5.6:1, a step of; and
(8) The compound IVIs->The proportion is 1-10:1, a mixture of two or more of the above-mentioned materials; for example 5-7:1; and for example 6:1.
7. The process for the preparation of compound III-1 or III-2 according to claim 5 or 6, further comprising the steps of: in the solvent, in (DHQD) 2 In the presence of PHAL, potassium osmium sulfate and a co-oxidant, the compound VI undergoes asymmetric dihydroxylation; the solvent is a mixed solvent of tetrahydrofuran and water; obtaining a compound V;
the compound VIs->Mixtures in any ratio.
8. The process for the preparation of compound III-1 or III-2 according to claim 7, wherein one or more of the following conditions are satisfied:
(1) In the asymmetric dihydroxylation reaction, the volume ratio of the tetrahydrofuran to the water in the mixed solvent is 1-20:1; preferably, 4-8:1; for example 6.5:1;
(2) In the asymmetric dihydroxylation reaction, the volume-mass ratio of the tetrahydrofuran to the compound VI is 1-50mL/g; for example 13mL/g;
(3) In the asymmetric dihydroxylation reaction, the potassium osmium is a hydrate of potassium osmium, such as potassium osmium dihydrate;
(4) In the asymmetric dihydroxylation reaction, the auxiliary oxidant is 4-methylmorpholine oxide and/or potassium ferricyanide; for example 4-methylmorpholine oxide;
(5) In the asymmetric dihydroxylation reaction, the compounds VI and (DHQD) 2 The mole ratio of PHAL is 1:0.0001-1; preferably, the ratio is 1:0.01-0.5; for example 1:0.02;
(6) In the asymmetric dihydroxylation reaction, the molar ratio of the compound VI to the auxiliary oxidant is 1:1-10; preferably, the ratio is 1:2-4; for example 1:3;
(7) In the asymmetric dihydroxylation reaction, the molar ratio of the compound VI to potassium hundredthate is 1:0.0001-1; more preferably, 1:0.005-0.02; for example 1:0.02;
(8) In the asymmetric dihydroxylation reaction, the reaction temperature of the asymmetric dihydroxylation reaction is-30-50 ℃, for example-10-0 ℃;
(9) The reaction time of the asymmetric dihydroxylation reaction is 1-50h, for example 12h;
(10) The asymmetric dihydroxylation reaction also comprises the following post-treatment steps: quenching reaction of sodium sulfite and extraction of organic solvent;
(11) The asymmetric dihydroxylation reaction is carried out by the following steps:
step 1: preparation of aqueous potassium osmium acid solutions, said aqueous potassium osmium acid solutions and (DHQD) 2 Mixing PHAL and tetrahydrofuran to obtain a mixture A;
step 2: said mixture a is mixed with said co-oxidant and said compound VI;
in step 1, preferably, the aqueous solution of potassium osmium is combined with (DHQD) at a temperature of-10 to 0 DEG C 2 Mixing PHAL and tetrahydrofuran, and stirring for 10-20min to obtain mixture A;
in step 2, preferably, the mixture a is mixed with the pro-oxidant and the compound VI sequentially, for example, after the mixture a is mixed with the pro-oxidant, a mixture B is obtained, and the compound VI is added to the mixture B; for another example, the compound VI is added to the mixture B in such a way that a tetrahydrofuran solution of the compound VI is added dropwise to the mixture B; and
(12) Compound VIs->The proportion is 5-7:1, for example 5.6:1.
9. the process for the preparation of compound III-1 or III-2 according to claim 7 or 8, further comprising the steps of: in a solvent, in the presence of alkali, performing nucleophilic addition reaction on the compound VII and a phosphorus ylide reagent to obtain a compound VI;
10. The process for the preparation of compound III-1 or III-2 according to claim 9, characterized in that it satisfies one or more of the following conditions:
(1) In the nucleophilic addition reaction, the solvent is a polar solvent, for example, a polar ether solvent, and further, for example, tetrahydrofuran;
(2) In the nucleophilic addition reaction, the volume to mass ratio of the solvent to the compound VII is 5-30mL/g, for example 20mL/g;
(3) In the nucleophilic addition reaction, the phosphorus ylide reagent is methyl triphenyl phosphorus bromide;
(4) In the nucleophilic addition reaction, the molar ratio of the phosphorus ylide reagent to the compound VII is 1-5:1, preferably 2-3:1, for example 2.05:1;
(5) In the nucleophilic addition reaction, the base is an organic base, such as an alkali metal alkoxide, and further such as potassium tert-butoxide and/or sodium tert-butoxide;
(6) In the nucleophilic addition reaction, the molar ratio of the base to the compound VII is 1-5:1, preferably 2-3:1, for example 2:1;
(7) The reaction temperature of the nucleophilic addition reaction is 0-50 ℃, for example 20-25 ℃;
(8) The reaction time of the nucleophilic addition reaction is 0.5 to 5 hours, for example 1 to 3 hours;
(9) The nucleophilic addition reaction is carried out under anhydrous and anaerobic conditions;
(10) The nucleophilic addition reaction comprises the following post-treatment steps: quenching, extracting and concentrating; and
(11) The nucleophilic addition reaction comprises the following steps:
s1: mixing alkali, phosphorus ylide reagent and organic solvent to obtain a mixture, and reacting the mixture for 1-2h;
s2: to the mixture, compound VII is added; the compound VII is preferably added dropwise to the mixture after the compound VII forms a solution with the organic solvent.
11. A process for the preparation of compound I, characterized in that it comprises the steps of: in a solvent, in the presence of alkali, carrying out substitution reaction on the compound III-1 or III-2 and PGCl to obtain a compound I;
the PG isWherein R is 1 、R 2 And R is 3 Each independently is C 1-4 An alkyl group.
12. A process for the preparation of compound I according to claim 11, characterized in that it satisfies one or more of the following conditions:
(1) The PGCl is trimethyl chlorosilane, triethyl chlorosilane, tri-tert-butyl chlorosilane, tert-butyl diphenyl chlorosilane, triisopropyl chlorosilane, dimethyl isopropyl chlorosilane, tert-butyl dimethyl chlorosilane, methyl diisopropyl chlorosilane or triisopropyl chlorosilane; preferably t-butyldimethylchlorosilane;
(2) The PG is trimethyl silicon base, triethyl silicon base, tri-tert-butyl silicon base, tert-butyl diphenyl silicon base, triisopropyl silicon base, dimethyl isopropyl silicon base, tert-butyl dimethyl silicon base, methyl diisopropyl silicon base or triisopropyl silicon base; preferably tert-butyldimethylsilyl, i.e. the compound I is
(3) In the substitution reaction, the base is an organic base, such as imidazole;
(4) In the substitution reaction, the molar ratio of the base to the compound III-1 or III-2 is 2 to 5:1, for example 3:1;
(5) In the substitution reaction, the solvent is halogenated hydrocarbon, such as chlorinated hydrocarbon; further for example dichloromethane;
(6) In the substitution reaction, the volume-mass ratio of the solvent to the III-1 or III-2 is 8-16mL/g, for example, 12mL/g;
(7) In the substitution reaction, the molar ratio of PGCl to III-1 or III-2 is 0.8-2:1, for example, 1.2:1; and
(8) The preparation method of the compound I also comprises the following steps of; the steps are method 1 or method 2:
in the method 1, in a solvent, a compound IV reacts with fumaric acid to form a salt to obtain a compound III-1;
the compound IVIs->Mixtures in any ratio; the salification reaction may be as defined in any one of claims 2 and 4 to 10;
In the method 2 and in a solvent, the compound IV and R-binaphthol phosphate react to form a salt to obtain a compound III-2;
the compound IVIs->Mixtures in any ratio; the salification reaction may be as defined in any one of claims 3 and 4 to 10.
13. A process for the preparation of compound II, characterized in that it comprises the steps of: in a solvent, reacting the compound I with succinic acid to form salt to obtain a compound II;
the PG being as defined in claim 11 or 12.
14. The process for the preparation of compound II according to claim 13, characterized in that it satisfies one or more of the following conditions:
(1) The compound II is
(2) In the salification reaction, the solvent is an ether solvent and/or an alcohol solvent; the ether solvent can be C 3-7 An ether solvent of (2); the alcohol solvent can be C 1-4 Alcohol solvents; for example, the solvent is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, and methanol;
(3) In the salification reaction, the volume-mass ratio of the solvent to the compound I is 2-20mL/g, preferably 2-15mL/g, such as 3mL/g or 13mL/g;
(4) In the salification reaction, the molar ratio of the succinic acid to the compound I is 0.1-2:1; for example 1.2:1;
(5) The temperature of the salification reaction is 10-80 ℃, such as 50 ℃ or 20-25 ℃;
(6) The reaction time of the salification reaction is 0.5-48h, for example 4-10h;
(7) The salification reaction comprises the following steps: mixing the compound I with the solvent at 20-25 ℃, adding an alcohol solution of succinic acid, heating to 50-60 ℃, reacting for 0.5-4h, and cooling to 20-25 ℃;
(8) The salification reaction also comprises the following post-treatment steps: concentrating to obtain concentrate after the reaction is finished; pulping; preferably, the solvent for beating is preferably 2-methyltetrahydrofuran and methyl tertiary butyl ether; preferably, the concentration further comprises a process of adding 2-methyltetrahydrofuran for rotary evaporation; more preferably, the pulping process is to add 2-methyltetrahydrofuran, react for 1-3 hours, then add methyl tertiary butyl ether, react for 3-5 hours; for example, the volume to mass ratio of the 2-methyltetrahydrofuran to the concentrate is 10-20mL/g, and the volume to mass ratio of the methyl tertiary butyl ether to the concentrate is 10-20mL/g; the methyl tertiary butyl ether is added dropwise; and
(9) The preparation method of the compound II further comprises the following steps: in a solvent, in the presence of alkali, carrying out substitution reaction on the compound III-1 or III-2 and PGCl to obtain a compound I;
The PG being as defined in claim 11 or 12; the substitution reaction may be as described in claim 11 or 12.
15. A process for the preparation of compound I, characterized in that it comprises the steps of: in a solvent, in the presence of alkali, performing hydrolysis reaction on the compound II to obtain a compound I;
the PG being as defined in claim 11 or 12.
16. A process for the preparation of compound I according to claim 15, characterized in that it satisfies one or more of the following conditions:
(1) In the hydrolysis reaction, the solvent is halogenated hydrocarbon, and is, for example, chlorinated hydrocarbon; and for example dichloromethane;
(2) In the hydrolysis reaction, the base is an inorganic base such as a metal carbonate, for example, sodium carbonate;
(3) The alkali is in the form of an aqueous alkali solution;
(4) The amount of base is such that the pH of the system is adjusted to 8-10, e.g. to 8-9;
(5) The temperature of the hydrolysis reaction is 10-80 ℃, for example 10-35 ℃; for example, from 20 to 25 ℃;
(6) The reaction time of the hydrolysis reaction is 0.5-48h, for example 4-10h;
(7) The hydrolysis reaction also comprises the following post-treatment steps: extracting, concentrating to obtain concentrate, pulping with organic solvent, and filtering; the organic solvent may be a hydrocarbon solvent, such as n-heptane; the volume mass of the organic solvent and the concentrate may be 6-12mL/g; for example 10mL/g; and
(8) The preparation method of the compound I also comprises the following steps: in a solvent, reacting the compound I with succinic acid to form salt to obtain a compound II;
the PG being as defined in claim 11 or 12; the salification reaction may be as described in claim 13 or 14.
17. A pyrrolidine compound, characterized in that it is any one of the following compounds:
wherein the PG is as defined in claim 11 or 12A mixture of III-1 and III-1' in any proportion;Is a mixture of III-2 and III-2' in any proportion.
18. A process for the preparation of a pyrrolidine compound, characterized in that it comprises the steps of:
the steps are method 1 or method 2:
in the method 1, in a solvent, reacting a compound IV-1 with fumaric acid to form a salt to obtain a compound III-1;
the salification reaction may be as claimed in claim 2; or (b)
In the method 2 and in a solvent, the compound IV-1 and R-binaphthol phosphate react to form a salt to obtain a compound III-2;
the salification reaction can be as claimed in claim 4.
19. Application of fumaric acid as chiral resolving agent of pyrrolidine compound, wherein the pyrrolidine compound isSaid->Is->Mixtures in any ratio; preferably, in said application, said pyrrolidine compound is reacted with fumaric acid to form a salt, said salt forming reaction being as defined in claim 1 or 2.
Use of R-binaphthol phosphate or S-binaphthol phosphate as chiral resolving agent for pyrrolidine compounds, said pyrrolidine compounds beingSaid->Is->Mixtures in any ratio; preferably, in the application, the pyrrolidine compound reacts with R-binaphthol phosphate to form a salt, and the salt forming reaction can be as described in claim 3 or 4.
21. A process for the preparation of compound V, characterized in that it comprises the following steps: in the solvent, in (DHQD) 2 In the presence of PHAL, potassium osmium sulfate and a co-oxidant, the compound VI undergoes asymmetric dihydroxylation; obtaining a compound V; the solvent is a mixed solvent of tetrahydrofuran and water;
the compound VIs->Mixtures in any ratio;
the asymmetric dihydroxylation reaction may be as described in claim 7 or 8;
the preparation method of the compound V can further comprise the following steps: in a solvent, in the presence of alkali, performing nucleophilic addition reaction on the compound VII and a phosphorus ylide reagent to obtain a compound VI;
the nucleophilic addition reaction may be as described in claim 9 or 10. />
CN202210834303.8A 2022-07-14 2022-07-14 Pyrrolidine compound and preparation method thereof Pending CN117430540A (en)

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