CN106928114B - Cyclic chiral amino compound containing carbamido group and its amplifying process and use - Google Patents
Cyclic chiral amino compound containing carbamido group and its amplifying process and use Download PDFInfo
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- CN106928114B CN106928114B CN201511027676.0A CN201511027676A CN106928114B CN 106928114 B CN106928114 B CN 106928114B CN 201511027676 A CN201511027676 A CN 201511027676A CN 106928114 B CN106928114 B CN 106928114B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D207/04—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 no double bonds between ring members or between ring members and non-ring members
- C07D207/10—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 no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/14—Nitrogen atoms not forming part of a nitro radical
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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Abstract
A cyclic chiral amino compound containing ureido used as medical intermediate for preparing various cyclic chiral acyl containing ureidoAn ammonia compound. A process for preparing the cyclic chiral amino compound containing ureido includes such steps as reaction between amino alcohol hydrochloride and substituted carbamoyl under alkaline condition to obtain cyclic alcohol compound of ureido, reaction with sulfonyl chloride in the presence of acid-binding agent to obtain activated sulfonate compound, reaction with ammonia, sodium azide or hexamethyl ammonium silicate to obtain cyclic amino compound of ureido, reaction with Boc2The O reaction gives the Boc protected ureido cyclic amino compound. The process provided by the invention utilizes cheap and easily available raw and auxiliary materials, has the advantages of good atomic economy of process route, simple reaction, mild conditions, easy control, simple post-treatment, high yield and easy scale-up production.
Description
Technical Field
The invention relates to a medical intermediate of a cyclic amino compound, in particular to a medical intermediate compound for preparing a cyclic chiral amide compound containing carbamido and a scalable process thereof, so that the industrial production is easy.
Background
In recent years, a novel cyclic chiral amino compound containing carbamido is an important intermediate for treating diseases such as cancer and the like (US2009/76005A 1; Journal of Medicinal Chemistry,46,7,2003, 1116-9; WO2004/76410A 2; US2003/130280A 1; US2003/92917A 1). However, the current production process of the key intermediate has the problems of high raw material cost, unstable supply, long route, high pollution, low yield, poor process safety, complicated post-treatment and purification and the like, and greatly limits the drug expansion variety, application and industrialization prospects of the intermediate taking the compound as the key intermediate.
Disclosure of Invention
An object of the present invention is to provide a compound which is useful as a pharmaceutical intermediate for the preparation of cyclic chiral amides containing a ureido group.
The invention also aims to provide a cyclic chiral amino compound containing carbamido, which can be used in a scale-up process and is easy for industrial production.
The invention provides a compound shown as a formula II, and application of the compound serving as a medical intermediate in preparation of cyclic chiral amide compounds containing carbamido
In the formula, n is 1,2, 3, 4, 5 or the like, and 2 or 3 is preferred.
R1And R2Independently selected from hydrogen, methyl, ethyl, isopropyl, N-butyl, isobutyl, benzyl, 4-methoxybenzyl, 2, 4-dimethoxybenzyl, phenyl and substituted phenyl such as methylphenyl, methoxyphenyl, halophenyl, trifluoromethylphenyl, trifluoromethoxyphenyl, furylmethyl, thienylmethyl, thiazolylmethyl, aziridine, azetidine, tetrahydropyrrole, piperidine, morpholine, piperazine, N-methylpiperazine, N-ethylpiperazine, N-isopropylpiperazine, N-phenylpiperazine, N-benzylpiperazine, N- (substituted methylbenzyl) piperazine or N- (substituted methoxybenzyl) piperazine and the like, preferably hydrogen, methyl, ethyl or isopropyl.
X is an oxygen atom or a sulfur atom.
Y is selected from amino, methylamino, ethylamino, propylamino, isopropylamino, benzylamino, α -methylbenzylamine, (R) - α -methylbenzylamine, (S) - α -methylbenzylamine or anilino, and preferably amino, methylamino, ethylamino or benzylamino.
The configuration of the chiral carbon atom on the ring is RS, R or S, preferably R or S.
The invention provides a compound shown as a formula III, and application of the compound serving as a medical intermediate in preparation of cyclic chiral amide compounds containing carbamido
In the formula, n is 1,2, 3, 4, 5 or the like, and 2 or 3 is preferred.
R1And R2Independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, n-butyl, isobutyl, benzyl, 4-methoxybenzyl, 2, 4-dimethoxybenzyl, phenyl and substituted phenyl such as methylphenyl, methoxyphenyl, halophenyl, trifluoromethylphenyl, trifluoromethoxyphenyl, furylmethyl, thienylmethyl, thiazolylmethyl, aziridine, azetidine, tetrahydroxybenzyl, and mixtures thereofPyrrole, piperidine, morpholine, piperazine, N-methylpiperazine, N-ethylpiperazine, N-isopropylpiperazine, N-phenylpiperazine, N-benzylpiperazine, N- (substituted methylbenzyl) piperazine, N- (substituted methoxybenzyl) piperazine or the like, and hydrogen, methyl, ethyl or isopropyl is preferred.
R3Selected from hydrogen, methyl, ethyl, propyl, isopropyl, benzyl, α -methylbenzyl, (R) - α -methylbenzyl, (S) - α -methylbenzyl or phenyl, and preferably hydrogen, methyl, ethyl or benzyl.
X is an oxygen atom or a sulfur atom.
The ring chiral carbon is RS, R or S, preferably R or S.
The invention provides a cyclic chiral amino compound containing carbamido, which can be used for preparing a cyclic amino compound of carbamido shown in a formula II by taking amino alcohol hydrochloride shown in a formula I as a reactant.
In the formula, n is 1,2, 3, 4, 5 or the like, and 2 or 3 is preferred.
R1And R2Independently selected from hydrogen, methyl, ethyl, isopropyl, N-butyl, isobutyl, benzyl, 4-methoxybenzyl, 2, 4-dimethoxybenzyl, phenyl and substituted phenyl such as methylphenyl, methoxyphenyl, halophenyl, trifluoromethylphenyl, trifluoromethoxyphenyl, furylmethyl, thienylmethyl, thiazolylmethyl, aziridine, azetidine, tetrahydropyrrole, piperidine, morpholine, piperazine, N-methylpiperazine, N-ethylpiperazine, N-isopropylpiperazine, N-phenylpiperazine, N-benzylpiperazine, N- (substituted methylbenzyl) piperazine or N- (substituted methoxybenzyl) piperazine and the like, preferably hydrogen, methyl, ethyl or isopropyl.
X is an oxygen atom or a sulfur atom.
Y is selected from amino, methylamino, ethylamino, propylamino, isopropylamino, benzylamino, α -methylbenzylamine, (R) - α -methylbenzylamine, (S) - α -methylbenzylamine, anilino and the like, and preferably amino, methylamino, ethylamino or benzylamino.
The configuration of the chiral carbon atom on the ring is RS, R or S, preferably R or S.
The invention provides a method, which is characterized in that amino alcohol hydrochloride shown in a formula I is used as a reactant, a compound shown in a formula IV is firstly prepared through condensation and sulfoacid esterification, and then the compound is reacted with ammonia or hexamethyl ammonium silicate to obtain a cyclic amino compound of carbamido shown in a formula II, or the cyclic amino compound of carbamido shown in a formula II is obtained through reaction with sodium azide and catalytic hydrogenation.
R4Selected from methyl, ethyl, trifluoromethyl, propyl, isopropyl, isobutyl, n-butyl, benzyl, phenyl, 4-methylphenyl, nitrophenyl and halophenyl, and preferably selected from methyl and trifluoromethyl.
The invention provides another cyclic chiral amino compound containing carbamido, which can be used for preparing a cyclic amino compound of carbamido protected by Boc shown in a formula III by taking a cyclic amino compound of carbamido shown in a formula II as a reactant.
In the formula, n is 1,2, 3, 4, 5 or the like, and 2 or 3 is preferred.
R1And R2Independently selected from hydrogen, methyl, ethyl, isopropyl, N-butyl, isobutyl, benzyl, 4-methoxybenzyl, 2, 4-dimethoxybenzyl, phenyl and substituted phenyl such as methylphenyl, methoxyphenyl, halophenyl, trifluoromethylphenyl, trifluoromethoxyphenyl, furylmethyl, thienylmethyl, thiazolylmethyl, aziridine, azetidine, tetrahydropyrrole, piperidine, morpholine, piperazine, N-methylpiperazine, N-ethylpiperazine, N-isopropylpiperazine, N-phenylpiperazine, N-benzylpiperazine, N- (substituted methylbenzyl) piperazine or N- (substituted methoxybenzyl) piperazine, and the like, preferably hydrogen, methyl, ethylOr an isopropyl group.
R3Selected from hydrogen, methyl, ethyl, propyl, isopropyl, benzyl, α -methylbenzyl, (R) - α -methylbenzyl, (S) - α -methylbenzyl or phenyl, and preferably hydrogen, methyl, ethyl or benzyl.
X is an oxygen atom or a sulfur atom.
Y is selected from amino, methylamino, ethylamino, propylamino, isopropylamino, benzylamino, α -methylbenzylamine, (R) - α -methylbenzylamine, (S) - α -methylbenzylamine, anilino and the like, and preferably amino, methylamino, ethylamino or benzylamino.
The ring chiral carbon atom configuration is RS, R or S, preferably R or S.
The invention provides another cyclic chiral amino compound containing carbamido, which comprises the following synthesis steps:
in the above formula, n is 1,2, 3, 4, 5, etc., preferably 2 or 3.
R1And R2Independently selected from hydrogen, methyl, ethyl, isopropyl, N-butyl, isobutyl, benzyl, 4-methoxybenzyl, 2, 4-dimethoxybenzyl, phenyl and substituted phenyl such as methylphenyl, methoxyphenyl, halophenyl, trifluoromethylphenyl, trifluoromethoxyphenyl, furylmethyl, thienylmethyl, thiazolylmethyl, aziridine, azetidine, tetrahydropyrrole, piperidine, morpholine, piperazine, N-methylpiperazine, N-ethylpiperazine, N-isopropylpiperazine, N-phenylpiperazine, N-benzylpiperazine, N- (substituted methylbenzyl) piperazine or N- (substituted methoxybenzyl) piperazine and the like, preferably hydrogen, methyl, ethyl or isopropyl.
R3Selected from hydrogen, methyl, ethyl, propyl, isopropyl, benzyl, α -methylbenzyl, (R) - α -methylbenzyl, (S) - α -methylbenzyl or phenyl, and preferably hydrogen, methyl, ethyl or benzyl.
R4Selected from methyl, ethyl, trifluoromethyl, propyl, isopropyl, isobutyl, n-butyl, benzyl, phenyl, 4-methylphenyl, nitrophenyl and halophenyl, and preferably selected from methyl and trifluoromethyl.
The ring chiral carbon atom configuration is RS, R or S, preferably R or S.
X is an oxygen atom or a sulfur atom.
Y is selected from amino, methylamino, ethylamino, propylamino, isopropylamino, benzylamino, α -methylbenzylamine, (R) - α -methylbenzylamine, (S) - α -methylbenzylamine or anilino, and preferably amino, methylamino, ethylamino or benzylamino.
The reaction scheme for each step of formula V or formula VII is as follows:
the first step is as follows: reacting amino alcohol hydrochloride with substituted amino formyl or isocyanate or isothiocyanate under alkaline conditions to obtain a cyclic alcohol compound of carbamido;
bases used are as follows: but are not limited to triethylamine, diisopropylamine, diisopropylethylamine, pyridine, sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide and the like, preferably triethylamine and diisopropylethylamine, and these bases alone or in combination are used in the present invention;
the molar ratio of the amino alcohol hydrochloride, the substituted carbamoyl or the isocyanate or the isothiocyanate to the base is 1.0: 1.0-3.0: 2.0-6.0, preferably 1.0: 1.0-1.5: 2.0-3.0;
substituted carbamoyl such as: but are not limited to, dimethylcarbamoyl chloride;
isocyanates such as: but are not limited to, methyl isocyanate, ethyl isocyanate, propyl isocyanate, isopropyl isocyanate, phenyl isocyanate, and the like, which are used alone or in combination in the present invention;
isothiocyanates such as: but are not limited to, methyl isothiocyanate, ethyl isothiocyanate, propyl isothiocyanate, isopropyl isothiocyanate and phenyl isothiocyanate; these compounds are used in the present invention alone or in combination.
The solvents used in this step are: but are not limited to, methylene chloride, 1, 2-dichloroethane, THF, 2-methyltetrahydrofuran, 1, 4-dioxane, 1, 2-dimethoxyethane, etc., with methylene chloride being preferred;
the reaction temperature is 0-40 ℃, and the recommended temperature is 0-25 ℃;
the second step is that: reacting a cyclic alcohol compound of carbamido with sulfonyl chloride in the presence of an acid-binding agent to obtain an activated sulfonic acid ester compound;
acid-binding agents used were as follows: but are not limited to triethylamine, diisopropylamine, diisopropylethylamine, pyridine, sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide and the like, and triethylamine and diisopropylethylamine are preferably selected;
sulfonyl chlorides used were as follows: but are not limited to methanesulfonyl chloride, ethylsulfonyl chloride, trifluoromethanesulfonic anhydride, benzenesulfonyl chloride, 4-methylbenzenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride and the like, methanesulfonyl chloride being preferred;
the molar ratio of the cyclic alcohol compound of the carbamido group, the sulfonyl chloride compound and the acid-binding agent is 1.0: 1.0-3.0, and the molar ratio is preferably 1.0: 1.0-1.2: 1.0-2.0;
the solvents used in this step are: but are not limited to, methylene chloride, 1, 2-dichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylformamide, 1, 4-dioxane, 1, 2-dimethoxyethane, etc., with methylene chloride being preferred;
the reaction temperature is 0-40 ℃, and the preferred temperature is 10-25 ℃;
the third step: reacting the activated sulfonate compound with ammonia to obtain a cyclic amino compound of ureido;
the ammonia used is as follows: but are not limited to, aqueous ammonia, methanol solution of ammonia, ethanol solution of ammonia, tetrahydrofuran solution of ammonia, 2-methyltetrahydrofuran solution of ammonia, isopropanol solution of ammonia, n-propanol solution of ammonia, n-butanol solution of ammonia, 1, 4-dioxane solution of ammonia, acetonitrile solution of ammonia, liquid ammonia, sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, lithium bis (trimethylsilyl) amide, etc., with preference given to aqueous ammonia, methanol solution of ammonia, and sodium bis (trimethylsilyl) amide;
the molar ratio of the activated sulfonate compound to ammonia is 1.0: 1.0-50.0, preferably 1.0: 1.0-15.0;
the reaction temperature is 25-100 ℃, and 45-80 ℃ is preferred;
the fourth step: cyclic amino compound of ureido with Boc2O reaction to obtain cyclic amino compound of ureido protected by Boc;
the solvents used in this step are: but are not limited to, water, methanol, ethanol, isopropanol, dichloromethane, dichloroethane, water/methanol, water/ethanol, dioxane, DMF, DMSO, etc.;
cyclic amino compound of ureido, Boc2The ratio of O to alkali is 1: 1-3; the molar ratio is preferably 1: 1-1.5; preferentially selecting methanol;
the reaction temperature is 0-40 deg.C, preferably 10-25 deg.C.
The invention provides another cyclic chiral amino compound containing carbamido, which comprises the following synthetic steps shown in formula VI or formula VIII:
in the above formula, n is 1,2, 3, 4, 5, etc., preferably 2 or 3;
R1and R2Independently selected from hydrogen, methyl, ethyl, isopropyl, N-butyl, isobutyl, benzyl, 4-methoxybenzyl, 2, 4-dimethoxybenzyl, phenyl and substituted phenyl such as methylphenyl, methoxyphenyl, halophenyl, trifluoromethylphenyl, trifluoromethoxyphenyl, furylmethyl, thienylmethyl, thiazolylmethyl, aziridine, azetidine, tetrahydropyrrole, piperidine, morpholine, piperazine, N-methylpiperazine, N-ethylpiperazine, N-isopropylpiperazine, N-phenylpiperazine, N-benzylpiperazine, N- (substituted methylbenzyl) piperazine or N- (substituted methoxybenzyl) piperazine and the like, preferably hydrogen, methyl, ethyl or isopropyl;
R3is hydrogen;
y is amino;
R4selected from methyl, ethyl, trifluoromethyl, propyl, isopropyl, isobutyl, n-butyl, benzyl, phenyl, 4-methylphenyl, nitrophenyl or halophenyl, etc. Methyl or trifluoromethyl, etc. are preferably selected;
the ring chiral carbon atom configuration is RS, R or S, preferably R or S;
x is an oxygen atom or a sulfur atom.
The reaction scheme for each step of formula VI or formula VIII is as follows:
the first step is as follows: reacting amino alcohol hydrochloride with substituted amino formyl or isocyanate or isothiocyanate under alkaline conditions to obtain a cyclic alcohol compound of carbamido;
bases used are as follows: but are not limited to triethylamine, diisopropylamine, diisopropylethylamine, pyridine, sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide and the like, preferably triethylamine and diisopropylethylamine, and these bases alone or in combination are used in the present invention;
the molar ratio of the amino alcohol hydrochloride, the substituted carbamoyl or the isocyanate or the isothiocyanate to the base is 1.0: 1.0-3.0: 2.0-6.0, preferably 1.0: 1.0-1.5: 2.0-3.0;
substituted carbamoyl such as: but are not limited to, dimethylcarbamoyl chloride;
isocyanates such as: but are not limited to, methyl isocyanate, ethyl isocyanate, propyl isocyanate, isopropyl isocyanate, phenyl isocyanate, and the like, which are used alone or in combination in the present invention;
isothiocyanates such as: but are not limited to, methyl isothiocyanate, ethyl isothiocyanate, propyl isothiocyanate, isopropyl isothiocyanate and phenyl thiocyanate, alone or in combination, as used in the present invention;
the solvents used in this step are: but are not limited to, methylene chloride, 1, 2-dichloroethane, THF, 2-methyltetrahydrofuran, 1, 4-dioxane, 1, 2-dimethoxyethane, etc., with methylene chloride being preferred;
the reaction temperature is 0-40 ℃, and the recommended temperature is 0-25 ℃;
the second step is that: reacting a cyclic alcohol compound of carbamido with sulfonyl chloride in the presence of an acid-binding agent to obtain an activated sulfonic acid ester compound;
acid-binding agents used were as follows: but are not limited to triethylamine, diisopropylamine, diisopropylethylamine, pyridine, sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide and the like, and triethylamine and diisopropylethylamine are preferably selected;
sulfonyl chlorides used were as follows: but are not limited to methanesulfonyl chloride, ethylsulfonyl chloride, trifluoromethanesulfonic anhydride, benzenesulfonyl chloride, 4-methylbenzenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride and the like, methanesulfonyl chloride being preferred;
the molar ratio of the cyclic alcohol compound of the carbamido group, the sulfonyl chloride compound and the acid-binding agent is 1.0: 1.0-3.0, and the molar ratio is preferably 1.0: 1.0-1.2: 1.0-2.0;
the solvents used in this step are: but are not limited to, methylene chloride, 1, 2-dichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylformamide, 1, 4-dioxane, 1, 2-dimethoxyethane, etc., with methylene chloride being preferred;
the reaction temperature is 0-40 ℃, and the preferred temperature is 10-25 ℃;
the third step: reacting the activated sulfonate compound with sodium azide to obtain a process product (i.e., as shown in formula IX below);
wherein n is 1,2, 3, 4, 5, etc., preferably 2 or 3;
R1and R2Independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, N-butyl, isobutyl, benzyl, 4-methoxybenzyl, 2, 4-dimethoxybenzyl, phenyl and substituted phenyl such as methylphenyl, methoxyphenyl, halophenyl, trifluoromethylphenyl, trifluoromethoxyphenyl, furylmethyl, thienylmethyl, thiazolylmethyl, aziridine, azetidine, tetrahydropyrrole, piperidine, morpholine, piperazine, N-methylpiperazine, N-ethylpiperazine, N-isopropylpiperazine, N-benzenePiperazine, N-benzylpiperazine, N- (substituted methylbenzyl) piperazine, N- (substituted methoxybenzyl) piperazine or the like, preferably hydrogen, methyl, ethyl or isopropyl;
x is oxygen atom or sulfur atom;
the molar ratio of the activated sulfonic acid ester compound to the sodium azide is 1.0: 1.0-50.0, and the molar ratio is preferably 1.0: 1.0-15.0;
the reaction temperature is 25-100 ℃, and 45-80 ℃ is preferred;
the fourth step: the cyclic amino compound (shown as formula II) of the carbamido can be obtained by the conventional catalytic hydrogenation of the product of the process.
The fifth step: cyclic amino compound of ureido with Boc2O reaction to obtain cyclic amino compound of ureido protected by Boc;
the solvents used in this step are: but are not limited to, water, methanol, ethanol, isopropanol, dichloromethane, dichloroethane, water/methanol, water/ethanol, dioxane, DMF, DMSO, etc.;
cyclic amino compound of ureido, Boc2The ratio of O to alkali is 1: 1-3; preferably selecting the molar ratio of 1: 1-1.5; methanol, ethanol, or isopropanol is preferably selected;
the reaction temperature is 0-40 deg.C, preferably 10-25 deg.C.
The technical scheme of the invention has the following beneficial effects:
the compound provided by the invention is used as a medical intermediate to easily prepare various cyclic chiral amide compounds containing carbamido.
The invention provides a cyclic chiral amino compound containing carbamido, which is an important medical intermediate, namely the cyclic chiral amino compound containing carbamido, and is prepared by adopting amino alcohol hydrochloride as an initial raw material, combining carbamido on amino, penetrating through the whole process, and adopting four-step methods of condensation, sulfonic ester synthesis, ammonolysis, Boc protection and the like. The process provided by the invention has the advantages of stable raw material supply, good atomic economy, simple operation, easy purification, high yield, less pollution, relatively low cost, easy industrialization, less waste residues and liquid, and simple solvent treatment, and can be recycled.
Detailed Description
The technical solution of the present invention is described in detail below. Although the present invention has been described in detail with reference to the preferred embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the spirit and scope of the invention as defined in the appended claims.
Example 1 Synthesis of (3S) -3- [ (tert-butoxy) carbonylamino ] -1-N, N-dimethylpyrrolidine
The first step is as follows: condensation of
Adding 1450M L of dichloromethane and 145g (1.173mol and 1.0eq) of (R) -3-hydroxypyrrolidine hydrochloride into a 2L three-neck flask in sequence, cooling to 5-10 ℃, slowly adding 249g (2.461mol and 2.1eq) of triethylamine, slowly dropwise adding 140.5g (1.307mol and 1.1eq) of dimethylcarbamoyl chloride, controlling the temperature to 5-10 ℃ in the dropwise adding process, naturally heating to 25-30 ℃ in the air after dropwise adding, preserving the temperature for reaction for 5 hours, filtering after the reaction is finished, and directly using the filtrate for the next step, wherein the purity of HP L C is 97.52%, and ESI (M +1) is 159.
The second step is that: sulfonate synthesis
Adding dichloromethane of the intermediate 2 prepared in the previous step into a 2L reaction bottle, adding 178.0g (1.759mol, 1.5eq) of triethylamine into the system at room temperature, cooling the system in an ice-water bath to control the temperature of the system to be below 10 ℃, slowly adding 140.5g (1.307mol, 1.1eq) of methylsulfonyl chloride dropwise, stirring at room temperature after the dropwise adding is finished, detecting that the raw material disappears and reacts completely by T L C, adding water to quench the reaction, standing and separating the liquid, washing the organic phase twice by water, drying the organic phase by anhydrous sodium sulfate, filtering, and concentrating under reduced pressure at 45 ℃ in a water bath to obtain 3238.5g of the intermediate, wherein the yield is 85.5%, the ee value is 99.85%, the HP L C is 95.6%, and the ESI (M +1) is 237.
The third step: ammonolysis
Adding 3100g (0.423mol) of intermediate into a 2L autoclave, adding 500M L25% ammonia water, sealing the system, heating to 75-80 ℃, keeping the temperature, stirring for reaction for 6 hours, sampling HP L C, detecting the reaction is complete, cooling, washing an ammonia water phase with 100M L× 3 dichloromethane, combining dichloromethane phases, washing with 100M L water, combining water phases, carrying out water bath decompression concentration at 60-65 ℃ until the mixture is dry, obtaining a yellow oily compound 4, wherein the ee value is 98.5%, directly entering the next step, and ESI (M +1): 158.
The fourth step: boc protection
Adding 870M L methanol and 42.8g triethylamine (0.423mol) into the yellow oily compound 4 in the previous step, slowly dropwise adding 96.9g (0.444mol) di-tert-butyl dicarbonate in a water bath under the condition of cooling, reacting at room temperature for 2 hours after the dropwise addition is finished, completely reacting, concentrating the system at 45 ℃ in a water bath under reduced pressure, pulping the system at the room temperature by 100M L methyl tert-butyl ether, filtering, drying a filter cake to obtain 44g of white powdery compound 5, wherein the two-step yield is 39.7%, the ESI (M +1) is 258, the ee value is 100%, the purity of HP L C is 99.8%, and HNMR (300MHz, CDCl)3,ppm)：1.45(s,9H),2.05-2.12(m,1H),2.84(s,6H),3.21-3.24(dd,1H),3.41-3.61(m,3H),4.17(brs,1H),4.72(brs,1H)。
EXAMPLE 2 Synthesis of (3S) -3- [ (tert-butoxy) carbonylamino ] -1-N, N-dimethylpyrrolidine
The first step is as follows: condensation of
500M of L of dichloromethane and 45g (0.364mol and 1.0eq) of (R) -3-hydroxypyrrolidine hydrochloride are sequentially added into a three-necked bottle of 1L, the temperature is reduced to 5-10 ℃, 77.2g (0.765mol and 2.1eq) of triethylamine is slowly added, 43.0g (0.400mol and 1.1eq) of dimethylcarbamoyl chloride is dropwise added, the temperature is controlled to 5-10 ℃ in the dropwise adding process, the temperature is naturally raised to 25-30 ℃ in the air after the dropwise adding is finished, the temperature is kept for 5 hours for reaction, the reaction is filtered after the reaction is finished, and the filtrate is directly used for the next step, wherein the purity of HP L C is 97.83 percent, and ESI (M +1) is 159.
The second step is that: sulfonate synthesis
Adding dichloromethane of the intermediate 2 prepared in the previous step into a 1L reaction bottle, adding 55.3g (0.546mol, 1.5eq) of triethylamine into the system at room temperature, cooling the system in an ice-water bath to control the temperature of the system to be below 10 ℃, slowly adding 45.9g (0.400mol, 1.1eq) of methylsulfonyl chloride dropwise, stirring at room temperature after the dropwise addition is finished, detecting that the raw material disappears and reacts completely at T L C, adding water to quench the reaction, standing and separating the liquid, washing the organic phase twice with water, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure at 45 ℃ in a water bath to obtain 383.47g of the intermediate, wherein the yield is 97.0%, the ee value is 100%, the HP L C is 97.48%, and the ESI (M +1) is 237.
The third step: ammonolysis (requiring ammonia methanol solution)
80g (0.339mol,1.0eq) of compound B is added into a 500M L autoclave, then 360M L26% ammonia methanol solution is added, the system is sealed, the temperature is raised to 60 ℃, the temperature is kept and the stirring is carried out for 20 hours, a sample HP L C is taken to detect that the reaction is complete, the ee value is 99.2%, ESI (M +1):158 is carried out, the temperature is reduced, and the methanol solution is directly carried out for the next step.
The fourth step: boc protection
650M L methanol and 34.2g triethylamine (0.338mol, 1.0eq) are added into the mixture, 81.3g (0.372mol, 1.1eq) di-tert-butyl dicarbonate is slowly added dropwise while the temperature of a water bath is reduced, the reaction is completed after the dropwise addition, the system is dried by concentration under reduced pressure at 45 ℃, the system is pulped with 80M L methyl tert-butyl ether at room temperature, filtered, and the filter cake is dried to obtain 39.2g white powder with yield of 45.1%, ee value of 99.9%, purity of HP L C of 100%, ESI (M +1):258, HNMR (300MHz, CDCl3, ppm): 1.45(s,9H),2.05-2.12(M,1H),2.84(s,6H),3.21-3.24(dd,1H),3.41-3.61(M,3H),4.17(brs,1H),4.72(brs, 1H).
EXAMPLE 3 Synthesis of (3S) -3- [ (tert-butoxy) carbonylamino ] -1-N, N-dimethylpyrrolidine
The first step is as follows: condensation of
1155M of L g of dichloromethane and 104.5g (0.846mol and 1.0eq) of (R) -3-hydroxypyrrolidine hydrochloride are sequentially added into a three-neck bottle of 2L, the temperature is reduced to 5-10 ℃, 171.2g (1.692mol and 2.0eq) of triethylamine is slowly added, 100.0g (0.930mol and 1.1eq) of dimethylcarbamoyl chloride is dropwise added, the temperature is controlled to be 5-10 ℃ in the dropwise adding process, the temperature is naturally raised to 25-30 ℃ in the air after the dropwise adding is finished, the temperature is kept for 5 hours for reaction, the reaction is finished, and then the filtrate is filtered, wherein the purity of the filtrate is 98.56 percent in the next step HP L C, and the ESI (M +1) is 159.
The second step is that: sulfonate synthesis
Adding dichloromethane of the intermediate 2 prepared in the previous step into a 2L reaction bottle, adding 128.4g (1.269mol, 1.5eq) triethylamine into the system at room temperature, cooling the system in an ice-water bath to below 10 ℃, slowly adding 106.6g (0.931mol, 1.1eq) methanesulfonyl chloride dropwise, stirring at room temperature after the dropwise addition is finished, detecting that the raw material disappears and reacts completely by T L C, adding water to quench the reaction, standing and separating the liquid, washing the organic phase twice, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating the organic phase under reduced pressure at 45 ℃ in a water bath to obtain 3178.6g of the intermediate, wherein the yield is 89.4%, the ee value is 100%, the HP L C is 94.3%, and the ESI (M +1) is 237
The third step: ammonolysis (Azolyze)
310g (0.042mol) of the compound is added into a 100M L three-necked bottle, DMF 20M L is added, sodium azide 3.3g (0.051mol) is slowly added into the three-necked bottle at room temperature under stirring, the temperature of the system is slowly raised to 80 ℃ and the reaction is kept at the temperature, the temperature is reduced after the reaction is completed, 50M L water and 50M L dichloromethane are added, the mixture is stirred, kept stand and separated, an organic phase is washed once by 50M L water, the organic phase is dried by anhydrous sodium sulfate and filtered, and the filtrate is concentrated to obtain 6.4g, the yield is 82.8 percent, and the ESI (M +1): 184. ee value is 99.5 percent.
The fourth step: boc protection
6.4g (0.035mol) of the compound 3B, 70m L of methanol, 0.7g of 10% palladium carbon containing 60% of water and 0.7g of 10% palladium carbon are added into a 100m L three-neck flask, hydrogen balloon gas is supplied after hydrogen replacement, the system is stirred and reacted for 18 hours at 25-30 ℃, after the reaction is finished, the system is filtered, a small amount of methanol is used for leaching filter cakes, the filtrate is concentrated to be dry, 50m L water and 50m L dichloromethane are added into the concentrate, the mixture is stirred and kept stand for liquid separation, the water phase is extracted once by 20m L dichloromethane, the dichloromethane phases are combined and concentrated to be dry under reduced pressure, 30m L methanol and 3.5g of triethylamine (0.035mol) are added into the concentrate, 8.0g (0.037mol) of di-tert-butyl dicarbonate is slowly added, after the reaction is finished, the system is concentrated to be dry, the system is pulped by 20m L methyl tert-butyl ether at room temperature, the filter is filtered, after the drying is finished, the filter cake is dried to obtain 3.3.3.3 g, the yield is 36.7% ee value MR is 99.6%, the HN MR (300MHz, CDCl3 ppm, 1.45 ppm, 2.9H, 3.5H, 2H, 3.6-13H, 3.6-1.
Example 4 Synthesis of (3S) -3- [ (tert-butoxy) carbonylamino ] -1-N, N-dimethylpyrrolidine
The first step is as follows: condensation of
1155M of L g of dichloromethane and 104.5g (0.846mol and 1.0eq) of (R) -3-hydroxypyrrolidine hydrochloride are sequentially added into a three-neck bottle of 2L, the temperature is reduced to 5-10 ℃, 171.2g (1.692mol and 2.0eq) of triethylamine is slowly added, 100.0g (0.930mol and 1.1eq) of dimethylcarbamoyl chloride is dropwise added, the temperature is controlled to be 5-10 ℃ in the dropwise adding process, the temperature is naturally raised to 25-30 ℃ in the air after the dropwise adding is finished, the temperature is kept for 5 hours for reaction, the reaction is finished, and then the filtrate is filtered, wherein the purity of the filtrate is 98.56 percent in the next step HP L C, and the ESI (M +1) is 159.
The second step is that: sulfonate synthesis
Adding dichloromethane of the intermediate 2 prepared in the previous step into a 2L reaction bottle, adding 128.4g (1.269mol, 1.5eq) of triethylamine into the system at room temperature, cooling the system in an ice-water bath to control the temperature of the system to be below 10 ℃, slowly adding 106.6g (0.931mol, 1.1eq) of methylsulfonyl chloride dropwise, stirring at room temperature after the dropwise addition is finished, detecting that the raw material disappears and reacts completely at T L C, adding water to quench the reaction, standing and separating the liquid, washing the organic phase twice with water, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure at 45 ℃ in a water bath to obtain 3178.6g of the intermediate, wherein the yield is 89.4%, the ee value is 100%, the HP L C is 94.3%, and the ESI (M +1) is 237.
The third step: ammonolysis
Adding 35.0g (0.021, 1.0eqmol) of the compound into a 100M L three-neck bottle, adding anhydrous THF (25M L), cooling to-60 to-40 ℃ under nitrogen replacement protection and stirring, slowly adding sodium hexamethyldisilazide (NaHMDS) (1M THF solution, 25M L, 0.025mol and 1.0eq), keeping the temperature for reaction, heating to room temperature after the reaction is completed, dropwise adding 2% aqueous solution of hydrogen chloride, stirring for 0.5 hour, adjusting the pH to 8.5-9.0 by using saturated aqueous solution of sodium bicarbonate, decompressing and concentrating the system to obtain yellow oily matter, and directly entering the next step.
The fourth step: boc protection
20m L methanol and 2.1g triethylamine (0.021mol) are added into the concentrate of the previous step, 4.8g di-tert-butyl dicarbonate (0.022mol) is slowly added dropwise, the system is decompressed and concentrated to dryness after the reaction is finished, 30m L dichloromethane is added, the system is washed with 20m L× 3 water, the organic phase is decompressed and concentrated to dryness, the mixture is pulped with 10m L methyl tert-butyl ether at room temperature, the mixture is filtered, and the filter cake is dried to obtain 1.14g, the yield is 21.0%, the ee value is 97.3%, HNMR (300MHz, CDCl3, ppm): 1.45(s,9H),2.05-2.12(m,1H),2.84(s,6H),3.21-3.24(dd,1H),3.41-3.61(m,3H),4.17(brs,1H),4.72(brs, 1H).
EXAMPLE 5 Synthesis of (3S) -3- [ (tert-butoxy) carbonylamino ] -1-N, N-dimethylpyrrolidine
The first step is as follows: condensation of
25g (0.202mol, 1.0eq) of 275M L dichloromethane, (S) -3-hydroxypyrrolidine hydrochloride and 25g (0.404mol, 2.0eq) are sequentially added into a three-necked bottle of 500M L, the temperature is reduced to 5-10 ℃, 40.9g (0.404mol, 2.0eq) of triethylamine is slowly added, 23.9g (0.222mol, 1.1eq) of dimethylcarbamoyl chloride is dropwise added, the temperature is controlled to 5-10 ℃ in the dropwise adding process, the temperature is naturally raised to 25-30 ℃ in the air after the dropwise adding is finished, the temperature is kept for 5 hours for reaction, the reaction is finished, and then the filtrate is filtered, and the purity of the filtrate is directly used for the next step HP L C, 98.32%, and ESI (M +1) is 159.
The second step is that: sulfonate synthesis
Adding dichloromethane of the intermediate 7 into a 500M L reaction bottle, adding 30.7g (0.303mol, 1.5eq) of triethylamine into the system at room temperature, cooling the system in an ice-water bath at the temperature of below 10 ℃, slowly adding 25.5g (0.222mol, 1.1eq) of methylsulfonyl chloride dropwise, stirring at room temperature after the dropwise addition is finished, adding water to quench the reaction after the T L C detects that the raw materials completely disappear, standing and separating the liquid, washing the organic phase twice with water, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure at 45 ℃ in a water bath to obtain 843.0g of the intermediate, wherein the yield is 90.0%, the ee value is 99.7%, the HP L C is 96.6%, and the ESI (M +1) is 237.
The third step: azolyzing
810g (0.042mol) of the compound is added into a 100m L three-necked bottle, DMF 20m L is added, 3.3g (0.051mol) of sodium azide is slowly added into the three-necked bottle at room temperature under stirring, the temperature of the system is slowly raised to 80 ℃ and the reaction is kept at the temperature, the temperature is reduced after the reaction is completed, 50m L water and 50m L dichloromethane are added, the mixture is stirred, kept stand and separated, the organic phase is washed once by 50m L water, the organic phase is dried by anhydrous sodium sulfate and filtered, and the filtrate is concentrated to obtain 7.53g, the yield is 97.2 percent, and the ee value is 92.7 percent.
The fourth step: boc protection
Adding 96.9g (0.038mol) of compound, 70m of methanol L and 0.7g of 10% palladium carbon containing 60% of water into a 100m L three-neck flask, supplying gas to a hydrogen balloon after hydrogen replacement, stirring and reacting at 25-30 ℃ for 18 hours, filtering the system after the reaction is finished, leaching a filter cake with a small amount of methanol, concentrating the filtrate to dryness, adding 50m L water and 50m L dichloromethane into the concentrate, stirring, standing, separating, extracting the aqueous phase with 20m L dichloromethane once, combining dichloromethane phases, concentrating the filtrate under reduced pressure, adding 10m L methanol and 3.8g of triethylamine (0.038mol) into the concentrate, slowly adding 6.1g (0.038mol) of di-tert-butyl dicarbonate, concentrating the system to dryness after the reaction is finished, pulping with 10m L methyl tert-butyl ether at room temperature, filtering, drying the filter cake to obtain 3.7g, wherein the yield is 41.2% ee value MR 99.8%, HNH (300MHz, DMSO-d6, 1.38 ppm, 1.9H, 1.9H, 1.3H, 3H 3.3H 3-3H 3, 3m, 3H 3-3H 3, 3H 3-3H 3, 3H 3-3H 3, 3H 3m, 3H.
Claims (14)
1. An amplification process of a cyclic chiral amino compound containing carbamido is characterized in that the cyclic amino compound of the carbamido shown in a formula II is prepared by taking amino alcohol hydrochloride shown in a formula I as a reactant,
wherein n is 2 or 3;
R1and R2Independently selected from hydrogen, methyl, ethyl, isopropyl, n-butyl, isobutyl;
x is oxygen atom or sulfur atom;
y is selected from amino;
the configuration of the chiral carbon atom on the ring is RS, R or S;
the amino alcohol hydrochloride shown in the formula I is a reactant, a compound shown in the formula IV is prepared firstly through condensation and sulfoacid esterification, and then the compound reacts with ammonia or hexamethyl ammonium silicate to obtain a cyclic amino compound of carbamido shown in the formula II, or the cyclic amino compound of carbamido shown in the formula II is obtained through reaction with sodium azide and catalytic hydrogenation;
wherein n is 2 or 3;
R1and R2Independently selected from hydrogen, methyl, ethyl, isopropyl, n-butyl, isobutyl;
x is oxygen atom or sulfur atom;
R4selected from methyl, ethyl, trifluoromethyl, propyl, isopropyl, isobutyl and n-butyl.
2. An amplification process of a cyclic chiral amino compound containing carbamido is characterized in that a cyclic amino compound of carbamido shown in a formula II is used as a reactant to prepare a cyclic amino compound of carbamido protected by Boc shown in a formula III,
wherein n is 2 or 3;
R1and R2Independently selected from hydrogen, methyl, ethyl, isopropyl, n-butyl, isobutyl;
R3is selected from hydrogen;
x is oxygen atom or sulfur atom;
y is selected from amino.
3. The process for amplifying cyclic chiral amino compounds containing ureido groups according to claim 1 or claim 2, wherein R is1And R2Independently selected from hydrogen, methyl, ethyl or isopropyl.
4. An amplification process of a cyclic chiral amino compound containing carbamido is characterized by comprising the following synthesis steps:
wherein n is 2 or 3;
R1and R2Independently selected from hydrogen, methyl, ethyl, isopropyl, n-butyl, isobutyl;
R3is selected from hydrogen;
R4selected from methyl, ethyl, trifluoromethyl, propyl, isopropyl, isobutyl, n-butyl;
x is oxygen atom or sulfur atom;
y is selected from amino;
the ring chiral carbon atom configuration is RS, R or S;
the first step is: reacting amino alcohol hydrochloride with substituted amino formyl or isocyanate or isothiocyanate under alkaline conditions to obtain a cyclic alcohol compound of carbamido;
the base is selected from one or at least two of triethylamine, diisopropylamine, diisopropylethylamine, pyridine, sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide;
the molar ratio of the amino alcohol hydrochloride, the substituted carbamoyl or the isocyanate or the isothiocyanate to the base is 1.0: 1.0-3.0: 2.0-6.0;
the substituted carbamoyl is dimethylcarbamoyl chloride;
the isocyanate is selected from one or more of methyl isocyanate, ethyl isocyanate, propyl isocyanate, isopropyl isocyanate and phenyl isocyanate;
the isothiocyanate is selected from one or at least two of methyl isothiocyanate, ethyl isothiocyanate, propyl isothiocyanate, isopropyl isothiocyanate and phenyl thiocyanate;
the solvent is one or the combination of at least two of dichloromethane, 1, 2-dichloroethane, THF, 2-methyltetrahydrofuran, 1, 4-dioxane and 1, 2-dimethoxyethane;
the second step is: reacting a cyclic alcohol compound of carbamido with sulfonyl chloride in the presence of an acid-binding agent to obtain an activated sulfonic acid ester compound;
the acid-binding agent is selected from one or a combination of at least two of triethylamine, diisopropylamine, diisopropylethylamine, pyridine, sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide;
the sulfonyl chloride is selected from one or more of methanesulfonyl chloride, ethylsulfonyl chloride, trifluoromethanesulfonic anhydride, benzenesulfonyl chloride, 4-methylbenzenesulfonyl chloride and 4-nitrobenzenesulfonyl chloride;
the molar ratio of the cyclic alcohol compound of the carbamido group, the sulfonyl chloride compound and the acid-binding agent is 1.0: 1.0-3.0;
the solvent is one or the combination of at least two of dichloromethane, 1, 2-dichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylformamide, 1, 4-dioxane and 1, 2-dimethoxyethane;
the reaction temperature is 0-40 ℃;
the third step is: reacting the activated sulfonic acid ester compound with ammonia or hexamethyl ammonium silicate to obtain a cyclic amino compound of carbamido;
the fourth step is: cyclic amino compound of ureido with Boc2O reaction is carried out to obtain a cyclic amino compound of ureido protected by Boc, and the reaction temperature is 0-40 ℃; cyclic amino compound of ureido, Boc2The ratio of O to the alkali is 1: 1-3.
5. The process for amplifying cyclic chiral amino compounds containing ureido groups according to claim 4, wherein the process comprises the following synthesis step (VII):
the R is5And R4Same as R in the formula6And R3The same is true.
6. The scalable process of claim 4, wherein the reaction temperature of the cyclic amino compound of the ureido group obtained by reacting the activated sulfonate compound with ammonia is 25 to 100 ℃, and the molar ratio of the activated sulfonate compound to ammonia is 1.0:1.0 to 50.0.
7. The scalable process of cyclic chiral amino compounds containing a ureido group according to claim 4, wherein the ammonia is selected from the group consisting of aqueous ammonia, methanolic ammonia, ethanolic ammonia, tetrahydrofuran ammonia, 2-methyltetrahydrofuran ammonia, isopropanol ammonia, n-propanol ammonia, n-butanol ammonia, 1, 4-dioxane ammonia, acetonitrile ammonia, and liquid ammonia.
8. An amplification process of a cyclic chiral amino compound containing carbamido is characterized by comprising the following synthesis steps:
in the above formula, n is 2 or 3;
R1and R2Independently selected from hydrogen, methyl, ethyl, isopropyl, n-butyl, isobutyl;
R3is hydrogen;
y is amino;
R4selected from methyl, ethyl, trifluoromethyl, propyl, isopropyl, isobutyl, n-butyl;
the ring chiral carbon atom configuration is RS, R or S;
x is oxygen atom or sulfur atom;
the first step is as follows: reacting amino alcohol hydrochloride with substituted amino formyl or isocyanate or isothiocyanate under alkaline conditions to obtain a cyclic alcohol compound of carbamido;
the base is selected from one or at least two of triethylamine, diisopropylamine, diisopropylethylamine, pyridine, sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide;
the molar ratio of amino alcohol hydrochloride, substituted carbamoyl or isocyanate or isothiocyanate to base is 1.0: 1.0-3.0: 2.0-6.0;
the substituted carbamoyl is dimethylcarbamoyl chloride;
the isocyanate is selected from one or at least two of methyl isocyanate, ethyl isocyanate, propyl isocyanate, isopropyl isocyanate and phenyl isocyanate;
the isothiocyanate is selected from one or at least two of methyl isothiocyanate, ethyl isothiocyanate, propyl isothiocyanate, isopropyl isothiocyanate and phenyl thiocyanate;
the solvent is dichloromethane, 1, 2-dichloroethane, THF, 2-methyltetrahydrofuran, 1, 4-dioxane and 1, 2-dimethoxyethane;
the reaction temperature is 0-40 ℃;
the second step is that: reacting a cyclic alcohol compound of carbamido with sulfonyl chloride in the presence of an acid-binding agent to obtain an activated sulfonic acid ester compound;
the acid-binding agent is selected from one or a combination of at least two of triethylamine, diisopropylamine, diisopropylethylamine, pyridine, sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide;
the sulfonyl chloride is selected from one or at least two of methane sulfonyl chloride, ethyl sulfonyl chloride, trifluoromethanesulfonic anhydride, benzene sulfonyl chloride, 4-methylbenzene sulfonyl chloride and 4-nitrobenzene sulfonyl chloride;
the molar ratio of the cyclic alcohol compound of the carbamido group, the sulfonyl chloride compound and the acid-binding agent is 1.0: 1.0-3.0;
the solvent is one or the combination of at least two of dichloromethane, 1, 2-dichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylformamide, 1, 4-dioxane and 1, 2-dimethoxyethane;
the reaction temperature is 0-40 ℃;
the third step: reacting the activated sulfonic acid ester compound with sodium azide to obtain a process product;
the fourth step: then the cyclic amino compound of carbamido can be obtained by conventional catalytic hydrogenation;
the fifth step: cyclic amino compound of ureido with Boc2O reaction is carried out to obtain a cyclic amino compound of ureido protected by Boc, and the reaction temperature is 0-40 ℃; cyclic amino compound of ureido, Boc2The ratio of O to the alkali is 1: 1-3.
9. The cyclic chiral amino compound containing a ureido group of claim 8 wherein the solvent is methylene chloride.
10. The amplification process of the cyclic chiral amino compound containing ureido according to claim 8, wherein the reaction temperature of the activated sulfonate compound with the sodium azide to obtain the cyclic amino compound of ureido is 25-100 ℃, and the molar ratio of the activated sulfonate compound to the sodium azide is 1.0: 1.0-50.0.
11. The process for amplifying the cyclic chiral amino compounds containing ureido groups according to claim 4 or 8, wherein the amino alcohol hydrochloride and the substituted carbamoyl group or the substituted isocyanate or the isothiocyanate are reacted under alkaline conditions to obtain the cyclic alcohol compound of the ureido group, wherein the reaction temperature is 0 ℃ to 25 ℃; the base is selected from one or the combination of at least two of triethylamine and diisopropylethylamine; the molar ratio of the amino alcohol hydrochloride, the substituted carbamoyl or the isocyanate or the isothiocyanate to the base is 1.0: 1.0-1.5: 2.0-3.0.
12. The amplification process of the cyclic chiral amino compound containing ureido according to claim 4 or 8, wherein the reaction temperature of the cyclic alcohol compound of ureido and sulfonyl chloride in the presence of an acid-binding agent to prepare the activated sulfonate compound is 10-25 ℃; the molar ratio of the cyclic alcohol compound of the carbamido group, the sulfonyl chloride compound and the acid-binding agent is 1.0: 1.0-1.2: 1.0-2.0; the acid-binding agent is selected from one or the combination of at least two of triethylamine and diisopropylethylamine.
13. The process for amplifying the cyclic chiral amino compounds containing ureido groups according to claim 4 or 8, wherein the cyclic amino compound of ureido group is reacted with Boc2The reaction temperature of the cyclic amino compound of the ureido protected by Boc reaction is 0-40 ℃; cyclic amino compound of ureido, Boc2The ratio of O to the alkali is 1: 1-1.5, and the reaction solvent is methanol.
14. The process for amplifying cyclic chiral amino compounds containing ureido according to claim 4 or claim 8, wherein R is1And R2Independently selected from hydrogen, methyl, ethyl or isopropyl.
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