CN120590331A - A preparation method of (2S,6S)-2,6-dimethyl-1-piperazinecarboxylic acid tert-butyl ester - Google Patents
A preparation method of (2S,6S)-2,6-dimethyl-1-piperazinecarboxylic acid tert-butyl esterInfo
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- CN120590331A CN120590331A CN202411513306.7A CN202411513306A CN120590331A CN 120590331 A CN120590331 A CN 120590331A CN 202411513306 A CN202411513306 A CN 202411513306A CN 120590331 A CN120590331 A CN 120590331A
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- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
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- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/20—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
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- C07C309/63—Esters of sulfonic acids
- C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/73—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
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Abstract
本发明涉及一种(2S,6S)‑2,6‑二甲基‑1‑哌嗪羧酸叔丁酯的制备方法。具体地，本发明公开了一种采用价格便宜的L‑苏氨酸为原料制备(2S,6S)‑2,6‑二甲基‑1‑哌嗪羧酸叔丁酯的方法，该方法操作简单，原料易得，反应收率高，纯度好，易于工业化生产。The present invention relates to a method for preparing tert-butyl (2S,6S)-2,6-dimethyl-1-piperazinecarboxylate. Specifically, the present invention discloses a method for preparing tert-butyl (2S,6S)-2,6-dimethyl-1-piperazinecarboxylate using inexpensive L-threonine as a raw material. The method is simple to operate, has readily available raw materials, a high reaction yield, good purity, and is easy to industrialize.
Description
Technical Field
The invention belongs to the field of preparation of medical intermediates, and particularly relates to a preparation method of (2S, 6S) -2, 6-dimethyl-1-piperazine carboxylic acid tert-butyl ester.
Background
The (2S, 6S) -2, 6-dimethyl-1-piperazine carboxylic acid tert-butyl ester and the derivative thereof are important chemical intermediates, are widely applied to the fields of medicines, pesticides, materials and the like, and have important application values in industry. Such as the psychotropic drugs linka tut-tut, the sarcin drugs sparfloxacin and obisafloxacin, etc.
The literature (j. Org. Chem., vol.60, no.13,1995) reports a synthetic method of (2 s,6 s) -2, 6-dimethyl-1-piperazine or its derivatives, the synthetic route of which is as follows:
The method needs borane dimethyl sulfide and aluminum lithium hydride to reduce amide respectively, has higher safety risk and production cost, is unfavorable for industrial production, and has the problems of selectivity and excessive reaction to obtain double Boc protection when the final product (2S, 6S) -2, 6-dimethyl-1-piperazine of the synthetic method is further subjected to Boc protection, thus being difficult to purify and low in yield.
Patent (CN 103265498) discloses a synthetic method, the synthetic route of which is:
the scheme has a long route, and sodium borohydride is used for reducing and lithium aluminum hydride is used for reducing amide, so that the cost is high and the safety production is not facilitated.
Therefore, there is an urgent need in the art to develop a preparation method of (2 s,6 s) -2, 6-dimethyl-1-piperazine carboxylic acid tert-butyl ester which is environment-friendly, low in production cost, low in safety risk, high in yield and purity, and easy for industrial production.
Disclosure of Invention
The invention aims to provide a preparation method of (2S, 6S) -2, 6-dimethyl-1-piperazine carboxylic acid tert-butyl ester, which is environment-friendly, low in safety risk, high in reaction yield, good in product purity and suitable for industrial production.
In a first aspect of the present invention there is provided a process for the preparation of a compound of formula I, the process comprising the steps of:
(a) In the presence of an inert solvent and alkali, carrying out C-N coupling reaction on the compound of the formula IV and L-aminopropanol, so as to prepare a compound of the formula III with a trans-chiral structure;
(b) In the presence of an inert solvent and alkali, performing ring closure reaction on the compound of the formula II prepared from the compound of the formula III, thereby preparing the compound of the formula I;
Wherein, the
R is selected from the group consisting of tosyl (Ms), mesyl (Ts), 2-nitrobenzenesulfonyl (Ns), and trifluorosulfonyl (Tf).
In another preferred embodiment, the process for preparing the intermediate compound of formula IV comprises the steps of:
l-threonine is used as a raw material, and the compound shown in the formula IV is obtained through high-temperature decarboxylation, cbz protection and TsCl esterification reaction.
In another preferred embodiment, the process for preparing a compound of formula II from a compound of formula III comprises the steps of:
in an inert solvent, carrying out Boc protection, esterification reaction and Cbz protection removal on the compound of the formula III, thereby preparing the compound of the formula II;
Wherein, the
R is selected from the group consisting of tosyl (Ms), mesyl (Ts), 2-nitrobenzenesulfonyl (Ns), and trifluorosulfonyl (Tf).
In another preferred embodiment, the important intermediate is selected from the group consisting of:
Wherein, the
R is selected from the group consisting of tosyl (Ms), mesyl (Ts), 2-nitrobenzenesulfonyl (Ns), trifluorosulfonyl (Tf);
r 1 is selected from the group consisting of H, boc;
R 2 is selected from the group H, cbz.
In another preferred embodiment, the inert solvent in steps a and b is selected from the group consisting of alcohol solvents, halogenated alkanes, ether solvents, benzene solvents, acetonitrile, or combinations thereof.
In another preferred example, the inert solvent in the step a is selected from the group consisting of alcohol solvents such as methanol, ethanol and isopropanol, halogenated alkanes such as methylene chloride and dichloroethane, ether solvents such as tetrahydrofuran, methyl tert-butyl ether, dioxane and 2-methyltetrahydrofuran, acetonitrile, toluene and xylene benzene solvents, or a combination thereof, and preferably methylene chloride.
In another preferred example, the inert solvent in the step b is selected from the group consisting of alcohol solvents such as methanol, ethanol, isopropanol, n-butanol, halogenated alkanes such as dichloroethane, ether solvents such as tetrahydrofuran, methyl tert-butyl ether, dioxane, 2-methyltetrahydrofuran, acetonitrile, toluene, xylene benzene solvents, or combinations thereof, and is preferably n-butanol.
In another preferred embodiment, the base in step a is selected from the group consisting of trimethylamine, triethylamine, diisopropylethylamine, tripropylamine, pyridine, 2-methylpyridine, 2, 6-dimethylpyridine, DMAP, DABCO, DBU, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium phosphate, sodium phosphate, or a combination thereof, preferably pyridine.
In another preferred embodiment, the base in step b is selected from the group consisting of trimethylamine, triethylamine, diisopropylethylamine, tripropylamine, pyridine, 2-methylpyridine, 2, 6-dimethylpyridine, DMAP, DABCO, DBU, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium phosphate, sodium phosphate, or a combination thereof, preferably diisopropylethylamine.
In another preferred embodiment, the amount of base used in step a is 1.0 to 20.0 equivalents, preferably 3.0 to 4.0 equivalents, of the compound of formula IV.
In another preferred embodiment, the amount of base used in step b is 1.0 to 20.0 equivalents, preferably 3.0 to 4.0 equivalents, of the compound of formula II.
In another preferred embodiment, the reaction temperature of step a is from 0 to 80 ℃, preferably from 50 to 60 ℃.
In another preferred embodiment, the reaction temperature of step b is from 0 to 80 ℃, preferably from 50 to 60 ℃.
In another preferred embodiment, the reaction time of step a is 2 to 24 hours, preferably 18 to 20 hours.
In another preferred embodiment, the reaction time of step b is 2-24 hours, preferably 18-20 hours.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.
Detailed Description
Through extensive and intensive studies, the inventors of the present invention have surprisingly found that a compound of formula III having a trans-chiral structure can be obtained by performing a C-N coupling reaction of a compound of formula IV with L-aminopropanol to cause valcanines to turn over, and that a compound of formula I having a-Boc group can be prepared in a high yield and with good purity by performing a ring closure reaction of a compound of formula II. The method disclosed by the invention does not need to use a strong reducing agent, is environment-friendly, low in safety risk and less in impurity, and is easy for industrial production. On this basis, the inventors completed the present invention.
Terminology
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
As used herein, the terms "comprising," "including," and "containing" are used interchangeably, and include not only closed-form definitions, but also semi-closed-form and open-form definitions. In other words, the terms include "consisting of" and "consisting essentially of.
As used herein, the terms "method of the invention", "preparation method of the invention", "industrial preparation method of the invention" are used in combination and refer to the method described in the first aspect of the invention.
The compound of the formula I is (2S, 6S) -2, 6-dimethyl-1-piperazine carboxylic acid tert-butyl ester, and the structural formula is as follows:
The important intermediates of the present invention are selected from the group consisting of:
wherein R, R 1、R2 is as defined above.
In another preferred embodiment, R, R 1 and R 2 are the groups corresponding to the specific compounds of the invention.
As used herein, the protecting group-Cbz has the structure
The structure of the protecting group-Boc is that
The "inert solvent" as used herein refers to a solvent that does not react with the compounds in the reaction system.
Preparation method
Typically, the preparation process according to the invention is as follows, wherein the starting materials and reagents used, unless otherwise specified, are commercially available.
The invention provides a preparation method of (2S, 6S) -2, 6-dimethyl-1-piperazine carboxylic acid tert-butyl ester, which comprises the following steps:
(a-1) taking L-threonine as a raw material, and performing high-temperature decarboxylation to generate a compound IV-1;
(a-2) the compound IV-1 obtained in the step a-1 is subjected to Cbz protection to obtain a compound IV-2;
(a-3) esterifying the compound IV-2 obtained in the step a-2 with TsCl to obtain a compound IV;
(a) C-N substitution reaction is carried out on the compound IV obtained in the step a-3 to obtain a compound III;
(b-1) the compound III obtained in the step a is subjected to Boc protection to obtain a compound II-1;
(b-2) subjecting the compound II-1 obtained in the step b-1 to an esterification reaction to obtain a compound II-2;
(b-3) subjecting the compound II-2 obtained in the step b-2 to Cbz removal to obtain a compound II;
(b) And b, closing the ring of the compound II obtained in the step b-3 to obtain a final product compound I.
Specifically, the preparation method of the invention comprises the following steps:
Step a-1, which is a decarboxylation reaction. In an inert solvent, the L-threonine undergoes decarboxylation reaction under the action of high temperature to prepare the compound shown in the formula IV-1.
Wherein the inert solvent is selected from the group consisting of high boiling point solvents such as tetraethylene glycol dimethyl ether, ethylene glycol, 1, 3-propylene glycol and the like, or a combination thereof.
Preferably, the inert solvent is tetraethylene glycol dimethyl ether.
The reaction temperature is 160-200 ℃, preferably 170-180 ℃.
The reaction time is 2 to 10 hours, preferably 3 to 5 hours.
Step a-2 the method and conditions for Cbz protection of this step are both conventional methods and conditions for the present neighborhood. And (3) dropwise adding Cbz-Cl into the compound of the formula IV-1 in an inert solvent or water under the action of alkali, layering after the reaction is finished, and concentrating the solvent to obtain the compound of the formula IV-2.
Wherein the inert solvent is selected from halogenated alkanes such as methylene dichloride and dichloroethane, ether solvents such as tetrahydrofuran, methyl tertiary butyl ether, dioxane and 2-methyltetrahydrofuran, acetonitrile, toluene and xylene benzene solvents or a combination thereof.
Preferably, the inert solvent is dichloromethane.
The alkali is selected from trimethylamine, triethylamine, diisopropylethylamine, tripropylamine, pyridine, 2-methylpyridine, 2, 6-dimethylpyridine, DMAP, DABCO, DBU and other organic bases commonly used for organic synthesis, and sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium phosphate, sodium phosphate and other common inorganic bases.
Preferably, the base is potassium carbonate.
The equivalent weight of Cbz-Cl is 1.0-20.0 times that of the compound of the formula IV-1.
Preferably, the equivalent of Cbz-Cl is 1.0 to 2.0 times the equivalent of the compound of formula IV-1.
The equivalent of the base is 1.0 to 20.0 times the equivalent of the compound of formula IV-1.
Preferably, the equivalent of the base is 1.0 to 2.0 times the equivalent of the compound of formula IV-1.
The reaction temperature is 20-80 ℃, preferably 20-30 ℃.
The reaction time is 2 to 20 hours, preferably 2 to 3 hours.
Step a-3 the esterification method and conditions in this step are all conventional methods and conditions in the present neighborhood. And (3) dropwise adding TsCl into the compound of the formula IV-2 in an inert solvent under the action of alkali, carrying out acid washing and alkali washing after the reaction is finished, concentrating the solvent, and crystallizing to obtain the compound of the formula IV.
Wherein the inert solvent is selected from halogenated alkanes such as methylene dichloride and dichloroethane, ether solvents such as tetrahydrofuran, methyl tertiary butyl ether, dioxane and 2-methyltetrahydrofuran, acetonitrile, toluene and xylene benzene solvents or a combination thereof.
Preferably, the inert solvent is dichloromethane.
The alkali is selected from trimethylamine, triethylamine, diisopropylethylamine, tripropylamine, pyridine, 2-methylpyridine, 2, 6-dimethylpyridine, DMAP, DABCO, DBU and other organic bases commonly used for organic synthesis, and sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium phosphate, sodium phosphate and other common inorganic bases.
Preferably, the base is triethylamine.
The equivalent of TsCl is 1.0-20.0 times the equivalent of the compound of formula IV-2.
Preferably, the equivalent of TsCl is 1.0-2.0 times the equivalent of the compound of formula IV-2.
The equivalent of the base is 1.0 to 20.0 times the equivalent of the compound of formula IV-2.
Preferably, the equivalent of the base is 1.0 to 2.0 times the equivalent of the compound of formula IV-2.
The reaction temperature is 0-80 ℃, preferably 20-30 ℃.
The reaction time is 2 to 24 hours, preferably 20 to 24 hours.
The method and the condition of the C-N coupling in the step a are the conventional method and the condition of the neighborhood. And adding the compound IV and L-aminopropanol into an inert solvent under the action of alkali, heating for reaction, extracting and layering after the reaction is finished, washing with water, washing with alkali, and concentrating the solvent to obtain the compound of the formula III.
Wherein the inert solvent is selected from alcohol solvents such as methanol, ethanol, isopropanol, halogenated alkanes such as methylene dichloride and dichloroethane, ether solvents such as tetrahydrofuran, methyl tertiary butyl ether, dioxane and 2-methyltetrahydrofuran, benzene solvents such as acetonitrile, toluene and xylene, or a combination thereof.
Preferably, the inert solvent is acetonitrile.
The alkali is selected from trimethylamine, triethylamine, diisopropylethylamine, tripropylamine, pyridine, 2-methylpyridine, 2, 6-dimethylpyridine, DMAP, DABCO, DBU and other organic bases commonly used for organic synthesis, and sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium phosphate, sodium phosphate and other commonly used inorganic bases.
Preferably, the base is pyridine.
The equivalent of the base is 1.0 to 20.0 times the equivalent of the compound of formula IV.
Preferably, the equivalent of the base is 2.0 to 3.0 times the equivalent of the compound of formula IV.
Wherein the equivalent of L-aminopropanol is 1.0-20.0 times the equivalent of the compound of formula IV.
Preferably, the equivalent of L-aminopropanol is 1.5-2.5 times the equivalent of the compound of formula IV.
The reaction temperature is 0-80 ℃, preferably 50-60 ℃.
The reaction time is 2 to 24 hours, preferably 18 to 20 hours.
Step b-1 the Boc protection method and conditions of this step are all conventional methods and conditions of this neighborhood. And (3) dropwise adding Boc 2 O into the compound of the formula III in an inert solvent under the action of alkali and a catalyst, adding water for layering after the reaction is finished, and concentrating the solvent to obtain the compound of the formula II-1.
Wherein the inert solvent is selected from halogenated alkanes such as methylene dichloride and dichloroethane, ether solvents such as tetrahydrofuran, methyl tertiary butyl ether, dioxane and 2-methyltetrahydrofuran, acetonitrile, toluene and xylene benzene solvents or a combination thereof.
Preferably, the inert solvent is dichloromethane.
The alkali is selected from trimethylamine, triethylamine, diisopropylethylamine, tripropylamine, pyridine, 2-methylpyridine, 2, 6-dimethylpyridine, DMAP, DABCO, DBU and other organic bases commonly used for organic synthesis, and sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium phosphate, sodium phosphate and other commonly used inorganic bases.
Preferably, the base is triethylamine.
The catalyst is DMAP.
The equivalent of Boc 2 O is 1.0-20.0 times of the equivalent of the compound shown in the formula III.
Preferably, the equivalent of Boc 2 O is 1.0-1.2 times the equivalent of the compound of formula III.
The equivalent of the base is 1.0-20.0 times of the equivalent of the compound shown in the formula III.
Preferably, the equivalent of the base is 1.0 to 2.0 times the equivalent of the compound of formula III.
The equivalent of the catalyst is 0.01-0.1 times of the equivalent of the compound shown in the formula III.
Preferably, the equivalent of the catalyst is 0.02 to 0.04 times the equivalent of the compound represented by formula III.
The reaction temperature is 20-80 ℃, preferably 20-30 ℃.
The reaction time is 2 to 20 hours, preferably 16 to 20 hours.
Step b-2 the esterification method and conditions of this step are all conventional methods and conditions of the present neighborhood. And (3) dropwise adding a reagent RCl Or (RO) 2 O into the compound of the formula II-1 in an inert solvent under the action of alkali, carrying out acid washing and alkali washing after the reaction is finished, concentrating the solvent, and crystallizing to obtain the compound of the formula II-2.
Wherein R is selected from the group consisting of tosyl (Ms), mesyl (Ts), 2-nitrobenzenesulfonyl (Ns) and trifluorosulfonyl (Tf).
The inert solvent is selected from halogenated alkanes such as methylene dichloride and dichloroethane, ether solvents such as tetrahydrofuran, methyl tertiary butyl ether, dioxane and 2-methyltetrahydrofuran, acetonitrile, toluene and xylene benzene solvents or a combination thereof.
Preferably, the inert solvent is dichloromethane.
The alkali is selected from trimethylamine, triethylamine, diisopropylethylamine, tripropylamine, pyridine, 2-methylpyridine, 2, 6-dimethylpyridine, DMAP, DABCO, DBU and other organic bases commonly used for organic synthesis, and sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium phosphate, sodium phosphate and other commonly used inorganic bases.
Preferably, the base is triethylamine.
The equivalent weight of RCl Or (RO) 2 O is 1.0-20.0 times the equivalent weight of the compound of formula II-1.
Preferably, the equivalent of RCl Or (RO) 2 O is 1.0 to 2.0 times the equivalent of the compound of formula II-1.
The equivalent of the base is 1.0 to 20.0 times the equivalent of the compound of formula II-1.
Preferably, the equivalent of the base is 1.0 to 2.0 times the equivalent of the compound of formula II-1.
The reaction temperature is 0-80 ℃, preferably 20-30 ℃.
The reaction time is 2 to 24 hours, preferably 20 to 24 hours.
Step b-3 the hydrogenation method and conditions of this step are conventional methods and conditions for the hydrogenation of the present neighborhood. In an inert solvent, under the action of a catalyst, carrying out hydrogenation reaction on the compound shown as the formula II-2, and after the reaction is finished, simply filtering and concentrating the solvent to obtain the compound shown as the formula II.
Wherein R is selected from the group consisting of tosyl (Ms), mesyl (Ts), 2-nitrobenzenesulfonyl (Ns) and trifluorosulfonyl (Tf).
The inert solvent is selected from the group consisting of C1-C8 alcohol solvents, ester solvents, ether solvents, or combinations thereof.
In another preferred example, the alcohol solvent is selected from the group consisting of methanol, ethanol, isopropanol, isobutanol, n-butanol, and combinations thereof, the ester solvent is selected from the group consisting of ethyl acetate, methyl acetate, isopropyl acetate, n-butyl acetate, and combinations thereof, and the ether solvent is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, ethylene glycol dimethyl ether, and combinations thereof.
Preferably, the inert solvent is methanol or ethanol.
The catalyst is selected from Raney nickel, pd/C, ru/C, rh/C, or a combination thereof.
Preferably, the catalyst is Pd/C.
The amount of the inert solvent is 1-20 times that of the compound of the formula II-2.
Preferably, the inert solvent is used in an amount of 10 times that of the compound of formula II-2.
The hydrogen pressure is 0.1-2.0MPa, preferably 0.3MPa.
The hydrogen reaction is 20-80 ℃, preferably 40-50 ℃.
And b, the intramolecular method and the conditions of the step are the conventional method and conditions of the neighborhood. And (3) adding the compound of the formula II into an inert solvent under the protection of nitrogen and the action of alkali, washing with water and alkali after the reaction is finished, concentrating the solvent, and crystallizing to obtain the compound of the formula I.
Wherein the inert solvent is selected from alcohol solvents such as methanol, ethanol, isopropanol, n-butanol, halogenated alkanes such as dichloroethane, ether solvents such as tetrahydrofuran, methyl tertiary butyl ether, dioxane, 2-methyltetrahydrofuran, benzene solvents such as acetonitrile, toluene, xylene, or a combination thereof.
Preferably, the inert solvent is n-butanol.
The alkali is selected from trimethylamine, triethylamine, diisopropylethylamine, tripropylamine, pyridine, 2-methylpyridine, 2, 6-dimethylpyridine, DMAP, DABCO, DBU and other organic bases commonly used for organic synthesis, and sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium phosphate, sodium phosphate and other commonly used inorganic bases.
Preferably, the base is diisopropylethylamine.
The equivalent of the base is 1.0 to 20.0 times the equivalent of the compound of formula II.
Preferably, the equivalent of the base is 3.0 to 4.0 times the equivalent of the compound of formula II.
The reaction temperature is 0-80 ℃, preferably 50-60 ℃.
The reaction time is 2 to 24 hours, preferably 18 to 20 hours.
The invention also provides a preparation method of the L-aminopropanol, which comprises the following specific steps:
L-alanine methyl ester is used as a raw material, and is reduced by a reducing agent to prepare the L-aminopropanol.
The invention has the main advantages that:
1. the invention provides a method for preparing (2S, 6S) -2, 6-dimethyl-1-piperazine carboxylic acid tert-butyl ester by using L-threonine as a raw material, wherein the raw material is low in price and has a larger cost advantage.
2. Step a in the process of the present invention is chiral in inversion, unexpectedly yielding a compound of formula III having a trans-chiral structure.
3. The invention can prepare the compound of the product formula I with high yield through the ring closure reaction in the step b, and the difficult purification is not needed.
4. The method disclosed by the invention is simple to operate, high in product yield (the yield of each step is 79% -99%), good in purity, less in three wastes, relatively mild in reaction condition and easy for industrial production.
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the present invention. The preferred methods and materials described herein are presented for illustrative purposes only.
In the present invention, the structure of the compound is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR was performed using a Bruker AVANCE-400 nuclear magnetic resonance apparatus. LCMS was measured using a Waters2695 liquid Mass Spectrometry (MS model: micromass ZQ).
HPLC was performed using Agilent 1100 high pressure liquid chromatograph (ZORBAX SP-C18 250X4.6mm column, eclipse Plus-C18 250X4.6mm column).
The following examples were carried out at atmospheric pressure unless otherwise indicated.
Example 1
Tetraethylene glycol dimethyl ether (700 ml), L-threonine (100 g), 2-cyclohexenone (5 g) are added into a reactor with a stirring and temperature controlling device, the temperature is raised to 170-180 ℃ and the stirring reaction is carried out for 3-5 hours until the system is clear and transparent, and no gas is generated. After the reaction, the mixture was concentrated under reduced pressure, and distilled to give a product (50.4 g) in 80% yield and 98.1% purity by GC.
MS(ESI+)m/z:76[M+H+]。
Example 2
Dichloromethane (500 mL), water (500 mL), a compound (100 g) of formula IV-1, potassium carbonate (202 g) and Cbz-Cl (230 g) are added into a reactor with a stirring and temperature controlling device, the temperature is controlled to be 0-10 ℃, and stirring reaction is carried out for 4 hours at the temperature of 10-20 ℃. After the reaction, the organic phase was separated, washed with 5% citric acid and 5% sodium bicarbonate, and concentrated to dryness under reduced pressure to give the compound (236 g), yield 85%, purity 89.7% by HPLC.
MS(ESI+)m/z:210[M+H+]。
Example 3
Dichloromethane (500 mL), triethylamine (96.5 g), a compound of formula IV-2 (100 g), trimethylamine hydrochloride (6 g) are added into a reactor with a stirring and temperature controlling device under the protection of nitrogen, a solution of TsCl (164 g) in dichloromethane (300 mL) is dropwise added at the temperature of 0-10 ℃ after the addition, and the temperature is controlled to be 10-20 ℃ for stirring reaction for 16 hours. After the reaction, 500ml of water was added to separate the solution, the organic phase was washed twice with 5% sodium bicarbonate, the organic phase was concentrated to dryness under reduced pressure, and ethanol was added to recrystallize to give the compound (158 g), yield 91%, and purity 98.9% by HPLC.
MS(ESI+)m/z:364[M+H+]。
Example 4
Under the protection of nitrogen, adding L-aminopropanol (20.6 g), acetonitrile (600 mL), pyridine (30.5 g) into a reactor with a stirring and temperature controlling device, controlling the temperature to be 60-65 ℃, adding 100g of a compound IV (50 g) in batches, and reacting for 20h at the temperature of 60-65 ℃. After the reaction, methylene chloride (500 mL), water (500 mL) was added, the mixture was separated, the aqueous phase was extracted once with methylene chloride, and the organic phase was concentrated to dryness to give the compound (29 g), yield 79%, and purity 97.6% by HPLC.
MS(ESI+)m/z:267[M+H+]。
Example 5
Dichloromethane (500 mL), a compound of formula III (60 g), triethylamine (27.3 g) and DMAP (4 g) are added into a reactor with a stirring and temperature controlling device, boc 2 O (54 g) is added dropwise at the temperature of 0-10 ℃ after the addition, and the temperature is controlled to be 10-20 ℃ for stirring reaction for 4 hours. After the completion of the reaction, the mixture was concentrated to dryness under reduced pressure to give the compound (80.8 g), with a yield of 98%, and a purity of 97.0% as measured by HPLC.
MS(ESI+)m/z:367[M+H+]。
Example 6
Dichloromethane (500 mL), triethylamine (19 g), a compound of formula II-1 (36 g) and a solution of TsCl (26.6 g) in dichloromethane (300 mL) are added into a reactor with a stirring and temperature controlling device under the protection of nitrogen, the temperature is controlled to be 0-10 ℃, and stirring reaction is carried out for 16 hours at the temperature of 10-20 ℃. After the reaction, water is added to quench the reaction, the organic phase is washed twice with 5% sodium bicarbonate, the organic phase is concentrated to dryness under reduced pressure, then ethanol is added to recrystallize to obtain the compound II-2 (47.8 g), the yield is 92%, and the purity is 98.9% by HPLC detection.
MS(ESI+)m/z:521[M+H+]。
Example 7
Methanol, the compound of formula II-2 (30 g), wet Pd/C (3 g) were charged into the hydrogenation vessel and reacted at a reaction temperature of 50℃under a hydrogen pressure of 10atm for 24 hours. After the reaction, pd/C was filtered off and concentrated to dryness to give the compound (22.0 g) in 99% yield.
MS(ESI+)m/z:387[M+H+]。
Example 8
N-butanol (200 mL), DIPEA (10.5 g) and a compound of formula II (10 g) are added into a reactor with a stirring and temperature controlling device under the protection of nitrogen, and the temperature is raised to 110-120 ℃ for stirring reaction for 12 hours. After the reaction, 10% aqueous sodium carbonate solution and ethyl acetate were added and stirred to separate layers, the aqueous phase was extracted once with ethyl acetate, and the combined organic phases were concentrated to dryness under reduced pressure and recrystallized from toluene to give the compound of formula I (4.7 g) in 84% yield.
MS(ESI+)m/z:215[M+H+]。
All documents mentioned in this disclosure are incorporated by reference in this disclosure as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.
Claims (10)
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