CN114031542A - Novel preparation method of azabicyclo medical intermediate - Google Patents

Novel preparation method of azabicyclo medical intermediate Download PDF

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CN114031542A
CN114031542A CN202111504898.2A CN202111504898A CN114031542A CN 114031542 A CN114031542 A CN 114031542A CN 202111504898 A CN202111504898 A CN 202111504898A CN 114031542 A CN114031542 A CN 114031542A
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CN114031542B (en
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张玉红
于洋
石清爱
黄国东
李浩然
朱根林
刘晓庆
胡瑞君
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Zhejiang University ZJU
Zhejiang NHU Co Ltd
Shangyu NHU Biological Chemical Co Ltd
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Zhejiang University ZJU
Zhejiang NHU Co Ltd
Shangyu NHU Biological Chemical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses

Abstract

The invention relates to an azabicyclo drug intermediate, in particular to a synthesis method of 6,6-dimethyl-3-azabicyclo [3.1.0] hexane or a derivative thereof, wherein a heteroatom bicyclic compound is constructed by cyclization of intramolecular diazo groups and olefinic bonds, and a target product is finally obtained through amination reaction and reduction reaction.

Description

Novel preparation method of azabicyclo medical intermediate
Technical Field
The invention belongs to the field of pharmaceutical chemicals, in particular relates to a preparation method of a drug intermediate, and particularly relates to a preparation method of a drug intermediate 6,6-dimethyl-3-azabicyclo [3.1.0] hexane or a derivative thereof
Background
Pharmaceutical intermediate compounds are important supply chain links in the pharmaceutical industry, and the stability of yield and quality of the supply chain is increasingly emphasized by the whole industry, especially during the period of the epidemic of infectious diseases leading to the drastic increase of drug demand.
It is known that 6,6-Dimethyl-3-azabicyclo [3.1.0] hexane (6,6-Dimethyl-3-azabicyclo [3.1.0] hexane; CAS number: 943516-54-9) is an important pharmaceutical intermediate, an important starting material used in the synthesis of many drugs, such as the hepatitis C protease inhibitor Boceprevir (Boceprevir) and oral drugs for the treatment of new coronaviruses (PF-07321332).
They have the following formula:
Figure BDA0003403822260000011
the common synthesis route of 6,6-dimethyl-3-azabicyclo [3.1.0] hexane mainly uses ethyl chrysanthemate, cyhalothric acid or hydroxyl protected isopentenol as raw materials to synthesize an intermediate, namely caronic anhydride, and the caronic anhydride is subjected to amination and reduction reaction to prepare the 6,6-dimethyl-3-azabicyclo [3.1.0] hexane.
Document 1 discloses a method for preparing caronic acid from hydroxyl-protected isoamylene alcohol and ethyl diazoacetate, which comprises the following main steps:
Figure BDA0003403822260000021
the method takes prenyl alcohol ester as a raw material, and obtains the caronic acid through cyclization reaction, hydrolysis and oxidation of diazo groups. However, the method has long reaction steps and low atom economy, and a large amount of oxidant is needed to oxidize the carane aldehydic acid or the carane aldehydic acid lactone into the caronic acid, so that the yield of the cis-form product is low, and a large amount of waste water and waste salt are generated, thereby causing serious environmental pollution.
Further, document 2 discloses a synthetic route for preparing 6,6-dimethyl-3-azabicyclo [3.1.0] hexane using caronic anhydride as a starting material, which is as follows:
Figure BDA0003403822260000022
the method needs a large amount of expensive lithium aluminum hydride reducing agent to reduce the caronic anhydride to obtain the 6,6-dimethyl-3-azabicyclo [3.1.0] hexane, and has high production cost.
Certainly, other researchers do a certain discussion on the synthetic route of 6,6-dimethyl-3-azabicyclo [3.1.0] hexane and the precursor caronic acid (anhydride) thereof, but in consideration of the rapid requirements brought by the treatment of hepatitis C and new coronary pneumonia at present and in the future, how to obtain a novel method for preparing the azabicyclo derivative with environmental protection and high atom economy is a difficult problem which needs to be solved at present.
Cited documents:
document 1: CN104163759B
Document 2: CN101384551B
Disclosure of Invention
Problems to be solved by the invention
As mentioned previously, although the prior art provides some routes for the preparation of 6,6-dimethyl-3-azabicyclo [3.1.0] hexane and its precursor, caronic acid (anhydride), the following problems have been found in long-term industrial synthetic practice:
document 1 discloses that prenol or a derivative thereof is used as a raw material, caronic acid and caronic anhydride are prepared, and then the caronic anhydride is reduced to obtain 6,6-dimethyl-3-azabicyclo [3.1.0] hexane. The method has long reaction steps and low atom economy. A large amount of oxidant is needed in the preparation of the caronic acid, a large amount of wastewater and waste salt are generated, and the environmental pollution is serious; the prepared caronic acid is a cis-trans mixture, trans-caronic anhydride needs to be heteroformed into cis-caronic anhydride at high temperature, steps are increased, and energy consumption is huge. In addition, two carbonyls of the caronic anhydride are required to be reduced, so that the dosage of the expensive lithium aluminum hydride reducing agent is greatly increased, and the production cost is high.
6,6-dimethyl-3-azabicyclo [3.1.0] hexane can be conveniently obtained using caronic anhydride as a starting material in document 2. However, the caronic anhydride in the method takes the ethyl chrysanthemate or the kungfu acid as raw materials, the raw materials are difficult to prepare, the scale of manufacturers is small and limited, and the synthesized caronic anhydride has high cost and cannot meet the increasing dosage requirement.
Based on the defects in the prior art, the invention provides a novel synthesis method of 6,6-dimethyl-3-azabicyclo [3.1.0] hexane and functional derivatives thereof. In the method, in the presence of a ligand, an intramolecular cyclization reaction is utilized to obtain a high cis-selectivity heteroatom bicyclic compound, and then the target product is finally obtained through (amination reaction and) reduction reaction, so that the oxidation step is eliminated, and the discharge of waste water and waste salt is greatly reduced; the high cis-selectivity avoids the energy consumption of the trans-isomer in the high temperature isomerization process; the oxidation-reduction process is bypassed, and the amount of the reducing agent is greatly reduced. The method is green, mild and high in atom economy, is suitable for industrial large-scale production, and provides raw material guarantee for synthesizing downstream products such as hepatitis C protease inhibitor drug compounds or drugs for treating novel coronavirus (COVID-19) and the like.
Means for solving the problems
After long-term intensive research by the inventor group, the technical problems can be solved by implementing the following technical scheme:
[1] the present invention firstly provides a method for synthesizing 6,6-dimethyl-3-azabicyclo [3.1.0] hexane or a derivative thereof, wherein the method comprises:
a step of subjecting a compound represented by general formula (1) to a cyclization reaction to obtain a cyclized product represented by a compound represented by general formula (2),
Figure BDA0003403822260000041
wherein the content of the first and second substances,
x represents an oxygen atom or an-NH-group;
r represents a hydrogen atom or a polar group.
[2] The process according to [1], wherein the cyclization reaction step is carried out in the presence of a metal (salt) and an organic ligand, preferably, the metal (salt) comprises one or more of rhodium, palladium, cobalt, copper and salts thereof, and the organic ligand comprises one or more of nitrogen-oxygen, nitrogen-nitrogen polydentate ligands
[3] The process according to [2], wherein the organic ligand is selected from one or more of the following general formulae La, Lb, Lc, Ld or Le:
Figure BDA0003403822260000051
in the formula La, R1May represent a hydrogen atom, a halogen atom, a cyano group, a nitro group, a haloalkyl group, an ester group, an alkyl group having a substituted or unsubstituted, an aralkyl group having a substituted or unsubstituted, an aryl group having a substituted or unsubstituted, or a cycloalkyl group having a substituted or unsubstituted; r2Represents a hydrogen atom, an alkyl group or an aryl group;
in formula Lb, Q1May represent a divalent linking group or a direct bond, and is preferably a carbonyl group, a substituted or unsubstituted alkylene group, a substituted or unsubstituted arylalkylene group, a substituted or unsubstituted arylene groupOr a heteroarylene group having a substituent or unsubstituted;
in the formula Lc, R3、R4、R5、R10May be the same or different and represents a hydrogen atom, a halogen atom, a cyano group, a nitro group, a haloalkyl group, an ester group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted cycloalkyl group;
in the formula Ld, R6、R7May be the same or different and represents a hydrogen atom, a halogen atom, a cyano group, a nitro group, a haloalkyl group, an ester group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted cycloalkyl group;
in the formula Le, R8、R9May be the same or different and represents a hydrogen atom, a halogen atom, a cyano group, a nitro group, a haloalkyl group, an ester group, an alkyl group with a substitution or non-substitution, an aralkyl group with a substitution or non-substitution, an aryl group with a substitution or non-substitution, or a cycloalkyl group with a substitution or non-substitution; q2May represent a divalent linking group or a direct bond, and is preferably a carbonyl group, an alkylene group with a substitution or non-substitution, an arylalkylene group with a substitution or non-substitution, an arylene group with a substitution or non-substitution, a cycloalkylene group with a substitution or non-substitution, or a heteroarylene group with a substitution or non-substitution.
[4] The process according to any one of [1] to [3], wherein the cyclization reaction is carried out in an organic solvent; the temperature of the cyclization reaction is-10-120 ℃, preferably 60-80 ℃, and the reaction time is 2-64 hours, preferably 2-15 hours, and further preferably 2-6 hours.
[5] The process according to any one of [1] to [4], wherein X is an oxygen atom, and the cyclized product is a compound represented by the general formula (2-1), and further comprising:
i) subjecting the compound of the general formula (2-1) to an amination reaction to obtain a compound of a general formula (3); and
ii) subjecting the compound of the general formula (3) to a reduction reaction to obtain a compound of the general formula (4),
Figure BDA0003403822260000061
wherein R is as defined in claim 1.
[6] The process according to any one of [1] to [4], wherein X is an-NH-group, and the cyclized product is a compound represented by the general formula (3), and further comprising:
subjecting the compound of the general formula (3) to a reduction reaction to obtain a compound of the general formula (4),
wherein the general formula (3), the general formula (4) and R are as defined in claim 5.
[7] The method according to any one of [1] to [6], wherein R is a hydrogen atom, a carboxylic acid (salt) group, an ester group, a halogen atom or a cyano group.
[8] Further, the present invention also provides a method for producing a pharmaceutical intermediate, wherein the method comprises a method for synthesizing an azabicyclo pharmaceutical intermediate according to any one of the above [1] to [7].
[9] Further, the present invention also provides a method for producing a pharmaceutical compound, wherein the method comprises the method according to [8] above.
[10] The method of [9], wherein the pharmaceutical compound comprises a hepatitis C protease inhibitor-based pharmaceutical compound or a pharmaceutical compound for treating a novel coronavirus (COVID-19).
ADVANTAGEOUS EFFECTS OF INVENTION
Through the implementation of the technical scheme, the invention can obtain the following technical effects:
1) the preparation method avoids the steps of hydrolysis and oxidation for preparing the caronic anhydride, greatly shortens the preparation route, reduces the generation of a large amount of industrial wastewater and waste salt, has high reaction yield, is particularly beneficial to industrial large-scale production, and can meet the huge requirements of terminal drug production.
2) The intramolecular cyclization reaction catalyst of the invention adopts the combination of rhodium, palladium, cobalt, copper or copper salt and the like and ligand, the yield reaches 98.5 percent, and the proportion of cis form and trans form is more than 100:1, saving a little high-temperature isomerization step, greatly reducing the production energy consumption and simultaneously ensuring the high yield of the azabicyclo product.
3) The preparation method greatly reduces the dosage of the expensive catalyst in the reduction reaction process and obviously improves the economy.
4) The synthesis method provided by the invention can flexibly obtain drug intermediates with various structures, thereby meeting the synthesis requirements of different drugs.
Drawings
FIG. 1: schemes for synthesis reactions are presented in some embodiments of the invention.
Detailed Description
The present invention will be described in detail below. The technical features described below are explained based on typical embodiments and specific examples of the present invention, but the present invention is not limited to these embodiments and specific examples. It should be noted that:
in the present specification, the numerical range represented by "numerical value a to numerical value B" means a range including the end point numerical value A, B.
In the present specification, the numerical ranges indicated by "above" or "below" mean the numerical ranges including the numbers.
In the present specification, the meaning of "may" includes both the meaning of performing a certain process and the meaning of not performing a certain process.
In the present specification, the use of "optional" or "optional" means that certain substances, components, performance steps, application conditions, and the like are used or not used, and that the manner of use is not limited.
In the present specification, the unit names used are all international standard unit names, and the "%" used means weight or mass% content, if not specifically stated.
In the present specification, reference to "some particular/preferred embodiments," "other particular/preferred embodiments," "embodiments," and the like, means that a particular element (e.g., feature, structure, property, and/or characteristic) described in connection with the embodiment is included in at least one embodiment described herein, and may or may not be present in other embodiments. In addition, it is to be understood that the described elements may be combined in any suitable manner in the various embodiments.
Further, in the present specification, the following structures or substituents are explained by the following definitions unless otherwise specified:
the term "alkyl" refers to an aliphatic hydrocarbon group, which may be straight or branched chain, and which includes from 1 to 20 carbon atoms in the chain. Preferred alkyl groups include 1 to 12 carbon atoms in the chain. More preferred alkyl groups include 1 to 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. "lower alkyl" refers to a group having 1 to 6 carbon atoms in the chain, which may be straight or branched.
The term "aryl" refers to an aromatic monocyclic or polycyclic ring system comprising 6 to 14 carbon atoms, preferably 6 to 10 carbon atoms. Non-limiting examples of suitable aryl groups include phenyl and naphthyl.
The term "aralkyl" refers to an aryl-alkyl-group, wherein aryl and alkyl are as previously described. Preferred aralkyl groups contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenylethyl and naphthylmethyl. The bond to the parent moiety is through the alkyl group. "arylalkylene" refers to an alkylene group substituted with an aryl group, preferably, the arylalkylene group includes lower alkylene groups. And "lower alkyl" refers to an alkylene group having 1 to 6 carbon atoms in the chain, which may be straight or branched.
The term "cycloalkyl" refers to a non-aromatic mono-or polycyclic ring system comprising 3 to 10 carbon atoms, preferably 5 to 10 carbon atoms. Preferred cycloalkyl rings include 5 to 7 carbon atoms. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of suitable polycyclic cycloalkyl groups include 1-decalin, norbornyl, adamantyl, and the like.
The term "halogen atom" means fluorine, chlorine, bromine or iodine. Preferred are fluorine, chlorine or bromine, and more preferred are bromine and chlorine.
The term "substituted" means that the subject group being described may be substituted with one or more substituents, which may be the same or different, each substituent being independently selected from the group consisting of halogen atoms, alkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, -NH (alkyl), -NH (cycloalkyl), -N (alkyl)2Carboxyl and-C (O) O-alkyl. And, for the substitution of an aryl group or a heteroaryl group, the aryl group as a substituent may exist in a form of a ring. Non-limiting examples of "alkyl" as indicated in this paragraph as substituents include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, heptyl, nonyl, decyl and cyclopropylmethyl.
The invention provides a synthesis method of 6,6-dimethyl-3-azabicyclo [3.1.0] hexane or derivatives thereof, which is characterized in that a heteroatom bicyclic compound is constructed by cyclization of intramolecular diazo groups and olefinic bonds, and a target product is finally obtained through amination reaction and reduction reaction. Among them, 6,6-dimethyl-3-azabicyclo [3.1.0] hexane or derivatives thereof can be used as intermediates in the synthesis of drugs.
In the present invention, the derivatives of 6,6-dimethyl-3-azabicyclo [3.1.0] hexane refer to the case where the substituent R is changed to another substituent through a chemical reaction as described below.
In particular, the synthesis method of the present invention comprises, at first, a step of cyclization reaction, and the cyclization reaction is essentially cyclopropanation of one of the diazo groups with the olefinic bond. The cyclopropanation reaction is typically one in which the carbon to which the diazo group is attached is bonded to two carbons of the olefinic bond to form a tricyclic cyclopropane ring structure.
In the present invention, the cyclization reaction is a reaction in which a compound represented by the general formula (1) as a starting material is cyclized to obtain a cyclized product represented by a compound represented by the general formula (2),
Figure BDA0003403822260000101
wherein X represents an oxygen atom or an-NH-group. R represents a hydrogen atom or a polar group, and the polar group is preferably selected from a carboxylic acid (salt) group, an ester group, a halogen atom or a cyano group. And, more preferably, the R is a hydrogen atom, a formate group or an ester group of formic acid with an alkyl group, a substituted alkyl group, an aryl group, a substituted aryl group, an aralkyl group or a substituted aralkyl group, a cycloalkyl group or a substituted cycloalkyl group.
In some preferred embodiments of the invention, the compound of formula (1) has the structure of formula:
Figure BDA0003403822260000111
further, the compounds of the above structures can be obtained commercially or synthesized in a laboratory, and for example, the compounds can be obtained by diazotization (nitrite, acidic conditions) using a (primary) amino acetate having a double bond in the ester moiety.
Further, in some embodiments, the cyclization reaction of the present invention is carried out in the presence of a catalyst and a solvent; in other embodiments, the cyclization reaction of the present invention may be carried out under microwave irradiation.
In some specific embodiments, the catalyst comprises a metal (salt) of rhodium, palladium, cobalt, copper, or the like, and an organic ligand.
For the metal (salt), it includes one or more of metal, inorganic acid salt of metal, organic acid salt of metal, halide of metal. In some specific embodiments of the invention, at least copper or copper salts are included. Further, the copper salt of the present invention is selected from one or more of cuprous chloride, cuprous bromide, cuprous iodide, cuprous trifluoromethanesulfonate, cupric sulfate, cupric acetate, cupric trifluoromethanesulfonate and cupric chloride, and preferably, the copper salt is selected from one or more of cuprous chloride, cuprous trifluoromethanesulfonate, cupric sulfate, cupric trifluoromethanesulfonate and cupric chloride. In addition, the metal (salt) may include other metals or metal salts, such as rhodium, ruthenium, and the like, in addition to the above copper (salt) component.
For organic ligands, the organic ligands of the present invention include one or more of nitrogen-oxygen, nitrogen-nitrogen polydentate ligands.
For nitrogen-oxygen, nitrogen-nitrogen polydentate ligands, coordination to the metal is usually achieved through the nitrogen and/or oxygen in the heteroaromatic ring. The organic ligand is selected from one or more of the following general formulas La, Lb, Lc, Ld or Le:
Figure BDA0003403822260000121
in the formula La, R1May represent a hydrogen atom, a halogen atom, a cyano group, a nitro group, a haloalkyl group, an ester group, an alkyl group having a substituted or unsubstituted, an aralkyl group having a substituted or unsubstituted, an aryl group having a substituted or unsubstituted, or a cycloalkyl group having a substituted or unsubstituted; r2Represents a hydrogen atom, an alkyl group or an aryl group;
in formula Lb, Q1May represent a divalent linking group or a direct bond, preferably a carbonyl group, an alkylene group with a substitution or non-substitution, an arylalkylene group with a substitution or non-substitution, an arylene group with a substitution or non-substitution, a cycloalkylene group with a substitution or non-substitution, or a heteroarylene group with a substitution or non-substitution;
in the formula Lc, R3、R4、R5、R10May be the same or different and represents a hydrogen atom, a halogen atom, a cyano group, a nitro group, a haloalkyl group, an ester group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aralkyl groupSubstituted or unsubstituted aryl or substituted or unsubstituted cycloalkyl;
in the formula Ld, R6、R7May be the same or different and represents a hydrogen atom, a halogen atom, a cyano group, a nitro group, a haloalkyl group, an ester group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted cycloalkyl group;
in the formula Le, R8、R9May be the same or different and represents a hydrogen atom, a halogen atom, a cyano group, a nitro group, a haloalkyl group, an ester group, an alkyl group with a substitution or non-substitution, an aralkyl group with a substitution or non-substitution, an aryl group with a substitution or non-substitution, or a cycloalkyl group with a substitution or non-substitution; q2May represent a divalent linking group or a direct bond, and is preferably a carbonyl group, an alkylene group with a substitution or non-substitution, an arylalkylene group with a substitution or non-substitution, an arylene group with a substitution or non-substitution, a cycloalkylene group with a substitution or non-substitution, or a heteroarylene group with a substitution or non-substitution.
In some embodiments of the invention, for the ligand of formula La, an organic compound of the following structure may be employed:
Figure BDA0003403822260000141
for the ligand of general formula Lb, an organic compound of the following structure may be employed:
Figure BDA0003403822260000142
for ligands of the general formula Lc, organic compounds of the following structure can be employed:
Figure BDA0003403822260000151
for ligands of general formula Ld, organic compounds of the following structure may be employed:
Figure BDA0003403822260000152
for ligands of the general formula Le, organic compounds of the following structure can be employed:
Figure BDA0003403822260000153
further, from the viewpoint of increasing the yield of the cyclized product and increasing the cis-to trans-ratio of the cyclized product, the preferable organic ligand may be any one or more of the following L1 to L3:
Figure BDA0003403822260000161
the ratio of the organic ligand to the metal (salt) used in the catalyst may be (molar ratio) 1 to 5:1, preferably 2 to 3:1, in some specific embodiments. The ratio of the metal (salt) to the compound of formula (1) may be 0.1:1 or less, preferably 0.01 to 0.09:1, and more preferably 0.02 to 0.08: 1.
Further, the cyclization reaction is carried out in the presence of an organic solvent, and the kind of the organic solvent is not particularly limited in principle as long as it does not significantly affect the stability of the diazonium structure. In some preferred embodiments, the organic solvent is selected from a mixed solvent of one or more of an aromatic solvent, a halogenated hydrocarbon solvent, a sulfone solvent, an amide solvent, acetonitrile, and the like; more preferably, it may be selected from one or more of Toluene (tolumen), Dichloroethane (DCE), dimethyl sulfoxide (DMSO), Dimethylformamide (DMF), acetonitrile.
With respect to the cyclization reaction conditions, in some specific embodiments of the present invention, after the catalyst is dissolved in the cyclization reaction using a solvent, the compound of formula (1) is added, preferably, the compound of formula (1) is added dropwise or a solution in which the compound of formula (1) is dissolved is added, to ensure the safety and yield of the reaction. The cyclization reaction of the present invention may be preferably carried out under the protection of an inert gas, which may be nitrogen, argon or a mixed gas thereof. Regarding the reaction temperature and the reaction time, in some specific embodiments, the temperature of the cyclization reaction is-10 to 120 ℃, preferably 60 to 80 ℃, and the reaction time is 2 to 64 hours, preferably 2 to 15 hours, and further preferably 2 to 6 hours.
Further, other control conditions for the cyclization reaction are not particularly limited, but it is preferable to perform auxiliary means such as mechanical stirring or magnetic stirring simultaneously with the reaction.
In the present invention, the compound having the structure of the above general formula (2) can be obtained by the above cyclization reaction. In some preferred embodiments, the yield of the cyclization reaction of the present invention may be 75% or more, preferably 80% or more, more preferably 90% or more. The cis-trans ratio (dr value) of the compound with the structure of the general formula (2) is more than 100:1, and the compound has high selectivity.
In addition, for the purification of the cyclization reaction product, typically, the product can be isolated and purified by means of distillation under reduced pressure or the like.
After obtaining the compound of formula (2), the subsequent synthesis steps are carried out according to the specific type of the X atom in formula (2).
In some embodiments of the invention, formula (2) has the structure of formula (2-1),
Figure BDA0003403822260000171
furthermore, the synthesis method of the invention further comprises the following steps:
i) subjecting the compound of the general formula (2-1) to amination reaction to obtain a compound of the general formula (3); and
ii) subjecting the compound of the general formula (3) to a reduction reaction to obtain a compound of the general formula (4),
Figure BDA0003403822260000172
wherein R is as defined in the general formula (1).
In step i, specific conditions for the amination reaction are not particularly limited, and amination reaction conditions conventional in the art may be employed.
In some particular embodiments of the invention, the amination reaction is carried out with the aid of an alcoholic solvent of ammonia gas, and for alcoholic solvents, methanol is preferred from the point of view of convenience.
Typically, the compound of formula (2-1) may be dissolved in an alcohol solvent, and an ammonia-alcohol reagent is added, and the reaction is performed at a temperature of not higher than 10 ℃, preferably-10 to 5 ℃, and more preferably-5 to 0 ℃, and the reaction time is not particularly limited, and may be 1 to 3 hours.
Further, after the reaction in step i is finished, the product with the structure of the general formula (3) can be separated by means of reduced pressure distillation.
In step ii, the carbonyl structure of formula (3) is reduced. For the reduction reaction, it may be carried out with the aid of a solvent and a reducing agent. As the solvent, one or more of aprotic solvents such as ester solvents, amide solvents, ether solvents, cyclic ether solvents, ketone solvents, sulfone solvents, aromatic hydrocarbon solvents, and the like; preferably, one or more of tetrahydrofuran, 1, 4-dioxane, diethyl ether, benzene, toluene, ethylene glycol dimethyl ether may be used. As the reducing agent, at least one selected from lithium aluminum hydride, sodium borohydride/boron trifluoride diethyl etherate, borane, and sodium 2-hydrobis (dimethoxyethoxy) aluminate, and further preferably, the reducing agent is lithium aluminum hydride or sodium borohydride/boron trifluoride diethyl etherate. In some embodiments of the invention, lithium aluminum hydride may be used as the catalyst. Other reaction conditions for step ii are not particularly limited, and reduction reaction conditions commonly used in the art may be employed. In a typical manner, for example, the molar ratio of lithium aluminum hydride to the compound of the general formula (3) in the reduction reaction is 1 to 4: 1, the reaction time is 2-3 hours, and the reaction temperature is-5-10 ℃. After the reaction is finished, the final product represented by the general formula (4) can be obtained by phase separation extraction and reduced pressure distillation.
In addition, for step ii of the present invention, it is particularly suitable that R is hydrogen, and in the case where R is a polar group, R may be temporarily protected with an optional protecting group or the carbonyl group may be subjected to a reduction treatment by another reduction method, if necessary.
In some specific embodiments, the overall yield of steps i and ii may be 90% or greater.
In other specific embodiments of the present invention, the general formula (2) as the cyclization product has the structure of the general formula (3), and the above-mentioned step ii may be directly carried out in the subsequent reaction after the cyclization reaction to obtain the final product represented by the general formula (4).
Further, a typical synthetic route of the present invention is illustrated in FIG. 1:
the method comprises the steps of taking diazoacetic acid (2-methyl-2-butylene) as a raw material, firstly carrying out intramolecular cyclization reaction to prepare an intermediate formula a, and carrying out amination and reduction reaction on the intermediate formula a to obtain a product 6,6-dimethyl-3-azabicyclo [3.1.0] hexane;
or diazo (2-methyl-2-butene) acetamide is used as a raw material, an intramolecular cyclization reaction is firstly carried out to prepare an intermediate b, and the intermediate b is subjected to one-step acylation reduction reaction to obtain the product 6,6-dimethyl-3-azabicyclo [3.1.0] hexane.
Further, by adjusting the substituent of R in the general formula (1) as a raw material of the present invention, the present invention can obtain various pharmaceutical intermediates, typically:
when R is hydrogen, a compound of the following formula (A) can be obtained; when R is an ester group, a compound of the following formula (B) can be obtained. And, it is self-evident that when R is changed to another polar group (e.g., -CN, such as a compound of formula (C)). It is also possible to change R to other desired radicals R by any subsequent chemical process1(R1May be a pharmaceutically active group), the kind and manner of change thereof are not particularly limitedBy way of limitation, it is also possible, for example, to obtain compounds of the formula B by subsequent treatment of the-CN group in compounds of the formula C.
Figure BDA0003403822260000191
Further, based on the novel synthesis method provided by the invention, the production of related drug intermediates can be efficiently provided, and the novel synthesis method can be used as an intermediate synthesis step in drug synthesis.
Meanwhile, the synthesis method of the invention can also provide improved environmental protection and synthesis flexibility, and is particularly suitable for stably providing raw material supply of the drug synthesis industry with high yield.
In addition, the drug intermediate provided by the synthetic method can be used for preparing a drug compound comprising a hepatitis C protease inhibitor or a drug compound for treating novel coronavirus (COVID-19).
Examples
Hereinafter, the present invention will be further described with reference to specific examples.
(Source of raw materials)
The compound diazoacetic acid (2-methyl-2-butene) ester (obtained by self-made):
Figure BDA0003403822260000201
the compound diazo (2-methyl-2-butene) acetamide (made by seiko):
Figure BDA0003403822260000202
(intermediate stereo structure of formula a):
cis structure
Figure BDA0003403822260000203
Trans structure
Figure BDA0003403822260000204
(intermediate b-configuration):
cis structure
Figure BDA0003403822260000211
Trans structure
Figure BDA0003403822260000212
Example 1 (preparation of intermediate formula a)
196mg of cuprous chloride, 680mg of ligand L1 and 100mL of dichloroethane solution were added to a 200mL flask, stirred at room temperature for 1 hour, heated to 75 ℃ and slowly added dropwise with 15.4g
Figure BDA0003403822260000213
And (3 h) distilling the intermediate product of the formula a under reduced pressure after the reaction is finished, wherein the yield is 93.1%, and the ratio of cis form to trans form is more than 100: 1.
examples 2 to 14(preparation intermediate formula a)
The difference from example 1 is in the control of reaction parameters, and specific reaction parameters and reaction effects are shown in table 1.
Example 15
12.6g of the intermediate of formula a prepared in example 1 was dissolved in methanol, 100mL of 5mol/L methanolic ammonia solution was added and stirred at 0 ℃ for 1h to give intermediate of formula b, and the solution was directly distilled under reduced pressure to give 12g of crude product. Adding tetrahydrofuran solution 150mL into the crude product, adding 7.6g of lithium aluminum hydride at 0 ℃, stirring for 2h, adding ethyl acetate 200mL after the reaction is finished, quenching the reaction, adding water 50mL, extracting, layering, combining organic phases, and distilling the organic phases under reduced pressure to obtain the product, namely the compound of the formula A, 10.1g, with the total yield of the two steps of 91.0%.
Example 16
196mg of cuprous chloride, 680mg of ligand L1 and 100mL of dichloroethane solution were added to a 200mL flask, stirred at room temperature for 1 hour, heated to 75 ℃ and slowly added dropwise with 15.2g
Figure BDA0003403822260000221
And (3 h) distilling the intermediate compound shown in the formula b under reduced pressure after the reaction is finished, wherein the product yield is 92.8%, and the cis-form and trans-form ratio is more than 100: 1.
adding 150mL of tetrahydrofuran solution into 12.5g of the intermediate compound b prepared above; adding 7.6g of lithium aluminum hydride at 0 ℃, stirring for 2h, adding 200mL of ethyl acetate after the reaction is finished, quenching the reaction, adding 50mL of water, extracting for layering, combining organic phases, and distilling the organic phase under reduced pressure to obtain 10.3g of the compound of the formula A with the yield of 92.7%.
TABLE 1 (examples 1 to 14) reaction parameters
Figure BDA0003403822260000231
It should be noted that, although the technical solutions of the present invention are described by specific examples, those skilled in the art can understand that the present disclosure should not be limited thereto.
Having described embodiments of the present disclosure, the foregoing description is intended to be exemplary, not exhaustive, and not limited to the disclosed embodiments. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the described embodiments. The terminology used herein is chosen in order to best explain the principles of the embodiments, the practical application, or improvements made to the technology in the marketplace, or to enable others of ordinary skill in the art to understand the embodiments disclosed herein.
Industrial applicability
The synthesis method provided by the invention can be used for industrially preparing the pharmaceutical intermediate compound.

Claims (10)

1. A novel method for preparing an azabicyclo pharmaceutical intermediate, the method comprising:
a step of subjecting a compound represented by general formula (1) to a cyclization reaction to obtain a cyclized product represented by a compound represented by general formula (2),
Figure FDA0003403822250000011
wherein the content of the first and second substances,
x represents an oxygen atom or an-NH-group;
r represents a hydrogen atom or a polar group.
2. The process according to claim 1, wherein the step of cyclization is carried out in the presence of a metal (salt) and an organic ligand, preferably wherein the metal (salt) comprises one or more of rhodium, palladium, cobalt, copper and salts thereof and the organic ligand comprises one or more of a nitrogen-oxygen, nitrogen-nitrogen polydentate ligand.
3. The process according to claim 2, wherein the organic ligand is selected from one or more of the following general formulae La, Lb, Lc, Ld or Le:
Figure FDA0003403822250000012
Figure FDA0003403822250000021
in the formula La, R1May represent a hydrogen atom, a halogen atom, a cyano group, a nitro group, a haloalkyl group, an ester group, an alkyl group having a substituted or unsubstituted, an aralkyl group having a substituted or unsubstituted, an aryl group having a substituted or unsubstituted, or a cycloalkyl group having a substituted or unsubstituted; r2Represents a hydrogen atom, an alkyl group orAn aryl group;
in formula Lb, Q1May represent a divalent linking group or a direct bond, preferably a carbonyl group, an alkylene group with a substitution or non-substitution, an arylalkylene group with a substitution or non-substitution, an arylene group with a substitution or non-substitution, a cycloalkylene group with a substitution or non-substitution, or a heteroarylene group with a substitution or non-substitution;
in the formula Lc, R3、R4、R5、R10May be the same or different and represents a hydrogen atom, a halogen atom, a cyano group, a nitro group, a haloalkyl group, an ester group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted cycloalkyl group;
in the formula Ld, R6、R7May be the same or different and represents a hydrogen atom, a halogen atom, a cyano group, a nitro group, a haloalkyl group, an ester group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted cycloalkyl group;
in the formula Le, R8、R9May be the same or different and represents a hydrogen atom, a halogen atom, a cyano group, a nitro group, a haloalkyl group, an ester group, an alkyl group with a substitution or non-substitution, an aralkyl group with a substitution or non-substitution, an aryl group with a substitution or non-substitution, or a cycloalkyl group with a substitution or non-substitution; q2May represent a divalent linking group or a direct bond, and is preferably a carbonyl group, an alkylene group having a substituent or non-substituent, an arylalkylene group having a substituent or non-substituent, an arylene group having a substituent or non-substituent, a cycloalkylene group having a substituent or non-substituent, or a heteroarylene group having a substituent or non-substituent.
4. A process according to any one of claims 1 to 3, wherein the cyclisation reaction is carried out in an organic solvent; the temperature of the cyclization reaction is-10-120 ℃, preferably 60-80 ℃, and the reaction time is 2-64 hours, preferably 2-15 hours, and further preferably 2-6 hours.
5. The process according to any one of claims 1 to 4, wherein X is an oxygen atom, and the cyclized product is a compound represented by the general formula (2-1), and further comprising:
i) subjecting the compound of the general formula (2-1) to an amination reaction to obtain a compound of a general formula (3); and
ii) subjecting the compound of the general formula (3) to a reduction reaction to obtain a compound of the general formula (4),
Figure FDA0003403822250000031
wherein R is as defined in claim 1.
6. The method according to any one of claims 1 to 4, wherein X is an-NH-group, and the cyclized product is a compound represented by the general formula (3), and further comprising:
subjecting the compound of the general formula (3) to a reduction reaction to obtain a compound of the general formula (4),
wherein the general formula (3), the general formula (4) and R are as defined in claim 5.
7. The method according to any one of claims 1 to 6, wherein R is a hydrogen atom, a carboxylic acid (salt) group, an ester group, a halogen atom or a cyano group.
8. A method for preparing a pharmaceutical intermediate, comprising the novel method for preparing an azabicyclo pharmaceutical intermediate according to any one of claims 1-7.
9. A process for the preparation of a pharmaceutical compound, said process comprising the process according to claim 8.
10. The method of claim 9, wherein the pharmaceutical compound comprises a hepatitis c protease inhibitor-based pharmaceutical compound or a pharmaceutical compound for treating a novel coronavirus (COVID-19).
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