CN114605308A - Preparation method of azabicyclo medical intermediate of paroxetine and intermediate - Google Patents

Preparation method of azabicyclo medical intermediate of paroxetine and intermediate Download PDF

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CN114605308A
CN114605308A CN202210271416.1A CN202210271416A CN114605308A CN 114605308 A CN114605308 A CN 114605308A CN 202210271416 A CN202210271416 A CN 202210271416A CN 114605308 A CN114605308 A CN 114605308A
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蔡凡平
郑加宇
符义明
白雪
刘旭
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Fuxin Fulongbao Pharmaceutical Technology Co ltd
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Abstract

The invention discloses a preparation method of an azabicyclo medical intermediate of palovir, which comprises the following steps: a step of cyclization and amidation, in which the compound shown in the general formula (III) is subjected to cyclization and amidation to obtain a cyclization product shown in a structural formula (VI), wherein X1、X2Identical or different, selected from halogens. The compound shown in the general formula (III) can be easily obtained through methyl carpronilate, the compound shown in the general formula (III) is subjected to ring closing under the action of strong alkali, then reacts with ammonia gas at high temperature to form a cyclization product shown in a structural formula (VI), and the compound shown in the structural formula (VII) (namely 6, 6-dimethyl-3-azabicyclo [3.1.0] can be obtained through reduction reaction]Hexane). The method has the characteristics of easily obtained raw materials, environmental friendliness and simplicity and convenience in operation, and is suitable for industrial production.

Description

Preparation method of azabicyclo medical intermediate of paroxetine and intermediate
Technical Field
The invention relates to the technical field of pharmacy, in particular to a preparation method of an azabicyclo medical intermediate of paluvirde and an intermediate.
Background
Covid2019 has abuse worldwide for more than 2 years, and the appearance of specific medicines brings hope to terminating new life for human beings. The pfizer company targets a protease that plays a key role in viral replication as a target for antiviral drug development and ultimately optimizes the production of PF-07321332. The actual components of the oral administration of the novel coronavid drug of the pfrovir are PF-07321332 and a low dose of ritonavir adjuvant. 22/12/2021, Paxlovid approved by the U.S. food and drug administration.
6, 6-dimethyl-3-azabicyclo [3.1.0] hexane is a key intermediate in the synthesis of Paxlovid. The synthesis routes reported in the literature at present are all that are generated by dehydrating caproic acid to form caproic anhydride, converting the caproic anhydride into succinamide and finally reducing the succinamide to generate amine
Figure BDA0003554792570000011
At present, two synthesis processes of caronic acid are reported in the literature.
Caronic anhydride Synthesis route 1
Figure BDA0003554792570000012
The above route is currently the most common synthetic route for caronic acid. Ethyl chrysanthemate is used as a starting material, firstly oxidized to obtain the monoethyl carbazonate, and then hydrolyzed by sodium hydroxide to obtain the carbazolone acid. The ethyl chrysanthemate has fewer manufacturers and higher price. A large amount of potassium permanganate is used in the oxidation reaction, the operation is dangerous, and a large amount of manganese-containing waste is contained to cause environmental pollution. Meanwhile, the consumption of acetone in the oxidation reaction is very large, and the cost is very high.
Caronic acid synthetic route 2:
Figure BDA0003554792570000013
to overcome the drawbacks of scheme 1, the above new synthesis process was developed by qintog et al and published in CN 104163759. Firstly, diazoacetic acid ethyl ester and isopentenol acetate have carbene insertion reaction under the catalysis of copper to form a three-membered ring. Then, ester group hydrolysis and ether bond rupture are carried out to obtain carboxylic acid containing primary alcohol, and finally TEMPO is catalyzed and oxidized to obtain the caronic acid.
The yield of the prepared caronic acid by the ethyl diazoacetate process is only about 40 percent, and the key ligand is not disclosed, so that the results of the patent are difficult to repeat.
No matter which route is used for preparing the caronic acid, and then the caronic anhydride is prepared by dehydration, the yield is only 50-60%; in addition, the final succinimide reduction reaction also has a low yield of not more than 70%, and requires the use of a large amount of reducing agent due to the bisamide structure.
In summary, at present, there is no process route which has the advantages of easily available raw materials, simple operation, safety and reliability, and is suitable for industrial amplification.
Disclosure of Invention
Object of the Invention
In order to overcome the defects, the invention aims to provide a preparation method and an intermediate of an azabicyclo medical intermediate of paluvirde.
The compound shown in the general formula (III) can be easily obtained through methyl carpimelate, the compound shown in the general formula (III) is subjected to ring closing under the action of strong alkali, then reacts with ammonia gas at high temperature to form a cyclization product shown in a structural formula (VI), and the compound shown in the structural formula (VII) (namely 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane which is an azabicyclo medical intermediate of paloviride) can be obtained through reduction reaction. The method has the characteristics of easily obtained raw materials, environmental friendliness and simplicity and convenience in operation, and is suitable for industrial production.
Solution scheme
In order to realize the purpose of the invention, the technical scheme adopted by the invention is as follows:
in one aspect, the invention provides a preparation method of an azabicyclo pharmaceutical intermediate of paluvirde, which comprises the following steps:
a step of cyclization and amidation reaction, in which a compound shown in a general formula (III) is subjected to cyclization and amidation reaction to obtain a cyclization product shown in a structural formula (VI),
Figure BDA0003554792570000021
wherein, X1、X2Identical or different, selected from halogens.
Further, X1、X2Each independently selected from F, Cl or Br; alternatively, X1、X2Are respectively and independently selected from Cl or Br; alternatively, X1、X2Are all Br; optionally X1、X2Are all Cl.
The compound represented by the general formula (III) may be referred to as 4, 5-dihalo-3, 3-dimethylvaleryl chloride.
Further, in the step of cyclization and amidation, after the compound shown in the general formula (III), an organic liquid and an organic strong base are mixed and reacted, ammonia is introduced to react at 100-300 ℃, and a cyclization product shown in a structural formula (VI) is prepared by a one-pot method;
Figure BDA0003554792570000031
further, the ammonia is ammonia gas or organic liquid dissolved with ammonia. Generally, ammonia water is not adopted, and the ammonia water cannot effectively complete closed loop and generate more byproducts.
Further, in the mixed reaction of the compound shown in the general formula (III), the organic liquid and the organic strong base, the reaction time is 1-5 hours, optionally 2-4 hours, optionally 3 hours.
Further, in the mixed reaction of the compound shown in the general formula (III), the organic liquid and the organic strong base, the molar ratio of the compound shown in the general formula (III) to the organic strong base is 1: 1.2-5, optionally 1: 1.2-3, optionally 1: 1.5-2.5; optionally 1: 2-2.5.
Further, in the mixing reaction of the compound shown in the general formula (III), the organic liquid and the organic strong base, the molar ratio of the compound shown in the general formula (III) to the organic liquid is 1: 5-30, optionally 1: 10-25.
Further, in the mixing reaction of the compound shown in the general formula (III), the organic liquid and the organic strong base, the reaction temperature is 40-65 ℃, optionally 45-55 ℃, optionally 50 ℃.
Further, introducing ammonia to react at 100-300 ℃, wherein the reaction time is 1-6 hours, optionally 3-5 hours, optionally 4-5 hours;
further, ammonia is introduced into the reaction at 100-300 ℃, wherein the reaction temperature is 150-300 ℃, 150-250 ℃, 160-230 ℃ and 160-180 ℃.
Further, the ammonia is introduced to react at 100-300 ℃, and the molar ratio of the compound shown in the general formula (III) to the ammonia gas is 1: 1.5-5, optionally 1: 2-4, optionally 1: 2-3, optionally 1: 3.
Further, the organic liquid is selected from one or more of alcohol organic substances, ether organic substances or aprotic polar solvents; optionally, the alcohol organic substance is selected from C1-C5 alcohol substances, optionally one or two of methanol and ethanol; optionally, the ethers include one or more of methyltetrahydrofuran, dioxane and dimethoxyethane; optionally, the aprotic polar solvent comprises one or more of DMF, DMA, NMP and HMPA; optionally, the organic liquid is selected from one or both of methanol and ethanol.
Further, the organic strong base is selected from one or more of sodium alkoxide, potassium alkoxide or amino metal salt; optionally, the sodium alkoxide comprises one or more of sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide and sodium tert-amylate; optionally, the potassium alkoxide comprises one or more of potassium methoxide, potassium ethoxide, potassium tert-butoxide and potassium tert-pentoxide; optionally, the amino metal salt comprises sodium amide, potassium amide, LiHMDS (lithium bis amide, formula [ (CH)3)3Si]2NLi), NaHMDS (bis-aminyl sodium, formula [ (CH)3)3Si]2NNa) and LDA (lithium diisopropylamide, formula is [ (CH)3)2CH]2One or more of NLi); optionally, the organic strong base is selected from one or more of sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, sodium tert-pentoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide and potassium tert-pentoxide; alternatively, the strong organic base is selected from sodium tert-butoxide or potassium tert-butoxide; optionally, the strong organic base is potassium tert-butoxide.
Further, adding a catalyst when ammonia is introduced to react at 100-300 ℃; optionally, the catalyst is selected from a sodium salt of an organic acid or a potassium salt of an organic acid; optionally, the catalyst is selected from one or more of sodium acetate, potassium acetate, sodium pivalate and potassium pivalate; optionally, the catalyst is selected from sodium pivalate or potassium pivalate; optionally, the catalyst is sodium pivalate; optionally, the amount of the catalyst added is 0.1-3.0% of the weight of the compound represented by the general formula (III).
As an alternative, in the step of the cyclization and amidation reaction, the compound represented by the general formula (III) is replaced with a compound represented by the general formula (IV) (i.e., the Intermediate (IV) described below);
Figure BDA0003554792570000041
wherein, X1、X2Identical or different, selected from halogen; r is alkoxy or secondary amino;
alternatively, R is an alkoxy group selected from C1-C10Alkoxy, optionally selected from C1-C3Alkoxy, optionally selected from-OCH3、-O CH2CH3or-OCH2(CH3)2；
Alternatively, R is a secondary amine group selected from C1-C10A secondary amine group, optionally selected from C1-C3A secondary amine group, optionally selected from C3A secondary amino group;
alternatively, X1、X2Each independently selected from F, Cl or Br; alternatively, X1、X2Each independently selected from Cl or Br; alternatively, X1、X2Are all Br; alternatively X1、X2Are all Cl.
The cyclization and amidation reaction steps can be a one-pot reaction, and specifically comprise the following steps: mixing the compound shown in the general formula (III) (or the compound shown in the general formula (IV)) and an organic liquid, adding an organic strong base, heating to 40-65 ℃, carrying out heat preservation reaction for 1-5 h, introducing ammonia gas into the reaction liquid, adding a catalyst, heating to 100-300 ℃ (preferably 160-180 ℃), carrying out reaction for 1-6 h, concentrating the organic liquid, and carrying out reduced pressure distillation to obtain a cyclization product shown in the structural formula (VI).
The cyclization and amidation reaction steps can also be carried out step by step, and specifically comprise:
s1, esterifying or amidating the compound represented by the general formula (III) with a compound RH to form an Intermediate (IV);
s2, cyclopropanizing the Intermediate (IV) under the action of strong organic base to generate an intermediate (V);
s3, reacting the intermediate (V) with ammonia at 100-300 ℃ to obtain a cyclized product shown in a structural formula (VI),
Figure BDA0003554792570000051
wherein R is alkoxy or secondary amino.
Further, R is alkoxy, and the alkoxy is selected from C1-C10Alkoxy, optionally selected from C1-C3Alkoxy, optionally selected from-OCH3、-O CH2CH3or-OCH2(CH3)2；
Further, R is a secondary amine group selected from C1-C10A secondary amine group, optionally selected from C1-C3A secondary amine group, optionally selected from C3The secondary amine group, RH, can be propylamine.
Further, in the step S2, the organic strong base is selected from one or more of sodium alkoxide, potassium alkoxide, or an amino metal salt; optionally, the sodium alkoxide comprises one or more of sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide and sodium tert-amylate; optionally, the potassium alkoxide comprises one or more of potassium methoxide, potassium ethoxide, potassium tert-butoxide and potassium tert-pentoxide; optionally, the amino metal salt comprises sodium amide, potassium amide, LiHMDS (lithium bis amide, formula [ (CH)3)3Si]2NLi), NaHMDS (bis-aminyl sodium, formula [ (CH)3)3Si]2NNa) and LDA (lithium diisopropylamide, formula [ (CH)3)2CH]2One or more of NLi); optionally, the organic strong base is selected from one or more of sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, sodium tert-pentoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide and potassium tert-pentoxide; optionally, theThe organic strong base is selected from sodium tert-butoxide or potassium tert-butoxide; optionally, the strong organic base is potassium tert-butoxide.
Further, the step S2 is performed in an organic solvent, where the organic solvent is one or more selected from an alcohol organic substance, an ether organic substance, or an aprotic polar solvent; optionally, the alcohol organic substance is selected from C1-C5 alcohol substances, optionally one or two of methanol and ethanol; optionally, the ethers include one or more of methyltetrahydrofuran, dioxane and dimethoxyethane; optionally, the aprotic polar solvent comprises one or more of DMF, DMA, NMP and HMPA; optionally, the organic solvent is selected from one or both of methanol or ethanol.
Further, in the step S2, compound RH is added in excess.
Further, in the step S2, the reaction time is 1 to 5 hours, optionally 2 to 4 hours.
Further, in the step S2, the molar ratio of the Intermediate (IV) to the strong organic base is 1:1.2 to 5, optionally 1:1.2 to 3, optionally 1:1.5 to 2.5; optionally 1: 1.5-2.
Further, in the step S2, the molar ratio of the Intermediate (IV) to the organic solvent is 1:8 to 30, and optionally 1:12 to 25.
Further, the reaction temperature in the step S2 is 40-65 ℃, optionally 45-55 ℃, optionally 50 ℃.
Further, in the step S3, the ammonia is ammonia gas or an organic liquid in which ammonia is dissolved.
Further, in the step S3, the molar ratio of the compound represented by the general formula (V) to ammonia is 1:2 to 20, optionally 1:2 to 10, optionally 1:3 to 8.
Further, in the step S3, the reaction time is 1 to 5 hours, optionally 2 to 4 hours.
Further, in the step S3, the reaction temperature is 100 to 300 ℃, optionally 150 to 250 ℃, optionally 180 to 230 ℃, optionally 180 to 220 ℃.
Further, in the step S3, the reaction pressure is 10 to 25 kg.
Further, the step S3 is performed in an organic solvent, where the organic solvent is one or more selected from an alcohol organic substance, an ether organic substance, or an aprotic polar solvent; optionally, the alcohol organic substance is selected from C1-C5 alcohol substances, optionally one or more selected from methanol and ethanol; optionally, the ethers include one or more of methyltetrahydrofuran, dioxane and dimethoxyethane; optionally, the aprotic polar solvent comprises one or more of DMF, DMA, NMP and HMPA; optionally, the organic solvent is selected from one or both of methanol or ethanol.
The step S1 may specifically be: and (3) dripping excessive RH compound into the reaction solution of the compound shown in the general formula (III) under reflux, refluxing for 1 hour after the dripping is finished, and distilling off the excessive RH compound to obtain an Intermediate (IV).
The step S2 may specifically be: mixing the Intermediate (IV) with an organic solvent, adding an organic strong base, heating to 40-65 ℃, reacting for 1-5 h, adding a large amount of water and the organic solvent for extraction, combining oil phase extraction layers, drying (drying by sodium sulfate can be adopted), and recovering the extracted organic solvent to obtain an oily substance containing the intermediate (V).
The step S3 may specifically be: and (3) adding the oily matter containing the intermediate (V) into a pressure kettle, reacting under the pressure of 10-25 kg, adding excessive ammonia-organic liquid (namely liquid dissolved with ammonia), heating to 100-300 ℃, keeping the temperature, reacting for 1-5 h, and recovering methanol to obtain a cyclized product shown in the structural formula (VI).
Further, the preparation method of the compound represented by the general formula (III) comprises the following steps: using methyl ester (I) or cardia acid as raw material, making acyl chlorination and halogen-adding reaction to obtain the invented product;
Figure BDA0003554792570000071
further, when methyl cardiate is used as a raw material, the methyl cardiate is hydrolyzed, added with acid to generate cardiate acid, and then subjected to acyl chlorination and halogen addition reaction.
Further, the reagent for acyl chlorination reaction is selected from one or more of thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride and triphosgene; optionally, the acyl chlorination reaction is performed in a heating reflux for 1-5 hours, optionally 2-5 hours, optionally 3-5 hours.
Further, acyl chlorination reaction is carried out to generate an intermediate (II), and the intermediate (II) is added with halogen to react to generate a compound shown in a general formula (III);
Figure BDA0003554792570000072
further, the halogenation reaction is carried out in a solvent-free or organic halogenated solvent, and the raw material for the halogenation reaction is selected from F2、Cl2、Br2One or more of the above; optionally, the raw material for the halogenation reaction is chlorine; optionally, the organic halogenated solvent is selected from one or more of dichloromethane, dichloroethane and tetrachloroethylene.
Further, the reaction temperature of the halogenation reaction is 0-5 ℃.
The specific steps for preparing the compound shown in the general formula (III) by using the methyl cardianate (I) can be as follows: methyl cardia acid, an organic solvent, water and sodium hydroxide (or other strong bases such as potassium hydroxide) are subjected to reflux reaction for 1-5 hours, after the reaction is finished, the organic solvent is recovered by normal pressure distillation, hydrochloric acid is added and the organic solvent is extracted, the organic solvent is recovered after an oil layer is dried by sodium sulfate, an oil layer containing the cardia acid is obtained, and the cardia acid and thionyl chloride are subjected to reflux reaction to obtain the cardia acyl chloride (namely an intermediate (II)). Mixing the cardia acyl chloride with an organic halogenated solvent, and introducing halogen at 0-5 ℃ for carrying out a halogenation reaction to prepare the compound shown in the general formula (III). It is generally preferred to add chlorine, dissolve with a chlorinated organic solvent and add chlorine.
Figure BDA0003554792570000081
The extractant in the application can be methyl tertiary butyl ether, dichloromethane and the like.
Further, the method also comprises the following reduction reaction: the cyclized product shown in the structural formula (VI) is subjected to reduction reaction to generate a compound shown in a structural formula (VII),
Figure BDA0003554792570000082
optionally, the reducing agent in the reduction reaction is borohydride; optionally, the reducing agent in the reduction reaction is selected from one or more of sodium borohydride, potassium borohydride and lithium borohydride;
optionally, the reduction reaction is carried out in an organic solvent, wherein the organic solvent of the reduction reaction is selected from ether solvents, optionally one or more of tetrahydrofuran, methyltetrahydrofuran, DME and DG;
alternatively, the reduction reaction comprises: mixing a cyclization product shown in a structural formula (VI) with an organic solvent, cooling to 0-5 ℃, adding a reducing agent borohydride in batches, dropwise adding an organic solvent containing boron trifluoride, heating to 55-70 ℃ after dropwise adding, carrying out heat preservation reaction, cooling, recovering the organic solvent, dropwise adding an inorganic strong alkali aqueous solution, and refining to obtain a compound shown in a structural formula (VII); alternatively, the aqueous solution of an inorganic strong base is selected from aqueous sodium hydroxide or potassium hydroxide.
In another aspect, there is provided a compound of formula (III) in the preparation process, having the formula:
Figure BDA0003554792570000083
wherein, X1、X2Identical or different, selected from halogen;
further, X1、X2Each independently selected from F, Cl or Br; alternatively, X1、X2Each independently selected from Cl or Br; alternatively, X1、X2Are all Br; optionally X1、X2Are all Cl.
Thus, in the present application, there are at least two reaction routes for the preparation of the cyclization product of formula (VII) starting from methyl ester of cardiac acid (I):
1)
Figure BDA0003554792570000091
2)
Figure BDA0003554792570000092
advantageous effects
(1) The compound shown in the general formula (III) can be easily obtained through methyl carpimelate, the compound shown in the general formula (III) is subjected to ring closing under the action of strong alkali, then reacts with ammonia gas at high temperature to form a cyclization product shown in a structural formula (VI), and the compound shown in the structural formula (VII) (namely 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane which is an azabicyclo medical intermediate of paloviride) can be obtained through reduction reaction. The method has the characteristics of easily obtained raw materials, environmental friendliness and simplicity and convenience in operation, and is suitable for industrial production.
(2) The compound shown in the general formula (III) can smoothly obtain a cyclized product shown in the structural formula (VI) through a high-temperature reaction regardless of cis-form or trans-form intermediates, and the yield can reach 50-62%.
(3) The compound shown in the general formula (III) is halogenated acyl chloride, a cyclization product shown in a structural formula (VI) can be obtained easily through a one-step method or a multi-step method, and catalysts (sodium acetate and the like) used in the preparation process are simple and easy to obtain and do not need expensive Ru catalysts.
(4) The compound shown in the general formula (III) of the invention uses raw material of methyl ester of cardia acid, can obtain the cardia acid almost quantitatively by hydrolysis and acid addition, can obtain the cardia acyl chloride almost quantitatively, and can obtain the dichloro cardia acid acyl chloride with near quantitative yield by chlorination addition reaction of the cardia acyl chloride, and then obtains the dichloro cardia acid methyl ester with near quantitative yield by esterification reaction. The method is simple and easy to operate, and can avoid using a chlorinating agent which is ozone-destroying and is not economical.
(5) The cyclization product shown in the structural formula (VI) can obtain a compound (6, 6-dimethyl-3-azabicyclo [3.1.0] hexane) shown in the structural formula (VII) through a common reducing agent, the use of the reducing agent in an amide reduction reaction is greatly reduced, the waste salt of a byproduct is reduced, and the method is favorable for environmental protection, compared with the method for preparing the 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane through the reduction reaction of the traditional carbazolone succinimide, the method only needs to reduce the carbonyl of the monoamide, can obviously save the reducing agent, has the reduction yield of over 90 percent, has the yield of the reduction reaction of the carbazolone succinimide in the traditional process of below 70 percent, is greatly improved compared with the prior art, and the raw material, namely the methyl carpronite, is cheap and easy to obtain, and can be widely applied to industrial production, the production cost is reduced.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are a part of the embodiments of the present invention, but not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Furthermore, in the following detailed description, numerous specific details are set forth in order to provide a better understanding of the present invention. It will be understood by those skilled in the art that the present invention may be practiced without some of these specific details. In some embodiments, materials, elements, methods, means, and the like that are well known to those skilled in the art are not described in detail in order to not unnecessarily obscure the present invention.
Throughout the specification and claims, unless explicitly stated otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element or component but not the exclusion of any other element or component.
The contents of the intermediates (II) to (VI) in examples 1 to 6 were confirmed by gas chromatography, so the amounts of the raw materials used in examples 1 to 6 refer to the raw material weights converted by detection and confirmation, the intermediates (II) to (VI) prepared in examples may not be purified during use, and the purification of each intermediate in examples 1 to 6 is for better calculation of yield.
Example 1
Preparation of cardia chloride
Figure BDA0003554792570000101
Example 1a cardiac acid methyl ester 142 g, methanol 200 ml, water 300 ml, sodium hydroxide 48 g, after 2 hours of reflux reaction, after the reaction was over, 250 g of low boiling fraction was distilled off at normal pressure to recover methanol, then 30% hydrochloric acid was added about 150 g, 200 ml of methyl tert-butyl ether was used for extraction, after the organic layer was dried with sodium sulfate, methyl tert-butyl ether was recovered to obtain an oil layer containing cardiac acid, the oil layer containing cardiac acid and 170 g of thionyl chloride were refluxed for three hours to obtain cardiac acyl chloride 138 g by distillation with a yield of 94.5%.
Example 1b cardia acid methyl ester 142 g, ethanol 200 ml, water 200 ml, potassium hydroxide 68 g, after 2 hours of reflux reaction, after the reaction is over, distilling off 210 g of low boiling point fraction at normal pressure to recover ethanol, then adding about 150 g of 30% hydrochloric acid, extracting the aqueous layer with 200 ml of dichloromethane, drying the organic layer with sodium sulfate, recovering the solvent to obtain an oil layer containing cardia acid, refluxing the oil layer containing cardia acid and 219 g of phosphorus oxychloride for 4 hours, distilling to obtain 135 g of cardia acyl chloride with a yield of 92%.
Example 2: preparation of 4, 5-dihalo-3, 3-dimethylacid chloride (formula (III))
Figure BDA0003554792570000111
Example 2 a: dissolving 1 kg of cardia acyl chloride in 2000 ml of dichloroethane, introducing 500 g of chlorine at 0-5 ℃, and recovering the dichloroethylene after the reaction is finishedAlkane to prepare 4, 5-dichloro-3, 3-dimethyl acyl chloride with yield near 100%. Namely X1、X2Are all Cl.
Example 2 b: under the condition of 147 g of cardia acyl chloride without solvent, 162 g of bromine is dripped at the temperature of 0-20 ℃ to obtain 4, 5-dibromo-3, 3-dimethyl valeryl chloride, and the yield is close to 100%. Namely X1、X2Are all Br.
Example 3: preparation of the compound of formula (VI) by 4, 5-dihalo-3, 3-dimethylvaleryl chloride (formula (III)) in one-pot
Figure BDA0003554792570000112
Example 3 a: 217.5 g of 4, 5-dichloro-3, 3-dimethylvaleryl chloride is dissolved in 400 ml of methanol, 238 g of potassium tert-butoxide is added, after reaction for 3 hours at 50 ℃, 51 g of ammonia gas is introduced into the reaction liquid, 1 g of sodium pivalate is added, the temperature is raised to 180 ℃, the reaction is carried out for 4 hours, after methanol concentration, the reduced pressure distillation is carried out, thus obtaining 77.5 g of the compound shown in the formula (VI), and the yield is 62%. Namely X1、X2Are all Cl.
Example 3 b:4, 5-dibromo-3, 3, -dimethylvaleryl chloride 306 g and 34 g methanol are reacted under reflux for 2 hours, then 500 ml of DMF is added, 70 g of sodium methoxide is added and reacted for 5 hours at 40 ℃ to obtain a reaction solution, 1500 ml of water is added, methyl tert-butyl ether is used for extraction, drying and desolventization to obtain a material, 500 ml of 7M ammonia methanol solution and 1 g of sodium pivalate are added and heated to 160 ℃ for reaction for 5 hours, and as a result, 75 g of the compound of the formula (VI) is obtained through aftertreatment, and the yield is 60%.
The following examples 4,5 are examples of the multi-step preparation of compounds of formula (VI) from 4, 5-dichloro-3, 3-dimethylvaleryl chloride (formula (III)).
Figure BDA0003554792570000121
EXAMPLE 44, 5-dichloro-3, 3-dimethylvaleryl chloride (formula (III)) preparation of Dichlorocardian acid ester or amide (IV)
Figure BDA0003554792570000122
Wherein R is an alkoxy group or a secondary group.
Example 4a preparation of methyl Dichloropentenoate
Dissolving 1 kg of cardia acyl chloride in 2000 ml of dichloroethane, introducing 500 g of chlorine at 0-5 ℃, recovering the dichloroethane after the reaction is finished, then dropwise adding 250 g of methanol under reflux, refluxing for 1 hour after the dropwise adding is finished, distilling off the excessive methanol to obtain 1300 g of 4, 5-dichloro-3, 3-dimethyl methyl valerate, and the yield is 89%.
Example 4b preparation of Ethyl Dichloropentenoate
Dissolving 1 kg of cardia acyl chloride in 2000 ml of dichloromethane, introducing 500 g of chlorine at 0-5 ℃, recovering dichloroethane after the reaction is finished, then dropwise adding 359 g of ethanol under reflux, refluxing for 1 hour after the dropwise adding is finished, distilling off excessive ethanol to obtain 1417 g of 4, 5-dichloro-3, 3-dimethyl ethyl valerate, wherein the yield is 91%.
Example 4c preparation of Dichlorocardia propionamide
Dissolving 1 kg of cardia acyl chloride in 2000 ml of dichloromethane, introducing 500 g of chlorine at 0-5 ℃, dropwise adding 845 g of propylamine after the reaction is finished, reacting for 1 hour at room temperature, filtering, distilling to obtain 1383 g of dichloro cardia acid propionamide with the yield of 84%.
Example 4d preparation of N, N-dimethyldichlorocardiamide
Dissolving 1 kg of cardia-acyl chloride in 2000 ml of dichloromethane, introducing 500 g of chlorine at 0-5 ℃, introducing 645 g of dimethylamine after the reaction is finished, reacting for 1 hour at room temperature, filtering, and distilling to obtain 1435 g of N, N-dimethyl dichloro-cardia-amide with the yield of 93%.
Example 5 preparation of Compound of formula (VI) with Dichlorocardiac acid ester or amide (IV)
Figure BDA0003554792570000131
Example 5a 4, 5-dichloro-3, 3-dimethylpentanoic acid methyl ester 213 g dissolved in 500 ml of methanol, sodium methoxide 81 g added, reaction at 50 ℃ for 2 hours, addition of 1000 ml of water, extraction twice with 500 ml of methyl tert-butyl ether, combination of the methyl tert-butyl ether extraction layers, drying with sodium sulfate, recovery of methyl tert-butyl ether to give an oil, addition to a pressure vessel, addition of 7M methanolic ammonia 500 ml, sodium acetate 2 g, warming to 180 ℃ for 2 hours, transfer of the reaction solution, recovery of methanol, and distillation under reduced pressure to give 69 g of compound of formula (VI) in 55% yield. The 7M methanolic ammonia solution in this example is a methanol solution containing 7mol/L ammonia (this solution is commercially available).
Example 5b Ethyl 4, 5-dichloro-3, 3-dimethylpentanoate 227 g dissolved in 500 ml DMF, sodium ethoxide 102 g reacted at 50 ℃ for 2 hours, 1000 ml water was added and extracted twice with 500 ml dichloromethane, after dichloromethane was combined, dried over sodium sulfate and dichloromethane was recovered to give an oil which was added to a pressure vessel, 2M aqueous ammonia solution 1750 ml, potassium acetate 3 g was added, the temperature was raised to 210 ℃ and held for 2 hours, the reaction solution was transferred out, ethanol was recovered and distilled under reduced pressure to give the compound of formula (VI) 66 g with a yield of 53%. The 2M ammonia methanol solution in this example refers to an ethanol solution (obtainable by passing ammonia gas through ethanol) containing 2mol/L ammonia.
Example 5c N, N-dimethyl-4, 5-dichloro-3, 3-dimethylvaleramide 225 g was dissolved in 500 ml tetrahydrofuran, 168 g potassium tert-butoxide was added and the reaction was carried out at 50 ℃ for 3 hours, 1000 ml water was added and extracted twice with 500 ml dichloromethane, after dichloromethane was combined and dried over sodium sulfate, dichloromethane was recovered to give an oil which was added to the autoclave, 1750 ml 2M aminoethanol solution and 2 g sodium acetate were added and the temperature was raised to 230 ℃ and kept for 3 hours, the reaction solution was transferred off and after solvent recovery, 64 g of the compound of formula (VI) was obtained by distillation under reduced pressure with a yield of 51%. The 2M ammonia methanol solution in this example refers to an ethanol solution (obtainable by passing ammonia gas through ethanol) containing 2mol/L ammonia.
Example 6: reduction of a compound of formula (VI) to produce a product of formula (VII)
Figure BDA0003554792570000132
Example 6a 2500 g of the compound of formula (VI) prepared in example 3a was dissolved in 25000 ml of tetrahydrofuran, cooled to 0 ℃, added in portions 1520 g of sodium borohydride, added dropwise with 7500 g of boron trifluoride tetrahydrofuran, gradually warmed to 65 ℃ after completion of the addition, allowed to react for 4 hours under incubation, cooled to 0-10 ℃, added dropwise with 1000 ml of water, then recovered tetrahydrofuran under normal pressure, added dropwise with 2700 ml of 30% aqueous sodium hydroxide solution, extracted three times with methyl t-butyl ether (12000 ml, 6000 ml each time) after refluxing for 3 hours, combined with methyl t-butyl ether, and rectified to obtain 2064 g of product with 93% yield. Boron trifluoride tetrahydrofuran in this example refers to a solution of boron trifluoride and tetrahydrofuran in a molar ratio of 1:1.
Example 6b 2500 g of the compound of formula (VI) prepared in example 5a were dissolved in 25000 ml of ethylene glycol dimethyl ether, cooled to 0 deg.C, 875 g of lithium borohydride was added in portions, 7500 g of boron trifluoride tetrahydrofuran was added dropwise, after the dropwise addition was completed, the temperature was gradually raised to 60 deg.C, the reaction was maintained for 4 hours, cooled to 0-10 deg.C, 1000 ml of water was added dropwise, ethylene glycol dimethyl ether was recovered under normal pressure, 30% aqueous sodium hydroxide solution was added dropwise thereto in 2700 ml, and after refluxing for 3 hours, dichloromethane was extracted three times (12000 ml, 6000 ml each time, respectively), and after combining the dichloromethane, the product was distilled to 1998 g with a yield of 90%.
Finally, it should be noted that: the above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some technical features may be equivalently replaced; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions of the embodiments of the present invention.

Claims (10)

1. A process for preparing a paroxetine bicyclic azabicyclic pharmaceutical intermediate comprising:
a step of cyclization and amidation reaction, in which a compound shown in a general formula (III) is subjected to cyclization and amidation reaction to obtain a cyclization product shown in a structural formula (VI),
Figure FDA0003554792560000011
wherein, X1、X2Identical or different, selected from halogens.
2. The method according to claim 1, wherein X is1、X2Each independently selected from F, Cl or Br; alternatively, X1、X2Each independently selected from Cl or Br; alternatively, X1、X2Are all Br; optionally X1、X2Are all Cl.
3. The preparation method according to claim 1 or 2, wherein in the step of cyclization and amidation, after the compound represented by the general formula (III), the organic liquid and the organic strong base are mixed and reacted, ammonia is introduced to react at 100-300 ℃, and a cyclization product represented by the structural formula (VI) is prepared by a one-pot method;
Figure FDA0003554792560000012
optionally, the ammonia is ammonia gas or an organic liquid in which ammonia is dissolved;
optionally, in the mixed reaction of the compound shown in the general formula (III), the organic liquid and the organic strong base, the reaction time is 1-5 hours, optionally 2-4 hours, optionally 3 hours;
optionally, in the mixed reaction of the compound shown in the general formula (III), the organic liquid and the organic strong base, the molar ratio of the compound shown in the general formula (III) to the organic strong base is 1: 1.2-5, optionally 1: 1.2-3, optionally 1: 1.5-2.5; optionally 1: 2-2.5;
optionally, in the mixed reaction of the compound shown in the general formula (III), the organic liquid and the organic strong base, the molar ratio of the compound shown in the general formula (III) to the organic liquid is 1: 5-30, optionally 1: 10-25;
optionally, in the mixed reaction of the compound shown in the general formula (III), the organic liquid and the organic strong base, the reaction temperature is 40-65 ℃, optionally 45-55 ℃, optionally 50 ℃;
optionally, introducing ammonia to react at 100-300 ℃, wherein the reaction time is 1-6 h, optionally 3-5 h, optionally 4-5 h;
optionally, introducing ammonia to react at 100-300 ℃, wherein the reaction temperature is 150-300 ℃, 150-250 ℃, 160-230 ℃ and 160-180 ℃;
optionally, the ammonia is introduced to react at 100-300 ℃, and the molar ratio of the compound represented by the general formula (III) to the ammonia gas is 1: 1.5-5, optionally 1: 2-4, optionally 1: 2-3, optionally 1: 3.
4. The preparation method according to claim 3, wherein the organic liquid is one or more selected from alcohol organic substances, ether organic substances or aprotic polar solvents; optionally, the alcohol organic substance is selected from C1-C5 alcohol substances, optionally one or two of methanol and ethanol; optionally, the ethers include one or more of methyltetrahydrofuran, dioxane and dimethoxyethane; optionally, the aprotic polar solvent comprises one or more of DMF, DMA, NMP and HMPA; optionally, the organic liquid is selected from one or two of methanol or ethanol;
and/or the organic strong base is selected from one or more of sodium alkoxide, potassium alkoxide or amino metal salt; optionally, the sodium alkoxide comprises one or more of sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide and sodium tert-amylate; optionally, the potassium alkoxide comprises one or more of potassium methoxide, potassium ethoxide, potassium tert-butoxide and potassium tert-pentoxide; optionally, the amino metal salt comprises one or more of sodium amide, potassium amide, LiHMDS, NaHMDS and LDA; optionally, the organic strong base is selected from one or more of sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, sodium tert-pentoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide and potassium tert-pentoxide; alternatively, the strong organic base is selected from sodium tert-butoxide or potassium tert-butoxide; optionally, the strong organic base is potassium tert-butoxide;
and/or adding a catalyst when ammonia is introduced to react at 100-300 ℃; optionally, the catalyst is selected from a sodium salt of an organic acid or a potassium salt of an organic acid; optionally, the catalyst is selected from one or more of sodium acetate, potassium acetate, sodium pivalate and potassium pivalate; optionally, the catalyst is selected from sodium pivalate or potassium pivalate; optionally, the catalyst is sodium pivalate; optionally, the amount of the catalyst added is 0.1-3.0% of the weight of the compound represented by the general formula (III).
5. The production method according to any one of claims 1 to 4, wherein in the step of the cyclization and amidation reaction, the compound represented by the general formula (III) is replaced with a compound represented by the general formula (IV);
Figure FDA0003554792560000021
wherein, X1、X2Identical or different, selected from halogen; r is alkoxy or secondary amino;
alternatively, R is an alkoxy group selected from C1-C10Alkoxy, optionally selected from C1-C3Alkoxy, optionally selected from-OCH3、-O CH2CH3or-OCH2(CH3)2；
Alternatively, R is a secondary amine group selected from C1-C10A secondary amine group, optionally selected from C1-C3A secondary amine group, optionally selected from C3A secondary amino group;
alternatively, X1、X2Each independently selected from F, Cl or Br; alternatively, X1、X2Each independently selected from Cl or Br; alternatively, X1、X2Are all Br; optionally X1、X2All are Cl.
6. The process according to claim 1 or 2, wherein the cyclization and amidation reaction step comprises:
s1, the compound shown in the general formula (III) and a compound RH are esterified or amidated to generate an Intermediate (IV);
s2, cyclopropanizing the Intermediate (IV) under the action of strong organic base to generate an intermediate (V);
s3, reacting the intermediate (V) with ammonia at 100-300 ℃ to obtain a cyclized product shown in a structural formula (VI),
Figure FDA0003554792560000031
wherein R is alkoxy or secondary amino;
alternatively, R is an alkoxy group selected from C1-C10Alkoxy, optionally selected from C1-C3Alkoxy, optionally selected from-OCH3、-O CH2CH3or-OCH2(CH3)2；
Alternatively, R is a secondary amine group selected from C1-C10A secondary amine group, optionally selected from C1-C3A secondary amine group, optionally selected from C3A secondary amino group.
7. The preparation method according to claim 6, wherein in the step S2, the organic strong base is selected from one or more of sodium alkoxide, potassium alkoxide or amino metal salt; optionally, the sodium alkoxide comprises one or more of sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide and sodium tert-amylate; optionally, the potassium alkoxide comprises one or more of potassium methoxide, potassium ethoxide, potassium tert-butoxide and potassium tert-pentoxide; optionally, the amino metal salt comprises one or more of sodium amide, potassium amide, LiHMDS, NaHMDS and LDA; optionally, the organic strong base is selected from one or more of sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, sodium tert-pentoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide and potassium tert-pentoxide; alternatively, the strong organic base is selected from sodium tert-butoxide or potassium tert-butoxide; optionally, the strong organic base is potassium tert-butoxide;
and/or, the step S2 is performed in an organic solvent, where the organic solvent is one or more selected from alcohol organic substances, ether organic substances, or aprotic polar solvents; optionally, the alcohol organic substance is selected from C1-C5 alcohol substances, optionally one or two of methanol and ethanol; optionally, the ethers include one or more of methyltetrahydrofuran, dioxane and dimethoxyethane; optionally, the aprotic polar solvent comprises one or more of DMF, DMA, NMP and HMPA; optionally, the organic solvent is selected from one or both of methanol or ethanol;
and/or, in the step S2, compound RH is added in excess;
and/or in the step S2, the reaction time is 1-5 h, optionally 2-4 h;
and/or in the step S2, the molar ratio of the Intermediate (IV) to the strong organic base is 1: 1.2-5, optionally 1: 1.2-3, optionally 1: 1.5-2.5; optionally 1: 1.5-2;
and/or in the step S2, the molar ratio of the Intermediate (IV) to the organic solvent is 1: 8-30, optionally 1: 12-25;
and/or, in the step S2, the reaction temperature is 40 to 65 ℃, optionally 45 to 55 ℃, optionally 50 ℃;
and/or in the step S3, the ammonia is ammonia gas or organic liquid dissolved with ammonia;
and/or in the step S3, the molar ratio of the compound shown in the general formula (V) to ammonia is 1: 2-20, optionally 1: 2-10, optionally 1: 3-8;
and/or in the step S3, the reaction time is 1-5 h, optionally 2-4 h;
and/or in the step S3, the reaction temperature is 100-300 ℃, optionally 150-250 ℃, optionally 180-230 ℃, optionally 180-220 ℃;
and/or in the step S3, the reaction pressure is 10-25 kg;
and/or, the step S3 is performed in an organic solvent, wherein the organic solvent is one or more selected from an alcohol organic matter, an ether organic matter or an aprotic polar solvent; optionally, the alcohol organic substance is selected from C1-C5 alcohol substances, optionally one or two of methanol and ethanol; optionally, the ethers include one or more of methyltetrahydrofuran, dioxane and dimethoxyethane; optionally, the aprotic polar solvent comprises one or more of DMF, DMA, NMP and HMPA; optionally, the organic solvent is selected from one or both of methanol or ethanol.
8. The process according to any one of claims 1 to 7, wherein the process for producing the compound represented by the general formula (III) comprises: using methyl ester (I) or cardia acid as raw material, making acyl chlorination and halogen-adding reaction to obtain the invented product;
Figure FDA0003554792560000051
optionally, hydrolyzing the raw material of methyl cardiate, adding acid to generate the methyl cardiate, performing acyl chlorination, and adding halogen to perform reaction;
optionally, the reagent for acyl chlorination reaction is selected from one or more of thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride and triphosgene; optionally, the acyl chlorination reaction is carried out for 1-5 hours, optionally 2-5 hours, optionally 3-5 hours in a heating reflux process;
alternatively, acyl chlorination reaction generates an intermediate (II), and the intermediate (II) is added with halogen to generate a compound shown in a general formula (III);
Figure FDA0003554792560000052
optionally, the halogenation reaction is carried out in a solvent-free or organic halogenated solvent, and the raw material for the halogenation reaction is selected from F2、Cl2、Br2One or more of the above; optionally, the raw material for the halogenation reaction is chlorine; optionally, the organic halogenated solvent is selected from one or more of dichloromethane, dichloroethane and tetrachloroethylene;
optionally, the reaction temperature of the halogenation reaction is 0-5 ℃.
9. The production method according to any one of claims 1 to 8, characterized by further comprising a reduction reaction: the cyclized product shown in the structural formula (VI) is subjected to reduction reaction to generate a compound shown in a structural formula (VII),
Figure FDA0003554792560000053
optionally, the reducing agent in the reduction reaction is borohydride; optionally, the reducing agent in the reduction reaction is selected from one or more of sodium borohydride, potassium borohydride and lithium borohydride;
optionally, the reduction reaction is carried out in an organic solvent, wherein the organic solvent of the reduction reaction is selected from ether solvents, optionally one or more of tetrahydrofuran, methyltetrahydrofuran, DME and DG;
alternatively, the reduction reaction comprises: mixing a cyclization product shown in a structural formula (VI) with an organic solvent, cooling to 0-5 ℃, adding a reducing agent borohydride in batches, dropwise adding an organic solvent containing boron trifluoride, heating to 55-70 ℃ after dropwise adding, carrying out heat preservation reaction, cooling, recovering the organic solvent, dropwise adding an inorganic strong alkali aqueous solution, and refining to obtain a compound shown in a structural formula (VII); alternatively, the aqueous solution of an inorganic strong base is selected from aqueous sodium hydroxide or potassium hydroxide.
10. A compound of formula (III) in the preparation process according to any one of claims 1 to 9, having the formula:
Figure FDA0003554792560000061
wherein, X1、X2Identical or different, selected from halogen;
alternatively, X1、X2Each independently selected from F, Cl or Br; alternatively, X1、X2Each independently selected from Cl or Br; alternatively, X1、X2Are all Br; optionally X1、X2Are all Cl.
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