CN114605308B - Preparation method of azabicyclo medicine intermediate of Pa Luo Weide and intermediate - Google Patents

Preparation method of azabicyclo medicine intermediate of Pa Luo Weide and intermediate Download PDF

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CN114605308B
CN114605308B CN202210271416.1A CN202210271416A CN114605308B CN 114605308 B CN114605308 B CN 114605308B CN 202210271416 A CN202210271416 A CN 202210271416A CN 114605308 B CN114605308 B CN 114605308B
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CN114605308A (en
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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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    • C07C233/04—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C233/05—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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Abstract

The invention discloses a preparation method of an azabicyclo medicine intermediate of Pa Luo Weide, which comprises the following steps: cyclizing and amidating the compound shown in the general formula (III) to obtain a cyclized product shown in the structural formula (VI), wherein X 1 、X 2 The same or different, optionallyFrom halogen. The compound shown in the general formula (III) can be easily obtained by methyl cardiac pavilion, the compound shown in the general formula (III) is closed under the action of strong alkali and then reacts with ammonia gas at high temperature to form a cyclized product shown in the structural formula (VI), and the cyclized product is subjected to reduction reaction to obtain the compound shown in the structural formula (VII) (namely 6, 6-dimethyl-3-azabicyclo [ 3.1.0)]Hexane). The invention has the characteristics of easily obtained raw materials, environmental friendliness and simple and convenient operation, and is suitable for industrial production.

Description

Preparation method of azabicyclo medicine intermediate of Pa Luo Weide and intermediate
Technical Field
The invention relates to the technical field of pharmacy, in particular to a preparation method of an azabicyclo medicine intermediate of Pa Luo Weide and the intermediate.
Background
The advent of specific drugs, over 2 years worldwide, by Covid2019 would bring promise to human end-of-life. The psilon company aims at a protease which plays a key role in virus replication and is used as a target point for developing antiviral drugs, and finally, the compound PF-07321332 is optimally generated. The actual components of the new oral crown drug Paxlovid of the best is PF-07321332 and ritona Wei Zuoji at low dosage. The U.S. food and drug administration approves Paxlovid at 22, 12, 2021.
6, 6-dimethyl-3-azabicyclo [3.1.0] hexane is a key intermediate in the synthesis of Paxlovid. The synthetic routes reported in the current literature are all that the Carbonic acid is dehydrated to generate Carbonic anhydride, the Carbonic anhydride is converted into butanediamide, and finally the Carbonic anhydride is reduced to generate amine
At present, two synthetic processes of the caronic acid are reported in the literature.
Carbonic anhydride Synthesis route 1
The above route is currently the most common synthetic route for caronic acid. The method comprises the steps of taking ethyl chrysanthemate as a starting raw material, firstly oxidizing to obtain monoethyl caronate, and then hydrolyzing with sodium hydroxide to obtain caronic acid. The ethyl chrysanthemate manufacturers are few, and the price is high. The oxidation reaction uses a large amount of potassium permanganate, the operation is dangerous, and the environment pollution is caused by a large amount of manganese-containing waste. Meanwhile, the use amount of acetone in the oxidation reaction is very large, and the cost is very high.
Carbonic acid Synthesis route 2:
to overcome the drawbacks of scheme 1, qin Dongguang et al developed the above new synthesis process and published in CN 104163759. First, diazoacetic acid ethyl ester and isopentenol acetic acid ester undergo a carbene insertion reaction under copper catalysis to form a three-membered ring. Then, the ester group is hydrolyzed and ether bond is broken to obtain carboxylic acid containing primary alcohol, and finally, the carboxylic acid is oxidized under the catalysis of TEMPO to obtain the Caronic acid.
The yield of the prepared Carbonic acid is only about 40% by the diazoacetic acid ethyl ester process, and key ligands are not disclosed, so that the patent results are difficult to repeat.
No matter which route is used for preparing the caronic acid, and the step of preparing the caronic anhydride by dehydration is carried out, the yield is only 50-60 percent; in addition, the yield of the final succinimide reduction reaction is low, not more than 70%, and a large amount of reducing agent is required due to the bisamide structure.
In summary, no process route with easily available raw materials, simple operation, safety and reliability and suitability for industrial amplification exists at present.
Disclosure of Invention
Object of the Invention
In order to overcome the defects, the invention aims to provide a preparation method of an azabicyclo medicine intermediate of Pa Luo Weide and an intermediate.
The compound shown in the general formula (III) can be easily obtained through methyl cardiac pavilion, the compound shown in the general formula (III) is closed under the action of strong alkali, then the compound reacts with ammonia gas at high temperature to form a cyclized product shown in the structural formula (VI), and the compound shown in the structural formula (VII) (namely the azabicyclo medicine intermediate of Pa Luo Weide, namely 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane) can be obtained through reduction reaction. The invention has the characteristics of easily obtained raw materials, environmental friendliness and simple and convenient operation, and is suitable for industrial production.
Solution scheme
In order to achieve the purpose of the invention, the technical scheme adopted by the invention is as follows:
in one aspect, the invention provides a method for preparing an azabicyclo pharmaceutical intermediate of pa Luo Weide, comprising:
cyclizing and amidating, namely cyclizing and amidating the compound shown in the general formula (III) to obtain a cyclized product shown in the structural formula (VI),
wherein X is 1 、X 2 The same or different are selected from halogen.
Further, X 1 、X 2 Each independently selected from F, cl or Br; alternatively, X 1 、X 2 Each independently selected from Cl or Br; alternatively, X 1 、X 2 Are all Br; optionally X 1 、X 2 All are Cl.
The compound represented by the general formula (III) may be referred to as 4, 5-dihalo-3, 3-dimethylpentanoyl chloride.
In the step of cyclization and amidation reaction, after the compound shown in the general formula (III), organic liquid and organic strong base are mixed and reacted, ammonia is introduced to react at 100-300 ℃, and a cyclization product shown in the structural formula (VI) is prepared by a one-pot method;
further, the ammonia is ammonia gas or organic liquid dissolved with ammonia. Generally, ammonia water is not adopted, the closed loop of the ammonia water cannot be effectively completed, and more byproducts are generated.
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 h, optionally 2-4 h, optionally 3h.
Further, in the mixing reaction of the compound shown in the general formula (III), the organic liquid and the organic alkali, the molar ratio of the compound shown in the general formula (III) to the organic alkali 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 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 ℃.
Further, the ammonia is introduced to react at 100-300 ℃ for 1-6 hours, optionally 3-5 hours, optionally 4-5 hours;
further, in the reaction of the introduced ammonia at 100-300 ℃, the reaction temperature is selected to be 150-300 ℃, 150-250 ℃, 160-230 ℃ or 160-180 ℃.
Further, in the reaction of the introduced ammonia at 100-300 ℃, the molar ratio of the compound shown in the general formula (III) to the ammonia gas is 1:1.5-5, alternatively 1:2-4, alternatively 1:2-3, alternatively 1:3.
Further, the organic liquid is selected from one or more of alcohol organic matters, ether organic matters or aprotic polar solvents; optionally, the alcohol organic matter is selected from C1-C5 alcohol matter, and 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.
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-amyl alcohol; optionally, the potassium alkoxide comprises one or more of potassium methoxide, potassium ethoxide, potassium tert-butoxide and potassium tert-amyl alcohol; optionally, the metal amide salt comprises sodium amide, potassium amide, liHMDS (lithium bisamide, formula [ (CH) 3 ) 3 Si] 2 NLi), naHMDS (sodium bisaminoamide, chemical formula [ (CH) 3 ) 3 Si] 2 NNa) and LDA (lithium diisopropylamide, the chemical formula is [ (CH) 3 ) 2 CH] 2 One 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-amyl alcohol, potassium methoxide, potassium ethoxide, potassium tert-butoxide and potassium tert-amyl alcohol; alternatively, the organic strong base is selected from sodium tert-butoxide or potassium tert-butoxide; optionally, the organic strong base is potassium tert-butoxide.
Further, ammonia is introduced to react at 100-300 ℃ and a catalyst is also added; optionally, the catalyst is selected from organic acid sodium salt or organic acid potassium salt; optionally, the catalyst is selected from one or more of sodium acetate, potassium acetate, sodium pivalate and potassium pivalate; alternatively, the catalyst is selected from sodium or potassium pivalate; optionally, the catalyst is sodium pivalate; alternatively, the catalyst is added in an amount of 0.1 to 3.0% by weight based on the compound of the formula (III).
As an alternative, in the step of 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., intermediate (IV) described below);
wherein X is 1 、X 2 The same or different is selected from halogen; r is an alkoxy or secondary amine group;
alternatively, R is an alkoxy group selected from C 1 -C 10 Alkoxy, optionally selected from C 1 -C 3 Alkoxy, optionally selected from-OCH 3 、-O CH 2 CH 3 or-OCH 2 (CH 3 ) 2 ；
Alternatively, R is a secondary amino group selected from C 1 -C 10 Secondary amine groups, optionally selected from C 1 -C 3 Secondary amine groups, optionally selected from C 3 A secondary amine group;
alternatively, X 1 、X 2 Each independently selected from F, cl or Br; alternatively, X 1 、X 2 Each independently selected from Cl or Br; alternatively, X 1 、X 2 Are all Br; optionally X 1 、X 2 All are Cl.
The cyclization and amidation steps can be one-pot reaction, and specifically include: mixing a compound shown in a general formula (III) (or a compound shown in a general formula (IV)) with an organic liquid, adding an organic strong base, heating to 40-65 ℃, keeping the temperature for reaction for 1-5 hours, introducing ammonia gas into the reaction liquid, adding a catalyst, heating to 100-300 ℃ (preferably 160-180 ℃), reacting for 1-6 hours, concentrating the organic liquid, and distilling under reduced pressure to obtain a cyclized product shown in a structural formula (VI).
The steps of cyclization and amidation reaction can also be carried out stepwise, specifically:
s1, esterifying or amidating a compound shown in the general formula (III) with a compound RH to generate an Intermediate (IV);
s2, performing cyclopropanation reaction on the Intermediate (IV) under the action of organic alkali 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),
wherein R is an alkoxy group or a secondary amine group.
Further, R is an alkoxy group selected from C 1 -C 10 Alkoxy, optionally selected from C 1 -C 3 Alkoxy, optionally selected from-OCH 3 、-O CH 2 CH 3 or-OCH 2 (CH 3 ) 2 ；
Further, R is a secondary amino group selected from C 1 -C 10 Secondary amine groups, optionally selected from C 1 -C 3 Secondary amine groups, optionally selected from C 3 The secondary amine group, RH, may be propylamine.
Further, in the step S2, the organic strong base is selected from one or more of sodium alkoxide, potassium alkoxide, or metal amide salts; optionally, the sodium alkoxide comprises one or more of sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide and sodium tert-amyl alcohol; optionally, the potassium alkoxide comprises one or more of potassium methoxide, potassium ethoxide, potassium tert-butoxide and potassium tert-amyl alcohol; optionally, the metal amide salt comprises sodium amide, potassium amide, liHMDS (lithium bisamide, formula [ (CH) 3 ) 3 Si] 2 NLi), naHMDS (sodium bisaminoamide, chemical formula [ (CH) 3 ) 3 Si] 2 NNa) and LDA (lithium diisopropylamide, the chemical formula is [ (CH) 3 ) 2 CH] 2 One 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-amyl alcohol, potassium methoxide, potassium ethoxide, potassium tert-butoxide and potassium tert-amyl alcohol; alternatively, the organic strong base is selected from sodium tert-butoxide or potassium tert-butoxide; optionally, the organic strong base is potassium tert-butoxide.
Further, the step S2 is performed in an organic solvent, wherein the organic solvent is selected from one or more of alcohol organic matters, ether organic matters or aprotic polar solvents; optionally, the alcohol organic matter is selected from C1-C5 alcohol matter, and 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; alternatively, the organic solvent is selected from one or two of methanol or ethanol.
Further, in the step S2, the compound RH is added in excess.
Further, in the step S2, the reaction time is 1 to 5 hours, alternatively 2 to 4 hours.
Further, in the step S2, the molar ratio of the Intermediate (IV) to the organic alkali is 1:1.2-5, optionally 1:1.2-3, optionally 1:1.5-2.5; 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, alternatively 1:12 to 25.
Further, the reaction temperature in step S2 is 40 to 65 ℃, optionally 45 to 55 ℃, optionally 50 ℃.
Further, in the step S3, the ammonia is ammonia gas or an organic liquid containing dissolved ammonia.
Further, in the step S3, the molar ratio of the compound represented by the general formula (V) to ammonia is 1:2 to 20, alternatively 1:2 to 10, alternatively 1:3 to 8.
Further, in the step S3, the reaction time is 1 to 5 hours, alternatively 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, wherein the organic solvent is selected from one or more of alcohol organic matters, ether organic matters or aprotic polar solvents; optionally, the alcohol organic matter is selected from C1-C5 alcohol matter, and optionally is selected from one or more 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; alternatively, the organic solvent is selected from one or two of methanol or ethanol.
The step of the step S1 may specifically be: and (3) dropwise adding an excessive RH compound into a reaction solution of the compound shown in the general formula (III) under reflux, and refluxing for 1 hour after the completion of dropwise adding, and distilling off the excessive RH compound to obtain an Intermediate (IV).
The step of the step S2 may specifically be: mixing the Intermediate (IV) with an organic solvent, adding organic strong alkali, heating to 40-65 ℃ for reaction for 1-5 h, adding a large amount of water and the organic solvent for extraction, combining the oil phase extraction layers, drying (drying by sodium sulfate), and recovering the extracted organic solvent to obtain oily substance containing the intermediate (V).
The step of the step S3 may specifically be: adding the oily matter containing the intermediate (V) into an autoclave, wherein the reaction pressure is 10-25 kg, adding excessive ammonia-organic liquid (namely liquid dissolved with ammonia gas), heating to 100-300 ℃, reacting for 1-5 h at a temperature maintaining temperature, and recovering methanol to obtain a cyclized product shown in the structural formula (VI).
Further, the preparation method of the compound shown in the general formula (III) comprises the following steps: the method is characterized in that methyl cardiac acid (I) or cardiac acid is used as a raw material to carry out acyl chlorination and halogen adding reaction to obtain the product;
further, when methyl cardiac benzoate is used as a raw material, the methyl cardiac benzoate is hydrolyzed and acid is added to generate the cardiac acid, and then acyl chlorination and halogen adding reaction are carried out.
Further, the reagent for acyl chlorination reaction is one or more selected from thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride and triphosgene; alternatively, the acid chloride reaction is carried out in a heated reflux for 1 to 5 hours, alternatively 2 to 5 hours, alternatively 3 to 5 hours.
Further, the acyl chlorination reaction is carried out to generate an intermediate (II), and the intermediate (II) is added with halogen to generate a compound shown in a general formula (III);
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 F 2 、Cl 2 、Br 2 One or more of the following; optionally, the raw material for the halogen adding 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 halogen adding reaction is 0-5 ℃.
The specific steps for preparing the compound shown in the general formula (III) by using methyl cardiac sulfonate (I) can be as follows: methyl cardiac acid, organic solvent, water, sodium hydroxide (or other strong base such as potassium hydroxide) and the like, carrying out reflux reaction for 1-5 h, distilling at normal pressure to recover the organic solvent after the reaction is finished, then adding hydrochloric acid and extracting the organic solvent, drying an oil layer by sodium sulfate, recovering the extracted organic solvent to obtain an oil layer containing cardiac acid, and carrying out reflux reaction on cardiac acid and thionyl chloride to obtain cardiac acid chloride (namely an intermediate (II)). Mixing the cardiac acyl chloride with an organic halogenated solvent, and introducing halogen at 0-5 ℃ to perform halogen adding reaction to prepare the compound shown in the general formula (III). It is generally preferred to add chlorine, dissolve with chlorinated organic solvents and add chlorine.
The extractant in this application may be methyl tertiary butyl ether, methylene chloride, etc.
Further, the method also comprises the following steps of reduction reaction: the cyclized product shown in the structural formula (VI) is subjected to reduction reaction to generate a compound shown in the structural formula (VII),
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 selected from ether solvents, optionally one or more of tetrahydrofuran, methyltetrahydrofuran, DME and DG;
alternatively, the reduction reaction includes: mixing a cyclized product shown in a structural formula (VI) with an organic solvent, cooling to 0-5 ℃, adding a reducing agent borohydride in batches, dropwise adding the organic solvent containing boron trifluoride, heating to 55-70 ℃ after the dropwise adding is finished, carrying out heat preservation reaction, cooling, recovering the organic solvent, dropwise adding an inorganic strong alkaline water solution, and refining to obtain a compound shown in the structural formula (VII); alternatively, the aqueous 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 above preparation method, which has the following formula:
wherein X is 1 、X 2 The same or different is selected from halogen;
further, X 1 、X 2 Each independently selected from F, cl or Br; alternatively, X 1 、X 2 Each independently selected from Cl or Br; alternatively, X 1 、X 2 Are all Br; optionally X 1 、X 2 All are Cl.
Thus, in this application, there are at least two reaction schemes for preparing the cyclized product represented by structural formula (VII) starting from methyl cardiac maleate (I):
1)
2)
advantageous effects
(1) The compound shown in the general formula (III) can be easily obtained through methyl cardiac pavilion, the compound shown in the general formula (III) is closed under the action of strong alkali, then the compound reacts with ammonia gas at high temperature to form a cyclized product shown in the structural formula (VI), and the compound shown in the structural formula (VII) (namely the azabicyclo medicine intermediate of Pa Luo Weide, namely 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane) can be obtained through reduction reaction. The invention has the characteristics of easily obtained raw materials, environmental friendliness and simple and convenient operation, and is suitable for industrial production.
(2) The compound shown in the general formula (III) can smoothly obtain the cyclized product shown in the structural formula (VI) through high-temperature reaction, and the yield can reach 50-62 percent.
(3) The compound shown in the general formula (III) is halogenated acyl chloride, a cyclized product shown in the structural formula (VI) can be obtained by a one-step method or a multi-step method, and the catalyst (sodium acetate and the like) used in the preparation process is simple and easy to obtain, and does not need to use an expensive Ru catalyst.
(4) The compound shown in the general formula (III) can obtain the methyl cardiac acid almost quantitatively by using the methyl cardiac acid raw material through hydrolysis and acid addition, and can obtain the methyl cardiac acid chloride almost quantitatively through the chlorination addition reaction of the methyl cardiac acid chloride, and can obtain the dichloro methyl cardiac acid chloride near the quantitative yield, and then the esterification reaction and the dichloro methyl cardiac acid near the quantitative yield. The method is simple and easy to operate, and can avoid using chloridizing reagent which destroys the ozone layer and is uneconomical.
(5) The cyclized product shown in the structural formula (VI) can obtain the compound shown in the structural formula (VII) (6, 6-dimethyl-3-azabicyclo [3.1.0] hexane) through a general reducing agent, so that the use of the reducing agent in the amide reduction reaction is greatly reduced, the byproduct waste salt is reduced, the environment is protected, compared with the traditional method for preparing the 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane through the reduction reaction of the carbofuran Long Dinger imide, the method only needs to reduce the carbonyl of the monoamide, the reducing agent can be obviously saved, the reduction yield can reach more than 90%, the reduction reaction yield of the carbofuran Long Dinger imide in the traditional process is generally lower than 70%, compared with the prior art, the raw material methyl cardiac-pavilion is cheap and easy to obtain, and the method can be widely applied to industrial production and the production cost is reduced.
Detailed Description
For the purpose of making the objects, technical solutions and advantages of the embodiments of the present invention more apparent, the technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is apparent that the described embodiments are some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
In addition, numerous specific details are set forth in the following description in order to provide a better illustration of the 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, etc. well known to those skilled in the art are not described in detail in order to highlight the gist of the present invention.
Throughout the specification and claims, unless explicitly stated otherwise, the term "comprise" or variations thereof such as "comprises" or "comprising", etc. will be understood to include the stated element or component without excluding other elements or components.
Since the contents of the intermediates (II) to (VI) in examples 1 to 6 were all confirmed by a gas chromatograph, the amounts of the raw materials used in examples 1 to 6 refer to the weight of the raw materials converted by detection and confirmation, and 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 the yield.
Example 1
Preparation of cardia pavilion acyl chloride
Example 1a methyl cardiac acid 142 g, methanol 200 ml, water 300 ml, sodium hydroxide 48 g, after 2 hours of reflux reaction, after the reaction, distilled off 250 g low boiling point fraction at normal pressure to recover methanol, then added with 30% hydrochloric acid about 150 g, extracted with 200 ml methyl tert-butyl ether, after the organic layer dried with sodium sulfate, recovered methyl tert-butyl ether, obtained cardiac acid-containing oil layer, cardiac acid-containing oil layer and thionyl chloride 170 g reflux three hours, distilled to obtain cardiac acid chloride 138 g, yield 94.5%.
Example 1b methyl cardiac acid 142 g, ethanol 200 ml, water 200 ml, potassium hydroxide 68 g, reflux reaction for 2 hours, after the reaction, distillation of 210 g low boiling point fraction at normal pressure to recover ethanol, then adding 30% hydrochloric acid about 150 g, extracting water layer with 200 ml dichloromethane, drying organic layer with sodium sulfate, recovering solvent, obtaining oil layer containing cardiac acid, oil layer containing cardiac acid and phosphorus oxychloride 219 g reflux 4 hours, distillation to obtain cardiac acid chloride 135 g, yield 92%.
Example 2: preparation of 4, 5-dihalo-3, 3-dimethylacyl chloride (formula (III))
Example 2a:1 kg of cardiac acyl chloride is dissolved in 2000 ml of dichloroethane, 500 g of chlorine is introduced at 0-5 ℃, after the reaction is finished, the dichloroethane is recovered, and 4, 5-dichloro-3, 3-dimethyl acyl chloride is prepared, and the yield is close to 100%. I.e. X 1 、X 2 All are Cl.
Example 2b: 147 g of cardia acyl chloride is added with 162 g of bromine dropwise under the condition of no solvent and at the temperature of 0-20 ℃ to obtain 4, 5-dibromo-3, 3-dimethyl pentanoyl chloride, and the yield is close to 100%. I.e. X 1 、X 2 Are all Br.
Example 3: one-pot preparation of 4, 5-dihalo-3, 3-dimethyl pentanoyl chloride (formula (III)) for preparing compound of formula (VI)
Example 3a: 217.5 g of 4, 5-dichloro-3, 3-dimethyl valeryl chloride is dissolved in 400 ml of methanol, 238 g of potassium tert-butoxide is added, after reaction is carried out for 3 hours at 50 ℃, 51 g of ammonia gas is introduced into the reaction solution, 1 g of sodium pivalate is added, the temperature is raised to 180 ℃ for reaction for 4 hours, after methanol is concentrated, 77.5 g of compound of formula (VI) is obtained by reduced pressure distillation, and the yield is 62%. I.e. X 1 、X 2 All are Cl.
Example 3b: after reflux reaction of 306 g of 4, 5-dibromo-3, 3-dimethylvaleryl chloride and 34 g of methanol for 2 hours, 500 ml of DMF,70 g of sodium methoxide at 40 ℃ are added for reaction for 5 hours to obtain a reaction solution, 1500 ml of water are added, the reaction solution is extracted, dried and desolventized by methyl tertiary butyl ether to obtain a material, 500 ml of 7M methanolic ammonia solution, 1 g of sodium pivalate is added, the reaction solution is heated to 160 ℃ for 5 hours, 75 g of compound of formula (VI) is obtained after the reaction, and the yield is 60 percent.
Examples of the preparation of the compound of formula (VI) in a multistage process are described below for example 4, example 5 being 4, 5-dichloro-3, 3-dimethylpentanoyl chloride (formula (III)).
Example 44,5-dichloro-3, 3-dimethylvaleryl chloride (formula (III)) preparation of dichloro cardiac acid ester or amide (IV)
Wherein R is an alkoxy group or a secondary group.
EXAMPLE 4a preparation of methyl dichloropsequoyiate
1 kg of cardiac acyl chloride is dissolved in 2000 ml of dichloroethane, 500 g of chlorine is introduced at 0-5 ℃, after the reaction is finished, the dichloroethane is recovered, then 250 g of methanol is added dropwise under reflux, after the dropwise addition is finished, the reflux is carried out for 1 hour, and the excess methanol is distilled off to obtain 1300 g of 4, 5-dichloro-3, 3-dimethyl valerate with the yield of 89%.
EXAMPLE 4b preparation of ethyl dichloropycardiate
1 kg of cardiac acyl chloride is dissolved in 2000 ml of dichloromethane, 500 g of chlorine is introduced at 0-5 ℃, after the reaction is finished, dichloroethane is recovered, 359 g of ethanol is added dropwise under reflux, after the dropwise addition is finished, reflux is carried out for 1 hour, excess ethanol is distilled off, and 1417 g of 4, 5-dichloro-3, 3-dimethylvalerate is obtained, and the yield is 91%.
EXAMPLE 4c preparation of dichloro cardia-propionamide
1 kg of cardiac acid chloride is dissolved in 2000 ml of dichloromethane, 500 g of chlorine is introduced at the temperature of 0-5 ℃, 845 g of propylamine is added dropwise after the reaction is finished, the reaction is carried out for 1 hour at room temperature, filtration and distillation are carried out, 1383 g of dichloro cardiac acid propionamide is obtained, and the yield is 84%.
EXAMPLE 4d preparation of N, N-dimethyldichlorocardiac amide
1 kg of cardia-pavilion acyl chloride is dissolved in 2000 ml of dichloromethane, 500 g of chlorine is introduced at 0-5 ℃, 645 g of dimethylamine is introduced after the reaction is finished, the reaction is carried out for 1 hour at room temperature, filtration and distillation are carried out, 1435 g of N, N-dimethyl dichloro cardia-pavilion amide is obtained, and the yield is 93%.
EXAMPLE 5 preparation of the Compound of formula (VI) from the Dichlorocardiac acid ester or amide (IV)
EXAMPLE 5a 213 g of methyl 4, 5-dichloro-3, 3-dimethylvalerate, dissolved in 500 ml of methanol, 81 g of sodium methoxide was added to react at 50℃for 2 hours, 1000 ml of water was added, extracted twice with 500 ml of methyl tert-butyl ether, the methyl tert-butyl ether extract was combined, dried over sodium sulphate, methyl tert-butyl ether was recovered, an oil was obtained, which was then added to an autoclave, 500 ml of 7M methanolic ammonia solution was added, 2 g of sodium acetate was added, the temperature was raised to 180℃for 2 hours, the reaction solution was transferred, methanol was recovered, 69 g of the compound of formula (VI) was obtained by distillation under reduced pressure, and the yield was 55%. The methanolic ammonia solution of 7M in this example is a methanolic ammonia solution containing 7mol/L ammonia (this solution is commercially available).
EXAMPLE 5b 4, 5-dichloro-3, 3-dimethylvaleric acid ethyl ester 227 g was dissolved in 500 ml DMF, 102 g of sodium ethoxide was added to react for 2 hours at 50℃and 1000 ml of water was added, extracted twice with 500 ml of dichloromethane, after combining dichloromethane, dried over sodium sulfate and recovering dichloromethane, an oil was obtained after recovery of dichloromethane, added to autoclave, 1750 ml of 2M aminoethanol solution was added, potassium acetate 3 g was warmed to 210℃and kept for 2 hours, the reaction solution was transferred out, and after recovery of ethanol, 66 g of the compound of formula (VI) was obtained by distillation under reduced pressure, and the yield was 53%. The 2M methanolic ammonia solution in this example is an ethanol solution containing 2mol/L ammonia (which can be obtained by introducing ammonia gas into ethanol).
EXAMPLE 5c N, N-dimethyl-4, 5-dichloro-3, 3-dimethylpentanamide 225 g was dissolved in 500 ml of tetrahydrofuran, 168 g of potassium t-butoxide was added, reacted at 50℃for 3 hours, 1000 ml of water was added, extracted twice with 500 ml of methylene chloride, after methylene chloride was combined, dried over sodium sulfate, and after methylene chloride was recovered, an oily substance was obtained, which was added to a autoclave, 1750 ml of a 2M aminoethanol solution, 2 g of sodium acetate was added, the temperature was raised to 230℃and kept for 3 hours, the reaction solution was transferred, and after recovering the solvent, 64 g of the compound of the formula (VI) was obtained by distillation under reduced pressure, and the yield was 51%. The 2M methanolic ammonia solution in this example is an ethanol solution containing 2mol/L ammonia (which can be obtained by introducing ammonia gas into ethanol).
Example 6: reduction of the compound of formula (VI) to produce the product of formula (VII)
Example 6a 2500 g of the compound of formula (VI) prepared in example 3a, dissolved in 25000 ml of tetrahydrofuran, cooled to 0℃and added with 1520 g of sodium borohydride in portions, 7500 g of boron trifluoride is added dropwise, after the addition, the temperature is gradually raised to 65℃and the reaction is carried out for 4 hours at a temperature of between 0 and 10℃and 1000 ml of water is added dropwise, then tetrahydrofuran is recovered under normal pressure, 2700 ml of 30% aqueous sodium hydroxide solution is added dropwise, after 3 hours of reflux, methyl tert-butyl ether is extracted three times (12000 ml, 6000 ml and 6000 ml each time), after merging methyl tert-butyl ether, 2064 g of product is obtained by rectification, and the yield is 93%. 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, dissolved in 25000 ml of ethylene glycol dimethyl ether, cooled to 0℃and added with 875 g of lithium borohydride in portions, and then added with 7500 g of boron trifluoride tetrahydrofuran dropwise, after the dropwise addition, the temperature is gradually raised to 60℃and the reaction is kept for 4 hours, cooled to 0-10℃and added with 1000 ml of water dropwise, then ethylene glycol dimethyl ether is recovered under normal pressure, then 2700 ml of 30% aqueous sodium hydroxide solution is added dropwise, refluxed for 3 hours, extracted with methylene dichloride three times (12000 ml, 6000 ml and 6000 ml each time), and after the methylene dichloride is combined, 1998 g of product is obtained by rectification, and the yield is 90%.
Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention, and are not limiting; although the 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 scheme described in the foregoing embodiments can be modified or some technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims (56)

1. A process for the preparation of an azabicyclo pharmaceutical intermediate of pampers Luo Weide comprising:
cyclizing and amidating, namely cyclizing and amidating the compound shown in the general formula (III) to obtain a cyclized product shown in the structural formula (VI), ，
wherein X is 1 、X 2 The same or different is selected from halogen;
in the cyclization and amidation reaction steps, after the compound shown in the general formula (III), organic liquid and organic strong base are mixed and reacted, ammonia is introduced to react at 100-300 ℃, and a cyclization product shown in the structural formula (VI) is prepared by a one-pot method;
，
the ammonia is ammonia gas or organic liquid dissolved with ammonia;
the organic liquid is selected from one or more of alcohol organic matters, methyltetrahydrofuran, dioxane, dimethoxyethane, DMF, DMA, NMP and HMPA; the alcohol organic matter is selected from C1-C5 alcohol matters;
and adding a catalyst when ammonia is introduced to react at 100-300 ℃, wherein the catalyst is selected from organic acid sodium salt or organic acid potassium salt, and the adding amount of the catalyst is 0.1-3.0% of the weight of the compound shown in the general formula (III).
2. The method of claim 1, wherein X is 1 、X 2 Each independently selected from F, cl or Br.
3. The method of claim 1, wherein X is 1 、X 2 Each independently selected from Cl or Br.
4. The method of claim 1, wherein X is 1 、X 2 Are all Br.
5. The method of claim 1, wherein X is 1 、X 2 All are Cl.
6. The preparation method according to claim 1, wherein the reaction time is 1-5 h in the mixing reaction of the compound represented by the general formula (III), the organic liquid and the organic strong base.
7. The preparation method according to claim 6, wherein the reaction time is 2-4 hours in the mixing reaction of the compound represented by the general formula (III), the organic liquid and the organic strong base.
8. The method according to claim 6, wherein the reaction time is 3 hours in the mixed reaction of the compound represented by the general formula (III), the organic liquid and the organic strong base.
9. The preparation method of claim 6, wherein 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 strong base is 1:1.2-5.
10. The preparation method according to claim 9, wherein the molar ratio of the compound represented by the general formula (III) to the organic strong base is 1:1.2 to 3.
11. The preparation method according to claim 9, wherein the molar ratio of the compound represented by the general formula (III) to the organic strong base is 1:1.5 to 2.5.
12. The preparation method according to claim 9, wherein the molar ratio of the compound represented by the general formula (III) to the organic strong base is 1:2 to 2.5.
13. The preparation method according to any one of claims 1 to 12, wherein in the mixing reaction of the compound represented by the general formula (III), the organic liquid and the organic strong base, the molar ratio of the compound represented by the general formula (III) to the organic liquid is 1:5 to 30.
14. The preparation method of claim 13, wherein 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 1:10-25.
15. The preparation method according to any one of claims 1 to 12, wherein in the mixing reaction of the compound represented by the general formula (III), the organic liquid and the organic strong base, the reaction temperature is 40 to 65 ℃.
16. The preparation method according to claim 15, wherein the reaction temperature is 45-55 ℃ in the mixing reaction of the compound represented by the general formula (III), the organic liquid and the organic strong base.
17. The method according to claim 15, wherein the reaction temperature in the mixing reaction of the compound represented by the general formula (III), the organic liquid and the organic strong base is 50 ℃.
18. The method according to any one of claims 1 to 12, wherein the ammonia is introduced for a reaction time of 1 to 6 hours at 100 to 300 ℃.
19. The method according to claim 18, wherein the ammonia is introduced for 3 to 5 hours at 100 to 300 ℃.
20. The method according to claim 18, wherein the ammonia is introduced for 4 to 5 hours at 100 to 300 ℃.
21. The method according to any one of claims 1 to 12, wherein the introduced ammonia is reacted at 150 to 300 ℃.
22. The method according to claim 21, wherein ammonia is introduced to react at 150-250 ℃.
23. The method of claim 21, wherein ammonia is introduced to react at 160-230 ℃.
24. The method of claim 21, wherein ammonia is introduced to react at 160-180 ℃.
25. The method according to any one of claims 1 to 12, wherein the molar ratio of the compound of formula (III) to ammonia gas is 1:1.5 to 5 in the reaction of ammonia at 100 to 300 ℃.
26. The method according to claim 25, wherein the molar ratio of the compound represented by the general formula (III) to ammonia gas is 1:2 to 4.
27. The method according to claim 25, wherein the molar ratio of the compound represented by the general formula (III) to ammonia gas is 1:2 to 3.
28. The process of claim 25, wherein the molar ratio of the compound of formula (III) to ammonia is 1:3.
29. The method according to any one of claims 1 to 12, wherein the alcoholic organic substance is selected from one or both of methanol and ethanol.
30. The preparation method according to any one of claims 1 to 12, wherein the organic strong base is selected from one or more of sodium alkoxide, potassium alkoxide, or metal amide salts.
31. The method of claim 30, wherein the sodium alkoxide comprises one or more of sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, and sodium tert-amyl alcohol.
32. The method of claim 30, wherein the potassium alkoxide comprises one or more of potassium methoxide, potassium ethoxide, potassium tert-butoxide, and potassium tert-butoxide.
33. The method of claim 30, wherein the metal amide salt comprises one or more of sodium amide, potassium amide, liHMDS, naHMDS, and LDA.
34. The preparation method according to any one of claims 1 to 12, wherein the organic strong base is selected from one or more of sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide and potassium tert-butoxide.
35. The process according to any one of claims 1 to 12, wherein the strong organic base is selected from sodium tert-butoxide or potassium tert-butoxide.
36. The preparation method according to claim 1, wherein the catalyst is one or more selected from sodium acetate, potassium acetate, sodium pivalate and potassium pivalate.
37. The preparation method according to claim 1, wherein the catalyst is selected from sodium pivalate or potassium pivalate.
38. The method of claim 1, wherein the catalyst is sodium pivalate.
39. The production method according to any one of claims 1 to 12, wherein the production method of the compound represented by the general formula (III) comprises: the method is characterized in that methyl cardiac acid (I) or cardiac acid is used as a raw material to carry out acyl chlorination and halogen adding reaction to obtain the product;
。
40. the process of claim 39 wherein the methyl cardiac acid is hydrolyzed and acid is added to produce the acid and then the acid chloride is added to the acid halide.
41. The process of claim 40 wherein the agent for the acid chlorination reaction is one or more selected from the group consisting of thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride and triphosgene.
42. The method of claim 40, wherein the acid chloride is reacted in a heated reflux for 1-5 hours.
43. The method of claim 42, wherein the acid chloride is reacted in a heated reflux for 2-5 hours.
44. The method of claim 42, wherein the acid chloride is reacted in a heated reflux for 3 to 5 hours.
45. The process of claim 40 wherein the acid chloride is reacted to form intermediate (II) and the intermediate (II) is halogenated to form a compound of formula (III);。
46. the process of claim 45 wherein the halogenation is carried out in a solvent-free or organohalogenated solvent, the starting material for the halogenation being selected from F 2 、Cl 2 、Br 2 One or more of them.
47. The process of claim 46 wherein the starting material for the halogenation reaction is chlorine.
48. The process of claim 46 wherein the organic halogenated solvent is selected from one or more of methylene chloride, ethylene dichloride and tetrachloroethylene.
49. The process of claim 46, wherein the reaction temperature for the halogenation reaction is 0-5 ℃.
50. The production method according to any one of claims 1 to 12, 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 the structural formula (VII),。
51. the process of claim 50 wherein the reducing agent in the reduction reaction is borohydride.
52. The process of claim 50 wherein the reducing agent is one or more of sodium borohydride, potassium borohydride and lithium borohydride in the reduction reaction.
53. The process according to claim 50, wherein the reduction is carried out in an organic solvent selected from the group consisting of ether solvents.
54. The process of claim 53 wherein the ethereal solvent is selected from one or more of tetrahydrofuran, methyltetrahydrofuran, DME and DG.
55. The method of claim 54, wherein the reduction reaction comprises: mixing a cyclized product shown in a structural formula (VI) with an organic solvent, cooling to 0-5 ℃, adding a reducing agent borohydride in batches, dropwise adding the organic solvent containing boron trifluoride, heating to 55-70 ℃ after the dropwise adding is finished, carrying out heat preservation reaction, cooling, recovering the organic solvent, dropwise adding an inorganic strong alkaline water solution, and refining to obtain the compound shown in the structural formula (VII).
56. The process of claim 55 wherein the aqueous inorganic strong base is selected from the group consisting of aqueous sodium hydroxide and aqueous potassium hydroxide.
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