CN111646991A - Preparation method of avibactam sodium intermediate - Google Patents
Preparation method of avibactam sodium intermediate Download PDFInfo
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- CN111646991A CN111646991A CN202010738784.3A CN202010738784A CN111646991A CN 111646991 A CN111646991 A CN 111646991A CN 202010738784 A CN202010738784 A CN 202010738784A CN 111646991 A CN111646991 A CN 111646991A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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Abstract
The invention relates to a preparation method of an avibactam sodium key intermediate compound (VII), which is characterized in that the compound (VII) is obtained by cyclization and deprotection reaction of a compound (V). The preparation method has the advantages of good chiral selectivity, simple and easy operation, high yield, good purity, cheap and easily obtained raw materials and industrial value
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of an avibactam sodium intermediate.
Background
Abamebactam sodium, English name Avibactam sodium, chemical name: [ (2S,5R) -2-carbamoyl-7-carbonyl-1, 6-diazabicyclo [3.2.1] oct-6-yl ] sulfuric acid monosodium salt, having the following structural formula:
abamebactam sodium belongs to diazabicyclooctanone compounds, and is a novel beta-lactamase inhibitor which is considered to be good at present. It has no obvious antibacterial activity, but has broad-spectrum antibacterial activity when being combined with various cephalosporin and carbapenem antibiotics. Abamebactam sodium is jointly developed by Forest Lab and Aslicon and is purchased by the Pesper; the compound preparation of abamectin sodium/ceftazidime is approved by FDA to be marketed in 2015 and approved by EMA in 2016.
Patent documents CN102056901B and CN103649051B report a preparation method of avibactam sodium as shown in scheme one. Taking protected L-pyroglutamic acid ester 2 as a starting material, reacting with trimethyl sulfoxide iodide and benzyloxyamine salt in sequence, and performing cyclization reaction and reduction reaction to obtain a (2S,5R) -configuration disubstituted piperidine compound 6; after a compound 7 is obtained by amine ester exchange reaction, protecting piperidine nitrogen, reacting with a carbonylation reagent, and carrying out deprotection to form a ring, so as to obtain a bridge ring compound 9; then hydrogenating, debenzylating and carrying out sulfuric acid esterification to obtain tetrabutyl ammonium salt to obtain a compound 10; finally, the avibactam sodium is prepared by cation exchange. In the process of converting the compound 7 into the compound 9, because the amido of the piperidine ring and the amido of the benzyloxyamine salt have similar reaction activities with the carbonylation reagent, the amido of the piperidine ring must be protected firstly, otherwise, the carbonylation reagent can form a ring between the unsubstituted formamido group and the piperidine ring, so that the reaction yield is greatly reduced, and the yield is lower than 50%; in order to ensure the conversion yield, expensive Fmoc-Cl reagent is selected for protecting the amine group of the piperidine ring, thereby greatly increasing the cost of the final product.
Patent document CN103649051B also reports a synthetic method of avibactam sodium intermediate 9 shown in scheme two: the disubstituted piperidine compound 6 is reacted with a carbonylation reagent to produce an ester intermediate 11, which is then converted to an amide intermediate 9. Because the bridged ring structure with ester group has poor stability to nucleophilic reagent, when it is directly reacted with various 'ammonia' source reagents, its yield is not high, or it needs autoclave, or it needs expensive enzyme catalysis; if the ester group is hydrolyzed to a carboxyl group, the carboxyl group is reactivated to an acid anhydride, and then amidation is performed, the number of steps increases.
Patent document CN103649051B also designs a synthetic scheme as shown in route three, starting from protected pyroglutamic acid amide 12, preparing avibactam sodium by a method similar to route one; in the example, the yield reported in the case of the benzyl group as R is very low, the yield of the intermediate 16 is only 21.3%, and the intermediates 13 and 14 need column chromatography for separation and purification, so that the method is not suitable for industrial scale-up production.
Patent document CN105061425B reports a preparation method as shown in scheme four: after reacting Boc-protected pyroglutamic acid amide 12 with trimethyl sulfoxide iodide to obtain an intermediate 13, firstly closing a ring to obtain a 5-keto piperidine amide compound 18, then reducing a keto group to obtain a hydroxyl compound 19, carrying out sulfonylation (20) and nucleophilic substitution on the hydroxyl group to obtain a hydroxyl compound 21, and carrying out deprotection to obtain an intermediate 16. Route four is longer than route three. The present inventors have repeated experiments according to the preparation method of this document and found that several steps of the reaction are not reproducible, for example, the step of preparing intermediate 18 by ring closure of intermediate 13 easily removes the Boc protecting group and the yield is low.
In conclusion, the existing synthesis routes of the avibactam sodium have the defects of difficult raw material obtaining, long route, high cost, low atom utilization rate and the like, and the total yield is generally only 20-50%. Therefore, it is necessary to develop a process route which has high atom economy, simple operation and is beneficial to industrial production.
Disclosure of Invention
According to the purpose of the invention, the invention provides a preparation method of an avibactam sodium key intermediate compound (VII), and the preparation method has the advantages of better chiral selectivity, high yield, good purity, simple and convenient operation, low cost and suitability for large-scale industrial production.
The structural formula of the key intermediate compound (VII) of the avibactam sodium is shown as follows, and the avibactam sodium can be obtained from the compound (VII) through several steps of reactions according to the preparation method described in the prior literature, such as the contents disclosed in patent literatures CN1468242A, CN102056901A, CN103649051A and CN 105753867A. The following is a typical reaction route, and the compound (VII) is subjected to debenzylation, sulfation, tetrabutyl ammonium salt formation and cation exchange to obtain the avibactam sodium.
One of the technical schemes of the invention is as follows: a preparation method of an avibactam intermediate compound (VII) is provided, which comprises the following steps:
cyclizing the compound (V) or a salt thereof in an organic solvent by using a carbonylation reagent under the condition of alkali or no alkali to obtain a compound (VI); deprotecting the compound (VI) under the action of an acidic reagent to obtain a compound (VII); wherein the salt of the compound (V) is selected from one of hydrochloride, hydrobromide, formate, acetate, propionate, oxalate, fumarate or citrate, and Bn represents benzyl.
In the above production method, the salt of the compound (V) is preferably an oxalate salt.
In the above preparation method, the organic solvent is selected from one or more of ethyl acetate, isopropyl acetate, methyl tert-butyl ether, dichloromethane, chloroform, tetrahydrofuran, acetonitrile, toluene or chlorobenzene; preferably, the organic solvent is selected from one or more of ethyl acetate, isopropyl acetate, dichloromethane, chloroform, tetrahydrofuran, acetonitrile, toluene or chlorobenzene.
In the above preparation method, the carbonylation reagent is selected from one of diphosgene, triphosgene, N' -carbonyldiimidazole, methyl chloroformate, ethyl chloroformate, isopropyl chloroformate, isobutyl chloroformate, N-butyl chloroformate, phenyl chloroformate, benzyl chloroformate or di-tert-butyl dicarbonate; preferably, the carbonylation reagent is selected from N, N' -carbonyldiimidazole or triphosgene.
In the preparation method, the alkali is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, pyridine, 2, 6-lutidine, triethylamine or diisopropylethylamine; preferably, the base is selected from sodium hydroxide, sodium bicarbonate, potassium bicarbonate, triethylamine or diisopropylethylamine.
In the above production method, the molar ratio of the compound (V) or a salt thereof to the carbonylation reagent and the base is 1: 0.3-2: 0 to 5; preferably, the molar ratio of the compound (V) or its oxalate salt to the carbonylation reagent and base is 1: 0.3-1.2: 0-5.
In the preparation method, the temperature of the cyclization reaction is 0-80 ℃, and the time is 2-24 hours; preferably, the temperature of the cyclization reaction is 0-40 ℃ and the time is 2-24 hours.
In the preparation method, the carbonylation reagent is added in batches according to the actual reaction condition.
In the above preparation method, HPLC method is used for monitoring until the cyclization reaction is completed, and then conventional post-treatment methods such as quenching, washing, concentration, recrystallization and the like are used to obtain the pure compound (VI).
In the above production method, the acidic reagent used for the deprotection is selected from a protonic acid or a Lewis acid, and preferably the acidic reagent used for the deprotection is selected from a Lewis acid. Definitions for protic acids and lewis acids are well known to those skilled in the art. Preferably, the acidic reagent is selected from one of hydrogen chloride, hydrogen bromide, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, aluminum trichloride, zinc dichloride, titanium tetrachloride, tetraisopropyl titanium, boron trifluoride, and boron trifluoride complex. More preferably, the acidic reagent is selected from boron trifluoride or a boron trifluoride complex. Boron trifluoride complexes include, but are not limited to, boron trifluoride acetic acid complex, boron trifluoride diethyl etherate complex, boron trifluoride acetonitrile complex, boron trifluoride tetrahydrofuran complex, and the like.
In the above production method, the molar ratio of the compound (VI) to the acidic reagent is 1: 0.1-10. Preferably, the molar ratio of compound (VI) and acidic reagent is 1: 2-9.
In the above preparation method, the solvent for the deprotection reaction is selected from one or more of dichloromethane, chloroform, toluene, xylene, chlorobenzene, methyl tert-butyl ether, diethyl ether, diisopropyl ether, tetrahydrofuran or methyl tetrahydrofuran. Preferably, the solvent for the deprotection reaction is selected from one or more of dichloromethane, chloroform, toluene and tetrahydrofuran.
In the preparation method, the deprotection reaction is carried out at the temperature of 0-80 ℃ for 2-18 hours. Preferably, the deprotection reaction is carried out at the temperature of 40-80 ℃ for 10-18 hours.
In the preparation method, an HPLC method is adopted to monitor the deprotection reaction process, after the reaction is finished, the deprotection reaction solution is quenched into a low-temperature alkaline aqueous solution, a reaction solvent is used for extraction, decompression and desolventization, and 4-methyl-2-pentanone is pulped to obtain the pure compound (VII).
In the preparation method of the key intermediate compound (VII) of abamectin, the compound (VII) is obtained by two steps of simple cyclization and deprotection through reasonable design and preferably selecting the amide compound (V) with tertiary butyl as N substituent or salt thereof as a raw material. The prior art amide compound without substituent on N (such as 5R-benzyloxyaminopiperidine-2S-formamide) and the prior art amide compound with substituent on N being benzyl or substituted benzyl (such as N-benzyl (or substituted benzyl) -5R-benzyloxyaminopiperidine-2S-formamide or N, N-dibenzyl (or substituted benzyl) -5R-benzyloxyaminopiperidine-2S-formamide) are not selected as raw materials in the design, which has the following advantages: 1. the compound (V) can be directly cyclized with a carbonylation reagent to obtain the compound (VI) without protecting the amino group on the piperidine ring, the operation is simple and convenient, the cyclization side reaction between an amide group and the ortho-position piperidine cyclic amino group during cyclization is greatly reduced, the yield is obviously improved (more than 85 percent), and the method has industrial value. 2. The deprotection reaction condition is mild, the operation is convenient, the danger and the operation difficulty of the hydrogenation debenzylation adopted in the synthesis route of the amide compound of which the raw material is N-benzyl or N-substituted benzyl are avoided, and according to the description on page 638 of protecting group in organic synthesis (university of eastern China university Press): the benzyl amide is cracked by hydrogenolysis, the reaction speed of removing the benzyl is far lower than that of the benzyloxy, and the benzyl on the amide is almost impossible to remove by hydrogenolysis. On scale up, hydrodebenzylation tends to be more difficult, either the reaction is very slow, or very high pressures are required, the reaction is not easy to control, and is not suitable for industrialization.
According to the purpose of the invention, the second technical scheme of the invention is as follows: there is provided a process for producing compound (V) or a salt thereof, comprising the steps of:
step (1): reacting the compound (I) with trimethyl sulfoxide iodide in an organic solvent in the presence of alkali, extracting with ethyl acetate or isopropyl acetate after the reaction is finished, and washing and concentrating extract liquor to obtain a solution containing a compound (II);
step (2): reacting the solution containing the compound (II) obtained in the step (1) with benzyloxyamine salt, and after the reaction is finished, washing and concentrating to obtain a solution containing a compound (III);
and (3): treating the solution containing the compound (III) obtained in the step (2) with acid to remove Boc protecting group, cyclizing under the action of alkali, washing and concentrating after the reaction is finished to obtain a solution containing the compound (IV);
and (4): reacting the solution containing the compound (IV) obtained in the step (3) with a reducing agent in the presence of a first acid to obtain a compound (V), or further reacting the compound (V) with a second acid to form a salt, cooling and crystallizing to obtain a salt of the compound (V);
wherein, the salt of the compound (V) is selected from one of hydrochloride, hydrobromide, formate, acetate, propionate, oxalate, fumarate or citrate, and Boc represents tert-butyloxycarbonyl.
Preferably, the salt of compound (V) is the oxalate salt.
In the step (1), the organic solvent is selected from one of tert-butyl alcohol, N-dimethylformamide or dimethyl sulfoxide; preferably, the organic solvent is selected from N, N-dimethylformamide or dimethylsulfoxide.
In the step (1), the base is selected from one of potassium carbonate, potassium tert-butoxide, sodium hydride, sodium hydroxide, triethylamine, pyridine, diisopropylamine or diisopropylethylamine; preferably, the base is selected from potassium tert-butoxide or sodium hydride; more preferably, the base is potassium tert-butoxide.
In step (1), the molar ratio of compound (I) to base is 1: 1-2; preferably, the molar ratio of compound (I) to base is 1: 1-1.2.
In the step (1), the molar ratio of the compound (I) to trimethyl sulfoxide iodide is 1: 1-2. Preferably, the molar ratio of compound (I) to trimethyl sulphoxide iodide is 1: 1-1.3.
The reaction temperature of the step (1) is 10-25 ℃.
In the step (1), the base is preferably added to the solution of trimethyl sulfoxide iodide in the organic solvent in portions, and then the mixture is slowly added to the solution of the compound (I) in the organic solvent, so that the generation of impurities can be effectively reduced.
In the step (1), monitoring the reaction process by using an HPLC method, and after the reaction is finished, carrying out conventional post-treatment such as quenching, extraction, washing, concentration and the like to obtain a solution containing a compound (II); preferably, the extraction solvent is ethyl acetate or isopropyl acetate; the specific operation is as follows: adding saturated ammonium chloride aqueous solution to quench the reaction, extracting the product with ethyl acetate or isopropyl acetate for 3-4 times, combining the obtained extracts, washing with saturated saline, and concentrating under vacuum to obtain a solution containing the compound (II), which can be directly used in the next reaction.
In the step (2), the benzyloxyamine salt is selected from benzyloxyamine hydrochloride or benzyloxyamine hydrobromide.
In the step (2), the molar ratio of the compound (II) to the benzyloxyamine salt was 1: 1-1.5; preferably 1: 1-1.2.
The reaction temperature of the step (2) is 50-60 ℃, and the reaction time is 3-4 hours.
Monitoring the reaction process by adopting an HPLC method, and after the reaction is finished, carrying out conventional post-treatment such as cooling, washing, concentrating and the like to obtain a solution containing a compound (III); the specific operation is as follows: the reaction-completed solution was cooled, washed with water, and concentrated in vacuo to give a solution containing compound (III) which was used directly in the next reaction.
In the step (3), the acid used for the acid treatment is selected from one of hydrochloric acid, hydrobromic acid, formic acid or methanesulfonic acid; preferably, the acid is selected from hydrochloric acid or methanesulfonic acid.
In the step (3), the molar ratio of the compound (III) to the acid is 1: 1-5; preferably 1: 2-3.
The reaction temperature of the acid treatment in the step (3) is 20-30 ℃, and the reaction time is 2-3 hours.
The acid treatment in step (3) employs an HPLC method to monitor the progress of the reaction until the compound (III) disappears and the reaction is completed.
After the acid treatment in the step (3) is finished, cyclizing the product under the action of alkali, wherein the alkali is selected from one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, pyridine, diisopropylamine or diisopropylethylamine; sodium hydroxide or potassium bicarbonate is preferred.
In step (3), the molar ratio of the compound (III) to the base is 1: 1-10; preferably 1: 3-5.
The cyclization reaction temperature of the step (3) is 40-50 ℃, and the reaction time is 2-3 hours.
In the step (3), acid is required to be added dropwise to the solution of the compound (III) during acid treatment, and the mixture obtained by acid treatment is required to be added dropwise to the alkali liquor during cyclization.
Monitoring the cyclization reaction in the step (3) by adopting an HPLC method until the cyclization reaction is finished, and then carrying out conventional post-treatment such as washing, concentration and the like to obtain a solution containing a compound (IV); the specific operation is as follows: the cyclization reaction-completed solution was washed with saturated brine and concentrated in vacuo to give a solution containing compound (IV) which was used directly in the next reaction.
In the step (4), the first acid is selected from one of sulfuric acid, aluminum trichloride, lithium chloride, zinc chloride or cobalt chloride; preferably, the first acid is sulfuric acid; more preferably, the first acid is 98% concentrated sulfuric acid.
In step (4), the molar ratio of the compound (IV) to the first acid is 1: 4-8; preferably 1: 4-6.
In the step (4), the reducing agent is selected from one of potassium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride or sodium triacetoxyborohydride; preferably, the reducing agent is selected from sodium triacetoxyborohydride or sodium tripropoyloxyborohydride.
In step (4), the molar ratio of the compound (IV) to the reducing agent is 1: 1-3; preferably 1: 1-2.
The reduction reaction temperature of the step (4) is-20-10 ℃, and the reaction time is 2-3 hours.
In the step (4), the solution containing the compound (IV) is mixed with the first acid to form a mixed solution, and the reducing agent is added in portions or dropwise.
The reduction reaction in step (4) is monitored by HPLC method until the reaction is completed, and then a solution containing compound (V) is obtained by conventional post-treatments such as quenching, neutralization, washing, concentration, etc. the specific operations are as follows: the reaction was quenched by addition of water, then neutralized with aqueous ammonia, the organic layer was washed with water and concentrated in vacuo to give a solution containing compound (V).
In the step (4), further, reacting the compound (V) with a second acid in the form of a salt, and cooling and crystallizing to obtain a salt of the compound (V), wherein the second acid is selected from one of hydrochloric acid, hydrobromic acid, formic acid, acetic acid, propionic acid, oxalic acid, fumaric acid and citric acid. Preferably, the second acid is oxalic acid.
In step (4), the molar ratio of compound (V) to the second acid is 1: 1-2. Preferably, the molar ratio of compound (V) to oxalic acid is 1: 1-2.
In the step (4), the temperature of the salt forming reaction is 40-50 ℃, and the time of the salt forming reaction is 1-2 hours.
In the step (4), the temperature of crystallization is 0-10 ℃, and the time of crystallization is 0.5-1 hour. After the crystallization is completed, the salt of the compound (V) is obtained by conventional post-treatment such as solid-liquid separation, washing, drying and the like. The specific operation is as follows: after crystallization, solid-liquid separation is carried out, the solid is washed by a mixed solution of ethyl acetate/isopropyl acetate and ethanol, and vacuum drying is carried out to obtain the salt of the compound (V).
The second technical scheme of the invention preferably provides a preparation method of the oxalate of the compound (V), which comprises the following steps:
step (1): reacting compound (I) in dimethyl sulfoxide in the presence of potassium tert-butoxide and trimethyl sulfoxide iodide at 10-25 ℃ for 1-2 hours, wherein the molar ratio of compound (I) to potassium tert-butoxide is 1: 1-1.2, the molar ratio of compound (I) to trimethyl sulphoiodide is 1: 1-1.3, after the reaction is finished, extracting with ethyl acetate or isopropyl acetate, washing the extract by saturated saline, and concentrating in vacuum to obtain a solution containing a compound (II);
step (2): reacting the solution containing the compound (II) obtained in the step (1) with benzyloxyamine hydrochloride at 50-60 ℃ for 3-4 hours, wherein the molar ratio of the compound (II) to the benzyloxyamine hydrochloride is 1: 1-1.2, after the reaction is finished, washing by water, and carrying out vacuum concentration to obtain a solution containing a compound (III);
and (3): and (3) treating the solution containing the compound (III) obtained in the step (2) with hydrochloric acid or methanesulfonic acid at the temperature of 20-30 ℃ to remove the Boc protecting group, wherein the molar ratio of the compound (III) to the hydrochloric acid or the methanesulfonic acid is 1: 1-3, and performing cyclization reaction for 2-3 hours at 40-50 ℃ under the action of potassium bicarbonate, wherein the molar ratio of the compound (III) to the potassium bicarbonate is 1: 3-5, after the reaction is finished, washing by saturated saline, and carrying out vacuum concentration to obtain a solution containing the compound (IV);
and (4): reacting the solution containing the compound (IV) obtained in the step (3) with a reducing agent sodium triacetoxyborohydride or sodium triacetoxyborohydride at the temperature of-20-10 ℃ to obtain a compound (V), wherein the molar ratio of the compound (IV) to sulfuric acid is 1: 4-6, the molar ratio of compound (IV) to sodium triacetoxyborohydride or sodium tripropoyloxyborohydride is 1: 1.5-2, after the reduction reaction is finished, salifying reacting a compound (V) with oxalic acid for 1-2 hours at 40-50 ℃, wherein the molar ratio of the compound (V) to the oxalic acid is 1: 1-2, and then cooling and crystallizing for 0.5-1 hour at the temperature of 0-10 ℃ to obtain the oxalate of the compound (V).
The preparation method of the starting material compound (I) can be reported in the literature, for example, in patent document CN 105061425B.
The second technical scheme of the invention is that the compound (V) or the salt thereof is prepared by using the cheap and easily-obtained compound (I) as the starting material, a 'one-pot' process is adopted, a target intermediate is not required to be separated in the process, the yield of the intermediate is greatly improved (compared with the prior document of 20-50%, the yield of the invention is more than or equal to 60%), the post-treatment process is reduced, the cost is reduced, and in the salifying and purifying process of the compound (V), the target intermediate with high optical purity can be obtained (the content of diastereoisomer is less than 0.5%), and impurities can be effectively controlled.
Further, the compound (V) or a salt thereof obtained by the second technical scheme of the present invention can be used for preparing the intermediate compound (VII) of avibactam according to the preparation method of the first technical scheme of the present invention.
According to the purpose of the invention, the third technical scheme of the invention is as follows: provides another preparation method of the avibactam intermediate compound (VII), which comprises the following steps:
step (i): reacting the compound (VIII) with trimethyl sulfoxide iodide in the presence of alkali to obtain a compound (IX);
step (ii): reacting the compound (IX) with a benzyloxyamine salt to give a compound (X);
step (iii): treating the compound (X) with acid to remove Boc protecting group, and cyclizing under the action of alkali to obtain a compound (XI);
step (iv): reacting compound (XI) with a reducing agent in the presence of a first acid to give compound (XII), or further reacting compound (XII) with a second acid to give a salt of compound (XII);
step (v): cyclizing the compound (XII) or a salt thereof with a carbonylation reagent in the presence or absence of a base to obtain a compound (XIII);
step (vi): deprotecting compound (XIII) under the action of an acidic reagent to obtain compound (VII);
wherein R is-CR1R2R3，R1、R2And R3Each independently selected from C1-6Alkyl or phenyl, Boc represents tert-butyloxycarbonyl and Bn represents benzyl.
Preferably, R is selected from tert-amyl or α, α -dimethylbenzyl.
The preferable conditions of each step in the third technical scheme of the invention are as follows:
in step (i), the base is selected from one or more of potassium carbonate, potassium tert-butoxide, sodium hydride, sodium hydroxide, triethylamine, pyridine, diisopropylamine or diisopropylethylamine; one of potassium tert-butoxide, sodium hydride, or pyridine is preferred.
Step (i) is preferably carried out in the presence of an organic solvent selected from one or more of tert-butanol, N-dimethylformamide or dimethylsulfoxide; dimethyl sulfoxide is preferred.
In step (ii), the benzyloxyamine salt is selected from benzyloxyamine hydrochloride or benzyloxyamine hydrobromide.
Step (ii), preferably in the presence of an organic solvent selected from one or more of ethyl acetate, isopropyl acetate, diethyl carbonate, methyl tert-butyl ether or toluene; ethyl acetate or isopropyl acetate is preferred.
In step (iii), the acid is selected from one or more of hydrochloric acid, hydrobromic acid, formic acid or methanesulfonic acid; hydrochloric acid or methanesulfonic acid is preferred.
In step (iii), the base is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, pyridine, diisopropylamine or diisopropylethylamine; potassium bicarbonate is preferred.
In step (iii), it is preferably carried out in the presence of an organic solvent selected from one or more of ethyl acetate, isopropyl acetate, diethyl carbonate, methyl tert-butyl ether or toluene; ethyl acetate or isopropyl acetate is preferred.
In step (iv), the first acid is selected from one or more of sulfuric acid, aluminum trichloride, lithium chloride, zinc chloride or cobalt chloride; sulfuric acid is preferred.
In step (iv), the reducing agent is selected from one or more of potassium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride or sodium triacetoxyborohydride; preferably potassium borohydride, sodium triacetoxyborohydride or sodium tripropionyloxyborohydride.
In step (iv), the second acid is selected from one of hydrochloric acid, hydrobromic acid, formic acid, acetic acid, propionic acid, oxalic acid, fumaric acid or citric acid.
In step (iv), the salt of compound (XII) is selected from one of hydrochloride, hydrobromide, formate, acetate, propionate, oxalate, fumarate or citrate.
In step (iv), it is preferably carried out in the presence of an organic solvent selected from one or more of ethyl acetate, isopropyl acetate, diethyl carbonate, methyl tert-butyl ether or toluene; ethyl acetate or isopropyl acetate is preferred.
In step (v), the carbonylation reagent is selected from one or more of diphosgene, triphosgene, N' -carbonyldiimidazole, methyl chloroformate, ethyl chloroformate, isopropyl chloroformate, isobutyl chloroformate, N-butyl chloroformate, phenyl chloroformate, benzyl chloroformate or di-tert-butyl dicarbonate; the carbonylation reagent is preferably triphosgene, N' -carbonyldiimidazole or phenyl chloroformate.
In step (v), the base is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, pyridine, 2, 6-lutidine, triethylamine or diisopropylethylamine; preferably, the base is selected from pyridine, triethylamine or diisopropylethylamine.
In step (v), it is preferred to carry out in the presence of an organic solvent selected from one or more of ethyl acetate, isopropyl acetate, methyl tert-butyl ether, dichloromethane, chloroform, tetrahydrofuran, acetonitrile, toluene or chlorobenzene; dichloromethane is preferred.
In step (vi), the acidic reagent used for deprotection is selected from a protic acid or a lewis acid. Definitions for protic acids and lewis acids are well known to those skilled in the art. Preferably, the acidic reagent is selected from one or more of hydrogen chloride, hydrogen bromide, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, aluminum trichloride, zinc dichloride, titanium tetrachloride, tetraisopropyl titanium, boron trifluoride complex.
In step (vi), it is preferable to carry out in the presence of an organic solvent selected from one or more of dichloromethane, chloroform, toluene, xylene, chlorobenzene, methyl tert-butyl ether, diethyl ether, diisopropyl ether, tetrahydrofuran or methyl tetrahydrofuran.
The material feeding amount is as follows:
in step (i), the molar ratio of compound (VIII) to base is 1: 1-2, the molar ratio of compound (VIII) to trimethyl sulphoiodide is 1: 1-2.
In step (ii), the molar ratio of compound (IX) to benzyloxyamine salt was 1: 1-1.5.
In step (iii), the molar ratio of compound (X) to acid is 1: 1-5; the molar ratio of compound (X) to base is 1: 1-10.
In step (iv), the molar ratio of compound (XI) to first acid is 1: 4-8; the molar ratio of compound (XI) to reducing agent is 1: 1-3; the molar ratio of compound (XII) to second acid is 1: 1-2.
In step (v), the molar ratio of the compound (XII) or a salt thereof to the carbonylation reagent and the base is 1: 0.1-2: 0 to 5; preferably, the molar ratio of the compound (XII) or salt thereof to the carbonylation reagent and base is 1: 0.3-1.5: 0.1-3.
In step (vi), the molar ratio of the compound (XIII) to the acidic reagent is 0.1 to 10.
The reaction conditions were as follows:
in step (i), the reaction may be carried out at 10 to 25 ℃.
In step (ii), the reaction may be carried out at 40 to 60 ℃.
In step (iii), the acid treatment may be carried out at 20 to 30 ℃ and the cyclization reaction may be carried out at 40 to 50 ℃.
In the step (iv), the reduction reaction can be carried out at-20 to 10 ℃, the salt-forming reaction can be carried out at 40 to 50 ℃, and the temperature for cooling and crystallizing is 0 to 10 ℃ after the salt-forming reaction is finished.
In step (v), the ring closure reaction may be carried out at 10 to 40 ℃.
In step (vi), the deprotection reaction may be carried out at 0 to 80 ℃.
The third technical proposal of the invention adopts an HPLC method to monitor the reaction process.
In the third technical scheme of the invention, after the reaction of each step is finished, the post-treatment is carried out by adopting a conventional method in the field, or the reaction is directly used for the next step without post-treatment according to actual conditions.
In the third technical scheme, a compound (VIII) is selected as a starting material through reasonable design, wherein R is-CR1R2R3(R1、R2And R3Each independently selected from C1-6Alkyl or phenyl) and has N-Boc protection, thus protecting amino before forming piperidine ring, simultaneously the intermediate compound (XII) can directly form cyclic urea with carbonylation reagent, reducing operation steps, greatly reducing side reaction of cyclization between amide group and ortho-position piperidine cyclic amino during cyclic urea, obviously improving yield, mild deprotection reaction condition of the compound (XIII) and convenient operation, avoiding danger and operation difficulty of using hydrogenation to remove benzyl, having good chiral selectivity of product, high yield, good purity, cheap and easily available raw material, and having industrial value.
Detailed description of the preferred embodiments
In order to better understand the technical solution of the present invention, the following examples are further provided to illustrate the present invention, but the present invention is not limited to the following examples.
The starting materials used in the examples are conventional in the art and are commercially available, and the purity specifications used are either analytically or chemically pure. The analytical methods and instruments used in the examples are as follows:
the instrument comprises the following steps: agilent 1260 hplc, supplier: agilent.
Reagent: acetonitrile (HPLC grade), water (HPLC grade), potassium dihydrogen phosphate (AR grade).
Chromatographic conditions are as follows: chromatography column, Waters Xbridge, 4.6X 250mm,5 μm; flow rate, 1.0 mL/min; column temperature, 30 ℃; detector, UV, 210 nm; sample volume, 10. mu.L.
Mobile phase: a, buffer solution, 2.72g of potassium dihydrogen phosphate is weighed, 1000mL of water is added for dissolution, and the solution is filtered by a 0.45 mu m filter membrane for standby; and B, acetonitrile.
Elution gradient:
| time (min) | A(％) | B(％) |
| 0.0 | 90 | 10 |
| 3.0 | 90 | 10 |
| 25.0 | 20 | 80 |
| 30.0 | 20 | 80 |
| 31.0 | 90 | 10 |
| 38.0 | 90 | 10 |
Example 1: preparation of Compound (I)
Compound (I) was obtained according to the method described in examples in patent document CN 105061425B.
Example 2: preparation of oxalate salt of Compound (V)
Step (1): compound (I)(II) preparation of
Trimethyl sulfoxide iodide (77.4g, 352mmol, 1.0eq) and potassium tert-butoxide (39.5g, 352mmol, 1.0eq) were added successively to a solution of dimethyl sulfoxide (500mL) at 10-15 deg.C and the mixture was stirred for 1-1.5 h. The mixture was added slowly to a solution of compound (I) (100.0g, 352mmol, 1.0eq) in dimethylsulfoxide (500mL) at 20-25 deg.C and the mixture was stirred at 20-25 deg.C for 1-2 hours until the reaction was complete as monitored by HPLC method. The reaction was quenched by the addition of saturated aqueous ammonium chloride (900 mL). The product was extracted 3-4 times with ethyl acetate (1800mL) and the resulting organic solution was washed with saturated brine. The organic solution was concentrated under vacuum to a final volume of 1000mL to give a solution containing compound (II) which was directly subjected to the next reaction.
Step (2): preparation of Compound (III)
Benzyloxyamine hydrochloride (56.1g, 351mmol, 1.0eq) was added to the solution containing compound (II) obtained in step (1) and the mixture was stirred at 50-60 ℃ for 3-4 h until the reaction was monitored by HPLC method to be complete. The reaction solution was cooled to 20-25 ℃ and washed with water. The organic solution was concentrated under vacuum to a final volume of 500mL to give a solution containing compound (III) which was directly subjected to the next reaction.
And (3): preparation of Compound (IV)
Methanesulfonic acid (68.2mL, 1.05mol, 3eq) was added to the solution containing compound (III) obtained in step (2) at 20-25 ℃ and the mixture was stirred for 2-3 hours until the reaction was complete as monitored by HPLC. The reaction solution was added to a solution of potassium bicarbonate (175.4g, 1.75mol, 5eq) in water (600mL) and the mixture was stirred at 40-50 ℃ for 2-3 hours until the reaction was complete as monitored by HPLC method. The organic layer was washed with saturated brine and concentrated under vacuum to a final volume of 600mL to give a solution containing compound (IV) which was directly subjected to the next reaction.
And (4): preparation of oxalate salt of Compound (V)
Adding a reducing agent of sodium triacetoxyborohydride (178.8g, 704mmol, 2eq) to the solution containing the compound (IV) obtained in the step (3) in batches at-10 DEG CAnd 98% concentrated sulfuric acid (76.1mL, 1.40mol, 4eq), and the mixture was stirred for 2-3 hours until the reaction was complete as monitored by HPLC. The reaction was quenched by the addition of water (300mL) and then neutralized to pH8-9 with aqueous ammonia. The organic layer was washed with water and concentrated to 400mL under vacuum. Ethanol (300mL) was added, heated to 40-45 ℃ and then a solution of the prepared oxalic acid dihydrate (44.2g, 351mmol, 1eq) in ethanol (160mL) was added, stirred for 1-2 hours with constant temperature. Cooling the mixture to 0-10 deg.C, maintaining the temperature for 0.5-1 hr, separating solid from liquid to obtain product, washing the solid with mixed solution of ethyl acetate and ethanol, vacuum drying at 40 deg.C for 4-8 hr to obtain oxalate salt of compound (V) (1:1) (83.8g, 212mmol, total yield 60.2%, HPLC purity 99.5%, diastereoisomer content 0.4%).1H NMR(400MHz,DMSO)7.51–7.16(m,5H),7.10(s,1H),6.47(d,J＝5.9Hz,1H)，4.57(s,2H),3.11(dd,J＝12.1,2.5Hz,1H),2.85(dd,J＝10.9,2.6Hz,1H),2.75(m,1H),2.21(dd,J＝12.0,10.2Hz,1H),1.88–1.72(m,2H),1.24(m,10H),1.20–1.14(m,1H),1.10(m,1H)。MS(m/z)：306(M+1)。
Example 3: preparation of oxalate salt of Compound (V)
Step (1): preparation of Compound (II)
Trimethyl sulfoxide iodide (154.8g, 703mmol, 2.0eq) and sodium hydride (60%, 28.1g, 703mmol, 2.0eq) were added sequentially to a solution of dimethyl sulfoxide (500mL) at 10-15 deg.C, and the mixture was stirred for 1-1.5 hours. The mixture was added slowly to a solution of compound (I) (100.0g, 352mmol, 1.0eq) in dimethylsulfoxide (500mL) at 20-25 deg.C and the mixture was stirred at 20-25 deg.C for 1-2 hours until the reaction was complete as monitored by HPLC method. The reaction was quenched by the addition of saturated aqueous ammonium chloride (900 mL). The product was extracted 3-4 times with isopropyl acetate (1800mL) and the resulting organic solution was washed with saturated brine. The organic solution was concentrated under vacuum to a final volume of 1000mL to give a solution containing compound (II) which was directly subjected to the next reaction.
Step (2): preparation of Compound (III)
Benzyloxyamine hydrochloride (84.2g, 528mmol, 1.5eq) was added to the solution containing compound (II) obtained in step (1) and the mixture was stirred at 50-60 ℃ for 3-4 h until the reaction was monitored by HPLC method to be complete. The reaction solution was cooled to 20-25 ℃ and washed with water. The organic solution was concentrated under vacuum to a final volume of 500mL to give a solution containing compound (III) which was directly subjected to the next reaction.
And (3): preparation of Compound (IV)
A solution of HCl in isopropyl acetate (2M, 350mL, 0.7mol, 2eq) was added to the solution containing compound (III) obtained in step (2) at 20-25 deg.C and the mixture was stirred for 2-3 hours until the reaction was complete as monitored by HPLC method. The reaction solution was added to a solution of sodium hydroxide (42.0g, 1.05mol, 3eq) in water (600mL) and the mixture was stirred at 40-50 ℃ for 2-3 hours until the reaction was complete as monitored by HPLC method. The organic layer was washed with saturated brine and concentrated under vacuum to a final volume of 600mL to give a solution containing compound (IV) which was directly subjected to the next reaction.
And (4): preparation of oxalate salt of Compound (V)
Adding sodium borohydride (13.3g, 352mmol, 1eq) as a reducing agent to a mixed solution of the compound (IV) containing solution obtained in the step (3) and 98% concentrated sulfuric acid (95.2mL, 1.75mol, 5eq) in portions at-20 to 0 ℃, and stirring the mixture for 2 to 3 hours until the reaction is monitored by an HPLC method to be complete. The reaction was quenched by the addition of water (300mL) and then neutralized to pH8-9 with aqueous ammonia. The organic layer was washed with water and concentrated to 400mL under vacuum. Ethanol (300mL) was added, heated to 40-45 ℃ and then a solution of the prepared oxalic acid dihydrate (44.2g, 351mmol, 1eq) in ethanol (160mL) was added, stirred for 1-2 hours with constant temperature. Cooling the mixture to 0-10 deg.C, maintaining the temperature for 0.5-1 hr, separating solid from liquid to obtain product, washing the solid with the mixed solution of isopropyl acetate and ethanol, and vacuum drying at 40 deg.C for 4-8 hr to obtain oxalate (1:1) of compound (V) (79.3g, 201mmol, total yield 57.1%, HPLC purity 99.4%, diastereomer content 0.3%). The identification data for the product obtained in example 3 is in agreement with the identification data for the product obtained in example 2.
Example 4: preparation of oxalate salt of Compound (V)
Step (1)): preparation of Compound (II)
Trimethyl sulfoxide iodide (10.0g, 45.4mmol, 1.3eq) and potassium tert-butoxide (4.7g, 42mmol, 1.2eq) were added sequentially to a solution of dimethyl sulfoxide (50mL) at 10-15 deg.C and the mixture was stirred for 1-1.5 hours. The mixture was added slowly to a solution of compound (I) (10.0g, 35.2mmol, 1.0eq) in dimethylsulfoxide (50mL) at 20-25 deg.C and the mixture was stirred at 20-25 deg.C for 1-2 hours until the reaction was complete as monitored by HPLC method. The reaction was quenched by the addition of saturated aqueous ammonium chloride (90 mL). The product was extracted 3-4 times with isopropyl acetate (180mL) and the resulting organic solution was washed with saturated brine. The organic solution was concentrated under vacuum to a final volume of 100mL to give a solution containing compound (II) which was directly subjected to the next reaction.
Step (2): preparation of Compound (III)
Benzyloxyamine hydrochloride (6.7g, 42mmol, 1.2eq) was added to the solution containing compound (II) obtained in step (1) and the mixture was stirred at 50-60 ℃ for 3-4 h until the reaction was monitored by HPLC method to be complete. The reaction solution was cooled to 20-25 ℃ and washed with water. The organic solution was concentrated under vacuum to a final volume of 50mL to give a solution containing compound (III) which was directly subjected to the next reaction.
And (3): preparation of Compound (IV)
Methanesulfonic acid (6.8mL, 105mol, 3eq) was added to the solution containing compound (III) obtained in step (2) at 20-25 ℃ and the mixture was stirred for 2-3 hours until the reaction was complete as monitored by HPLC. The reaction solution was added to a solution of potassium bicarbonate (10.6g, 106mol, 3eq) in water (60mL) and the mixture was stirred at 40-50 ℃ for 2-3 hours until the reaction was complete as monitored by HPLC method. The organic layer was washed with saturated brine and concentrated under vacuum to a final volume of 60mL to give a solution containing compound (IV) which was directly subjected to the next reaction.
And (4): preparation of oxalate salt of Compound (V)
Adding a reducing agent sodium triacetoxyborohydride (11.2g, 52.8mmol, 1.5eq) in portions to a mixed solution of the solution containing the compound (IV) obtained in the step (3) and 98% concentrated sulfuric acid (11.5mL, 211mmol, 6eq) at-20 to 0 ℃, and stirring the mixture for 2 to 3 hours until the reaction is completed as monitored by an HPLC method. The reaction was quenched by the addition of water (30mL) and then neutralized to pH8-9 with aqueous ammonia. The organic layer was washed with water and concentrated to 40mL under vacuum. Ethanol (30mL) was added, heated to 40-45 ℃ and then a solution of the prepared oxalic acid dihydrate (8.86g, 70.3mmol, 2eq) in ethanol (160mL) was added, stirred for 1-2 hours with constant temperature. Cooling the mixture to 0-10 deg.C, maintaining the temperature for 0.5-1 hr, separating solid from liquid to obtain product, washing the solid with the mixed solution of isopropyl acetate and ethanol, and vacuum drying at 40 deg.C for 4-8 hr to obtain oxalate (1:1) of compound (V) (8.6g, 21.7mmol, total yield 61.8%, HPLC purity 99.4%, diastereomer content 0.4%). The identification data for the product obtained in example 4 is in agreement with the identification data for the product obtained in example 2.
Example 5: preparation of Compound (VI)
A solution of sodium hydroxide (4.05g, 101.mmol, 2.0eq) in water (100mL) was added to a solution of the oxalate salt of compound (V) obtained in example 2 (20.0g, 50.6mmol, 1.0eq) in dichloromethane (200mL) at 0-10 deg.C, and the mixture was stirred for 1-2 hours and separated. The organic phase was concentrated under reduced pressure to a volume of about 100mL to give an organic phase containing compound (V). N, N' -carbonyldiimidazole (9.7g, 59.8mmol, 1.2eq) was added to the organic phase containing compound (V) at 20-25 deg.C and the mixture was stirred for 10-14 hours until the reaction was monitored by HPLC method to be complete. The reaction solution was washed with 9% dilute hydrochloric acid and water. Concentrating under vacuum to obtain a liquid, recrystallizing with ethyl acetate (200mL) and n-heptane (400mL), stirring at 0-10 deg.C for 30min, separating solid and liquid to obtain the product, washing the solid with n-heptane 100mL, and vacuum drying at 40 deg.C to obtain compound (VI) (14.4g, 43.4mmol, yield 85.9%, HPLC purity 98.8%).1H-NMR(400MHz,CDCl3)7.53–7.32(m,5H),6.69(s,1H),4.99(dd,J＝58.1,11.4Hz,2H),3.89(d,J＝7.5Hz,1H),3.30(s,1H),3.05(d,J＝11.4Hz,1H),2.75(d,J＝11.4Hz,1H),2.35(dt,J＝37.2,18.5Hz,1H),2.00(m,1H),1.87(m,1H),1.69–1.59(m,1H),1.34(s,9H)。MS(m/z)：332(M+1)。
Example 6: compound (V)I) Preparation of
The oxalate salt of the compound (V) obtained in example 2 (40.0g, 101mmol, 1.0eq) was added to a toluene solution (200mL) at 0 to 10 ℃ followed by triethylamine (51.1g, 505mmol, 5.0eq), and a solution of triphosgene (9.0g, 30.3mmol, 0.3eq) in toluene (200mL) was added dropwise at the same temperature, followed by stirring for 1 to 2 hours under heat preservation. An aqueous solution of phosphoric acid (40.0g of 85% phosphoric acid and 160g of water) was slowly added dropwise, and after the addition was complete, the temperature was naturally raised to 20-25 ℃ and stirred for 24h until the reaction was complete as monitored by HPLC. And (3) dropwise adding a saturated solution of sodium bicarbonate to adjust the pH of the system to 7-8, separating, extracting an aqueous phase with toluene (100mL), concentrating a combined organic phase under vacuum until no liquid is discharged, recrystallizing with ethyl acetate (50mL) and n-heptane (150mL), keeping the temperature at 0-10 ℃ and stirring for 30min, carrying out solid-liquid separation to obtain a product, washing the solid with 50mL of n-heptane, and drying under vacuum at 40 ℃ to obtain the compound (VI) (29.2g, 88.1mmol, the yield is 87.1%, and the HPLC purity is 98.4%). The identification data for the product obtained in example 6 is in agreement with the identification data for the product obtained in example 5.
Example 7: preparation of Compound (VI)
A solution of potassium hydrogencarbonate (2.5g, 25mmol, 2.0eq) in water (25mL) was added to a solution of oxalate (5.0g, 12.6mmol, 1.0eq) of compound (V) obtained in example 3 in isopropyl acetate (50mL) at 0 to 10 ℃ and the mixture was stirred for 1 to 2 hours and separated. The organic phase was concentrated under reduced pressure to a volume of about 25mL to give an organic phase containing compound (V). Diisopropylethylamine (8.2g, 63.4mmol, 5.0eq) was added to the organic phase containing compound (V), and a solution of triphosgene (3.8g, 12.8mmol, 1.0eq) in isopropyl acetate (25mL) was added dropwise at 0-10 deg.C and stirred at 30-40 deg.C for 2h until the reaction was complete as monitored by HPLC. And (3) dropwise adding a saturated solution of sodium bicarbonate to adjust the pH of the system to 7-8, separating, extracting an aqueous phase with isopropyl acetate (25mL), concentrating the combined organic phases under vacuum until no liquid appears, performing primary recrystallization with ethyl acetate (10mL) and n-heptane (30mL), keeping the temperature at 0-10 ℃ and stirring for 30min, performing solid-liquid separation to obtain a product, washing the solid with 10mL of n-heptane, and performing vacuum drying at 40 ℃ to obtain the compound (VI) (3.2g, 9.66mmol, the yield of 76.6% and the HPLC purity of 97.3%). The identification data for the product obtained in example 7 is in agreement with the identification data for the product obtained in example 5.
Example 8: preparation of Compound (VII)
Boron trifluoride acetic acid complex (38mL, 36% mass content, 271mmol) was added to a solution of the compound (VI) obtained in example 5 (10.0g, 30.2mmol) in dichloromethane (100mL) at 20-25 ℃ and the mixture was stirred at 40-45 ℃ for 10 hours until the reaction was monitored by HPLC method to be complete. The reaction solution was washed with saturated aqueous sodium carbonate (100mL) and water (100 mL). 4-methyl-2-pentanone (20mL) was added, concentrated to 10mL under vacuum, and the procedure was repeated three times. The mixture was cooled and the solid-liquid separated to give the product, which was washed with 4-methyl-2-pentanone and dried under vacuum at 40 ℃ to give compound (VII) (6.2g, 22.5mmol, yield 74.6%, HPLC purity 99.5%).1H-NMR(400MHz,DMSO)7.57–7.34(m,6H),7.29(s,1H),4.93(q,J＝11.3Hz,2H),3.69(d,J＝6.9Hz,1H),3.62(s,1H),2.90(s,2H),2.16–1.99(m,1H),1.92–1.75(m,1H),1.75–1.55(m,2H)。MS(m/z)：276(M+1)。
Example 9: preparation of Compound (VII)
Boron trifluoride acetonitrile complex (25mL, 19% mass content, 61.7mmol) was added to a solution of compound (VI) obtained in example 6 (10.0g, 30.2mmol) in toluene (50mL) at 20-25 deg.C, and the mixture was stirred at 70-80 deg.C for 10 hours until the reaction was monitored by HPLC method to be complete. The reaction solution was washed with saturated aqueous sodium carbonate (100mL) and water (100 mL). 4-methyl-2-pentanone (20mL) was added, concentrated to 10mL under vacuum, and the procedure was repeated three times. The mixture was cooled and the solid-liquid separated to give the product, which was washed with 4-methyl-2-pentanone and dried under vacuum at 40 ℃ to give compound (VII) (5.4g, 19.6mmol, yield 65.0%, HPLC purity 98.9%). The identification data for the product obtained in example 9 is in agreement with the identification data for the product obtained in example 8.
Example 10: preparation of Compound (VII)
Boron trifluoride tetrahydrofuran complex (10mL, 50% by mass, 93.6mmol) was added to a solution of the compound (VI) obtained in example 6 (10.0g, 30.2mmol) in chloroform (50mL) at 20-25 deg.C, and the mixture was stirred at 60-70 deg.C for 18 hours until the reaction was monitored by HPLC method to be complete. The reaction solution was washed with saturated aqueous sodium carbonate (100mL) and water (100 mL). 4-methyl-2-pentanone (20mL) was added, concentrated to 10mL under vacuum, and the procedure was repeated three times. The mixture was cooled and the solid-liquid separated to give the product, which was washed with 4-methyl-2-pentanone and dried under vacuum at 40 ℃ to give compound (VII) (4.9g, 17.8mmol, yield 58.9%, HPLC purity 98.3%). The identification data for the product obtained in example 10 is in agreement with the identification data for the product obtained in example 8.
Claims (15)
1. A preparation method of an avibactam sodium key intermediate compound (VII) is characterized by comprising the following steps:
cyclizing a compound (V) or an oxalate thereof in an organic solvent by using a carbonylation reagent under the condition of alkali or no alkali to obtain a compound (VI); deprotecting the compound (VI) under the action of an acidic reagent to obtain a compound (VII); wherein Bn represents a benzyl group.
2. The method according to claim 1, wherein the organic solvent is one or more selected from ethyl acetate, isopropyl acetate, dichloromethane, chloroform, tetrahydrofuran, acetonitrile, toluene, and chlorobenzene.
3. The method of claim 1, wherein the carbonylation reagent is selected from the group consisting of triphosgene and N, N' -carbonyldiimidazole.
4. The method according to claim 1, wherein the base is selected from sodium hydroxide, sodium bicarbonate, potassium bicarbonate, triethylamine, and diisopropylethylamine.
5. The process according to claim 1, wherein the molar ratio of compound (V) or its oxalate salt to the carbonylation reagent and base is 1: 0.3-1.2: 0-5.
6. The method according to claim 1, wherein the temperature of the cyclization reaction is 0 to 40 ℃ and the time is 2 to 24 hours.
7. The process according to claim 1, wherein the acidic reagent used for the deprotection is selected from Lewis acids; preferably, the acidic agent is selected from boron trifluoride or a boron trifluoride complex; more preferably, the acidic reagent is selected from the group consisting of boron trifluoride acetic acid complex, boron trifluoride acetonitrile complex or boron trifluoride tetrahydrofuran complex.
8. The process according to claim 7, wherein the molar ratio between compound (VI) and the acidic reagent is 1: 2-9.
9. The preparation method according to claim 8, wherein the solvent for the deprotection reaction is one or more selected from dichloromethane, chloroform, toluene and tetrahydrofuran, and the temperature of the deprotection reaction is 40-80 ℃ and the time is 10-18 hours.
10. The method of any one of claims 1-9, further comprising the steps of:
step (1): reacting the compound (I) with trimethyl sulfoxide iodide in an organic solvent in the presence of alkali, extracting with ethyl acetate or isopropyl acetate after the reaction is finished, and washing and concentrating extract liquor to obtain a solution containing a compound (II);
step (2): reacting the solution containing the compound (II) obtained in the step (1) with benzyloxyamine salt, and after the reaction is finished, washing and concentrating to obtain a solution containing a compound (III);
and (3): treating the solution containing the compound (III) obtained in the step (2) with acid to remove Boc protecting group, cyclizing under the action of alkali, washing and concentrating after the reaction is finished to obtain a solution containing the compound (IV);
and (4): reacting the solution containing the compound (IV) obtained in the step (3) with a reducing agent in the presence of a first acid to obtain a compound (V), or further reacting the compound (V) with oxalic acid to form a salt, cooling and crystallizing to obtain an oxalate of the compound (V); wherein Boc represents a tert-butoxycarbonyl group.
11. The method according to claim 10, wherein in the step (1), the organic solvent is selected from N, N-dimethylformamide or dimethylsulfoxide, the base is selected from potassium tert-butoxide or sodium hydride, and the molar ratio of the compound (I) to the base is 1: 1-2, the molar ratio of compound (I) to trimethyl sulphoxide iodide is 1: 1-2, wherein the reaction temperature of the step (1) is 10-25 ℃.
12. The process according to claim 10, wherein in step (2), the benzyloxyamine salt is selected from benzyloxyamine hydrochloride or benzyloxyamine hydrobromide salt, and the molar ratio of compound (II) to benzyloxyamine salt is 1:1 to 1.5, the reaction temperature of the step (2) is 50 to 60 ℃, and the reaction time is 3 to 4 hours.
13. The production method according to claim 10, wherein in the step (3), the acid used for the acid treatment is selected from hydrochloric acid or methanesulfonic acid, and the molar ratio of the compound (III) to the acid is 1: 2-3, the reaction temperature of the acid treatment is 20-30 ℃, the reaction time of the acid treatment is 2-3 hours, the alkali is selected from sodium hydroxide or potassium bicarbonate, the molar ratio of the compound (III) to the alkali is 1: 3 to 5, the temperature of the cyclization reaction is 40 to 50 ℃, and the time of the cyclization reaction is 2 to 3 hours.
14. The method according to claim 10, wherein in the step (4), the first acid is selected from one of sulfuric acid, aluminum trichloride, lithium chloride, zinc chloride and cobalt chloride, the reducing agent is selected from one of potassium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and sodium tripropoyloxyborohydride, and the molar ratio of the compound (IV) to the first acid is 1: 4-8, the molar ratio of compound (IV) to reducing agent is 1: 1-2, wherein the temperature of the reduction reaction is-20-10 ℃, the time of the reduction reaction is 2-3 hours, and the molar ratio of the compound (V) to the oxalic acid is 1: 1-2, the temperature of the salt forming reaction is 40-50 ℃, the time of the salt forming reaction is 1-2 hours, the temperature of crystallization is 0-10 ℃, and the time of crystallization is 0.5-1 hour.
15. The method of claim 10, comprising the steps of:
step (1): reacting compound (I) in dimethyl sulfoxide in the presence of potassium tert-butoxide and trimethyl sulfoxide iodide at 10-25 ℃ for 1-2 hours, wherein the molar ratio of compound (I) to potassium tert-butoxide is 1: 1-1.2, the molar ratio of compound (I) to trimethyl sulphoiodide is 1: 1-1.3, after the reaction is finished, extracting with ethyl acetate or isopropyl acetate, washing the extract by saturated saline, and concentrating in vacuum to obtain a solution containing a compound (II);
step (2): reacting the solution containing the compound (II) obtained in the step (1) with benzyloxyamine hydrochloride at 50-60 ℃ for 3-4 hours, wherein the molar ratio of the compound (II) to the benzyloxyamine hydrochloride is 1: 1-1.2, after the reaction is finished, washing by water, and carrying out vacuum concentration to obtain a solution containing a compound (III);
and (3): and (3) treating the solution containing the compound (III) obtained in the step (2) with hydrochloric acid or methanesulfonic acid at the temperature of 20-30 ℃ to remove the Boc protecting group, wherein the molar ratio of the compound (III) to the hydrochloric acid or the methanesulfonic acid is 1: 1-3, and performing cyclization reaction for 2-3 hours at 40-50 ℃ under the action of potassium bicarbonate, wherein the molar ratio of the compound (III) to the potassium bicarbonate is 1: 3-5, after the reaction is finished, washing by saturated saline, and carrying out vacuum concentration to obtain a solution containing the compound (IV);
and (4): reacting the solution containing the compound (IV) obtained in the step (3) with a reducing agent sodium triacetoxyborohydride or sodium triacetoxyborohydride at the temperature of-20-10 ℃ to obtain a compound (V), wherein the molar ratio of the compound (IV) to sulfuric acid is 1: 4-6, the molar ratio of compound (IV) to sodium triacetoxyborohydride or sodium tripropoyloxyborohydride is 1: 1.5-2, after the reduction reaction is finished, salifying reacting a compound (V) with oxalic acid for 1-2 hours at 40-50 ℃, wherein the molar ratio of the compound (V) to the oxalic acid is 1: 1-2, and then cooling and crystallizing for 0.5-1 hour at the temperature of 0-10 ℃ to obtain the oxalate of the compound (V).
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